Systematic review of prevalence and predictors of frailty in individuals with human immunodeficiency virus

Objectives To describe the prevalence and predictors of frailty in individuals with the human immunodeficiency virus (HIV) using systematic review methodology. Design Review. Setting Community. Participants Older adults with HIV. Measurements Medline, CINAHL, EMBASE, PsychInfo, and PubMed were searched for original observational studies with populations including individuals with HIV in which frailty was assessed using the frailty phenotype or a variant thereof. Studies were examined for frailty prevalence and predictors of the syndrome in those with HIV. Results Thirteen of 322 citations were included for full review. All demonstrated the presence of frailty in individuals with HIV, with prevalence ranging from 5% to 28.6% depending on population studied. HIV was a risk factor for frailty. Predictors of frailty included older age, comorbidities, diagnosis of acquired immunodeficiency syndrome, and low current CD4+ cell count. Conclusion HIV appears to be an independent risk factor for frailty, with frailty occurring in individuals with HIV at rates comparable with older individuals without HIV. Heterogeneity in study populations and frailty assessment measures hamper accurate description of the problem. Future longitudinal work with standardized methodology is needed to describe prevalence accurately and confirm predictors

Preventing phosphorylation of dystroglycan ameliorates the dystrophic phenotype in mdx mouse

Loss of dystrophin protein due to mutations in the DMD gene causes Duchenne muscular dystrophy. Dystrophin loss also leads to the loss of the dystrophin glycoprotein complex (DGC) from the sarcolemma which contributes to the dystrophic phenotype. Tyrosine phosphorylation of dystroglycan has been identified as a possible signal to promote the proteasomal degradation of the DGC. In order to test the role of tyrosine phosphorylation of dystroglycan in the aetiology of DMD, we generated a knock-in mouse with a phenylalanine substitution at a key tyrosine phosphorylation site in dystroglycan, Y890. Dystroglycan knock-in mice (Dag1Y890F/Y890F) had no overt phenotype. In order to examine the consequence of blocking dystroglycan phosphorylation on the aetiology of dystrophin-deficient muscular dystrophy, the Y890F mice were crossed with mdx mice an established model of muscular dystrophy. Dag1Y890F/Y890F/mdx mice showed a significant improvement in several parameters of muscle pathophysiology associated with muscular dystrophy, including a reduction in centrally nucleated fibres, less Evans blue dye infiltration and lower serum creatine kinase levels. With the exception of dystrophin, other DGC components were restored to the sarcolemma including α-sarcoglycan, α-/β-dystroglycan and sarcospan. Furthermore, Dag1Y890F/Y890F/mdx showed a significant resistance to muscle damage and force loss following repeated eccentric contractions when compared with mdx mice. While the Y890F substitution may prevent dystroglycan from proteasomal degradation, an increase in sarcolemmal plectin appeared to confer protection on Dag1Y890F/Y890F/mdx mouse muscle. This new model confirms dystroglycan phosphorylation as an important pathway in the aetiology of DMD and provides novel targets for therapeutic intervention

Non-Raft AC2 Defines a cAMP Signaling Compartment That Selectively Regulates IL-6 Expression in Airway Smooth Muscle Cells

Adenylyl cyclase (AC) isoforms differ in their tissue distribution, cellular localization, regulation, and protein interactions. Most cell types express multiple AC isoforms. We hypothesized that cAMP produced by different AC isoforms regulates unique cellular responses in human bronchial smooth muscle cells (BSMC). Overexpression of AC2, AC3, or AC6 had distinct effects on forskolin (Fsk)-induced expression of a number of known cAMP-responsive genes. These data show that different AC isoforms can differentially regulate gene expression. Most notable, overexpression and activation of AC2 enhanced interleukin 6 (IL-6) expression, but overexpression of AC3 or AC6 had no effect. IL-6 production by BSMC was induced by Fsk and select G protein-coupled receptor (GPCR) agonists, though IL-6 levels did not directly correlate with global cAMP levels. Treatment with PKA selective 6-Bnz-cAMP or Epac selective 8-CPT-2Me-cAMP cAMP analogs revealed a predominant role for PKA in cAMP-mediated induction of IL-6. IL-6 promoter mutations demonstrated that AP-1 and CRE transcription sites were required for Fsk to stimulate IL-6 expression. Our present study defines an AC2 cAMP signaling compartment that specifically regulates IL-6 expression in BSMC via Epac and PKA and demonstrates that other AC isoforms are excluded from this pool

