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Biomedical subjects

M G Miller

Publications and source records attributed to M G Miller.

At least 19 recordsLinked to original sources
PubMed1992

Species differences in membrane susceptibility to lipid peroxidation.

The susceptibility of liver microsomes to lipid peroxidation was evaluated in seven species: rat, rabbit, trout, mouse, pig, cow, and horse. Lipid peroxidation was measured as thiobarbituric acid reactive substances formed in the presence of either FeCl3-ADP/ascorbate or FeCl2/H2O2 initiating systems. For rat, rabbit, and trout microsomes, the order of susceptibility to peroxidation was rat greater than rabbit much greater than trout. The lack of peroxidation in trout microsomes could be explained by high microsomal vitamin E levels. Membrane fatty acid levels differed between species. Docosahexaenoic acid predominated in the trout, arachidonic acid in the rat, and linoleic acid in the rabbit. The contribution of individual fatty acids to lipid peroxidation reflected the degree of unsaturation with docosahexaenoic greater than arachidonic much much greater than linoleic. For all species except trout, the predicted susceptibility to peroxidation, based on the response of individual fatty acids, agreed well with directly measured microsomal peroxidation. With the exception of the trout, vitamin E content ranged from 0.083-0.311 nmol/mg microsomal protein between species, and low levels did not influence susceptibility to peroxidation. Trout microsomes peroxidized only after vitamin E depletion by prolonged incubation. The data indicate that below a vitamin E threshold, species differences in membrane susceptibility to peroxidation can be reasonably predicted based only on content of individual peroxidizable fatty acids.

Animals↗
PubMed1991

Species differences in susceptibility to 1,3-dinitrobenzene-induced testicular toxicity and methemoglobinemia.

The testicular toxicity and methemoglobinemia induced by 1,3-dinitrobenzene (1,3-DNB) was compared in two species, the Sprague-Dawley rat and the golden Syrian hamster. A marked difference in susceptibility to both endpoints of toxicity was observed. The hamster showed no testicular lesions at dose levels up to 50 mg/kg whereas, as previously reported by others, damage to rat testicular tubules in later stages of spermatogenesis was readily apparent at a 25 mg/kg dose level. Similarly, administration of 1,3-DNB induced substantially less methemoglobinemia in the hamster than in the rat. For example, at the 25 mg/kg dose level peak levels of methemoglobin in the hamster were 15% compared with 80% in the rat. Mortality in the rat also occurred at lower doses than in the hamster (50 vs 100 mg/kg, respectively). In in vitro studies, the capacity of 1,3-DNB and 1,3-DNB metabolites (nitroaniline, nitroacetanilide, aminoacetanilide, diacetamidobenzene) to induce methemoglobinemia was examined in suspensions of red blood cells obtained from both species. Only 1,3-DNB caused the formation of methemoglobin and rat red blood cells were twice as sensitive as hamster red blood cells. The species difference in susceptibility to both methemoglobinemia and testicular toxicity could indicate differences in 1,3-DNB clearance and/or formation of toxic metabolites. Additional metabolic work is under way. This study demonstrates that the hamster is more resistant than the rat to the testicular lesion and methemoglobinemia induced by 1,3-DNB.

Animals↗
PubMed1991

Thrombocytopenia associated with carbamazepine: a case series.

Carbamazepine is increasingly being used in the acute and maintenance treatment of patients with bipolar disorder. Thrombocytopenia represents a serious adverse effect of carbamazepine with which clinicians need to be familiar. The authors describe the course of thrombocytopenia associated with carbamazepine in four patients with bipolar disorder. In all cases, thrombocytopenia appeared 14 to 16 days after the initiation of carbamazepine; also in all cases the platelet count completely recovered within 7 days after the carbamazepine treatment was discontinued. Thrombocytopenia secondary to carbamazepine appears soon after the initiation of treatment and is rapidly followed by recovery after drug discontinuation.

Adolescent↗
PubMed1989

Adverse outcomes and lack of health insurance among newborns in an eight-county area of California, 1982 to 1986.

