Genetic analysis of the corticosterone response to ethanol in BXD recombinant inbred mice.

The genetic control over the corticosterone response to ethanol (EtOH) and its possible relationship to other EtOH-related traits was examined using BXD recombinant inbred (RI) strains derived from an F2 cross of C57BL/6J (B6) and DBA/2J (D2) progenitor strains. Quantitative trait locus (QTL) analysis of corticosterone levels 1 hr following EtOH suggested the influence of a single major gene on this trait. Two loci were predicted to account for 47% of the genetic variance in plasma corticosterone levels 6 hr following EtOH, whereas 3 loci were predicted to account for 78% of the genetic variance in corticosterone levels 7 hrs following EtOH. Markers associated with corticosterone levels 7 hrs following EtOH and corrected corticosterone levels 6 hrs post-EtOH overlapped with ones found to influence acute and chronic EtOH withdrawal severity, suggesting some degree of common genetic determination between these traits. Overall these results indicate that gene action significantly influences stress responsiveness and suggest possible chromosomal locations of these genes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Identification of quantitative trait loci involved in contextual and auditory-cued fear conditioning in BXD recombinant inbred strains.

Fear conditioning shows associations formed between contextual or auditory stimuli with an unconditioned stimulus. Inbred mouse strains differ in their ability to demonstrate fear conditioning, suggesting at least a partial genetic influence. The present study identified the possible chromosomal loci regulating fear conditioning in BXD recombinant inbred strains using quantitative trait loci (QTL) analysis. Estimates of heritability for all 3 measures of conditioning were about .28. Correlational analyses between genetic markers and strain means identified multiple putative QTLs. The strongest associations were on Chromosomes 1 and 17 for freezing to the context, Chromosome 12 for freezing to an altered context, and Chromosome 1 for freezing to the auditory stimulus. Overlapping QTLs may indicate some common genes that underlie aspects of this learning task. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Voluntary alcohol consumption in vervet monkeys: individual, sex, and age differences

The patterns of voluntary alcohol consumption were studied in 35 vervet monkeys (Cercopithecus aethiops), classified into four groups. Each monkey showed a fairly steady rate during the studied period, resulting in individual differences that became more evident as the treatment evolved. Females showed higher alcohol intake frequencies than males. This sexual difference was maintained among adults and juveniles. Age differences were also observed: juveniles showed higher frequencies of intake than adults, both in general and in each sex group. Intake frequency was not related to age in prepubertal subjects, neither in general nor in each particular sex. The origin of these sex and age alcohol consumption differences remains to be studied, but differences in alcohol metabolism and factors related to puberty are possible influences.     

Escape deficits induced by uncontrollable foot-shock in recombinant inbred strains of mice

Although uncontrollable stressors reliably induce numerous behavioral disturbances, considerable interindividual variability exists in this respect. Inasmuch as genetic factors may be fundamental in determining vulnerability to stressor effects, the present investigation assessed alterations in escape performance following exposure to uncontrollable foot-shock in the BALB/cByJ and C57BL/6ByJ mice and seven recombinant inbred strains. Exposure to uncontrollable foot-shock disrupted shuttle escape performance in a strain-specific manner; however, any differences due to gender were not particularly remarkable. The profile of stressor effects in the recombinant strains (i.e., performance deficits greater, lesser or intermediate to the progenitor strains) suggest that the stressor effects on escape performance may be subserved by two or more genetic determinants. The findings are related to central mechanisms that may potentially account for strain differences.     

Altered polyamine metabolism in the PRO/Re strain of inbred mice

The PRO/Re strain of inbred mice are characterized by abnormally high concentrations of proline in both blood (hyperprolinaemia) and urine (prolinuria). They excrete increased amounts of polyamines in their urine. Male PRO/Re mice excreted putrescine at 175% and spermidine at 300% the amount of male C57BL/6J controls. Female PRO/Re mice excreted putrescine at 115% and spermidine at 150% of the amount in the urine of female controls. Examination of the enzymes involved in polyamine biosynthesis revealed that ornithine decarboxylase, the initial enzyme in the polyamine-biosynthetic pathway, was increased by 150% in the kidneys and by 100% in the liver of male PRO/Re mice. There was no significant difference between PRO/Re and C57BL/6J male mice for either putrescine- or spermidine-stimulated S-adenosylmethionine decarboxylase activity. Female PRO/Re mice showed no significant difference from female C57BL/6J mice for any of the enzymes examined. When the concentrations of the polyamines in the tissues of the PRO/Re mice were determined, spermidine and spermine concentrations in the kidneys of the male PRO/Re mice were twice those of the controls. Spermidine concentration in the livers of both male and female PRO/Re mice was approx. 130% that of the controls. Polyamine concentrations in the brains were similar in controls and mutants. The increased polyamine biosynthesis and excretion in the PRO/Re mutant mice may be a mechanism to decrease the extent of proline accumulation.     

