BannMI deciphers potential n-to-1 information transduction in signaling pathways to unravel message of intrinsic apoptosis.

Motivation: Cell fate decisions, such as apoptosis or proliferation, are communicated via signaling pathways. The pathways are heavily intertwined and often consist of sequential interaction of proteins (kinases). Information integration takes place on the protein level via n-to-1 interactions. A state-of-the-art procedure to quantify information flow (edges) between signaling proteins (nodes) is network inference. However, edge weight calculation typically refers to 1-to-1 interactions only and relies on mean protein phosphorylation levels instead of single cell distributions. Information theoretic measures such as the mutual information (MI) have the potential to overcome these shortcomings but are still rarely used. Results: This work proposes a Bayesian nearest neighbor-based MI estimator (BannMI) to quantify n-to-1 kinase dependency in signaling pathways. BannMI outperforms the state-of-the-art MI estimator on protein-like data in terms of mean squared error and Pearson correlation. Using BannMI, we analyze apoptotic signaling in phosphoproteomic cancerous and noncancerous breast cell line data. Our work provides evidence for cooperative signaling of several kinases in programmed cell death and identifies a potential key role of the mitogen-activated protein kinase p38. Availability and implementation: Source code and applications are available at: https://github.com/zuiop11/nn_info and can be downloaded via Pip as Python package: nn-info.

Association between cardiovascular mortality and STOP-Bang questionnaire scores in a cohort of hospitalized patients: a prospective study.

OBJECTIVE: Obstructive sleep apnea (OSA) is associated with an increased risk of mortality and cardiometabolic diseases. The STOP-Bang questionnaire is a tool to screen populations at risk of OSA and prioritize complementary studies. Our objective was to evaluate the clinical utility of this questionnaire in identifying patients at an increased risk of mortality after discharge in a cohort of hospitalized patients. METHODS: This was a prospective cohort study involving consecutive patients admitted to an internal medicine unit between May and June of 2017 who were reevaluated three years after discharge. At baseline, we collected data on comorbidities (hypertension, obesity, diabetes, and fasting lipid profile) and calculated STOP-Bang scores, defining the risk of OSA (0-2 score, no risk; ≥ 3 score, risk of OSA; and ≥ 5 score, risk of moderate-to-severe OSA), which determined the study groups. We also recorded data regarding all-cause and cardiovascular mortality at the end of the follow-up period. RESULTS: The sample comprised 435 patients. Of those, 352 (80.9%) and 182 (41.8%) had STOP-Bang scores ≥ 3 and ≥ 5, respectively. When compared with the group with STOP-Bang scores of 0-2, the two groups showed higher prevalences of obesity, hypertension, diabetes, and dyslipidemia. Multivariate analysis showed an independent association between cardiovascular mortality and STOP-Bang score ≥ 5 (adjusted hazard ratio = 3.12 [95% CI, 1.39-7.03]; p = 0.01). Additionally, previous coronary heart disease was also associated with cardiovascular mortality. CONCLUSIONS: In this cohort of hospitalized patients, STOP-Bang scores ≥ 5 were able to identify patients at an increased risk of cardiovascular mortality three years after discharge.

Da vida marinha ao sentimento oceânico: Alister Hardy e o estudo da experiência religiosa / From the marine life to the ocean feeling: Alister Hardy and the study of religious experience

Um reconhecido biólogo britânico, premiadíssimo por suas contribuições no estudo da vida marinha, imediatamente após se aposentar na Universidade de Oxford, no Reino Unido, aos 73 anos, passa a se dedicar integralmente ao estudo da vitalidade do fenômeno religioso, fundando uma Unidade de Pesquisa em Experiência Religiosa (RERU). Trata-se de Alister Hardy (1896-1985), cujas história, principais obras e concepções, influências recebidas e contribuições decorrentes para a Psicologia da Religião são focos deste artigo,de cunho teórico e historiográfico, escrito por ocasião dos 50 anos de fundação da referida unidade. Atualmente, situada em Lampeter, País de Gales, acolhida pela University of Wales Trinity University, desde 2000, recebe o nome de Alister Hardy Religious Experience Research Centre (RERC).

