Foxp3+ regulatory T cells protect the liver from immune damage and compromise virus control during acute experimental hepatitis B virus infection in mice

The strength of antiviral T cell responses correlates with clearance of hepatitis B virus (HBV) infection, but the immunological mechanisms mitigating or suppressing HBV-specific T cells are still poorly understood. In this study, we examined the role of CD4(+) Foxp3(+) regulatory T cells (Tregs) in a mouse model of acute HBV infection. We initiated HBV infection via an adenoviral vector transferring a 1.3-fold overlength HBV genome (AdHBV) into transgenic DEREG mice, where Tregs can be transiently but selectively depleted by injection of diphtheria toxin. The effect of Treg depletion on the outcome of HBV infection was characterized by detailed virological, immunological, and histopathological analysis. Numbers of Tregs increase in the liver rapidly after initiation of HBV replication. Initial depletion of Tregs revealed their complex regulatory function during acute infection. Tregs mitigated immunomediated liver damage by down-regulating the antiviral activity of effector T cells by limiting cytokine production and cytotoxicity, but did not influence development of HBV-specific CD8 T cells or development of memory T cells. Furthermore, Tregs controlled the recruitment of innate immune cells such as macrophages and dendritic cells to the infected liver. As a consequence, Tregs significantly delayed clearance of HBV from blood and infected hepatocytes. Conclusion: Tregs limit immunomediated liver damage early after an acute infection of the liver, thereby contributing to conservation of tissue integrity and organ function at the cost of prolonging virus clearance. (HEPATOLOGY 2012;56:873-883).     

The nuclear receptors NUR77, NURR1 and NOR1 in obesity and during fat loss

Background:Adipose tissue is critical for systemic metabolic health. Identifying key factors regulating adipose tissue function is a research priority. The NR4A subfamily of nuclear receptors (NRs) (NR4A1/NUR77, NR4A2/NURR1 and NR4A3/NOR1) has emerged as important proteins in different disease states and in the regulation of metabolic tissues, particularly in liver and muscle. However, the expression of the NR4A members in human adipose tissue has not previously been described, and their target genes are largely unknown.Objective:To determine whether the NR4As are differentially expressed in human adipose tissue in obesity, and identify potential NR4A target genes.Design:Prospective analysis of s.c. adipose tissue before and 1 year after fat loss, and during in vitro differentiation of primary human preadipocytes. Case-control comparison of omental (OM) adipose tissue.Subjects:A total of 13 extremely obese patients undergoing biliopancreatic diversion with duodenal switch for fat loss, 12 extremely obese patients undergoing laparoscopic sleeve gastrectomy and 37 lean individuals undergoing hernia repair or laparotomy were included in the study. Measurements were done by quantitative PCR gene expression analysis of the NR4A members and in silico promoter analysis based on microarray data.Results:There was a strong upregulation of the NR4As in extreme obesity and normalization after fat loss. The NR4As were expressed at the highest level in stromal-vascular fraction compared with adipocytes, but were downregulated in both fractions after fat loss. Their expression levels were also significantly higher in OM compared with s.c. adipocytes in obesity. The NR4As were downregulated during differentiation of primary human preadipocytes. Moreover, the NR4As were strongly induced within 30?min of tissue incubation. Finally, promoter analysis revealed potential NR4A target genes involved in stress response, immune response, development and other functions. Our data show altered adipose tissue expression of the NR4As in obesity, suggesting that these stress responsive nuclear receptors may modulate pathogenic potential in humans.     

Parkinson’s disease: considerations for dental hygienists

Abstract: The prevalence of Parkinson’s disease (PD) is expected to double over the next 20 years owing to the increase in life expectancy. This progressive disease has several implications relating to oral health, and many are manageable with proper awareness and knowledge about the disease. This article reviews the epidemiology, pathophysiology, and characteristics of PD, as well as the treatments and oral health considerations to enable dental hygienists to undertake an informed approach to patient management strategies and provide optimal care.     

Crosstalk in the retinal neurovascular unit - lessons for the diabetic retina

Diabetic retinopathy shares important features with neurodegenerative retinal diseases, including loss of ganglion cells and retinal thinning. The impact on vasoregression and subsequent ischemia-driven changes such as macular edema and proliferative retinopathy are not established. Studies using adult neurodegenerative animal models such as the transgenic TGR(CMV-PKD2(1/703)HA) rat imply early activation of the innate immunity system and the complement system as well as microglia playing a role in the damage of the retinal neurovascular unit.     

