Gene Expression Profiling in Limb-Girdle Muscular Dystrophy 2A

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a recessive genetic disorder caused by mutations in calpain 3 (CAPN3). Calpain 3 plays different roles in muscular cells, but little is known about its functions or in vivo substrates. The aim of this study was to identify the genes showing an altered expression in LGMD2A patients and the possible pathways they are implicated in. Ten muscle samples from LGMD2A patients with in which molecular diagnosis was ascertained were investigated using array technology to analyze gene expression profiling as compared to ten normal muscle samples. Upregulated genes were mostly those related to extracellular matrix (different collagens), cell adhesion (fibronectin), muscle development (myosins and melusin) and signal transduction. It is therefore suggested that different proteins located or participating in the costameric region are implicated in processes regulated by calpain 3 during skeletal muscle development. Genes participating in the ubiquitin proteasome degradation pathway were found to be deregulated in LGMD2A patients, suggesting that regulation of this pathway may be under the control of calpain 3 activity. As frizzled-related protein (FRZB) is upregulated in LGMD2A muscle samples, it could be hypothesized that β-catenin regulation is also altered at the Wnt signaling pathway, leading to an incorrect myogenesis. Conversely, expression of most transcription factor genes was downregulated (MYC, FOS and EGR1). Finally, the upregulation of IL-32 and immunoglobulin genes may induce the eosinophil chemoattraction explaining the inflammatory findings observed in presymptomatic stages. The obtained results try to shed some light on identification of novel therapeutic targets for limb-girdle muscular dystrophies

Health-related quality of life in prisoners with attention-deficit hyperactivity disorder and head injury

Abstract Background Attention-deficit hyperactivity disorder (ADHD) and head injury (including traumatic brain injury (TBI)) manifest in high levels across prison samples and guidance from the National Institute for Health and Care Excellence notes that people with acquired brain injury may have increased prevalence of ADHD. We aimed to examine the association of ADHD with TBI and the impact of the association upon health-related quality of life (HRQoL) and service use among imprisoned adults. Methods An observational study was performed in 2011–2013, at Porterfield Prison, Inverness, United Kingdom (UK). The all male sample included 390 adult prison inmates with capacity to consent and no history of moderate or severe intellectual disability. Head injury was measured with a series of self-reported questions, addressing history of hits to the head: frequency, severity, loss of consciousness (LOC), and sequelae. Participants were interviewed using the Diagnostic Interview for ADHD in Adults 2.0. The Health Utilities Index Mark 3 was used to measure health status, and to calculate attribute specific HRQoL and Quality-Adjusted Life Year (QALY) scores. Results 72% of prisoners sampled reported at least one head injury in their lifetime. Among those, 70% of head injuries occurred before age 16 and 70% experienced LOC. Prisoners with ADHD were nearly twice more likely to have TBI. Prisoners with ADHD-only and ADHD with co-morbid TBI had significantly lower scores in several HRQoL attributes, compared with TBI only or the absence of either condition. Adjusted logistic regression models indicated an average reduction of 0.20 QALYs in inmates with ADHD-only and 0.30 QALY loss in those with ADHD with co-morbid TBI compared with inmates with neither condition. Conclusions There is a robust association between ADHD and TBI, and ADHD with co-morbid TBI confers significantly greater impairment in terms of HRQoL. Managing the short and long-term consequences of TBI is essential to improving care for prisoners and to addressing the criminogenic factors related to them

The economic consequences of attention-deficit hyperactivity disorder in the Scottish prison system

