Linkage analysis of anorexia and bulimia nervosa cohorts using selected behavioral phenotypes as quantitative traits or covariates.

To increase the likelihood of finding genetic variation conferring liability to eating disorders, we measured over 100 attributes thought to be related to liability to eating disorders on affected individuals from multiplex families and two cohorts: one recruited through a proband with anorexia nervosa (AN; AN cohort); the other recruited through a proband with bulimia nervosa (BN; BN cohort). By a multilayer decision process based on expert evaluation and statistical analysis, six traits were selected for linkage analysis (1): obsessionality (OBS), age at menarche (MENAR), and anxiety (ANX) for quantitative trait locus (QTL) linkage analysis; and lifetime minimum body mass index (BMI), concern over mistakes (CM), and food-related obsessions (OBF) for covariate-based linkage analysis. The BN cohort produced the largest linkage signals: for QTL linkage analysis, four suggestive signals: (for MENAR, at 10p13; for ANX, at 1q31.1, 4q35.2, and 8q13.1); for covariate-based linkage analyses, both significant and suggestive linkages (for BMI, one significant [4q21.1] and three suggestive [3p23, 10p13, 5p15.3]; for CM, two significant [16p13.3, 14q21.1] and three suggestive [4p15.33, 8q11.23, 10p11.21]; and for OBF, one significant [14q21.1] and five suggestive [4p16.1, 10p13.1, 8q11.23, 16p13.3, 18p11.31]). Results from the AN cohort were far less compelling: for QTL linkage analysis, two suggestive signals (for OBS at 6q21 and for ANX at 9p21.3); for covariate-based linkage analysis, five suggestive signals (for BMI at 4q13.1, for CM at 11p11.2 and 17q25.1, and for OBF at 17q25.1 and 15q26.2). Overlap between the two cohorts was minimal for substantial linkage signals.     

Thioether analogues of baclofen, phaclofen and saclofen

Analogues of baclofen, phaclofen and saclofen, incorporating a sulfur atom within the methylene chain, have been tested against responses induced by baclofen for activity at gamma-aminobutyric acid-B (GABAB) receptor sites, using a number of preparations including the guinea-pig isolated ileum and vas deferens, rat brain cortical slices and displacement of (-)-[3H]baclofen in rat cerebellar membranes. Results indicate that 2-([2-amino-1-(4-chlorophenyl)ethyl]thio)ethanephosphonic acid 2d is the most active of the new compounds. 2d is some 2-5 times weaker than phaclofen as a GABAB antagonist and approximately half as potent as phaclofen as an inhibitor of GABAB binding.     

Evaluation of a one-year Masters of Public Health program for medical students between their third and fourth years.

For physicians to better treat and advise their patients on the roles of behavioral and social factors in health and disease, greater levels of competency in social and behavioral sciences are needed. Physicians should also understand the structure, financing, and administration of the health care delivery system, so that they will be able to practice medicine effectively and participate in planning and managing the delivery of care. And, improving overall public health requires that physicians understand the basic tenets of population-based medicine. One way to achieve these goals is to develop education and training programs for integrating formal public health training with formal medical training.There are many models by which a medical student or practitioner can obtain a master of public health (MPH) degree. In this article, the authors describe an accelerated one-year MPH program for competitively selected New York City medical students who have completed their third year of training and enroll at the Mailman School of Public Health, Columbia University. The Macy Scholars Program, offered between 1999 and 2007 to 12 students per year, is completed between the third and fourth years of medical school. Under full-tuition scholarships, students complete a practicum experience, attend seminars, and write a master-level paper or thesis, among other requirements. Data from an evaluation of this program demonstrate participant satisfaction and support of the program, outstanding academic performance, and the effect of public health training on their residency and career choices.     

EGFR gene amplification in breast cancer: correlation with epidermal growth factor receptor mRNA and protein expression and HER-2 status and absence of EGFR-activating mutations.

