Potential Impact of Antiretroviral Chemoprophylaxis on HIV-1 Transmission in Resource-Limited Settings

Background. The potential impact of pre-exposure chemoprophylaxis (PrEP) an heterosexual transmission of HIV-1 infection in resource-limited settings is uncertain. Methodology/Principle Findings. A deterministic mathematical model was used to simulate the effects of antiretroval PreP on an HIV-1 epidemic in sub-Saharan Africa under different scenarios (optimistic neutral and pessimistic) both with and without sexual disinhibition. Sensitivity analyses were used to evaluate the effect of uncertainty in input parameters on model output and included calculation of partial rank correlations and standardized rank regressions. In the scenario without sexual disinhibition after PrEP initiation, key parameters influencing infections prevented were effectiveness of PrEP (partial rank correlation coefficient (PRCC) = 0.94), PrEP discontinuation rate (PRCC=-0.94), level of coverage (PRCC=0.92), and time to achieve target coverage (PRCC=-082). In the scenario with sexual disinhibition, PrEP effectiveness and the extent of sexual disinhibition had the greatest impact on prevention. An optimistic scenario of PrEP with 90% effectiveness and 75% coverage of the general population predicted a 74% decline in cumulative HIV-1 infections after 10 years, and a 28.8% decline with PrEP targeted to the highest risk groups (16% of the population). Even With a 100% increase in at-risk behavior from sexual disinhibition, a beneficial effect (23.4%-62.7% decrease in infections) was seen with 90% effective PrEP across a broad range of coverage (25%-75%). Similar disinhibition led to a rise in infections with lower effectiveness of PrEP (≤50%). Conclusions/Significance. Mathematical modeling supports the potential public health benefit of PrEP. Approximately 2.7 to 3.2 million new HIV-1 infections could be averaged in southern sub-Saharan Africa over 10 years by targeting PrEP (having 90% effectiveness) to those at highest behavioral risk and by preventing sexual disinhibition. This benefit could be lost, however, by sexual disinhibition and by high PrEP discontinuation, especially with lower PrEP effectiveness (≤:50%). © 2007 Abbas et al

Nephrotoxicity in survivors of Wilms' tumours in the North of England

One aspect of concern for survivors of Wilms' tumour has been the late outcome in terms of renal function. Previous studies have documented low glomerular filtration rate and high blood pressure in some patients. Furthermore, disorders in tubular function (especially urinary concentration defects) have been suggested but not confirmed in small studies. The aim of this study was to determine the prevalence and nature of subclinical and overt glomerular, proximal and distal renal tubular toxicity in a population based cohort of survivors of Wilms' tumour. Forty patients (24 female) with a median age of 4.3 years (3 months–11.8 years) at diagnosis were studied. Median follow-up was 8.8 (range 0.06–27.5) years. Glomerular filtration rate was measured by 51Cr-EDTA plasma clearance, proximal tubular function by electrolyte fractional excretions, urine excretion of low molecular weight proteins (retinol-binding protein) and renal tubular enzymes (alanine aminopeptidase; N-acetylglucosaminidase) and distal tubular function by the osmolality of the first two urines of the day on 3 consecutive days. Renal size (ultrasound) and blood pressure were also measured. Mean (range) glomerular filtration rate was 100 (61–150) ml min−1 1.73 m−2. Nine were below the reference range for healthy individuals with two kidneys. Most serum electrolyte concentrations (sodium, potassium, chloride, calcium, magnesium and phosphate) fell within the normal range for age, as did the fractional excretions. The values that fell outside the normal range were only marginally abnormal. Subclinical measures of tubular toxicity (retinal-binding protein, alanine aminopeptidase, N-acetylglucosaminidase) were abnormal in only four patients. Thirty-seven patients achieved maximal urine osmolalities ⩾800 mOsm kg−1, but three failed to achieve this value even after DDAVP administration. Two patients had evidence of increased urinary albumin excretion. Compensatory renal hypertrophy was seen in all but two patients, but blood pressure was within normal limits in all patients. Current and past treatment for Wilms' tumour does not have any clinically important nephrotoxic effect in the majority of patients. This finding will enable paediatric oncologists to reassure patients and parents that treatment for Wilms' tumour rarely causes long-term renal impairment

Chronic escitalopram treatment attenuated the accelerated rapid eye movement sleep transitions after selective rapid eye movement sleep deprivation: a model-based analysis using Markov chains

BackgroundShortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet.ResultsChronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis.Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5 inverted question mark9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD.ConclusionIn conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern

Degradation, Bioactivity, and Osteogenic Potential of Composites Made of PLGA and Two Different Sol–Gel Bioactive Glasses