In this study of hospital discharge data on births to residents of an eight-county region of California, we found an increasing lack of health insurance that was associated with an elevated and increasing risk of adverse outcomes in newborns. Between 1982 and 1986, the percentage of newborns without health insurance increased overall by 45 percent (from 5.5 to 8.0 percent; P less than 0.001); the increases were larger among Asians (by 54 percent [from 7.8 to 12.0 percent]; P less than 0.001) and Latinos (by 140 percent [from 8.2 to 19.7 percent]; P less than 0.001). By 1986, the odds ratio for an adverse hospital outcome (defined as a prolonged hospital stay, transfer of the newborn to another institution, or death) was 1.31 (95 percent confidence interval, 1.17 to 1.46) in uninsured as compared with privately insured newborns, with control for race or ethnic group. There was a significant increase in risk over time (P less than 0.03); the comparable odds ratios in 1982 and 1984 were 1.11 (95 percent confidence interval, 0.93 to 1.33) and 1.19 (1.05 to 1.35), respectively. In 1986 the risks were especially elevated for uninsured as compared with privately insured blacks and Latinos (odds ratios, 2.24 [95 percent confidence interval, 1.60 to 3.13] and 1.56 [1.26 to 1.94], respectively); the increases in risk over time were the most marked in these groups. We believe that the elevated and increasing risks for uninsured newborns are explained at least in part by inadequate and diminishing access to care and that this burden is borne disproportionately by blacks and Latinos.

California↗
PubMed1989

Gas chromatographic analysis of free and bound malonaldehyde in rat liver homogenates.

A gas chromatographic method for the measurement of free and bound malonaldehyde (MA) in rat liver homogenate was developed to investigate biological damage caused by lipid peroxidation. Free MA was derivatized 1-methylpyrazole (1-MP), which was subsequently analyzed by capillary gas chromatography (GC). Bound forms of MA were determined by first hydrolyzing samples in acetic acid, then measuring the free MA as 1-MP. Bound MA in rat liver was released within 15 min by acid hydrolysis. A slight increase in bound MA levels in rat liver was observed 1 hr after CCl4 treatment, with bound MA then returning to control levels. Free MA levels and thiobarbituric acid assay (TBA) values did not show appreciable changes over a 24-hr period after CCl4 administration. However, the TBA values were approximately ten times the MA values in most samples.

Animals↗
PubMed1987

Mechanisms of fasting-induced potentiation of acetaminophen hepatotoxicity in the rat.

The effects of an acute fast on acetaminophen metabolism and hepatotoxicity were investigated in male Long Evans Hooded rats. Histologic studies confirmed that fasting potentiated acetaminophen-induced hepatic necrosis. The previous known fasting-induced decrease in hepatic levels of glutathione and depletion of glycogen levels were also confirmed. Pharmacokinetic studies revealed that, at high dose levels of acetaminophen, fasting decreased the overall rate of elimination as evidence by a longer blood half-life of the drug. The decreased clearance was largely the result of decreases in the apparent rate constants for glucuronidation (ca. 40%) and for sulfation (ca. 30%). Fasting had no significant effects on the apparent rate constants for formation of either acetaminophen mercapturate or the methylthio derivatives. The depression of the nontoxic glucuronidation and sulfation pathways resulted in an increased proportion of the dose converted to the toxic metabolite and, hence, contributed to the potentiation of liver injury in fasted rats. In addition, these studies demonstrated that significant glucuronidation capacity (ca. 60% of that in fed rats) was maintained in fasted rats, indicating that: the glucuronidation capacity was not directly correlated with glycogen levels; and in fasted rats the glucose required for UDP-glucuronic acid formation for acetaminophen glucuronidation was supplied from sources other than glycogen.

Acetaminophen↗
PubMed1987

Iron deficiency in cystic fibrosis.

Iron state was measured as part of the comprehensive assessment of 165 patients with cystic fibrosis. Of 127 patients, 41 (32%) had low serum ferritin concentrations and at least this proportion were iron deficiency. Iron state did not correlate with clinical score, radiological score, or results of sputum culture. There was no evidence that patients with iron deficiency were either in better or worse clinical condition than those with better iron stores.

Adolescent↗
PubMed1987

Mania following head trauma.

The authors present psychiatric and neurologic data on 20 patients who developed mania after closed head trauma. An association was seen between severity of head trauma (based on length of posttraumatic amnesia), posttraumatic seizure disorder, and type of bipolar disorder. The manic episodes were characterized by irritable mood rather than euphoria and by assaultiveness. Psychosis occurred in only 15% of the sample, and 70% had no depressive episodes. Bipolar disorders were absent among 85 first-degree relatives. The authors suggest that posttraumatic seizures may be a predisposing factor in posttraumatic mania.

