DOCSLIB.ORG

Nutritional Rickets: Vitamin D, Calcium, and the Genetic Make-Up

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Nutritional Rickets: Vitamin D, Calcium, and the Genetic Make-Up nature publishing group Articles Translational Investigation Nutritional rickets: vitamin D, calcium, and the genetic make-up Mohamed El Kholy1, Heba Elsedfy1, Monica Fernández-Cancio2, Rasha Tarif Hamza1, Nermine Hussein Amr1, Alaa Youssef Ahmed1, Nadin Nabil Toaima1 and Laura Audí2 BACKGROUND: The prevalence of vitamin D (vitD) deficiency pigmentation are therefore main determinants of circulat- presenting as rickets is increasing worldwide. Insufficient sun ing vitD levels (2) that can be increased through dietary vitD exposure, vitD administration, and/or calcium intake are the intake (3). Interindividual differences in aspects of the vitD main causes. However, vitD system-related genes may also endocrine system have been well documented. They could be have a role. caused by genetic differences in important proteins in the vitD METHODS: Prospective study: 109 rachitic children com- endocrine system, such as VDR (4–6). pleted a 6-mo study period or until rachitic manifestations Multiple polymorphic variations exist in the VDR gene: disappeared. Thirty children were selected as controls. Clinical 5’-promoter variations can affect mRNA expression pat- and biochemical data were evaluated at baseline in patients terns and levels while 3’-UTR sequence variations can affect and controls and biochemistry re-evaluated at radiological mRNA stability and/or protein translation efficiency (7–10). healing. Therapy was stratified in three different protocols. Other genes encoding proteins in the vitD endocrine sys- Fifty-four single-nucleotide polymorphisms (SNPs) of five vitD tem (25-hydroxylase (CP2R1), 1-α-hydroxylase (CYP27B1), system genes (VDR, CP2R1, CYP27B1, CYP24A1, and GC) were 24-hydroxylase (CYP24A1), and vitamin D binding globulin genotyped and their association with clinical and biochemcial (GC)) also present polymorphic variations that could influ- data was analyzed. ence vitD synthesis efficiency and circulating 25-OH-D circu- RESULTS: Therapy response was similar in terms of radiologi- lating levels (9). cal healing although it was not so in terms of biochemical nor- It has long been speculated that genetic predisposition may malization. Only VDR gene (promoter, start-codon, and intronic influence the manifestations of vitD deficiency. Accordingly, in a genotypes) was rickets-associated in terms of serum 25-OH-D, prospective series of rickets patients, we attempted to analyze the calcium, radiological severity and time needed to heal. Eight role of genotypes of VDR and other genes related to the vitD sys- patients with sufficient calcium intake and 25-OH-D levels car- tem on rickets predisposition, severity, and response to therapy. ried a VDR genotype lacking minor allele homozygous geno- types at SNPs spread along the gene. METHODS CONCLUSION: Although patients presented epidemiologic Patients and Controls factors strongly contributing to rickets, genetic modulation Rachitic infants and children attending the Pediatric Outpatient affecting predisposition, severity, and clinical course is exerted, Clinic, Ain Shams University, Cairo, Egypt (latitude 30.01N) were included. Participation was voluntary and written informed con- at least in part, by VDR gene polymorphic variation. sent was obtained from parents or guardians. The study protocol was approved by the Ethics Committee of the University. This was a prospective study: 168 consecutive rachitic patients he prevalence of vitamin D (vitD) deficiency presenting as presenting within a time frame of 12 mo were included (recruitment period included winter and summer, as the sun is shining all the year Trickets in children is increasing worldwide owing to insuf- round in Egypt). Only 109 children either completed the 6-mo fol- ficient vitD intake and lack of exposure to sunlight. However, low-up period or continued on treatment until their rachitic manifes- considering that relatively few children with low serum tations disappeared. Inclusion criteria included clinical and radiological evidence of 25-hydroxyvitamin D (25-OH-D) levels have symptoms, rickets and age from 7 mo to 3 y. Children were excluded if they had genetic factors may additionally be linked to the manifestation taken vitD or calcium supplements during the 6 mo prior to the study, of vitD deficiency and rickets (1). if they had a history of kidney disease, tuberculosis, liver disease, pre- As natural food contains scant amounts of vitD, humans maturity, intestinal, cardiac, central nervous system, or other chronic disease. Bone disease (with the exclusion of rickets) or a history of naturally obtain vitD through precursor photosynthesis of hereditary forms of rickets together with weight <60% of the mean UVB-dependent vitamin D3. Sunlight exposure and skin weight for height were also exclusion criteria. 