Factor analyses of alcohol and water consumption in laboratory mice.

Tested 99 mice from 9 different genotypes for 10 consecutive days in a 2-choice situation with drinking tubes containing water and dilute ethanol. Separate recordings of alcohol and water consumption were taken according to the light cycle, at 9:30 AM and 9:30 PM on each day. The 20 measures of alcohol and water consumption were factor analyzed separately by alpha analysis with varimax rotation. 2 factors with eigenvalues greater than 1 were obtained for alcohol and 3 for water consumption. Factors differed strikingly depending on the fluid involved. Water-consumption factors reflected the nocturnal-diurnal activity cycle. Alcohol-consumption factors were related to changes over days but not to the activity cycle. (French summary) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass

BACKGROUND & AIMS: Alcoholic liver disease purportedly develops more readily in women than in men. Some studies have demonstrated faster rates of alcohol elimination in women. This study examined whether gender differences in alcohol metabolism are related to differences in liver volume and/or differences in lean body mass. METHODS: Ten men and 10 women had alcohol elimination rates determined by clamping of the breath alcohol concentration at 50 mg/dL by means of a constant rate of intravenous infusion of 6% ethanol. Liver volume was determined by computed tomography. RESULTS: Mean alcohol elimination rate and mean computed liver volume were not significantly different in men and women. Lean body mass was 42% greater in men than in women. Consequently, the calculated alcohol elimination rate and liver volume per kilogram of lean body mass were 33% and 38% higher in women than in men, respectively. When the alcohol elimination rate was calculated per unit liver volume, no gender-related difference was found. CONCLUSIONS: Women have greater clearance of ethanol per unit lean body mass, confirming previous oral alcohol administration studies. Women have approximately the same liver volume as men, explaining the equivalent alcohol elimination rates seen when men and women are compared on the basis of liver size.     

Langerhans cell density in normal human oral mucosa and skin: relationship to age, smoking and alcohol consumption

Hyperthyroidism is a common endocrinologic disorder affecting many organ systems. Musculoskeletal and neurological involvement present themselves as fatigue, muscle weakness and paralysis. Electromyography (EMG) is essential for differential diagnosis of muscle weakness. Well defined neuropathy and myopathy have been described in these patients. In the present study 17 hyperthyroid patients were evaluated with electrophysiological tests in addition to physical and neurological examinations and biochemical laboratory studies. Needle EMG, motor and sensory conduction velocities, median and tibial somatosensory evoked potentials (SEP) were studied. For assessment of the activity of disease clinical status, neurological symptom and disability scores and serum T3, T4 and TSH levels were examined. Statistical analysis of neuroelectrophysiological findings of the patient and the control groups yielded meaningful difference in the needle EMG, sensory conduction velocity and evoked potential findings. Abnormalities were observed in 80% of the proximal muscles besides polyphasic potentials that were seen in 20% of the extensor digitorum brevis muscle. Median, ulnar and sural nerve sensory action potential amplitudes were found to be lower than that of the control group. Sural sensory nerve conduction velocity of patients was decreased in 35.5%, prolongation of median SEP latencies and increase in the amplitudes were not however statistically significant. Prolongation of Tibial SEP N1, P2 latencies were seen in 47%, amplitudes of N1 were increased in 88.2%, P2 in 58.8%, N2 in 47%. The thyroid clinical status score was correlated with Tibial SEPs amplitude. These findings suggest the presence of an initial axonal type of mild polyneuropathy. As a conclusion electrophysiological studies can be useful in the diagnosis of asymptomatic polyneuropathy in hyperthyroid patients.     

Relationship of alcohol consumption to changes in HDL-subfractions

Epidemiological studies have consistently shown an apparent protective effect of moderate alcohol consumption on coronary artery disease (CAD). This has been considered to be due to the rise in the high-density cholesterol lipoprotein (HDL-cholesterol). Since the response of the HDL-subfractions to moderate or heavy dose of alcohol is less clear, we now compared the high-density lipoprotein cholesterol status between groups consuming different amounts of alcohol. In this population-based survey serum total high-density lipoprotein cholesterol and its HDL2 and HDL3 subfractions were blindly compared between 264 consecutive middle-aged men (37 teetotallers, 137 moderate drinkers, 90 heavy drinkers) participating in a voluntary health screening and 104 male alcoholics. Alcohol consumption correlated significantly (P < 0.001) with total HDL-cholesterol, HDL2, HDL3 when all subjects (n = 368) were included but the correlation disappeared when alcoholics were excluded (n = 264). In comparison with teetotallers, alcoholics had significantly higher total HDL-cholesterol, HDL2 and HDL3 values (P < 0.001). Moderate or heavy intake of alcohol had no effect on HDL2 but increased the HDL3-fraction. If the protective effect of moderate alcohol consumption is mediated by high-density lipoprotein, it may not be accounted for by changes in the HDL2-fraction. The observed increases in the concentration of the HDL3-fraction, however, suggest that this subfraction may not be inert with respect to coronary disease and could possibly have a role in the protective effect.     

Genetic resistance to urethan-induced pulmonary adenomas in SMXA recombinant inbred mouse strains

Development of pulmonary adenomas (PAs) in mice is under the genetic control of multiple host genes. We have established a new set of SMXA recombinant inbred strains from PA-susceptible A/J and PA-resistant SM/J mice. The number of urethan-induced PAs was variable among substrains of the SMXA recombinant inbred strains, indicating the involvement of multiple genes. SMXA24 mice were highly resistant to PA, although they had susceptible alleles at all four known susceptibility genes, including kras2 and MHC. To identify the resistance gene in SMXA24, progeny of reciprocal F1 crosses and progeny of backcrosses to A/J were given urethan at 4 weeks of age and examined for induced PA at the age of 5 months. In reciprocal F1 cross progeny, the incidence of PA was very low, indicating that the resistance was a semidominant trait. Quantitative trait analysis of the backcross generation revealed significant linkages to loci on chromosome 12 (logarithm of odds score, 6.47) and chromosome 11 (logarithm of odds score, 4.35). To date, two PA resistance (PAR) genes, Par1 (located on chromosome 11) and Par2 (located on chromosome 18), have been reported. From the map position, one of the resistance genes on chromosome 11 was indistinguishable from Par1. However, another resistance gene on chromosome 12 was new, and we named this gene Par3. A likely candidate gene for Par3 is nPKCn, which is expressed exclusively in skin and lung and is down-regulated in PA. Par1 and Par3 seemed to act synergistically.     

Genetic determinants of sensitivity to ethanol in inbred mice.

Mice from 15 inbred strains (n?=?27–40 per strain) differed in sensitivity to ethanol-induced effects on open-field activity, hypothermia, rotarod ataxia, and anesthesia. Sensitivities to the different behavioral responses were generally uncorrelated. This suggests that the genetic determinants of behavioral sensitivity to one domain of ethanol effects are unrelated to those determining other responses. On the other hand, some variables were genetically related. For example, those strains sensitive to the loss of righting reflex induced by higher doses of ethanol showed reduced activity in the open field at lower doses and were more sensitive to ethanol-induced decreases in rearing. More generally, the pattern of results suggests that genetically influenced sensitivity to ethanol is not a monolithic phenomenon. Rather, it is specific to the particular response variable studied. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Genetic determinants of sensitivity to diazepam in inbred mice.

Mice from 15 standard inbred strains were tested for sensitivity to several effects of acute diazepam (DZ). Strains differed in sensitivity to DZ-induced: low-dose stimulation and high-dose depression of locomotor activity, hypothermia, and ataxia assessed on a rotarod. Correlations among strain means indicated that sensitivity to a particular effect of DZ generalized well across doses. Sensitivities to some of the different behavioral responses also were significantly correlated. For example, strains sensitive to DZ-induced increases in activity were significantly less sensitive to the drug's hypothermic effects. These results suggest that there are multiple genetic determinants of behavioral sensitivity to DZ effects. That is, genetically influenced sensitivity to DZ is not monolithic but is somewhat specific to the particular response variable studied, a result that also characterizes genetic control of responses to other drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Disorganization of attachment in relation to maternal alcohol consumption.

The relation between maternal alcohol consumption and infant attachment behavior at 1 year of age was investigated. Alcohol consumption was estimated by self-report questionnaires that were filled out by mothers over 30 years of age regarding the amount of alcohol they had consumed prior to, during, and following pregnancy. The attachment behavior of infants was observed using the Ainsworth "strange-situation" procedure. Infants were classified as secure (Group B); insecure–avoidant (Group A); or insecure–ambivalent/resistant (Group C). Additionally, a new classification of insecure–disorganized/disoriented (Group D), developed by Main and Solomon (1986), was used. The majority of infants of mothers who had consumed more alcohol were insecure in comparison with a minority of insecure infants of mothers who had been abstinent or light drinkers. The classification of infants as insecure–disorganized/disoriented helped to identify a large number of infants who were insecure in the group of heavy-drinking mothers. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sensitivity to ethanol in inbred mice: Genotypic correlations among several behavioral responses.

