RESUMO
The effects of salicylaldoxime, 2-(OH)C6H4CH = NOH, on the action potential duration, transient outward K+ current and slow inward Ca2+ current were studied in isolated rat ventricular myocytes. The application of salicylaldoxime (0.1-2.0 mM) reversibly increased the action potential duration and reduced in a dose-dependent manner both the transient outward K+ and the slow inward Ca2+ currents. The effect of salicylaldoxime on these two ionic currents was similar to that of 2,3-butanedione monoxime, but was about ten times more potent. Compounds which block both K+ and Ca2+ currents may represent a new type of Class III antiarrhythmic agent which counteracts arrhythmias initiated by re-entry with reduced proarrhythmic risk via triggered activity.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Coração/efeitos dos fármacos , Oximas/farmacologia , Bloqueadores dos Canais de Potássio , Potenciais de Ação/efeitos dos fármacos , Animais , Antiarrítmicos/farmacologia , Células Cultivadas , Relação Dose-Resposta a Droga , Miocárdio/citologia , RatosRESUMO
When BDM is added to the perfusion solutions used during the preparation of single, enzymatically dispersed mammalian cardiomyocytes, higher yields of calcium-tolerant cells are obtained. As the principal component of a storage solution, BDM also improves the survival of myocytes maintained in cold storage. These data support the hypothesis that BDM can act as a cardioprotective agent under certain conditions.
Assuntos
Diacetil/análogos & derivados , Coração/efeitos dos fármacos , Animais , Separação Celular , Sobrevivência Celular/efeitos dos fármacos , Diacetil/farmacologia , Miocárdio/citologia , Ratos , Ratos Wistar , Fatores de TempoRESUMO
Autosomal recessive osteopetrosis (OP) is characterized by insufficient osteoclast activity resulting in defective bone resorption and marked increase in skeletal mass and density. OP has been successfully treated with hematopoietic cell transplantation (HCT), secondary to engraftment of donor-derived functioning osteoclasts resulting in remodeling of bone and establishment of normal hematopoiesis. Although hypercalcemia is a common presenting feature of OP, it may be observed following HCT due to engraftment of osteoclasts differentiated from the hematopoietic precursors. To characterize hypercalcemia after HCT-who is at risk, onset, duration and response to treatment-we evaluated 15 patients with OP treated at the University of Minnesota from 2000 to 2009. Hypercalcemia, defined as any single calcium >11.0 mg/100 ml after the first transplant, was found in 40% of patients. Median onset of hypercalcemia was 23 days and the duration was 2-24 days. Hypercalcemia was more common in patients older than 2 years of age at the time of HCT. Treatment with hydration, furosemide and s.c. calcitonin resolved hypercalcemia and resulted in no severe adverse events. In conclusion, hypercalcemia is common in patients with OP within the first 4 weeks after HCT, and more likely in older patients. Isotonic saline, furosemide and s.c. calcitonin were well-tolerated and effective treatments in our study population.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hipercalcemia/complicações , Osteopetrose/terapia , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Hipercalcemia/terapia , Lactente , Adulto JovemRESUMO
Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution's experience with HCT treatment of four Wolman patients, two of whom are long-term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has age-appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Wolman/terapia , Sistema Endócrino/patologia , Feminino , Trato Gastrointestinal/patologia , Sistema Hematopoético/patologia , Humanos , Lactente , Recém-Nascido , Fígado/patologia , Masculino , Sobreviventes , Doença de Wolman/metabolismo , Doença de Wolman/patologia , Doença de Wolman/psicologiaRESUMO
Investigations have been made to determine the relationship between indoor radon concentrations and ventilation rates and to find the sources for radon in different rooms. The results show that the radon concentration can be estimated by a simple mathematic model in the case of periodical ventilation. The results of measurements carried out in office rooms demonstrate that soil is the main source for indoor radon. The possibility to use radon for the determination of ventilation rates is discussed.