A well-known British biologist, knighted for his contributions to the study of marine life, devoted his life after retiring from Oxford University in the United Kingdom, at 73 years old, to the study of the vitality of the religious phenomenon by founding a Research Unit in Religious Experience (RERU) in Oxford. The biologist was Sir Alister Hardy (1896-1985), whose stories, main works and conceptions, influences and ensuing contributions to the Psychology of Religion are the focus of this paper. It reflects the theoretical and historiographical impact of his work, written on the occasion of the 50th anniversary of the RERU. Currently it is located in Lampeter, Wales, hosted by the University of Wales Trinity University since 2000, and named Alister Hardy Religious Experience Research Centre (RERC).

Association between cardiovascular mortality and STOP-Bang questionnaire scores in a cohort of hospitalized patients: a prospective study / Associação entre mortalidade cardiovascular e pontuação do questionário STOP-Bang em uma coorte de pacientes hospitalizados: um estudo prospectivo

ABSTRACT Objective: Obstructive sleep apnea (OSA) is associated with an increased risk of mortality and cardiometabolic diseases. The STOP-Bang questionnaire is a tool to screen populations at risk of OSA and prioritize complementary studies. Our objective was to evaluate the clinical utility of this questionnaire in identifying patients at an increased risk of mortality after discharge in a cohort of hospitalized patients. Methods: This was a prospective cohort study involving consecutive patients admitted to an internal medicine unit between May and June of 2017 who were reevaluated three years after discharge. At baseline, we collected data on comorbidities (hypertension, obesity, diabetes, and fasting lipid profile) and calculated STOP-Bang scores, defining the risk of OSA (0-2 score, no risk; ≥ 3 score, risk of OSA; and ≥ 5 score, risk of moderate-to-severe OSA), which determined the study groups. We also recorded data regarding all-cause and cardiovascular mortality at the end of the follow-up period. Results: The sample comprised 435 patients. Of those, 352 (80.9%) and 182 (41.8%) had STOP-Bang scores ≥ 3 and ≥ 5, respectively. When compared with the group with STOP-Bang scores of 0-2, the two groups showed higher prevalences of obesity, hypertension, diabetes, and dyslipidemia. Multivariate analysis showed an independent association between cardiovascular mortality and STOP-Bang score ≥ 5 (adjusted hazard ratio = 3.12 [95% CI, 1.39-7.03]; p = 0.01). Additionally, previous coronary heart disease was also associated with cardiovascular mortality. Conclusions: In this cohort of hospitalized patients, STOP-Bang scores ≥ 5 were able to identify patients at an increased risk of cardiovascular mortality three years after discharge.

RESUMO Objetivo: A apneia obstrutiva do sono (AOS) está associada a um risco maior de mortalidade e doenças cardiometabólicas. O questionário STOP-Bang é uma ferramenta para rastrear populações em risco de AOS e assim priorizar estudos complementares. Nosso objetivo foi avaliar a utilidade clínica desse questionário na identificação de pacientes com risco aumentado de mortalidade após a alta em uma coorte de pacientes hospitalizados. Métodos: Estudo de coorte prospectivo com pacientes consecutivos internados em uma unidade de medicina interna entre maio e junho de 2017 que foram reavaliados três anos após a alta. No momento basal, coletamos dados sobre comorbidades (hipertensão, obesidade, diabetes e perfil lipídico em jejum) e calculamos as pontuações no STOP-Bang, definindo o risco de OSA (pontuação 0-2, sem risco; pontuação ≥ 3, risco de AOS; e pontuação ≥ 5, risco de AOS moderada a grave), que determinou os grupos de estudo. Também registramos dados sobre mortalidade por todas as causas e mortalidade cardiovascular ao final do período de acompanhamento. Resultados: Foram incluídos 435 pacientes. Desses, 352 (80,9%) e 182 (41,8%) apresentaram pontuações no STOP-Bang ≥ 3 e ≥ 5, respectivamente. Quando comparados com o grupo com pontuação no STOP-Bang de 0-2, os outros dois grupos apresentaram prevalências mais elevadas de obesidade, hipertensão, diabetes e dislipidemia. A análise multivariada mostrou uma associação independente entre mortalidade cardiovascular e pontuação no STOP-Bang ≥ 5 (razão de risco ajustada = 3,12 [IC95%, 1,39-7,03]; p = 0,01). Além disso, doença coronariana prévia também foi associada à mortalidade cardiovascular. Conclusões: Nesta coorte de pacientes hospitalizados, pontuações no STOP-Bang ≥ 5 foram capazes de identificar pacientes com risco aumentado de mortalidade cardiovascular três anos após a alta.

