RESUMO
OBJECTIVE: Hospitalized patients with liver cirrhosis are predisposed to acute renal failure. We sought to identify the role of liver disease severity, infectious complications, and in-hospital treatment with aminoglycosides as risk factors for acute renal failure among patients with cirrhosis. METHODS: In a retrospective, case-control study at the Albuquerque VA Medical Center, electronic and manual chart review was employed to identify all hospitalized patients with a diagnosis of cirrhosis and normal renal function (serum creatinine < or = 1.3 mg/dl) at the time of hospitalization. Cases were defined as patients who developed renal dysfunction (increase in creatinine of > or = 1.0 mg/dl) within 15 days of hospitalization, and the remaining patients were controls. RESULTS: Of 93 patients, there were 23 cases and 70 controls. There were no significant differences in age, etiology of cirrhosis, serum levels of albumin, or bilirubin, prothrombin time, encephalopathy, bacteremia, urinary tract infection, or occurrence of esophageal variceal bleeding. Patients who developed renal dysfunction were more likely to have ascites (87% vs 41%, p < 0.01), spontaneous bacterial peritonitis (44% vs 1%, p < 0.01), and treatment with i.v. aminoglycosides (48% vs 19%, p < 0.01). In a multivariate logistic regression analysis, aminoglycosides treatment was a strong risk factor for renal dysfunction (adjusted odds ratio = 4.0, 95% CI = 1.4-11), independent of the severity of liver disease or peritonitis. CONCLUSION: Avoidance of aminoglycoside antibiotics may reduce the occurrence of renal dysfunction in hospitalized patients with cirrhosis. In addition, close monitoring of renal function should be employed among patients with ascites and/or spontaneous bacterial peritonitis.
Assuntos
Injúria Renal Aguda/etiologia , Cirrose Hepática/complicações , Injúria Renal Aguda/sangue , Aminoglicosídeos , Antibacterianos/efeitos adversos , Infecções Bacterianas/complicações , Estudos de Casos e Controles , Creatinina/sangue , Hospitalização , Humanos , Cirrose Hepática/diagnóstico , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de RiscoRESUMO
The effect of the helical conformation of DNA on the binding of antibodies to DNA-carcinogen adducts was evaluated. The efficiency of antibody binding to adducts produced in DNA by treatment with (+)-trans-7 beta, 8 alpha-dihydroxy-9 alpha, 10 alpha-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) was modulated by varying the winding angle of the DNA helix using heat denaturation, organic solvents, and cations. Unwinding and complete denaturation of the DNA helix increased the binding efficiency of anti-bodies to DNA-BPDE adducts 4- to 8-fold over that to BPDE adducts in the unperturbed double helical DNA. The antibody binding efficiency increased in proportion to the degree of unwinding of the double helix induced by dimethylsulfoxide, ethylene glycol, or glycerol. Conversely, winding of the double helix with monovalent cations (Na+, K+, Rb+, Li+, Cs+ and NH4+) and more effectively with divalent cations (Mg2+, Ca2+, Mn2+, Sn2+ and Ba2+) decreased antibody binding to DNA-BPDE adducts. We suggest that the molecular orientation of BPDE adducts within helical grooves modulates adduct accessibility for binding with antibody molecules. By the opening and/or unwinding of the helix, BPDE adducts (or their immunogenic sites) partially "buried" within the grooves may be exposed to varying degrees for antibody binding. Conversely, winding of the helix shielded the BPDE adducts from antibody recognition and binding.
Assuntos
Benzopirenos/imunologia , DNA/metabolismo , 7,8-Di-Hidro-7,8-Di-Hidroxibenzo(a)pireno 9,10-óxido , Anticorpos/metabolismo , DNA de Cadeia Simples/metabolismo , Dimetil Sulfóxido/farmacologia , Etilenoglicol , Etilenoglicóis/farmacologia , Glicerol/farmacologia , Conformação de Ácido Nucleico , Desnaturação de Ácido NucleicoRESUMO
Activation of polycyclic aromatic hydrocarbons (PAHs) was examined in the Reuber H4-II-E established cell line without the use of exogenous enzyme preparations. Metabolism of PAHs to genotoxic products was determined by the induction of sister-chromatid exchanges (SCEs). The induction of SCEs followed a dose-response pattern with plateaus at high doses of PAH. The effects of metabolic enzyme inducers (3-methylcholanthrene, phenobarbital, Aroclor 1254) and the epoxide hydrase inhibitor 1,1,1-trichloropropylene oxide were assessed as changes in SCE induction and enhanced production of water-soluble metabolites. Results indicate that Reuber H4-II-E cells can be employed in the testing of carcinogens activated by the P1-450 monooxygenase system and would be a useful in vitro system for the study of mechanisms of metabolic induction and their effect on genetic toxicity.
