When is genetic testing useful in patients suspected to have inherited cardiac arrhythmias?

PURPOSE OF REVIEW: In this article, we will review the appropriate use of genetic testing in those patients suspected to have inherited arrhythmogenic diseases, with specific focus on the indications for testing and the expected probability of positive genotyping. RECENT FINDINGS: Important advances have been made in the identification of new genes, associated mutations, and polymorphisms that modulate susceptibility of acquired arrhythmias. We will examine the most recent advances relevant to the rational application of genetic analysis, guided by genotype-phenotype correlations derived from disease and patient-specific evaluation, as well as discussing novel technologies and recently published cost-effectiveness data. SUMMARY: Genetic analysis can be performed to identify the molecular substrate in those patients suspected to be affected by an inherited arrhythmogenic disease; however, the clinical usefulness of this information is often not straightforward. We hope to emphasize the concept that there is a significant difference in the impact of genetic testing within the various arrhythmogenic disorders, and the benefit of accessing genetic testing is not the same in all patients. The resultant integration between the expected yield of genetic screening and cost may allow the formation of criteria to prioritize access for those who could derive the most clinical benefit

The effect of sea temperature and food availability on the spawning success of Cape Anchovy engraulis capensis in the Southern Benguela

Data on the thermal structure, copepod biomass and production, and total number of eggs of the Cape anchovy Engraulis capensis were obtained from monthly surveys during the periods August 1993 – March1994 and September 1994 – March 1995 on the western Agulhas Bank and off the South-Western Cape, South Africa. Previous work suggested that anchovy spawn on the western Agulhas Bank in temperaturesbetween 16 and 19°C, where they feed predominantly on copepods. This study shows that the western Bank is a more suitable spawning area for anchovy, having greater thermal stability, a larger area of 16–19°Cwater and a more consistent food environment than off the South-Western Cape. Also, copepod production on the western Bank was highest in 16–19°C water. To identify factors controlling the area of this watermass, a cluster analysis was used on a suite of hydrographic variables. Three periods were identified: winter (August-September), spring (October-December) and summer (January-March), reflecting changes in theextent of the 16–19°C water and anchovy spawning, both of which peaked during spring. Spring was further characterized by infrequent surface upwelling. During summer, upwelling frequently reached the surface andthe upwelling front migrated offshore, constricting the area of 16–19°C water. It is hypothesized that spawning success in anchovy is dependent upon the extent of suitable spawning habitat, both spatially (16–19°Cwater) and temporally (spring). To put this concept into a predictive framework, the number of anchovy eggs was regressed against the area of 16–19°C water; a significant, positive relationship (p < 0.001, r2 = 0.56, n = 17) was found. An implication of the hypothesis is that the duration of spawning may be important to recruitment

Improved social functioning following social recovery therapy in first episode psychosis: Do social cognition and neurocognition change following therapy, and do they predict treatment response?

There is a need to develop and refine psychosocial interventions to improve functioning in First Episode Psychosis (FEP). Social cognition and neurocognition are closely linked to functioning in psychosis; examinations of cognition pre- and post- psychosocial intervention may provide insights into the mechanisms of these interventions, and identify which individuals are most likely to benefit. Method: Cognition was assessed within a multi-site trial of Social Recovery Therapy (SRT) for individuals with FEP experiencing poor functioning (<30 h weekly structured activity). Fifty-nine participants were randomly allocated to the therapy group (SRT + Early intervention), and 64 were allocated to treatment as usual group (TAU - early intervention care). Social cognition and neurocognition were assessed at baseline and 9 months; assessors were blind to group allocation. It was hypothesized that social cognition would improve following therapy, and those with better social cognition prior to therapy would benefit the most from SRT. Results: There was no significant impact of SRT on individual neurocognitive or social cognitive variables, however, joint models addressing patterns of missingness demonstrate improvement across a number of cognitive outcomes following SRT. Further, regression analyses showed those who had better social cognition at baseline were most likely to benefit from the therapy (ß = 0.350; 95% CI = 0.830 to 8.891; p = .019). Conclusion: It is not clear if SRT impacts on social cognitive or neurocognitive function, however, SRT may be beneficial in those with better social cognition at baseline

Natural killer cells attenuate cytomegalovirus-induced hearing loss in mice

<div><p>Congenital cytomegalovirus (CMV) infection is the most common non-hereditary cause of sensorineural hearing loss (SNHL) yet the mechanisms of hearing loss remain obscure. Natural Killer (NK) cells play a critical role in regulating murine CMV infection via NK cell recognition of the Ly49H cell surface receptor of the viral-encoded m157 ligand expressed at the infected cell surface. This Ly49H NK receptor/m157 ligand interaction has been found to mediate host resistance to CMV in the spleen, and lung, but is much less effective in the liver, so it is not known if this interaction is important in the context of SNHL. Using a murine model for CMV-induced labyrinthitis, we have demonstrated that the Ly49H/m157 interaction mediates host resistance in the temporal bone. BALB/c mice, which lack functional Ly49H, inoculated with mCMV at post-natal day 3 developed profound hearing loss and significant outer hair cell loss by 28 days of life. In contrast, C57BL/6 mice, competent for the Ly49H/m157 interaction, had minimal hearing loss and attenuated outer hair cell loss with the same mCMV dose. Administration of Ly49H blocking antibody or inoculation with a mCMV viral strain deleted for the m157 gene rendered the previously resistant C57BL/6 mouse strain susceptible to hearing loss to a similar extent as the BALB/c mouse strain indicating a direct role of the Ly49H/m157 interaction in mCMV-dependent hearing loss. Additionally, NK cell recruitment to sites of infection was evident in the temporal bone of inoculated susceptible mouse strains. These results demonstrate participation of NK cells in protection from CMV-induced labyrinthitis and SNHL in mice.</p></div

