Mandibulofacial Dysostosis, Severe Lower Eyelid Coloboma, Cleft Palate, and Alopecia: A New Distinct Form of Mandibulofacial Dysostosis or a Severe Form of Johnson-McMillin Syndrome?

We describe a patient with a phenotype characterized by mandibulofacial dysostosis with severe lower eyelid coloboma, cleft palate, abnormal ears, alopecia, delayed eruption and crowded teeth, and sensorioneural hearing loss. The karyotype and the screening for mutations in the coding region of TCOF1 gene were normal. The clinical signs of our case overlap the new mandibulofacial dysostosis described by Stevenson et al. [2007] and the case with Johnson-McMillin syndrome described by Cushman et al. [2005]. The similar clinical signs, mainly, the severe facial involvement observed in these cases suggest that they can represent a new distinct form of mandibulofacial dysostosis or the end of the spectrum of Johnson McMillin syndrome. (C) 2010 Wiley-Liss, Inc.

Involvement of the AT(1) receptor in the venoconstriction induced by angiotensin II in both the inferior vena cava and femoral vein

Although angiotensin II-induced venoconstriction has been demonstrated in the rat vena cava and femoral vein, the angiotensin II receptor subtypes (AT(1) or AT(2)) that mediate this phenomenon have not been precisely characterized. Therefore, the present study aimed to characterize the pharmacological receptors involved in the angiotensin II-induced constriction of rat venae cavae and femoral veins, as well as the opposing effects exerted by locally produced prostanoids and NO upon induction of these vasomotor responses. The obtained results suggest that both AT(1) and AT(2) angiotensin II receptors are expressed in both veins. Angiotensin II concentration-response curves were shifted toward the right by losartan but not by PD 123319 in both the vena cava and femoral vein. Moreover, it was observed that both 10(-5) M indomethacin and 10(-4) M L-NAME improve the angiotensin II responses in the vena cava and femoral vein. In conclusion, in the rat vena cava and femoral vein, angiotensin II stimulates AT(1) but not AT(2) to induce venoconstriction, which is blunted by vasodilator prostanoids and NO. (C) 2010 Elsevier Inc. All rights reserved.

Fatores de risco para morte em pacientes diabéticos e não diabéticos em tratamento hemodialítico

A mortalidade dos pacientes diabéticos, quando iniciam tratamento hemodialítico, ainda é muito elevada, significativamente maior do que a dos pacientes não diabéticos. As doenças cardíacas são a principal causa de morte nestes pacientes. O diabetes, por si só, está associado a uma alta prevalência de hipertensão, doença cardiovascular e insuficiência cardíaca, resultando em morbi-mortalidade significativas. Tradicionalmente, a mortalidade tem sido associada à cardiopatia isquêmica. A mortalidade cardiovascular, entretanto, não está relacionada apenas à isquemia, mas também à insuficiência cardíaca e à morte súbita. O objetivo deste estudo foi analisar o papel da doença cardiovascular como fator prognóstico para a morte de pacientes diabéticos e não diabéticos, que iniciam hemodiálise, levando em consideração outros fatores. Este foi um estudo prospectivo de uma coorte de 40 pacientes diabéticos e 28 não diabéticos, que iniciaram programa de hemodiálise, de agosto de 1996 a junho de 1999, em 5 hospitais de Porto Alegre, Brasil. O tempo total de acompanhamento foi de 4,25 anos. A avaliação inicial, realizada entre o 20 e o 30 mês de hemodiálise, incluiu: um questionário com características demográficas, história do diabetes e suas complicações, história de hipertensão e acidente vascular cerebral; o exame físico incluindo avaliação nutricional e exame oftalmológico; e avaliação laboratorial com medidas de parâmetros nutricionais, bioquímicos, hormonais, perfil lipídico, e controle metabólico do diabetes, além da avaliação da adequação da diálise. Para a avaliação cardiovascular foram utilizados: questionário Rose, ECG em repouso, cintilografia em repouso e sob dipiridamol, e ecocardiograma bi-dimensional e com Doppler. A mortalidade foi analisada ao final dos 51 meses, e as causas de morte, definidas pelos registros médicos, atestados de óbito ou informações do médico assistente ou familiar. Na análise estatística, foram empregados o teste t de Student, o qui-quadrado (χ2) ou teste exato de Fisher. Para a análise da sobrevida, o método de Kaplan-Meier foi utilizado, e, para identificar os principais fatores associados à mortalidade, construiu-se um modelo de regressão múltipla de Cox. O nÍvel de significância adotado foi de 5%. Ao final do estudo, os pacientes diabéticos tiveram um índice de mortalidade significativamente mais elevado do que os pacientes sem diabetes (47,5% vs. 7,1%; P=0,0013, log rank test). Na análise de Cox, o padrão pseudonormal ou restritivo de disfunção diastólica esteve associado a um risco de 3,2 (IC 95%:1,2-8,8; P=0,02), e a presença de diabetes, a um risco de 4,7 (IC 95%:1,03-21,4; P=0,04) para a morte. Concluiu-se que a disfunção diastólica do ventrículo esquerdo foi o principal preditor de mortalidade nesta coorte de pacientes que estão iniciando tratamento hemodialítico.