Assuntos
Troca Genética/efeitos dos fármacos , Neoplasias Hepáticas Experimentais/fisiopatologia , Compostos Policíclicos/toxicidade , Troca de Cromátide Irmã/efeitos dos fármacos , 9,10-Dimetil-1,2-benzantraceno/toxicidade , Animais , Benzo(a)pireno , Benzopirenos/toxicidade , Técnicas In Vitro , Cinética , Metilcolantreno/toxicidade , Mutagênicos/toxicidade , Relação Estrutura-AtividadeRESUMO
Frequencies of sister chromatid exchanges (SCE) were analyzed in bone marrow cells of mice injected with mitomycin C (MMC) both before and during infusion with bromodeoxyuridine (BrdU). Administration of MMC at 1, 6.5, and 13 hours after the onset of BrdU infusion resulted in the induction of approximately 45 SCE/cell, independent of time of administration. When MMC was injected 26 hours prior to BrdU infusion, only baseline levels of SCE were noted. The effects of multiple doses of MMC (chronic administration) were examined in mice treated with 1--5 mg/kg on a weekly or bimonthly basis. SCE analysis was performed one week after the final injection. At all doses and with all treatment regimes, SCE frequencies did not differ from control levels. The results indicate that most or all MMC-induced DNA damage that results in SCE formation is removed in a single cell cycle after its administration.
Assuntos
Troca Genética/efeitos dos fármacos , Mitomicinas/toxicidade , Troca de Cromátide Irmã/efeitos dos fármacos , Animais , Células da Medula Óssea , Bromodesoxiuridina , Divisão Celular/efeitos dos fármacos , Cinética , Masculino , Camundongos , Fatores de TempoRESUMO
The hepatic tumor cell line (HTC) was tested for the ability to produce sister chromatid exchanges (SCEs) in response to chemical carcinogens which require activation. Without the addition of exogenous microsomal enzyme preparations, cyclophosphamide, N-nitrosodiethylamine (DEN) and aflatoxin B1 (AFB1) induced significant levels of SCEs in these cells. Mitomycin C (MMC) and ultraviolet light, which do not require activation, also produced significant levels of SCEs. The induction of SCEs in HTC cells by AFB1 was shown to be inhibited by estradiol, a known inhibitor of microsomal activating enzymes. For the carcinogens tested, the HTC cell SCE assay was quite sensitive and comparable to other mammalian test systems. Exceptional sensitivity was found in the case of AFB1. SCE analysis of HTC cells offers a simplified system of detecting carcinogens requiring activation. This system also has the potential of investigating interactions between agents such as steroid hormones and carcinogens.
Assuntos
Carcinógenos/farmacologia , Cromátides/efeitos dos fármacos , Troca Genética , Neoplasias Hepáticas Experimentais/ultraestrutura , Mutagênicos , Troca de Cromátide Irmã , Aflatoxinas/farmacologia , Animais , Linhagem Celular , Cromátides/efeitos da radiação , Ciclofosfamida/farmacologia , Dimetilnitrosamina/farmacologia , Mitomicinas/farmacologia , Testes de Mutagenicidade/métodos , Ratos , Raios UltravioletaRESUMO
We have identified a group of 8 (among 39) human tumour cell strains deficient in the ability to support the growth of adenovirus 5 preparations treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), but able to support the growth of non-treated adenovirus normally. This deficient behaviour defines the Mer- phenotype. Strains having the Mer- phenotype were found to arise from tumours originating in four different organs. Relative to Mer+ strains, Mer- tumour strains showed greater sensitivity to MNNG-produced killing, greater MNNG-stimulated "DNA repair synthesis and a more rapid MNNG-produced decrease in semi-conservative DNA synthesis. Here we report that (1) Mer- strains are deficient in removing O6-methylguanine (O6-MeG) from their DNA after [Me-14C]MMNG treatment (Table 1); (2) Mer- tumour strains originate from tumours arising in patients having Mer+ normal fibroblasts (Fig. 1a, b); (3) SV40 transformation of (Mer+) human fibroblasts often converts them to Mer- strains (Fig. 1c, d); (4) MNNG produces more sister chromatid exchanges (SCEs) in Mer- than in Mer+ cell strains (Fig. 2).
