Structural approaches to HIV prevention

Recognition that social, economic, political, and environmental factors directly affect HIV risk and vulnerability has stimulated interest in structural approaches to HIV prevention. Progress in the use of structural approaches has been limited for several reasons: absence of a clear definition; lack of operational guidance; and limited data on the effectiveness of structural approaches to the reduction of HIV incidence. In this paper we build on evidence and experience to address these gaps. We begin by defining structural factors and approaches. We describe the available evidence on their effectiveness and discuss methodological challenges to the assessment of these often complex efforts to reduce HIV risk and vulnerability. We identify core principles for implementing this kind of work. We also provide recommendations for ensuring the integration of structural approaches as part of combined prevention strategies.     

Activation of p38 mitogen-activated protein kinase contributes to the early cardiodepressant action of tumor necrosis factor.

OBJECTIVES: The purpose of this study was to determine whether p38 mitogen-activated protein kinase (p38-MAPK) contributes to tumor necrosis factor-alpha (TNFalpha)-induced contractile depression. BACKGROUND: Tumor necrosis factor has both beneficial and detrimental consequences that may result from the activation of different downstream pathways. Tumor necrosis factor activates p38-MAPK, a stress-responsive kinase implicated in contractile depression and cardiac injury. METHODS: In isolated hearts from mice lacking the p38-MAPK activator, MAPK kinase 3 (MKK3), perfused at constant coronary pressure or flow, we measured the left ventricular developed pressure (LVDP) and the relationship between end-diastolic volume and LVDP in the presence and absence of 10 ng/ml TNFalpha. RESULTS: Within 15 min at constant pressure, TNFalpha significantly reduced LVDP and coronary flow in outbred and mkk3(+/+) mice. This early negative inotropic effect was associated with a marked phosphorylation of both p38-MAPK and its indirect substrate, HSP27. In hearts lacking MKK3, TNFalpha failed to activate p38-MAPK or to cause significant contractile dysfunction. The actions of TNFalpha were similarly attenuated in MAPK-activated protein kinase 2 (MK2)-deficient hearts, which have a marked reduction in myocardial p38-MAPK protein content, and by the p38-MAPK catalytic site inhibitor SB203580 (1 micromol/l). Under conditions of constant coronary flow, the p38-MAPK activation and contractile depression induced by TNFalpha, though attenuated, remained sensitive to the absence of MKK3 or the presence of SB203580. The role of p38-MAPK in TNFalpha-induced contractile depression was confirmed in isolated murine cardiac myocytes exposed to SB203580 or lacking MKK3. CONCLUSIONS: Tumor necrosis factor activates p38-MAPK in the intact heart and in isolated cardiac myocytes through MKK3. This activation likely contributes to the early cardiodepressant action of TNFalpha.     

The Role of Procurement Biopsies in Acceptance Decisions for Kidneys Retrieved for Transplant

Background and objectives

There is a shortage of kidneys for transplant, and many patients on the deceased donor kidney transplant waiting list would likely benefit from kidneys that are currently being discarded. In the United States, the most common reason given for discarding kidneys retrieved for transplant is procurement biopsy results. This study aimed to compare biopsy results from discarded kidneys with discard attributed to biopsy findings, with biopsy results from comparable kidneys that were successfully transplanted.

Design, setting, participants, & measurements

In this retrospective, observational, case-control study, biopsy reports were examined from 83 kidneys discarded in 2010 due to biopsy findings (cases), 83 contralateral transplanted kidneys from the same donor (contralateral controls), and 83 deceased donors randomly matched to cases by donor risk profile (randomly matched controls). A second procurement biopsy was obtained in 64 of 332 kidneys (19.3%).

Results

The quality of biopsy reports was low, with amounts of tubular atrophy, interstitial inflammation, arteriolar hyalinosis, and acute tubular necrosis often not indicated; 69% were wedge biopsies and 94% used frozen tissue. The correlation between first and second procurement biopsies was poor; only 25% of the variability (R²) in glomerulosclerosis was explained by biopsies being from the same kidney. The percentages of glomerulosclerosis overlapped substantially between cases, contralateral controls, and randomly matched controls: 17.1%±15.3%, 9.0%±6.6%, and 5.0%±5.9%, respectively. Of all biopsy findings, only glomerulosclerosis>20% was independently correlated with discard (cases versus contralateral controls; odds ratio, 15.09; 95% confidence interval, 2.47 to 92.41; P=0.003), suggesting that only this biopsy result was used in acceptance decisions. One-year graft survival was 79.5% and 90.7% in contralateral and randomly matched controls, respectively, versus 91.6% among all deceased donor transplants in the Scientific Registry of Transplant Recipients.

Conclusions

Routine use of biopsies could lead to unnecessary kidney discards.     

Epilepsy Surgery in Children: Why,When and How?

Epilepsy surgery is safe and effective treatment in children who fail to respond to antiepileptic medications. After failure of two appropriate antiepileptic medications, chances that the child will become seizure free with more or different medications is <5 %, and she should be diagnosed with “refractory epilepsy”. A consideration for surgical candidacy should be given to all children who fulfill the definition of refractory epilepsy. In appropriately selected children, epilepsy surgery offers a high chance of seizure freedom without incurring any new post-operative neurological deficits. No age is bar to epilepsy surgery. Even infants can safely have epilepsy surgery if they are surgical candidates. For most children, who are surgical candidates, a good history and physical examination, video EEG evaluation, and a high quality brain MRI are sufficient to make surgical decision. These tools are increasingly available all over the world. Better education of families, Pediatricians, Pediatric Neurologists and community care-givers is necessary to salvage children early from mortality and morbidity of untreated, sometimes life long, epilepsy.     

Critical design aspects involved in the study of Paneth cells and the intestinal microbiota

Paneth cells are long-lived secretory cells that reside in the base of the crypts of Lieberkühn of the small intestine. They produce an arsenal of molecules that are involved in numerous biological processes, ranging from the control of gut microbial populations to supporting the intestinal stem cell niche. Because of these important functions, Paneth cell abnormalities are becoming implicated in a variety of disease processes. As such, it is necessary to establish parameters that will allow for the comprehensive study of Paneth cells in health and disease. In this addendum, we highlight critical design aspects involved in the study of Paneth cells and their downstream effects on the intestinal microbiota. The importance of this approach is demonstrated by our recent findings that Nod2 does not regulate mouse Paneth cell antimicrobial function, in contrast to previous reports. This work defines key issues to consider when studying Paneth cells in mouse systems.