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Castration-resistant prostate cancer (CRPC) is a lethal stage of disease in which androgen receptor (AR) signaling is persistent despite androgen deprivation therapy (ADT). Most studies have focused on investigating cell-autonomous alterations in CRPC, while the contributions of the tumor microenvironment are less well understood. Here we sought to determine the role of tumor-associated macrophages in CRPC, based upon their role in cancer progression and therapeutic resistance. In a syngeneic model that reflected the mutational landscape of CRPC, macrophage depletion resulted in a reduced transcriptional signature for steroid and bile acid synthesis, indicating potential perturbation of cholesterol metabolism. As cholesterol is the precursor of the five major types of steroid hormones, we hypothesized that macrophages were regulating androgen biosynthesis within the prostate tumor microenvironment. Macrophage depletion reduced androgen levels within prostate tumors and restricted AR nuclear localization in vitro and in vivo. Macrophages were also cholesterol-rich and were able to transfer cholesterol to tumor cells in vitro. AR nuclear translocation was inhibited by activation of liver X receptor (LXR)-β, the master regulator of cholesterol homeostasis. Consistent with these data, macrophage depletion extended survival during ADT and the presence of macrophages correlated with therapeutic resistance in patient-derived explants. Taken together, these findings support the therapeutic targeting of macrophages in CRPC. Significance: These results suggest that macrophage-targeted therapies can be combined with androgen deprivation therapy to treat patients with prostate cancer by limiting cholesterol bioavailability and the production of intratumoral androgens. See related commentary by Al-Janabi and Lewis, p. 5399

The cemented Exeter V40 stem is known to migrate distally. Several previous studies have reported on the extent of stem migration and its influence on clinical outcome. However, no studies have investigated the influence of stem migration on Patient Reported Outcome Measures (PROM).One hundred and twelve total hip arthroplasties (THA) were included in a 2-year follow-up using Radiostereometric Analysis (RSA). Patients were evaluated using the Oxford Hip Score (OHS) and EQ-5D-3L PROMs. The purpose of this study was to assess the influence of stem migration, measured by Maximum Total Point Motion (MTPM), on the 2-year postoperative score (OHS and EQ-5D). Furthermore, the influence of pre-operative PROM, age, gender, acetabular component and BMI was associated with the 2-year postoperative OHS and EQ-5D scores.MTPM was a non-significant predictor of the 2-year postoperative OHS (regression coefficient (B) = - 2.38 (CI - 5.44; .69)) and of the 2-year postoperative EQ-5D (B = - .01 (CI - .04; .02)). The only significant predictor of the 2-year postoperative OHS and 2-year postoperative EQ-5D was gender (B = 8.71 (CI 3.52; 13.90)) and (B = .13 (CI .07; .18)), respectively.Stem migration did not significantly influence PROMs at 2 years post-operatively. Using a patient-focused approach, our results seem to corroborate results reported by previous studies, showing that slow migration of the Exeter V40 stem does not seem to influence the clinical outcome.

Very few studies have investigated the interrelations between proprotein convertase subtilisin/kexin type 9 (PCSK9) metabolism, cholesterol synthesis, and cholesterol absorption. We aimed to address this issue in a large clinical trial of 245 patients with hypercholesterolemia. Serum lipids, PCSK9, lathosterol (cholesterol synthesis marker), campesterol, and sitosterol (cholesterol absorption markers) were measured before and 4–8 weeks after the start of treatment with PCSK9-antibodies (alirocumab or evolocumab). The patients had mean (standard error) LDL-cholesterol and PCSK9 concentrations of 3.87 (0.10) mmol/l and 356 (17) ng/ml, respectively. Eighty-four patients received no lipid-lowering pretreatment, 26 ezetimibe, 38 statins, and 97 ezetimibe + statins. Circulating PCSK9 increased in parallel with the potency of lipid-lowering pretreatment with circulating PCSK9 being highest in the ezetimibe + statin group (P < 0.001). Treatment with PCSK9-antibodies strongly decreased LDL-cholesterol, lathosterol, campesterol, and sitosterol (all P < 0.001) but hardly affected noncholesterol sterol to cholesterol ratios. Lipid-lowering pretreatment was not associated with the effects of PCSK9-antibodies on noncholesterol sterols (all P > 0.05). Summing up, circulating PCSK9 is increased by cholesterol synthesis and absorption inhibitors. Increased PCSK9 expression may partly explain the strong reductions of LDL-cholesterol achieved with PCSK9-antibodies after such pretreatment. On the other hand, treatment with PCSK9-antibodies does not significantly change the balance between cholesterol synthesis and absorption.

