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Als gemeinsame Einrichtung von MDC und Charité fördert das Experimental and Clinical Research Center die Zusammenarbeit zwischen Grundlagenwissenschaftlern und klinischen Forschern. Hier werden neue Ansätze für Diagnose, Prävention und Therapie von Herz-Kreislauf- und Stoffwechselerkrankungen, Krebs sowie neurologischen Erkrankungen entwickelt und zeitnah am Patienten eingesetzt. Sie sind eingelanden, um uns beizutreten. Bewerben Sie sich! A 53-year-old man presented to the infectious disease clinic with a 4-month history of progressively enlarging, painless nodules on his scalp and perianal region. He had undergone liver and kidney transplantation 2 years ago and was receiving tacrolimus, mycophenolate mofetil, and prednisolone for immunosuppression. What is the most likely diagnosis?

Drug-induced reaction

Malakoplakia

Pyoderma gangrenosum

Sarcoidosis

Pyogenic granuloma

The correct answer is malakoplakia. Cultures grew Escherichia coli and Pseudomonas aeruginosa. The patient underwent biopsy of his lesions, which identified basophilic inclusions characteristic of Michaelis-Gutmann bodies. These are pathognomonic for malakoplakia, which is a chronic granulomatous condition that can occur in immunocompromised patients. The patient was treated with antibiotics and a reduction in the immunosuppression regimen. The lesions regressed with some residual scarring. Als Malakoplakie bezeichnet man eine seltene chronisch entzündliche Erkrankung, die mit makroskopisch sichtbaren plaqueartigen oder tumorförmigen, weiß-grauen Ablagerungen meistens im Bereich von Nieren, Harnleitern oder der Harnblase einhergeht. Es kann auch zu einer diffusen Infiltration des Nierenparenchyms kommen. Die Plaques entstehen vorwiegend im Rahmen chronischer Harnwegsentzündungen, meist aufgrund von Colibakterien. Oft liegt zusätzlich eine Abwehrschwäche (Immundefekt) oder ein Tumorleiden vor. Seltener sind andere Organe wie Magen-Darm-Trakt, Lunge oder Haut betroffen. Das histologische Korrelat sind große, polygonal geformte Makrophagen mit schaumigem, eosinophilem Zytoplasma (von Hansemann-Zellen). Pathognomonisch sind PAS-positive, körnchenförmige Mikrofoto von Malakoplakie mit Ablagerungen (Granula), die als Michaelis Gutmann Körperchen Michaelis-Gutmann-Körperchen (HE- bezeichnet werden. Man nimmt an, dass die Michaelis Gutmann Färbung) Körperchen die Reste von Phagosomen darstellen, die Die Malakoplakie ist eine chronisch- unvollständig verdaute Bakterien sowie Ablagerungen von entzündliche granulomatöse Calcium und Eisen enthalten. Der zugrunde liegende Zelldefekt Multisystem-Erkrankung und ist wahrscheinlich die verminderte Fähigkeit, aufgenommene gekennzeichnet durch einzelne oder Bakterien abzutöten. Charakteristische Symptome sind hohes multiple weiche Plaques auf Fieber, Flankenschmerz und eventuell ein tastbarer Tumor. Auch verschiedenen Organen des Körpers. akutes Nierenversagen wurde beschrieben. Häufig wird zunächst an einen bösartigen Tumor von Niere oder ableitenden Harnwegen gedacht, bis die feingewebliche Untersuchung die Diagnose beweist. Die Diagnostik der Malakoplakie umfasst Urinkultur, Blutkultur, bildgebende Diagnostik sowie eine Zystoskopie mit Biopsie der Läsionen. Die Therapie der Malakoplakie erfolgt mit Langzeitantibiose (Fluorchinolonen) oder chirurgischer Sanierung. Das Pyoderma gangraenosum, auch Dermatitis ulcerosa genannt, ist eine schmerzhafte Erkrankung der Haut, bei der es großflächig, in der Regel an einer Stelle, zu einer Geschwürbildung (Ulzeration oder Ulkus) und zu einem Absterben (Gangrän) der Haut kommt. Die Erkrankung wird nicht durch eine Infektion verursacht, weshalb die Behandlung mit Antibiotika wirkungslos ist, sondern wahrscheinlich durch eine überschießende Reaktion des Immunsystems (Autoimmunerkrankung). Dabei kommt es zu einer Neutrophilenaktivierung, welche nicht durch Gewebe-Proteinaseinhibitoren ausreichend reguliert wird. Sie wird daher auch mit Immunsuppressiva, wie beispielsweise Glucocorticoiden, Dapson oder Cyclosporin A, behandelt, die das Immunsystem unterdrücken. Das Pyoderma gangraenosum tritt teilweise im Rahmen anderer vorbestehender Erkrankungen auf, beispielsweise bei Morbus Crohn, Colitis ulcerosa, rheumatischen Erkrankungen wie Rheumatoider Arthritis und Vaskulitiden, Leukämien oder chronischer Leberentzündung (Hepatitis). Außerdem kann ein Pyoderma gangraenosum nach Hautverletzungen in Erscheinung treten oder zur gangränösen Transformation von Operationswunden führen, so dass diese durch starke Immunsuppressiva behandelt werden müssen. Kontraindiziert sind iodhaltige Medikamente. Während die Krankheit sich in vielen Fällen langsam entwickelt, kann es zu massiven Ausbrüchen kommen, welche auch Amputationen erforderlich machen können. Die häufigste Lokalisation des Pyoderma gangraenosum ist die Vorderseite des Unterschenkels. Es kann aber auch an jeder anderen Stelle der Haut auftreten. Die Sarkoidose (von griechisch σαρκωειδής sarkoeidés ‚fleischartig‘, ‚fleischig‘), auch als Morbus Boeck (buːk) oder Morbus Schaumann-Besnier bezeichnet, ist eine systemische Erkrankung des Bindegewebes mit Granulombildung, die meistens zwischen dem 20. und 40. Lebensjahr auftritt. Die genaue Ursache der Krankheit ist bis heute unbekannt. Bei der Sarkoidose bilden sich mikroskopisch kleine Knötchen (Granulome) in dem betroffenen Organgewebe, verbunden mit einer verstärkten Immunantwort. Bei der Sarkoidose bilden sich mikroskopisch kleine Knötchen (Granulome) in dem betroffenen Organgewebe, verbunden mit einer verstärkten Immunantwort. Man unterscheidet eine zunächst akut verlaufende Form der Sarkoidose, das sogenannte Löfgren- Syndrom, von der schleichend und symptomarm einsetzenden chronischen Verlaufsform. In Deutschland tritt die Sarkoidose in 20 bis 30 Fällen auf 100.000 Einwohner auf. Erstmals war sie von Ernest Besnier und Cæsar Peter Møller Boeck in den Jahren 1889 und 1899 als Hauterkrankung beschrieben worden. Im Jahre 1924 erkannte Jörgen Nilsen Schaumann, dass es sich hierbei um eine systemische Erkrankung verschiedener Organe handelt. Der Schwede Sven Halvar Löfgren beschrieb 1953 die nach ihm benannte akute Verlaufsform. Tofacitinib (JAK STAT inhibitor) Treatment and Molecular Analysis of Cutaneous Sarcoidosis. NEJM Dec. 2018 Das pyogene Granulom (lat Granuloma pyogenicum) ist ein erworbener gutartiger vaskulärer Hauttumor aus der Gruppe der Hämangiome. Es handelt sich um eine exophytische Gefäßproliferation. Dieser stark proliferierende Tumor (eine Hyperplasie) wird häufig als maligner Tumor (Krebs) fehlgedeutet. Das pyogene Granulom hat kein spezifisches histologisches Erscheinungsbild. Daher erhielt es in der Vergangenheit eine Vielzahl von Namen, unter anderem Granuloma pediculatum, Pediculatum, Epulis granulomatosa, Granuloma teleangiectaticum, Epulis angiomatosa, Wundgranulom, Stielknollen, Teleangiectaticum, Pseudobotryomykom, teleangiektatisches Wundgranulom, eruptives Angiom und proliferierendes Angiom. Die weit verbreitete Bezeichnung pyogenes Granulom ist ein Namensirrtum (Misnomer), da es sich nicht um eine Infektion bakterieller Natur (pyogen = ‚Eiter bildend‘), sondern um eine entzündliche Hyperplasie handelt. Auch die Bezeichnung Granulom ist genau genommen falsch. Einige Autoren bevorzugen daher die Bezeichnung lobuläres kapilläres Hämangiom (engl. lobular capillary hemangioma, LCH), während andere Autoren beim pyogenen Granulom zwei Unterarten unterscheiden: besagtes lobuläres kapilläres Hämangiom und einen Nicht-LCH-Typ (non- LCH). Beide Subtypen unterscheiden sich in ihrer Histologie. Ein großes pyogenes Granulom am linken Oberschenkel einer 28-jährigen Patientin mit HIV. Bakterielle Endokarditis

