Circulating CD14brightCD16+ 'intermediate' monocytes exhibit enhanced parasite pattern recognition in human helminth infection.

Circulating monocyte sub-sets have recently emerged as mediators of divergent immune functions during infectious disease but their role in helminth infection has not been investigated. In this study we evaluated whether 'classical' (CD14brightCD16-), 'intermediate' (CD14brightCD16+), and 'non-classical' (CD14dimCD16+) monocyte sub-sets from peripheral blood mononuclear cells varied in both abundance and ability to bind antigenic material amongst individuals living in a region of Northern Senegal which is co-endemic for Schistosoma mansoni and S. haematobium. Monocyte recognition of excretory/secretory (E/S) products released by skin-invasive cercariae, or eggs, of S. mansoni was assessed by flow cytometry and compared between S. mansoni mono-infected, S. mansoni and S. haematobium co-infected, and uninfected participants. Each of the three monocyte sub-sets in the different infection groups bound schistosome E/S material. However, 'intermediate' CD14brightCD16+ monocytes had a significantly enhanced ability to bind cercarial and egg E/S. Moreover, this elevation of ligand binding was particularly evident in co-infected participants. This is the first demonstration of modulated parasite pattern recognition in CD14brightCD16+ intermediate monocytes during helminth infection, which may have functional consequences for the ability of infected individuals to respond immunologically to infection

Homocysteine and Familial Longevity: The Leiden Longevity Study

Homocysteine concentrations are a read-out of methionine metabolism and have been related to changes in lifespan in animal models. In humans, high homocysteine concentrations are an important predictor of age related disease. We aimed to explore the association of homocysteine with familial longevity by testing whether homocysteine is lower in individuals that are genetically enriched for longevity. We measured concentrations of total homocysteine in 1907 subjects from the Leiden Longevity Study consisting of 1309 offspring of nonagenarian siblings, who are enriched with familial factors promoting longevity, and 598 partners thereof as population controls. We found that homocysteine was related to age, creatinine, folate, vitamin B levels and medical history of hypertension and stroke in both groups (all p<0.001). However, levels of homocysteine did not differ between offspring enriched for longevity and their partners, and no differences in the age-related rise in homocysteine levels were found between groups (p for interaction 0.63). The results suggest that homocysteine metabolism is not likely to predict familial longevity

Enhanced Pro-Inflammatory Cytokine Responses following Toll-Like-Receptor Ligation in Schistosoma haematobium-Infected Schoolchildren from Rural Gabon

BACKGROUND: Schistosoma infection is thought to lead to down-regulation of the host's immune response. This has been shown for adaptive immune responses, but the effect on innate immunity, that initiates and shapes the adaptive response, has not been extensively studied. In a first study to characterize these responses, we investigated the effect of Schistosoma haematobium infection on cytokine responses of Gabonese schoolchildren to a number of Toll-like receptor (TLR) ligands. METHODOLOGY: Peripheral blood mononuclear cells (PBMCs) were collected from S. haematobium-infected and uninfected schoolchildren from the rural area of Zile in Gabon. PBMCs were incubated for 24 h and 72 h with various TLR ligands, as well as schistosomal egg antigen (SEA) and adult worm antigen (AWA). Pro-inflammatory TNF-alpha and anti-inflammatory/regulatory IL-10 cytokine concentrations were determined in culture supernatants. PRINCIPAL FINDINGS: Infected children produced higher adaptive IL-10 responses than uninfected children against schistosomal antigens (72 h incubation). On the other hand, infected children had higher TNF-alpha responses than uninfected children and significantly higher TNF-alpha to IL-10 ratios in response to FSL-1 and Pam3, ligands of TLR2/6 and TLR2/1 respectively. A similar trend was observed for the TLR4 ligand LPS while Poly(I:C) (Mda5/TLR3 ligand) did not induce substantial cytokine responses (24 h incubation). CONCLUSIONS: This pilot study shows that Schistosoma-infected children develop a more pro-inflammatory TLR2-mediated response in the face of a more anti-inflammatory adaptive immune response. This suggests that S. haematobium infection does not suppress the host's innate immune system in the context of single TLR ligation

