Hutchinson-Gilford progeria syndrome: Rejuvenating old drugs to fight accelerated ageing.

What if the next generation of successful treatments was hidden in the current pharmacopoeia? Identifying new indications for existing drugs, also called the drug repurposing or drug rediscovery process, is a highly efficient and low-cost strategy. First reported almost a century ago, drug repurposing has emerged as a valuable therapeutic option for diseases that do not have specific treatments and rare diseases, in particular. This review focuses on Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder that induces accelerated and precocious aging, for which drug repurposing has led to the discovery of several potential treatments over the past decade.

Replenishing NAD+ content reduces aspects of striated muscle disease in a dog model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene and loss of the protein dystrophin, which ultimately leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Among the developed therapeutic strategies for DMD, gene therapy approaches partially restore micro-dystrophin or quasi-dystrophin expression. However, despite extensive attempts to develop definitive therapies for DMD, the standard of care remains corticosteroid, which has only palliative benefits. Animal models have played a key role in studies of DMD pathogenesis and treatment development. The golden retriever muscular dystrophy (GRMD) dog displays a phenotype aligning with the progressive course of DMD. Therefore, canine studies may translate better to humans. Recent studies suggested that nicotinamide adenine dinucleotide (NAD+) cellular content could be a critical determinant for striated muscle function. We showed here that NAD+ content was decreased in the striated muscles of GRMD, leading to an alteration of one of NAD+ co-substrate enzymes, PARP-1. Moreover, we showed that boosting NAD+ content using nicotinamide (NAM), a natural NAD+ precursor, modestly reduces aspects of striated muscle disease. Collectively, our results provide mechanistic insights into DMD.

Actin-microtubule cytoskeletal interplay mediated by MRTF-A/SRF signaling promotes dilated cardiomyopathy caused by LMNA mutations.

Mutations in the lamin A/C gene (LMNA) cause dilated cardiomyopathy associated with increased activity of ERK1/2 in the heart. We recently showed that ERK1/2 phosphorylates cofilin-1 on threonine 25 (phospho(T25)-cofilin-1) that in turn disassembles the actin cytoskeleton. Here, we show that in muscle cells carrying a cardiomyopathy-causing LMNA mutation, phospho(T25)-cofilin-1 binds to myocardin-related transcription factor A (MRTF-A) in the cytoplasm, thus preventing the stimulation of serum response factor (SRF) in the nucleus. Inhibiting the MRTF-A/SRF axis leads to decreased α-tubulin acetylation by reducing the expression of ATAT1 gene encoding α-tubulin acetyltransferase 1. Hence, tubulin acetylation is decreased in cardiomyocytes derived from male patients with LMNA mutations and in heart and isolated cardiomyocytes from Lmnap.H222P/H222P male mice. In Atat1 knockout mice, deficient for acetylated α-tubulin, we observe left ventricular dilation and mislocalization of Connexin 43 (Cx43) in heart. Increasing α-tubulin acetylation levels in Lmnap.H222P/H222P mice with tubastatin A treatment restores the proper localization of Cx43 and improves cardiac function. In summary, we show for the first time an actin-microtubule cytoskeletal interplay mediated by cofilin-1 and MRTF-A/SRF, promoting the dilated cardiomyopathy caused by LMNA mutations. Our findings suggest that modulating α-tubulin acetylation levels is a feasible strategy for improving cardiac function.

Brain activity and upper limb movement analysis in children with Down syndrome undergoing transcranial direct current stimulation combined with virtual reality training: study protocol for a randomized controlled trial.

BACKGROUND: Children with Down syndrome have poorer functional and sensory skills compared to children with typical development. Virtual reality (VR) training could help improve these skills. Moreover, transcranial direct current stimulation (tDCS) has achieved promising results in terms of enhancing the effects of physical and sensory therapy by modulating cortical excitability. METHODS/DESIGN: Two investigations are proposed: (1) an observational study with a convenience sample consisting of children with Down syndrome (group 1-cognitive age of 6 to 12 years according to the Wechsler Abbreviated Scale of Intelligence) and children with typical development 6 to 12 years of age (group 2). Both groups will undergo evaluations on a single day involving a three-dimensional analysis of upper limb movements, an analysis of muscle activity of the biceps and brachial triceps muscles and an analysis of visuospatial and cognitive-motor variables. (2) Analysis of clinical intervention: a pilot study and clinical trial will be conducted involving individuals with Down syndrome (cognitive age of 6 to 12 years according to the Wechsler Abbreviated Scale of Intelligence). The sample will be defined after conducting a pilot study with the same methodology as that to be used in the main study. The participants will be randomly allocated to two groups: An experimental group submitted to anodal tDCS combined with a VR game and a manual motor task and a control group submitted to sham tDCS combined with a VR game and a manual motor task. The training protocol will involve 10 sessions of active or sham tDCS during memory and motor task games. Three 20-min sessions will be held per week for a total of 10 sessions. Evaluations will be performed on three different occasions: pre-intervention, post-intervention (after 10 sessions) and follow-up (1 month after the intervention). Evaluations will consist of analyses of electroencephalographic signals, electromyographic signals of the biceps and triceps brachii, and the three-dimensional reconstruction of the reaching movement. The results will be analyzed statistically with the significance level set at 5% (p ≤ 0.05). DISCUSSION: The optimization of the results obtained with virtual reality training is believed to be related to the interactive experience with a wide range of activities and scenarios involving multiple sensory channels and the creation of exercises, the intensity of which can be adjusted to the needs of children. Therefore, the proposed study aims to complement the literature with further information on tDCS and VR training considering different variables to provide the scientific community with clinical data on this combination of interventions. TRIAL REGISTRATION: Brazilian Clinical Trials Registry (REBEC) protocol number RBR-43pk59 registered on 2019 March 27 https://ensaiosclinicos.gov.br/rg/RBR-43pk59 and Human Research Ethics Committee number 3.608.521 approved on 2019 September 30. Protocol version 2021 October 20. Any changes to the protocol will be reported to the committees and approved. Informed consent will be obtained from all participants by the clinical research coordinator and principal investigator.

