The role of PPAR gamma agonists - rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 in experimental cyclosporine A hepatotoxicity.

Cyclosporine A (CsA) is an immunosuppressive drug used in transplantation and treatment of autoimmune diseases. Experimental studies revealed impairments in liver function and morphology among cyclosporine-treated animals. The aim of the study was to evaluate hepatoprotective activity of peroxisome-proliferator-activated receptors γ (PPARγ) ligands: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2) on CsA-induced hepatotoxicity in experimental animals. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPARγ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 µg/kg/day. CsA induced liver injury was evidenced by increased serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin. Concentrations of glutathione (GSH) and glutathione disulfide (GSSG), lipid peroxidation products, nicotinamide adenine dinucleotide+/nicotinamide adenine dinucleotide hydrogen (NAD+/NADH), nicotinamide adenine dinucleotide phosphate+/nicotinamide adenine dinucleotide phosphate hydrogen (NADP+/NADPH) and adenosine diphosphate/adenosine triphosphate (ADP/ATP) ratios and caspase 3 activity that were measured in the liver tissue showed, that CsA induced oxidative stress, evoked an imbalanced redox state and apoptosis in the liver. Microscope examination showed sinusoidal dilatation, mononuclear cell infiltration, necrosis of hepatocytes, intracellular vacuolar degeneration and microvesicular steatosis and apoptopic cells. The biochemical and morphological changes induced by CsA were limited by administration of both PPARγ agonist - rosiglitazone and PGDJ2. Our biochemical and liver histopathological examination indicate that both PPARγ agonists may play an important role in protecting against CsA-induced hepatotoxicity.

Variation in mothers' arginine vasopressin receptor 1a and dopamine receptor D4 genes predicts maternal sensitivity via social cognition.

We examined the extent to which the arginine vasopressin receptor 1a (AVPR1a) and dopamine receptor D4 (DRD4) were related to sensitive maternal behavior directly or indirectly via maternal social cognition. Participants were 207 (105 European-American and 102 African-American) mothers and their children (52% females). Sensitive maternal behavior was rated and aggregated across a series of tasks when infants were 6 months, 1 year and 2 years old. At 6 months, mothers were interviewed about their empathy, attributions about infant behavior and beliefs about crying to assess their parenting-related social cognition. Mothers with long alleles for AVPR1a and DRD4 engaged in more mother-oriented social cognition (i.e. negative attributions and beliefs about their infants' crying, ß = 0.13, P < 0.05 and ß = 0.16, P < 0.05, respectively), which in turn predicted less sensitive maternal behavior (ß = -0.23, P < 0.01). Both indirect effects were statistically significant independent of one another and covariates [95% confidence interval (CI): -0.22, -0.03 and ß = -0.03 for AVPR; 95% CI: -0.20, -0.03 and ß = -0.04 for DRD4]. There were no significant direct effects of AVPR1a or DRD4 on maternal sensitivity (ß = 0.02, P = .73 and ß = -0.10, P = .57, respectively). The results did not vary for African-American and European-American mothers (Δχ2 = 18.76, Δdf = 16, P = 0.28). Results support the view that one mechanism by which maternal genes are associated with parental behavior is via social cognition.

Tissue electrical properties in head and neck tumors before and after surgery: Preliminary observations.

Context: Bioelectrical impedance analysis (BIA) detects changes in tissue electrical properties and has been seen as a prognostic tool in several chronic conditions, including cancer. AIMS: The study was conducted to investigate whether there are any tissue electrical differences in patients with head and neck cancer (H and NC) before and after surgery treatment. Settings and Design: The observational study was performed at the Otolaryngology Department, Head and Neck Oncology. Materials and Methods : Tissue electrical properties were assessed in 31 patients with H and NC before and 2 weeks after surgery treatment. Direct bioimpedance measures [resistance, reactance, phase angle (PA)] were determined by BIA. Statistical Analysis Used: The Shapiro-Wilk test was used to assess the distribution conformity of examined parameters with a normal distribution; the Fisher (F) test was used to assess variance homogeneity. For group comparisons of metric data we used the Mann-Whitney U test. P value < 0.05 was considered as statistically significant. The statistical analysis for this study was performed using the computer software STATISTICA v. 8.0 (StatSoft). Results: PA at 50 kHz was found to be significantly (P = 0.000009) lower after surgery in patients with H and NC than before treatment (4.69° ±0.71 vs. 4.22 ± 0.83, respectively). Resistance was significantly (P = 0.0005) greater after surgery in patients with H and NC than before (596.24 ± 96.31 ohm vs 647.64 ± 276.11 ohm, respectively). Conclusions: There are tissue electrical differences before and after surgery in patients diagnosed with H and NC. Further observations would be useful to feedback in support therapy planning of individual patients.

