Metabolic abnormalities associated with skeletal myopathy in severe anorexia nervosa.

The aim of this study was to characterize the metabolic disturbance associated with the skeletal myopathy resulting from extreme weight loss in anorexia nervosa. Muscle function was examined in eight female patients with severe (40%) weight loss due to anorexia nervosa and histologically confirmed myopathy. A wide range of biochemical and hematologic investigations were carried out, including serum enzymes and the response of plasma lactate to ischemic exercise of forearm muscles. All patients showed proximal muscular weakness. A diminished lactate response to ischemic exercise was a consistent finding, and a reduction of serum carnosinase activity was also found. There were no other consistent biochemical or hematologic abnormalities apart from lymphopenia of no clinical consequence. These findings contribute to our understanding of severe protein-energy malnutrition on the musculoskeletal system. The resulting disorder is a metabolic myopathy from which the patients recover rapidly as their nutrition improves. Although the patients admitted to a variety of abnormal eating behaviors, no correlation was found between a specific type of abnormal eating behavior and subsequent biochemical abnormalities. Reinstating appropriate eating behavior will treat the myopathy.

Structural and functional changes in skeletal muscle in anorexia nervosa.

Protein-energy malnutrition in anorexia nervosa is an under-recognised cause of muscle dysfunction. To characterise the skeletal myopathy that occurs in patients with severe anorexia nervosa, muscle function and structure were comprehensively examined in eight young adult female patients with severe (40%) self-induced weight loss. All of the patients showed impaired muscle function on strength and exercise measurement. The maximum voluntary contraction force for the patient group was significantly less than predicted values. Electromyography revealed myopathy in five of the patients, four of whom also had electro-physiological evidence of neuropathy. However, muscle biopsy specimens consistently showed myopathic changes with severe type 2 fibre atrophy but with no evidence of neuropathic changes. Ultrastructurally, there was separation and segmental loss of myofibrils and most biopsy samples contained abundant glycogen granules; we have previously reported that one of the most consistent biochemical abnormalities in these patients is impaired ischaemic lactate responses to forearm exercise. The result of severe protein-energy malnutrition on the musculo-skeletal system is a metabolic myopathy. Although the patients admitted to a variety of abnormal dieting behaviours, such as over-exercising and self-induced vomiting, no association was found between any of these and quantitative histological changes in the muscle biopsy samples. It is recommended that myopathy in anorexia nervosa be treated by instituting an appropriate refeeding programme.

Assessment of neuronal density in the putamen in human immunodeficiency virus (HIV) infection. Application of stereology and spatial analysis of quadrats.

Human immunodeficiency virus causes neuronal loss in various brain regions, but it has not been reported in the putamen. However, decrease in the volume of the putamen has been observed by magnetic resonance imaging. In order to clarify this issue two complementary methods; the stereological probe, the disector, and spatial analysis of quadrats, were applied in nondemented individuals who had died of acquired immune deficiency syndrome. A 21% decrease in neuronal density was observed in the human immunodeficiency virus group, especially those cases with human immunodeficiency virus encephalitis; however the statistical significance of this finding was borderline.

Neuronal density in the superior frontal and temporal gyri does not correlate with the degree of human immunodeficiency virus-associated dementia.

Human immune deficiency virus (HIV) disease may be associated, neuropathologically, with significant neuronal loss and clinically with a severe dementia. However, the significance of neuronal loss in the development of dementia has not been established. In this study we have undertaken a stereological determination of the neuronal numerical density and neuronal volumes in post mortem tissue from the superior frontal and superior temporal gyri in 32 patients who died of acquired immune deficiency syndrome (AIDS). All were prospectively clinically characterized, with dementia identified or excluded, and antiretroviral medication documented. This study combines morphometric techniques with prospective clinical assessment of dementia. As previously demonstrated, all patients dying with AIDS showed neuronal loss, but this was not related to the presence of HIV-associated dementia.

Neuronal loss in the hippocampus in Huntington's disease: a comparison with HIV infection.

The hippocampus is usually affected in primary dementias and the pathological changes may be severe. Knowledge of hippocampal pathology in HIV infection and Huntington's disease (HD), however, is extremely limited. A stereological technique (the optical "disector") has been used to assess neuronal populations in four areas of the hippocampus in 11 patients with HIV infection and in nine patients with HD. The HIV patients died without opportunistic infections or neoplasms affecting the brain; they had HIV encephalitis or minimal changes. The HD cases were all clinically diagnosed, had a positive family history and showed the characteristic lesions in the caudate nucleus. The neuronal counts were compared with those in nine controls. In the granule cell layer of the dentate, CA3 and CA4, there was no significant difference in the neuronal numerical density between the three groups. A striking difference between the HIV and HD groups was seen in the CA1 region. The neuronal numerical density in the CA1 area was significantly lower in the HD patients than in either the HIV patients or the controls (mean (SD) 37.5 (5.0); 70.1 (13.4); 57.9 (15.4) x 10(3) per mm3, p < 0.001 (Students' t test)). This difference represents a neuronal loss of 35%. In all four hippocampal areas the neuronal density was higher in the HIV group than in the controls but the differences were not significant and can be explained by the higher average age of the control group. These findings contribute to the understanding of the mechanism of dementia in both AIDS and in Huntington's disease.

