Impact of HIV-Status Disclosure on Adherence to Antiretroviral Therapy Among HIV-Infected Children in Resource-Limited Settings: A Systematic Review

Pediatric HIV remains a significant global health dilemma, especially in resource-constrained nations. As access to ART increases around the world, areas of concern in pediatric HIV treatment include age-appropriate disclosure of HIV status to children and development of adherence habits over time. This review was conducted to synthesize quantitative associations reported between disclosure and adherence among children living with HIV in resource-limited settings. An electronic database search of PubMed, MEDLINE and Cochrane returned 1348 results after removal of duplicates, 14 of which were found to meet inclusion criteria. Review of these reports showed conflicting results regarding the impact of disclosure on adherence, with 5 showing no association, 4 showing a negative impact of disclosure on adherence, and 5 showing positive benefits of disclosure for adherence habits. Thus, there was no clear consensus on the effect, if any, that disclosure has on medication adherence. Longitudinal, prospective research needs to be conducted to evaluate further impacts that disclosure may have on adherence habits over time, and interventions must be structured to link the two processes together in order to maximize health benefit to the child or adolescent.     

Capturing fleeting intermediates in a catalytic C–H amination reaction cycle

We have applied an ambient ionization technique, desorption electrospray ionization MS, to identify transient reactive species of an archetypal C–H amination reaction catalyzed by a dirhodium tetracarboxylate complex. Using this analytical method, we have detected previously proposed short-lived reaction intermediates, including two nitrenoid complexes that differ in oxidation state. Our findings suggest that an Rh-nitrene oxidant can react with hydrocarbon substrates through a hydrogen atom abstraction pathway and raise the intriguing possibility that two catalytic C–H amination pathways may be operative in a typical bulk solution reaction. As highlighted by these results, desorption electrospray ionization MS should have broad applicability for the mechanistic study of catalytic processes.     

Quaternary dynamics and plasticity underlie small heat shock protein chaperone function

Small Heat Shock Proteins (sHSPs) are a diverse family of molecular chaperones that prevent protein aggregation by binding clients destabilized during cellular stress. Here we probe the architecture and dynamics of complexes formed between an oligomeric sHSP and client by employing unique mass spectrometry strategies. We observe over 300 different stoichiometries of interaction, demonstrating that an ensemble of structures underlies the protection these chaperones confer to unfolding clients. This astonishing heterogeneity not only makes the system quite distinct in behavior to ATP-dependent chaperones, but also renders it intractable by conventional structural biology approaches. We find that thermally regulated quaternary dynamics of the sHSP establish and maintain the plasticity of the system. This extends the paradigm that intrinsic dynamics are crucial to protein function to include equilibrium fluctuations in quaternary structure, and suggests they are integral to the sHSPs’ role in the cellular protein homeostasis network.     

The Evolution of Transcranial Laser Therapy for Acute Ischemic Stroke, Including a Pooled Analysis of NEST-1 and NEST-2

Intravenous tissue plasminogen activator is the only proven therapy for acute ischemic stroke. Not enough patients are eligible for treatment and additional new therapies are needed. Recently, laser technology has been applied to acute ischemic stroke. This noninvasive technique uses near-infrared wavelengths applied to the scalp within 24 h of symptom onset. The mechanism is incompletely understood but may involve increased mitochondrial adenosine triphosphate production. Animal models demonstrated safety and efficacy warranting randomized controlled trials in humans. NEST-1 (phase 2) and NEST-2 (phase 3) confirmed the safety of transcranial laser therapy, although efficacy was not found in NEST-2. Pooled analysis of NEST-1 and NEST-2 revealed a significantly improved success rate in patients treated with laser therapy. Further phase 3 testing is planned and may create a new paradigm for the treatment of acute ischemic stroke.     

Topical application of the anti-microbial chemical triclosan induces immunomodulatory responses through the S100A8/A9-TLR4 pathway

The anti-microbial compound triclosan is incorporated into numerous consumer products and is detectable in the urine of 75% of the general United States population. Recent epidemiological studies report positive associations with urinary triclosan levels and allergic disease. Although not sensitizing, earlier studies previously found that repeated topical application of triclosan augments the allergic response to ovalbumin (OVA) though a thymic stromal lymphopoietin (TSLP) pathway in mice. In the present study, early immunological effects following triclosan exposure were further evaluated following topical application in a murine model. These investigations revealed abundant expression of S100A8/A9, which reportedly acts as an endogenous ligand for Toll-like Receptor 4 (TLR4), in skin tissues and in infiltrating leukocytes during topical application of 0.75–3.0% triclosan. Expression of Tlr4 along with Tlr1, Tlr2 and Tlr6 increased in skin tissues over time with triclosan exposure; high levels of TLR4 were expressed on skin-infiltrating leukocytes. In vivo antibody blockade of the TLR4/MD-2 receptor complex impaired local inflammatory responses after four days, as evidenced by decreased Il6, Tnfα, S100a8, S100a9, Tlr1, Tlr2, Tlr4 and Tlr6 expression in the skin and decreased lymph node cellularity and production of IL-4 and IL-13 by lymph node T-cells. After nine days of triclosan exposure with TLR4/MD-2 blockade, impaired T-helper cell type 2 (T_H2) cytokine responses were sustained, but other early effects on skin and lymph node cellularity were lost; this suggested alternative ligands/receptors compensated for the loss of TLR4 signaling. Taken together, these data suggest the S100A8/A9-TLR4 pathway plays an early role in augmenting immunomodulatory responses with triclosan exposure and support a role for the innate immune system in chemical adjuvancy.     

From the Cover: Loss of phosphatidylinositol 4-kinase 2α activity causes late onset degeneration of spinal cord axons

Phosphoinositide (PI) lipids are intracellular membrane signaling intermediates and effectors produced by localized PI kinase and phosphatase activities. Although many signaling roles of PI kinases have been identified in cultured cell lines, transgenic animal studies have produced unexpected insight into the in vivo functions of specific PI 3- and 5-kinases, but no mammalian PI 4-kinase (PI4K) knockout has previously been reported. Prior studies using cultured cells implicated the PI4K2α isozyme in diverse functions, including receptor signaling, ion channel regulation, endosomal trafficking, and regulated secretion. We now show that despite these important functions, mice lacking PI4K2α kinase activity initially appear normal. However, adult Pi4k2a^GT/GT animals develop a progressive neurological disease characterized by tremor, limb weakness, urinary incontinence, and premature mortality. Histological analysis of aged Pi4k2a^GT/GT animals revealed lipofuscin-like deposition and gliosis in the cerebellum, and loss of Purkinje cells. Peripheral nerves are essentially normal, but massive axonal degeneration was found in the spinal cord in both ascending and descending tracts. These results reveal a previously undescribed role for aberrant PI signaling in neurological disease that resembles autosomal recessive hereditary spastic paraplegia.     

Silent somatotroph pituitary adenomas: an update

Silent growth hormone adenomas (SGHA) are a rare entity of non-functioning pituitary neuroendocrine tumors. Diagnosis is invariably made post-operatively of a tumor immunopositive for GH (and Pit-1 in selected cases) but without clinical acromegaly. Mainly young females are affected, and tumors are often uncovered by investigation for headaches or oligoamenorrhea. Integration of clinical, pathological and biochemical data is required for proper diagnosis. Beside normal IGF-1 levels, a third of SGHAs displays elevated GH levels and some will eventually progress to acromegaly. Almost two-thirds will be mixed GH-prolactin tumors and sparsely-granulated monohormonal GH tumors seems the more aggressive subtype. Recurrence and need for radiation is higher than other non-functioning tumors so close follow-up is warranted.