Functional STAT3 deficiency compromises the generation of human T follicular helper cells

T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.     

VA Location and Structural Factors Associated with On-Site Availability of Reproductive Health Services

INTRODUCTION

With the increasing number of women Veterans enrolling in the Veterans Health Administration (VA), there is growing demand for reproductive health services. Little is known regarding the on-site availability of reproductive health services at VA and how this varies by site location and type.

OBJECTIVE

To describe the on-site availability of hormonal contraception, intrauterine device (IUD) placement, infertility evaluation or treatment, and prenatal care by site location and type; the characteristics of sites providing these services; and to determine whether, within this context, site location and type is associated with on-site availability of these reproductive health services.

METHODS

We used data from the 2007 Veterans Health Administration Survey of Women Veterans Health Programs and Practices, a national census of VA sites serving 300 or more women Veterans assessing practice structure and provision of care for women. Hierarchical models were used to test whether site location and type (metropolitan hospital-based clinic, non-metropolitan hospital-based clinic, metropolitan community-based outpatient clinic [CBOC]) were associated with availability of IUD placement and infertility evaluation/treatment. Non-metropolitan CBOCs were excluded from this analysis (n?=?2).

RESULTS

Of 193 sites, 182 (94 %) offered on-site hormonal contraception, 97 (50 %) offered on-site IUD placement, 57 (30 %) offered on-site infertility evaluation/treatment, and 11 (6 %) offered on-site prenatal care. After adjustment, compared with metropolitan hospital based-clinics, metropolitan CBOCs were less likely to offer on-site IUD placement (OR 0.33; 95 % CI 0.14, 0.74).

CONCLUSION

Compared with metropolitan hospital-based clinics, metropolitan CBOCs offer fewer specialized reproductive health services on-site. Additional research is needed regarding delivery of specialized reproductive health care services for women Veterans in CBOCs and clinics in non-metropolitan areas.

     

Body Dissatisfaction in Women Across the Lifespan: Results of the UNC‐SELF and Gender and Body Image (GABI) Studies

To explore age differences in current and preferred silhouette and body dissatisfaction (current ? preferred silhouette discrepancy) in women aged 25–89 years using figural stimuli [range: 1 (very small) to 9 (very large)]. Data were abstracted from two online convenience samples (N = 5868). t‐tests with permutation‐adjusted p‐values examined linear associations between mean silhouette scores (current, preferred, discrepancy score) and age with/without stratification by body mass index (BMI). Modal current silhouette was 5; modal preferred silhouette was 4; mean discrepancy score was 1.8. There was no significant association between current silhouette and age, but a positive linear association between preferred silhouette and age remained after stratification by BMI. A significant inverse linear association of silhouette discrepancy score and age was found only prior to stratification by BMI. Body dissatisfaction exists in women across the adult life span and is influenced by BMI. Copyright © 2012 John Wiley & Sons, Ltd and Eating Disorders Association.     

Diabetes and cardiovascular events in women with polycystic ovary syndrome: a 20-year retrospective cohort study

BackgroundPolycystic ovary syndrome (PCOS) is the most common endocrine problem in women of reproductive age with a reported prevalence of up to 15%. Women with PCOS are potentially at increased risk of cardiovascular (CV) diseases from well-established risk factors, including insulin resistance, obesity, and type 2 diabetes. However data showing excess CV events in this population are still lacking.MethodsWe investigated the incidence and prevalence of type 2 diabetes and cardiovascular events (myocardial infarction, angina, heart failure, stroke and CV death) in a retrospective cohort of women with PCOS (total follow-up >12 000 person-years) The cohort consisted of 2301 women attending a specialty clinic from 1988 to 2009 in Leicestershire, UK (mean age 29·6 years [SD 9·1]).FindingsIncidence of type 2 diabetes, myocardial infarction, angina, heart failure, stroke, and CV death was respectively 3·6, 0·8, 1·0, 0·3, 0·0, and 0·4 per 1000 person-years. At the end of follow-up, prevalence of myocardial infarction in the age groups 45–54, 55–64, and older than 65 years were, respectively, 1·9%, 6·0%, and 27·3%, and of angina were 2·6%, 6·0%, and 27·3%. Age-group-specific odds ratios for prevalence of myocardial infarction and angina compared with the local female population (n=434 859) ranged between 2·6 (95% CI 1·0–6·3) and 12·9 (3·4–48·6) with the highest ratio being for myocardial infarction in the over-65 age group. Age, history of hypertension, and smoking had significant correlations with CV outcomes in women with PCOS (adjusted odds ratio 1·08 [95% CI 1·03–1·12], p<0·01 vs 9·94 (3·77–26·19), p<0·01 vs 3·33 [1·23–8·59], p<0·01).InterpretationWe have shown a high incidence and age-group-specific prevalence of type 2 diabetes, myocardial infarction, and angina in women with PCOS, with more than a quarter of those aged over 65 years having had a myocardial infarction or angina. These findings should be considered in treatment strategies, long-term planning, and CV risk reduction programmes for women with PCOS.FundingBritish Endocrine Society, National Institute for Health Research, and University of Leicester.     

