Statin-Induced Autoimmune Myopathy: A Diagnostic Challenge in Muscle Weakness.

BACKGROUND Statin-induced myopathy can present with symptoms ranging from mild myalgia to significant muscle weakness. Muscle-related adverse effects of statins have been very challenging in clinical practice and they necessitate high clinical suspicion. This case report highlights how statin-induced autoimmune myopathy often goes undiagnosed. CASE REPORT We present a 69-year-old man with a past medical history of coronary artery disease who presented with myalgia and progressive proximal muscle weakness for 2 months, with a creatinine kinase of 8323 U/L. Atorvastatin was held on admission and the patient received intravenous (IV) fluid as treatment for presumed rhabdomyolysis. Although CK was trending down, he did not show significant improvement in muscle weakness or myalgia. At this point, myositis was suspected, so a myositis panel including anti-HMG Co-A reductase antibody was ordered and he was started on IV steroids. Anti-HMG Co-A reductase antibody was positive, and the rest of myopathy workup was negative. Meanwhile, the patient's muscle weakness significantly improved with IV steroid. He was discharged on methylprednisolone with close outpatient rheumatology follow-up. CONCLUSIONS Muscle-related adverse effects of statins, including rhabdomyolysis and myopathy, can fail to respond to conservative management. It is crucial to identify and manage statin-induced autoimmune myopathy as a possible differential diagnosis in patients with muscle weakness and elevated CK while on statin therapy who do not respond to intravenous fluid alone.

[Summary of the best evidence for early exercise rehabilitation in patients with mechanically ventilated ICU-acquired weakness].

OBJECTIVE: To integrate the best evidence for early rehabilitation of mechanically ventilated ICU-acquired weakness (ICU-AW) patients using evidence-based methods, providing evidence-based basis for standardized evaluation and intervention of early exercise therapy for mechanically ventilated ICU-AW patients. METHODS: A systematic search was conducted on the American Thoracic Society (ATS) Clinical Practice Guidelines, Registered Nurses' Association of Ontario (RNAO), Guidelines International Network (GIN), Canadian Medical Association Clinical Practice Guideline Library (CMACPGL), BMJ Clinical Evidence, UpToDate, Scottish Intercollegiate Guidelines Network (SIGN), PubMed, Cochrane Library, National Guideline Clearinghouse (NGC), Embase, Cumulative Index to Nursing and Allied Health Literature (CINAHL), UM-library, Physiotherapy Evidence Database (PEDro), National Institute for Health and Care Excellence (NICE), New Zealand Guidelines Group (NZGG), Chinese Medical Pulse Guidelines Website, CNKI and Wanfang data and other Chinese and English databases, professional team websites, and guideline websites for expert consensus, guidelines, randomized collected trial (RCT), systematic reviews and other evidence on early exercise rehabilitation for mechanically ventilated ICU-AW patients. The search time limit was from the establishment of the database to December 31, 2023. Literature search, screening, evaluation, information extraction was independently conducted by two evaluators with cross checking, and quality evaluation of the included literature was conducted. RESULTS: A total of 21 literatures were enrolled, including 5 guidelines, 5 systematic reviews, 4 expert consensuses, and 7 RCT, all of which with high evidence level and all were enrolled. They were summarized into seven aspects with assessment screening, exercise safety standards, precautions, setting of exercise time, exercise intensity, exercise sequence, and recommended exercise content as the core, and 32 best evidences. CONCLUSIONS: The evidence summarized can provide evidence-based basis for standardized assessment and intervention of early exercise rehabilitation in mechanically ventilated ICU-AW patients. ICU medical practitioners need to combine the actual clinical environment, individual differences and rehabilitation goals of patients, to provide targeted health guidance and intervention for the prevention of ICU-AW in mechanically ventilated patients.

A meta-analysis of the association between vasopressor use and intensive care unit-acquired weakness.

