Effectiveness of telehealth-delivered massed trauma-focused psychotherapy among veterans with posttraumatic stress disorder.

Trauma-focused psychotherapies can be effectively delivered using a massed delivery format. Telehealth treatment for posttraumatic stress disorder (PTSD) using evidence-based interventions has been shown to be as effective as in-person treatment. However, the effectiveness of evidence-based treatments for PTSD over telehealth using the massed delivery format requires further examination. To examine the effectiveness of telehealth massed PTSD treatment, we report on a quality improvement study of 33 veterans (75.8% male; MAge = 42.3, SD = 11.0) who participated in a virtual 4-week massed PTSD program at a Department of Veterans Affairs (VA) medical center. Twenty-seven (81.8%) veterans completed the treatment and reported large reductions in PTSD (d = 1.48) and depressive symptoms (d = 1.08) at Week 4 and at 1-month follow-up (PTSD, d = 1.34; depression, d = 0.70). Results suggested that evidence-based treatment for PTSD can be effectively delivered in a massed format over telehealth in a VA medical setting. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Troriluzole rescues glutamatergic deficits, amyloid and tau pathology, and synaptic and memory impairments in 3xTg-AD mice.

Alzheimer's disease (AD) is a neurodegenerative condition in which clinical symptoms are highly correlated with the loss of glutamatergic synapses. While later stages of AD are associated with markedly decreased glutamate levels due to neuronal loss, in the early stages, pathological accumulation of glutamate and hyperactivity contribute to AD pathology and cognitive dysfunction. There is increasing awareness that presynaptic dysfunction, particularly synaptic vesicle (SV) alterations, play a key role in mediating this early-stage hyperactivity. In the current study, we sought to determine whether the 3xTg mouse model of AD that exhibits both beta-amyloid (Aß) and tau-related pathology would exhibit similar presynaptic changes as previously observed in amyloid or tau models separately. Hippocampal cultures from 3xTg mice were used to determine whether presynaptic vesicular glutamate transporters (VGlut) and glutamate are increased at the synaptic level while controlling for postsynaptic activity. We observed that 3xTg hippocampal cultures exhibited increased VGlut1 associated with an increase in glutamate release, similar to prior observations in cultures from tau mouse models. However, the SV pool size was also increased in 3xTg cultures, an effect not previously observed in tau mouse models but observed in Aß models, suggesting the changes in pool size may be due to Aß and not tau. Second, we sought to determine whether treatment with troriluzole, a novel 3rd generation tripeptide prodrug of the glutamate modulator riluzole, could reduce VGlut1 and glutamate release to restore cognitive deficits in 8-month-old 3xTg mice. Treatment with troriluzole reduced VGlut1 expression, decreased basal and evoked glutamate release, and restored cognitive deficits in 3xTg mice. Together, these findings suggest presynaptic alterations are early events in AD that represent potential targets for therapeutic intervention, and these results support the promise of glutamate-modulating drugs such as troriluzole in Alzheimer's disease.

Safety of pulsed field ablation in more than 17,000 patients with atrial fibrillation in the MANIFEST-17K study.

Pulsed field ablation (PFA) is an emerging technology for the treatment of atrial fibrillation (AF), for which pre-clinical and early-stage clinical data are suggestive of some degree of preferentiality to myocardial tissue ablation without damage to adjacent structures. Here in the MANIFEST-17K study we assessed the safety of PFA by studying the post-approval use of this treatment modality. Of the 116 centers performing post-approval PFA with a pentaspline catheter, data were received from 106 centers (91.4% participation) regarding 17,642 patients undergoing PFA (mean age 64, 34.7% female, 57.8% paroxysmal AF and 35.2% persistent AF). No esophageal complications, pulmonary vein stenosis or persistent phrenic palsy was reported (transient palsy was reported in 0.06% of patients; 11 of 17,642). Major complications, reported for ~1% of patients (173 of 17,642), were pericardial tamponade (0.36%; 63 of 17,642) and vascular events (0.30%; 53 of 17,642). Stroke was rare (0.12%; 22 of 17,642) and death was even rarer (0.03%; 5 of 17,642). Unexpected complications of PFA were coronary arterial spasm in 0.14% of patients (25 of 17,642) and hemolysis-related acute renal failure necessitating hemodialysis in 0.03% of patients (5 of 17,642). Taken together, these data indicate that PFA demonstrates a favorable safety profile by avoiding much of the collateral damage seen with conventional thermal ablation. PFA has the potential to be transformative for the management of patients with AF.

