The circadian Per1 and Per2 genes influence alcohol intake, reinforcement, and blood alcohol levels.

BACKGROUND: Perturbations in the function of core circadian clock components such as the Period (Per) family of genes are associated with alcohol use disorder, and disruptions in circadian cycles may contribute to alcohol abuse and relapse. This study tested ethanol consumption, reinforcement, and metabolism in mice containing functional mutations in Per1 and/or Per2 genes on an ethanol-preferring background, C57BL/6J mice. METHODS: Mice were tested in: (A) free-access intake with ascending concentrations of ethanol (2-16%, v/v), (B) conditioned place preference using ethanol (2g/kg for males; 2.5g/kg for females) vs. saline injections, (C) recovery of the righting reflex following a 4g/kg bolus of ethanol, and (D) blood ethanol levels 1h after a 2g/kg bolus of ethanol. RESULTS: All Per mutant (mPer) mice showed increased ethanol intake and condition place preference compared to controls. There were also genotypic differences in blood ethanol concentration: in males, only mPer1 mice showed a significantly higher blood ethanol concentration than WT mice, but in females, all mPer mice showed higher blood ethanol levels than WT mice. CONCLUSIONS: Mutation of either Per1 or Per2, as well as mutations of both genes, increases ethanol intake and reinforcement in an ethanol-preferring mouse model. In addition, this increase in ethanol seeking behavior seems to result both from a change in ethanol metabolism and a change in reward responding to ethanol, but not from any change in sensitivity to ethanol's sedating effects.

Meiotic origin of trisomy in neoplasms: evidence in a case of erythroleukaemia.

Trisomic cells in neoplasms may represent abnormal clones originated from a tissue-confined mosaicism, and arise therefore by a meiotic error. We report on a 16-month-old child with erythroleukaemia (AML-M6), whose marrow karyotype at onset was 48,XX,del(13)(q12q14),del(14)(q22q32),+21,+21. The parental origin of the supernumerary chromosomes 21 was investigated by comparing 10 polymorphic loci scattered along the whole chromosome on the patient's marrow and her parents' leukocytes. Three loci were informative for the presence of three alleles, two of which were of maternal origin; two further loci showed a maternal allele of higher intensity. Lymphocytes and skin fibroblasts showed a normal karyotype, and molecular analysis on leukocytes at remission, buccal smear and urinary sediment cells consistently showed only one maternal allele, whereas neonatal blood from Guthrie spot showed two maternal alleles as in the marrow. An accurate clinical re-evaluation confirmed a normal phenotype. Our results indicate that tetrasomy 21 arose from a marrow clone with trisomy 21 of meiotic origin. To the best of our knowledge, this is the first evidence that supernumerary chromosomes in neoplastic clones may in fact be present due to a meiotic error. This demonstrates that a tissue-confined constitutional mosaicism for a trisomy may indeed represent the first event in multistep carcinogenesis.

Familial partial monosomy 7 and myelodysplasia: different parental origin of the monosomy 7 suggests action of a mutator gene.

Two sisters are reported, both with a myelodysplastic syndrome (MDS) associated with partial monosomy 7. A trisomy 8 was also present in one of them, who later developed an acute myeloid leukemia (AML) of the M0 FAB-type and died, whereas the other died with no evolution into AML. Besides FISH studies, microsatellite analysis was performed on both sisters to gather information on the parental origin of the chromosome 7 involved in partial monosomy and of the extra chromosome 8. The chromosomes 7 involved were of different parental origin in the two sisters, thus confirming that familial monosomy 7 is not explained by a germ-line mutation of a putative tumor-suppressor gene. Similar results were obtained in two other families out of the 12 reported in the literature. Noteworthy is the association with a mendelian disease in 3 out of 12 monosomy 7 families, which suggest that a mutator gene, capable of inducing both karyotype instability and a mendelian disorder, might act to induce chromosome 7 anomalies in the marrow. We postulate that, in fact, an inherited mutation in any of a group of mutator genes causes familial monosomy 7 also in the absence of a recognized mendelian disease, and that marrow chromosome 7 anomalies, in turn, lead to MDS/AML.