[Association between high vitamin B12 levels and one year mortality in older people admitted to the hospital]. / Asociación entre niveles de vitamina B-12 y mortalidad en pacientes hospitalizados adultos mayores.

BACKGROUND: Supplementation of vitamin B12 in older adults is a common practice to avoid vitamin B12 insufficiency. However, there is a paucity of information about the effects of cobalamin excess. AIM: To asses any potential effects of high levels vitamin B12 on mortality on adults aged ≥ 65 years admitted to an internal medicine service. MATERIAL AND METHODS: We Prospectively studied patients admitted to an internal medicine service of an academic hospital from September 2017 to September 2018, who were able to give their consent and answer questionnaires. We tabulated age, gender, medical history, comorbidity index (Charlson), frailty score (Fried scale), admission diagnosis and blood tests performed within 48 hours of admission. The primary outcome was death by any cause in less of 30 days or after one of year follow up, determined according to death certificates. RESULTS: We included 93 patients aged 65 to 94 years (53% males). Fifteen patients died during the year of follow up (five within 30 days of admission). Those who died had higher cobalamin levels than survivors (1080.07 ± 788.09 and 656.68 ± 497.33 pg/mL respectively, p = 0.02). Patients who died had also a significantly lower corrected serum calcium, sodium (p = 0.04) and a medical history of chronic liver disease (p = 0.03). In the multivariable analysis, only vitamin B12 preserved the association with mortality (p = 0.009). CONCLUSIONS: There was a significant association between high levels of cobalamin and all-cause mortality in this group of patients aged ≥ 65 years-old.

Asociación entre niveles de vitamina B-12 y mortalidad en pacientes hospitalizados adultos mayores / Association between high vitamin B12 levels and one year mortality in older people admitted to the hospital

Background: Supplementation of vitamin B12 in older adults is a common practice to avoid vitamin B12 insufficiency. However, there is a paucity of information about the effects of cobalamin excess. Aim: To asses any potential effects of high levels vitamin B12 on mortality on adults aged ≥ 65 years admitted to an internal medicine service. Material and Methods: We Prospectively studied patients admitted to an internal medicine service of an academic hospital from September 2017 to September 2018, who were able to give their consent and answer questionnaires. We tabulated age, gender, medical history, comorbidity index (Charlson), frailty score (Fried scale), admission diagnosis and blood tests performed within 48 hours of admission. The primary outcome was death by any cause in less of 30 days or after one of year follow up, determined according to death certificates. Results: We included 93 patients aged 65 to 94 years (53% males). Fifteen patients died during the year of follow up (five within 30 days of admission). Those who died had higher cobalamin levels than survivors (1080.07 ± 788.09 and 656.68 ± 497.33 pg/mL respectively, p = 0.02). Patients who died had also a significantly lower corrected serum calcium, sodium (p = 0.04) and a medical history of chronic liver disease (p = 0.03). In the multivariable analysis, only vitamin B12 preserved the association with mortality (p = 0.009). Conclusions: There was a significant association between high levels of cobalamin and all-cause mortality in this group of patients aged ≥ 65 years-old.

Agglutination of bacteria using polyvalent nanoparticles of aggregation-induced emissive thiophthalonitrile dyes.

A novel class of aggregation-induced emissive bis(phenylthio)phthalonitrile dyes were synthesized. These dyes assembled into nanoparticles that were equipped with mannose units. The nanoparticles underwent selective interactions with lectins and bacteria. The bright fluorescent aggregates aid in the visualization of the agglutination of bacteria.

About supramolecular systems for dynamically probing cells.

This article reviews the state of the art in the development of strategies for generating supramolecular systems for dynamic cell studies. Dynamic systems are crucial to further our understanding of cell biology and are consequently at the heart of many medical applications. Increasing interest has therefore been focused recently on rendering systems bioactive and dynamic that can subsequently be employed to engage with cells. Different approaches using supramolecular chemistry are reviewed with particular emphasis on their application in cell studies. We conclude with an outlook on future challenges for dynamic cell research and applications.

