Biomedical subjects
Publications and source records attributed to S Messina.
Two previously healthy women developed an inflammatory myopathy before the term of their first pregnancy. Skeletal muscle biopsy led to a diagnosis of T cell-mediated polymyositis. Both babies were healthy, but their serum creatine kinase levels remained elevated for a few months after birth. Their mothers did well after corticosteroid treatment.
Intense exercise is thought to increase oxidative stress and damage muscle tissue. Taurine is present in high concentration in skeletal muscle and may play a role in cellular defenses against free radical-mediated damage. The aim of this study was to determine if manipulating muscle levels of taurine would alter markers of free radical damage after exercise-induced injury. Adult male Sprague-Dawley rats were supplemented via the drinking water with either 3% (w/v) taurine (n = 10) or the competitive taurine transport inhibitor, beta-alanine (n = 10), for one month. Controls (n = 20) drank tap water containing 0.02% taurine and all rats were placed on a taurine free diet. All the rats except one group of sedentary controls (n = 10) were subjected to 90 minutes of downhill treadmill running. Markers of cellular injury and free radical damage were determined along with tissue amino acid content. The 3% taurine treatment raised plasma levels about 2-fold and 3% beta-alanine reduced plasma taurine levels about 50%. Taurine supplementation (TS) significantly increased plasma glutamate levels in exercised rats. Exercise reduced plasma methionine levels and taurine prevented its decline. Taurine supplementation increased muscle taurine content significantly in all muscles except the soleus. beta-alanine decreased muscle taurine content about 50% in all the muscles examined. Lipid peroxidation (TBARS) was significantly increased by exercise in the extensor digitorium longus (EDL) and gastrocnemius (GAST) muscles. Both taurine and beta-alanine completely blocked the increase in TBARs in the EDL, but had no effect in the GAST. Muscle content of the cytosolic enzyme, lactate dehydrogenase (LDH) was significantly decreased by exercise in the GAST muscle and this effect was attenuated by both taurine and beta-alanine. Muscle myeloperoxidase (MPO) activity was significantly elevated in the gastrocnemius muscle, but diet had no effect. MPO activity was significantly increased by exercise in the liver and both taurine and beta-alanine blocked this effect. There was no effect of either exercise or the diets on MPO activity in the lung or spleen. Running performance as assessed by a subjective rating scale was improved by taurine supplementation and there was a significant loss in body weight in the beta-alanine-treated rats 24 hours after exercise. In summary, taurine supplementation or taurine depletion had measurable cytoprotective actions to attenuate exercise-induced injury.
BACKGROUND/OBJECTIVE: Apoptosis, or programmed cell death, is an evolutionary conserved mechanism essential for morphogenesis and tissue homeostasis, but it plays an important role also in pathologic conditions, including neurologic disorders. Its execution pathway is critically regulated at the mitochondrial level. Evidence of apoptosis in muscle specimens was investigated in patients with genetically defined mitochondrial encephalomyopathies. METHODS: Thirty-three muscle biopsies from patients with genotypically different mitochondrial diseases (single and multiple deletions, A3243G/A8344G point mutations of the mitochondrial DNA) were studied. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) reaction was used as a marker of nuclear DNA fragmentation, as well as antibodies against pro- (Fas) or anti- (Bcl-2) apoptotic factors. Also, because one hallmark of apoptosis is morphologic, ultrastructural studies were performed on skeletal muscle from 18 of 33 patients, examining both phenotypically normal and ragged red fibers. RESULTS: In all muscle biopsies, no significant expression of either pro (Fas) and inhibiting (Bcl-2) apoptosis-related proteins was found, nor TUNEL positivity. This latter finding is confirmed by lack of morphologic evidence of apoptosis in all the fibers examined at the ultrastructural level. CONCLUSION: The authors' findings suggest that genetically determined defects of oxidative phosphorylation do not induce the apoptotic process and that apoptosis is not involved in the pathogenesis of mitochondrial disorders.
