A rationale approach for mortality risk stratification in Chagas' heart disease.
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Biomedical subjects
Publications and source records attributed to M A Rossi.
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In the acute phase of Chagas' disease, the micropathology of the heart reveals a diffuse focal myocarditis, sometimes of a phlegmonous type and of an intensity not seen in any other inflammatory heart disease. Foci of myocytolytic necrosis and degeneration are seen microscopically with an intense mononuclear infiltrate associated with exudative phenomena and marked parasitism of myofibers. Abnormalities of the coronary microcirculation have been demonstrated in acute chagasic myocarditis as possible cause of transient ischemia consistent with the hypothesis of microvascular factor as a cause of the myocardial changes. Considering that the endothelium plays a key role as controller of the vessel tone regulation and vascular permeability, this investigation was carried out to study the structure of the endothelial lining of the thoracic and abdominal aorta obtained from Trypanosoma cruzi-infected rats in the acute septicemic phase by using scanning and transmission electron microscopy. The findings clearly demonstrate that the infected rats developed changes of the endothelial layer characterized by endothelial cell swelling and a few points of cell cytoplasm discontinuity appearing as holes exposing the subendothelial collagen usually associated with platelet-fibrin aggregates. These changes could disturb the generation of vasoactive substances, impairing the equilibrium between opposing forces. The exposition of the subendothelial collagen due to holes in the endothelial lining would favor platelet-fibrin aggregation. This way, the present results allow speculation that similar endothelial cells changes could be present in the microcirculation, reflecting a reduction in the protective role of the endothelium, participating in the genesis of vasospasm and platelet aggregation within coronary microvessels, and leading to the focal pathology in acute chagasic myocarditis.
Infrarenal aortic coarctation and diffuse hypoplasia is a very uncommon vascular disease. It has been named as hypoplasia of the abdominal aorta, mid-aortic dysplasia, mid-aortic syndrome, atrophy of aorta, atresia of the terminal aorta, and atypical coarctation. The pathogenesis is still controversial. This is in part due to the fact that among the reported cases pathological studies have been rarely carried out. We recently came across an autopsy case of an adult patient with coarctation of the infrarenal aorta and severe hypoplasia of the aortoiliac-femoral system. The pathological findings found explain the pathogenesis of this particular case.
The deoxyuridine triphosphatase gene of vaccinia virus, encoded by the open reading frame F2L, was cloned into Escherichia coli and expressed under the control of a bacteriophage T7 promoter. After induction of T7 RNA polymerase by isopropyl beta-D-thiogalactopyranoside, a 16.5-kDa peptide accumulated to high levels. This 16.5-kDa protein was purified to homogeneity and characterized. Gel filtration of the purified protein revealed a trimeric native structure. Biochemical analysis revealed the enzyme to be a metalloenzyme; enzymatic activity is inhibited by EDTA. This inhibition was reversed by the addition of Mg2+, Mn2+, or Zn2+. While the enzyme activity was highly specific for dUTP with an apparent Km of 0.94 microM, inhibition studies show that 8-azido-ATP acted as a competitive inhibitor of dUTP with a Ki of approximately 173 microM. Also, protection studies demonstrated that nucleotide competitors inhibit photoincorporation of the photoaffinity analogues [gamma-32P]5-azido-dUTP and [gamma-32P]8-azido-ATP. This suggests that while catalytic activity is limited to dUTP, other nucleotides can bind the active site.
Congenital coronary arteriovenous fistula is an unusual, but not rare, coronary anomaly. Management of asymptomatic fistulas is controversial because of great variability in natural history. We describe an 82-year-old female patient with spontaneous rupture of a previously undetected left main coronary artery-to-pulmonary artery coronary arteriovenous fistula, with resulting hemopericardium and cardiac tamponade. Emergent surgical exploration and repair provided successful treatment.
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As a highly lipophilic drug, propofol may interact with lipophilic domains in addition to its likely primary site of action on the gamma-aminobutyrateA) (GABA(A)) receptor. Likely candidates for such interaction are the G protein-coupled membrane receptors for lipid intercellular mediators. The phospholipid lysophosphatidate (LP) has attracted attention as such a signaling molecule. It has a variety of biological actions, including vasoconstriction. We therefore studied the interaction between propofol and the LP receptor. Intracellular Ca2+ release in response to LP was assessed by measuring C1- flux through Ca(2+)-activated C1- channels in Xenopus oocytes. The average charge movement in response to LP 10(-7)M was 2.0 +/- 0.2 microCoulombs. Propofol in Intralipid (0.01%) dose-dependently inhibited LP signaling (50% inhibitory concentration [IC50] 5.38 microM). Propofol 28 microM inhibited LP signaling by 81%. Intralipid (0.01%) was without effect. To ascertain that intracellular signaling pathways and the Ca(2+)-activated C1- channel were not affected by propofol, we tested the effects of propofol (5.6 microM) on currents induced by methylcholine (10(-7)M) in oocytes expressing the m1 muscarinic acetylcholine receptor. No inhibition was observed. As both receptors share the same intracellular signaling pathway, we conclude that clinically relevant concentrations of propofol most likely inhibit the LP receptor or its G protein. Inhibition of LP signaling may explain some of propofol's vasodilating actions.
