S. Wassif

Serum S-100 Protein, Relationship to Clinical Outcome in Acute Stroke

The clinical significance of serum S-100 protein, a protein released by damaged brain tissue, was assessed in patients with acute ischaemic or haemorrhagic stroke and matched controls. Serum S-100 protein concentration was significantly elevated in patients with ischaemic stroke [median (SQR): 0·27 (0·09) μg/L, n = 68] and haemorrhagic stroke [0·43 (0·23) μg/L, n = 13] compared to controls [0·11 (0·03) μg/L, n = 51, P<0·0001]. Although patients with haemorrhagic stroke had higher serum S-100 concentrations compared to patients with ischaemic stroke, this was not quite statistically significant. Serum S-100 concentrations were related to infarct size, large (total anterior circulation) infarcts concentrations having the highest [0·40 (0·22) μg/L], and small vessel (‘lacunar’) infarcts concentrations having the lowest [0·20 (0·06) μg/L, P<0·0005] concentrations. S-100 protein concentration was also significantly related to clinical outcome at three months measured using three disability and handicap scales (n = 81): modified Barthel index (r s=–0·285, P = 0·01), modified Rankin score (r s = 0·313, P = 0·004) and Lindley score (r s = 0·262, P = 0·018) with high values associated with poor clinical outcome. Similarly high values of serum S-100 protein were observed in patients who died or were discharged to an institution [median (SQR): 0·63 (0·29) μg/L and 0·37 (0·13) μg/L, respectively] compared to those who were discharged home [0·26 (0·11) μg/L, P = 0·13]. The present study suggests measurement of serum S-100 protein could be a useful prognostic marker of clinical outcome in acute stroke. Whether S-100 concentrations can be altered by therapeutic intervention in acute stroke remains to be elucidated. Indexing terms: acute stroke/serum S-100/Barthel index/Rankin scale.

Structural and functional changes in skeletal muscle in anorexia nervosa.

Abstract 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.

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism

Abstract Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumours from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

Genetic studies of a family with hereditary hyperparathyroidism–jaw tumour syndrome

Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2 A (MEN1, MEN2A) and hyperparathyroidism–jaw tumour (HPT–JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow‐up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re‐analysed this family and performed genetic linkage to the HPT–JT locus in chromosome 1q21‐q32. Loss of heterozygosity studies of 1q21‐q32, 11q13 and X chromosome were also performed.

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.

Serum carnosinase activities in central nervous system disorders.

Serum carnosinase activity was assayed in five groups of patients with neurological disorders. Enzyme activities in patients with idiopathic epilepsy (mean +/- S.E.M., 148 +/- 11 nmol/ml per min) and motor neurone disease (155 +/- 15 nmol/ml per min) were similar to the control group (161 +/- 7 nmol/ml per min). Reduced serum carnosinase activity was observed in patients with Parkinsons disease (109 +/- 11 nmol/ml per min, P < 0.005), multiple sclerosis (82.5 +/- 10.0 nmol/ml per min, P < 0.005) and patients following a cerebrovascular accident (74.6 +/- 5.4 nmol/ml per min, P < 0.001) compared with the control group. Carnosinase activity, 5-10% of that found in serum, was detected in CSF samples. The cause of reduced serum carnosinase activities in central nervous system disorders is unclear, although anoxic damage to carnosinase-producing cells or disruption of the blood-brain barrier may be responsible.

Effects of lisinopril and amlodipine on antioxidant status in experimental hypertension

The objective of this investigation was to compare changes in antioxidant status (together with other metabolites relevant to hypertension) in plasma and cardiac tissue from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), following 8 weeks of treatment with lisinopril (angiotensin converting enzyme inhibitor) or amlodipine (Ca(2+) channel antagonist) respectively. There was no significant difference in the levels of total antioxidant capacity, retinol, urea, albumin or triglyceride in plasma from SHR or WKY rats, with or without lisinopril or amlodipine treatment. However in SHR rats, levels of alpha-tocopherol were substantially reduced in both plasma (-54% WKY, P<0.01) and cardiac tissue (-43% WKY, P<0.05). Treatment with lisinopril ameliorated reduced levels of plasma alpha-tocopherol in SHR rats, but not in cardiac tissue. Amlodipine treatment had no effect on alpha-tocopherol levels in plasma or cardiac tissue in SHR rats. In SHR rats total cholesterol levels were significantly lower thanWKY controls (-36%, P<0.001). This effect was reversed in lisinopril treated SHR rats (+27%, P<0.01). Plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were reduced in untreated SHR rats (P<0.025) when compared to WKY controls; neither lisinopril nor amlodipine treatment significantly altered these parameters. These findings suggest possible alternative mechanisms of action for lisinopril, and reinforce its use in hypertensive patients or patients with left ventricular hypertrophy.