1Pediatrics Department, Ain Shams University, Cairo, Egypt; 2Pediatric Endocrinology Research Unit, VHIR (Vall d’Hebron Institut de Recerca), Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, CIBERER (Center for Biomedical Research on Rare Diseases), Instituto de Salud Carlos III, Barcelona, Spain. Correspondence: Laura Audí ([email protected]) Received 7 June 2016; accepted 23 August 2016; advance online publication 14 December 2016. doi:10.1038/pr.2016.222 356 Pediatric Research Volume 81 | Number 2 | February 2017 Copyright © 2017 International Pediatric Research Foundation, Inc. Rickets: nutrition and genetics Articles Thirty age- and sex-matched children were selected as controls Serum 25-OH-D was measured by an enzyme-linked immuno- from siblings of nonrachitic patients attending the outpatient clinic assay method (Immunodiagnostik AG, Bensheim, Germany). The or children with minor illnesses such as upper respiratory tract detection limit of the assay was 2.24 ng/ml. infections. Intact PTH was assayed by enzyme-linked immunoassay using Data Collection reagents supplied by Biosource (Biosource Europe SA, Nivelles, Belgium). Assay sensitivity was 2 pg/ml (range 15–1,040 pg/ml). Nutritional data collection included: type of feeding, whether breast In patients, 25-OH-D and intact PTH were measured in baseline fed or not, duration of breast feeding, and weaning. Dietary calcium samples and again at the end of the study (X-ray score of zero). In con- and caloric intake were calculated according to a food frequency trols, 25-OH-D and intact PTH were measured in baseline samples. questionnaire based on the pattern of diet in Egypt and compiled by the National Nutrition Institute (11). Calcium insufficiency was arbi- Radiological Evaluation trarily defined as an intake <50% of the recommended dietary allow- Assessment of rickets severity was made using standard X-rays of both ance (RDI) (12). Parents were asked to report the whole dietary intake wrists and knees. A 10-point scoring system was used (zero “normal”) in detail on the preceding day on two separate occasions. to a maximum score of 10 (19). Radiographs were examined by two Nutritional status was determined according to the Wellcome Trust independent observers and the score was taken as the mean of their Classification (13). scores. X-ray scores were determined at baseline, 2 wk after the start Sunlight exposure evaluation included children’s type of clothing of treatment and then monthly till radiological healing. The criterion and time spent outdoors every day. Sun exposure of 2 h per week for healing was an X-ray score of zero and time to healing was calcu- on the face and hands was considered sufficient to maintain normal lated as months needed to achieve a null X-ray score. 25-OH-D concentrations (14). The amount of sun exposure was mea- Vitamin D System Gene Polymorphisms sured by calculating the total body surface area exposed to the sun while wearing usual clothes using the Lund and Browder charts (15). Genotyping of 28 single-nucleotide polymorphisms (SNP) of VDR Exposure duration was calculated by finding the average time spent (Table 1), 4 SNPs of CP2R1 (25-hydroxylase: rs10741657, rs12794714, outdoors per week (in hours) during the period of direct sunlight rs10500804 and rs1993116), 1 SNP of CYP27B1 (1-α-hydroxylase: (0900–1500 h), where sun exposure index = hours of sun exposure rs4646536), 10 SNPs of CYP24A1 (24-hydroxylase: rs4809960, per week × fraction of body surface area exposed to sunlight (16). rs2181874, rs6022994, rs6022993, rs912505, rs751089, rs1570670, Assessment of socioeconomic status was done according to the cri- rs927651, rs927650, and rs4809957), and 11 SNPs of GC (vitamin D teria of El-Bohy (17), based on: paternal profession, educational level, binding globulin: rs222020, rs222016, rs1491719, rs4364228, rs4752, type of housing, family income, income source (regular or irregular). rs222035, rs7041, rs4588, rs2298850, rs3755967, and rs2282679), was performed using Applied Biosystems TaqMan and OpenArray tech- Patient Classifications and Therapeutic Groups nologies (Life Technologies, Carlsbad, CA). Patients were stratified from the start in three groups according to Statistical Analysis adequacy of sun exposure and calcium intake. The aim was to deter- mine whether by history alone, the cause of nutritional rickets could JMP 7.01 (SAS Institute, Cary, NC) was used for data entry and analy- be established and the appropriate treatment chosen. sis. Numeric variables were expressed as mean ± SD when normally Group 1: Thirty patients with adequate sun exposure (sun expo- distributed and as median and interquartile range when nonpara- sure ≥2 h/week) and inadequate calcium intake (<50% RDI).
