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Objective: The present placebo-controlled study was designed to compare the effect of acute pretreatment with dexfenfluramine and fluoxetine on the plasma aldosterone response to metoclopramide. Study Participants and Design: Ten healthy ambulatory male volunteers participated. Following a single-blind, randomised design, each volunteer received metoclopramide as an intravenous bolus of 10mg at 0700 hours on each experimental day. Participants were pretreated at 2200 hours the previous evening and 0500 hours in the morning with one of the following: fluoxetine 20mg, dexfenfluramine 30mg, or placebo. Results: In response to metoclopramide administration, the maximum concentration was significantly higher (p = 0.004) than baseline with placebo, fluoxetine and dexfenfluramine. The area under the curve of dexfenfluramine was significantly larger than that with both placebo (p = 0.007) and fluoxetine (p = 0.004), while that of fluoxetine was significantly larger than that of placebo (p = 0.01). Conclusion: Acute pretreatment with both dexfenfluramine and fluoxetine caused an enhancement of metoclopramide-induced aldosterone secretion, probably by augmenting serotonergic neurotransmission via serotonin (5-HT) receptors. The plasma aldosterone levels were significantly higher with dexfenfluramine compared with fluoxetine, probably as a result of larger 5-HT concentrations being available for stimulation of glomerulosa cell activity. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to establish the implications of a normal pancreatogram in patients with pancreatic cancer. Methods: We reviewed all ERCP done at our institution for the period 1983–92 and studied 62 of 727 patients who had a diagnosis of pancreatic ( n= 416) or biliary ( n= 311) cancer but a normal pancreatic duct. Results: Thirty of the 62 patients had pancreatic cancer. In 15 cases, the ERCP diagnosis was incorrect, and in 19 cases, Santorini's duct was not visualized. Other imaging revealed a pancreatic head mass in 25 patients (2.5–>7 cm). Only three patients had resectable tumors; another eight underwent laparotomy. Five had bypass surgery, 10 required biliary stenting, and nine had no treatment. Four patients died in hospital, and eight were lost to follow-up. In the remaining 18 patients, median survival was 7 months (range, 1–30 months). Conclusion: A normal pancreatogram does not exclude the diagnosis of pancreatic cancer, nor does it confer a better prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background The recent developments in microarray technology has allowed for the simultaneous measurement of gene expression levels. The large amount of captured data challenges conventional statistical tools for analysing and finding inherent correlations between genes and samples. The unsupervised clustering approach is often used, resulting in the development of a wide variety of algorithms. Typical clustering algorithms require selecting certain parameters to operate, for instance the number of expected clusters, as well as defining a similarity measure to quantify the distance between data points. The diffraction‐based clustering algorithm however is designed to overcome this necessity for user‐defined parameters, as it is able to automatically search the data for any underlying structure. Methods The diffraction‐based clustering algorithm presented in this paper is tested using five well‐known expression datasets pertaining to cancerous tissue samples. The clustering results are then compared to those results obtained from conventional algorithms such as the k‐means, fuzzy c‐means, self‐organising map, hierarchical clustering algorithm, Gaussian mixture model and density‐based spatial clustering of applications with noise (DBSCAN). The performance of each algorithm is measured using an average external criterion and an average validity index. Results The diffraction‐based clustering algorithm is shown to be independent of the number of clusters as the algorithm searches the feature space and requires no form of parameter selection. The results show that the diffraction‐based clustering algorithm performs significantly better on the real biological datasets compared to the other existing algorithms. Conclusion The results of the diffraction‐based clustering algorithm presented in this paper suggest that the method can provide researchers with a new tool for successfully analysing microarray data.

Glycolytic oscillations have been studied for well over 60 years, but aspects of their function, and mechanisms of regulation and synchronisation remain unclear. Glycolysis is amenable to mechanistic mathematical modelling, as its components have been well characterised, and the system can be studied at many organisational levels: in vitro reconstituted enzymes, cell free extracts, individual cells, and cell populations. In recent years, the emergence of individual cell analysis has opened new ways of studying this intriguing system., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Purpose: The isolated ex vivo retina is the standard model in retinal physiology and neuroscience. During isolation, the retina is peeled from the retinal pigment epithelium (RPE), which plays a key role in the visual cycle. Here we introduce the choroid-attached bovine retina as an in vivo-like model for retinal physiology. We find that-in the bovine eye-the choroid and retina can be peeled from the sclera as a single thin sheet. Importantly, the retina remains tightly associated with the RPE, which is sandwiched between the retina and the choroid. Furthermore, bovine tissue is readily available and cheap, and there are no ethical concerns related to the use of animals solely for research purposes., Methods: We combine multi-electrode array and single-cell patch-clamp recordings to characterize light responses in the choroid-attached bovine ex vivo retina., Results: We demonstrate robust and consistent light responses in choroid-attached preparations. Importantly, light responses adapt to different levels of background illumination and rapidly recover from photobleaching. The choroid-attached retina is also thin enough to permit targeted electrophysiological recording from individual retinal neurons using standard differential interference contrast microscopy. We also characterize light responses and membrane properties of bovine retinal ganglion cells and compare data obtained from bovine and murine retinas., Conclusions: The choroid-attached retinal model retains the advantages of the isolated retina but with an intact visual cycle and represents a useful tool to elucidate retinal physiology.

Phototransduction is mediated by distinct types of G protein cascades in different animal taxa: bilateral invertebrates typically utilise the Gαq pathway whereas vertebrates typically utilise the Gαt(i/o) pathway. By contrast, photoreceptors in jellyfish (Cnidaria) utilise the Gαs intracellular pathway, similar to olfactory transduction in mammals 1 . How this habitually slow pathway has adapted to support dynamic vision in jellyfish remains unknown. Here we study a light-sensing protein (rhodopsin) from the box jellyfish Carybdea rastonii and uncover a mechanism that dramatically speeds up phototransduction: an uninterrupted G protein-coupled receptor - G protein complex. Unlike known G protein-coupled receptors (GPCRs), this rhodopsin constitutively binds a single downstream Gαs partner to enable G-protein activation and inactivation within tens of milliseconds. We use this GPCR in a viral gene therapy to restore light responses in blind mice., (© 2023. The Author(s).)