Direct experimental evidence that early-life farm environment influences regulation of immune responses.

BACKGROUND: In mammals, early-life environmental variations appear to affect microbial colonization and therefore competent immune development, and exposure to farm environments in infants has been inversely correlated with allergy development. Modelling these effects using manipulation of neonatal rodents is difficult due to their dependency on the mother, but the relatively independent piglet is increasingly identified as a valuable translational model for humans. This study was designed to correlate immune regulation in piglets with early-life environment. METHODS: Piglets were nursed by their mother on a commercial farm, while isolator-reared siblings were formula fed. Fluorescence immunohistology was used to quantify T-reg and effector T-cell populations in the intestinal lamina propria and the systemic response to food proteins was quantified by capture ELISA. RESULTS: There was more CD4(+) and CD4(+) CD25(+) effector T-cell staining in the intestinal mucosa of the isolator-reared piglets compared with their farm-reared counterparts. In contrast, these isolator-reared piglets had a significantly reduced CD4(+) CD25(+) Foxp3(+) regulatory T-cell population compared to farm-reared littermates, resulting in a significantly higher T-reg-to-effector ratio in the farm animals. Consistent with these findings, isolator-reared piglets had an increased serum IgG anti-soya response to novel dietary soya protein relative to farm-reared piglets. CONCLUSION: Here, we provide the first direct evidence, derived from intervention, that components of the early-life environment present on farms profoundly affects both local development of regulatory components of the mucosal immune system and immune responses to food proteins at weaning. We propose that neonatal piglets provide a tractable model which allows maternal and treatment effects to be statistically separated.

Establishment of normal gut microbiota is compromised under excessive hygiene conditions.

BACKGROUND: Early gut colonization events are purported to have a major impact on the incidence of infectious, inflammatory and autoimmune diseases in later life. Hence, factors which influence this process may have important implications for both human and animal health. Previously, we demonstrated strong influences of early-life environment on gut microbiota composition in adult pigs. Here, we sought to further investigate the impact of limiting microbial exposure during early life on the development of the pig gut microbiota. METHODOLOGY/PRINCIPAL FINDINGS: Outdoor- and indoor-reared animals, exposed to the microbiota in their natural rearing environment for the first two days of life, were transferred to an isolator facility and adult gut microbial diversity was analyzed by 16S rRNA gene sequencing. From a total of 2,196 high-quality 16S rRNA gene sequences, 440 phylotypes were identified in the outdoor group and 431 phylotypes in the indoor group. The majority of clones were assigned to the four phyla Firmicutes (67.5% of all sequences), Proteobacteria (17.7%), Bacteroidetes (13.5%) and to a lesser extent, Actinobacteria (0.1%). Although the initial maternal and environmental microbial inoculum of isolator-reared animals was identical to that of their naturally-reared littermates, the microbial succession and stabilization events reported previously in naturally-reared outdoor animals did not occur. In contrast, the gut microbiota of isolator-reared animals remained highly diverse containing a large number of distinct phylotypes. CONCLUSIONS/SIGNIFICANCE: The results documented here indicate that establishment and development of the normal gut microbiota requires continuous microbial exposure during the early stages of life and this process is compromised under conditions of excessive hygiene.

Restricting microbial exposure in early life negates the immune benefits associated with gut colonization in environments of high microbial diversity.