Load more

Recommended publications
  • Prospective Isolation of NKX2-1–Expressing Human Lung Progenitors Derived from Pluripotent Stem Cells
    The Journal of Clinical Investigation RESEARCH ARTICLE Prospective isolation of NKX2-1–expressing human lung progenitors derived from pluripotent stem cells Finn Hawkins,1,2 Philipp Kramer,3 Anjali Jacob,1,2 Ian Driver,4 Dylan C. Thomas,1 Katherine B. McCauley,1,2 Nicholas Skvir,1 Ana M. Crane,3 Anita A. Kurmann,1,5 Anthony N. Hollenberg,5 Sinead Nguyen,1 Brandon G. Wong,6 Ahmad S. Khalil,6,7 Sarah X.L. Huang,3,8 Susan Guttentag,9 Jason R. Rock,4 John M. Shannon,10 Brian R. Davis,3 and Darrell N. Kotton1,2 2 1Center for Regenerative Medicine, and The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA. 3Center for Stem Cell and Regenerative Medicine, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, Texas, USA. 4Department of Anatomy, UCSF, San Francisco, California, USA. 5Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA. 6Department of Biomedical Engineering and Biological Design Center, Boston University, Boston, Massachusetts, USA. 7Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts, USA. 8Columbia Center for Translational Immunology & Columbia Center for Human Development, Columbia University Medical Center, New York, New York, USA. 9Department of Pediatrics, Monroe Carell Jr. Children’s Hospital, Vanderbilt University, Nashville, Tennessee, USA. 10Division of Pulmonary Biology, Cincinnati Children’s Hospital, Cincinnati, Ohio, USA. It has been postulated that during human fetal development, all cells of the lung epithelium derive from embryonic, endodermal, NK2 homeobox 1–expressing (NKX2-1+) precursor cells.
    [Show full text]
  • Reciprocal Regulation of TEAD4 and CCN2 for the Trophectoderm Development of the Bovine Blastocyst
    155 6 REPRODUCTIONRESEARCH Reciprocal regulation of TEAD4 and CCN2 for the trophectoderm development of the bovine blastocyst Hiroki Akizawa1,2, Ken Kobayashi3, Hanako Bai1, Masashi Takahashi1, Shinjiro Kagawa1, Hiroaki Nagatomo1,† and Manabu Kawahara1 1Laboratory of Animal Genetics and Reproduction, Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan, 2Japan Society for the Promotion of Science (JSPS Research Fellow), Tokyo, Japan and 3Laboratory of Cell and Tissue Biology, Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan Correspondence should be addressed to M Kawahara; Email: [email protected] †(Hiroaki Nagatomo is now at Department of Biotechnology, Faculty of Life and Environmental Science, University of Yamanashi, Kofu, Japan) Abstract The first segregation at the blastocyst stage is the symmetry-breaking event to characterize two cell components; namely, inner cell mass (ICM) and trophectoderm (TE). TEA domain transcription factor 4 (TEAD4) is a well-known regulator to determine TE properties of blastomeres in rodent models. However, the roles of bovine TEAD4 in blastocyst development have been unclear. We here aimed to clarify the mechanisms underlining TE characterization by TEAD4 in bovine blastocysts. We first found that the TEAD4 mRNA expression level was greater in TE than in ICM, which was further supported by TEAD4 immunofluorescent staining. Subsequently, we examined the expression patterns of TE-expressed genes; CDX2, GATA2 and CCN2, in the TEAD4-knockdown (KD) blastocysts. These expression levels significantly decreased in the TEAD4 KD blastocysts compared with controls. Of these downregulated genes, the CCN2 expression level decreased the most. We further analyzed the expression levels of TE-expressed genes; CDX2, GATA2 and TEAD4 in the CCN2 KD blastocysts.
