On the physiological effects of severe and protracted muscular exercise; with special reference to its influence upon the excretion of nitrogen.

"Reprinted from the New York medical journal, June, 1871."

The muscular tension reflex and two of its modifying conditions

"References": p. [22]

Voluntary Muscular work recorded and Measured

The student is fatiguing the muscles of his left hand ... (source: Physiology at Michigan, 1850-1923 by Horace W. Davenport)

La ola verde : revista satirica en un acto, cuatro cuadros, tres cuadritos y una apoteosis muscular /

Imprint on cover: "Sociedad de Autores Españoles."

Muscular contraction and the reflex control of movement,

"A chronological list of important contributions to the physiology of muscle": p. 53-55.

Constraints on muscular performance: trade-offs between power output and fatigue resistance

An important functional and evolutionary constraint on the physical performance of vertebrates is believed to be the trade-off between speed and endurance capacity. However, despite the pervasiveness of physiological arguments, most studies have found no evidence of the trade-off when tested at the whole-animal level. We investigated the existence of this trade-off at the whole-muscle level, the presumed site of this physiological conflict, by examining inter-individual variation in both maximum power output and fatigue resistance for mouse extensor digitorum longus (EDL) muscle using the work-loop technique. We found negative correlations between several measures of in vitro maximum power output and force production with fatigue resistance for individual mouse EDL muscles, indicating functional trade-offs between these performance parameters. We suggest that this trade-off detected at the whole-muscle level has imposed an important constraint on the evolution of vertebrate physical performance.

Sleep-related breathing disorder in Duchenne muscular dystrophy: Disease spectrum in the paediatric population

Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease with death usually occurring because of respiratory failure. Signs of early respiratory insufficiency are usually first detectable in sleep. Objective: To study the presentation of sleep-related breathing disorder (SRBD) in patients with DMD. Method:> A retrospective review of patients with DMD attending a tertiary paediatric sleep disorder clinic over a 5-year period. Symptoms, lung function and polysomnographic indices were reviewed. Results: A total of 34 patients with DMD were referred for respiratory assessment (1-15 years). Twenty-two (64%) reported sleep-related symptomatology. Forced vital capacity (FVC) was between 12 and 107% predicted (n = 29). Thirty-two progressed to have polysomnography of which 15 were normal studies (median age: 10 years) and 10 (31%) were diagnostic of obstructive sleep apnoea (OSA) (median age: 8 years). A total of 11 patients (32%) showed hypoventilation (median age: 13 years) during the 5-year period and non-invasive ventilation (NIV) was offered to them. The median FVC of this group was 27% predicted. There was a significant improvement in the apnoea/hypopnoea index (AHI) (mean difference = 11.31, 95% CI = 5.91-16.70, P = 0.001) following the institution of NIV. Conclusions: The prevalence of SRBD in DMD is significant. There is a bimodal presentation of SRBD, with OSA found in the first decade and hypoventilation more commonly seen at the beginning of the second decade. Polysomnography is recommended in children with symptoms of OSA, or at the stage of becoming wheelchair-bound. In patients with the early stages of respiratory failure, assessment with polysomnography-identified sleep hypoventilation and assisted in initiating NIV.

Rapid Atrophy of the Lumbar Multifidus Follows Experimental Disc or Nerve Root Injury.

Study Design. Experimental study of muscle changes after lumbar spinal injury. Objectives. To investigate effects of intervertebral disc and nerve root lesions on cross-sectional area, histology and chemistry of porcine lumbar multifidus. Summary of Background Data. The multifidus cross-sectional area is reduced in acute and chronic low back pain. Although chronic changes are widespread, acute changes at 1 segment are identified within days of injury. It is uncertain whether changes precede or follow injury, or what is the mechanism. Methods. The multifidus cross-sectional area was measured in 21 pigs from L1 to S1 with ultrasound before and 3 or 6 days after lesions: incision into L3 - L4 disc, medial branch transection of the L3 dorsal ramus, and a sham procedure. Samples from L3 to L5 were studied histologically and chemically. Results. The multifidus cross-sectional area was reduced at L4 ipsilateral to disc lesion but at L4 - L6 after nerve lesion. There was no change after sham or on the opposite side. Water and lactate were reduced bilaterally after disc lesion and ipsilateral to nerve lesion. Histology revealed enlargement of adipocytes and clustering of myofibers at multiple levels after disc and nerve lesions. Conclusions. These data resolve the controversy that the multifidus cross-sectional area reduces rapidly after lumbar injury. Changes after disc lesion affect 1 level with a different distribution to denervation. Such changes may be due to disuse following reflex inhibitory mechanisms.

S. cerevisiae as a model for studying mutations in the human gene OPA1 associated with dominant optic atrophy and for drug discovery

