Enhanced intestinal adenomatous polyp formation in Pms2-/-;Min mice

Analysis of two human familial cancer syndromes, hereditary nonpolyposis colorectal cancer and familial adenomatous polyposis, indicates that mutations in either one of four DNA mismatch repair gene homologues or the adenomatous polyposis coli (APC) gene, respectively, are important for the development of colorectal cancer. To further investigate the role of DNA mismatch repair in intestinal tumorigenesis, we generated mice with mutations in both Apc and the DNA mismatch repair gene, Pms2. Whereas Pms2-deficient mice do not develop intestinal tumors, mice deficient in Pms2 and heterozygous for Min, an allele of Apc, develop approximately three times the number of small intestinal adenomas and four times the number of colon adenomas relative to Min and Pms2+/-;Min mice. Although Pms2 deficiency clearly increases adenoma formation in the Min background, histological analysis indicated no clear evidence for progression to carcinoma.     

A phorbol ester binding domain of protein kinase C gamma. High affinity binding to a glutathione-S-transferase/Cys2 fusion protein

Cysteine-rich regions of protein kinase C (PKC) are implicated in diacylglycerol-dependent regulation of kinase activity. The second cysteine-rich region (residues 92-173) of PKC gamma was expressed as a fusion protein with glutathione-S-transferase in Escherichia coli and purified to homogeneity by affinity chromatography. This fusion protein displayed high affinity phorbol dibutyrate (PDBu) binding (Kd 23 nM). The phosphatidylserine dependence of PDBu binding was highly cooperative with Hill numbers (near 4.5) similar to those previously reported for PKC gamma (Burns, D. J., and Bell, R. M. (1991) J. Biol. Chem. 266, 18330-18338). The fusion protein specifically bound 4 beta-hydroxy-PDBu but not the 4 alpha-stereoisomer. Furthermore, sn-1,2-dioctanoylglycerol (diC8) stereoselectively competed for PDBu binding. The cysteine-rich region was sufficient for association of the fusion protein to liposome preparations containing phosphatidylserine and phosphatidylcholine. Association was significantly enhanced in a stereospecific manner by the presence of PDBu as well as diC8. These results establish that a single cysteine-rich domain (residues 92-173) of PKC gamma contains regions necessary and sufficient for lipid-dependent stereospecific interactions with PDBu and diC8. Furthermore, the region is sufficient to confer translocation of a fusion protein to liposomes in a PDBu- and diC8-dependent fashion. Thus, a single cysteine-rich region of PKC gamma displays many of the properties characteristic of PKC.     

Memorizing and recalling spatial-temporal patterns in an oscillator model of the hippocampus

We describe the model of the hippocampus consisting of interactive oscillators with input from the entorhinal cortex (modulating the main information flow by a theta rhythm) and the septum (a theta rhythm generator). When interconnections between oscillators are allowed to strengthen in an adaptive way, the network can be trained using a series of lessons. This results in a connection matrix that memorizes the temporal sequence of inputs. Presenting one of the lessons to the trained network results in reproduction of the remainder of the sequence. In this paper, we create such a connection matrix, derive from it an appropriate Markov chain and simulate the chain to illustrate its dynamics.     

Accelerated radiotherapy regimen for malignant gliomas using stereotactic concomitant boosts for dose escalation

Parvovirus B19 (PV B19) infection was investigated in 29 pregnant women with fetal hydrops, after exclusion of feto-maternal incompatibility within red blood cell antigens, TORCH infections, feto-maternal hemorrhage and genetics reasons. The active viral infection was detected in 9 women (31%) by PCR amplification of DNA B19; in 2 of them IgM and IgG, in 1 IgM and in 4 IgG antibodies were also present. In 6 women (20%) IgG antibodies were only found, but not IgM and DNA B19, which confirmed infection in the past. In addition in 9 cases DNA B19 was evaluated in the fetal blood. The results in the mothers and their fetuses were concordant (4 positive, 5 negative). Our conclusion is that in nonimmune hydrops fetalis, PV B19 infection should be based on the viral DNA evaluation in the blood of mother (or fetus). IgM antibodies, in time of fetal disorders, might not be detected.     

Increased use of mammography among Hispanic women: baseline results from the NCI Cooperative Group on Cancer Prevention in Hispanic Communities

BACKGROUND: The Healthy People 2000 report set the objective of increasing the percentage of women 40 or older who had ever received a mammogram and clinical breast examination to 80% by the year 2000. The report used a baseline of 36% for all American women and 20% for Hispanic women. The purpose of this study was to compare baseline estimates with data obtained in five Hispanic communities. METHODS: Common survey measures were administered in five studies participating in a National Cancer Institute Cooperative agreement. The surveys evaluated history of mammography in five Hispanic communities in the southwestern Unites States. RESULTS: Across the five communities, the rates of mammography use were significantly higher than the national baseline. Among women 40-49 years of age, 55% had completed mammography (95% confidence interval [CI] = 52%, 57%). Among women 50 years of age or older, 64% had received a mammogram (95% CI = 62%, 66%). Older women (above age 50) were significantly more likely to have completed the test than younger women (younger than age 50), and mammography was obtained less often among women who were uninsured and those who had lower levels of acculturation. CONCLUSIONS: We conclude that the rate of mammography use among Hispanic women has increased significantly over the last few years and that we are on track to reach the goal of 80% mammography compliance for Hispanic women 40 years and older by the year 2000.     

Cocaine does not compromise cerebral or myocardial oxygen delivery in fetal sheep

Aprikalim, a K+ ATP channel opener, is a potent vasodilator with demonstrated cardioprotective properties against ischemia/reperfusion injury. It is still unknown if K+ ATP channel openers exert their beneficial effects via interaction with oxygen-derived free radicals. Therefore, we investigated the cardioprotective effects of aprikalim against oxygen-derived free radicals. Isolated rabbit hearts were perfused at constant pressure (85 cm H2O) or constant flow (30-35 ml/min). Heart rate, left ventricular developed pressure (LVDP), and either coronary flow or coronary perfusion pressure (CPP) were monitored. Free radicals were produced by electrolysis of the perfusate (0.6 mA, direct current), and 10 microM aprikalim was infused before and after exposure to free radicals. In the constant perfusion pressure experiments, 10 min of exposure to free radicals resulted in a significant reduction of heart rate (137 to 129 beats/min), LVDP (112 to 91 mmHg) and coronary flow (37 to 29 ml/min); coronary flow was more markedly impaired than contractile function. Acetylcholine-induced coronary dilation was also significantly attenuated in the presence of free radicals. After 30 min of recovery, both coronary flow and LVDP were still significantly decreased while acetylcholine-induced coronary dilation had fully recuperated. Aprikalim completely abated the coronary and cardiac depressant actions of free radicals. Constant flow experiments indicated that exposure to free radicals increased CPP (+40%, p < 0.05), an effect totally suppressed by aprikalim. These results demonstrate that aprikalim reverses the cardiodepressant actions of free radicals. The cardioprotection it afforded involves both contractile function and the coronary vasculature. Acetylcholine-induced coronary dilation was blunted by free radicals, an indication of complex interactions at the coronary endothelial level.     

The influence of the HLA-DRB1*13 allele on measles vaccine response

BACKGROUND: Measles remains a public health threat in the United States with over 50,000 cases being reported from 1989 through 1991 with continued smaller outbreaks. Measles vaccine failure is in part to blame for these large-scale outbreaks. The human leukocyte antigen (HLA) genes are important determinants of immune response to measles virus and vaccine. To examine the influence that HLA polymorphisms may have on measles vaccine antibody response, we compared the distribution of HLA-DRB1 alleles between measles vaccine nonresponders and hyper-responders. METHODS: We determined the seroprevalence of measles antibody in 881 school children immunized with measles-mumps-rubella-II at age 15 months using a whole virus IgG EIA. We performed class II HLA-DR typing by PCR with sequence specific primers (PCR-SSP) on 81 nonresponders (IgG seronegative) and 65 hyper-responders (from the upper 10th percentile of IgG levels of all subjects). We then compared the distribution of alleles between nonresponders and hyper-responders. RESULTS: The distribution of HLA-DRB1 alleles among nonresponders compared to hyper-responders was significantly different (p = 0.014). Nonresponders were significantly less likely to carry the HLA-DRB1*13 alleles than were hyper-responders (7.4% vs 16.2%;p = 0.02). Nonresponders also had an excess of HLA-DRB1*07 alleles (15.4% vs 6.2%; p = 0.015). CONCLUSIONS: The absence of HLA-DRB1*13 alleles is associated with measles vaccine nonresponse. The absence of this allele has also been associated with susceptibility to other infectious diseases. The role of this gene in the immunogenetic response to infectious diseases requires further study.