The non-muscle ADF/cofilin-1 controls sarcomeric actin filament integrity and force production in striated muscle laminopathies.

Cofilins are important for the regulation of the actin cytoskeleton, sarcomere organization, and force production. The role of cofilin-1, the non-muscle-specific isoform, in muscle function remains unclear. Mutations in LMNA encoding A-type lamins, intermediate filament proteins of the nuclear envelope, cause autosomal Emery-Dreifuss muscular dystrophy (EDMD). Here, we report increased cofilin-1 expression in LMNA mutant muscle cells caused by the inability of proteasome degradation, suggesting a protective role by ERK1/2. It is known that phosphorylated ERK1/2 directly binds to and catalyzes phosphorylation of the actin-depolymerizing factor cofilin-1 on Thr25. In vivo ectopic expression of cofilin-1, as well as its phosphorylated form on Thr25, impairs sarcomere structure and force generation. These findings present a mechanism that provides insight into the molecular pathogenesis of muscular dystrophies caused by LMNA mutations.

Need for NAD+: Focus on Striated Muscle Laminopathies.

Laminopathies are a heterogeneous group of rare diseases caused by genetic mutations in the LMNA gene, encoding A-type lamins. A-type lamins are nuclear envelope proteins which associate with B-type lamins to form the nuclear lamina, a meshwork underlying the inner nuclear envelope of differentiated cells. The laminopathies include lipodystrophies, progeroid phenotypes and striated muscle diseases. Research on striated muscle laminopathies in the recent years has provided novel perspectives on the role of the nuclear lamina and has shed light on the pathological consequences of altered nuclear lamina. The role of altered nicotinamide adenine dinucleotide (NAD+) in the physiopathology of striated muscle laminopathies has been recently highlighted. Here, we have summarized these findings and reviewed the current knowledge about NAD+ alteration in striated muscle laminopathies, providing potential therapeutic approaches.

The Effects of Transcranial Direct Current Stimulation (tDCS) Combined With Proprioceptive Training for Blind Individuals: The Study Protocol for a Randomized Controlled Clinical Trial.

To maintain the balance, the postural system needs to integrate the three main sensorial systems: visual, vestibular, and somatosensory to keep postural control within the limits of stabilization. Damage of one of these systems, in this case, the vision, will have a great disturbance on the postural control influencing the behavior of the balance, resulting in falls. The aim of this study protocol for a randomized, controlled clinical trial is to analyze the effects of transcranial direct current stimulation (tDCS) combined with proprioceptive exercises on postural control in individuals with congenital and acquired blindness. In this randomized, controlled, double-blind, clinical trial, male, and female individuals with blindness between 18 and 55 years of age will participate in this study divided into three phases: 1-Determine differences in postural control and gait between individuals with congenital and acquired blindness with and without the use of a guide stick when wearing shoes and when barefoot; 2-A pilot study to analyze the effects a bilateral cerebellar anodal tDCS on postural on postural control and gait; and 3-A treatment protocol will be conducted in which the participants will be allocated to four groups: G1-active tDCS + dynamic proprioceptive exercises; G2-sham tDCS + dynamic proprioceptive exercises; G3-active tDCS + static proprioceptive exercises; and G4-sham tDCS + static proprioceptive exercises. Evaluations will involve a camera system for three-dimensional gait analysis, a force plate, and electromyography. Dynamic stability will be determined using the Timed Up and Go test and static stability will be analyzed with the aid of the force plate. The viability of this study will allow the determination of differences in postural control between individuals with congenital and acquired blindness, the analysis of the effect of tDCS on postural control, and the establishment of a rehabilitation protocol.

Radiosynthesis and reactivity of N-[11C]methyl carbamoylimidazole.