In many developed countries, human life expectancy has doubled over the last 180 years. Underlying this higher life expectancy is a change in how we age. Biomarkers of ageing are used to quantify changes in the aging process and to determine biological age. Perceived age is such a biomarker that correlates with biological age. Here we present a unique database rich with possibilities to study the human ageing process. Using perceived age enables us to collect large amounts of data on biological age through a citizen science project, where people upload facial pictures and guess the ages of other people at www.ageguess.org. The data on perceived age we present here span birth cohorts from the years 1877 to 2012. The database currently contains around 220,000 perceived age guesses. Almost 4500 citizen scientists from over 120 countries of origin have uploaded ~4700 facial photographs. Beyond studying the ageing process, the data present a wealth of possibilities to study how humans guess ages and who is better at guessing ages., Measurement(s)Demographics • perceived ageTechnology Type(s)digital curation • computational modeling technique • Citizen Science crowd sourcingFactor Type(s)age • sex • ethnicity • birth country • age in photographSample Characteristic - OrganismHomo sapiensSample Characteristic - Locationworldwide Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.9934316

Rationale & Objective Clinical practice guidelines for dietary intake in hemodialysis focus on individual nutrients. Little is known about associations of dietary patterns with survival. We evaluated the associations of dietary patterns with cardiovascular and all-cause mortality among adults treated by hemodialysis. Study Design Prospective cohort study. Setting & Participants 8,110 of 9,757 consecutive adults on hemodialysis (January 2014 to June 2017) treated in a multinational private dialysis network and with analyzable dietary data. Exposures Data-driven dietary patterns based on the GA2LEN food frequency questionnaire. Participants received a score for each identified pattern, with higher scores indicating closer resemblance of their diet to the identified pattern. Quartiles of standardized pattern scores were used as primary exposures. Outcomes Cardiovascular and all-cause mortality. Analytical Approach Principal components analysis with varimax rotation to identify common dietary patterns. Adjusted proportional hazards regression analyses with country as a random effect to estimate the associations between dietary pattern scores and mortality. Associations were expressed as adjusted HRs with 95% CIs, using the lowest quartile score as reference. Results During a median follow-up of 2.7 years (18,666 person-years), there were 2,087 deaths (958 cardiovascular). 2 dietary patterns, “fruit and vegetable” and “Western,” were identified. For the fruit and vegetable dietary pattern score, adjusted HRs, in ascending quartiles, were 0.94 (95% CI, 0.76-1.15), 0.83 (95% CI, 0.66-1.06), and 0.91 (95% CI, 0.69-1.21) for cardiovascular mortality and 0.95 (95% CI, 0.83-1.09), 0.84 (95% CI, 0.71-0.99), and 0.87 (95% CI, 0.72-1.05) for all-cause mortality. For the Western dietary pattern score, the corresponding estimates were 1.10 (95% CI, 0.90-1.35), 1.11 (95% CI, 0.87-1.41), and 1.09 (95% CI, 0.80-1.49) for cardiovascular mortality and 1.01 (95% CI, 0.88-1.16), 1.00 (95% CI, 0.85-1.18), and 1.14 (95% CI, 0.93-1.41) for all-cause mortality. Limitations Self-reported food frequency questionnaire, data-driven approach. Conclusions These findings did not confirm an association between mortality among patients receiving long-term hemodialysis and the extent to which dietary patterns were either high in fruit and vegetables or consistent with a Western diet.

Determination of predictive biomarkers by immunohistochemistry (IHC) relies on antibodies with high selectivity. RNA in situ hybridization (RNA ISH) may be used to confirm IHC and may potentially replace it if suitable antibodies are not available or are insufficiently selective to discriminate closely related protein isoforms. We validated RNA ISH as specificity control for IHC and as a potential alternative method for selecting patients for treatment with MET inhibitors. MET, the HGF receptor, is encoded by the MET proto-oncogene that may be activated by mutation or amplification. MET expression and activity were tested in a panel of control cell lines. MET could be detected in formalin fixed paraffin, embedded (FFPE) samples by IHC and RNA ISH, and this was confirmed by sandwich immunoassays of fresh frozen samples. Gastric cancer cell lines with high MET expression and phosphorylation of tyrosine-1349 respond to the MET inhibitor, BAY-853474. High expression and phosphorylation of MET is a predictive biomarker for response to MET inhibitors. We then analyzed MET expression and activity in a matched set of FFPE vs. fresh frozen tumor samples consisting of 20 cases of gastric cancer. Two of 20 clinical samples investigated exhibited high MET expression with RNA ISH and IHC. Both cases were shown by sandwich immunoassays to exhibits strong functional activity. Expression levels and functional activity in these two cases were in a range that predicted response to treatment. Our findings indicate that owing to its high selectivity, RNA ISH can be used to confirm findings obtained by IHC and potentially may replace IHC for certain targets if no suitable antibodies are available. RNA ISH is a valid platform for testing predictive biomarkers for patient selection.