OBJECTIVE: This study aims to clarify the uncertain association between vasopressor administration and the development of intensive care unit-acquired weakness (ICUAW) in critically ill adult patients. METHODS: We conducted a comprehensive search of PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials up to October 10, 2023. Titles and abstracts were independently screened by two authors, who then reviewed full texts and extracted relevant data from the studies that met the inclusion criteria. This review included prospective and retrospective cohort studies that explored the relationship between vasopressor use and ICUAW utilizing univariate or multivariate analysis in adult ICU patients. RESULTS: A total of 15 studies were included in our review, collectively indicating a statistically significant association between the use of vasopressors and the occurrence of ICUAW (odds ratio [OR], 3.43; 95% confidence intervals [CI], 1.95-6.04), including studies utilizing multivariate analysis (OR, 3.43; 95% CI, 1.76-6.70). Specifically, the use of noradrenaline was significantly associated with ICUAW (OR, 4.42; 95% CI, 1.69-11.56). Subgroup and sensitivity analyses further underscored the significant relationship between vasopressor use and ICUAW, particularly in studies focusing on patients with clinical weakness, varying study designs, different sample sizes, and relatively low risk of bias. However, this association was not observed in studies limited to patients with abnormal electrophysiology. CONCLUSIONS: Our review underscores a significant link between the use of vasopressors and the development of ICUAW in critically ill adult patients. This finding helps better identify patients at higher risk of ICUAW and suggests considering targeted therapies to mitigate this risk.

Theory-based and evidence-based nursing interventions for the prevention of ICU-acquired weakness in the intensive care unit: A systematic review.

OBJECTIVES: To synthesise and map the evidence of a theory- and evidence-based nursing intervention for the prevention of ICU-acquired weakness and evaluate its effectiveness in terms of the incidence of ICU-acquired weakness, incidence of delirium, and length of hospital stay. METHODS: We searched PubMed, CINAHL, MEDLINE, Academic Search Complete, Embase, Scopus, Web of Science and the Cochrane Library from database inception to November 2023. The eligible studies focused on critically ill patients in the intensive care unit, used a theory- and evidence-based nursing intervention, and reported the incidence of ICU-acquired weakness and/or used the Medical Research Council Scale. The methodological quality of the included studies was critically appraised by two authors using the appropriate Joanna Briggs Institute appraisal tool for randomised controlled trials, quasi-experimental studies, and cohort studies. Additionally, the weighted kappa coefficient was used to assess inter-rater agreement of the quality assessment. Data were reported using a narrative synthesis. This systematic review was registered by the International Prospective Register of Systematic Review (PROSPERO; CRD42023477011). RESULTS: A total of 5162 studies were initially retrieved, and 9 studies were eventually included after screening. This systematic review revealed that preventive nursing interventions for ICU-acquired weakness mainly include (a) physiotherapy, including neuromuscular electrical stimulation and early rehabilitation, and (b) nutritional support. In addition, (c) airway management, (d) sedation and analgesia management, (e) complication prevention (delirium, stress injury and deep vein thrombosis prevention), and (f) psychological care were also provided. The theories are dominated by goal-oriented theories, and the evidence is mainly the ABCDE bundle in the included studies. The results show that theory- or evidence-based nursing interventions are effective in reducing the incidence of ICU-acquired weakness (or improving the Medical Research Council Scale scores), decreasing the incidence of delirium, shortening the length of hospital stay, and improving patients' self-care and quality of life. CONCLUSION: Theory- and evidence-based nursing interventions have good results in preventing ICU-acquired weakness in critically ill patients. Current nursing interventions favour a combination of multiple interventions rather than just a single intervention. Therefore, preventive measures for ICU-acquired weakness should be viewed as complex interventions and should be based on theory or evidence. This systematic review is based on a small number of trials. Thus, more high-quality randomised controlled trials are needed to draw definitive conclusions about the impact of theory- and evidence-based nursing interventions on the prevention of ICU-acquired weakness.

Associação de dinapenia, sarcopenia, aptidão física e capacidade funcional em adultos fisicamente ativos no Brasil / Association of dynapenia, sarcopenia, physical fitness and functional capacity in physically active adults in Brazil

Contexto e objetivo: O envelhecimento está associado a diversas alterações fisiológicas que podem afetar a aptidão física e a capacidade funcional, como a sarcopenia e a dinapenia. O presente estudo teve como objetivo descrever e comparar aspectos físicos e funcionais de adultos em relação aos critérios de sarcopenia e dinapenia. Desenho e local: Os participantes faziam parte do Projeto Misto Longitudinal de Aptidão Física e Capacidade Funcional de São Caetano do Sul, que busca avaliar e acompanhar a saúde e o desempenho físico de idosos na região. A amostra foi composta por 1480 participantes com idade acima de 50 anos e média de 66,5 anos. Métodos: Para a classificação da sarcopenia e dinapenia, foram adotados os critérios do Asian Working Group for Sarcopenia e do European Working Group on Sarcopenia in Older People. Uma análise estatística foi realizada utilizando a análise de covariância ANCOVA não paramétrica, ajustada pelo sexo, idade e índice de massa corporal (IMC), buscando comparar a capacidade funcional entre os grupos. Foi adotado um nível de significância de P < 0,05 e o software utilizado para as análises foi o SPSS versão 25. Resultados: A prevalência de sarcopenia na amostra foi de 3% e de dinapenia, 62,3%. Foram identificadas diferenças estatisticamente significativas nas variáveis de aptidão física e capacidade funcional. Conclusão: A massa muscular isoladamente pode não ser um critério adequado para definir sarcopenia em adultos, pela não-linearidade da relação entre massa muscular e capacidade físico-funcional.

