Predictors of functional outcomes in patients with facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies characterized by considerable variability in severity, rates of progression and functional outcomes. Few studies follow FSHD cohorts long enough to understand predictors of disease progression and functional outcomes, creating gaps in our understanding, which impacts clinical care and the design of clinical trials. Efforts to identify molecularly targeted therapies create a need to better understand disease characteristics with predictive value to help refine clinical trial strategies and understand trial outcomes. Here we analysed a prospective cohort from a large, longitudinally followed registry of patients with FSHD in the USA to determine predictors of outcomes such as need for wheelchair use. This study analysed de-identified data from 578 individuals with confirmed FSHD type 1 enrolled in the United States National Registry for FSHD Patients and Family members. Data were collected from January 2002 to September 2019 and included an average of 9 years (range 0-18) of follow-up surveys. Data were analysed using descriptive epidemiological techniques, and risk of wheelchair use was determined using Cox proportional hazards models. Supervised machine learning analysis was completed using Random Forest modelling and included all 189 unique features collected from registry questionnaires. A separate medications-only model was created that included 359 unique medications reported by participants. Here we show that smaller allele sizes were predictive of earlier age at onset, diagnosis and likelihood of wheelchair use. Additionally, we show that females were more likely overall to progress to wheelchair use and at a faster rate as compared to males, independent of genetics. Use of machine learning models that included all reported clinical features showed that the effect of allele size on progression to wheelchair use is small compared to disease duration, which may be important to consider in trial design. Medical comorbidities and medication use add to the risk for need for wheelchair dependence, raising the possibility for better medical management impacting outcomes in FSHD. The findings in this study will require further validation in additional, larger datasets but could have implications for clinical care, and inclusion criteria for future clinical trials in FSHD.

The history of acetylcholinesterase inhibitors in the treatment of myasthenia gravis.

The beneficial effects of acetylcholinesterase inhibitors for the treatment of myasthenia gravis (MG) was a major discovery that came about through one young physician putting together a string of previous observations. To understand how this discovery came to light, we must first go back to earlier times when men hunted by bow-and-arrow to capture their prey. The substance used to poison the prey was eventually was identified as curare. Centuries later, a connection was made between the physiological effects of curare and a disease entity with no known pathological mechanism or treatment, myasthenia gravis. In 1935, house officer Dr. Mary Walker was the first physician to try physostigmine in the treatment of MG, which had previously been used to treat curare poisoning. What she saw was a dramatic improvement in the symptoms experienced in patients with MG, and thus became the first documented case of use of physostigmine, an acetylcholinesterase inhibitor, in the treatment of MG. This article is a summary of the history of the use of acetylcholinesterase inhibitors in the treatment of myasthenia gravis. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Deletion of the insulin receptor in sensory neurons increases pancreatic insulin levels.

Insulin is known to have neurotrophic properties and loss of insulin support to sensory neurons may contribute to peripheral diabetic neuropathy (PDN). Here, genetically-modified mice were generated in which peripheral sensory neurons lacked the insulin receptor (SNIRKO mice) to determine whether disrupted sensory neuron insulin signaling plays a crucial role in the development of PDN and whether SNIRKO mice develop symptoms of PDN due to reduced insulin neurotrophic support. Our results revealed that SNIRKO mice were euglycemic and never displayed significant changes in a wide range of sensorimotor behaviors, nerve conduction velocity or intraepidermal nerve fiber density. However, SNIRKO mice displayed elevated serum insulin levels, glucose intolerance, and increased insulin content in the islets of Langerhans of the pancreas. These results contribute to the growing idea that sensory innervation of pancreatic islets is key to regulating islet function and that a negative feedback loop of sensory neuron insulin signaling keeps this regulation in balance. Our results suggest that a loss of insulin receptors in sensory neurons does not lead to peripheral nerve dysfunction. The SNIRKO mice will be a powerful tool to investigate sensory neuron insulin signaling and may give a unique insight into the role that sensory neurons play in modifying islet physiology.