Effects of NALCN-Encoded Na+ Leak Currents on the Repetitive Firing Properties of SCN Neurons Depend on K+-Driven Rhythmic Changes in Input Resistance.

Neurons in the suprachiasmatic nucleus (SCN) generate circadian changes in the rates of spontaneous action potential firing that regulate and synchronize daily rhythms in physiology and behavior. Considerable evidence suggests that daily rhythms in the repetitive firing rates (higher during the day than at night) of SCN neurons are mediated by changes in subthreshold potassium (K+) conductance(s). An alternative "bicycle" model for circadian regulation of membrane excitability in clock neurons, however, suggests that an increase in NALCN-encoded sodium (Na+) leak conductance underlies daytime increases in firing rates. The experiments reported here explored the role of Na+ leak currents in regulating daytime and nighttime repetitive firing rates in identified adult male and female mouse SCN neurons: vasoactive intestinal peptide-expressing (VIP+), neuromedin S-expressing (NMS+) and gastrin-releasing peptide-expressing (GRP+) cells. Whole-cell recordings from VIP+, NMS+, and GRP+ neurons in acute SCN slices revealed that Na+ leak current amplitudes/densities are similar during the day and at night, but have a larger impact on membrane potentials in daytime neurons. Additional experiments, using an in vivo conditional knockout approach, demonstrated that NALCN-encoded Na+ currents selectively regulate daytime repetitive firing rates of adult SCN neurons. Dynamic clamp-mediated manipulation revealed that the effects of NALCN-encoded Na+ currents on the repetitive firing rates of SCN neurons depend on K+ current-driven changes in input resistances. Together, these findings demonstrate that NALCN-encoded Na+ leak channels contribute to regulating daily rhythms in the excitability of SCN neurons by a mechanism that depends on K+ current-mediated rhythmic changes in intrinsic membrane properties.SIGNIFICANCE STATEMENT Elucidating the ionic mechanisms responsible for generating daily rhythms in the rates of spontaneous action potential firing of neurons in the suprachiasmatic nucleus (SCN), the master circadian pacemaker in mammals, is an important step toward understanding how the molecular clock controls circadian rhythms in physiology and behavior. While numerous studies have focused on identifying subthreshold K+ channel(s) that mediate day-night changes in the firing rates of SCN neurons, a role for Na+ leak currents has also been suggested. The results of the experiments presented here demonstrate that NALCN-encoded Na+ leak currents differentially modulate daily rhythms in the daytime/nighttime repetitive firing rates of SCN neurons as a consequence of rhythmic changes in subthreshold K+ currents.

ICON 2020-International Scientific Tendinopathy Symposium Consensus: the development of a core outcome set for gluteal tendinopathy.

Gluteal tendinopathy (GT) is common and can be debilitating and challenging to manage. A lack of condition specific and appropriate outcome measures compromise evidence synthesis for treatment and limits clinical guideline development. Our objective was to develop a core outcome measurement set for GT (COS-GT). Participants were patients with GT and expert health professionals (HPs). A scoping review identified measures used in GT research, which were mapped to the nine International Scientific Tendinopathy Symposium Consensus core domains, and included in two surveys of HPs. The first survey identified the feasible and true measures for each domain. The second survey refined the list which a patient focus group then considered. Meeting online, HPs reached consensus (agreement ≥70%) on the most appropriate COS-GT measures. 34 HPs and seven patients were recruited. 57 measures were mapped to the nine core domains. Six measures did not proceed past survey one. Of those that progressed, none had adequate clinimetric properties for a COS-GT. Thus, participants decided on interim measures: the global rating of change, pain at night, time to pain onset with single limb stance, pain with stair walking, pain self-efficacy and hip abduction strength. HP participants additionally recommended that pain over the last week, the European Quality of Life-5 dimensions-5 levels and the Victorian Institute of Sport Assessment-Gluteal be considered in clinical trials, as they currently provide best easures of the relevant tendinopathy domains. In conclusion this interim COS-GT should guide outcome measure selection in clinical practice and future research trials in patients with GT.

Post-traumatic stress disorder is associated with a higher rate of polypectomy independent of an increased frequency of colonoscopy in Australian veterans: a retrospective review.

BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with extensive physical comorbidities, including lower gastrointestinal symptoms. Diagnostic uncertainty and poor therapeutic responses may result in more frequent colonoscopies than clinically necessary. Polypectomy is standard practice when polyps are identified, and if PTSD is a risk factor for polyp formation, one would expect a higher rate of polyp detection and removal in veterans with PTSD than those without PTSD. AIM: To determine the association between PTSD and the rate of colonoscopy and polypectomy in Australian veterans. METHODS: Diagnostic and therapeutic colonoscopy rates in Australian male Veterans aged ≥50 years were examined by reviewing case records of veterans who accessed Department of Veterans' Affairs funded health services between 1 January 2013 and 31 December 2018. RESULTS: A total of 138 471 veterans was included, of whom 28 018 had a diagnosis of PTSD; 56.4% were aged ≥65 years. Twenty-one percent of the entire cohort underwent at least one colonoscopy during the study period. Increased rates of diagnostic colonoscopy and polypectomy were associated with the presence of PTSD across all age brackets. The effect was empirically large as veterans with PTSD experience colonoscopy rates 76-81% greater than those without PTSD. Similarly, veterans with PTSD experienced polypectomy rates 76-81% greater than veterans without PTSD, and this increase persisted when controlling for the increased number of diagnostic colonoscopies they undergo. CONCLUSION: The presence of PTSD has a marked impact on colonoscopy rates in Australian veterans. The increased polypectomy rate independent of increased colonoscopy rate suggests that PTSD is a risk factor for colonic polyp formation.

The impact of posttraumatic stress disorder on upper gastrointestinal investigations in Australian Defence Force veterans: a retrospective review.

Veterans with posttraumatic stress disorder (PTSD) commonly exhibit associated gastrointestinal (GI) symptoms. We compared upper GI endoscopy and abdominal ultrasound rates in veterans with and without PTSD. Veterans with PTSD were 77-81% more likely to undergo these procedures than those without PTSD. PTSD symptomatology influences GI investigation rate and more emphasis on clinician and patient education is recommended regarding stress-related gut symptoms.

Computerised health interventions targeting Australian veterans and their families: A scoping review.

ISSUE ADDRESSED: Australian veterans suffer higher rates of both mental and physical health conditions than civilians, yet many do not seek treatment. Computerised Interventions (CIs) may provide an alternative approach to management, which can overcome some barriers to treatment uptake. We aim to evaluate the scope and quality of CIs designed specifically for Australian veterans and their families. METHODS: A manual search of the Department of Veterans' Affairs and other Ex-service organisation websites was performed to map and describe CIs for Australian veterans and their families, followed by a scoping review of four databases to identify evaluations of relevant CIs. RESULTS: Our search identified 10 CIs specific to Australian veterans and their families. The majority were structured, self-guided CIs, designed to elicit cognitive/behavioural change that addressed mental health and psychosocial needs during transition. Three evaluations examined previously identified CIs. The results showed mixed reviews from participants and clinicians, in two separate evaluations, regarding user experience, quality and perceived benefit. In addition, positive psychological outcomes, including the reduction of post-traumatic stress disorder (PTSD) symptoms, were demonstrated for participants of the online intervention. CONCLUSION: While Australian veteran-centric online interventions primarily focus on psychological conditions, the prevalent physical health concerns within the veteran population remain unaddressed. Additionally, despite the documented impact of military experience on family members, there is a lack of specific Australian interventions designed for families. Few tools have been formally evaluated, yet show promise as supportive self-directed resources for veterans with PTSD, and for navigating transition challenges. SO WHAT?: Further development of online interventions addressing prevalent physical and family needs, and conduction of comprehensive evaluations are needed to enhance overall quality, accessibility and holistic effectiveness of interventions for the Australian veteran community.

Outcome measures in the management of gluteal tendinopathy: a systematic review of their measurement properties.

OBJECTIVE: Evaluate properties of outcome measures for gluteal tendinopathy. DESIGN: Multistage scoping/systematic review. DATA SOURCES: Cochrane, PubMed, Embase, Scopus, Web of Science, PEDro, CINAHL, SPORTDISCUS were searched (December 2021) to identify measures used to evaluate gluteal tendinopathy. Measures were mapped to the core health domains for tendinopathy. Medline, CINAHL, Embase and PubMed were searched (December 2021) for studies evaluating measurement properties of gluteal tendinopathy outcome measures captured in the initial search. Both reviews included studies that evaluated a treatment in participants with gluteal tendinopathy, diagnosed by a professional. Consensus-based-Standards for the Selection of Health Instruments methodology were followed-including bias assessment and synthesis of findings. RESULTS: Six studies reported on the Victorian Institute of Sport Assessment-Gluteal Tendinopathy (VISA-G). One study reported on the Hip Outcome Score (HOS)-activities of daily living (ADL) and Sport.The VISA-G had moderate-quality evidence of sufficient construct validity (known group) and responsiveness (pre-post intervention), low-quality evidence of sufficient reliability, measurement error, comprehensibility and insufficient construct validity (convergent), and very low-quality evidence of sufficient comprehensiveness, relevance and responsiveness (comparison with other outcome measures).Both the HOS(ADL) and HOS(Sport) had very low-quality evidence of sufficient reliability, relevance and insufficient construct validity and comprehensiveness. The HOS(ADL) had very low-quality evidence of sufficient comprehensibility and insufficient measurement error. The HOS(Sport) had very low quality evidence of inconsistent comprehensibility and sufficient measurement error. CONCLUSION: Rigorously validated outcome measures for gluteal tendinopathy are lacking. The VISA-G is the preferred available option to capture the disability associated with gluteal tendinopathy.

