Impaired Whole-Blood Polymorphonuclear Leukocyte Migration as a Possible Predictive Marker for Infections in Preterm Premature Rupture of Membranes

Objectives: Steroids, used in pretermpremature rupture of membranes (pPROM), to reduce the risk of morbidity and mortality of the preterm neonate, impair the maternal polymorphonuclear leukocyte (PMN)-based immune system. In spite of combination with antibiotics, prenatal and postnatal bacterial infections of mother and child are frequent. This pilot study focuses on the influence of steroids in pPROM on maternal PMN functional capacity and subsequent infections. Methods: After opting for expectant management, eight women with pPROM and no signs of infection were treated by steroids (betamethasone 5.7 mg, i.m. every 24 hours, for three days) and antibiotic therapy with either amoxicillin and clavulanic acid, piperacillin or ampicillin i.v. up to delivery. The conventional inflammation parameters of PMN blood count and C-reactive protein (CRP) were measured daily in parallel with PMN migratory capacity towards N-formyl-methionyl-leucyI-phenylalanine stimulation and under blank conditions, estimated by a whole blood membrane filter assay. Results: In all patients PMN migration decreased during the application of steroids. Three patients showed a decrease in PMN migration below critical values and in spite of antibiotic prophylaxis acute pyelonephritis developed 2–6 days later. PMN count and CRP were not predictive of maternal infection. Conclusion: Reduced PMN function, caused by steroid treatment in pPROM, is suggested to be a reason for serious bacterial infections in spite of antibiotic prophylaxis. PMN migration reflects individual PMN defensive capacity

The demise of the randomised controlled trial: bibliometric study of the German-language health care literature, 1948 to 2004

BACKGROUND: In order to reduce systematic errors (such as language bias) and increase the precision of the summary treatment effect estimate, a comprehensive identification of randomised controlled trials (RCT), irrespective of publication language, is crucial in systematic reviews and meta-analyses. We identified trials in the German general health care literature. METHODS: Eight German language general health care journals were searched for randomised controlled trials and analysed with respect to the number of published RCTs each year and the size of trials. RESULTS: A total of 1618 trials were identified with a median total number of 43 patients per trial. Between 1970 and 2004 a small but constant rise in sample size from a median number of 30 to 60 patients per trial can be observed. The number of published trials was very low between 1948 and 1970, but increased between 1970 and 1986 to a maximum of 11.2 RCTs per journal and year. In the following time period a striking decline of the number of RCTs was observed. Between 1999 and 2001 only 0.8 RCTs per journal and year were published, in the next three years, the number of published trials increased to 1.7 RCTs per journal and year. CONCLUSION: German language general health care journals no longer have a role in the dissemination of trial results. The slight rise in the number of published RCTs in the last three years can be explained by a change of publication language from German to English of three of the analysed journals

Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling

Mutations of NPHS1 or NPHS2, the genes encoding nephrin and podocin, as well as the targeted disruption of CD2-associated protein (CD2AP), lead to heavy proteinuria, suggesting that all three proteins are essential for the integrity of glomerular podocytes, the visceral glomerular epithelial cells of the kidney. It has been speculated that these proteins participate in common signaling pathways; however, it has remained unclear which signaling proteins are actually recruited by the slit diaphragm protein complex in vivo. We demonstrate that both nephrin and CD2AP interact with the p85 regulatory subunit of phosphoinositide 3-OH kinase (PI3K) in vivo, recruit PI3K to the plasma membrane, and, together with podocin, stimulate PI3K-dependent AKT signaling in podocytes. Using two-dimensional gel analysis in combination with a phosphoserine-specific antiserum, we demonstrate that the nephrin-induced AKT mediates phosphorylation of several target proteins in podocytes. One such target is Bad; its phosphorylation and inactivation by 14-3-3 protects podocytes against detachment-induced cell death, suggesting that the nephrin-CD2AP-mediated AKT activity can regulate complex biological programs. Our findings reveal a novel role for the slit diaphragm proteins nephrin, CD2AP, and podocin and demonstrate that these three proteins, in addition to their structural functions, initiate PI3K/AKT-dependent signal transduction in glomerular podocytes

Distribution of Country of Origin in Studies Used in Cochrane Reviews

Inclusion in systematic reviews is one important component in judging the potential impact of clinical studies upon practice and hence the 'value for money' of spending for clinical research. This study aims to quantify the distribution of countries of origin of clinical studies used in Cochrane Reviews (CRs), and to link these data to the size of a country and to its spending on research. Random sample of publications used for CRs published in Issue 1 2008 and of publications used in CRs in the field of complementary and alternative medicine (CAM). Publications without original data were excluded. Likely countries of origin determined based on abstracts/full texts. CIA World Factbook (population data) and OECD database (economic data) were used. 1,000 random entries out of 140,005 references available in all specialities. In 876 (91.4%) of 959 eligible studies, country of origin was determined. The USA was the leading contributor (36.0% of the studies), followed by UK (13.4%), Canada (5.3%), Australia and Sweden (3.7%). In the CAM sample, country of origin was determined in 458 (93.5%) of 497 assessed studies. Again, the USA was the leading contributor (24.9%), with China also emerging as a significant contributor (24.7%) in this field. For both samples, the contribution of smaller countries (especially Scandinavian countries, Greece, and Ireland) became more noteworthy when considered in relation to population size and research spending. Our results support the leading roles of both the USA and the UK in publishing clinical papers. The emerging role of China can be seen, particularly related to CAM studies. Taking into account size of population and economic power, countries like France, Germany, Italy, and Spain provide small contributions. In contrast, smaller countries like Australia, Denmark, Finland, Ireland, New Zealand, and Sweden also play major roles