2 Major

1 Major + 3 Minor

0 Major + 5 Minor Partial Oral versus Intravenous Antibiotic Treatment of Endocarditis Patients with infective endocarditis on the left side of the heart are typically treated with intravenous antibiotic agents for up to 6 weeks. Whether a shift from intravenous to oral antibiotics once the patient is in stable condition would result in efficacy and safety similar to those with continued intravenous treatment is unknown. In a randomized, noninferiority, multicenter trial, we assigned 400 adults in stable condition who had endocarditis on the left side of the heart caused by streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci and who were being treated with intravenous antibiotics to continue intravenous treatment (199 patients) or to switch to oral antibiotic treatment (201 patients). In all patients, antibiotic treatment was administered intravenously for at least 10 days. If feasible, patients in the orally treated group were discharged to outpatient treatment. The primary outcome was a composite of all- cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from the time of randomization until 6 months after antibiotic treatment was completed. For a large proportion of patients, the main reason for staying in the hospital after the initial phase is to complete intravenous antibiotic treatment. Therefore, if oral antibiotic treatment might be safe and efficient, part of the treatment period for patients in stable condition could take place outside hospitals, without the need for an intravenous catheter.

Kaplan–Meier Plot of the Probability of the Primary Composite Outcome. The primary composite outcome was all-cause mortality, unplanned cardiac surgery, embolic events, or relapse of bacteremia with the primary pathogen, from randomization until 6 months after antibiotic treatment was completed. The oral treatment group shifted from intravenously administered antibiotics to orally administered antibiotics at a median of 17 days after the start of treatment. The inset shows the same data on an enlarged y axis.

Discussion In patients with endocarditis on the left side of the heart caused by streptococcus, E. faecalis, S. aureus, or coagulase-negative staphylococci, who were in clinically stable condition and who had had an adequate response to initial treatment, a shift from initial intravenous to oral antibiotic treatment was noninferior to continued intravenous antibiotic treatment. The patients in the orally treated group were shifted from intravenous to oral treatment on about day 17, the midpoint of the treatment period. Thus, during half the treatment period, the patients in the orally treated group were eligible for partial or complete outpatient treatment. The results seemed consistent across prespecified subgroups, including the subgroups defined according to type of valve affected (native valve or prosthetic valve) and according to type of treatment (surgery during the disease course or conservative treatment). It should also be noted that the primary outcome seemed similar across the four different bacterial types. However, the trial was not powered to assess the primary outcome in any of the prespecified subgroups. The high rate of the primary outcome in patients with coagulase-negative staphylococci probably reflects diagnostic delays combined with the fact that it often occurred in older and more frail patients who had serious coexisting conditions. Types of Bone & Joint Infections

Bone and joint infections include septic arthritis, prosthetic joint infections, osteomyelitis, spinal infections (discitis, vertebral osteomyelitis and epidural abscess) and diabetic foot osteomyelitis. All of these may present through the acute medical take. This article discusses the pathogenesis of infection and highlights the importance of taking a careful history and fully examining the patient. It also emphasises the importance of early surgical intervention in many cases. Consideration of alternative diagnoses, appropriate imaging and high-quality microbiological sampling is important to allow appropriate and targeted antimicrobial therapy. This article makes some The pathogenesis of osteomyelitis. (a) Haematogenous suggestions as to empiric antibiotic choice; however, bone infection results in medullary pus formation, acute therapy should be guided by local antimicrobial policies inflammation, systemic illness and often, secondary and infection specialists. Involvement of a bacteraemia. Pus may then track into joints or through the multidisciplinary team is essential for optimal outcomes. cortex. (b) In cases that progress to chronicity, a subperiosteal abscess may form leading to periosteal stripping and devitalisation of bone. Viable bone is resorbed leading to lucency. (c) Bacteria on the surface of dead bone persist leading to chronic suppuration, tissue destruction, sinus formation and often further bone death. Dead bone form sequestra. Involucrum is new bone formation outside existing bone as a result of periosteal stripping and then new bone growth from the periosteum. (d) This may be breached by cloacae, through which pus and fragments of dead bone escape. Oral versus Intravenous Antibiotics for Bone and Joint Infection The management of complex orthopedic infections usually includes a prolonged course of intravenous antibiotic agents. We investigated whether oral antibiotic therapy is noninferior to intravenous antibiotic therapy for this indication. We enrolled adults who were being treated for bone or joint infection at 26 U.K. centers. Within 7 days after surgery (or, if the infection was being managed without surgery, within 7 days after the start of antibiotic treatment), participants were randomly assigned to receive either intravenous or oral antibiotics to complete the first 6 weeks of therapy. Follow-on oral antibiotics were permitted in both groups. The primary end point was definitive treatment failure within 1 year after randomization. In the analysis of the risk of the primary end point, the noninferiority margin was 7.5 percentage points. Participants began their randomly assigned treatment strategy as soon as possible (but no more than 7 days) after definitive surgical intervention or, if the infection was being managed conservatively, the start of antibiotic therapy. Antibiotics were selected by accredited infection specialists with such factors as local epidemiology, antimicrobial susceptibility, bioavailability, previous infections, contraindications, allergies, and drug interactions taken into account; the choice of antibiotic was therefore assumed to be the most appropriate therapy for each participant. Route and Duration of Antibiotic Therapy. Panel A shows the percentage of participants receiving intravenous antibiotics from the start of the treatment episode (i.e., the date of definitive surgery or, if surgery was not performed, the start of planned curative antibiotic therapy) through day 60. Participants who had been randomly assigned to receive oral therapy and received intravenous therapy were doing so because they were prescribed intravenous antibiotics for up to 5 days for an intercurrent infection unrelated to the incident orthopedic infection (permitted by the protocol); were unable or unwilling to take oral therapy for any reason (secondary end point); were, subsequent to randomization, considered to have no suitable oral options for antibiotic therapy on the basis of emerging susceptibility results (secondary end point); or had had a potential treatment failure (primary end point). Most participants who had been randomly assigned to receive intravenous therapy but were receiving oral therapy over the same period were doing so because of a failure of intravenous access (secondary end point). Panel B shows the percentage of participants receiving any antibiotic through the final follow-up. The vertical line indicates 6 weeks after the start of treatment (i.e., the end of the intervention period). Differences in Risk According to the Analysis Performed. The point estimates for the differences in failure rates are shown with 90% (thick lines) and 95% (thin lines) two-sided confidence intervals. The noninferiority margin is indicated by the vertical dashed line. The use of two-sided 90% confidence intervals was prespecified in the trial protocol in accordance with the sample-size calculation. Because two-sided 95% confidence intervals are also now commonly included in noninferiority trials, they are shown here to assess the sensitivity of the results to a change in significance level. In the intention-to-treat population, missing data were imputed with the use of multiple imputation by chained equations. The modified intention-to-treat population included only the participants with complete end-point data. The worst-case sensitivity analysis shows the results based on the worst-case assumption that, for participants with missing data, all participants who were randomly assigned to receive oral therapy and no participants who were randomly assigned to receive intravenous therapy had definitive treatment failures, thus introducing the worst possible bias against the oral strategy. Early discontinuation of the randomly assigned treatment strategy was more common in the intravenous group than in the oral group (99 of 523 participants [18.9%] vs. 67 of 523 [12.8%], P=0.006), as were complications associated with the intravenous catheter (49 of 523 [9.4%] vs. 5 of 523 [1.0%], P<0.001). There was no significant difference in the incidence of C. difficile–associated diarrhea (9 of 523 [1.7%] in the intravenous group and 5 of 523 [1.0%] in the oral group, P=0.30) or the percentage of participants reporting at least one serious adverse event (146 of 527 [27.7%] in the intravenous group and 138 of 527 (26.2%) in the oral group, P=0.58). The median hospital stay was significantly longer in the intravenous group than in the oral group (14 days [interquartile range, 11 to 21] vs. 11 days [interquartile range, 8 to 20], P<0.001). Discussion In this trial, with regard to treatment failure assessed at 1 year, oral antibiotic therapy was noninferior to intravenous antibiotic therapy when used during the first 6 weeks of treatment for bone and joint infection; our results thereby challenge a widely accepted standard of care. Subgroup analyses did not identify significant heterogeneity, irrespective of baseline surgical procedure, retention of metalware, pathogen, or intended antibiotics at randomization. Oral therapy was associated with shorter hospital stays and fewer complications than intravenous therapy. Oral therapy may not be appropriate for some patients (e.g., those with poor enteral absorption) and pathogens (e.g., those with resistance to oral agents). Rifampin, which is considered by many to be an important agent in the treatment of certain biofilm-associated infections, was more commonly planned as treatment in early antibiotic regimens in the oral group than in the intravenous group, although a subgroup analysis showed no significant effect of planned use on outcome. Actual rifampin use at any time during treatment varied less between the groups than planned use, which suggests that the timing of adjunctive rifampin treatment was influenced by the randomly assigned treatment strategy. We found that appropriately selected oral antibiotic therapy was noninferior to intravenous therapy when used during the first 6 weeks in the management of bone and joint infection, as assessed by treatment failure within 1 year. Oral antibiotic therapy was associated with a shorter length of hospital stay and with fewer complications than intravenous therapy. Der Koronararterienbypass bzw. die koronare Bypass- OP ist ein chirurgisches Verfahren zur Behandlung einer koronaren Herzerkrankung (KHK) mit hochgradigen Koronarstenosen, wenn andere Verfahren (z.B. Ballon-Dilatation (PTCA), Stent- Implantation, Rotablation etc.) nicht indiziert oder erfolglos geblieben sind. Bei der koronaren Bypass-OP wird eine direkte Überbrückung von Koronarstenosen mit autologen arteriellen oder venösen Gefäßen (Grafts) durchgeführt. Arterielle Grafts haben eine bessere Langzeitoffenheitsrate als venöse Grafts. Daher sollte nach Möglichkeit eine komplett arterielle Revaskularisation angestrebt werden. Die Offenheitsrate von arteriellen Grafts nach 10 Jahren beträgt > 90 %. Die der venösen Grafts liegt bei ca. 50- 60 %. Die Arteria thoracica interna, auch Arteria mammaria interna genannt, ist ein kleiner Ast der Arteria subclavia, dessen weitere Verzweigungen unter anderem die Interkostalmuskulatur der Brustwand, das Zwerchfell und die Mamma versorgen. Die Arteria thoracica interna wird häufig als autologes Gefäßtransplantat verwendet, unter anderem bei koronarem Bypass. Hier werden im klinischen Sprachgebrauch häufig die Abkürzungen IMA (internal mammary artery), RIMA (right internal mammary artery) und LIMA (left internal mammary artery) verwendet. Bilateral versus Single Internal-Thoracic-Artery Grafts at 10 Years Multiple arterial grafts may result in longer survival than single arterial grafts after coronary-artery bypass grafting (CABG) surgery. We evaluated the use of bilateral internal-thoracic-artery grafts for CABG. We randomly assigned patients scheduled for CABG to undergo bilateral or single internal-thoracic-artery grafting. Additional arterial or vein grafts were used as indicated. The primary outcome was death from any cause at 10 years. The composite of death from any cause, myocardial infarction, or stroke was a secondary outcome. In the Arterial Revascularization Trial (ART), we randomly assigned patients to receive either bilateral internal-thoracic-artery grafts or a standard single left internal-thoracic- artery graft during CABG. A prespecified interim analysis at 5 years showed no significant differences between the two strategies with regard to all-cause mortality or the rate of the composite outcome of death from any cause, myocardial infarction, or stroke. A total of 644 patients (20.8% of the overall trial population) had died by 10 years, with 315 deaths (20.3%) occurring in the bilateral-graft group and 329 (21.2%) in the single-graft group (hazard ratio, 0.96; 95% confidence interval [CI], 0.82 to 1.12; P=0.62). Results were similar after adjustment for age, sex, diabetes status, and ejection fraction (hazard ratio, 0.97; 95% CI, 0.83 to 1.14). Approximately half the deaths were classified as being of noncardiovascular cause. Regarding the composite outcome of death from any cause, myocardial infarction, or stroke, there were 385 patients (24.9%) with an event in the bilateral-graft group and 425 (27.3%) with an event in the single-graft group (hazard ratio, 0.90; 95% CI, 0.79 to 1.03). Primary Outcome of Death from Any Cause and Composite Outcome of Death from Any Cause, Myocardial Infarction, or Stroke at 10 Years. Hazard ratios use the single-graft group as the reference. Insets show the same data on an enlarged y axis. Subgroup Analysis of Death from Any Cause. Shown are plots of the hazard ratios for death, with 95% confidence intervals, and the P values for interaction according to subgroups in the intention- to-treat population. The vertical dashed line indicates the hazard ratio for the overall population, and the diamond includes the hazard ratio with 95% confidence intervals. Hazard ratios use the single- graft group as the reference. The overall P value is for the comparison of the two groups. Discussion ART was a randomized trial that compared bilateral with single internal-thoracic-artery grafting for CABG. At 10 years, in intention-to- treat analyses, there were no significant between-group differences in all-cause mortality; in the rate of the composite outcome of death, myocardial infarction, or stroke; or in the rate of repeat revascularization. The results of this trial are not consistent with data from previous, nonrandomized studies. Potential benefits of use of the second internal thoracic artery for grafting were suggested by a combination of reported reductions in mortality in observational studies and strong evidence of superior rates of angiographic patency of both left and right internal-thoracic-artery grafts as compared with saphenous-vein grafts. Intravenous Iron in Patients Undergoing Maintenance Hemodialysis Intravenous iron is a standard treatment for patients undergoing hemodialysis, but comparative data regarding clinically effective regimens are limited. In a multicenter, open- label trial with blinded end-point evaluation, we randomly assigned adults undergoing maintenance hemodialysis to receive either high-dose iron sucrose, administered intravenously in a proactive fashion (400 mg monthly, unless the ferritin concentration was >700 μg per liter or the transferrin saturation was ≥40%), or low-dose iron sucrose, administered intravenously in a reactive fashion (0 to 400 mg monthly, with a ferritin concentration of <200 μg per liter or a transferrin saturation of <20% being a trigger for iron administration). The primary end point was the composite of nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, or death, assessed in a time-to-first-event analysis. These end points were also analyzed as recurrent events. Other secondary end points included death, infection rate, and dose of an erythropoiesis-stimulating agent. Noninferiority of the high-dose group to the low-dose group would be established if the upper boundary of the 95% confidence interval for the hazard ratio for the primary end point did not cross 1.25.

Iron Administration over Time. The mean cumulative doses of intravenous iron that were received by the patients in the two treatment groups are shown over time. Data plotted at month 0 represent the first administration of iron after randomization. At all the time points, patients in the group that received high-dose iron proactively received greater cumulative doses of iron than did the patients in the group that received low-dose iron reactively (P<0.001 for all time points). The cumulative doses of iron were compared between the treatment groups with the Wilcoxon rank-sum test. � bars indicate 95% confidence intervals. Primary and Secondary End Points.

Vascular access thrombosis occurred in 262 patients (24.0%) in the high-dose group and in 218 (20.8%) in the low-dose group. The rates of hospitalization for any cause and for infection were similar in the two treatment groups. The rate of all episodes of infection in the high-dose group was 63.3 events per 100 patient-years, as compared with 69.4 events per 100 patient-years in the low-dose group. Cumulative Incidence of the Primary Efficacy End Point, of Death from Any Cause, and of Death from Any Cause and a Composite of Cardiovascular Events as Recurrent Events. Panel A shows the cumulative event rates for the primary efficacy end point (a composite of death from any cause, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure). Panel B shows the rates of death from any cause, and Panel C shows the rates of death from any cause and a composite of myocardial infarction, stroke, and hospitalization for heart failure as recurrent events plotted in the form of mean frequency functions with the use of the method of Ghosh and Lin. The hazard ratios (with 95% confidence intervals) and rate ratio (with the 95% confidence interval) were adjusted for the baseline stratification variables of vascular access, diabetes status, and duration of dialysis treatment.

