Biomedical subjects

A Smolen

Publications and source records attributed to A Smolen.

At least 19 recordsLinked to original sources

PubMed2005

Artificial neural network computer prediction of ovarian malignancy in women with adnexal masses.

OBJECTIVE: Assessment of the usefulness of a neural model to predict which ovarian tumors are malignant. METHOD: Age, menopausal status, body mass index, grayscale and Doppler ultrasonographic features, as well as levels of specific markers (CA 125, tissue polypeptide specific antigen) were examined in 686 women with adnexal masses. The probability of malignancy was calculated using an artificial neural network software and the diagnostic efficiency of the received model was estimated using a receiver-operating characteristics (ROC) curve. RESULT: Of the 686 women, 431 (62.8%) had a benign and 255 (37.2%) had a malignant ovarian tumor. The significant malignancy predictors are age, menopausal status, maximum tumor diameter, internal wall structure of tumor, presence of septa and/or solid elements, tumor location, location of vessels, and blood flow indexes. The best network provided 96.0% sensitivity and 97.7% specificity. The area under the curve for the received model was 0.9716. CONCLUSIONS: An artificial neural network model based on clinical and ultrasonographic data allows to calculate the probability of tumor malignancy.

Adnexal Diseases↗

PubMed1995

Response of kynurenine pathway enzymes to pregnancy and dietary level of vitamin B-6.

The kynurenine pathway of tryptophan metabolism produces several neuroactive metabolites including 3-hydroxykynurenine, kynurenic acid, and quinolinic acid. This pathway is sensitive to reductions in vitamin B-6 availability because two key enzymes, kynurenine aminotransferase (KAT) and kynureninase (KYNase), require pyridoxal 5'-phosphate. During pregnancy abnormal concentrations of kynurenine metabolites are also found. We measured the effects of pregnancy and vitamin B-6 availability on KAT and KYNase in liver. DBA/2Ibg and A/Ibg mice were fed diets containing 0.25, 0.5, 2.0, 3.6, or 7.0 mg/kg pyridoxine-HCl (PN-HCl) for 4 weeks. Mitochondrial KAT and cytosolic KYNase were measured in control mice and pregnant mice on gestational days 16-18. The response of the two inbred strains was similar throughout. There were no marked alterations in KAT activity as a function of diet or pregnancy. In contrast, KYNase activities were significantly reduced by dietary restriction of vitamin B-6, and pregnant mice had significantly lower activity than nonpregnant controls for all but the highest dietary level of PN-HCl. These data show that pregnancy has a more pronounced effect on KYNase activity than vitamin B-6 restriction, and that the effects of pregnancy and diet are additive. The alteration in the kynurenine pathway in pregnancy is due to a reduction in KYNase activity, which is resistant to alleviation by vitamin B-6 supplementation.

Animals↗

PubMed1994

Individual differences in sensitivity to nicotine in mice: response to six generations of selective breeding.

Four hundred seventeen heterogeneous stock mice were tested for their relative sensitivity to a low dose of nicotine (0.75 mg/kg) using activity in an automated Y-maze and body temperature as response measures. A wide spectrum of individual responsiveness to nicotine, ranging from complete suppression of activity to stimulation above baseline activity, was found. Replicate measures taken 1 week later on the same animals showed the responses to nicotine to be reliable and reproducible. Activity levels and body temperatures following nicotine administration were highly correlated (r = 0.60, df = 415). From analysis of between-litter proportions of variance, the heritability of nicotine-influenced activity was estimated to be 0.12, indicating that selective breeding for differential responsiveness to nicotine would be possible. The 10 most activated and 10 most depressed male and female mice were chosen as breeders for replicate nicotine activated (NA) and nicotine depressed (ND) lines, respectively. The selection criterion was nicotine-induced activity corrected for baseline activity using regression residuals. After six generations of selective breeding a good response to selection was obtained, although the response was better for the ND than for the NA lines. Realized heritability for responsiveness to nicotine calculated from the six selected generations was found to be 0.20, or slightly greater than that estimated from the foundation population. There were no significant differences in response to selection between the replicate NA or ND lines. Nicotine-induced body temperature was measured as a correlated response to selection, and was found to remain highly correlated with nicotine-induced locomotor activity. The response was more robust for the ND lines than it was for the NA lines. In contrast to the large differences between the ND and NA lines in locomotor activity and body temperatures following nicotine administration, mean baseline activities and body temperatures remained nearly identical throughout. This indicates that selection acted specifically on nicotine-induced responses, and not on baseline measurements, as predicted for response to a selection criterion based on regression residuals.

Animals↗

PubMed1993

Alterations in regional brain GABA concentration and turnover during pregnancy.

During pregnancy, mice are more susceptible to flurothyl-induced seizures than are nonpregnant control mice. The potential role of brain GABA in mediating this behavior was examined in the present study. GABA concentrations in the cerebellum, hippocampus, striatum, midbrain, and cortex from individual control, pregnant (days 17-18) and delivery-day Heterogeneous Stock mice were assayed using a fluorometric method. Turnover of GABA was assessed by inhibiting metabolism with aminooxyacetic acid and measuring GABA accumulation over the next 2 h. Steady-state GABA concentrations decreased significantly from control in all brain regions during pregnancy. Reductions in GABA concentrations were approximately 25-30% in the affected regions. At parturition, GABA concentrations in the cerebellum and cortex returned to control levels, but hippocampal, striatal, and midbrain GABA levels remained significantly depressed. All the indices of GABA turnover--first-order rate constant, half-life, initial rate of synthesis, and turnover rate (product of first-order rate constant and initial concentration)--showed a significant reduction in pregnancy, which was continued through the time of delivery in all brain regions except the hippocampus. Half-life values for GABA increased nearly fourfold in the cerebellum and cortex. These results show that there is a significant alteration in GABAergic systems during pregnancy and parturition. We suggest that the reduction in GABA turnover is a compensatory anticonvulsant mechanism to offset the inherent seizure susceptibility brought about by the reduced level of the major inhibitory neurotransmitter in the brain.

Aminooxyacetic Acid↗

PubMed1991

Genetic selections for nicotine and cocaine sensitivity in mice.

We are using selective breeding to develop lines of mice which differ maximally in their responses to nicotine, and independent lines of mice which differ maximally in their responses to cocaine. The foundation population was the genetically heterogeneous HS mice. On day 1, baseline (saline injected) activity of each mouse was measured in an automated Y-maze over 3 minutes. On day 2, animals were tested for sensitivity to nicotine (0.75 mg/kg) in the same apparatus. A residual score, calculated from the regression of nicotine scores on saline scores for the whole population, was calculated for each animal. The most severely affected mice (lowest residual scores) were mated to form duplicate Nicotine-Depressed lines; the most stimulated mice (highest residual scores) were mated to form duplicate Nicotine-Activated lines. A random sampling of individuals was chosen without regard to residual scores for production of duplicate Control lines. Duplicate lines of mice activated and depressed by cocaine are being produced in an analogous fashion using 50 mg/kg cocaine as the test dose. Successful selective breeding for a drug-related trait provides clear evidence of a heritable component for that trait. These selected lines of mice will ultimately be used to study hypotheses involving genetic control of response to these drugs.

Animals↗

PubMed1990

Strain, sex and developmental profiles of cocaine metabolizing enzymes in mice.

Cocaine is a potent hepatotoxin in laboratory mice, although the cocaine-induced hepatotoxicity (CIH) is due to the action of a metabolite of cocaine. Cocaine can be hydrolyzed by serum cholinesterase (ChE) to inactive products, or be oxidized by hepatic cytochrome P-450 and FAD-containing monooxygenase (FADM). The oxidative pathway is thought to be responsible for production of the hepatotoxic metabolite of cocaine, presumably norcocaine nitroxide. Female mice are much more resistant to CIH than males of the same strain. We have found that immature male mice are as resistant as females to the development of CIH. Males did not show any CIH until the onset of puberty (30 days of age), indicating that the development of CIH in males was under hormonal control. To determine if the major cocaine-metabolizing enzymes were responsible for the regulation of CIH, we measured the activities of ChE, cocaine N-demethylation (CND) and FADM as a function of sex in C57BL/6Ibg and DBA/2Ibg mice 20-21, 30 +/- 1 and 65 +/- 5 days of age. There was a significant sex difference in ChE activity (females higher than males) but no effect of age. Cocaine N-demethylation increased in both males and females with age, but there was no consistent sex difference. Activity of FADM declined in males as a function of age, but remained constant in females. The lack of a consistent correlation between enzyme activities and sex-, strain-, and age-dependent differences in susceptibility to CIH, do not support a regulatory role for ChE, CND or FADM in mediating the hepatotoxic response.

Aging↗

PubMed1990

Developmental expression of cocaine hepatotoxicity in the mouse.