Colocalization of Protein Kinase A with Adenylyl Cyclase Enhances Protein Kinase A Activity during Induction of Long-Lasting Long-Term-Potentiation

The ability of neurons to differentially respond to specific temporal and spatial input patterns underlies information storage in neural circuits. One means of achieving spatial specificity is to restrict signaling molecules to particular subcellular compartments using anchoring molecules such as A-Kinase Anchoring Proteins (AKAPs). Disruption of protein kinase A (PKA) anchoring to AKAPs impairs a PKA-dependent form of long term potentiation (LTP) in the hippocampus. To investigate the role of localized PKA signaling in LTP, we developed a stochastic reaction-diffusion model of the signaling pathways leading to PKA activation in CA1 pyramidal neurons. Simulations investigated whether the role of anchoring is to locate kinases near molecules that activate them, or near their target molecules. The results show that anchoring PKA with adenylyl cyclase (which produces cAMP that activates PKA) produces significantly greater PKA activity, and phosphorylation of both inhibitor-1 and AMPA receptor GluR1 subunit on S845, than when PKA is anchored apart from adenylyl cyclase. The spatial microdomain of cAMP was smaller than that of PKA suggesting that anchoring PKA near its source of cAMP is critical because inactivation by phosphodiesterase limits diffusion of cAMP. The prediction that the role of anchoring is to colocalize PKA near adenylyl cyclase was confirmed by experimentally rescuing the deficit in LTP produced by disruption of PKA anchoring using phosphodiesterase inhibitors. Additional experiments confirm the model prediction that disruption of anchoring impairs S845 phosphorylation produced by forskolin-induced synaptic potentiation. Collectively, these results show that locating PKA near adenylyl cyclase is a critical function of anchoring

Molecular changes in the postmortem parkinsonian brain

Parkinson disease (PD) is the second most common neurodegenerative disease after Alzheimer disease. Although PD has a relatively narrow clinical phenotype, it has become clear that its etiological basis is broad. Post-mortem brain analysis, despite its limitations, has provided invaluable insights into relevant pathogenic pathways including mitochondrial dysfunction, oxidative stress and protein homeostasis dysregulation. Identification of the genetic causes of PD followed the discovery of these abnormalities, and reinforced the importance of the biochemical defects identified post-mortem. Recent genetic studies have highlighted the mitochondrial and lysosomal areas of cell function as particularly significant in mediating the neurodegeneration of PD. Thus the careful analysis of post-mortem PD brain biochemistry remains a crucial component of research, and one that offers considerable opportunity to pursue etiological factors either by ‘reverse biochemistry’ i.e. from defective pathway to mutant gene, or by the complex interplay between pathways e.g. mitochondrial turnover by lysosomes. In this review we have documented the spectrum of biochemical defects identified in PD post-mortem brain and explored their relevance to metabolic pathways involved in neurodegeneration. We have highlighted the complex interactions between these pathways and the gene mutations causing or increasing risk for PD. These pathways are becoming a focus for the development of disease modifying therapies for PD. Parkinson's is accompanied by multiple changes in the brain that are responsible for the progression of the disease. We describe here the molecular alterations occurring in postmortem brains and classify them as: Neurotransmitters and neurotrophic factors; Lewy bodies and Parkinson's-linked genes; Transition metals, calcium and calcium-binding proteins; Inflammation; Mitochondrial abnormalities and oxidative stress; Abnormal protein removal and degradation; Apoptosis and transduction pathways

A wake-active locomotion circuit depolarizes a sleep-active neuron to switch on sleep