VKORC1 Common Variation and Bone Mineral Density in the Third National Health and Nutrition Examination Survey

Osteoporosis, defined by low bone mineral density (BMD), is common among postmenopausal women. The distribution of BMD varies across populations and is shaped by both environmental and genetic factors. Because the candidate gene vitamin K epoxide reductase complex subunit 1 (VKORC1) generates vitamin K quinone, a cofactor for the gamma-carboxylation of bone-related proteins such as osteocalcin, we hypothesized that VKORC1 genetic variants may be associated with BMD and osteoporosis in the general population. To test this hypothesis, we genotyped six VKORC1 SNPs in 7,159 individuals from the Third National Health and Nutrition Examination Survey (NHANES III). NHANES III is a nationally representative sample linked to health and lifestyle variables including BMD, which was measured using dual energy x-ray absorptiometry (DEXA) on four regions of the proximal femur. In adjusted models stratified by race/ethnicity and sex, SNPs rs9923231 and rs9934438 were associated with increased BMD (p = 0.039 and 0.024, respectively) while rs8050894 was associated with decreased BMD (p = 0.016) among non-Hispanic black males (n = 619). VKORC1 rs2884737 was associated with decreased BMD among Mexican-American males (n = 795; p = 0.004). We then tested for associations between VKORC1 SNPs and osteoporosis, but the results did not mirror the associations observed between VKORC1 and BMD, possibly due to small numbers of cases. This is the first report of VKORC1 common genetic variation associated with BMD, and one of the few reports available that investigate the genetics of BMD and osteoporosis in diverse populations

Multivariable regression analysis in Schistosoma mansoni-infected individuals in the Sudan reveals unique immunoepidemiological profiles in uninfected, egg+ and non-egg+ infected individuals

Background: In the Sudan, Schistosoma mansoni infections are a major cause of morbidity in schoolaged children and infection rates are associated with available clean water sources. During infection, immune responses pass through a Th1 followed by Th2 and Treg phases and patterns can relate to different stages of infection or immunity. Methodology: This retrospective study evaluated immunoepidemiological aspects in 234 individuals(range 4–85 years old) from Kassala and Khartoum states in 2011. Systemic immune profiles(cytokines and immunoglobulins) and epidemiological parameters were surveyed in n = 110 persons presenting patent S. mansoni infections (egg+), n = 63 individuals positive for S. mansoni via PCR in sera but egg negative (SmPCR+) and n = 61 people who were infection-free (Sm uninf). Immunoepidemiological findings were further investigated using two binary multivariable regression analysis. Principal Findings: Nearly all egg+ individuals had no access to latrines and over 90% obtained water via the canal stemming from the Atbara River. With regards to age, infection and an egg+ status was linked to young and adolescent groups. In terms of immunology, S. mansoni infection per se was strongly associated with increased SEA-specific IgG4 but not IgE levels. IL-6, IL-13 and IL-10 were significantly elevated in patently-infected individuals and positively correlated with egg load. In contrast, IL-2 and IL-1β were significantly lower in SmPCR+ individuals when compared to Sm uninf and egg+ groups which was further confirmed during multivariate regression analysis. Conclusions/Significance: Schistosomiasis remains an important public health problem in the Sudan with a high number of patent individuals. In addition, SmPCR diagnostics revealed another cohort of infected individuals with a unique immunological profile and provides an avenue for future studies on non-patent infection states. Future studies should investigate the downstream signalling pathways/mechanisms of IL-2 and IL-1β as potential diagnostic markers in order to distinguish patent from non-patent individuals

The vicious cycle of dental fear: exploring the interplay between oral health, service utilization and dental fear