Characteristics of patients with myofascial pain syndrome of the low back.

The objective of this study is to determine characteristics of patients with myofascial pain syndrome (MPS) of the low back and the degree to which the low back pain in the patients examined can be attributed to MPS. Twenty-five subjects with myofascial trigger point(s) [MTrP(s)] on the low back participated in this cross-sectional study. The location, number, and type of selected MTrPs were identified by palpation and verified by ultrasound. Pain pressure threshold, physical function, and other self-reported outcomes were measured. Significant differences were found in Group 1 (Active), 2 (Latent), 3 (Atypical, no twitching but with spontaneous pain), and 4 (Atypical, no twitching and no spontaneous pain) of participants in the number of MTrPs, current pain, and worst pain in the past 24 h (p = .001-.01). There were interaction effects between spontaneous pain and twitching response on reports of physical function, current pain, and worst pain (p = .002-.04). Participants in Group 3 reported lower levels of physical function, and higher levels of current pain and worst pain compared to those in Group 4. Participants in Group 1 and 2 had similar levels of physical function, current pain, and worst pain. The number of MTrPs is most closely associated with the level of pain. Spontaneous pain report seems to be a decisive factor associated with poor physical function; however, twitching response is not.

Recently recycled synaptic vesicles use multi-cytoskeletal transport and differential presynaptic capture probability to establish a retrograde net flux during ISVE in central neurons.

Presynapses locally recycle synaptic vesicles to efficiently communicate information. During use and recycling, proteins on the surface of synaptic vesicles break down and become less efficient. In order to maintain efficient presynaptic function and accommodate protein breakdown, new proteins are regularly produced in the soma and trafficked to presynaptic locations where they replace older protein-carrying vesicles. Maintaining a balance of new proteins and older proteins is thus essential for presynaptic maintenance and plasticity. While protein production and turnover have been extensively studied, it is still unclear how older synaptic vesicles are trafficked back to the soma for recycling in order to maintain balance. In the present study, we use a combination of fluorescence microscopy, hippocampal cell cultures, and computational analyses to determine the mechanisms that mediate older synaptic vesicle trafficking back to the soma. We show that synaptic vesicles, which have recently undergone exocytosis, can differentially utilize either the microtubule or the actin cytoskeleton networks. We show that axonally trafficked vesicles traveling with higher speeds utilize the microtubule network and are less likely to be captured by presynapses, while slower vesicles utilize the actin network and are more likely to be captured by presynapses. We also show that retrograde-driven vesicles are less likely to be captured by a neighboring presynapse than anterograde-driven vesicles. We show that the loss of synaptic vesicle with bound molecular motor myosin V is the mechanism that differentiates whether vesicles will utilize the microtubule or actin networks. Finally, we present a theoretical framework of how our experimentally observed retrograde vesicle trafficking bias maintains the balance with previously observed rates of new vesicle trafficking from the soma.

Impact of dissociation on exposure therapy for PTSD outcomes and Adherence among U.S. Military service members.

Emotional engagement is necessary for successful exposure therapy for posttraumatic stress disorder (PTSD), but dissociation is considered a barrier to emotional engagement. Virtual reality exposure therapy (VRE) uses multi-sensory virtual environments to increase emotional engagement during exposure therapy, and average treatment outcomes are comparable to traditional exposure therapy. However, individual factors (e.g., depression) can predict differential responses to VRE. Studies have yet to investigate whether VRE would be more effective in treating patients with dissociation compared to traditional PE. This secondary analysis of a randomized clinical trial explores whether dissociation predicts treatment outcomes to exposure therapy among active-duty soldiers (N = 108) diagnosed with PTSD. We also examine whether individuals reporting dissociative symptoms demonstrated differential treatment responses to VRE and PE. Results indicated a significant two-way interaction between dissociation and time in treatment, such that dissociation blunted the negative relationship between time and PTSD symptoms. Dissociation was not associated with treatment session attendance or drop out. Results also revealed no significant effect of treatment group (PE or VRE) on the relationship between dissociation and PTSD symptoms. Findings contribute to a body of literature supporting the potential clinical and research utility of a dissociative subtype of PTSD.

A kinesin-1 adaptor complex controls bimodal slow axonal transport of spectrin in Caenorhabditis elegans.