Matrix-dependent adhesion mediates network responses to physiological stimulation of the osteocyte cell process

Osteocytes are bone cells that form cellular networks that sense mechanical loads distributed throughout the bone tissue. Interstitial fluid flow in the lacunar canalicular system produces focal strains at localized attachment sites around the osteocyte cell process. These regions of periodic attachment between the osteocyte cell membrane and its canalicular wall are sites where pN-level fluid-flow induced forces are generated in vivo. In this study, we show that focally applied forces of this magnitude using a newly developed Stokesian fluid stimulus probe initiate rapid and transient intercellular electrical signals in vitro. Our experiments demonstrate both direct gap junction coupling and extracellular purinergic P2 receptor signaling between MLO-Y4 cells in a connected bone cell network. Intercellular signaling was initiated by pN-level forces applied at integrin attachment sites along both appositional and distal unapposed cell processes, but not initiated at their cell bodies with equivalent forces. Electrical coupling was evident in 58% of all cell pairs tested with appositional connections; coupling strength increased with the increasing number of junctional connections. Apyrase, a nucleotide-degrading enzyme, suppressed and abolished force-induced effector responses, indicating a contribution from ATP released by the stimulated cell. This work extends the understanding of how osteocytes modulate their microenvironment in response to mechanical signals and highlights mechanisms of intercellular relay of mechanoresponsive signals in the bone network.     

Low back pain research – Future directions

Low back pain is a challenge for clinicians and researchers, due to the large variability in clinical presentation, lack of consensus regarding diagnostic criteria or clinical classification; wide variation in course and prognosis, and limited success in identifying effective treatments. However, increasing research efforts has generated an expanding body of evidence on the epidemiology, prognosis and treatment of back pain. This paper presents four key developments in research and clinical practice, and describes how these can influence the future direction of back pain research: (1) the increasing awareness of the impact of low back pain on population health; (2) new approaches to describing and investigating course and prognosis of back pain; (3) the need to better understand the bio-psycho-social mechanisms or pathways that explain impact and long-term outcomes in order to inform intervention research; and (4) the potential for stratified models of care to improve patient outcomes and efficiency of care for back pain.     

Adolescent Substance Use Assessment in a Primary Care Setting

Health initiatives suggest that adolescent substance use assessment may be beneficial as part of primary care to screen for early problematic behaviors. To examine the accuracy of such reporting, we compared the anonymous and confidential self-reports of 180 adolescents in a primary care setting. Matching samples to control for demographic variables, we found that adolescents were more likely to report marijuana use and substance use behaviors, such as selling drugs, when reporting anonymously vs. reporting confidentially. These results challenge the accuracy of confidential self-reports within this setting, and suggest further research is needed.     

Candida albicans and Enterococcus faecalis in the gut

The fungus Candida albicans and the gram-positive bacterium Enterococcus faecalis are both normal residents of the human gut microbiome and cause opportunistic disseminated infections in immunocompromised individuals. Using a nematode infection model, we recently showed that co-infection resulted in less pathology and less mortality than infection with either species alone and this was partly explained by an interkingdom signaling event in which a bacterial-derived product inhibits hyphal morphogenesis of C. albicans. In this addendum we discuss these findings in the contest of other described bacterial-fungal interactions and recent data suggesting a potentially synergistic relationship between these two species in the mouse gut as well. We suggest that E. faecalis and C. albicans promote a mutually beneficial association with the host, in effect choosing a commensal lifestyle over a pathogenic one.