Beta A4 deposition in the temporal cortex of adults with Down's syndrome.

The deposition of beta A4 has been quantified in the temporal cortex of 9 adults (4 male, 5 female) with Down's syndrome (DS), mean age (+/- SD) 54.7 +/- 8.8 years (range 41-67 years) at the time of death. Immunostaining with antibodies, raised to different portions of the beta A4 protein, showed a greater number of deposits than were seen with traditional silver impregnation or amyloid stains. Antibody to beta A4(1-10) identified fewer plaques than the antibody to beta A4(12-28), the mean ratio of beta A4(1-10)/beta A4(12-28) plaques being 0.30 +/- 0.10 (mean +/- SD). Morphologically, 'diffuse' and 'neuritic' deposits could be distinguished but there was no significant difference in the beta A4(1-10)/beta A4(12-28) ratio according to plaque morphology, nor did the ratio change with age. Quantitatively, the beta A4(12-28) load in the temporal cortex of DS patients was high, occupying some 14% of the field area, and it was not related to the age of the subject over the range studied. Similarly, the total beta A4(12-28) plaque count was high and not age-related. The proportion of morphological plaque types visualised by the Glees and Marsland silver impregnation and by beta A4(12-28) immunostaining were compared. In both techniques 'diffuse' plaques (D) were predominant in the younger subjects and the proportion of 'neuritic' plaques (N) increased with age. The relative proportions of cored plaques (Cp) and plaque cores (C) did not change significantly with age.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies raised against different portions of A4 protein identify a subset of plaques in Down's syndrome.

Antisera were raised to peptides corresponding to residues 1-10 and 12-28 of the published sequence of A4 protein, a 42/43 amino acid long peptide isolated from the brains of patients with Down's syndrome and Alzheimer's disease. Immunohistochemical studies performed on sections of temporal lobe from 12 cases of Down's syndrome showed that the number of senile plaques in the molecular layer of the dentate gyrus which were identified by antibody to A4(1-10) was only 23% (range 11-53%) of that recognised by antibody to A4(12-28). This observation has important consequences for both the diagnosis and the pathogenesis of Down's syndrome and Alzheimer's disease.

Neuropathy and myopathy in two patients with anorexia and bulimia nervosa.

Two adolescent patients with eating disorders and severe weight loss presented with neuromyopathy. The first was female and had a twenty months' history of bulimia nervosa with weight loss and episodic gorging and vomiting. The second was male with a two-year history of anorexia nervosa characterised by vegetarianism and increasing food restriction. Both had severe wasting and asymmetrical weakness of proximal limb muscles. The first patient deteriorated on refeeding and became temporarily paralysed. Both had a purpuric rash and haematological abnormalities. They made a complete recovery on a mixed diet: vitamin supplements were given to the first but not to the second patient.

The acute effects of alcohol on plasma creatine kinase (CK) activity in the rat.

The acute effect of a single intraperitoneal dose of alcohol (2 g kg-1 body weight) was studied in normally fed rats anaesthetised with sodium pentabarbitone . Rapidly achieved high blood alcohol levels were accompanied by an equally rapid but transient 4-fold increase in the total creatine kinase (CK) activity in the arterial plasma of animals of both sexes. Resting CK activity was significantly lower in female animals and although the magnitude of the alcohol-induced CK increase was the same in both sexes, the duration of the response was shorter in female rats. Electrophoresis showed the skeletal muscle-associated MM isoenzyme of CK to be predominant in resting plasma and also to account solely for the alcohol-induced increase in total CK activity. These results indicate that alcohol has a direct toxic action on skeletal muscle, causing transient loss of cellular integrity which permits the leakage of normally intracellular enzymes into the circulation.

The effects of murine muscular dystrophy on the metabolic and homeostatic functions of the skeletal muscles.

The maintenance of blood glucose is largely dependent on the ability of the skeletal muscles to regulate the supply of amino acids for hepatic glucose production. This study shows that when muscles are damaged in muscular dystrophy the mechanisms by which this control is exerted are impaired. In normally fed congenitally dystrophic mice the blood glucose level was raised and there were significant reductions of the levels of the principal gluconeogenic amino acids in the circulation. This was a result of abnormal exchange of amino acids between the dystrophic muscles and the blood, apparently due to the use of amino acids to a considerable extent in place of glucose for energy metabolism within the diseased muscles. When dystrophic animals were fasted, further reductions in the levels of amino acids in the circulation, to abnormally low values, were caused by an increased use of these amino acids by the liver for gluconeogenesis. Although the reason for the excessive metabolism of amino acids in dystrophic muscle is not clear, such changes will favour muscle protein breakdown, and a stress such as fasting will further aggravate the process of muscle wasting by depleting still further the pool of amino acids in the body.