Involvement of pp60c-src with two major signaling pathways in human breast cancer.

The phosphotyrosine residues of receptor tyrosine kinases serve as unique binding sites for proteins involved in intracellular signaling, which contain SRC homology 2 (SH2) domains. Since overexpression or activation of the pp60c-src kinase has been reported in a number of human tumors, including primary human breast carcinomas, we examined the interactions of the SH2 and SH3 domains of human SRC with target proteins in human carcinoma cell lines. Glutathione S-transferase fusion proteins containing either the SH2, SH3, or the entire SH3/SH2 region of human SRC were used to affinity purify tyrosine-phosphorylated proteins from human breast carcinoma cell lines. We show here that in human breast carcinoma cell lines, the SRC SH2 domain binds to activated epidermal growth factor receptor (EGFR) and p185HER2/neu. SRC SH2 binding to EGFR was also observed in a nontumorigenic cell line after hormone stimulation. Endogenous pp60c-src was found to tightly associate with tyrosine-phosphorylated EGFR. Association of the SRC SH2 with the EGFR was blocked by tyrosyl phosphopeptides containing the sequences surrounding tyrosine-530, the regulatory site in the SRC C terminus, or sequences surrounding the major sites of autophosphorylation in the EGFR. These results raise the possibility that association of pp60c-src with these receptor tyrosine kinases is an integral part of the signaling events mediated by these receptors and may contribute to malignant transformation.     

Cluster of iniencephaly in Miami

This report details a cluster of 5 cases of iniencephaly with anencephaly and rachischisis occurring over a 4-month period at Jackson Memorial Hospital/University of Miami Medical Center in Miami, Florida. All 5 cases of this rare, lethal, congenital malformation seen in the cluster included diaphragmatic defects with accompanying hernia, omphalocele, small adrenals, renal dysmaturity, gastrointestinal malformations, cleft lip and palate, and hypoplastic lungs. No single causative agent for this cluster was identified. A brief review of the literature regarding categorization of these malformations and as a discussion of the embryological basis for these lesions and possible etiologic factors are included.     

Cholecystokinin suppresses food intake in cats: structure-activity characterization

Our experimental models in this study were cats fitted with gastric fistulae. Intravenous infusion of sulfated CCK 8 and nonsulfated Boc CCK 7 inhibited both sham-feeding and feeding in fasted cats. The threshold dose (1.2 pmol/kg.hr) required for inhibition of sham-feeding was identical to that required to inhibit feeding in the same animals. However, the gastric secretory studies indicated that this dose was 90 times lower than the threshold dose stimulating gastric acid secretion (109 pmol/kg.hr). In nonfasted animals, sulfated CCK 8 and nonsulfated Boc CCK 7 (219 and 875 pmol/kg.hr) are both capable of decreasing the food intake at different intervals following the infusion with no significant effect on daily food intake. Our findings clearly show that there is no difference in the sensitivity of CCK's ability to inhibit sham-feeding and feeding, suggesting that CCK's suppressive effect on food intake does not solely involve gastric distension mechanisms. In contrast to gastric acid secretion, the sulfate group is not a "restrictive" factor for peripherally-induced CCK satiety.     

Coexpression of class I major histocompatibility antigen and viral RNA in central nervous system of mice infected with Theiler's virus: a model for multiple sclerosis.

Chronic infection of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in central nervous system (CNS) demyelination similar to multiple sclerosis. Demyelination induced by TMEV is mediated, in part, by class I-restricted CD8+ T lymphocytes. For these T cells to function, they must recognize virus-infected CNS targets in the presence of class I major histocompatibility complex (MHC) antigen. Therefore, we studied in vivo expression of class I MHC antigen and viral antigen-RNA in prototypic mouse strains that are susceptible (SJL/J) or resistant (C57BL/10SNJ) to TMEV-induced demyelination. In brains of resistant mice, viral antigen-RNA expression peaked on day 3 after infection and was effectively diminished by day 5 such that few virus-infected cells were ever detected in the spinal cord. In contrast, susceptible mice demonstrated delay in clearance of TMEV from the brain and a subsequent increase and persistence of viral antigen-RNA in the spinal cord for as long as 277 days. Viral infection resulted in "upregulation" of class I MHC expression in the CNS. Class I MHC antigens were expressed as early as 1 day after infection in the choroid plexus of both strains of mice before detection of viral antigen or inflammation. In resistant mice, class I MHC expression predominated in the gray matter of the brain and spinal cord on day 7 after infection but returned to undetectable levels by day 28. In susceptible mice, class I MHC expression in the CNS persisted and was intense in the white matter of the spinal cord throughout chronic infection and demyelination. No class I MHC expression was detected in the CNS of uninfected mice. Coexpression of viral RNA and class I MHC antigen was demonstrated in CNS cells by using simultaneous in situ hybridization and immunoperoxidase technique. These results support the hypothesis that a class I-restricted immune response directed against virus-infected cells may be important in the mechanism of demyelination.     

