Recombinogenic, genotoxic, and cytotoxic effects of azathioprine using in vivo assays.

Azathioprine (Aza) is a purine antimetabolite immunosuppressant that is widely employed for immunosuppressive therapy in post-transplant recipients or patients with autoimmune diseases. Chronic use of immunosuppressants might produce several side effects, including a high rate of neoplasms in these patients. Considering that genotoxic effects are associated with an increased risk of developing cancer, the aim of this study was to examine the recombinogenic, genotoxic, and cytotoxic effects of Aza using Somatic Mutation and Recombination Test (SMART) in Drosophila melanogaster, as well as comet and micronucleus assays in mouse bone marrow cells. Further, the adverse effects of Aza were determined in mouse hepatic and renal tissues using histopathological analysis. Data demonstrated that Aza induced significant increased genotoxicity in D. melanogaster and mouse bone marrow cells at all concentrations tested. Homologous recombination was the predominant genotoxic event noted for the first time to be initiated by Aza in SMART. In histopathological analysis, Aza did not show any marked toxic activity in mouse hepatic and renal tissues. Therefore, the high rate of neoplasms reported in patients with long-term use of Aza may be attributed, at least partially, to the genotoxic action of this drug.

Toxicity and genotoxicity induced by abacavir antiretroviral medication alone or in combination with zidovudine and/or lamivudine in Drosophila melanogaster.

Abacavir (ABC), zidovudine (AZT), and lamivudine (3TC) are nucleoside analog reverse transcriptase inhibitors (NRTIs) widely used as combination-based antiretroviral therapy against human immunodeficiency virus. Despite effective viral suppression using NRTI combinations, genotoxic potential of NRTIs can be increased when administered in combination. This study investigated the toxic and genotoxic potential of ABC when administered alone or in combination with AZT and/or 3TC using the somatic mutation and recombination test in Drosophila melanogaster. This test simultaneously evaluated two events related to carcinogenic potential: mutation and somatic recombination. The results indicated that ABC was responsible for toxicity when administered alone or in combination with AZT and/or 3TC. In addition, all treatment combinations increased frequencies of mutation and somatic recombination. The combination of AZT/3TC showed the lowest genotoxic activity compared to all combinations with ABC. Therefore, our results indicated that ABC was responsible for a significant portion of genotoxic activity of these combinations. Somatic recombination was the main genetic event observed, ranging from 83.7% to 97.7%.

Phenotypic aspects of oral strains of Candida albicans in children with Down's syndrome.

The aim of this article is to characterize the biological aspects of oral strains of C. albicans in children with Down's syndrome. These yeasts were analyzed as to their macromorphological and enzymatic aspects and were tested as to their in vitro susceptibility to antifungal drugs using broth microdilution to determine the minimum inhibitory concentration (MIC). The morphotyping revealed that all oral C. albicans isolates from children with Down's syndrome promoted the formation of fringes regardless of size, while the control group presented smaller fringes. All oral C. albicans strains produced proteinase, but those with phospholipolytic activity showed greater enzyme capacity in the test group. In vitro susceptibility showed that all oral C. albicans isolates were sensitive to the drugs used.

Phenotypic aspects of oral strains of Candida albicans in children with down's syndrome / Aspectos fenotípicos de cepas de Candida albicans orais em crianças com síndrome de down

The aim of this article is to characterize the biological aspects of oral strains of C. albicans in children with Down's syndrome. These yeasts were analyzed as to their macromorphological and enzymatic aspects and were tested as to their in vitro susceptibility to antifungal drugs using broth microdilution to determine the minimum inhibitory concentration (MIC). The morphotyping revealed that all oral C. albicans isolates from children with Down's syndrome promoted the formation of fringes regardless of size, while the control group presented smaller fringes. All oral C. albicans strains produced proteinase, but those with phospholipolytic activity showed greater enzyme capacity in the test group. In vitro susceptibility showed that all oral C. albicans isolates were sensitive to the drugs used.

O objetivo deste artigo foi caracterizar os aspectos biológicos de cepas de C. albicans orais em crianças com síndrome de Down. Estas leveduras foram analisadas quanto aos seus aspectos macromorfológicos e enzimáticos e foram testadas quanto a sua suscetibilidade in vitro a drogas antifúngicas, usando a microdiluição em caldo para a determinação da concentração inibitória mínima (CIM). A morfotipagem revelou que todos os isolados de C. albicans orais de crianças com síndrome de Down induziram à formação de franjas independente do tamanho, enquanto o grupo controle teve franjas menores. Todas as cepas de C. albicans orais produziram proteinase, mas aquelas com atividade fosfolipidolítica mostraram maior capacidade enzimática no grupo teste. A suscetibilidade in vitro mostrou que todos os isolados de C. albicans orais foram sensíveis a drogas empregadas.