beta-carotene attenuates the paradoxical effect of tobacco smoke on the mortality of rats after experimental myocardial infarction

The objective of this study was to investigate the effects of exposure to tobacco smoke (ETS) in rats that were or were not supplemented with dietary beta-carotene (BC), on ventricular remodeling and survival after myocardial infarction (MI). Rats (n = 189) were allocated to 4 groups: the control group, n = 45; group BC administered 500 mg/kg diet, n = 49, BC supplemented rats; group ETS, n = 55, rats exposed to tobacco smoke; and group BC+ETS, n = 40. Wistar rats weighing 100 g were administered one of the treatments until they weighed 200 to 250 g (similar to 5 wk). The ETS rats were exposed to cigarette smoke for 30 min 4 times/d, in a chamber connected to a smoking device. After reaching a weight of 200-250 g, rats were subjected to experimental MI (coronary artery occlusion) and mortality rates were determined over the next 105 d. In addition, echocardiographic, isolated heart, morphometrical, and biochemical studies were performed. Mortality data were tested using Kaplan-Meyer curves and other data by 2-way ANOVA. Survival rates were greater in the ETS group (58.2%) than in the control (33.3%) (P = 0.001) and BC+ETS rats (30.0%) (P = 0.007). The groups did not differ in the other comparisons. Left ventricular end-diastolic diameter normalized to body weight was greater and maximal systolic pressures were lower in the ETS groups than in non-ETS groups. Previous exposure to tobacco smoke induced a process of cardiac remodeling after MI. There is a paradoxical protector effect with tobacco smoke exposure, characterized by lower mortality, which is offset by BC supplementation.

Influence of the elevation of the left ventricular diastolic pressure on the values of the first temporal derivative of the ventricular pressure (dP/dt)

PURPOSE: To assess the effects of the elevation of the left ventricular end-diastolic pressure (LVEDP) on the value of the 1st temporal derivative of the ventricular pressure (dP/dt). METHODS: Nineteen anesthetized dogs were studied. The dogs were mechanically ventilated and underwent thoracotomy with parasympathetic nervous system block. The LVEDP was controlled with the use of a perfusion circuit connected to the left atrium and adjusted to the height of a reservoir. The elevation of the LVEDP was achieved by a sudden increase in the height of a reservoir filled with blood. Continuous recordings of the electrocardiogram, the aortic and ventricular pressures and the dP/dt were performed. RESULTS: Elevation of the LVEDP did not result in any variation of the heart rate (167±16.0bpm, before the procedure; 167±15.5bpm, after the procedure). All the other variables assessed, including systolic blood pressure (128±18.3mmHg and 150±21.5mmHg), diastolic blood pressure (98±16.9mmHg and 115±19.8mmHg), LVEDP (5.5±2.49 and 9.3±3.60mmHg), and dP/dt (4,855 ± 1,082 mmHg/s and 5,149±1,242mmHg/s) showed significant increases following the expansion of the ventricular cavity. Although the elevation of the dP/dt was statistically significant, 6 dogs curiously showed a decrease in the values of dP/dt. CONCLUSION: Sudden elevation of the LVEDP resulted in increased values of dP/dt; however, in some dogs, this response was not uniform.