Extracellular-to-body cell mass ratio and subjective global assessment in head-and-neck cancers.

BACKGROUND: The ratio of extracellular mass to body cell mass (ecm/bcm), determined by bioelectrical impedance analysis, has been found to be a potentially useful indicator of nutrition status. Subjective global assessment (sga) is a subjective method of evaluating nutrition status in head-and-neck cancer. The present study was conducted to investigate the association between ecm/bcm and sga in head-and-neck cancer. METHODS: Patients were classified as either well-nourished or malnourished by sga. Bioelectrical impedance analysis was conducted on a population of 75 patients with histologically confirmed head-and-neck cancer, and the ecm/bcm was calculated. Receiver operating characteristic curves were estimated using the nonparametric method to determine an optimal cut-off value of the ecm/bcm. RESULTS: Compared with malnourished patients, those who were well-nourished had a statistically significantly lower ecm/bcm (1.11 vs. 1.28, p = 0.005). An ecm/bcm cut-off of 1.194 was 76% sensitive and 63% specific in detecting malnutrition. CONCLUSIONS: The ecm/bcm can be an indicator that detects malnutrition in patients with head-and-neck cancer. Further observations are needed to validate the significance of the ecm/bcm and to monitor nutrition interventions.

The role of peroxisome-proliferator-activating receptor gamma agonists: rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2 in chronic experimental cyclosporine A-induced nephrotoxicity.

Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin-aldosterone system, upregulation of transforming growth factor beta (TGF-ß), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-γ) agonists: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2), against CsA-induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-γ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 µg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-ß was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-γ agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney.

Bioimpedance vector pattern in head and neck squamous cell carcinoma.

Direct bioimpedance measures (resistance, reactance, phase angle (PA)) determined by bioelectrical impedance analysis (BIA) detect changes in tissue electrical properties. The study was conducted to evaluate soft tissue hydration and mass through pattern analysis of vector plots as height, normalized resistance, and reactance measurements by bioelectric impedance vector analysis in patients with head and neck cancer. Whole-body measurements were made with ImpediMed bioimpedance analysis in 56 adult, white, male subjects 42 to 79 years old: 28 patients with head and neck squamous cell carcinoma (H&NC) and 28 healthy volunteers matched by sex, age and BMI as a control group. All patients were previously untreated and without active nutritional interventions. Mean vectors of H&NC group vs. the control group were characterized by an increased normalized resistance component with a reduced reactance component (separate 95% confidence limits, P<0.05), indicating a decreased ionic conduction (dehydration) with loss of dielectric mass (cell membranes and tissue interfaces) of soft tissue. Monitoring vector displacement trajectory toward the reference target vector position may represent useful feedback in support therapy planning of individual patients before surgery in patients with head and neck cancer in order to reduce post-operational complications.

Increased serum insulin-like growth factor-1 levels in women with gestational diabetes.

BACKGROUND: Insulin-like growth factor-1 (IGF-1), which has effects similar to insulin, reduces blood glucose level, improves insulin sensitivity and may play an important role in the pathogenesis of gestational diabetes (GDM). OBJECTIVE: The aim of the study was to estimate the concentration of IGF-1 in pregnant women with GDM and 3 months after delivery and find relationships between IGF-1 and clinical and biochemical parameters. MATERIALS AND METHODS: 67 women between 24th - 28th week of pregnancy were enrolled in the study (46 with GDM and 21 as a control group). All women underwent clinical and biochemical examinations. Concentrations of IGF-1, adiponectin, fasting glucose, insulin, lipids, CRP, fibrinogen were measured during pregnancy, additionally IGF-1 concentration was determined 3 months after delivery. RESULTS: IGF-1, glucose, insulin, CRP, fibrinogen, lipids concentrations and HOMA-IR were significantly higher in women with GDM than in the control group (p<0.05). A significant decrease in IGF-1 concentration was observed in both groups after delivery. In the GDM group significant correlations between IGF-1 and BMI (r=0.370, p<0.05), insulin (r=0.469, p<0.01) and HOMA-IR (r=0.439, p<0.01) were observed. Regression analysis with IGF-1 as a dependent parameter showed that only BMI and insulin remained as predictors, explaining 32% of plasma IGF-1 variation. Re-evaluation after delivery revealed impaired glucose tolerance in 9% of the population studied. CONCLUSIONS: Increased IGF-1 concentrations in pregnancy complicated with GDM may partly reflect metabolic disturbances, especially insulin resistance and hyperinsulinemia, and may be one of possible compensatory reactions of the organism in response to these disturbances.

Differential susceptibility in youth: evidence that 5-HTTLPR x positive parenting is associated with positive affect 'for better and worse'.

Positive affect has been implicated in the phenomenological experience of various psychiatric disorders, vulnerability to develop psychopathology and overall socio-emotional functioning. However, developmental influences that may contribute to positive affect have been understudied. Here, we studied youths' 5-HTTLPR genotype and rearing environment (degree of positive and supportive parenting) to investigate the differential susceptibility hypothesis (DSH) that youth carrying short alleles of 5-HTTLPR would be more influenced and responsive to supportive and unsupportive parenting, and would exhibit higher and lower positive affect, respectively. Three independent studies tested this gene-environment interaction (GxE) in children and adolescents (age range 9-15 years; total N=1874). In study 1 (N=307; 54% girls), positive/supportive parenting was assessed via parent report, in study 2 (N=197; 58% girls) via coded observations of parent-child interactions in the laboratory and in study 3 (N=1370; 53% girls) via self report. Results from all the three studies showed that youth homozygous for the functional short allele of 5-HTTLPR were more responsive to parenting as environmental context in a 'for better and worse' manner. Specifically, the genetically susceptible youth (that is, S'S' group) who experienced unsupportive, non-positive parenting exhibited low levels of positive affect, whereas higher levels of positive affect were reported by genetically susceptible youth under supportive and positive parenting conditions. These GxE findings are consistent with the DSH and may inform etiological models and interventions in developmental psychopathology focused on positive emotion, parenting and genetic susceptibility.

Comparison of diagnostic usefulness of predictive models in preliminary differentiation of adnexal masses.

The purpose of this study was to compare prognostic models evaluating the probability of an ovarian cancer occurrence based on a number of clinical and ultrasonographic data in women with adnexal masses. A total of 686 women with adnexal masses underwent the examinations between 1994 and 2002. The recorded parameters included: age, menopausal status, body mass index, the grayscale and Doppler ultrasonographic examination, and selected markers concentration levels. In order to find the best combination of features, which significantly influences the probability of malignancy, stepwise logistic regression analysis, as well as artificial neural network, was used. The diagnostic efficiency of received models was estimated and compared using receiver-operating characteristics (ROC) curve. The results indicate that 431 and 255 patients had a benign and malignant ovarian tumor, respectively. Application of stepwise logistic regression analysis revealed statistically significant importance of eight features. The sensitivity and specificity for the received model were 65.71% and 77.59%, respectively. Three-layer perceptron network shows 13 features as significant predictors of malignancy. The network gave a sensitivity of 85.7% and specificity of 93.1%. Comparison of area under ROC curve for received models was 0.9679 vs 0.9716. Prognostic values of the analyzed neural model are not optimal but seem to surpass logistic regression model in terms of the predictive possibilities.

Survivin antiapoptotic gene expression as a prognostic factor in non-small cell lung cancer: in situ hybridization study.

Survivin is an inhibitor of apoptosis that plays a significant role in cell cycle regulation and is important for survival prognosis in many neoplasms. Survivin expression was assessed by in situ hybridization (ISH) in 60 consecutive patients (54 males and 4 females) with NSCLC treated between 1993 and 1997. The examined patients had IIB and IIIA stage according to TNM system. In all cases the chemotherapy with cisplatin and etoposide (2 cycles) was administered prior the surgery; in patients responding to the therapy one more cycle was applied. Survivin gene overexpression was observed in 35 patients (58.3%). There was no correlation between survivin mRNA level and histological type of tumor, stage of cell differentiation, stage of disease according to TNM classification, performance status according to WHO and number of chemotherapy regimens administered (p > 0.05). However, the correlation between survivin gene expression and response to the chemotherapy was statistically significant (p = 0.04). Statistical analysis showed that median survival in patients with survivin gene overexpression was shorter (14.0 months) as compared to patients with no expression (60.0 months; p = 0.00002). In survival assessment by means of Kaplan-Meier test, 14.3% of five-year survival was achieved in the former group versus 60% in the latter (p = 0.00003). Univariate analysis (log-rank test) showed that significant independent prognostic factors in NSCLC included: stage of the disease according to TNM classification (p = 0.006), response to chemotherapy (p = 0.005) and pattern of survivin gene expression (p = 0.00003). Multivariate analysis utilizing Cox's model showed that for survival assessment the stage according to TNM, response to the chemotherapy and survivin expression estimated by means of ISH are of statistical significance (p=0.00001). The calculated predictive values showed that ISH technique was quite accurate in assessment of five-year survival. Our data show that survivin expression may be used as a prognostic factor and a target for therapy.