Since 2010 the guideline 'Guideline for perinatal policy in cases of extreme prematurity' has advised an active policy in infants born at 24 weeks gestation. We investigated how infants born at 24 and 25 weeks gestation in the first year following the implementation of the guideline had developed by the age of 2 years.Retrospective national cohort study.The study population consisted of all surviving infants born in the Netherlands at 24 or 25 weeks gestation in the period from 1 October 2010 to 1 October 2011. At a corrected age of 2 years the children underwent a general physical and neurological examination, and their cognitive scores were determined on the 'Bayley scales of infant and toddler development' (Bayley III). Examinations took place in the 10 neonatal intensive care units (NICU's) in the Netherlands.Of 185 extremely premature infants, 166 were admitted to a NICU. A total of 95 survived to a corrected age of 2 years; 78 (82%) children were examined. Their average cognitive score on the Bayley III scale was 88 (SD: 16). Among the children born at 24 weeks gestation, 20% had mild disabilities and 20% had moderate to severe disabilities. Among the children born at 25 weeks gestation, 17% had mild disabilities and 12% had moderate to severe disabilities.Of the children born at 24 weeks gestation in the first year after the introduction of active policy in the Netherlands and surviving to 2 years of age (46%), more than half had developed without disabilities. This was comparable to children born at 25 weeks gestation. Of all children born at 24 weeks gestation, 25% survived to 2 years of age without disabilities.

Individuals within populations can differ substantially in their life span and their lifetime reproductive success but such realized individual variation in fitness components need not reflect underlying heritable fitness differences visible to natural selection. Even so, biologists commonly argue that large differences in fitness components are likely adaptive, resulting from and driving evolution by natural selection. To examine this argument we use unique formulas to compute exactly the variance in life span and in lifetime reproductive success among individuals with identical (genotypic) vital rates (assuming a common genotype for all individuals). Such individuals have identical fitness but vary substantially in their realized individual fitness components. We show by example that our computed variances and corresponding simulated distribution of fitness components match those observed in real populations. Of course, (genotypic) vital rates in real populations are expected to differ by small but evolutionarily important amounts among genotypes, but we show that such differences only modestly increase variances in fitness components. We conclude that observed differences in fitness components may likely be evolutionarily neutral, at least to the extent that they are indistinguishable from distributions generated by neutral processes. Important consequences of large neutral variation are the following: Heritabilities for fitness components are likely to be small (which is in fact the case), small selective differences in life histories will be hard to measure, and the effects of random drift will be amplified in natural populations by the large variances among individuals.

Eur J Clin Invest 2010; 40 (2): 155–163 Abstract Background Iron overload may contribute to the pathogenesis of insulin resistance. We aimed to investigate the relationship among iron stores, liver transaminases and components of the metabolic syndrome in healthy teenagers in a cross-sectional study. Material and methods We determined body mass index (BMI), waist-to-hip-ratio (WHR), blood pressure, liver ultrasound, serum lipids, insulin, fasting glucose, liver transaminase levels, hsCRP, iron parameters in 325 of 341 (95·3%) students (234 men, 16·7 ± 1·7 years; 91 women, 16·5 ± 1·7 years) of one single high school. Male and female study participants were allocated to increasing quartiles of body iron stores as assessed by sTfr/ferritin and alanine aminotranspeptidase (ALT) levels, and the distribution of cardiometabolic risk factors along quartiles was analysed. Regression analysis was performed to confirm the independent relationship between parameters. Results In male students, BMI, WHR, systolic and diastolic blood pressure, serum triglyceride levels and hsCRP were higher in the top sTfR/ferritin and ALT quartiles compared with the lowest quartiles (P

Background Dental disease is more extensive in adults with chronic kidney disease, but whether dental health and behaviors are associated with survival in the setting of hemodialysis is unknown. Study Design Prospective multinational cohort. Setting & Participants 4,205 adults treated with long-term hemodialysis, 2010 to 2012 (Oral Diseases in Hemodialysis [ORAL-D] Study). Predictors Dental health as assessed by a standardized dental examination using World Health Organization guidelines and personal oral care, including edentulousness; decayed, missing, and filled teeth index; teeth brushing and flossing; and dental health consultation. Outcomes All-cause and cardiovascular mortality at 12 months after dental assessment. Measurements Multivariable-adjusted Cox proportional hazards regression models fitted with shared frailty to account for clustering of mortality risk within countries. Results During a mean follow-up of 22.1 months, 942 deaths occurred, including 477 cardiovascular deaths. Edentulousness (adjusted HR, 1.29; 95% CI, 1.10-1.51) and decayed, missing, or filled teeth score ≥ 14 (adjusted HR, 1.70; 95% CI, 1.33-2.17) were associated with early all-cause mortality, while dental flossing, using mouthwash, brushing teeth daily, spending at least 2 minutes on oral hygiene daily, changing a toothbrush at least every 3 months, and visiting a dentist within the past 6 months (adjusted HRs of 0.52 [95% CI, 0.32-0.85], 0.79 [95% CI, 0.64-0.97], 0.76 [95% CI, 0.58-0.99], 0.84 [95% CI, 0.71-0.99], 0.79 [95% CI, 0.65-0.95], and 0.79 [95% CI, 0.65-0.96], respectively) were associated with better survival. Results for cardiovascular mortality were similar. Limitations Convenience sample of clinics. Conclusions In adults treated with hemodialysis, poorer dental health was associated with early death, whereas preventive dental health practices were associated with longer survival.