Carboxyterminal propeptide of type I procollagen in osteomalacia

Carboxyterminal propeptide of type I procollagen (PICP) was measured in sera from 25 patients with osteomalacia due to privational vitamin D deficiency. The mean value of serum PICP was significantly raised in patients with osteomalacia compared with 40 normal subjects (mean±SD, 161±82 ng/ml and 113±31 ng/ml, respectively; P=0.01). The raised serum PICP reflected the accelerated bone turnover in this condition as did the elevated serum total alkaline phosphatase (ALP), but the variation in values of serum PICP noted in individual patients may reflect the different stages of osteomalacia. The normalization of serum PICP and ALP, indicating a healing process of the bone disorder, needed longer time of vitamin D and calcium therapy. In contrast, adjusted serum calcium and inorganic phosphate (IP) responded and normalized rapidly. Serum PICP and total ALP appeared to behave differently in the disease and in its response to vitamin D therapy suggesting that these two markers may represent different functions of osteoblasts in osteomalacia.

A comparative investigation into the effect of chronic alcohol feeding on the myocardium of normotensive and hypertensive rats: An electrophoretic and biochemical study

We investigated whether the imposition of chronic alcohol in hypertension leads to greater biochemical and cellular abnormalities of the myocardium than those arising in normotension. Fifteen‐week‐old spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats were fed ethanol‐containing diets for six weeks. Particular attention was focused on the composition of contractile proteins identified by sodium dodecyl sulfate‐polyacrylamide gel electrophoresis (SDS‐PAGE), fractional rate of protein synthesis, and synthesis rates relative to RNA (RNA activity) or DNA (cellular efficiency). In addition, myocardial enzymes and adenine nucleotides were measured. In both SHR and WKY rats chronic ethanol caused a general decrease in the contents of all nine contractile proteins with myosin heavy chain predominantly affected. Fractional rates of mixed (i.e., total) and myofibrillary proteins remained unaltered in both WKY rats and SHR, as were cellular efficiencies. The RNA activity was significantly reduced in ethanol‐treated SHR but not in WKY rats. In ethanol‐treated SHR, cardiac creatine kinase (CK) and malate dehydrogenase (MDH) activities were increased, AMP levels were elevated, whilst ATP levels and the energy charge were reduced. In WKY rats, the only significant change related to increased aspartate aminotransferase activities in response to alcohol feeding. Although there were only subtle differences between the response of the normotensive and hypertensive rats due to ethanol dosage, the reduced ATP levels and increased CK and MDH activities in SHR may reflect a greater susceptibility to ischaemic damage. Reduced contractile protein content, particularly myosin heavy chain, may contribute to contractile defects, a common feature of subclinical and clinical alcoholic cardiomyopathy.

The Effect of Eccentric Exercise on Serum Creatine Kinase Activity in Different Ethnic Groups

Eccentric exercise causes release of muscle creatine kinase (CK) 3–4 days after exercise. Racial variation in basal serum CK has been reported but the reasons for this are unknown. We studied 30 subjects of different ethnic origin (Caucasian, Afro-Caribbean, Asian) before and after eccentric exercise. Basal serum CK was significantly higher in the Afro-Caribbean group (201 ± 134IU/L, median ± SD) compared to Caucasians (81 ± 57 IU/L). The Asian group had intermediate CK values (144 ± 93 IU/L). The intra-individual range of peak post-exercise CK values obtained was very wide (95–30 200 IU/L) with little difference in median CK between the Afro-Caribbean (8450 ± 9020 IU/L) and Caucasian groups (7600 ± 8800 IU/L). The median value for the Asian group was lower (594 ± 5410 IU/L). A sub-group of 15 individuals undertook a second bout of exercise 2 weeks later and all subjects demonstrated a training effect resulting in a marked attenuation of enzyme efflux. The variation in CK between the ethnic groups was not related to measurements of muscle strength or body mass, although the torque: body mass ratio followed the same order as the basal CK, i.e. the Afro-Caribbeans had the highest values. These results highlight the importance of considering ethnic origin and previous exercise history when interpreting serum CK assay results.