Endoplasmic Reticulum Protein TXNDC5 Augments Myocardial Fibrosis by Facilitating Extracellular Matrix Protein Folding and Redox-Sensitive Cardiac Fibroblast Activation.

RATIONALE: Cardiac fibrosis plays a critical role in the pathogenesis of heart failure. Excessive accumulation of extracellular matrix (ECM) resulting from cardiac fibrosis impairs cardiac contractile function and increases arrhythmogenicity. Current treatment options for cardiac fibrosis, however, are limited, and there is a clear need to identify novel mediators of cardiac fibrosis to facilitate the development of better therapeutics. Exploiting coexpression gene network analysis on RNA sequencing data from failing human heart, we identified TXNDC5 (thioredoxin domain containing 5), a cardiac fibroblast (CF)-enriched endoplasmic reticulum protein, as a potential novel mediator of cardiac fibrosis, and we completed experiments to test this hypothesis directly. OBJECTIVE: The objective of this study was to determine the functional role of TXNDC5 in the pathogenesis of cardiac fibrosis. METHODS AND RESULTS: RNA sequencing and Western blot analyses revealed that TXNDC5 mRNA and protein were highly upregulated in failing human left ventricles and in hypertrophied/failing mouse left ventricle. In addition, cardiac TXNDC5 mRNA expression levels were positively correlated with those of transcripts encoding transforming growth factor ß1 and ECM proteins in vivo. TXNDC5 mRNA and protein were increased in human CF (hCF) under transforming growth factor ß1 stimulation in vitro. Knockdown of TXNDC5 attenuated transforming growth factor ß1-induced hCF activation and ECM protein upregulation independent of SMAD3 (SMAD family member 3), whereas increasing expression of TXNDC5 triggered hCF activation and proliferation and increased ECM protein production. Further experiments showed that TXNDC5, a protein disulfide isomerase, facilitated ECM protein folding and that depletion of TXNDC5 led to ECM protein misfolding and degradation in CF. In addition, TXNDC5 promotes hCF activation and proliferation by enhancing c-Jun N-terminal kinase activity via increased reactive oxygen species, derived from NAD(P)H oxidase 4. Transforming growth factor ß1-induced TXNDC5 upregulation in hCF was dependent on endoplasmic reticulum stress and activating transcription factor 6-mediated transcriptional control. Targeted disruption of Txndc5 in mice (Txndc5-/-) revealed protective effects against isoproterenol-induced cardiac hypertrophy, reduced fibrosis (by ≈70%), and markedly improved left ventricle function; post-isoproterenol left ventricular ejection fraction was 59.1±1.5 versus 40.1±2.5 (P<0.001) in Txndc5-/- versus wild-type mice, respectively. CONCLUSIONS: The endoplasmic reticulum protein TXNDC5 promotes cardiac fibrosis by facilitating ECM protein folding and CF activation via redox-sensitive c-Jun N-terminal kinase signaling. Loss of TXNDC5 protects against ß agonist-induced cardiac fibrosis and contractile dysfunction. Targeting TXNDC5, therefore, could be a powerful new therapeutic approach to mitigate excessive cardiac fibrosis, thereby improving cardiac function and outcomes in patients with heart failure.

Individuals with Persistent Greater Trochanteric Pain Syndrome Exhibit Impaired Pain Modulation, as well as Poorer Physical and Psychological Health, Compared with Pain-Free Individuals: A Cross-Sectional Study.