Previous exercise attenuates muscle sympathetic activity and increases blood flow during acute euglycemic hyperinsulinemia.

Insulin infusion causes muscle vasodilation, despite the increase in sympathetic nerve activity. In contrast, a single bout of exercise decreases sympathetic activity and increases muscle blood flow during the postexercise period. We tested the hypothesis that muscle sympathetic activity would be lower and muscle vasodilation would be higher during hyperinsulinemia performed after a single bout of dynamic exercise. Twenty-one healthy young men randomly underwent two hyperinsulinemic euglycemic clamps performed after 45 min of seated rest (control) or bicycle exercise (50% of peak oxygen uptake). Muscle sympathetic nerve activity (MSNA, microneurography), forearm blood flow (FBF, plethysmography), blood pressure (BP, oscillometric method), and heart rate (HR, ECG) were measured at baseline (90 min after exercise or seated rest) and during hyperinsulinemic euglycemic clamps. Baseline glucose and insulin concentrations were similar in the exercise and control sessions. Insulin sensitivity was unchanged by previous exercise. During the clamp, insulin levels increased similarly in both sessions. As expected, insulin infusion increased MSNA, FBF, BP, and HR in both sessions (23 +/- 1 vs. 36 +/- 2 bursts/min, 1.8 +/- 0.1 vs. 2.2 +/- 0.2 ml.min(-1).100 ml(-1), 89 +/- 2 vs. 92 +/- 2 mmHg, and 58 +/- 1 vs. 62 +/- 1 beats/min, respectively, P < 0.05). BP and HR were similar between sessions. However, MSNA was significantly lower (27 +/- 2 vs. 31 +/- 2 bursts/min), and FBF was significantly higher (2.2 +/- 0.2 vs. 1.8 +/- 0.1 ml.min(-1).100 ml(-1), P < 0.05) in the exercise session compared with the control session. In conclusion, in healthy men, a prolonged bout of dynamic exercise decreases MSNA and increases FBF. These effects persist during acute hyperinsulinemia performed after exercise.

Postexercise hypotension and hemodynamics: the role of exercise intensity.

AIM: Although postexercise hypotension (PEH) has already been extensively demonstrated, the influence of exercise intensity on its magnitude and mechanisms is still controversial. METHODS: Twenty-three normotensive subjects were submitted to a control (45 minutes of rest) and 3 exercise sessions (cycle ergometer, 45 minutes at 30%, 50% and 75% of .VO(2peak)) to investigate the role of exercise intensity on PEH. Blood pressure (BP - auscultatory), heart rate (HR - ECG), and cardiac output (CO - CO2 rebreathing) were measured before and after the control and exercise sessions. RESULTS: Systolic BP decreased significantly after exercise at 50% and 75% of .VO(2peak). Diastolic BP increased significantly during the control session, did not change after exercise at 30% of .VO(2peak), and decreased significantly after exercise at 50% and 75% of .VO(2peak). This fall was greater and longer after more intense exercise. CO and systemic vascular resistance (SVR) responses were similar between sessions, CO increased whereas SVR decreased significantly. Stroke volume (SV) increased and heart rate (HR) decreased following control and exercise at 30% of .VO(2peak) whereas SV decreased and HR increased after exercise at 50% and 75% of .VO(2peak). CONCLUSION: PEH is greater and longer after more intense exercise. BP profile is followed by a decrease in SVR and an increase in CO, what was not influenced by previous exercise. The increase in CO is caused by an increase in SV after rest and low intensity exercise and by an increase in HR after moderate and more intense aerobic exercise.

Spontaneous ovarian hyperstimulation and primary hypothyroidism with a naturally conceived pregnancy.

BACKGROUND: Ovarian hyperstimulation syndrome, not related to ovulation induction, is rare. A MEDLINE search from 1987 to 1997 using the key words "spontaneous ovarian stimulation," "pregnancy," and "hypothyroidism" revealed only five cases: three associated with pregnancies and two with primary hypothyroidism. CASE: A 25-year-old white gravida 2, para 1, at 11-12 weeks' gestation presented with mild distension of a nontender abdomen, myxedematous facies, and large bilateral, multilobulated ovarian cysts. Conception had occurred spontaneously. Thyroid stimulating hormone was elevated, and free triiodothyronine and free thyroxine were low. Hypothyroidism, associated with spontaneous ovarian hyperstimulation syndrome, was diagnosed, and oral levothyroxine (0.10 mg/day) was started. With TSH still elevated at 21 weeks, levothyroxine was increased to 0.20 mg/day, and by 24 weeks, TSH and ovarian size were normal. Vaginal delivery of a 1120 g male infant occurred at 28 weeks. CONCLUSION: A case of naturally conceived pregnancy associated with spontaneous ovarian hyperstimulation and primary hypothyroidism is reported.