Abstract Background Attention-deficit hyperactivity disorder (ADHD) is highly prevalent amongst prison inmates and the criminal justice system (CJS) likely bears considerable costs for offenders with ADHD. We aimed to examine the relationship between ADHD and health-related quality of life (HRQoL) and quality-adjusted life years (QALY) amongst imprisoned adults; and to estimate the annual expenditure associated with ADHD status in prison. Methods An observational study was performed in 2011–2013, at Porterfield Prison, Inverness, United Kingdom (UK). The all male sample included 390 adult prison inmates with capacity to consent and no history of moderate or severe intellectual disability. Participants were interviewed using the Diagnostic Interview for ADHD in Adults 2.0. The Health Utilities Index Mark 3 (HUI3) was used to measure health status, and to calculate attribute specific HRQoL scores and QALY. Health service utilisation was obtained through inspection of medical prison records. Inmates with ADHD were compared with inmates without ADHD. Results Inmates with ADHD had significantly lower QALYs, with a clinically significant adjusted difference of 0.13. Psychiatric co-morbidity accounted for the variation of ADHD on the HUI3 emotion domain only. Medical costs for inmates with ADHD were significantly higher; and behaviour-related prison costs were similar to prisoners without ADHD, reflecting a low frequency of recorded critical incidents. Conclusions ADHD may directly contribute to adverse health and quality of life through cognitive and executive function deficits, and co-morbid disorders. The extrapolation of conservative cost estimates suggests that the financial burden of medical and behavior-related prison care for inmates with ADHD in the UK is approximately £11.7 million annually. The reported cost estimates are conservative as there is great variability in recorded critical incidents in prisons. In turn, for some prison establishments the prison care costs associated with prisoners with ADHD may be considerably greater

Identification and treatment of offenders with attention-deficit/hyperactivity disorder in the prison population: a practical approach based upon expert consensus

Abstract Background Around 25% of prisoners meet diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD). Because ADHD is associated with increased recidivism and other functional and behavioural problems, appropriate diagnosis and treatment can be a critical intervention to improve outcomes. While ADHD is a treatable condition, best managed by a combination of medication and psychological treatments, among individuals in the criminal justice system ADHD remains both mis- and under-diagnosed and consequently inadequately treated. We aimed to identify barriers within the prison system that prevent appropriate intervention, and provide a practical approach to identify and treat incarcerated offenders with ADHD. Methods The United Kingdom ADHD Partnership hosted a consensus meeting to discuss practical interventions for youth (< 18 years) and adult (≥18 years) offenders with ADHD. Experts at the meeting addressed prisoners’ needs for effective identification, treatment, and multiagency liaison, and considered the requirement of different approaches based on age or gender. Results The authors developed a consensus statement that offers practical advice to anyone working with prison populations. We identified specific barriers within the prison and criminal justice system such as the lack of adequate: staff and offender awareness of ADHD symptoms and treatments; trained mental health staff; use of appropriate screening and diagnostic tools; appropriate multimodal interventions; care management; supportive services; multiagency liaison; and preparation for prison release. Through discussion, a consensus was reached regarding prisoners’ needs, effective identification, treatment and multiagency liaison and considered how this may differ for age and gender. Conclusions This practical approach based upon expert consensus will inform effective identification and treatment of offenders with ADHD. Appropriate intervention is expected to have a positive impact on the offender and society and lead to increased productivity, decreased resource utilization, and most importantly reduced rates of re-offending. Research is still needed, however, to identify optimal clinical operating models and to monitor their implementation and measure their success. Furthermore, government support will likely be required to effect change in criminal justice and mental health service policies

The culture of research communication in neonatal intensive care units: key stakeholder perspectives

OBJECTIVE: To assess the perspectives of neonatologists, neonatal nurses, and parents on research-related education and communication practices in the neonatal intensive care unit (NICU). STUDY DESIGN: Questionnaire circulated through interest groups and administered using the internet. RESULTS: 323 respondents responded to the survey. 52 were neonatologists, 188 were neonatal nurses, and 83 were parents of NICU graduates. Analysis was descriptive. Differences were noted between stakeholder groups with respect to whether current medications meet the needs of sick neonates, research as central to the mission of the NICU, availability of appropriate education/training for all members of the research team, and adequacy of information provided to parents before, during, and after a research study is completed. CONCLUSION: Engagement of nurses and parents at all stages of NICU research is currently suboptimal; relevant good practices, including education, should be shared among neonatal units

