Salmonella binding to and biofilm formation on cholesterol/gallstone surfaces in the chronic carrier state

The Gram-negative pathogen Salmonella enterica serovar Typhi is the etiologic agent of human typhoid fever, a systemic illness characterized by high fever, bradycardia, and muscle pain. A percentage of these infections can result in asymptomatic carriage of salmonellae in the bile-rich gallbladder, and we have previously demonstrated that salmonellae can form biofilms on the surface of human cholesterol gallstones as a mechanism that contributes to the development of the carrier state. To determine which genes/ligands mediate the ability of Salmonella to bind and form biofilms on cholesterol, mutants of S. enterica serovar Typhimurium were created through random transposon mutagenesis. These mutants were screened for impaired biofilm formation on cholesterol-coated Eppendorf tubes in the Tube Biofilm Assay (TBA) but normal biofilm formation on glass and plastic surfaces. Of the 49 mutants with this phenotype, 70% of the disrupted genes were involved in flagella or fimbriae biosynthesis. Independent assays demonstrated that the presence of flagella were important for adherence to cholesterol and biofilm initiation, while over-expression of fimbriae was inhibitory. The remaining transposon insertions, located in sseI and ompC, had no effect on cellular motility, suggesting a mechanism of action independent of flagellar-mediated adherence to cholesterol. Subsequent analysis of sseI and related mutations in the TBA suggested that SPI-2 genes are important for the formation of biofilms in the presence of bile, but unimportant for biofilm formation in the absence of bile. Similar analysis of ompC in the TBA demonstrated that the observed loss of biofilm formation was not due to changes in the osmolarity of the extracellular environment. These studies provide a better understanding of how salmonellae form biofilms in the presence of bile and suggest a target for therapies that may alleviate biofilm formation on cholesterol gallstones and the chronic carrier state.National Institutes of HealthOSU Public Health Preparedness for Infectious DiseasesNo embarg

The effects of age on health-related quality of life in cancer populations: A pooled analysis of randomized controlled trials using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 involving 6024 cancer patients.

Cancer incidence increases exponentially with advancing age, cancer patients live longer than in the past, and many new treatments focus on stabilizing disease and HRQOL. The objective of this study is to examine how cancer affects patients' HRQOL and whether their HRQOL is age-dependent.Data from 25 EORTC randomized controlled trials was pooled. EORTC QLQ-C30 mean scores for the cancer cohort and five general population cohorts were compared to assess the impact of cancer on patients' HRQOL. Within the cancer cohort, multiple linear regressions (two-sided level P-value = 0.05 adjusted for multiple testing.) were used to investigate the association between age and HRQOL, adjusted for gender, WHO performance status (PS), distant metastasis and stratified by cancer site. A difference of 10 points on the 0-100 scale was considered clinically important.Cancer patients generally have worse HRQOL compared to the general population, but the specific HRQOL domains impaired vary with age. When comparing the cancer versus the general population, young cancer patients had worse financial problems, social and role functioning, while the older cancer groups had more appetite loss. Within the cancer cohort, HRQOL was worse with increasing age for physical functioning and constipation, and better with increasing age for social functioning, insomnia and financial problems (all p < 0.05).HRQOL is impaired in cancer patients compared to the general population, but the impact on specific HRQOL domains varies by age. Within the cancer population, some HRQOL components improve with age while others deteriorate. Optimal care for older cancer patients should target HRQOL domains most relevant to this population

A Multicenter Pilot Evaluation of the National Institutes of Health Chronic Graft-versus-Host Disease (cGVHD) Therapeutic Response Measures: Feasibility, Interrater Reliability, and Minimum Detectable Change

The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of four consecutive pilot trials evaluating the feasibility and estimating the inter-rater reliability and minimum detectable change of these response criteria

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

Bone Mineral Density (BMD) is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR) method to identify single nucleotide polymorphisms (SNPs) associated with BMD by leveraging cardiovascular disease (CVD) associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD) at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity

Flagellated but Not Hyperfimbriated Salmonella enterica Serovar Typhimurium Attaches to and Forms Biofilms on Cholesterol-Coated Surfaces▿ †