An actin-spectrin lattice, the membrane periodic skeleton (MPS), protects axons from breakage. MPS integrity relies on spectrin delivery via slow axonal transport, a process that remains poorly understood. We designed a probe to visualize endogenous spectrin dynamics at single-axon resolution in vivo. Surprisingly, spectrin transport is bimodal, comprising fast runs and movements that are 100-fold slower than previously reported. Modeling and genetic analysis suggest that the two rates are independent, yet both require kinesin-1 and the coiled-coil proteins UNC-76/FEZ1 and UNC-69/SCOC, which we identify as spectrin-kinesin adaptors. Knockdown of either protein led to disrupted spectrin motility and reduced distal MPS, and UNC-76 overexpression instructed excessive transport of spectrin. Artificially linking spectrin to kinesin-1 drove robust motility but inefficient MPS assembly, whereas impairing MPS assembly led to excessive spectrin transport, suggesting a balance between transport and assembly. These results provide insight into slow axonal transport and MPS integrity.

Automated Signal Quality Assessment of Single-Lead ECG Recordings for Early Detection of Silent Atrial Fibrillation.

Atrial fibrillation (AF) is an arrhythmic cardiac disorder with a high and increasing prevalence in aging societies, which is associated with a risk for stroke and heart failure. However, early detection of onset AF can become cumbersome since it often manifests in an asymptomatic and paroxysmal nature, also known as silent AF. Large-scale screenings can help identifying silent AF and allow for early treatment to prevent more severe implications. In this work, we present a machine learning-based algorithm for assessing signal quality of hand-held diagnostic ECG devices to prevent misclassification due to insufficient signal quality. A large-scale community pharmacy-based screening study was conducted on 7295 older subjects to investigate the performance of a single-lead ECG device to detect silent AF. Classification (normal sinus rhythm or AF) of the ECG recordings was initially performed automatically by an internal on-chip algorithm. The signal quality of each recording was assessed by clinical experts and used as a reference for the training process. Signal processing stages were explicitly adapted to the individual electrode characteristics of the ECG device since its recordings differ from conventional ECG tracings. With respect to the clinical expert ratings, the artificial intelligence-based signal quality assessment (AISQA) index yielded strong correlation of 0.75 during validation and high correlation of 0.60 during testing. Our results suggest that large-scale screenings of older subjects would greatly benefit from an automated signal quality assessment to repeat measurements if applicable, suggest additional human overread and reduce automated misclassifications.

Procedural performance between two cryoballoon systems for ablation of atrial fibrillation depends on pulmonary vein anatomy.

Background: Cryoballoon ablation is a first-line therapy for atrial fibrillation. We compared the efficacy and safety of two ablation systems and addressed the influence of pulmonary vein (PV) anatomy on performance and outcome. Methods: We consecutively enrolled 122 patients who were planned for first-time cryoballoon ablation. Patients were assigned 1:1 for ablation with the POLARx or the Arctic Front Advance Pro (AFAP) system and followed-up for 12 months. Procedural parameters were recorded during the ablation. Before the procedure, a magnetic resonance angiography (MRA) of the PVs was generated and diameter, area, and shape of each PV ostium were assessed. We applied an evaluated PV anatomical scoring system on our MRA measurement data ranging from 0 (best anatomical combination) to 5. Results: Procedures performed with POLARx were associated with shorter time to balloon temperature -30°C (p < .001), lower balloon nadir temperature (p < .001), and longer thawing time till 0°C (p < .001) in all PVs, however, time to isolation was similar. We observed a decreasing performance with each increase in the score for the AFAP, whereas the POLARx performed constant regardless of the score. At 1 year, AF recurred in 14 of 44 patients treated with AFAP (31.8%) and in 10 of 45 patients treated with POLARx (22.2%) (hazard ratio, 0.61; 95% CI 0.28 to 1.37; p = .225). There was no significant correlation between PV anatomy and clinical outcome. Conclusion: We found significant differences in cooling kinetics, especially when anatomical conditions are difficult. However, both systems have a comparable outcome and safety profile.

MicroRNA-21 mediated cross-talk between cardiomyocytes and fibroblasts in patients with atrial fibrillation.