The aim of this study was to investigate whether the washout length between glycemic response tests influences their reliability. A total of 3 men and 12 women performed eight identical blood glucose tolerance tests: four tests on consecutive days (short interval) and four tests spread over 20–30 days, with 5–10 days between the tests (long interval). No difference was observed in the coefficient of variation (P=0.32) of the incremental area under the blood glucose response curve between the short and long interval, and there was no drift within the short (P=089) and long interval (P=0.20). The first test did not differ from any of the subsequent tests (P>0.99). In conclusion, glycemic response testing on consecutive days does not seem to influence the variability of glycemic response tests compared with longer intervals and it does not cause any data drift under conditions of earlier diet and habitual exercise control. In addition, familiarization trials do not seem to be necessary for glycemic response tests.

CL316243 is a highly selective and potent β 3 -adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.

Central needle embolization is a rare complication of intravenous drug abuse which has only been reported on a handful of occasions. Previously reported cases of needle embolization to the heart have been managed conservatively (observation alone) or by surgical intervention. We report a case of purulent pericarditis without evidence of valvular vegetations resulting from an embolized, infected needle fragment. In the present case, the needle was successfully removed from the right ventricle percutaneously. This case illustrates the unique finding of purulent pericarditis due to a persistent foreign body in the right ventricle, and the nontraditional intervention performed for needle fragment removal which resulted in full clinical recovery of the patient.

The pharmacokinetic properties and first clinical experiences with the antihypertensive dopamine (DA2) agonist, carmoxirole, are summarized. In man carmoxirole was rapidly absorbed. On oral administration the maximum plasma concentration was reached after 2-3 h. The drug was metabolized, mainly to an ester-type glucuronide, and was excreted (unchanged carmoxirole plus glucuronide) largely by the kidneys. The plasma half-life of the parent compound was 5.5 h. For the dose range tested (0.5 to 1.5 mg) the pharmacokinetics were linear. The drug was rapidly distributed in animals but only very small amounts penetrated the blood-brain barrier. Carmoxirole did not affect supine blood pressure in healthy subjects, but under the conditions of the Schellong's test some orthostatic reactions occurred with high doses. In patients the blood pressure was reduced for at least 8 h after single oral doses. On repeated administration for several weeks a relevant antihypertensive effect was still measurable 12 and 24 h after dose. The most frequently reported adverse events have been headache, dizziness, tiredness, nausea, and gastric disorders. These symptoms are considered to be mainly due to blood pressure reduction, as is frequently observed at the beginning of antihypertensive therapy. In patients the incidence of orthostatic reactions is appreciably lower than in healthy subjects, and in both change of position was sufficient to relieve the symptoms.

Background International research in recent years has begun to focus on the medical problems of individuals with intellectual disabilities and on family stress in accessing health services for persons with developmental disabilities. Less is known about the needs of individuals in different diagnostic groups, or about their experiences of systems of care. Therefore, we report the results of focus groups with parents of children or adults with fragile X syndrome, autism or Down syndrome. Methods Semi-structured group interviews with parents of children, youth or adults from each of three diagnostic groups probed perceptions of challenges and successes in obtaining and negotiating healthcare services in Ontario, Canada. Results Parents described diverse barriers to care, the need for advocacy in securing services, perceptions of service delivery and the role of healthcare professionals in regulating access to a wide range of services. Diagnostic services represented one area of central concern to parents from all three groups. Discussion Focus group data yielded a wide range of concerns. Suggestions for enhancing the system included expanding syndrome-specific education for medical students and health professionals and creating a centre that could offer service-related information for parents.

Genetic polymorphism of KIR2DL4 results in alleles with either 9 or 10 consecutive adenines in exon 6, which encodes the transmembrane domain. "10A" alleles encode a membrane-expressed receptor that is constitutively expressed on resting CD56bright NK cells and on CD56dim cells after culture. However, in some individuals with the 10A allele, KIR2DL4 cannot be detected on their resting CD56bright NK cells. "9A" alleles have been predicted to encode a secreted receptor due to the splicing out of the transmembrane region. In this publication, we show that those individuals with a 10A allele who lack detectable KIR2DL4 on CD56bright NK cells express a KIR2DL4 receptor in which the D0-domain is excised. This Delta-D0 receptor cannot be detected by the available anti-KIR2DL4 monoclonal antibodies. In such individuals, KIR2DL4 becomes detectable on cultured NK cells due to up-regulation of the full-length KIR2DL4 transcript. In all individuals with 10A alleles, KIR2DL4 ceases to be expressed at the cell surface 16 days after activation, despite the maintenance of maximal levels of KIR2DL4 mRNA transcription, suggesting the existence of a negative regulator of cell surface expression. Finally, we show that the 9A allele can produce a secreted KIR2DL4 receptor.