OBJECTIVES: To compare physical, sensory, and psychosocial factors between individuals with greater trochanteric pain syndrome and controls and to explore factors associated with pain and disability. DESIGN: Cross-sectional study. SETTING: General community. SUBJECTS: Patients with persistent, clinically diagnosed greater trochanteric pain syndrome and healthy controls. METHODS: Participants completed tests of thermal and pressure pain threshold, conditioned pain modulation, temporal summation, muscle strength, physical function, physical activity, psychological factors, and health-related quality of life. Standardized mean differences between groups were calculated, and multiple linear regression identified factors associated with pain and disability. RESULTS: Forty patients (95% female, average [SD] age = 51 [9] years) and 58 controls (95% female, average [SD] age = 53 [11] years) were included. Heat pain threshold, temporal summation, and pain catastrophizing were not different between groups. Compared with controls, patients displayed significantly poorer quality of life (standardized mean difference = -2.66), lower pressure pain threshold locally (-1.47, remotely = -0.57), poorer health status (-1.22), impaired physical function (range = 0.64-1.20), less conditioned pain modulation (-1.01), weaker hip abductor/extensor strength (-1.01 and -0.59), higher depression (0.72) and anxiety (0.61) levels, lower cold pain threshold locally (-0.47, remotely = -0.39), and less time spent in (vigorous) physical activity (range = -0.43 to -0.39). Twenty-six percent of pain and disability was explained by depression, hip abductor strength, and time to complete stairs. CONCLUSIONS: Patients with greater trochanteric pain syndrome exhibited poorer health-related quality of life, physical impairments, widespread hyperalgesia, and greater psychological distress than healthy controls. Physical and psychological factors were associated with pain and disability.

Design, Delivery, Maintenance, and Outcomes of Peer-to-Peer Online Support Groups for People With Chronic Musculoskeletal Disorders: Systematic Review.

BACKGROUND: Online support groups (OSGs) are one way for people with chronic diseases, their family or friends, and health professionals to communicate, gain information, and provide social support. As the number of peer-to-peer OSGs for chronic musculoskeletal conditions grows, it is important to gain insight into the different designs of groups available, who is accessing them, if and how they may be effective, and what strategies are being used to implement or increase consumer engagement. OBJECTIVE: The objectives of this systematic review of people with musculoskeletal conditions were to (1) describe the design features (functions, usage options, moderation, and expert input) of peer-to-peer OSGs, (2) describe the characteristics of the individuals using peer-to-peer OSGs, (3) synthesize the evidence on outcomes of participation, and (4) identify strategies used in the delivery and maintenance of OSGs. METHODS: A search comprising terms related to the population (people with musculoskeletal disorders) and the intervention (peer-to-peer OSGs) was conducted in 6 databases. Results were filtered from 1990 (internet inception) to February 2019. Studies identified in the search were screened according to predefined eligibility criteria using a 2-step process. Quantitative studies were appraised by 2 reviewers using the Risk Of Bias In Non-Randomized Studies of Interventions tool. Qualitative studies were appraised by 2 different reviewers using the Critical Appraisal Skills Programme checklist. Extracted data were synthesized narratively. RESULTS: We examined 21 studies with low to moderate risk of bias. Of these studies, 13 studies included OSGs hosted on public platforms, 11 studies examined OSGs that were conducted in English, and 6 studies used moderators or peer leaders to facilitate engagement. Studies either reported the number of OSG members (n=1985 across all studies) or the number of posts (range: 223-200,000). The majority of OSG members were females who were not full-time employees and with varied levels of education. There were no randomized controlled trials measuring the efficacy of OSGs. Qualitative and quantitative studies identified empowerment, social support, self-management behavior, and health literacy as primary constructs to measure OSG efficacy. Neutral or marginal improvement was reported in these constructs. Sharing experiences and a greater level of engagement appeared to have an important influence on OSGs efficacy. The extent to which members posted on the website influenced engagement. CONCLUSIONS: Across a diverse range of designs, languages, included features, and delivery platforms, peer-to-peer OSGs for chronic musculoskeletal conditions attract predominantly female participants of all ages and education levels. The level of participation of a member appears to be related to their perceived benefit, health literacy, and empowerment. Future studies are needed to identify which design and maintenance strategies have superior efficacy and whether there are concomitant improvements in health outcomes for people with chronic musculoskeletal conditions resulting from participation in OSGs. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42018090326; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018090326.

Exploring the Characteristics and Preferences for Online Support Groups: Mixed Method Study.