Chronic psychosocial stress is implicated in the onset and progression of noncommunicable diseases, and mechanisms underlying this relationship include alterations to the intracellular redox state. However, such changes are often investigated in isolation, with few studies adopting a system level approach. Here, male Wistar rats were exposed to 9.5 weeks of chronic unpredictable mild stress and redox status assays were subsequently performed on cardiac, hepatic, and brain tissues versus matched controls. The stressed rats displayed an anxious phenotype, with lowered plasma corticosterone levels (p = 0.04 vs. Controls) and higher plasma epinephrine concentrations (p = 0.03 vs. Controls). Our findings showed organ-specific redox profiles, with stressed rats displaying increased myocardial lipid peroxidation (p = 0.04 vs. Controls) in the presence of elevated nonenzymatic antioxidant capacity (p = 0.04 vs. Controls). Conversely, hepatic tissues of stressed rats exhibited lowered nonenzymatic antioxidant capacity (p < 0.001 vs. Controls) together with increased superoxide dismutase (SOD) activity (p = 0.05 vs. Controls). The brain displayed region-specific antioxidant perturbations, with increased SOD activity (p = 0.01 vs. Controls) in the prefrontal cortex of the stressed rats. These findings reveal distinct stress-related organ-specific vulnerability to redox perturbations and may provide novel insights into putative therapeutic targets., (© 2023 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Optogenetic gene therapies to restore vision are in clinical trials. Whilst current clinical approaches target the ganglion cells, the output neurons of the retina, new molecular tools enable efficient targeting of the first order retinal interneurons, the bipolar cells, with the potential to restore a higher quality of vision. Here we investigate retinal signaling and behavioral vision in blind mice treated with bipolar cell targeted optogenetic gene therapies. All tested tools, including medium-wave opsin, Opto-mGluR6, and two new melanopsin based chimeras restored visual acuity and contrast sensitivity. The best performing opsin was a melanopsin-mGluR6 chimera, which in some cases restored visual acuities and contrast sensitivities that match wild-type animals. Light responses from the ganglion cells were robust with diverse receptive-field types, inferring elaborate inner retinal signaling. Our results highlight the potential of bipolar cell targeted optogenetics to recover high-level vision in human patients with end-stage retinal degenerations., (© 2022. The Author(s).)

The poor assessment of child malnutrition impacts both national-level trends and prioritisation of regions and vulnerable groups based on malnutrition burden. Namibia has reported a high prevalence of malnutrition among children younger than 5 years of age. The present study's aim was to identify the optimal methods for estimating child stunting and wasting prevalence in Namibia using two datasets with suspected poor data quality: Namibia Demographic and Health Surveys (NDHS) (1992-2013) and Namibia Household Income and Expenditure Survey (NHIES), 2015/16. This comparative secondary data analysis used two prevalence estimation methods: WHO flags and PROBIT. WHO flags is the standard analysis method for most national household surveys, while the PROBIT method is recommended for poor quality anthropometry. In NHIES ( n 4960), the prevalence of stunting ( n 4780) was 30·3 and 20·9 % for the WHO flags and PROBIT estimates, respectively, and the national wasting prevalence ( n 4637) was 11·2 and 4·2 %, respectively. The trends in nutritional status from NDHS and NHIES showed improvement across WHO flags and PROBIT until 2013; however, from 2013 to 2016, PROBIT showed smaller increases in stunting and wasting prevalence (2·5 and 0·6 percentage points) than WHO flags (6·6 and 5·0 percentage points). PROBIT identified the Khoisan ethnic group and Northern geographical regions with the highest stunting and wasting prevalence, while WHO flags identified similar prevalence across most groups and regions. The present study supports the recommendation to use PROBIT when poor data quality is suspected for constructing trends, and for targeting regions and vulnerable groups., (© The Author(s) 2022.)

Gold nanoparticles (GNPs) have shown great potential in diagnostic and therapeutic applications in diseases, such as cancer. Despite GNP versatility, there is conflicting data regarding the toxicity of their overall functionalization chemistry for improved biocompatibility. This study aimed to determine the possible genotoxic effects of functionalized GNPs in Human hepatocellular carcinoma (HepG2) cells. GNPs were synthesized and biofunctionalized with seven common molecules used for biomedical applications. These ligands were bovine serum albumin (BSA), poly(sodium 4-styrene sulfonate) (PSSNA), trisodium citrate (citrate), mercaptoundecanoic acid (MUA), glutathione (GSH), polyvinylpyrrolidone (PVP), and polyethylene glycol (PEG). Before in vitro genotoxicity assessment, inductively coupled plasma mass spectrometry was used to determine GNP cellular internalization quantitatively, followed by cell-based assays; WST-1 to find IC 30 and ApoPercentage for apoptotic induction time-points. The effect of the GNPs on cell growth in real-time was determined by using xCELLigence, followed by a comet assay for genotoxicity determination. The HepG2 cells experienced genotoxicity for all GNP ligands; however, they were able to initiate repair mechanisms and recover DNA damage, except for two functionalization chemistries.

