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1.
Medicine (Baltimore) ; 99(33): e21734, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872058

RESUMO

To compare clinical characteristics and identify long-term outcomes of Chinese patients with systemic sclerosis (SSc) with and without muscle involvement.We retrospectively investigated the medical records, laboratory results, and computed tomography images of 204 consecutive SSc patients. Kaplan-Meier analysis was performed to determine survival rates. Patients were allocated into groups with and without myopathy.The prevalence of myopathy was 21.6%. The myopathy group was more likely to develop diffuse cutaneous involvement (90.9% vs 56%, P = .006), interstitial lung disease (90% vs 56%, P < .001), digestive system involvement (56.7% vs 29.3%, P = .001), pulmonary hypertension (29.5% vs 10.5%, P = .004), and pericardial effusion (25% vs. 10%, P = .019). Patients with myopathy had lower single-breath diffusing capacity of the lung for carbon oxide (46.5 ±â€Š11.1 vs 57.1 ±â€Š13.4, P < .001).Further, the myopathy group has similar results in interstitial lung disease associated higher resolution computed tomography score (186.8 ±â€Š64.5 vs 152.3 ±â€Š45.5, P = .037), Valentini score for disease activity (3.4 ±â€Š0.9 vs 2.0 ±â€Š0.9, P < .001) and modified Rodnan total skin score (19.4 ±â€Š6.1 vs 15.1 ±â€Š7.7, P = .002), compared with non-myopathy group. Kaplan-Meier survival analysis revealed decreased overall survival rate of the myopathy group (P = .028).SSc Patients with myopathy had more severe clinical manifestations and higher disease activity compared with those without, which affected survival rates and indicated worse prognosis.


Assuntos
Doenças Musculares/mortalidade , Escleroderma Sistêmico/mortalidade , Adulto , Idoso , China/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/etiologia , Estudos Retrospectivos , Escleroderma Sistêmico/complicações
2.
Medicine (Baltimore) ; 99(30): e21377, 2020 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-32791748

RESUMO

RATIONALE: It is recommended that patients with Rheumatic diseases that are at high risk of developing active infections be screened for Tuberculosis, Hepatitis B, and Hepatitis C before receiving second-line immunosuppressive therapies. With the emergence 2019 novel coronavirus (SARS-CoV-2), expanded guidelines have not been proposed for screening in these patients before starting advanced therapy. PATIENT CONCERNS: We present an unique circumstance whereas a patient with a 5 year history of inflammatory muscle disease, diagnosed by clinical history and muscle biopsy with elevated creatine kinase levels, suffered a hypoxemic cardiopulmonary arrest due to asymptomatic SARS-CoV-2 after receiving advanced immunosuppressive therapy. DIAGNOSES: The patient presented with an acute exacerbation of inflammatory muscle disease with dysphagia, muscle weakness, and elevated creatine kinase. INTERVENTIONS: After no improvement with intravenous immunoglobulin the patient received mycophenolate and plasma exchange therapy. OUTCOMES: Subsequently the patient suffered a fatal hypoxemic cardiopulmonary arrest. Polymerase chain reaction test was positive for SARS-CoV-2 RNA. LESSONS: We conclude that rheumatic patients, asymptomatic for SARS-CoV-2 infection, be screened and tested before initiating second-line immunosuppressive treatment.


Assuntos
Betacoronavirus , Infecções por Coronavirus/induzido quimicamente , Parada Cardíaca/virologia , Doenças Musculares/tratamento farmacológico , Pneumonia Viral/induzido quimicamente , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Evolução Fatal , Parada Cardíaca/induzido quimicamente , Humanos , Imunossupressores , Masculino , Pessoa de Meia-Idade , Doenças Musculares/virologia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/virologia
3.
Am J Cardiol ; 128: 168-173, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32650915

