Findings from aetiological investigation of Auditory Neuropathy Spectrum Disorder in children referred to cochlear implant programs.

OBJECTIVES: Auditory neuropathy spectrum disorder (ANSD) is an audiological diagnosis characterised by hearing dysfunction in the presence of intact outer hair cell function in the cochlea. ANSD is thought to account for 7-10% of all childhood permanent hearing impairment, and can result from a range of pathological processes. This paper describes the rationale, methods and findings from the aetiological investigation of ANSD. METHODS: Retrospective audit of four cochlear implant programmes. RESULTS: 97 patients were identified. 79% of patients were identified before the age of one. Prematurity and jaundice were the most frequently identified aetiological factors. 33 patients had cochlear nerve deficiency on imaging. Genetic diagnoses identified included otoferlin, SX010 gene, connexin 26 and A1FM1 gene mutations. ANSD was seen in conjunction with syndromes including Kallman syndrome, CHARGE syndrome, X-linked deafness, SOTOS syndrome, Brown Vieletto Van Laere syndrome, and CAPOS syndrome. DISCUSSION: We present a two-level system of aetiological investigation that is clinically practical. Patients with ANSD sufficiently severe to consider cochlear implantation are generally identified at an early age. Aetiological investigation is important to guide prognosis and identify comorbidity. CONCLUSION: Prematurity and jaundice are the most commonly identified aetiological factors in ANSD. Imaging findings identify crucial factors in a significant minority. An important minority may have genetic and syndromic diagnoses that require further management.

A tale of three stents: aortic stenting prior to oesophagectomy after oesophageal stents.

The use of endoluminal stents to treat anastomotic leaks post oesophagogastric resection remains controversial. While some advocate stents to expedite recovery, others advise caution due to the risk of major morbidity and mortality. We describe a case of anastomotic leak following total gastrectomy for adenocarcinoma treated with a self-expanding metallic stent. Complications with the initial stent were treated with a further stent, which compromised the function of the oesophagus and eroded into the aorta, necessitating a colonic reconstruction and endovascular aortic stenting.

Reduced global brain metabolism but maintained vascular function in amnestic mild cognitive impairment.

Amnestic mild cognitive impairment represents an early stage of Alzheimer's disease, and characterization of physiological alterations in mild cognitive impairment is an important step toward accurate diagnosis and intervention of this condition. To investigate the extent of neurodegeneration in patients with mild cognitive impairment, whole-brain cerebral metabolic rate of oxygen in absolute units of µmol O2/min/100 g was quantified in 44 amnestic mild cognitive impairment and 28 elderly controls using a novel, non-invasive magnetic resonance imaging method. We found a 12.9% reduction ( p = 0.004) in cerebral metabolic rate of oxygen in mild cognitive impairment, which was primarily attributed to a reduction in the oxygen extraction fraction, by 10% ( p = 0.016). Global cerebral blood flow was not found to be different between groups. Another aspect of vascular function, cerebrovascular reactivity, was measured by CO2-inhalation magnetic resonance imaging and was found to be equivalent between groups. Therefore, there seems to be a global, diffuse diminishment in neural function in mild cognitive impairment, while their vascular function did not show a significant reduction.

Peptide Binding for Bio-Based Nanomaterials.

Peptide-based strategies represent transformative approaches to fabricate functional inorganic materials under sustainable conditions by modeling the methods exploited in biology. In general, peptides with inorganic affinity and specificity have been isolated from organisms and through biocombinatorial selection techniques (ie, phage and cell surface display). These peptides recognize and bind the inorganic surface through a series of noncovalent interactions, driven by both enthalpic and entropic contributions, wherein the biomolecules wrap the metallic nanoparticle structure. Through these interactions, modification of the inorganic surface can be accessed to drive the incorporation of significantly disordered surface metal atoms, which have been found to be highly catalytically active for a variety of chemical transformations. We have employed synthetic, site-directed mutagenesis studies to reveal localized binding effects of the peptide at the metallic nanoparticle structure to begin to identify the biological basis of control over biomimetic nanoparticle catalytic activity. The protocols described herein were used to fabricate and characterize peptide-capped nanoparticles in atomic resolution to identify peptide sequence effects on the surface structure of the materials, which can then be directly correlated to the catalytic activity to identify structure/function relationships.