Multiclass classification and gene selection with a stochastic algorithm

Microarray technology allows for the monitoring of thousands of gene expressions in various biological conditions, but most of these genes are irrelevant for classifying these conditions. Feature selection is consequently needed to help reduce the dimension of the variable space. Starting from the application of the stochastic meta-algorithm “Optimal Feature Weighting” (OFW) for selecting features in various classification problems, focus is made on the multiclass problem that wrapper methods rarely handle. From a computational point of view, one of the main difficulties comes from the unbalanced classes situation that is commonly encountered in microarray data. From a theoretical point of view, very few methods have been developed so far to minimize the classification error made on the minority classes. The OFW approach is developed to handle multiclass problems using CART and one-vs-one SVM classifiers. Comparisons are made with other multiclass selection algorithms such as Random Forests and the filter method F-test on five public microarray data sets with various complexities. Statistical relevancy of the gene selections is assessed by computing the performances and the stability of these different approaches and the results obtained show that the two proposed approaches are competitive and relevant to selecting genes classifying the minority classes. Application to a pig folliculogenesis study follows and a detailed interpretation of the genes that were selected shows that the OFW approach answers the biological question

Guidelines for identification and treatment of individuals with attention deficit/hyperactivity disorder and associated fetal alcohol spectrum disorders based upon expert consensus

BACKGROUND: The association of attention deficit/hyperactivity disorder (ADHD) and fetal alcohol spectrum disorders (FASD) results in a complex constellation of symptoms that complicates the successful diagnosis and treatment of the affected individual. Current literature lacks formal guidelines, randomized control trials, and evidence-based treatment plans for individuals with ADHD and associated FASD. Therefore, a meeting of professional experts was organized with the aim of producing a consensus on identification and treatment guidelines that will aid clinicians in caring for this unique patient population. METHODS: Experts from multiple disciplines in the fields of ADHD and FASD convened in London, United Kingdom, for a meeting hosted by the United Kingdom ADHD Partnership (UKAP; www.UKADHD.com ) in June 2015. The meeting provided the opportunity to address the complexities of ADHD and FASD from different perspectives and included presentations, discussions, and group work. The attendees worked towards producing a consensus for a unified approach to ADHD and associated FASD. RESULTS: The authors successfully came to consensus and produced recommended guidelines with specific regards to identification and assessment, interventions and treatments, and multiagency liaisons and care management, highlighting that a lifespan approach to treatment needs to be adopted by all involved. Included in the guidelines are: 1) unique 'red flags', which when identified in the ADHD population can lead to an accurate associated FASD diagnosis, 2) a treatment decision tree, and 3) recommendations for multiagency care management. CONCLUSIONS: While clinically useful guidelines were achieved, more research is still needed to contribute to the knowledge base about the diagnosis, treatment, and management of those with ADHD and associated FASD

HIV induces synaptic hyperexcitation via cGMP-dependent protein kinase II activation in the FIV infection model

<div><p>Over half of individuals infected with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HANDs), yet the molecular mechanisms leading to neuronal dysfunction are poorly understood. Feline immunodeficiency virus (FIV) naturally infects cats and shares its structure, cell tropism, and pathology with HIV, including wide-ranging neurological deficits. We employ FIV as a model to elucidate the molecular pathways underlying HIV-induced neuronal dysfunction, in particular, synaptic alteration. Among HIV-induced neuron-damaging products, HIV envelope glycoprotein gp120 triggers elevation of intracellular Ca²⁺ activity in neurons, stimulating various pathways to damage synaptic functions. We quantify neuronal Ca²⁺ activity using intracellular Ca²⁺ imaging in cultured hippocampal neurons and confirm that FIV envelope glycoprotein gp95 also elevates neuronal Ca²⁺ activity. In addition, we reveal that gp95 interacts with the chemokine receptor, CXCR4, and facilitates the release of intracellular Ca²⁺ by the activation of the endoplasmic reticulum (ER)-associated Ca²⁺ channels, inositol triphosphate receptors (IP3Rs), and synaptic NMDA receptors (NMDARs), similar to HIV gp120. This suggests that HIV gp120 and FIV gp95 share a core pathological process in neurons. Significantly, gp95’s stimulation of NMDARs activates cGMP-dependent protein kinase II (cGKII) through the activation of the neuronal nitric oxide synthase (nNOS)-cGMP pathway, which increases Ca²⁺ release from the ER and promotes surface expression of AMPA receptors, leading to an increase in synaptic activity. Moreover, we culture feline hippocampal neurons and confirm that gp95-induced neuronal Ca²⁺ overactivation is mediated by CXCR4 and cGKII. Finally, cGKII activation is also required for HIV gp120-induced Ca²⁺ hyperactivation. These results thus provide a novel neurobiological mechanism of cGKII-mediated synaptic hyperexcitation in HAND.</p></div