Rate and Predictors of Ineffective HIV Protection in African Men Who Have Sex with Men Taking Pre-Exposure Prophylaxis

AIDS and Behavior - We investigated the rate and predictors of ineffective HIV protection in men who have sex with men (MSM) taking pre-exposure prophylaxis (PrEP) in a prospective cohort study...     

A National Study of Outcomes among HIV-Infected Kidney Transplant Recipients

Kidney transplantation is a viable treatment for select patients with HIV and ESRD, but data are lacking regarding long-term outcomes and comparisons with appropriately matched HIV-negative patients. We analyzed data from the Scientific Registry of Transplant Recipients (SRTR; 2002–2011): 510 adult kidney transplant recipients with HIV (median follow-up, 3.8 years) matched 1:10 to HIV-negative controls. Compared with HIV-negative controls, HIV-infected recipients had significantly lower 5-year (75.3% versus 69.2%) and 10-year (54.4% versus 49.8%) post-transplant graft survival (GS) (hazard ratio [HR], 1.37; 95% confidence interval [95% CI], 1.15 to 1.64; P<0.001) that persisted when censoring for death (HR, 1.43; 95% CI, 1.12 to 1.84; P=0.005). However, compared with HIV-negative/hepatitis C virus (HCV)–negative controls, HIV monoinfected recipients had similar 5-year and 10-year GS, whereas HIV/HCV coinfected recipients had worse GS (5-year: 64.0% versus 52.0%, P=0.02; 10-year: 36.2% versus 27.0%, P=0.004 [HR, 1.38; 95% CI, 1.08 to 1.77; P=0.01]). Patient survival (PS) among HIV-infected recipients was 83.5% at 5 years and 51.6% at 10 years and was significantly lower than PS among HIV-negative controls (HR, 1.34; 95% CI, 1.08 to 1.68; P<0.01). However, PS was similar for HIV monoinfected recipients and HIV-negative/HCV-negative controls at both times. HIV/HCV coinfected recipients had worse PS compared with HIV-negative/HCV-infected controls (5-year: 67.0% versus 78.6%, P=0.007; 10-year: 29.3% versus 56.23%, P=0.002 [HR, 1.57; 95% CI, 1.11 to 2.22; P=0.01]). In conclusion, HIV-negative and HIV monoinfected kidney transplant recipients had similar GS and PS, whereas HIV/HCV coinfected recipients had worse outcomes. Although encouraging, these results suggest caution in transplanting coinfected patients.     

Nitric oxide measurements in rat mesentery reveal disrupted venulo-arteriolar communication in diabetes

OBJECTIVE: Arteriolar tone is partially controlled by diffusing mediators released by closely paired venules and is reported to depend on venular shear and venular leukocyte adherence. In healthy rat mesentery, venule-initiated arteriolar dilation and consequent enhanced capillary flow appear to be tightly regulated by nitric oxide (NO). In contrast, diabetes inhibits NO-dependent vasodilation and is associated with dysfunctional microcirculation. The objective of this study was to investigate venule-dependent NO in diabetes. METHODS: Arteriolar and venular wall concentrations of NO were measured in control and diabetic (streptozotocin-induced) rat mesentery with fluorescent diaminofluorescein-2-diacetate (DAF-2-DA); tissue NO was measured with DAF-2. Venular leukocyte adherence and microvascular shear rates were also measured. RESULTS: Microvascular NO in diabetic rats was found to be significantly lower (<50%) than in controls. In normal rats, arteriolar NO demonstrated a positive correlation with venular NO and venular shear, and a negative correlation with venular leukocyte adherence. Diabetes eliminated all these correlations. No correlation was present between arteriolar NO and arteriolar shear in either normal or diabetic rats. CONCLUSIONS: Arteriolar NO appears to be enhanced by venular shear in normal but not in diabetic rats. This dysfunction could contribute to poor capillary perfusion in diabetes.     