Serious adverse events occurred in 709 patients (64.9%) in the high-dose group and in 671 (64.0%) in the low-dose group. The rates of the most common serious adverse events, analyzed according to MedDRA system organ class, were generally similar in the two treatment groups. Infection was the most common noncardiovascular cause of death, and the rates were similar in the two treatment groups. Discussion In contrast to results from observational studies, the results of this trial showed that the use of a high-dose intravenous iron regimen administered proactively was superior to the use of a low- dose intravenous iron regimen administered reactively and was associated with a lower risk of death or major adverse cardiovascular events. Patients who had been assigned to receive high- dose iron therapy were less likely to have a myocardial infarction or be hospitalized for heart failure than those who had been assigned to receive low-dose iron therapy. In addition, high- dose iron administered proactively appeared to protect against recurrent events. Although iron therapy has been associated with a lower risk of cardiovascular events in placebo-controlled trials involving patients with heart failure, such benefits have not been observed in an incident dialysis population (with a baseline prevalence of heart failure of <5%). Furthermore, patients who received high-dose iron therapy had fewer blood transfusions and received lower doses of erythropoiesis-stimulating agents to maintain target hemoglobin levels than those in the low- dose group; patients in the high-dose group also had a faster increase in the hemoglobin level. The cardiovascular safety profile that is associated with the use of high-dose intravenous iron therapy to maintain a target hemoglobin level is notable, given the safety concerns about using higher doses of erythropoiesis-stimulating agents to elevate the hemoglobin level. We speculate that the dose-sparing effect of intravenous iron therapy on erythropoiesis-stimulating agents might contribute to the cardiovascular profile of high-dose iron therapy that was observed in this trial. It is also possible that iron replacement in patients with iron deficiency has direct cardiovascular benefits. In conclusion, this trial showed that, among patients undergoing hemodialysis, the use of a high- dose regimen of intravenous iron administered proactively resulted in a significantly lower risk of death or major nonfatal cardiovascular events as compared with that observed with a reactive, low-dose regimen. Supported by Kidney Research UK, which was supported by an unrestricted grant from Vifor Fresenius Medical Care Renal Pharma. New Neuroscience of Homeostasis and Drives for Food, Water, and Salt (Frank Epstein Lecture) Bradford B. Lowell Well-being requires the maintenance of energy stores, water, and sodium within permissive zones. The brain, as ringleader, orchestrates their homeostatic control. It senses disturbances, decides what needs to be done next, and then restores balance by altering physiological processes (i.e., expenditure of energy and excretion of water and salt) and ingestive drives (i.e., hunger, thirst, and salt appetite). But how the brain orchestrates this control has been unknown until recently — largely because we have lacked the ability to elucidate and then probe the underlying neuronal “wiring diagrams.” This has changed with the advent of new, transformative neuroscientific tools. When targeted to specific neurons, these tools make it possible to selectively map a neuron’s connections, measure its responses to various homeostatic challenges, and experimentally manipulate its activity. In this review, I examine these approaches and then highlight how they are advancing, and in some cases profoundly changing, our understanding of energy, water, and salt homeostasis and the linked ingestive drives. Using Genetic Tools to Access Distinct Subsets of Neurons and Disambiguate the Brain Neurons are the functional units of the brain. To understand what a given neuron does, we need to know the wiring diagram within which it is embedded, how it responds to various events, and finally, what happens when we force it on or off. The complexity of the brain and its lack of an easily discernible order, however, pose a huge barrier to obtaining such information. Specifically, the mammalian brain contains many neurons (107 in mice and 1011 in humans), and each one makes numerous connections; in brain sites involved in homeostasis, neurons of unrelated and even opposite function sit side by side. By harnessing the discriminating power of differential gene expression, neuroscientists are now selectively accessing functionally distinct subsets of neurons. The basic approach has two components. First, it involves genetically encoded tools that allow neurons to be mapped, measured, and manipulated (more on these tools below). And second, the approach involves a means of directing these tools to distinct subsets of neurons. To accomplish the second component, mice are engineered to express DNA recombinases, usually Cre recombinase, in genetically distinct neurons. Typically, the recombinase coding sequence is inserted into an endogenous mouse gene that is itself uniquely expressed by a specific subset of neurons — hence co-opting that mouse gene to drive neuron subset–specific expression of recombinase. The brains of such mice are then injected with viruses that express the genetically encoded tools if, and only if, infected neurons express recombinase. Manipulating, Measuring, and Mapping Genetically Defined Neurons. Panel A shows the use of mouse genetic engineering and viral vectors to gain access to neurons. Cre recombinase targets the short sequences loxP and lox2272, inverting the intervening sequence and causing expression of the genetically encoded “tool.” Panel B shows examples of tools for manipulating, measuring, and mapping neurons. TVA is the receptor for the avian sarcoma leukosis virus envelope A glycoprotein (EnvA). ChR2 denotes channelrhodopsin-2, GPCR G protein–coupled receptor, RG rabies glycoprotein, and XFP any fluorescent protein. Typically, the recombinase coding sequence is inserted into an endogenous mouse gene that is itself uniquely expressed by a specific subset of neurons — hence co-opting that mouse gene to drive neuron subset–specific expression of recombinase (A). For manipulating neuronal activity, light-activated ion channels or ion pumps (optogenetic tools) or drug-activated G protein–coupled receptors or ion channels (chemogenetic tools) are experimentally expressed in specific subsets of neurons (B).