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Twenty-five novel HLA-B alleles are described in this paper: B*0729, B*1309, B*1814, B*1815, B*2724, B*2725, B*3539, B*3926, B*4037, B*4040, B*4042, B*4043, B*4044, B*4204, B*440203, B*4428, B*4429, B*4430, B*4505, B*5308, B*5309, B*5510, B*5511, B*570102, and B*5709. Most of the variants are single nucleotide substitutions. Two involve variants at the Bw4/Bw6 epitope. Two alleles carry substitutions of conserved amino acids.

This paper describes 17 novel HLA-A alleles: A*0244, A*0251, A*0254, A*0309, A*1111, A*2432, A*2434, A*2504, A*2618, A*2905, A*2906, A*3106, A*3107, A*3207, A*6820, A*7407, and A*7408. Most substitutions are found in other alleles.

Antibodies to heat shock protein (hsp) are strongly associated with atherosclerotic cardiovascular disease in the non-diabetic population as well as in patients with type 2 diabetes mellitus. In type 1 diabetes increased antibody titers to hsp were found to be a symptom of the autoimmune disease leading to beta-cell damage. We asked whether hsp antibody titers are related to metabolic control and late complications in type 1 diabetic patients. Serum neopterin, also an indicator of chronic inflammation, was also evaluated. The hsp65 antibody titer was determined in 138 patients with type 1 diabetes, 47 women and 91 men, aged 35.5 +/- 12 years with a mean diabetes duration of 16.6 +/- 10.5 years. A history of diabetic late complications and cardiovascular disease was taken. A fundoscopy and a neurological examination were performed, nephropathy was assessed by measurement of the urinary albumin excretion rate. For the measurement of the hsp antibody titer an enzyme-linked immunosorbent assay (ELISA) was applied, for neopterin a radio-immuno assay (RIA) was used. The hsp65 antibody titer was found to be positively related to the patients' age (r = 0.237; p < 0.035). Patients with retinopathy revealed significantly higher hsp65 antibody titers (307.2 +/- 38.6) than those without retinopathy (150.0 +/- 18.5;p < 0.003). No correlation was found between hsp antibody titer and metabolic control. Serum neopterin levels revealed a trend towards a positive relationship with diabetes duration (r = 0.205; p < 0.0539) and a significant correlation with serum cholesterol levels (r = 0.436; p < 0.001), but not with HbA1 c values. Our data add further information to the role of inflammatory markers in the development of diabetic microangiopathy.

At least 60 DRB1*02 positive individuals from each of four US population groups found within a hematopoietic stem cell volunteer donor registry - Caucasoids, African Americans, Asians/Pacific Islanders, and Hispanics - were randomly selected from a database of 82,979 individuals. DRB1*02 alleles were identified by DNA sequencing. A total of five of 23 known DRB1*02 alleles were detected. DRB1*15011 was the predominant DRB1*02 allele in Caucasoids and Hispanics. The most common DRB1*02 allele observed in African Americans was DRB1*1503, and DRB1*15021 in Asians/Pacific Islanders. Caucasoids were found to be the least diversified; only DRB1*15011 and DRB1*16011 were observed. A subset of individuals was also typed for DRB5 alleles by DNA sequencing. DRB5*01011, DRB5*0102, DRB5*0103, DRB5*0108N and DRB5*0202 were detected and nine DRB1-DRB5 haplotypes defined.

This paper describes two novel HLA-B locus alleles. B*0713 appears to have resulted from an interlocus recombinational event which inserted a sequence from an HLA-C allele into B*0702. This event altered a significant portion of the alpha-1 domain alpha helix. B*6702 shares much of its exon 2 sequence with B*0713 but is identical in exon 3 to several HLA-B locus alleles including B*67012.

