CD4 cell and CD8 cell-mediated resistance to HIV-1 infection in exposed uninfected intravascular drug users in Vietnam

OBJECTIVE: To identify mechanisms of resistance to HIV-1 infection in exposed uninfected individuals. DESIGN: We examined in-vitro cell susceptibility to HIV-1 infection in highly exposed Vietnamese intravascular drug users (IDU) who, despite a history of more than 10 years of drug use and a high prevalence of other blood-borne viral infections, remain apparently HIV uninfected. METHODS: Forty-five exposed uninfected IDU and 50 blood donors were included in the study. Peripheral blood mononuclear cells (PBMC) or CD4 cell susceptibilities to HIV infection were evaluated using three HIV-1 isolates with different tropisms. Polymerase chain reaction analysis of HIV-1-DNA replication intermediates was used to characterize the restriction of HIV-1 replication in CD4 cells. Homologous CD8 cells were mixed with infected CD4 cells to evaluate their role in virus suppression. RESULTS: We observed a relative resistance to PBMC infection with HIV-1 in 21 out of 45 exposed uninfected IDU, but only in five out of 50 unexposed controls (P < 0.001). PBMC resistance was related either to an inhibition of HIV-1 replication in CD4 cells or to CD8 cell-mediated viral suppression. HIV-1 replication in CD4 cells was restricted at the early stages of the viral cycle. CONCLUSION: Reduced PBMC susceptibility to HIV-1 infection was associated with resistance to infection in exposed uninfected IDU. Distinct mechanisms are involved in in-vitro resistance and may contribute to the apparent protection from HIV-1 transmission in this systemically exposed population.     

Atrial Appendage Thrombosis Risk Is Lower for Atrial Flutter Compared with Atrial Fibrillation

Background

The risk of stroke and thromboembolism in atrial fibrillation is established. However, the evidence surrounding the risk of thromboembolism in patients with atrial flutter is not as clear. We hypothesized that atrial flutter would have indicators of less risk for thromboembolism compared with atrial fibrillation on transesophageal echocardiography, thereby possibly leading to a lower stroke risk.

Loss of PTEN promotes podocyte cytoskeletal rearrangement,aggravating diabetic nephropathy

In diabetic nephropathy (DN), podocyte cytoskeletal rearrangement occurs followed by podocyte effacement and the development of proteinuria. PTEN (phosphatase and tensin homologue) is a ubiquitously expressed phosphatase that plays a critical role in cell proliferation, cytoskeletal rearrangement, and motility. In mouse models of diabetes mellitus, PTEN expression is reportedly decreased in mesangial cells, contributing to expansion of the mesangial matrix, but how PTEN in the podocyte influences the development of DN is unknown. We observed that PTEN expression is down‐regulated in the podocytes of diabetic db/db mice and patients with DN. In cultured podocytes, PTEN inhibition caused actin cytoskeletal rearrangement and this response was associated with unbalanced activation of the small GTPases Rac1/Cdc42 and RhoA. In mice treated with PTEN inhibitor, actin cytoskeletal rearrangement occurred in podocytes and was accompanied by increased albumin excretion. We also created mice with an inducible deletion of PTEN selectively in podocytes. These mice exhibited increased albumin excretion and moderate foot process effacement. When the mice were challenged with a high fat diet, podocyte‐specific knockout of PTEN resulted in substantially increased proteinuria and glomeruloclerosis compared to control mice fed a high fat diet or mice with PTEN deletion fed a normal diet. These results indicate that PTEN is involved in the regulation of cytoskeletal rearrangement in podocytes and that loss of PTEN predisposes to the development of proteinuria and DN. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Inherent correction of motion-induced phase errors in multishot spiral diffusion-weighted imaging