Energy Balance and Hunger eural Control of Energy Balance and Hunger. The anatomical location of key structures, the neuronal wiring diagram, and the synaptic mechanisms by which the arcuate nucleus–based system regulates hunger and satiety are shown. Agouti-related peptide (AgRP), proopiomelanocortin (POMC), and vesicular glutamate transporter 2 (VGLUT2) neurons in the arcuate nucleus project to and regulate the activity of melanocortin 4 receptor (MC4R)–expressing satiety neurons in the paraventricular nucleus of the hypothalamus (PVH). These PVH satiety neurons then project to and regulate the activity of satiety neurons in the lateral parabrachial nucleus (LPBN). α-MSH denotes alpha melanocyte- stimulating hormone, GABA γ-aminobutyric acid, and NPY neuropeptide Y. When leptin levels are low, expenditure is reduced and hunger is increased. Genetic deficiency of leptin or its receptor, in both mice and humans, “fools” the brain into thinking that fat stores are absent, resulting in extreme hunger and obesity. Proopiomelanocortin (POMC) neurons release alpha melanocyte-stimulating hormone (α-MSH) to promote weight loss, whereas agouti-related peptide (AgRP) neurons release AgRP and two inhibitory transmitters, neuropeptide Y (NPY) and γ-aminobutyric acid (GABA), to promote weight gain. The activities of AgRP neurons and POMC neurons are reciprocally and oppositely regulated by leptin and the fed or fasted state, reflecting their contrasting roles. Water Balance and Thirst Neural Control of Water Balance and Thirst. Neurons within three structures — the organum vasculosum of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO), and the subfornical organ (SFO), all in the lamina terminalis — play key roles in regulating water balance. Osmolality and angiotensin II are sensed by neurons in the OVLT and SFO, which are located outside the blood–brain barrier. Neurons in the OVLT and SFO then send projections to neurons in the MnPO, which then regulate water excretion and thirst through projections to other sites. VP denotes vasopressin. As the body’s universal solvent and as a means of removing excess heat, water is vital for survival. Because water moves freely across membranes, the concentration of water relative to dissolved osmoles is a critical parameter. With too little water, cells shrink; with too much, they swell. Thus, normal blood osmolality, approximately 290 mOsm per kilogram, is tightly defended. The brain senses perturbations in water primarily by detecting changes in blood osmolality and secondarily by detecting changes in angiotensin II. Three brain nuclei in the lamina terminalis along the anterior wall of the third ventricle play key roles in regulating water balance. From ventral to dorsal, they are the organum vasculosum of the lamina terminalis (OVLT), the median preoptic nucleus (MnPO), and the subfornical organ (SFO). The OVLT and SFO are circumventricular organs and hence lie outside the blood–brain barrier. Sodium Balance and Salt Appetite Neural Control of Sodium Balance and Salt Appetite. Angiotensin II–sensing neurons in the SFO and aldosterone-sensing neurons in the nucleus tractus solitarius converge on neurons in the ventral lateral area of the bed nucleus of the stria terminalis to drive sodium appetite. 11β-HSD2 denotes 11β- hydroxysteroid dehydrogenase 2. When sodium is deficient, the effective circulatory volume falls, kidneys produce renin, angiotensin II levels increase, and the adrenals secrete aldosterone. Angiotensin II and aldosterone, working synergistically on both the brain and the kidneys, reduce sodium excretion and stimulate appetite. Second, sodium intake occurs within a very narrow range among tens of thousands of persons across years and cultures; the mean (±SD) intake is 3.6±0.5 g per day, and for 90% of persons, the intake ranges from 3.07 to 4.38 g per day. The basis for the observed variation is not fully defined. Remarkably, the mean intake value (3.6 g per day) coincides with an inflection point at which lower intakes (<3.6 g per day) have been reported to elevate plasma renin activity, which is the initiator of angiotensin II and aldosterone production. Aversive Nature of Hunger and Important Aspects of Homeostasis Uncovered with the Use of Thirst Neurons New Neuroscientific Tools. Panel A shows that AgRP hunger neurons and MnPO thirst neurons cause an aversive state. Eating or drinking, by reducing the activity of hunger and thirst neurons, reduces this aversive state and is therefore rewarding. Panel B shows that AgRP neurons are regulated by feedback signals from the body that report the status of fat stores, as well as by two feed-forward signals, one from the environment that anticipates eating and the other from the gut that anticipates the effects of ingested food on fat stores. Salient cues from the environment that anticipate eating or drinking transiently decrease the activity of AgRP hunger neurons or MnPO thirst neurons. By reducing the aversive state, these cues and responses become positively reinforced. Since deprivation of food or water activates AgRP or MnPO neurons, and since their activation is necessary and sufficient for Important Aspects of Homeostasis Uncovered with induction of eating and drinking, these neurons and their the Use of New Neuroscientific Tools. Panel A downstream circuitry are the physical embodiment of hunger and shows that AgRP hunger neurons and MnPO thirst thirst. This realization then provides a powerful tool for probing neurons cause an aversive state. Eating or these drives. By forcing these neurons “on” or “off” in mice that drinking, by reducing the activity of hunger and are otherwise sated or deprived, and by doing so in the absence thirst neurons, reduces this aversive state and is of food or water, the effects of these “drive neurons” on mental therefore rewarding. Panel B shows that AgRP neurons are regulated by feedback signals from the state can be teased apart from confounding effects of the body that report the status of fat stores, as well as physiologic state or the acts of eating or drinking. by two feed-forward (Vorsteuerung) signals, one We know this because mice will avoid contexts (e.g., places) that from the environment that anticipates eating and scientists have artificially linked with these neurons being forced the other from the gut that anticipates the effects of on, and when these neurons are otherwise on, mice will work to ingested food on fat stores. Salient cues from the have them artificially forced off. A finding that is consistent with environment that anticipate eating or drinking transiently decrease the activity of AgRP hunger this observation and with the established downstream circuitry is neurons or MnPO thirst neurons. By reducing the that fasted and therefore naturally hungry mice prefer contexts in aversive state, these cues and responses become which their downstream, otherwise off, PVHMC4R satiety neurons positively reinforced. are artificially forced on. Feed-Forward Regulation Until recently, the greatest blind spot in homeostasis neuroscience was the responses of these drive neurons, moment to moment, to various events. Because of this lack of knowledge about how drive neurons respond, it had always been assumed that AgRP and MnPO neurons, as “homeostatic” neurons, were controlled exclusively by feedback signals related to fat stores and osmolality and were largely either tonically on or off. It was thus completely unexpected when three groups using different methods discovered that when “hungry” mice are exposed to food, AgRP neuron activity rapidly falls (within seconds). Shortly after that discovery, it was found that when dehydrated mice are exposed to water, the activity of SFO and MnPO thirst neurons and vasopressin neurons also drops rapidly (within seconds). Conversely, ingestion of food, which portends an increase in osmolality, rapidly increases the activity of thirst and vasopressin neurons, well before blood osmolality increases. It is as if these homeostatic neurons anticipate the consequences of certain actions or situations on energy and water balance. Thus, in addition to feedback “error detection and correction,” there is also feed-forward “error prevention,” a phenomenon well appreciated by cardiovascular physiologists. If reductions in the activity of AgRP and MnPO neurons (and hence, reductions in hunger and thirst) depended solely on feedback signals from fat and osmolality, then eating or drinking would be curtailed only after ingested food and water had been absorbed and assimilated. At that point, the gut would still contain large amounts of unabsorbed food and water. Thus, feed-forward signals from the gut provide an estimate of the future effect of ingested food and water on energy and water balance and allow for anticipatory decreases in the drive for further consumption. Again, the quotation from Roger Carpenter is germane. Maintenance of Drive Specificity in Higher Circuits We have known for centuries that deficiencies of food, water, or salt lead to motivated behaviors that are specific to just the one relevant goal. More recently, we have learned that each of these specific deficiencies activates, very selectively, a dedicated homeostatic neuron and that when these dedicated neurons are artificially activated, motivated behavior is generated, which is, again, completely specific to the one goal. However, to achieve these specific, goal-directed behaviors, the homeostatic neurons must use common psychological processes (e.g., incentive motivation and sensory cue bias) and common higher systems (e.g., the mesolimbic dopamine system, amygdala, and cortex). Given that common processes and systems are involved, how is specificity for the goal maintained? If we knew the answer, we would have a deeper understanding of how these important higher processes and systems work, and this understanding would probably extend well beyond deprivation-induced motivated behavior. Gibt es hier ein Risiko?!? (what is the risk here?) An 18-Year-Old Man with Abdominal Pain and Hematochezia The patient had been well until 20 days before this admission, when fevers and pain in the right lower quadrant developed during a trip to the southeastern United States for athletic training. One day later, the patient had mild postprandial nausea and loose stools. He presented to a local emergency department for evaluation. In the emergency department of the first hospital, the pulse was 59 beats per minute, the blood pressure 114/65 mm Hg, and the weight 72.1 kg. The results of the rest of the physical examination were not documented. The blood levels of electrolytes, calcium, alkaline phosphatase, total bilirubin, and lipase were normal. The results of computed tomography (CT) of the abdomen and pelvis, performed after the administration of oral and intravenous contrast material, were reportedly normal. After 5 hours of observation, the patient was discharged to his hotel without receiving a specific diagnosis. Urinalysis was normal In the emergency department of the second hospital, the patient reported pain in the right flank and abdomen and loss of appetite. The temperature was 38.9°C, the pulse 110 beats per minute, the blood pressure 124/76 mm Hg, the respiratory rate 16 breaths per minute, and the oxygen saturation 99% while he was breathing ambient air. The lower quadrants of the abdomen and the right flank were tender; the remainder of the examination was normal. The anion gap and blood levels of electrolytes, calcium, alkaline phosphatase, total bilirubin, and lipase were normal. Magnetic resonance imaging (MRI) of the abdomen and pelvis, performed after the administration of intravenous contrast material, reportedly revealed mildly distended, fluid-filled loops of small bowel in the left half of the abdomen and the presence of air–fluid levels in the rectum. Acetaminophen and intravenous fluids were administered, and the fever and tachycardia resolved. The team’s internist encouraged the patient to return to New for further medical evaluation. Two days later and 1 day before this admission, the patient was seen by the team’s internist at an outpatient clinic of this hospital. He reported that the abdominal and back pain persisted. He also reported that, earlier that day, he had had a temperature of 38.9°C, which had decreased after the administration of acetaminophen, and produced well-formed stools that contained blood. The patient appeared to be uncomfortable. Arrangements were made for an expedited colonoscopy to be performed by a gastroenterologist at this hospital the following afternoon. The next morning, the patient called the team’s internist and reported that, after he had taken the bowel-preparation regimen, he had had a bowel movement that contained a large volume of blood. The patient was admitted to the hospital. That evening, a temperature of 40.2°C developed, with associated rigors, and the patient appeared to be confused. The pulse was 145 beats per minute, the blood pressure 109/52 mm Hg, the respiratory rate 35 breaths per minute, and the oxygen saturation 97% while he was breathing ambient air. There was a new systolic ejection murmur (grade 2/6) that was best heard at the left upper sternal border; the remainder of the examination was unchanged. Another blood sample was obtained for culture. Cefepime, metronidazole, acetaminophen, and intravenous fluids were administered, and the vital signs and mental status normalized. Ninety minutes after the initiation of treatment, the microbiology laboratory reported that cultures of the blood that had been obtained in the emergency department 11.5 hours earlier had grown gram-negative rods, repeat blood cultures reportedly grew a second type of gram-negative rod. CT Scan of the Abdomen and Pelvis. An axial image obtained at the level of the pelvis (Panel A) and coronal reformatted images obtained at low and high magnification (Panels B and C, respectively) show a contained, extraluminal, air- filled collection (arrowheads) medial to the right common iliac artery (RCIA), with adjacent linear foci of gas (double arrowhead) that extend to the sigmoid colon (S). An axial image obtained at the level of the superior margin of the collection (Panel D, arrowheads) shows additional contiguous soft-tissue density (arrows) surrounding the RCIA, a finding that indicates inflammation of the arterial wall. In comparison, the left common iliac artery (LCIA) is normal, with an imperceptible wall. A sagittal reformatted image (Panel E) shows the collection (arrowheads) immediately anterior to the L5 vertebral body and L5–S1 intervertebral disk space; there is no evidence of diskitis or osteomyelitis. In retrospect, a coronal reformatted image obtained at high magnification (Panel F) shows an equivocal linear low-density structure (double arrowhead) adjacent to the collection (arrowheads) traversing the RCIA. Appendicitis In considering a diagnosis of appendicitis in this patient, I would ask the following questions. Was the pain in the right lower quadrant preceded by epigastric pain, and was it localized to McBurney’s point? Did the patient have a loss of appetite before loose stools and nausea developed? Diverticulitis Could this patient have diverticulitis? It would be helpful to know the ethnic background of the patient, because Asian patients most commonly have diverticulitis on the right side, in the cecum or ascending colon, whereas North American and European patients most commonly have diverticulitis on the left side, in the sigmoid colon, and present with this condition at an older age. Inflammatory Bowel Disease Does the patient have a family history of inflammatory bowel disease? This disease is 3 to 20 times as likely to develop in first-degree relatives of patients with Crohn’s disease as in the general population. A new diagnosis of Crohn’s disease is certainly a possible explanation of this patient’s presentation — given the rectal bleeding, pain in the right lower quadrant, nausea, and loose stools — provided that both the colon and the small bowel are involved. A diagnosis of ulcerative colitis is possible, given the rectal bleeding and mucous discharge. However, the ulcerations associated with ulcerative colitis are mucosal and are very unlikely to give rise to a bowel perforation, unless toxic megacolon develops. Infectious Colitis Infectious colitis that is due to organisms such as Salmonella enterica, Campylobacter jejuni, and Yersinia enterocolitica should be considered in this case. Stool samples were sent to the laboratory to be tested for salmonella and campylobacter, but there has been no mention of testing for yersinia. Colitis Associated with Nonsteroidal Antiinflammatory Drugs Colitis that is associated with the use of nonsteroidal antiinflammatory drugs should be in the differential diagnosis in this case, given the history of ibuprofen use. Meckel’s Diverticulum Meckel’s diverticulum with perforation is a compelling diagnosis in this case, given this patient’s young age. However, Meckel’s diverticulum with perforation usually occurs in early childhood. Ischemic Colitis Ischemic bowel disease is a rare and serious condition that causes lower gastrointestinal bleeding and has been described in marathon runners. Sigmoid or Cecal Volvulus Volvulus, which is a twist in the large bowel, accounts for 10 to 15% of cases of large-bowel obstruction Colon Colon cancer in the ascending colon or cecum with perforation should be in the differential diagnosis in this case, even though the patient is only 18 years old. Given the rising incidence of colon cancer among young people in the United States. Health Right Inguinal Hernia riskfactor The risk of an inguinal hernia with intermittent incarceration, which can lead to ischemic bowel, may be increased in athletes. However, this patient’s imaging studies do not show evidence of a hernia, and a targeted physical examination and ultrasonography of the groin have not been mentioned. Foreign Body I think that perforation of the large bowel by a foreign body is the most likely diagnosis in this case, given the slow tempo of the disease course, imaging findings, and baffling clinical picture. Since the history does not provide any clues about what may have pierced the bowel to cause a perforation, I would ask the patient to describe what he had eaten before the onset of abdominal pain. I would specifically ask whether he had eaten any fish with bones; chicken wings or other bone-in chicken parts; shellfish such Images Obtained during Endoscopy. During colonoscopy, blood was found throughout the sigmoid as crabs, lobsters, or mussels; or sandwiches held together colon (Panel A). A wooden toothpick was visible 25 cm with toothpicks, such as a turkey club. from the anal verge, with evidence that it had eroded the On the basis of the initial interpretation of the CT scan, a colon wall (Panels B and C). After the toothpick was colonoscopy was performed. The colonoscopy revealed a removed (Panel D), pulsatile bleeding occurred (Panel large amount of fresh blood in the sigmoid colon, which E). The bleeding was addressed with placement of nine was lavaged. A 5-cm wooden toothpick was found lodged in hemostatic clips and administration of a total of 10 ml of epinephrine (Panels F and G). Ongoing bleeding was the proximal sigmoid colon, 25 cm from the anal verge, and noted at the end of the procedure, and emergency there was evidence that it had eroded the colon wall on one surgical consultation was obtained. end. Because of life-threatening bleeding, the patient was urgently taken to a hybrid operating room, which is equipped with a variety of advanced medical devices. The interventional radiology service performed angiography, which revealed extravasation of contrast material from the right common iliac artery into the sigmoid colon. A decision was made to perform an exploratory laparotomy with repair of the injury of the right common iliac artery, since there was a relative contraindication to endovascular placement of a synthetic graft in the presumably contaminated field and the colon injury needed to be addressed. An occlusion balloon was placed in the right common iliac artery for temporary control of the bleeding. On exploration of the abdomen, we encountered an arterioenteric connection between the sigmoid colon and the right common iliac artery. Primary repair of the colon was performed, and the vascular surgery service was consulted for management of the arterial injury. The arterial segment was not viable, and thus a 3-cm segment of artery was excised. The superficial femoral vein was harvested from the ipsilateral leg to serve as an interposition graft.

