AAV9-Stathmin1 gene delivery improves disease phenotype in an intermediate mouse model of spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a devastating infantile genetic disorder caused by the loss of survival motor neuron (SMN) protein that leads to premature death due to loss of motor neurons and muscle atrophy. The approval of an antisense oligonucleotide therapy for SMA was an important milestone in SMA research; however, effective next-generation therapeutics will likely require combinatorial SMN-dependent therapeutics and SMN-independent disease modifiers. A recent cross-disease transcriptomic analysis identified Stathmin-1 (STMN1), a tubulin-depolymerizing protein, as a potential disease modifier across different motor neuron diseases, including SMA. Here, we investigated whether viral-based delivery of STMN1 decreased disease severity in a well-characterized SMA mouse model. Intracerebroventricular delivery of scAAV9-STMN1 in SMA mice at P2 significantly increased survival and weight gain compared to untreated SMA mice without elevating Smn levels. scAAV9-STMN1 improved important hallmarks of disease, including motor function, NMJ pathology and motor neuron cell preservation. Furthermore, scAAV9-STMN1 treatment restored microtubule networks and tubulin expression without affecting tubulin stability. Our results show that scAAV9-STMN1 treatment improves SMA pathology possibly by increasing microtubule turnover leading to restored levels of stable microtubules. Overall, these data demonstrate that STMN1 can significantly reduce the SMA phenotype independent of restoring SMN protein and highlight the importance of developing SMN-independent therapeutics for the treatment of SMA.

Muscle spindle alterations precede onset of sensorimotor deficits in Charcot-Marie-Tooth type 2E.

Charcot-Marie-Tooth (CMT) is the most common inherited peripheral neuropathy, affecting approximately 2.8 million people. The CMT leads to distal neuropathy that is characterized by reduced motor nerve conduction velocity, ataxia, muscle atrophy and sensory loss. We generated a mouse model of CMT type 2E (CMT2E) expressing human neurofilament light E396K (hNF-LE396K ), which develops decreased motor nerve conduction velocity, ataxia and muscle atrophy by 4 months of age. Symptomatic hNF-LE396K mice developed phenotypes that were consistent with proprioceptive sensory defects as well as reduced sensitivity to mechanical stimulation, while thermal sensitivity and auditory brainstem responses were unaltered. Progression from presymptomatic to symptomatic included a 50% loss of large diameter sensory axons within the fifth lumbar dorsal root of hNF-LE396K mice. Owing to proprioceptive deficits and loss of large diameter sensory axons, we analyzed muscle spindle morphology in presymptomatic and symptomatic hNF-LE396K and hNF-L control mice. Muscle spindle cross-sectional area and volume were reduced in all hNF-LE396K mice analyzed, suggesting that alterations in muscle spindle morphology occurred prior to the onset of typical CMT pathology. These data suggested that CMT2E pathology initiated in the muscle spindles altering the proprioceptive sensory system. Early sensory pathology in CMT2E could provide a unifying hypothesis for the convergence of pathology observed in CMT.

Expressing hNF-LE397K results in abnormal gaiting in a transgenic model of CMT2E.

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gaiting, exacerbation of neuropathy, sensory defects and deafness. We generated a novel line of CMT2E mice expressing an hNF-L(E397K) transgene, which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons and decreased nerve conduction velocity. In this study, we showed that hNF-L(E397K) mice developed abnormal gait of the hind limbs. The identification of severe gaiting defects in combination with previously observed muscle atrophy, reduced axon caliber and decreased nerve conduction velocity suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2E. Therefore, hNF-L(E397K) mice provide a context for potential therapeutic intervention.

Influence of the ageing process on the resistive and reactive properties of the respiratory system.

INTRODUCTION: In an increasingly old society, the study of the respiratory system changes and new techniques dedicated to older patients are of interest in physiologic studies as well as in the diagnosis of respiratory diseases. OBJECTIVES: (1) To investigate the impact of ageing on the resistive and reactive properties of the respiratory system, and (2) to compare the easiness of accomplishment of spirometry and forced oscillation for assessing lung function. METHODS: We conducted a cross-sectional study in which forced oscillation was used to investigate respiratory system resistive and reactive properties, while spirometry was used as a reference test to evaluate 80 normal subjects aged between 20 and 86 years. A questionnaire was used to evaluate the easiness of accomplishment of spirometry and forced oscillation. RESULTS: There was a significant increase in the respiratory system resonance frequency (p<0.003) and a reduction in the mean reactance (p<0.004) with increasing age. Respiratory system resistance and dynamic compliance were not related to the ageing process. The easiness of accomplishment of forced oscillation measurements was greater than that of spirometry. This result was particularly relevant in subjects over 70 years old (p<0.05). CONCLUSIONS: Respiratory system resistance and dynamic compliance are not modified with ageing. On the other hand, respiratory system homogeneity decreases during the ageing process. Forced oscillation is easy to perform and provides information complementary to spirometry. This technique may be a promising alternative and/or complement to other conventional exams used to evaluate older people who are unable to adequately perform spirometric tests.