SummaryCTLA-4 (CD152) is a surface molecule of activated T cells with sequence homology to CD28. Both molecules bind to the same ligands, B7.1 (CD80) and B7.2 (CD86) but have antagonistic functions. While CD28 is an important costimulator, CTLA-4 has an essential inhibitory function in maintaining the homeostasis of the immune system. Furthermore, CTLA-4 has a role in inducing a Th1 response and suppressing Th2 cytokines, an effect which is antagonized by CD28. Many autoimmune diseases are characterized by an overwhelming production of Th1 cytokines. Recently, the predominance of the Th1 cytokine pattern has been directly observed in the granulomatous inflammation of patients with Wegener's granulomatosis. The balance between CD28 and CTLA-4 expression by T lymphocytes could be a factor in the pathogenesis of autoimmune diseases. Down regulation of CD28 predominantly on CD8+ T cells has been described in Wegner's granulomatosis; however, analysis of CTLA-4 is complicated by its low expression levels. Here we have used potent signal enhancement to study CTLA-4 on PBMC in patients with Wegener's granulomatosis (n = 25) in comparison with healthy controls (n = 19). Expression levels of CTLA-4 were significantly increased selectively on CD4+ and possibly also on CD4−/CD8− T cells in Wegener's granulomatosis. High CTLA-4 expression by T lymphocytes was associated with more severe disease. In contrast, after stimulation with the mitogen PHA, CTLA-4 levels were strongly increased on T cells from controls but in T cells from Wegener's granulomatosis patients this response was severely impaired. Interestingly, while CTLA-4 was seen exclusively on T cells in control individuals, about half of the Wegener's patients showed CTLA-4 expression by a fraction of peripheral B lymphocytes. CTLA-4 positive B cells in the periphery were associated with less acute disease.

This paper describes 9 novel HLA-B locus alleles. All of the alleles carry sequence motifs observed in other HLA-B alleles.

This paper describes 29 novel HLA-B locus alleles identified during low-resolution typing. The majority of the novel alleles carry new patterns of previously known polymorphic motifs or codons. Three alleles carry alterations in the Bw4/Bw6 epitope. Five alleles carry novel substitutions.

Seven new HLA-B locus alleles have been described. B*44022 and B*44032 are silent substitutions altering known alleles. B*4411 carries a unique Bw4-like epitope. B*4420, B*4421, and B*4424 carry new combinations of motifs previously observed in other alleles. B*8301 appears to be the result of the replacement of exon 2 from B*4402 with exon 2 from B*5603.

This paper describes 13 novel HLA-B locus alleles, B*0809, B*0812, B*0813, B*0814, B*14062, B*3804, B*3806, B*3914, B*3915, B*3918, B*3919, B*3920, and B*3922 which represent new patterns of known polymorphic residues.

The aim of this study was to identify independent predictors of acquiring a nosocomial bloodstream infection (BSI) during extracorporeal membrane oxygenation (ECMO).This retrospective cohort consisted of 202 neonates treated with ECMO from 1989 to 1998 at the author' institution. Data collected included patient demographics, primary and secondary diagnoses, white blood cell counts, antibiotic usage, presence of central lines, operative procedures, and outcome. Surveillance blood cultures were drawn daily from the circuit using sterile technique to identify acquired pathogens. Statistical analyses included logistic regression, Cox proportional regression analysis, and discriminate analysis.There were 1,245 blood cultures drawn on 202 patients (6.2 cultures per patient), and a nosocomial BSI was identified in 7 patients (3.4%) during this 10-year span. These were infections that were neither present nor incubating on admission. Pre-ECMO diagnoses of patients who had a nosocomial BSI while on bypass included group B beta-hemolytic streptococcal sepsis (n = 2), herpes simplex viral sepsis (n = 1), congenital diaphragmatic hernia (n = 2), persistent pulmonary hypertension (n = 1), and congenital heart disease (n = 1). The median time on ECMO before obtaining a positive culture was 390 hours. The infectious agents responsible for these BSIs included Staphylococcus epidermidis (n = 5), Staphylococcus aureus (n = 1), and Escherichia coli (n = 1). The major factor associated with acquiring a nosocomial BSI on ECMO was the duration of bypass (391 v 141 hours, P =.002). Additionally, patients in the BSI group were more likely to have had an arterial catheter in place (16 v 7 days, P =.009) and to have received more screening blood cultures (16 v 6 cultures, P001). White blood cell counts, absolute neutrophil counts, and immature/total (I/T) ratios were not useful in predicting a nosocomial BSI. Of the 31 patients who required ECMO for more than 10 days, 7 (23%) had a positive blood culture, and 5 of these 7 infants (71%) died (P =.03).The only predictor of acquiring a nosocomial BSI on ECMO was the duration of support for greater than 10 days. Because classical predictors of infection are unreliable while the patient is on ECMO, the authors suggest that obtaining daily surveillance blood cultures beginning on the tenth day should be performed with prolonged ECMO courses. The authors confirmed previous reports of the association between a prolonged ECMO course and a high mortality rate. However, the authors speculate that, in actuality, the primary diagnosis leads to the prolonged course of support and is the major factor in the infant' demise.

This paper describes seven novel HLA-A locus alleles which carry previously observed polymorphisms.

