BAFF activation of the ERK5 MAP kinase pathway regulates B cell survival

B cell activating factor (BAFF) stimulation of the BAFF receptor (BAFF-R) is essential for the homeostatic survival of mature B cells. Earlier in vitro experiments with inhibitors that block MEK 1 and 2 suggested that activation of ERK 1 and 2 MAP kinases is required for BAFF-R to promote B cell survival. However, these inhibitors are now known to also inhibit MEK5, which activates the related MAP kinase ERK5. In the present study, we demonstrated that BAFF-induced B cell survival was actually independent of ERK1/2 activation but required ERK5 activation. Consistent with this, we showed that conditional deletion of ERK5 in B cells led to a pronounced global reduction in mature B2 B cell numbers, which correlated with impaired survival of ERK5-deficient B cells after BAFF stimulation. ERK5 was required for optimal BAFF up-regulation of Mcl1 and Bcl2a1, which are prosurvival members of the Bcl-2 family. However, ERK5 deficiency did not alter BAFF activation of the PI3-kinase-Akt or NF-κB signaling pathways, which are also important for BAFF to promote mature B cell survival. Our study reveals a critical role for the MEK5-ERK5 MAP kinase signaling pathway in BAFF-induced mature B cell survival and homeostatic maintenance of B2 cell numbers

Role of P-selectin in platelet sequestration in pulmonary capillaries during endotoxemia

Background: There is growing evidence that platelets accumulate in the lung and contribute to the pathogenesis of acute lung injury during endotoxemia. The aims of the present study were to localize platelet sequestration in the pulmonary microcirculation and to investigate the role of P-selectin as a molecular mechanism of platelet endothelial cell interaction. Methods: We used in vivo fluorescence microscopy to quantify the kinetics of fluorescently labeled erythrocytes and platelets in alveolar capillary networks in rabbit lungs. Results: Six hours after onset of endotoxin infusion we observed a massive rolling along and firm adherence of platelets to lung capillary endothelial cells whereas under control conditions no platelet sequestration was detected. P-selectin was expressed on the surface of separated platelets which were incubated with endotoxin and in lung tissue. Pretreatment of platelets with fucoidin, a P-selectin antagonist, significantly attenuated the endotoxin-induced platelet rolling and adherence. In contrast, intravenous infusion of fucoidin in endotoxin-treated rabbits did not inhibit platelet sequestration in pulmonary capillaries. Conclusion: We conclude that platelets accumulate in alveolar capillaries following endotoxemia. P-selectin expressed on the surface of platelets seems to play an important role in mediating this platelet-endothelial cell interaction. Copyright (c) 2006 S. Karger AG, Basel

A prospective study of rural drinking water quality and acute gastrointestinal illness

BACKGROUND: This study examined the relationship between the bacteriological contamination of drinking water from private wells and acute gastrointestinal illness (AGII), using current government standards for safe drinking water. METHODS: A prospective cohort study was conducted using 235 households (647 individuals) randomly selected from four rural hamlets. Data were collected by means of a self-administered questionnaire, a self-report diary of symptoms and two drinking water samples. RESULTS: Twenty percent of households sampled, had indicator bacteria (total coliform or Escherichia coli (E. coli)) above the current Canadian and United States standards for safe drinking water. No statistically significant associations between indicator bacteria and AGII were observed. The odds ratio (OR) for individuals exposed to E. coli above the current standards was 1.52 (95% confidence interval (CI), 0.33–6.92), compared to individuals with levels below current standards. The odds ratio estimate for individuals exposed to total coliforms above the current standards was 0.39 (95% CI, 0.10–1.50). CONCLUSIONS: This study observed a high prevalence of bacteriological contamination of private wells in the rural hamlets studied. Individual exposure to contaminated water defined by current standards may be associated with an increased risk of AGII

Social interaction, noise and antibiotic-mediated switches in the intestinal microbiota

The intestinal microbiota plays important roles in digestion and resistance against entero-pathogens. As with other ecosystems, its species composition is resilient against small disturbances but strong perturbations such as antibiotics can affect the consortium dramatically. Antibiotic cessation does not necessarily restore pre-treatment conditions and disturbed microbiota are often susceptible to pathogen invasion. Here we propose a mathematical model to explain how antibiotic-mediated switches in the microbiota composition can result from simple social interactions between antibiotic-tolerant and antibiotic-sensitive bacterial groups. We build a two-species (e.g. two functional-groups) model and identify regions of domination by antibiotic-sensitive or antibiotic-tolerant bacteria, as well as a region of multistability where domination by either group is possible. Using a new framework that we derived from statistical physics, we calculate the duration of each microbiota composition state. This is shown to depend on the balance between random fluctuations in the bacterial densities and the strength of microbial interactions. The singular value decomposition of recent metagenomic data confirms our assumption of grouping microbes as antibiotic-tolerant or antibiotic-sensitive in response to a single antibiotic. Our methodology can be extended to multiple bacterial groups and thus it provides an ecological formalism to help interpret the present surge in microbiome data.Comment: 20 pages, 5 figures accepted for publication in Plos Comp Bio. Supplementary video and information availabl

Monitoring Bacterial Community of Human Gut Microbiota Reveals an Increase in Lactobacillus in Obese Patients and Methanogens in Anorexic Patients