RESUMO

The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) is assessed controversially. LVHT is associated with other cardiac abnormalities and with neuromuscular disorders (NMD). Aim of the study was to assess cardiac and neurological findings as predictors of mortality rate in adult LVHT-patients. Included were patients with LVHT diagnosed between 1995 and 2019 in 1 echocardiographic laboratory. Patients underwent a baseline cardiologic examination and were invited for a neurological investigation. In January 2020, their survival status was assessed. End points were death or heart transplantation. LVHT was diagnosed by echocardiography in 310 patients (93 female, aged 53 ± 18 years) with a prevalence of 0.4%/year. A neurologic investigation was performed in 205 patients (67%). A specific NMD was found in 33 (16%), NMD of unknown etiology in 123 (60%) and the neurological investigation was normal in 49 (24%) patients. During follow-up of 84 ± 71 months, 59 patients received electronic devices, 105 patients died, and 6 underwent heart transplantation. The mortality was 4.7%/year, the rate of heart transplantation/death 5%/year. By multivariate analysis, the following parameters were identified to elevate the risk of mortality/heart transplantation: increased age (p = 0.005), inpatient (p = 0.001), presence of a specific NMD (p = 0.0312) or NMD of unknown etiology (p = 0.0365), atrial fibrillation (p = 0.0000), ventricular premature complexes (p = 0.0053), exertional dyspnea (p = 0.0023), left bundle branch block (p = 0.0201), and LVHT of the posterior wall (p = 0.0158). In conclusion, LVHT patients should be systematically investigated neurologically since neurological co-morbidity has a prognostic impact.


Assuntos
Fibrilação Atrial/epidemiologia , Bloqueio de Ramo/epidemiologia , Transplante de Coração/estatística & dados numéricos , Miocárdio Ventricular não Compactado Isolado/epidemiologia , Mortalidade , Doenças Neuromusculares/epidemiologia , Adulto , Idoso , Comorbidade , Ecocardiografia , Ecocardiografia Doppler , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doenças Musculares/epidemiologia , Distrofia Muscular de Duchenne/epidemiologia , Distrofia Miotônica/epidemiologia , Atrofia Óptica Hereditária de Leber/epidemiologia , Síndrome Pós-Poliomielite/epidemiologia , Prognóstico , Modelos de Riscos Proporcionais
4.
Adv Exp Med Biol ; 1207: 689-697, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671786

RESUMO

In addition to tumors and aging that are associated with autophagy, many other diseases are also regulated by autophagy, including liver disease, myopathy, immune pathogen infection, cardiovascular disease, and so on. This chapter will detail the relationship between autophagy and these diseases and their underlying molecular mechanisms. We summarized the current research status of autophagy as a target for the treatment of related diseases, and prospected the development of related drugs and therapeutic strategies. We hope to provide new ideas for finding new therapeutic targets through the autophagic signaling pathways.


Assuntos
Autofagia/efeitos dos fármacos , Doenças Cardiovasculares/tratamento farmacológico , Desenvolvimento de Medicamentos , Infecções/tratamento farmacológico , Hepatopatias/tratamento farmacológico , Doenças Musculares/tratamento farmacológico , Humanos , Transdução de Sinais/efeitos dos fármacos
5.
PLoS One ; 15(7): e0235702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634159

RESUMO

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.


Assuntos
Artrite Reumatoide/complicações , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Idoso , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores , Modelos Animais de Doenças , Feminino , Glicogênio/metabolismo , Humanos , Inflamação , Locomoção , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Mialgia/etiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Transcriptoma
8.
Vet Clin North Am Equine Pract ; 36(2): 353-378, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654785

RESUMO

There are 5 single-gene mutations that are known to cause muscle disease in horses. These mutations alter the amino acid sequence of proteins involved in cell membrane electrical conduction, muscle energy metabolism, muscle contraction, and immunogenicity. The clinical signs depend on the pathway affected. The likelihood that an animal with a mutation will exhibit clinical signs depends on the mode of inheritance, environmental influences, and interactions with other genes. Selection of a genetic test for use in diagnostic or breeding decisions requires a knowledge of clinical signs, mode of inheritance, breeds affected, and proper scientific test validation.


Assuntos
Doenças dos Cavalos/genética , Doenças Musculares/veterinária , Animais , Doenças dos Cavalos/metabolismo , Cavalos , Doenças Musculares/genética , Doenças Musculares/metabolismo
9.
Toxicol Appl Pharmacol ; 401: 115076, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479918

RESUMO

Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.


Assuntos
Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Sinvastatina/toxicidade , Vitamina D/administração & dosagem , Animais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Doenças Musculares/metabolismo , Distribuição Aleatória
10.
Medicine (Baltimore) ; 99(21): e20233, 2020 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-32481297

RESUMO

BACKGROUND: Sepsis-induced myopathy (SIM) is a disease that causes motor dysfunction in patients with sepsis. There is currently no targeted treatment for this disease. Acupuncture has shown considerable efficacy in the treatment of sepsis and muscle weakness. Therefore, our research aims to explore the effects of acupuncture on the improvement of muscle structure and function in SIM patients and on activities of daily living. METHODS: The ACU-SIM pilot study is a single-center, propensity-score stratified, assessor-blinded, prospective pragmatic controlled trial (pCT) with a 1-year follow-up period. This study will be deployed in a multi-professional critical care department at a tertiary teaching hospital in Guangzhou, China. Ninety-eight intensive care unit subjects will be recruited and assigned to either the control group or the acupuncture group. Both groups will receive basic treatment for sepsis, and the acupuncture group will additionally receive acupuncture treatment. The primary outcomes will be the rectus femoris cross-sectional area, the Medical Research Council sum-score and time-to-event (defined as all-cause mortality or unplanned readmission to the intensive care unit due to invasive ventilation). The activities of daily living will be accessed by the motor item of the Functional Independence Measure. Recruitment will last for 2 years, and each patient will have a 1-year follow-up after the intervention. DISCUSSION: There is currently no research on the therapeutic effects of acupuncture on SIM. The results of this study may contribute to new knowledge regarding early muscle atrophy and the treatment effect of acupuncture in SIM patients, and the results may also direct new approaches and interventions in these patients. This trial will serve as a pilot study for an upcoming multicenter real-world study. TRIAL REGISTRATION: Chinese Clinical Trials Registry: ChiCTR-1900026308, registered on September 29th, 2019.


Assuntos
Terapia por Acupuntura/métodos , Debilidade Muscular/terapia , Atrofia Muscular/terapia , Doenças Musculares/terapia , Sepse/terapia , Atividades Cotidianas , Terapia por Acupuntura/efeitos adversos , China/epidemiologia , Cuidados Críticos/organização & administração , Seguimentos , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Mortalidade/tendências , Debilidade Muscular/etiologia , Debilidade Muscular/patologia , Atrofia Muscular/etiologia , Atrofia Muscular/patologia , Doenças Musculares/etiologia , Readmissão do Paciente/tendências , Projetos Piloto , Pontuação de Propensão , Estudos Prospectivos , Respiração Artificial/métodos , Respiração Artificial/estatística & dados numéricos , Sepse/complicações , Centros de Atenção Terciária/organização & administração , Resultado do Tratamento
11.
Zhonghua Er Ke Za Zhi ; 58(6): 476-481, 2020 Jun 02.
Artigo em Chinês | MEDLINE | ID: mdl-32521959