Pharmacological dose of alpha-tocopherol induces cardiotoxicity in Wistar rats determined by echocardiography and histology

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

CNS-selective noncompetitive cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline

LASSBio-767 [(-)-3-O-acetyl-spectaline] and LASSBio-822 [(-)-3-O-tert-Boc-spectaline] were recently described as cholinesterase inhibitors derived from the natural piperidine alkaloid (-)-spectaline, obtained from the flowers of Senna spectabilis (Fabaccae). We investigated their mechanism of inhibition of acetylcholinesterase and their efficacy in reversing scopolamine-induced amnesia. Competition assays with the substrate acetylthiocholine showed a concentration-dependent reduction in rat brain cholinesterase V-max without changes in apparent K-m. The kinetic data for LASSBio-767 and LASSBio-822 were best fit by a model of simple linear noncompetitive inhibition with K-i of 6.1 mu M and 7.5 mu M, respectively. A dilution assay showed a fast and complete reversal of inhibition, independent of incubation time. Simulated docking of the compounds into the catalytic gorge of Torpedo acetylcholinesterase showed interactions with the peripheral anionic site, but not with the catalytic triad. Anti-amnestic effects in mice were assessed in a step-down passive avoidance test and in the Morris water maze 30 min after injection of scopolamine (1 mg/kg i.p.). Saline, LASSBio-767, or LASSBio-822 was administered 15 min before scopolamine. Both compounds reversed the scopolamine-induced reduction in step-down latency at 0.1 mg/kg i.p. LASSBio-767 reversed scopolamine-induced changes in water maze escape latency at 1 mg/kg i.p. or p.o., while its cholinergic side effects were absent or mild up to 30 mg/kg i.p. (LD50 above 100 mg/kg i.p.). Thus, the (-)-spectaline derivatives are potent cholinergic agents in vivo, with a unique profile combining noncompetitive cholinesterase inhibition and CNS selectivity, with few peripheral side effects. (C) 2007 Elsevier B.V. All rights reserved.

The rate of force generation by the myocardium is not influenced by afterload

The influence of afterload on the rate of force generation by the myocardium was investigated using two types of preparations: the in situ dog heart (dP/dt) and isolated papillary muscle of rats (dT/dt). Thirteen anesthetized, mechanically ventilated and thoracotomized dogs were submitted to pharmacological autonomic blockade (3.0 mg/kg oxprenolol plus 0.5 mg/kg atropine). A reservoir connected to the left atrium permitted the control of left ventricular end-diastolic pressure (LVEDP). A mechanical constriction of the descending thoracic aorta allowed to increase the systolic pressure in two steps of 20 mmHg (conditions H1 and H2) above control values (condition C). After arterial pressure elevations (systolic pressure C: 119 ± 8.1; H1: 142 ± 7.9; H2 166 ± 7.7 mmHg; P<0.01), there were no significant differences in heart rate (C: 125 ± 13.9; H1: 125 ± 13.5; H2: 123 ± 14.1 bpm; P>0.05) or LVEDP (C: 6.2 ± 2.48; H1: 6.3 ± 2.43; H2: 6.1 ± 2.51 mmHg; P>0.05). The values of dP/dt did not change after each elevation of arterial pressure (C: 3,068 ± 1,057; H1: 3,112 ± 996; H2: 3,086 ± 980 mmHg/s; P>0.05). In isolated rat papillary muscle, an afterload corresponding to 50% and 75% of the maximal developed tension did not alter the values of the maximum rate of tension development (100%: 78 ± 13; 75%: 80 ± 13; 50%: 79 ± 11 g mm-2 s-1, P>0.05). The results show that the rise in afterload per se does not cause changes in dP/dt or dT/dt