[Hypertension associated with pregnancy. Epidemiologic study of 311 consecutive cases]. / Hipertensão associada à gravidez. Estudo epidemiológico de 311 casos consecutivos.

The epidemiologic aspects of 311 consecutive cases of hypertension associated with pregnancy seen in the Department of Obstetrics and Gynecology, Hospital de Santa Maria/University of Lisbon Medical School between January 1st 1988 and December 31st 1992, are reviewed. Seventeen cases were multifetal pregnancies. Using the criteria proposed by the American College of Obstetricians and Gynecologists the cases were classified as follows: Mild preeclampsia, 64 cases (7 in twins); severe preeclampsia 50 cases (5 in twins); chronic hypertensive disease, 81 (1 in twins); chronic hypertension with superimposed preeclampsia, 16 (all singleton pregnancies); transient hypertension of pregnancy, 84 (4 in twins); unclassified hypertension, 16 cases of singleton pregnancies. No maternal deaths occurred. The most frequent maternal complications (eclampsia, HELLP syndrome, abruptio placentae and acute renal failure) were seen in preeclampsia (mild and severe forms). Only 2 significant maternal complications were observed in the cases of superimposed preeclampsia on chronic hypertensive disease. In the other groups maternal complications were seldom seen. Excepting in transient hypertension, perinatal morbidity and mortality were frequent in all groups, specially in severe preeclampsia and superimposed preeclampsia, when the delivery occurred before 34 weeks; after that time of pregnancy there were no neonatal deaths in any of the groups and intrauterine growth retardation and fetal distress were the most common fetal complications in all groups. In the whole, uncomplicated chronic hypertension and transient hypertension of pregnancy were the clinical situations in which maternal and perinatal complications were milder and less frequent. No perinatal problems were found in the group of unclassified hypertension.

[Myasthenia gravis and pregnancy]. / Miastenia gravis e gravidez.

Four cases of pregnancy in patients with Myasthenia Gravis are presented. No significant pregnancy complications occurred; labour/delivery and puerperium did not present many differences from those expected in healthy women. The review of the literature along with our short experience allows us to conclude that pregnancy in myasthenic patients is a high risk situation, but must be seen with optimism.

[Doppler flowmetry of feto-maternal circulation: III --Absent and reverse diastolic flow in the umbilical artery]. / Fluxometria Doppler da circulação feto-materna: III--Ausência e inversão do fluxo diastólico na artéria umbilical.

Twelve cases of extreme umbilical blood flow impairement (8 cases with loss of end-diastolic blood flow and 4 cases with reversed flow) found among 658 pregnancies studied by continuous Doppler between April 1st 1989 and March 31st 1990, are reported. The findings were associated to intra-uterine growth retardation (92%), maternal hypertensive disease (50%) and perinatal death (33%); fetal Trisomy 21 was the sole problem in one of the cases with absent end-diastolic frequencies. Our results are discussed and compared to similar data reported recently. Clinical management is proposed, according to umbilical blood flow patterns, length of gestation and underlying clinical situations.

Acute effects of maternal cigarette smoking on fetal heart rate and fetal body movements felt by the mother.

Acute effects of maternal cigarette smoking on fetal heart rate (FHR) and fetal body movements felt by the mother (FM) were studied in 51 pregnant volunteers. Thirty four were chronic smokers (6 or more cigarettes per day, with an average of 14 cigarettes/day) and 17 were sporadic smokers (1 to 5 cigarettes per day, with an averaged of 3 cigarettes/day). In both groups the number of FM, fetal reactivity and short-term FHR variability decreased significantly in the 20 minutes following cigarette smoking; a sustained FHR rise of 10 or more beats/min was also found after the cigarette in more than 50% of the cases in the 2 groups. No statistically significant differences were found among the 2 groups when the post-cigarette data were compared. We conclude that maternal cigarette smoking produces important acute effects upon FM and FHR regardless the average daily number of cigarettes smoked by the mother.

An approach to interpretation and classification of sinusoidal fetal heart rate patterns.

Sinusoidal fetal heart rate (SHR) records were obtained in 8 cases, either antepartum (3 cases of fetal Rh disease) or intrapartum (one case with an acute episode of fetomaternal transfusion as possible cause, 2 after meperidine administration to the mother and 2 others without attributable causes). Characteristics of both SHR patterns and related clinical pictures are described and compared to similar cases published elsewhere. The possible underlying mechanisms of SHR are discussed. Two different profiles of SHR patterns (smooth and jagged waveforms) are characterized and correlated with their most usual clinical backgrounds and prognostic significance. A classification of SHR into 2 main types is proposed, with clinical use in mind.