Genetic analyses in consecutive israeli jewish colorectal cancer patients

OBJECTIVES: Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse. AIMS: To assess the contribution of E1317Q to CRC development in the Jewish population. METHODS: A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined. RESULTS: The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation. CONCLUSION: In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.     

Transitional implants in a patient with Williams-Beuren syndrome: a four-year follow-up

Williams-Beuren syndrome (WBS) is characterized by several diagnostic features, including oligodontia. Restoration of congenitally missing teeth in patients with WBS is a challenge, both emotionally and clinically. In the atrophied alveolar bone process of a juvenile patient with WBS, the maxillary lateral incisors were replaced with two Immediate Provisional Implants (IPI). Early implant loading was used with temporary acrylic resin crowns that were replaced by semi-permanent restorations; the case has been followed for four years. Restoration of the missing maxillary lateral incisors with IPIs and temporary crowns proved to be a convenient, long-lasting and psychologically acceptable solution to the patient and her family.     

Olfactory learning prevents MK-801-induced psychosis-like behaviour in an animal model of schizophrenia.

There is mounting evidence to support the concept that education is associated with the formation of a functional reserve in the brain, a process that appears to provide some protection against certain aspects of severe central nervous system disorders. The goal of this study was to examine whether learning prevents psychosis-like behaviour in an animal model of schizophrenia. A series of behavioural tasks were used to assess olfactory learning-induced protection against the effects of NMDA channel blocker, MK801. This blocker caused sensory-motor disturbances, spatial learning acquisition deficit, and swimming strategy alterations in pseudo-trained and naive rats, but had a considerably lesser effect on trained rats. In sharp contrast, olfactory learning provided no protection against d-amphetamine application. Our data support the notion that learning-induced protection against schizophrenic behaviour is maintained by non-NMDA-mediated enhanced activation of local connections in the relevant cortical networks.     

The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis

Arginine is catabolized by NOS2 and other nitric oxide synthases to form nitric oxide. We evaluated the roles of dietary arginine and Nos2 in Apc-dependent intestinal tumorigenesis in Min mice with and without a functional Nos2 gene. NOS2 protein was expressed only in intestinal tissues of Apc(Min/+) Nos2+/+ mice. NOS3 expression was higher in intestinal tissues of mice lacking Nos2, mainly in the small intestine. When diet was supplemented with arginine (0.2% and 2% in drinking water), lack of Nos2 results in decreased tumorigenesis in both small intestine and colon. In Nos2 knockout mice, supplemental arginine (up to 2%) caused a decrease in small intestinal tumor number and size. The arginine-dependent decrease was associated with an increase in nitrotyrosine formation and apoptosis in the region of intestinal stem cells. Mice expressing Nos2 did not show these changes. These mice did, however, show an arginine-dependent increase in colon tumor number and incidence, while no effect on apoptosis was seen. These changes were associated with increased nitrotyrosine formation in epithelial cells. Mice lacking Nos2 did not show changes in tumorigenesis or nitrotyrosine formation, while demonstrating an arginine-dependent increase in apoptosis. These data suggest that Nos2 and dietary arginine have significant effects on intestinal and colonic tumorigenesis in Min mice. In both tissues, loss of Nos2 is associated with decreased tumorigenesis when mice are supplemented with dietary arginine. In the small intestine, Nos2 prevents the arginine-induced decrease in tumor number and size, which is associated with NOS3 expression and increased apoptosis. In the colon, Nos2 is required for the arginine-induced increase in tumor number and incidence.     

Modulation of dopamine transmission by 5HT2C and 5HT3 receptors: a role in the antidepressant response

Dopaminergic mesolimbic and mesocortical systems are fundamental in hedonia and motivation. Therefore their regulation should be central in understanding depression treatment. This review highlights the dopaminergic activity in relation to depressive behavior and suggests two putative receptors as potential targets for research and development of future antidepressants. In this article we review data that describe the role of serotonin in regulating dopamine release, via 5HT2C and 5HT3 receptors. This action of serotonin appears to be linked to depressive-like behavior and to onset of behavioral effects of antidepressants in an animal model of depression. We suggest that drugs or strategies that decrease 5HT2C and increase 5HT3 receptor-mediated dopamine release in the limbic areas of the brain may provide a fast onset of therapeutic effect. Clinical and basic research data supporting this hypothesis are discussed.     

A cellular correlate of learning-induced metaplasticity in the hippocampus

Metaplasticity, the plasticity of synaptic plasticity, is thought to have a pivotal role in activity-dependent modulation of synaptic connectivity, which underlies learning and memory. Metaplasticity is usually attributed to modifications in glutamate receptor-mediated synaptic transmission. However, experimental evidence and theoretical considerations suggest that learning reduces the predisposition for further synaptic strengthening, while behavioral studies show that learning capability is enhanced by prior learning. Here we show that enhanced neuronal excitability in CA1 pyramidal neurons, but not enhanced synaptic transmission, occurs prior to rule learning of an olfactory discrimination task. This transient enhancement lasts for 1 day after rule learning, is apparent throughout the cell population and results from reduction in the medium and slow after-hyperpolarizations that control spike frequency adaptation. Such olfactory learning-induced increased excitability in hippocampal neurons enhances the rats' learning capability in another hippocampus-dependent task, the Morris water maze. Once olfactory discrimination rule learning is acquired, its maintenance is not dependent on the reduced post-burst AHP in hippocampal neurons. However, the enhanced spatial learning capability of olfactory-trained rats in the water maze is diminished once the post burst AHP in CA1 pyramidal cells resumes its initial value. We suggest that enhanced excitability of CA1 neurons may serve as a mechanism for generalized enhancement of hippocampus-dependent learning capability. In the presence of such enhanced neuronal excitability, the hippocampal network enters into a 'learning mode' in which a variety of hippocampus-dependent skills are acquired rapidly and efficiently.     

Recto-vaginal/urethral fistula: repair with gracilis muscle transposition

This study was designed to assess the efficacy of gracilis muscle transposition in repairing recto-vaginal and rectourethral fistula. All patients had fecal diversion as a preliminary or concurrent step to fistula repair. Success was defined as healed fistula after stoma closure. Results: Six females and four males underwent gracilis muscle transposition from 1999 to 2006. Gracilis muscle transposition is a viable option for repairing fistulas between the urethra, vagina and the rectum, especially after failed perineal or trans-anal repair. It is associated with low morbidity and good success rate. Underlying Crohn's disease and previous radiation are associated with poor prognosis.