RESUMO

Objective: To evaluate and improve the performance of the newborn screening program for primary carnitine deficiency (PCD) based on tandem mass spectrometry and to investigate the incidence of PCD and molecular characteristics of SLC22A5 gene in Guangzhou. Methods: A total of 200 180 neonates born in Guangzhou from 2015 to 2019 were enrolled into the newborn screening program for PCD by tandem mass spectrometry at Guangzhou Newborn Screening Center. The positive results of screening for PCD was defined as free carnitine (C0) less than 10 µmol/L with decreased acylcarnitine species in dried blood spots of three to seven days after birth. Screen-positive newborns and their mothers were recalled for another blood spot sample. The diagnosis was confirmed based on decreased levels of C0 and acylcarnitine species in recalled blood spots and genetic analysis in SLC22A5 gene sequencing. The utility of using the sum of propionylcarnitine and palmitoylcarnitine (C3+C16) as a biomarker for acylcarnitine species in newborn screening was retrospectively evaluated. The levels of C0 and (C3+C16) at first screening were compared between newborns with PCD and newborns born to mothers with PCD by independent t test. The variant spectrum and known pathogenic variants carrier rate of SLC22A5 in 2 395 healthy children in Guangzhou Women and Children's Medical Center through whole exon sequencing were analyzed. Results: Among 200 180 neonates, 239 (0.12%) cases were screen-positive for PCD. A total of 37 patients including 15 newborns and 22 mothers had confirmed PCD. The incidence of PCD was 1/13 345 in newborns and 1/9 099 in mothers, respectively. The positive predictive value of this program was 15.5%. Taking cutoff values of C0<8.5 µmol/L or C0 8.5~9.9 µmol/L with (C3+C16)<2 µmol/L, the number of screen-positive cases would be reduced from 810 to 224 without additional false negative case, when compared with cutoff value C0<10 µmol/L only. Both levels of C0 and (C3+C16) at first screening were not significant difference between newborns with PCD and newborns born to mothers with PCD ((6.2±2.4) vs. (5.0±1.8) µmol/L, (1.4±0.4) vs. (1.2±0.5) µmol/L, t=3.826, 0.326; P=0.058, 0.572). Seven PCD mothers experienced moderate fatigue and dizziness in the morning. One of them presented with cardiomyopathy in pregnancy. Genetic analysis of the SLC22A5 gene showed that p.S467C, p.F17L, p.R254X were the three most common variants in newborns with PCD. In PCD mothers and healthy children, the p.S467C, p.F17L and R399W were the three most common whereas the severe variant p.R254X was rare. The population carrier rate for pathogenic variants was 1 in 65 and the estimated incidence of PCD was about 1/16 500. Conclusions: Newborn screening can detect PCD both in newborns and mothers. Adding a quantitative biomarker (C3+C16) <2 µmol/L into the newborn screening program can improve the PCD screen performance. The severe variant p.R253X was common in PCD newborns but rare in PCD mothers and healthy children, indicating that the current screening program maybe failed to detect all PCD newborns and under-estimated the incidence rate of PCD in Guangzhou.


Assuntos
Cardiomiopatias/genética , Carnitina/sangue , Carnitina/deficiência , Hiperamonemia/diagnóstico , Doenças Musculares/diagnóstico , Triagem Neonatal/métodos , Membro 5 da Família 22 de Carreadores de Soluto/genética , Cardiomiopatias/diagnóstico , Cardiomiopatias/metabolismo , Carnitina/genética , Criança , Feminino , Predisposição Genética para Doença , Humanos , Hiperamonemia/genética , Recém-Nascido , Doenças Musculares/genética , Gravidez , Estudos Retrospectivos , Espectrometria de Massas em Tandem
12.
Internist (Berl) ; 61(8): 854-859, 2020 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-32504300

RESUMO

A case report is presented of fulminant hydroxychloroquine-induced cardiomyopathy in a 57 year-old female patient with a long history of systemic lupus erythematosus. Diagnosis was established based on clinical findings, imaging (echocardiography and cardiac magnetic resonance imaging) as well as endomyocardial biopsy. Despite immediate discontinuation of the medication, the patient died from heart failure within a few days. Since the rare adverse effect described here might be reversible, early diagnosis and discontinuation of hydroxychloroquine are crucial for the prognosis of these patients.


Assuntos
Cardiomiopatias/induzido quimicamente , Insuficiência Cardíaca/mortalidade , Hidroxicloroquina/efeitos adversos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Biópsia , Cardiomiopatias/mortalidade , Ecocardiografia , Evolução Fatal , Feminino , Coração/efeitos dos fármacos , Insuficiência Cardíaca/induzido quimicamente , Humanos , Hidroxicloroquina/uso terapêutico , Imagem por Ressonância Magnética , Pessoa de Meia-Idade
15.
Lancet Diabetes Endocrinol ; 8(7): 594-605, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32559475

