RESUMO
Mitochondrial fusion is essential to mitochondrial fitness and cellular health. Neurons of patients with genetic neurodegenerative diseases often exhibit mitochondrial fragmentation, reflecting an imbalance in mitochondrial fusion and fission (mitochondrial dysdynamism). Charcot-Marie-Tooth (CMT) disease type 2A is the prototypical disorder of impaired mitochondrial fusion caused by mutations in the fusion protein mitofusin (MFN)2. Yet, cultured CMT2A patient fibroblast mitochondria are often reported as morphologically normal. Metabolic stress might evoke pathological mitochondrial phenotypes in cultured patient fibroblasts, providing a platform for the pre-clinical individualized evaluation of investigational therapeutics. Here, substitution of galactose for glucose in culture media was used to redirect CMT2A patient fibroblasts (MFN2 T105M, R274W, H361Y, R364W) from glycolytic metabolism to mitochondrial oxidative phosphorylation, which provoked characteristic mitochondrial fragmentation and depolarization and induced a distinct transcriptional signature. Pharmacological MFN activation of metabolically reprogrammed fibroblasts partially reversed the mitochondrial abnormalities in CMT2A and CMT1 and a subset of Parkinson's and Alzheimer's disease patients, implicating addressable mitochondrial dysdynamism in these illnesses.
Assuntos
GTP Fosfo-Hidrolases , Doenças Neurodegenerativas , Doença de Charcot-Marie-Tooth , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Humanos , Mitocôndrias/metabolismo , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Doenças Neurodegenerativas/metabolismo , FenótipoRESUMO
Charcot-Marie-Tooth disease type 2A (CMT2A) is an untreatable childhood peripheral neuropathy caused by mutations of the mitochondrial fusion protein, mitofusin (MFN) 2. Here, pharmacological activation of endogenous normal mitofusins overcame dominant inhibitory effects of CMT2A mutants in reprogrammed human patient motor neurons, reversing hallmark mitochondrial stasis and fragmentation independent of causal MFN2 mutation. In mice expressing human MFN2 T105M, intermittent mitofusin activation with a small molecule, MiM111, normalized CMT2A neuromuscular dysfunction, reversed pre-treatment axon and skeletal myocyte atrophy, and enhanced axon regrowth by increasing mitochondrial transport within peripheral axons and promoting in vivo mitochondrial localization to neuromuscular junctional synapses. MiM111-treated MFN2 T105M mouse neurons exhibited accelerated primary outgrowth and greater post-axotomy regrowth, linked to enhanced mitochondrial motility. MiM111 is the first pre-clinical candidate for CMT2A.
Charcot-Marie-Tooth disease type 2A is a rare genetic childhood disease where dying back of nerve cells leads to muscle loss in the arms and legs, causing permanent disability. There is no known treatment. In this form of CMT, mutations in a protein called mitofusin 2 damage structures inside cells known as mitochondria. Mitochondria generate most of the chemical energy to power a cell, but when mitofusin 2 is mutated, the mitochondria are less healthy and are unable to move within the cell, depriving the cells of energy. This particularly causes problems in the long nerve cells that stretch from the spinal cord to the arm and leg muscles. Now, Franco, Dang et al. wanted to see whether re-activating mitofusin 2 could correct the damage to the mitochondria and restore the nerve connections to the muscles. The researchers tested a new class of drug called a mitofusin activator on nerve cells grown in the laboratory after being taken from people suffering from CMT2A, and also from a mouse model of the disease. Mitofusin activators improved the structure, fitness and movement of mitochondria in both human and mice nerve cells. Franco, Dang et al. then tested the drug in the mice with a CMT2A mutation and found that it could also stimulate nerves to regrow and so reverse muscle loss and weakness. This is the first time scientists have succeeded to reverse the effects of CMT2A in nerve cells of mice and humans. However, these drugs will still need to go through extensive testing in clinical trials before being made widely available to patients. If approved, mitofusin activators may also be beneficial for patients suffering from other genetic conditions that damage mitochondria.