Assuntos
Reparo do DNA , Neoplasias/fisiopatologia , Vírus 40 dos Símios , Adenovírus Humanos/genética , Células Cultivadas , Guanina/análogos & derivados , Humanos , Metilação , Metilnitronitrosoguanidina/farmacologia , Troca de Cromátide Irmã/efeitos dos fármacosRESUMO
Frequencies of baseline and cyclophosphamide-induced sister chromatid exchanges (SCE) were measured in mouse maternal and fetal cells between days 11 and 19 of gestation. Baseline levels of SCE did not vary as a function of gestational age in either the mother or fetus. Cyclophosphamide-induced SCE frequencies remained constant in maternal cells but declined dramatically in the fetus throughout the latter half of development. Because cyclophosphamide is a metabolically activated mutagen, a direct-acting drug, mitomycin C, was given on days 11 and 15 to determine if the decline in induced SCE levels seen with gestational results from alterations in activating enzymes. A similar decline in mitomycin C-induced SCE levels was noted in fetal tissues as a function of gestational age. Dose-response curves to cyclophosphamide performed on day 13 of gestation showed increases in SCE as a function of cyclophosphamide concentration in both the mother and the fetus. When mutagen-induced SCE levels were compared in different fetal organs, the direct-acting drugs (mitomycin C and daunomycin) were found to induce similar levels in all tissues. Cyclophosphamide, which is metabolically activated, induced higher SCE levels in fetal liver than in lung or gut. Whereas cyclophosphamide induced similar SCE levels in fetal and maternal cells on day 13 of gestation, daunomycin produced fetal SCE levels that were approximately 50% of maternal levels. Simultaneous measurement of the distribution of [14C]cyclophosphamide and [3H]daunomycin in maternal and fetal cells revealed that the lower SCE induction by daunomycin was probably due to decreased ability to cross the placental barrier.
Assuntos
Carcinógenos/farmacologia , Troca Genética/efeitos dos fármacos , Mutagênicos/farmacologia , Prenhez/efeitos dos fármacos , Troca de Cromátide Irmã/efeitos dos fármacos , Animais , Ciclofosfamida/farmacologia , Daunorrubicina/farmacologia , Feminino , Idade Gestacional , Troca Materno-Fetal , Camundongos , Mitomicinas/farmacologia , Gravidez , Distribuição TecidualRESUMO
A study was undertaken to determine if gut flora contribute to the pathophysiology of experimental canine heatstroke. Fifty animals in four groups were anesthetized with sodium pentobarbital (25 mg/kg) intravenously. An air temperature of 42-46 degrees C was maintained adjacent to the dog with a water-heated blanket for approximately 2 h until rectal temperatures rose to 43.5 +/- 0.4 degrees C. Animals were then cooled passively in room air (28 degrees C, 20% RH) until death or until 18 h elapsed, and were euthanized. Reduction of intestine stool and bacterial contents with antibiotics, cathartics, and enemas prior to heatstroke increased the incidence of 18-h survival from 20.0% to 70.6%; antibiotics administered after heatstroke did not alter the incidence of survival over control values. These data suggest that gut flora, presumably through endotoxemia, contribute to the evolution of heatstroke pathophysiology.