RESUMO

BACKGROUND: Disordered thyroid hormone transport, due to mutations in the SLC16A2 gene encoding monocarboxylate transporter 8 (MCT8), is characterised by intellectual and motor disability resulting from cerebral hypothyroidism and chronic peripheral thyrotoxicosis. We sought to systematically assess the phenotypic characteristics and natural history of patients with MCT8 deficiency. METHODS: We did an international, multicentre, cohort study, analysing retrospective data from Jan 1, 2003, to Dec 31, 2019, from patients with MCT8 deficiency followed up in 47 hospitals in 22 countries globally. The key inclusion criterion was genetically confirmed MCT8 deficiency. There were no exclusion criteria. Our primary objective was to analyse the overall survival of patients with MCT8 deficiency and document causes of death. We also compared survival between patients who did or did not attain full head control by age 1·5 years and between patients who were or were not underweight by age 1-3 years (defined as a bodyweight-for-age Z score <-2 SDs or <5th percentile according to WHO definition). Other objectives were to assess neurocognitive function and outcomes, and clinical parameters including anthropometric characteristics, biochemical markers, and neuroimaging findings. FINDINGS: Between Oct 14, 2014, and Jan 17, 2020, we enrolled 151 patients with 73 different MCT8 (SLC16A2) mutations. Median age at diagnosis was 24·0 months (IQR 12·0-60·0, range 0·0-744·0). 32 (21%) of 151 patients died; the main causes of mortality in these patients were pulmonary infection (six [19%]) and sudden death (six [19%]). Median overall survival was 35·0 years (95% CI 8·3-61·7). Individuals who did not attain head control by age 1·5 years had an increased risk of death compared with patients who did attain head control (hazard ratio [HR] 3·46, 95% CI 1·76-8·34; log-rank test p=0·0041). Patients who were underweight during age 1-3 years had an increased risk for death compared with patients who were of normal bodyweight at this age (HR 4·71, 95% CI 1·26-17·58, p=0·021). The few motor and cognitive abilities of patients did not improve with age, as evidenced by the absence of significant correlations between biological age and scores on the Gross Motor Function Measure-88 and Bayley Scales of Infant Development III. Tri-iodothyronine concentrations were above the age-specific upper limit in 96 (95%) of 101 patients and free thyroxine concentrations were below the age-specific lower limit in 94 (89%) of 106 patients. 59 (71%) of 83 patients were underweight. 25 (53%) of 47 patients had elevated systolic blood pressure above the 90th percentile, 34 (76%) of 45 patients had premature atrial contractions, and 20 (31%) of 64 had resting tachycardia. The most consistent MRI finding was a global delay in myelination, which occurred in 13 (100%) of 13 patients. INTERPRETATION: Our description of characteristics of MCT8 deficiency in a large patient cohort reveals poor survival with a high prevalence of treatable underlying risk factors, and provides knowledge that might inform clinical management and future evaluation of therapies. FUNDING: Netherlands Organisation for Health Research and Development, and the Sherman Foundation.


Assuntos
Biomarcadores/análise , Transtornos Mentais/patologia , Transportadores de Ácidos Monocarboxílicos/deficiência , Doenças Musculares/patologia , Transtornos do Neurodesenvolvimento/patologia , Simportadores/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Agências Internacionais , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Transportadores de Ácidos Monocarboxílicos/genética , Doenças Musculares/etiologia , Mutação , Transtornos do Neurodesenvolvimento/etiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Simportadores/genética , Adulto Jovem
16.
PLoS One ; 15(6): e0234207, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32497100

RESUMO

The misfolding and aggregation of proteins is often implicated in the development and progression of degenerative diseases. Heat shock proteins (HSPs), such as the ubiquitously expressed Type II Hsp40 molecular chaperone, DNAJB6, assist in protein folding and disaggregation. Historically, mutations within the DNAJB6 G/F domain have been associated with Limb-Girdle Muscular Dystrophy type 1D, now referred to as LGMDD1, a dominantly inherited degenerative disease. Recently, novel mutations within the J domain of DNAJB6 have been reported in patients with LGMDD1. Since novel myopathy-causing mutations in the Hsp40 J domain have yet to be characterized and both the function of DNAJB6 in skeletal muscle and the clients of this chaperone are unknown, we set out to assess the effect of these mutations on chaperone function using the genetically tractable yeast system. The essential yeast Type II Hsp40, Sis1, is homologous to DNAJB6 and is involved in the propagation of yeast prions. Using phenotypic, biochemical, and functional assays we found that homologous mutations in the Sis1 J domain differentially alter the processing of specific yeast prion strains, as well as a non-prion substrate. These data suggest that the newly-identified mutations in the J domain of DNAJB6 cause aberrant chaperone function that leads to the pathogenesis in LGMDD1.


Assuntos
Proteínas de Choque Térmico HSP40/química , Proteínas de Choque Térmico HSP40/genética , Doenças Musculares/genética , Mutação , Processamento de Proteína Pós-Traducional , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica , Proteínas de Choque Térmico HSP40/metabolismo , Humanos , Camundongos , Modelos Moleculares , Domínios Proteicos , Redobramento de Proteína
17.
Physiother Theory Pract ; 36(6): 663-668, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: covidwho-291096

RESUMO

This manuscript provides support for physical therapists to focus on the long-term, as well as the short-term, consequences of acute respiratory distress syndrome (ARDS) associated with COVID-19. Since late November 2019, COVID-19 has become a global health pandemic and threat. Although most people have no or mild symptoms, COVID-19 spreads aggressively and can lead to ARDS rapidly in a proportion of individuals. The evidence supports that gas exchange and countering the negative effects of bed rest and immobility are priorities in severely affected patients admitted to the intensive care unit (ICU). However, in recent years, research has focused on poor long-term functional outcomes in patients with ARDS, often associated with ICU-acquired weakness, deconditioning, and myopathies and neuropathies. In addition to physical therapists providing respiratory support in the ICU, the literature unequivocally supports the view that early intervention for ICU management of patients with ARDS secondary to COVID-19 needs to focus on reducing contributors to impaired long-term function, with direct attention paid to preventing or managing ICU-acquired weakness, deconditioning, and myopathies and neuropathies, in conjunction with respiratory care.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças Musculares/prevenção & controle , Doenças Musculares/virologia , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/virologia , Infecções por Coronavirus/terapia , Cuidados Críticos , Humanos , Pandemias , Pneumonia Viral/terapia
18.
Nat Commun ; 11(1): 2417, 2020 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-32415060

RESUMO

Striated muscle contraction is regulated by the translocation of troponin-tropomyosin strands over the thin filament surface. Relaxation relies partly on highly-favorable, conformation-dependent electrostatic contacts between actin and tropomyosin, which position tropomyosin such that it impedes actomyosin associations. Impaired relaxation and hypercontractile properties are hallmarks of various muscle disorders. The α-cardiac actin M305L hypertrophic cardiomyopathy-causing mutation lies near residues that help confine tropomyosin to an inhibitory position along thin filaments. Here, we investigate M305L actin in vivo, in vitro, and in silico to resolve emergent pathological properties and disease mechanisms. Our data suggest the mutation reduces actin flexibility and distorts the actin-tropomyosin electrostatic energy landscape that, in muscle, result in aberrant contractile inhibition and excessive force. Thus, actin flexibility may be required to establish and maintain interfacial contacts with tropomyosin as well as facilitate its movement over distinct actin surface features and is, therefore, likely necessary for proper regulation of contraction.


Assuntos
Citoesqueleto de Actina/metabolismo , Actinas/química , Doenças Musculares/patologia , Animais , Animais Geneticamente Modificados , Cardiomiopatia Hipertrófica , Biologia Computacional , Drosophila melanogaster/metabolismo , Feminino , Voo Animal , Humanos , Ligação de Hidrogênio , Masculino , Microscopia de Fluorescência , Simulação de Dinâmica Molecular , Contração Muscular , Mutação , Análise de Componente Principal , Multimerização Proteica , Eletricidade Estática , Transgenes , Tropomiosina/química
19.
Physiother Theory Pract ; 36(6): 663-668, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32419564