The risk of tuberculosis in transplant candidates and recipients: a TBNET consensus statement

Tuberculosis (TB) is a possible complication of solid organ and hematopoietic stem cell transplantation. The identification of candidates for preventive chemotherapy is an effective intervention to protect transplant recipients with latent infection with Mycobacterium tuberculosis from progressing to active disease. The best available proxy for diagnosing latent infection with M. tuberculosis is the identification of an adaptive immune response by the tuberculin skin test or an interferon-γ based ex vivo assay. Risk assessment in transplant recipients for the development of TB depends on, among other factors, the locally expected underlying prevalence of infection with M. tuberculosis in the target population. In areas of high prevalence, preventive chemotherapy for all transplant recipients may be justified without immunodiagnostic testing while in areas of medium and low prevalence, preventive chemotherapy should only be offered to candidates with positive M. tuberculosis-specific immune responses. The diagnosis of TB in transplant recipients can be challenging. Treatment of TB is often difficult due to substantial interactions between anti-TB drugs and immunosuppressive medications. This management guideline summarises current knowledge on the prevention, diagnosis and treatment of TB related to solid organ and hematopoietic stem cell transplantation and provides an expert consensus on questions where scientific evidence is still lacking.     

Drotaverine hydrochloride versus hyoscine-N-butylbromide in augmentation of labor

Objectives: To study and compare the efficacy and side effects of drotaverine hydrochloride and hyoscine-N-butylbromide in the augmentation of labor. Methods: A prospective randomized trial of 150 women in active labor included 50 women given drotaverine (group 1), 50 women given hyoscine-N-butylbromide (group 2), and 50 women given no medication (group 3). Duration of labor, rate of cervical dilation, mode of delivery, side effects, and neonatal outcome were compared among the groups. Results: The mean duration of the active phase of labor was 4.48 ± 2.26 h, 3.9 ± 2.42 h, and 3.6 ± 2.07 h in groups 1, 2, and 3, respectively. The mean rate of cervical dilation was 2.6 cm/h, 2.4 cm/h, and 2.5 cm/h, respectively. The differences were not statistically significant. There was no difference in the duration of the second and third stages of labor. No adverse maternal or fetal outcomes were noted. Conclusion: Drotaverine hydrochloride and hyoscine-N-butylbromide do not have a role in augmentation of labor.     

Development of metoprolol tartrate extended-release matrix tablet formulations for regulatory policy consideration

This research study was designed to develop model extended-release (ER) matrix tablet formulations for metoprolol tartrate (100 mg) sufficiently sensitive to manufacturing variables and to serve as the scientific basis for regulatory policy development on scale-up and post approval changes for modified-release dosage forms (SUPAC-MR). Several grades and levels of hydroxypropyl methylcellulose (Methocel K4M, K15M, K100M and K100LV), fillers and binders were studied. Three granulation processes were evaluated; direct compression, fluid-bed or high-shear granulation. Lubrication was performed in a V-blender and tablets were compressed on an instrumented rotary tablet press. Direct compression formulations exhibited poor flow, picking and sticking problems during tableting. High-shear granulation resulted in the formation of hard granules that were difficult to mill but yielded good tablets. Fluid-bed granulations were made using various binders and appeared to be satisfactory in terms of flow and tableting performance. In vitro drug release testing was performed in pH 6.8 phosphate buffer using USP apparatus 2 (paddle) at 50 rpm. At a fixed polymer level, drug release from the higher viscosity grades (K100M) was slower as compared to the lower viscosity grades (K100LV). In addition, release from K100LV was found to be more sensitive to polymer level changes. Increase in polymer level from 10 to 40% and/or filler change from lactose to dicalcium phosphate resulted in about 25–30% decrease in the amount of metoprolol release after 12 h. The results of this study led to the choice of Methocel K100LV as the hydrophilic matrix polymer and fluid-bed granulation as the process of choice for further evaluation of critical and non-critical formulation and processing variables.     