Assuntos
Exaustão por Calor/mortalidade , Intestinos/microbiologia , Animais , Antibacterianos/uso terapêutico , Temperatura Corporal , Catárticos/uso terapêutico , Cães , Enema , Feminino , Exaustão por Calor/fisiopatologia , Exaustão por Calor/prevenção & controle , Sulfato de Magnésio/uso terapêutico , Masculino , Neomicina/uso terapêutico , Penicilina G/uso terapêutico , Pré-Medicação , Tetraciclina/uso terapêuticoRESUMO
Fourteen patients with a variety of neoplasms not responsive to standard forms of therapy underwent whole body hyperthermia for a maximum 4 h at 41.8 degrees C. This was a phase-I cancer trial designed to develop whole body hyperthermia as an adjuvant to systemic chemotherapy. Intravenous analgesia was used to sedate patients, obviating the need for general endotracheal anesthesia. Hyperthermia was induced by means of a high-flow water perfusion suit. Cardiovascular performance was evaluated using a flow-directed pulmonary artery catheter. Patients developed a twofold mean increase in cardiac index without evidence of cardiac damage by ECG or creatine phosphokinase (CPK) isoenzymes. An acute fall in serum magnesium and phosphate and an acute rise in arterial pH, serum CPK values, and granulocyte count occurred in all patients. There were no clotting abnormalities. Toxicity included fatigue, diarrhea, nausea, and transient elevations in liver enzymes. Four patients were febrile for 36 h after initial defervescence. Peripheral neuropathy developed in four. These results show that with carefully monitored conditions whole body hyperthermia is feasible.
Assuntos
Temperatura Alta/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/terapia , Adolescente , Adulto , Sistema Cardiovascular/fisiopatologia , Enzimas/análise , Feminino , Temperatura Alta/efeitos adversos , Humanos , Contagem de Leucócitos , Masculino , Pessoa de Meia-IdadeRESUMO
Controversy exists concerning the effect of aging on replicating cell systems. This review summarizes a number of studies which indicate that both in vivo and in vitro, cell replication is significantly altered during aging. In vitro, studies of both human lymphocytes and fibroblasts indicated that a number of replication kinetic parameters are influenced by the age of the cell donor. In vivo, the application of the bromodeoxyuridine-(BrdU)-differential chromatid staining techniques to the analysis of cellular replication kinetics has permitted us to demonstrate that cellular replication is also significantly diminished with aging in mouse and rat cell populations. Therefore, both in vivo and in vitro in human as well as rodent cell populations, the rates of cellular replication are significantly decreased with cellular aging.
Assuntos
Envelhecimento , Divisão Celular , Sobrevivência Celular , Animais , Bromodesoxiuridina/metabolismo , Células Cultivadas , Cromossomos/metabolismo , Técnicas Citológicas , DNA/biossíntese , Fibroblastos/citologia , Linfócitos/citologiaRESUMO
The concept of critical thermal maximum (CTM) has been defined in the literature as the minimal high deep-body temperature that is lethal to an animal. In man the CTM has been estimated at 41.6--42.0 degrees C. Data are presented for sedated, unacclimatized, well-hydrated men heated 1 h at esophageal temperatures of 41.6--42.0 degrees C, without sequelae, except for modest elevation of serum enzymes in two of five patients. These data when combined with other observations in the literature suggest that CTM be redefined as the particular combination of exposure time at elevated body temperatures that results in either subclinical (CTM)s) or clinical (CTMc) injuries. Also presented is a mathematical technique, equivalent time at 42 degrees C (Teq 42 degrees), for expressing hyperthermia in terms of body temperature and exposure time.
Assuntos
Febre/fisiopatologia , Exaustão por Calor/fisiopatologia , Adolescente , Pressão Sanguínea , Temperatura Corporal , Enzimas/sangue , Esôfago , Frequência Cardíaca , Humanos , Hipnóticos e Sedativos , Masculino , Reto , Respiração , Fatores de TempoRESUMO
This study was undertaken to compare cooling in room air (27 degrees C, 20% RH), ice slush surface cooling, and peritoneal lavage cooling (6-10 degrees C) as methods for lowering body temperature in an anesthetized dog heatstroke model. We anesthetized 19 animals with sodium pentobarbital (25 mg/kg) intravenously, and maintained them in an ambient temperature of 42-46 degrees C with a water heating blanket approximately 2.0 h until rectal temperatures rose to 43.2 +/- 0.2 degrees C. At the maximum rectal temperature, the heating blankets were removed, and animals were cooled, observed until death occurred or 18 h elapsed, and then sacrificed. The data demonstrate that maximum cooling rates of rectal temperature were: peritoneal lavage, 0.56 degrees C/min; ice slush, 0.11 degrees C/min; and 27 degrees C air cooling, 0.06 degrees C/min. The incidence of 18-h survival for lavage-cooled dogs when supported with normothermic dialysis every 4 h was significantly greater than for either ice slush or air cooled dogs.