Multishot spiral imaging is a promising alternative to echo‐planar imaging for high‐resolution diffusion‐weighted imaging and diffusion tensor imaging. However, subject motion in the presence of diffusion‐weighting gradients causes phase inconsistencies among different shots, resulting in signal loss and aliasing artifacts in the reconstructed images. Such artifacts can be reduced using a variable‐density spiral trajectory or a navigator echo, however at the cost of a longer scan time. Here, a novel iterative phase correction method is proposed to inherently correct for the motion‐induced phase errors without requiring any additional scan time. In this initial study, numerical simulations and in vivo experiments are performed to demonstrate that the proposed method can effectively and efficiently correct for spatially linear phase errors caused by rigid‐body motion in multishot spiral diffusion‐weighted imaging of the human brain. Magn Reson Med, 2012. © 2011 Wiley Periodicals, Inc.     

Superior prognostic utility of gross and metabolic tumor volume compared to standardized uptake value using PET/CT in head and neck squamous cell carcinoma patients treated with intensity-modulated radiotherapy

Objective

To compare the prognostic utility of the 2-[¹⁸F] fluoro-2-deoxy-d-glucose (FDG) maximum standardized uptake value (SUV_max), primary gross tumor volume (GTV), and FDG metabolic tumor volume (MTV) for disease control and survival in patients with head and neck squamous cell carcinoma (HNSCC) undergoing intensity-modulated radiotherapy (IMRT).

Methods

Between 2007 and 2011, 41 HNSCC patients who underwent a staging positron emission tomography with computed tomography and definitive IMRT were identified. Local (LC), nodal (NC), distant (DC), and overall (OC) control, overall survival (OS), and disease-free survival (DFS) were assessed using the Kaplan?CMeier product-limit method.

Results

With a median follow-up of 24.2?months (range 2.7?C56.3?months) local, nodal, and distant recurrences were recorded in 10, 5, and 7 patients, respectively. The median SUV_max, GTV, and MTV were 15.8, 22.2?cc, and 7.2?cc, respectively. SUV_max did not correlate with LC (p?=?0.229) and OS (p?=?0.661) when analyzed by median threshold. Patients with smaller GTVs (<22.2?cc) demonstrated improved 2-year actuarial LC rates of 100 versus 56.4?% (p?=?0.001) and OS rates of 94.4 versus 65.9?% (p?=?0.045). Similarly, a smaller MTV (<7.2?cc) correlated with improved 2-year actuarial LC rates of 100 versus 54.2?% (p?p?=?0.04). Smaller GTV and MTV correlated with improved NC, DC, OC, and DFS, as well.

Conclusion

GTV and MTV demonstrate superior prognostic utility as compared to SUV_max, with larger tumor volumes correlating with inferior local control and overall survival in HNSCC patients treated with definitive IMRT.     

Limited M1 Disease: A Significant Prognostic Factor for Stage IV Breast Cancer

Purpose

The prognosis of patients with breast cancer presenting with distant metastasis can vary depending on disease extent. This study evaluates a definition of limited M1 disease in association with survival in a cohort of women presenting with metastatic breast cancer.

Methods

The study cohort comprised 692 women referred to the BC Cancer Agency between 1996 and 2005 with M1 breast cancer at presentation. Limited M1 disease was defined as <5 metastatic lesions confined to one anatomic subsite. Extensive M1 disease was defined as ??5 lesions or disease in more than one subsite. Clinicopathologic and treatment characteristics and overall survival (OS) were compared between subjects with limited (n?=?233) versus extensive (n?=?459) M1 disease. Multivariable analysis was performed by Cox regression modeling.

Results

Median follow-up time was 1.9?years. Five-year Kaplan-Meier OS was significantly higher in patients with limited compared to extensive M1 disease (29.7 vs. 13.1?%, p?p?Conclusions Limited M1 disease, defined as <5 metastatic lesions confined to one anatomic subsite, is a relevant favorable prognostic factor in patients with stage IV breast cancer. This definition may be used in conjunction with other clinicopathologic factors to select patients for more aggressive systemic and locoregional treatments.