Biofilm formation is a risk factor for mortality in patients with Candida albicans bloodstream infection-Scotland, 2012-2013.

Bloodstream infections caused by Candida species remain a significant cause of morbidity and mortality in hospitalized patients. Biofilm formation by Candida species is an important virulence factor for disease pathogenesis. A prospective analysis of patients with Candida bloodstream infection (n = 217) in Scotland (2012-2013) was performed to assess the risk factors associated with patient mortality, in particular the impact of biofilm formation. Candida bloodstream isolates (n = 280) and clinical records for 157 patients were collected through 11 different health boards across Scotland. Biofilm formation by clinical isolates was assessed in vitro with standard biomass assays. The role of biofilm phenotype on treatment efficacy was also evaluated in vitro by treating preformed biofilms with fixed concentrations of different classes of antifungal. Available mortality data for 134 patients showed that the 30-day candidaemia case mortality rate was 41%, with predisposing factors including patient age and catheter removal. Multivariate Cox regression survival analysis for 42 patients showed a significantly higher mortality rate for Candida albicans infection than for Candida glabrata infection. Biofilm-forming ability was significantly associated with C. albicans mortality (34 patients). Finally, in vitro antifungal sensitivity testing showed that low biofilm formers and high biofilm formers were differentially affected by azoles and echinocandins, but not by polyenes. This study provides further evidence that the biofilm phenotype represents a significant clinical entity, and that isolates with this phenotype differentially respond to antifungal therapy in vitro. Collectively, these findings show that greater clinical understanding is required with respect to Candida biofilm infections, and the implications of isolate heterogeneity.

Socio-demographic patterns of physical activity and sedentary behaviour in Chile: results from the National Health Survey 2009-2010.

BACKGROUND: Surveillance of physical activity (PA) is essential for the development of health promotion initiatives. The aim of the present study was to examine the prevalence of PA and sedentary behaviour with respect to socio-demographic factors in Chile. METHODS: A representative sample of 5434 adults aged ≥15 years (59% women) who participated in the Chilean National Health Survey (2009-2010) were included. Socio-demographic data (age, sex, environment, education level, income level and smoking status) were collected for all participants. PA levels were assessed using the Global Physical Activity Questionnaire. RESULTS: 19.8% [95% CI: 18.1-21.6] of the Chilean population did not meet PA recommendations (≥600 MET min week(-1)). The prevalence of physical inactivity was higher in participants aged ≥65 years, compared with the youngest age groups and was higher in women than in men. However, it was lower for participants with high, compared with low, education or income levels. The overall prevalence of sedentary risk behaviour (spending >4 h sitting per day) was 35.9% [95% CI: 33.7-38.2]. CONCLUSION: Physical inactivity correlates strongly with socio-demographic factors such as age, gender and educational level. Results identify social and economic groups to which future public health interventions should be aimed to increase PA in the Chilean population.

Instrumented assessment of test battery for physical capability using an accelerometer: a feasibility study.

Recent work has identified subdomains (tests) of physical capability that are recommended for assessment of the healthy ageing phenotype (HAP). These include: postural control, locomotion, endurance, repeated sit-to-stand-to-sit and TUG. Current assessment methods lack sensitivity and are error prone due to their lack of consistency and heterogeneity of reported outcomes; instrumentation with body worn monitors provides a method to address these potential weaknesses. This work proposes the use of a single tri-axial accelerometer-based device with appropriate algorithms (referred to here as a body worn monitor, BWM) for the purposes of instrumented testing during physicality capability assessment. In this pilot study we present 14 BWM-based outcomes across the subdomains which include magnitude, frequency and spatio-temporal characteristics. Where possible, we compared BWM outcomes with manually recorded values and found no significant differences between locomotion and TUG tasks (p ≥ 0.319). Significant differences were found for the total distance walked during endurance (p = 0.037) and times for repeated sit-to-stand-to-sit transitions (p < 0.000). We identified reasons for differences and make recommendations for future testing. We were also able to quantify additional characteristics of postural control and gait which could be sensitive outcomes for future HAP assessment. Our findings demonstrate the feasibility of this method to enhance measurement of physical capacity. The methodology can also be applied to a wide variety of accelerometer-based monitors and is applicable to a range of intervention-based studies or pathological assessment.

iCap: Instrumented assessment of physical capability.