    [Show full text]
  • Rickets: Not a Disease of the Past LINDA S
    Rickets: Not a Disease of the Past LINDA S. NIELD, M.D., West Virginia University School of Medicine, Morgantown, West Virginia PRASHANT MAHAJAN, M.D., M.P.H., Wayne State University School of Medicine, Detroit, Michigan APARNA JOSHI, M.D., Children’s Hospital of Michigan, Detroit, Michigan DEEPAK KAMAT, M.D., PH.D., Wayne State University School of Medicine, Detroit, Michigan Rickets develops when growing bones fail to mineralize. In most cases, the diagnosis is established with a thorough his- tory and physical examination and confirmed by laboratory evaluation. Nutritional rickets can be caused by inadequate intake of nutrients (vitamin D in particular); however, it is not uncommon in dark-skinned children who have limited sun exposure and in infants who are breastfed exclusively. Vitamin D–dependent rickets, type I results from abnor- malities in the gene coding for 25(OH)D3-1-a-hydroxylase, and type II results from defective vitamin D receptors. The vitamin D–resistant types are familial hypophosphatemic rickets and hereditary hypophosphatemic rickets with hyper- calciuria. Other causes of rickets include renal disease, medications, and malabsorption syndromes. Nutritional rickets is treated by replacing the deficient nutrient. Mothers who breastfeed exclusively need to be informed of the recom- mendation to give their infants vitamin D supplements beginning in the first two months of life to prevent nutritional rickets. Vitamin D–dependent rickets, type I is treated with vitamin D; management of type II is more challenging. Familial hypophosphatemic rickets is treated with phosphorus and vitamin D, whereas hereditary hypophosphatemic rickets with hypercalciuria is treated with phosphorus alone.
    [Show full text]
  • Regulation of the Tumor Suppressor Homeogene Cdx2 by Hnf4a in Intestinal Cancer
    Oncogene (2013) 32, 3782–3788 & 2013 Macmillan Publishers Limited All rights reserved 0950-9232/13 www.nature.com/onc SHORT COMMUNICATION Regulation of the tumor suppressor homeogene Cdx2 by HNF4a in intestinal cancer T Saandi1,2, F Baraille3,4,5, L Derbal-Wolfrom1,2, A-L Cattin3,4,5, F Benahmed1,6, E Martin1,2, P Cardot3,4,5, B Duclos1,2,7, A Ribeiro3,4,5, J-N Freund1,2,8 and I Duluc1,2,8 The gut-specific homeotic transcription factor Cdx2 is a crucial regulator of intestinal development and homeostasis, which is downregulated in colorectal cancers (CRC) and exhibits a tumor suppressor function in the colon. We have previously established that several endodermal transcription factors, including HNF4a and GATA6, are involved in Cdx2 regulation in the normal gut. Here we have studied the role of HNF4a in the mechanism of deregulation of Cdx2 in colon cancers. Crossing ApcD14/ þ mice prone to spontaneous intestinal tumor development with pCdx2-9LacZ transgenic mice containing the LacZ reporter under the control of the 9.3-kb Cdx2 promoter showed that this promoter segment contains sequences recapitulating the decrease of Cdx2 expression in intestinal cancers. Immunohistochemistry revealed that HNF4a, unlike GATA6, exhibited a similar decrease to Cdx2 in genetic (Apcmin/ þ and ApcD14/ þ ) and chemically induced (Azoxymethane (AOM) treatment) models of intestinal tumors in mice. HNF4a and Cdx2 also exhibited a comparable deregulated pattern in human CRC. Correlated patterns were observed between HNF4a and Cdx2 in several experimental models of human colon cancer cell lines: xenografts in nude mice, wound healing and glucose starvation.
    [Show full text]
  • 341 Nutrient Deficiency Or Disease Definition/Cut-Off Value
    10/2019 341 Nutrient Deficiency or Disease Definition/Cut-off Value Any currently treated or untreated nutrient deficiency or disease. These include, but are not limited to, Protein Energy Malnutrition, Scurvy, Rickets, Beriberi, Hypocalcemia, Osteomalacia, Vitamin K Deficiency, Pellagra, Xerophthalmia, and Iron Deficiency. Presence of condition diagnosed, documented, or reported by a physician or someone working under a physician’s orders, or as self-reported by applicant/participant/caregiver. See Clarification for more information about self-reporting a diagnosis. Participant Category and Priority Level Category Priority Pregnant Women 1 Breastfeeding Women 1 Non-Breastfeeding Women 6 Infants 1 Children 3 Justification Nutrient deficiencies or diseases can be the result of poor nutritional intake, chronic health conditions, acute health conditions, medications, altered nutrient metabolism, or a combination of these factors, and can impact the levels of both macronutrients and micronutrients in the body. They can lead to alterations in energy metabolism, immune function, cognitive function, bone formation, and/or muscle function, as well as growth and development if the deficiency is present during fetal development and early childhood. The Centers for Disease Control and Prevention (CDC) estimates that less than 10% of the United States population has nutrient deficiencies; however, nutrient deficiencies vary by age, gender, and/or race and ethnicity (1). For certain segments of the population, nutrient deficiencies may be as high as one third of the population (1). Intake patterns of individuals can lead to nutrient inadequacy or nutrient deficiencies among the general population. Intakes of nutrients that are routinely below the Dietary Reference Intakes (DRI) can lead to a decrease in how much of the nutrient is stored in the body and how much is available for biological functions.