Adult↗
PubMed1987

The clinical effect of correction of vitamin E depletion in cystic fibrosis.

Thirty patients with cystic fibrosis, 24 of whom had longstanding low serum vitamin E, were treated with 50 mg alpha-tocopherol acetate per day for periods of 18-24 months. None of the patients received haematinics during the study period. Throughout the period of study the overall clinical state of the patients did not alter significantly. The serum vitamin E level increased in all patients, but to a variable degree which was not related to the severity of steatorrhoea. A range of nutritional parameters, including anthropometry, vitamin levels, essential elements, haemoglobin and albumin, as well as dietary intake and faecal fat excretion, were assessed at the beginning and end of the study. Haemoglobin was the only parameter to change significantly from 13.14 to 13.47 g/100 ml. Twenty one of the 30 patients showed some increase in haemoglobin values and this increase could not be related to clinical state, fat absorption or dietary intake but was related to the improved vitamin E status.

Adolescent↗
PubMed1986

Mechanisms of toxicity of naphthoquinones to isolated hepatocytes.

The possible mechanisms of naphthoquinone-induced toxicity to isolated hepatocytes were investigated using three structurally-related naphthoquinones, 1,4-naphthoquinone (1,4-NQ), 2-methyl-1,4-naphthoquinone (2-Me-1,4-NQ) and 2,3-dimethyl-1, 4-naphthoquinone (2,3-diMe-1,4-NQ). 1,4-NQ was more toxic than 2-Me-1,4-NQ whereas 2,3-diMe-1,4-NQ did not cause cell death at the solubility-limited concentrations used. All three naphthoquinones extensively depleted intracellular glutathione (GSH). However, the depletion of GSH induced by 1,4-NQ and 2-Me-1,4-NQ prior to cell death was more rapid and extensive than that induced by the nontoxic 2,3-diMe-1,4-NQ. Further studies demonstrated that 2,3-diMe-1,4-NQ was cytotoxic in the presence of dicoumarol, a compound which also potentiates the cytotoxicity of 1,4-NQ and 2-Me-1,4-NQ. To investigate the differential cytotoxicity of these three naphthoquinones, their relative capacities to redox cycle and to bind covalently to cellular nucleophiles were assessed. Redox cycling was investigated using rat liver microsomes where the order of potency for quinone-stimulated redox cycling was 1,4-NQ approximately 2-Me-1,4-NQ much greater than 2,3-diMe-1,4-NQ as indicated by nonstoichiometric amounts of NADPH oxidation and O2 consumption. NADPH-cytochrome P-450 reductase was implicated as the enzyme primarily responsible for naphthoquinone-stimulated redox cycling. The reactivity of the naphthoquinones with glutathione and, by implication, with other cellular nucleophiles was 1,4-NQ greater than 2-Me-1,4-NQ much greater than greater than 2,3-diMe-1,4-NQ. Overall, these studies indicate that 2,3-diMe-1,4-NQ is not cytotoxic (except in the presence of dicoumarol) and this lack of toxicity may be related either to its lesser capacity to redox cycle and/or its inability to react directly with cellular nucleophiles.

Animals↗
PubMed1986

Acetaminophen hepatotoxicity: studies on the mechanism of cysteamine protection.

Inhibition of the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite was investigated as a possible mechanism for cysteamine protection against acetaminophen hepatotoxicity. Studies in isolated hamster hepatocytes indicated that cysteamine competitively inhibited the cytochrome P-450 enzyme system as represented by formation of the acetaminophen-glutathione conjugate. However, cysteamine was not a potent inhibitor of glutathione conjugate formation (Ki = 1.17 mM). Cysteamine also weakly inhibited the glucuronidation of acetaminophen (Ki = 2.44 mM). In vivo studies were in agreement with the results obtained in isolated hepatocytes; cysteamine moderately inhibited both glucuronidation and the cytochrome P-450-dependent formation of acetaminophen mercapturate. The overall elimination rate constant (beta) for acetaminophen was correspondingly decreased. Since cysteamine decreased both beta and the apparent rate constant for mercapturate formation (K'MA), the proportion of the dose of acetaminophen which is converted to the toxic metabolite (K'MA/beta) was not significantly decreased in the presence of cysteamine. Apparently, cysteamine does inhibit the cytochrome P-450-dependent formation of the acetaminophen-reactive metabolite, but this effect is not sufficient to explain antidotal protection.