BACKGROUND: Acquisition of the intestinal microbiota in early life corresponds with the development of the mucosal immune system. Recent work on caesarean-delivered infants revealed that early microbial composition is influenced by birthing method and environment. Furthermore, we have confirmed that early-life environment strongly influences both the adult gut microbiota and development of the gut immune system. Here, we address the impact of limiting microbial exposure after initial colonization on the development of adult gut immunity. METHODOLOGY/PRINCIPAL FINDINGS: Piglets were born in indoor or outdoor rearing units, allowing natural colonization in the immediate period after birth, prior to transfer to high-health status isolators. Strikingly, gut closure and morphological development were strongly affected by isolator-rearing, independent of indoor or outdoor origins of piglets. Isolator-reared animals showed extensive vacuolation and disorganization of the gut epithelium, inferring that normal gut closure requires maturation factors present in maternal milk. Although morphological maturation and gut closure were delayed in isolator-reared animals, these hard-wired events occurred later in development. Type I IFN, IL-22, IL-23 and Th17 pathways were increased in indoor-isolator compared to outdoor-isolator animals during early life, indicating greater immune activation in pigs originating from indoor environments reflecting differences in the early microbiota. This difference was less apparent later in development due to enhanced immune activation and convergence of the microbiota in all isolator-reared animals. This correlated with elevation of Type I IFN pathways in both groups, although T cell pathways were still more affected in indoor-reared animals. CONCLUSIONS/SIGNIFICANCE: Environmental factors, in particular microbial exposure, influence expression of a large number of immune-related genes. However, the homeostatic effects of microbial colonization in outdoor environments require sustained microbial exposure throughout development. Gut development in high-hygiene environments negatively impacts on normal succession of the gut microbiota and promotes innate immune activation which may impair immune homeostasis.

Symptom presentation, interventions, and outcome of emotionally-distressed patients in primary care.

BACKGROUND: Patients with psychosocial problems often present somatic symptoms in primary care. OBJECTIVE: The authors compare interventions and outcomes of emotionally-distressed patients by presenting physical disease, somatoform symptoms, or psychological symptoms. METHOD: General practitioners (N=191) documented data from 1,286 patients with psychosocial problems. Experts rated the presented reasons for encounter. RESULTS: Somatoform symptoms, as well as physical disease, result in patients' receiving physical treatments. Psychologically-oriented treatment is more likely with psychological presentation, but not significantly related to somatoform symptoms. CONCLUSION: These findings underline the importance of a specific treatment approach for patients with somatoform symptoms, so as to avoid inappropriate treatment.

Environmentally-acquired bacteria influence microbial diversity and natural innate immune responses at gut surfaces.

BACKGROUND: Early microbial colonization of the gut reduces the incidence of infectious, inflammatory and autoimmune diseases. Recent population studies reveal that childhood hygiene is a significant risk factor for development of inflammatory bowel disease, thereby reinforcing the hygiene hypothesis and the potential importance of microbial colonization during early life. The extent to which early-life environment impacts on microbial diversity of the adult gut and subsequent immune processes has not been comprehensively investigated thus far. We addressed this important question using the pig as a model to evaluate the impact of early-life environment on microbe/host gut interactions during development. RESULTS: Genetically-related piglets were housed in either indoor or outdoor environments or in experimental isolators. Analysis of over 3,000 16S rRNA sequences revealed major differences in mucosa-adherent microbial diversity in the ileum of adult pigs attributable to differences in early-life environment. Pigs housed in a natural outdoor environment showed a dominance of Firmicutes, in particular Lactobacillus, whereas animals housed in a hygienic indoor environment had reduced Lactobacillus and higher numbers of potentially pathogenic phylotypes. Our analysis revealed a strong negative correlation between the abundance of Firmicutes and pathogenic bacterial populations in the gut. These differences were exaggerated in animals housed in experimental isolators. Affymetrix microarray technology and Real-time Polymerase Chain Reaction revealed significant gut-specific gene responses also related to early-life environment. Significantly, indoor-housed pigs displayed increased expression of Type 1 interferon genes, Major Histocompatibility Complex class I and several chemokines. Gene Ontology and pathway analysis further confirmed these results. CONCLUSION: Early-life environment significantly affects both microbial composition of the adult gut and mucosal innate immune function. We observed that a microbiota dominated by lactobacilli may function to maintain mucosal immune homeostasis and limit pathogen colonization.

Deficiency of glutaredoxin 5 reveals Fe-S clusters are required for vertebrate haem synthesis.