Cocaine may be metabolized either by ester hydrolysis to inactive products or by oxidation via a cytochrome P-450 and FAD-monooxygenase pathway to a hepatotoxic metabolite, presumably norcocaine nitroxide. Mice are the species most susceptible to cocaine-induced hepatotoxicity (CIH), and marked strain differences in response have been found. Female mice are very resistant to CIH, whereas males are susceptible, indicating that hormonal factors may be involved. We treated mice of 5 inbred strains with cocaine at three ages: 20 days (weanling), 30 days (adolescent) and 60 days (adult). The CIH response was assessed by measurement of plasma alanine aminotransferase (ALT) activity 18 hours later. For each of the strains females of all three age groups were resistant to CIH, and males did not begin to develop CIH until approximately 30 days of age. The degree of CIH in 30-day-old males was intermediate between the levels found in 20-day-old males and adult males. These data suggest that the enzyme, or enzymes, responsible for the production of the toxic metabolite are absent, or at very low levels, in female and immature male mice, and that they are either inducible by androgens or are repressed by estrogens or progestins. It is possible that these enzymes may be involved in the production of toxic metabolites of compounds other than cocaine.

Aging↗

PubMed1990

Relationship between blood, liver and brain pyridoxal phosphate and pyridoxamine phosphate concentrations in mice.

Plasma pyridoxal 5'-phosphate (PLP) concentrations are considered to be the most reliable single indicator of vitamin B-6 nutritional status and are thought to reflect tissue PLP and pyridoxamine 5'-phosphate (PMP) levels. We investigated the relationship between dietary level of pyridoxine hydrochloride (PN-HCl) and concentrations of PLP in blood and PLP and PMP in liver and brain of mice. Female heterogeneous stock mice, 60 to 90 d old, were fed purified diets containing 0.5, 1.0, 2.0, 3.0, 5.0, or 7.0 mg PN-HCl/kg diet for 5 wk. PLP and PMP concentrations were determined by a spectrophotometric apotryptophanase assay. PLP content of plasma, erythrocytes, whole blood, liver and brain and PMP levels in liver and brain were highly correlated with dietary level of PN-HCl (r values ranged from 0.81 to 0.94, n per correlation = 32 to 43). By using the entire range of dietary levels of PN-HCl, both plasma and erythrocyte PLP were found to be significantly correlated with tissue PLP and PMP concentrations. For any one dietary level, however, correlations between plasma or erythrocyte PLP and tissue PLP and PMP concentrations were low and nonsignificant. These results suggest that plasma PLP levels may be suitable to determine vitamin B-6 status of populations, but not to reliably predict tissue concentrations of PLP or PMP in individuals.

Administration, Oral↗

PubMed1990

Vitamin B-6 metabolic enzymes in blood and placenta of pregnant mice.

Plasma pyridoxal 5'-phosphate (PLP) concentrations decrease 50% in pregnant mice and erythrocyte PLP levels increase threefold over nonpregnant levels. These studies were designed to determine whether changes in the enzymes involved in synthesis and degradation of PLP in blood are altered during pregnancy. We measured net synthesis of PLP in erythrocytes and the activity of enzymes involved in the regulation of plasma and erythrocyte PLP concentration: erythrocyte pyridoxal kinase (PLK) and neutral phosphatase, and plasma and tissue alkaline phosphatase (ALP). Net synthesis of PLP and activities of erythrocyte PLK and neutral phosphatase in erythrocytes remained unchanged during pregnancy. We were unable to detect any dephosphorylation of PLP in erythrocytes of pregnant or nonpregnant mice. Mouse erythrocytes were devoid of ALP activity; neutral phosphatase was inactive with PLP and PLP was an uncompetitive inhibitor of the enzyme. Plasma ALP activity decreased 50% in the pregnant mice; therefore, it likely does not participate in the reduction of plasma PLP levels during pregnancy. Placenta had high levels of PLP-phosphatase activity (ALP) and, if it is active as an ectoenzyme in this tissue as it is in others, it may be the most important mediator of plasma PLP levels in pregnancy.

Alkaline Phosphatase↗

PubMed1989

Changes in pyridoxal phosphate and pyridoxamine phosphate in blood, liver and brain in the pregnant mouse.

A decrease in plasma pyridoxal-5'-phosphate (PLP) occurs during pregnancy in humans and experimental animals for reasons that are not known. To determine if mice also develop decreased plasma PLP concentrations during pregnancy, and if plasma PLP levels in pregnancy reflect tissue levels of PLP and pyridoxamine-5'-phosphate (PMP), we measured PLP concentrations in plasma, erythrocytes and whole blood, and liver and brain PLP and PMP in control and pregnant mice. Mice were fed a nonpurified diet containing 8.13 mg pyridoxine-HCl/kg. The PLP analyses were performed in our newly developed apotryptophanase method in which the substrate S-benzyl-L-cysteine is hydrolyzed to benzyl mercaptan, reacted with Ellman's reagent and measured spectrophotometrically. During pregnancy, plasma PLP levels decreased 50% below control levels, but erythrocyte and whole blood PLP levels increased 2.9- and 1.6-fold, respectively. Liver PLP and PMP decreased 25%, in parallel with plasma PLP, but brain PLP and PMP concentrations were unchanged during pregnancy. These results suggest that metabolism or utilization of vitamin B-6 is altered in pregnancy, and that plasma PLP concentrations alone may not be a good indicator of nutritional status in pregnancy.

Animals↗

PubMed1989

Reproducibility of ethanol elimination rates in long-sleep and short-sleep mice.

Ethanol metabolism was measured in long-sleep (LS) and short-sleep (SS) mice on two occasions separated by 1 week to test for repeatability. Mice were injected intraperitoneally with either 1.5 or 4.0 g/kg ethanol and the linear decline of blood ethanol level was measured. The parameters measured in each animal were linear ethanol elimination rate (EER), peak blood ethanol level, volume of distribution and Widmark ratio (r). Reproducibility was assessed using two statistical methods, paired t tests and Pearson correlations. Paired t tests indicated good reproducibility since the two replicate determinations did not differ significantly from each other. The other widely used indicator of reproducibility, the correlation coefficient (Pearson r) between the two measurements, was nonsignificant in almost every case, indicating poor reproducibility. This occurs because the range of values of EER is fairly narrow; thus, an individual is likely to fall anywhere within that narrow range from one day to the next, and the rank ordering of the individuals may not be maintained. Although parameters such as EER and volume of distribution appear to be reproducible for populations, they may have little or no utility as covariates in genetic analyses of individual differences in response to ethanol.

Animals↗

PubMed1987

Alterations in brain catecholamines during pregnancy.

During pregnancy mice are more susceptible to flurothyl-induced seizures than are non-pregnant controls. The potential role of brain catecholamines in mediating this behavior was examined in the present study. The concentration and turnover of norepinephrine (NE) and dopamine (DA) were measured in hippocampus, striatum, midbrain and cortex in control, pregnant and delivery-day mice. There were no significant changes from control in DA levels during pregnancy and parturition. The turnover of DA was not altered during pregnancy, except for a small increase in turnover rate in the hippocampus. The concentration of NE decreased during pregnancy, and rose at parturition. This effect was most striking in the hippocampus. The turnover of NE was markedly depressed during pregnancy, with the hippocampus again being most affected. These data imply a role for NE, but not DA in the mediation of increased seizure susceptibility during pregnancy.

Animals↗

PubMed1987

Genetic variation in paraoxonase activity and sensitivity to diisopropylphosphofluoridate in inbred mice.

The mechanism underlying genetic variation in the acute and chronic responses of mice to diisopropylphosphofluoridate (DFP) are unknown. We investigated whether variation in metabolism of organophosphates by A-esterase, as exemplified by the enzyme paraoxonase, was correlated to the degree of sensitivity to DFP in four inbred mouse strains. LD50s and plasma paraoxonase were measured in each strain. We observed genetic variation in both of these measures, but there was no significant correlation between the two measures. We conclude that plasma paraoxonase activity does not underlie genetic variation in sensitivity to the lethal effects of DFP in mice since it does not determine the degree of sensitivity or resistance to DFP.

Animals↗

PubMed1987

Cross-tolerance between muscarinic agonists: role of muscarinic receptors.

In order to explore the relationship between response to muscarinic agonists and brain muscarinic receptors, two mouse strains that differ in acute sensitivity (DBA and C3H) were injected chronically with DFP or infused with oxotremorine. Chronic DFP-treated DBA mice were not tolerant to DFP's effects on any measure, but they were cross-tolerant to the effects of oxotremorine on heart rate and body temperature. DFP-treated C3H mice were not tolerant to DFP or cross-tolerant to oxotremorine on any measure. Oxotremorine infusion resulted in tolerance to oxotremorine in both mouse strains, and chronically infused DBA mice were cross-tolerant to DFP on five of the six measures. Oxotremorine-infused C3H mice were cross-tolerant to DFP on two of the measures. These results suggest that genetic factors influence the development of tolerance or cross-tolerance. These genetic factors do not seem to be related to changes in brain QNB binding. Both mouse strains showed comparable changes in QNB binding following chronic DFP and oxotremorine with DFP eliciting reductions in QNB binding in striatum and hippocampus and oxotremorine eliciting reductions in nearly every brain region. However, tolerance and cross-tolerance did not seem to correlate with changes in binding which suggests that the relationship between receptor changes and responses to muscarinic agonists must be examined further.