Background: Studies of the bacterial communities of the gut microbiota have revealed a shift in the ratio of Firmicutes and Bacteroidetes in obese patients. Determining the variations of microbial communities in feces may be beneficial for the identification of specific profiles in patients with abnormal weights. The roles of the archaeon Methanobrevibacter smithii and Lactobacillus species have not been described in these studies. Methods and Findings: We developed an efficient and robust real-time PCR tool that includes a plasmid-based internal control and allows for quantification of the bacterial divisions Bacteroidetes, Firmicutes, and Lactobacillus as well as the methanogen M. smithii. We applied this technique to the feces of 20 obese subjects, 9 patients with anorexia nervosa, and 20 normal-weight healthy controls. Our results confirmed a reduction in the Bacteroidetes community in obese patients (p<0.01). We found a significantly higher Lactobacillus species concentration in obese patients than in lean controls (p = 0.0197) or anorexic patients (p = 0.0332). The M. smithii concentration was much higher in anorexic patients than in the lean population (p = 0.0171). Conclusions: Lactobacillus species are widely used as growth promoters in the farm industry and are now linked to obesity in humans. The study of the bacterial flora in anorexic patients revealed an increase in M. smithii. This increase might represent an adaptive use of nutrients in this population

Midgut microbiota of the malaria mosquito vector Anopheles gambiae and Interactions with plasmodium falciparum Infection

The susceptibility of Anopheles mosquitoes to Plasmodium infections relies on complex interactions between the insect vector and the malaria parasite. A number of studies have shown that the mosquito innate immune responses play an important role in controlling the malaria infection and that the strength of parasite clearance is under genetic control, but little is known about the influence of environmental factors on the transmission success. We present here evidence that the composition of the vector gut microbiota is one of the major components that determine the outcome of mosquito infections. A. gambiae mosquitoes collected in natural breeding sites from Cameroon were experimentally challenged with a wild P. falciparum isolate, and their gut bacterial content was submitted for pyrosequencing analysis. The meta-taxogenomic approach revealed a broader richness of the midgut bacterial flora than previously described. Unexpectedly, the majority of bacterial species were found in only a small proportion of mosquitoes, and only 20 genera were shared by 80% of individuals. We show that observed differences in gut bacterial flora of adult mosquitoes is a result of breeding in distinct sites, suggesting that the native aquatic source where larvae were grown determines the composition of the midgut microbiota. Importantly, the abundance of Enterobacteriaceae in the mosquito midgut correlates significantly with the Plasmodium infection status. This striking relationship highlights the role of natural gut environment in parasite transmission. Deciphering microbe-pathogen interactions offers new perspectives to control disease transmission.Institut de Recherche pour le Developpement (IRD); French Agence Nationale pour la Recherche [ANR-11-BSV7-009-01]; European Community [242095, 223601]info:eu-repo/semantics/publishedVersio

Association between egg consumption and cardiovascular disease events, diabetes and all-cause mortality

Purpose The association between egg consumption and cardiovascular disease (CVD) or type 2 diabetes (T2D) remains controversial. We investigated the association between egg consumption and risk of CVD (primary outcome), T2D and mortality in the Caerphilly prospective cohort study (CAPS) and National Diet and Nutritional Survey (NDNS). Methods CAPS included 2512 men aged 45–59 years (1979–1983). Dietary intake, disease incidence and mortality were updated at 5-year intervals. NDNS included 754 adults aged 19–64 years from 2008 to 2012. Results Men free of CVD (n = 1781) were followed up for a mean of 22.8 years, egg consumption was not associated with new incidence of CVD (n = 715), mortality (n = 1028) or T2D (n = 120). When stroke (n = 248), MI (n = 477),heart failure (n = 201) were investigated separately, no associations between egg consumption and stroke and MI were identified, however, increased risk of stroke in subjects with T2D and/or impaired glucose tolerance (IGT, fasting plasma glucose ≥ 6.1 mmol/L), adjusted hazard ratios (95% CI) were 1.0 (reference), 1.09 (0.41, 2.88), 0.96 (0.37, 2.50), 1.39 (0.54, 3.56) and 2.87 (1.13, 7.27) for egg intake (n) of 0 ≤ n ≤ 1, 1 < n ≤ 2, 2 < n ≤ 3, 3 < n < 5, and n ≥ 5 eggs/wk, respectively (P = 0.01). In addition, cross-sectional analyses revealed that higher egg consumption was significantly associated with elevated fasting glucose in those with T2D and/or IGT (CAPS: baseline P = 0.02 and 5-year P = 0.04; NDNS: P = 0.05). Conclusions Higher egg consumption was associated with higher blood glucose in subjects with T2D and/or IGT. The increased incidence of stroke with higher egg consumption among T2D and/or IGT sub-group warrants further investigation

In-training assessment using direct observation of single-patient encounters: a literature review

We reviewed the literature on instruments for work-based assessment in single clinical encounters, such as the mini-clinical evaluation exercise (mini-CEX), and examined differences between these instruments in characteristics and feasibility, reliability, validity and educational effect. A PubMed search of the literature published before 8 January 2009 yielded 39 articles dealing with 18 different assessment instruments. One researcher extracted data on the characteristics of the instruments and two researchers extracted data on feasibility, reliability, validity and educational effect. Instruments are predominantly formative. Feasibility is generally deemed good and assessor training occurs sparsely but is considered crucial for successful implementation. Acceptable reliability can be achieved with 10 encounters. The validity of many instruments is not investigated, but the validity of the mini-CEX and the ‘clinical evaluation exercise’ is supported by strong and significant correlations with other valid assessment instruments. The evidence from the few studies on educational effects is not very convincing. The reports on clinical assessment instruments for single work-based encounters are generally positive, but supporting evidence is sparse. Feasibility of instruments seems to be good and reliability requires a minimum of 10 encounters, but no clear conclusions emerge on other aspects. Studies on assessor and learner training and studies examining effects beyond ‘happiness data’ are badly needed

Differential DARC/ACKR1 expression distinguishes venular from non-venular endothelial cells in murine tissues

This work was supported by the National Institutes of Health (NIH) grant AI112521 and the John and Virginia Kaneb Fellowship