Introduction: Traditional plaster and fiberglass casts are not waterproof. This experimental study compares the water-resistant and drying properties of two commercially available orthoses with traditional cast liners., Methods: Two orthotic brace systems were selected for comparative waterproof testing with plaster and fiberglass traditional cast liners. This entailed water submersion for 10 seconds, followed by light drip drying for another 10 seconds. Moisture levels were then measured at four different locations immediately after drip drying and then every 15 minutes up to 45 minutes., Results: The Zero-Cast Wx orthosis retained the least moisture after initial immersion and was fully dry within 45 minutes. The Exos upper extremity brace also demonstrated a low initial mean moisture content but lost little moisture during drying. In comparison, both the cotton-lined plaster cast and Delta Dr. cast liner systems demonstrated the greatest amount of water absorbed and moisture retention., Discussion: Both orthotic brace systems demonstrated markedly less water absorption compared with the cotton-lined plaster cast and Delta Dr. cast liner systems. The Zero-Cast Wx was the only orthosis to fully dry in 45 minutes., Conclusion: Both orthotic brace systems provide superior water-resistant properties to traditional cotton-lined plaster cast or fiberglass Delta Dr. cast liner systems., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Purpose: Obstructive sleep apnoea (OSA) is a common sleep disorder and is associated with a number of comorbid conditions, including the frequent occurrence of depression. Notably, there is a considerate overlap in day- as well as night-time symptomatology in depression and OSA. In light of this, we aimed to disentangle the distinct effects of OSA and depression severity on day- and night-time symptomatology., Methods: This pilot study (N = 320) utilized a retrospective chart review design and included both males and females who met the minimum diagnostic criteria for OSA. Daytime symptoms (sleepiness and fatigue) were assessed via questionnaires, while night-time symptoms were measured via polysomnography., Results: Main findings include the following: (a) no association between OSA and depression severity, (b) depression severity significantly predicted increased sleepiness and fatigue (c) OSA severity significantly predicted increased stage 2 non-rapid eye movement sleep percentage, (d) OSA significantly predicted decreased stage 3 non-rapid eye movement sleep percentage and rapid eye movement sleep percentage. Overall, depression severity exerts the strongest influence on daytime symptomatology, while OSA severity exerts the strongest influence on night-time symptomatology. Moreover, with the exception of sleepiness, no overlap between day- and night-time findings was detected., Conclusion: OSA and depression, although comorbid, possibly constitute distinct disease processes in this population group. Consequently, solely devising treatment targeting a reduction in apnoea-hypopnoea index might not be sufficient in alleviating debilitating daytime symptoms in treatment-seeking individuals.

Background: In December 2018, the South African 24-hour movement guidelines for birth to 5 years were released. This article describes the process used to develop these guidelines., Methods: The Grading of Recommendations Assessment, Development, and Evaluation-ADOLOPMENT approach was followed, with some pragmatic adaptions, using the Australian guidelines for the early years as a starting point. A consensus panel, including stakeholders in early childhood development and academics, was formed to assist with the development process., Results: At a face-to-face meeting of the panel, global and local literatures were considered. Following this meeting, a first draft of the guidelines (including a preamble) was formulated. Further reviews of these drafts by the panel were done via e-mail, and a working draft was sent out for stakeholder consultation. The guidelines and preamble were amended based on stakeholder input, and an infographic was designed. Practical "tips" documents were also developed for caregivers of birth to 5-year-olds and early childhood development practitioners. The guidelines (and accompanying documents) were released at a launch event and disseminated through various media channels., Conclusions: These are the first movement guidelines for South African and the first such guidelines for this age group from a low- and middle-income country.

Background: Dreaming is a universal experience, yet there is considerable inter-individual variability in dream recall frequency (DRF). One dominant model, the "arousal-retrieval" model, posits that intra-sleep wakefulness is required for dream traces to be encoded into long-term storage, essentially proposing that a better memory for dreams underlie increased DRF. A recent study utilizing polysomnography combined with an event-related potentials paradigm, provides direct support for this model by demonstrating increased intra-sleep wakefulness in a healthy population by comparing high frequency recallers (HFRs) and low frequency recallers (LFRs). Another study by the same group demonstrated increased regional cerebral blood flow in regions associated with dream production, supporting the premise that HFRs also may produce more dreams., Hypotheses: This study investigated the profile of nocturnal awakenings and dream production in healthy HFRs and LFRs. Hypothesis (1a): HFRs will spend significantly more time awake after sleep onset; (1b): HFRs will experience significantly more awakenings across the night, and from rapid eye movement (REM) sleep in particular; (2) HFRs will have significantly higher rates of dream production across the night as measured by REM density., Methods: We studied two groups of healthy adults: HFRs ( n = 19) and LFRs ( n = 17) who underwent polysomnographic recordings on two non-consecutive nights., Results: Hypothesis (1a) was confirmed: HFRs spent significantly more time awake after sleep onset. Hypothesis (1b) was partially confirmed: HFRs experienced significantly more awakenings across the night; however, awakenings from REM sleep were comparable. Interestingly, HFRs had significantly more awakenings, as well as a higher number of longer awakenings, from non-rapid eye movement (NREM) stage 2 sleep. Hypothesis (2) was not confirmed: There was no significant difference in rates of REM density between groups., Conclusion: This is the first study to provide evidence that awakenings from NREM 2 sleep might underlie increased DRF in HFRs. This finding coupled with null findings in relation to REM sleep variables, support the premise that inter-individual variability in DRF cannot be ascribed to differences in REM sleep parameters in healthy individuals. Instead, the data indicates that awakenings from NREM sleep is of particular importance in relation to DRF in a healthy population., (Copyright © 2019 van Wyk, Solms and Lipinska.)

In dealing with Mycobacterium tuberculosis , the causative agent of the deadliest human disease-tuberculosis (TB)-utilization of cholesterol as a carbon source indicates the possibility of using cholesterol catabolic genes/proteins as novel drug targets. However, studies on cholesterol catabolism in mycobacterial species are scarce, and the number of mycobacterial species utilizing cholesterol as a carbon source is unknown. The availability of a large number of mycobacterial species' genomic data affords an opportunity to explore and predict mycobacterial species' ability to utilize cholesterol employing in silico methods. In this study, comprehensive comparative analysis of cholesterol catabolic genes/proteins in 93 mycobacterial species was achieved by deducing a comprehensive cholesterol catabolic pathway, developing a software tool for extracting homologous protein data and using protein structure and functional data. Based on the presence of cholesterol catabolic homologous proteins proven or predicted to be either essential or specifically required for the growth of M. tuberculosis H37Rv on cholesterol, we predict that among 93 mycobacterial species, 51 species will be able to utilize cholesterol as a carbon source. This study's predictions need further experimental validation and the results should be taken as a source of information on cholesterol catabolism and genes/proteins involved in this process among mycobacterial species.