SUMMARYCTLA-4 (CD152) is a surface molecule of activated T cells with sequence homology to CD28. Both molecules bind to the same ligands, B7.1 (CD80) and B7.2 (CD86) but have antagonistic functions. While CD28 is an important costimulator, CTLA-4 has an essential inhibitory function in maintaining the homeostasis of the immune system. Down- regulation of CD28 predominantly on CD8+ T cells has been described in HIV infection, but analysis of CTLA-4 is complicated by its low expression levels. Here we have used potent signal enhancement to study CTLA-4 on peripheral blood mononuclear cells (PBMC) during HIV infection. CTLA-4 was expressed only on T cells. Expression levels were significantly increased selectively on CD4+ T cells during all stages of HIV infection, while CTLA-4 expression on CD8+ T cells was always low. In contrast, after stimulation with the mitogen phytohaemagglutinin (PHA), CTLA-4 levels were strongly increased on T cells from controls but in T cells from HIV patients this response was severely impaired. Our data suggest that in HIV infection CD4+ and CD8+ T cells may be less responsive to B7 costimuli due to two different mechanisms: increase in CTLA-4 expression by CD4+ cells and down-regulation of CD28 by CD8+ cells.

The impact of increasing enrollment in Medicare HMOs will require health care providers to develop new strategies in care delivery systems. Key strategies in managing risk include health risk appraisals, proactive case management, disease management, provider education, and the use of inpatient physician managers. Implementing an integrated care management system requires a team approach. The physician inpatient manager, nurse case manager, geriatric clinical nurse specialist, and social worker composed the health care team charged with implementing a care management system responsive to enrollees' needs. A quality management plan is essential for tracking patient outcomes and quality indicators across the continuum. The focus of promoting wellness and preventing illness represents a paradigm shift from the traditional model of episodic care that can yield positive financial results.

Postpartum fistulas are frequent in the tropical environment. They are mostly found in very young women who live in remote areas. Without treatment women with fistulas will be condemned to the disconsolate life of social outcasts. Good operative treatment is crucial. The different operative methods are discussed. The operation through vaginal approach can be performed in any hospital. It does not need special surgical skill. More important than surgery is prevention of postpartum fistulas through a well-organised primary health care program which reaches out into the villages and which includes adequate prenatal controls and competent midwifery.In tropical environments, fistulas between the vagina and the bladder or rectum are common in postpartum women. This condition is most frequent in very young women from remote rural areas whose deliveries are attended by midwives untrained in the management of obstructed labor. As a result of the continuous seepage of urine and/or feces associated with this condition, women with fistulas face social ostracism. Thus, the prevention and adequate treatment of postpartum fistulas are important tasks for health services in the tropics. Unlike complicated transperitoneal procedures, a vaginal approach to fistula treatment does not require special surgical skills and can be performed under spinal anesthesia. 75-85% of first surgeries for postpartum fistula are successful (defined as no leakage of urine or feces and resumption of normal sexual relations). The success rate depends, however, on factors such as the exact localization and extension of the fistula, involvement of the urethra, the closing mechanism of the bladder, and the experience of the surgeon. Prevention of postpartum fistula requires good prenatal care, including the referral of primiparas with small or abnormal pelvic proportions to a hospital for delivery, and adequate maternity facilities, especially the availability of midwifery staff trained in vacuum extractor use and symphysiotomy performance.

Surgery is an important part of primary health care in remote rural areas of third world countries. It is essential that doctors and nurses who are working in rural hospitals are adequately trained in surgery. Special consideration should be given to the surgical pathology encountered in the rural tropical environment. Teaching should take place in the set-up of the rural hospital and should include anaesthesia, sterilisation and maintenance of equipment. A concept of teaching in surgery in peripheral hospitals is presented.

The murine monoclonal antibody (MAb) 425 (mMAb 425) directed against the human EGFR (epidermal growth factor receptor) was reshaped (rMAb 425) in order to improve its therapeutical potential in humans. The pharmacokinetic properties of [125I]-mMAb and [125I]-rMAb 425 were compared in three animal species. Whereas the clearance curves of both antibodies decreased biphasically in rats and nude mice bearing human mammary carcinoma, a monophasic decline was observed in Cynomolgus monkeys. Plasma elimination half-lives of murine and reshaped MAb 425 were similar, short in the monkey (26 h for mMAb 425 and 31 h for rMAb 425) and long in rats (240 h for mMAb 425 and 225 h for rMAb 425). In xenografted nude mice however, the half-life of mMAb 425 (203 h) was about twice as long as that of rMAb 425 (124 h). The half-lives of intact rMAb 425 in the three species obtained by ELISA differed at most by a factor of two from those obtained by radioactivity measurements. Biodistribution studies of [125I]-rMAb 425 revealed a tumor/blood ratio of 1.2 on d 1 and 5.1 on d 18, respectively. Fifty-four and thirty-eight percent of the radioactive dose were excreted with urine in nude mice (within 12 d) and rats (within 11 d), respectively. Specific localization of [125I]-rMAb 425 in human mammary carcinoma xenografted to nude mice was demonstrated.