Ventricular remodeling induced by retinoic acid supplementation in adult rats

Retinoic acid (RA) plays a role in regulating cardiac geometry and function throughout life. The aim of this study was to analyze the cardiac effects of RA in adult rats. Wistar rats were randomly allocated to a control group (n = 18) receiving standard rat chow and a group treated with RA (n = 14) receiving standard rat chow supplemented with RA for 90 days. All animals were evaluated by echocardiography, isolated papillary muscle function, and morphological studies. Whereas the RA-treated group developed an increase in both left ventricular (LV) mass and LV end-diastolic diameter, the ratio of LV wall thickness to LV end-diastolic diameter remained unchanged when compared with the control group. In the isolated papillary muscle preparation, RA treatment decreased the time to peak developed tension and increased the maximum velocity of isometric relengthening, indicating that systolic and diastolic function was improved. Although RA treatment produced an increase in myocyte cross-sectional area, the myocardial collagen volume fraction was similar to controls. Thus our study demonstrates that small physiological doses of RA induce ventricular remodeling resembling compensated volume-overload hypertrophy in rats.

Ventricular remodeling and diastolic myocardial dysfunction in rats submitted to protein-calorie malnutrition

The effects of protein-calorie malnutrition (PCM) on heart structure and function are not completely understood. We studied heart morphometric, functional, and biochemical characteristics in undernourished young Wistar rats. They were submitted to PCM from birth (undernourished group, UG). After 10 wk, left ventricle function was studied using a Langendorff preparation. The results were compared with age-matched rats fed ad libitum (control group, CG). The UG rats achieved 47% of the body weight and 44% of the left ventricular weight (LVW) of the CG. LVW-to-ventricular volume ratio was smaller and myocardial hydroxyproline concentration was higher in the UG. Left ventricular systolic function was not affected by the PCM protocol. The myocardial stiffness constant was greater in the UG, whereas the end-diastolic pressure-volume relationship was not altered. In conclusion, the heart is not spared from the adverse effects of PCM. There is a geometric alteration in the left ventricle with preserved ventricular compliance despite the increased passive myocardial stiffness. The systolic function is preserved.

β-carotene attenuates the paradoxical effect of tobacco smoke on the mortality of rats after experimental myocardial infarction

The objective of this study was to investigate the effects of exposure to tobacco smoke (ETS) in rats that were or were not supplemented with dietary β-carotene (BC), on ventricular remodeling and survival after myocardial infarction (Ml). Rats (n = 189) were allocated to 4 groups: the control group, n = 45; group BC administered 500 mg/kg diet, n = 49, BC supplemented rats; group ETS, n - 55, rats exposed to tobacco smoke; and group BC+ETS, n = 40. Wistar rats weighing 10O g were administered one of the treatments until they weighed 200 to 250 g (∼5 wk). The ETS rats were exposed to cigarette smoke for 30 min 4 times/d, in a chamber connected to a smoking device. After reaching a weight of 200-250 g, rats were subjected to experimental MI (coronary artery occlusion) and mortality rates were determined over the next 105 d. In addition, echocardiographic, isolated heart, morphometrical, and biochemical studies were performed. Mortality data were tested using Kaplan-Meyer curves and other data by 2-way ANOVA. Survival rates were greater in the ETS group (58.2%) than in the control (33.3%) (P = 0.001) and BC+ETS rats (30.0%) (P = 0.007). The groups did not differ in the other comparisons. Left ventricular end-diastolic diameter normalized to body weight was greater and maximal systolic pressures were lower in the ETS groups than in non-ETS groups. Previous exposure to tobacco smoke induced a process of cardiac remodeling after MI. There is a paradoxical protector effect with tobacco smoke exposure, characterized by lower mortality, which is offset by BC supplementation. © 2005 American Society for Nutritional Sciences.