Validation of computerized three-dimensional reconstruction of intravascular ultrasound: measurements of absolute luminal diameter and cross-sectional area in ex vivo human coronary arteries

Computer based 3-dimensional reconstruction transforms 2-dimensional intravascular ultrasound images into a longitudinal format facilitating analysis of luminal narrowing. To validate the accuracy of current software in measuring coronary artery diameter and cross-sectional area, in arteries with atherosclerosis, we performed 3-dimensional reconstruction in 10 human pathologic coronary arterial segments of 10-25mm length. Images were obtained using a 4.8 French catheter with pullback speed of 1mm/sec acquired at 3 frames/sec onto VHS tape. The data were digitized and intraluminal 3-dimensional reconstruction performed using a voxel-based program. Pathologic sections were obtained every 3mm, and dimensions were measured with a resolution of 0.01 mm. Maximum, minimum, and 3 other representative diameters were recorded by an observer blinded to the ultrasound diameters. Average histo-pathologic diameters were reported, and specimen cross-sectional area was then calculated. Results: In 53 sections, pathological diameters ranged from 1.4-4.5mm (mean 2.7 +/- 0.68mm) while 3-dimensional reconstructed diameters were 1.9 to 3.8mm (mean 2.6 +/- 0.54mm). Pathologic and ultrasound derived 3-dimensional reconstruction diameters had an excellent correlation (r=0.86, SEE=+/-0.36). Pathology and 3-dimensional reconstruction cross-sectional area also correlated closely (r=0.88, SEE=+/-1.50). Diameters less than 2.0mm were systematically overestimated and diameters greater than 3.5mm underestimated by 3-dimensional reconstruction. Most 3 dimensional reconstruction values were within +/- 10% of pathology, but diverged at each diameter extreme, approaching +/- 20%. Thus, computerized 3-dimensional reconstruction of ultrasound images shows excellent quantification of luminal size in the 2.0-3.5mm range, suggesting important investigative and clinical applications.     

The societal and organizational contexts of culturally sensitive mental health services: findings from an evaluation of bilingual/bicultural psychiatric programs

The Hispanic mental health literature focuses mostly on cultural and clinical issues. This paper argues that researchers and practitioners concerned with mental health services for Hispanics and other minority groups need to pay more attention to the societal and organizational contexts that facilitate or impede the development of effective culturally sensitive psychiatric programs. Utilizing data from an evaluation of three New York psychiatric programs for seriously mentally ill (SMI) Hispanic patients, the paper discusses societal and organizational factors that influenced the programs' development. Among societal forces were the significance of Hispanics as a voting bloc, the political organization of Hispanic mental health professionals, the philosophy of ethnic assimilation in American society, prevailing views about the place of cultural knowledge in psychiatric treatment, and fiscal crises, and the shortage of Hispanic mental health professionals. Among organizational factors, hospital administrative support and program leadership mediated the effects of societal forces upon the programs, while ethnic competition and lack of coordination between the program and other organizational units acted as barriers to the programs' development. The findings are relevant to any innovative mental health service in an organizational setting.     

Multiple sclerosis: basic concepts and hypothesis

Multiple sclerosis, an inflammatory disease of the central nervous system, is characterized by primary destruction of myelin. This review covers recent advances in neuropathology, immunogenetics, neuroimmunology, and neurovirology that have provided insights regarding its pathogenesis. Three hypotheses are discussed: (1) autoimmunity, (2) "bystander" demyelination, and (3) immune destruction of persistently infected oligodendrocytes. A paradigm for induction of primary demyelination is proposed in which immune cells recognize "foreign" antigens on the surface of oligodendrocytes in the context of major histocompatibility complex gene products. The final result of this scheme may be "dying-back gliopathy," the alteration being noted first in the most distal extension of the oligodendrocyte--that is, the myelin sheaths.     

Therapeutic criteria in hydrocephalic children

The xanthine, hypoxanthine, and total oxypurine levels were determined in the CSF of 28 hydrocephalic patients (age from newborn to 2 years) and 8 healthy controls using HPLC. The Evans' index, the mean weekly increase in cranial circumference, and the intracranial pressure were also measured. Of the hydrocephalic patients 13 were self-compensated and the other 15 had a shunt implanted during the course of the study. The mean xanthine, hypoxanthine, and total oxypurine levels in the normal children were 5.20, 5.94, and 11.29 mol/l, respectively. In the self-compensated hydrocephalics these levels were 5.17, 5.71, and 10.79 mol/l, respectively. In the noncompensated hydrocephalics, they were 9.90, 9.91, and 19.82 mol/l. The differences between the latter group and the first two are statistically significant (P<0.001). The mean Evans' index and the mean weakly increase in cranial circumference in the self-compensated hydrocephalics were 0.35 and 0.25 cm, respectively. In the noncompensated hydrocephalics, they were 0.55 and 0.95 cm. The differences between the two groups are statistically significant (P<0.001). Two weeks after implantation of shunts in the noncompensated cases, the mean xanthine, hypoxanthine, and total oxypurine levels fell to 4.22, 4.57, and 8.80 mol/l, respectively. These changes are statistically significant (P<0.001). We think that the two criteria (clinical and biochemical) are equally useful for the prediction of self-compensation in hydrocephalic children and that the oxypurine values after shunt implantation can be used to monitor progress in noncompensated cases.