OBJECTIVES: The aims of this study were to (i) investigate instrumented physical capability (iCap) as a valid method during a large study and (ii) determine whether iCap can provide important additional features of postural control and gait to categorise cohorts not previously possible with manual recordings. STUDY DESIGN: Cross-sectional analysis involving instrumented testing on 74 adults who were recruited as part of a pilot intervention study; LiveWell. Participants wore a single accelerometer-based monitor (lower back) during standardised physical capability tests so that outcomes could be compared directly with manual recordings (stopwatch and measurement tape) made concurrently. MAIN OUTCOME MEASURES: Time, distance, postural control and gait characteristics. RESULTS: Agreement between manual and iCap ranged from moderate to excellent (0.649-0.983) with mean differences between methods low and deemed acceptable. Additionally, iCap successfully quantified (i) postural control characteristics which showed sensitivity to distinguish between 5 variations of the standing balance test and (ii) 14 gait characteristics known to be sensitive to age/pathology. CONCLUSIONS: Our findings show that iCap can provide robust quantitative data about physical capability during standardised tests while also providing sensitive (age/pathology) postural control and gait characteristics not previously quantifiable with manual recordings. The methodology which we propose may have practical utility in a wide range of clinical and public health surveys and studies, including intervention studies, where assessment could be undertaken within diverse settings. This will need to be tested in further validation studies in a wider range of settings.

DAPK2 regulates oxidative stress in cancer cells by preserving mitochondrial function.

Death-associated protein kinase (DAPK) 2 is a serine/threonine kinase that belongs to the DAPK family. Although it shows significant structural differences from DAPK1, the founding member of this protein family, DAPK2 is also thought to be a putative tumour suppressor. Like DAPK1, it has been implicated in programmed cell death, the regulation of autophagy and diverse developmental processes. In contrast to DAPK1, however, few mechanistic studies have been carried out on DAPK2 and the majority of these have made use of tagged DAPK2, which almost invariably leads to overexpression of the protein. As a consequence, physiological roles of this kinase are still poorly understood. Using two genetically distinct cancer cell lines as models, we have identified a new role for DAPK2 in the regulation of mitochondrial integrity. RNA interference-mediated depletion of DAPK2 leads to fundamental metabolic changes, including significantly decreased rate of oxidative phosphorylation in combination with overall destabilised mitochondrial membrane potential. This phenotype is further corroborated by an increase in the production of mitochondrial superoxide anions and increased oxidative stress. This then leads to the activation of classical stress-activated kinases such as ERK, JNK and p38, which is observed on DAPK2 genetic ablation. Interestingly, the generation of oxidative stress is further enhanced on overexpression of a kinase-dead DAPK2 mutant indicating that it is the kinase domain of DAPK2 that is important to maintain mitochondrial integrity and, by inference, for cellular metabolism.

DAPK2 is a novel modulator of TRAIL-induced apoptosis.

Targeting molecules involved in TRAIL-mediated signalling has been hailed by many as a potential magic bullet to kill cancer cells efficiently, with little side effects on normal cells. Indeed, initial clinical trials showed that antibodies against TRAIL receptors, death receptor (DR)4 and DR5, are well tolerated by cancer patients. Despite efficacy issues in the clinical setting, novel approaches to trigger TRAIL-mediated apoptosis are being developed and its clinical potential is being reappraised. Unfortunately, as observed with other cancer therapies, many patients develop resistance to TRAIL-induced apoptosis and there is thus impetuous for identifying additional resistance mechanisms that may be targetable and usable in combination therapies. Here, we show that the death-associated protein kinase 2 (DAPK2) is a modulator of TRAIL signalling. Genetic ablation of DAPK2 using RNA interference causes phosphorylation of NF-κB and its transcriptional activity in several cancer cell lines. This then leads to the induction of a variety of NF-κB target genes, which include proapoptotic DR4 and DR5. DR4 and DR5 protein expression is correspondingly increased on the cell surface and this leads to the sensitisation of resistant cells to TRAIL-induced killing, in a p53-independent manner. As DAPK2 is a kinase, it is imminently druggable, and our data thus offer a novel avenue to overcome TRAIL resistance in the clinic.