BACKGROUND: Osteoarthritis (OA) is a chronic, disabling, and prevalent disorder. As there is no cure for OA, long-term self-management is paramount. Support groups (SGs) can facilitate self-management among people living with OA. Understanding preferences in design and features of SGs, including online SGs (OSGs), among people with OA can inform future development of SG interventions for this condition. OBJECTIVE: The objective of this study was to investigate health care- and health information-seeking behavior, digital literacy, and preferences for the design of SGs in people with OA. The study also explored the perceived barriers and enablers to being involved in OSGs. METHODS: An online survey study was conducted with a mixed method design (quantitative and qualitative). Individuals aged ≥45 years with knee, hip, or back pain for ≥3 months were recruited from an extant patient database of the Institute of Bone and Joint Research via email invitations. Quantitative elements of the survey included questions about sociodemographic background; health care- and health information-seeking behavior; digital literacy; and previous participation in, and preferences for, SGs and OSGs. Respondents were classified into 2 groups (Yes-SG and No-SG) based on previous participation or interest in an SG. Group differences were assessed with Chi-square tests (significance level set at 5%). Responses to free-text questions relating to preferences regarding OSG engagement were analyzed qualitatively using an inductive thematic analysis. RESULTS: A total of 415 people with OA completed the survey (300/415, 72.3% females; 252/415, 61.0% lived in a major city). The Yes-SG group included 307 (307/415, 73.9%) participants. Between the Yes-SG and No-SG groups, there were no differences in sociodemographic characteristics, health care- and health information-seeking behavior, and digital literacy. An online format was preferred by 126/259 (48.7%) of the Yes-SG group. Trained peer facilitators were preferred, and trustworthiness of advice and information were highly prioritized by the respondents. Qualitative analysis for OSG participation revealed 5 main themes. Lack of time and motivation were the main barriers identified. The main enablers were related to accessibility, enjoyment of the experience, and the content of the discussed information. CONCLUSIONS: These findings highlight the preferences in design features and content of SGs and OSGs and may assist in the further development of such groups.

Education plus exercise versus corticosteroid injection use versus a wait and see approach on global outcome and pain from gluteal tendinopathy: prospective, single blinded, randomised clinical trial.

OBJECTIVE: To compare the effects of a programme of load management education plus exercise, corticosteroid injection use, and no treatment on pain and global improvement in individuals with gluteal tendinopathy. DESIGN: Prospective, three arm, single blinded, randomised clinical trial. SETTING: Brisbane and Melbourne, Australia. PARTICIPANTS: Individuals aged 35-70 years, with lateral hip pain for more than 3 months, at least 4/10 on the pain numerical rating scale, and gluteal tendinopathy confirmed by clinical diagnosis and MRI; and with no corticosteroid injection use in previous 12 months, current physiotherapy, total hip replacement, or neurological conditions. INTERVENTIONS: A physiotherapy led education and exercise programme of 14 sessions over 8 weeks (EDX; n=69), one corticosteroid injection (CSI; n=66), and a wait and see approach (WS; n=69). MAIN OUTCOMES: Primary outcomes were patient reported global rating of change in hip condition (on an 11 point scale, dichotomised to success and non-success) and pain intensity in the past week (0=no pain, 10=worst pain) at 8 weeks, with longer term follow-up at 52 weeks. RESULTS: Of 204 randomised participants (including 167 women; mean age 54.8 years (SD 8.8)), 189 (92.6%) completed 52 week follow-up. Success on the global rating of change was reported at 8 weeks by 51/66 EDX, 38/65 CSI, and 20/68 WS participants. EDX and CSI had better global improvement scores than WS (risk difference 49.1% (95% CI 34.6% to 63.5%), number needed to treat 2.0 (95% CI 1.6 to 2.9); 29.2% (13.2% to 45.2%), 3.4 (2.2 to 7.6); respectively). EDX had better global improvement scores than CSI (19.9% (4.7% to 35.0%); 5.0 (2.9 to 21.1)). At 8 weeks, reported pain on the numerical rating scale was mean score 1.5 (SD 1.5) for EDX, 2.7 (2.4) for CSI, and 3.8 (2.0) for WS. EDX and CSI participants reported less pain than WS (mean difference -2.2 (95% CI -2.89 to -1.54); -1.2 (-1.85 to -0.50); respectively), and EDX participants reported less pain than CSI (-1.04 (-1.72 to -0.37)). Success on the global rating of change was reported at 52 weeks by 51/65 EDX, 36/63 CSI, and 31/60 WS participants; EDX was better than CSI (20.4% (4.9% to 35.9%); 4.9 (2.8 to 20.6)) and WS (26.8% (11.3% to 42.3%); 3.7 (2.4 to 8.8)). Reported pain at 52 weeks was 2.1 (2.2) for EDX, 2.3 (1.9) for CSI, and 3.2 (2.6) for WS; EDX did not differ from CSI (-0.26 (-1.06 to 0.55)), but both treatments did better than WS (1.13 (-1.93 to -0.33); 0.87 (-1.68 to -0.07); respectively). CONCLUSIONS: For gluteal tendinopathy, education plus exercise and corticosteroid injection use resulted in higher rates of patient reported global improvement and lower pain intensity than no treatment at eight weeks. Education plus exercise performed better than corticosteroid injection use. At 52 week follow-up, education plus exercise led to better global improvement than corticosteroid injection use, but no difference in pain intensity. These results support EDX as an effective management approach for gluteal tendinopathy. TRIAL REGISTRATION NUMBER: Prospectively registered at the Australian New Zealand Clinical Trials Registry (ACTRN12612001126808).