Sleep-active neurons depolarize during sleep to suppress wakefulness circuits. Wake-active wake-promoting neurons in turn shut down sleep-active neurons, thus forming a bipartite flip-flop switch. However, how sleep is switched on is unclear because it is not known how wakefulness is translated into sleep-active neuron depolarization when the system is set to sleep. Using optogenetics in Caenorhabditis elegans, we solved the presynaptic circuit for depolarization of the sleep-active RIS neuron during developmentally regulated sleep, also known as lethargus. Surprisingly, we found that RIS activation requires neurons that have known roles in wakefulness and locomotion behavior. The RIM interneurons-which are active during and can induce reverse locomotion-play a complex role and can act as inhibitors of RIS when they are strongly depolarized and as activators of RIS when they are modestly depolarized. The PVC command interneurons, which are known to promote forward locomotion during wakefulness, act as major activators of RIS. The properties of these locomotion neurons are modulated during lethargus. The RIMs become less excitable. The PVCs become resistant to inhibition and have an increased capacity to activate RIS. Separate activation of neither the PVCs nor the RIMs appears to be sufficient for sleep induction; instead, our data suggest that they act in concert to activate RIS. Forward and reverse circuit activity is normally mutually exclusive. Our data suggest that RIS may be activated at the transition between forward and reverse locomotion states, perhaps when both forward (PVC) and reverse (including RIM) circuit activity overlap. While RIS is not strongly activated outside of lethargus, altered activity of the locomotion interneurons during lethargus favors strong RIS activation and thus sleep. The control of sleep-active neurons by locomotion circuits suggests that sleep control may have evolved from locomotion control. The flip-flop sleep switch in C. elegans thus requires an additional component, wake-active sleep-promoting neurons that translate wakefulness into the depolarization of a sleep-active neuron when the worm is sleepy. Wake-active sleep-promoting circuits may also be required for sleep state switching in other animals, including in mammals

Barriers for user acceptance of Mobile Health applications for Diabetic patients: Applying the UTAUT model

The literature illustrates that technology will widen health disparity if its use is restricted to patients who are already motivated and demonstrate good self-management behaviours. Additionally, despite the availability of free mobile health (m-health) applications for diabetes self-management, usage is low. There are also limited studies of m-health acceptance in South Africa. This research is delineated to the Western Cape, South Africa. The populace suffers from increasing numbers of diabetic patients. Segments of the population also suffer from technological forms of exclusion, such as limited internet access. Therefore, the objective of this study was to identify challenges for user acceptance that discourages the use of m-health applications. This study analysed 130 semi-structured interviews, using thematic content analysi

Characteristics of foot structure and footwear associated with hallux valgus: a systematic review

Objective Factors associated with the development of hallux valgus (HV) are multifactorial and remain unclear. The objective of this systematic review and meta-analysis was to investigate characteristics of foot structure and footwear associated with HV. Design Electronic databases (Medline, Embase, and CINAHL) were searched to December 2010. Cross-sectional studies with a valid definition of HV and a non-HV comparison group were included. Two independent investigators quality rated all included papers. Effect sizes and 95% confidence intervals (CIs) were calculated (standardized mean differences (SMDs) for continuous data and risk ratios (RRs) for dichotomous data). Where studies were homogeneous, pooling of SMDs was conducted using random effects models. Results A total of 37 papers (34 unique studies) were quality rated. After exclusion of studies without reported measurement reliability for associated factors, data were extracted and analysed from 16 studies reporting results for 45 different factors. Significant factors included: greater first intermetatarsal angle (pooled SMD = 1.5, CI: 0.88–2.1), longer first metatarsal (pooled SMD = 1.0, CI: 0.48–1.6), round first metatarsal head (RR: 3.1–5.4), and lateral sesamoid displacement (RR: 5.1–5.5). Results for clinical factors (e.g., first ray mobility, pes planus, footwear) were less conclusive regarding their association with HV. Conclusions Although conclusions regarding causality cannot be made from cross-sectional studies, this systematic review highlights important factors to monitor in HV assessment and management. Further studies with rigorous methodology are warranted to investigate clinical factors associated with HV