    [Show full text]
  • Role of Cdx Factors in Early Mesodermal Fate Decisions Tanya E
    © 2019. Published by The Company of Biologists Ltd | Development (2019) 146, dev170498. doi:10.1242/dev.170498 RESEARCH ARTICLE Role of Cdx factors in early mesodermal fate decisions Tanya E. Foley, Bradley Hess, Joanne G. A. Savory, Randy Ringuette and David Lohnes* ABSTRACT Cdx1−/− or Cdx2+/− phenotypes, indicative of functional overlap Murine cardiac and hematopoietic progenitors are derived from Mesp1+ between Cdx family members (Faas and Isaacs, 2009; Savory et al., mesoderm. Cdx function impacts both yolk sac hematopoiesis and 2011; van den Akker et al., 2002; van Nes et al., 2006; Young et al., Cdx2 cardiogenesis in zebrafish, suggesting that Cdx family members 2009). The derivation and analysis of conditional mutants regulate early mesoderm cell fate decisions. We found that Cdx2 (Savory et al., 2009a; Stringer et al., 2012) and compound mutant occupies a number of transcription factor loci during embryogenesis, derivatives (van den Akker et al., 2002; Savory et al., 2011; Verzi including key regulators of both cardiac and blood development, and et al., 2011; van Rooijen et al., 2012; Stringer et al., 2012; Grainger that Cdx function is required for normal expression of the cardiogenic et al., 2010; Hryniuk et al., 2012) further substantiated the transcription factors Nkx2-5 and Tbx5. Furthermore, Cdx and Brg1, an functional overlap between family members. Analysis of these ATPase subunit of the SWI/SNF chromatin remodeling complex, co- mutants also revealed a requirement for Cdx genes in diverse occupy a number of loci, suggesting that Cdx family members regulate processes in development and in the adult intestinal track. These target gene expression through alterations in chromatin architecture.
    [Show full text]
  • CDX2 As a Useful Marker of Colorectal Adenocarcinoma Metastases to Lung in Pre-Operative Biopsy Specimens
    87-92 1/6/07 12:56 Page 87 ONCOLOGY REPORTS 18: 87-92, 2007 87 CDX2 as a useful marker of colorectal adenocarcinoma metastases to lung in pre-operative biopsy specimens SHIGEBUMI TANAKA1, KANA SAITO1,2, TOMOKAZU ITO1, KOHEI TAJIMA3, AKIRA MOGI3, YOSHINORI SHITARA4, TAKAAKI SANO2 and HIROYUKI KUWANO1 Departments of 1General Surgical Science, 2Tumor Pathology, Gunma Graduate School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511; 3Department of Surgery, Fujioka General Hospital, 942-1 Fujioka, Fujioka, Gunma 375-8503; 4Department of Surgery, Isesaki General Hospital, 12-1 Tsunatorihoncho, Isesaki, Gunma 372-0821, Japan Received January 12, 2007; Accepted April 17, 2007 Abstract. Although distinguishing metastatic colorectal as a solitary nodule. Differential diagnosis between metastatic adenocarcinoma from primary lung adenocarcinoma is often adenocarcinoma of colorectal origin and primary lung adeno- difficult, pre- or intra-operative identification is very important, carcinoma using imaging techniques such as chest computed as the resection areas for each diagnosis differ substantially. tomography (CT) is thus often difficult in patients with a CDX2, a recently cloned homeobox gene, represents a highly history of colorectal cancer. However, this differentiation is specific and sensitive marker of colorectal adenocarcinoma. crucial for therapeutic and prognostic purposes (1). Particularly We evaluated CDX2 expression using pre- and intra-operative in cases with operative indications, pre- or intra-operative biopsy specimens. The study examined 50 consecutive colo- identification is very important, as the resection areas differ rectal adenocarcinoma metastases to the lung, including 20 substantially between the diagnoses. If the tumor is a solitary biopsy specimens and 66 resected specimens, and 21 primary metastatic colorectal carcinoma to the lung, partial lung lung adenocarcinomas.