Iron is required to produce haem and iron-sulphur (Fe-S) clusters, processes thought to occur independently. Here we show that the hypochromic anaemia in shiraz (sir) zebrafish mutants is caused by deficiency of glutaredoxin 5 (grx5), a gene required in yeast for Fe-S cluster assembly. We found that grx5 was expressed in erythroid cells of zebrafish and mice. Zebrafish grx5 rescued the assembly of grx5 yeast Fe-S, showing that the biochemical function of grx5 is evolutionarily conserved. In contrast to yeast, vertebrates use iron regulatory protein 1 (IRP1) to sense intracellular iron and regulate mRNA stability or the translation of iron metabolism genes. We found that loss of Fe-S cluster assembly in sir animals activated IRP1 and blocked haem biosynthesis catalysed by aminolaevulinate synthase 2 (ALAS2). Overexpression of ALAS2 RNA without the 5' iron response element that binds IRP1 rescued sir embryos, whereas overexpression of ALAS2 including the iron response element did not. Further, antisense knockdown of IRP1 restored sir embryo haemoglobin synthesis. These findings uncover a connection between haem biosynthesis and Fe-S clusters, indicating that haemoglobin production in the differentiating red cell is regulated through Fe-S cluster assembly.

Cytokine stimulation by Pseudomonas aeruginosa--strain variation and modulation by pulmonary surfactant.

Pulmonary surfactant and its components are part of the first-line immune defense within the lung. Here the authors show that the surfactant protein (SP) SP-D, but not SP-A, agglutinates some clinical isolates of Pseudomonas aeruginosa and Stenotrophomonas maltophilia. No agglutination of Staphylococcus aureus or Burkholderia cepacia was observed. The SP-D-induced agglutination of P. aeruginosa was not dependent on a specific lipopolysaccharide (LPS) serotype. The authors also show that SP-D, but not SP-A, increased the tumor necrosis factor (TNF alpha) release from human monocytic cells in response to a subset of P. aeruginosa and P. aeruginosa LPS. A clinical preparation of surfactant (Alveofact) blocked the TNF alpha release from monocytic cells induced by P. aeruginosa or its LPS. SP-A reversed the inhibitory effect of Alveofact in 6/8 strains of P. aeruginosa and 2/9 preparations of P. aeruginosa LPS. SP-D did not significantly alter the TNF alpha production induced by vital P. aeruginosa in the presence of Alveofact but markedly increased the TNF alpha release induced by a preparation of rough and smooth P. aeruginosa LPS. In summary, this study shows that the immunomodulatory properties of SP-A and SP-D specifically depend on the colonizing strain of P. aeruginosa. In addition, the authors show that the function of SP-A and SP-D is modulated in the presence of surfactant lipids.

Site-independent prognostic value of chromosome 9q loss in primary gastrointestinal stromal tumours.

Although the significance of tumour site for estimating malignant potential in gastrointestinal stromal tumours (GISTs) has recently been recognized, site-specific genetic patterns have not to date been defined. This study examined 52 c-kit-positive primary GISTs (with a mean follow-up of 42.3 months in 51 cases) from three different locations (35 gastric, 12 small intestinal, and five colorectal) using comparative genomic hybridization (CGH). In general, tumour site correlated with key prognostic factors, including tumour size, mitotic rate, proliferative activity, and probable malignant potential. Furthermore, several DNA copy number changes showed a site-dependent pattern. These included losses at 14q (gastric 83%, intestinal 35%; p = 0.001), losses at 22q (gastric 46%, intestinal 82%; p = 0.02), losses at 1p (gastric 23%, intestinal 88%; p = 1 x 10(-5)), losses at 15q (gastric 14%, intestinal 59%; p = 0.002), losses at 9q (gastric 14%, intestinal 53%; p = 0.006), and gains at 5p (gastric 11%, intestinal 53%; p = 0.002). These data demonstrate strong site-dependent genetic heterogeneity in GISTs that may form a basis for subclassification. Prognostic evaluation of DNA copy number changes identified losses at 9q as a site-independent prognostic marker associated with shorter disease-free survival (p = 0.03) and overall survival (p = 0.002). Furthermore, 9q loss also appeared to carry prognostic value in predicting overall survival for patients with advanced or progressive GISTs (p = 0.003).

Detection of circulating prostate cells during radical prostatectomy by standardized PSMA RT-PCR: association with positive lymph nodes and high malignant grade.

