RESUMO
X-linked myotubular myopathy (XLMTM) is a congenital disorder caused by mutations of the myotubularin gene, MTM1. Myotubularin belongs to a large family of conserved lipid phosphatases that include both catalytically active and inactive myotubularin-related proteins (i.e., "MTMRs"). Biochemically, catalytically inactive MTMRs have been shown to form heteroligomers with active members within the myotubularin family through protein-protein interactions. However, the pathophysiological significance of catalytically inactive MTMRs remains unknown in muscle. By in vitro as well as in vivo studies, we have identified that catalytically inactive myotubularin-related protein 12 (MTMR12) binds to myotubularin in skeletal muscle. Knockdown of the mtmr12 gene in zebrafish resulted in skeletal muscle defects and impaired motor function. Analysis of mtmr12 morphant fish showed pathological changes with central nucleation, disorganized Triads, myofiber hypotrophy and whorled membrane structures similar to those seen in X-linked myotubular myopathy. Biochemical studies showed that deficiency of MTMR12 results in reduced levels of myotubularin protein in zebrafish and mammalian C2C12 cells. Loss of myotubularin also resulted in reduction of MTMR12 protein in C2C12 cells, mice and humans. Moreover, XLMTM mutations within the myotubularin interaction domain disrupted binding to MTMR12 in cell culture. Analysis of human XLMTM patient myotubes showed that mutations that disrupt the interaction between myotubularin and MTMR12 proteins result in reduction of both myotubularin and MTMR12. These studies strongly support the concept that interactions between myotubularin and MTMR12 are required for the stability of their functional protein complex in normal skeletal muscles. This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder.
Assuntos
Miopatias Congênitas Estruturais/genética , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Proteínas/genética , Peixe-Zebra/genética , Animais , Catálise , Linhagem Celular , Humanos , Camundongos , Músculo Esquelético , Músculos/metabolismo , Músculos/fisiopatologia , Mutação , Miopatias Congênitas Estruturais/fisiopatologia , Estabilidade Proteica , Proteínas Tirosina Fosfatases não Receptoras/genética , Proteínas/química , Proteínas/metabolismoRESUMO
OBJECTIVE: The global fight against COVID-19 has required mass vaccination clinics as well as mass recruitment of personnel, including many who may not regularly administer intramuscular deltoid immunizations, potentially increasing the incidence of improper intramuscular injection. Shoulder injury related to vaccine administration (SIRVA) is a well-described, preventable injury resulting from improper injection into anatomic structures adjacent to the deltoid muscle leading to mechanical and chemical trauma augmented by an inflammatory immune response to the vaccine and/or adjuvants. SIRVA is best described in the setting of influenza vaccination, and little is known about it as it pertains to COVID-19 vaccination. This study aims to describe SIRVA in the current pandemic, increase clinician awareness, and offer considerations for prevention. METHODS: To identify clinical characteristics of patients with post-COVID-19-vaccination shoulder injuries, we performed a systematic review of the cases of vaccination-related shoulder injuries reported in the literature and conducted a review of the public Vaccine Adverse Event Reporting System (VAERS). RESULTS: We identified 305 cases of SIRVA in the VAERS database and 28 cases of SIRVA in the setting of COVID-19 vaccination from the literature (n = 333). Patients had a mean age of 51.8 years and a median of 51.5 (range: 19-90) years. Of these, 76.3% were female and 23.7% male. Most patients sought medical evaluation with 54 of the 305 VAERS cases reporting utilizing emergency services. Of patients with imaging-confirmed SIRVA (n = 95), the most common diagnoses were adhesive capsulitis and bursitis, and the most common symptoms were pain (97.7%) and limited range of motion (68.1%). Most patients reported requiring treatment with the majority receiving physical therapy (56.3%), followed by cortisone injection (34.4%). Other modalities used were non-steroidal anti-inflammatory drugs, oral steroids, and surgery. Only 5 patients from this group reported recovery while 60 stated they had not yet recovered. Of those, 23.3% reported disability. CONCLUSION: SIRVA should be regarded as an under-reported, significant cause of post-vaccination morbidity. In the setting of COVID-19 mass vaccination, clinicians must be aware of signs and symptoms of SIRVA as well as appropriate diagnostic modalities and treatment options. Additionally, standardization and proper education regarding injection technique and appropriate needle length is imperative to reducing harm.
Assuntos
Bursite , Vacinas contra COVID-19 , COVID-19 , Lesões do Ombro , Bursite/diagnóstico , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lesões do Ombro/induzido quimicamente , Vacinação/efeitos adversos , Vacinas/efeitos adversosRESUMO
BACKGROUND Deep sea diving can cause decompression illness which comprises both decompression sickness and arterial gas embolism. Decompression sickness is a clinical diagnosis with symptoms including dizziness, joint pain, rash, and myalgias and is due to nitrogen bubbles that form in tissues during ascent. These gas bubbles can be clinically silent even in the absence of decompression sickness and can rarely predispose a patient to venous thrombus, for which the role of hyperbaric oxygen (HBO) is undefined. The following case describes a male diver who developed portal and mesenteric venous thrombosis secondary to silent nitrogen venous bubbles. CASE REPORT A 48-year-old man developed abdominal pain 1 day after diving to a maximum depth of 13.7 m, without clinical symptoms of decompression sickness after surfacing. He presented to the Emergency Department 10 days later, and magnetic resonance angiogram revealed a diagnosis of gas containing superior mesenteric and portal vein thrombus. Due to the lack of guidelines of HBO with the presence of a thrombus and timing since onset, HBO therapy was not pursued. Oral anticoagulation was initiated, and symptoms resolved. CONCLUSIONS This patient developed gastrointestinal illness 1 day after diving that was later found to be due to thrombosis. Other etiologies were ruled out, making silent nitrogen bubbles within the venous system the most likely etiology. Vascular thrombosis is a rare complication of diving and lacks guidelines for treatment. While HBO is a known treatment for decompression sickness, there are no clinical guidelines for diving-associated thrombi, representing an area for further research.