Scoring-Systeme bei peripherer arterieller Verschlusskrankheit

Background

In recent years new scoring systems to predict the outcome of distinctive revascularization methods in the myriad of peripheral arterial disease treatment options have been introduced.

Aim

In this article it will be demonstrated whether scoring systems in the course of the demographic development can be of assistance for clinical decision making.

Material and methods

The scoring systems are presented and differentiated according to the morphological and functional approach and the evidential value as well as practical relevance are discussed.

Results

Simple morphological scoring systems, such as the Bollinger score and the Society for Vascular Surgery (SVS) score are differentiated from new systems which include risk factors as well as functional parameters. Physician and patient oriented outcome predictors, such as Finnvasc and the LEGS score or the BASIL survival predictor must be differentiated. The scoring systems presented vary greatly with respect to the application and evidential value. The best validation has been carried out for the P III risk score and the Finnvasc score. The CRAB index extends the latter by an important risk factor and together with the CLI score they are the only ones to consider the functional patient status before intervention.

Conclusion

Scoring systems can provide valuable support for difficult decision making on the necessity for treatment.     

Sequential mTOR inhibitor treatment with temsirolimus in metastatic renal cell carcinoma following failure of VEGF receptor tyrosine kinase inhibitors

Purpose

Agents targeting the mammalian target of rapamycin (mTOR) pathway, e. g. everolimus, can provide clinical benefit in pretreated patients with metastatic renal cell carcinoma (mRCC), but data from randomized trials on the sequential use of temsirolimus are lacking. We retrospectively studied the efficacy and safety of temsirolimus therapy following failure of rTKI therapy.

Methods

Twenty-nine patients treated with temsirolimus (25 mg/week) following progression on rTKI therapy were studied at four institutions. All patients had failed at least one prior rTKI therapy (sunitinib, n = 6; sorafenib, n = 1; both, n = 22). Over 80% had two or more prior therapies. Data on efficacy (response assessment, progression-free survival [PFS], overall survival [OS]) and safety (NCI-CTC) were analyzed.

Results

Adverse events occurred in 90% of patients with the majority being grade 1 (n = 4, 14%) or grade 2 (n = 12, 41%). Most grade 3/4 toxicities (n = 10, 34%) were manageable and included anemia (n = 4, 14%), leukopenia/neutropenia (n = 2, 7%), hyperglycemia (n = 1, 3%), acidosis/alkalosis (n = 2, 7%), and infection (n = 1, 3%). One patient discontinued temsirolimus for grade 3 pneumonitis. Median (range) PFS and OS were 5.1 months (1–10.4) and 18.0 months (12.6–23.3), respectively. Best response included partial response (n = 1) and stable disease (n = 15) for a disease control rate of 55%, and disease progression of 45% (n = 13).

Conclusions

Temsirolimus after rTKI failure appears to provide promising safety and efficacy comparable to other treatment options in pretreated patients with mRCC.     

Value of Scintigraphy for Assessing Delayed Gastric Emptying After Pancreatic Surgery

Background

Delayed gastric emptying (DGE) occurs frequently after pancreatic surgery. Recently a consensus definition of DGE was introduced, and this grading system is currently widely used. The aim of this study was to compare results of gastric emptying scintigraphy with the grade of DGE after pancreatic surgery.

Methods

In 44 patients undergoing exploration for a pancreatic head or periampullary tumor, 28 pancreatoduodenectomies (PDs) and 16 double-bypass procedures were performed. All patients underwent preoperative and postoperative gastric emptying scintigraphy. We investigated whether the incidence of DGE was correlated with the results of gastric emptying scintigraphy.

Results

DGE occurred in 19 (43 %) patients. Clinically relevant DGE (grades B and C) prevailed in the PD group. Median postoperative residual activity at t = 2 h (%RA120) in these groups was 36 % (no DGE), 75 % (grade A), 93 % (grade B), and 95 % (grade C). DGE grade B or C was found in 7 of 10 patients with %RA120 of ≥94 % on postoperative day (POD) 7.

Conclusions

Postoperative %RA120 on scintigraphy is positively associated with severity of DGE. Gastric emptying scintigraphy on POD 7 can predict the severity of DGE. When postoperative gastric emptying scintigraphy shows high residual radioactivity, the likelihood of further progression to grade B or C DGE is high and warrants investigation for underlying causes.