RESUMO

This manuscript provides support for physical therapists to focus on the long-term, as well as the short-term, consequences of acute respiratory distress syndrome (ARDS) associated with COVID-19. Since late November 2019, COVID-19 has become a global health pandemic and threat. Although most people have no or mild symptoms, COVID-19 spreads aggressively and can lead to ARDS rapidly in a proportion of individuals. The evidence supports that gas exchange and countering the negative effects of bed rest and immobility are priorities in severely affected patients admitted to the intensive care unit (ICU). However, in recent years, research has focused on poor long-term functional outcomes in patients with ARDS, often associated with ICU-acquired weakness, deconditioning, and myopathies and neuropathies. In addition to physical therapists providing respiratory support in the ICU, the literature unequivocally supports the view that early intervention for ICU management of patients with ARDS secondary to COVID-19 needs to focus on reducing contributors to impaired long-term function, with direct attention paid to preventing or managing ICU-acquired weakness, deconditioning, and myopathies and neuropathies, in conjunction with respiratory care.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Doenças Musculares/prevenção & controle , Doenças Musculares/virologia , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/virologia , Infecções por Coronavirus/terapia , Cuidados Críticos , Humanos , Pandemias , Pneumonia Viral/terapia
20.
Phys Ther ; 100(9): 1681-1689, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32367136

RESUMO

OBJECTIVE: There is limited knowledge on how exercise impacts the pelvic floor muscles (PFM) and prevalence of stress urinary incontinence (SUI) and pelvic organ prolapse (POP) postpartum. The purpose of this study was to investigate whether early onset of general exercise postpartum negatively affects the PFM and/or increases the risk of SUI and POP 12 months postpartum. METHODS: This study used a prospective cohort design. At 6 weeks postpartum, 57 women classified as exercisers (exercising ≥3 times at ≥30 min/wk) were compared with 120 nonexercisers (mean age = 29 years, SD = 4.3). Manometry was used to measure vaginal resting pressure, PFM strength, and PFM endurance, and symptoms of SUI and POP were assessed using questionnaires. Data were presented as standardized beta coefficients (B) and odds ratios (OR). RESULTS: No differences were found between exercisers (n = 57) and non-exercisers (n = 120) at 6 weeks postpartum on vaginal resting pressure (B = -0.04 [95% CI = -3.4 to 2.1]), PFM strength (B = 0.03 [95% CI = -4.7 to 7.4]), PFM endurance (B = -0.02 [95% CI = -59 to 46]), or symptoms of SUI (OR = 0.51 [95% CI = 0.25 to 1.1]) or POP (OR = 0.62 [95% CI = 0.26 to 1.5]) measured at 12 months postpartum. Adjusting for covariates, women with body mass index between 25 and 29.9 and >30 were more likely to report SUI 12 months postpartum (OR = 2.2 [95% CI = 1.0 to 4.7] and OR = 3.3 [95% CI = 1.2 to 9.4], respectively). Women with physically strenuous occupations were more likely to report POP 12 months postpartum (OR = 3.0 [95% CI = 1.2 to 7.3]). CONCLUSIONS: This study suggests that regular exercise 6 weeks postpartum has no negative effect on PFM function or on SUI or POP. Being overweight, however, was associated with more SUI, and women with physically strenuous occupations reported more POP. IMPACT: Results from this study suggest that first-time mothers should be encouraged to start general exercise within the first 6 weeks after giving birth. Women at risk for PFD should be advised accordingly and potentially modifiable risk factors should be addressed prior to delivery. LAY SUMMARY: First-time mothers are encouraged to talk with a physical therapist about starting regular general exercise in the early postpartum weeks. Health care providers should advise patients on possible preventive measures for women at risk for PFD.


Assuntos
Exercício Físico/fisiologia , Doenças Musculares/epidemiologia , Diafragma da Pelve/fisiologia , Período Pós-Parto/fisiologia , Adulto , Feminino , Humanos , Manometria , Força Muscular/fisiologia , Ocupações , Sobrepeso/complicações , Paridade , Prolapso de Órgão Pélvico/epidemiologia , Prolapso de Órgão Pélvico/etiologia , Gravidez , Prevalência , Estudos Prospectivos , Incontinência Urinária por Estresse/epidemiologia , Incontinência Urinária por Estresse/etiologia , Vagina/fisiologia
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