We have developed poly(l-lactide-co-glycolide) (PLGA) based composites using sol–gel derived bioactive glasses (S-BG), previously described by our group, as composite components. Two different composite types were manufactured that contained either S2—high content silica S-BG, or A2—high content lime S-BG. The composites were evaluated in the form of sheets and 3D scaffolds. Sheets containing 12, 21, and 33 vol.% of each bioactive glass were characterized for mechanical properties, wettability, hydrolytic degradation, and surface bioactivity. Sheets containing A2 S-BG rapidly formed a hydroxyapatite surface layer after incubation in simulated body fluid. The incorporation of either S-BG increased the tensile strength and Young’s modulus of the composites and tailored their degradation rates compared to starting compounds. Sheets and 3D scaffolds were evaluated for their ability to support growth of human bone marrow cells (BMC) and MG-63 cells, respectively. Cells were grown in non-differentiating, osteogenic or osteoclast-inducing conditions. Osteogenesis was induced with either recombinant human BMP-2 or dexamethasone, and osteoclast formation with M-CSF. BMC viability was lower at higher S-BG content, though specific ALP/cell was significantly higher on PLGA/A2-33 composites. Composites containing S2 S-BG enhanced calcification of extracellular matrix by BMC, whereas incorporation of A2 S-BG in the composites promoted osteoclast formation from BMC. MG-63 osteoblast-like cells seeded in porous scaffolds containing S2 maintained viability and secreted collagen and calcium throughout the scaffolds. Overall, the presented data show functional versatility of the composites studied and indicate their potential to design a wide variety of implant materials differing in physico-chemical properties and biological applications. We propose these sol–gel derived bioactive glass–PLGA composites may prove excellent potential orthopedic and dental biomaterials supporting bone formation and remodeling

Treatment of Acne Keloidalis Nuchae: A Systematic Review of the Literature

Acne keloidalis nuchae (AKN) is a chronic inflammatory condition that leads to fibrotic plaques, papules and alopecia on the occiput and/or nape of the neck. Traditional medical management focuses on prevention, utilization of oral and topical antibiotics, and intralesional steroids in order to decrease inflammation and secondary infections. Unfortunately, therapy may require months of treatment to achieve incomplete results and recurrences are common. Surgical approach to treatment of lesions is invasive, may require general anesthesia and requires more time to recover. Light and laser therapies offer an alternative treatment for AKN. The present study systematically reviews the currently available literature on the treatment of AKN. While all modalities are discussed, light and laser therapy is emphasized due to its relatively unknown role in clinical management of AKN. The most studied modalities in the literature were the 1064-nm neodymium-doped yttrium aluminum garnet laser, 810-nm diode laser, and CO(2) laser, which allow for 82–95% improvement in 1–5 sessions. Moreover, side effects were minimal with transient erythema and mild burning being the most common. Overall, further larger-scale randomized head to head control trials are needed to determine optimal treatments

A distinct role for B1b lymphocytes in T cell-independent immunity

Pathogenesis of infectious disease is not only determined by the virulence of the microbe but also by the immune status of the host. Vaccination is the most effective means to control infectious diseases. A hallmark of the adaptive immune system is the generation of B cell memory, which provides a long-lasting protective antibody response that is central to the concept of vaccination. Recent studies revealed a distinct function for B1b lymphocytes, a minor subset of mature B cells that closely resembles that of memory B cells in a number of aspects. In contrast to the development of conventional B cell memory, which requires the formation of germinal centers and T cells, the development of B1b cell-mediated long-lasting antibody responses occurs independent of T cell help. T cell-independent (TI) antigens are important virulence factors expressed by a number of bacterial pathogens, including those associated with biological threats. TI antigens cannot be processed and presented to T cells and therefore are known to possess restricted T cell-dependent (TD) immunogenicity. Nevertheless, specific recognition of TI antigens by B1b cells and the highly protective antibody responses mounted by them clearly indicate a crucial role for this subset of B cells. Understanding the mechanisms of long-term immunity conferred by B1b cells may lead to improved vaccine efficacy for a variety of TI antigens

The role of unintegrated DNA in HIV infection

Integration of the reverse transcribed viral genome into host chromatin is the hallmark of retroviral replication. Yet, during natural HIV infection, various unintegrated viral DNA forms exist in abundance. Though linear viral cDNA is the precursor to an integrated provirus, increasing evidence suggests that transcription and translation of unintegrated DNAs prior to integration may aid productive infection through the expression of early viral genes. Additionally, unintegrated DNA has the capacity to result in preintegration latency, or to be rescued and yield productive infection and so unintegrated DNA, in some circumstances, may be considered to be a viral reservoir. Recently, there has been interest in further defining the role and function of unintegrated viral DNAs, in part because the use of anti-HIV integrase inhibitors leads to an abundance of unintegrated DNA, but also because of the potential use of non-integrating lentiviral vectors in gene therapy and vaccines. There is now increased understanding that unintegrated viral DNA can either arise from, or be degraded through, interactions with host DNA repair enzymes that may represent a form of host antiviral defence. This review focuses on the role of unintegrated DNA in HIV infection and additionally considers the potential implications for antiviral therapy