IL-24 intrinsically regulates Th17 cell pathogenicity in mice

In certain instances, Th17 responses are associated with severe immunopathology. T cell–intrinsic mechanisms that restrict pathogenic effector functions have been described for type 1 and 2 responses but are less well studied for Th17 cells. Here, we report a cell-intrinsic feedback mechanism that controls the pathogenicity of Th17 cells. Th17 cells produce IL-24, which prompts them to secrete IL-10. The IL-10–inducing function of IL-24 is independent of the cell surface receptor of IL-24 on Th17 cells. Rather, IL-24 is recruited to the inner mitochondrial membrane, where it interacts with the NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 13 (also known as Grim19), a constituent of complex I of the respiratory chain. Together, Grim19 and IL-24 promote the accumulation of STAT3 in the mitochondrial compartment. We propose that IL-24–guided mitochondrial STAT3 constitutes a rheostat to blunt extensive STAT3 deflections in the nucleus, which might then contribute to a robust IL-10 response in Th17 cells and a restriction of immunopathology in experimental autoimmune encephalomyelitis.     

Temporal changes in key maternal and fetal factors affecting birth outcomes: A 32-year population-based study in an industrial city

Background

In Australia and internationally, there is concern about the growing proportion of women giving birth by caesarean section. There is evidence of increased risk of placenta accreta and percreta in subsequent pregnancies as well as decreased fertility; and significant resource implications. Randomised controlled trials (RCTs) of continuity of midwifery care have reported reduced caesareans and other interventions in labour, as well as increased maternal satisfaction, with no statistically significant differences in perinatal morbidity or mortality. RCTs conducted in the UK and in Australia have largely measured the effect of teams of care providers (commonly 6–12 midwives) with very few testing caseload (one-to-one) midwifery care. This study aims to determine whether caseload (one-to-one) midwifery care for women at low risk of medical complications decreases the proportion of women delivering by caesarean section compared with women receiving 'standard' care. This paper presents the trial protocol in detail.

Methods/design

A two-arm RCT design will be used. Women who are identified at low medical risk will be recruited from the antenatal booking clinics of a tertiary women's hospital in Melbourne, Australia. Baseline data will be collected, then women randomised to caseload midwifery or standard low risk care. Women allocated to the caseload intervention will receive antenatal, intrapartum and postpartum care from a designated primary midwife with one or two antenatal visits conducted by a 'back-up' midwife. The midwives will collaborate with obstetricians and other health professionals as necessary. If the woman has an extended labour, or if the primary midwife is unavailable, care will be provided by the back-up midwife. For women allocated to standard care, options include midwifery-led care with varying levels of continuity, junior obstetric care and community based general medical practitioner care. Data will be collected at recruitment (self administered survey) and at 2 and 6 months postpartum by postal survey. Medical/obstetric outcomes will be abstracted from the medical record. The sample size of 2008 was calculated to identify a decrease in caesarean birth from 19 to 14% and detect a range of other significant clinical differences. Comprehensive process and economic evaluations will be conducted.

Trial registration

Australian New Zealand Clinical Trials Registry ACTRN012607000073404.     

Performance of cobas® 4800 and m2000 real-time™ assays for detection of Chlamydia trachomatis and Neisseria gonorrhoeae in rectal and self-collected vaginal specimen

A prospective, multicenter trial was designed to compare the performance characteristics of the cobas® 4800 (Roche Diagnostics, Indianapolis, IN, USA) and m2000 real-time™ (Abbott Molecular Inc., Des Plaines, IL, USA) assays for detection of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) in rectal and self-collected vaginal swabs. Rectal (n = 234) or self-collected vaginal swabs (n = 687) were obtained from consenting individuals visiting their general practitioners, dermatologists, gynecologists, sexually transmitted disease clinics, or family planning centers from May 2010 to February 2011. High concordance rates (≥96%) were observed between the cobas® 4800 and m2000 real-time™ assays for CT/NG detection in both rectal and self-collected vaginal swabs. The performance profiles confirm the usefulness of both kinds of swab types for CT and NG detection using described nucleic acid amplification tests assays. Based on this study, rectal and self-collected vaginal swabs offer a noninvasive alternative, which may improve screening for CT and NG infections.     