This article endeavored to determine the topics of discussion during open-ended peer mentoring between adolescents and young adults living with chronic illness. This study occurred alongside a study of the iPeer2Peer Program. Fifty-two calls (7 mentor-mentee pairings) were audio recorded, transcribed verbatim, and analyzed using inductive coding with an additional 30 calls (21 mentor-mentee pairings) coded to ensure representativeness of the data. Three categories emerged: (1) illness impact (e.g., relationships, school/work, self-identity, personal stories), (2) self-management (e.g., treatment adherence, transition to adult care, coping strategies), and (3) non-illness-related adolescent issues (e.g., post-secondary goals, hobbies, social environments). Differences in discussed topics were noted between sexes and by diagnosis. Peer mentors provided informational, appraisal, and emotional support to adolescents.

Background: Patients with complex health care needs require the expertise of many health care providers. Communication, collaboration, and patient-centered care positively impact care quality and patient outcomes. Few technologies exist that facilitate collaboration between providers across settings of care and also engage the patient. We developed a Web-based clinical collaboration system, Loop, to address this gap. The likelihood of a technological system's uptake is associated with its perceived ease of use and perceived usefulness. We engaged stakeholders in the conceptualization and development of Loop in an effort to maximize its intuitiveness and utility., Objective: This study aimed to report end users' perceptions about the ease of use and usefulness of Loop captured during usability tests of Loop., Methods: Participants represented three user types (patients, caregivers, and health care providers) recruited from three populations (adults with cancer, adolescents and young adults with cancer, and children with medical complexity). We conducted usability testing over three iterative cycles of testing and development in both laboratory-based and off-site environments. We performed a content analysis of usability testing transcripts to summarize and describe participant perceptions about the ease of use and usefulness of Loop., Results: Participants enjoyed testing Loop and were able to use the core functions-composing, posting, and reading messages-with little difficulty. They had difficulty interpreting certain visual cues and design elements or the purpose of some features. This difficulty negatively impacted perceived ease of use but was primarily limited to auxiliary features. Participants predicted that Loop could improve the efficiency and effectiveness of communication between care team members; however, this perceived usefulness could be compromised by disruptions to personal workflow such as additional time or task requirements., Conclusions: Loop was perceived to have value as a collaboration system; however, usability testing findings indicate that some design and functional elements need to be addressed to improve ease of use. Additionally, participant concerns highlight the need to consider how a system can be implemented so as to minimize impact on workflow and optimize usefulness., (©Allison M Kurahashi, Jennifer N Stinson, Margaret van Wyk, Stephanie Luca, Trevor Jamieson, Peter Weinstein, Joseph A Cafazzo, Bhadra Lokuge, Eyal Cohen, Adam Rapoport, Amna Husain. Originally published in JMIR Human Factors (http://humanfactors.jmir.org), 09.01.2018.)

Sporotrichosis is an emerging chronic, granulomatous, subcutaneous, mycotic infection caused by Sporothrix species. Sporotrichosis is treated with the azole drug itraconazole as ketoconazole is ineffective. It is a well-known fact that azole drugs act by inhibiting cytochrome P450 monooxygenases (P450s), heme-thiolate proteins. To date, nothing is known about P450s in Sporothrix schenckii and the molecular basis of its resistance to ketoconazole. Here we present genome-wide identification, annotation, phylogenetic analysis and comprehensive P450 family-level comparative analysis of S. schenckii P450s with pathogenic fungi P450s, along with a rationale for ketoconazole resistance by S. schenckii based on in silico structural analysis of CYP51. Genome data-mining of S. schenckii revealed 40 P450s in its genome that can be grouped into 32 P450 families and 39 P450 subfamilies. Comprehensive comparative analysis of P450s revealed that S. schenckii shares 11 P450 families with plant pathogenic fungi and has three unique P450 families: CYP5077, CYP5386 and CYP5696 (novel family). Among P450s, CYP51, the main target of azole drugs was also found in S. schenckii. 3D modeling of S. schenckii CYP51 revealed the presence of characteristic P450 motifs with exceptionally large reductase interaction site 2. In silico analysis revealed number of mutations that can be associated with ketoconazole resistance, especially at the channel entrance to the active site. One of possible reason for better stabilization of itraconazole, compared to ketoconazole, is that the more extended molecule of itraconazole may form a hydrogen bond with ASN-230. This in turn may explain its effectiveness against S. schenckii vis-a-vis resistant to ketoconazole. This article is part of a Special Issue entitled: Cytochrome P450 biodiversity and biotechnology, edited by Erika Plettner, Gianfranco Gilardi, Luet Wong, Vlada Urlacher, Jared Goldstone., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Study Design Longitudinal observational clinimetric study with repeated measures. Background No validated multidimensional pain measure for children and youth with juvenile idiopathic arthritis exists. Objective To determine the test-retest reliability, construct validity, and responsiveness of English and French versions of the Standardized Universal Pain Evaluations for Rheumatology Providers for Children and Youth (SUPER-KIDZ). Methods Measurement properties of the SUPER-KIDZ (older child, younger child, and parent versions) were prospectively evaluated in patients (aged 4 to 18 years) with juvenile idiopathic arthritis at 2 centers. Internal consistency of the 3 subscales was measured using ordinal reliability alpha. Test-retest reliability for each subscale was evaluated with intraclass correlation coefficients (ICCs) from participants assumed to have stable pain (over a 1-week period with no change in treatment). Correlations of SUPER-KIDZ scores with validated measures determined construct validity. Responsiveness of SUPER-KIDZ subscales was evaluated in patients with improvement in pain, using standardized response mean and linear mixed-model regression. Results Seventy-one children aged 8 to 18 years and 29 parent-child dyads aged 4 to 7 years were included. Seventy-four percent of participants were female, with a median of 3 active joints (interquartile range, 1-5). Internal consistency was strong (α = .78-.96) for pain characteristics, interference, and emotional functioning SUPER-KIDZ subscales. Good test-retest reliability (ICC≥0.80) was found for the pain characteristics subscale in older- and younger-child versions. Most other subscales had satisfactory reliability coefficients (ICC≥0.70). Correlations of 0.50 or greater were found between the older-child SUPER-KIDZ scores and the Childhood Health Assessment Questionnaire and Patient-Reported Outcomes Measurement Information System depressive symptoms items, as well as the younger-child pain-intensity item and the Faces Pain Scale-Revised. Strong responsiveness was found for all subscales (standardized response mean, 0.63-1.54; significant linear mixed-model regression), except for the older-child emotional functioning subscale. Conclusion The SUPER-KIDZ has shown good internal consistency and responsiveness, and satisfactory test-retest reliability. Construct validity was moderate for the younger- and older-child versions, but weak for the parent version. J Orthop Sports Phys Ther 2017;47(10):731-740. Epub 4 Sep 2017. doi:10.2519/jospt.2017.7375.