N-Methyl carbamoylimidazole is a safe and practical alternative to methyl isocyanate for carbamoylation reactions. We have developed a new chemical route for its synthesis from methyl iodide and applied this to the synthesis of N-[11C]methyl carbamoylimidazole as a new [11C]synthon to radiolabel biomolecules for PET imaging research. N-[11C]methyl carbamoylimidazole was prepared from [11C]methyl iodide in 70-74% radiochemical yield (decay corrected) and can be used in situ for further reaction without purification. The reactivity of N-[11C]methyl carbamoylimidazole was demonstrated in a series of [11C]carbamoylation reactions.

Paresia unilateral do terceiro nervo após uso de Metronidazol oral / Unilateral third nerve palsy after use of oral Metronidazole

Resumo Paciente do sexo feminino, 19 anos, com queixa de diplopia, náusea e vômito de início súbito. Ao exame físico, a paciente apresentava rotação da cabeça para a esquerda e limitação da adução do olho direito, sugerindo paresia do músculo reto medial. Ausência de ptose palpebral ou paresia de outra musculatura ocular extrínseca e sem outras alterações na avaliação oftalmológica. Foi relatado pelo paciente o uso de Metronidazol, duas doses de 500 mg, no mesmo dia em que os sintomas começaram. A ressonância magnética do crânio foi solicitada. O resultado mostrou um cisto da glândula pineal, estando os outros aspectos dentro da normalidade. A paresia do músculo reto medial e diplopia persistiram por 14 dias, mesmo após a suspensão do antibiótico, optando, assim, por iniciar a corticoterapia oral, evoluindo com boa resposta clínica, melhora dos sintomas e regressão da paresia muscular.

Abstract Female patient, 19 years old, with a complaint of diplopia, nausea and vomiting of sudden onset. Upon physical examination, the patient presented herself with the head position rotated to the left and limitation of adduction of the right eye, suggesting paresis of the medial rectus muscle. Absence of palpebral ptosis or paresis of other extrinsic musculature of the eye, and without other alterations in the ophthalmological evaluation. It was reported by the patient the use of Metronidazole, two doses of 500 mg, the same day the symptoms started. The magnetic resonance imaging of the skull was requested. The result showed a cyst of the pineal gland, the other aspects being within normality. The paresis of the medial rectus muscle and diplopia persisted for 14 days, even after the antibiotic was discontinued, thus opting to initiate oral corticosteroid therapy, evolving with good clinical response, improvement of symptoms and regression of muscular paresis.

Tratamento pós-operatório de tenorrafias dos tendões flexores da mão: uma revisão narrativa / Post-operative treatment of tenorrhaphies of the flexor tendons of the hand: a narrative review

Objetivos: Revisar a literatura quanto à conduta pós-operatória mais adequada para o tratamento das lesões dos tendões flexores da mão. Métodos: Foi realizada uma pesquisa na base de dados MEDLINE/PUBMED, com as seguintes palavras indexadas "digitorum profundus tendon", "digitorum superficialis tendon", "hand tendon injuries", "hand tendon repair", "hand tendon surgery", "early passive mobilization", "controlled active motion", "flexor tendon repair surgery", "postoperative hand rehabilitation". A data de seleção se restringiu entre os anos de 2010 a 2018. Foram encontrados 149 artigos e, desses, 9 foram escolhidos para a análise deste estudo, por atenderem os critérios de inclusão. Resultados: É consenso entre os artigos analisados que o movimento dos dígitos após a cirurgia é fundamental para a recuperação do déficit motor da mão. O movimento na intensidade apropriada previne rupturas e aderências tendíneas. Além do movimento, há um impasse quanto ao modo de imobilização do punho. Conclusão: A análise dos estudos indica que a melhor opção de tratamento pós-operatório é a mobilização ativa precoce, pelo fato de o índice de adesão tendínea ser baixíssimo. Resta dúvida se a posição do punho pode interferir no índice de ruptura dos tendões.

Objectives: To review the literature on the most appropriate postoperative question for the treatment of injuries of the flexor tendons of the hand. Methods: A search was performed in the MEDLINE / PUBMED database, with the following words indexed "digitorum profundus tendon", "digitorum superficialis tendon", "hand tendon injuries", "hand tendon repair", "hand tendon surgery", "early passive mobilization, "" controlled active motion, "" flexor tendon repair surgery, "" postoperative hand rehabilitation. "The selection date was restricted between 2010 and 2018. 149 articles were found and 9 were selected for analysis of this study, because they met the inclusion criteria. Results: It is a consensus among the articles that concern the movement of patients after surgery is fundamental, for a recovery of the motor deficit of the hand. The movement in the struggle for correction prevents tendinous ruptures and adhesions. In addition, there is a stalemate regarding the mode of immobilization of the wrist. Conclusion: The analysis of the studies indicates that the best option for postoperative treatment is active early mobilization, because the tendon adhesion index is very low. Whether the wrist position may interfere with tendon rupture rates remains to be questioned.