Comprehensive four-year disease progression assessment of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a heterogeneous neuromuscular disorder characterized by progressive muscle weakness and myotonia. This study investigates the progression of muscular strength and function over a four-year period. Patients with DM1 were examined at baseline and four years later. The following metrics were assessed over time: muscle strength (Medical Research Council-sumscore), hand-grip strength (Martin-Vigorimeter), hand-grip relaxation time (myotonia), and limitations in activities of daily living and (DM1ActivC questionnaire). A total of 648 patients entered the registry. Recruitment and follow-up is ongoing. In our manuscript, we focus on, 187 patients who were followed for 4 years. A significant decline in MRC sum score was observed, with distal muscles showing more deterioration. Hand-grip strength decreased significantly, with notable differences between sex and phenotype classified by disease onset. Surprisingly, an improvement of myotonia was observed. Follow-up analysis revealed a significant interaction between myotonia and grip-strength over time. Thus, the improvement in myotonia is likely explained by decreased in grip strength. Finally, there was a significant reduction in DM1ActivC score, indicating decreased activity and social participation. This study demonstrated variability in disease progression depending on sex, phenotype and disease status. This research demonstrates a nuanced pattern of disease progression, highlighting the need to combine different outcome measures to fully understand the complexity of DM1.

The Kinematics of 3D Arm Movements in Sub-Acute Stroke: Impaired Inter-Joint Coordination is Attributable to Both Weakness and Flexor Synergy Intrusion.

BACKGROUND: It has long been of interest to characterize the components of the motor abnormality in the arm after stroke. One approach has been to decompose the hemiparesis phenotype into negative signs, such as weakness, and positive signs, such as intrusion of synergies. We sought to identify the contributions of weakness and flexor synergy to motor deficits in sub-acute stroke. METHODS: Thirty-three sub-acute post-stroke participants and 16 healthy controls performed two functional arm movements; one within flexor synergy (shoulder and elbow flexion), and the other outside flexor synergy (shoulder flexion and elbow extension). We analyzed upper limb 3D kinematics to assess both overall task performance and intrusion of pathological synergies. Weakness and spasticity were also measured. RESULTS: Both tasks produced similar impairments compared to controls. Analysis of elbow and shoulder multi-joint coordination patterns revealed intrusion of synergies in the out-of-synergy reaching task based on the time spent within a flexion-flexion pattern and the correlation between shoulder and elbow angles. Regression analysis indicated that both weakness and synergy intrusion contributed to motor impairment in the out-of-synergy reaching task. Notably, the Fugl-Meyer Assessment (FMA) was abnormal even when only weakness caused the impairment, cautioning that it is not a pure synergy scale. CONCLUSIONS: Weakness and synergy intrusion contribute to motor deficits in the sub-acute post-stroke period. An abnormal FMA score cannot be assumed to be due to synergy intrusion. Careful kinematic analysis of naturalistic movements is required to better characterize the contribution of negative and positive signs to upper limb impairment after stroke.

Dysphagia Revealing a Pharyngeal-cervical-brachial Variant of Guillain-Barré Syndrome in Pediatric Cases.

We report the case of a 13-year-old child presenting an unusual case of Guillian-Barre Syndrome (SGB). Its presentation is usually a progression of symmetrical muscle weakness that ascends from the lower extremities, moves toward a more proximal pathway, and is accompanied by absent or depressed tendon reflexes. Here, the patient presented with a rare presentation of Pharyngeal-Cervical-Brachial (PCB) variant of Guillain-Barré syndrome, where the symptomatology began with dysphagia and dyspnea, and the weakness was descending paralysis. The objective of this clinical case report is to highlight this extremely rare presentation of PCB variant of Guillain-Barré syndrome.