Images Obtained during Angiography. Because of uncontrolled bleeding, emergency angiography of the right common iliac artery was performed. It revealed extravasation into the sigmoid colon (Panel A). To temporarily stop the bleeding, an occlusion balloon was placed in the right common iliac artery (Panel B). The arterial segment was not viable, and thus a 3-cm segment of artery was excised. The superficial femoral vein was harvested from the ipsilateral leg to serve as an interposition graft. Given that there was an ischemic time of 3.5 hours, that ligation of the ipsilateral superficial femoral vein causes venous hypertension, and that the patient was to remain intubated, with an associated risk of the development of the compartment syndrome, we performed prophylactic four- compartment fasciotomy of the right lower leg. As we performed ligation of the deep venous system, we mapped out the greater saphenous vein to protect it during the fasciotomy, since this vein was to serve as his major venous outflow tract until collateral veins developed. At the end of the procedure, we were unable to close the abdomen, and thus we performed a temporary abdominal closure with negative-pressure wound therapy (vacuum-assisted dressing). The patient underwent diuresis during the ensuing 24 hours and was taken back to the operating room the following day for abdominal closure and skin closure over the fasciotomy sites. Anatomy of the Toothpick Injury. The illustration shows the patient’s injury, Patients with perforation by a foreign body are usually including perforation of the sigmoid colon by unable to remember ingesting the foreign body. Most a toothpick and an associated arterioenteric ingested foreign bodies pass without consequence, but fistula (inset). 10 to 20% need to be removed endoscopically and 1% surgically. Toothpick ingestion is associated with a particularly high risk of complications; 79% of cases lead to perforation and 10% to death. Poly(ADP-Ribose)-Polymerase 1 (PARP-1) ist ein körpereigenes Enzym, welches an der DNA- Reparatur beteiligt ist. Die Hemmung des Enzyms führt dazu, dass Brüche in einzelsträngiger DNA (ssDNA) nur noch mithilfe homologer Rekombination behoben werden können. Daher können möglicherweise Krebszellen, bei denen häufig die homologe Rekombination defekt ist, mit Substanzen, die PARP-1 hemmen, abgetötet werden. Der proteolytische Abbau von PARP-1 durch Caspase-3 ist ein Zwischenschritt des programmierten Zelltods (Apoptose). In verschiedenen Spezies ist die Langlebigkeit von Zellen mit der PARP-1- Aktivität korreliert. Auch ist PARP-1 in Neuronen aktiv, die Teil des Langzeitgedächtnisses sind. Im Mausmodell wurde weiterhin gefunden, dass eine Überexpression von PARP-1 und daraus folgender Energiemangel, der Mechanismus für die Toxizität des Streptozotocins für Pankreaszellen ist. PARP-1-freie Mäuse zeigen eine Telomer-Verkürzung und mangelnde Stabilität im gesamten Genom. Die durch PARP-1 katalysierte ADP-Ribosylierung von Chromatinproteinen (wie beispielsweise Histon H1) ist eine bei allen Eukaryotenvorkommende posttranslationale Modifikation, die insbesondere bei DNA-Brüchen in PARP1 modifies nuclear proteins by Gang kommt und eine Rolle bei der DNA-Reparatur und adding units of PAR to them, a der Erholung der Zelle nach Schäden an der DNA process known as polyADP- ribosylation. spielt. Das Protein Alpha-Synuclein gilt als mögliche Ursache für die Parkinsonkrankheit. α-Synuclein (auch α-Synuklein) ist ein kleines, lösliches Protein im Gehirn von Wirbeltieren, das unter anderem die Dopamin-Ausschüttung reguliert. Es ist in der Lage, Membrankanäle zu bilden und ist daher ein Transportprotein. Mutationen im SNCA-Gen sind verantwortlich für Synucleinopathien, wie die erblichen Formen 1 und 4 der Parkinson-Krankheit und der Lewy- Körperchen-Demenz. Trotz intensiver Studien ist die genaue Rolle von SNCA noch nicht klar definiert: Es gibt Anzeichen dafür, dass SNCA bei der Aufrechterhaltung des synaptischen Vesikel-Pools eine Rolle spielt und die Dopaminfreisetzung moduliert, aber SNCA-knockout-Mäuse haben keinen offensichtlichen Phänotyp. wird eine toxische Wirkung auf bestimmte α-Synuclein-Färbung eines Lewy Nervenzellen, vor allem aber auf dopaminerge Neurone Körperchen in der Substantia nigra bei der Substantia nigra zugeschrieben, in denen es in Parkinson-Erkrankung. Form von Protofibrillen als Mitverursacher oxidativen Stresses und daraus resultierenden neuronalen Zelltodes angesehen wird. Auch eine Bedeutung der α- Synucleine bei der Entstehung von Prionen Krankheiten oder der Alzheimerschen Krankheit wird diskutiert. Die Gruppe neurodegenerativer Erkrankungen, bei denen es zu einer pathologischen Akkumulation von α-Synuclein im zentralen Nervensystem kommt, bezeichnet man als Synucleinopathien. Poly(ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson’s disease (Science)