Patellar and Achilles tendinopathies are predominantly peripheral pain states: a blinded case control study of somatosensory and psychological profiles.

STUDY DESIGN: Case-control design. BACKGROUND: Tendinopathy is characterised by pain on tendon loading. In persistent cases of upper limb tendinopathy, it is frequently associated with central nervous system sensitisation, whereas less commonly linked in the case of persistent lower limb tendinopathies. OBJECTIVES: Compare somatosensory and psychological profiles of participants with persistent patellar (PT) and Achilles tendinopathies (AT) with pain-free controls. METHODS: A comprehensive battery of Quantitative Sensory Testing (QST) was assessed at standardised sites of the affected tendon and remotely (lateral elbow) by a blinded assessor. Participants completed the Victorian Institute of Sports Assessment, a health-related quality of life questionnaire, the Hospital Anxiety and Depression Scale and the Active Australia Questionnaire. Independent t-test and analysis of covariance (sex-adjusted and age-adjusted) were performed to compare groups. RESULTS: Participants with PT and AT did not exhibit differences from controls for the QST at the remote site, but there were differences at the affected tendon site. Compared with controls, participants with PT displayed significantly lower pressure pain threshold locally at the tendon (p=0.012) and fewer single limb decline squats before pain onset, whereas participants with AT only displayed fewer single heel raises before pain onset, but this pain was of a higher intensity. CONCLUSION: PT and AT appear to be predominantly local not widespread pain states related to loading of tendons without significant features of central sensitisation. LEVEL OF EVIDENCE: Level 4.

Early remodeling of repolarizing K+ currents in the αMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy (HCM), linked to mutations in myosin, myosin-binding proteins and other sarcolemmal proteins, is associated with increased risk of life threatening ventricular arrhythmias, and a number of animal models have been developed to facilitate analysis of disease progression and mechanisms. In the experiments here, we use the αMHC403/+ mouse line in which one αMHC allele harbors a common HCM mutation (in ßMHC, Arg403 Gln). Here, we demonstrate marked prolongation of QT intervals in young adult (10-12week) male αMHC403/+ mice, well in advance of the onset of measurable left ventricular hypertrophy. Electrophysiological recordings from myocytes isolated from the interventricular septum of these animals revealed significantly (P<0.001) lower peak repolarizing voltage-gated K+ (Kv) current (IK,peak) amplitudes, compared with cells isolated from wild type (WT) littermate controls. Analysis of Kv current waveforms revealed that the amplitudes of the inactivating components of the total outward Kv current, Ito,f, Ito,s and IK,slow, were significantly lower in αMHC403/+, compared with WT, septum cells, whereas Iss amplitudes were similar. The amplitudes/densities of IK,peak and IK,slow were also lower in αMHC403/+, compared with WT, LV wall and LV apex myocytes, whereas Ito,f was attenuated in αMHC403/+ LV wall, but not LV apex, cells. These regional differences in the remodeling of repolarizing Kv currents in the αMHC403/+ mice would be expected to increase the dispersion of ventricular repolarization and be proarrhythmic. Quantitative RT-PCR analysis revealed reductions in the expression of transcripts encoding several K+ channel subunits in the interventricular septum, LV free wall and LV apex of (10-12week) αMHC403/+ mice, although this transcriptional remodeling was not correlated with the observed decreases in K+ current amplitudes.

Utility of clinical tests to diagnose MRI-confirmed gluteal tendinopathy in patients presenting with lateral hip pain.