Assuntos
Poluentes Radioativos do Ar/análise , Poluentes Atmosféricos/análise , Habitação , Radônio/análise , Ventilação , Poluentes Ocupacionais do Ar/análise , Humanos , Indicadores e Reagentes , Matemática , Fatores de TempoRESUMO
Our major aim was to investigate the consequences of ileal autotransplantation in pigs with proximal small intestinal resection on biliary lipids and metabolism of bile acids. Biliary lipid secretion rates and bile acid absorption were assessed by measuring dietary and biliary lipids, fractional cholesterol absorption, and fecal excretion of cholesterol and bile acids. In addition, serum bile acids and cholesterol, biliary and fecal bile acid species, and ileal villus height were determined after resection of the proximal 75% of the jejunoileum (n = 15) and autotransplantation of the remaining ileum with systemic venous drainage (n = 15) or transection (n = 5). Autotransplantation further increased fecal excretion of neutral and acidic steroids and serum concentration of bile acids after proximal resection (P < .05 for all); autotransplantation significantly decreased serum cholesterol, ileal villus height, fractional bile acid and cholesterol absorption, and biliary molar percentage of total and primary bile acids, whereas biliary secretion of bile acids, enriched by secondary bile acids, and cholesterol remained unchanged. At 14 weeks, ileal villus height, fractional bile acid and cholesterol absorption, biliary molar percentage of bile acids, and proportion of secondary biliary bile acids were altered by transplantation from the respective postresection values of 864 +/- 22 microm, 97.9 +/- 0.6%, 26.9 +/- 3.9%, 91.8 +/- 1.2% and 9.2 +/- 1.3% to 428 +/- 21 microm, 91.1 +/- 1.5%, 9.5 +/- 1.1%, 83.9 +/- 1.4% and 52.5 +/- 3.5% (P < .005 for all). Posttransplantation biliary bile acid secretion correlated positively with fractional reabsorption (r = .70) and biliary molar percentage (r = .73) of bile acids and ileal villus height (r = .65; P < .01 for all). Decreased absorption efficiency and biliary molar percentage of bile acids, increased biliary secondary bile acids, and short ileal villi point to bacterial overgrowth-induced bile acid malabsorption, which with decreased absorptive area may contribute to malabsorption of other lipids after ileal autotransplantation. Compensatory increase in cholesterol synthesis in the pigs with autotransplanted ileum appeared sufficient for constant biliary secretion of cholesterol and bile acids.
Assuntos
Ácidos e Sais Biliares/metabolismo , Bile/metabolismo , Colesterol/metabolismo , Íleo/transplante , Intestino Delgado/cirurgia , Metabolismo dos Lipídeos , Absorção , Animais , Ácidos e Sais Biliares/análise , Ácidos e Sais Biliares/sangue , Colesterol/sangue , Fezes/química , Feminino , Suínos , Transplante AutólogoRESUMO
Cholesterol absorption occurs primarily in the upper small intestine. Our aim was to assess absorption of cholesterol during ileal adaptation after proximal small intestinal resection. In vivo absorption and elimination of cholesterol, plasma cholesterol, cholesterol precursors, and plant sterols were related to intestinal morphology and transit 4 (n = 5), 8 (n = 5), and 14 (n = 5) weeks after a 75% proximal resection of porcine small intestine, and compared to preoperative (n = 5) and transected (n = 5) control animals. Fractional cholesterol absorption, the daily amount of cholesterol absorbed, plasma cholesterol, and plant sterol to cholesterol proportions were significantly (P < 0.05 or less) decreased, whereas fecal loss of cholesterol as neutral steroids, less so as bile acids, plasma cholesterol precursor proportions, and ileal mass and villus height were significantly increased (P < 0.05 or less) after 8 weeks of the resection. Cholesterol absorption efficiency, decreased by the resection, was gradually increased from 5.4 +/- 2.2 to 26.9 +/- 3.9% during the 14 postoperative weeks (P < 0.0001) simultaneously with a 46% increase in villus height compared with transection (P < 0.0001), but absorption remained still below control levels (80.4 +/- 2.5%, P < 0.0001). In resected and control animals, villus height correlated positively with cholesterol absorption efficiency (r = 0.85, P < 0.0001; r = 0.76, P = 0.01) and plasma plant sterol proportions (r = 0.94-0.95, P < 0.0001; r = 0.78-0.85, P < 0.008), respectively. In conclusion, after massive proximal small bowel resection, adaptation of intestinal cholesterol absorption efficiency occurs in the distal ileum closely parlleling villus hypertrophy.
Assuntos
Colesterol/metabolismo , Íleo/metabolismo , Absorção Intestinal/fisiologia , Intestino Delgado/metabolismo , Adaptação Fisiológica , Animais , Ácidos e Sais Biliares/química , Peso Corporal , Colesterol/análise , Colesterol na Dieta/análise , Colesterol na Dieta/metabolismo , Estudos de Coortes , Feminino , Íleo/cirurgia , Intestino Delgado/anatomia & histologia , Intestino Delgado/cirurgia , Jejuno/cirurgia , Distribuição Aleatória , SuínosRESUMO
The 22-residue toxic peptide (WTX1) from the venom of the Southeast Asian snake Trimeresurus wagleri has multiple sites of action, but its lethal effect has been attributed to blocking the postsynaptic acetylcholine receptor at the neuromuscular junction. The 3-dimensional structure of WTX1 was studied using 2-dimensional nuclear magnetic resonance spectroscopy, circular dichroism, and computer simulations. In aqueous solution, WTX1 was shown to have extended and flexible "tails" defined by a short, rigid disulfide-bonded loop. The flexible regions can undergo structural rearrangement when moved from an aqueous to a less polar environment and may contribute to its effectiveness at different receptor sites. By substituting Gly or Phe for His at position 10, significant effects on the disulfide bond formation and, thereby, the activity of the peptide were observed. These results suggest that even subtle differences in single residues can have profound effects on the dynamics of folding, disulfide bond formation, and activity of this toxic peptide.