Neurohormonal, hemodynamic, and electrocardiographic evaluations of healthy dogs receiving long-term administration of doxorubicin

Objective - To evaluate diagnostic testing that could be used to establish an early diagnosis of cardiotoxicosis induced by long-term administration of doxorubicin. Animals - 13 adult mixed-breed dogs. Procedures - 7 dogs were administered doxorubicin chloride (30 mg/m2, IV, q 21 d for 168 days [cumulative dose, 240 mg/m2]), and 6 dogs received saline (0.9% NaCl) solution (5 mL, IV, q 21 d for 168 days; control group). Echocardiography, ECG, arterial blood pressure, plasma renin activity (PRA), and plasma concentrations of norepinephrine and brain natriuretic peptide (BNP) were assessed before each subsequent administration of doxorubicin and saline solution. Results - Dogs that received doxorubicin had a significant decrease in R-wave amplitude, compared with values for the control group, from 30 to 210 mg/m2. Doxorubicin-treated dogs had decreases in fractional shortening and left ventricular ejection fraction evident as early as 30 mg/m2, but significant differences between groups were not detected until 90 mg/m2 was reached. There was also a significant increase in PRA (≥ 120 mg/m2) and left ventricular end-systolic and end-diastolic dimensions (≥ 60 and ≥ 180 mg/m2, respectively). Systemic arterial pressure, remaining echocardiographic variables, and concentrations of norepinephrine and BNP had significant variations, but of no clinical importance, during doxorubicin administration. Conclusions and clinical relevance - Doxorubicin-induced cardiotoxicosis developed at 120 mg/m2, but there were no clinical signs of dilated cardiomyopathy or congestive heart failure. Echocardiography and determination of PRA were able to detect early cardiac alterations during the development of dilated cardiomyopathy, despite apparently differing degrees of sensitivity to development of doxorubicin-induced cardiotoxicosis.

Efectos de la administración de betabloqueante en la remodelación ventricular inducida por el tabaquismo en ratas

Background: The role of the adrenergic system on ventricular remodeling induced by cigarette smoking is unknown. Objective: To investigate the influence of propranolol on ventricular remodeling induced by exposure to tobacco smoke. Methods: Rats were divided into three groups: 1) C, n=10 - control group; 2) F, n=10 - animals exposed to tobacco smoke; 3) BB, n=10 - animals receiving propranolol and exposed to tobacco smoke (40 mg/kg/day). After 2 months, the animals underwent echocardiographic and morphometric analyses. One-way ANOVA (mean ± standard deviation) or the Kruskal-Wallis test (median and interquartile interval) was used. Results: Group BB showed a lower heart rate than group F (C = 358 ± 74 bpm, F = 374 ± 53 bpm, BB = 297± 30; P = 0.02). Group F showed greater end-diastolic diameters (C = 18.6 ± 3.4 mm/kg, F = 22.8 ± 1.8 mm/kg, BB = 21.7 ± 1.8 mm/kg; P = 0.003) and left ventricular (LV) end-systolic diameters (C = 8.6 ± 2.1 mm/kg, F = 11.3 ± 1.3 mm/kg, BB = 9.9 ± 1.2 mm/kg; P = 0.004), adjusted for body weight (BW) and a tendency towards a lower ejection fraction (C = 0.90 ± 0.03, F = 0.87 ± 0.03, BB =0.90 ± 0.02; P = 0.07) than group C. Group BB showed a tendency towards a lower LV/BW ratio than group F (C = 1.94 (1.87 - 1.97), F = 2.03 (1.9-2.1) mg/g, BB = 1.89 (1.86-1.94); P = 0.09). Conclusion: Administration of propranolol attenuated some of the variables of ventricular remodeling induced by the exposure to tobacco smoke in rats.

O coração é um orgão-alvo na pré-eclâmpsia

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Ultrassonografia convencional e Doppler da glândula mamária de caprinos para diagnóstico de mastite

Pós-graduação em Medicina Veterinária - FCAV