L’atrofia ottica dominante (ADOA) è una malattia mitocondriale caratterizzata da difetti visivi, che si manifestano durante l’infanzia, causati da progressiva degenerazione delle cellule gangliari della retina (RGC). ADOA è una malattia genetica associata, nella maggior parte dei casi, a mutazioni nel gene OPA1 che codifica per la GTPasi mitocondriale OPA1, appartenente alla famiglia delle dinamine, principalmente coinvolta nel processo di fusione mitocondriale e nel mantenimento del mtDNA. Finora sono state identificate più di 300 mutazioni patologiche nel gene OPA1. Circa il 50% di queste sono mutazioni missenso, localizzate nel dominio GTPasico, che si pensa agiscano come dominanti negative. Questa classe di mutazioni è associata ad una sindrome più grave nota come “ADOA-plus”. Nel lievito Saccharomyces cerevisiae MGM1 è l’ortologo del gene OPA1: nonostante i due geni abbiano domini funzionali identici le sequenze amminoacidiche sono scarsamente conservate. Questo costituisce una limitazione all’uso del lievito per lo studio e la validazione di mutazioni patologiche nel gene OPA1, infatti solo poche sostituzioni possono essere introdotte e studiate nelle corrispettive posizioni del gene di lievito. Per superare questo ostacolo è stato pertanto costruito un nuovo modello di S. cerevisiae, contenente il gene chimerico MGM1/OPA1, in grado di complementare i difetti OXPHOS del mutante mgm1Δ. Questo gene di fusione contiene una larga parte di sequenza corrispondente al gene OPA1, nella quale è stato inserito un set di nuove mutazioni trovate in pazienti affetti da ADOA e ADOA-plus. La patogenicità di queste mutazioni è stata validata sia caratterizzando i difetti fenotipici associati agli alleli mutati, sia la loro dominanza/recessività nel modello di lievito. A tutt’oggi non è stato identificato alcun trattamento farmacologico per la cura di ADOA e ADOA-plus. Per questa ragione abbiamo utilizzato il nostro modello di lievito per la ricerca di molecole che agiscono come soppressori chimici, ossia composti in grado di ripristinare i difetti fenotipici indotti da mutazioni nel gene OPA1. Attraverso uno screening fenotipico high throughput sono state testate due differenti librerie di composti chimici. Questo approccio, noto con il nome di drug discovery, ha permesso l’identificazione di 23 potenziali molecole attive.

AS ESCALAS WECHSLER NO DIAGNÓSTICO NEUROPSICOLÓGICO DE CRIANÇAS COM DISTROFIA MUSCULAR DE DUCHENNE

Esta pesquisa teve por objetivo fazer uma avaliação neuropsicológica das funções cognitivas de crianças com Distrofia Muscular de Duchenne. Avaliou dez meninos, com idade entre seis e quinze anos. Utilizou-se da Escala de Inteligência Wechsler para crianças, WISC III, fazendo uma análise quantitativa e qualitativa dos dados. Os resultados quantitativos indicaram QIV muito diversificado entre os sujeitos, variando entre 53 e 97, sendo o QIVM = 77.4. A mesma variação foi observada no QIE, com resultados variando entre 57 e 88, com QIEM=71.2. O QITM foi de 71.4. . Esses resultados localizam-se na faixa limítrofe, dentro das variações normais da inteligência. A análise qualitativa fatorial segundo Figueiredo, registrou maior rebaixamento no fator III, Resistência à Distração, seguido do fator IV, Velocidade de Processamento. Na Escala Verbal, os subtestes que implicavam em utilização da Memória foram os mais comprometidos, comprovando pesquisas anteriores. Na Escala de Execução, o maior prejuízo observado foi devido à dificuldade em códigos e símbolos, sob pressão de tempo. Não foi observada nas crianças com resultados mais baixos, diferença significativa entre o QIV e o QIE. A transposição dos dados para a leitura neuropsicológica utilizou-se do diagrama de McFie. A grande diversidade dos resultados individuais recomenda estudos posteriores.

Multiple system atrophy: laminar distribution of the pathological changes in frontal and temporal neocortex--a study in ten patients

OBJECTIVE: To determine the distribution of the pathological changes in the neocortex in multiple-system atrophy (MSA). METHOD: The vertical distribution of the abnormal neurons (neurons with enlarged or atrophic perikarya), surviving neurons, glial cytoplasmic inclusions (GCI) and neuronal cytoplasmic inclusions (NI) were studied in alpha-synuclein-stained material of frontal and temporal cortex in ten cases of MSA. RESULTS: Abnormal neurons exhibited two common patterns of distribution, viz., density was either maximal in the upper cortex or a bimodal distribution was present with a density peak in the upper and lower cortex. The NI were either located in the lower cortex or were more uniformly distributed down the cortical profile. The distribution of the GCI varied considerably between gyri and cases. The density of the glial cell nuclei was maximal in the lower cortex in the majority of gyri. In a number of gyri, there was a positive correlation between the vertical densities of the abnormal neurons, the total number of surviving neurons, and the glial cell nuclei. The vertical densities of the GCI were not correlated with those of the surviving neurons or glial cells but the GCI and NI were positively correlated in a small number of gyri. CONCLUSION: The data suggest that there is significant degeneration of the frontal and temporal lobes in MSA, the lower laminae being affected more significantly than the upper laminae. Cortical degeneration in MSA is likely to be secondary to pathological changes occurring within subcortical areas.

A quantitative study of the pathological changes in white matter in multiple system atrophy

The density and spatial distribution of the vacuoles, glial cell nuclei and glial cytoplasmic inclusions (GCI) were studied in the white matter of various cortical and subcortical areas in 10 cases of multiple system atrophy (MSA). Vacuolation was more prevalent in subcortical than cortical areas and especially in the central tegmental tract. Glial cell nuclei widespread in all areas of the white matter studied; overall densities of glial cell nuclei being significantly greater in the central tegmental tract and frontal cortex compared with areas of the pons. The GCI were present most consistently in the external and internal capsules, the central tegmental tract and the white matter of the cerebellar cortex. The density of the vacuoles was greater in the MSA brains than in the control brains but glial cell density was similar in both groups. In the majority of areas, the pathological changes were distributed across the white matter randomly, uniformly, or in large diffuse clusters. In most areas, there were no spatial correlations between the vacuoles, glial cell nuclei and GCI. These results suggest: (i) there is significant degeneration of the white matter in MSA characterized by vacuolation and GCI; (ii) the central tegmental tract is affected significantly more than the cortical tracts; (iii) pathological changes are diffusely rather than topographically distributed across the white matter; and (iv) the development of the vacuoles and GCI appear to be unrelated phenomena. © 2007 Japanese Society of Neuropathology.