PURPOSE: Gluteal tendinopathy (GT) is a source of lateral hip pain, yet common clinical diagnostic tests have limited validity. Patients with GT are often misdiagnosed, resulting in inappropriate management, including surgery. This study determined the diagnostic utility of clinical tests for GT, using MRI as the reference standard. METHODS: 65 participants with lateral hip pain were examined to evaluate the ability of clinical tests to detect MRI-determined GT (an increase in intratendinous signal intensity on T2-weighted images). Palpation of the greater trochanter and several clinical pain provocation tests applying compressive and tensile loads on the gluteal tendons were investigated. MRI of the painful hip was examined by a radiologist, blind to clinical findings. RESULTS: Pain reported within 30 s of standing on the affected limb conclusively moves a (nominal) 50% pretest probability of GT presence on MRI to a post-test probability of 98% (specificity 100%, positive likelihood ratio ∼12), whereas no pain on palpation (80% sensitivity) would rule out its presence. 20 participants (31%) had GT on MRI but clinically negative (ie, not positive on palpation and another test). CONCLUSIONS: Keeping in mind that the sample size was small (ie, possibly underpowered for indices of diagnostic utility with low precision), the results of this study indicate that a patient who reports lateral hip pain within 30 s of single-leg-standing is very likely to have GT. Patients with lateral hip pain who are not palpably tender over the greater trochanter are unlikely to have MRI-detected GT.

Exercise and load modification versus corticosteroid injection versus 'wait and see' for persistent gluteus medius/minimus tendinopathy (the LEAP trial): a protocol for a randomised clinical trial.

BACKGROUND: Lateral hip pain is common, particularly in females aged 40-60 years. The pain can affect sleep and daily activities, and is frequently recalcitrant. The condition is often diagnosed as trochanteric bursitis, however radiological and surgical studies have revealed that the most common pathology is gluteus medius/minimus tendinopathy. Patients are usually offered three treatment options: (a) corticosteroid injection (CSI), (b) physiotherapy, or (c) reassurance and observation. Research on Achilles and patellar tendons has shown that load modification and exercise appears to be more effective than other treatments for managing tendinopathy, however, it is unclear whether a CSI, or a load modification and exercise-based physiotherapy approach is more effective in gluteal tendinopathy. This randomised controlled trial aims to compare the efficacy on pain and function of a load modification and exercise-based programme with a CSI and a 'wait and see' approach for gluteal tendinopathy. METHODS: Two hundred one people with gluteal tendinopathy will be randomly allocated into one of three groups: (i) CSI; (ii) physiotherapist-administered load modification and exercise intervention; and (iii) wait and see approach. The CSI therapy will consist of one ultrasound (US) guided CSI around the affected tendons and advice on tendon care. Education about load modification will be delivered in physiotherapy clinics and the exercise programme will be both home-based and supervised. The group allocated the wait and see approach will receive basic tendon care advice and reassurance in a single session by a trial physiotherapist. Outcomes will be evaluated at baseline, 4, 8, 12, 26 and 52 weeks using validated global rating of change, pain and physical function scales, psychological measures, quality of life and physical activity levels. Hip abductor muscle strength will be measured at baseline and 8 weeks. Economic evaluation will be performed to investigate the cost-effectiveness of the active interventions compared with the wait and see approach. Analyses will be conducted on an intention-to-treat basis using logistic and linear mixed regression models and the economic evaluation will report incremental cost-utility ratios. The trial reporting will comply with CONSORT guidelines. DISCUSSION: This study will provide clinicians with directly applicable evidence of the relative efficacy of three common approaches to the management of gluteal tendinopathy. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry ACTRN12612001126808. Date Registered: 22/10/2012.

Current and future advances in practice: tendinopathies of the hip.

Tendinopathy describes persistent tendon pain and loss of function related to mechanical loading. Two common hip tendinopathies seen in practice are gluteal tendinopathy and proximal hamstring tendinopathy. Both conditions can be frustrating for patients and clinicians due to the delay in diagnosis, significant disability caused and lack of response to common treatments. Tendinopathy is a clinical diagnosis and can most often be made using findings from the patient interview and pain provocation tests, without the need for imaging. Specific education and progressive exercise offer a low-risk and effective option for gluteal tendinopathy and result in greater rates of treatment success than corticosteroid injection, both in the short term (8 weeks) and at 1 year. Proximal hamstring tendinopathy is a common, but less researched, and under-recognized cause of persistent ischial pain. As research on proximal hamstring tendinopathy is limited, this review summarizes the available evidence on diagnosis and treatment following similar principles to other well-researched tendinopathies.

Loss of Intracellular Fibroblast Growth Factor 14 (iFGF14) Increases the Excitability of Mature Hippocampal and Cortical Pyramidal Neurons.