Assuntos
Crioterapia , Exaustão por Calor/terapia , Peritônio , Irrigação Terapêutica/métodos , Animais , Cães , Feminino , MasculinoRESUMO
This study was undertaken to develop an anesthetized dog heatstroke model. Forty-six animals were anesthetized with pentobarbital sodium (25 mg/kg) intravenously, and maintained at an ambient temperature of (42-46 degrees C) with a water-heated blanket over 2.5-3.0 h until rectal temperatures rose to 43.0-44.5 degrees C. Animals then cooled passively until death occurred or until 18 h elapsed, and were prepared for autopsy. Liver, kidney, and brain temperature, mean weighted skin temperature, mean weighted surface heat loss, and metabolic rates were obtained. There were no significant differences between liver, kidney, brain, and rectal temperatures during the heating and cooling periods. Cardiac output rose to 127% of initial value, and dropped rapidly to zero at 43.4 degrees C rectal temperature. The rapid decline was accompanied by a doubling of heart rate and a rapid drop in blood pressure and respiratory rate. Cheyne-Stokes respiration and apnea preceded bradycardia followed by asystole or ventricular fibrillation. Certain serum constituents demonstrated modest elevations suggestive of widespread tissue damage. Autopsy did not reveal a clear pattern of heat injury, with the exception of consistent congestion of the major organs and karyorrhexis of lymphocytes. These data are in agreement with similar data from human heatstroke victims and other heatstroke modeling in dogs, and support the concept that the anesthetized dog can in many respects provide an adequate model for human heatstroke.
Assuntos
Anestesia Intravenosa , Modelos Animais de Doenças , Exaustão por Calor/induzido quimicamente , Pentobarbital , Animais , Temperatura Corporal , Regulação da Temperatura Corporal , Cães , Feminino , Exaustão por Calor/fisiopatologia , Temperatura Alta , Masculino , Temperatura CutâneaRESUMO
Heat acclimatization was induced in a group of healthy male test subjects by repetitive treadmill walking (5.6 km-h-1, 49 degrees/27 degrees C dry/wet bulb, 90 min-day-1, 7 days). A second group of men, paired for maximal O2 consumption and body weight, remained sedentary under identical environmental conditions. Total plasma protein increased significantly after 45 (P less than 0.05) and 90 (P less than 0.025) min of exercise on the first day of heat exposure, yet after 7 days no increments occurred. Even after heat acclimatization was achieved (day 7), plasma levels of creatine phosphokinase increased during the 90-min walk in the heat (time O vs. 90, P less than 0.025), as was also the case on day 1 (P less than 0.05). Levels of lactate dehydrogenase, glutamate-oxaloacetate transaminase, and glutamate-pyruvate transaminase were not significantly affected by exercise in the heat either before or after heat acclimatization. No correlations could be drawn between base-line enzyme levels and state of physical conditioning.
Assuntos
Alanina Transaminase/sangue , Aspartato Aminotransferases , Creatina Quinase/sangue , Temperatura Alta , L-Lactato Desidrogenase/sangue , Esforço Físico , Aclimatação , Adulto , Ambiente Controlado , Humanos , MasculinoRESUMO
Heat acclimatization was induced in a group of healthy young men by walking on a treadmill (5.6 km/h, 49 degrees C/27 degrees C dry/wet bulb, 90 min/day, 7 d) and confirmed by observing significantly reduced final rectal temperatures and heart rates on the seventh day of exercise in the heat. A second group of men, paired for maximal oxygen consumption and body weight, remained sedentary under identical environmental conditions. While the mild exercise combined with the severe heat conditions induced significant hyperkalemia (p less than 0.02, minimal significance) on both the first and final days, there did occur an attenuated response with significantly (p less than 0.01) reduced plasma K+ after 45 min on the seventh day when compared with first day levels. No significant inter- or intragroup differences in plasma Na+ content of 24-h urine samples showed that men exercising in the heat retained an increased ability to conserve Na+, while sedentary individuals consistently displayed increased excretion of Na+. Thus, we concluded that even the mild exercise described herein effected hyperkalemia at each sampling time, but the level of hyperkalemia was attenuated after acclimatization, and while Na+ was conserved in the exercising men, no such adaptive processes occurred in sedentary individuals.