Relationship between Gene Body DNA Methylation and Intragenic H3K9me3 and H3K36me3 Chromatin Marks

To elucidate the relationship between intragenic DNA methylation and chromatin marks, we performed epigenetic profiling of chromosome 19 in human bronchial epithelial cells (HBEC) and in the colorectal cancer cell line HCT116 as well as its counterpart with double knockout of DNMT1 and DNMT3B (HCT116-DKO). Analysis of H3K36me3 profiles indicated that this intragenic mark of active genes is associated with two categories of genes: (i) genes with low CpG density and H3K9me3 in the gene body or (ii) genes with high CpG density and DNA methylation in the gene body. We observed that a combination of low CpG density in gene bodies together with H3K9me3 and H3K36me3 occupancy is a specific epigenetic feature of zinc finger (ZNF) genes, which comprise 90% of all genes carrying both histone marks on chromosome 19. For genes with high intragenic CpG density, transcription and H3K36me3 occupancy were not changed in conditions of partial or intensive loss of DNA methylation in gene bodies. siRNA knockdown of SETD2, the major histone methyltransferase responsible for production of H3K36me3, did not reduce DNA methylation in gene bodies. Our study suggests that the H3K36me3 and DNA methylation marks in gene bodies are established largely independently of each other and points to similar functional roles of intragenic DNA methylation and intragenic H3K9me3 for CpG-rich and CpG-poor genes, respectively

The genetic study of three population microisolates in South Tyrol (MICROS): study design and epidemiological perspectives

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence of the important role that small, isolated populations could play in finding genes involved in the etiology of diseases. For historical and political reasons, South Tyrol, the northern most Italian region, includes several villages of small dimensions which remained isolated over the centuries.</p> <p>Methods</p> <p>The MICROS study is a population-based survey on three small, isolated villages, characterized by: old settlement; small number of founders; high endogamy rates; slow/null population expansion. During the stage-1 (2002/03) genealogical data, screening questionnaires, clinical measurements, blood and urine samples, and DNA were collected for 1175 adult volunteers. Stage-2, concerning trait diagnoses, linkage analysis and association studies, is ongoing. The selection of the traits is being driven by expert clinicians. Preliminary, descriptive statistics were obtained. Power simulations for finding linkage on a quantitative trait locus (QTL) were undertaken.</p> <p>Results</p> <p>Starting from participants, genealogies were reconstructed for 50,037 subjects, going back to the early 1600s. Within the last five generations, subjects were clustered in one pedigree of 7049 subjects plus 178 smaller pedigrees (3 to 85 subjects each). A significant probability of familial clustering was assessed for many traits, especially among the cardiovascular, neurological and respiratory traits. Simulations showed that the MICROS pedigree has a substantial power to detect a LOD score ≥ 3 when the QTL specific heritability is ≥ 20%.</p> <p>Conclusion</p> <p>The MICROS study is an extensive, ongoing, two-stage survey aimed at characterizing the genetic epidemiology of Mendelian and complex diseases. Our approach, involving different scientific disciplines, is an advantageous strategy to define and to study population isolates. The isolation of the Alpine populations, together with the extensive data collected so far, make the MICROS study a powerful resource for the study of diseases in many fields of medicine. Recent successes and simulation studies give us confidence that our pedigrees can be valuable both in finding new candidates loci and to confirm existing candidate genes.</p

Extending in vitro digestion models to specific human populations: Perspectives, practical tools and bio-relevant information

[EN] Background In vitro digestion models show great promise in facilitating the rationale design of foods. This paper provides a look into the current state of the art and outlines possible future paths for developments of digestion models recreating the diverse physiological conditions of specific groups of the human population. Scope and approach Based on a collective effort of experts, this paper outlines considerations and parameters needed for development of new in vitro digestion models, e.g. gastric pH, enzymatic activities, gastric emptying rate and more. These and other parameters are detrimental to the adequate development of in vitro models that enable deeper insight into matters of food luminal breakdown as well as nutrient and nutraceutical bioaccessibility. Subsequently, we present an overview of some new and emerging in vitro digestion models mirroring the gastro-intestinal conditions of infants, the elderly and patients of cystic fibrosis or gastric bypass surgery. Key findings and conclusions This paper calls for synchronization, harmonization and validation of potential developments in in vitro digestion models that would greatly facilitate manufacturing of foods tailored or even personalized, to a certain extent, to various strata of the human population.Shani-Levi, C.; Alvito, P.; Andrés Grau, AM.; Assunção, R.; Barbera, R.; Blanquet-Diot, S.; Bourlieu, C.... (2017). Extending in vitro digestion models to specific human populations: Perspectives, practical tools and bio-relevant information. Trends in Food Science & Technology. 60:52-63. https://doi.org/10.1016/j.tifs.2016.10.017S52636

Long-term Mortality in HIV-Positive Individuals Virally Suppressed for >3 Years With Incomplete CD4 Recovery

Virally suppressed HIV-positive individuals on combination antiretroviral therapy who do not achieve a CD4 count >200 cells/µL have substantially increased long-term mortality. The increased mortality was seen across different patient groups and for all causes of deat

Impact of CD4 and CD8 dynamics and viral rebounds on loss of virological control in HIV controllers

Objective: HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control. Methods: HICs were identified in COHERE on the basis of \ue2\u89\ua55 consecutive viral loads (VL) \ue2\u89\ua4500 copies/mL over \ue2\u89\ua51 year whilst ART-naive, with the last VL \ue2\u89\ua4500 copies/mL measured \ue2\u89\ua55 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL &gt;2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models. Results: We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds. Discussion: Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs