Risk factors for the development of renal dysfunction in hospitalized patients with cirrhosis.

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.

Effect of DNA conformation on the binding of antibodies to benzo[a]pyrene diol-epoxide DNA adducts.

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.

Effects of acute and chronic administration of mitomycin C on the induction of sister chromatid exchanges in vivo.

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.

Defective repair of alkylated DNA by human tumour and SV40-transformed human cell strains.

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).

In utero analysis of sister chromatid exchange: alterations in suscptibility to mutagenic damage as a function of fetal cell type and gestational age.

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.

Induced hyperthermia in sedated humans and the concept of critical thermal maximum.

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.

Recurrent heat exposure: enzymatic responses in resting and exercising men.

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.