Background: Mindfulness-based interventions (MBIs) have emerged as a promising strategy for individuals with a chronic illness, given their versatility in targeting both physical and mental health outcomes. However, research to date has focused on adult or community-based populations., Objectives: To systematically review and critically appraise MBIs in clinical pediatric samples living with chronic physical illness., Data Sources: Electronic searches were conducted by a Library Information Specialist familiar with the field by using EMBASE, PsycINFO, MEDLINE, CINAHL, Web of Science, and EBM Reviews databases. Study Eligibility, Participants, and Interventions: Published English peer-reviewed articles of MBIs in clinical samples of children and adolescents (3-18 years) with chronic physical illness., Study Appraisal and Synthesis Methods: Two reviewers independently selected articles for review and extracted data. Results are narratively described, and the reporting quality of each study was assessed via the STROBE Checklist., Results: Of a total 4710 articles, 8 articles met inclusion criteria. All studies were small (n < 20, except 1 study of n = 59), included only outpatient adolescent samples, and focused on feasibility and acceptability of MBI; only 1 study included a comparison group (n = 1). No studies included online components or remote attendance. All studies found that MBI was acceptable to adolescents, whereas feasibility and implementation outcomes were mixed. Many studies were underpowered to detect significant differences post-MBI, but MBI did demonstrate improvements in emotional distress in several studies. Conclusions and Implications of Key Findings: The literature on MBIs is preliminary in nature, focusing on adapting and developing MBI for adolescents. Although MBIs appear to be a promising approach to coping with symptoms related to chronic illness in adolescents, future research with adequate sample sizes and rigorous research designs is warranted.

Recent studies have demonstrated the safety and efficacy of ocular gene therapy based on adeno-associated viral vectors (AAVs). Accordingly, a surge in promising new gene therapies is entering clinical trials, including the first optogenetic therapy for vision restoration. To date, optogenetic therapies for vision restoration target either the retinal ganglion cells (GCs) or presynaptic ON-bipolar cells (OBCs). Initiating light responses at the level of the OBCs has significant advantages over optogenetic activation of GCs. For example, important neural circuitries in the inner retina, which shape the receptive fields of GCs, remain intact when activating the OBCs. Current drawbacks of AAV-mediated gene therapies targeting OBCs include (1) a low transduction efficiency, (2) off-target expression in unwanted cell populations, and (3) a poor performance in human tissue compared to the murine retina. Here, we examined side-by-side the performance of three state-of-the art AAV capsid variants, AAV7m8, AAVBP2, and AAV7m8(Y444F) in combination with the 4x GRM6 -SV40 promoter construct in the healthy and degenerated mouse retina and in human post-mortem retinal explants. We find that (1) the 4x GRM6 -SV40 promoter is not OBC specific, (2) that all AAV variants possess broad cellular transduction patterns, with differences between the transduction patterns of capsid variants AAVBP2 and AAV7m8 and, most importantly, (3) that all vectors target OBCs in healthy tissue but not in the degenerated rd1 mouse model, potentially limiting the possibilities for an OBC-targeted optogenetic therapy for vision restoration in the blind.

The pathogenic species of Cryptococcus are a major cause of mortality owing to severe infections in immunocompromised as well as immunocompetent individuals. Although antifungal treatment is usually effective, many patients relapse after treatment, and in such cases, comparative analyses of the genomes of incident and relapse isolates may reveal evidence of determinative, microevolutionary changes within the host. Here, we analyzed serial isolates cultured from cerebrospinal fluid specimens of 18 South African patients with recurrent cryptococcal meningitis. The time between collection of the incident isolates and collection of the relapse isolates ranged from 124 days to 290 days, and the analyses revealed that, during this period within the patients, the isolates underwent several genetic and phenotypic changes. Considering the vast genetic diversity of cryptococcal isolates in sub-Saharan Africa, it was not surprising to find that the relapse isolates had acquired different genetic and correlative phenotypic changes. They exhibited various mechanisms for enhancing virulence, such as growth at 39°C, adaptation to stress, and capsule production; a remarkable amplification of ERG11 at the native and unlinked locus may provide stable resistance to fluconazole. Our data provide a deeper understanding of the microevolution of Cryptococcus species under pressure from antifungal chemotherapy and host immune responses. This investigation clearly suggests a promising strategy to identify novel targets for improved diagnosis, therapy, and prognosis. IMPORTANCE Opportunistic infections caused by species of the pathogenic yeast Cryptococcus lead to chronic meningoencephalitis and continue to ravage thousands of patients with HIV/AIDS. Despite receiving antifungal treatment, over 10% of patients develop recurrent disease. In this study, we collected isolates of Cryptococcus from cerebrospinal fluid specimens of 18 patients at the time of their diagnosis and when they relapsed several months later. We then sequenced and compared the genomic DNAs of each pair of initial and relapse isolates. We also tested the isolates for several key properties related to cryptococcal virulence as well as for their susceptibility to the antifungal drug fluconazole. These analyses revealed that the relapsing isolates manifested multiple genetic and chromosomal changes that affected a variety of genes implicated in the pathogenicity of Cryptococcus or resistance to fluconazole. This application of comparative genomics to serial clinical isolates provides a blueprint for identifying the mechanisms whereby pathogenic microbes adapt within patients to prolong disease., (Copyright © 2017 Chen et al.)