Mitochondrial disorders are human genetic diseases with extremely variable clinical and genetic features. To better define them, we made a genotype-phenotype correlation in a series of 207 affected patients, and we examined most of them with six laboratory examinations (serum CK and basal lactate levels, EMG, cardiac and EEG studies, neuroradiology). We found that, depending on the genetic abnormality, hyperckemia occurs most often with either chronic progressive external ophthalmoplegia (CPEO) and ptosis or with limb weakness. Myopathic EMGs are more common than limb weakness, except in patients with A8344G mutations. Peripheral neuropathy, when present, is always axonal. About 80% of patients with A3243G and A8344G mutations have high basal lactate levels, whereas pure CPEO is never associated with increased lactate levels. Cardiac abnormalities mostly consist of conduction defects. Abnormalities on CT or MRI of the brain are relatively common in A3243G mutations independently of the clinical phenotype. Patients with multiple mtDNA deletions are somehow "protected" against the development of abnormalities with any of the tests. We conclude that, despite the phenotypic heterogeneity of mitochondrial disorders, correlation of clinical features and laboratory findings may give the clinician important clues to the genetic defect, allowing earlier diagnosis and counselling.
To evaluate the influence of pediatric age and antiepileptic comedication on the single-dose pharmacokinetics of lamotrigine, 19 patients with epilepsy (10 comedicated with enzyme inducers and 9 comedicated with valproic acid) aged 8 months to 30 years received a single oral dose of lamotrigine (0.6 to 2.2 mg/kg) after an overnight fast. Blood samples were collected for at least 36 hours and plasma lamotrigine concentrations were determined by high-performance liquid chromatography. Pharmacokinetic parameters were calculated by noncompartmental analysis. Lamotrigine half-life (T1/2) and oral clearance (Cl/F) values were significantly lower and significantly higher, respectively, in patients comedicated with enzyme inducers than in those receiving valproic acid (T1/2 = 8.1 vs. 41.7 hours respectively, P < 0.001; Cl/F = 0.11 vs. 0.04 L/h per kg respectively, P < 0.005, geometric means), whereas Cmax and Tmax values were comparable in the two groups. The differences in pharmacokinetic parameters persisted when comparisons were made within subgroups stratified according to age. Within groups of patients homogeneous for type of comedication, Cmax and AUC values tended to be lower in children aged less than 12 years than in older patients. There was no significant relationship between half-life values and age. The authors conclude that both age and type of comedication influence lamotrigine pharmacokinetics. The reduction in lamotrigine concentrations caused by enzyme inducers and the elevation caused by valproic acid can be explained by stimulation and inhibition, respectively, of lamotrigine glucuronidation. On the other hand, the lower plasma lamotrigine levels in children than in adolescents and older patients may not be explainable solely by differences in metabolic rate.
Taurine is present in high concentrations in mammalian tissues and has been implicated in cardiovascular control mechanisms. The aim of the present study was to evaluate the ability of taurine to attenuate salt-induced elevations in blood pressure and markers of damage to the kidney and cardiovascular system in stroke prone spontaneously hypertensive rats (SPSHR). Male SPSHR (6 weeks old) were placed on high salt diets that contained 1% (w/w) NaCl added to their normal chow for 84 days and then were switched to 3% added NaCl for the remaining 63 days of the study. SPSHR was given 1.5% taurine in the drinking water (n = 8), a taurine free diet (n = 8) or normal chow (n = 8). A final control group (n = 6) was not given high salt diets. High salt diets caused an acceleration in the development of hypertension in all groups. Taurine supplementation reduced ventricular hypertrophy and decreased urinary excretion of protein and creatinine. The taurine free diet did not alter serum or urinary excretion of taurine, but did result in elevated urinary nitrogen excretion, increased serum cholesterol levels, and impaired performance in a spatial learning task. Alterations in dietary taurine intake did not alter urinary or serum electrolytes (Na+, K+), but taurine supplementation did attenuate a rise in serum calcium seen with the high salt diets. Urinary excretion (microg/24h) of epinephrine and dopamine was significantly reduced in SPSHR given 1% NaCl in the diet, but this effect was not seen in SPSHR on taurine free or supplemented diets. Taurine supplementation showed cardioprotective and renoprotective effects in SPSHR given high salt diets.