Background: Atrial fibrosis represents a major hallmark in disease progression of atrial fibrillation (AF). We have previously shown that circulating microRNA-21 (miR-21) correlates with the extent of left atrial fibrosis in patients undergoing catheter ablation for AF and can serve as a biomarker to predict ablation success. In this study, we aimed to validate the role of miR-21-5p as a biomarker in a large cohort of AF patients and to investigate its pathophysiological role in atrial remodeling. Methods: For the validation cohort, we included 175 patients undergoing catheter ablation for AF. Bipolar voltage maps were obtained, circulating miR-21-5p was measured, and patients were followed-up for 12 months including ECG holter monitoring. AF was simulated by tachyarrhythmic pacing of cultured cardiomyocytes, the culture medium was transferred to fibroblast, and fibrosis pathways were analysed. Results: 73.3% of patients with no/minor LVAs, 51.4% of patients with moderate LVAs and only 18.2% of patients with extensive LVAs were in stable sinus rhythm (SR) 12 months after ablation (p < 0.01). Circulating miR-21-5p levels significantly correlated with the extent of LVAs and event-free survival. In-vitro tachyarrhythmic pacing of HL-1 cardiomyocytes resulted in an increased miR-21-5p expression. Transfer of the culture medium to fibroblasts induced fibrosis pathways and collagen production. The HDAC1 inhibitor mocetinostat was found to inhibit atrial fibrosis development. Conclusion: We validated miR-21-5p as a biomarker that reflects the extent of left atrial fibrosis in AF patients. Furthermore, we found that miR-21-5p is released in-vitro from cardiomyocytes under tachyarrhythmic conditions and stimulates fibroblasts in a paracrine mode to induce collagen production.

[Tachycardiomyopathy]. / Tachykardiomyopathie.

Tachycardiomyopathy (TMP) is the development of heart failure due to a cardiac arrhythmia - triggered by rapid and/or irregular ventricular actions. TMP is in principle a (at least partially) reversible disease, so that control of the arrhythmia is of central importance. This article provides an overview of the causes, diagnosis and therapy.

rTg(TauP301L)4510 mice exhibit increased VGlut1 in hippocampal presynaptic glutamatergic vesicles and increased extracellular glutamate release.

The molecular pathways that contribute to the onset of symptoms in tauopathy models, including Alzheimer's disease (AD), are difficult to distinguish because multiple changes can happen simultaneously at different stages of disease progression. Understanding early synaptic alterations and their supporting molecular pathways is essential to develop better pharmacological targets to treat AD. Here, we focus on an early onset rTg(TauP301L )4510 tauopathy mouse model that exhibits hyperexcitability in hippocampal neurons of adult mice that is correlated with presynaptic changes and increased extracellular glutamate levels. However, it is not clear if increased extracellular glutamate is caused by presynaptic changes alone, or if presynaptic changes are a contributing factor among other factors. To determine whether pathogenic tau alters presynaptic function and glutamate release, we studied cultured hippocampal neurons at 14-18 days in vitro (DIV) from animals of both sexes to measure presynaptic changes in tauP301L positive mice. We observed that presynaptic vesicles exhibit increased vesicular glutamate transporter 1 (VGlut1) using immunohistochemistry of fixed cells and an established pH-sensitive green fluorescent protein approach. We show that tauP301L positive neurons exhibit a 40% increase in VGlut1 per vesicle compared to tauP301L negative littermates. Further, we use the extracellular glutamate reporter iGluSnFR to show that increased VGlut1 per vesicle directly translates into a 40% increase in extracellular glutamate. Together, these results show that increased extracellular glutamate levels observed in tauP301L mice are not caused by increased vesicle exocytosis probability but rather are directly related to increased VGlut1 transporters per synaptic vesicle.

Personalized Medicine Approach in a DCM Patient with LMNA Mutation Reveals Dysregulation of mTOR Signaling.

BACKGROUND: Mutations in the Lamin A/C (LMNA) gene are responsible for about 6% of all familial dilated cardiomyopathy (DCM) cases which tend to present at a young age and follow a fulminant course. METHODS: We report a 47-year-old DCM patient with severely impaired left ventricular ejection fraction and NYHA functional class IV despite optimal heart failure treatment. Whole-exome sequencing revealed an LMNA E161K missense mutation as the pathogenetic cause for DCM in this patient. We generated a patient-specific LMNA-knock in (LMNA-KI) in vitro model using mES cells. RESULTS: Beta adrenergic stimulation of cardiomyocytes derived from LMNA-KI mES cells resulted in augmented mTOR signaling and increased dysregulation of action potentials, which could be effectively prevented by the mTOR-inhibitor rapamycin. A cardiac biopsy confirmed strong activation of the mTOR-signaling pathway in the patient. An off-label treatment with oral rapamycin was initiated and resulted in an improvement in left ventricular ejection fraction (27.8% to 44.5%), NT-BNP (8120 ng/L to 2210 ng/L) and NYHA functional class. CONCLUSION: We have successfully generated the first in vitro model to recapitulate a patient-specific LMNA E161K mutation which leads to a severe form of DCM. The model may serve as a template for individualized and specific treatment of heart failure.