RésuméNous décrivons le cas d'un enfant âgé de 13 ans présentant une manifestation inhabituelle du syndrome de Guillain-Barré (SGB). Habituellement, le SGB se caractérise par une faiblesse musculaire symétrique ascendante des deux membres inférieurs, accompagnée d'une perte des réflexes ostéotendineux. Dans ce cas, le patient présentait une variante rare du SGB, appelée la variante Pharyngo-Cervico-Brachiale, où les symptômes ont débuté par une dysphagie et une dyspnée, et la faiblesse musculaire était descendante. L'objectif de cet article est de documenter cette présentation extrêmement rare de la variante Pharyngo-Cervico-Brachiale du syndrome de Guillain-Barré.

Respiratory physiological mechanism of two types of equal-intensity inspiratory muscle training in stable patients with chronic obstructive pulmonary disease.

PURPOSE: This study aimed to investigate the respiratory physiological changes resulting from short-term inspiratory resistance training (R-IMT) and inspiratory threshold training (T-IMT) in patients with chronic obstructive pulmonary disease (COPD) and to compare the mechanisms of the two training methods. PATIENTS AND METHODS: A total of 75 stable patients with COPD combined with inspiratory muscle weakness were randomly allocated to three groups: R-IMT (n = 26), T-IMT (n = 24), and control (n = 25). Before and after 8 weeks of inspiratory muscle training(IMT), cardiopulmonary exercise tests were conducted to assess respiratory patterns, respiratory central drive, exercise tolerance, and ventilation efficiency. RESULTS: After 8 weeks of IMT, Inspiratory muscle strength, represented by MIP (maximum inspiratory mouth pressure) and exercise capacity increased during exercise in both IMT groups (P < 0.05). In the R-IMT group, inspiratory time (Ti) prolonged (P < 0.05), tidal volume (Vt) increased (P < 0.05), ventilation efficiency (represented by ventilation-center coupling) increased (P < 0.05) during exercise. Conversely, the T-IMT group did not exhibit any of these changes after IMT (P > 0.05). CONCLUSION: In summary, the improvement in exercise tolerance was associated with an increase in inspiratory muscle reserve in both R-IMT and T-IMT. However, only R-IMT was associated with deeper and slower breathing, as well as improved ventilation efficiency.

A Reversible Etiology of Progressive Motor Decline in a Previously Healthy Child.

We describe the clinical presentation and evaluation of a 10-year-old boy who presented to our medical center with years of progressive proximal muscle weakness, muscle atrophy, and weight loss. In addition to a myopathic phenotype, he was found to have tachycardia, tremor, and learning difficulties. Electromyography revealed chronic myopathic changes and laboratory screening was notable for undetectable thyroid stimulating hormone. Follow-up testing revealed elevated thyroid peroxidase antibodies and thyroid stimulating immunoglobulins. Ultrasound examination revealed an enlarged heterogeneous thyroid gland. Four weeks after treatment with atenolol and methimazole, his strength and cognition began to improve. This case highlights the importance of evaluating for potentially reversible toxic-metabolic etiologies in children presenting with any progressive neurologic symptoms.

Respiratory muscle strength in stroke: a case-control study.

AIM: The aim of the study was to determine the respiratory muscle strength of stroke patients and compare them with healthy individuals. METHOD: The study was conducted with 171 patients who had a stroke between 2017 and 2021 and 32 healthy controls. Respiratory muscle strength and inspiratory and expiratory mouth pressure (MIP and MEP) were measured using the portable MicroRPM device (Micro Medical, Basingstoke, UK). RESULTS: The stroke group exhibited significantly lower values in both MIP for men (p<0.001) and women (p=0.013) and maximal expiratory pressure for men (p<0.001) and women (p=0.042), compared with the healthy control group. Notably, there was a significant difference in the MIPmen (p=0.026) and MEPmen (p=0.026) values when comparing the reference values, which were calculated based on age and sex, with those of the healthy group. The baseline values calculated according to age for stroke patients were as follows: MIPmen 31.68%, MIPwomen 63.58%, MEPmen 22.54%, and MEPwomen 42.30%. CONCLUSION: This study highlights the significant respiratory muscle weakness experienced by stroke patients, with gender-specific differences. It highlights the importance of incorporating respiratory assessments and interventions into stroke rehabilitation protocols to improve the overall health and well-being of stroke patients.