Using logistic regression analysis in preliminary differential diagnosis of adnexal masses.

The aim of our study was to generate predictive model, which would allow to estimate the influence of analyzed parameters on predictive accuracy of differential diagnosis of adnexal masses and to evaluate prospectively diagnostic efficacy of the statistic model in the new set of patients. A total of 686 women diagnosed and surgically treated in the Gynecological and Obstetrical Teaching Hospital of University of Medical Sciences in Poznan, Poland, were recruited into the study. Preoperative diagnostics included gynecological examination, ultrasonographic evaluation, tumor Doppler blood flow analysis, and serum levels of CA125 and TPS. In order to find the best combination of features and to calculate the individual probability of the malignancy, stepwise logistic regression analysis with quasi-Newton estimation was applied. The essential part of the best prognostic model, described by foregoing variables, is as follows: [z = -6.005 + 0.058 x age + 1.174 x septa + 1.317 x tumor localization + 1.185 x ascites + 2.28 x solid element + 2.429 x vessels localization -2.386 x PI + 0.084 x MEDV]. The highest sensitivity and specificity for the obtained model were 87.84% and 93.74%, respectively. Prognostic model, constructed with the use of logistic regression analysis, is characterized by higher sensitivity and specificity than individually applied diagnostic tests. Prospective evaluation of this model application in a larger group of patients with adnexal masses will enable precise assessment of its objective clinical usefulness.

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.

[Family labor from the father's point of view]. / Poród rodzinny postrzegany z perspektywy ojca.

Family labor becomes increasingly popular in our country. The aim of the study was answering the question: what the main motive for the men attending to labor was, whether fathers were satisfied of their participation and what the main reason of their satisfaction was. The study was performed in the district and local hospitals in south-eastern Poland during 7 months. 110 fathers were in the study group, 78 (70.9%) of urban population, and 32 (29.1%) of rural. The obtained results indicate firm acceptance of such a way of labor among majority of fathers. It was supported by the fact that almost all of them were satisfied of their participation in labor, and wished to attend the next one. The main reason for inclining them for the participation in labor was the granting of the partners' request, and internal willing. The source of satisfaction from sharing of the labor was providing the safety for the partner and setting up early contact with the baby. Significant influence of the labor schools on the feeling of readiness for delivery and the level of father's satisfaction were not evident.

[Ultrasound fetal biometry and birth weight prognosis with the use of Aoki method and classical regression analysis]. / Zastosowanie modelu predykcyjnego Aoki i klasycznego modelu regresji w ultrasonograficznym i analitycznym przewidywaniu masy urodzeniowej noworodka.

We have attempted to estimate prognostic value of neonatal birth weight prediction with the use of fetal sonographic data: biparietal diameter, femur length, transverse and longitudinal abdominal diameter. Clinical and ultrasound data from 265 pregnant women with singleton gestation who delivered within 7 days from the last ultrasound scan were analyzed. For the fetal weight estimation we have calculated fetal abdominal area in the equation proposed by Aoki in 1990. Predicted and observed neonatal birth weight centiles and coefficients of determination were calculated with the use of regression analysis. Prediction method of neonatal weight with Aoki method explained 70% of variability in our population. In contrast, regression analysis on ultrasound data explained 99% of observer variability in neonatal birth weight. We conclude that own method of birth weight prediction could be of value, however it should be tested in a new prospectively examined population.

[Changes in carbohydrate metabolism of PCOS patients in cycle stimulated by rFSH]. / Zmiany gospodarki weglowodanowej u pacjentek z PCOS w cyklu stymulowanym rFSH.

UNLABELLED: 24 patients with clomiphene citrate-resistant PCOS were enrolled in the study. We used low-dose step up protocol of recombinant FSH administration. Ovulation induction by rFSH injection was commenced on 3 day of cycle, at a dose of 50 IU for 7 days initially. The dose was continued at 50 IU, and ultrasonographic scans were performed daily until a dominant follicle had developed to a size of at least 18-20 mm, at which point 5,000 IU of hCG was administrated. If no response was noted after 7 days, the dose was increased by 50 IU for a further 7 days. Insulin and glucose serum levels were determined 7 times: in days 3, 5, 8 of a cycle and later when diameter of ovarian follicle was 10, 12, 16 mm and in the day of hCG injection. Estradiol serum level was determined in 8 day of cycle and when diameter of ovarian follicle was 10, 12, 16 mm and in the day of hCG injection. BMI and WHR was determined in the day of admission to hospital. RESULTS: The correlation between mean insulin level in the examined cycle and BMI and as well as the correlation between mean insulin level and WHR were determined. Mean level of serum glucose increased as the level of estradiol raised. No influence of growth level on insulin level was detected.

[Men's acceptance of continuous hormone therapy]. / Akceptacja ciaglej terapii hormonalnej wsród mezczyzn.

The aim of the study was the assessment of males' willingness to long-term administration of hormonal drugs in substitutive and contraceptive means. Eighty males in their third and fifth decade were inquired a questionnaire. The patients were divided according to age into two groups: A (20-30 yrs of age) 55 males, and B (41-50 yrs of age) 25 males. University education was a condition required to be enrolled into the study. The results was statistically analyzed with Chi 2 test. 65.5% of males in their third decade would not accept hormonal contraception. 40% of males declared their acceptance for hormonal substitutive therapy and they were also aware of the necessity of prophylactic examinations, 7.3% accepted the therapy but without regular follow-ups, 16.3% did not accept the therapy and 36.4% did not consider it as necessary. 56% of the respondents from group B would accept an administration of contraceptive pill. 44% would not accept hormonal substitutive therapy, 24% did not see the necessity of the therapy, 16% would accept the therapy and the necessity of regular prophylaxis, and the last 16% would accept the therapy, however without control examining.

Relationships between Pregnancy and Vitamin B-6 Nutriture on Brain 3-Hydroxykynurenine Concentrations in Mice.

The kynurenine (KYN) pathway of tryptophan metabolism produces several neuroactive metabolites, including 3-hydroxykynurenine (3HK). The pathway is subject to regulation by a number of effectors including pregnancy and availability of vitamin B-6. Vitamin B-6 depleted humans and animals excrete abnormally high concentrations of KYN metabolites in urine. In pregnancy, vitamin B-6 deficiency is commonly seen, and tryptophan metabolism is often found to be altered. We measured concentrations of 3HK in brains of DBA/2Ibg and A/Ibg mice as functions of pregnancy and dietary level of vitamin B-6. Pregnant DBA mice are more susceptible to flurothyl-induced seizures than controls, pregnant A mice are not. Significant elevations of 3HK were found in brains of pregnant mice, and the increases were greater in the pregnancy-associated seizure prone DBA, than in the A mice. In the A mice, brain 3HK concentrations were negatively correlated with dietary vitamin B-6 levels, as expected; however, in the DBA mice these correlations were positive, indicating an unusual response to vitamin B-6 restriction. The accumulation of a cytotoxic, excitatory metabolite, 3HK, in brain may contribute to the increased seizure susceptibility of susceptible pregnant mice, perhaps though its effects as an endogenous modulator of excitatory amino acid receptor systems.

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.

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.

Aminotransferase activities in mouse, Mus domesticus, erythrocytes separated according to age.

Erythrocyte aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities are often used as indices of vitamin B-6 nutritional status; however, results using a mixed population of erythrocytes can be quite variable. Erythrocytes from two strains of mice (Mus domesticus), A/Ibg and DBA/Ibg, were separated according to age by centrifugation through discontinuous Percoll density gradients into three fractions: top (least dense, youngest), middle and bottom (most dense, oldest). A sufficient yield of age-fractionated erythrocytes was obtained from a single mouse for all of the enzyme measurements. The activities of AST, ALT and three age-marker enzymes, pyruvate kinase, acetylcholinesterase and hexokinase, were found to be significantly higher in the youngest cell fractions, and declined in the older, more dense fractions. A mice had significantly lower AST and ALT activities in the age separated fractions than did DBA mice. The measurement of enzyme activities in low density, young cells may be especially useful in studies involving conditions in which the proportion of young erythrocytes may be elevated with respect to the entire erythrocyte mass.