BACKGROUND: The purpose of this study was to establish a quantitative standardized RT-PCR for the detection of Prostate Specific Membrane Antigen (PSMA)-expressing circulating cells and to evaluate clinical relevance in patients undergoing radical retropubic prostatectomy (RRP) for clinically localized prostate cancer (PCa). MATERIALS AND METHODS: An external standard molecule (PSMA MIMIC) was constructed for standardization of PSMA RT-PCR reactions. It has the same sequence as endogenous PSMA, except for a central 85 bp deletion, allowing the amplification of both targets simultaneously with nearly the same amplification characteristics as in a nested PCR. PSMA RT-PCR was performed from peripheral blood samples of 73 patients with clinically localized PCa, 4 with metastatic PCa, 27 with benign prostatic hyperplasia (BPH) and 27 controls. Pre, intra- and postoperative blood samples were tested for circulating PSMA expressing cells in 54 out of 73 patients with clinically localized PCa. We also tested intraoperative blood samples of 19 BPH patients treated by transurethral or open surgery. RESULTS: Endogenous PSMA signals from PCa patients varied between 850 and 9900 transcript molecules, corresponding to 2-20 PSMA-expressing cells/ml blood. Standardized RT-PCR using the PSMA MIMIC molecule revealed a significant decrease of "false-positives" in cancer-free controls (p = 0.004). Controls could clearly be distinguished from prostate cancer patients based on PSMA PCR positivity (p = 0.003). Thirty-two % of patients with localized prostate cancer, 11% of BPH patients and 7% of healthy controls were positive in standardized assays compared to 48%, 30% and 27% without PSMA MIMIC, respectively. Preoperatively, a correlation with tumor stage (p = 0.030), grade (p = 0.035) and Gleason Score (p = 0.03) could be demonstrated in clinically localized PCa patients. Dissemination of prostate cells during surgery occurred in 32% of the RRPs and 21% of BPH patients. Positive PCR signals from intraoperative blood samples correlated with positive lymph node status (p = 0.007) and tumor grade (p = 0.005). Postoperative positive results correlated with grade (p = 0.012) and Gleason Score (p = 0.035). CONCLUSION: Counseling the patient with clinically localized prostate cancer can be challenging. Surgery may be, in retrospect, inappropriate in a number of patients due to preoperative understaging. This newly constructed external standard allows quantitative detection of circulating prostate cells, and therefore may open new perspectives for PSMA RT-PCR techniques as diagnostic assays and tools for post-therapeutic follow-up.

Surfactant protein A and D differently regulate the immune response to nonmucoid Pseudomonas aeruginosa and its lipopolysaccharide.

We investigated the role of the surfactant proteins (SPs) A and D in the pulmonary immune defense of nonmucoid strains of Pseudomonas aeruginosa, the most etiologic agents of nosocomial Pseudomonas pneumonia. We first examined the interactions of recombinant human SP-D dodecamers and purified natural or recombinant human SP-A with two smooth, and two rough, clinical isolates of nonmucoid P. aeruginosa. SP-D bound to all four isolates, but agglutinated only one rough and one smooth strain. SP-D functioned as an opsonin to enhance the uptake of all four strains by the human monocytic cell line Mono Mac 6 (MM6). SP-D also enhanced tumor necrosis factor-alpha secretion by MM6 cells in response to purified lipopolysaccharide (LPS) isolated from the rough, but not the smooth, strains. Although SP-A bound to all four strains, it did not cause bacterial aggregation or enhance uptake. It showed small but statistically significant inhibitory effects on the cytokine response of MM6 cells to one strain of smooth organisms, but did not significantly alter the response to purified LPS. This study in combination with previously published data strongly suggests that SP-D may play important roles in the local innate pulmonary defense against nonmucoid P. aeruginosa of diverse LPS phenotypes, and preferentially augments the cellular response to rough P. aeruginosa endotoxin.

Gender and health in adolescence / by Petra Kolip and Bettina Schmidt

The series Health Policy for Children and Adolescents (HEPCA) is a WHO document series mainly based on results of the international survey "Health Behaviour in School-aged Children" (HBSC) and on other relevant international studies. It focuses on the implications of scientific results for health policy in developed countries. The target groups are politicians and experts, especially those concerned with the health of young people. The HEPCA series consists of reports on particular topics of high political relevance, including survey data on child and adolescent health, reports on specific health situations and suggestions for future investment in health policies for the young generation