Group therapy for people with bulimia nervosa: systematic review and meta-analysis.

BACKGROUND: Approximately 25% of people with bulimia nervosa (BN) who undertake therapy are treated in groups. National guidelines do not discriminate between group and individual therapy, yet each has potential advantages and disadvantages and it is unclear how their effects compare. We therefore evaluated how group therapy for BN compares with individual therapy, no treatment, or other therapies, in terms of remission from binges and binge frequency. METHOD: We performed a systematic review and meta-analysis of randomized controlled trials of group therapies for BN, following standard guidelines. RESULTS: A total of 10 studies were included. Studies were generally small with unclear risk of bias. There was low-quality evidence of a clinically relevant advantage for group cognitive behavioural therapy (CBT) over no treatment at therapy end. Remission was more likely with group CBT versus no treatment [relative risk (RR) 0.77, 95% confidence interval (CI) 0.62-0.96]. Mean weekly binges were lower with group CBT versus no treatment (2.9 v. 6.9, standardized mean difference = -0.56, 95% CI -0.96 to -0.15). One study provided low-quality evidence that group CBT was inferior compared with individual CBT to a clinically relevant degree for remission at therapy end (RR 1.24, 95% CI 1.03-1.50); there was insufficient evidence regarding frequency of binges. CONCLUSIONS: Conclusions could only be reached for CBT. Low-quality evidence suggests that group CBT is effective compared with no treatment, but there was insufficient or very limited evidence about how group and individual CBT compared. The risk of bias and imprecise estimates of effect invite further research to refine and increase confidence in these findings.

Serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs.

BACKGROUND: Studies in humans identified the synthesis and secretion of inhibin from adrenocortical tumors, but not pheochromocytoma (PHEO). Inhibin has not been examined in dogs as a serum biomarker for adrenal gland tumors. OBJECTIVE: To determine serum inhibin concentration in dogs with adrenal gland disease and in healthy dogs. ANIMALS: Forty-eight neutered dogs with adrenal disease including pituitary-dependent hyperadrenocorticism (PDH, 17), adrenocortical tumor (18), and PHEO (13), and 41 healthy intact or neutered dogs. METHODS: Prospective observational study. Dogs were diagnosed with PDH, adrenocortical tumor (hyperadrenocorticism or noncortisol secreting), or PHEO based on clinical signs, endocrine function tests, abdominal ultrasound examination, and histopathology. Inhibin concentration was measured by radioimmunoassay in serum before and after ACTH stimulation, and before and after treatment. RESULTS: In neutered dogs, median inhibin concentration was significantly higher in dogs with adrenocortical tumors (0.82 ng/mL) and PDH (0.16 ng/mL) than in dogs with PHEO and healthy dogs (both undetectable). Median inhibin concentration was significantly higher in dogs with adrenocortical tumors than in those with PDH and decreased after adrenalectomy. Median inhibin concentration was significantly higher in intact than in neutered healthy dogs and was similar in pre- and post-ACTH stimulation. Sensitivity, specificity, and accuracy of serum inhibin concentration for identifying an adrenal tumor as a PHEO were 100, 88.9, and 93.6%, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Adrenocortical tumors and PDH but not PHEOs are associated with increased serum inhibin concentration; undetectable inhibin is highly supportive of PHEO in neutered dogs with adrenal tumors.

Non-Viral Generation of Neural Precursor-like Cells from Adult Human Fibroblasts.