We describe the use of phage libraries to derive new antibodies against p21Ras to be used for intracellular expression in mammalian cells. A panel of single-chain antibody fragments, binding to Ras, were analyzed and characterized for their capacity to interfere in vitro with (a) the intrinsic GTPase activity of Ras and (b) the binding of Ras to its effector Raf, and were found not to neutralize its function, according to these biochemical criteria. When expressed intracellularly in mouse 3T3 K-Ras transformed cells all the anti-Ras single-chain variable fragments (scFv) tested inhibited cell proliferation, as assessed by bromodeoxyuridine incorporation. Double immunofluorescence analysis of transfected cells using confocal microscopy confirmed that anti-Ras antibody fragments colocalize with endogenous Ras, at subcellular locations where the protein Ras is not normally found. These data suggest that the ability of phage-derived anti-Ras scFv fragments to inhibit the function of Ras in vivo is a rather general and frequent property and that the range of antibodies that can be successfully used for intracellular inhibition studies is much greater than anticipated, exploiting the mode of action of diverting protein traffic.
We describe the clinicopathologic features of a 56-year-old woman affected with Churg-Strauss syndrome with major peripheral nerve involvement. The patient presented with a 1-month history of mainly distal upper-limb symmetrical paresthesias and hypostenia (bilateral "wrist drop"), palpable purpura and eosinophilia. Multiple pulmonary infiltrates and asthma had been present since the age of 52. Skin biopsy demonstrated an eosinophilic necrotizing vasculitis. During the hospitalization she was submitted to cardiac, bronchopulmonary, renal, and gastrointestinal evaluation and EMG. Peripheral nerve and skeletal muscle biopsies were performed. Sural nerve biopsy showed a marked degree of demyelination. A perivascular cellular infiltrate within the epineurium was immunoreactive for T lymphocytes and macrophages. Strong HLA-DR immunostaining was present in the endoneurium. IgM, IgE and fibrinogen deposition was found in some epi- and endoneurial vessels. Muscle biopsy showed neurogenic changes and 1 thrombosed vessel surrounded by mononuclear cells. Membrane attack complex (MAC) deposition was present in a few capillaries and major histocompatibility complex products I (MHCP I) was expressed at the subsarcolemmal level in a few isolated perivascular muscle fibers. After immunosuppressive therapy, the patient showed progressive improvement of both clinical symptoms and neurophysiological parameters.
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The anti-p21ras Y13-259 single-chain Fv fragment (scFv) neutralizes the activity of p21-ras when intracellularly expressed in different systems. We have studied the mode of action of this inhibition in 3T3 K-ras fibroblasts and demonstrated that (i) this antibody fragment is highly aggregating when cytoplasmically expressed and (ii) the p21-ras antigen is sequestered in these aggregates in an antibody-dependent manner. This co-segregation leads to an efficient inhibition of DNA synthesis. These results suggest that an antigen can be diverted from its normal location inside the cells in an antibody mediated way, prospecting a new mode of action for intracellular antibodies in vivo.
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SLE is a complex systemic disease which probably has a multifactorial genesis. The basis alteration takes the form of a severe immunoregulation disorders. From an epidemiological point of view, there are no certain links with country of origin or race; knowledge of the disease's etiology is equally limited. Clinical symptoms are widely variable according to the prevalent organ or apparatus pathology. The symptomatology of SLE is in fact highly polymorphous thus making it complex and sometimes difficult to diagnose. From a prognostic point of view, over recent years the future of these patients has appeared brighter than in the past. The current therapeutic approach uses a number of measures which can be used in combination or sequentially. It is precisely this varying combination of therapies that has led to a marked prolongation of survival and long disease-free periods.
The authors take the opportunity of 11 cases of pulmonary hamartomas observed during the last 10 years, to specify the clinical and diagnostic problems and the therapeutic possibilities of this rare pulmonary neoplasm. The hamartochondroma is found mainly in the male sex, between the age of the fifth and sixth decades of life; the size of the neoplasm varies from 2 to 4 cm, rarely exceeding 10 cm. In 8 cases the operation was the simple enucleation of the hamartochondroma or its removal by atypical resection: in only one case, become of the conspicuous dimensions of the neoplasm, was it necessary to perform a typical lobectomy. The follow-up did not demonstrate any relapse, or the appearance of carcinoma of the lung in any of the cases under observation and surgically treated.
The paper reports a case of intrathoracic hemangiopericytoma localised in mediastinum which was brought to the authors attention and treated surgically. Having analysed the tumour's macro- and microscopic histological and biological features and the most suitable methods of diagnosis, the authors stress that, in line with international literature, radical surgery extended to the surrounding tissues is the elective surgical treatment for hemangiopericytoma in a mediastinal site.
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Explore the source record for details and available documents.
Explore the source record for details and available documents.