Isochromosome (7)(q10) in Shwachman syndrome without MDS/AML and role of chromosome 7 anomalies in myeloproliferative disorders.

Shwachman syndrome (SS) is an autosomal recessive disorder in which bone marrow dysfunction is observed, with development of myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML) in up to one third of the cases. Inconclusive data are available as to increased chromosome breakage in SS, while chromosome 7 anomalies, and often an isochromosome (7)(q10), are frequent in cases with MDS/AML. We report on the consistent presence of an i(7)(q10) in the bone marrow and blood lymphocytes in one of two sisters affected with SS without any clinical or cytological signs of MDS/AML. Thus, this patient was either a case of constitutional mosaicism for the i(7)(q10), or this had to be acquired in a nondysplastic and non-neoplastic marrow clone. DNA polymorphism analysis demonstrated the paternal origin of the i(7q). We postulate that the SS mutation acts as a mutator gene, and causes karyotype instability; abnormal clones would thus arise in the marrow, and chromosome 7 anomalies, i(7q) in particular, will in turn lead to MDS/AML. If this interpretation is correct, it would be also an indication to consider chromosome 7 anomalies in general, out of SS, as primary changes in MDS/AML pathogenesis.

Perceptual-motor, visual and cognitive ability in very low birthweight preschool children without neonatal ultrasound abnormalities.

Thirty-six children born preterm with very low birth weight without neonatal brain disorders and normal cerebral ultrasound findings were examined at pre-school age: visual, perceptual motor, attention, behaviour and cognitive assessments were performed in the study group as well as in a control group of term children matched for age, sex and parental educational and occupational status. The results showed a significant lower scoring in perceptual motor skills in the study group, associated with a defect of accuracy in spatial attention and a higher incidence of stereopsis impairment related with perceptual motor disabilities. Behavioural disorders, in terms of emotional maturation and hyperactivity, were significantly more frequent in the study group. To prevent behavioural and learning problems at school, a complete longitudinal assessment including visual functions and perceptual motor abilities seems mandatory in preterm born children, even in the absence of neonatal brain disorders including abnormal cerebral ultrasound findings.

Noninvasive evaluation of asymptomatic athletes with cardiac murmur.

The increasing number of amateur sportsmen enhances the need for a correct evaluation of subjects suspected of overt and mild cardiac disease. Out of 4000 athletes, 72 subjects were clinically preselected by the sport doctor during an annual routine examination. They were studied with mono and 2D echo, pulsed color (PW) and continuous wave Doppler. Five asymptomatic patients are reported with congenital or acquired valvular diseases.

Smoking habits and sporting activity among adolescents in north Italy.

A cross-sectional survey of the smoking habits of 330 17-19 year-old males practising physical activity as members of sports teams, and of 366 male students in the same age range was carried out in Brescia, North Italy. A total of 23.3% of the athletes and 30.9% of the students smoked at least one cigarette a week (chi 2 = 4.60, p less than 0.05), and 17.3% and 19.7% smoked at least one cigarette a day, respectively (chi 2 = 0.51; p greater than 0.05). The smoking athletes had on average 50.3 cigarettes/week and students 47.0 (t-test: 0.46; p greater than 0.05). No difference was found with respect to age at their first experience with smoking, while athletes began to smoke regularly before than students, proportionally (chi 2 for linear trend: 5.29, p less than 0.05). Sporting activity was negatively associated with current smoking by multiple logistic regression: the odds ratio of current smoking for athletes with respect to students was 0.5 (95% CI: 0.4-0.8). Among a set of social, environmental and behavioural variables, best friend's and girlfriend's smoking was the one most strongly associated with current smoking in both groups.