Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes.

Listeria monocytogenes is an important cause of maternal-fetal infections and serves as a model organism to study these important but poorly understood events. L. monocytogenes can infect non-phagocytic cells by two means: direct invasion and cell-to-cell spread. The relative contribution of each method to placental infection is controversial, as is the anatomical site of invasion. Here, we report for the first time the use of first trimester placental organ cultures to quantitatively analyze L. monocytogenes infection of the human placenta. Contrary to previous reports, we found that the syncytiotrophoblast, which constitutes most of the placental surface and is bathed in maternal blood, was highly resistant to L. monocytogenes infection by either internalin-mediated invasion or cell-to-cell spread. Instead, extravillous cytotrophoblasts-which anchor the placenta in the decidua (uterine lining) and abundantly express E-cadherin-served as the primary portal of entry for L. monocytogenes from both extracellular and intracellular compartments. Subsequent bacterial dissemination to the villous stroma, where fetal capillaries are found, was hampered by further cellular and histological barriers. Our study suggests the placenta has evolved multiple mechanisms to resist pathogen infection, especially from maternal blood. These findings provide a novel explanation why almost all placental pathogens have intracellular life cycles: they may need maternal cells to reach the decidua and infect the placenta

Competing risk and heterogeneity of treatment effect in clinical trials

It has been demonstrated that patients enrolled in clinical trials frequently have a large degree of variation in their baseline risk for the outcome of interest. Thus, some have suggested that clinical trial results should routinely be stratified by outcome risk using risk models, since the summary results may otherwise be misleading. However, variation in competing risk is another dimension of risk heterogeneity that may also underlie treatment effect heterogeneity. Understanding the effects of competing risk heterogeneity may be especially important for pragmatic comparative effectiveness trials, which seek to include traditionally excluded patients, such as the elderly or complex patients with multiple comorbidities. Indeed, the observed effect of an intervention is dependent on the ratio of outcome risk to competing risk, and these risks – which may or may not be correlated – may vary considerably in patients enrolled in a trial. Further, the effects of competing risk on treatment effect heterogeneity can be amplified by even a small degree of treatment related harm. Stratification of trial results along both the competing and the outcome risk dimensions may be necessary if pragmatic comparative effectiveness trials are to provide the clinically useful information their advocates intend

Acupuncture and chiropractic care for chronic pain in an integrated health plan: a mixed methods study

<p>Abstract</p> <p>Background</p> <p>Substantial recent research examines the efficacy of many types of complementary and alternative (CAM) therapies. However, outcomes associated with the "real-world" use of CAM has been largely overlooked, despite calls for CAM therapies to be studied in the manner in which they are practiced. Americans seek CAM treatments far more often for chronic musculoskeletal pain (CMP) than for any other condition. Among CAM treatments for CMP, acupuncture and chiropractic (A/C) care are among those with the highest acceptance by physician groups and the best evidence to support their use. Further, recent alarming increases in delivery of opioid treatment and surgical interventions for chronic pain--despite their high costs, potential adverse effects, and modest efficacy--suggests the need to evaluate real world outcomes associated with promising non-pharmacological/non-surgical CAM treatments for CMP, which are often well accepted by patients and increasingly used in the community.</p> <p>Methods/Design</p> <p>This multi-phase, mixed methods study will: (1) conduct a retrospective study using information from electronic medical records (EMRs) of a large HMO to identify unique clusters of patients with CMP (e.g., those with differing demographics, histories of pain condition, use of allopathic and CAM health services, and comorbidity profiles) that may be associated with different propensities for A/C utilization and/or differential outcomes associated with such care; (2) use qualitative interviews to explore allopathic providers' recommendations for A/C and patients' decisions to pursue and retain CAM care; and (3) prospectively evaluate health services/costs and broader clinical and functional outcomes associated with the receipt of A/C relative to carefully matched comparison participants receiving traditional CMP services. Sensitivity analyses will compare methods relying solely on EMR-derived data versus analyses supplementing EMR data with conventionally collected patient and clinician data.</p> <p>Discussion</p> <p>Successful completion of these aggregate aims will provide an evaluation of outcomes associated with the real-world use of A/C services. The trio of retrospective, qualitative, and prospective study will also provide a clearer understanding of the decision-making processes behind the use of A/C for CMP and a transportable methodology that can be applied to other health care settings, CAM treatments, and clinical populations.</p> <p>Trial registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01345409">NCT01345409</a></p

Controversies in the management of advanced prostate cancer

For advanced prostate cancer, the main hormone treatment against which other treatments are assessed is surgical castration. It is simple, safe and effective, however it is not acceptable to all patients. Medical castration by means of luteinizing hormone-releasing hormone (LH-RH) analogues such as goserelin acetate provides an alternative to surgical castration. Diethylstilboestrol, previously the only non-surgical alternative to orchidectomy, is no longer routinely used. Castration reduces serum testosterone by around 90%, but does not affect androgen biosynthesis in the adrenal glands. Addition of an anti-androgen to medical or surgical castration blocks the effect of remaining testosterone on prostate cells and is termed combined androgen blockade (CAB). CAB has now been compared with castration alone (medical and surgical) in numerous clinical trials. Some trials show advantage of CAB over castration, whereas others report no significant difference. The author favours the view that CAB has an advantage over castration. No study has reported that CAB is less effective than castration. Of the anti-androgens which are available for use in CAB, bicalutamide may be associated with a lower incidence of side-effects compared with the other non-steroidal anti-androgens and, in common with nilutamide, has the advantage of once-daily dosing. Only one study has compared anti-androgens within CAB: bicalutamide plus LH-RH analogue and flutamide plus LH-RH analogue. At 160-week follow-up, the groups were equivalent in terms of survival and time to progression. However, bicalutamide caused significantly less diarrhoea than flutamide. Withdrawal and intermittent therapy with anti-androgens extend the range of treatment options. © 1999 Cancer Research Campaig

Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review

This review deals with podocyte proteins that play a significant role in the structure and function of the glomerular filter. Genetic linkage studies has identified several genes involved in the development of nephrotic syndrome and contributed to the understanding of the pathophysiology of glomerular proteinuria and/or focal segmental glomerulosclerosis. Here, we describe already well-characterized genetic diseases due to mutations in nephrin, podocin, CD2AP, alpha-actinin-4, WT1, and laminin β2 chain, as well as more recently identified genetic abnormalities in TRPC6, phospholipase C epsilon, and the proteins encoded by the mitochondrial genome. In addition, the role of the proteins which have shown to be important for the structure and functions by gene knockout studies in mice, are also discussed. Furthermore, some rare syndromes with glomerular involvement, in which molecular defects have been recently identified, are briefly described. In summary, this review updates the current knowledge of genetic causes of congenital and childhood nephrotic syndrome and provides new insights into mechanisms of glomerular dysfunction

Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to 300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m 2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years