Assessed the sensitivity of 20 inbred strains of mice for ethanol's effects on activity, body temperature, ataxia, balance, and the righting reflex. Genotypic correlations among the mean responses for the strains were estimated as indices of pleiotropic influences of genes on drug responses. Three major groups of genetic influence were detected: (a) hypothermic sensitivity to ethanol, (b) activity change, and (c) high basal activity. In the 1st group of variables, strains that had large reductions in body temperature after being given ethanol had high baseline temperatures, a pronounced ataxic response to ethanol, and a long-lasting loss of righting reflex. The 2nd group was composed largely of ethanol-induced increases and decreases in activity. Strains with larger increases in activity showed more rapid loss of balance after ethanol. The 3rd group indicated that high levels of basal activity in an open field and in the home cage were determined by the action of common genes. Strains with higher basal activity levels had reduced sensitivity to ambulatory ataxia following ethanol. Thus, there were substantial pleiotropic effects of common genes on several behavioral responses to ethanol. Conversely, the 3 major groups were not systematically correlated with one another to a major extent. This suggests the influence of 3 reasonably distinct sets of genes on these responses to ethanol. (25 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Linkage analysis of susceptibility to ozone-induced lung inflammation in inbred mice

Through a survey of all departments of pediatrics, neurology and neuropathology in Germany, we calculated the incidence of all major forms of leukodystrophy. Only diagnoses based on specific biochemical tests in association with typical findings and/or neuroradiologically proven white matter involvement were accepted. In accordance with these strict criteria, 617 cases of leukodystrophy were found (incidence of all forms: app. 2.0/100,000). Minimal incidence was estimated at 0.8/100,000 for adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN), 0.6/100,000 for metachromatic leukodystrophy (MLD), and 0.6/100,000 for Krabbe disease. Thus ALD/AMN is apparently underdiagnosed in Germany. A considerable proportion of leukodystrophies could not be classified in spite of adequate diagnostic procedures in experienced centers.     

Transferrin isoform distribution: gender and alcohol consumption

Transferrin (Tf) has different isoforms based on the degree of sialylation of its two N-linked oligosaccharide chains. The least sialylated isoforms of Tf; with 0 (asialo Tf), 1 (monosialo Tf), and 2 (disialo Tf) sialic acids are referred to as carbohydrate-deficient transferrin (CDT). CDT has been reported to be a specific and sensitive marker for the detection and monitoring of alcohol abuse. However, the possible differences between the three CDT isoforms in males and females relative to alcohol consumption has not been known. The present study included 82 males (M) and 43 females (F) with well documented drinking habits. The Tf isoforms were separated by FPLC and measured by RIA in the collected fractions, as well as by a commercially available method (CDTect RIA). The results were expressed as relative values and absolute values. Female low consumers compared to male low consumers had higher levels of asialo Tf (p < 0.01) and monosialo Tf (p < 0.01), but not of disialo Tf or sum of asialo, monosialo, and disialo Tf. Male high consumers and chronic consumers compared to male low consumers had 53% and 219% higher levels of asialo Tf, 4% and 28% higher monosialo Tf, 57% and 148% higher disialo Tf, and 48% and 134% higher sum of CDT isoforms, respectively. The corresponding increases in females were for asialo Tf 68% and 249%, for monosialo Tf 36% and 58%, for disialo Tf 54% and 225%, and for sum of CDT isoforms 52% and 192%, respectively. For both genders, total Tf, trisialo Tf, and the levels of more sialylated transferrin isoforms were constant when comparing the consumption groups. Results expressed as relative values and absolute values were in good agreement. In conclusion, the present study indicates that alcohol consumption strongly increases the levels of asialo Tf and disialo Tf and slightly increases the level of monosialo Tf. However, women had higher asialo Tf and monosialo Tf levels than men. Alcohol consumption does not increase trisialo or more sialyated Tf subfractions. Expressing the CDT results as absolute or relative values made no obvious difference in diagnostic efficiency.     

Mediterranean mysteries: mechanisms of declining alcohol consumption

The efficacy of intraoperative radiotherapy (IORT) for the local recurrence of rectal cancer was evaluated. Operations were performed for a total of 43 patients with local recurrence of rectal cancer, and among them 13 cases received IORT. These patients were divided into two groups those with a suspicion of cancer remaining in the surgical margin macroscopically (EW+ group) or those with no such suspicion (EW- group). The length of pain relieving period and total survival between the IORT and no IORT groups in EW- patients showed no statistical difference. Though the same result was found in EW+ patients, in the patients whose area of positive surgical margin was less than 10 cm2 and given IORT, the pain relief period was prolonged compared with the no IORT patients such as 270 days v.s. 218 days. IORT did not show efficacy in terms of the survival period, but if the local remnant area was small, it was beneficial for the patients in terms of the pain period.     

Newborn organ weight and spontaneous hypertension: recombinant inbred strain study

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20-25, PN50-55, or PN90-95, separate groups of rats were tested in a Morris water maze on a visible "cue" condition (visible platform in a fixed location of the maze), a spatial "place" condition (submerged platform in a fixed location), or a no-contingency "random" condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20-25) or as adults (PN50-55 and PN90-95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm.