US 20090215895A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0215895 A1 Ferrante et al. (43) Pub. Date: Aug. 27, 2009

(54) THERAPEUTIC AND CARRIERMOLECULES A6IP 29/00 (2006.01) A6IP 25/6 (2006.01) (75) Inventors: Antonio Ferrante, South Australia A6IP 25/08 (2006.01) (AU); Deborah Ann Rathjen, A6IP 25/22 (2006.01) South Australia (AU) A6IP 25/24 (2006.01) A6IP 9/12 (2006.01) Correspondence Address: A6IP 9/10 (2006.01) SCULLY, SCOTT, MURPHY & PRESSER, P.C. A6IP3/04 (2006.01) 400 GARDEN CITY PLAZA, SUITE 300 A6IP 25/28 (2006.01) GARDEN CITY, NY 11530 (US) A6IP 25/30 (2006.01) A6IP 25/18 (2006.01) Newstead (AU) (52) U.S. Cl...... 514/560 (21) Appl. No.: 10/588,094 (57) ABSTRACT (22) PCT Filed: Jan. 28, 2005 The present invention relates generally to compounds com (86). PCT No.: PCT/AUOS/OOO98 prising a hydrocarbon chain portion and more particular to compounds comprising chemical derivatizations of the S371 (c)(1), hydrocarbon chain which are useful therapeutic and prophy (2), (4) Date: May 7, 2009 lactic molecules. The present invention further provides com pounds where the hydrocarbon chain portion is a carrier mol Related U.S. Application Data ecule for functional groups, moieties or agents. The compounds of the present invention are particularly useful in (60) Provisional application No. 60/540,604, filed on Jan. the treatment and prophylaxis of a range of conditions includ 30, 2004. ing cancers, protein kinase c(PKC)- or NFkB-related- or -as O O Sociated conditions, cardiovascular conditions, pain, inflam Publication Classification matory conditions, Vascular or immunological conditions (51) Int. Cl. Such as diabetes, neurological conditions and infection by a A6 IK 3L/202 (2006.01) range of viruses or prokaryotic or eukaryotic organisms. The A6IP 25/06 (2006.01) present invention further provides pharmaceutical composi A6IP 25/00 (2006.01) tions and methods of medical treatment.

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a

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Neutrophis A E. on namination dits

Figure 1 Patent Application Publication Aug. 27, 2009 Sheet 2 of 16 US 2009/0215895 A1

Effect of EPUFA on oxygen radical production

250

g 200 s

150 5 E 2 2 ) 100 S4 A

50

O Vehicle AA PT2

Treatment

Figure 2 Patent Application Publication Aug. 27, 2009 Sheet 3 of 16 US 2009/0215895 A1

100

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Figure 3 Patent Application Publication Aug. 27, 2009 Sheet 4 of 16 US 2009/0215895 A1

Zld (6X/6uuOOL) Treatment

Figure 4 Patent Application Publication Aug. 27, 2009 Sheet 5 of 16 US 2009/0215895 A1

AR10-2=7-5-3-Sl E1616 NE119, 21,n1 23 .

Figure 5

E-selectin 2. 2 o

o

20

8 2 s 2. incubation time (h)

Figure 6 Patent Application Publication Aug. 27, 2009 Sheet 6 of 16 US 2009/0215895 A1

100 100 9. s E 5 80 E 5 80 E 5 60 3 60 a ESS. 5 & 40 40 n 20 g 20 O 24h 72 B-oxa-23:4n-6 Neutrophills Mononuclear Cells

Figure 7 Patent Application Publication Aug. 27, 2009 Sheet 7 of 16 US 2009/0215895 A1

a -r ... - crisis . ... i. 's .." :- ... " ul- - - ar... r " ... s. is: 3. -- ES-25E2... ..M. - - a h r. sail. . . . . - ifr * Sr * i. TNF ------

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Figure 8 Patent Application Publication Aug. 27, 2009 Sheet 8 of 16 US 2009/0215895 A1

low - High High Control Diabetic Diabetic Glucose Glucose Glucose Glucose rat rat rat HMP5 +MP5 --MP5

Figure 9 Patent Application Publication Aug. 27, 2009 Sheet 9 of 16 US 2009/0215895A1

140 120.

1OO

8 O

6 O

4 O

2 O

Control B-oxa 23:4n-6 PMA 22:6n-3 Treatment

Figure 10 Patent Application Publication Aug. 27, 2009 Sheet 10 of 16 US 2009/0215895 A1

140 Natural PUFA

120

100 B-oxa-PUFA B-thia-PUFA

Figure 11 Patent Application Publication Aug. 27, 2009 Sheet 11 of 16 US 2009/0215895 A1

140 55 120 5 SS 100 3. 80 C 9. 60 C 40 is 20 9 O O 9. t O c5 O O St. CO CN co O (Y) t c S. O w 8 st t 8 & C 8 v(S C (s s cy 8 8 s CA Ch. 3. Fatty acid or derivative

Figure 12 Patent Application Publication Aug. 27, 2009 Sheet 12 of 16 US 2009/0215895 A1

140 E-Selectin 120 100 80 60 3 2 40

20 O control p-oxa-23:in-8

14 O.

120 100

80

60 40 20

140 120

1 OO 80

60

40

20

O 4 8 12 16 20 24 Incubation time (h)

Figure 13 Patent Application Publication Aug. 27, 2009 Sheet 13 of 16 US 2009/0215895 A1

1OO A o 80 : - 60 : O

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O 24h 72 h, OTH :Neutrophis Mononuclear cells Footpad reaction : Peritoneal inflammation inflammatory response

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B-oxa-23:4n-6 E-selectin in aortic endothelium

Figure 14 Patent Application Publication Aug. 27, 2009 Sheet 14 of 16 US 2009/0215895 A1

B-oxa-23:4 (n-6)

OH /= 1N

8-monohydro- fox-23:4n-6) 15 monohydro- fox-23:4n-6) Xy a ( - Xy a ( ~a

OH 18 monohydro- fox-23:4 n-7)

Figure 15 Patent Application Publication US 2009/0215895 A1

100 CO?NOOCD Patent Application Publication Aug. 27, 2009 Sheet 16 of 16 US 2009/0215895 A1

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Figure 17 US 2009/0215895 A1 Aug. 27, 2009

THERAPEUTIC AND CARRIERMOLECULES reduced Susceptibility to breakdown and, hence, are far less likely to cause the production of oxygen radicals which is the BACKGROUND OF THE INVENTION consequence of the metabolism of the natural ()-3 fatty acids. PT Series' PUFAs also have this property of resisting break 0001 1. Field of the Invention down but in addition are more soluble. MP-PT hybrids are 0002 The present invention relates generally to com particularly useful anti-inflammatory agents. pounds comprising a hydrocarbon chain portion and more 0011. As indicated above, naturally occurring ()-3 fatty particular to compounds comprising chemical derivatizations acids have been found to be useful in treating a range of of the hydrocarbon chain which are useful therapeutic and conditions including rheumatoid arthritis, multiple Sclerosis, prophylactic molecules. The present invention further pro inflammatory bowel disease and systemic lupus. The PUFAs vides compounds where the hydrocarbon chain portion is a of the MP, PT, LX and MP-PT hybrid series have also been carrier molecule for functional groups, moieties or agents. proposed for the treatment of malaria, to stimulate or inhibit The compounds of the present invention are particularly use neutrophil activity, to treat T-cell diseases and in the treatment ful in the treatment and prophylaxis of a range of conditions of cancer. including cancers, protein kinase c(PKC)- or NFKB-related 0012. There is a need to determine the full range of activi or -associated conditions, cardiovascular conditions, pain, ties of the PUFAs and to identify naturally occurring mem inflammatory conditions, vascular or immunological condi bers or to generate synthetic derivatives which have therapeu tions such as diabetes, neurological conditions and infection tic potential. by a range of viruses or prokaryotic or eukaryotic organisms. SUMMARY OF THE INVENTION The present invention further provides pharmaceutical com positions and methods of medical treatment. 0013 Throughout this specification, unless the context 0003 2. Description of the Prior Art requires otherwise, the word “comprise', or variations such 0004 Bibliographic details of references in the subject as “comprises' or “comprising, will be understood to imply specification are also listed at the end of the specification. the inclusion of a stated element or integer or group of ele 0005 Reference to any prior art in this specification is not, ments or integers but not the exclusion of any other element or and should not be taken as, an acknowledgment or any form integer or group of elements or integers. of Suggestion that that prior art forms part of the common 0014. In accordance with the present invention, it is pro general knowledge in any country. posed that the PUFAs are useful in the treatment interalia of conditions associated with or involving protein kinase CB 0006 Fatty acids are one of the most extensively studied (PKCB) and/or NFKB and in the treatment of pain, inflam classes of compounds due to their important role in biological mation, vascular or immunological conditions such as diabe systems (Ferrante et al. In The Neutrophils: New outlook for tes, cardiovascular conditions, atherosclerosis, neurological the old cells Ed Garbilovich Imperial College Press 4:79 conditions and infection by a range of viruses, prokaryotes or 150, 1999: Sinclair and Gibson (Eds) Invited papers from the eukaryotes. Third International Congress, American Oil 0015. In particular, the present invention contemplates a Chemists Society, Champaign, Ill., 1-482, 1992). Fatty acids method for the treatment or prophylaxis of a condition consist of saturated, monosaturated and polyunsaturated fatty selected from the list consisting of an NFKB-related or -as acids having a chain length from 4 to 30 carbonatoms. Poly sociated condition, a PKCB-related or associated condition, unsaturated fatty acids (PUFAs) contain 16 to 30 carbon vascular or immunological conditions such as diabetes, atoms with two or more methylene-interrupted cis-double inflammation, neurological conditions, cardiovascular dis bonds. ease and pain in a subject, said method comprising adminis 0007 PUFA nomenclature includes recitation of the num ber of carbon atoms in the hydrocarbon chain, the number of tering to said Subject an effective amount of a compound double bonds and the position of the first double bond from having the structure of Formula (I): the terminal methyl group (the ()-carbonatom). For example, the PUFA, arachidonic acid, contains 20 carbon atoms and four methylene-interrupted cis-double bonds commencing (I) six carbons from the ()-carbon, viz: this PUFA is referred to as “arachidonic acid (20:6 n-6). 0008 PUFAs can be divided into four families based on R4ld Rsler the fatty acids from which they are derived: linoleic acid (18:2 n-6), C-linolenic acid (18:3 n-3), oleic acid (18:1 n-9) and palmitoleic acid (16:1 n-7). The n-6 and n-3 PUFAs cannot be wherein synthesized by mammals and are known as essential fatty 0016 R is a saturated or unsaturated hydrocarbon acids (EFAs). They are acquired by mammalian bodies indi chain of from about 9 to about 26 carbon atoms and rectly through desaturation or elongation of linoleic and C-li which optionally carries one or more of a oxa, thia, nolenic acids, which must be Supplied in the diet. hydroxy, hydroperoxy, epoxy and peroxy Substitution; 0009. It is now well appreciated that c)-3 fatty acids confer 0017 R. R. and R may be the same or different and Some protection against a range of diseases. Synthetic fats each is selected from O., NO, NO, S(O), C(H), H, have been synthesized which are useful in the treatment of a COOH, PCX)(Y), N(H), C=O, OH, variety of conditions. 0010 International Patent Publication Nos. WO 96/11908, WO 96/13507, WO 97/38688, WO 01/21172 and WO 01/21575 describe a range of PUFAs referred to as the MP Series, PT Series, LX Series and MP-PT hybrid series. Some of these PUFAs, such as those of the MP Series, have US 2009/0215895 A1 Aug. 27, 2009

C. alkyl, C- alkoxy, amino, mono-acid di-C alky 1, 2 or 3 and X is O.S or NRs. Y is OR, SR or NRR and lamino, Ce alkylthio. S(O), C alkyl, Calkoxycarbo Rs. Ro, Ro R and R2 are selected from H. alkyl, alkenyl, nyl, halo selected from fluoro, chloro, bromo and iodo, OXo, alkynyl, aryland heteroaryl, 8 is 0 or 1; amidino and guanidino, C-2 alkenyl, C-2 alkynyl, aryl, (0029 each of Rs. Rs and R, is respectively (CH.), heteroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0. (COOH), (CH2)(COOH), and (CH2)(COOH), 1, 2 or 3 and X is O.S or NRs. Y is OR SR or NRR and , wherein each of j. m and p is 0, 1, 2, 3, 4, 5 or 6, each Rs, Ro Ro, R and R2 are selected from H. alkyl, alkenyl, of k, n and q is 0, 1 or 2, and each of 1, o and r is 0 or 1, alkynyl, aryland heteroaryl, 8 is 0 or 1; 0030 each of c, i and f is 0 or 1 or 2; and 10018) each of Rs. Rs and R, is respectively (CH.), 0.031 each of a, d and g is 0 or 1 or 2: (COOH), (CH2)(COOH), and (CH2)(COOH), 0032 each of b, e and h is 0 or 1 or 2. , wherein each of j. m and p is 0, 1, 2, 3, 4, 5 or 6, each of k, n and q is 0, 1 or 2, and each of 1, o and r is 0 or 1, BRIEF DESCRIPTION OF THE FIGURES 0019 each of c i and f is 0 or 1 or 2: 0033 FIG. 1 is a diagrammatic representation showing the 0020 each of a, d and g is 0 or 1 or 2: principle mechanism involving T-lymphocytes, leukocytes, 0021 each of b, e and h is 0 or 1 or 2: macrophages and other cells of the immune system. 0022 said administration being for a time and under 0034 FIG. 2 is a graphical representation of the activation conditions sufficient to prevent the condition or to ame of neutrophil NADPH oxidase in the presence of 20 uM fatty liorate one or more symptoms of the condition. acid as determined by lucigenin-dependent chemilumines 0023 The present invention extends to isolated naturally CCCC. occurring PUFAs as well as synthetic or modified molecules. 0035 FIG. 3 is a graphical representation showing the The Subject molecules also include a range of hybrids in analgesic effects of PT2 in PO writhing test. which the PUFA is conjugated to an L- or D-amino acid or a 0036 FIG. 4 is a graphical representation showing the chemical analog of an amino acid. analgesic effects of PT2 in the formalin test. 0024. The present invention further extends to compounds 0037 FIG. 5 is a diagrammatic representation of a struc of general Formula (I) as defined above in isolated form or in ture of MP3 (B-Oxa-23:4n-6). a composition Such as a pharmaceutical composition or for 0038 FIG. 6 is a diagrammatic representation showing the mulation. suppression of TNF-stimulated endothelial cell adhesion 0025. The present invention further provides for the use of molecule expression by cells were pre-treated with MP3 (1 h) a compound of general Formula (I) as defined above in the before being stimulated with TNF for the times indicated. manufacture of a medicament for the treatment of a condition Adhesion molecule expression was determined by ELISA. selected from the list consisting of a condition associated with 0039 FIG. 7 is a diagrammatic representation showing the or involving NFKB, PKCB, pain, vascular or immunological suppression of LPS-stimulated leukocyte infiltration into the conditions such as diabetes and cardiovascular disease, ath peritoneal cavity (a) and Suppression of E-selectin expression erosclerosis, neurological conditions, inflammation and by aortic endothelium (b) by MP3. infection by a range of viruses, prokaryotes and eukaryotes. 0040 FIG. 8 is a diagrammatic representation showing the 0026. The present invention also provides a compound of prevention of TNF-stimulated loss of IKBO. in HUVEC by Formula (I): MP3 or 22:6n-3 cells were pre-treated with MP3 or 22:6n-3 (1 hr), stimulated with TNF (15 min) lysed and the lysate sub jected to Western blot analysis using anti-IKBO. antibody. (I) Role Rill, 0041 FIG.9 is a diagrammatic representation showing the Suppression of PKCB1 translocation in glucose-stimulated mesangial cells (a) and in the glomeruli of a diabetic rat (b). Mesangial cells were pre-treated with MP5 or vehicle (etha R4ld Rsler nol) for 1 hr before being incubated with 25 mM glucose for 5 days. Male rats were rendered diabetic with streptozotocin wherein and MP5 or vehicle (ethanol) was administered for 7 days 0027 R is a saturated or unsaturated hydrocarbon after confirmation of diabetes. The cells and glomeruli were chain of from about 9 to about 26 carbon atoms and sonicated and particulate fraction-associated PKCB1 was which is optionally carries one or more of a oxa, thia, determined by Western blot analysis. High glucose and dia hydroxy, hydroperoxy, epoxy and peroxy Substitution; betes increased PKCB1 in the particulate fraction. MP5 inhib 0028. R. R. and R may be the same or different and ited this effect. each is selected from O., NO, NO. S(O), C(H), H, 0042 FIG. 10 is a representation showing comparison of COOH, PCX)(Y), N(H), C=O, OH, the ability of MP3 (B-oxa-23:4n-6) PMA (100 nmol/l) and 22:6n-3 to stimulate the neutrophil respiratory burst. Neutro phils were treated with DPC (Control), 23:4n-6, PMA or O 22:6n-3 and then tested for chemiluminescence activity. The fatty acids were used at 20 umol/l. The results are the -C-NH-, meant-SEM of quadruplicates and is representative of two other experimental runs. C. alkyl, C. alkoxy, amino, mono-acid di-C alky 0043 FIG. 11 is a representation showing effect of B-oxa: lamino, Ce alkylthio. S(O), C alkyl, Calkoxycarbo B-thia and natural PUFA on TNF-enhanced neutrophiladher nyl, halo selected from fluoro, chloro, bromo and iodo, OXo, ence to HUVEC. HUVEC were pre-treated with the fatty amidino and guanidino, C2-12 alkenyl, C2-12 alkynyl, aryl, acids (20 umol/l) for 60 minat37°C. before being stimulated heteroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0. with TNF (125 U/200ul medium) for 4 hr at 37° C. The cells US 2009/0215895 A1 Aug. 27, 2009 were then co-incubated with neutrophils (5x10 cells/well) at expressed as % of control, are presented as meant-SEM of 10 37° C. for 30 min and the degree of neutrophil adherence and 5 mice for DTH and peritoneal inflammation, respec quantitated. The results are expressed as % of control and tively. Analysis of data by two-tailed student's t-test: **p<0. represent the meant-SEM of three separate experiments each 01, ***p<0.001. (B) Shows the effect of B-Oxa-23:4n-6 on performed in triplicate. * p-0.05, **p<0.001, for significant LPS-induced expression of E-selectin in aortic endothelium of BALB/C mice. Mice were treated intravenously with the differences between pre-treatment with fatty acid and control fatty acid and 2 hr later injected intraperitoneally with LPS. (one-way analysis of variance followed by the Dunnett test After 5 hr the aortas were isolated, cut into small pieces and for multiple comparisons). incubated with a monoclonal antibody to mouse E-selection 0044 FIG. 12 is a representation showing effect of MP3 (or isotype matched control) (Becton Dickinson, California) derivatives on TNF-enhanced neutrophil adherence to followed by an HRP-conjugated secondary antibody and then with the substrate ABTS (ELISA method). The data, HUVEC. HUVEC were pre-treated with MP3 (20 umol/l), expressed as % of control, are presented as mean-SEM often B-Oxa-23:4n-6 derivatives (20 umol/l) or diluent (control) for mice per group and is representative of two experimental 60 min and then challenged with TNF (125 U/200 ul medium) runs. Analysis of the data by the two-tailed student's t-test: for a further 4hr. The ability of HUVEC to adhere neutrophils **p-0.01. was then assessed. The results are expressed as % of control 0047 FIG. 15 is a representation showing the chemical and represent the meant-SEM of three separate experiments structure of MP3 (B-Oxa-23:4n-6) and of the monohydroxy each performed in triplicate. ***p<0.001, for significant dif lated derivatives of 3-oxa-23:4n-6 formed via the lipoxyge ferences between pre-treatment with MP3 (B-Oxa-23:4n-6) or nase pathway in HUVECs (15-monohydroperoxy-f-oxa-23: derivative and control (one-way analysis of variance followed 4n-6 was the predominant product). 0048 FIG. 16 is a representation showing the effects of by the Dunnett test for multiple comparisons). Abbreviations lipoxygenase/cyclooxygenase inhibitors and antioxidants on used: B-Oxa-23:4n-6ME, B-Oxa-23:4n-6 methyl ester: B-Oxa the modulation of E-selectin expression on HUVEC by 23:0, saturated form of B-Oxa-23:4n-6: B-Oxa-23:4n-6OH, B-Oxa-23:4n-6. HUVEC were pre-treated with NDGA, baica 18-monohydroxy-3-oxa-23:4n-6: B-Oxa-23:4n-6OOH, lein, MK886, indomethacin, Vitamin E, or diluent (control) 18-monohydroperoxy-f-Oxa-23:4n-6. for 15 min. The cells were then further incubated with 20 004.5 FIG. 13 is a representation showing effect of MP3 umol/l B-Oxa-23:4n-6 or diluent (control) for 60 min followed (B-Oxa-23:4n-6) and 20:4n-6 on time-related changes in by TNF-C. (125 U/200 ul medium) for 4 hr and the expression of E-selectin adhesion molecule was determined. The results TNF-C-induced E-selectin, ICAM-1 and VCAM-1 expres are expressed as % inhibition of the suppressive effect of sion on HUVEC. HUVEC were pre-treated with 20 umol/l B-Oxa-23:4n-6 and represent the meant-SEM of three sepa B-Oxa-23:4n-6 (closed triangles), 20 umol/l 20:4n-6 (open rate experiments each performed in quadruplicate. * p-0.01, squares), or DPC (control) for 60 min and then further incu for significant differences between pre-treatment with inhibi bated with TNF-C. (125 U/200ul medium) for up to 24hr. The tor and corresponding control (one-way analysis of variance expression of E-selectin, ICAM-1 and VCAM-1 adhesion followed by the Dunnett test for multiple comparisons). molecules was determined by ELISA. The results are 0049 FIG. 17 is a representation showing (A) the effect of expressed as % of control and represent the meant-SEM of MP3 (B-oxa 23:4n-6) and DHA on TNF-induced degradation three separate experiments each performed in triplicate. * of IKBC in HUVEC. Cells were pre-treated with the fatty p-0.05, **p<0.01, ***p<0.001, for significant differences acids (20 umol/l) for 30 min and then stimulated with TNF (125 U/ml) for 10 min. After cell lysis the proteins were between pre-treatment with fatty acid and corresponding con analyzed by Western blots using anti-IKBO. antibodies. (B) trol at a particular time point (one-way analysis of variance The effects of B-Oxa-23:4n-6 on TNF-induced activation of followed by the Dunnett test for multiple comparisons). Inset: transcriptional factor, NFKB in HUVEC. Cells were pre The effect of B-Oxa-23:4n-6 on TNF-C-induced expression of treated with B-Oxa-23:4n-6 (20 umol/l) for 30 min and then E-selectin mRNA in HUVEC. HUVEC were pre-incubated stimulated with TNF for 2 hr. After cell lysis, nuclear frac with 3-oxa-23:4n-6 (20 umol/l) or DPC (control) in 1 ml of tions were prepared, nuclear proteins separated by SDS medium at 37°C. for 60 min. After the addition of TNF-C., the PAGE (12% w/v gel), transferred to nitrocellulose and probed cells were further incubated at 37° C. for 2 hr. E-selectin with an anti-NFKB p65 antibody (Santa Cruz). Densitometric analysis of data from three experiments showed that B-Oxa mRNA expression was then determined and the results 23:4n-6 reduced TNF-stimulated nuclear accumulation of expressed as relative%. Results are the meant-SEM of three NFkB by 66+2% (meaniSEM) (p<0.001, two-tailed stu separate experiments each performed in quadruplicate. p-0. dent's t-test). (C) The effect of B-oxa 23:4n-6 on TNF-stimu 0001, for significant differences between pre-treatment with lated activation of IKK. Cells were pre-treated with 3-oxa B-Oxa-23:4n-6, and control (two-tailed Student's t-test for 23:4n-6 (20 umol/l) for 30 min and then stimulated with TNF unpaired data). for 5 min. After cell lysis IKK was immunoprecipitated with 0046 FIG. 14 is a representation showing (A) effect of anti-IKKC. antibody and kinase activity determined. MP3 on in vivo inflammatory response measured as delayed DETAILED DESCRIPTION OF THE PREFERRED type hypersensitivity (DTH) to sheep erythrocytes and LPS EMBODIMENTS induced influx of neutrophils and mononuclear cells in the 0050. The present invention provides compounds of gen peritoneal cavity in BALB/c mice. In the DTH experiments eral Formula (I): mice were injected with sheep erythrocytes Subcutaneously, challenged with the antigen in the hind foot pad 6 days later and the amount of footpadswelling measured 48 hr later. One (I) hour prior to challenge mice were given 10 mg/kg body weight of 3-oxa fatty acid in 7% w/v. DMSO as vehicle intraperitoneally. For the peritoneal cavity inflammation, mice were given intravenously 40 mg/kg MP3 intravenously and 6hr later injected with LPS intraperitoneally. The cellular infiltrates were examined 24 and 72 hr later. The data, US 2009/0215895 A1 Aug. 27, 2009

wherein heteroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0. 0051 R is a saturated or unsaturated hydrocarbon 1, 2 or 3 and X is O.S or NRs. Y is OR, SR or NRR and chain of from about 9 to about 26 carbon atoms and Rs. Ro, Ro R and R2 are selected from H. alkyl, alkenyl, which is optionally carries one or more of a oxa, thia, alkynyl, aryland heteroaryl, 8 is 0 or 1; hydroxy, hydroperoxy, epoxy and peroxy Substitution; I0060 each of Rs. Rs and R, is respectively (CH), 0052 R. R. and R may be the same or different and (COOH), (CH2)(COOH), and (CH2)(COOH), each is selected from O., NO, NO. S(O), C(H), H, , wherein each of j. m and p is 0, 1, 2, 3, 4, 5 or 6, each COOH, PCX)(Y), N(H), C=O, OH, of k, n and q is 0, 1 or 2, and each of 1, o and r is 0 or 1, 0061 each of c i and f is 0 or 1 or 2: O 0062 each of a, d and g is 0 or 1 or 2: 0063 each of b, e and h is 0 or 1 or 2: -C-NH-, 0.064 said administration being for a time and under conditions sufficient to prevent the condition or to ame C. alkyl, C. alkoxy, amino, mono-acid di-C alky liorate one or more symptoms of the condition. lamino, Ce alkylthio. S(O)C alkyl, Calkoxycarbonyl, 0065. The compound of Formula (I) may comprise, when halo selected from fluoro, chloro, bromo and iodo, oxo, ami i, c and fare 0, a straight hydrocarbon chain such as that dino and guanidino, Calkenyl, C-2 alkynyl, aryl, het shown in Formula (II): eroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0, 1, 2 or 3 and X is O, S or NRs. Y is OR, SR or NRR and C(H), (II) Rs, Ro Ro, R and R2 are selected from H. alkyl, alkenyl, 0.066 which represents a hydrocarbon chain of a' car alkynyl, aryland heteroaryl, 8 is 0 or 1; bons in length from about 9 to about 26 carbon atoms, I0053) each of Rs. Rs and R, is respectively (CH), which hydrocarbon chain is saturated or unsaturated and (COOH), (CH2)(COOH), and (CH2)(COOH), which carries one or more of a oxa, thia, hydroxy, hydro , wherein each of j. m and p is 0, 1, 2, 3, 4, 5 or 6, each peroxy, epoxy and/or peroxy Substitution; a' may be 0, 1, of k, n and q is 0, 1 or 2, and each of 1, o and r is 0 or 1, 2 or 3. 0054 each of c, i and f is 0 or 1 or 2; and 0067. The compound of Formula I may also comprise two 0055 each of a, d and g is 0 or 1 or 2: of 1, c or f being 0 and one of the remaining i, c or f being 1. 0056 each of b, e and h is 0 or 1 or 2. For example, wherei and fare each 0, the resulting compound 0057 More particularly, the present invention contem has the structure of Formula (III): plates a method for the treatment or prophylaxis of a condi R-R-R), (III) tion selected from the list consisting of an NFKB-related or -associated condition, a PKCB related or associated condi wherein R. R. R. a and b are as defined above. tion, vascular or immunological conditions such as diabetes, 0068. When the compound of Formula (III) comprises inflammation, neurological conditions, cardiovascular dis each of a, o and b being 1, the resulting compound has the ease and pain in a subject, said method comprising adminis structure of Formula (IV): tering to said Subject an effective amount of a compound having the structure of Formula (I): R-Rs (IV) wherein R and R are as defined above. (0069 Given that R, is (CH),(COOH).J. Formula (IV) (I) can be represented as a compound of Formula (V): R-(CH2),(COOH), (V) wherein R, j, k and 1 are as represented above. R4ld Rsler 0070. In a preferred embodiment, 1 is a saturated or unsat urated fatty acid. In another preferred embodiment, the satu wherein rated or unsaturated fatty acid carries one or more of a B-oxa, 0.058 R is a saturated or unsaturated hydrocarbon C-oxa, Y-oxa, B-thia, C.-thia, Y-thia, hydroxy, hydroperoxy, chain of from about 9 to about 26 carbon atoms and epoxy, peroxy, peracetyl or other protected hydroperoxy Sub which is optionally carries one or more of a oxa, thia, stitution. Substitutions may be at the level of a carbonatom or hydroxy, hydroperoxy, epoxy and peroxy Substitution; hydrogen atom. 0059 R. R. and R may be the same or different and 0071 Examples of compounds of Formula (V) include: each is selected from O., NO, NO. S(O), C(H), H, COOH, PCX)(Y), N(H), C=O, OH, O C -C-NH-, 18:3n-3

o o o COOH C. alkyl, C- alkoxy, amino, mono-acid di-C alky lamino, Ce alkylthio. S(O), C alkyl, Calkoxycarbo nyl, halo selected from fluoro, chloro, bromo and iodo, OXo, 22:6n-3 amidino and guanidino, C2-12 alkenyl, C2-12 alkynyl, aryl, US 2009/0215895 A1 Aug. 27, 2009

-continued -continued

B-thia-21:0 (MP2) 20:4n-6 o o o S N1 COOH COOH

B-thia-25:6n-3 (MP14) 23:4n-6 s1NcooH

CD B-thia-21:3n-6 (MP9) 20:5-3 S COO

0072 Examples of compounds where R comprises a sub B-thia-23:4n-6 (MP8) stitution include:

O B-thia-21:3n-3 (MP10) COOH

OOH 15-OOH-20:4n-6 S COOH

O COOH Cucarbocarboxyme?-thia-23:4n-6 (MP15)

B-Oxa-23:4n-6 (MP3) (0073. When each of Ral-R.I., (R)-Rs, and/or o1 NcooH Ral-IRs) are presented in multiple forms, then the mul tiple forms may be represented linearly. For example, ifi and B-Oxa-21:4n-3 (MP7) fare each 0, a is 3, b is 1 and c is 1, then the compound may be represented as in Formula (VI): R-R-R-R-Rs (VI)

B-Oxa-21:3n-6 (MP4) 0074. If, on the other hand, c is 2, then the compound is represented as Formula (VII):

(VII)

16-OH-B-Oxa-21:3n-6 (TR1)

B-Oxa-21:3n-3 (MP5)

0075. In one non-limiting example, in the case when the compound is a carboxymethyl derivative, then the values in Formula (I) are as follows: 16-OH-B-Oxa-21:3n-3 (TR2) 0076 i is 0, each of c and f is 1, each of a and d is 0 and o o o O COOH each of Rs and Rs is (CH2)(COOH), and (CH), N1 (COOH), respectively where, in one example, 0.077 each of and m is 0. 0078 each of 1 and o is 1; and 0079 each of k and n is 1, US 2009/0215895 A1 Aug. 27, 2009

0080 resulting in a compound of Formula (VIII): D-O-methylglutamine, D-O-methylhistidine, D-O-methyli soleucine, D-O-methyleucine, D-O-methyllysine, D-O-me thylmethionine, D-O-methylornithine, D-O-methylphenyla (VIII) lanine, D-O-methylproline, D-C.-methylserine, D-C.- R-COOH methylthreonine, D-O-methyltryptophan, D-O- COOH methyltyrosine, D-O-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine, D-N-methy 0081 More commonly, however, maybe 1, and m may be laspartate, D-N-methylcysteine, D-N-methylglutamine, 2 resulting a compound of Formula (IX): D-N-methylglutamate, D-N-methylhistidine, D-N-methyli soleucine, D-N-methyleucine, D-N-methyllysine, N-meth ylcyclohexylalanine, D-N-methylornithine, N-methylgly (IX) cine, N-methylaminoisobutyrate, N-(1-methylpropyl) R-CH-COOH glycine, N-(2-methylpropyl)glycine, D-N- methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, CH y-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-ho CH mophenylalanine, L-O-methylarginine, L-O-methylaspar tate, L-O-methylcysteine, L-O-methylglutamine, L-O-meth COOH ylhistidine, L-O-methylisoleucine, L-O-methyleucine, L-O- methylmethionine, L-O-methylnorvaline, L-C.- 0082 Reference to “from about 9 to about 26 carbon methylphenylalanine, L-O-methylserine, L-C.- atoms' herein includes 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, methyltryptophan, L-O-methylvaline, N-(N-(2,2- 20, 21, 22, 23, 24, 25 and 26 carbon atoms. diphenylethyl)carbamylmethyl)glycine and 1-carboxy-1-(2, 0083. The compound of Formula (I) may have each of i, c 2-diphenyl-ethylamino)cyclopropane. and fas 0 (zero), two of i, c and fas 0 (zero) or one of i, cand I0089. Examples of cytokines include but are not limited to fas 0 (zero); or each of i, c and fas 1; two of i, c and f as 1 or BDNF, CNTF, EGF, EPO, FGF1, FGF2, FGF3, FGF4, FGF5, one of i, c and fas 1; or each of i, c and fas two, two of i, cand FGF6, FGF7, FGF8, FGF9, FGF10, FGF11, FGF12, FGF12, fas two, or one of i, c and f as two. FGF13, FGF14, FGF15, FGF16, FGF17, FGF18, FGF19, 0084. The compound of Formula (I) may have each of g, a FGF20, FGF21, FGF22, FGF23, G-CSF, GM-CSF, IFNo. and das 0 (zero), two of g, a and das 0 (zero) or one of g, a and IFNB, IFNY, IL1, IL2, IL3, IL4, IL5, IL6, IL7, IL8, IL9, IL 10, das 0 (zero); or each of g, a and das 1; two of g, a and das 1 IL11, IL12, IL13, IL14, IL15, LIF, MCP1, MCP2, MCP3, or one of g, a and das 1; or each of g, a and d as two, two of MCP4, MCP5, M-CSF, MIP1, MIP2, NGF, NT3, NT4, NT5, g, a and d as two, or one of g, a and d as two. NT6, NT7, OSM, PBP, PBSF, PDGF, PF4, RANTES, SCF, 0085. The compound of Formula (I) may have each of h, b TGFC, TGFB, TNFC, TNFB, TPO, VEGF, GH, insulin and and eas 0 (zero), two of h, b and eas 0 (zero) or one ofh, band the like. eas 0 (zero); or each of h, band eas 1; two of h, b and e as 1 0090. Examples of apoptotic proteins include but are not or one of h, b and eas 1; or each of h, b and eas two, two of limited to A1, A9, A20, A46R, A52R, A53, A238L, Aac11, h, b and eas two, or one of h, b and eas two. AATF. AATYK, ABIN1, ABIN-1, ABIN2, acidic sphigomy I0086. These aspects of the present invention cover natu elinase, Acinus, Act 1, Act2, activin, AD3LP, AD5, ADAR, rally occurring PUFAs as well as synthetic, modified or adrenomedulin, aggrecan, AMAM17, 33, AI1, AIF, AILIM, derivatized PUFAs. Furthermore, modified PUFAs encom AIM2, AIR, AITR, Akt, ALCAM, ALG2, ALG3, ALG4, passed by Formulae (I) through (VIII) include naturally ALP, Alix, Armadillo, AMAC1, AMH, AMID, Amida, angio occurring or synthetic, derivatized or modified PUFAs con tensinogen, Ankyrin, ANT1, AO7, AP1, Apaf-1. APC, APC2. jugated to an L- or D-amino acid or amino acid analog or a APCL, APE1820, APJ, APO-1, APO-2, APO-3, Apopain, sequence of amino acids such as in peptide, polypeptide or a APP1, APP2, Apr, APRIL, ARA54, ARC, ARF, arkadia, protein. The latter aspect includes proteins in the form of ARIH1, 2, ASC, Ash2, Ask1, Ask2, ASPP1, ASPP2, AT2R1, cytokines, growth factors, proteases, enzymes, apoptotic pro AT2R2, ATAR, ATF1, ATF2, ATF3, ATF4, ATM, atona, teins and pro-Survival proteins. ATR1, AUF1, Aven, AVP, Avra, AvrBsT, AXam, Axin, AXin 0087. Examples of L-amino acids include alanine, argin 2, Axi, b-catenin, b-TrCP, B28R, B7-1, B7-2, B7h2, B7RP1, ine, asparagine, aspartic acid, cysteine, glutamine, glutamic Bach2, Bad, BAFF, BAG-1, -2, -3, -4, -5, Bak, BALF1, acid, glycine, histidine, isoleucine, leucine, lysine, methion Bam32, BAP-1, BAP31, BAP29, BAR, BARD1, BAT3, Bax, ine, phenylalanine, proline, serine, threonine, tryptophan, BBc3, BCA1, BCAN, Bcl-2, BCL2, Bcl-3, Bcl-10, BCL10, tyrosine and valine. Bcl-G, Bcl-Rambo, Bcl-w, Bcl-X, beclin, BEHAB, BERP, 0088. Examples of chemical analogs of amino acids Bfl-1, BFL1, BG1, BG2, BG4, BG5, BHP1, BHRF1, BI-1, include, but are not limited, to C.-aminobutyric acid, C.-amino Bid, Bif-1, Bik, Bis, Bim, Bimp-1, Bimp1, Bimp2, Bimp3. C.-methylbutyrate, aminocyclopropane-, carboxylate, ami BIR1, BIRP. BL-CAM, BLC, Blk, BLNK, BLR1, BLyS, noisobutyric acid, aminonorbornyl-, carboxylate, cyclohexy BMI-1, BmP109, BNIP3, BNIP3a, BNIP3L, Bok, bonesia lalanine, cyclopentylalanine, D-alanine, D-arginine, loprotein, bonus, Boo, BPI, BRAL1, BRAG-1, BRAP Bravo, D-aspartic acid, methylmethionine, D-cysteine, N-methyl BRCA1, BRN3a, BRN3b, BRN3c, brevican, BPR, BSAC, norleucine, D-glutamine, D-glutamic acid, methylornithine, BUFFY, C1q, C1r, C1s, C2, C3, C4a, C4b, C5, C6, C7, C8a, D-histidine, N-methylphenylalanine, D-isoleucine, D-leu C8b, C8g, C9, C1qBP. C3aR, C4BPa,b, C5R1, CR2, CIITA, cine, D-lysine, D-methionine, D-Ornithine, D-phenylalanine, C5L, c-E10, c-FLIP. c-Fms, c-Fos, c-IAP1, cIAP1, c-IAP-1, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, c-IAP2, cIAP2, c-IAP-2, c-Jun, c-Myc, c-Rel, cactus, CAD, D-valine, D-O-methylalanine, D-O-methylarginine, D-O-me cadherin, E., N, P. VE, calcineurin, CARD4, CARD7, thylasparagine, D-O-methylaspartate, D-O-methylcysteine, CARD9, CARD10, CARD11 CARD12, CARD14, CAR

US 2009/0215895 A1 Aug. 27, 2009

I0099 LX Series, Nitroanalogues of Fatty Acids Retardation, Unspecified Mental Retardation, Autistic Disor 0100. The present invention is directed inter alia to the der, Pervasive Development Disorder NOS, Attention-Deficit treatment of pain, cancers, PKC- and/or NFKB-associated or Hyperactivity Disorder, Conduct Disorder, Group Type, Con -related conditions, vascular and/or immunological condi duct Disorder, Solitary Aggressive Type, Conduct Disorder, tions, inflammatory conditions, neurological conditions and Undifferentiated Type, Tourettes Disorder, Chronic Motor or infection. Vocal Tic Disorder, Transient Tic Disorder, Tic Disorder 0101. Other compounds contemplated by the present NOS, Primary Degenerative Dementia of the Alzheimer invention include f3-oxa 23:0, B-thia 23:0, B-oxa 23:4 (n-6), Type, Senile Onset, Uncomplicated, Primary Degenerative B-oxa 21:3 (n-6); f-oxa 21:3 (n-3), B-oxa 25:6 (n-3), B-oxa Dementia of The Alzheimer Type, Senile Onset, with 21:4 (n-3), f-thia 23:4 (n-6), B-thia 21:3 (n-6), B-thia 21:3 Delirium, Primary Degenerative Dementia of the Alzheimer (n-3), Y-thia 24:4 (n-6), Y-thia 22:3 (n-6), Y-thia 22:3 (n-3), Type, Senile Onset, with Delusions, Primary Degenerative B-thia 25:6 (n-3), C.-CHCOH-B-thia 23:4 (n-6), Dementia of the Alzheimer Type, Senile Onset, with Depres 15-OOCMeOMe 20:4 (n-6), 15-OOCMeOMe 3-oxa 23:4 sion, Primary Degenerative Dementia of the Alzheimer Type, (n-6), 13-OH-B-oxa 21:3 (n-6), 13-OH-B-oxa 21:3 (n-3), 20:4 Presenile Onset, Uncomplicated, Primary Degenerative (n-6)-gly, 20:4 (n-6)-asp. 20:5 (n-3)-gly, 20:5 (n-3)-asp, 22:6 Dementia of the Alzheimer Type, Presenile Onset, with (n-3)-gly, 22:6 (n-3)-asp. 18:3 (n-6)-gly, 18:3 (n-6)-asp, 18:3 Delirium, Primary Degenerative Dementia of the Alzheimer (n-3)-gly, 18:3 (n-3)-asp, 19:0-NO, 19:3 (n-3)-NO, 19:3 Type, Presenile Onset, with Delusions, Primary Degenerative (n-6)-NO, 21:4 (n-6)-NO. 23:6 (n-3)-NO, Y-NO, 21:0, Dementia of the Alzheimer Type, Presenile Onset, with Y-NO. 23:4 (n-6) and Y.Y(COOH), 21:4 (n-6)NO. Depression, Multi-infarct dementia, Uncomplicated, Multi 0102 The present invention is particularly directed to the infarct dementia, with Delirium, Multi-infarct Dementia, treatment of pain including inter alia neuropathic or neuro with Delusions, Multi-infarct Dementia, with Depression, logical pain, chronic pain, acute pain, migraine, headache Senile Dementia NOS, Presenile Dementia NOS, Alcohol inflammatory pain, post-operative pain, pain due to multiple Withdrawal Delirium, Alcohol Hallucinosis, Alcohol sclerosis, Parkinson's disease or other neurological or Dementia Associated with Alcoholism, Amphetamine or autoimmune disorder or following or during periods of anxi Similarly Acting Sympathomimetic Intoxication, Amphet ety, delayed onset muscle Soreness, burns or during or fol amine or Similarly Acting Sympathomimetic Delusional Dis lowing infection or a convulsion, post-poliomyelitic pain, order, Cannabis Delusional Disorder, Cocaine Intoxication, bipolar disorder, panic attack or epilepsy. Cocaine Delirium, Cocaine Delusional Disorder, Hallucino (0103) Neurological disease states which can be treated in gen Hallucinosis, Hallucinogen Delusional Disorder, Hallu accordance with the present invention include depression, cinogen Mood Disorder, Hallucinogen Posthallucinogen Per including major depression (single episode, recurrent, mel ception Disorder, Phencyclidine (PCP or Similarly Acting ancholic), atypical, dysthymia, sub-syndromal, agitated, Arylcyclohexylamine Intoxication, Phencyclidine (PCP) or retarded, co-morbid with cancer, diabetes, or post-myocar Similarly Acting Arylcyclohexylamine Delirium, Phencycli dial infarction, involutional, bipolar disorder, psychotic dine (PCP) or Similarly Acting Arylcyclohexylamine Delu depression, endogenous and reactive, obsessive-compulsive sional. Disorder, Phencyclidine (PCP) or Similarly Acting disorder, or bulimia. In addition, NAALADase inhibitors can Arylcyclohexylamine Hood Disorder, Phencyclidine (PCP) be used to treat patients suffering from pain (given alone or in or Similarly Acting Arylcyclohexylamine Organic Mental combination with morphine, codeine, or dextropropo Disorder NOS, Other or unspecified Psychoactive Substance Syphene), obsessive-compulsive personality disorder, post Intoxication, Other or Unspecified Psychoactive Substance traumatic stress disorder, hypertension, atherosclerosis, anxi Delirium, Other or Unspecified Psychoactive Substance ety, anorexia nervosa, panic, social phobia, stuttering, sleep Dementia, Other or Unspecified Psychoactive Substance disorders, chronic fatigue, cognition deficit associated with Delusional Disorder. Other or Unspecified Psychoactive Sub Alzheimer's disease, alcohol abuse, appetite disorders, stance Hallucinosis, Other or Unspecified Psychoactive Sub weight loss, agoraphobia, improving memory, amnesia, stance Mood Disorder. Other or Unspecified Psychoactive Smoking cessation, nicotine withdrawal syndrome symp Substance Anxiety Disorder. Other or Unspecified Psychoac toms, disturbances of mood and/or appetite associated with tive Substance Personality Disorder. Other or Unspecified pre-menstrual syndrome, depressed mood and/or carbohy Psychoactive Substance Organic Mental Disorder NOS, drate craving associated with pre-menstrual syndrome, dis Delirium, Dementia, Organic Delusional Disorder, Organic turbances of mood, disturbances of appetite or disturbances Hallucinosis, Organic Mood Disorder, Organic Anxiety Dis which contribute to recidivism associated with nicotine with order, Organic Personality Disorder, Organic Mental Disor drawal, circadian rhythm disorder, borderline personality dis der, Obsessive Compulsive Disorder, Post-traumatic Stress order, hypochondriasis, premenstrual syndrome (PMS), late Disorder, Generalized Anxiety Disorder, Anxiety Disorder luteal phase dysphoric disorder, premenstrual dysphoric dis NOS, Body Dysmorphic Disorder, Hypochondriasis (or order, trichotillomania, symptoms following discontinuation Hypochondriacal Neurosis). Somatization Disorder, Undif of other anti-depressants, aggressive/intermittent explosive ferentiated Somatoform Disorder, Somatoform Disorder disorder, compulsive gambling, compulsive spending, com NOS, Intermittent Explosive Disorder, Kleptomania, Patho pulsive sex, psychoactive substance use disorder, sexual dis logical Gambling, Pyromania, Trichotillomania and Impulse order, Schizophrenia, premature ejaculation, or psychiatric Control Disorder NOS. Symptoms selected from stress, worry, anger, rejection sensi 0105. Additional examples of pathological or psychologi tivity, and lack of mental or physical energy. cal conditions which may be treated as described in this 0104) Other examples of pathological or psychological invention include Schizophrenia, Catatonic, Sub-chronic, conditions which may be treated in accordance with this Schizophrenia, Catatonic, Chronic, Schizophrenia, Cata invention include, but are not limited to: Moderate Mental tonic, Sub-chronic with Acute Exacerbation, Schizophrenia, Retardation, Severe Mental Retardation, Profound Mental Catatonic, Chronic with Acute Exacerbation, Schizophrenia, US 2009/0215895 A1 Aug. 27, 2009

Catatonic, in Remission, Schizophrenia, Catatonic, Unspeci Acanthosis Nigricans, Acanthosis Bullosa, Acanthosis Nig fied, Schizophrenia, Disorganized, Chronic, Schizophrenia, ricans With Insulin Resistance Type A, Acanthosis Nigricans Disorganized, Subchronic with Acute Exacerbation, Schizo With Insulin Resistance Type B, Acanthotic Nevus, Acata phrenia, Disorganized, Chronic with Acute Exacerbation, lasemia, Acatalasia, ACC. Accessory Atrioventricular Path Schizophrenia, Disorganized, in Remission, Schizophrenia, ways, Accessory Atrioventricular. Pathways, Acephaly, ACF Disorganized, Unspecified, Schizophrenia, Paranoid, Sub with Cardiac Defects, Achalasia, Achard-Thiers Syndrome, chronic, Schizophrenia, Paranoid, Chronic, Schizophrenia, ACHARD (Marfan variant), Achard's syndrome, Acholuric Paranoid, Sub-chronic with Acute Exacerbation, Schizophre Jaundice, Achondrogenesis, Achondrogenesis Type IV. nia, Paranoid, Chronic with Acute Exacerbation, Schizophre Achondrogenesis Type III, Achondroplasia, Achondroplasia nia, Paranoid, in Remission, Schizophrenia, Paranoid, Unspecified, Schizophrenia, Undifferentiated, Sub-chronic, Tarda, Achondroplastic Dwarfism, Achoo Syndrome, Achro Schizophrenia, Undifferentiated, Chronic, Schizophrenia, mat, Achromatope, Achromatopic, Achromatopsia, Achro Undifferentiated, Sub-chronic with Acute Exacerbation, mic Nevi, Acid Ceramidase Deficiency, Acid Maltase Defi Schizophrenia, Undifferentiated, Chronic with Acute Exac ciency, Acid B-glucosidase Deficiency, Acidemia erbation, Schizophrenia, Undifferentiated, in Remission, Methylmalonic, Acidemia Propionic, Acidemia with Epi Schizophrenia, Undifferentiated, Unspecified, Schizophre sodic Ataxia and Weakness, Acidosis, Aclasis Tarsoepiphy nia, Residual, Sub-chronic, Schizophrenia, Residual, seal, ACM, Acoustic Neurilemoma, Acoustic Neuroma, Chronic, Schizophrenia, Residual, Subchronic with Acute ACPS with Leg Hypoplasia, ACPS II, ACPS IV, ACPS III, Exacerbation, Schizophrenia, Residual, Chronic with Acute Acquired Aphasia with Convulsive Disorder, Acquired Exacerbation, Schizophrenia, Residual, in Remission, Brown Syndrome, Acquired Epileptic Aphasia, Acquired Schizophrenia, Residual, unspecified, Delusional (Paranoid) Factor XIII Deficiency, Acquired Form of ACC (caused by Disorder, Brief Reactive Psychosis, Schizophreniform Dis infection while still in womb). Acquired Hyperoxaluria, order, Schizoaffective Disorder, induced Psychotic Disorder, Acquired Hypogammaglobulinemia, Acquired Immunodefi Psychotic Disorder NOS (Atypical Psychosis), Bipolar Dis ciency Syndrome (AIDS), Acquired Iron Overload, Acquired order, Mixed, Severe, without Psychotic Features, Bipolar Lipodystrophy, Acquired Partial Lipodystrophy, Acquired Disorder, Manic, Severe, without Psychotic Features, Bipolar Wandering Spleen, ACR, Acral Dysostosis with Facial and Disorder, Depressed, Severe, without Psychotic Features, Genital Abnormalities, Acro Renal, Acrocallosal Syndrome Bipolar Disorder, Mixed, with Psychotic Features, Bipolar Schinzel Type, AcrocephaloSyndactyly, Acrocephalosyndac Disorder, Manic, with Psychotic Features, Bipolar Disorder, tyly Type I, Acrocephalosyndactyly Type I Subtype I, Acro Depressed, with Psychotic Features, Bipolar Disorder NOS, cephalopolysyndactyly Type II, Acrocephalopolysyndactyly Major Depression, Single Episode, with Psychotic Features, Type III, Acrocephalopolysyndactyly Type IV. Acrocephalo syndactyly V (ACS5 or ACSV) Subtype I, Acrocephaly Skull Major Depression, Recurrent with Psychotic Features Per Asymmetry and Mild Syndactyly, Acrocephaly, Acrochon sonality Disorders, Paranoid Personality Disorders, Schizoid, drohyperplasia, Acrodermatitis Enteropathica, Acrodysosto Personality Disorders, Schizotypal, Personality Disorders, sis, Acrodystrophic Neuropathy, Acrofacial Dysostosis Anti-social, Personality Disorders and Borderline. Nager Type, Acrofacial Dysostosis Postaxial Type, Acrofa 010.6 Anxiety disorders which may be treated in accor cial Dysostosis Type Genee-Wiedep, Acrogeria Familial, dance with this invention include, but are not limited to Anxi Acromegaly, Acromelalgia Hereditary, Acromesomelic Dys ety Disorders, Panic Disorder, Panic Disorder with Agora plasia, Acromesomelic Dwarfism, Acromicric Skeletal Dys phobia, Panic Disorder without Agoraphobia, Agoraphobia plasia, Acromicric Dysplasia, Acroosteolysis with without History of Panic Disorders, Social Phobia, Simple Osteoporosis and Changes in Skull and Mandible, Acroost Phobia, Organic Anxiety Disorder, Psychoactive Substance eolysis, Acroparesthesia, ACSI, ACS Type II, ACS Type III, Anxiety Disorder, Separation Anxiety Disorder, Avoidant ACS, ACS3, ACTH Deficiency, Action Myoclonus, Acute Disorder of Childhood or Adolescence, and Overanxious Dis Brachial Neuritis Syndrome, Acute Brachial Radiculitis Syn order. drome, Acute Cerebral Gaucher Disease, Acute Cholangitis, 0107 Reference to cardiovascular disease includes Acute Disseminated Encephalomyeloradiculopathy, Acute strokes and any condition of the systemic vasculature and Disseminated Histiocytosis-X, Acute Hemorrhagic Polioen includes atherosclerosis, chronic heart failure and general cephalitis, Acute Idiopathic Polyneuritis, Acute Immune-Me heart disease. diation Polyneuritis, Acute Infantile Pelizaeus-Merzbacher 0108. Other conditions contemplated herein include but Brain Sclerosis, Acute Intermittant Porphyria, Acute Porphy are not limited to Adult Respiratory distress syndrome, A-B- rias, Acute Sarcoidosis, Acute Shoulder Neuritis, Acute Toxic Lipoproteinemia, A-V. A B-2-Microglobulin Amyloidosis, Epidermolysis, Acyl-CoA Dehydrogenase Deficiency Long A-T, A1 AD. A 1AT, Aagenaes, Aarskog syndrome, Aarskog Chain, Acyl-CoA Dehydrogenase Deficiency Short-Chain, Scott Syndrome, Aase-Smith syndrome, Aase Syndrome, Acyl-CoA Dihydroxyacetone Acyltransferase, Acyl-coen AAT. Abderhalden-Kaufmann-Lignac Syndrome, Abdomi Zyme A Oxidase Deficiency, ADA, ADA Deficiency, Adam nal Muscle Deficiency Syndrome, Abdominal Wall Defect, Complex, Adamantiades-Behcet’s Syndrome, Adamanti Abdominal Epilepsy, Abdominal Migraine, Abductor Spas noma, Adams Oliver Syndrome, Adaptive Colitis, ADD com modic Dysphonia, Abductor Spastic Dysphonia, Abercrom bined type, ADD, Addison Disease with Cerebral Sclerosis, bie Syndrome, blepharon-Macrostomia Syndrome, ABS, Addison's Anemia, Addison's Disease, Addison-Biermer Absence of HPRT. Absence of Corpus Callosun Schinzel Anemia, Addison-Schilder Disease, Addisonian Pernicious Typ. Absence Defect of Limbs Scalp and Skull, Absence of Anemia, Adducted Thumbs-Mental Retardation, Adductor Menstruation Primar, Absence of HGPRT. Absorptive Hyper Spasmodic Dysphonia, Adductor Spastic Dysphonia, oxaluriaor Enteric, Abt-Letterer-Siwe Disease, ACADL, Adenoma Associated Virilism of Older Women, Adenomato ACADM Deficiency, ACADM, ACADS, Acanthocytosis sis of the Colon and Rectum, Adenomatous polyposis of the Neurologic Disorder, Acanthocytosis, Acantholysis Bullosa, Colon, Adenomatous Polyposis Familial, Adenosine Deami US 2009/0215895 A1 Aug. 27, 2009

nase Deficiency, Adenylosuccinase deficiency, ADHD pre Childhood, Alzheimer's Disease, Amaurotic Familial Idiocy, dominantly hyperactive-impulsive type, ADHD predomi Amaurotic Familial Idiocy Adult, Amaurotic Familial Infan nantly inattentive type, ADHD, Adhesive Arachnoiditis, Adie tile Idiocy, Ambiguous Genitalia, AMC, AMD, Ameloblas Syndrome, Adie's Syndrome, Adie's Tonic Pupil, Adie's toma, Amelogenesis Imperfecta, Amenorrhea-Galactorrhea Pupil, Adipogenital Retinitis Pigmentosa Polydactyly, Adi Nonpuerperal, Amenorrhea-Galactorrhea-FSH Decrease pogenital-Retinitis Pigmentosa Syndrome, Adiposa Dolo Syndrome, Amenorrhea, Amino Acid Disorders, Aminoaci rosa, Adiposis Dolorosa, Adiposogenital Dystrophy, Adoles duria-Osteomalacia-Hyperphosphaturia Syndrome, AMN, cent Cystinosis, ADPKD, Adrenal Cortex Adenoma, Adrenal Amniocentesis, Amniotic Bands, Amniotic Band Syndrome, Disease, Adrenal Hyperfunction resulting from Pituitary Amniotic Band Disruption Complex, Amniotic Band ACTH Excess, Adrenal Hypoplasia, Adrenal Insufficiency, Sequence, Amniotic Rupture Sequence, Amputation Con Adrenal Neoplasm, Adrenal Virilism, Adreno-Retinitis Pig genital, AMS, Amsterdam Dwarf Syndrome de Lange, mentosa-Polydactyly Syndrome, Adrenocortical Insuffi Amylo-16-Glucosidase Deficiency, Amyloid Arthropathy of ciency, Adrenocortical Hypofunction, Adrenocorticotropic Chronic Hemodialysis, Amyloid Corneal Dystrophy, Amy Hormone Deficiency Isolated, Adrenogenital Syndrome, loid Polyneuropathy, Amyloidosis, Amyloidosis of Familial Adrenoleukodystrophy, Adrenomyeloneuropathy, Adreno Mediterranean Fever, Amylopectinosis, Amyoplasia Con Retinitis Pigmentosa-Polydactyly Syndrome, Adult Cystino genita, Amyotrophic Lateral Sclerosis, Amyotrophic Lateral sis, Adult Dermatomyositis, Adult Hypophosphatasia, Adult Sclerosis, Amyotrophic Lateral Sclerosis-Polyglucosan Bod Macula Lutea Retinae Degeneration, Adult Onset ALD, ies, AN, AN 1, AN 2, Anal Atresia, Anal Membrane, Anal Adult-Onset Ceroidosis, Adult Onset Medullary Cystic Dis Rectal Malformations, Anal Stenosis, Analine 60 Amyloido ease, Adult Onset Pernicious Anemia, Adult Onset Schindler sis, Analphalipoproteinemia, Analrectal, Analrectal, Ana Disease. Adult-Onset Subacute Necrotizing Encephalomyel plastic Astrocytoma, Andersen Disease, Anderson-Fabry opathy, Adult Polycystic Kidney Disease, Adult Onset Med Disease, Andersen Glycogenosis, Anderson-Warburg Syn ullary Cystic Disease, AdynloSuccinate Lyase Deficiency, drome, Andre Syndrome, Andre Syndrome Type II, Andro AE, AEC Syndrome, AFD, Afibrinogenemia, African Sidero gen Insensitivity, Androgen Insensitivity Syndrome Partial, sis, AGA, Aganglionic Megacolon, Age Related Macular Androgen Insensitivity Syndrome Partial, Androgenic Ste Degeneration, Agenesis of Commissura Magna Cerebri, roids, Anemia Autoimmune Hemolytic, Anemia Blackfan Agenesis of Corpus Callosum, Agenesis of Corpus Callo Diamond, Anemia, Congenital, Triphalangeal Thumb Syn Sum-Infantile Spasms-Ocular Anomalies, Agenesis of Cor drome, Anemia Hemolytic Cold Antibody, Anemia pus Callosum and Chorioretinal Abnormality, Agenesis of Hemolytic with PGK Deficiency, Anemia Pernicious, Anen Corpus CalloSum-Chorioretinitis Abnormality, Aggressive cephaly, Angelman Syndrome, Angio-Osteohypertrophy mastocytosis, Agnosis Primary, AGR Triad, AGU, Agyria, Syndrome, Angiofollicular Lymph Node Hyperplasia, Agyria-pachygria-band spectrum, AHC, AHD. AHDS, AHF Angiohemophilia, Angiokeratoma Corporis, Angiokeratoma Deficiency, AHG Deficiency, AHO, Ahumada Del Castillo, Corporis Diffusum, Angiokeratoma Diffuse, Angiomatosis Aicardi Syndrome, AIED, AIMP, AIP, AIS, Akinetic Seizure, Retina, Angiomatous Lymphoid, Angioneurotic Edema ALA-D Porphyria, Alactasia, Alagille Syndrome, Aland Hereditary, Anhidrotic Ectodermal Dysplasia, Anhidrotic Island Eye Disease (X-Linked), Alaninuria, Albers-Schon X-Linked Ectodermal Dysplasias, Aniridia, Aniridia-Am berg Disease, Albinism, Albinismus, Albinoidism, Albright biguous Genitalia-Mental Retardation, Aniridia Associated Hereditary Osteodystrophy, Alcaptonuria, Alcohol-Related with Mental Retardation, Aniridia-Cerebellar Ataxia-Mental Birth Defects, Alcoholic Embryopathy, Ald, ALD, ALD, Deficiency, Aniridia Partial-Cerebellar Ataxia-Mental Retar Aldosterone, Aldosteronism With Normal Blood Pressure, dation, Aniridia Partial-Cerebellar Ataxia-Oligophrenia, Aldrich Syndrome, Alexander's Disease, Alexanders Dis Aniridia Type I, Aniridia Type II, Aniridia-Wilms Tumor ease, Algodystrophy, Algoneurodystrophy, Alkaptonuria, Association, Aniridia-Wilms Tumor-Gonadoblastoma, Alkaptonuric Ochronosis, Alkyl DHAP synthase deficiency, Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate, Allan-Herndon-Dudley Syndrome, Allan-Herndon Syn Ankylosing Spondylitis, Annular groves, Anodontia, drome, Allan-Herndon-Dudley Mental Retardation, Allergic Anodontia Vera, Anomalous Trichromasy, Anomalous Dys Granulomatous Antitis, Allergic Granulomatous Angiitis of plasia of Dentin, Coronal Dentin Dysplasia, Anomic Aphasia, Cronkhite-Canada, Alobar Holoprosencephaly, Alopecia Anophthalmia, Anorectal. Anorectal Malformations, Areata, Alopecia Celsi, Alopecia Cicatrisata, Alopecia Cir Anosmia, Anterior Bowing of the Legs with Dwarfism, Ante cumscripta, Alopecia-Poliosis-Uveitis-Vitiligo-Deafness rior Membrane Corneal Dystrophy, Anti-Convulsant Syn Cutaneous-Uveo-O, Alopecia Seminuniversalis, Alopecia drome, Anti-Epstein-Barr Virus Nuclear Antigen (EBNA) Totalis, Alopecia Universalis, Alpers Disease, Alpers Diffuse Antibody Deficiency, Antibody Deficiency, Antibody Defi Degeneration of Cerebral Gray Matter with Hepatic Cirrho ciency with near normal Immunoglobulins, Anti-hemophilic sis, Alpers Progressive Infantile Poliodystrophy, Alpha-1- Factor Deficiency, Anti-hemophilic Globulin Deficiency, Antitrypsin Deficiency, C-1 4 Glucosidase Deficiency, C.-Ga Anti-phospholipid Syndrome, Anti-phospholipid Antibody lactosidase A Deficiency, C.-Galactosidase B Deficiency, a Syndrome, Anti-thrombin III Deficiency, Anti-thrombin III High-Density Lipoprotein Deficiency, C-L-Fucosidase Defi Deficiency Classical (Type I), Anti-trypsin Deficiency, Ant ciency Fucosidosis Type 3, C.-GalNAc Deficiency Schindler ley-Bixler Syndrome, Antoni’s Palsy, Anxietas Tibialis, Aorta Type, Alphalipoproteinemia, Alpha Mannosidosis, Cl-N- Arch Syndrome, Aortic and Mitral Atresia with Hypoplasic Acetylgalactosaminidase Deficiency Schindler Type, Left Heart Syndrome, Aortic Stenosis, Aparoschisis, APC, C.-NAGADeficiency Schindler Type, C-Neuraminidase Defi APECED Syndrome, Apert Syndrome, Aperts, Aphasia, ciency, C.-Thalassemia/mental retardation syndrome non-de Aplasia Axialis Extracorticales Congenital, Aplasia Cutis letion type, C.-lipoproteinemia, Alport Syndrome, ALS, Congenita, Aplasia Cutis Congenita with Terminal Trans Alstroem’s Syndrome. Alstroem, Alstrom Syndrome. Alter verse Limb Defects, Aplastic Anemia, Aplastic Anemia with nating Hemiplegia Syndrome. Alternating Hemiplegia of Congenital Anomalies, APLS, Apnea, Appalachian Type US 2009/0215895 A1 Aug. 27, 2009

Amyloidosis, Apple Peel Syndrome, Apraxia, Apraxia Buc conus, Autosomal Recessive Polycystic Kidney Disease, cofacial, Apraxia Constructional, Apraxia Ideational, Autosomal Recessive Severe Combined Immunodeficiency, Apraxia Ideokinetic, Apraxia Ideomotor, Apraxia Motor, AV, AVM, AVSD, AWTA, Axilla Abscess, Axonal Neuropa Apraxia Oculomotor, APS, Arachnitis, Arachnodactyly Con thy Giant, Azorean Neurologic Disease, B-K Mole Syn tractural Beals Type, Arachnodactyly, Arachnoid Cysts, drome, Babinski-Froelich Syndrome. BADS, Baillarger's Arachnoiditis Ossificans, Arachnoiditis, Aran-Duchenne, Syndrome, Balkan Disease, Baller-Gerold Syndrome, Bal Aran-Duchenne Muscular Atrophy, Are generative Anemia, looning Mitral Valve, Balo Disease Concentric Sclerosis, Arginase Deficiency, Argininemia, Arginino Succinase Defi Baltic Myoclonus Epilepsy, Bannayan-Zonaria syndrome ciency, Argininosuccinase Deficiency, Argininosuccinate (BZS), Bannayan-Riley-Ruvalcaba syndrome, Banti’s Dis Lyase Deficiency, Argininosuccinic-Acid Lyase-ASL, ease, Bardet-Biedl Syndrome, Bare Lymphocyte Syndrome, Argininosuccinic Acid Synthetase Deficiency, Argininosuc Barlow's syndrome, Barraquer-Simons Disease, Barrett cinic Aciduria, Argonz-Del Castillo Syndrome, Arhinenceph Esophagus, Barrett Ulcer, Barth Syndrome, Bartter's Syn aly, Armenian Syndrome, Arnold-Chiari Malformation, drome, Basal Cell Nevus Syndrome, Basedow Disease, Bas Arnold-Chiari Syndrome, ARPKD, Arrhythmic Myoclonus, sen-Kornzweig Syndrome, Batten Disease, Batten-Mayou Arrhythmogenic Right Ventricular Dysplasia, Arteriohepatic Syndrome, Batten-Spielmeyer-Vogt's Disease, Batten Turner Dysplasia, Arteriovenous Malformation, Arteriovenous Mal Syndrome, Batten Turner Type Congenital myopathy, Batten formation of the Brain, Arteritis Giant Cell, Arthritis, Arthritis Vogt Syndrome, BBB Syndrome, BBB Syndrome (Opitz), Urethritica, Arthro-Dento-Osteodysplasia, Arthro-Ophthal BBB Syndrome, BBBG Syndrome, BCKD Deficiency, BD, mopathy, Arthrochalasis Multiplex Congenita, Arthrogrypo BDLS, BE, Beals Syndrome, Beals Syndrome, Beals-Hecht sis Multiplex Congenita, Arthrogryposis Multiplex Con Syndrome, Bean Syndrome, BEB, Bechterew Syndrome, genita, Distal, Type IIA, ARVD. Arylsulfatase-B Deficiency, Becker Disease, Becker Muscular Dystrophy, Becker Nevus, AS, ASA Deficiency, Ascending Paralysis, ASD, Atrioseptal Beckwith Wiedemann Syndrome, Beckwith-Syndrome, Defects, ASH, Ashermans Syndrome, Ashkenazi Type Amy Begnez-Cesar's Syndrome, Behcet’s syndrome, Behcet’s loidosis, ASL Deficiency, Aspartylglucosaminuria, Aspar Disease, Behr 1, Behr 2, Bell's Palsy, Benign Acanthosis tylglycosaminuria, Asperger's Syndrome, Asperger's Type Nigricans, Benign Astrocytoma, Benign Cranial Nerve Autism, Asphyxiating Thoracic Dysplasia, Asplenia Syn Tumors, Benign Cystinosis, Benign Essential Ble drome, ASS Deficiency, Asthma, Astrocytoma Grade I (Be pharospasm, Benign Essential Tremor, Benign Familial nign), Astrocytoma Grade II (Benign), ASymnmetric Crying Hematuria, Benign Focal Amyotrophy, Benign Focal Amyo Facies with Cardiac Defects, Asymmetrical septal hypertro trophy of ALS, Benign Hydrocephalus, Benign Hypermobil phy, Asymptomatic Callosal Agenesis, AT, ATIII Deficiency, ity Syndrome, Benign Keratosis Nigricans, Benign Paroxys AT III Variant IA, AT III Variant Ib, AT3, Ataxia, Ataxia mal Peritonitis, Benign Recurrent Hematuria, Benign Telangiectasia, Ataxia with Lactic Acidosis Type II, Ataxia Recurrent Intrahepatic Cholestasis, Benign Spinal Muscular Cerebral Palsy, Ataxiadynamia, Ataxiophemia, ATD, Athe Atrophy with Hypertrophy of the Calves, Benign Symmetri toid Cerebral Palsy, Atopic Eczema, Atresia of Esophagus cal Lipomatosis, Benign Tumors of the Central Nervous Sys with or without Tracheoesophageal Fistula, Atrial Septal tem, Berardinelli-Seip Syndrome, Berger's Disease, Beriberi, Defects, Atrial Septal Defect Primum, Atrial and Septal and Berman Syndrome, Bernard-Horner Syndrome, Bernard Small Ventricular Septal Defect, Atrial Flutter, Atrial Fibril Soulier Syndrome, Besnier Prurigo, Best Disease, B-Alanine lation, Atriodigital Dysplasia, Atrioseptal Defects, Atrioven Pyruvate Aminotransferase, B-Galactosidase Deficiency tricular Block, Atrioventricular Canal Defect, Atrioventricu Morquio Syndrome, B-Glucuronidase Deficiency, f Oxida lar Septal Defect, Atrophia Bulborum Hereditaria, Atrophic tion Defects, B Thalassemia Major. B Thalassemia Minor, Beriberi, Atrophy Olivopontocerebellar, Attention Deficit B-lipoprotein Deficiency, Bethlem myopathy, Beuren Syn Disorder, Attention Deficit Hyperactivity Disorder, Attenu drome, BH4. Deficiency, Biber-Haab-Dimmer Corneal Dys ated Adenomatous Polyposis Coli, Atypical Amyloidosis, trophy, Bicuspid Aortic Valve, Biedl-Bardet, Bifid Cranium, Atypical Hyperphenylalaninemia, Auditory Canal Atresia, Bifunctional Enzyme Deficiency, Bilateral Acoustic Neurofi Auriculotemporal Syndrome, Autism, Autism Asperger's bromatosis, Bilateral Acoustic Neuroma, Bilateral Right-Sid Type, Autism Dementia Ataxia and Loss of Purposeful Hand edness Sequence, Bilateral Renal Agenesis, Bilateral Tempo Use, Autism Infantile Autism, Autoimmune Addison's Dis ral Lobe Disorder, Bilious Attacks, Bilirubin ease, Autoimmune Hemolytic Anemia, Autoimmune Hepati Glucuronosyltransferase Deficiency Type I, Binder Syn tis, Autoimmune-Polyendocrinopathy-Candidias, Autoim drome, Binswanger's Disease, Binswanger's Encephalopa mune Polyglandular Disease Type I, Autosomal Dominant thy, Biotinidase deficiency, Bird-Headed Dwarfism Seckel Albinism, Autosomal Dominant Compelling Heliooph Type, Birth Defects, Birthmark, Bitemporal Forceps Marks thalmic Outburst Syndrome, Autosomal Dominant Desmin Syndrome, Biventricular Fibrosis, Bjornstad Syndrome, B-K Distal myopathy with Late Onset, Autosomal Dominant Mole Syndrome, Black Locks-Albinism-Deafness of Senso EDS, Autosomal Dominant Emery-Dreifuss Muscular Dys neural Type (BADS), Blackfan-Diamond Anemia, Blennor trophy, Autosomal Dominant Keratoconus, Autosomal rheal Idiopathic Arthritis, Blepharophimosis, Ptosis, Epican Dominant Pelizaeus-Merzbacher Brain Sclerosis, Autosomal thus Inversus Syndrome, Blepharospasm, Blepharospasm Dominant Polycystic Kidney Disease, Autosomal Dominant Benign Essential, Blepharospasm Oromandibular Dystonia, Spinocerebellar Degeneration, Autosomal Recessive Agam Blessig Cysts, BLFS, Blindness, Bloch-Siemens Incontinen maglobulinemia, Autosomal Recessive Centronuclear tia Pigmenti Melanoblastosis Cutis Linearis, Bloch-Siemens myopathy, Autosomal Recessive Conradi-Hunermann Syn Sulzberger Syndrome, Bloch-Sulzberger Syndrome, Blood drome, Autosomal Recessive EDS, Autosomal Recessive types, Blood type A, Blood type B, Blood type AB, Blood Emery-Dreifuss Muscular Dystrophy, Autosomal Recessive type O, Bloom Syndrome, Bloom-Torre-Mackacek Syn Forms of Ocular Albinism, Autosomal Recessive Inheritance drome, Blue Rubber Bleb Nevus, Blue Baby, Blue Diaper Agenesis of Corpus Callosum, Autosomal Recessive Kerato Syndrome, BD, BOD, BOFS, Bone Tumor-Epidermoid Cyst US 2009/0215895 A1 Aug. 27, 2009

Polyposis, Bonnet-Dechaume-Blanc. Syndrome, Bonnevie Primary, Carnitine Deficiency Secondary, Carnitine Defi Ulrich Syndrome, Book Syndrome, BOR Syndrome, BORJ, ciency Secondary to MCAD Deficiency, Carnitine Defi Borjeson Syndrome, Borjeson-Forssman-Lehmann Syn ciency Syndrome, Carnitine Palmitoyl Transferase I & II drome, Bowen Syndrome, Bowen-Conradi Syndrome, (CPTI & II), Carnitine Palmitoyltransferase Deficiency, Car Bowen-Conradi Hutterite, Bowen-Conradi Type Hutterite nitine Palmitoyltransferase Deficiency Type 1, Carnitine Syndrome, Bowman's Layer, BPEI, BPES, Brachial Neuritis, Palmitoyltransferase Deficiency Type 2 benign classical mus Brachial Neuritis Syndrome, Brachial Plexus Neuritis, Bra cular form included severe infantile form included, Carnitine chial-Plexus-Neuropathy, Brachiocephalic Ischemia, Brach Transport Defect (Primary Carnitine Deficiency), Carnosi mann-de Lange Syndrome, Brachycephaly, Brachymorphic nase Deficiency, Carnosinemia, Caroli Disease, Carpenter Type Congenital, Bradycardia, Brain Tumors, Brain Tumors syndrome, Carpenter's, Cartilage-Hair Hypoplasia, Castle Benign, Brain Tumors Malignant, Branched Chain C.-Ke man's Disease, Castleman's Disease Hyaline Vascular Type, toacid Dehydrogenase Deficiency, Branched Chain Keto Castleman's Disease Plasma Cell Type, Castleman Tumor, nuria I, Brancher Deficiency, Branchio-Oculo-Facial Syn Cat Eye Syndrome, Cat's Cry Syndrome, Catalayse defi drome, Branchio-Oto-Renal Dysplasia, Branchio-Oto-Renal ciency, Cataract-Dental Syndrome, Cataract X-Linked with Syndrome, Branchiooculofacial Syndrome, Branchiootic Hutchinsonian Teeth, Catecholamine hormones, Catel-Man Syndrome, Brandt Syndrome, Brandywine Type Dentino Zke Syndrome, Catel-Manzke Type Palatodigital Syndrome, genesis Imperfecta, Brandywine type Dentinogenesis Imper Caudal Dysplasia, Caudal Dysplasia Sequence, Caudal fecta, Breast Cancer, BRIC Syndrome, Brittle Bone Disease, Regression Syndrome, Causalgia Syndrome Major, Caverno Broad B Disease, Broad Thumb Syndrome, Broad Thumbs mas, Cavernous Angioma, Cavernous Hemangioma, Cavern and Great Toes Characteristic Facies and Mental Retardation, ous Lymphangioma, Cavernous Malformations, Cayler Syn Broad Thumb-Hallux, Broca's Aphasia, Brocq-Duhring Dis drome, Cazenave's Vitiligo, CBGD, CBPS, CCA, CCD, ease, Bronze Diabetes, Bronze Schilder's Disease, Brown CCHS, CCM Syndrome, CCMS, CCO, CD, CDG 1a, Albinism, Brown Enamel Hereditary, Brown-Sequard Syn CDG1A, CDGSType Ia, CDGS, CDI, CdLS, Celiac Disease, drome, Brown Syndrome, BRRS, Brueghel Syndrome, Bru Celiac sprue, Celiac Sprue-Dermatitis, Cellular Immunode ton’s AY-globulinemia Common, BS, BSS, Buchanan’s Syn ficiency with Purine Nucleoside Phosphorylase Deficiency, drome, Budd's Syndrome, Budd-Chiari Syndrome, Buerger Celsus' Vitiligo, Central Apnea, Central Core Disease, Cen Gruetz Syndrome, Bulbospinal Muscular Atrophy-X-linked, tral Diabetes Insipidus, Central Form Neurofibromatosis, Bulldog Syndrome, Bullosa Hereditaria, Bullous CIE, Central HypoVentilation, Central Sleep Apnea, Centrifugal Bullous Congenital Ichthyosiform Erythroderma, Bullous Lipodystrophy, Centronuclear myopathy, CEP, Cephalocele, Ichthyosis, Bullous Pemphigoid, Burkitt's Lymphoma, Bur Cephalothoracic Lipodystrophy, Ceramide Trihexosidase kitt's Lymphoma African type, Burkitt's Lymphoma Non Deficiency, Cerebellar Agenesis, Cerebellar Aplasia, Cer african type, BWS, Byler's Disease, C Syndrome, C1 ebellar Hemiagenesis, Cerebellar Hypoplasia, Cerebellar Esterase Inhibitor Dysfunction Type II Angioedema, Vermis Aplasia. Cerebellar Vermis Agenesis-Hypernea-Epi C1-INH, C1 Esterase Inhibitor Deficiency Type I sodic Eye Moves-Ataxia-Retardation, Cerebellar Syndrome, Angioedema, C1 NH, Cacchi-Ricci Disease, CAD, CADA Cerebellarparenchymal Disorder IV. Cerebellomedullary SIL, CAH, Calcaneal Valgus, Calcaneovalgus, Calcium Malformation Syndrome, Cerebello-Oculocutaneous Pyrophosphate Dihydrate Deposits, Callosal Agenesis and Telangiectasia, Cerebelloparenchymal Disorder IV Familial, Ocular Abnormalities, Calves-Hypertrophy of Spinal Mus Cerebellopontine Angle Tumor, Cerebral Arachnoiditis, cular Atrophy, Campomelic Dysplasia, Campomelic Dwarf Cerebral Autosomal Dominant Arteriopathy with Subcortical ism, Campomelic Syndrome, Camptodactyly-Cleft Palate Infarcts and Leukodystrophy, Cerebral Beriberi, Cerebral Clubfoot, Camptodactyly-Limited Jaw Excursion, Diplegia, Cerebral Gigantism, Cerebral Malformations Vas Camptomelic Dwarfism, Camptomelic Syndrome, Camp cular, Cerebral Palsy, Cerebro-Oculorenal Dystrophy, Cere tomelic Syndrome Long-Limb Type, Camurati-Engelmann bro-Oculo-Facio-Skeletal Syndrome, Cerebrocostomandibu Disease, Canada-Cronkhite Disease, Canavan disease, Cana lar syndrome, Cerebrohepatorenal Syndrome, Van's Disease Included, Canavan's Leukodystrophy, Cancer, Cerebromacular Degeneration, Cerebromuscular Dystrophy Cancer Family Syndrome Lynch Type, Cantrell Syndrome, Fukuyama Type, Cerebroocular Dysgenesis, Cerebroocular Cantrell-Haller-Ravich Syndrome, Cantrell Pentalogy, Car Dysplasia-Muscular Dystrophy Syndrome, Cerebrooculofa bamyl Phosphate Synthetase Deficiency, Carbohydrate Defi cioskeletal Syndrome, Cerebroretinal Arteriovenous Aneu cient Glycoprotein Syndrome, Carbohydrate-Deficient Gly rysm, Cerebroside Lipidosis, Cerebrosidosis, Cerebrotendi coprotein Syndrome Type Ia, Carbohydrate-Induced nous Xanthomatosis, Cerebrovascular Ferrocalcinosis, Hyperlipemia, Carbohydrate Intolerance of Glucose Galac Ceroid-Lipofuscinosis Adult form, Cervical Dystonia, Cer tose, Carbon Dioxide Acidosis, Carboxylase Deficiency Mul vical Dystonia, Cervico-Oculo-Acoustic Syndrome, Cervical tiple, Cardiac-Limb Syndrome, Cardio-auditory Syndrome, Spinal Stenosis, Cervical Vertebral Fusion, CES, CF, CFC Cardioauditory Syndrome of Jervell and Lange-Nielsen, Car syndrome, CFIDS, CFND, CGD, CGF, Chalasodermia Gen diocutaneous Syndrome, Cardio-facial-cutaneous syndrome, eralized, Chanarin Dorfman Disease, Chanarin Dorfman Cardiofacial Syndrome Cayler Type, Cardiomegalia Glyco Syndrome, Chanarin Dorfman Ichthyosis Syndrome, Chan genica Diffusa, Cardiomyopathic Lentiginosis, Cardiomy dler's Syndrome, Charcot's Disease, Charcot-Marie-Tooth, opathy, Cardiomyopathy Associated with Desmin Storage Charcot-Marie-Tooth Disease, Charcot-Marie-Tooth Disease myopathy, Cardiomyopathy Due to Desmin Defect, Cardi Variant, Charcot-Marie-Tooth-Roussy-Levy Disease, omyopathy-Neutropenia Syndrome, Cardiomyopathy-Neu CHARGE Association, Charge Syndrome, CHARGE Syn tropenia Syndrome Lethal Infantile Cardio myopathy, Car drome, Chaund's Ectodermal Dysplasias, Chediak-Higashi diopathic Amyloidosis, Cardiospasm, Cardocardiac Syndrome, Chediak-Steinbrinck-Higashi Syndrome, Cheili Syndrome, Carnitine-Acylcarnitine Translocase Deficiency, tis Granulomatosa, Cheiloschisis, Chemke Syndrome, Carnitine Deficiency and Disorders, Carnitine Deficiency Cheney Syndrome, Cherry Red Spot and Myoclonus Syn US 2009/0215895 A1 Aug. 27, 2009

drome, CHF, CHH, Chiari's Disease, Chiari Malformation I, Tetrasomy 9p Mosaicism, Chromosome 9 Trisomy 9p (Mul Chiari Malformation, Chiari Type I (Chiari Malformation I). tiple Variants), Chromosome 9 Trisomy 9 (pter-p21 to q32), Chiari Type II (Chiari Malformation II), Chiari I Syndrome, Chromosome 9 Trisomy Mosaic, Chromosome 9 Trisomy Chiari-Budd Syndrome, Chiari-Frommel Syndrome, Chiari Mosaic, Chromosome 10 Distal Trisomy 10q, Chromosome Malformation II, CHILD Syndrome, CHILD Ichthyosis Syn 10 Monosomy, Chromosome 10 Monosomy 10p, Chromo drome, CHILD Syndrome Ichthyosis, Childhood Adrenoleu some 10, Partial Deletion (short arm), Choromsome 10, 10p kodystrophy, Childhood Dermatomyositis, Childhood-onset Partial, Chromosome 10 Partial Trisomy 10q24-qter, Chro Dystonia, Childhood Cyclic Vomiting, Childhood Giant mosome 10 Trisomy 10q2, Partial Monosomy of Long Arm Axonal Neuropathy, Childhood Hypophosphatasia, Child of Chromosome 11, Chromosome 11 Partial Monosomy 11q, hood Muscular Dystrophy, CHN, Cholestasis, Cholestasis Chromosome 11 Partial Trisomy, Chromosome 11 Partial Hereditary Norwegian Type, Cholestasis Intrahepatic, Trisomy 11q13-qter, Chromosome 11 Partial Trisomy Cholestasis Neonatal, Cholestasis of Oral Contraceptive 11q21-qter, Chromosome 11 Partial Trisomy 11q23-qter, Users, Cholestasis with Peripheral Pulmonary Stenosis, Chromosome 11q, Partial Trisomy, Chromosome 12 Isoch Cholestasis of Pregnancy, Cholesterol Desmolase Defi romosome 12p Mosaic, Chromosome 13 Partial Monosomy ciency, Chondrodysplasia Punctata, Chondrodystrophia Cal 13q, Chromosome 13, Partial Monosomy of the Long Arm, cificans Congenita, Chondrodystrophia Fetalis, Chondrodys Chromosome 14 Ring, Chromosome 14 Trisomy, Chromo trophic Myotonia, Chondrodystrophy, Chondrodystrophy some 15 Distal Trisomy 15q, Chromosome r15, Chromosome with Clubfeet, Chondrodystrophy Epiphyseal, Chondrodys 15 Ring, Chromosome 15 Trisomy 15q2, Chromosome 15q. trophy Hyperplastic Form, Chondroectodermal Dysplasias, Partial Duplication Syndrome, Chromosome 17 Interstitial Chondrogenesis Imperfecta, Chondrohystrophia, Chon Deletion 17p, Chromosome 18 Long Arm Deletion Syn droosteodystrophy, Choreoacanthocytosis, Chorionic Villi drome, Chromosome 18 Monosomy 18p, Chromosome 18 Sampling, Chorioretinal Anomalies, Chorioretinal Anoma Monosomy 18Q, Chromosome 18 Ring, Chromosome 18 lies with ACC, Chorireninal Coloboma-Joubert Syndrome, Tetrasomy 18p, Chromosome 18q-Syndrome, Chromosome Choroidal Sclerosis, Choroideremia, Chotzen Syndrome, 21 Mosaic 21 Syndrome, Chromosome 21 Ring, Chromo Christ-Siemens-Touraine Syndrome, Christ-Siemans-Tou some 21 Translocation 21 Syndrome, Chromosome 22 raine Syndrome, Christmas Disease, Christmas Tree Syn Inverted Duplication (22pter-22d 11), Chromosome 22 Par drome, Chromosome 3 Deletion of Distal 3p, Chromosome 3 tial Trisomy (22pter-22q11), Chromosome 22 Ring, Chromo Distal 3p Monosomy, Chromosome 3-Distal 3q2 Duplica some 22 Trisomy Mosaic, Chromosome 48 XXYY. Chromo tion, Chromosome 3-Distal 3q2 Trisomy, Chromosome 3 some 48 XXXY, Chromosome r15, Chromosomal Monosomy 3p2, Chromosome 3q Partial Duplication Syn Triplication, Chromosome Triplication, Chromosome Trip drome, Chromosome 3q, Partial Trisomy Syndrome, Chro loidy Syndrome, Chromosome X, Chromosome XXY. mosome 3-Trisomy 3q2, Chromosome 4 Deletion 4q31-qter Chronic Acholuric Jaundice, Chronic Adhesive Arachnoidi Syndrome, Chromosome 4 Deletion 4q32-qter Syndrome, tis, Chronic Adrenocortical Insufficiency, Chronic Cavern Chromosome 4 Deletion 4q33-qter Syndrome, Chromosome ositis, Chronic Congenital Aregenerative Anemia, Chronic 4 Long Arm Deletion, Chromosome 4 Long Arm Deletion, Dysphagocytosis, Chronic Familial Granulomatosis, Chromosome 4 Monosomy 4q, Chromosome 4-Monosomy Chronic Familial Icterus, Chronic Fatigue Immune Dysfunc 4q, Chromosome 4 Monosomy Distal 4q, Chromosome 4 tion Syndrome (CFIDS), Chronic Granulomatous Disease, Partial Deletion 4p, Chromosome 4, Partial Deletion of the Chronic Guillain-Barre Syndrome, Chronic Idiopathic Jaun Short Arm, Chromosome 4 Partial Monosomy of Distal 4q, dice, Chronic Idiopathic Polyneuritis (CIP), Chronic Inflam Chromosome 4 Partial Monosomy 4p, Chromosome 4 Partial matory Demyelinating Polyneuropathy, Chronic Inflamma Trisomy 4 (q25-qter), Chromosome 4 Partial Trisomy 4 (q26 tory Demyelinating Polyradiculoneuropathy, Chronic Motor or q27-qter), Chromosome 4 Partial Trisomy 4 (q31 or Tic, Chronic Mucocutaneous Candidiasis, Chronic Multiple 32-qter), Chromosome 4 Partial Trisomy 4p, Chromosome 4 Tics, Chronic Non-Specific Ulcerative Colitis, Chronic Oblit Partial Trisomies 4q2 and 4q3, Chromosome 4 Partial Tri erative Cholangitis, Chronic Peptic Ulcer and Esophagitis Somy Distal 4, Chromosome 4 Ring, Chromosome 4 4q Ter Syndrome, Chronic Progressive Chorea, Chronic Progressive minal Deletion Syndrome, Chromosome 4q-Syndrome, External Ophthalmoplegia Syndrome, Chronic Progressive Chromosome 4q-Syndrome, Chromosome 4 Trisomy 4, External Ophthalmoplegia and myopathy, Chronic Progres Chromosome 4 Trisomy 4p, Chromosome 4 XY/47 XXY sive External Ophthalmoplegia with Ragged Red Fibers, (Mosiac), Chromosome 5 Monosomy 5p, Chromosome 5, Chronic Relapsing Polyneuropathy, Chronic Sarcoidosis, Partial Deletion of the Short Arm Syndrome, Chromosome 5 Chronic Spasmodic Dysphonia, Chronic Vomiting in Child Trisomy 5p, Chromosome 5 Trisomy 5p Complete (5p11 hood, CHS, Churg-Strauss Syndrome, Cicatricial Pemphig pter), Chromosome 5 Trisomy 5p Partial (5p3 or 14-pter), oid, CIP. Cirrhosis Congenital Pigmentary, Cirrhosis, Cisti Chromosome 5p-Syndrome, Chromosome 6 Partial Trisomy nuria, Citrullinemia, CJD. Classic Schindler Disease, Classic 6q, Chromosome 6 Ring, Chromosome 6 Trisomy 6q2, Chro Type Pfeiffer Syndrome, Classical Maple Syrup Urine Dis mosome 7 Monosomy 7p2, Chromosome 7 Partial Deletion ease, Classical Hemophilia, Classical Form Cockayne Syn of Short Arm (7p2-), Chromosome 7 Terminal 7p Deletion, drome Type I (Type A), Classical Leigh's Disease, Classical Chromosome 8 Monosomy 8p2, Chromosome 8 Monosomy Phenylketonuria, Classical X-Linked Pelizaeus-Merzbacher 8p21-pter, Chromosome 8 Partial Deletion (short arm), Chro Brain Sclerosis, CLE, Cleft Lip/Palate Mucous Cysts Lower mosome 8 Partial Monosomy 8p2, Chromosome 9 Complete Lip PP Digital and Genital Anomalies, Cleft Lip-Palate Ble Trisomy 9P, Chromosome 9 Partial Deletion of Short Arm, pharophimosis Lagopthalmos and Hypertelorism, Cleft Lip/ Chromosome 9 Partial Monosomy 9p, Chromosome 9 Partial Palate with Abnormal Thumbs and Microcephaly, Cleft pal Monosomy 9p22, Chromosome 9 Partial Monosomy 9p22 ate-joint contractures-dandy walker malformations, Cleft pter, Chromosome 9 Partial Trisomy 9P Included, Chromo Palate and Cleft Lip, Cleidocranial Dysplasia w/ Microg some 9 Ring, Chromosome 9 Tetrasomy 9p, Chromosome 9 nathia, Absent Thumbs, & Distal Aphalangia, Cleidocranial US 2009/0215895 A1 Aug. 27, 2009

Dysostosis, Cleidocranial Dysplasia, Click murmur Syn nation Neuropathy, Congenital Hypomyelination, Congeni drome, CLN1, Clonic Spasmodic, Cloustons Syndrome, tal Hypomyelination (Onion Bulb) Polyneuropathy, Con Clubfoot, CMDI, CMM, CMT, CMTC, CMTX, COA Syn genital Ichthyosiform Erythroderma, Congenital drome, Coarctation of the aorta, Coats Disease, Cobblestone Keratoconus, Congenital Lactic Acidosis, Congenital Lac dysplasia, Cochin Jewish Disorder, Cockayne Syndrome, tose Intolerance, Congenital Lipodystrophy, Congenital COD-MD Syndrome, COD, Coffin Lowry Syndrome, Coffin Liver Cirrhosis, Congenital Lobar Emphysema, Congenital Syndrome, Coffin Siris Syndrome, COFS Syndrome, Cogan Localized Emphysema, Congenital Macroglossia, Congeni Corneal Dystrophy, Cogan Reese Syndrome, Cohen Syn tal Medullary Stenosis, Congenital Megacolon, Congenital drome, Cold Agglutinin Disease, Cold Antibody Disease, Melanocytic Nevus, Congenital Mesodermal Dysmorphod Cold Antibody Hemolytic Anemia, Colitis Ulcerative, Colitis yStrophy, Congenital Mesodermal Dystrophy, Congenital Gravis, Colitis Ulcerative Chronic Non-Specific Ulcerative MicroVillus Atrophy, Congenital Multiple Arthrogryposis, Colitis, Collodion Baby, Coloboma Heart Defects Atresia of Congenital Myotonic Dystrophy, Congenital Neuropathy the Choanae Retardation of Growth and Development Geni caused by Hypomyelination, Congenital Pancytopenia, Con tal and Urinary Anomalies and Ear Anomalies, Coloboma, genital Pernicious Anemia, Congenital Pernicious Anemia Colonic Neurosis, Colorblindness, Colour blindness, Colpo due to Defect of Intrinsic Factor, Congenital Pernicious Ane cephaly, Columnar-Like Esophagus, Combined Cone-Rod mia due to Defect of Intrinsic Factor, Congenital Pigmentary Degeneration, Combined Immunodeficiency with Immuno Cirrhosis, Congenital Porphyria, Congenital Proximal globulins, Combined Mesoectodermal Dysplasia, Common myopathy Associated with Desmin Storage myopathy, Con Variable Hypogammaglobulinemia, Common Variable genital Pulmonary Emphysema, Congenital Pure Red Cell Immunodeficiency, Common Ventricle, Communicating Anemia, Congenital Pure Red Cell Aplasia, Congenital Reti Hydrocephalus, Complete Absence of Hypoxanthine-Gua nal Blindness, Congenital Retinal Cyst, Congenital Retinitis nine Phosphoribosyltransferase, Complete Atrioventricular Pigmentosa, Congenital Retinoschisis, Congenital Rod Dis Septal Defect, Complement Component 1 Inhibitor Defi ease, Congenital Rubella Syndrome, Congenital Scalp ciency, Complement Component C1 Regulatory Component Defects with Distal Limb Reduction Anomalies, Congenital Deficiency, Complete Heart Block, Complex Carbohydrate Sensory Neuropathy, Congenital SMA with arthrogryposis, Intolerance, Complex Regional Pain Syndrome, Complex V Congenital Spherocytic Anemia, Congenital Spondyloepi ATP Synthase Deficiency, Complex I, Complex I NADH physeal Dysplasia, Congenital Tethered Cervical Spinal Cord dehydrogenase deficiency, Complex II, Complex II Succinate Syndrome, Congenital Tyrosinosis, Congenital Varicella dehydrogenase deficiency, Complex III, Complex III Syndrome, Congenital Vascular Cavernous Malformations, Ubiquinone-cytochrome c oxidoreductase deficiency, Com Congenital Vascular Veils in the Retina, Congenital Word plex IV, Complex IV Cytochrome C Oxidase Deficiency, Blindness, Congenital Wandering Spleen (Pediatric), Con Complex IV Deficiency, Complex V. Cone-Rod Degenera gestive Cardio myopathy, Conical Cornea, Conjugated tion, Cone-Rod Degeneration Progressive, Cone Dystrophy, Hyperbilirubinemia, Conjunctivitis, Conjunctivitis Ligne Cone-Rod Dystrophy, Confluent Reticular Papillomatosis, ous, Conjunctivo-Urethro-Synovial Syndrome, Conn's Syn Congenital with low PK Kinetics, Congenital Absence of drome, Connective Tissue Disease, Conradi Disease, Conradi Abdominal Muscles, Congenital Absence of the Thymus and Hunermann Syndrome, Constitutional Aplastic Anemia, Parathyroids, Congenital Achromia, Congenital Addison's Constitutional Erythroid Hypoplasia, Constitutional Eczema, Disease, Congenital Adrenal Hyperplasia, Congenital Constitutional Liver Dysfunction, Constitutional Thromb Adreneal Hyperplasia, Congenital Afibrinogenemia, Con opathy, Constricting Bands Congenital, Constrictive Peri genital Alveolar HypoVentilation, Congenital Anemia of carditis with Dwarfism, Continuous Muscle Fiber Activity Newborn, Congenital Bilateral Persylvian Syndrome, Con Syndrome, Contractural Arachnodactyly, Contractures of genital Brown Syndrome, Congenital Cardiovascular Feet Muscle Atrophy and Oculomotor Apraxia, Convulsions, Defects, Congenital Central HypoVentilation Syndrome, Cooley's anemia, CopperTransport Disease, Coproporphyria Congenital Cerebral Palsy, Congenital Cervical Synostosis, Porphyria Hepatica, Cor Triatriatum, Cor Triatriatum Sinis Congenital Clasped Thumb with Mental Retardation, Con trum, Cor Triloculare Biatriatum, Cor Biloculare, Cori Dis genital Contractural Arachnodactyly, Congenital Contrac ease, Cornea Dystrophy, Corneal Amyloidosis, Corneal tures Multiple with Arachnodactyly, Congenital Cyanosis, Clouding-Cutis Laxa-Mental Retardation, Corneal Dystro Congenital Defect of the Skull and Scalp, Congenital Dilata phy, Cornelia de Lange Syndrome, Coronal Dentine Dyspla tion of Intrahepatic Bile Duct, Congenital Dysmyelinating sia, Coronary Artery Disease, Coronary Heart Disease, Cor Neuropathy, Congenital Dysphagocytosis, Congenital Dys pus Callosum Agenesis, Cortical-Basal Ganglionic plastic Angiectasia, Congenital Erythropoietic Porphyria, Degeneration, Corticalis Deformaris, Cortico-Basal Gangli Congenital Factor XIII Deficiency, Congenital Failure of onic Degeneration (CBGD), Corticobasal Degeneration, Autonomic Control of Respiration, Congenital Familial Non Corticosterone Methyloxidase Deficiency Type I, Corticos hemolytic Jaundice Type I, Congenital Familial Protracted terone Methyloxidase Deficiency Type II, Cortisol, Costello Diarrhea, Congenital Form Cockayne Syndrome Type II Syndrome, Cot Death, COVESDEM Syndrome, COX, COX (Type B), Congenital Generalized Fibromatosis, Congenital Deficiency, COX Deficiency French-Canadian Type, COX German Measles, Congenital Giant Axonal Neuropathy, Deficiency Infantile Mitochondrial myopathy de Toni-Fan Congenital Heart Block, Congenital Heart Defects, Congeni coni-Debre included, COX Deficiency Type Benign Infantile tal Hemidysplasia with Ichthyosis Erythroderma and Limb Mitochondrial Myopathy, CP, CPEO, CPEO with myopathy, Defects, Congenital Hemolytic Jaundice, Congenital CPEO with Ragged-Red Fibers, CPPD Familial Form, CPT Hemolytic Anemia, Congenital Hepatic Fibrosis, Congenital Deficiency, CPTD, Cranial Arteritis, Cranial Meningoen Hereditary Corneal Dystrophy, Congenital Hereditary cephalocele, Cranio-Oro-Digital Syndrome, Craniocarpotar Lymphedema, Congenital Hyperchondroplasia, Congenital sal dystrophy, Craniocele, Craniodigital Syndrome-Mental Hypomyelinating Polyneuropathy, Congenital Hypomyeli Retardation Scott Type, Craniofacial Dysostosis, Craniofa US 2009/0215895 A1 Aug. 27, 2009 cial Dysostosis-PDArteriosus-Hypertrichosis-Hypoplasia of dywine type, Dentinogenesis Imperfecta Shields Type, Den Labia, Craniofrontonasal Dysplasia, Craniometaphyseal tinogenesis Imperfecta Type III, Dento-Oculo-Osseous Dys Dysplasia, Cranioorodigital Syndrome, Cranioorodigital plasia, Dentooculocutaneous Syndrome, Denys-Drash Syndrome Type II, Craniostenosis Crouzon Type, Cranios Syndrome, Depakene, DepakeneTM exposure, Depakote, tenosis, Craniosynostosis-Choanal Atresia-Radial Humeral Depakote Sprinkle, Depigmentation-Gingival Fibromatosis Synostosis, Craniosynostosis-Hypertrichosis-Facial and Microphthalmia, Dercum Disease, Dermatitis Atopic, Der Other Anomalies, Craniosynostosis Midfacial Hypoplasia matitis Exfoliativa, Dermatitis Herpetiformis, Dermatitis and Foot Abnormalities, Craniosynostosis Primary, Cranio Multiformis, Dermatochalasia Generalized, Dermatolysis Synostosis-Radial Aplasia Syndrome, Craniosynostosis with Generalized, Dermatomegaly, Dermatomyositis sine myosi Radial Defects, Cranium Bifidum, CREST Syndrome, tis, Dermatomyositis, Dermatosparaxis, Dermatostomatitis Creutzfeldt Jakob Disease, Cri du Chat Syndrome, Crib Stevens Johnson Type, Desbuquois Syndrome. Desmin Stor Death, Crigler Naijar Syndrome Type I, Crohn's Disease, age myopathy, Desquamation of Newborn, Deuteranomaly, Cronkhite-Canada Syndrome, Cross Syndrome, Cross Syn Developmental Reading Disorder, Developmental Gerst drome, Cross-McKusick-Breen Syndrome, Crouzon, Crou mann Syndrome, Devergie Disease, Devic Disease, Devic Zon Syndrome, Crouzon Craniofacial Dysostosis, Cryoglo Syndrome, Dextrocardia-Bronchiectasis and Sinusitis, Dex bulinemia Essential Mixed, Cryptophthalmos-Syndactyly trocardia with Situs Inversus, DGS, DGSX Golabi-Rosen Syndrome, Cryptorchidism-Dwarfism-Subnormal Mentality, Syndrome Included, DH. DHAP alkyl transferase deficiency, Crystalline Corneal Dystrophy of Schnyder, CS, CSD, CSID, DHBS Deficiency, DHOF, DHPR Deficiency, Diabetes CSO, CST Syndrome, Curly Hair-Ankyloblephanon-Nail Insipidus, Diabetes Insipidus Diabetes Mellitus Optic Atro Dysplasia, Curschmann-Batten-Steinert Syndrome, Curth phy and Deafness, Diabetes Insipidus Neurohypophyseal, Macklin Type Ichthyosis Hystric, Curth-Macklin Type, Diabetes Insulin Dependent, Diabetes Mellitus, Diabetes Cushings, Cushing Syndrome, Cushing's III, Cutaneous Mellitus Addison's Disease Myxedema, Diabetic Acidosis, Malignant Melanoma Hereditary, Cutaneous Porphyrias, Diabetic Bearded Woman Syndrome, Diamond-Blackfan Cutis Laxa, Cutis Laxa-Growth Deficiency Syndrome, Cutis Anemia, Diaphragmatic Apnea, Diaphyseal Aclasis, Marmorata Telangiectatica Congenita, CVI. CVID, CVS, Diastrophic Dwarfism, Diastrophic Dysplasia, Diastrophic Cyclic vomiting syndrome, Cystic Disease of the Renal Nanism Syndrome, Dicarboxylic Aminoaciduria, Dicar Medulla, Cystic Hygroma, Cystic Fibrosis, Cystic Lymphan boxylicaciduria Caused by Defect in B-Oxidation of Fatty gioma, Cystine-Lysine-Arginine-Ornithinuria, Cystine Stor Acids, Dicarboxylicaciduria due to Defect in B-Oxidation of age Disease, Cystinosis, Cystinuria, Cystinuria with Dibasic Fatty Acids, Dicarboxylicaciduria due to MCADH Defi Aminoaciduria, Cystinuria Type I, Cystinuria Type II, Cysti ciency, Dichromasy, Dicker-Opitz, DIDMOAD. Diencepha nuria Type III, Cysts of the Renal Medulla Congenital, Cyto lic Syndrome, Diencephalic Syndrome of Childhood, Dien chrome C. Oxidase Deficiency, Dacryosialoadenopathy, cephalic Syndrome of Emaciation, Dienoyl-CoA Reductase Dacryosialoadenopathia, Dalpro, Dalton, Daltonism, Dan Deficiency, Diffuse Cerebral Degeneration in Infancy. Dif bolt-Cross Syndrome, Dancing Eyes-Dancing Feet Syn fuse Degenerative Cerebral Disease. Diffuse Idiopathic Skel drome, Dandy-Walker Syndrome, Dandy-Walker Cyst, etal Hyperostosis, Diffusum-Glycopeptiduria, DiGeorge Dandy-Walker Deformity, Dandy Walker Malformation, Syndrome, Digital-Oro-Cranio Syndrome, Digito-Oto-Pala Danish Cardiac Type Amyloidosis (Type III), Darier Disease, tal Syndrome, Digito-Oto-Palatal Syndrome Type I, Digito Davidson's Disease, Davies’ Disease, DBA, DBS, DC, DD, Oto-Palatal Syndrome Type II, Dihydrobiopterin Synthetase De Barsy Syndrome, De Barsy-Moens-Diercks Syndrome, Deficiency, Dihydropteridine Reductase Deficiency, Dihy de Lange Syndrome, De Morsier Syndrome, De Santis Cac droxyacetonephosphate synthase, Dilated (Congestive) Car chione Syndrome, de Toni-Fanconi Syndrome, Deafness diomyopathy, Dimitri Disease, Diplegia of Cerebral Palsy, Congenital and Functional Heart Disease, Deafness-Dwarf Diplo-Y Syndrome, Disaccharidase Deficiency, Disaccha ism-Retinal Atrophy, Deafness-Functional Heart Disease, ride Intolerance I, Discoid Lupus, Discoid Lupus Erythema Deafness Onychodystrophy Osteodystrophy and Mental tosus, DISH, Disorder of Cornification, Disorder of Cornifi Retardation, Deafness and Pili Torti Bjornstad Type, Deaf cation Type I, Disorder of Cornification 4, Disorder of ness Sensorineural with Imperforate Anus and Hypoplastic Cornification 6, Disorder of Cornification 8, Disorder of Thumbs, Debrancher Deficiency, Deciduous Skin, Defect of Cornification 9 Netherton's Type, Disorder of Cornification Enterocyte Intrinsic Factor Receptor, Defect in Natural Killer 11 Phytanic Acid Type, Disorder of Cornification 12 (Neutral Lymphocytes, Defect of Renal Reabsorption of Carnitine, Lipid Storage Type); Disorder of Conification 13, Disorder of Deficiency of Glycoprotein Neuraminidase, Deficiency of Cornification 14, Disorder of Cornification 14 Trichothiod Mitochondrial Respiratory Chain Complex IV, Deficiency of ystrophy Type, Disorder of Cornification 15 (Keratitis Deaf Platelet Glycoprotein Ib, Deficiency of Von Willebrand Fac ness Type), Disorder of Cornification 16, Disorder of Corni tor Receptor, Deficiency of Short-Chain Acyl-CoA Dehydro fication 18 Erythrokeratodermia Variabilis Type, Disorder of genase (ACADS), Deformity with Mesomelic Dwarfism, Cornification 19, Disorder of Cornification 20, Disorder of Degenerative Chorea, Degenerative Lumbar Spinal Stenosis, Cornification 24, Displaced Spleen, Disseminated Lupus Degos Disease, Degos-Kohlmeier Disease, Degos Syn Erythematosus, Disseminated Neurodermatitis, Dissemi drome, DEH. Dejerine-Roussy Syndrome, Deerine Sottas nated Sclerosis, Distal 11q Monosomy, Distal 11q-Syn Disease, Deletion 9p Syndrome Partial, Deletion 11q Syn drome, Distal Arthrogryposis Multiplex Congenita Type IIA, drome Partial, Deletion 13q Syndrome Partial, Delleman Distal Arthrogryposis Multiplex Congenita Type IIA, Distal Oorthuys Syndrome, Delleman Syndrome, Dementia with Arthrogryposis Type IIA, Distal Arthrogryposis Type 2A, Lobar Atrophy and Neuronal Cytoplasmic Inclusions, Demy Distal Duplication 6q Distal Duplication 10q, Dup(10q) elinating Disease. DeMyer Syndrome, Dentin Dysplasia Syndrome, Distal Duplication 15q Distal Monosomy 9p, Coronal, Dentin Dysplasia Radicular, Dentin Dysplasia Type Distal Trisomy 6q Distal Trisomy 10q Syndrome, Distal I, Dentin Dysplasia Type II, Dentinogenesis Imperfecta Bran Trisomy 11q, Divalproex, DJS, DKC, DLE, DLPIII, DM, US 2009/0215895 A1 Aug. 27, 2009

DMC Syndrome, DMC Disease, DMD, DNS Hereditary, Erosiva Pluriorificialis, Ectopia Lentis, Ectopia Vesicae, DOC 11, DOC2, DOC 4, DOC 6 (Harlequin Type), DOC 8 Ectopic ACTH Syndrome, Ectopic Adrenocorticotropic Hor Curth-Macklin Type, DOC 11 Phytanic Acid Type, DOC 12 mone Syndrome, Ectopic Anus, Ectrodactilia of the Hand, (Neutral Lipid Storage Type), DOC 13, DOC 14, DOC 14 Ectrodactyly, Ectrodactyly-Ectodermal Dysplasia-Clefting Trichothiodystrophy Type, DOC 15 (Keratitis Deafness Syndrome, Ectrodactyly Ectodermal Dysplasias Clefting Type), DOC 16, DOC 16 Unilateral Hemidysplasia Type, Syndrome, Ectrodactyly Ectodermal Dysplasia Cleft Lip/ DOC 18, DOC 19, DOC20, DOC 24, Dohle's Bodies-Myel Cleft Palate, Eczema, Eczema-Thrombocytopenia-Immuno opathy, Dolichospondylic Dysplasia, Dolichostenomelia, deficiency Syndrome, EDA, EDMD, EDS, EDS Arterial Dolichostenomelia Syndrome, Dominant Type Kenny-Caffe Ecchymotic Type, EDS Arthrochalasia, EDS Classic Severe Syndrome, Dominant Type Myotonia Congenita, Donahue Form, EDS Dysfibronectinemic, EDS Gravis Type, EDS Syndrome, Donath-Landsteiner Hemolytic Anemia, Donath Hypermobility, EDS Kyphoscoliotic, EDS Kyphoscoliosis, Landsteiner Syndrome, DOOR Syndrome, DOORS Syn EDS Mitis Type, EDSOcular-Scoliotic, EDS Progeroid, EDS drome, Dopa-responsive Dystonia (DRD), Dorfman Cha Periodontosis, EDS Vascular, EEC Syndrome, EFE, EHBA, narin Syndrome, Dowling-Meara Syndrome, Down EHK, Ehlers Danlos Syndrome, Ehlers-Danlos syndrome, Syndrome, DR Syndrome, Drash Syndrome, DRD, Dreifuss Ehlers Danlos IX, Eisenmenger Complex, Eisenmenger's Emery Type Muscular Dystrophy with Contractures, Dressler complex, Eisenmenger Disease, Eisenmenger Reaction, Syndrome, Drifting Spleen, Drug-induced Acanthosis Nigri Eisenmenger Syndrome, Ekbom Syndrome, Ekman-Lob cans, Drug-induced Lupus Erythematosus, Drug-related stein Disease, Ektrodactyly of the Hand, EKV, Elastin fiber Adrenal Insufficiency, Drummond's Syndrome, Dry Beri disorders, Elastorrhexis Generalized, Elastosis Dystrophica beri, Dry Eye, DTD, Duane's Retraction Syndrome, Duane Syndrome, Elective Mutism (obsolete), Elective Mutism, Syndrome, Duane Syndrome Type IA 1B and 1C, Duane Electrocardiogram (ECG or EKG), Electron Transfer Fla Syndrome Type 2A2B and 2C, Duane Syndrome Type 3A3B voprotein (ETF) Dehydrogenase Deficiency: (GAII & and 3C, Dubin Johnson Syndrome, Dubowitz Syndrome, MADD), Electrophysiologic study (EPS), Elephant Nails Duchenne, Duchenne Muscular Dystrophy, Duchenne's From Birth, Elephantiasis Congenita Angiomatosa, Hemang Paralysis, Duhring's Disease, Duncan Disease, Duncan's iectatic Hypertrophy, Elfin Facies with Hypercalcemia, Ellis Disease, Duodenal Atresia, Duodenal Stenosis, Duodenitis, van Creveld Syndrome, Ellis Van Creveld Syndrome, Duplication 4p Syndrome, Duplication 6q Partial, Dupuy's Embryoma Kidney, Embryonal Adenomyosarcoma Kidney, Syndrome, Dupuytren’s Contracture, Dutch-Kennedy Syn Embryonal Carcinosarcoma Kidney, Embryonal Mixed drome, Dwarfism, Dwarfism Campomelic, Dwarfism Corti Tumor Kidney, EMC, Emery Dreyfus Muscular Dystrophy, cal Thickening of the Tubular Bones & Transient Hypocalce Emery-Dreifuss Muscular Dystrophy, Emery-Dreifuss Syn mia, Dwarfism Levi’s Type, Dwarfism Metatropic, drome, EMF, EMG Syndrome, Empty Sella Syndrome, Dwarfism-Onychodysplasia, Dwarfism-Pericarditis, Dwarf Encephalitis Periaxialis Diffusa, Encephalitis Periaxialis ism with Renal Atrophy and Deafness, Dwarfism with Rick Concentrica, Encephalocele, Encephalofacial Angiomatosis, ets, DWM. Dyggve Melchior Clausen Syndrome, Dysauto Encephalopathy, Encephalotrigeminal Angiomatosis, nomia Familial, Dysbetalipoproteinemia Familial, Enchondromatosis with Multiple Cavernous Hemangiomas, Dyschondrodysplasia with Hemangiomas, Dyschondrosteo Endemic Polyneuritis, Endocardial Cushion Defect, sis, Dyschromatosis Universalis Hereditaria, Dysencephalia Endocardial Cushion Defects, Endocardial Dysplasia, Splanchinocystica, Dyskeratosis Congenita, Dyskeratosis Endocardial Fibroelastosis (EFE). Endogenous Hypertrig Congenita Autosomal Recessive, Dyskeratosis Congenita lyceridemia, Endolymphatic Hydrops, Endometrial Growths, Scoggins Type, Dyskeratosis Congenita Syndrome, Dyskera Endometriosis, Endomyocardial Fibrosis, Endothelial Cor tosis Follicularis Vegetans, Dyslexia, Dysmyelogenic Leu neal Dystrophy Congenital, Endothelial Epithelial Corneal kodystrophy, Dysmyelogenic Leukodystrophy-Megalobare, Dystrophy, Endothelium, Engelmann Disease, Enlarged Dysphonia Spastica, Dysplasia Epiphysialis Punctata, Dys Tongue, Enterocolitis, Enterocyte Cobalamin Malabsorption, plasia Epiphyseal Hemimelica, Dysplasia of Nails With Hyp Eosinophia Syndrome, Eosinophilic Cellulitis, Eosinophilic odontia, Dysplasia Cleidocranial, Dysplasia Fibrous, Dyspla Fasciitis, Eosinophilic Granuloma, Eosinophilic Syndrome, sia Gigantism Syndromex-Linked, Dysplasia Osteodental, Epidermal Nevus Syndrome, Epidermolysis Bullosa, Epider Dysplastic Nevus Syndrome, Dysplastic Nevus Type, Dys molysis Bullosa Acquisita, Epidermolysis Bullosa Heredi synergia Cerebellaris Myoclonica, Dyssynergia Esophagus, taria, Epidermolysis Bullosa Letalias, Epidermolysis Heredi Dystonia, Dystopia Canthorum, Dystrophia Adiposogeni taria Tarda, Epidermolytic Hyperkeratosis, Epidermolytic talis, Dystrophia Endothelialis Cornea, Dystrophia Mesoder Hyperkeratosis (Bullous CIE), Epilepsia Procursiva, Epi malis, Dystrophic Epidermolysis Bullosa, Dystrophy, lepsy, Epinephrine, Epiphyseal Changes and High Myopia, Asphyxiating Thoracic, Dystrophy Myotonic, E-D Syn Epiphyseal Osteochondroma Benign, Epiphysealis drome, Eagle-Barrett Syndrome, Eales Retinopathy, Eales Hemimelica Dysplasia, Episodic-Abnormal Eye Movement, Disease, Ear Anomalies-Contractures-Dysplasia of Bone Epithelial Basement Membrane Corneal Dystrophy, Epithe with Kyphoscoliosis, Ear Patella Short Stature Syndrome, lial Corneal Dystrophy of Meesmann Juvenile, Epithelioma Early Constraint Defects, Early Hypercalcemia Syndrome tosis Multiplex with Nevus, Epithelium, Epival, EPS, with Elfin Facie, Early-onset Dystonia, Eaton Lambert Syn Epstein-Barr Virus-Induced Lymphoproliferative Disease in drome, EB, Ebstein's anomaly, EBV Susceptibility (EBVS), Males, Erb-Goldflam syndrome, Erdheim Chester Disease, EBVS, ECD, ECPSG, Ectodermal Dysplasias, Ectodermal Erythema Multiforme Exudativum, Erythema Polymorphe Dysplasia Anhidrotic with Cleft Lip and Cleft Palate, Ecto Stevens Johnson Type, Erythroblastophthisis, Erythroblasto dermal Dysplasia-Exocrine Pancreatic Insufficiency, Ecto sis Fetalis, Erythroblastosis Neonatorum, Erythroblastotic dermal Dysplasia Rapp-Hodgkin type, Ectodermal and Anemia of Childhood, Erythrocyte Phosphoglycerate Kinase Mesodermal Dysplasia Congenital, Ectodermal and Meso Deficiency, Erythrogenesis Imperfecta, Erythrokeratodermia dermal Dysplasia with Osseous Involvement, Ectodermosis Progressiva Symmetrica, Erythrokeratodermia Progressiva US 2009/0215895 A1 Aug. 27, 2009 20

Symmetrica Ichlithyosis, Erythrokeratodermia Variabilis, Fanconi's Anemia Complementation Group B, Fanconi's Erythrokeratodermia Variabilis Type, Erythrokeratolysis Anemia Complementation Group C, Fanconi's Anemia Hiemalis, Erythropoietic Porphyrias, Erythropoietic Porphy Complementation Group D, Fanconi's Anemia Complemen ria, Escobar Syndrome, Esophageal Atresia, Esophageal tation Group E, Fanconi's Anemia Complementation Group Aperistalsis, Esophagitis-Peptic Ulcer, Esophagus Atresia G. Fanconi's Anemia Complementation Group H, Fanconi's and/or Tracheoesophageal Fistula, Essential Familial Hyper Anemia Estren-Dameshek Variant, FANF, FANG, FANH, lipemia, Essential Fructosuria, Essential Hematuria, Essen FAP, FAPG, Farber's Disease, Farber's Lipogranulomatosis, tial Hemorrhagic Thrombocythemia, Essential Mixed Cryo FAS, Fasting Hypoglycemia, Fat-Induced Hyperlipemia, globulinemia, Essential Moschowitz Disease, Essential Fatal Granulomatous Disease of Childhood, Fatty Oxidation Thrombocythemia. Essential Thrombocytopenia, Essential Disorders, Fatty Liver with Encephalopathy, FAV, FCH, Thrombocytosis, Essential Tremor, Esterase Inhibitor Defi FCMD, FCS Syndrome, FD, FDH, Febrile Mucocutaneous ciency, Estren-Dameshek variant of Fanconi Anemia, Estro Syndrome Stevens Johnson Type, Febrile Neutrophilic Der gen-related Cholestasis, ET, ETF, Ethylmalonic Adipicaci matosis Acute, Febrile Seizures, Feinberg's syndrome, Feiss duria, Eulenburg Disease, pc, EVCS, Exaggerated Startle inger-Leroy-Reiter Syndrome. Female Pseudo-Turner Syn Reaction, EXencephaly, Exogenous Hypertriglyceridemia, drome, Femoral Dysgenesis Bilateral-Robin Anomaly, Exomphalos-Macroglossia-Gigantism Syndrome, Exoph Femoral Dysgenesis Bilateral, Femoral Facial Syndrome, thalmic Goiter, Expanded Rubella Syndrome, Exstrophy of Femoral Hypoplasia-Unusual Facies Syndrome, Fetal Alco the Bladder, EXT, External Chondromatosis Syndrome, hol Syndrome, Fetal Anti-Convulsant Syndrome, Fetal Cys Extrahepatic Biliary Atresia, Extramedullary Plasmacytoma, tic Hygroma, Fetal Effects of Alcohol, Fetal Effects of Chick Exudative Retinitis, Eye Retraction Syndrome, FA1, FAA, enpox, Fetal Effects of Thalidomide, Fetal Effects of Fabry Disease, FAC, FACB, FACD, FACE, FACF, FACG, Varicella Zoster Virus, Fetal Endomyocardial Fibrosis, Fetal FACH, Facial Nerve Palsy, Facial Paralysis, Facial Ectoder Face Syndrome, Fetal Iritis Syndrome, Fetal Transfusion mal Dysplasias, Facial Ectodermal Dysplasia, Facio Syndrome, Fetal Valproate Syndrome, Fetal Valproic Acid Scapulo-Humeral Dystrophy, Facio-Auriculo-Vertebral Exposure Syndrome, Fetal Varicella Infection, Fetal Varicella Spectrum, Facio-cardio-cutaneous syndrome, Facio-Fronto Zoster Syndrome, FFDD Type II, FG Syndrome, FGDY. Nasal Dysplasia, Faciocutaneoskeletal Syndrome, Faciodigi FHS, Fibrin Stabilizing Factor Deficiency, Fibrinase Defi togenital syndrome, Faciogenital dysplasia, Faciogenito ciency, Fibrinoid Degeneration of Astrocytes, Fibrinoid Leu popliteal Syndrome, Faciopalatoosseous Syndrome, kodystrophy, Fibrinoligase Deficiency, Fibroblastoma Faciopalatoosseous Syndrome Type II, Facioscapulohumeral Perineural, Fibrocystic Disease of Pancreas, Fibrodysplasia muscular dystrophy, Factitious Hypoglycemia, Factor VIII Ossificans Progressiva, Fibroelastic Endocarditis, Fibromy Deficiency, Factor IX Deficiency, Factor XI Deficiency, Fac algia, Fibromyalgia-Fibromyositis, Fibromyositis, Fibrosing tor XII deficiency, Factor XIII Deficiency, Fahr Disease, Cholangitis, Fibrositis, Fibrous Ankylosis of Multiple Joints, Fahr's Disease, Failure of Secretion Gastric Intrinsic Factor, Fibrous Cavernositis, Fibrous Dysplasia, Fibrous Plaques of Fairbank Disease, Fallot's Tetralogy, Familial Acrogeria, the Penis, Fibrous Sclerosis of the Penis, Fickler-Winkler Familial Acromiciria, Familial Adenomatous Colon Polypo Type, Fiedler Disease, Fifth Digit Syndrome, Filippi Syn sis, Familial Adenomatous Polyposis with Extraintestinal drome, Finnish Type Amyloidosis (Type V), First Degree Manifestations, Familial Alobar Holoprosencephaly, Famil Congenital Heart Block, First and Second Branchial Arch ial Alpha-Lipoprotein Deficiency, Familial Amyotrophic Syndrome, Fischer's Syndrome, Fish Odor Syndrome, Fis Chorea with Acanthocytosis, Familial Arrhythmic Myoclo sured Tongue, Flat Adenoma Syndrome, Flatau-Schilder Dis nus, Familial Articular Chondrocalcinosis, Familial Atypical ease, Flavin Containing Monooxygenase 2, Floating B Dis Mole-Malignant Melanoma Syndrome, Familial Broad Beta ease, Floating-Harbor Syndrome, Floating Spleen, Floppy Disease, Familial Calcium Gout, Familial Calcium Pyro Infant Syndrome, Floppy Valve Syndrome, Fluent Aphasia, phosphate Arthropathy, Familial Chronic Obstructive Lung FMD, FMF, FMO Adult Liver Form, FMO2, FND, Focal Disease, Familial Continuous Skin Peeling, Familial Cutane Dermal Dysplasia Syndrome, Focal Dermal Hypoplasia, ous Amyloidosis, Familial Dysproteinemia, Familial Emphy Focal Dermato-Phalangeal Dysplasia, Focal Dystonia, Focal sema, Familial Enteropathy Microvillus, Familial Foveal Epilepsy, Focal Facial Dermal Dysplasia Type II, Focal Neu Retinoschisis, Familial Hibernation Syndrome, Familial romyotonia, FODH, Folling Syndrome, Fong Disease, FOP, High Cholesterol, Familial Hemochromatosis, Familial High Forbes Disease, Forbes-Albright Syndrome, Forestier's Dis Blood Cholesterol, Familial High-Density Lipoprotein Defi ease. Forsius-Eriksson Syndrome (X-Linked), Fothergill ciency, Familial High Serum Cholesterol, Familial Hyperlipi Disease, Fountain Syndrome, Foveal Dystrophy Progressive, dema, Familial Hypoproteinemia with Lymphangietatic FPO Syndrome Type II, FPO, Fraccaro Type Achondrogen Enteropathy, Familial Jaundice, Familial Juvenile Nephro esis (Type IB), Fragile X syndrome, Franceschetti-Zwalen nophtisis-Associated Ocular Anomaly, Familial Lichen Klein Syndrome, Francois Dyscephaly Syndrome, Francois Amyloidosis (Type IX), Familial Lumbar Stenosis, Familial Neetens Speckled Dystrophy, Flecked Corneal Dystrophy, Lymphedema Praecox, Familial Mediterranean Fever, Famil Fraser Syndrome, FRAXA, FRDA, Fredrickson Type I ial Multiple Polyposis, Familial Nuchal Bleb, Familial Par Hyperlipoproteinemia, Freeman-Sheldon Syndrome, Freire oxysmal Polyserositis, Familial Polyposis Coli, Familial Pri Maia Syndrome, Frey's Syndrome, Friedreich's Ataxia, Frie mary Pulmonary Hypertension, Familial Renal Glycosuria, dreich's Disease, Friedreich's Tabes, FRNS, Froelich's Syn Familial Splenic Anemia, Familial Startle Disease, Familial drome. Frommel-Chiari Syndrome. Frommel-Chiari Visceral Amyloidosis (Type VIII), FAMMM, FANCA, Syndrome Lactation-Uterus Atrophy, Frontodigital Syn FANCB, FANCC, FANCD, FANCE, Fanconi Panmyelopa drome. Frontofacionasal Dysostosis, Frontofacionasal Dys thy, Fanconi Pancytopenia, Fanconi II, Fanconi's Anemia, plasia, Frontonasal Dysplasia, Frontonasal Dysplasia with Fanconi's Anemia Type I, Fanconi's Anemia Complementa Coronal Craniosynostosis, Fructose-1-Phosphate Aldolase tion Group, Fanconi's Anemia Complementation Group A, Deficiency, Fructosemia, Fructosuria, Fryns Syndrome, FSH. US 2009/0215895 A1 Aug. 27, 2009

FSHD, FSS, Fuchs Dystrophy, Fucosidosis Type 1, Fucosi cogenosis Type VIII, Glycolic Aciduria, Glycolipid Lipido dosis Type2, Fucosidosis Type 3, Fukuhara Syndrome, Fuku sis, GM2 Gangliosidosis Type 1, GM2 Gangliosidosis Type yama Disease, Fukuyama Type Muscular Dystrophy, 1, GNPTA, Goitrous Autoimmune Thyroiditis, Goldenhar Fumarylacetoacetase Deficiency, Furrowed Tongue, G Syn Syndrome, Goldenhar-Gorlin Syndrome, Goldscheider's drome, G6PD Deficiency, G6PD, GAI, GA IIB, GA IIA, GA Disease, Goltz Syndrome, Goltz-Gorlin Syndrome, Gonadal II, GAII & MADD, Galactorrhea-Amenorrhea Syndrome Dysgenesis 45 X, Gonadal Dysgenesis XO, Goniodysgen Nonpuerperal, Galactorrhea-Amenorrhea without Preg esis-Hypodontia, Goodman Syndrome, Goodman, Goodpas nancy, Galactosamine-6-Sulfatase Deficiency, Galactose-1- ture Syndrome, Gordon Syndrome, Gorlin's Syndrome, Gor Phosphate Uridyl Transferase Deficiency, Galactosemia, lin-Chaudhry-Moss Syndrome, Gottron GALB Deficiency, Galloway-Mowat Syndrome, Galloway Erythrokeratodermia Congenitalis Progressiva Symmetrica, Syndrome, GALT Deficiency, Gammaglobulin Deficiency, Gottron's Syndrome, Gougerot-Carteaud Syndrome, Graft GAN, Ganglioside Neuraminidase Deficiency, Ganglioside versus Host Disease, Grand Mal Epilepsy, Granular Type Sialidase Deficiency, Gangliosidosis GM1 Type 1, Gangli Corneal Dystrophy, Granulomatous Arteritis, Granuloma osidosis GM2 Type 2, Gangliosidosis f Hexosaminidase B tous Colitis, Granulomatous Dermatitis with Eosinophilia, Deficiency, Gardner Syndrome, Gargoylism, Garies-Mason Granulomatous Ileitis, Graves Disease, Graves Hyperthy Syndrome, Gasser Syndrome, Gastric Intrinsic Factor Failure roidism, Graves Disease, Greig Cephalopolysyndactyly of Secretion, Enterocyte Cobalamin, Gastrinoma, Gastritis, Syndrome, Groenouw Type I Corneal Dystrophy, Groenouw Gastroesophageal Laceration-Hemorrhage, Gastrointestinal Type II Corneal Dystrophy, Gronblad-Strandberg Syndrome, Polyposis and Ectodermal Changes, Gastroschisis, Gaucher Grotton Syndrome, Growth Hormone Receptor Deficiency, Disease, Gaucher-Schlagenhaufer, Gayet-Wernicke Syn Growth Hormone Binding Protein Deficiency, Growth Hor drome, GBS, GCA, GCM Syndrome, GCPS, Gee-Herter mone Deficiency, Growth-Mental Deficiency Syndrome of Disease, Gee-Thaysen Disease, Gehrig's Disease, Gelineau's Myhre. Growth Retardation-Rieger Anomaly, GRS. Gruber Syndrome, Genee-Wiedemann Syndrome, Generalized Dys Syndrome, GS, GSD6, GSD8, GTS, Guanosine Triphos tonia, Generalized Familial Neuromyotonia, Generalized phate-Cyclohydrolase Deficiency, Guanosine Triphosphate Fibromatosis, Generalized Flexion Epilepsy, Generalized Cyclohydrolase Deficiency, Guenther Porphyria, Guerin Glycogenosis, Generalized Hyperhidrosis, Generalized Stern Syndrome, Guillain-Barré, Guillain-BarréSyndrome, Lipofuscinosis, Generalized Myasthenia Gravis, Generalized Gunther Disease, H Disease, H. Gottron's Syndrome, Habit Myotonia, Generalized Sporadic Neuromytonia, Genetic Spasms, HAE, Hageman Factor Deficiency, Hageman factor, Disorders, Genital Defects, Genital and Urinary Tract Haim-Munk Syndrome, Hajdu–Cheney Syndrome, Hajdu Defects, Gerstmann Syndrome, Gerstmann Tetrad, GHBP. Cheney, HAL Deficiency, Hall-Pallister Syndrome, Haller GHD, GHR, Giant Axonal Disease, Giant Axonal Neuropa mann-Streiff-Francois Syndrome, Hallermann-Streiff Syn thy, Giant Benign Lymphoma, Giant Cell Glioblastoma drome, Hallervorden-Spatz Disease, Hallervorden-Spatz Astrocytoma, Giant Cell Arteritis, Giant Cell Disease of the Syndrome, Hallopeau-Siemens Disease, Hallux Duplication Liver, Giant Cell Hepatitis, Giant Cell of Newborns Cirrho Postaxial Polydactyly and Absence of Corpus Callosum, sis, Giant Cyst of the Retina, Giant Lymph Node Hyperplasia, Halushi-Behcet’s Syndrome, Hamartoma of the Lymphatics, Giant Platelet Syndrome Hereditary, Giant Tongue, Macular Hand-Schueller-Christian Syndrome, HANE, Hanhart Syn Dystrophy, Gilbert's Disease, Gilbert Syndrome, Gilbert drome, Happy Puppet Syndrome, Harada Syndrome, Dreyfus Syndrome, Gilbert-Lereboullet Syndrome, Gilford HARD--/-E Syndrome, HARD Syndrome, Hare Lip, Harle Syndrome, Gilles de la Tourette's syndrome, Gillespie Syn quin Fetus, Harlequin Type DOC 6, Harlequin Type Ichthyo drome, Gingival Fibromatosis-Abnormal Fingers Nails Nose sis, Harley Syndrome, Harrington Syndrome, Hart Syn Ear Splenomegaly, GLA Deficiency, GLA, GLB1, Glioma drome, Hartnup Disease, Hartnup Disorder, Hartnup Retina, Global Aphasia, Globoid Leukodystrophy, Glossop Syndrome, Hashimoto's Disease, Hashimoto-Pritzker Syn tosis Micrognathia and Cleft Palate, Glucocerebrosidase drome, Hashimoto's Syndrome, Hashimoto's Thyroiditis, Deficiency, Glucocerebrosidosis, Glucose-6-Phosphate Hashimoto-Pritzker Syndrome, Hay Well’s Syndrome, Hay Dehydrogenase Deficiency, Glucose-6-Phosphate Tranport Wells Syndrome of Ectodermal Dysplasia, HCMM, HCP Defect, Glucose-6-Phospate Translocase Deficiency, Glu HCTD, HD, Heart-Hand Syndrome (Holt-Oram Type), Heart cose-G-Phosphatase Deficiency, Glucose-Galactose Malab Disease, Hecht Syndrome, HED, Heerferdt-Waldenstrom Sorption, Glucosyl Ceramide Lipidosis, Glutaric Aciduria I, and Lofgren's Syndromes, Hegglin's Disease, Heinrichs Glutaric Acidemia I, Glutaric Acidemia II, Glutaric Aciduria bauer Syndrome, Hemangiomas, Hemangioma Familial, II, Glutaric Aciduria Type II, Glutaric Aciduria Type III, Hemangioma-Thrombocytopenia Syndrome, Hemangioma Glutaricacidemia I, Glutaricacidemia II, Glutaricaciduria I, tosis Chondrodystrophica, Hemangiomatous Branchial Glutaricaciduria II, Glutaricaciduria Type IIA, Glutaricaci Clefts-Lip Pseudocleft Syndrome, Hemifacial Microsomia, duria Type IIB, Glutaryl-CoA Dehydrogenase Deficiency, Hemimegalencephaly, Hemiparesis of Cerebral Palsy, Glutaurate-Aspartate Transport Defect, Gluten-Sensitive Hemiplegia of Cerebral Palsy, Hemisection of the Spinal Enteropathy, Glycogen Disease of Muscle Type VII, Glyco Cord, Hemochromatosis, Hemochromatosis Syndrome, gen Storage Disease I, Glycogen Storage Disease III, Glyco Hemodialysis-Related Amyloidosis, Hemoglobin Lepore gen Storage Disease IV. Glycogen Storage Disease Type V. Syndromes, Hemolytic Anemia of Newborn, Hemolytic Cold Glycogen Storage Disease VI, Glycogen Storage Disease VII, Antibody Anemia, Hemolytic Disease of Newborn, Glycogen Storage Disease VIII, Glycogen Storage Disease Hemolytic-Uremic Syndrome, Hemophilia, Hemophilia A, Type II, Glycogen Storage Disease-Type II, Glycogenosis, Hemophilia B, Hemophilia BFactor IX, Hemophilia C, Hem Glycogenosis Type I. Glycogenosis Type IA, Glycogenosis orrhagic Dystrophic Thrombocytopenia, Hemorrhagica Type IB, Glycogenosis Type II, Glycogenosis Type II, Gly Aleukia, Hemosiderosis, Hepatic Fructokinase Deficiency, cogenosis Type III, Glycogenosis Type IV, Glycogenosis Hepatic Phosphorylase Kinase Deficiency, Hepatic Porphy Type V. Glycogenosis Type VI, Glycogenosis Type VII, Gly ria, Hepatic Porphyrias, Hepatic Veno-Occlusive Disease, US 2009/0215895 A1 Aug. 27, 2009 22

Hepato-Renal Syndrome, Hepatolenticular Degeneration, Hand Syndrome, Homocystinemia, Homocystinuria, Hepatophosphorylase Deficiency, Hepatorenal Glycogeno Homogentisic Acid Oxidase Deficiency, Homogentisic Aci sis, Hepatorenal Syndrome, Hepatorenal Tyrosinemia, dura, Homozygous C.-1.-Antitrypsin Deficiency, HOOD, Hor Hereditary Acromelalgia, Hereditary Alkaptonuria, Heredi ner Syndrome, Horton's, disease, HOS, HOS1, Houston-Har tary Amyloidosis, Hereditary Angioedema, Hereditary ris Type Achrondrogenesis (Type IA), HPS, HRS, HS, HSAN Areflexic Dystasia, Heredopathia Atactica Polyneuritiformis, Type I, HSAN Type II, HSAN-III, HSMN, HSMN Type III, Hereditary Ataxia, Hereditary Ataxia Friedrich's Type, HSN I, HSN-III, Huebner-Herter Disease, Hunner's Patch, Hereditary Benign Acanthosis Nigricans, Hereditary Cer Hunner's Ulcer, Hunter Syndrome, Hunter-Thompson Type ebellar Ataxia, Hereditary Chorea, Hereditary Chronic Pro Acromesomelic Dysplasia, Huntington's Chorea, Hunting gressive Chorea, Hereditary Connective Tissue Disorders, ton's Disease, Hurler Disease, Hurler Syndrome, Hurler Hereditary Coproporphyria, Hereditary Coproporphyria Por Scheie Syndrome, HUS, Hutchinson-Gilford Progeria Syn phyria, Hereditary Cutaneous Malignant Melanoma, Heredi drome, Hutchinson-Gilford Syndrome, Hutchinson-Weber tary Deafness-Retinitis Pigmentosa, Heritable Disorder of Peutz Syndrome, Hutterite Syndrome Bowen-Conradi Type, Zinc Deficiency, Hereditary DNS, Hereditary Dystopic Lipi Hyaline Panneuropathy, Hydranencephaly, Hydrocephalus, dosis, Hereditary Emphysema, Hereditary Fructose Intoler Hydrocephalus Agyria and Retinal Dysplasia, Hydroceph ance, Hereditary Hemorrhagic Telangiectasia, Hereditary alus Internal Dandy-Walker Type, Hydrocephalus Noncom Hemorrhagic Telangiectasia Type I, Hereditary Hemorrhagic municating Dandy-Walker Type, Hydrocephaly, Hydroneph Telangiectasia Type III, Hereditary Hyperuricemia and rosis With Peculiar Facial Expression, Hydroxylase Choreoathetdsis Syndrome, Hereditary Leptocytosis Major, Deficiency, Hygroma Colli, Hyper-IgE Syndrome, Hyper Hereditary Leptocytosis Minor, Hereditary Lymphedema, IgM Syndrome, Hyperaldosteronism, Hyperaldosteronism Hereditary Lymphedema Tarda, Hereditary Lymphedema With Hypokalemic Alkatosis, Hyperaldosteronism Without Type I, Hereditary Lymphedema Type II, Hereditary Motor Hypertension, Hyperammonemia, Hyperammonemia Due to Sensory Neuropathy, Hereditary Motor Sensory Neuropathy Carbamylphosphate Synthetase Deficiency, Hyperammone I, Hereditary Motor Sensory Neuropathy Type III, Hereditary mia Due to Ornithine Transcarbamylase Deficiency, Hyper Nephritis, Hereditary Nephritis and Nerve Deafness, Heredi ammonemia Type II. Hyper-B Carnosinemia, Hyperbiliru tary Nephropathic Amyloidosis, Hereditary Nephropathy and binemia I, Hyperbilirubinemia II, Hypercalcemia Familial Deafness, Hereditary Nonpolyposis Colorectal Cancer, with Nephrocalcinosis and Indicanuria, Hypercalcemia-Sup Hereditary Nonpolyposis Colorectal Carcinoma, Hereditary ravalvar Aortic Stenosis, Hypercalciuric Rickets, Hypercap Nonspherocytic Hemolytic Anemia, Hereditary Onychoost nic acidosis, Hypercatabolic Protein-Losing Enteropathy, eodysplasia, Hereditary Optic Neuroretinopathy, Hereditary Hyperchloremic acidosis, Hypercholesterolemia, Hypercho Polyposis Coli, Hereditary Sensory and Autonomic Neuropa lesterolemia Type IV. Hyperchylomicronemia, Hypercysti thy Type I, Hereditary Sensory and Autonomic Neuropathy nuria, Hyperekplexia, Hyperextensible joints, Hyperglobu Type II, Hereditary Sensory and Autonomic Neuropathy Type linemic Purpura, Hyperglycinemia with Ketoacidosis and III, Hereditary Sensory Motor Neuropathy, Hereditary Sen Lactic Acidosis Propionic Type, Hyperglycinemia Nonke sory Neuropathy Type I, Hereditary Sensory Neuropathy totic, Hypergonadotropic Hypogonadism, Hyperimmuno Type I, Hereditary Sensory Neuropathy Type II, Hereditary globulin E Syndrome, Hyperimmunoglobulin E-Recurrent Sensory Neuropathy Type III, Hereditary Sensory Radicular Infection Syndrome, Hyperimmunoglobulinemia E-Staphy Neuropathy Type I, Hereditary Sensory Radicular Neuropa lococcal, Hyperkalemia, Hyperkinetic Syndrome, Hyper thy Type I, Hereditary Sensory Radicular Neuropathy Type II, lipemic Retinitis, Hyperlipidemia I, Hyperlipidemia IV. Hereditary Site Specific Cancer, Hereditary Spherocytic Hyperlipoproteinemia Type I, Hyperlipoproteinemia Type Hemolytic Anemia, Hereditary Spherocytosis, Hereditary III, Hyperlipoproteinemia Type IV. Hyperoxaluria, Hyper Tyrosinemia Type I, Heritable Connective Tissue Disorders, phalangy-Clinodactyly of Index Finger with Pierre Robin Herlitz Syndrome, Hermians-Herzberg Phakomatosis, Her Syndrome, Hyperphenylalanemia, Hyperplastic Epiderinoly mansky-Pudlak Syndrome, Hermaphroditism, Herpes sis Bullosa, Hyperpnea, Hyperpotassemia, Hyperprebeta-Li Zoster, Herpes Iris Stevens-Johnson Type, Hers Disease, Het poproteinemia, Hyperprolinemia Type I, Hyperprolinemia erozygous B Thalassemia, Hexoaminidase C-Subunit Defi Type II, Hypersplenism, Hypertelorism with Esophageal ciency (Variant B), Hexoaminidase C-Subunit Deficiency Abnormalities and Hypospadias, Hypertelorism-Hypospa (Variant B), HFA, HFM, HOPS, HH, HHHO, HHRH, HHT, dias Syndrome, Hypertrophic Cardio myopathy, Hyper Hiatal Hernia-Microcephaly-Nephrosis Galloway Type, trophic Interstitial Neuropathy, Hypertrophic Interstitial Hidradenitis Suppurativa, Hidrosadenitis Axillaris, Hidro Neuritis, Hypertrophic Interstitial Radiculoneuropathy, sadenitis Suppurativa, Hidrotic Ectodermal Dysplasias, HIE Hypertrophic Neuropathy of Refsum, Hypertrophic Obstruc Syndrome, High Imperforate Anus, High Potassium, High tive Cardiomyopathy, Hyperuricemia Choreoathetosis Self Scapula, HIM, Hirschsprung's Disease, Hirschsprung's Dis mutilation Syndrome, Hyperuricemia-Oligophrenia, Hyper ease Acquired, Hirschsprung Disease Polydactyly of Ulnar & valinemia, Hypocalcified (Hypomineralized) Type, Big Toe and VSD, Hirschsprung Disease with Type D Hypochondrogenesis, Hypochrondroplasia, Hypo-y-globu Brachydactyly, Hirsutism, HIS Deficiency. Histidine Ammo linemia, Hypo-y-globulinemia Transient of Infancy, Hypo nia-Lyase (HAL) Deficiency. Histidase Deficiency. His genital Dystrophy with Diabetic Tendency, Hypoglossia-Hy tidinemia, Histiocytosis. Histiocytosis X, HLHS, HLP Type podactylia Syndrome, Hypoglycemia, Exogenous II, HMG, HMI, HMSNI, HNHA, HOCM, Hodgkin Disease, Hypoglycemia, Hypoglycemia with Macroglossia, Hypogly Hodgkin's Disease, Hodgkin's Lymphoma, Hollaender-Si cosylation Syndrome Type 1a, Hypoglycosylation Syndrome mons Disease, Holmes-Adie Syndrome, Holocarboxylase Type 1a, Hypogonadism with Anosmia, Hypogonadotropic Synthetase Deficiency, Holoprosencephaly, Holoprosen Hypogonadism and Anosmia, Hypohidrotic Ectodermal Dys cephaly Malformation Complex, Holoprosencephaly plasia, Hypohidrotic Ectodermal Dysplasia Autosomal Sequence, Holt-Oram Syndrome, Holt-Oram Type Heart Dominant type, Hypohidrotic Ectodermal Dysplasias Auto US 2009/0215895 A1 Aug. 27, 2009 recessive, Hypokalemia, Hypokalemic Alkalosis with Hyper INCL, Inclusion body myositis, Incomplete Atrioventricular calciuria, Hypokalemic Syndrome, Hypolactasia, Septal Defect, Incomplete Testicular Feminization, Inconti Hypomaturation Type (Snow-Capped Teeth), Hypomelano nentia Pigmenti, Incontinenti Pigmenti Achromians, Index sis of Ito, Hypomelia-Hypotrichosis-Facial Hemangioma Finger Anomaly with Pierre Robin Syndrome, Indiana Type Syndrome, Hypomyelination Neuropathy, Hypoparathyroid Amyloidosis (Type II), Indolent systemic mastocytosis, ism, Hypophosphatasia, Hypophosphatemic Rickets with Infantile Acquired Aphasia, Infantile Autosomal Recessive Hypercalcemia, Hypopigmentation, Hypopigmented macu Polycystic Kidney Disease, Infantile Beriberi, Infantile Cere lar lesion, Hypoplasia of the Depressor Anguli Oris Muscle bral Ganglioside, Infantile Cerebral Paralysis, Infantile Cys with Cardiac Defects, Hypoplastic Anemia, Hypoplastic tinosis, Infantile Epileptic, Infantile Fanconi Syndrome with Congenital Anemia, Hypoplastic Chondrodystrophy, Hypo Cystinosis, Infantile Finnish Type Neuronal Ceroid Lipofus plastic Enamel-Onycholysis-Hypohidrosis, Hypoplastic cinosis, Infantile Gaucher Disease, Infantile Hypoglycemia, (Hypoplastic-Explastic) Type, Hypoplastic Left Heart Syn Infantile Hypophasphatasia, Infantile Lobar Emphysema, drome, Hypoplastic-Triphalangeal Thumbs, Hypopotas Infantile Myoclonic Encephalopathy, Infantile Myoclonic semia Syndrome, Hypospadias-Dysphagia Syndrome, Encephalopathy and Polymyoclonia, Infantile Myofibroma Hyposmia, Hypothalamic Hamartoblastoma Hypopituitar tosis, Infantile Necrotizing Encephalopathy, Infantile Neu ism Imperforate Anus Polydactyly, Hypothalamic Infanti ronal Ceroid Lipofuscinosis, Infantile Neuroaxonal Dystro lism-Obesity, Hypothyroidism, Hypotonia-Hypomentia-Hy phy, Infantile Onset Schindler Disease, Infantile Phytanic pogonadism-Obesity Syndrome, Hypoxanthine-Guanine Acid Storage Disease, Infantile Refsum Disease (IRD), Phosphoribosyltransferase Defect (Complete Absence of), Infantile Sipoidosis GM-2 Gangliosideosis (Type S), Infan I-Cell Disease, Iatrogenic Hypoglycemia, IBGC, IBIDS Syn tile Sleep Apnea, Infantile Spasms, Infantile Spinal Muscular drome, IBM, IBS, IC, I-Cell Disease, ICD, ICE Syndrome Atrophy (all types), Infantile Spinal Muscular Atrophy ALS, Cogan-Reese Type, Icelandic Type Amyloidosis (Type VI). Infantile Spinal Muscular Atrophy Type I, Infantile Type I-Cell Disease, Ichthyosiform Erythroderma Corneal Neuronal Ceroid Lipofuscinosis, Infectious Jaundice, Involvement and Deafness, Ichthyosiform Erythroderma Inflammatory Breast Cancer, Inflammatory Linear Nevus Hair Abnormality Growth and Men, Ichthyosiform Erythro Sebaceous Syndrome. Iniencephaly. Insulin Resistant Acan derma with Leukocyte Vacuolation, Ichthyosis, Ichthyosis thosis Nigricans, Insulin Lipodystrophy, Insulin dependent Congenita, Ichthyosis Congenital with Trichothiodystrophy, Diabetes, Intention Myoclonus, Intermediate Cystinosis, Ichthyosis Hystrix, Ichthyosis Hystrix Gravior, Ichthyosis Intermediate Maple Syrup Urine Disease, Intermittent Ataxia Linearis Circumflexa, Ichthyosis Simplex, Ichthyosis Tay with Pyruvate Dehydrogenase Deficiency, Intermittent Syndrome, Ichthyosis Vulgaris, Ichthyotic Neutral Lipid Maple Syrup Urine Disease, Internal Hydrocephalus, Inter Storage Disease, Icteric Leptospirosis, Icterohemorrhagic stitial Cystitis, Interstitial Deletion of 4q Included, Intestinal Leptospirosis, Icterus (Chronic Familial), Icterus Gravis Lipodystrophy, Intestinal Lipophagic Granulomatosis, Intes Neonatorum, Icterus Intermittens Juvenalis, Idiopathic tinal Lymphangiectasia, Intestinal Polyposis I, Intestinal Alveolar Hypoventilation, Idiopathic Amyloidosis, Idio Polyposis II, Intestinal Polyposis III, Intestinal Polyposis pathic Arteritis of Takayasu, Idiopathic Basal Ganglia Calci Cutaneous Pigmentation Syndrome, Intestinal Pseudoob fication (IBGC), Idiopathic Brachial Plexus Neuropathy, struction with External Ophthalmoplegia, Intra-cranial Neo Idiopathic Cervical Dystonia, Idiopathic Dilatation of the plasm, Intra-cranial Tumors, Intracranial Vascular Pulmonary Artery, Idiopathic Facial Palsy, Idiopathic Famil Malformations, Intra-uterine Dwarfism, Intra-uterine Syn ial Hyperlipemia, Idiopathic Hypertrophic Subaortic Steno echiae, Inverted Smile And Occult Neuropathic Bladder, sis, Idiopathic Hypoproteinemia, Idiopathic Immunoglobulin Iowa Type Amyloidosis (Type IV), IP, IPA, Iridocorneal Deficiency, Idiopathic Neonatal Hepatitis, Idiopathic Non Endothelial Syndrome, Iridocorneal Endothelial (ICE) Syn Specific Ulcerative Colitis, Idiopathic Peripheral Periphlebi drome Cogan-Resse Type, Iridogoniodysgenesis With tis, Idiopathic Pulmonary Fibrosis, Idiopathic Refractory Somatic Anomalies, Iris Atrophy with Corneal Edema and Sideroblastic Anemia, Idiopathic Renal Hematuria, Idio Glaucoma, Iris Nevus Syndrome, Iron Overload Anemia, pathic Steatorrhea, Idiopathic Thrombocythemia, Idiopathic Iron Overload Disease, Irritable Bowel Syndrome, Irritable Thrombocytopenic Purpura, Idiopathic Thrombocytopenia Colon Syndrome, Isaacs Syndrome, Isaacs-Merten Syn Purpura (ITP), IDPA, IgA Nephropathy, IHSS, Ileitis, Ileo drome, Ischemic Cardiomyopathy, Isolated Lissencephaly colitis, Illinois Type Amyloidosis, ILS, IM, IMD2, IMD5, Sequence, Isoleucine 33 Amyloidosis, Isovaleric Acid CoA Immune Defect due to Absence of Thymus, Immune Dehydrogenase Deficiency, Isovaleric Acidaemia, Isovaleri Hemolytic Anemia Paroxysmal Cold, Immunodeficiency cacidemia, Isovaleryl CoA Carboxylase Deficiency, ITO with Ataxia Telangiectasia, Immunodeficiency Cellular with Hypomelanosis, ITO, ITP, IVA, Ivemark Syndrome, Iwanoff Abnormal Immunoglobulin Synthesis, Immunodeficiency Cysts, Jackknife Convulsion, Jackson-Weiss Craniosynosto Common Variable Unclassifiable. Immunodeficiency with sis, Jackson-Weiss Syndrome, Jacksonian Epilepsy, Jacobsen Hyper-IgM, Immunodeficiency with Leukopenia, Immuno Syndrome, Jadassohn-Lewandowsky Syndrome, Jaffe-Li deficiency-2, Immunodeficiency-5 (IMD5). Immunoglobu chenstein Disease, Jakob's Disease, Jakob-Creutzfeldt Dis lin Deficiency, Imperforate Anus, Imperforate Anus with ease, Janeway I, Janeway Dysgammaglobulinemia, Jansen Hand Foot and Ear Anomalies, Imperforate Nasolacrimal Metaphyseal Dysostosis, JansenType Metaphyseal Chondro Duct and Premature Aging Syndrome, Impotent Neutrophil dysplasia, Jarcho-Levin Syndrome, Jaw-Winking, JBS. Syndrome, Inability To Open Mouth Completely And Short JDMS, Jegher's Syndrome, Jejunal Atresia, Jeunitis, Finger-Flexor, INAD. Inborn Error of Urea Synthesis Argin Jejunoileitis, Jervell and Lange-Nielsen Syndrome, Jeune ase Type, Inborn Error of Urea Synthesis Arginino Succinic Syndrome, JMS, Job Syndrome, Job-Buckley Syndrome, Type, Inborn Errors of Urea Synthesis Carbamyl Phosphate Johanson-Blizzard Syndrome, John Dalton, Johnson-Stevens Type, Inborn Error of Urea Synthesis Citrullinemia Type, Disease, Jonston's Alopecia, Joseph's Disease, Joseph's Dis Inborn Errors of Urea Synthesis Glutamate Synthetase Type, ease Type I, Joseph's Disease Type II, Joseph's Disease Type US 2009/0215895 A1 Aug. 27, 2009 24

III, Joubert Syndrome, Joubert-Bolthauser Syndrome, JRA, Intolerance of Adulthood, Lactose Intolerance, Lactose Intol Juberg Hayward Syndrome, Juberg-Marsidi Syndrome, erance of Childhood, LADD Syndrome, LADD, Lafora Dis Juberg-Marsidi Mental Retardation Syndrome, Jumping ease Included, Lafora Body Disease, Laki-Lorand Factor Frenchmen, Jumping Frenchmen of Maine, Juvenile Arthri Deficiency, LAM, Lambert Type Ichthyosis, Lambert-Eaton tis, Juvenile Autosomal Recessive Polycystic Kidney Dis Syndrome, Lambert-Eaton Myasthenic Syndrome, Lamellar ease, Juvenile Cystinosis, Juvenile (Childhood) Dermato Recessive Ichthyosis, Lamellar Ichthyosis, Lancereaux myositis (JDMS), Juvenile Diabetes, Juvenile Gaucher Mathieu-Weil Spirochetosis, Landau-Kleffner Syndrome, Disease, Juvenile Gout Choreoathetosis and Mental Retarda Landouzy Deerine Muscular Dystrophy, Landry Ascending tion Syndrome, Juvenile Intestinal Malabsorption of Vit B12, Paralysis, Langer-Salidino Type Achondrogensis (Type II), Juvenile Intestinal Malabsorption of Vitamin B12, Juvenile Langer Giedion Syndrome, Langerhans-Cell Granulomato Macular Degeneration, Juvenile Pernicious Anemia, Juvenile sis, Langerhans-Cell Histiocytosis (LCH), Large Atrial and Retinoschisis, Juvenile Rheumatoid Arthritis, Juvenile Spinal Ventricular Defect, Laron Dwarfism, Laron Type Pituitary Muscular Atrophy Included, Juvenile Spinal Muscular Atro Dwarfism, Larsen Syndrome, Laryngeal Dystonia, Latah phy ALS Included, Juvenile Spinal Muscular Atrophy Type (Observed in Malaysia), Late Infantile Neuroaxonal Dystro III, Juxta-Articular Adiposis Dolorosa, Juxtaglomerular phy, Late Infantile Neuroaxonal Dystrophy, Late Onset Hyperplasia, Kabuki Make-Up Syndrome, Kahler Disease, Cockayne Syndrome Type III (Type C), Late-Onset Dystonia, Kallmann Syndrome, Kanner Syndrome, Kanzaki Disease, Late-Onset Immunoglobulin Deficiency, Late Onset Peliza Kaposi Disease, K-Light Chain Deficiency, Karsch-Neuge eus-Merzbacher Brain Sclerosis, Lattice Corneal Dystrophy, bauer Syndrome, Kartagener Syndrome-Chronic Sinobron Lattice Dystrophy, Launois-Bensaude, Launois-Cleret Syn chial Disease and Dextrocardia, Kartagener Triad, Kasabach drome, Laurence Syndrome, Laurence-Moon Syndrome, Merritt Syndrome, Kast Syndrome, Kawasaki Disease, Laurence-Moon/Bardet-Biedl, Lawrence-Seip Syndrome, Kawasaki Syndrome, KBG Syndrome, KD, Kearns-Sayre LCA, LCAD Deficiency, LCAD, LCAD, LCADH Defi Disease, Kearns-Sayre Syndrome, Kennedy Disease, ciency, LCH. LCHAD, LCPD, LeJeune Syndrome, Leband Kennedy Syndrome, Kennedy Type Spinal and Bulbar Mus Syndrome, Leber's Amaurosis, Leber's Congenital Amauro cular Atrophy, Kennedy-Stefanis Disease, Kenny Disease, sis, Congenital Absence of the Rods and Cones, Leber's Con Kenny Syndrome, Kenny Type Tubular Stenosis, Kenny genital Tapetoretinal Degeneration, Leber's Congenital Tape Caffe Syndrome, Keratitis Ichthyosis Deafness Syndrome, toretinal Dysplasia, Leber's Disease, Leber's Optic Atrophy, Keratoconus, Keratoconus Posticus Circumscriptus, Kera Leber's Optic Neuropathy, Left Ventricular Fibrosis, Leg tolysis, Keratolysis Exfoliativa Congenita, Keratolytic Win Ulcer, Legg-Calve-Perthes Disease, Leigh's Disease, Leigh's ter Erythema, Keratomalacia, Keratosis Follicularis, Kerato Syndrome, Leigh's Syndrome (Subacute Necrotizing sis Follicularis Spinulosa Decalvans, Keratosis Follicularis Encephalomyelopathy), Leigh Necrotizing Encephalopathy, Spinulosa Decalvans Ichthyosis, Keratosis Nigricans, Kera Lennox-Gastaut Syndrome, Lentigio-Polypose-Digestive tosis Palmoplantaris with Periodontopathia and Onychogry Syndrome, Lenz, Dysmorphogenetic Syndrome, Lenz, Dys posis, Keratosis Palmoplantaris Congenital Pes Planus Ony plasia, Lenz, Microphthalmia Syndrome, Lenz Syndrome, chogryposis Periodontosis Arachnodactyly, Keratosis LEOPARD Syndrome, Leprechaunism, Leptomeningeal Palmoplantaris Congenital, Pes Planus, Onychogryphosis, Angiomatosis, Leptospiral Jaundice, Leri-Weill Disease, Periodontosis, Arachnodactyly, Acroosteolysis, Keratosis Leri-Weil Dyschondrosteosis, Leri-Weil Syndrome, Ler Rubra Figurata, Keratosis Seborrheica, Ketoacid Decarboxy moyeZ Syndrome, Leroy Disease, Lesch Nyhan Syndrome, lase Deficiency, Ketoaciduria, Ketotic Glycinemia, KFS, Lethal Infantile Cardiomyopathy, Lethal Neonatal Dwarfism, KID Syndrome, Kidney Agenesis, Kidneys Cystic-Retinal Lethal Osteochondrodysplasia, Letterer-Siwe Disease, Leu Aplasia Joubert Syndrome, Killian Syndrome, Killian/Te kocytic Anomaly Albinism, Leukocytic Inclusions with schler-Nicola Syndrome, Kiloh-Nevin Syndrome III, Kinky Platelet Abnormality, Leukodystrophy, Leukodystrophy with Hair Disease, Kinsbourne Syndrome, Kleeblattschadel Rosenthal Fibers, Leukoencephalitis Periaxialis Concentric, Deformity, Kleine-Levin Syndrome, Kleine-Levin Hiberna Levine-Critchley Syndrome, Levulosuria, Levy-Hollister tion Syndrome, Klinefelter, Klippel-Feil Syndrome, Klippel Syndrome, LGMD, LGS, LHON, LIC, Lichen Ruber Acumi Feil Syndrome Type I, Klippel-Feil Syndrome Type II, Klip natus, Lichen Acuminatus, Lichen Amyloidosis, Lichen Pla pel-Feil Syndrome Type III, Klippel Trenaunay Syndrome, nus, Lichen Psoriasis, Lignac-Debre-Fanconi Syndrome, Klippel-Trenaunay-Weber Syndrome, Kluver-Bucy Syn Lignac-Fanconi Syndrome, Ligneous Conjunctivitis, Limb drome, KMS, Kniest Dysplasia, Kniest Syndrome, Kobner's Girdle Muscular Dystrophy, Limb Malformations-Dento Disease, Koebberling-Dunnigan Syndrome, Kohlmeier Digital Syndrome, Limit Dextrinosis, Linear Nevoid Hyper Degos Disease, Kok Disease, Korsakoff Psychosis, Korsa melanosis, Linear Nevus Sebacous Syndrome, Linear koff’s Syndrome, Krabbe's Disease Included, Krabbe's Leu Scleroderma, Linear Sebaceous Nevus Sequence, Linear kodystrophy, Kramer Syndrome, KSS, KTS, KTW Sebaceous Nevus Syndrome, Lingua Fissurata, Lingua Pli Syndrome, Kufs Disease, Kugelberg-Welander Disease, cata, Lingua Scrotalis, Linguofacial Dyskinesia, Lip Kugelberg-Welander Syndrome, Kussmaul-Landry Paraly Pseudocleft-hemangiomatous Branchial Cyst Syndrome, sis, KWS, L-3-Hydroxy-Acyl-CoA Dehydrogenase Lipid Granulomatosis, Lipid Histiocytosis, Lipid Kerasin (LCHAD) Deficiency, Laband Syndrome, Labhart-Willi Type, Lipid Storage Disease, Lipid-Storage Myopathy Asso Syndrome, Labyrinthine Syndrome, Labyrinthine Hydrops, ciated with SCAD Deficiency, Lipidosis Ganglioside Infan Lacrimo-Auriculo-Dento-Digital Syndrome, Lactase Iso tile, Lipoatrophic Diabetes Mellitus, Lipodystrophy, Lipoid lated Intolerance, Lactase Deficiency, Lactation-Uterus Atro Corneal Dystrophy, Lipoid Hyperplasia-Male Pseudoher phy, Lactic Acidosis Leber Hereditary Optic Neuropathy, maphroditism, Lipomatosis of Pancreas Congenital, Lipo Lactic and Pyruvate Acidemia with Carbohydrate Sensitivity, mucopolysaccharidosis Type I, Lipomyelomeningocele, Lactic and Pyruvate Acidemia with Episodic Ataxia and Lipoprotein Lipase Deficiency Familial, LIS, LIS1, Lissen Weakness, Lactic and Pyruvate, Lactic Acidosis, Lactose cephaly 1, Lissencephaly Type T. Lissencephaly Variants US 2009/0215895 A1 Aug. 27, 2009

With Agenesis of the Corpus Callosum Cerebellar Hypopla Marfan's Variant, Marfanoid Hypermobility Syndrome, Mar sia or Other Anomalies, Little Disease, Liver Phosphorylase ginal Corneal Dystrophy, Marie's Ataxia, Marie Disease, Deficiency, LKS, LMSyndrome, Lobar Atrophy, Lobar Atro Marie-Sainton Disease, Marie Strumpell Disease, Marie phy of the Brain, Lobar Holoprosencephaly, Lobar Tension Strumpell Spondylitis, Marinesco–Sjogren Syndrome, Mari Emphysema in Infancy, Lobstein Disease (Type I), Lobster nesco-Sjogren-Gorland Syndrome, Marker X Syndrome, Claw Deformity, Localized Epidermolysis Bullosa, Local Maroteaux Lamy Syndrome, Maroteaux Type Acrome ized Lipodystrophy, Localized Neuritis of the Shoulder somelic Dysplasia, Marshall's Ectodermal Dysplasias With Girdle, Loeffler's Disease, Loeffler Endomyocardial Fibrosis Ocular and Hearing Defects, Marshall-Smith Syndrome, with Eosinophilia, Loeffler Fibroplastic Parietal Endocardi Marshall Syndrome, Marshall Type Deafness-Myopia-Cata tis, Loken Syndrome, Loken-Senior Syndrome, Long-Chain ract-Saddle Nose, Martin-Albright Syndrome, Martin-Bell 3-hydroxyacyl-CoA Dehydrogenase (LCHAD), Long Chain Syndrome, Martorell Syndrome, MASA Syndrome, Massive Acyl CoA Dehydrogenase Deficiency, Long-Chain Acyl Myoclonia, Mast Cell Leukemia, Mastocytosis, Mastocyto CoA Dehydrogenase (ACADL), Long-Chain Acyl-CoA sis With an Associated Hematologic Disorder, Maumenee Dehydrogenase Deficiency, Long QT Syndrome without Corneal Dystrophy, Maxillary Ameloblastoma, Maxillofa Deafness, Lou Gehrig's Disease, Lou Gehrig's Disease cial Dysostosis, Maxillonasal Dysplasia, Maxillonasal Dys Included, Louis-Bar Syndrome, Low Blood Sugar, Low-Den plasia Binder Type, Maxillopalpebral Synkinesis, May-Heg sity B Lipoprotein Deficiency, Low Imperforate Anus, Low glin Anomaly, MCAD Deficiency, MCAD, McArdle Potassium Syndrome, Lowe syndrome, Lowe's Syndrome, Disease, McCune-Albright, MCD, McKusick Type Meta Lowe-Bickel Syndrome, Lowe-Terry-MacLachlan Syn physeal Chondrodysplasia, MCR, MCTD, Meckel Syn drome, LS, LTD, Lubs Syndrome, Luft Disease, Lumbar drome, Meckel-Gruber Syndrome, Median Cleft Face Syn Canal Stenosis, Lumbar Spinal Stenosis, Lumbosacral Spinal drome, Mediterranean Anemia, Medium-Chain Acyl-CoA Stenosis, Lundborg-Unverricht Disease, Lundborg-Unver Dehydrogenase (ACADM), Medium Chain Acyl-CoA Dehy richt Disease Included, Lupus, Lupus Erythematosus, Lus drogenase (MCAD) Deficiency, Medium-Chain Acyl-CoA chka-Magendie Foramina Atresia, Lyell Syndrome, Lyelles Dehydrogenase Deficiency, Medullary Cystic Disease, Med Syndrome, Lymphadenoid Goiter, Lymphangiectatic Pro ullary Sponge Kidney, MEF, Megaesophagus, Megalenceph tein-Losing Enteropathy, Lymphangioleiomatosis, Lym aly, Megalencephaly with Hyaline Inclusion, Megalenceph phangioleimyomatosis, Lymphangiomas, Lymphatic Mal aly with Hyaline Panneuropathy, Megaloblastic Anemia, formations, Lynch Syndromes, Lynch Syndrome I, Lynch Megaloblastic Anemia of Pregnancy, Megalocornea-Mental Syndrome II, Lysosomal Cl-N-Acetylgalactosaminidase Retardation Syndrome, Meier-Gorlin Syndrome, Meige's Deficiency Schindler Type, Lysosomal Glycoaminoacid Lymphedema, Meige's Syndrome, Melanodermic Leukodys Storage Disease-Angiokeratoma Corporis Diffusum, Lyso trophy, Melanoplakia-Intestinal Polyposis, Melanoplakia-In somal Glucosidase Deficiency, MAA, Machado Disease, testinal Polyposis, MELAS Syndrome, MELAS, Melkersson Machado-Joseph Disease, Macrencephaly, Macrocephaly, Syndrome, Melnick-Fraser Syndrome, Melnick-Needles Macrocephaly Hemihypertrophy, Macrocephaly with Mul Osteodysplasty, Melnick-Needles Syndrome, Membranous tiple Lipomas and Hemangiomata, Macrocephaly with Lipodystrophy, Mendes Da Costa Syndrome, Meniere Dis Pseudo-papilledema and Multiple Hemangiomata, Macro ease, Méniere's Disease, Meningeal Capillary Angiomatosis, globulinemia, Macroglossia, Macroglossia-Omphalocele Menkes Disease, Menke's Syndrome I, Mental Retardation Visceromegaly Syndrome, Macrostomia Ablepheron Syn Aphasia Shuffling Gait Adducted Thumbs (MASA), Mental drome, Macrothrombocytopenia Familial Bernard-Soulier Retardation-Deafness-Skeletal Abnormalities-Coarse Face Type, Macula Lutea Degeneration, Macular Amyloidosis, with Full Lips, Mental Retardation with Hypoplastic 5th Fin Macular Degeneration, Macular Degeneration Disciform, gernails and Toenails, Mental Retardation with Osteocarti Macular Degeneration Senile, Macular Dystrophy, Macular laginous Abnormalities, Mental Retardation-X-linked with Type Corneal Dystrophy, MAD, Madelung’s Disease, Maf Growth Delay-Deafness-Microgenitalism, Menzel Type flucci Syndrome, Major Epilepsy, Malabsorption, Malab OPCA, Mermaid Syndrome, MERRF, MERRF Syndrome, Sorption-Ectodermal Dysplasia-Nasal Alar Hypoplasia, Merten-Singleton Syndrome, MES, Mesangial IGA Nephr Maladie de Roger, Maladie de Tics, Male Malformation of opathy, Mesenteric Lipodystrophy, Mesiodens-Cataract Syn Limbs and Kidneys, Male Turner Syndrome, Malignant drome, Mesodermal Dysmorphodystrophy, Mesomelic Acanthosis, Malignant Acanthosis Nigricans, Malignant Dwarfism-Madelung Deformity, Metabolic Acidosis, Astrocytoma, Malignant Atrophic Papulosis, Malignant Metachromatic Leukodystrophy, Metatarsus Varus, Metatro Fever, Malignant Hyperphenylalaninemia, Malignant Hyper pic Dwarfism. Syndrome, Metatropic Dysplasia, Metatropic pyrexia, Malignant Hyperthermia, Malignant Melanoma, Dysplasia I, Metatropic Dysplasia II, Methylmalonic Aci Malignant Tumors of the Central Nervous System, Mallory demia, Methylmalonic Aciduria, Meulengracht's Disease, Weiss Laceration, Mallory-Weiss Tear, Mallory-Weiss Syn MFD1, MG, MH, MHA, Micrencephaly, Microcephalic Pri drome, Mammary Paget's Disease, Mandibular Ameloblas mordial Dwarfism I, Microcephaly, Microcephaly-Hiatal toma, Mandibulofacial Dysostosis, Manic Depression Illness Hernia-Nephrosis Galloway Type, Microcephaly-Hiatal Her Disease, Mannosidosis, Map-Dot-Fingerprint Type Corneal nia-Nephrotic Syndrome, Microcystic Corneal Dystrophy, Dystrophy, Maple Syrup Urine Disease, Marble Bones, Mar Microcythemia, Microlissencephaly, Microphthalmia, chiafava-Micheli Syndrome, Marcus Gunn Jaw-Winking Microphthalmia or Anopthalmos with Associated Anomalies, Syndrome, Marcus Gunn Phenomenon, Marcus Gunn Ptosis Micropolygyria With Muscular Dystrophy, Microtia Absent, with Jaw-Winking, Marcus Gunn Syndrome, Marcus Gunn Patellae Micrognathia Syndrome, MicroVillus Inclusion Dis (Jaw-Winking) Syndrome, Marcus Gunn Ptosis (with Jaw ease, MID, Midsystolic-Click-Late Systolic Murmur Syn Winking), Marden-Walker Syndrome, Marden-Walker Type drome, Miescher's Type I Syndrome, Mikulicz. Syndrome, Connective Tissue Disorder, Marfan's Abiotrophy, Marfan Mikulicz-Radecki Syndrome, Mikulicz-Sjogren Syndrome, Achard Syndrome, Marfan Syndrome, Marfan's Syndrome I, Mild Autosomal Recessive, Mild Intermediate Maple Syrup US 2009/0215895 A1 Aug. 27, 2009 26

Urine Disease, Mild Maple Syrup Urine Disease, Miller Syn tiple Familial Polyposis, Multiple Lentigines Syndrome, drome, Miller-Dieker Syndrome, Miller-Fisher Syndrome, Multiple Myeloma, Multiple Neuritis of the Shoulder Girdle, Milroy Disease, Minkowski-Chauffard Syndrome, Minor Multiple Osteochondromatosis, Multiple Peripheral Neuritis, Epilepsy, Minot-Von Willebrand Disease, Mirror-Image Multiple Polyposis of the Colon, Multiple Pterygium Syn Dextrocardia, Mitochondrial B-Oxidation Disorders, Mitro drome, Multiple Sclerosis, Multiple Sulfatase Deficiency, chondrial and Cytosolic, Mitochondrial Cytopathy, Mito Multiple Symmetric Lipomatosis, Multiple System Atrophy, chondrial Cytopathy, Keam-Sayre Type, Mitochondrial Multi-synostotic Osteodysgenesis, Multi-synostotic Osteod Encephalopathy, Mitochondrial Encephalo Myopathy Lactic ysgenesis with Long Bone Fractures, Mulvihill-Smith Syn Acidosis and Strokelike Episodes, Mitochondrial Myopathy, drome, MURCS Association, Murk Jansen Type Metaphy Mitochondrial Myopathy Encephalopathy Lactic Acidosis seal Chondrodysplasia, Muscle Carnitine Deficiency, Muscle Stroke-Like Episode, Mitochondrial PEPCK Deficiency, Core Disease, Muscle Phosphofructokinase Deficiency, Mus Mitral-valve prolapse, Mixed Apnea, Mixed Connective Tis cular Central Core Disease, Muscular Dystrophy, Muscular Sue Disease, Mixed Hepatic Porphyria, Mixed Non-Fluent Dystrophy Classic X-linked Recessive, Muscular Dystrophy Aphasia, Mixed Sleep Apnea, Mixed Tonic and Clonic Tor Congenital With Central Nervous System Involvement, Mus ticollis, MJD, MKS, ML I, ML II, ML III, ML IV. ML cular Dystrophy Congenital Progressive with Mental Retar Disorder Type I, ML Disorder Type II, ML Disorder Type III, dation, Muscular Dystrophy Facioscapulohumeral, Muscular ML Disorder Type IV, MLNS, MSyndrome, MND, MNGIE, Rheumatism, Muscular Rigidity-Progressive Spasm, Muscu MNS, Mobitz I, Mobitz II, Mobius Syndrome, Moebius Syn loskeletal Pain Syndrome, Mutilating Acropathy, Mutism, drome, Moersch-Woltmann Syndrome, Mohr Syndrome, mvp, MVP. MWS, Myasthenia Gravis, Myasthenic Syn Monilethrix, Monomodal Visual Amnesia, Mononeuritis drome of Lambert-Eaton, Myelinoclastic Diffuse Sclerosis, Multiplex, Mononeuritis Peripheral, Mononeuropathy Myelomatosis, Myhre Syndrome, Myoclonic Astatic Petit Peripheral, Monosomy 3p2, Monosomy 9p Partial, Mono Mal Epilepsy, Myoclonic Dystonia, Myoclonic Encephal somy 11q Partial, Monosomy 13q Partial, Monosomy 18q. opathy of Infants, Myoclonic Epilepsy, Myoclonic Epilepsy Syndrome, Monosomy X, Monostotic Fibrous Dysplasia, Hartung Type, Myoclonus Epilepsy Associated with Ragged Morgagni-Turner-Albright Syndrome, Morphea, Morquio Red Fibers, Myoclonic Epilepsy and Ragged-Red Fiber Dis Disease, Morquio Syndrome, Morquio Syndrome A. ease, Myoclonic Progressive Familial Epilepsy, Myoclonic Morquio Syndrome B. Morquio-Brailsford Syndrome, Mor Progressive Familial Epilepsy, Myoclonic Seizure, Myoclo van Disease, Mosaic Tetrasomy 9p, Motor Neuron Disease, nus, Myoclonus Epilepsy, Myoencephalopathy Ragged-Red Motor Neuron Syndrome, Motor Neurone Disease, Moto Fiber Disease, Myofibromatosis, Myofibromatosis Congeni neuron Disease, Motoneurone Disease, Motor System Dis tal, Myogenic Facio-Scapulo-Peroneal Syndrome, Myo ease (Focal and Slow), Moya-Moya Disease, MPS, MPS I, neurogastointestinal Disorder and Encephalopathy, Myo MPS I H, NPS 1H/S Hurler/Scheie Syndrome, MPS I S pathic Arthrogryposis Multiplex Congenita, Myopathic Scheie Syndrome, MPS II, MPS IIA, MPS IIB, MPS II-AR Carnitine Deficiency, Myopathy Central Fibrillar, Myopathy Autosomal Recessive Hunter Syndrome, MPS II-XR, MPS Congenital Nonprogressive, Myopathy Congenital Nonpro II-XR Severe Autosomal Recessive, MPS III, MPS IIIA, B, C gressive with Central Axis, myopathy with Deficiency of and D, Sanfiloppo A, MPS IV, MPS IV A and B Morquio A, Carnitine Palmitoyltransferase, myopathy-Marinesco MPSV, MPS VI Severe Intermediate Mild Maroteaux-Lamy, Sjogren Syndrome, myopathy-Metabolic Carnitine Palmi MPS VII Sly Syndrome, MPS VIII, MPS Disorder, MPS toyltransderase Deficiency, Myopathy Mitochondrial-En Disorder VI, MRS, MS, MSA, MSD, MSL, MSS, MSUD, cephalopathy-Lactic Acidosis-Stroke, Myopathy with MSUD, MSUD Type Ib, MSUD Type II, Mucocutaneous Sarcoplasmic Bodies and Intermediate Filaments, Myophos Lymph Node Syndrome. Mucolipidosis I. Mucolipidosis II, phorylase Deficiency, Myositis Ossificans Progressive, Myo Mucolipidosis III, Mucolipidosis IV. Mucopolysaccharido tonia Atrophica, Myotonia Congenita, Myotonia Congenita sis, Mucopolysaccharidosis I-H. Mucopolysaccharidosis I-S, Intermittens, Myotonic Dystrophy, Myotonic Myopathy Mucopolysaccharidosis II. Mucopolysaccharidosis III, Dwarfism Chondrodystrophy Ocular and Facial Anomalies, Mucopolysaccharidosis IV. Mucopolysaccharidosis VI, Myotubular Myopathy, Myotubular Myopathy X-linked, Mucopolysaccharidosis VII, Mucopolysaccharidosis Type I, My proic Acid, Myriachit (Observed in Siberia), Myxedema, Mucopolysaccharidosis Type II. Mucopolysaccharidosis N-Acetylglucosamine-1-Phosphotransferase Deficiency, Type III, Mucopolysaccharidosis Type VII, Mucosis, Muco N-Acetyl Glutamate Synthetase Deficiency, NADH-COQ sulfatidosis, Mucous Colitis, Mucoviscidosis, Mulibrey Reductase Deficiency, Naegeli Ectodermal Dysplasias, Dwarfism, Mulibrey Nanism Syndrome, Mullerian Duct Nager Syndrome, Nager Acrofacial Dysostosis Syndrome, Aplasia-Renal Aplasia-Cervicothoracic Somite Dysplasia, Nager Syndrome, NAGS Deficiency, Nail Dystrophy-Deaf Mullerian Duct-Renal-Cervicothoracic-Upper Limb. ness Syndrome, Nail Dysgenesis and Hypodontia, Nail-Pa Defects, Mullerian Duct and Renal Agenesis with Upper tella Syndrome, Nance-Horan Syndrome, Nanocephalic Limb and Rib Anomalies, Mullerian-Renal-Cervicothoracic Dwarfism, Nanocephaly, Nanophthalmia, Narcolepsy, Nar Somite Abnormalities, Multi-Infarct Dementia Binswanger's coleptic syndrome, NARP, Nasal-fronto-faciodysplasia, Type, Multicentric Castleman's Disease, Multifocal Eosino Nasal Alar Hypoplasia Hypothyroidism Pancreatic Achylia philic Granuloma, Multiple Acyl-CoA Dehydrogenase Defi Congenital Deafness, Nasomaxillary Hypoplasia, Nasu ciency, Multiple Acyl-CoA Dehydrogenase Deficiency/Glu Lipodystrophy, NBIA1, ND, NDI, NDP. Necrotizing taric Aciduria Type II, Multiple Angiomas and Encephalomyelopathy of Leigh's, Necrotizing Respiratory Endochondromas, Multiple Carboxylase Deficiency, Mul Granulomatosis, Neill-Dingwall Syndrome, Nelson Syn tiple Cartilaginous Enchondroses, Multiple Cartilaginous drome, Nemaline myopathy, Neonatal Adrenoleukodystro Exostoses, Multiple Enchondromatosis, Multiple Endocrine phy, Neonatal Adrenoleukodystrophy (NALD), Neonatal Deficiency Syndrome Type II, Multiple Epiphyseal Dyspla Adrenoleukodystrophy (ALD), Neonatal Autosomal Reces sia, Multiple Exostoses, Multiple Exostoses Syndrome, Mul sive Polycystic Kidney Disease, Neonatal Dwarfism, Neona US 2009/0215895 A1 Aug. 27, 2009 27 tal Hepatitis, Neonatal Hypoglycemia, Neonatal Lactose tonia Dementia Syndrome, Nutritional Neuropathy, Nyhan Intolerance, Neonatal Lymphedema due to Exudative Enter Syndrome, OAV Spectrum, Obstructive Apnea, Obstructive opathy, Neonatal Progeroid Syndrome, Neonatal Pseudo-Hy Hydrocephalus, Obstructive Sleep Apnea, OCC Syndrome, drocephalic Progeroid Syndrome of Wiedemann-Rauten Occlusive Thromboaortopathy, OCCS, Occult Intra-cranial strauch, Neoplastic Arachnoiditis, Nephroblastom, Vascular Malformations, Occult Spinal Dysraphism Nephrogenic Diabetes Insipidus, Nephronophthesis Familial Sequence, Ochoa Syndrome, Ochronosis, Ochronotic Arthri Juvenile, Nephropathic Cystinosis, Nephropathy-Pseudoher tis, OCR, OCRL, Octocephaly, Ocular Albinism, Ocular Her maphroditism-Wilms Tumor, Nephrosis-Microcephaly Syn pes, Ocular Myasthenia Gravis, Oculo-Auriculo-Vertebral drome, Nephrosis-Neuronal Dysmigration Syndrome, Neph Dysplasia, Oculo-Auriculo-Vertebral Spectrum, Oculo rotic-Glycosuric-Dwarfism-Rickets-Hypophosphatemic Bucco-Genital Syndrome, Oculo-cerebral Syndrome with Syndrome, Netherton Disease, Netherton Syndrome, Nether Hypopigmentation, Oculo-cerebrocutaneous Syndrome, ton Syndrome Ichthyosis, Nettleship Falls Syndrome Oculo-Cerebro-Renal, Oculo-cerebrorenal Dystrophy, (X-Linked), Neu-Laxova Syndrome, Neuhauser Syndrome, Oculo-cerebrorenal Syndrome, Oculo-craniosomatic Syn Neural-Tube Defects, Neuralgic Amyotrophy, Neuramini drome (obsolete), Oculocutaneous Albinism, Oculocutane dase Deficiency, Neuraocutaneous Melanosis, Neurinoma of ous Albinism Chediak-Higashi Type, Oculo-Dento-Digital the Acoustic Nerve, Neurinoma, Neuroacanthocytosis, Neu Dysplasia, Oculo-dentodigital Syndrome, Oculo-Dento-Os roaxonral Dystrophy Schindler Type, Neurodegeneration seous Dysplasia, Oculo Gastrointestinal Muscular Dystro with Brain Iron Accumulation Type 1 (NBIA1). Neurofi phy, Oculo Gastrointestinal Muscular Dystrophy, Oculo broma of the Acoustic Nerve, Neurogenic Arthrogryposis mandibulodyscephaly with Hypotrichosis, Oculo Multiplex Congenita, Neuromyelitis Optica, Neuromyoto mandibulo-facial Syndrome, Oculo-motor with Congenital nia, Neuromyotonia, Focal, Neuromyotonia, Generalized, Contractures and Muscle Atrophy, Oculosympathetic Palsy, Familial, Neuromyotonia, Generalized, Sporadic, Neuronal ODD Syndrome, ODOD, Odontogenic Tumor, Odontotri Axonal Dystrophy Schindler Type, Neuronal Ceroid Lipofus chomelic Syndrome, OFD, OFD Syndrome, Ohio Type Amy cinosis Adult Type, Neuronal Ceroid Lipofuscinosis Juvenile loidosis (Type VII), OI. OI Congenita, OI Tarda, Oldfield Type, Neuronal Ceroid Lipofuscinosis Type 1, Neurono Syndrome, Oligohydramnios Sequence, Oligophrenia pathic Acute Gaucher Disease, Neuropathic Amyloidosis, Micropthalmos, Oligophrenic Polydystrophy, Olivoponto Neuropathic Beriberi, Neuropathy Ataxia and Retinitis Pig cerebellar Atrophy, Olivopontocerebellar Atrophy with mentosa, Neuropathy of Brachialpelxus Syndrome, Neur Dementia and Extrapyramidal Signs, Olivopontocerebellar opathy Hereditary Sensory Type I, Neuropathy Hereditary Atrophy with Retinal Degeneration, Olivopontocerebellar Sensory Type II, Neutral Lipid Storage Disease, Nevii, Atrophy I, Olivopontocerebellar Atrophy II, Olivopontocer Nevoid Basal Cell Carcinoma Syndrome, Nevus, Nevus Cav ebellar Atrophy III, Olivopontocerebellar Atrophy IV. ernosus, Nevus Comedonicus, Nevus Depigmentosus, Nevus Olivopontocerebellar Atrophy V. Ollier Disease, Ollier Sebaceous of Jadassohn, Nezelof's Syndrome, Nezelof's Osteochondromatosis, Omphalocele-Visceromegaly-Macro Thymic Aplasia, Nezelof Type Severe Combined Immuno glossia Syndrome, Ondine's Curse, Onion-Bulb Neuropathy, deficiency, NF, NF1, NF2, NF-1, NF-2, NHS, Niemann Pick Onion Bulb Polyneuropathy, Onychoosteodysplasia, Ony Disease, Nieman Pick Disease Type A (acute neuronopathic chotrichodysplasia with Neutropenia, OPCA, OPCA I, form), Nieman Pick disease Type B, Nieman Pick Disease OPCA II, OPCA III, OPCA IV, OPCA V, OPD Syndrome, Type C (chronic neuronopathic form), Nieman Pick Disease OPD Syndrome Type I, OPD Syndrome Type II, OPD I Type D (Nova Scotia variant), Nieman Pick Disease Type E, Syndrome, OPD II Syndrome, Ophthalmoarthropathy, Oph Nieman Pick Disease Type F (sea-blue histiocyte disease), thalmoplegia-Intestinal Pseudo-obstruction, Ophthalmople Night Blindness, Nigrospinodentatal Degeneration, gia, Pigmentary Degeneration of the Retina and Cardiomy Niikawakuroki Syndrome, NLS, NM, Noack Syndrome Type opathy, Ophthalmoplegia Plus Syndrome, Ophthalmoplegia I, Nocturnal Myoclonus Hereditary Essential Myoclonus, Syndrome, Opitz BBBSyndrome, Opitz BBB/G Compound Nodular Cornea Degeneration, Non-Bullous CIE, Non Syndrome, Opitz BBBG Syndrome, Opitz-Frias Syndrome, Bullous Congenital Ichthyosiform Erythroderma, Non-Com Opitz, G. Syndrome, Opitz G/BBB Syndrome, Opitz, Hyper municating Hydrocephalus, Non-Deletion Type O.-Thalas telorism-Hypospadias Syndrome, Opitz-Kaveggia Syn semia/Mental Retardation syndrome. Non-Ketonic drome, Opitz, Oculo-genito-laryngeal Syndrome, Opitz Hyperglycinemia Type I (NKHI), Non-Ketotic Hyperglycin Trigonocephaly Syndrome, Opitz Syndrome, OpSoclonus, emia, Non-Lipid Reticuloendotheliosis, Non-Neuronopathic Opsoclonus-Myoclonus, Ophthalmoneuromyelitis, Optic Chronic Adult Gaucher Disease, Non-Scarring Epidermoly Atrophy Polyneuropathy and Deafness, Optic Neuroen sis Bullosa, Non-arteriosclerotic Cerebral Calcifications, cephalomyelopathy, Optic Neuromyelitis, Opticomyelitis, Non-articular Rheumatism, Non-cerebral, Juvenile Gaucher Optochiasmatic Arachnoiditis, Oral-Facial Clefts, Oral-Fa Disease, Non-diabetic Glycosuria, Non-ischemic Cardiomy cial Dyskinesia, Oral Facial Dystonia, Oral-Facial-Digital opathy, Non-ketotic Hypoglycemia and Carnitine Deficiency Syndrome, Oral-Facial-Digital Syndrome Type I, Oral-Fa due to MCAD Deficiency, Non-ketotic Hypoglycemia cial-Digital Syndrome I, Oral-Facial-Digital Syndrome II, Caused by Deficiency of Acyl-CoA Dehydrogenase, Non Oral-Facial-Digital Syndrome III, Oral-Facial-Digital Syn ketotic Glycinemia, Nonne's Syndrome. Nonne-Milroy drome IV. Orbital Cyst with Cerebral and Focal Dermal Mal Meige Syndrome. Nonopalescent Opalescent Dentine, Non formations, Ornithine Carbamyl Transferase Deficiency, puerperal Galactorrhea-Amenorrhea, Non-secretory Ornithine Transcarbamylase Deficiency, Orocraniodigital Myeloma, Non-spherocytic Hemolytic Anemia, Non-tropi Syndrome, Orofaciodigital Syndrome, Oromandibular Dys cal Sprue, Noonan Syndrome, Norepinephrine, Normal Pres tonia, Orthostatic Hypotension, Osler-Weber-Rendu Disease, sure Hydrocephalus, Norman-Roberts Syndrome, Norrbott Osseous-Oculo-Dento Dysplasia, Osseous-Oculo-Dento nian Gaucher Disease, Norrie Disease, Norwegian Type Dysplasia, Osteitis Deformans, Osteochondrodystrophy Hereditary Cholestasis, NPD, NPS, NS, NSA, Nuchal Dys Deformans, Osteochondroplasia, Osteodysplasty of Melnick US 2009/0215895 A1 Aug. 27, 2009 28 and Needles, Osteogenesis Imperfect, Osteogenesis Imper Obstructive Sleep Apnea, Peeling Skin Syndrome, Pelizaeus fecta, Osteogenesis Imperfecta Congenita, Osteogenesis Merzbacher Disease, Pelizaeus-Merzbacher Brain Sclerosis, Imperfecta Tarda, Osteohypertrophic Nevus Flammeus, Pellagra-Cerebellar Ataxia-Renal Aminoaciduria Syndrome, Osteopathia Hyperostotica Scleroticans Multiplex Infantalis, Pelvic Pain Syndrome, Pemphigus Vulgaris, Pena Shokeir II Osteopathia Hyperostotica Scleroticans Multiplex Infantalis, Syndrome, Pena Shokeir Syndrome Type II, Penile Fibroma Osteopathyrosis, Osteopetrosis, Qsteopetrosis Autosomal tosis, Penile Fibrosis, Penile Induration, Penta X Syndrome, Dominant Adult Type, Osteopetrosis Autosomal Recessive Pentalogy of Cantrell, Pentalogy Syndrome, Pentasomy X, Malignant Infantile Type, Osteopetrosis-Mild Autosomal PEPCK Deficiency, Pepper Syndrome, Perheentupa Syn Recessive Intermediate Type, Osteosclerosis Fragilis Gener drome, Periarticular Fibrositis, Pericardial Constriction with alisata, Osteosclerotic Myeloma, Ostium Primum Defect (en Growth Failure, Pericollagen Amyloidosis, Perinatal Poly docardial cushion defects included), Ostium Secundum cystic Kidney Diseases, Perineal Anus, Periodic Amyloid Defect, OTC Deficiency, Oto-Palato-Digital Syndrome, Oto Syndrome, Periodic Peritonitis Syndrome, Periodic Somno Palato-Digital Syndrome Type I, Oto-Palatal-Digital Syn lence and Morbid Hunger, Periodic Syndrome, Peripheral drome Type II, Otodental Dysplasia, Otopalatodigital Syn Cystoid Degeneration of the Retina, Peripheral Dysostosis drome, Otopalataldigital Syndrome Type II, Oudtshoorn Nasal Hypoplasia-Mental Retardation, Peripheral Neuritis, Skin, Ovarian Dwarfism Turner Type, Ovary Aplasia Turner Peripheral Neuropathy, Peritoneopericardial Diaphragmatic Type, OWR, Oxalosis. Oxidase Deficiency, Oxycephaly, Hernia, Pernicious Anemia, Peromelia with Micrognathia, Oxycephaly-Acrocephaly, P-V, PA, PAC, Pachyonychia Ich Peroneal Muscular Atrophy, Peroneal Nerve Palsy, Peroutka tyosiforme, Pachyonychia Congenita with Natal Teeth, Sneeze, Peroxisomal Acyl-CoA Oxidase, Peroxisomal Pachyonychia Congenita, Pachyonychia Congenita Keratosis B-Oxidation Disorders, Peroxisomal Bifunctional Enzyme, Disseminata Circumscripta (follicularis), Pachyonychia Peroxisomal Thiolase, Peroxisomal Thiolase Deficiency, Per Congenita Jadassohn-Lewandowsky Type, PAF with MSA, sistent Truncus Arteriosus, Perthes Disease, Petit Mal Epi Paget's Disease, Paget’s Disease of Bone, Paget’s Disease of lepsy, Petit Mal Variant, Peutz-Jeghers Syndrome, Peutz the Breast, Paget’s Disease of the Nipple, Paget's Disease of Touraine Syndrome, Peyronie Disease, Pfeiffer, Pfeiffer the Nipple and Areola, Pagon Syndrome, Painful Ophthal Syndrome Type I, PGA I, PGA II, PGA III, PGK, PHType I, moplegia, PAIS, Palatal Myoclonus, Palato-Oto-Digital Syn PH Type I, Pharyngeal Pouch Syndrome, PHD Short-Chain drome, Palatal-Oto-Digital Syndrome Type I, Palatal-Oto Acyl-CoA Dehydrogenase Deficiency, Phenylalanine Digital Syndrome Type II, Pallister Syndrome, Pallister-Hall Hydroxylase Deficiency, Phenylalaninemia, Phenylketo Syndrome, Pallister-Killian Mosaic Syndrome, Pallister nuria, Phenylpyruvic Oligophrenia, Phocomelia, Phocomelia Mosaic Aneuploidy, Pallister Mosaic Syndrome, Pallister Syndrome, Phosphoenolpyruvate Carboxykinase Deficiency, Mosaic Syndrome Tetrasomy 12p, Pallister-W Syndrome, Phosphofructokinase Deficiency, Phosphoglycerate Kinase Palmoplantar Hyperkeratosis and Alopecia, Palsy, Pancreatic Deficiency, Phosphoglycerokinase, Phosphorylase 6 Kinase Fibrosis, Pancreatic Insufficiency and Bone Marrow Dys Deficiency, Phosphorylase Deficiency Glycogen Storage function, Pancreatic Ulcerogenic Tumor Syndrome, Panmy Disease, Phosphorylase Kinase Deficiency of Liver, Photic elophthisis, Panmyelopathy, Pantothenate Kinase Associated Sneeze Reflex, Photic Sneezing, Phototherapeutic Keratec Neurodegeneration (PKAN), Papillon-Lefevre Syndrome, tomy, PHS, Physicist John Dalton, Phytanic Acid Storage Papillotonic Psuedotabes, Paralysis Periodica Paramyo Disease, Pi Phenotype ZZ, PI, Pick Disease of the Brain, tonica, Paralytic Beriberi, Paralytic Brachial Neuritis, Para Pick's Disease, Pickwickian Syndrome, Pierre Robin median Lower Lip Pits-Popliteal Pyerygium Syndrome, Anomalad, Pierre Robin Complex, Pierre Robin Sequence, Paramedian Diencephalic Syndrome, Paramyeloidosis, Pierre Robin Syndrome, Pierre Robin Syndrome with Hyper Paramyoclonus Multiple, Paramyotonia Congenita, phalangy and Clinodactyly, Pierre-Marie's Disease, Pigmen Paramyotonia Congenita of Von Eulenburg, Parkinson's Dis tary Degeneration of Globus Pallidus Substantia Nigra Red ease, Paroxysmal Atrial Tachycardia, Paroxysmal Cold Nucleus, Pili Torti and Nerve Deafness, Pili Torti-Senso Hemoglobinuria, Paroxysmal Dystonia, Paroxysmal Dysto rineural Hearing Loss, Pituitary Dwarfism II, Pituitary Tumor nia Choreathetosis, Paroxysmal Kinesigenic Dystonia, Par after Adrenalectomy, Pityriasis Pilaris, Pityriasis Rubra oxysmal Nocturnal Hemoglobinuria, Paroxysmal Normal Pilaris, PJS, PKAN, PKD. PKD1, PKD2, PKD3, PKU, Hemoglobinuria, Paroxysmal Sleep, Parrot Syndrome, Parry PKU1, Plagiocephaly, Plasma Cell Myeloma, Plasma Cell Disease, Parry-Romberg Syndrome, Parsonage-Turner Syn Leukemia, Plasma Thromboplastin Component Deficiency, drome, Partial Androgen Insensitivity Syndrome, Partial Plasma Transglutaminase Deficiency, Plastic Induration Cor Deletion of the Short Arm of Chromosome 4, Partial Deletion pora Cavernosa, Plastic Induration of the Penis, PLD, Pli of the Short Arm of Chromosome 5, Partial Deletion of Short cated Tongue, PLS, PMD, Pneumorenal Syndrome, PNH, Arm of Chromosome 9, Partial Duplication 3q Syndrome, PNM, PNP Deficiency, POD, POH, Poikiloderma Atrophi Partial Duplication 15q Syndrome, Partial Facial Palsy With cans and Cataract, Poikiloderma Congenital, Poland Urinary Abnormalities, Partial Gigantism of Hands and Feet Anomaly, Poland Sequence, Poland Syndactyly, Poland Syn Nevi-Hemihypertrophy-Macrocephaly, Partial Lipodystro drome, Poliodystrophia Cerebri Progressiva, Polyarthritis phy, Partial Monosomy of Long Arm of Chromosome 11, Enterica, Polyarteritis Nodosa, Polyarticular-Onset Juvenile Partial Monosomy of the Long Arm of Chromosome 13, Arthritis Type I, Polyarticular-Onset Juvenile Arthritis Type Partial Spinal Sensory Syndrome, Partial Trisomy 11q, Par II, Polychondritis, Polycystic Kidney Disease, Polycystic tington Syndrome, PAT, Patent Ductus Arteriosus, Pathologi Kidney Disease Medullary Type, Polycystic Liver Disease, cal Myoclonus, Pauciarticular-Onset Juvenile Arthritis, Pau Polycystic Ovary Disease, Polycystic Renal Diseases, Poly litis, PBC, PBS, PC Deficiency, PC Deficiency Group A, PC dactyly-Joubert Syndrome, Polydysplastic Epidermolysis Deficiency Group B, PC, Eulenburg Disease, PCC Defi Bullosa, Polydystrophia Oligophrenia, Polydystrophic ciency, PCH, PCLD, PCT, PD, PDA, PDH Deficiency, Pear Dwarfism, Polyglandular Autoimmune Syndrome Type III, son Syndrome Pyruvate Carboxylase Deficiency, Pediatric Polyglandular Autoimmune Syndrome Type II, Polyglandu US 2009/0215895 A1 Aug. 27, 2009 29 lar Autoimmune Syndrome Type I, Polyglandular Autoim tis Idiopathic, Progeria of Adulthood, Progeria of Childhood, mune Syndrome Type II, Polyglandular Syndromes, Poly Progeroid Nanism, Progeriod Short Stature with Pigmented morphic Macula Lutea Degeneration, Polymorphic Macular Nevi, Progeroid Syndrome of De Barsy, Progressive Auto Degeneration, Polymorphism of Platelet Glycoprotien Ib. nomic Failure with Multiple System Atrophy, Progressive Polymorphous Corneal Dystrophy Hereditary, Polymyalgia Bulbar Palsy, Progressive Bulbar Palsy Included, Progressive Rheumatica, Polymyositis and Dermatomyositis, Primary A Cardiomyopathic Lentiginosis, Progressive Cerebellar y-globulinemia, Polyneuritis Peripheral, Polyneuropathy Ataxia Familial, Progressive Cerebral Poliodystrophy, Pro Deafness-Optic Atrophy, Polyneuropathy Peripheral, Poly gressive Choroidal Atrophy, Progressive Diaphyseal Dyspla neuropathy and Polyradiculoneuropathy, Polyostotic Fibrous sia, Progressive Facial Hemiatrophy, Progressive Familial Dysplasia, Polyostotic Sclerosing Histiocytosis, Polyposis Myoclonic Epilepsy, Progressive Hemifacial Atrophy, Pro Familial, Polyposis Gardner Type, Polyposis Hamartomatous gressive Hypoerythemia, Progressive Infantile Poliodystro Intestinal, Polyposis-Osteomatosis-Epidermoid Cyst Syn phy, Progressive Lenticular Degeneration, Progressive Lipo drome, Polyposis Skin Pigmentation Alopecia and Fingernail dystrophy, Progressive Muscular Dystrophy of Childhood, Changes, Polyps and Spots Syndrome, Polyserositis Recur Progressive Myoclonic Epilepsy, Progressive Osseous Het rent, Polysomy Y. Polysyndactyly with Peculiar Skull Shape, eroplasia, Progressive Pallid Degeneration Syndrome, Pro Polysyndactyly-Dysmorphic Craniofacies Greig Type, gressive Spinobulbar Muscular Atrophy, Progressive Supra Pompe Disease, Pompe Disease, Popliteal Pterygium Syn nuclear Palsy, Progressive Systemic Sclerosis, Progressive drome, Porcupine Man, Porencephaly, Porencephaly, Por Tapetochoroidal Dystrophy, Proline Oxidase Deficiency, phobilinogen deaminase (PBG-D), Porphyria, Porphyria Propionic Acidemia, Propionic Acidemia Type I (PCCA Acute Intermittent, Porphyria ALA-D, Porphyria Cutanea Deficiency), Propionic Acidemia Type II (PCCB Deficiency), Tarda, Porphyria Cutanea Tarda Hereditaria, Porphyria Cuta Propionyl CoA Carboxylase Deficiency, Protanomaly, Pro nea Tarda Symptomatica, Porphyria Hepatica Variegate, Por tanopia, Protein-Losing Enteropathy Secondary to Conges phyria Swedish Type, Porphyria Variegate, Porphyriam Acute tive Heart Failure, Proteus Syndrome, Proximal Deletion of Intermittent, Porphyrins, Porrigo Decalvans, Port Wine 4q Included, PRP PRS, Prune Belly Syndrome, PS, Pseudo Stains, Portuguese Type Amyloidosis, Post-Infective Poly Hurler Polydystrophy, Pseudo-Polydystrophy, Pseudoacan neuritis, Postanoxic Intention Myoclonus, Postaxial Acrofa thosis Nigricans, Pseudoachondroplasia, Pseudocholinest cial Dysostosis, Postaxial Polydactyly, Postencephalitic erase Deficiency, Pseudogout Familial, Pseudohemophilia, Intention Myoclonus, Posterior Corneal Dystrophy Heredi Pseudohermaphroditism, Pseudohermaphroditism-Nephron tary, Posterior Thalamic Syndrome, Post-myelographic Disorder-Wilm's Tumor, Pseudohypertrophic Muscular Dys Arachnoiditis, Post-natal Cerebral Palsy, Post-operative trophy, Pseudohypoparathyroidism, Pseudohypophosphata Cholestasis, Postpartum Galactorrhea-Amenorrhea Syn sia, Pseudopolydystrophy, Pseudothalidomide Syndrome, drome, Postpartum Hypopituitarism, Postpartum Panhypopi Pseudoxanthoma Elasticum, Psoriasis, Psorospermosis Fol tuitary Syndrome, Postpartum Panhypopituitarism, Postpar licularis, PSP, PSS, Psychomotor Convulsion, Psychomotor tum Pituitary Necrosis, Postural Hypotension, Potassium Epilepsy, Psychomotor Equivalent Epilepsy, PTC Defi Losing Nephritis, Potassium Loss Syndrome, Potter Type ciency, Pterygium, Pterygium Colli Syndrome, Pterygium I-Infantile Polycystic Kidney Diseases, Potter Type III Poly Universale, Pterygolymphangiectasia, Pulmonary Atresia, cystic Kidney Disease, PPH, PPS, Prader-Willi Syndrome, Pulmonary Lymphangiomyomatosis, Pulmonary Stenosis, Prader-Labhart-Willi Fancone Syndrome, Prealbumin Tyr-77 Pulmonic Stenosis-Ventricular Septal Defect, Pulp Stones, Amyloidosis, Pre-excitation Syndrome, Pregnenolone Defi Pulpal Dysplasia, Pulseless Disease, Pure Alymphocytosis, ciency, Premature Atrial Contractions, Premature Senility Pure Cutaneous Histiocytosis, Purine Nucleoside Phospho Syndrome, Premature Supraventricular Contractions, Prema rylase Deficiency, Purpura Hemorrhagica, Purtilo Syndrome, ture Ventricular Complexes, Pre-natal or Con-natal Neuroax PXE, PXE Dominant Type, PXE Recessive Type, Pycnody onal Dystrophy, Pre-senile Dementia, Pre-senile Macula sostosis, Pyknodysostosis, Pyknoepilepsy, Pyroglutamic Lutea Retinae Degeneration, Primary Adrenal Insufficiency, Aciduria, Pyroglutamicaciduria, Pyrroline. Carboxylate Primary Ay-globulinemias, Primary Aldosteronism, Primary Dehydrogenase Deficiency, Pyruvate Carboxylase Defi Alveolar HypoVentilation, Primary Amyloidosis, Primary ciency, Pyruvate Carboxylase Deficiency Group A, Pyruvate Anemia, Primary Beriberi, Primary Biliary, Primary Biliary Carboxylase Deficiency Group B, Pyruvate Dehydrogenase Cirrhosis, Primary Brown Syndrome, Primary Carnitine Deficiency, Pyruvate Kinase Deficiency, q25-qter, q26 or Deficiency, Primary Central Hypoventilation Syndrome, Pri q27-qter, q31 or 32-qter, QT Prolongation with Extracellular mary Ciliary Dyskinesia Kartagener Type, Primary Cutane Hypohypocalcinemia, QT Prolongation without Congenital ous Amyloidosis, Primary Dystonia, Primary Failure Adreno Deafness, QT Prolonged with Congenital Deafness, Quadri cortical Insufficiency, Primary Familial Hypoplasia of the paresis of Cerebral Palsy, Quadriplegia of Cerebral Palsy, Maxilla, Primary Hemochromatosis, Primary Hyperhidrosis, Quantal Squander, Quantal Squander, ra, ro, r14, r 18, r21, Primary Hyperoxaluria Type I, Primary Hyperoxaluria r22, Rachischisis Posterior, Radial Aplasia-Amegakaryo Type I (PHI), Primary Hyperoxaluria Type I, Primary Hyper cytic Thrombocytopenia, Radial Aplasia-Thrombocytopenia oxaluria Type II, Primary Hyperoxaluria Type III, Primary Syndrome, Radial Nerve Palsy, Radicular Neuropathy Sen Hypogonadism, Primary Intestinal Lymphangiectasia, Pri sory, Radicular Neuropathy Sensory Recessive, Radicular mary Lateral Sclerosis, Primary Non-hereditary Amyloido Dentin Dysplasia, Rapid-Onset Dystonia-Parkinsonism, sis, Primary Obliterative Pulmonary Vascular Disease, Pri Rapp-Hodgkin Syndrome, Rapp-Hodgkin (hypohidrotic) mary Progressive Multiple Sclerosis, Primary Pulmonary Ectodermal Dysplasia syndrome, Rapp-Hodgkin Hypo Hypertension, Primary Reading Disability, Primary Renal hidrotic Ectodermal Dysplasias, Rare Hereditary Ataxia With Glycosuria, Primary Sclerosing Cholangitis, Primary Throm Polyneuritic Changes and Deafness Caused by a Defect in the bocythemia, Primary Tumors of Central Nervous System, Enzyme Phytanic Acid Hydroxylase, Rautenstrauch-Wiede Primary Visual Agnosia, Proctocolitis Idiopathic, Proctocoli mann Syndrome, Rautenstrauch-Wiedemann Type Neonatal US 2009/0215895 A1 Aug. 27, 2009 30

Progeria, Raynaud's Phenomenon, RDP. Reactive Functional Sion, Sacral Agenesis Congenital, SAE, Saethre-Chotzen Hypoglycemia, Reactive Hypoglycemia Secondary to Mild Syndrome, Sakati, Sakati Syndrome, Sakati-Nyhan Syn Diabetes, Recessive Type Kenny-Caffe Syndrome, Recklin drome, Salaam Spasms, Salivosudoriparous Syndrome, Salz Recessive Type Myotonia Congenita, Recklinghausen Dis man Nodular Corneal Dystrophy, Sandhoff Disease, Sanfil ease. Rectoperineal Fistula, RecurrentVomiting, Reflex Neu ippo Syndrome, Sanfilippo Type A, Sanfilippo Type B, rovascular Dystrophy, Reflex Sympathetic Dystrophy Syn Santavuori Disease, Santavuori-Haltia Disease, Sarcoid of drome, Refractive Errors, Refractory Anemia, Refrigeration Boeck, Sarcoidosis, Sathre-chotzen, Saturday Night Palsy, Palsy, Refsum Disease, Refsum's Disease, Regional Enteri SBMA, SC Phocomelia Syndrome, SC Syndrome, SCA 3. tis, Reid-Barlow's syndrome, Reifenstein Syndrome, Reiger SCAD Deficiency, SCAD Deficiency Adult-Onset Localized, Anomaly-Growth Retardation, Reiger Syndrome, Reimann SCAD Deficiency Congenital Generalized, SCAD, SCADH Periodic Disease, Reimann's Syndrome, Reis-Bucklers Cor Deficiency, Scalded Skin Syndrome, Scalp Defect Congeni neal Dystrophy, Reiter's Syndrome, Relapsing Guillain tal, Scaphocephaly, Scapula Elevata, Scapuloperoneal Barre Syndrome, Relapsing-Remitting Multiple Sclerosis, Myopathy, Scapuloperoneal Muscular Dystrophy, Scapulop Renal Agenesis, Renal Dysplasia-Blindness Hereditary, eroneal Syndrome Myopathic Type, Scarring Bullosa, Renal Dysplasia-Retinal Aplasia Loken-Senior Type, Renal SCHAD, Schaumann's Disease, Scheie Syndrome, Schere Glycosuria, Renal Glycosuria Type A, Renal Glycosuria Type shevkii-Turner Syndrome, Schilder Disease, Schilder B. Renal Glycosuria Type O, Renal-Oculocerebrodystrophy, Encephalitis, Schilder's Disease, Schindler Disease Type I Renal-Retinal Dysplasia with Medullary Cystic Disease, (Infantile Onset), Schindler Disease Infantile Onset, Schin Renal-Retinal Dystrophy Familial, Renal-Retinal Syndrome, dler Disease, Schindler DiseaseType II (Adult Onset), Schin Rendu-Osler-Weber Syndrome, Respiratory Acidosis, Respi Zel Syndrome, Schinzel-Giedion Syndrome, Schinzel Acro ratory Chain Disorders, Respiratory Myoclonus, Restless callosal Syndrome, Schinzel-Giedion Midface-Retraction Legs Syndrome, Restrictive Cardiomyopathy, Retention Syndrome, Schizencephaly, Schmid Type Metaphyseal Hyperlipemia, Rethore Syndrome (obsolete), Reticular Dys Chondrodysplasia, Schmid Metaphyseal Dysostosis, genesis, Retinal Aplastic-Cystic Kidneys-Joubert Syndrome, Schmid-Fraccaro Syndrome, Schmidt Syndrome, Schopf Retinal Cone Degeneration, Retinal Cone Dystrophy, Retinal Schultz-Passarge Syndrome, Schueller-Christian Disease, Cone-Rod Dystrophy, Retinitis Pigmentosa, Retinitis Pig Schut-Haymaker Type, Schwartz-Jampel-Aberfeld Syn mentosa and Congenital Deafness, Retinoblastoma, Retinol drome, Schwartz-Jampel Syndrome Types 1A and 1B, Deficiency, Retinoschisis, Retinoschisis Juvenile, Retraction Schwartz-Jampel Syndrome Type 2, SCID, Scleroderma, Syndrome, Retrobulbar Neuropathy, Retrolenticular Syn Sclerosis Familial Progressive Systemic, Sclerosis Diffuse drome, Rett Syndrome, Reverse Coarction, Reye's Syn Familial Brain, Scott Cranio-digital Syndrome With Mental drome, RGS, Rh Blood Factors, Rh Disease, Rh Factor Retardation, Scrotal Tongue, SCS, SD, SDS, SDYS, Seasonal Incompatibility, Rh Incompatibility, Rhesus Incompatibility, Conjunctivitis, Sebaceous Nevus Syndrome, Sebaceous Rheumatic Fever, Rheumatoid Arthritis, Rheumatoid Myosi nevus, Seborrheic Keratosis, Seborrheic Warts, Seckel Syn tis, Rhinosinusogenic Cerebral Arachnoiditis, Rhizomelic drome, Seckel Type Dwarfism, Second Degree Congenital Chondrodysplasia Punctata (RCDP), Acatalasemia, Classical Heart Block, Secondary Amyloidosis, Secondary Ble Refsum Disease, RHS, Rhythmical Myoclonus, Rib Gap pharospasm, Secondary Non-tropical Sprue, Secondary Defects with Micrognathia, Ribbing Disease (obsolete), Rib Brown Syndrome, Secondary Beriberi, Secondary General bing Disease, Richner-Hanhart Syndrome, Rieger Syndrome, ized Amyloidosis, Secondary Dystonia, Secretory Compo Rieter's Syndrome, Right Ventricular Fibrosis, Riley-Day nent Deficiency, Secretory IgA Deficiency, SED Tarda, SED Syndrome, Riley-Smith Syndrome, Ring Chromosome 14, Congenital, SEDC, Segmental Linear Achromic Nevus, Seg Ring Chromosome 18, Ring 4. Ring 4 Chromosome, Ring 6. mental Dystonia, Segmental Myoclonus, Seip Syndrome, Ring 6 Chromosome, Ring 9, Ring 9 Chromosome Ro, Ring Seitelberger Disease, Seizures, Selective Deficiency of IgG 14, Ring 15, Ring 15 Chromosome (mosaic pattern), Ring 18, Sub-classes, Selective Mutism, Selective Deficiency of IgG Ring Chromosome 18, Ring 21, Ring 21 Chromosome, Ring Sub-class, Selective IgM Deficiency, Selective Mutism, 22, Ring 22 Chromosome, Ritter Disease, Ritter-Lyell Syn Selective IgA Deficiency, Self-Healing Histiocytosis, Semi drome, RLS, RMSS, Roberts SC-Phocomelia Syndrome, lobar Holoprosencephaly, Seminiferous Tubule Dysgenesis, Roberts Syndrome, Roberts Tetraphocomelia Syndrome, Senile Retinoschisis, Senile Warts, Senior-Loken Syndrome, Robertson's Ectodermial Dysplasias, Robin Anomalad, Sensory Neuropathy Hereditary Type I, Sensory Neuropathy Robin Sequence, Robin Syndrome, Robinow Dwarfism, Hereditary Type II, Sensory Radicular Neuropathy, Sensory Robinow Syndrome, Robinow Syndrome Dominant Form, Radicular Neuropathy Recessive Sepsis, Septic Progressive Robinow Syndrome Recessive Form, Rod Myopathy, Roger Granulomatosis, Septo-Optic Dysplasia, Serous Circum Disease, Rokitansky's Disease, Romano-Ward Syndrome, scribed Meningitis, Serum Protease Inhibitor Deficiency, Romberg Syndrome, Rootless Teeth, Rosenberg-Chutorian Serum Carnosinase Deficiency, Setleis Syndrome, Severe Syndrome, Rosewater Syndrome, Rosselli-Gulienatti Syn Combined Immunodeficiency. Severe Combined Immunode drome, Rothmund-Thonison Syndrome, Roussy-Levy Syn ficiency with Adenosine Deaminase Deficiency, Severe Com drome, RP, RSX-Linked, RS, RSDS, RSH Syndrome, RSS, bined Immunodeficiency (SCID), Sex Reversal, Sexual RSTS, RTS, Rubella Congenital, Rubinstein Syndrome, Infantilism, SGB Syndrome. Sheehan Syndrome, Shields Rubinstein-Taybi Syndrome, Rubinstein Taybi Broad Type Dentinogenesis Imperfecta, Shingles, Varicella-Zoster Thumb-Hallux Syndrome, Rufous Albinism, Ruhr's Syn Virus, Ship Beriberi, SHORT Syndrome, Short Arm 18 Dele drome, Russell's Diencephalic Cachexia, Russell's Syn tion Syndrome, Short Chain Acyl CoA Dehydrogenase Defi drome, Russell-Silver Dwarfism, Russell-Silver Syndrome, ciency, Short Chain Acyl-CoA Dehydrogenase (SCAD) Defi Russell-Silver Syndrome X-linked, Ruvalcaba-Myhre-Smith ciency, Short Stature and Facial Telangiectasis, Short Stature syndrome (RMSS), Ruvalcaba Syndrome, Ruvalcaba Type Facial/Skeletal Anomalies-Retardation-Macrodontia, Short Osseous Dysplasia with Mental Retardation, Sacral Regres Stature-Hyperextensibility-Rieger Anomaly-Teething Delay, US 2009/0215895 A1 Aug. 27, 2009

Short Stature-Onychodysplasia, Short Stature Telangiectatic Spondyloepiphyseal Dysplasia Tarda, Spondylothoracic Erythema of the Face, SHORT Syndrome, Shoshin Beriberi, Dysplasia, Spondylotic Caudal Radiculopathy, Sponge Kid Shoulder Girdle Syndrome, Shprintzen-Goldberg Syndrome, ney, Spongioblastoma Multiforme, Spontaneous Hypoglyce Shulman Syndrome, Shwachman-Bodian Syndrome, mia, Sprengel Deformity, Spring Ophthalmia, SRS, ST, Stale Shwachman-Diamond Syndrome, Shwachman Syndrome, Fish Syndrome, Staphyloccal Scalded Skin Syndrome, Star Shwachman-Diamond-Oski Syndrome, Shy Drager Syn gardt's Disease, Startle Disease, Status Epilepticus, Steele drome, Shy-Magee Syndrome, SI Deficiency, Sialidase Defi Richardson-Olszewski Syndrome, Steely Hair Disease, ciency, Sialidosis Type IJuvenile, Sialidosis Type II Infantile, Stein-Leventhal Syndrome, Steinert Disease, Stengel's Syn Sialidosis, Sialolipidosis, Sick Sinus Syndrome, Sickle Cell drome, Stengel-Batten-Mayou-Spielmeyer-Vogt-Stock Dis Anemia, Sickle Cell Disease, Sickle Cell-Hemoglobin C Dis ease, Stenosing Cholangitis, Stenosis of the Lumbar Vertebral ease, Sickle Cell-Hemoglobin D Disease, Sickle Cell-Thalas Canal, Stenosis, Steroid Sulfatase Deficiency, Stevanovic's semia Disease, Sickle Cell Trait, Sideroblastic Anemias, Sid Ectodermal Dysplasias, Stevens Johnson Syndrome, STGD, eroblastic Anemia, Sideroblastosis, SIDS, Siegel-Cattan Stickler Syndrome, Stiff-Man Syndrome, Stiff Person Syn Mamou Syndrome, Siemens-Bloch Type Pigmented drome, Still's Disease, Stilling-Turk-Duane Syndrome, Stil Dermatosis, Siemens Syndrome, Siewerling-Creutzfeldt lis Disease, Stimulus-Sensitive Myoclonus, Stone Man Syn Disease, Siewert Syndrome, Silver Syndrome, Silver-Russell drome, Stone Man, Streeter Anomaly, Striatonigral Dwarfism, Silver-Russell Syndrome, Simmond's Disease, Degeneration Autosomal Dominant Type, Striopallidoden Simons Syndrome, Simplex Epidermolysis Bullosa, Simp tate Calcinosis, Stroma, Descemet's Membrane, Stromal son Dysmorphia Syndrome, Simpson-Golabi-Behmel Syn Corneal Dystrophy, Struma Lymphomatosa, Sturge-Kalis drome, Sinding-Larsen-Johansson Disease, Singleton cher-Weber Syndrome, Sturge Weber Syndrome, Sturge-We Merten Syndrome, Sinus Arrhythmia, Sinus Venosus, Sinus ber Phakomatosis, Sub-acute Necrotizing Encephalomyel Tachycardia, Sirenomelia Sequence, Sirenomelus, Situs opathy, Sub-acute Spongiform Encephalopathy, Sub-acute Inversus Bronchiectasis and Sinusitis, SJA Syndrome, Necrotizing Encephalopathy, Sub-acute Sarcoidosis, Sub Sjogren Larsson Syndrome Ichthyosis, Sjogren Syndrome, acute Neuronopathic, Sub-aortic Stenosis, Subcortical Arte Sjögren's Syndrome, SJS, Skeletal Dysplasia, Skeletal Dys riosclerotic Encephalopathy, Subendocardial Sclerosis, Suc plasia Weismann Netter Stuhl Type, Skin Peeling Syndrome, cinylcholine Sensitivity, Sucrase-Isomaltase Deficiency Skin Neoplasms, Skull Asymmetry and Mild Retardation, Congenital. Sucrose-Isomaltose Malabsorption Congenital, Skull Asymmetry and Mild Syndactyly, SLE, Sleep Epilepsy, Sucrose Intolerance Congenital, Sudanophilic Leukodystro Sleep Apnea, SLO, Sly Syndrome, SMA, SMA Infantile phy ADL, Sudanophilic Leukodystrophy Pelizaeus-Merz Acute Form, SMA I, SMA III, SMA Type I, SMA Type II, bacher Type, Sudanophilic Leukodystrophy Included, Sud SMA Type III, SMA3, SMAX1; SMCR, Smith Lemli Opitz den Infant Death Syndrome, Sudeck's Atrophy, Sugio-Kajii Syndrome, Smith Magenis Syndrome, Smith-Magenis Chro Syndrome, Summerskill Syndrome, Summit Acrocephalo mosome Region, Smith-McCort Dwarfism, Smith-Opitz-In Syndactyly, Summitt's Acrocephalosyndactyly, Summitt born Syndrome, Smith Disease, Smoldering Myeloma, SMS, Syndrome, Superior Oblique Tendon Sheath Syndrome, SNE, Sneezing From Light Exposure, Sodium Valproate, Suprarenal Glands, Supravalvular Aortic Stenosis, Supraven Solitary Plasmacytoma of Bone, Sorsby Disease, Sotos Syn tricular Tachycardia, Surdicardiac Syndrome, Surdocardiac drome, Souques-Charcot Syndrome, South African Genetic Syndrome, SVT Sweat Gland Abscess, Sweating Gustatory Porphyria, Spasmodic Dysphonia, Spasmodic Torticollis, Syndrome, Sweet Syndrome, Swiss Cheese Cartilage Syn Spasmodic Wryneck, Spastic Cerebral Palsy, Spastic Colon, drome, Syndactylic Oxycephaly, Syndactyly Type I with Spastic Dysphonia, Spastic Paraplegia, SPD Calcinosis, Spe Microcephaly and Mental Retardation, Syndromatic Hepatic cific Antibody Deficiency with Normal Immunoglobulins, Ductular Hypoplasia, Syringomyelia, Systemic Aleukemic Specific Reading Disability, SPH2, Spherocytic Anemia, Reticuloendotheliosis, Systemic Amyloidosis, Systemic Car Spherocytosis, Spherophakia-Brachymorphia Syndrome, nitine Deficiency, Systemic Elastorrhexis, Systemic Lupus Sphingomyelin Lipidosis, Sphingomyelinase Deficiency, Erythematosus, Systemic Mast Cell Disease, Systemic Mas Spider Fingers, Spielmeyer-Vogt Disease, Spielmeyer-Vogt tocytosis, Systemic-Onset Juvenile Arthritis, Systemic Scle Batten Syndrome, Spina Bifida, Spina Bifida Aperta, Spinal rosis, Systopic Spleen, T-Lymphocyte Deficiency, Tachyali Arachnoiditis, Spinal Arteriovenous Malformation, Spinal mentation Hypoglycemia, Tachycardia, Takahara Syndrome, Ataxia Hereditofanilial, Spinal and Bulbar Muscular Atro Takayasu Disease, Takayasu Arteritis, Talipes Calcaneus, phy, Spinal Diffuse Idiopathic Skeletal Hyperostosis, Spinal Talipes Equinovarus, Talipes Equinus, Talipes Varus, Talipes DISH, Spinal Muscular Atrophy, Spinal Muscular Atrophy Valgus, Tandem Spinal Stenosis, Tangier Disease, Tapetoreti All Types, Spinal Muscular Atrophy Type ALS, Spinal Mus nal Degeneration, TARSyndrome, Tardive Dystonia, Tardive cular Atrophy-Hypertrophy of the Calves, Spinal Muscular Muscular Dystrophy, Tardive Dyskinesia, Tardive Oral Dys Atrophy Type I, Spinal Muscular Atrophy Type III, Spinal kinesia, Tardive Dystonia, Tardy Ulnar Palsy, Target Cell Muscular Atrophy-Hypertrophy of the Calves, Spinal Ossi Anemia, Tarsomegaly, Tarui Disease, TAS Midline Defects fying Arachnoiditis, Spinal Stenosis, Spinocerebellar Ataxia, Included, TAS Midline Defect, Tay Sachs Sphingolipidosis, Spinocerebellar Atrophy Type I, Spiuocerebellar Ataxia Type Tay Sachs Disease, Tay Syndrome Ichthyosis, Tay Sachs I (SCA1), Spinocerebellar Ataxia Type II (SCAII), Spinocer Sphingolipidosis, Tay Syndrome Ichthyosis, Taybi Syndrome ebellar Ataxia Type III (SCAIII), Spinocerebellar Ataxia Type I, Taybi Syndrome, TCD, TCOF1, TCS, TD, TDOSyn Type IV (SCAIV), Spinocerebellar Ataxia Type V (SCAV), drome, TDO-I. TDO-II, TDO-III, Telangiectasis, Telecan Spinocerebellar Ataxia Type VI (SCAVI), Spinocerebellar thus with Associated Abnormalities, Telecanthus-Hypospa Ataxia Type VII (SCAVII), Spirochetal Jaundice, Splenic dias Syndrome, Temporal Lobe Epilepsy, Temporal Arteritis/ Agenesis Syndrome, Splenic Ptosis, Splenoptosis, Split Hand Giant Cell Arteritis, Temporal Arteritis, TEN, Tendon Sheath Deformity-Mandibulofacial Dysostosis, Split Hand Defor Adherence Superior Obliqu, Tension Myalgia, Terminal mity, Spondyloarthritis, Spondylocostal Dysplasia-Type I. Deletion of 4q Included, Terrian Corneal Dystrophy, US 2009/0215895 A1 Aug. 27, 2009 32

Teschler-Nicola/Killian Syndrome, Tethered Spinal Cord ciency, TS, TTP, TTTS, Tuberous Sclerosis, Tubular Ectasia, Syndrome, Tethered Cord Malformation Sequence, Tethered Turcot Syndrome, Turner Syndrome, Turner-Kieser Syn Cord Syndrome, Tethered Cervical. Spinal Cord Syndrome, drome, Turner Phenotype with Normal Chromosomes Tetrahydrobiopterin Deficiencies, Tetrahydrobiopterin Defi (Karyotype), Turner-Varny Syndrome, Turricephaly, Twin ciencies, Tetralogy of Fallot, Tetraphocomelia-Thrombocy Twin Transfusion Syndrome, Twin-to-Twin Transfusion Syn topenia Syndrome, Tetrasomy Short Arm of Chromosome 9, drome, Type A, Type B, Type AB, Type O, Type I Diabetes, Tetrasomy 9p, Tetrasomy Short Arm of Chromosome 18, Type I Familial Incomplete Male, Type I Familial Incomplete Thalamic Syndrome, Thalamic Pain Syndrome, Thalamic Male Pseudohermaphroditism, Type I Gaucher Disease, Type Hyperesthetic Anesthesia, Thalassemia Intermedia, Thalas I (PCCA Deficiency). Type I Tyrosinemia, Type II Gaucher semia Minor, Thalassemia Major. Thiamine Deficiency, Disease, Type II Histiocytosis, Type II (PCCB Deficiency), Thiamine-Responsive Maple Syrup Urine Disease. Thin Type II Tyrosinnemia, Type IIA Distal Arthrogryposis Mul Basement-Membrane Nephropathy, Thiolase Deficiency, tiplex Congenita, Type III Gaucher Disease, Type III RCDP. Acyl-CoA Dihydroxyacetonephosphate Acyltrans Tyrosinemia, Type III Dentinogenesis Imperfecta, Typical ferase. Third and Fourth Pharyngeal Pouch Syndrome. Third Retinoschisis, Tyrosinase Negative Albinism (Type I), Tyro Degree Congenital (Complete) Heart Block, Thomsen Dis sinase Positive Albinism (Type II), Tyrosinemia Type I Acute ease, Thoracic-Pelvic-Phalangeal Dystrophy, Thoracic Spi Form, Tyrosinemia Type I Chronic Form, Tyrosinosis, UCE, nal Canal, Thoracoabdominal Syndrome, Thoracoabdominal Ulcerative Colitis, Ulcerative Colitis Chronic Non-Specific, Ectopia Cordis Syndrome. Three M Syndrome, Three-M Ulnar-Mammary Syndrome, Ulnar-Mammary Syndrome of Slender-Boned Nanism, Thrombasthenia of Glanzmann and Pallister, Ulnar Nerve Palsy, UMS, Unclassified FODs, Naegeli. Thrombocythemia Essential, Thrombocytopenia Unconjugated Benign Bilirubinemiav. Underactivity of Par Absent Radius Syndrome, Thrombocytopenia-Hemangioma athyroid, Unilateral Ichthyosiform Erythroderma with Ipsi Syndrome, Thrombocytopenia-Absent Radii Syndrome, lateral Malformations Limb, Unilateral Chondromatosis, Thrombophilia Hereditary Due to ATIII, Thrombotic Throm Unilateral Defect of Pectoralis Muscle and Syndactyly of the bocytopenic Purpura, Thromboulcerative Colitis, Thymic Hand, Unilateral Hemidysplasia Type, Unilateral Megalen Dysplasia with Normal Immunoglobulins, Thymic Agenesis, cephaly, Unilateral Partial Lipodystrophy, Unilateral Renal Thymic Aplasia DiGeorge Type, Thymic Hypoplasia A Agenesis, Unstable Colon, Unverricht Disease. Unverricht y-globulinemias Primary Included, Thymic Hypoplasia Lundborg Disease, Unverricht-Lundborg-Laf Disease, DiGeorge Type, Thymus Congenital Aplasia, Tic Dou Unverricht Syndrome, Upper Limb-Cardiovascular Syn loureux, Tics, Tinel’s Syndrome, Tolosa Hunt Syndrome, drome (Holt-Oram), Upper Motor Neuron Disease, Upper Tonic Spasmodic Torticollis, Tonic Pupil Syndrome, Tooth Airway Apnea, Urea Cycle Defects or Disorders, Urea Cycle and Nail Syndrome, Torch Infection, TORCH Syndrome, Disorder Arginase Type, Urea Cycle Disorder Arginino Suc Torsion Dystonia, Torticollis, Total Lipodystrophy, Total cinaseType, Urea Cycle Disorders Carbamyl Phosphate Syn Anomalous Pulmonary Venous Connection, Touraine's Aph thetase Type, Urea Cycle Disorder Citrullinemia Type, Urea thosis, Tourette Syndrome, Tourette's Disorder, Townes Cycle Disorders N-Acrtyl Glutamate Synthetase Typ, Urea Brocks Syndrome, Townes Syndrome, Toxic Paralytic Ane Cycle Disorder OTC Type, Urethral Syndrome, Urethro mia, Toxic Epidermal Necrolysis, Toxopachyosteose Oculo-Articular Syndrome, Uridine Diphosphate Glucu Diaphysaire Tibio-Peroniere, Toxopachyosteose, Toxoplas ronosyltransferase Severe Def. Type I, Urinary Tract Defects, mosis. Other Agents Rubella Cytomegalovirus Herpes Sim Urofacial Syndrome, Uroporphyrinogen III cosynthase, Urti plex, Tracheoesophageal Fistula with or without Esophageal caria pigmentosa, Usher Syndrome, Usher Type I, Usher Atresia, Tracheoesophageal Fistula, Transient Neonatal Type II, Usher Type III, Usher Type IV. Uterine Synechiae, Myasthenia Gravis, Transitional Atrioventricular Septal Uoporphyrinogen I-synthase, Uveitis, Uveomeningitis Syn Defect, Transposition of the Great Arteries, Transtelephonic drome, V-CJD, VACTEL Association, VACTERL Associa Monitoring, Transthyretin Methionine-30 Amyloidosis tion, VACTERL Syndrome, Valgus Calcaneus, Valine Tran (Type I), Trapezoidocephaly-Multiple Synostosis Syndrome, saminase Deficiency, Valinemia, Valproic Acid, Valproate Treacher Collins Syndrome, Treacher Collins-Franceschetti Acid exposure, Valproic Acid exposure, Valproic acid, Van Syndrome 1, Trevor Disease, Triatrial Heart, Tricho-Dento Buren's Disease, Van der Hoeve-Habertsma-Waardenburg Osseous Syndrome, Trichopoliodystrophy, Trichorhinopha Gauldi Syndrome, Variable Onset Immunoglobulin Defi langeal Syndrome, Tricuspid atresia, Trifunctional Protein ciency Dys Y-globulinemia, Variant Creutzfeldt-Jakob Dis Deficiency, Trigeminal Neuralgia, Triglyceride Storage Dis ease (V-CJD), Varicella Embryopathy, Variegate Porphyria, ease Impaired Long-Chain Fatty Acid Oxidation, Trigonitis, Vascular Birthmarks, Vascular Dementia Binswanger's Type, Trigonocephaly, Trigonocephaly Syndrome, Trigonocephaly Vascular Erectile Tumor, Vascular Hemophilia, Vascular “C” Syndrome, Trimethylaminuria, Triphalangeal Thumbs Malformations, Vascular Malformations of the Brain, Vascu Hypoplastic Distal Phalanges-Onychodystrophy, Tripha litis, Vasomotor Ataxia, Vasopressin-Resistant Diabetes langeal Thumb Syndrome, Triple Symptom Complex of Beh Insipidus, Vasopressin-Sensitive Diabetes Insipidus, VATER cet, Triple X Syndrome, Triplo X Syndrome, Triploid Association, Vcf Syndrome, Vcfs, Velo Cardio Facial Syn Syndrome, Triploidy, Triploidy Syndrome, Trismus drome, VeloCardioFacial Syndrome, Venereal Arthritis, Pseudocamptodactyly Syndrome, Trisomy, Trisomy G Syn Venous Malformations, Ventricular Fibrillation, Ventricular drome, Trisomy X, Trisomy 6q Partial, Trisomy 6q Syndrome Septal Defects, Congenital Ventricular Defects, Ventricular Partial, Trisomy 9 Mosaic, Trisomy 9P Syndrome (Partial) Septal Defect, Ventricular Tachycardia, Venual Malforma Included, Trisomy 11q Partial, Trisomy 14 Mosaic, Trisomy tions, VEOHD, Vermis Aplasia, Vermis Cerebellar Agenesis, 14 Mosaicism Syndrome, Trisomy 21 Syndrome, Trisomy 22 Vernal Keratoconjunctivitis, Verruca, Vertebral Anal Trache Mosaic, Trisomy 22 Mosaicism Syndrome, TRPS, TRPS1, oesophageal Esophageal Radial, Vertebral Ankylosing TRPS2, TRPS3, True Hermaphroditism, Truncus arteriosus, Hyperostosis, Very Early Onset Huntington's Disease, Very Tryptophan Malabsorption, Tryptophan Pyrrolase Defi Long Chain Acyl-CoA Dehydrogenase (VLCAD) Defi US 2009/0215895 A1 Aug. 27, 2009

ciency, Vestibular Schwannoma, Vestibular Schwannoma leukodystrophy (X-ALD), X-linked Adult Onset Spinobulbar Neurofibromatosis, Vestibulocerebellar, Virchow's Oxyceph Muscular Atrophy, X-linked Adult Spinal Muscular Atrophy, aly, Visceral Xanthogranulomatosis, Visceral Xantho-Granu X-Linked A Y-globulinemia with Growth Hormone Defi lomatosis, Visceral Myopathy-External Ophthalmoplegia, ciency, X-Linked A Y-globulinemia, Lymphoproliferate Visceromegaly-Umbilical Hernia-Macroglossia Syndrome, X-Linked Syndrome, X-linked Cardiomyopathy and Neutro Visual Amnesia, Vitamin A Deficiency, Vitamin B-1 Defi penia, X-Linked Centronuclear Myopathy, X-linked Copper ciency, Vitelline Macular Dystrophy, Vitiligo, Vitiligo Capi Deficiency, X-linked Copper Malabsorption, X-Linked tis, Vitreoretinal Dystrophy, VKC, VKHSyndrome, VLCAD, Dominant Conradi-Hunermann Syndrome, X-Linked Domi Vogt Syndrome, Vogt CephaloSyndactyly, Vogt Koyanagi nant Inheritance Agenesis of Corpus Callosum, X-Linked Harada Syndrome, Von Bechterew-Strumpell Syndrome, Von Dystonia-Parkinsonism, X Linked Ichthyosis, X-Linked Eulenburg Paramyotonia Congenita, Von Frey's Syndrome, Infantile A Y-globulinemia, X-Linked Infantile Nectrotizing Encephalopathy, X-linked Juvenile Retinoschisis, X-linked Von Gierke Disease, Von Hippel-Lindau Syndrome, Von Lissencephaly, X-linked Lymphoproliferative Syndrome, Mikulicz. Syndrome, Von Recklinghausen Disease, Von Will X-linked Mental Retardation-Clasped Thumb Syndrome, ebrandt Disease, VP. Vrolik Disease (Type II), VSD. Vulgaris X-Linked Mental Retardation with Hypotonia, X-linked Type Disorder of Cornification, Vulgaris Type Ichthyosis, W Mental Retardation and Macroorchidism, X-Linked Progres Syndrome, Waardenburg Syndrome, Waardenburg-Klein sive Combined Variable Immunodeficiency, X-Linked Syndrome, Waardenburg Syndrome Type I (WS1), Waarden Recessive Conradi-Hunermann Syndrome, X-Linked Reces burg Syndrome Type II (WS2), Waardenburg Syndrome Type sive Severe Combined Immunodeficiency, X-Linked Retin IIA (WS2A), Waardenburg Syndrome Type IIB (WS2B), oschisis, X-linked Spondyloepiphyseal Dysplasia, Xanthine Waardenburg Syndrome Type III (WS3), Waardenburg Syn Oxidase Deficiency (Xanthinuria Deficiency, Hereditary), drome Type IV (WS4), Waelsch's Syndrome, WAGR Com Xanthinuria Deficiency, Hereditary (Xanthine Oxidase Defi plex, WAGR Syndrome, Waldenstroem's Macroglobuline ciency), Xanthogranulomatosis Generalized, Xanthoma mia, Waldenstrom's Purpura, Waldenstrom's Syndrome, Tuberosum, Xeroderma Pigmentosum, Xeroderma Pigmen Waldmann Disease, Walker-Warburg Syndrome, Wandering tosum Dominant Type, Xeroderma Pigmentosum Type A I Spleen, Warburg Syndrome, Warm Antibody Hemolytic Ane XPA Classical Form, Xeroderma Pigmentosum Type B II mia, Warm Reacting Antibody Disease, Wartenberg Syn XPB, Xeroderma Pigmentosum Type E V XPE, Xeroderma drome, WAS. Water on the Brain, Watson Syndrome, Watson Pigmentosum Type C III XPC, Xeroderma Pigmentosum Alagille Syndrome, Waterhouse-Friderichsen Syndrome, Type D IV XPD, Xeroderma Pigmentosum Type F VI XPF, Waxy Disease, WBS, Weaver Syndrome, Weaver-Smith Syn Xeroderma Pigmentosum Type G VII XPG, Xeroderma Pig drome, Weber-Cockayne Disease, Wegener's Granulomato mentosum Variant Type XP-V. Xeroderma-Talipes- and sis, Weil Disease, Weil Syndrome, Weill-Marchesani, Weill Enamel Defect, Xerodermic Idiocy, Xerophthalmia, Xerotic Marchesani Syndrome, Weill-Reyes Syndrome, Weismann Keratitis, XLP, XO Syndrome, XP, XX Male Syndrome, Sex Netter-Stuhl Syndrome, Weissenbacher-Zweymuller Reversal, XXXXX Syndrome, XXY Syndrome, XYY Syn Syndrome, Wells Syndrome, Wenckebach, Werdnig-Hoff drome, XYY Chromosome Pattern, Yellow Mutant Albinism, man Disease, Werdnig-Hoffman Paralysis, Werlhof's Dis Yellow Nail Syndrome, YKLYoung Female Arteritis, Yunis ease, Werner Syndrome, Wernicke's (C) I Syndrome, Wer Varon Syndrome, YY Syndrome, Z-E Syndrome, Z- and nicke's Aphasia, Wernicke-Korsakoff Syndrome, West -Protease Inhibitor Deficiency, Zellweger Syndrome, Zell Syndrome, Wet Beriberi, WHCR, Whipple's Disease, Whis weger Cerebro-Hepato-Renal Syndrome, ZES, Ziehen-Op tling Face Syndrome. Whistling Face-Windmill Vane Hand penheim Disease (Torsion Dystonia), Zimmermann-Laband Syndrome, White-Darier Disease, Whitnall-Norman Syn Syndrome, Zinc Deficiency Congenital, Zinsser-Cole-Eng drome, Whorled Nevoid Hypermelanosis, WHS, Wieacker man Syndrome, ZLS, and/or Zollinger-Ellison Syndrome. Syndrome, Wieacher Syndrome, Wieacker-Wolff Syndrome, Wiedmann-Beckwith Syndrome, Wiedemann-Rautenstrauch 0109. It is to be understood that unless otherwise indi Syndrome, Wildervanck Syndrome, Willebrand-Juergens cated, the Subject invention is not limited to specific formu Disease, Willi-Prader Syndrome, Williams Syndrome, Will lations of components, manufacturing methods, dosage regi iams-Beuren Syndrome, Wilms Tumor, Wilms Tumor mens or the like, as such may vary. It is also to be understood Aniridia-Gonadoblastoma-Mental Retardation Syndrome, that the terminology used herein is for the purpose of describ Wilms Tumor Aniridia Gonadoblastoma Mental Retardation, ing particular embodiments only and is not intended to be Wilms Tumor-Aniridia-Genitourinary Anomalies-Mental limiting. Retardation Syndrome, Wilms Tumor-Pseudohermaphrodit 0110. The singular forms “a”, “an and “the include plu ism-Nephropathy, Wilms Tumor and Pseudohermaphrodit ral aspects unless the context clearly dictates otherwise. Thus, ism, Wilms Tumor-Pseudohermaphroditism-Glomerulopa for example, reference to a PUFA includes reference to a thy, Wilson's Disease, Winchester Syndrome, Winchester single PUFA as well as two or more PUFAs or families of Grossman Syndrome, Wiskott-Aldrich Syndrome, Wiskott PUFAs, an agent includes a single agent, as well as two or Aldrich Type Immunodeficiency. Witkop Ectodermal more agents. Dysplasias. Witkop Tooth-Nail Syndrome. Wittmaack-Ek 0111. In describing and claiming the present invention, the bom Syndrome, WMSyndrome, WMS, WNS, Wohlfart-Dis following terminology is used in accordance with the defini ease, Wohlfart-Kugelberg-Welander Disease, Wolf Syn tions set forth below. drome, Wolf-Hirschhorn Chromosome Region (WHCR), 0112 The terms “compound”, “active agent”, “chemical Wolf-Hirschhorn Syndrome, Wolff-Parkinson-White Syn agent”, “pharmacologically active agent”, “medicament'. drome, Wolfram Syndrome, Wolman Disease (Lysomal Acid “active' and "drug” are used interchangeably herein to refer Lypase Deficiency), Woody Guthrie's Disease, WPW Syn to a chemical compound that induces a desired pharmacologi drome, Writer's Cramp, WS, WSS, WWS, Wyburn-Mason cal and/or physiological effect. All Such terms also cover Syndrome, X-Linked Addison's Disease, X-linked Adreno naturally occurring PUFAs and derivatives or modified forms US 2009/0215895 A1 Aug. 27, 2009 34 thereof. The terms also encompass pharmaceutically accept tible individual as well as treatment of a clinically symptom able and pharmacologically active ingredients of those active atic individual by ameliorating the symptoms of the condi agents specifically mentioned herein including but not lim tion. ited to salts, esters, amides, prodrugs, active metabolites, I0120 A“subject' as used herein refers to an animal, pref analogs and the like. When the terms “compound”, “active erably a mammal and more preferably a human who can agent”, “chemical agent’ “pharmacologically active agent'. benefit from the pharmaceutical formulations and methods of “medicament”, “active' and “drug” are used, then it is to be the present invention. There is no limitation on the type of understood that this includes the active agent perse as well as animal that could benefit from the presently described phar pharmaceutically acceptable, pharmacologically active salts, maceutical formulations and methods. A subject regardless of esters, amides, prodrugs, metabolites, analogs, etc. whether a human or non-human animal may be referred to as 0113 Reference to a “compound”, “active agent'. an individual, patient, animal, host or recipient. The com “chemical agent”99 “pharmacologically&g active agent”, “medi pounds and methods of the present invention have applica cament”, “active' or “drug includes combinations of two or tions in human medicine, Veterinary medicine as well as in more actives such as two or more PUFAs or families of general, domestic or wild animal husbandry. Non-human ani PUFAs. A “combination' also includes multi-part such as a mals contemplated herein include livestock animals (e.g. two-part composition where the agents are provided sepa sheep, pigs, cows, horses, donkeys), laboratory test animals rately and given or dispensed separately or admixed together (e.g. mice, rabbits, rats, guinea pigs), companion animals prior to dispensation. For example, a multi-part pharmaceu (e.g. dogs, cats) and captive wild animals. tical pack may have two or more agents separately main I0121 The term “animals” include avian species such as tained. poultry birds (e.g. chickens, ducks, turkeys, geese) and wild 0114. The term “combination' in addition, encompasses and game birds (e.g. wild ducks, pheasants, emus) and aviary multivalent PUFAs such as two or more PUFAs linked via birds. chemical bond formation. 0.122 The present invention is further described by the 0115. In addition, the PUFAs may be co-administered following non-limiting Examples. with a range of other therapeutic agents including pain reliev erS Such as opiates, preferably morphine, buprenorphine, EXAMPLE 1. levomethadone, codeine, tramadol or tilidine, non-sterioidal analgesics, for example, acetylsalicylic acid, paracetamol. Chemical Engineering of Fats diclofenac, meloxicam, ibuprofen, ibuprofen lysinate, ibu profen in extruded form (as described in WO 99/06038), I0123 Compounds were generated by the method gabapentine or anti-depressants, preferably imipramine, described in WO 96/11908, WO 96/13507, WO 97/38688, maprotiline, mianserine, fluoxetine, Viloxazine, tranyl WO 01/21 172 and WO 01/21575 and are designated MP cypromine and/or moclobemide. series, PT series and MP-PT hybrids. Molecules of the MP 0116. The terms “effective amount” and “therapeutically series possess the property of increased stability to oxidative effective amount of an agent as used herein meana Sufficient breakdown. This reduced susceptibility to breakdown means amount of the agent (e.g. an agent Such as a PUFA or a that they are far less likely to cause the production of oxygen derivative thereof) to provide the desired therapeutic orphysi radicals which is the consequence of the metabolism of the ological effect or outcome. Undesirable effects, e.g. side natural omega-3 fatty acids. Molecules of the PT series also effects, are sometimes manifested along with the desired have this property but in addition are more soluble. The therapeutic effect; hence, a practitioner balances the potential hybrid MP-PT series possess the above properties and dem benefits against the potential risks in determining what is an onstrate an expected outcome of higher antiinflammatory appropriate “effective amount. The exact amount required activity. will vary from Subject to Subject, depending on the species, 0.124. The structure of a natural fish oil fatty acid, ecosa age and general condition of the Subject, mode of adminis pentaenoic acid, is shown in structure (a). The features of tration and the like. Thus, it may not be possible to specify an these types offatty acids is a long carbon chain, unsaturation exact “effective amount'. However, an appropriate “effective (double bonds) and a carboxyl group (acid group) at one end amount in any individual case may be determined by one of of the chain. ordinary skill in the art using only routine experimentation. 0117. By “pharmaceutically acceptable' carrier, excipient or diluent is meant a pharmaceutical vehicle comprised of a (a) material that is not biologically or otherwise undesirable, i.e. the material may be administered to a subject along with the selected active agent without causing any or a substantial O adverse reaction. Carriers may include excipients and other Fish oil fatty acid additives such as diluents, detergents, coloring agents, wet ting or emulsifying agents, pH buffering agents, preserva 0.125. The chemical engineering takes the form of inter tives, and the like. alia Substituting an oxygen atom (or Sulphur) for the carbon, 0118 Similarly, a “pharmacologically acceptable' salt, second from the carboxyl group end (b). This is called the ester, emide, prodrug or derivative of a compound as provided B-position. It is this area on the molecule to which the enzyme herein is a salt, ester, amide, prodrug orderivative that this not involved in the metabolism of the fats binds. Due to this biologically or otherwise undesirable. change, the enzyme cannot act on this group as efficiently as 0119 “Treating a subject may involve prevention of a in the unsubstituted molecule. Thus, the fat is handled differ condition or other adverse physiological event in a suscep ently by body tissues. US 2009/0215895 A1 Aug. 27, 2009 35

sequence, Some have been screened in two animal models of pain. The engineered polyunsaturates of the present invention (b) were found to act in a similar manner to aspirin but by a different pathway, providing major advantages over toxicity problems associated with long term use of aspirin. One par ticular useful compound is PT2 (c). This is a polyunsaturated fatty acid which contains an amino acid covalently bound to its carboxyl group:

EXAMPLE 2 (c) Treating Inflammatory Disease

0126 The naturally occurring co-3 polyunsaturates (such 4. COOH as fish oil) have found use in the treatment of inflammatory NH COOH diseases. These include the highly debilitating chronic forms Such as rheumatoid arthritis, multiple Sclerosis, inflammatory bowel disease and systemic lupus erythrocytosis. These are 20:4n-6 Asp (PT2) life-long diseases which are managed but cannot be cured. The principle mechanisms involve the T-lymphocyte and macrophage and other white blood cells of the immune sys I0131 The chemical nature of these novel molecules sug tem (see FIG. 1). These inappropriately attach to either joint gests that they are easily delivered by skin application or oral tissue (in arthritis), blood vessel (in lupus), brain (multiple administration. Investigations have demonstrated that after Sclerosis) and gut tissue (inflammatory bowel disease) and ingestion, they soon appear in target organs (brain, kidney, then damage the tissue. lungs or skin). In preliminary studies in rats, active anti 0127. The PUFAs of the present invention target T-lym inflamatory levels of these molecules do not display any toxic phocytes. When T-lymphocytes are exposed to MP5, for side effects. The significant anti-inflammatory property as example, the cell takes up the fat as a nutritional requirement well as the analgesic value of these molecules and their like any other fat but in this case the MP5 has a slight but vital benign non-toxic nature makes the compounds ideal pharma change in its structure. MP5 stops the flow of a signal inside ceuticals. this cell preventing T-lymphocyte activation. EXAMPLE 6 EXAMPLE 3 Analgesic Properties of PT2 Transplantation 0128 Management of patients with transplants involves Screening of PT2 on Neutrophil Activation in Vitro the use of immunosuppressive medications, e.g. cyclosporin 0.132. The structure of PT2 is shown in (c) above. In this which stops T-lymphocyte activation. Rejection of trans screening assay, neutrophils were prepared from the blood of planted tissues involves T-lymphocytes and macrophages in a healthy volunteers. Freshly collected blood was layered onto similar manner to the delayed-type hypersensitivity (DTH) a Hypaque-Ficoll medium of density 1.114 and centrifuged at reaction. Thus, MP5 has the potential to be used as a suitable 400 g for 30 mins at room temperature. After centrifugation, immunosuppressive agent in transplantation especially the leukocytes resolved into two distinct bands, with neutro because of the advantages it confers regarding safety com phils being present in the secondband (Ferrante and Thong, J. pared to presently used immunosuppressants. Immun. Methods 48:81-85, 1982). (0.133 Activation of the neutrophil NADPH oxidase was EXAMPLE 4 measured by lucigenin-dependent chemiluminescence fol Treating Asthma and Allergy lowing a 10 min incubation of PT2 (20 uM, final concentra tion) with 1x10° neutrophils from different donors (Power et 0129. Tissues can be stimulated to produce fatty acid al, J. Immunol. 159:2952-2959, 1997). Arachidonic acid (20: derived hormone like molecules called “eicosanoids' such as 4, n-6) was used as a positive stimulator of the oxidase the leukotrienes. Production of these in an uncontrolled man ner is known to lead to the appearance of serious diseases. I0134. It can be seen that PT2 lacks the ability to stimulate These include asthma and allergic conditions. For example, the neutrophil respiratory burst. In contrast, arachidonic acid Some leukotrienes act on the Smooth muscle of the broncus of (and other natural PUFAs) are able to elicit a strong respira the airway preventing its relaxation leading to breathing dif tory burst (FIG. 2). ficulties as in asthma. In accordance with the present inven tion, a new form of polyunsaturates is provided as inhibitors Analgesic Properties of PT2 of eicosanoid production and hence as potential medication to I0135) Investigations of the effects of PT2 on pain induced treat asthma and allergic conditions. by phenylduinolic acid (PQ writhing) and formalin have been made. In both the PQ writhing test (FIG. 3) and the formalin EXAMPLE 5 algesia test (FIG. 4), PT2 administered by intraperitoneal Treating Pain inoculation reduced pain and compared favourably with pain reduction by aspirin (oral, 100 mg/kg). In these tests, the 0130. Some evidence has suggested that the novel fats EPUFA was administered 30 min before the pain stimulus may act on pathways involved in generating pain. As a con and effects recorded over the following 20 min. US 2009/0215895 A1 Aug. 27, 2009 36

0.136 Investigations of PT2 in the formalin-induced anal poorly. The data in Table 2 show that the activation of apop gesia model looking specifically at the biphasic response have totic protective isozyme e is markedly inhibited by LX7 with also been undertaken and are shown in Table 1. It is well out much inhibition of the activation of 8 which promotes documented that in this model, aspirin Suppresses only pain apoptosis. Therefore, the cell dies. In contrast with Lx8 both related to the inflammatory process (15-20 mins post-admin isozymes are inhibited. The net effect is survival. istration of formalin), while morphine Suppresses pain in both 0140. With LX9, the compound is also strong in killing phases of the response (0-5 min and 15-20 min). From Table cancer cells and there is balanced (+) inhibition of both 8 and 1, it can be seen that PT2 acts similarly to aspirin in having its E. major effect on the later phase of the pain response. MP5 was much less effective in inhibiting pain in this model. EXAMPLE 8

TABLE 1. Treatment of Systemic Vasculature Effect of PT2 on pain induced by formalin 0.141. The aim of the experiment was to establish condi tions for optimal activity of 3-oxa 23:4n-6 (MP3) in relation 90 inhibition of pain response to inhibition of up-regulation of adhesion molecular expres sion on the endothelium in vivo and to determine whether or Treatment Phase I (0-5 mins) Phase II (15-20 mins) not MP3 possesses anti-atherosclerotic properties in experi PBS O O mental models. PT2 (30 mg/kg) O 41 PT2 (100 mg/kg) 30 97 0142. It is proposed that f-oxa 23:4n-6 (MP3), through its MP5 (100 mg/kg) 34 37 ability to selectively inhibit the IKB kinase-NFKB signalling Aspirin (300 mg/kg) 30 91 pathway, inhibits the expression cell adhesion molecules on Morphine (10 mg/kg) 85 100 and the adherence of monocytes to the aortic endothelium, thus preventing the development of atherosclerosis in vivo. 0.137 Compounds were administered intraperationedly 0.143 Atherosclerosis is a chronic inflammatory vascular (ip) 30 min prior to the administration of formalin (0.02 ml, disease which is characterized by a thickening of the vascular 1% solution) via Subplantar injection into the right hind paw. wall (atheroma) due to lipid accumulation and infiltration of Reduction of the induced hind paw licking time recorded circulating monocytes and T-lymphocytes. The recruitment during the following 0-5 min period (Phase I response) or of monocytes into the intima in lesion prone-sites is a key 15-20 min period (Phase II response) was determined. The event in early atherogenesis. For this to occur, monocytes data in Table 1 are the mean responses of 5 animals in each must first adhere to the endothelium at sites of endothelial group. injury or dysfunction caused by factors such as oxidized LDL, chylomicron remnants and/or advanced glycation end EXAMPLE 7 products (AGE) (Koya et al. Diabetes 47:859-866, 1998). Leukocyte adhesion to the endothelium and the Subsequent Effects of Nitroanalog (LX) of PUFA on PKC Acti emigration into the intima is mediated by leukocyte-endothe Vation lial cell adhesion molecules (CAMs). These CAMs include the leukocyte L-selectin and the endothelial E-selectin, P-se 0.138. The effects of nitroanalogs of PUFAs on PKC acti lectin, intercellular adhesion molecule (ICAM)-1 which Vation were determined. LX compounds at a concentration of binds neutrophils and vascular cell adhesion molecule 20 uM were incubated with the HL-60 cell line (final condi (VCAM)-1 which binds monocytes and T cells. The process tion 10° cells/ml) for 60 min. PKC activation was then begins by E-, L-, and P-selectin-mediated rolling of the leu attempted to be induced by PMA. PKC enzyme translocation kocytes along the endothelial surface. This is followed by was quantitated by Western blot. The results are shown in firm adhesion involving the B1 and B2 integrins and immu Table 2. noglobulin adhesion superfamily members such as ICAM-1 and VCAM-1. The leukocytes then migrate into the intima in TABLE 2 response to hypercholesterolemia-induced production of Inhibition of PKC Activation chemoattractants (Koya et al., 1998 supra) and other activat ing molecules produced by the underlying vascular Smooth PKC muscle cells (Chou et al. Curr Biol. 8:1069-77, 1998). The isozyme LX1 LX2 LX3 LX4 LX5 LX6 LX7 LX8 LX9 monocytes differentiate into macrophages and ingest modi C. ---- ND +++ +++ fied forms of LDL to become foam cells which give rise to B1 ------ND +++ ++ ---- fatty streaks. Activated macrophages release inflammatory B2 ------ND +++ +++ +++ 8 ------ND ------cytokines and growth factors that may recruit additional 8 -- ND +++ +++ -- blood monocytes into the developing lesion and stimulate Smooth muscle cell migration and proliferation. These pro +++ = strong inhibition of PKC activation, cesses set the scene for the development of more advanced - = no inhibition of PKC activation, lesions which include a fibrofatty matrix of connective tissue, ND = not determined smooth muscle and foam cells, followed by the formation of 0139. It is evident that there are substantial differences in dense fibrous plaques (Koya et al., 1998 supra). ability to inhibit the spectrum of five PKC isozymes by the 0144. There is overwhelming evidence that CAMs play different LX compounds. For anti-cancer effect, 8 and e are of key roles in atherogenesis. Many atherogenic factors, e.g. interest. These have been clearly associated with cell survival hypercholesterolemia, lysophosphatidylcholine and AGE (e) and cell death (ö). In the examples of LX7 and LX8, LX7 have been reported to increase ICAM-1 and VCAM-1 expres kills cancer cells very effectively, yet LX8 kills cells very sion on endothelial cells (Jaken et al. Bioessays 22:245-254, US 2009/0215895 A1 Aug. 27, 2009 37

2000). While oxidized LDL enhances VCAM-1 expression, it effective than MP3 at antagonizing the action of TNF on this only does so in endothelial cells stimulated with cytokines pathway, consistent with its weaker ability than MP3 at Sup such as tumour necrosis factor C. (TNF) and interleukin 1B pressing CAM expression. The focus of this embodiment of (Jaken et al., 2000 supra), which are produced at sites of the subject invention is, therefore, the efficacy of MP3 at inflammation. In vivo, increases in CAM expression is local Suppressing adhesion molecule expression in vivo and the ized to human arteries with atherosclerotic lesions and in development of atherosclerosis. lesion-prone sites on the aortae of mice and rabbits (Koya et al, 1998 supra: Xia et al., J. Clin. Invest. 98:2018-2026, 1996). EXAMPLE 9 Studies in animal models have also demonstrated that pre venting the expression of CAMS through inactivating muta Animal Models and MP3 tions caused by homologous recombination (Jaken et al., 2000 0147 The animal model used comprised the apolipopro supra; Koya et al., J. Clin. Invest. 100:115-126, 1997: Scivit tein E-deficient (ApoE) mice on a C57BL/6J background. taro et al, Am. J. Physiol. 278:F676-F683, 2000; Way et al. Another model comprised using NZ white rabbits. The ability Diabetic Medicine 18:945-959, 2001), and antibody neutral of MP3 to protect against atherogenesis in two different mod ization of CAMs reduce the recruitment of monocytes to els, each displaying a different degree of atherosclerosis atherosclerotic plaques and reduce lesion size (Jaken et al. development, will be a better indicator of MP3's efficacy in 2000 supra; Ferrante et al., J. Clin. Invest. 99:1445-1452, protecting against atherogenesis. 1997). Consequently, strategies to reduce CAM expression 0148 ApoE, a 34 kDa glycoprotein that is synthesized are attractive approaches to reduce or impede the develop predominantly in the liver, is a structural component of all ment of atherosclerosis and this forms the focus of this appli lipoproteins other than LDL. One of its most important func cation. tions is to mediate the clearance via the liver of very low 0145 One of the essential factors that is required for the density lipoprotein (VLDL) and intermediate density lipo up-regulation of CAM expression on the endothelium is the protein (IDL) via the LDL receptor and of chylomicron rem transcription factor, NFKB. The activity of NFkB is tightly nants via both the LDL receptors and chylomicron remnant regulated by cytokines and other stimuli. In the resting cells, receptors (Pitt et al., 1997 Supra). Humans with ApoE defi NFKB dimers are sequestered in the cytoplasm by IKB pro ciency have type III hyperlipoproteinemia with elevated teins. Upon activation, IKB is phosphorylated by a signalo plasma cholesterol, early development ofatherosclerosis and some complex of IKB kinases. The phosphorylated IKB dis yellow lipid-laden Xanthomatous skin nodules, although trig sociates from NFKB and undergoes proteosome-mediated lyceride levels are near normal (Pitt et al., 1997 Supra). The degradation, permitting the nuclear translocation of NFKB. ApoE mouse has marked hypercholesterolemia and spon Inhibition of NFkB activation results in the suppression of taneously develop lesion patterns characteristics of human CAM expression. Thus, the NFKB signalling pathway is an atherosclerosis. Extensive fatty streak formation and attractive target for the development of drugs to suppress advanced plaques are observed in many regions of the arterial inflammatory diseases (Huang et al. Circ. Res. 8.0:149-158, tree, e.g. aortic root, curvature of the aortic arch, principal 1997), including atherosclerosis. branches of the aorta and in the pulmonary and carotid arter 0146 Then-3 fatty acids and fish oil are currently believed ies of 30-40 week old ApoE mice (Costabile etal, J. Immu to possess cardioprotective actions and one well-studied mol. 167:2980-2987, 2001: Jirousek et al., J. Med. Chem. action is the suppression of CAM expression (Pitt etal, Chem. 39:2664-2671, 1996). However, signs of early atherosclerotic Phys. Lipids. 92:63-39, 1998). In accordance with the present development is evident in lesion-prone sites, e.g. aortic arch, invention, a novel engineered polyunsaturated fatty acid, orifice of the bronchiocephalic artery, and branching sites of |B-Oxa-23:4n-6 (MP3) (FIG. 5) is identified which has the the abdominal aorta can be detected as early as 5-6 weeks of hall-marks of a new class of pharmaceuticals based on poly age (Dekker et al, Biochem J. 347:285-289, 2000). If fed a unsaturated fatty acids and which can be used to prevent Western-type diet, lesion development is accelerated and are and/or treat cardiovascular disease. MP3 suppresses the more advanced than mice fed a normal chow diet (Costabile expression of CAM and hence leukocyte-endothelium inter et al., J. Immunol. 167:2980-2987: Dekker et al., 2000 supra: action (FIG. 6). This molecule, containing an oxygenatom in Couperetal, Diabetologia 37:533-535, 1994). This mouse is the B position of the carbon backbone, is better than docosa being regarded as an excellent model for histological studies. hexaenoic acid (22:6n-3) at Suppressing tumour necrosis fac Of particular relevance to this study is the demonstration in tor (TNF)- , lipopolysaccharide (LPS)- or phorbol the ApoE mouse that increased expression of CAM at 12-myristate 13-acetate (PMA)-induced expression of E-se atherosclerosis-prone sites on the aortic endothelium has lectin, ICAM-1 and VCAM-1 in vitro. However, unlike been observed (Dekker et al., 2000 supra; Couper et al., 1994 22:6n-3 which is a strong stimulator of the phagocyte respi supra). More importantly, the concept that blocking CAM ratory burst (AF30) and hence is a promoter of neutrophil expression blocks leukocyte adherence to the endothelium at mediated tissue damage, MP3 is relatively poor at Stimulating relevant lesion-prone sites of the aorta and consequently this response. Preliminary studies have found MP3 to be reduces atherogenesis has been validated in the ApoE effective in vivo at Suppressing LPS-stimulated up-regulation model, using both genetic approaches and blocking antibod of E-selectin expression in the aortae of mice and prevents the ies of various CAM (Koya et al., 1998 supra; Scivittaro et al. infiltration of leukocytes, including monocytes, into sites of 2000 supra, Way et al., 2001 supra, Ferrante et al., 1997 supra). inflammation (FIG. 7). Given at 50 mg/kg intravenously Furthermore, the experiments proposed to be conducted (i.v.), MP3 did not cause any observable signs of distress to using the ApoE mouse. the animals for the duration of the experiments (4 days). 0149. The NZ white rabbit develops atherosclerotic Preliminary data have also demonstrated that MP3 inhibits lesions when given a high fat-high cholesterol Western-type the ability of TNF to activate IKB kinase-NFKB signalling diet. By 16 weeks, the animals are overtly hypercholester pathway (FIG. 5). Docosahexaenoic acid (22:6 n-3) was less olemic, and histological studies at this time reveal that US 2009/0215895 A1 Aug. 27, 2009

50-80% of aortic intima is covered by atheroscleroticlesions, intense and this was further increased in mice fed a Western including fatty streaks and plaques (Kikawa et al. Diabetolo type diet. For experiments, the mice were weaned at 4 weeks gia 37:838–841, 1994). Cell proliferation, foam celland T cell of age (Dekker et al., 2000 supra). It is proposed to use 12 accumulation and lipid deposition are normal in the intima of ApoE mice/group (C-0.5, B=0.1) and these werehoused in these animals (Kikawa et al., 1994 supra). groups of 6-7 per cage. Some animals have been excluded I0150. A colony of ApoE mice (Animal Resource Cen owing to the presence of severe non-Xanthomatous skin tre, Perth) has been established at the Women's and Chil lesions or murine urological syndrome (Lallena et al. Mol. dren's Hospital, Adelaide, South Australia and in preliminary Cell. Biol. 19:2180-2188, 1999). At 5 weeks, one group of studies, have confirmed the presence of atherosclerotic mice were fed a Western-type diet while the other were main lesions in the aortic arch of 16 week old mice fed on standard tained on standard chow. The fifth week was chosen to start chow. All ApoE animals for experimentation will be kept treatment in order to maximize the difference between control on standard chow (4.5% fat, 0.02% cholesterol, w/w) to start and MP3-treated groups. Two regimes of MP3 treatment were with. When appropriate, their diets will be changed to high tested. In the first, mice were treated with MP3, DPC or MP1 fat/high cholesterol Western-type diet (w/w) (21% fat poly by intraperitoneal injection a day prior to diet modification. unsaturated:saturated=0.07, 0.15% cholesterol). Other studies have demonstrated the engineered fatty acids are effective at Suppressing footpad inflammation when EXAMPLE 10 administered intraperitoneally (AF45). Treatment continued once daily for 5 or 15 weeks. The mice were sacrificed and Effects of MP3 Administration on the Adhesiveness adhesion molecule expression were determined as described of the Endothelium in Mice above. To gauge the degree of Suppression of adhesion mol Adhesion Molecule Expression ecule expression by MP3, the results were compared with 0151. It is evident from the data that MP3 inhibits the those obtained in age-matched ApoE-1- and C57BL/6J mice activation of the IKB-NFKB pathway and the up-regulation of fed normal chow and treated with DPC. It was expected that endothelial CAM expression in vitro and LPS-stimulated chow-fed C57BL/6J mice would have very low levels of E-selectin expression in vivo). The aim of this application CAM expression, chow-fed ApoE mice would have inter was to determine whether MP3 also inhibits the expression of mediate levels of expression and ApoET mice on Western VCAM-1 and ICAM-1. For this, C57BL/6J mice (6-8 ani type diet would have the highest level of expression. If MP3 mals per group, a number which was sufficient in the Balb/c is efficacious, the levels of CAM expression would be less experiments to give statistically significant differences) were than that in DPC- or MP1-treated ApoE mice on Western pre-treated for 1 day (one dose) or 1 week (one dose/day) with type diet. In the second regime, mice were treated with MP3 either 40 mg/kg or 80 mg/kg of MP3 intravenously. These or MP1, commencing at 8 weeks after diet modification and concentrations and the route of administration were used CAM expression would be determined after 10 weeks of MP3 previously to demonstrate the suppression of LPS-stimulated treatment. This allowed the inventors to determine whether E-selectin expression by MP3 in the aorta of Balb/c mice. The MP3 stopped or reversed atherogenesis. fatty acid were presented in DPC (dipalmitoylcholine) micelles (1:4, MP3:DPC, w/w), prepared by Sonication. Con Adherence of Macrophages to the Endothelium trol mice receive an equivalent amount of DPC. After the 0153. To confirm that MP3 reduces the adhesiveness of the pre-treatment period, the mice were injected intraperitoneally endothelium for leukocytes in vivo, an assay based on that with LPS (50 ug), an agent which induces the expression of described by Ferrante et al (J. Clin. Invest. 99:1445-1452, E-selectin, ICAM-1 and VCAM-1. 24 hr after LPS adminis 1997) would be adopted. Peritoneal macrophages (from tration, the animals were sacrificed by CO asphyxiation and C57BL/6J mice) loaded with fluorescent microspheres (Mo the aortae encompassing the ascending part of the aortic arch lecular Probes) were injected intravenously into ApoE through to the bifurcation to the common iliac arteries were mice and 48 hr later, the number adhering to the aortic root at isolated. Each aorta was then separated into two pieces of the level of the sinus of Valsalva would be scored. Although equal length and minced. The tissue were fixed in 0.25% V/v unprimed blood monocytes would also adhere to the endot glutaraldehyde and processed for enzyme immunoassay. One helium under identical conditions, the level of adherence was half of the aorta was stained with monoclonal antibody to found to be higher with peritoneal macrophages than mono mouse VCAM-1 and the other half stained with isotype cytes and hence peritoneal macrophages were chosen (Fer matched control IgG. In addition, adhesion molecule expres rante et al., 1997 supra). In ApoE mice, the most advanced sion were assessed by immunohistochemistry using gold lesions were found over the aortic cusps at the level of the conjugated reagents (Dekker et al., 2000 Supra). Once sinus of Valsalva (Couper et al. Diabetologia 37:533-535, conditions have been optimized with respect to pre-treatment 1994). Fed on normal chow, increased adherence of mono time and the dose of MP3 to be used, the experiments were cytes to the endothelium was observable by 6 weeks of age repeated to examine the effects of MP3 on ICAM-1 expres (Couper et al., 1994 supra). Again, 5 week old ApoET mice, sion. As a negative control, MP1 (B-Oxa-23:0), a novel fatty in groups of 12 animals, were fed a Western-type diet (opti acid that is biologically inactive in in vitro assays, was also mal period on this diet would be based on the results obtained tested. above). Mice were treated with MP3, MP1 or DPC. On the 0152 Next, the ability of MP3 to reduce the expression of last day of treatment, mice were injected intravenously; with CAM, e.g. VCAM-1, in ApoE mice was investigated. microsphere-loaded macrophages (1x10" in 0.2 ml). After 48 Expression of E-selectin and ICAM-1 was investigated. A h, the mice were sacrificed, perfused with heparinized saline previous study found slightly increased expression of by injection through the apex of the left ventricle, and the base VCAM-1 at lesion-prone sites in ApoE' mice compared to of the hearts and ascending aortae isolated, mounted in Tissue control mice as early as 5 weeks of age (Dekker et al., 2000 Tex freezing media and frozen in liquid N. Hematoxylin supra). By 8 weeks of age, VCAM-1 staining was more stained sections (200 consecutive 5um sections) covering the US 2009/0215895 A1 Aug. 27, 2009 39 proximal 1 mm of the aortic root were analyzed by light and frozen sections in the abdominal aorta around the renal arter fluorescent microscopy, and the number of adherent fluores ies were stained to detect the lipid laden cells. Lesion size cent monocytes be counted in a blinded fashion. As a positive were determined as described above and results expressed as control, mice which had not been treated with a fatty acid the percentage of lesion area relative to the total internal were administered anti-C. integrin or ICAM-1 antibody surface. Older mice (30 weeks) known to have advanced (positive control) prior to the injection of microsphere-loaded lesions were also treated with MP3 over a period of 15 weeks macrophages (Ferrante et al., 1997 Supra). to determine whether atherosclerosis could be halted or 0154) To provide another comparison for the degree of reversed. Suppression of macrophage-endothelium interaction by MP3, macrophage adhesion were also determined in DPC-treated 0157. The experiments above were then repeated but with age-matched C57BL/6J mice fed a chow diet. It was envis MP3 or control agents given orally. Being a fatty acid, it was aged that very few or no macrophages would adhere to the expected for MP3 to be absorbed across the intestinal wall endothelium of these mice. into the blood stream. Indeed, previous studies with another engineered fatty acid, MP5, have demonstrated that this fatty EXAMPLE 11 acid is present in the blood and various organs after oral administration. Studies in dogs have shown that a saturated Effect of MP3 on the Development of Atherosclero B-oxa fatty acid is readily absorbed when given orally (Hii et sis al, J. Biol. Chem. 266:20238-20243, 1991). Thus, it was investigated whether MP3 is efficacious at suppressing ath O155 The anti-atherosclerotic effect of MP3 were exam erosclerosis when given orally. The experiment essentially ined first in ApoE' mice feda Western diet. In these mice fed followed the schedule outlined above to determine whether a normal chow diet, foam cell lesions were evident as early as MP3 prevented the development of atherosclerosis. Mice 8 weeks of age and advanced lesions were observable by 15 were administered MP3 or a control compound daily by gav weeks (Couper et al., 1994 supra). Mice fed a Western diet has age for the appropriate length of time (see above) and the more advanced lesions than those on normal chow (Couperet degree of atherosclerosis assessed. Finally, the anti-athero al, 1994 supra). sclerotic effects of MP3 were tested using NZ white rabbits. 0156 Mice (12 pergroup), weaned at 4 weeks of age, were After 16 weeks on a high cholesterol diet, these animals were switched from a chow diet to a Western-type diet at 5 weeks shown to be overtly hypercholesterolemic and histological of age and maintained on this diet for up to 20 weeks. Daily studies at this time show that 50-80% of aortic intima was treatment with MP3 (40 mg/kg), MP1 or DPC commenced at covered by atheroscleroticlesions, including fatty streaks and the time of the Switch. As a positive control, another group of plaques. For the experiments, rabbits fed on standard chow, mice were treated with probucol which Suppresses atherogen weighing 1.8-2.2 kg and with serum cholesterol of less than esis (Suzuma et al., J. Biol. Chem. 277: 1047-1057, 2002). At 100 mg/dl., were selected. They were divided into five groups various times, e.g. 5 and 20 weeks after the Switch, mice are of eight animals each: standard chow+DPC, standard chow+ sacrificed and the degree of atherosclerosis assessed as pre MP3, high cholesterol (2% w/w) diet.--DPC, high cholesterol viously described (Costabile et al., 2001 supra, Jirouseket al. diet--MP3 and high cholesterol diet--probucol (0.25%). Treat 1996 supra) but with modifications. Briefly, the vascular tree ment with MP3 (40 mg/kg) would coincide with the switch to were perfused via the heart with paraformaldehyde (4% w/v) a high cholesterol diet. The animals were kept on their diets and the heart and aortae down to the bifurcation at the com and treated with MP3 for 16 weeks. At the end of this period, mon iliac arteries were isolated intact. The heart and an the animals were sacrificed by heart puncture under ketamine. approximately 5 mm length of ascending aorta were removed The thoracic aortae were removed, sectioned longitudinally, from the remainder of the aorta and fixed in formalin. After one halfpinned on to boards, fixed and stained with Oil red O. embedding in paraffin, 4 um-thick sections at 25um intervals The sections were photographed as described above and the were made beginning with the ascending aorta and proceed extent of Oil red O positive area between the first and fifth ing through the entire aortic sinus until the Ventricular cham intercostal aortic branches were determined inablinded fash ber was reached. The sections are stained with Hematoxylin ion and expressed as a percentage of the total internal Surface. and Eosin and assessed using an Olympus BX51 microscope The other half were processed for light microscopy and 4 um for foam cell infiltration, cellular proliferation and the pres sections were taken from a 5 mm segment around the first ence of fibrous plaques or atheromatous lesions complicated intercostal branch. After mounting on slides, lesion area was by ulcerations or thrombosis. Images are captured using an assessed as described above. These sections were also immu Olympus DP12 digital camera. Lesion size (mean cross sec nostained for macrophages using the rabbit macrophageanti tional area) and the percentage of the lumen area occupied by lesion were determined by using a computer assisted image body, RAM 11 (Dako, Calif.). measurement program (Measure Master, Leading Edge, Aus 0158 Statistical analysis of the results were performed by tralia). Where appropriate, sections were stained with elastic one way ANOVA followed by an appropriate post test, e.g. Van Gieson and Masson's trichrome to detect collagen. Some Bonferroni test for multiple comparison or Mann-Whitney sections were also immunostained for macrophages using the U-test. Results were considered statistically significant when anti-mouse macrophageantibody, MAC 3 (Sigma Aldrich). It P.O.O.5. was also possible to grade these lesions according to the classification described by Stary and co-workers (Lallena et EXAMPLE 12 al, Mol. Cell. Biol. 19:2180-2188, 1999). The remaining sec tion of the aorta were pinned on to a board, sectioned longi Effects of PUFAS on Diabetes tudinally, one half fixed in formalin, stained with Oil red O/Sudan IV and counter-stained with Hematoxylin Eosin to 0159. The overall aim of this Example was to evaluate the detect lipid laden cells. The other half were fixed and 12 um potential for a chemically engineered polyunsaturated fatty US 2009/0215895 A1 Aug. 27, 2009 40 acid, MP5 (B-Oxa-21:3n-3), to treat pathogenesis associated glycemia-induced increase in endothelial cell permeability to with diabetes by targeting the protein kinase C(PKC) system. macromolecules, another characteristic systemic vascular The specific aims were to: abnormality in diabetes, can be reproduced by the addition 0160 (1) characterize the effects of MP5 on glucose or PMA and PKCB has been implicated in causing this change in advanced glycosylation end product-stimulated activation permeability (Koya et al., 1998 supra). In the microVessels of PKC, e.g. prevent agonist-stimulated association of and macroVessels, hyperglycemia-induced vasodilation and PKCB with a particulate fraction in mesangial cells; increase in contractility, respectively, can be reversed by (0161 (2) determine whether esterification of MP5 into inhibitors of PKC (Koya et al., 1998 supra). One of the factors diacylglycerol was essential for the action of MP5; that cause these changes in renal tissues is the glucose-in 0162 (3) investigate whether MP5 is efficacious at pre duced increase in the activity of the renin-angiotensin System, venting glucose-induced responses in vitro, e.g. glucose and PKC has been implicated in the actions of angiotensin stimulated TGFB production in mesangial cells, and in vivo (Koya et al., 1998 Supra). Increased angiogenesis, neovascu in Streptozotocin diabetic rats. larization and over-expression of the extracellular matrix pro 0163 MP5, by virtue of its incorporation into membrane teins are also hallmarks of diabetes, and these are believed to phospholipids and diacylglycerol, selectively targets the pro be due to glucose-induced production of vascular-endothelial tein kinase C3 isoforms in mesangial cells by preventing PKC cell growth factor (VEGF) and TGFB. While inhibition of translocation. This prevents glucose and advanced glycosy PKC inhibits the actions of VEGF on endothelial cell prolif lation end products from causing functional changes in eration (Xia et al., J. Clin. Invest. 98:2018-2026, 1996), inhi mesangial cells in culture and in the kidneys of streptozotocin bition of PKCB effectively blocks hyperglycemia-induced diabetic rats. production of TGFB in mesangial cells and renal glomeruli 0164. The majority of diabetic patients were not able to (Koya et al., 1997 supra) and the associated expansion of the attain near normal glycaemia. This pre-disposed them to the extracellular matrix. Furthermore, decreases in the activity of development of diabetic microvascular and macrovascular the Nat K"-ATPase in vascular and neuronal tissues are complications. Therefore, novel approaches to prevent the widely reported in diabetic patients, and glucose-induced effects of hyperglycemia were essential to the future manage reduction in the Na' K' ATPase activity in mesangial cells ment of diabetes. Recent focus centred on identifying the and aortic Smooth muscle cells has been found to be depen hyperglycemia-induced biochemical changes that were sig dent on PKCB. Current evidence also suggests that arachi nificant in causing vascular and neurological dysfunction. donic acid, produced by the sequential activation of PKC and One consistent observation was that glucose stimulated the cytosolic phospholipase A, is responsible for the action of activity and expression of protein kinase C(PKC) in tissues at glucose on the Sodium pump. risk of developing diabetic complications (Koya et al., 1998 0167. When the engineered polyunsaturates were exam supra). This raises the likelihood that PKC may be an impor ined for biological activity in human umbilical vein endothe tant mediator of the actions of glucose in these tissues. lial cells (HUVEC) and other cell-types, several were found 0.165 PKC is a ubiquitous phospholipid-activated Ser/Thr to display a more selective range of actions than their natural kinase. Consisting of at least 11 isozymes, PKC is divided counterparts. One of these, MP5 (B-Oxa-21:3n-3), inhibited into classical (C., BI, BII and Y), novel (Ö, e, 0, m, and PKD) PMA-stimulated translocation of PKCBI and BII to the par and atypical ( and / ) isozymes (Chou et al., 1998 supra). ticulate fraction in these cell-types. MP5 had minimal effects The activity of the classical PKC isozymes is stimulated when (<15%) on PKCe translocation and no effects on the translo diacylglycerol (DAG) and Ca" accumulate in appropriately cation of the other PKC isozymes in Jurkat cells. Preliminary stimulated cells while activation of the novel PKC isozymes data from glucose-stimulated mesangial cells (FIG. 9a) and requires only DAG. Both the classical and novel PKC can also the glomeruli of diabetic rats (FIG.9b) have confirmed the be activated directly by phorbol esters such as phorbol ability of MP5 to prevent the translocation of PKCBI, the 12-myristate 13-acetate (PMA). Activation of the atypical main B isoform in mesangial cells, to a particulate fraction. isozymes is regulated by other means, e.g. ceramide and Long term in vivo experiments (up to three months) showed phosphorylation (Chou et al., 1998 Supra). In unstimulated that treatment with MP5 (up to 100 mg/kg) had no visible cells, PKC is generally found in the cytoplasm and it trans adverse effects on the well-being of the animals, e.g. coat locates to particulate fractions upon stimulation where it appearance and activity/mobility, and exerted no adverse associates with binding partners such as RACKS (receptor for effects on liver and kidney function and electrolyte levels. activated C kinase) (Jaken et al., 2000 supra). These data indicate that MP5 has the hallmarks of a lead 0166 PKC regulates a diverse range of cellular processes compound for blocking the actions of glucose. in an isozyme(s)-specific manner. There is very strong evi (0168 While LY33531 inhibits PKCB by binding to the dence to implicate PKC, especially PKCB, in mediating the ATP-binding site of the kinase (Jirousek et al., 1996 supra), actions of glucose in diabetes. This includes the activation of MP5 acts by reducing the association of PKCB with the PKCB in renal glomeruli, retina, aorta and heart of diabetic particulate fraction. Because of this unique mode of action, animals and in glucose-stimulated cells (Koya et al., 1998 i.e. MP5 is not a kinase inhibitor, the likelihood of MP5 supra). More importantly, inhibition of PKCB with the directly affecting the activity of any kinase is extremely PKCB-specific inhibitor, LY333531, reverses/blocks the remote. The potential for a kinase inhibitor such as LY333531 actions of glucose in these tissues. For example, in the retinae and derivatives to affect the activity of other kinases has been of diabetic patients and animals with a short history of the recently voiced (Jirouseketal, 1996 supra). Depending on the disease, retinal blood flow is decreased due to glucose-in concentrations used, the preliminary data in HUVEC have duced vasoconstriction (Koya et al., 1998 supra). While direct demonstrated that MP5 is able to distinguish between PKCBI stimulation of PKC with a phorbol ester causes retinal vaso and PKCBII. constriction, inhibition of PKC activity normalizes retinal 0169. The objective of this Example was to determine blood flow in diabetic dogs (Koya et al., 1998 supra). Hyper whether EPUFA such as MP5 could be developed into novel US 2009/0215895 A1 Aug. 27, 2009

therapeutics to prevent the severe and life-threatening pathol PKC mRNA are normalized by comparison with the level of ogy associated with diabetes using the kidney as a model. glyceraldehyde 3-phosphate dehydrogenase mRNA in the This is achieved by testing the ability of MP5 to block glu same sample. cose- or AGE-stimulated activation of PKCB and whether this 0173 Mesangial cells express PKCC, BI, e, 8 and (Koya requires esterification of MP5 into membrane phospholipids. etal, 1997 supra, Kikkawa et al., 1994 Supra), and BII at lower Finally, MP5 is tested for efficacious at inhibiting glucose levels (Koya et al., 1997 supra). To examine the effect of MP5 stimulated responses in mesangial cells in vitro and hyperg on the ability of other PKC isozymes in mesangial cells to lycemia-induced renal damage in an experimental animal translocate to the particulate fraction, the cells were pre model of diabetes. treated with MP5 before being stimulated with PMA (1-100 nM). This agent stimulated the translocation of all the classi cal and novel isozymes. The studies in HUVEC have demon EXAMPLE 13 strated that MP5 suppressed PMA-stimulated association of PKCBI and BII with the particulate fraction. The studies were Effects of MP5 (B-oxa 21:3n-3) on the Activation/ extended to other isozymes. For PKCY (expressed mainly by Translocation of Different PKC Isozymes neuronal cells), the effect of MP5 are tested using PMA stimulated PC12 rat pheochromocytoma cells. To assess the 0170 Since glucose has been demonstrated to stimulate effect of MP5 on the activation of atypical PKC isozymes the translocation of PKCC. and BI in mesangial cells (Koya et such as PKC, NIH3T3 cells were pre-treated with MP5 al, 1997 supra), the effects of MP5 on the association of before being stimulated with tumour necrosis factor q.(1000 PKCC. and BI with the particulate fraction in glucose-stimu U/ml) which stimulates PKC activity in these cells (Lallena lated mesangial cells is determined. Preliminary studies in et al., 1999 Supra). The isozyme were immunoprecipitated glucose-stimulated mesangial cells have indicated that MP5 (antibody from Santa Cruz) and kinase activity was deter can preventPKCBI from translocating the particulate fraction mined using a PKCe pseudosubstrate peptide or myelin basic (FIG. 9). Mesangial cells are prepared as previously protein as a substrate (Suzuma et al., 2002 supra). described (Couper et al., 1994 supra). 0171 Four groups of cells were set up: 5.5 mM glucose-- EXAMPLE 1.4 ethanol (0.1% w/v or v/v), 5.5 mM glucose--MP5 (20 uM Incorporation of MP5 into Diacylglycerol which is effective in the studies), 25 mM glucose--ethanol and 25 mM glucose+MP5. In some experiments, an additional 0.174. In MP5-treated HUVEC, the ratio of non-esterified group of cells are treated with MP1 (B-oxa 23:0) (20 uM), an MP5 to non-esterified arachidonic acid is as high as 5:1. Thus, inactive fatty acid. Cells were pre-incubated (30 min-24 h) incubation of mesangial cells with glucose and MP5 is likely with MP5 before being challenged with glucose for 4 days. to result in the formation of DAG that contains MP5. The The kinetics studies have found that glucose-stimulated PKC formation of a more polar and conformationally different translocation in mesangial cells reaches a maximum at day 4 MP5-containing DAG can conceivably interfere with the of treatment, consistent with findings from previous reports ability of natural DAG to stimulate PKC translocation. The (Koya et al 1997 Supra). Cells are then be washed, sonicated hypothesis is first tested that MP5 does not inhibit glucose and the amount of each PKC isozyme in the particulate frac stimulated accumulation of DAG but leads to the formation of tion determined by Western blot analysis. The soluble frac M5-containing DAG. Mesangial cells were incubated with tions were kept for estimation of soluble PKC (non-particu MP5 (30 uM. 1 h) before increasing the glucose concentration late fraction-associated). The inventors’ studies demonstrated to 25 mM. After 4 days, lipids were extracted (CHCl: that a 30 min pre-treatment period with MP5 was sufficient to CHOH=2:1), DAG isolated by thin layer chromatography inhibit agonist-stimulated increase in the association of PKC (TLC), eluted from the silica and the presence of MP5 in DAG with the particulate fraction and block agonist-stimulated were determined and quantitated by GC/GCMS after functional responses, but the ICso decreased with increasing hydrolysis of the esterified fatty acids (Hii et al., 1991 Supra) time of pre-treatment. The cells remained viable throughout from DAG and conversion of the liberated MP5 to its methyl the period of study as judged by the trypan blue exclusion test. ester derivative. 19:0 methyl ester were used as a standard The studies were repeated with cells stimulated with AGE (Robinson et al, Biochem J. 336:611-617, 1998) and this human serum albumin (HSA) since AGE-HSA was demon method is used successfully to determine the content of strated to stimulate PKCBII translocation without affecting EPUFA in DAG and phospholipids. To quantitate DAG, an PKCO. translocation (Scivittaro et al., 2000 supra). AGE-HSA assay developed and validated in mesangial cells were used (pyrogen-free) were prepared by incubating the protein in the (Musial et al. J. Biol. Chem. 270:21632-21638, 1995). DAG presence of glucose essentially as previously described that is extracted from the TLC plates were acetylated with (Scivittaro et al., 2000 supra). Control HSA were incubated in '''C-acetic anhydride and pyridine. After rechromatography the absence of glucose. Analysis of the extent of AGE-HSA by TLC, the DAG-acetate, after autoradiography, were sub formation and AGE-HSA purification were carried out as jected to liquid Scintillation counting. Some cultures were described (Scivittaro et al., 2000 supra). After removal of incubated with the inactive MP1. If MP1 was also incorpo remaining glucose (centricon, 10 kDa cut-off), AGE-HSA rated, it would imply that the biological activity of an EPUFA were tested at 0.1-10 uM. was governed by its structural elements. The rationale for the (0172. The effects of MP5 on glucose-stimulated PKC synthesis of EPUFA was based on this concept. The esterifi expression were investigated since glucose increased the cation of MP5 into DAG was next determined as to whether expression of PKCB in mesangial cells (Koya et al., 1997 this was required for the inhibition of glucose-stimulated supra). This was achieved by determining the level of PKCB PKCBI-particulate fraction association. It is mandatory that mRNA by slot blot analysis (Ferrante et al., 1997 supra). All fatty acids were converted to their coenzyme A derivatives for classical and novel PKC isozymes were probed. The level of metabolism, including esterification into DAG. Cells were US 2009/0215895 A1 Aug. 27, 2009 42 pre-incubated with DMSO (control) or triacin C, a commonly specifically inhibiting PKCB translocation, ionomycin used inhibitor of long chain acyl coenzyme A synthetase stimulated cFLA activity would not be affected by the fatty (Korchak et al., J. Biol. Chem. 269:30281-30287, 1994), for acid. 10 min before being incubated with MP5 (20 uM) for 1 hr since this pre-treatment time was sufficient to block PMA NaK ATPase: stimulated PKCB translocation in glucose stimulated 0.178 In addition to its central role in nerve function, the HUTVEC and mesangial cells. The cells were then stimu Na' K' ATPase may also regulate barrier permeability and lated with PMA (100 nM, 0.5-3 min) or vehicle (DMSO) cellular integrity in the glomeruli. Glucose and diabetes have instead of glucose to shorten the time required for PKC acti been widely reported to inhibit the activity of the Nat K vation and to minimize the effect of triacin C on normal fatty ATPase in the glomeruli/mesangial cells and aortic Smooth acid metabolism. The amount of PKCBI and BII in particulate muscle cells (Koya et al., 1998 Supra, Koya et al., 1997 supra). fraction were determined. Triacin C-mediated inhibition of This effect was believed to be due to glucose-stimulated H-palmitic acid incorporation into DAG and phosphatidyl accumulation of arachidonic acid, and inhibition of PKCB choline (PC) (Hii et al., 1991 Supra) serves to confirm that the prevented the inhibition of the Nat KATPase by glucose in triacin C is active. aortic Smooth muscle cells and mesangial cells (Koya et al. 1998 supra, Koya et al., 1997 supra). To determine whether EXAMPLE 1.5 MP5 blocked the action of glucose on the activity of the Na' K' ATPase, the cells were pre-incubated with MP5 (see above) and then incubated in the presence of 25 mM glucose Effects of MP5 on Glucose- or Diabetes-Induced for 4 days. Rb" uptake, a standard assay for Na' K' Functional Changes Associated with Pathogenesis ATPase, was determined as described (Koya et al., 1997 Supra). (0175. Once it was confirmed that MP5 inhibited the asso ciation of PKCB with the particulate fraction in mesangial cells, MP5 were examined for its ability to inhibit in vitro In Vivo Studies parameters of glucose-induced functional changes. The data (0179 The ability of MP5 to inhibit renal TGFB production were normalised for cellular protein content. These investi and albuminuria in Streptozotocin-induced diabetic Sprague gations were followed by an examination of the efficacy of Dawley rats were investigated. MP5 is non toxic to rats given MP5 in protecting against hyperglycemia-induced functional at up to 100 mg/kg chronically as determined by liver and changes in the kidneys of diabetic rats. kidney biochemical and electrolyte markers. It is taken up by tissues, including kidneys, and incorporated into phospholip In Vitro Studies ids following oral administration. Animals (130-150 g) were placed randomly in one of five groups: control, MP5-treated, Suppression of Glucose-Stimulated Production of TGFB diabetic, diabetic--MP5 and diabetic--MP1. Power analysis (C.-0.5, B=0.1) (expecting at least a 50% reduction and an SD 0176 Glucose-induced expansion of the extracellular of 30% of mean) indicate that 7-8 animals/group were matrix via the production of TGFB by mesangial cells was a needed. The rats were rendered diabetic using streptozotocin major contributor to diabetic nephropathy and this action of (65 mg/kg.I.P) and blood glucose levels were measured 48 hr glucose could be blocked by inhibitors of PKCB (Koya et al. later to confirm the onset of diabetes (glucoses 15 mM). Con 1998 supra, Koya et al., 1997 supra). Thus, the ability of MP5 trol and diabetic groups were administered vehicle (ethanol) to inhibit glucose-stimulated TGFB production were investi or an EPUFA by gavage. Two doses were tested, 20 mg/kg gated. Cells were pre-treated with MP5 (seeabove) in DMEM and 50 mg/kg. The studies on the actions of EPUFA in vivo (5.5 mM glucose) before being stimulated with glucose (25 have demonstrated that the fatty acids were effective when mM) for 4 days. The amount of TGFB present in the incuba given orally. Treatment was once daily for a period of 12 tion medium was determined using a commercially available weeks (Koya et al., 1997 supra). Blood glucose was measured ELISA kit (Biosource, USA). MP1 was used as a negative every week. The animals were treated with 2U of long acting control. LY333531 was tested as a positive control. insulin daily to maintain body weight and to prevent ketoaci dosis but without normalizing hyperglycemia. At the end of Suppression of Phospholipase A Activity the MP5 treatment period, rats were sacrificed and the level of TGFB mRNA (Kikkawa et al 1994 supra) in the glomeruli 0177. Hyperglycemia-induced production of prostaglan were determined by slot blot analysis (Ferrante et al., 1997 din E and I have been implicated as contributing factors to supra) and normalized by comparison with the level of glomerular hyperfiltration in diabetes (Koya et al., 1998 GAPDH (glyceraldehyde 3-phosphate dehydrogenase) supra). These vasodilatory prostanoids were derived from mRNA in the same sample (Ferrante et al., 1997 supra). The arachidonic acid via the action of the cytosolic phospholipase amount of albumin in the urine were measured by using a A (cPLA), and glucose stimulates the activity of cFLA in commercial kit (EXOCELL Inc. Philadelphia, Pa.). It was mesangial cells in a PKC-dependent manner (Koya et al., 1997 determined whether MP5 could halt/reverse complications in supra). Cells were pre-treated with MP5 before being stimu animals with more advanced (e.g. 15 weeks) diabetes. The lated with glucose. At the end of the incubation period, the diabetic animals were treated with MP5 (20 or 50 mg/kg, cells were harvested, lysed and the activity of cFLA deter depending on the above results) once daily together with mined (Robinson et al., 1998 supra) using a commercial kit insulin (as above) for 12 weeks. Other parameters such as the (Cayman Chemical, USA). The ability of MP5 to inhibit production of hepatocyte growth factor by the glomeruli PKC-independent activation of clLA by ionomycin (0.1 (Couper et al., 1994 supra) may also be examined if time uM, 15 min) was also determined. If the fatty acid acted by permits. US 2009/0215895 A1 Aug. 27, 2009 43

EXAMPLE 16 enzyme-linked immunosorbent assay (ELISA) or as mRNA using a slot blot technique (Huang et al 1997 Supra). Polyunsaturated Fatty Acid (PUFA) Regulation of 0187. The LPS-induced expression of E-selectin in the the Activation of the IKB Pathway aortic endothelium of BALB/c mice was determined follow 0180. The objective of this Example is to make agents ing injection of 50 ug LPS intraperitoneally and aortas which are PUFA based, with many of the properties of PUFA, encompassing the ascending part of the aortic arch through to Such as absorption following oral administration and incor the bifurcation to the common iliac arteries isolated after 5 hr. poration into membrane phospholipids, but with more selec Each was cut into two pieces of equal length, minced, fixed in tive biological activities skewed towards anti-inflammatory 0.25% V/v glutaraldehyde, incubated with a monoclonal anti effects. body to mouse E-selectin (one half) or isotype matched con trol (other half) (Becton Dickinson, Ca) followed by an HRP Materials and Methods conjugated secondary antibody and then with the Substrate ABTS (ELISA method). Fatty Acids Measurements of Lipoxygenase Products 0181. The fatty acids, arachidonic acid (20:4n-6), ecosa pentaenoic acid 20:5n-3(EPA) and docosahexaenoic acid 0188 Lipids were extracted from the HUVEC culture 22:6n-3(DHA) were purchased from Sigma Chemical Co., St medium and oxygenated fatty acid derivatives were isolated Louis. Mo. The B-Oxa and B-thia compounds were synthe by thin-layer chromatography. The recovered oxygenated sized using published techniques. B-Oxa-23:4n-6 methyl ester derivatives of B-Oxa-23:4n-6 were characterized by electro was formed by the treatment of B-Oxa-23:4n-6 with diaz spray mass spectrometry according to Pitt et al (Pitt et al. omethane in diethyl ether, B-Oxa-23:0 was prepared by hydro 1998 supra). Electrospray ionisation mass spectra (ESI-MS) genation off-Oxa-23:4n-6 in the presence of platinum oxide were recorded on a Finnigan LCQ spectrometer, operating at (Huang et al., 1997 Supra), and 18-monohydroperoxy-f-Oxa a spray voltage of 5.20 kV, capillary temperature of 200° C. 23:4n-6 was prepared by incubation of B-Oxa-23:4n-6 with and capillary voltage of 35V. Analyses were performed in soybean lipoxidase (Huang et al., 1997 Supra). 18-monohy methanol, and ions were reported as their M+H+, M+Na+, or droxy-f-oxa-23:4n-6 was obtained by reduction of the M+K+ ions. 18-monohydroperoxy product with sodium borohydride (Huang et al., 1997 supra). Preparation of Cell Lysates 0182. The products were not individually purified, but 0189 Cell lysates were prepared as previously described were separated by ID TLC (Et2O/hexane/acetic acid; 60:40: for IKB kinase (IKK) activity (Lee etal, Proc. Natl. Acad. Sci. 1). The appropriate lipid Zones were visualized under UV USA 95:9319-9324, 1998), IkBC. degradation, MAP kinase light with dichlorofluoroscein (0.2% v/v) in ethanol and iden activity (Hii et al., 1998 supra) and nuclear translocation of tified by comparison of RFs with those of similar structured analogs. No other mono-hydroxylated materials were evi NFKB (p65 rel) (Jersmann et al. Infect. Immun. 69:1273 dent, but more polar polyhydroxylated compounds would 1279, 2001). have been present in the polar fractions of the chromatogram Western Blot Analysis to Detect NFkB and IKBC. (at the baseline). 0183 Fatty acids and derivatives were dissolved in ethanol (0190. Proteins (50 ug) were separated by SDS PAGE (0.1% final, V/v) (in vitro), dipalmitoylphosphatidylcholine (12% w/v gel), transferred to nitrocellulose and probed with (DPC) (Ferrante et al., 1997 supra) or DSMO (7% v?v) (in an anti-NFKB p65 or anti-IKBC. antibody (Santa Cruz Bio vivo). At these concentrations these diluents did not affect tech, Santa Cruz, Calif.). Immunocomplexes were detected cellular functions. Thin-layer chromatography and gas-liquid by enhanced chemiluminescence (Hii et al., 1998 supra). chromatography-mass spectrometry showed that the lipids were at least 98% pure. IKB Kinase Kinase (IKK) Assay 0191 IKK was immunoprecipitated with anti-IKKO. Neutrophil Respiratory Burst (M-280) antibody (sc-7182, Santa Cruz, Biotech) and kinase 0184 Neutrophil respiratory burst was determined as pre activity determined using GST-IKBA (residues 5-55) as pre viously described (Lee et al., 1998 supra). Proteins were frac viously described (Li et al., J. Clin. Invest. 97:1605-1609, tionated by SDS PAGE and radioactivity associated with 1996). GST-IKBC. (residues 5-55) determined using an instant Neutrophil Adhesion to Human Umbilical Vein Endothelial imager. Cells (HUVEC) Measurement of the Activity of p38, ERK and JNK (0192 ERK and p38 were precipitated with anti-ERK2 0185. Adhesion of neutrophils, prepared by the rapid (C-14, sc-154) and anti-p38 (C-20, sc-535) antibody, respec single-step method (Ferrante et al., J. Immun. Methods tively (Santa Cruz, Biotech) and the activity determined using 36:109-117, 1980), to HUVEC isolated from umbilical cords myelin basic protein as a substrate (Hii et al., 1995 supra, Hii was carried out essentially as described (Huang et al., 1997 et al., 1998 Supra). JNK activity was determined in a solid Supra). phase assay using GST c-Jun (residues-1-79) as a Substrate (Hii et al., 1995 supra, Hii et al., 1998 supra). Measurement of Endothelial Cell Adhesion Molecules Inflammatory Reactions 0186 HUVEC were stimulated with TNF, bacterial lipopolysaccharide (LPS) or PMA for 24 hr. Expression of (0193 Effect of MP3 (B-Oxa-23:4n-6) on the in vivo E-selectin, ICAM-1 and VCAM-1 was determined by an inflammatory response was measured as a delayed type US 2009/0215895 A1 Aug. 27, 2009 44 hypersensitivity (DTH) reaction and LPS-induced influx of the parent molecule but also that the structure of the parent neutrophils and mononuclear cells in the peritoneal cavity in molecule is critical for activity. BALB/c mice. For DTH experiments, mice were injected subcutaneously with 100 ul of 10% hematocrit sheep eryth Effects on TNF-Induced Expression of Adhesion Molecules rocytes, challenged with the antigen (25ul of 40%) in the hind on EC. foot pad 6 days later and the degree of foot pad Swelling measured 48 hr later (Ferrante et al. Clin. & Exp. Immunol. (0197) The inhibitory effect of B-Oxa-23:4n-6 on adhesion 38:70-76, 1979). One hour prior to challenge mice were given was consistent with the ability of B-Oxa-PUFA to suppress the 10 mg/kg body weight of the fatty acid, intraperitoneally. For TNF-C-induced expression of E-selectin (CD62E), intercel peritoneal inflammation, mice were injected with 50 g of lular adhesion molecule-1 (ICAM-1, CD54) and vascular cell LPS intraperitoneally 6 hr after intravenous fatty acid treat adhesion molecule-1 (VCAM-1, CD106) adhesion mol ment. At 24 hr and 72 hr the peritoneal exudate was harvested ecules on HUVEC. As shown in FIG. 13, maximum inhibi and the number and proportion of neutrophils and macroph tion of TNF-C-stimulated E-selectin, ICAM-1 and VCAM-1 expression was observed after 4, 6 and 12 hr of cytokine ages determined microscopically from Giemsa stained treatment respectively, after which there was recovery (par SeaS. ticularly in the case of E-selectin and ICAM-1) up to 24hr. Results The ability of the cells to regain their capacity to express adhesion molecules confirms that the synthetic fatty acid did Effects on the Neutrophil Respiratory Burst not affect their viability. B-Oxa-23:4n-6 inhibited the expres 0194 Unlike natural PUFA, the B-oxa and B-thia com sion of E-selectin, ICAM-1 and VCAM-1 molecules in a pounds are not readily B-oxidized and hence show high levels concentration-dependent manner, which corresponded with of intracellular stability (Pitt et al., 1998 Supra). Compared the levels required to reduce neutrophil adherence. 20:4n-6 with 20:4n-6 and 22:6n-3, B-substituted PUFA were found to had no significant effect on HUVEC adhesion molecule be weak at Stimulating the oxygen radical production in expression compared with 3-oxa-23:4n-6. TNF-C-induced human neutrophils. In the case of MP3 (B-oxa 23:4n-6), a increase in expression of E-selectin mRNA was found to be concentration of up to 30 Jumol/l failed to cause any signifi substantially depressed by B-Oxa-23:4n-6 treatment (FIG. cant respiratory burst (chemiluminescence response), while 13). B-Oxa-23:4n-6 also inhibited LPS and PMA-induced, the same concentration of 22:6n-3 produced marked up-regulation of E-selectin, ICAM-1 and VCAM-1 induced responses, similar to the strong neutrophil activator, PMA by these agonists. (FIG. 10). In Vivo Activity of B-Oxa-23:4n-6 (MP3). 0198 The B-oxa fatty acid was also found to be active in Effects on TNF-Induced Up-Regulation of Neutrophil Adher vivo. Mice sensitized with sheep erythrocytes were inhibited ence to HUVEC in ability to manifesta delayed type hypersensitivity reaction to this antigen if given an injection of B-oxa 23:4n-61 day (0195 Data in FIG. 11 show that pre-treatment of HUVEC prior to antigen challenge (FIG. 14A). This illustrated an for 1 hr with B-Oxa-PUFA (B-Oxa-23:4n-6, 3-oxa-21:3n-6, effect on chronic inflammation probably through the inhibi B-Oxa-21:3n-3) or B-thia-PUFA (B-thia-23:4n-6, B-thia-21: tion of T cells and monocytes binding to the endothelium. 3n-6 f-thia-21:3n-3) inhibited their ability to be stimulated When an acute inflammatory reaction (24 hr) was induced in by tumour necrosis factor-O. (TNF-C.) for enhanced neutro mice by intraperitoneal injection of LPS, treatment with phil adhesion. In contrast, pre-treatment with the naturally B-oxa 23:4n-6 inhibited the neutrophil influx (FIG. 11A). A occurring PUFA, 20:4n-6, octadecadienoic acid (linoleic similar inhibition of chronic inflammation was seen in terms acid, 18:2n-6) and 22:6n-3, had no significant effect on the of the inhibition of the mononuclear cell infiltrate after 72 hr cytokine-induced adhesion of leukocytes to HUVEC. (FIG. 14A). Although the fatty acids were presented to the cells with ethanol as diluent (0.1% V/v final concentration), similar 0199 The in vitro effects of B-Oxa-23:4n-6 on adhesion results were obtained using mixed fatty acid-DPC micelles. molecule expression on endothelial cells was confirmed in Trypan blue exclusion and lack of Cr chromate release mice treated with LPS (FIG. 14B). Mice treated with B-Oxa from labeled cells showed that the cells remained viable 23:4n-6 showed a significant reduction in LPS-induced E-se under these experimental conditions. Furthermore, the engi lectin expression in aortic endothelium. neered fatty acids did not affect DNA synthesis, glucose metabolism and G3PDH mRNA expression in HUVEC. MP3 Metabolism of B-oxa 23:4n-6 in HUVEC. caused the greatest suppression of TNF-C.-induced neutrophil (0200. After incubation of HUVEC with B-Oxa-23:4n-6 for adhesion to HUVEC (FIG. 11) and was, therefore, employed 60 min, Small amounts of three oxygenated fatty acids prod in further studies. The magnitude of the suppressive effect of ucts were observed. The totalion chromatogram produced by -MP3 was dependent on-pre-treatment time and concentra electrospray MS of the combined products showed a molecu tion with significant effects observed with a pre-treatment lar ion at m/z. 365 (M+1) (expected for mono-hydroxylated time of 1 hr and a concentration of 25 umol/l. In addition, analogs off-Oxa-23:4n-6). Three daughter ions were found at B-oxa 23:4n-6 inhibited the increase in neutrophiladhesion to m/Z 264. 224 and 132 corresponding to loss of a CHO, HUVEC induced by bacterial lipopolysaccharide (LPS) or CH7O and CHO fragment, resulting from C7-Cs. C PMA. Cs and C7-C bond cleavage, respectively. These fragments Effects of Derivatives of MP3 (B-Oxa-23:4n-6) unambiguously confirm the identification of the three oxy 0196) Derivatization of MP3 to methylated, saturated and genated products with mono hydroxyl group at carbons 18, 18-monohydroxy- and hydroperoxy-forms abolished its 15, and 8 (FIG. 15). The 15-hydroxylated derivative was the inhibitory effect on TNF-C.-stimulated neutrophiladhesion to major component (>90%). Pre-treatment of HUVEC with HUVEC (FIG. 12), demonstrating not only the specificity of nordihydroguairetic acid (NDGA, a non-selective lipoxyge US 2009/0215895 A1 Aug. 27, 2009

nase inhibitor) markedly suppressed the formation of the (0204. The effects of B-oxa 23:4n-6 on TNF induced acti oxygenated fatty acid products of B-oxa 23:4n-6, whereas vation of NFkB was confirmed by examining the transloca indomethacin (a cyclooxygenase inhibitor) had no effect. tion of the NFKB to the nucleus. The data showed inhibition Together, these results provide evidence that HUVEC con of translocation of NFkB to the nucleus (FIG. 17B) verted B-Oxa-23:4n-6 to 18-, 15- and 8-mono-hydroxylated (0205 To see whether the effects of B-oxa 23:4n-6 on IKBC. derivatives (FIG. 15) by the lipoxygenase enzyme pathway, degradation could be due to inhibition of IKK activation, cells i.e. an enzymatic process rather than by auto-oxidation. Iso were pre-treated with B-oxa 23:4n-6, then stimulated with meric forms of monohydroxylated 20:4n-6 are synthesized TNF and assayed for IKK activation. The results showed that from 20:4n-6 by cells via the action of stereo-specific lipoxy B-oxa 23:4n-6 significantly inhibited the activation IKK (FIG. 17C). genase enzymes (Spector et al. Prog. Lipid. Res. 27:271-323, 0206. The data demonstrate that by placing an oxygen or 1988). In HUVEC the lipoxygenase activity is mainly attrib sulphur atom in the f-position of a PUFA, molecules can be uted to the 15-lipoxygenase (Buchanan et al. Haemostasis generated which vary in biological activities from the natural 18:360-375, 1988). The lipoxygenase positional isomer n-3 PUFA. An important characteristic of the B-Oxa/B-thia specificity is determined by the carbon chain length from the compounds was their greatly reduced ability to stimulate the methyl end of the fatty acid substrates. Since B-Oxa-23:4n-6 neutrophils respiratory burst but which retained or increased has three additional carbon atoms in its chain compared to anti-inflammatory properties displayed by then-3PUFA. The 20:4n-6, it is likely that the 18-, 15- and 8-monohydroxylated 3-oxa and B-thia PUFA significantly decreased the agonist derivatives of B-Oxa-23:4n-6 are formed by the 15-, 12- and induced increase of neutrophil adhesion to the endothelium, 5-lipoxygenases respectively in HUVEC. while 20:4n-6 and 22:6n-3 showed no inhibition of this response under these conditions. However, longer term expo The Importance of the 12-LO in the Action of B-oxa 23:4n-6 sure of HUVEC to 22:6n-3 had previously been shown to decrease up-regulation of adhesion properties of these cells 0201 Confluent second-passage HUVEC in 96-well tis (De Caterina etal, Arterioscler Thromb. 14:1929-1936, 1994, sue culture plates were pre-treated with 10 umol/l NDGA Weber et al, Arterioscler Thromb. Vasc. Biol. 15:622-628, (non-selective lipoxygenase inhibitor); 10 Jumol/lbaicalein (a 1995). The most active of these newly synthesized com specific 12-lipoxygenase inhibitor); 500 nM MK886 (an pounds was 3-oxa 23:4n-6. The corresponding 3-thia 23:4n-6 inhibitor of the 5-lipoxygenase activating protein), 10 mmol/l was less active than this f-oxa compound. This illustrates indomethacin (a cyclooxygenase inhibitor); 10 Limol/l Vita how fatty acids bearing the same structural elements can vary min E (an antioxidant); or diluent (control) for 15 min. The dramatically in activity depending on whether these contain cells were then further incubated with 20 umol/l B-Oxa-23: an oxygen or Sulphur atom in the B-position. The novel PUFA 4n-6 or diluent (control) for 60 min followed by TNF-C. (125 and in particular B-oxa 23:4n-6, are therefore, similar in bio logical properties to the 15-HPETE which was shown to lack U) for 4 h. The expression of E-selectin adhesion molecule the ability to stimulate oxygen radicals in neutrophils but was determined by ELISA. While none of the inhibitors/ inhibited leukocyte adhesion to endothelial cells (Huang etal, antioxidants affected the ability of TNF to enhance E-selectin 1997 supra, Sethi et al., J. Lab. Clin. Med. 128:27-38, 1996) expression on HUVEC, the ability of B-oxa 23:4n-6 to sup and TNF production by macrophages (Ferrante et al., 1997 press the action of TNF was reduced when the cells were Supra). pre-treated with either NDGA or baicalein but not with 0207 Those skilled in the art will appreciate that the indomethacin, Vitamin E or MK886 (FIG.16). This indicated invention described herein is susceptible to variations and that conversion off-Oxa-23:4n-6 to an oxygenated product(s) modifications other than those specifically described. It is to via the 12-lipoxygenase pathway was important for the be understood that the invention includes all such variations inhibitory activity of the fatty acid. It is unlikely that oxygen and modifications. The invention also includes all of the steps, ated products formed by the 15-lipoxygenase are involved in features, compositions and compounds referred to or indi the inhibitory action of B-Oxa-23:4n-6 because the 18-mono cated in this specification, individually or collectively, and hydroxy/hydroperoxy derivatives were inactive (FIG. 12). any and all combinations of any two or more of said steps or features. Effects of B-oxa 23:4n-6 (MP3) on TNF-Induced Activation BIBLIOGRAPHY of Intracellular Signalling Molecules. 0208 Buchanan et al, Haemostasis 18:360-375, 1988 0202) Examination of the effects of B-oxa 23:4n-6 on 0209 Chou et al, Curr Biol. 8:1069-77, 1998 intracellular signalling molecules involved in TNF-induced 0210 Costabile et al., J. Immunol. 167:2980-2987, 2001 expression of these adhesion molecules, showed that pre 0211 Couper et al, Diabetologia 37:533-535, 1994 treatment of HUVECs with the fatty acid did not affect the 0212 De Caterina et al. Arterioscler Thromb. 14:1929 1936, 1994 ability of TNF to stimulate p38, ERK and JNK. 0213 Dekker et al, Biochem J. 347:285-289, 2000 0203 The effects of the B-oxa PUFA on the IKK-NFKB 0214) Ferrante et al., Clin. & Exp. Immunol. 38:70-76, pathway were also examined which is important in the stimu 1979 lation of expression of adhesion molecules on endothelial 0215 Ferrante etal, J. Immun. Methods 36:109-117, 1980 cells (Read etal, J. Biol. Chem. 272:2753-61, 1997). In this 0216 Ferrante and Thong, J. Immun. Methods 48:81-85, pathway, IkB, which ordinarily sequesters NFKB in the cyto 1982 plasm, is phosphorylated by IKK. This phosphorylation tar 0217 Ferrante et al., J. Clin. Invest. 99:1445-1452, 1997 gets IKB for degradation, thereby allowing the nuclear trans 0218 Ferrante et al. In The Neutrophils: New outlook for location of NFkB. HUVEC pre-treated with B-oxa 23:4n-6 the old cells Ed Garbilovich Imperial College Press 4:79 showed marked inhibition of IKBC. degradation (>92%) 150, 1999 induced by TNF (FIG. 17A). In comparison, the same con 0219. Hietal, J. Biol. Chem. 266:20238-20243, 1991 centration of DHA caused less than 50% inhibition of TNF 0220 Hii et al., J. Biol. Chem. 270:42.01-4204, 1995 stimulated IKB degradation (FIG. 17A). 0221 Hietal, J. Biol. Chem. 273:19277-19282, 1998 US 2009/0215895 A1 Aug. 27, 2009 46

0222 Huang et al., Circ. Res. 80:149-158, 1997 heteroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0. 0223 Jaken et al, Bioessays 22:245-254, 2000 1, 2 or 3 and X is O.S or NRs. Y is OR, SR or NRR and 0224 Jersmann et al., Infect. Immun. 69:1273-1279, 2001 Rs. Ro, Ro R and R2 are selected from H. alkyl, alkenyl, 0225. Jirousek et al., J. Med. Chem. 39:2664-2671, 1996 alkynyl, aryland heteroaryl, 8 is 0 or 1; 0226 Kikkawa et al, Diabetologia 37:838–841, 1994 each of Rs. Rs and R, is respectively (CH2)(COOH), 0227 Korchak et al., J. Biol. Chem. 269:30281-30287, (CH,), (COOH), and (CH,)(COOH), wherein 1994 each of, m and p is 0, 1, 2, 3, 4, 5 or 6, each of k, n and 0228. Koya et al., J. Clin. Invest. 100:115-126, 1997 q is 0, 1 or 2, 0229. Koya et al. Diabetes 47:859-866, 1998 and each of 1, o and r is 0 or 1, 0230. Lallena et al, Mol. Cell. Biol. 19:2180-2188, 1999 each of c i and f is 0 or 1 or 2; 0231. Lee etal, Proc. Natl. Acad. Sci. USA 95:9319-9324, each of a, d and g is 0 or 1 or 2; 1998 each of b, e and h is 0 or 1 or 2: 0232 Lietal, J. Clin. Invest. 97:1605-1609, 1996 said administration being for a time and under conditions 0233. Musial etal, J. Biol. Chem. 270:21632-21638, 1995 sufficient to prevent the condition or to ameliorate one or 0234 Pitt et al. Synthesis 11:1240-1242, 1997 more symptoms of the condition. 0235 Pitt et al, Chem. Phys. Lipids. 92:63-39, 1998 2. The method of claim 1 wherein the subject is a mammal. 0236 Powell et al., J. Immunol. 159:2952-2959, 1997 3. The method of claim 2 wherein the mammal is a human. 0237 Read etal, J. Biol. Chem. 272:2753-61, 1997 4. The method of claim 1 wherein in Formula (I) each of i, 0238 Robinson etal, Biochem J. 336:611-617, 1998 c and f is 0 (zero), two of i, c and f is 0 (zero) or one of i, cand 0239 Scivittaro et al, Am. J. Physiol. 278:F676-F683, f is 0 (zero); or each of i, c and f is 1; two of i, c and f is 1 or 2OOO one of i, c and fis 1; or each of i, c and fis two, two of i, c and 0240 Sethi et al., J. Lab. Clin. Med. 128:27-38, 1996 f is two, or one of i, c and f is two. 0241 Sinclair and Gibson (Eds) Invited papers from the 5. The method of claim 1 wherein in Formula (I) each of g, Third International Congress, American Oil Chemists a and d is 0 (zero), two of g, a and d is 0 (zero) or one of g, a Society, Champaign, Ill., 1-482, 1992 and d is 0 (zero); or each of g, a and d is 1; two of g, a and d 0242 Spector et al. Prog. Lipid Res. 27:271-323, 1988 is 1 or one of g, a and d is 1; or each of g, a and d is two, two 0243 Suzuma et al., J. Biol. Chem. 277: 1047-1057, 2002 of g, a and d is two, or one of g, a and d is two. 0244 Way et al, Diabetic Medicine 18:945-959, 2001 6. The method of claim 1 wherein in Formula (I) each of h, 0245 Weber et al. Arterioscler Thromb. Vasc. Biol. b and e is 0 (zero), two of h, b and e is 0 (zero) or one of h, b 15:622-628, 1995 and e is 0 (zero); or each of h, b and e is 1; two of h, bande is 0246 Xia et al., J. Clin. Invest. 98:2018-2026, 1996 1 or one of h, band e is 1; or each of h, band e is two, two of 1. A method for the treatment or prophylaxis of a condition h, b and e is two, or one of h, b and e is two. selected from a NFKB related or associated condition, a 7. The method of claim 1 wherein the L-amino acid is PKCB related or associated condition, vascular or immuno selected from alanine, arginine, asparagine, aspartic acid, logical conditions such as diabetes, inflammation, neurologi cysteine, glutamine, glutamic acid, glycine, histidine, isoleu cal conditions, cardiovascular disease and pain in a subject cine, leucine, lysine, methionine, phenylalanine, proline, said method comprising administering to said Subject an serine, threonine, tryptophan, tyrosine and Valine. effective amount of a compound having the structure of For 8. The method of claim 1 wherein a chemical analog of an mula (I): amino acid is selected from C.-aminobutyric acid, C.-amino C.-methylbutyrate, aminocyclopropane-, carboxylate, ami noisobutyric acid, aminonorbornyl-, carboxylate, cyclohexy (I) Role-Ryll, lalanine, cyclopentylalanine, D-alanine, D-arginine, D-aspartic acid, methylmethionine, D-cysteine, N-methyl R1-R2 R3. norleucine, D-glutamine, D-glutamic acid, methylornithine, D-histidine, N-methylphenylalanine, D-isoleucine, D-leu cine, D-lysine, D-methionine, D-Ornithine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine, wherein D-valine, D-O-methylalanine, D-O-methylarginine, D-O-me R is a saturated or unsaturated hydrocarbon chain of from thylasparagine, D-O-methylaspartate, D-O-methylcysteine, about 9 to about 26 carbonatoms and which is optionally D-O-methylglutamine, D-O-methylhistidine, D-O-methyli carries one or more of a oxa, thia, hydroxy, hydroperoxy, soleucine, D-O-methyleucine, D-O-methyllysine, D-O-me epoxy and peroxy Substitution; thylmethionine, D-O-methylornithine, D-O-methylphenyla each of R. RandR is selected from O NO, NO, S(O), lanine, D-O-methylproline, D-C.-methylserine, D-C.- methylthreonine, D-O-methyltryptophan, D-O- C(H), H, COOH, P(x)(Y), N(H), C-O,OH, methyltyrosine, D-O-methylvaline, D-N-methylalanine, D-N-methylarginine, D-N-methylasparagine, D-N-methy O laspartate, D-N-methylcysteine, D-N-methylglutamine, D-N-methylglutamate, D-N-methylhistidine, D-N-methyli -C-NH soleucine, D-N-methyleucine, D-N-methyllysine, N-meth ylcyclohexylalanine, D-N-methylornithine, N-methylgly C. alkyl, C- alkoxy, amino, mono-acid di-C alky cine, N-methylaminoisobutyrate, N-(1-methylpropyl) lamino, Ce alkylthio. S(O), C alkyl, Calkoxycarbo glycine, N-(2-methylpropyl)glycine, D-N- nyl, halo selected from fluoro, chloro, bromo and iodo, OXo, methyltryptophan, D-N-methyltyrosine, D-N-methylvaline, amidino and guanidino, C2-12 alkenyl, C2-12 alkynyl, aryl, y-aminobutyric acid, L-t-butylglycine, L-ethylglycine, L-ho

US 2009/0215895 A1 Aug. 27, 2009 50

-continued -continued

19:3 (n-3)-

COO

23:4 (n-y-NO2

19:3 (n-6)-2

COOH

NO

COOH

Y, Y(COOH), 19:0-2

23:6 (n-3)-2

22:6n-3 Gly (PT5) 13. The method of claim 1 wherein the treatment is for pain including interalia neuropathic or neurological pain, chronic pain, acute pain, migraine, headache inflammatory pain, post operative pain, pain due to multiple Sclerosis, Parkinson's NH A COO disease or other neurological or autoimmune disorder or fol lowing or during periods of anxiety, delayed onset muscle Soreness, burns or during or following infection or a convul 18:3n-3 Asp (PT10) Sion, post-poliomyelitic pain, bipolar disorder, panic attack or NO epilepsy. 14. The method of claim 1 wherein the treatment is for depression, including major depression (single episode, 19:0- recurrent, melancholic), atypical, dysthymia, Subsyndromal, agitated, retarded, co-morbid with cancer, diabetes, or post NO myocardial infarction, involutional, bipolar disorder, psy chotic depression, endogenous and reactive, obsessive-com COO pulsive disorder, or bulimia. In addition, NAALADase inhibitors can be used to treat patients suffering from pain (given alone or in combination with morphine, codeine, or dextroproposyphene), obsessive-compulsive personality dis order, post-traumatic stress disorder, hypertension, athero US 2009/0215895 A1 Aug. 27, 2009

Sclerosis, anxiety, anorexia nervosa, panic, social phobia, Delusional Disorder. Other or Unspecified Psychoactive Sub Stuttering, sleep disorders, chronic fatigue, cognition deficit stance Hallucinosis. Other or Unspecified Psychoactive Sub associated with Alzheimer's disease, alcohol abuse, appetite stance Mood Disorder. Other or Unspecified Psychoactive disorders, weight loss, agoraphobia, improving memory, Substance Anxiety Disorder. Other or Unspecified Psychoac amnesia, Smoking cessation, nicotine withdrawal syndrome tive Substance Personality Disorder. Other or Unspecified symptoms, disturbances of mood and/or appetite associated Psychoactive Substance Organic Mental Disorder NOS, with pre-menstrual syndrome, depressed mood and/or carbo Delirium, Dementia, Organic Delusional Disorder, Organic hydrate craving associated with pre-menstrual syndrome, Hallucinosis, Organic Mood Disorder, Organic Anxiety Dis disturbances of mood, disturbances of appetite or distur order, Organic Personality Disorder, Organic Mental Disor bances which contribute to recidivism associated with nico der. Obsessive Compulsive Disorder, Post-traumatic Stress tine withdrawal, circadian rhythm disorder, borderline per Disorder, Generalized Anxiety Disorder, Anxiety Disorder Sonality disorder, hypochondriasis, pre-menstrual syndrome NOS, Body Dysmorphic Disorder, Hypochondriasis (or (PMS), late luteal phase dysphoric disorder, pre-menstrual Hypochondriacal Neurosis), Somatization Disorder. Undif dysphoric disorder, trichotillomania, symptoms following ferentiated Somatoform Disorder, Somatoform Disorder discontinuation of other antidepressants, aggressive/intermit NOS, Intermittent Explosive Disorder, Kleptomania, Patho tent explosive disorder, compulsive gambling, compulsive logical Gambling, Pyromania, Trichotillomania and Impulse spending, compulsive sex, psychoactive Substance use disor der, sexual disorder, Schizophrenia, premature ejaculation, or Control Disorder NOS. psychiatric symptoms selected from stress, worry, anger, 16. The method of claim 1 wherein the treatment is for rejection sensitivity, and lack of mental or physical energy. Schizophrenia, Catatonic, Subchronic, Schizophrenia, Cata 15. The method of claim 1 wherein the treatment is for tonic, Chronic, Schizophrenia, Catatonic, Subchronic with Moderate Mental Retardation, Severe Mental Retardation, Acute Exacerbation, Schizophrenia, Catatonic, Chronic with Profound Mental Retardation, Unspecified Mental Retarda Acute Exacerbation, Schizophrenia, Catatonic, in Remission, tion, Autistic Disorder, Pervasive Development Disorder Schizophrenia, Catatonic, Unspecified, Schizophrenia, Dis NOS, Attention-Deficit Hyperactivity Disorder, Conduct organized, Chronic, Schizophrenia, Disorganized, Sub Disorder, Group Type, Conduct Disorder, Solitary Aggres chronic with Acute Exacerbation, Schizophrenia, Disorga sive Type, Conduct Disorder. Undifferentiated Type, nized, Chronic with Acute Exacerbation, Schizophrenia, Tourette's Disorder, Chronic Motor or Vocal Tic Disorder, Disorganized, in Remission, Schizophrenia, Disorganized, Transient Tic Disorder, Tic Disorder NOS, Primary Degen Unspecified, Schizophrenia, Paranoid, Subchronic, Schizo erative Dementia of the Alzheimer Type, Senile Onset, phrenia, Paranoid, Chronic, Schizophrenia, Paranoid, Sub Uncomplicated, Primary Degenerative Dementia of The chronic with Acute Exacerbation, Schizophrenia, Paranoid, Alzheimer Type, Senile Onset, with Delirium, Primary Chronic with Acute Exacerbation, Schizophrenia, Paranoid, Degenerative Dementia of the Alzheimer Type, Senile Onset, in Remission, Schizophrenia, Paranoid, Unspecified, Schizo with Delusions, Primary Degenerative Dementia of the phrenia, Undifferentiated, Subchronic, Schizophrenia, Alzheimer Type, Senile Onset, with Depression, Primary Undifferentiated, Chronic, Schizophrenia, Undifferentiated, Degenerative Dementia of the Alzheimer Type, Presenile Subchronic with Acute Exacerbation, Schizophrenia, Undif Onset, Uncomplicated, Primary Degenerative Dementia of ferentiated, Chronic with Acute Exacerbation (295.94), the Alzheimer Type, Presenile Onset, with Delirium, Primary Schizophrenia, Undifferentiated, in Remission, Schizophre Degenerative Dementia of the Alzheimer Type, Presenile Onset, with Delusions, Primary Degenerative Dementia of nia, Undifferentiated, Unspecified, Schizophrenia, Residual, the Alzheimer Type, Presenile Onset, with Depression, Multi Subchronic, Schizophrenia, Residual, Chronic, Schizophre infarct dementia, Uncomplicated, Multi-infarct dementia, nia, Residual, Subchronic with Acute Exacerbation, Schizo with Delirium, Multi-infarct Dementia, with Delusions, phrenia, Residual, Chronic with Acute Exacerbation, Schizo Multi-infarct Dementia, with Depression, Senile Dementia phrenia, Residual, in Remission, Schizophrenia, Residual, NOS, Presenile Dementia NOS, Alcohol Withdrawal unspecified, Delusional (Paranoid) Disorder, Brief Reactive Delirium, Alcohol Hallucinosis, Alcohol Dementia Associ Psychosis, Schizophreniform Disorder, Schizoaffective Dis ated with Alcoholism, Amphetamine or Similarly Acting order, induced Psychotic Disorder, Psychotic Disorder NOS Sympathomimetic Intoxication, Amphetamine or Similarly (Atypical Psychosis), Bipolar Disorder, Mixed, Severe, with Acting Sympathomimetic Delusional Disorder, Cannabis out Psychotic Features, Bipolar Disorder, Manic, Severe, Delusional Disorder, Cocaine Intoxication, Cocaine without Psychotic Features, Bipolar Disorder, Depressed, Delirium, Cocaine Delusional Disorder, Hallucinogen Hallu Severe, without Psychotic Features, Bipolar Disorder, Mixed, cinosis (305.30), Hallucinogen Delusional Disorder, Hallu with Psychotic Features, Bipolar Disorder, Manic, with Psy cinogen Mood Disorder, Hallucinogen Posthallucinogen Per chotic Features, Bipolar Disorder, Depressed, with Psychotic ception Disorder, Phencyclidine (PCP or Similarly Acting Features, Bipolar Disorder NOS, Major Depression, Single Arylcyclohexylamine Intoxication, Phencyclidine (PCP) or Episode, with Psychotic Features, Major Depression, Recur Similarly Acting Arylcyclohexylamine Delirium, Phencycli rent with Psychotic Features Personality Disorders, Paranoid dine (PCP) or Similarly Acting Arylcyclohexylamine Delu Personality Disorders, Schizoid, Personality Disorders, sional Disorder, Phencyclidine (PCP) or Similarly Acting Schizotypal, Personality Disorders, Antisocial, Personality Arylcyclohexylamine Hood Disorder, Phencyclidine (PCP) Disorders and Borderline. or Similarly Acting Arylcyclohexylamine Organic Mental 17. The method of claim 1 wherein the treatment is for Disorder NOS, Other or unspecified Psychoactive Substance Anxiety Disorders, Panic Disorder), Panic Disorder with Intoxication. Other or Unspecified Psychoactive Substance Agoraphobia, Panic Disorder without Agoraphobia, Agora Delirium, Other or Unspecified Psychoactive Substance phobia without History of Panic Disorders, Social Phobia, Dementia, Other or Unspecified Psychoactive Substance Simple Phobia, Organic Anxiety Disorder, Psychoactive Sub US 2009/0215895 A1 Aug. 27, 2009 52 stance Anxiety Disorder, Separation Anxiety Disorder, each of R. RandR is selected from O., NO, NO, S(O), Avoidant Disorder of Childhood or Adolescence, and Over C(H), H, COOH, PCX)(Y), N(H), C=O,OH, anxious Disorder. 18. The method of claim 1 wherein the treatment is for O cardiovascular disease includes strokes and any condition of the systemic vasculature and includes atherosclerosis, -C-NH chronic heart failure and general heart disease. C- alkyl, C- alkoxy, amino, mono-acid di-C alky 19. A compound of general Formula (I) lamino, Ce alkylthio. S(O), C alkyl, Calkoxycarbo nyl, halo selected from fluoro, chloro, bromo and iodo, OXo, amidino and guanidino, C2-12 alkenyl, C2-12 alkynyl, aryl, (I) Role-Ryll, heteroaryland cyano, wherein X and Z are 0, 1 or 2 and y is 0. 1, 2 or 3 and X is O.S or NRs. Y is OR, SR or NRR and k- R2 R3. Rs. Ro Ro, R., and R2 are selected from H. alkyl, alkenyl, alkynyl, aryland heteroaryl, 8 is 0 or 1; each of Rs. Rs and R7 is respectively (CH),(COOH), (CH),(COOH), and (CH)(COOH), wherein each of, m and p is 0, 1, 2, 3, 4, 5 or 6, each of k, n and wherein q is 0, 1 or 2, and each of 1, o and r is 0 or 1, each of c, i and f is 0 or 1 or 2; and R is a saturated or unsaturated hydrocarbon chain of from each of a, d and g is 0 or 1 or 2; about 9 to about 26 carbonatoms and which is optionally each of b, e and h is 0 or 1 or 2. carries one or more of a oxa, thia, hydroxy, hydroperoxy, epoxy and peroxy Substitution; c c c c c