Acetaminophen↗
PubMed1986

Anomalous susceptibility of the fasted hamster to acetaminophen hepatotoxicity.

The effect of an acute fast on susceptibility to acetaminophen-induced hepatotoxicity was investigated in male Golden Syrian hamsters. Overnight starvation markedly elevated hepatic levels of glutathione throughout the diurnal cycle (peak concentration: 10.6 +/- 0.06 mM vs 7.3 +/- 0.3mM in controls). However, despite this apparent increase in the glutathione protective capacity of the liver, acetaminophen-induced hepatic necrosis was modestly potentiated by fasting, as judged by liver histology and elevation of serum transaminase (SGOT) activity. Parallel pharmacokinetic studies indicated that the overall elimination rate constant for acetaminophen was decreased in fasted animals, due largely to decreases in the apparent rate constants for formation of acetaminophen glucuronide and acetaminophen mercapturate. Formation of acetaminophen sulfate was not affected by fasting. Since the major nontoxic pathway (glucuronide) and the toxic pathway (as measured by mercapturate) decreased to a similar extent, the data indicate that the anomalous lack of protection cannot be explained on the basis of altered metabolic disposition of the drug. Measurement of hepatic glutathione levels revealed that, despite the higher initial level of glutathione in the fasted animals, the nadir to which liver glutathione levels fell after acetaminophen was the same in fed and fasted animals. Comparison of the amount of acetaminophen mercapturate in the urine with the amount of glutathione which disappeared from the liver showed close agreement for fed animals, but a major discrepancy for fasted hamsters. These data indicate that a major fraction of glutathione in the liver of the fasted hamsters is not utilized for detoxification of the acetaminophen reactive metabolite and hence does not contribute to the glutathione protective capacity.

Acetaminophen↗
PubMed1986

Finger clubbing in cystic fibrosis.

Finger clubbing was measured in 73 of 105 patients with cystic fibrosis undergoing full assessment. The sign correlated well with the chest x ray score and indices of pulmonary function and infection but not with weight, height, age, liver function, or degree of fat malabsorption. The presence of clubbing suggests appreciable pulmonary involvement. Most probably its progression indicates a deterioration in pulmonary state. In both instances increased efforts should be made to treat the infection.

Adolescent↗
PubMed1986

Essential element nutritional status in cystic fibrosis.

Serum calcium, magnesium, iron, copper and zinc were measured in 117 patients with cystic fibrosis. Apart from serum iron levels, all the other essential element levels were well maintained and there was no evidence of a need for supplementation. Serum iron was frequently low and the need for iron supplements must be considered after further investigation. The subjects studied covered a wide age range, had widely varying fat malabsorption and clinical grading, and also varying degrees of pulmonary involvement. We found no evidence that any of these parameters directly influenced essential element status as assessed by serum levels.

Adolescent↗
PubMed1986

The role of taste in dietary self-selection in rats.

In order to study the role of taste in dietary self-selection, rats were subjected to two degrees of gustatory deafferentation. The chorda tympani was sectioned alone or in combination with the glossopharyngeal nerve and the pharyngeal branch of the vagus. The animals chose from two diets, only one of which contained protein. After surgery, deficits were observed in body weight, food and water intake, and diet selection, proportional to the extent of deafferentation. Some 76% of the animals increased protein and decreased carbohydrate intake, but all rats continued to select a nutritionally balanced diet (Experiment 1). When subjected to a nutritional challenge of intragastric protein or carbohydrate supplementation, the rats compensated for calories and nutrients by selectively adjusting oral intake (Experiment 2). In saccharin preference tests, the preference as well as the total consumption of the test solutions was reduced (Experiment 3). The findings are contrasted to the effects of oral somatosensory deafferentation and are interpreted as a change in preference within the limits of metabolic requirements. The different roles/mechanisms of the two sensory systems in regard to dietary self-selection are discussed.

Animals↗