The genes for streptokinase, the most important prokaryotic plasmingoen activator, exhibit allelic variation predominantly due to the polymorphism of an internal 220-base pair fragment that divides the phylogenetic tree of their products into two primary branches. Current molecular genetic research seeks functional correlates of the allelic variation, aims at analyzing the genomic environment of the streptokinase gene, skc, and focuses on understanding its expression. Of the six genes cloned and sequenced in the skc region of Streptococcus equisimilis H46A, skc is expressed most abundantly in a fashion that involves two overlapping core promoters and upstream sequences rich of AT tracts. Transcription of skc is terminated at a hypersymmetrical site that functions bidirectionally and prevents convergent transcription of the oppositely oriented skc and rel-orf1 genes whose mRNA abundance differs by a factor of at least three orders of magnitude.

To assess the significance of deficiency of circulating proinsulin in patients with type I diabetes mellitus, we studied the metabolic effects of biosynthetic human proinsulin in 24 patients. After withdrawing insulin, an infusion of proinsulin to physiological plasma levels did not prevent elevations of plasma glucose or beta-hydroxybutyrate. During steady state infusions of insulin and proinsulin, 13.7 times the steady state plasma level of proinsulin compared to insulin was required to maintain euglycemia. This finding indicates that proinsulin is approximately 7.3% as biologically active as insulin on a molar basis in maintaining glucose control. The MCRs of insulin and proinsulin during these steady state infusions were 12.5 +/- 2.2 (+/- SEM) and 2.62 +/- 0.33 ml/kg X min, respectively. After maintaining euglycemia overnight with an infusion of insulin or proinsulin and then acutely stopping these infusions, the rise in plasma glucose after proinsulin was delayed significantly compared to insulin, consistent with proinsulin's slower clearance. Further studies are necessary to determine whether biosynthetic human proinsulin has a specific role in the treatment of diabetes.

Brain neurotransmitters play an essential role in central regulation of hypothalamic factors which stimulate or inhibit the secretion of pituitary hormones. Insight in this complex system might be obtained by analysing changes in pituitary and peripheral hormone secretion following the administration of neuroactive drugs which influence the action of neurotransmitters. Desipramine is well-known to inhibit presynaptic norepinephrine reuptake, clomipramine on the other hand interferes with the serotoninergic system. In 15 male volunteers, the effects of single-dose administration of each drug were studied in comparison to placebo. Basal concentrations of ACTH and cortisol, as well as the rise of both hormones following insulin-induced hypoglycemia, were studied. Basal cortisol values and the response to hypoglycemia were not affected by either pharmacon in this study. Slight differences could be seen in the ACTH responses, which were however not significant.

A 39-year-old woman contracted visceral leishmaniasis on a 14-day visit to southern Italy and died of staphylococcal septicaemia before specific treatment could be effective, diagnostic efforts over four months having failed to make the diagnosis until four weeks before death. Eight further cases reported in German-speaking medical journals illustrate similar diagnostic difficulties. The disease is accompanied by septic temperatures, frequently with two daily spikes, hepato- and splenomegaly, normochromic anaemia and leucocytopenia. But diagnosis can only be made by specific tests. The organisms can be discovered in sternal puncture and organ biopsies only if the Giemsa stain is used. Complement-fixation reaction for leishmania should be tried repeatedly, in case the disease is suspected.

Ninety CSA-treated kidney transplants recipients entered the study. The patients were allocated to three groups based on serum creatinine at 12 months and kidney biopsy findings: control group (serum creatinine less than 177 mumol/l), rejection group (verified by biopsy, serum creatinine greater than 177 mumol/l), nephrotoxicity group (verified by biopsy, serum creatinine greater than 177 mumol/l). Thirty variables were systematically evaluated. The following parameters had a predictive value for the development of chronic CSA-nephrotoxicity: number of CSA-induced episodes of acute deterioration of renal function, CSA trough level (day 0-30, day 31-90), number of unexplained episodes of acute deterioration of renal function, number of nephrotoxic drugs, number of rejection treatments, number of rejection episodes and primary poor renal function. The results indicate that all factors leading to acute renal failure, favor the development of CSA-nephrotoxicity.

The computerized X-ray tomography uses for the information of the images besides a highly developed computer technology a special CT-algorithm, i.e. preprocessing of detected "projections", their "high-pass" convolution and back-projection. The diagnostic success of computerized X-ray tomography gave rise to the investigation of other carriers of information besides X-radiation for the production of cross-sectional pictures using CT reconstruction principles. Examples are: Emission-CT, Proton-CT, Nuclear Magnetic Resonance CT, Ultrasound-CT, Impedance-CT and Mikrowave-CT. This paper gives a review of such methods, their basis properties and an estimation of their capabilities for medical application. This discussion is opened by a summary of the basis CT principles.

Die cytologischen Untersuchungen der Verff. beziehen sich auf 18 020 Untersuchungsmaterialien von 5812 Patienten. Erwiesene Thoraxgeschwulste hatten 1585 Patienten, davon waren 1482 primare Geschwulste.