Virtual Standardized Patients for Mental Health Education.

PURPOSE OF REVIEW: The training of psychiatrists and other mental health professionals requires education on a range of interpersonal, communication, and psychotherapy techniques. Classroom and workshop training must be augmented by experiential learning with feedback for skill implementation with fidelity. Virtual standardized patients (VSPs) are computerized conversational agents that can support experiential learning through standardized, consequence-free training environments at reduced costs. RECENT FINDINGS: Research on mental health VSPs is rife with feasibility and acceptability pilot studies across various training populations and settings. Users have generally reported positive reactions to training with VSPs, though frustrations with some VSP speech recognition or VSP response relevance has been reported. Several studies have demonstrated a promising transfer of clinical skills from VSP training to human standardized patients and randomized trials supporting improved skill relative to reading or academic study are encouraging. As technology improves and natural language processing and accurate computer response generation for broad ranging conversational topics emerges, the field would benefit from research on the characteristics of effective VSPs for a range of purposes and trainee populations. Well-designed randomized evaluations of VSPs relative to best practices in education are needed, particularly regarding the impact of VSPs on clinical practice among actual patients.

Myosin V Regulates Spatial Localization of Different Forms of Neurotransmitter Release in Central Synapses.

Synaptic active zone (AZ) contains multiple specialized release sites for vesicle fusion. The utilization of release sites is regulated to determine spatiotemporal organization of the two main forms of synchronous release, uni-vesicular (UVR) and multi-vesicular (MVR). We previously found that the vesicle-associated molecular motor myosin V regulates temporal utilization of release sites by controlling vesicle anchoring at release sites in an activity-dependent manner. Here we show that acute inhibition of myosin V shifts preferential location of vesicle docking away from AZ center toward periphery, and results in a corresponding spatial shift in utilization of release sites during UVR. Similarly, inhibition of myosin V also reduces preferential utilization of central release sites during MVR, leading to more spatially distributed and temporally uniform MVR that occurs farther away from the AZ center. Using a modeling approach, we provide a conceptual framework that unites spatial and temporal functions of myosin V in vesicle release by controlling the gradient of release site release probability across the AZ, which in turn determines the spatiotemporal organization of both UVR and MVR. Thus myosin V regulates both temporal and spatial utilization of release sites during two main forms of synchronous release.

Psychophysiology during exposure to trauma memories: Comparative effects of virtual reality and imaginal exposure for posttraumatic stress disorder.

BACKGROUND: This investigation involved an in-depth examination of psychophysiological responses during exposure to the trauma memory across 10 sessions among active duty soldiers with combat-related posttraumatic stress disorder (PTSD) treated by Prolonged Exposure (PE) or Virtual Reality Exposure (VRE). We compared psychophysiological changes, session-by-session, between VRE and traditional imaginal exposure. METHODS: Heart rate (HR), galvanic skin response (GSR), and peripheral skin temperature were collected every 5 min during exposure sessions with 61 combat veterans of Iraq/Afghanistan and compared to the PTSD Checklist (PCL-C) and Clinician-Administered PTSD Scale (CAPS) outcomes using multilevel modeling. RESULTS: Over the course of treatment, participants in the PE group had higher HR arousal compared to participants in the VRE group. With reference to GSR, in earlier sessions, participants demonstrated a within-session increase, whereas, in later sessions, participants showed a within-session habituation response. A significant interaction was found for GSR and treatment assignment for within-session change, within-person effect, predicting CAPS (d = 0.70) and PCL-C (d = 0.66) outcomes. CONCLUSION: Overall, these findings suggest that exposure to traumatic memories activates arousal across sessions, with GSR being most associated with reductions in PTSD symptoms for participants in the PE group.

Specific Point-of-Care Testing of Coagulation in Patients Treated with Dabigatran.