Assuntos
Doença de Charcot-Marie-Tooth/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Proteínas Mitocondriais/metabolismo , Junção Neuromuscular/metabolismo , Animais , Axônios/metabolismo , Axônios/fisiologia , Doença de Charcot-Marie-Tooth/fisiopatologia , Feminino , GTP Fosfo-Hidrolases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias Musculares/metabolismo , Mitocôndrias Musculares/fisiologia , Proteínas Mitocondriais/genética , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , Células Musculares/metabolismo , Células Musculares/fisiologia , Mutação/genética , Junção Neuromuscular/fisiologiaRESUMO
OBJECTIVE: To determine whether use of uterine balloon tamponade (UBT) for management of uncontrolled postpartum hemorrhage (PPH) by community-based providers in a resource-limited setting could be feasible, effective, and safe. METHODS: In rural South Sudan, community providers were trained and equipped with a simple UBT device consisting of a catheter, condom, and syringe. Snowball sampling identified cases of UBT use since training. Semi-structured interviews were conducted among community providers, referral facility providers, patients, and patient family members. Interview transcripts were analyzed using qualitative methods. RESULTS: Thirteen cases were identified and 24 interviews related to community-based UBT use were conducted. Qualitative analysis revealed several major themes. Community providers applied UBT in appropriate clinical situations. UBT was effective for controlling PPH, even among severely ill patients. Referral was difficult and lengthy owing to the austere setting, but simple UBT appeared to mitigate these challenges. Communities had some initial fears, yet ultimately embraced UBT. Equipment and supplies were largely maintained. There was universal satisfaction with UBT among patients, family members, and providers. One death occurred among the 13 cases, although it was probably not attributable to PPH. CONCLUSION: Training and UBT device provision are simple, affordable, and effective for managing uncontrolled PPH in a resource-limited setting.
Assuntos
Serviços de Saúde Comunitária/métodos , Hemorragia Pós-Parto/terapia , Tamponamento com Balão Uterino/métodos , Serviços de Saúde Comunitária/economia , Países em Desenvolvimento , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Entrevistas como Assunto , Satisfação do Paciente , Hemorragia Pós-Parto/fisiopatologia , Gravidez , Encaminhamento e Consulta , Índice de Gravidade de Doença , Sudão , Fatores de Tempo , Resultado do Tratamento , Tamponamento com Balão Uterino/efeitos adversos , Tamponamento com Balão Uterino/economiaRESUMO
A 28-year-old nursing student working in Juba, South Sudan, suddenly developed a rash over her mid-right clavicle. Beginning as a 10-cm-diameter erythematous patch with an irregular border, within 24 hours it had developed an increasingly gray, necrotic center, appearing similar to a burn. The patient was seen by 2 local physicians without a diagnosis being made. Ultimately, it was diagnosed as being caused by the toxic hemolymph, pederin, from the Nairobi fly (Paederus). The rash usually affects body parts not covered by clothing; healing time ranges from 7 to 28 days, usually with permanent skin discoloration. Preventive measures include typical antivector precautions, including bed nets, long-sleeve clothing, and avoiding fluorescent lights. If the beetles are found on the skin, brushing them off, rather than crushing them, avoids producing dermatitis. Treatment includes rapidly washing the affected area, applying cold, wet compresses, and possibly treating with antibiotics, steroids, and antihistamines.
Assuntos
Besouros , Dermatite/diagnóstico , Piranos/intoxicação , Toxinas Biológicas/intoxicação , Adulto , Animais , Dermatite/patologia , Feminino , Humanos , Sudão/epidemiologiaRESUMO
The study assessed differences in sensorimotor processing as reflected in measurements of saccadic latencies at 3 different stages in the menstrual cycle (menstruation, early luteal, and premenstruation) in naturally cycling women (n = 13), and at the same time intervals in women taking an oral contraceptive (n = 6), and male controls (n = 8). Subjects (M age = 22.0 yr., SD = 2.2 yr.) were recruited by questionnaire from the student population of the University of Cambridge. Latencies were measured using a portable infrared scleral oculometer. Changes in latency across the menstrual cycle occurred only in the naturally cycling women (F(2.11) = 5.95, p < .05). Premenstrual latencies were greater (199.3 +/- 12.7 msec., M +/- SD) compared to those during menstruation (191.9 +/- 11.1 msec.) or midcycle (196.9 +/- 12.7 msec.). These findings could account for the loss of musculoskeletal coordination reported by some women prior to menstruation and suggests that administration of an oral contraceptive may alleviate this effect.