    [Show full text]
  • VITAMIN DEFICIENCIES in RELATION to the EYE* by MEKKI EL SHEIKH Sudan VITAMINS Are Essential Constituents Present in Minute Amounts in Natural Foods
    Br J Ophthalmol: first published as 10.1136/bjo.44.7.406 on 1 July 1960. Downloaded from Brit. J. Ophthal. (1960) 44, 406. VITAMIN DEFICIENCIES IN RELATION TO THE EYE* BY MEKKI EL SHEIKH Sudan VITAMINS are essential constituents present in minute amounts in natural foods. If these constituents are removed or deficient such foods are unable to support nutrition and symptoms of deficiency or actual disease develop. Although vitamins are unconnected with energy and protein supplies, yet they are necessary for complete normal metabolism. They are, however, not invariably present in the diet under all circumstances. Childhood and periods of growth, heavy work, childbirth, and lactation all demand the supply of more vitamins, and under these conditions signs of deficiency may be present, although the average intake is not altered. The criteria for the fairly accurate diagnosis of vitamin deficiencies are evidence of deficiency, presence of signs and symptoms, and improvement on supplying the deficient vitamin. It is easy to discover signs and symptoms of vitamin deficiencies, but it is not easy to tell that this or that vitamin is actually deficient in the diet of a certain individual, unless one is able to assess the exact daily intake of food, a process which is neither simple nor practical. Another way of approach is the assessment of the vitamin content in the blood or the measurement of the course of dark adaptation which demon- strates a real deficiency of vitamin A (Adler, 1953). Both tests entail more or less tedious laboratory work which is not easy in a provincial hospital.
    [Show full text]
  • Pathogenesis and Diagnostic Criteria for Rickets and Osteomalacia
    Endocrine Journal 2015, 62 (8), 665-671 OPINION Pathogenesis and diagnostic criteria for rickets and osteomalacia —Proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society Seiji Fukumoto1), Keiichi Ozono2), Toshimi Michigami3), Masanori Minagawa4), Ryo Okazaki5), Toshitsugu Sugimoto6), Yasuhiro Takeuchi7) and Toshio Matsumoto1) 1)Fujii Memorial Institute of Medical Sciences, Tokushima University, Tokushima 770-8503, Japan 2)Department of Pediatrics, Osaka University Graduate School of Medicine, Suita 565-0871, Japan 3)Department of Bone and Mineral Research, Research Institute, Osaka Medical Center for Maternal and Child Health, Izumi 594-1101, Japan 4)Department of Endocrinology, Chiba Children’s Hospital, Chiba 266-0007, Japan 5)Third Department of Medicine, Teikyo University Chiba Medical Center, Ichihara 299-0111, Japan 6)Internal Medicine 1, Shimane University Faculty of Medicine, Izumo 693-8501, Japan 7)Division of Endocrinology, Toranomon Hospital Endocrine Center, Tokyo 105-8470, Japan Abstract. Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases.
    [Show full text]
  • Expression Pattern of the Class I Homeobox Genes in Ovarian Carcinoma
    J Gynecol Oncol Vol. 21, No. 1:29-37, March 2010 DOI:10.3802/jgo.2010.21.1.29 Original Article Expression pattern of the class I homeobox genes in ovarian carcinoma Jin Hwa Hong1, Jae Kwan Lee1, Joong Jean Park2, Nak Woo Lee1, Kyu Wan Lee1, Jung Yeol Na1 Departments of 1Obstetrics and Gynecology, 2Physiology, Korea University College of Medicine, Seoul, Korea Objective: Although some sporadic reports reveal the link between the homeobox (HOX) genes and ovarian carcinoma, there is no comprehensive analysis of the expression pattern of the class I homeobox genes in ovarian carcinoma that determines the candidate genes involved in ovarian carcinogenesis. Methods: The different patterns of expression of 36 HOX genes were analyzed, including 4 ovarian cancer cell lines and 4 normal ovarian tissues. Using a reverse transcription-polymerase chain reaction (RT-PCR) and quantification analysis, the specific gene that showed a significantly higher expression in ovarian cancer cell lines than in normal ovaries was selected, and western blot analysis was performed adding 7 ovarian cancer tissue specimens. Finally, immunohistochemical and immunocytochemical analyses were performed to compare the pattern of expression of the specific HOX gene between ovarian cancer tissue and normal ovaries. Results: Among 36 genes, 11 genes had a different level of mRNA expression between the cancer cell lines and the normal ovarian tissues. Of the 11 genes, only HOXB4 had a significantly higher level of expression in ovarian cancer cell lines than in normal ovaries (p=0.029). Based on western blot, immunohistochemical, and immunocytochemical analyses, HOXB4 was expressed exclusively in the ovarian cancer cell lines or cancer tissue specimens, but not in the normal ovaries.