Electrodiagnosis for mitigating false-negative non-responsiveness in electrical evoked contractions: A case series exploring probable polyneuromyopathy induced by nonuse.

INTRODUCTION: The revised international standards for neurological classification of spinal cord injury (ISNCSCI) have facilitated the documentation of non-spinal cord injury-related impairments, such as chronic peripheral nerve injuries and muscle weakness due to immobility. This advancement addresses potential biases in muscle strength examinations. Utilizing electrically evoked contractions from paralyzed muscles, enhanced by electrodiagnosis, holds promise in identifying false-negative diagnoses of non-responsiveness to neuromuscular electrical stimulation. This concept prompts the exploration of polyneuromyopathy arising from nonuse in paralyzed muscles. CASE SERIES PRESENTATION: To substantiate our hypothesis, we recruited nine participants for a case series aimed at elucidating the potential benefits of incorporating the stimulus electrodiagnostic test (SET) to mitigate non-responsiveness during preparation for functional electrical stimulation (FES)-assisted cycling. In our convenience sample (n = 5), we conducted neurological mapping based on ISNCSCI and applied SET on the quadriceps. The SET guided optimal dosimetry for evoking contractions and revealed responses similar to those observed in peripheral neuropathies, with α coefficients equal to or lower than 2.00. This observation is likely attributable to nonuse of paralyzed muscles, indicative of an ongoing polyneuropathy in individuals with chronic spinal cord injury (SCI). DISCUSSION: Among the nine initially recruited subjects, seven exhibited responsiveness to neuromuscular electrical stimulation (78% responsiveness), with two participants excluded based on exclusion criteria. In the final five reported cases, all displayed α coefficient values indicating impaired neuromuscular accommodation, and one presented no α coefficient within the normal range. The inclusion of electrodiagnosis appears effective in averting non-responsiveness, suggesting the presence of ongoing polyneuropathies in paralyzed muscles.

Anti-HMGCR myopathy: Diversity of clinical presentations in a national cohort in New Zealand.

AIMS: We describe the varied clinical presentations, barriers in diagnosis and outcomes of anti-HMGCR myopathy in a large national cohort. METHODS: Adults found positive for serum anti-HMGCR autoantibodies via line blot or enzyme-immunoassay followed by immunoprecipitation were included in the study. RESULTS: Of 75 patients identified, the records of 72 (96 %) described weakness as the presenting symptom. The records of 65 gave a reliable description of proximal weakness. In 22/65 (33.8 %) the weakness was described as predominantly or solely lower limb weakness. Forty-five of 75 (60 %) presented with a subacute onset (duration of symptoms >4 weeks -≤6 months), whilst 22/75 (29.3 %) presented with a more indolent chronic onset (duration of symptoms >6 months). Eighteen of 75 (24 %) suffered falls and 2/75 (2.7 %) had "general decline". In three patients no weakness was described: two presented with myalgia and one with a skin rash characterized as Jessner lymphocytic skin rash. Median creatine kinase at presentation was 7337 U/L (range 1050-25,500). Muscle biopsy was performed in 38 (50.7 %). Associated malignancy was infrequent. Four patients recovered without immunosuppression. Five-year and 10-year survival was 92.7 % (95 % CI 80.6-97.4 %), and 82.5 % (95 % CI 61.2-92.8 %) respectively. CONCLUSION: Recurrent falls, a long prodrome and dominant lower limb proximal weakness were common in this anti-HMGCR myopathy cohort. These features overlap with frailty syndrome and sporadic inclusion body myositis emphasizing the importance of considering anti-HMGCR myopathy in that clinical context. A minority of patients recover after statin withdrawal alone.

Characterization of Clinical Phenotypes in Congenital Myasthenic Syndrome Associated with the c.1327delG Frameshift Mutation in CHRNE Encoding the Acetylcholine Receptor Epsilon Subunit.