PAR promotes α-synuclein toxicity How pathologic α-synuclein (α-syn) leads to neurodegeneration in Parkinson's disease (PD) remains poorly understood. Kam et al. studied the α-syn preformed fibril (α-syn PFF) model of sporadic PD (see the Perspective by Brundin and Wyse). They found that pathologic α-syn–activated poly(adenosine 5′-diphosphate–ribose) (PAR) polymerase–1 (PARP-1) and inhibition of PARP or knockout of PARP-1 protected mice from pathology. The generation of PAR by α-syn PFF–induced PARP-1 activation converted α-syn PFF to a Vicious cycle of PARP activity in strain that was 25-fold more toxic, termed PDPARP1 produces PAR, which PAR–α-syn PFF. An increase of PAR in the accelerates the fibrillization of α- cerebrospinal fluid and evidence of PARP synuclein and triggers parthanatos, a PARP-dependent form of cell death. This activation in the substantia nigra of PD may contribute to the progressive patients indicates that PARP activation The addition of PAR (bottom) neurodegeneration observed in PD. contributes to the pathogenesis of PD accelerates pathogenic α-synuclein through parthanatos and conversion of α-syn fibrillization. to a more toxic strain. PARP-1 is activated by a-synuclein PFF and PAR mediates cell death. Inhibition of PARP or deletion of PARP-1 reduces a-synuclein PFF–induced cell death. In a feed-forward loop, PAR causes the formation of a more toxic a-synuclein strain, resulting in accelerated pathologic a-synuclein transmission and toxicity. PARP Inhibitors and Parkinson’s Disease Parkinson’s disease is a common and debilitating age- related neurodegenerative disease that is increasing rapidly in prevalence and is expected to affect 14 million people worldwide by 2040. The disorder is defined pathologically by the accumulation of a misfolded protein, α-synuclein, and the death of dopaminergic neurons in the substantia nigra. Despite extensive research, there remain fundamental questions about the mechanisms underlying α-synuclein toxicity and debates about the role of different forms of α-synuclein, cell-to-cell (prionlike) transmission of toxic α-synuclein, nuclear events, and cell-death mechanisms. Furthermore, clinical trials are hampered by a lack of biomarkers, challenges in translating discoveries in model systems to humans, and the number of patients and intensive resources required to conduct large trials. Drug repurposing has emerged as a promising therapeutic strategy to reduce the costs and safety failures associated with the development of new drugs. α-synuclein preformed fibrils injected into mouse brain induce A new mechanism is described driving α-synuclein toxicity, nitric oxide–mediated DNA damage; this activates poly(adenosine 5′-diphosphate-ribose) (PAR) polymerase 1 “ ” as well as a potential biomarker and a repurposing (PARP1), which generates PAR. In turn, PAR interacts directly target: poly(adenosine 5′-diphosphate-ribose) (PAR) and with α-synuclein to accelerate α-synuclein fibrillization and PAR polymerase 1 (PARP1), respectively. PARP1 modifies neurotoxicity in the cytoplasm, extracellular space, and also nuclear proteins by adding units of PAR to them, a process possibly in the nucleus with respect to the fibrillar nuclear α- known as polyADP-ribosylation. Since the discovery of this synuclein inclusions found in multiple-system atrophy. Patients protein’s role in DNA damage repair, PARP1 has been with Parkinson’s disease have an increased level of PAR in the cerebrospinal fluid (CSF), which makes PAR a candidate found to participate in several cellular processes, including biomarker. As shown in Panel B, PARP inhibitors block the the regulation of chromatin structure, alterations in formation of PAR, thereby reducing α-synuclein fibrillization, transcriptional machinery, RNA processing, and spread, and related cell death through the parthanatos pathway. parthanatos (PARP1-dependent cell death, a form of If PAR were validated as a biomarker, PARP inhibitors would be programmed cell death). predicted to reduce levels of PAR in the CSF. Statin therapy has been shown to reduce major vascular events and vascular mortality in a wide range of individuals, but there is uncertainty about its efficacy and safety among older people. We undertook a meta-analysis of data from all large statin trials to compare the effects of statin therapy at different ages. In this meta-analysis, randomised trials of statin therapy were eligible if they aimed to recruit at least 1000 participants with a scheduled treatment duration of at least 2 years. We analysed individual participant data from 22 trials (n=134 537) and detailed summary data from one trial (n=12 705) of statin therapy versus control, plus individual participant data from five trials of more intensive versus less intensive statin therapy (n=39 612). We subdivided participants into six age groups (55 years or younger, 56–60 years, 61–65 years, 66–70 years, 71–75 years, and older than 75 years). We estimated effects on major vascular events (ie, major coronary events, strokes, and coronary revascularisations), cause-specific mortality, and cancer incidence as the rate ratio (RR) per 1·0 mmol/L reduction in LDL cholesterol. We compared proportional risk reductions in different age subgroups by use of standard χ2 tests for heterogeneity when there were two groups, or trend when there were more than two groups.

Sperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment. This parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18– 43 years) had a body-mass index of 19–35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0– 20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18–55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up.

Lactoferrin (genauer: Lactotransferrin, aus lateinisch lacteus ‚Milch‘ und lat. ferrum ‚Eisen‘ und lat. transferre ‚hinübertragen‘) ist ein in Säugetieren vorkommendes Protein mit multifunktionalen Enzymaktivitäten. Lactoferrin gehört zur Proteinfamilie der Transferrine. Transferrine kommen nicht nur bei Säugetieren vor, homologe Gene finden sich auch bei anderen Wirbeltieren und Wirbellosen. Lactoferrin besitzt sowohl antivirale, als auch antimikrobielle Eigenschaften. Es fungiert einerseits als Peptidase (Spaltung von Peptiden), weshalb es der Gruppe der Serinproteasen zugeordnet wird, aber auch als eisen-bindendes Protein – ähnlich dem Transferrin – und zeigt zusätzlich Desoxyribonuklease- und Ribonuklease-Aktivitäten, womit es den Nukleasen (EC 3.1.21.1) zugerechnet wird. Außerdem ist es ein starker Inhibitor für Tryptase. Lactoferrin ist in vielen Körperflüssigkeiten der Säugetiere, in deren Milch, Tränen, Speichel, Schweiß, Vaginalsekret, Seminalplasma, Nasen- und Bronchialsekret sowie anderen Sekretionen zu finden. Außerdem ist es in weißen Blutkörperchen lokalisiert.