Recent studies have reported direct reprogramming of human fibroblasts to mature neurons by the introduction of defined neural genes. This technology has potential use in the areas of neurological disease modeling and drug development. However, use of induced neurons for large-scale drug screening and cell-based replacement strategies is limited due to their inability to expand once reprogrammed. We propose it would be more desirable to induce expandable neural precursor cells directly from human fibroblasts. To date several pluripotent and neural transcription factors have been shown to be capable of converting mouse fibroblasts to neural stem/precursor-like cells when delivered by viral vectors. Here we extend these findings and demonstrate that transient ectopic insertion of the transcription factors SOX2 and PAX6 to adult human fibroblasts through use of non-viral plasmid transfection or protein transduction allows the generation of induced neural precursor (iNP) colonies expressing a range of neural stem and pro-neural genes. Upon differentiation, iNP cells give rise to neurons exhibiting typical neuronal morphologies and expressing multiple neuronal markers including tyrosine hydroxylase and GAD65/67. Importantly, iNP-derived neurons demonstrate electrophysiological properties of functionally mature neurons with the capacity to generate action potentials. In addition, iNP cells are capable of differentiating into glial fibrillary acidic protein (GFAP)-expressing astrocytes. This study represents a novel virusfree approach for direct reprogramming of human fibroblasts to a neural precursor fate.

"A computer isn't gonna judge you": a qualitative study of users' views of an internet-based cognitive behavioural guided self-care treatment package for bulimia nervosa and related disorders.

Little is known about what determines uptake and acceptability of internet-based treatments in eating disorders, and users' experience with such treatments. We investigated these factors in participants of a randomized controlled trial of an internet-based cognitive- behavioural treatment (iCBT) package (Overcoming bulimia online). Nine participants were interviewed using purposive sampling. The content of interviews were analyzed using thematic analysis. Additionally, participants received questionnaires about their impressions of iCBT. Participants talked about their experience of using iCBT, its impact and compared it to other treatments. Questionnaire responses echoed themes identified in the interviews. iCBT was received positively as a way of fitting treatment into busy lives. Comments on the layout of some of the package content and the practitioner support offered were identified as areas that could be modified or improved.

A randomized controlled trial of internet-based cognitive-behavioural therapy for bulimia nervosa or related disorders in a student population.

BACKGROUND: Bulimic eating disorders are common among female students, yet the majority do not access effective treatment. Internet-based cognitive-behavioural therapy (iCBT) may be able to bridge this gap. METHOD: Seventy-six students with bulimia nervosa (BN) or eating disorder not otherwise specified (EDNOS) were randomly assigned to immediate iCBT with e-mail support over 3 months or to a 3-month waiting list followed by iCBT [waiting list/delayed treatment control (WL/DTC)]. ED outcomes were assessed with the Eating Disorder Examination (EDE) at baseline, 3 months and 6 months. Other outcomes included depression, anxiety and quality of life. RESULTS: Students who had immediate iCBT showed significantly greater improvements at 3 and 6 months than those receiving WL/DTC in ED and other symptoms. CONCLUSIONS: iCBT with e-mail support is efficacious in students with bulimic disorders and has lasting effects.

The neuropsychiatric phenotype in Darier disease.

BACKGROUND: Darier disease (DD) is a rare autosomal dominantly inherited skin disorder in which co-occurrence of neuropsychiatric abnormalities has been frequently reported by dermatologists. It is caused by mutations in a single gene, ATP2A2, which is expressed in the skin and brain. OBJECTIVES: To conduct the first systematic investigation of the neuropsychiatric phenotype in DD. METHODS: One hundred unrelated individuals with DD were assessed using a battery of standardized neuropsychiatric measures. Data were also obtained on a number of clinical features of DD. RESULTS: Individuals with DD were found to have high lifetime rates of mood disorders (50%), specifically major depression (30%) and bipolar disorder (4%), and suicide attempts (13%) and suicidal thoughts (31%). These were more common in DD when compared with general population data. The prevalence of epilepsy (3%) in the sample was also higher than the prevalence in the general population. There was no consistent association of specific dermatological features of DD and presence of psychiatric features. CONCLUSIONS: These findings highlight the need for clinicians to assess and recognize neuropsychiatric symptoms in DD. The results do not suggest that neuropsychiatric symptoms are simply a psychological reaction to having a skin disease, but are consistent with the pleiotropy hypothesis that mutations in the ATP2A2 gene, in addition to causing DD, confer susceptibility to neuropsychiatric features. Further research is needed to investigate genotype-phenotype correlations between the types and/or locations of pathogenic mutations within ATP2A2 and the expressed neuropsychiatric phenotypes.