Reconciling conflicting clinical studies of antioxidant supplementation as HIV therapy: a mathematical approach

<p>Abstract</p> <p>Background</p> <p>Small, highly reactive molecules called reactive oxygen species (ROS) play a crucial role in cell signalling and infection control. However, high levels of ROS can cause significant damage to cell structure and function. Studies have shown that infection with the human immunodeficiency virus (HIV) results in increased ROS concentrations, which can in turn lead to faster progression of HIV infection, and cause CD4⁺T-cell apoptosis. To counteract these effects, clinical studies have explored the possibility of raising antioxidant levels, with mixed results.</p> <p>Methods</p> <p>In this paper, a mathematical model is used to explore this potential therapy, both analytically and numerically. For the numerical work, we use clinical data from both HIV-negative and HIV-positive injection drug users (IDUs) to estimate model parameters; these groups have lower baseline concentrations of antioxidants than non-IDU controls.</p> <p>Results</p> <p>Our model suggests that increases in CD4⁺T cell concentrations can result from moderate levels of daily antioxidant supplementation, while excessive supplementation has the potential to cause periods of immunosuppression.</p> <p>Conclusion</p> <p>We discuss implications for HIV therapy in IDUs and other populations which may have low baseline concentrations of antioxidants.</p

Sepsis Enhances Epithelial Permeability with Stretch in an Actin Dependent Manner

Ventilation of septic patients often leads to the development of edema and impaired gas exchange. We hypothesized that septic alveolar epithelial monolayers would experience stretch-induced barrier dysfunction at a lower magnitude of stretch than healthy alveolar epithelial monolayers. Alveolar epithelial cells were isolated from rats 24 hours after cecal ligation and double puncture (2CLP) or sham surgery. Following a 5-day culture period, monolayers were cyclically stretched for 0, 10, or 60 minutes to a magnitude of 12% or 25% change in surface area (ΔSA). Barrier function, MAPk and myosin light chain (MLC) phosphorylation, tight junction (TJ) protein expression and actin cytoskeletal organization were examined after stretch. Significant increases in epithelial permeability were observed only in 2CLP monolayers at the 12% ΔSA stretch level, and in both 2CLP and sham monolayers at the 25% ΔSA stretch level. Increased permeability in 2CLP monolayers was not associated with MAPk signaling or alterations in expression of TJ proteins. 2CLP monolayers had fewer actin stress fibers before stretch, a more robust stretch-induced actin redistribution, and reduced phosphorylated MLCK than sham monolayers. Jasplakinolide stabilization of the actin cytoskeleton in 2CLP monolayers prevented significant increases in permeability following 60 minutes of stretch to 12% ΔSA. We concluded that septic alveolar epithelial monolayers are more susceptible to stretch-induced barrier dysfunction than healthy monolayers due to actin reorganization

Traditional and new composite endpoints in heart failure clinical trials: facilitating comprehensive efficacy assessments and improving trial efficiency

Composite endpoints are commonly used as the primary measure of efficacy in heart failure clinical trials to assess the overall treatment effect and to increase the efficiency of trials. Clinical trials still must enrol large numbers of patients to accrue a sufficient number of outcome events and have adequate power to draw conclusions about the efficacy and safety of new treatments for heart failure. Additionally, the societal and health system perspectives on heart failure have raised interest in ascertaining the effects of therapy on outcomes such as repeat hospitalization and the patient's burden of disease. Thus, novel methods for using composite endpoints in clinical trials (e.g. clinical status composite endpoints, recurrent event analyses) are being applied in current and planned trials. Endpoints that measure functional status or reflect the patient experience are important but used cautiously because heart failure treatments may improve function yet have adverse effects on mortality. This paper discusses the use of traditional and new composite endpoints, identifies qualities of robust composites, and outlines opportunities for future research

Immunolocalization of the mercurial-insensitive water channel and glycerol intrinsic protein in epithelial cell plasma membranes

Two water channel homologs were cloned recently from rat kidney, mercurial-insensitive water channel (MIWC) and glycerol intrinsic protein (GLIP). Polyclonal antibodies were raised against synthetic C-terminal peptides and purified by affinity chromatography. MIWC and CLIP antibodies recognized proteins in rat kidney with an apparent molecular mass of 30 and 27 kDa, respectively, and did not cross-react, By immunofluorescence, MIWC and GLIP were expressed together on the basolateral plasma membrane of collecting duct principal cells in kidney, By immunohistochemistry, MIWC and GLIP were expressed on tracheal epithelial cells with greater expression of GLIP on the basal plasma membrane and Mn;VC on the lateral membrane; only MIWC was expressed in bronchial epithelia, In eye, GLIP was expressed in conjunctival epithelium, whereas MIWC was found in iris, ciliary body, and neural cell layers in retina, MIWC and GLIP colocalized on the basolateral membrane of villus epithelial cells in colon and brain ependymal cells, Expression of MIWC and GLIP was not detected in small intestine, liver, spleen, endothelia, and cells that express water channels CHIP28 or WCH-CD, These studies suggest water/solute transporting roles for MIWC and GLIP in the urinary concentrating mechanism, cerebrospinal fluid absorption, ocular fluid balance, fecal dehydration, and airway humidification. The unexpected membrane colocalization of MIWC and GLIP in several tissues suggests an interaction at the molecular and/or functional levels

An analysis of near misses identified by anesthesia providers in the intensive care unit

© 2015 Lipshutz et al. Background: Learning from adverse events and near misses may reduce the incidence of preventable errors. Current literature on adverse events and near misses in the ICU focuses on errors reported by nurses and intensivists. ICU nea

Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues

It was shown recently that water channel homologs MIWC (mercurial insensitive water channel) and GLIP (glycerol intrinsic protein) colocalized in basolateral membranes of kidney collecting duct, tracheal and colonic epithelia, and in brain pia mater, We report here an extensive immunolocalization study of MIWC and GLIP in non-epithelial and glandular epithelial tissues in rat, Immunogold electron microscopy confirmed colocalization of MIWC and GLIP in basolateral membrane of principal cells in kidney collecting duct, However, in other epithelia, MIWC but not GLIP was expressed in basolateral membrane of parietal cells in stomach, and in excretory tubules of salivary and lacrimal glands; GLIP but not MIWC was expressed in transitional epithelium of urinary bladder and skin epidermis, Zn the central nervous system, Mn;VC was strongly expressed in the ependymal layer lining the aqueductal system, and in astrocytes throughout the spinal cord and in selected regions of brain, MIWC was also expressed in a plasma membrane pattern in skeletal, but not smooth or cardiac muscle, Neither protein was expressed in small intestine, testis, liver, spleen and nerve, The tissue-specific expression of MIWC suggests a role in fluid transport and/or cell volume regulation in stomach and glandular epithelia, The functional role of MIWC expression in the neuromuscular system and of GLIP expression in skin and urinary bladder is uncertain, The specific cellular sites of MIWC expression (astrocytes, trachea, sarcolemma, gastric parietal cells and kidney principal cells) correspond exactly to sites where orthogonal arrays of particles (OAPs) have been visualized by freeze-fracture electron microscopy, suggesting that MIWC may be the OAF protein