Effect of interventions to control sexually transmitted disease on the incidence of HIV infection in female sex workers

OBJECTIVE: To compare the seroincidence of HIV infection among female sex workers in Abidjan, C?te d'Ivoire before and during an intervention study to control sexually transmitted diseases (STD) and to study the effect of two STD diagnosis and treatment strategies on the prevalence of STD and on the seroincidence of HIV infection. METHOD: A screening facility for STD and HIV had been available since October 1992 for female sex workers. From June 1994, women who were HIV seronegative or HIV-2 positive during the screening could enroll in the intervention study in which participants reported once a month to a confidential clinic where they received health education, condoms and STD treatment if indicated. Women in the study were randomized either to a basic STD diagnosis and treatment strategy, which included a gynecologic examination when symptomatic, or to an intensive strategy that included a gynecologic examination regardless of symptoms. An outcome assessment every 6 months included a gynecologic examination, HIV serology and laboratory tests for STD. RESULTS: Of 542 women enrolled in the study, 225 (42%) had at least one outcome assessment. The HIV-1 seroincidence rate during the intervention study was significantly lower than before the study (6.5 versus 16.3 per 100 person-years; P = 0.02). During the study, the HIV-1 seroincidence rate was slightly lower in the intensive than in the basic strategy (5.3 versus 7.6 per 100 person-years; P = 0.5). CONCLUSION: National AIDS control programs should consider adopting as policy the type of integrated approach used in this intervention study for HIV prevention in female sex workers.     

A Bone Anabolic Effect of RANKL in a Murine Model of Osteoporosis Mediated Through FoxP3+ CD8 T Cells

TNF‐α and IL‐17 secreted by proinflammatory T cells (T_EFF) promote bone erosion by activating osteoclasts. We previously demonstrated that in addition to bone resorption, osteoclasts act as antigen‐presenting cells to induce FoxP3 in CD8 T cells (Tc_REG). The osteoclast‐induced regulatory CD8 T cells limit bone resorption in ovariectomized mice (a murine model of postmenopausal osteoporosis). Here we show that although low‐dose receptor activator of NF‐κB ligand (RANKL) maximally induces Tc_REG via Notch signaling pathway to limit bone resorption, high‐dose RANKL promotes bone resorption. In vitro, both TNF‐α and IL‐17, cytokines that are abundant in ovariectomized animals, suppress Tc_REG induction by osteoclasts by repressing Notch ligand expression in osteoclasts, but this effect can be counteracted by addition of RANKL. Ovariectomized mice treated with low‐dose RANKL induced Tc_REG that suppressed bone resorption, decreased T_EFF levels, and increased bone formation. High‐dose RANKL had the expected osteolytic effect. Low‐dose RANKL administration in ovariectomized mice lacking CD8 T cells was also osteolytic, confirming that Tc_REG mediate this bone anabolic effect. Our results show that although RANKL directly stimulates osteoclasts to resorb bone, it also controls the osteoclasts' ability to induce regulatory T cells, engaging an important negative feedback loop. In addition to the conceivable clinical relevance to treatment of osteoporosis, these observations have potential relevance to induction of tolerance and autoimmune diseases. © 2015 American Society for Bone and Mineral Research.     

Thioaptamer conjugated liposomes for tumor vasculature targeting

Recent developments in multi-functional nanoparticles offer a great potential for targeted delivery of therapeutic compounds and imaging contrast agents to specific cell types, in turn, enhancing therapeutic effect and minimizing side effects. Despite the promise, site specific delivery carriers have not been translated into clinical reality. In this study, we have developed long circulating liposomes with the outer surface decorated with thioated oligonucleotide aptamer (thioaptamer) against E-selectin (ESTA) and evaluated the targeting efficacy and PK parameters. In vitro targeting studies using Human Umbilical Cord Vein Endothelial Cell (HUVEC) demonstrated efficient and rapid uptake of the ESTA conjugated liposomes (ESTA-lip). In vivo, the intravenous administration of ESTA-lip resulted in their accumulation at the tumor vasculature of breast tumor xenografts without shortening the circulation half-life. The study presented here represents an exemplary use of thioaptamer and liposome and opens the door to testing various combinations of thioaptamer and nanocarriers that can be constructed to target multiple cancer types and tumor components for delivery of both therapeutics and imaging agent.     

Le sacrifice du genou chez l’amputé transtibial traumatique. À propos de cinq cas

When the knee must be sacrificed in young patients who have undergone an initial transtibial amputation of traumatic origin, functional performance objectives should guide the choice of level and technique of the subsequent amputation. The results obtained and the type of prosthesis used differ according to whether a tibiofemoral disarticulation, a Gritti amputation or a transfemoral amputation is performed. Following a brief review of the advantages and disadvantages of these techniques, five clinical cases are presented.