BACKGROUND: Based on the hypothesis that a vicious cycle of dental fear exists, whereby the consequences of fear tend to maintain that fear, the relationship between dental fear, self-reported oral health status and the use of dental services was explored. METHODS: The study used a telephone interview survey with interviews predominantly conducted in 2002. A random sample of 6,112 Australian residents aged 16 years and over was selected from 13 strata across all States and Territories. Data were weighted across strata and by age and sex to obtain unbiased population estimates. RESULTS: People with higher dental fear visited the dentist less often and indicated a longer expected time before visiting a dentist in the future. Higher dental fear was associated with greater perceived need for dental treatment, increased social impact of oral ill-health and worse self-rated oral health. Visiting patterns associated with higher dental fear were more likely to be symptom driven with dental visits more likely to be for a problem or for the relief of pain. All the relationships assumed by a vicious cycle of dental fear were significant. In all, 29.2% of people who were very afraid of going to the dentist had delayed dental visiting, poor oral health and symptom-driven treatment seeking compared to 11.6% of people with no dental fear. CONCLUSION: Results are consistent with a hypothesised vicious cycle of dental fear whereby people with high dental fear are more likely to delay treatment, leading to more extensive dental problems and symptomatic visiting patterns which feed back into the maintenance or exacerbation of existing dental fear

The Rotterdam Study: 2012 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

Myosin binding protein C: implications for signal-transduction

Myosin binding protein C (MYBPC) is a crucial component of the sarcomere and an important regulator of muscle function. While mutations in different myosin binding protein C (MYBPC) genes are well known causes of various human diseases, such as hypertrophic (HCM) and dilated (DCM) forms of cardiomyopathy as well as skeletal muscular disorders, the underlying molecular mechanisms remain not well understood. A variety of MYBPC3 (cardiac isoform) mutations have been studied in great detail and several corresponding genetically altered mouse models have been generated. Most MYBPC3 mutations may cause haploinsufficiency and with it they may cause a primary increase in calcium sensitivity which is potentially able to explain major features observed in HCM patients such as the hypercontractile phenotype and the well known secondary effects such as myofibrillar disarray, fibrosis, myocardial hypertrophy and remodelling including arrhythmogenesis. However the presence of poison peptides in some cases cannot be fully excluded and most probably other mechanisms are also at play. Here we shall discuss MYBPC interacting proteins and possible pathways linked to cardiomyopathy and heart failure

Equine Torovirus (BEV) Induces Caspase-Mediated Apoptosis in Infected Cells

Toroviruses are gastroenteritis causing agents that infect different animal species and humans. To date, very little is known about how toroviruses cause disease. Here, we describe for the first time that the prototype member of this genus, the equine torovirus Berne virus (BEV), induces apoptosis in infected cells at late times postinfection. Observation of BEV infected cells by electron microscopy revealed that by 24 hours postinfection some cells exhibited morphological characteristics of apoptotic cells. Based on this finding, we analyzed several apoptotic markers, and observed protein synthesis inhibition, rRNA and DNA degradation, nuclear fragmentation, caspase-mediated cleavage of PARP and eIF4GI, and PKR and eIF2α phosphorylation, all these processes taking place after peak virus production. We also determined that both cell death receptor and mitochondrial pathways are involved in the apoptosis process induced by BEV. BEV-induced apoptosis at late times postinfection, once viral progeny are produced, could facilitate viral dissemination in vivo and contribute to viral pathogenesis

Rationale and design of the B-PROOF study, a randomized controlled trial on the effect of supplemental intake of vitamin B12 and folic acid on fracture incidence

Background: Osteoporosis is a major health problem, and the economic burden is expected to rise due to an increase in life expectancy throughout the world. Current observational evidence suggests that an elevated homocysteine concentration and poor vitamin B12and folate status are associated with an increased fracture risk. As vitamin B12and folate intake and status play a large role in homocysteine metabolism, it is hypothesized that supplementation with these B-vitamins will reduce fracture incidence in elderly people with an elevated homocysteine concentration. Methods/Design. The B-PROOF (B-Vitamins for the PRevention Of Osteoporotic Fractures) study is a randomized double-blind placebo-controlled trial. The intervention comprises a period of two years, and includes 2919 subjects, aged 65 years and older, independently living or institutionalized, with an elevated homocysteine concentration ( 12 mol/L). One group receives daily a tablet with 500 g vitamin B12and 400 g folic acid and the other group receives a placebo tablet. In both tablets 15 g (600 IU) vitamin D is included. The primary outcome of the study is osteoporotic fractures. Measurements are performed at baseline and after two years and cover bone health