Background: Congenital myasthenic syndromes (CMS) are a group of rare but often treatable inherited disorders of neuromuscular transmission characterized by fatigable skeletal muscle weakness. In this paper we present the largest phenotypic analysis to date of a cohort of patients carrying the pathogenic variant c.1327delG in the CHRNE gene, leading to CHRNE-CMS. Objective: This study aims to identify the phenotypic variability in CMS associated with c.1327delG mutation in the CHRNE gene. Methods: Disease specific symptoms were assessed using specific standardized tests for autoimmune myasthenia (Quantitative Myasthenia Gravis score) as well as patient-reported scales for symptom severity. Evaluated clinical manifestations included ocular symptoms (ophthalmoparesis and ptosis), bulbar weakness, axial muscle weakness, proximal and distal muscle weakness, and respiratory function. Patients were allocated into three groups according to clinical impression of disease severity: mild, moderate, and severe. Results: We studied 91 Bulgarian Roma patients, carrying the same causative homozygous CHRNE c.1327delG mutation. Bulbar weakness was present in patients throughout all levels of severity of CHRNE-CMS in this study. However, difficulties in eating and swallowing are more prominent characteristics in the moderate and severe clinical phenotypes. Diplopia and ptosis resulting from fatigue of the extraocular muscles were permanent features regardless of disease severity or age. Levels of axial, proximal and distal muscle weakness were variable between disease groups. The statistical analysis showed significant differences between the patients in the three groups, emphasizing a possible variation in symptom manifestation in the evaluated patient population despite the disease originating from the same genetic mutation. Impairment of respiratory function was more prominent in severely affected patients, which might result from loss of compensatory muscle function in those individuals. Conclusion: Results from our study indicate significant phenotypic heterogeneity leading to mild, moderate, or severe clinical manifestation in CHRNE-CMS, despite the genotypic homogeneity.

Association of handgrip strength asymmetry and weakness with depression among middle-aged and older population in China: A cohort study.

BACKGROUND: Handgrip strength (HGS) weakness and asymmetry were recently reported to be associated with age-related health conditions. However, little is known about their combined effects on depression. We aimed to explore the joint association of HGS asymmetry and weakness with depressive symptoms in Chinese middle and older aged population. METHODS: 8700 participants aged ≥45 years were enrolled from China Health and Retirement Longitudinal Study (2015-2018). HGS weakness was determined as maximal HGS < 28 kg in males and <18 kg in females. HGS asymmetry was measured by HGS ratio and was defined using two different rules. Specifically, HGS ratio < 0.90 or >1.10 (10 % rule) and <0.80 or >1.20 (20 % rule) were considered as asymmetry. Participants were classified into four groups: normal and symmetric HGS, asymmetry only, weakness only, and both weakness and asymmetry. Depressive symptoms were assessed by the 10-item Center for Epidemiologic Studies Depression Scale, with scores ≥12 defined as depression. The logistic regression and multiple linear regression models were conducted to estimate the associations between HGS status and depressive symptoms. RESULTS: The three-year incidence of depression was 19.2 %. After adjusting for covariates, compared to normal and symmetric HGS, participants with both HGS asymmetry and weakness showed the greatest risk of incident depression (10 % rule: OR 1.55, 95 % CI 1.19-2.02; 20 % rule: OR 1.71, 95 % CI 1.16-2.50). The coexistence of asymmetry and weakness was related to a significant increase in depression score (10 % rule: ß 0.96, 95 % CI 0.38-1.54; 20 % rule: ß 0.94, 95 % CI 0.08-1.81). The complete case analysis supported the results, and the associations were not modified by age, sex, and hand dominance. LIMITATIONS: Depressive assessment was based on self-reported screening instrument. CONCLUSIONS: The presence of both HGS asymmetry and weakness was associated with a higher risk of depression. Examining HGS asymmetry along with weakness may aid in identifying individuals at risk of depression to enable early interventions.

Alterations in coenzyme Q10 status in a cybrid line harboring the 3243A>G mutation of mitochondrial DNA is associated with abnormal mitochondrial bioenergetics and dysregulated mitochondrial biogenesis.

Mitochondrial DNA (mtDNA) mutations, including the m.3243A>G mutation that causes mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), are associated with secondary coenzyme Q10 (CoQ10) deficiency. We previously demonstrated that PPARGC1A knockdown repressed the expression of PDSS2 and several COQ genes. In the present study, we compared the mitochondrial function, CoQ10 status, and levels of PDSS and COQ proteins and genes between mutant cybrids harboring the m.3243A>G mutation and wild-type cybrids. Decreased mitochondrial energy production, defective respiratory function, and reduced CoQ10 levels were observed in the mutant cybrids. The ubiquinol-10:ubiquinone-10 ratio was lower in the mutant cybrids, indicating blockage of the electron transfer upstream of CoQ, as evident from the reduced ratio upon rotenone treatment and increased ratio upon antimycin A treatment in 143B cells. The mutant cybrids exhibited downregulation of PDSS2 and several COQ genes and upregulation of COQ8A. In these cybrids, the levels of PDSS2, COQ3-a isoform, COQ4, and COQ9 were reduced, whereas those of COQ3-b and COQ8A were elevated. The mutant cybrids had repressed PPARGC1A expression, elevated ATP5A levels, and reduced levels of mtDNA-encoded proteins, nuclear DNA-encoded subunits of respiratory enzyme complexes, MNRR1, cytochrome c, and DHODH, but no change in TFAM, TOM20, and VDAC1 levels. Alterations in the CoQ10 level in MELAS may be associated with mitochondrial energy deficiency and abnormal gene regulation. The finding of a reduction in the ubiquinol-10:ubiquinone-10 ratio in the MELAS mutant cybrids differs from our previous discovery that cybrids harboring the m.8344A>G mutation exhibit a high ubiquinol-10:ubiquinone-10 ratio.

Clinical spreading of muscle weakness in amyotrophic lateral sclerosis (ALS): a study in 910 patients.

BACKGROUND: Neuroanatomical staging of sporadic amyotrophic lateral sclerosis (ALS) indicates that neurodegeneration may spread corticofugally. METHODS: We conducted an observational study to define the initial sites of disease onset and the clinical progression ('spreading patterns') of motor deficits in a cohort of 910 ALS patients in Germany. RESULTS: Mean age of ALS onset was 59.0 ± 12.6 years for males and 61.2 ± 10.5 years for females, the mean ALSFRS-R was 35.1 ± 9.2, and 7.7% of the cohort reported a family history. Onset of motor symptoms was bulbar/upper limb in 26.8%/35.9%, the right arm initially being slightly more often affected than the left (18.5% vs.16.3%). Testing on concordance of handedness and onset in the dominant arm did not reach significance. Lower limb onset was observed in 37.3%. Unilateral limb onset patients reported horizontal spreading about three times more often than vertical spreading. 71/244 bulbar onset patients reported spreading pattern to the legs, and 17/339 lumbar onset patients reported spreading secondarily to the bulbar region. DISCUSSION: Our results indicate that, although the phenotype of so-called 'spinal' or 'intraspinal' spreading predominated, we also observed an additional clinical spreading pattern: 29.1% of patients with bulbar onset experienced spreading clinically to the legs (vice versa in 5.0% of lumbar onset patients). For obvious neuroanatomical reasons, this pattern hardly can be explained solely by a 'spinal' or an 'intraspinal' pattern of spreading. Instead, these findings complement insights from previous clinical and clinicopathological studies supporting a cortical initiation of ALS.

Shoulder muscle weakness and proprioceptive impairments in type 2 diabetes mellitus: exploring correlations for improved clinical management.

Background: Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder with systemic implications, potentially affecting musculoskeletal health. This study aimed to assess shoulder muscle strength and joint repositioning accuracy in individuals with T2DM, exploring potential correlations and shedding light on the musculoskeletal consequences of the condition. The objectives were two-fold: (1) to assess and compare shoulder strength and joint repositioning accuracy between individuals with T2DM and asymptomatic counterparts, and (2) to examine the correlation between shoulder strength and joint repositioning accuracy in individuals with T2DM. Methods: A cross-sectional study enrolled 172 participants using the convenience sampling method, including 86 individuals with T2DM and an age-matched asymptomatic group (n = 86). Shoulder strength was assessed using a handheld dynamometer, while joint repositioning accuracy was evaluated with an electronic digital inclinometer. Results: Individuals with T2DM exhibited reduced shoulder muscle strength compared to asymptomatic individuals (p < 0.001). Additionally, joint repositioning accuracy was significantly lower in the T2DM group (p < 0.001). Negative correlations were observed between shoulder strength and joint repositioning accuracy in various directions (ranging from -0.29 to -0.46, p < 0.001), indicating that higher muscle strength was associated with improved joint repositioning accuracy in individuals with T2DM. Conclusion: This study highlights the significant impact of T2DM on shoulder muscle strength and joint repositioning accuracy. Reduced strength and impaired accuracy are evident in individuals with T2DM, emphasizing the importance of addressing musculoskeletal aspects in diabetes management. The negative correlations suggest that enhancing shoulder muscle strength may lead to improved joint repositioning accuracy, potentially contributing to enhanced physical functioning in this population.