Mutations in FGF14 , which encodes intracellular fibroblast growth factor 14 (iFGF14), have been linked to spinocerebellar ataxia type 27 (SCA27), a multisystem disorder associated with progressive deficits in motor coordination and cognitive function. Mice ( Fgf14 -/- ) lacking iFGF14 display similar phenotypes, and we have previously shown that the deficits in motor coordination reflect reduced excitability of cerebellar Purkinje neurons, owing to the loss of iFGF14-mediated regulation of the voltage-dependence of inactivation of the fast transient component of the voltage-gated Na + (Nav) current, I NaT . Here, we present the results of experiments designed to test the hypothesis that loss of iFGF14 also attenuates the intrinsic excitability of mature hippocampal and cortical pyramidal neurons. Current-clamp recordings from adult mouse hippocampal CA1 pyramidal neurons in acute in vitro slices, however, revealed that repetitive firing rates were higher in Fgf14 -/- , than in wild type (WT), cells. In addition, the waveforms of individual action potentials were altered in Fgf14 -/- hippocampal CA1 pyramidal neurons, and the loss of iFGF14 reduced the time delay between the initiation of axonal and somal action potentials. Voltage-clamp recordings revealed that the loss of iFGF14 altered the voltage-dependence of activation, but not inactivation, of I NaT in CA1 pyramidal neurons. Similar effects of the loss of iFGF14 on firing properties were evident in current-clamp recordings from layer 5 visual cortical pyramidal neurons. Additional experiments demonstrated that the loss of iFGF14 does not alter the distribution of anti-Nav1.6 or anti-ankyrin G immunofluorescence labeling intensity along the axon initial segments (AIS) of mature hippocampal CA1 or layer 5 visual cortical pyramidal neurons in situ . Taken together, the results demonstrate that, in contrast with results reported for neonatal (rat) hippocampal pyramidal neurons in dissociated cell culture, the loss of iFGF14 does not disrupt AIS architecture or Nav1.6 localization/distribution along the AIS of mature hippocampal (or cortical) pyramidal neurons in situ .

Stabilization of Kv4 protein by the accessory K(+) channel interacting protein 2 (KChIP2) subunit is required for the generation of native myocardial fast transient outward K(+) currents.

The fast transient outward K(+) current (Ito,f) underlies the early phase of myocardial action potential repolarization, contributing importantly to the coordinated propagation of activity in the heart and to the generation of normal cardiac rhythms. Native Ito,f channels reflect the tetrameric assembly of Kv4 pore-forming (α) subunits, and previous studies suggest roles for accessory and regulatory proteins in controlling the cell surface expression and the biophysical properties of Kv4-encoded Ito,f channels. Here, we demonstrate that the targeted deletion of the cytosolic accessory subunit, K(+) channel interacting protein 2 (KChIP2), results in the complete loss of the Kv4.2 protein, the α subunit critical for the generation of mouse ventricular Ito,f. Expression of the Kcnd2 (Kv4.2) transcript in KChIP2(-/-) ventricles, however, is unaffected. The loss of the Kv4.2 protein results in the elimination of Ito,f in KChIP2(-/-) ventricular myocytes. In parallel with the elimination of Ito,f, the slow transient outward K(+) current (Ito,s) is upregulated and voltage-gated Ca(2+) currents (ICa,L) are decreased. In addition, surface electrocardiograms and ventricular action potential waveforms in KChIP2(-/-) and wild-type mice are not significantly different, suggesting that the upregulation of Ito,s and the reduction in ICa,L compensate for the loss of Ito,f. Additional experiments revealed that Ito,f is not 'rescued' by adenovirus-mediated expression of KChIP2 in KChIP2(-/-) myocytes, although ICa,L densities are increased. Taken together, these results demonstrate that association with KChIP2 early in the biosynthetic pathway and KChIP2-mediated stabilization of Kv4 protein are critical determinants of native cardiac Ito,f channel expression.

"Just working in a team was a great experience " - Student perspectives on the learning experiences of an interprofessional education program.

Interprofessional education (IPE) programs aim to improve collaboration between health- and social-care professionals and to optimize clinical outcomes. Such programs are complex to design, and evaluation of effectiveness is difficult. Combining qualitative and quantitative data may provide greater understanding of how a program affects participants and what aspects are influential on attitudes and behavior. This qualitative study used semi-structured interviews and interpretative phenomenological analysis to explore undergraduate student perspectives on what attributes of a 4-week IPE program they considered contributed to a successful learning experience. Due to the fact that the students were not formally assessed, the realistic context of the activities and the quality of the facilitators created an environment where the students felt empowered to interact freely without fear of reproach. Learning the roles of other professions and their contribution to a healthcare team broadened the students' perspectives on healthcare and increased their sense of self-worth and pride in their professions. In addition, being able to identify the relevance of the learning experience to their future practice motivated the students. This information can be used to create optimal learning environments for facilitating the development of successful future healthcare teams.