The human epidermal growth factor receptor (HER) family of receptor tyrosine kinase has been extensively studied in breast cancer; however, systematic studies of EGFR gene amplification and protein overexpression in breast carcinoma are lacking. We studied EGFR gene amplification by chromogenic in situ hybridization (CISH) and protein expression by immunohistochemistry in 175 breast carcinomas, using tissue microarrays. Tumors with >5 EGFR gene copies per nucleus were interpreted as positive for gene amplification. Protein overexpression was scored according to standardized criteria originally developed for HER-2. EGFR mRNA levels, as measured by Affymetrix U133 Gene Chip microarray hybridization, were available in 63 of these tumors. HER-2 gene amplification by fluorescence in situ hybridization (FISH) and protein overexpression by immunohistochemistry were also studied. EGFR gene amplification (copy number range: 7-18; median: 12) was detected in 11/175 (6%) tumors, and protein overexpression was found in 13/175 (7%) tumors. Of the 11 tumors, 10 (91%) with gene amplification also showed EGFR protein overexpression (2+ or 3+ by immunohistochemistry). The EGFR mRNA level, based on Affymetrix U133 chip hybridization data, was increased relative to other breast cancer samples in three of the five tumors showing gene amplification. Exons 19 and 21 of EGFR, the sites of hotspot mutations in lung adenocarcinomas, were screened in the 11 EGFR-amplified tumors but no mutations were found. Three of these 11 tumors also showed HER-2 overexpression and gene amplification. Approximately 6% of breast carcinomas show EGFR amplification with EGFR protein overexpression and may be candidates for trials of EGFR-targeted antibodies or small inhibitory molecules.     

Interleukin-15 is not required for the induction or maintenance of orally induced peripheral tolerance

Orally induced tolerance is a physiologically relevant form of peripheral tolerance, which is believed to be important for the prevention of pathological immune responses in the gut. Of several mechanisms proposed to mediate oral tolerance, one that has received much attention recently is the concept of regulatory CD4+ T cells. As recent studies have suggested that interleukin (IL)-15 may be important for the differentiation and maintenance of regulatory CD4+ T cells, we have examined the role of IL-15 in oral tolerance, using a soluble form of the IL-15 receptor (sIL-15R) which blocks the biological effects of IL-15 in vivo. Oral tolerance induced by feeding mice ovalbumin (OVA) in a low-dose regimen believed to induce regulatory T cell activity was not affected by the administration of sIL-15R during either the induction or maintenance phase of tolerance. Thus, oral tolerance does not involve an IL-15-dependent mechanism.     

The effect of noradrenaline on the toad skin potential

1. The electrical response of isolated toad skins to the presence of 4 x 10(-5)M noradrenaline in the inner medium has been studied.2. When skins were bathed in Ringer solution, noradrenaline initiated a partial depolarization of the skin potential (inside surface becoming less positive) followed by a hyperpolarization; however, noradrenaline depolarized skins in sulphate Ringer.3. The origin of the hyperpolarizing phase of the response to noradrenaline was studied by comparing the size of perturbations in the skin potential, produced by identical changes in external sodium, external chloride or internal potassium concentrations, before and during the response to noradrenaline.4. Measurements of skin conductance were made in different sulphate media in order to estimate the magnitudes of the conductance of the shunt pathway through the skin and the conductance of the pathway for actively transported sodium ions.5. Interpretation of both the variations in the perturbations of skin potential and the skin conductance measurements led to the conclusion that the hyperpolarizing phase of the response to noradrenaline was generated by an increase in the sodium to chloride permeability ratio for the outer barrier. It was considered that other evidence was compatible with this view.6. Similar experimental methods were employed to study the action of antidiuretic hormone (ADH) and an elevated external concentration of calcium on the outer barrier. It was found that ADH increased the sodium to chloride permeability ratio whereas calcium decreased it. The separate actions of ADH and calcium on the sodium permeability of the outer barrier did not interfere apparently with the subsequent ability of noradrenaline to increase the sodium to chloride permeability ratio for this barrier in the skin.