BACKGROUND AND PURPOSE: Accurate and rapid assessment of coagulation status is necessary to guide thrombolysis or reversal of anticoagulation in stroke patients, but commercially available point-of-care (POC) assays are not suited for coagulation testing in patients treated with direct oral anticoagulants (DOACs). We aimed to evaluate the direct thrombin monitoring (DTM) test card by Helena Laboratories (Texas, United States) for anti-IIa-specific POC coagulation testing, hypothesizing that its POC-ecarin clotting time (POC-ECT) accurately reflects dabigatran plasma concentrations. METHODS: A prospective single-center diagnostic study (ClinicalTrials.gov-identifier: NCT02825394) was conducted enrolling patients receiving a first dose of dabigatran and patients already on dabigatran treatment. Blood samples were collected before drug intake and 0.5, 1, 2, 8, and 12 hours after intake. POC-ECT was performed using whole blood (WB), citrated blood (CB), and citrated plasma (CP). Dabigatran plasma concentrations were determined by mass spectrometry. RESULTS: In total, 240 blood samples from 40 patients contained 0 to 275 ng/mL of dabigatran. POC-ECT with WB/CB/CP ranged from 20 to 186/184/316 seconds. Pearson's correlation coefficient showed a strong correlation between dabigatran concentrations and POC-ECT with WB/CB/CP (R2 = 0.78/0.90/0.92). Dabigatran concentrations >30 and >50 ng/mL (thresholds for thrombolysis, surgery, and reversal therapy according to clinical guidelines) were detected by POC-ECT with WB/CB/CP (>36/35/45 and >43/45/59 seconds) with 95/97/97 and 96/98/97% sensitivity, and 81/87/94 and 74/60/91% specificity. CONCLUSION: This first study evaluating DOAC-specific POC coagulation testing revealed an excellent correlation of POC-ECT with actual dabigatran concentrations. Detecting clinically relevant dabigatran levels with high sensitivity/specificity, the DTM assay represents a suitable diagnostic tool in acute stroke, hemorrhage, and urgent surgery.

[24h Electrocardiography: step by step]. / Langzeit-EKG ­ Schritt für Schritt.

24h electrocardiography is an important diagnostic tool in modern cardiology. It has the ability to detect cardiac arrythmias that occur intermittently and therefore can be missed in a standard ECG. However, interpretation of the Holter ECG traces can be difficult and ambiguous. Here, we suggest a step-wise approach to identify all major heart rhythm disorders.

Experience in screening for atrial fibrillation and monitoring arrhythmia using a single-lead ECG stick.

Atrial fibrillation (AF) is the most common arrhythmia and is highly associated with increased morbidity and mortality. Since many AF episodes remain subclinical, screening for AF is considered a desirable approach for timely diagnosis, prevention of sequelae and effective treatment. Recently, devices for AF detection-stand-alone or integrated in mobile health technology-have become available and show promising preliminary results in the detection and monitoring of arrhythmia. This review describes the technical aspects of a single-lead ECG stick and summarizes the current literature, experience in large-scale screening for AF in pharmacies and potential fields of application.

Loss of supervillin causes myopathy with myofibrillar disorganization and autophagic vacuoles.

The muscle specific isoform of the supervillin protein (SV2), encoded by the SVIL gene, is a large sarcolemmal myosin II- and F-actin-binding protein. Supervillin (SV2) binds and co-localizes with costameric dystrophin and binds nebulin, potentially attaching the sarcolemma to myofibrillar Z-lines. Despite its important role in muscle cell physiology suggested by various in vitro studies, there are so far no reports of any human disease caused by SVIL mutations. We here report four patients from two unrelated, consanguineous families with a childhood/adolescence onset of a myopathy associated with homozygous loss-of-function mutations in SVIL. Wide neck, anteverted shoulders and prominent trapezius muscles together with variable contractures were characteristic features. All patients showed increased levels of serum creatine kinase but no or minor muscle weakness. Mild cardiac manifestations were observed. Muscle biopsies showed complete loss of large supervillin isoforms in muscle fibres by western blot and immunohistochemical analyses. Light and electron microscopic investigations revealed a structural myopathy with numerous lobulated muscle fibres and considerable myofibrillar alterations with a coarse and irregular intermyofibrillar network. Autophagic vacuoles, as well as frequent and extensive deposits of lipoproteins, including immature lipofuscin, were observed. Several sarcolemma-associated proteins, including dystrophin and sarcoglycans, were partially mis-localized. The results demonstrate the importance of the supervillin (SV2) protein for the structural integrity of muscle fibres in humans and show that recessive loss-of-function mutations in SVIL cause a distinctive and novel myopathy.