    [Show full text]
  • Changes in Gene Expression During the Early to Mid-Luteal (Receptive Phase) Transition in Human Endometrium Detected by High-Density Microarray Screening
    Molecular Human Reproduction Vol.8, No.9 pp. 871–879, 2002 Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening Daniel D.Carson1,4, Errin Lagow1, Amantha Thathiah1, Rania Al-Shami1, Mary C.Farach-Carson1, Michael Vernon2, Lingwen Yuan3, Marc A.Fritz3 and Bruce Lessey3 1Department of Biological Sciences, University of Delaware, Newark, DE 19716, 2UNC Neuroscience Center and 3Department of Obstetrics and Gynecology, University of North Carolina, Chapel Hill, NC 27599–0001, USA 4To whom correspondence should be addressed. E-mail: [email protected] High density cDNA microarray screening was used to determine changes in gene expression occurring during the transition between the early luteal (prereceptive) and mid-luteal (receptive) phases in human endometrium. Of ~12 000 genes profiled, 693 (5.8%) displayed >2-fold differences in relative levels of expression between these stages. Of these, 370 genes (3.1%) displayed decreases ranging from 2- to >100-fold while 323 genes (2.7%) displayed increases ranging from 2- to >45-fold. Many genes correspond to mRNAs encoding proteins previously shown to change in a similar manner between the proliferative and mid-luteal phases, serving as one validation of the microarray screening results. In addition, novel genes were identified. Genes encoding cell surface receptors, adhesion and extracellular matrix proteins and growth factors accounted for 20% of the changes. Several genes were studied further by Northern blot analyses. These results confirmed that claudin-4/Clostridium perfringens enterotoxin (CPE) receptor and osteopontin (OPN) mRNA increased ~4- and 12-fold respectively, while betaig-H3 (BIGH3) decreased >80% during the early to mid-luteal transition.
    [Show full text]
  • Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition
    Research Article Deregulation of the HOXA10 Homeobox Gene in Endometrial Carcinoma: Role in Epithelial-Mesenchymal Transition Hiroyuki Yoshida,1 Russell Broaddus,2 Wenjun Cheng,1 SuSu Xie,2 and Honami Naora1 Departments of 1Molecular Therapeutics and 2Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas Abstract normally expressed during early urogenital development, and is expressed in renal tumors (6). PAX2 is thought to promote cell Homeobox genes encode transcription factors that control cell survival, and inhibiting PAX2 expression in cancer cells induces differentiation and play essential roles in developmental apoptosis (7). On the other hand, many homeobox genes that are patterning. Increasing evidence indicates that many homeo- normally expressed in differentiated tissues are lost or down- box genes are aberrantly expressed in cancers, and that their regulated in tumors. Nkx3.1 controls prostate morphogenesis and deregulation significantly contributes to tumor progression. is normally expressed in the prostate during development and in The homeobox gene HOXA10 controls uterine organogenesis the adult (8). NKX3.1 is frequently deleted in prostate cancers (9), during embryonic development and functional endometrial and enforced expression of NKX3.1 in prostate cancer cells differentiation in the adult. We investigated whether HOXA10 inhibits cell growth (10). Many other homeobox genes contribute expression is deregulated in endometrial carcinomas, and to tumor progression by promoting cell growth and/or survival how counteracting this aberrant expression modifies tumor (4, 5). However, given the important role of homeobox genes in behavior. We found that down-regulation of HOXA10 expres- cell differentiation, surprisingly little is known regarding their role sion in endometrial carcinomas strongly correlates with in EMT.
    [Show full text]