The asymptomatic, chronic carrier state of Salmonella enterica serovar Typhi occurs in the bile-rich gallbladder and is frequently associated with the presence of cholesterol gallstones. We have previously demonstrated that salmonellae form biofilms on human gallstones and cholesterol-coated surfaces in vitro and that bile-induced biofilm formation on cholesterol gallstones promotes gallbladder colonization and maintenance of the carrier state. Random transposon mutants of S. enterica serovar Typhimurium were screened for impaired adherence to and biofilm formation on cholesterol-coated Eppendorf tubes but not on glass and plastic surfaces. We identified 49 mutants with this phenotype. The results indicate that genes involved in flagellum biosynthesis and structure primarily mediated attachment to cholesterol. Subsequent analysis suggested that the presence of the flagellar filament enhanced binding and biofilm formation in the presence of bile, while flagellar motility and expression of type 1 fimbriae were unimportant. Purified Salmonella flagellar proteins used in a modified enzyme-linked immunosorbent assay (ELISA) showed that FliC was the critical subunit mediating binding to cholesterol. These studies provide a better understanding of early events during biofilm development, specifically how salmonellae bind to cholesterol, and suggest a target for therapies that may alleviate biofilm formation on cholesterol gallstones and the chronic carrier state

Indigenous Lifescripts: A tool for modifying lifestyle risk factors for chronic disease.

BACKGROUND: A national chronic disease strategy has been described focusing on health promotion and lifestyle change, screening and evidence based disease management. The Lifescripts resources complement this strategy by focusing on health promotion and lifestyle change. OBJECTIVE: To provide an overview of the role of the recently developed indigenous Lifescripts resources as a tool for health checks and chronic disease prevention and management. DISCUSSION: Effective indigenous health promotion requires appropriate tools for behavioural modification and community engagement. This involves a greater emphasis on the social determinants of health to reduce the barriers to healthy behaviours. The indigenous Lifescripts provide a flexible tool for health care providers in the indigenous health sector to deliver lifestyle related brief interventions that accommodate local community resources and support structures. However, to maximise their potential, a systematic approach to incorporating these tools into practice must be adopted

Distribution of cortical bone in the femoral neck and hip fracture: a prospective case-control analysis of 143 incident hip fractures; the AGES-REYKJAVIK Study.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field.In this prospective nested case-control study we analyzed the circumferential differences in estimated cortical thickness (Est CTh) of the mid femoral neck as a risk factor for osteoporotic hip fractures in elderly women and men. Segmental QCT analysis of the mid femoral neck was applied to assess cortical thickness in anatomical quadrants. The superior region of the femoral neck was a stronger predictor for hip fracture than the inferior region, particularly in men. There were significant gender differences in Est CTh measurements in the control group but not in the case group. In multivariable analysis for risk of femoral neck (FN) fracture, Est CTh in the supero-anterior (SA) quadrant was significant in both women and men, and remained a significant predictor after adjustment for FN areal BMD (aBMD, dimensions g/cm², DXA-like), (p=0.05 and p<0.0001, respectively). In conclusion, Est CTh in the SA quadrant best discriminated cases (n=143) from controls (n=298), especially in men. Cortical thinning superiorly in the hip might be of importance in determining resistance to fracture.NIH N01-AG-1-2100 NIA Icelandic Heart association Icelandic Parliament Icelandic Centre of Research University of Iceland Arthritis Research UK Cambridge NIHR Biomedical Research Centr

The prevalence and risk of symptom and function clusters in colorectal cancer survivors

PurposeOur purpose was to describe the prevalence and predictors of symptom and function clusters in a diverse cohort of colorectal cancer survivors.MethodsWe used data from a cohort of 909 adult colorectal cancer survivors. Participants were surveyed at a median of 9&nbsp;months after diagnosis to ascertain the co-occurrence of eight distinct symptom and functional domains. We used factor analysis to identify co-occurring domains and latent profile analysis (LPA) to identify subgroups of survivors with different symptom and function clusters. Multinomial logistic regression models were used to identify risk/protective factors.ResultsFactor analysis demonstrated a single underlying factor structure that included all eight health domains with depression and anxiety highly correlated (r = 0.87). The LPA identified three symptom and function clusters, with 30% of survivors in the low health-related quality of life (HRQOL) profile having the highest symptom burden and lowest functioning. In multivariable models, survivors more likely to be in the low HRQOL profile included being non-White, female, those with a history of cardiac or mental health conditions, and chemotherapy recipients. Survivors less likely to be in the low HRQOL profile included those with older age, greater financial well-being, and more spirituality.ConclusionNearly one-third of colorectal cancer survivors experienced a cluster of physical and psychosocial symptoms that co-occur with clinically relevant deficits in function.Implications for cancer survivorsImproving the identification of risk factors for having the highest symptom and lowest function profile can inform the development of clinical interventions to mitigate their adverse impact on cancer survivors' HRQOL