Análise da relação entre o tempo de realização do Timed Get Up and Go e episódios de quedas recorrentes relatadas pelos pacientes idosos inseridos em serviço ambulatorial / Analyses of the relationship between the time of performance of the Timed Get Up and Go Test and recurrent falls related by the aged patients inserted in anambulatory service

As quedas adquirem maior relevância com o aumento da população idosa em termos de saúde pública e de aspectos socioeconômicos. As médias do tempo de realização do Timed Get Up and Go (TGUG) em pacientes idosos ambulatoriais com relato de quedas acidentais e recorrentes foram comparadas neste estudo de corte longitudinal retrospectivo. Observa-se que o tempo de realização do TGUG, em média, foi significativamente maior nos idosos com relato de quedas recorrentes.(AU)

Falls obtain more relevance with the rise of the aged population in terms of public health and socioeconomic issues. The averages of the time to perform the Timed Get Up and Go test (TGUG) in ambulatory elderly patients with story of accidental and recurrent falls were compared in this retrospective and longitudinal study. It is noted that the time to perform the TGUG, in average, was significantly higher in the elderly with story of recurrent falls.(AU)

Análise da relação entre o tempo de realização do Timed Get Up and Go e episódios de quedas recorrentes relatadas pelos pacientes idosos inseridos em serviço ambulatorial / Analyses of the relationship between the time of performance of the Timed Get Up and Go Test and recurrent falls related by the aged patients inserted in anambulatory service

As quedas adquirem maior relevância com o aumento da população idosa em termos de saúde pública e de aspectos socioeconômicos. As médias do tempo de realização do Timed Get Up and Go (TGUG) em pacientes idosos ambulatoriais com relato de quedas acidentais e recorrentes foram comparadas neste estudo de corte longitudinal retrospectivo. Observa-se que o tempo de realização do TGUG, em média, foi significativamente maior nos idosos com relato de quedas recorrentes...

Falls obtain more relevance with the rise of the aged population in terms of public health and socioeconomic issues. The averages of the time to perform the Timed Get Up and Go test (TGUG) in ambulatory elderly patients with story of accidental and recurrent falls were compared in this retrospective and longitudinal study. It is noted that the time to perform the TGUG, in average, was significantly higher in the elderly with story of recurrent falls...

Physical training program in arterial hypertension. A long-term prospective follow-up.

A long-term training program was performed on 30 chronic hypertensive female patients, stages I-II, WHO criteria. The effect on blood pressure (BP) and other physiological parameters, as exercise BP, heart rate, physical working capacity, VO2max, double product, were studied. Four phases were outlined throughout the trial: (1) 3 months training at 70% of the maximal heart rate; (2) 3 months without training; (3) 1 year training at the same level as phase I, and (4) 12 or more months with increasing intensity training over 70% of the maximal heart rate. Serial ergometric work tests were performed every 3 months. We observed a close relationship between physical working capacity and VO2max increases with training intensity. Resting BP fell significantly with training (182/114-161/97 mm Hg; p less than 0.001) but increased again when training was discontinued (161/97-179/115 mm Hg; p less than 0.001). BP persisted low throughout the trial, but there was a tendency to a further but not significant decrease when training intensity was raised over 70% of the maximal heart rate. Both the submaximal and maximal exercise BP showed similar changes to those found in the resting BP throughout the trial. The submaximal heart rate and the double product (BP X heart rate) also fell significantly with training but with maximal values not changing significantly throughout the whole follow-up period.

Cardiac rehabilitation after acute myocardial infarction. 9-year controlled follow-up study.

Since the effect of cardiac rehabilitation (CR) on morbidity and mortality due to myocardial infarction on a long-term basis appears controversial, a controlled follow-up survey was conducted from 1973 to 1981 in 193 patients suffering a first acute myocardial infarction (AMI). The admission criteria included absence of contraindications to CR during the acute phase of AMI. Patients were divided into two matched groups: 93 patients followed a CR program, exercising 30 min three times a week (means 42; range 6-108 months) and the remaining 100 patients served as controls. Age, sex, location and extension of the myocardial damage, frequency of coronary risk factors and complications during the acute phase were comparable. At 9 years, there were 24 cardiac deaths (15 AMI, 7 sudden deaths and 2 heart failures) among the controls and 13 deaths in the CR group (7 AMI, 4 sudden deaths, 2 heart failures), mortality rates being 5.2 and 2.9% per year (p less than 0.1 greater than 0.05; NS), respectively. There were 23 recurrent AMI in the control versus 16 in the CR patients, the corresponding rates being 4.9 and 3.6% per year, respectively (NS). Nor were any differences observed in the incidence of myocardial ischemia, severe arrhythmias or cerebrovascular strokes between both groups, but the appearance of angina was significantly lower in the CR group compared with the controls (5.1 and 10.2% per year, respectively, p less than 0.005). It is concluded that CR on a long-term basis seems to improve the mortality rate of AMI and to reduce the frequency of anginal pain.

Influence of the ageing process on the resistive and reactive properties of the respiratory system

INTRODUCTION: In an increasingly old society, the study of the respiratory system changes and new techniques dedicated to older patients are of interest in physiologic studies as well as in the diagnosis of respiratory diseases. OBJECTIVES: (1) To investigate the impact of ageing on the resistive and reactive properties of the respiratory system, and (2) to compare the easiness of accomplishment of spirometry and forced oscillation for assessing lung function. METHODS: We conducted a cross-sectional study in which forced oscillation was used to investigate respiratory system resistive and reactive properties, while spirometry was used as a reference test to evaluate 80 normal subjects aged between 20 and 86 years. A questionnaire was used to evaluate the easiness of accomplishment of spirometry and forced oscillation. RESULTS: There was a significant increase in the respiratory system resonance frequency (p<0.003) and a reduction in the mean reactance (p<0.004) with increasing age. Respiratory system resistance and dynamic compliance were not related to the ageing process. The easiness of accomplishment of forced oscillation measurements was greater than that of spirometry. This result was particularly relevant in subjects over 70 years old (p<0.05). CONCLUSIONS: Respiratory system resistance and dynamic compliance are not modified with ageing. On the other hand, respiratory system homogeneity decreases during the ageing process. Forced oscillation is easy to perform and provides information complementary to spirometry. This technique may be a promising alternative and/or complement to other conventional exams used to evaluate older people who are unable to adequately perform spirometric tests.