Animals↗

PubMed1987

Sex differences in the recovery of brain acetylcholinesterase activity following a single exposure to DFP.

Male and female C57BL, DBA, and C3H mice were injected intraperitoneally with a single 6.33 mg/kg dose of diisopropylphosphofluoridate (DFP). The time course of recovery of acetylcholinesterase (AChE) activity as well as effects on choline acetyltransferase (ChAT) activity and brain muscarinic and nicotinic receptors were measured. DFP treatment did not affect ChAT activity or the muscarinic and nicotinic receptors. Near control levels of AChE activity were regained in female mice within the first 20 days. However, levels of whole brain AChE activity remained depressed for as long as 40 days following a single dose of DFP in male mice. An analysis of the recovery of AChE activity in several brain regions indicated that control activity was regained in striatum, hindbrain, and hippocampus, but not in cortex, midbrain, and hypothalamus. These data are discussed in terms of potential neurotoxicity induced by a single dose of DFP.

Acetylcholinesterase↗

PubMed1987

Relationship between acute ethanol-related responses in long-sleep and short-sleep mice.

Long sleep (LS) and short sleep (SS) lines of mice were derived from a heterogeneous stock of mice (HS) and have been selectively bred on the basis of the time the animals were devoid of the righting reflex (sleep time) following acute ethanol administration. We have tested a large group of the HS mice for sleep time response to ethanol. Animals were then selected from the extremes of the HS sleep time response and designated short sleep (HS-SS) or long sleep (HS-LS). The ED50 value for loss of righting reflex was compared between these mice (HS-SS and HS-LS) and animals that had undergone 25 generations of selection (SS and LS mice). The ED50 value was not significantly different for the HS-LS (1.9 g/kg) and LS (2.17 g/kg) mice but was markedly different between HS-SS (3.02 g/kg) and SS (4.21 g/kg) mice. The ED50 values for the eight inbred strains that constituted the HS stock ranged only from 2.33 to 2.78 g/kg. The value for LD50 one hour after ethanol administration was found to be 9.03 g/kg and for SS mice 6.94 g/kg for LS mice, in contrast to our previous findings of no difference in LD50 values between SS and LS mice when ascertained 24 hr after the ethanol dose. Since the two lines were selected only for a sleep time difference, a differential sensitivity to other consequences of acute ethanol exposure, such as the lethal dose, would not be expected unless the effects shared a common genetic mechanism of action with ethanol sleep time.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Demonstration of a threshold concentration for ethanol at the time of regaining the righting response in long-sleep and short-sleep mice.

The duration of loss of the righting response (sleep time) is often used to assess central nervous system sensitivity to ethanol. It has been assumed that there is a threshold concentration of ethanol at which an animal will regain the righting response, and that this level should not change with dose or route of administration of ethanol. Five hypnotic doses of ethanol were given to Long-sleep and Short-sleep mice by intraperitoneal injection. At the time of awakening, blood and brain ethanol levels were measured. It was found that within a line, the animals awoke at the same blood and brain ethanol concentration irrespective of the ethanol dose given. The threshold blood ethanol level was 265 mg% for Long-Sleep males and 484 mg% for Short-Sleep males. These results indicate that there is a threshold value for ethanol, and that this threshold is characteristic for a given mouse line.

Animals↗

PubMed1986

Genetic influence on increased seizure susceptibility in pregnancy.

In previous studies we have reported that flurothyl-induced clonic seizure threshold was significantly reduced in pregnant mice. In the present study eight strains of mice were tested for flurothyl seizure susceptibility during pregnancy in an effort to find one which lacked this trait. Latency to myoclonus, latency to clonus, and the interval between these seizures were measured. Two inbred strains, A/Ibg and BALB/cByJ, were resistant to the pregnancy-associated increase in seizure susceptibility. These strains will be used, along with others which show the increased seizure trait, to investigate the neurochemical mechanisms which underlie the increased seizure susceptibility in pregnancy.

Animals↗