23,61 € 21,24 € Infections acquired in hospital are an important cause of morbidity and mortality in very preterm infants. Several small trials have suggested that supplementing the enteral diet of very preterm infants with lactoferrin, an antimicrobial protein processed from cow's milk, prevents infections and associated complications. The aim of this large randomised controlled trial was to collect data to enhance the validity and applicability of the evidence from previous trials to inform practice. In this randomised placebo-controlled trial, we recruited very preterm infants born before 32 weeks' gestation in 37 UK hospitals and younger than 72 h at randomisation. Exclusion criteria were presence of a severe congenital anomaly, anticipated enteral fasting for longer than 14 days, or no realistic prospect of survival. Eligible infants were randomly assigned (1:1) to receive either enteral bovine lactoferrin (150 mg/kg per day; maximum 300 mg/day; lactoferrin group) or sucrose (same dose; control group) once daily until 34 weeks' postmenstrual age. Web-based randomisation minimised for recruitment site, gestation (completed weeks), sex, and single versus multifetal pregnancy. Parents, caregivers, and outcome assessors were unaware of group assignment. The primary outcome was microbiologically confirmed or clinically suspected late-onset infection (occurring >72 h after birth), which was assessed in all participants for whom primary outcome data was available by calculating the relative risk ratio with 95% CI between the two groups.

Denis Parsons Burkitt FRS (28 February 1911 – 23 March 1993) was a surgeon who made significant advances in health, such as the etiology of a pediatric cancer, now called Burkitt's lymphoma, and the finding that the rates of is higher in those who eat limited dietary fiber. Burkitt was born in Enniskillen, , Ireland. He was the son of James Parsons Burkitt, a civil engineer. Aged eleven he lost his right eye in an accident. He attended Portora Royal School in Enniskillen and Dean Close School, England. In 1929 Burkitt entered Trinity College, Dublin, to study engineering, but believing his evangelical calling was to be a doctor, he transferred to medicine. In 1938 he passed the Edinburgh Royal College of Surgeons fellowship examinations. On 28 July 1943 he married Olive Rogers. During World War II, Burkitt served with the Royal Army Medical Corps in England and later in and . After the war, Burkitt decided his future lay in medical service in the developing world and he moved to . He eventually settled in and remained there until 1964. Burkitt was president of the Christian Medical Fellowship and wrote frequently on religious/medical themes. He received the Bower Award and Prize in 1992. He died on 23 March 1993 in Gloucester and was buried in Bisley, Gloucestershire, England. Previous systematic reviews and meta-analyses explaining the relationship between carbohydrate quality and health have usually examined a single marker and a limited number of clinical outcomes. We aimed to more precisely quantify the predictive potential of several markers, to determine which markers are most useful, and to establish an evidence base for quantitative recommendations for intakes of dietary fibre. We did a series of systematic reviews and meta-analyses of prospective studies published from database inception to April 30, 2017, and randomised controlled trials published from database inception to Feb 28, 2018, which reported on indicators of carbohydrate quality and non-communicable disease incidence, mortality, and risk factors. Studies were identified by searches in PubMed, Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, and by hand searching of previous publications. We excluded prospective studies and trials reporting on participants with a chronic disease, and weight loss trials or trials involving supplements. Searches, data extraction, and bias assessment were duplicated independently. Robustness of pooled estimates from random-effects models was considered with sensitivity analyses, meta-regression, dose-response testing, and subgroup analyses. The GRADE approach was used to assess quality of evidence.

Der Ausdruck Anthropozän (Anthropocene) zu altgriechisch ἄνθρωπος ánthropos, deutsch ‚Mensch‘ und καινός ‚neu‘) ist ein Vorschlag zur Benennung einer neuen geochronologischen Epoche: nämlich des Zeitalters, in dem der Mensch zu einem der wichtigsten Einflussfaktoren auf die biologischen, geologischen und atmosphärischen Prozesse auf der Erde geworden ist. 2008 fand die stratigraphische Kommission der Geological Society of London, der weltweit ältesten geowissenschaftlichen Vereinigung, überzeugende Eine Satellitenaufnahme der Erde gibt anhand der Argumente für die These, dass das als Holozän sichtbar gemachten Lichtverschmutzung einen Eindruck der Größenordnung anthropogener bezeichnete zwischeneiszeitliche Zeitalter mit stabilen Umweltbeeinflussung Klimaverhältnissen an sein Ende gelangt und in einen stratigraphischen Abschnitt eingetreten sei, für den „in den letzten Millionen Jahren keine Entsprechung zu finden sei“. Hierbei spielen der Anstieg der Produktion von Treibhausgasen, die menschengemachten landschaftlichen Veränderungen, welche in ihrem Umfang derweil die natürliche jährliche Sedimentproduktion erheblich übertreffen, die Übersäuerung der Ozeane sowie die fortdauernde Vernichtung von Biota eine Rolle. Sie warnen davor, dass „die Kombination von Artensterben, weltweiter Artenwanderung und der verbreiteten Verdrängung natürlicher Vegetation durch landwirtschaftliche Monokulturen ein unmissverständliches biostratigraphisches Signal unserer Zeit darstellt. Diese Auswirkungen sind bleibend, da die zukünftige Entwicklung auf den überlebenden (und häufig anthropogen verschobenen) Beständen aufbaut. Food systems have the potential to nurture human health and support environmental sustainability; however, they are currently threatening both. Providing a growing global population with healthy diets from sustainable food systems is an immediate challenge. Although global food production of calories has kept pace with population growth, more than 820 million people have insufficient food and many more consume low-quality diets that cause micronutrient deficiencies and contribute to a substantial rise in the incidence of diet-related obesity and diet-related non-communicable diseases, including coronary heart disease, stroke, and diabetes. Unhealthy diets pose a greater risk to morbidity and mortality than does unsafe sex, and alcohol, drug, and tobacco use combined. Because much of the world's population is inadequately nourished and many environmental systems and processes are pushed beyond safe boundaries by food production, a global transformation of the food system is urgently needed.

Not one word addressing over population „Abenteuer Diagnose: A rare case of visceral leishmaniasis in an immunocompetent traveler returning to the United States from Europe

A young, healthy traveler returning to the United States presented with fever, night sweats, splenomegaly, and pancytopenia. Bone marrow biopsy revealed leishmaniasis (Leishmania infantum), likely acquired in southern France. Although many cases of endemic visceral leishmaniasis (VL) have been reported in Europe, this is a rare case of imported VL in a healthy traveler returning from Europe to the US. Despite successful initial treatment with liposomal amphotericin B (LamB), relapse occurred. Treatments for VL in immunocompetent individuals are highly effective, but relapse can occur. There is more extensive experience in endemic areas with treating relapse that may be lacking in North America. This case alerts physicians in the US that immunocompetent adults can acquire VL during brief visits to endemic areas in Europe. It is important that travelers be counseled on preventive measures. Patients should be monitored after treatment for relapse. Giant spleens: 1.Malaria Bone marrow aspirate reveals macrophages with numerous 2.Schistosoma mansoni nuclei of intracellular amastigotes and adjacent kinetoplasts of 3.CML Leishmania parasites. 4.Leishmaniasis 5.Gauchier disease Weibliche Sandmücke der Art Phlebotomus papatasi bei der Blutmahlzeit

A 49-year-old previously healthy man presented to the emergency department with a 5-month history of fever, abdominal pain, fatigue, and an unintentional 15-kg weight loss. The physical examination was notable for an enlarged liver and spleen. Laboratory studies showed a white-cell count of 2040 per cubic millimeter (reference range, 4000 to 10,000), a hemoglobin level of 9.2 g per deciliter (reference range, 14.0 to 18.0), and a platelet count of 50,000 per cubic millimeter (reference range, 140,000 to 400,000). Blood cultures as well as tests for human immunodeficiency virus, hepatitis B virus, hepatitis C virus, cytomegalovirus, and Epstein–Barr virus were negative. Computed tomography of the abdomen confirmed the presence of an enlarged liver and markedly enlarged spleen (Panel A). Examination of a bone marrow aspirate revealed amastigotes, each with a nucleus (Panel B, blue arrow) and a kinetoplast (Panel B, red arrow), within histiocytes. This is the typical appearance of leishmaniasis, and polymerase-chain-reaction testing of the bone marrow aspirate confirmed the diagnosis. Transmitted by sandflies, Leishmania infantum is endemic to Italy and the Mediterranean region. The patient started treatment with liposomal amphotericin B. At a follow-up visit 1 month later, the fever, abdominal pain, and fatigue had resolved, and physical examination revealed resolution of the splenomegaly.