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Several in vitro techniques have been developed, which are able to quantify the bactericidal activity of a determined antibacterial drug against an infective agent. The Serum Bactericidal Rate (SBR) is proposed as a complementary technique for the determination of the "killing curve", the serum bactericidal test or the minimal bactericidal concentration. SBR takes into account the most advantageous features of both of them. SBR is based on quantifying at different times the survival of the bacterial inoculum exposed to the patient's serum. Thus, bactericide speed is evaluated in the first hours of contact with the microorganism (as in the "killing curve"), but taking into account drug concentrations which have been reached by the patient (as in the serum bactericidal test). Preliminary assays suggest that SBR may have greater capacity to discriminate an infectious agent in answer to different therapeutic schemes than other determinations, although prospective studies are required to evaluate its predictive value.
The aim of the study was to investigate gonadal function and LH reserve in patients on chronic therapy with supraphysiological doses of GC. We clinically evaluated 17 male subjects (aged 23-56 years-old) on chronic GC therapy. In four subjects (aged 23-39 years-old) randomly selected, three basal blood samples were drawn and pooled for measurement of SHBG, total, free and bioavailable testosterone. Following baseline samples, a GnRH stimulation test was performed. Starting with a priming of 5 micrograms, a bolus of 50 micrograms of GnRH was injected intravenously and samples obtained every 30 minutes for assessment of LH. Four healthy men (aged 24-28 years-old) were used as controls. Patients on steroids referred decreased libido (58%) and impotence (52%) and lower back pain (41%). Total, free and bioavailable serum testosterone were significantly lower than controls (p < 0.01, p < 0.05 and p < 0.05, respectively) while SHBG levels persisted unchanged. Baseline LH and its rise after GnRH was normal. This study shows that chronic GC administration involves gonadal function reducing sexual steroids without changes in baseline and stimulated LH secretion. In addition, the priming with physiological doses of GnRH optimizes the pituitary response to higher GnRH doses.
In this study of the effect of an orotic-acid (O.A.) diet on the activity of membrane-bound phosphoinositide-specific phospholipase C (PL-C) of rat liver, its enzymatic activity was evaluated in vitro on membranes obtained from the hepatic tissue of male Wistar rats fed a diet containing 1% O.A. for 2 and 5 days and from control rats. The rate of breakdown of labelled phosphatidylinositol-4,5-bisphosphate (Ptdins-P2) added to the isolated membranes was measured both in the absence and in the presence of guanosine-5'-O-thiotriphosphate (GTP gamma S). The enzyme stimulation by bombesin was also analysed. PL-C activity proved to be deeply and early modified by O.A. The basal activity was increased 2 days after feeding on the O.A.-supplemented diet, but the difference from control rats was no more significant after 5 days of this diet. The most interesting changes concerned the response to bombesin; the hormone failed to induce any stimulation of PL-C in O.A.-treated rats after either 2 or 5 days of diet, whereas it nearly doubled Ptdins-P2 breakdown in the liver membranes from control rats. The lack of any stimulation of the phospholipase C by bombesin in O.A.-treated rats indicates a deep impairment of this signal transmission system; its possible causes and consequences are discussed.
Different approaches are used to determine the cause of Cushing's syndrome (CS). In this study we evaluated the validity of nocturnal high dose dexamethasone and metyrapone tests in patients with CS of different etiology. A total of 61 patients (51 women, 10 men), aged 13-61, were studied. Definitive etiological diagnosis was established on imaging, surgical and pathological findings, and/ or the clinical evolution after treatment. On that basis, the patients were classified as follows: 41 with Cushing's disease, 16 with adrenal tumors (11 adenomas and 5 carcinomas) and 4 with ectopic CS. Nocturnal dexamethasone (8 mg) test was carried out in all the patients; in 43 out of the 61 patients, 11-deoxicortisol responses to metyrapone were also determined. The sensitivity, specificity, accuracy and positive predictive power for the diagnosis of pituitary CS were calculated for both tests. For the nocturnal dexamethasone test, values were 85, 100, 90 and 100%, respectively (n = 61); the sensitivity and specificity increased to 95 and 97% by repeating the test in six false negative patients. Results for the metyrapone test were 90, 85, 88 and 93%, respectively (n = 43). When both tests were considered together, the values were 97, 100, 98 and 100% higher, although not significantly, than those for each separate test (n = 43). In conclusion, we believe that the combination of metyrapone and nocturnal high dose dexamethasone tests carried out on an outpatient basis has enough sensitivity, specificity, diagnostic accuracy and positive predictive value to be employed as an easy and low cost strategy in the etiological diagnosis of CS.
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We recently came across a case of a patient in the indeterminate phase of Chagas' disease who died suddenly with cardiac arrhythmia associated with acute infarction of the right carotid body due to occlusive thrombosis in the glomic artery. Although the available data in this case do not offer definite evidence to support a cause-and-effect relationship between carotid body infarction and patient's sudden cardiac arrest, it is very likely that the acute infarction of the carotid body could be the distinct morphological counterpart of the functional disturbance. The infarction would affect the vagal-sympathetic interactions augmenting sympathetic action.
The evidence provided by both human and animal studies on chronic Chagas' heart disease suggests that the cardiomyopathy occurs as a consequence of several physiopathological processes occurring after infection interacting with unidentified host factors. The development of the chronic fibrosing myocarditis is related to progressive and additive focal cellular necrosis, and associated inflammatory lymphomononuclear infiltrate and reactive and reparative myocardial fibrosis and surrounding myocyte hypertrophy. These processes may be initiated and perpetuated by alterations in the myocardial microcirculation and by autoimmune factors. The autonomic impairment and/or the chronic fibrosing myocarditis and the left ventricular dysfunction could act as factors predisposing one to an increased risk of sudden cardiac death.
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