Neuromodulation and the role of electrodiagnostic techniques

Electrodiagnostic techniques have been utilized in surgery since the early 1960s. These techniques have been primarily used in neurosurgery; however, with the introduction of neuromodulation for voiding dysfunction, these techniques have now found their way into the field of female pelvic medicine. This article will review techniques applicable to evaluate pelvic floor function as it relates to neuromodulation. It will also review the literature describing how these techniques are used to help determine appropriate candidates as well as improve surgical outcomes. A PubMed search was conducted using the terms neuromodulation, Interstim, electrodiagnosis, electrodiagnostic techniques, electromyography with limits to the pelvic floor, and voiding dysfunction. Eight articles and three abstracts were found that directly related to the use of electrodiagnostic techniques as they apply to neuromodulation. Electrodiagnostic techniques may play a role in helping predict appropriate candidates for neuromodulation as well as improve surgical outcomes

A transcriptome-driven analysis of epithelial brushings and bronchial biopsies to define asthma phenotypes in U-BIOPRED

RATIONALE AND OBJECTIVES: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. We used transcriptomic profiling of airway tissues to help define asthma phenotypes. METHODS: The transcriptome from bronchial biopsies and epithelial brushings of 107 moderate-to-severe asthmatics were annotated by gene-set variation analysis (GSVA) using 42 gene-signatures relevant to asthma, inflammation and immune function. Topological data analysis (TDA) of clinical and histological data was used to derive clusters and the nearest shrunken centroid algorithm used for signature refinement. RESULTS: 9 GSVA signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper type 2 (Th-2) cytokines and lack of corticosteroid response (Group 1 and Group 3). Group 1 had the highest submucosal eosinophils, high exhaled nitric oxide (FeNO) levels, exacerbation rates and oral corticosteroid (OCS) use whilst Group 3 patients showed the highest levels of sputum eosinophils and had a high BMI. In contrast, Group 2 and Group 4 patients had an 86% and 64% probability of having non-eosinophilic inflammation. Using machine-learning tools, we describe an inference scheme using the currently-available inflammatory biomarkers sputum eosinophilia and exhaled nitric oxide levels along with OCS use that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSION: This analysis demonstrates the usefulness of a transcriptomic-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target Th2-mediated inflammation and/or corticosteroid insensitivity

Single donor ionization energies in a nanoscale CMOS channel

One consequence of the continued downwards scaling of transistors is the reliance on only a few discrete atoms to dope the channel, and random fluctuations of the number of these dopants is already a major issue in the microelectonics industry. While single-dopant signatures have been observed at low temperature, studying the impact of only one dopant up to room temperature requires extremely small lengths. Here, we show that a single arsenic dopant dramatically affects the off-state behavior of an advanced microelectronics field effect transistor (FET) at room temperature. Furthermore, the ionization energy of this dopant should be profoundly modified by the close proximity of materials with a different dielectric constant than the host semiconductor. We measure a strong enhancement, from 54meV to 108meV, of the ionization energy of an arsenic atom located near the buried oxide. This enhancement is responsible for the large current below threshold at room temperature and therefore explains the large variability in these ultra-scaled transistors. The results also suggest a path to incorporating quantum functionalities into silicon CMOS devices through manipulation of single donor orbitals

The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia.

Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.Funding in the Huntly laboratory comes from Cancer Research UK, Leukemia Lymphoma Research, the Kay Kendal Leukemia Fund, the Leukemia lymphoma Society of America, the Wellcome Trust, The Medical Research Council and an NIHR Cambridge Biomedical Research Centre grant. Patient samples were processed in the Cambridge Blood and Stem Cell Biobank.This is the author accepted manuscript. The final version is available via NPG at http://dx.doi.org/10.1038/onc.2015.9

Physiotherapy, and speech and language therapy intervention for patients with refractory chronic cough: a multicentre randomised control trial.

BACKGROUND: Physiotherapy, and speech and language therapy are emerging non-pharmacological treatments for refractory chronic cough. We aimed to investigate the efficacy of a physiotherapy, and speech and language therapy intervention (PSALTI) to improve health-related quality of life (HRQoL) and to reduce cough frequency in patients with refractory chronic cough. METHODS: In this multicentre randomised controlled trial, patients with refractory chronic cough were randomised to four weekly 1:1 sessions of either PSALTI consisting of education, laryngeal hygiene and hydration, cough suppression techniques, breathing exercises and psychoeducational counselling or control intervention consisting of healthy lifestyle advice. We assessed the change in HRQoL at week 4 with the Leicester Cough Questionnaire (LCQ). Secondary efficacy outcomes included 24-hour objective cough frequency (Leicester Cough Monitor) and cough reflex sensitivity. The primary analysis used an analysis of covariance adjusted for baseline measurements with the intention-to-treat population. This study was registered at UK Clinical Research Network (UKCRN ID 10678). FINDINGS: Between December 2011 and April 2014, we randomly assigned 75 participants who underwent baseline assessment (34 PSALTI and 41 controls). In the observed case analysis, HRQoL (LCQ) improved on average by 1.53 (95% CI 0.21 to 2.85) points more in PSALTI group than with control (p=0.024). Cough frequency decreased by 41% (95% CI 36% to 95%) in PSALTI group relative to control (p=0.030). The improvements within the PSALTI group were sustained up to 3 months. There was no significant difference between groups in the concentration of capsaicin causing five or more coughs. INTERPRETATION: Greater improvements in HRQoL and cough frequency were observed with PSALTI intervention. Our findings support the use of PSALTI for patients with refractory chronic cough. TRIAL REGISTRATION NUMBER: UKCRN ID 10678 and ISRCTN 73039760; Results