Genetics of inflammation and atopy

Multiple chromosomal regions and polymorphisms of several candidate genes have been linked to or associated with atopic diseases (hayfever, asthma, allergic eczema and rhinitis). In this mini-review, we present data demonstrating that the genetic regulation of the inflammatory response makes a major contribution to the risk of atopy. These data also suggest that the quantity (or quality) of the inflammation affects the priming phase of atopy, i.e., that induced by allergens or infectious agents in early childhood.     

Pathological Processing Techniques and Final Diagnosis of Breast Cancer Sentinel Lymph Nodes

Background

Recommendations for intraoperative and postoperative breast sentinel lymph node (SLN) processing differ widely. Micrometastases and isolated tumor cells (ITC) have recently been proposed as prognostically and therapeutically relevant. We compared 3 SLN protocols with regard to intraoperative and postoperative diagnosis.

Materials and Methods

SLN in cohort I (270 patients) were intraoperatively assessed by stereomicroscopy. Intraoperative frozen section (IFS) was used only in stereomicroscopically suspicious SLN. In cohort II (197 patients), all SLN were examined with only 1 IFS. Final SLN workup in cohorts I and II consisted of complete step sectioning with immunohistochemistry. In cohort III (268 patients) 2 or more IFS were performed followed by 3 step sections and immunohistochemistry.

Results

pN1 stages were significantly higher in cohorts I and II (33.3% and 34.0% respectively) than in cohort III (24.6%). Intraoperative false negativity for the detection of metastases (pN1) ranged from 54.4% (cohort I) and 35.8% (cohort II) to 21.2% (cohort III). In contrast, ITC were detected significantly more frequently in cohort I (9.3%) and cohort II (14.7%) than in cohort III (1.9%).

Conclusions

Higher rates of SLN metastases and ITC in cohort I/II compared to cohort III suggest that IFS may result in tissue loss thus increasing the risk of missing metastases. Sparse IFS but complete postoperative SLN workup with step sectioning and immunohistochemistry provides more accurate information regarding minimal disease in SLN, but often results in delayed axillary lymph node dissection. This is important for preoperative patient information and recommendations in SLN processing protocols.     

Tissue engineering of tendons and ligaments by human bone marrow stromal cells in a liquid fibrin matrix in immunodeficient rats: Results of a histologic study

Introduction The original complex structure and mechanical properties are not fully restored after ligament and tendon injuries. Due to their high proliferation rate and differentiation potential, Bone Marrow Stromal Cells (BMSC) are considered to be an ideal cell source for tissue engineering to optimize the healing process. Ideal matrices for tissue engineering of ligaments and tendons should allow for homogenous cell seeding and offer sufficient stability. Material and methods A mixture of human BMSC and liquid fibrin glue was injected into a standardized full-thickness window defect of the patellar tendon of immunodeficient rats (BMSC group). The histology of the tissue was analysed 10 and 20 days postoperatively and compared to four control groups. These groups consisted of a cohort with a mixture of human fibroblasts and fibrin glue, fibrin glue without cells, a defect group without treatment, and a group with uninjured patellar tendon tissue. Results Tendon defects in the BMSC group revealed dense collagen fibres and spindle-shaped cells, which were mainly orientated along the loading axis. Histologic sections of the control groups, especially of untreated defects and of defects filled with fibrin glue only, showed irregular patterns of cell distribution, irregular formed cell nucleoli and less tissue maturation. Compared to healthy tendon tissue, higher numbers of cells and less intense matrix staining was observed in the BMSC group. No ectopic bone or cartilage formation was observed in any specimen. Conclusions Injection of human BMSC in a fibrin glue matrix appears to lead to more mature tissue formation with more regular patterns of cell distribution. Advantages of this “in-vivo” tissue engineering approach are a homogenous cell-matrix mixture in a well-known and approved biological matrix, and simple, minimally-invasive application by injection.