Academics often develop software for teaching and learning purposes with the best of intentions, only to be disappointed by the low acceptance rate of the software by their students once it is implemented. In this study, the focus is on software that was designed to enable veterinary students to record their clinical skills. A pilot of the software clearly showed that the program had not been received as well as had been anticipated, and therefore the researchers used a group interview and a questionnaire with closed-ended and open-ended questions to obtain the students' feedback. The open-ended questions were analysed with conceptual content analysis, and themes were identified. Students made valuable suggestions about what they regarded as important considerations when a new software program is introduced. The most important lesson learnt was that students cannot always predict their needs accurately if they are asked for input prior to the development of software. For that reason student input should be obtained on a continuous and regular basis throughout the design and development phases.

Objective: Disrupted sleep is a central feature of posttraumatic stress disorder (PTSD). The precise nature of that disruption is not agreed upon, however, and there is no explanation for why sleep disruptions are detected in some PTSD-diagnosed individuals but not in others. We tested the novel proposition that PTSD-diagnosed individuals with prominent hyperarousal symptoms will have more disrupted sleep than those without such symptoms., Method: We assigned each of 57 female volunteers to 1 of 4 groups: PTSD + Hyperarousal (PTSD + HYP; n = 14), PTSD - Hyperarousal (n = 13), depression (n = 14), or healthy control (n = 16). Each experienced 1 night of polysomnographic recording in a sleep laboratory., Results: General linear modeling confirmed that group status (i.e., being in the PTSD + HYP group rather than the other groups) predicted disrupted sleep quality most strongly. PTSD patients with prominent hyperarousal symptoms, relative to those without such symptoms, experienced reduced sleep efficiency, spent more time awake after sleep onset, and self-reported poorer sleep quality., Conclusion: These preliminary findings, although requiring replication in larger samples, suggest an important association between hyperarousal symptoms and sleep quality in PTSD, and may help explain why some PTSD-diagnosed individuals experience markedly disrupted sleep whereas others do not. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Since the initial identification of cytochrome P450 monooxygenases (CYPs/P450s), great progress has been made in understanding their structure-function relationship, diversity and application in producing compounds beneficial to humans. However, the molecular evolution of P450s in terms of their dynamics both at protein and DNA levels and functional conservation across kingdoms still needs investigation. In this study, we analyzed 17 598 P450s belonging to 113 P450 families (bacteria -42; fungi -19; plant -28; animal -22; plant and animal -1 and common P450 family -1) and found highly conserved and rapidly evolving P450 families. Results suggested that bacterial P450s, particularly P450s belonging to mycobacteria, are highly conserved both at protein and DNA levels. Mycobacteria possess the highest P450 diversity percentage compared to other microbes and have a high coverage of P450s (≥1%) in their genomes, as found in fungi and plants. Phylogenetic and functional analyses revealed the functional conservation of P450s despite belonging to different biological kingdoms, suggesting the adherence of P450s to their innate function such as their involvement in either generation or oxidation of steroids and structurally related molecules, fatty acids and terpenoids. This study's results offer new understanding of the dynamic structural nature of P450s.

We determined the toxicity of oil refinery waste in three soils using the springtail Folsomia candida (Collembola) in bioassays. Sublethal exposure to a concentration series of API-sludge presented EC50's for reproduction of 210 mg/kg in site soil; 880 mg/kg in LUFA2.2- and 3260 mg/kg in OECD-soil. The sludge was the least toxic in the OECD-soil with the highest clay and organic matter content, the highest maximum water holding capacity, and the least amount of sand. It was the most toxic in the reference site soil with the lowest organic matter content and highest sand content. The results emphasized the important role of soil characteristics such as texture and organic matter content in influencing toxicity, possibly by affecting bioavailability of toxicants.

Adolescents with chronic pain are often socially isolated, having never met others with chronic pain, and often feel misunderstood by healthy peers. Adolescence is a sensitive period for developing one's sense of self and autonomy, which often occurs in the context of peer relationships. This developmental process is disrupted in adolescents when their chronic pain interferes with their social interactions. Peer mentoring is proposed as a developmentally timely intervention. The aim of this study is to develop and test the feasibility, acceptability, and impact of the iPeer2Peer program. The iPeer2Peer program is a tailored peer mentorship program that provides modeling and reinforcement by peers (trained young adults with chronic pain aged 18-25 years who have learned to successfully manage their pain). This program aimed to enhance self-management of chronic pain in adolescents through 10 Skype video calls over the course of 8 weeks. A pilot randomized controlled trial design using waitlist controls was used in an adolescent chronic pain sample. Twenty-eight adolescents aged 14.8 ± 1.6 years (93% female) completed the trial (intervention: n = 12; control n = 16). Three adolescents completed the intervention after completing their participation in the control arm. The iPeer2Peer program was feasible and acceptable, provided the adolescents were given more time to complete all 10 calls. When compared with controls, adolescents who completed the iPeer2Peer program had significant improvement in self-management skills and their coping efforts were more successful. The iPeer2Peer program is a promising peer mentoring intervention that complements standard care for adolescents with chronic pain.

Purpose: Recent advances in optogenetics and gene therapy have led to promising new treatment strategies for blindness caused by retinal photoreceptor loss. Preclinical studies often rely on the retinal degeneration 1 (rd1 or Pde6b(rd1)) retinitis pigmentosa (RP) mouse model. The rd1 founder mutation is present in more than 100 actively used mouse lines. Since secondary genetic traits are well-known to modify the phenotypic progression of photoreceptor degeneration in animal models and human patients with RP, negligence of the genetic background in the rd1 mouse model is unwarranted. Moreover, the success of various potential therapies, including optogenetic gene therapy and prosthetic implants, depends on the progress of retinal degeneration, which might differ between rd1 mice. To examine the prospect of phenotypic expressivity in the rd1 mouse model, we compared the progress of retinal degeneration in two common rd1 lines, C3H/HeOu and FVB/N., Methods: We followed retinal degeneration over 24 weeks in FVB/N, C3H/HeOu, and congenic Pde6b(+) seeing mouse lines, using a range of experimental techniques including extracellular recordings from retinal ganglion cells, PCR quantification of cone opsin and Pde6b transcripts, in vivo flash electroretinogram (ERG), and behavioral optokinetic reflex (OKR) recordings., Results: We demonstrated a substantial difference in the speed of retinal degeneration and accompanying loss of visual function between the two rd1 lines. Photoreceptor degeneration and loss of vision were faster with an earlier onset in the FVB/N mice compared to C3H/HeOu mice, whereas the performance of the Pde6b(+) mice did not differ significantly in any of the tests. By postnatal week 4, the FVB/N mice expressed significantly less cone opsin and Pde6b mRNA and had neither ERG nor OKR responses. At 12 weeks of age, the retinal ganglion cells of the FVB/N mice had lost all light responses. In contrast, 4-week-old C3H/HeOu mice still had ERG and OKR responses, and we still recorded light responses from C3H/HeOu retinal ganglion cells until the age of 24 weeks. These results show that genetic background plays an important role in the rd1 mouse pathology., Conclusions: Analogous to human RP, the mouse genetic background strongly influences the rd1 phenotype. Thus, different rd1 mouse lines may follow different timelines of retinal degeneration, making exact knowledge of genetic background imperative in all studies that use rd1 models.

Photoreceptor degeneration is one of the most prevalent causes of blindness. Despite photoreceptor loss, the inner retina and central visual pathways remain intact over an extended time period, which has led to creative optogenetic approaches to restore light sensitivity in the surviving inner retina. The major drawbacks of all optogenetic tools recently developed and tested in mouse models are their low light sensitivity and lack of physiological compatibility. Here we introduce a next-generation optogenetic tool, Opto-mGluR6, designed for retinal ON-bipolar cells, which overcomes these limitations. We show that Opto-mGluR6, a chimeric protein consisting of the intracellular domains of the ON-bipolar cell-specific metabotropic glutamate receptor mGluR6 and the light-sensing domains of melanopsin, reliably recovers vision at the retinal, cortical, and behavioral levels under moderate daylight illumination.

Objective: This study was conducted to determine the prevalence of hazardous, harmful and dependent drinking among hostel-dwelling students on the main campus of the University of the Free State (UFS), and the influence of sex and academic year on the habit., Method: A quarter of all hostel-dwelling students of UFS were selected by systematic random sampling. Willing participants completed a questionnaire comprising a demographic section and the Alcohol Use Disorders Identification Test (AUDIT)., Results: Of the 339 participants with total AUDIT scores, 15.6% exhibited hazardous drinking, 4.1% harmful drinking and 5.6% alcohol dependence. Male students had a statistically significant higher prevalence (32.8%) of hazardous, harmful or dependent drinking than female students (18.9%). Women, however, are biologically more vulnerable to the ill effects of alcohol due to altered pharmacokinetics and pharmacodynamics of alcohol. In addition, intoxicated women suffer more biological and social risks. When the cut-off point for hazardous drinking was adapted to account for the increased biological vulnerability of women, the difference between female and male participants was no longer significant. First year male students were less likely to engage in unsafe drinking than senior students. Female students in the alcohol dependent category showed an increasing trend over advancing academic year., Conclusions: Follow-up studies are needed to confirm whether a significant difference in hazardous drinking of first year male students compared to seniors reflects the influence of university policy or merely precedes drinking acculturation.

Background: Health care trainees⁄students lack knowledge and skills for the comprehensive clinical assessment and management of pain. Moreover, most teaching has been limited to classroom settings within each profession., Objectives: To develop and evaluate the feasibility and preliminary outcomes of the 'Pain-Interprofessional Education (IPE) Placement', a five-week pain IPE implemented in the clinical setting. The utility (content validity, readability, internal consistency and practical considerations) of the outcome measures was also evaluated., Methods: A convenience sample of 21 trainees from eight professions was recruited over three Pain-IPE Placement cycles. Pre- and postcurriculum assessment included: pain knowledge (Pediatric Pain Knowledge and Attitudes Survey), IPE attitudes (Interdisciplinary Education Perception Scale [IEPS]) and IPE competencies (Interprofessional Care Core Competencies Global Rating Scales [IPC-GRS]), and qualitative feedback on process⁄acceptability., Results: Recruitment and retention met expectations. Qualitative feedback was excellent. IPE measures (IEPS and IPC-GRS) exhibited satisfactory utility. Postcurriculum scores improved significantly: IEPS, P<0.05; IPC-GRS constructs, P<0.01; and competencies, P<0.001. However, the Pediatric Pain Knowledge and Attitudes Survey exhibited poor utility in professions without formal pharmacology training. Scores improved in the remaining professions (n=14; P<0.01)., Discussion: There was significant improvement in educational outcomes. The IEPS and IPC-GRS are useful measures of IPE-related learning. At more advanced training levels, a single pain-knowledge questionnaire may not accurately reflect learning across diverse professions., Conclusion: The Pain-IPE Placement is a successful collaborative learning model within a clinical context that successfully changed interprofessional competencies. The present study represents a first step at defining and assessing change in interprofessional competencies gained from Pain-IPE.

Patients with cryptococcal meningitis in sub-Saharan Africa frequently relapse following treatment. The natural history and etiology of these recurrent episodes warrant investigation. Here, we used multilocus sequence typing (MLST) to compare the molecular genotypes of strains of Cryptococcus neoformans and Cryptococcus gattii isolated from serial episodes of cryptococcal meningitis that were separated by at least 110 days. The most common MLST genotypes among the isolates were the dominant global clinical genotypes (M5 and M4) of molecular type VNI, as well as the VNI genotypes apparently restricted to southern Africa. In addition, there was considerable genetic diversity among these South African isolates, as 15% of the patients had unique genotypes. Eleven percent of the patients were reinfected with a genetically different strain following their initial diagnosis and treatment. However, the majority of serial episodes (89%) were caused by strains with the same genotype as the original strain. These results indicate that serial episodes of cryptococcosis in South Africa are frequently associated with persistence or relapse of the original infection. Using a reference broth microdilution method, we found that the serial isolates of 11% of the patients infected with strains of C. neoformans var. grubii with identical genotypes exhibited ≥4-fold increases in the MICs to fluconazole. Therefore, these recurrent episodes may have been precipitated by inadequate induction or consolidation of antifungal treatment and occasionally may have been due to increased resistance to fluconazole, which may have developed during the chronic infection., (Copyright © 2014, American Society for Microbiology. All Rights Reserved.)

Rationale: The superior mediastinal space is confined by the sterno-manubrium anteriorly and the vertebral column posterior. An abnormal relationship between the superior mediastinal structures may result in compression of the left main bronchus. In patients with right-sided pneumonectomy an exaggerated compensatory response may lead to stretching and compression of the remainder of the intra-thoracic airway. Lymphobronchial TB mimics pneumonectomy when it causes compression of the bronchus intermedius, between nodal lymphnode groups with resultant volume loss in the right lung and displacement of the mediastinum to the right. The left main bronchus may be at risk of compression due to rotation and displacement of the major vessels., Aim: To report pediatric cases of right-sided lymphobronchial TB with volume loss, demonstrate the use of angle measurements to quantify mediastinal dynamics and support a pathogenetic theory for left main bronchus compression., Materials and Methods: CT scans in children with TB and right lung volume loss, were compared retrospectively with controls using angle measurements based on descriptions of the aorta-carinal syndrome and the post-pneumonectomy syndrome. The Mann-Whitney U-test was used to compare groups., Results: The "Pulmonary bifurcation angle" between the main pulmonary arteries reached statistical significance (P = 0.025). The "Pulmonary outflow tract rotation" angle (pulmonary trunk with the mid sagittal plane) approached statistical significance (P = 0.078). The left main bronchus ranged from complete obliteration in two patients to 0.7 cm. In 16 of 30 patients the size was reduced to less than 75% of expected., Conclusion: In children with right lung volume loss from TB, the compression of the contralateral bronchus is due to narrowing of the pulmonary artery bifurcation angle as the main trunk rotates towards the midline. This is comparable to the post-pneumonectomy syndrome., (© 2012 Wiley Periodicals, Inc.)

This paper examines the role of inhibition in generating the receptive-field properties of local edge detector (LED) ganglion cells in the rabbit retina. We confirm that the feed-forward inhibition is largely glycinergic but, contrary to a recent report, our data demonstrate that the glycinergic inhibition contributes to temporal tuning for the OFF and ON inputs to the LEDs by delaying the onset of spiking; this delay was more pronounced for the ON inputs (∼ 340 ms) than the OFF inputs (∼ 12 ms). Blocking glycinergic transmission reduced the delay to spike onset and increased the responses to flickering stimuli at high frequencies. Analysis of the synaptic conductances indicates that glycinergic amacrine cells affect temporal tuning through both postsynaptic inhibition of the LEDs and presynaptic modulation of the bipolar cells that drive the LEDs. The results also confirm that presynaptic GABAergic transmission contributes significantly to the concentric surround antagonism in LEDs; however, unlike presumed LEDs in the mouse retina, the surround is only partly generated by spiking amacrine cells.

Background: The genus emmonsia contains three species that are associated with human disease. Emmonsia crescens and Emmonsia parva are the agents that cause adiaspiromycosis, and one human case of Emmonsia pasteuriana infection has been described. We report a fungal pathogen within the genus emmonsia that is most closely related to E. pasteuriana in human immunodeficiency virus (HIV)-infected adults in South Africa., Methods: Between July 2008 and July 2011, we conducted enhanced surveillance to identify the cause of systemic, dimorphic fungal infections in patients presenting to Groote Schuur Hospital and other hospitals affiliated with the University of Cape Town, Cape Town, South Africa. DNA sequencing was used to identify pathogenic fungi., Results: A total of 24 cases of dimorphic fungal infection were diagnosed, 13 of which were caused by an emmonsia species. All 13 patients were HIV-infected, with a median CD4+ T-cell count of 16 cells per cubic millimeter (interquartile range, 10 to 44), and all had evidence of disseminated fungal disease. Three patients died soon after presentation, but the others had a good response to a variety of antifungal agents and antiretroviral therapy. Phylogenetic analysis of five genes (LSU, ITS1-2, and the genes encoding actin, β-tubulin, and intein PRP8) revealed that this fungus belongs in the genus emmonsia and is most closely related to E. pasteuriana., Conclusions: The findings suggest that these isolates of an emmonsia species represent a new species of dimorphic fungus that is pathogenic to humans. The species appears to be an important cause of infections in Cape Town.

Translational read-through-inducing drugs (TRIDs) promote read-through of nonsense mutations, placing them in the spotlight of current gene-based therapeutic research. Here, we compare for the first time the relative efficacies of new-generation aminoglycosides NB30, NB54 and the chemical compound PTC124 on retinal toxicity and read-through efficacy of a nonsense mutation in the USH1C gene, which encodes the scaffold protein harmonin. This mutation causes the human Usher syndrome, the most common form of inherited deaf-blindness. We quantify read-through efficacy of the TRIDs in cell culture and show the restoration of harmonin function. We do not observe significant differences in the read-through efficacy of the TRIDs in retinal cultures; however, we show an excellent biocompatibility in retinal cultures with read-through versus toxicity evidently superior for NB54 and PTC124. In addition, in vivo administration of NB54 and PTC124 induced recovery of the full-length harmonin a1 with the same efficacy. The high biocompatibilities combined with the sustained read-through efficacies of these drugs emphasize the potential of NB54 and PTC124 in treating nonsense mutation-based retinal disorders., (Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.)

Eucalyptus trees, mostly native to Australia, are widely planted in the tropics and Southern Hemisphere for the production of wood and pulp. Worldwide surveys of diseases on these trees have yielded a large collection of Ceratocystis isolates from dying trees or from wounds on their stems. The aim of this study was to characterise these isolates and to consider their relatedness to each other. Culture appearance, morphological features and a distinctive fruity odour in all cultures were typical of species in the Ceratocystis fimbriatasensu lato (s. lat.) complex. Phylogenetic analyses of sequences for the combined ITS, βt-1 and TEF1-α gene regions revealed a genetically diverse group of isolates residing in a single large clade, that were distinct from all other species in the C. fimbriatas. lat. complex. Based on morphology and phylogenetic inference, the Eucalyptus isolates are recognised as closely related. The South African isolates are described here as a new species, C. eucalypticola.