Activation of guanylate cyclase C signaling pathway protects intestinal epithelial cells from acute radiation-induced apoptosis.

Uroguanylin (UGN) is a peptide hormone that binds to and activates the intestinal epithelial cell (IEC) transmembrane receptor guanylate cyclase C (GC-C), which in turn increases intracellular cGMP. Gene targeting of murine UGN or GC-C results in significantly lower levels of cGMP in IECs. On the basis of effects of cGMP in nonintestinal systems, we hypothesized that loss of GC-C activation would increase intestinal epithelial apoptosis following radiation-induced injury. We first compared apoptosis from the proximal jejunum of C57BL/6 wild-type (WT) and GC-C knockout (KO) mice 3 h after they received 5 Gy of gamma-irradiation. We then investigated whether supplementation via intraperitoneal injection of 1 mM 8BrcGMP would mitigate radiation-induced apoptosis in these experimental animals. Identical experiments were performed in BALB/c UGN WT and KO mice. Apoptosis was assessed by quantitating morphological indications of cell death, terminal dUTP nick-end labeling, and cleaved caspase 3 immunohistochemistry. Both UGN KO and GC-C KO mice were more susceptible than their WT littermates in this in vivo model of apoptotic injury. Furthermore, cGMP supplementation in both GC-C and UGN KO animals ameliorated radiation-induced apoptosis. Neither WT strain demonstrated significant alteration in apoptotic susceptibility as a result of cGMP supplementation before radiation injury. These in vivo findings demonstrate increased radiosensitivity of IECs in UGN and GC-C KO mice and a role for cGMP as a primary downstream mediator of GC-C activation in the protection of these IECs from radiation-induced apoptosis.

New causes and treatments for infectious diarrhea in children.

Infectious diarrhea is a universal and important health problem in the pediatric population. An expanding number of potential viral, bacterial, and parasitic pathogens have been associated with diarrheal disease. However, the epidemiologic association of a microorganism with diarrhea is only one step in the process of identifying new pathogens. Once the virulence mechanisms of these organisms are elucidated, a causal relationship can be more readily defined. This article reviews the etiologic agents of diarrhea in the pediatric population and focuses on the newer treatment and prevention modalities, including probiotics and vaccinations, which are used increasingly to combat these diseases.

Periodic paralysis in quarter horses: a sodium channel mutation disseminated by selective breeding.

We recently reported on a linkage study within a Quarter Horse lineage segregating hyperkalaemic periodic paralysis (HYPP), an autosomal dominant condition showing potassium-induced attacks of skeletal muscle paralysis. HYPP co-segregated with the equine adult skeletal muscle sodium channel alpha subunit gene, the same gene that causes human HYPP. We now describe the Phe to Leu mutation in transmembrane domain IVS3 which courses the horse disease. This represents the first application of molecular genetics to an important horse disease, and the data will provide an opportunity for control or eradication of this condition.

Linkage of hyperkalaemic periodic paralysis in quarter horses to the horse adult skeletal muscle sodium channel gene.

A genetic disease observed in certain Quarter horses is hyperkalaemic periodic paralysis (HYPP). This disease causes attacks of paralysis which can be induced by ingestion of potassium. Recent studies have shown that HYPP in humans is due to single base changes within the adult skeletal muscle sodium channel gene. A large Quarter horse pedigree segregating dominant HYPP was studied to determine if mutations of the sodium channel gene are similarly responsible for HYPP in horses. We used cross-species, PCR-mediated, cDNA cloning and sequencing of the horse adult skeletal muscle sodium channel alpha-subunit gene to identify a polymorphism, and then used this polymorphism to see if the horse sodium channel gene was genetically linked to HYPP in horses. The sodium channel gene was indeed found to be tightly linked to HYPP (LOD = 2.7, theta = 0). Our results suggest that HYPP in horses involves the same gene as the clinically similar human disease, and indicates that these are homologous disorders. The future identification of the specific sodium channel mutation causing HYPP in Quarter horses will permit the development of accurate molecular diagnostics of this condition, as has been recently shown for humans.

A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.

Sunlight is a carcinogen to which everyone is exposed. Its UV component is the major epidemiologic risk factor for squamous cell carcinoma of the skin. Of the multiple steps in tumor progression, those that are sunlight-related would be revealed if they contained mutations specific to UV. In a series of New England and Swedish patients, we find that 14/24 (58%) of invasive squamous cell carcinomas of the skin contain mutations in the p53 tumor suppressor gene, each altering the amino acid sequence. Involvement of UV light in these p53 mutations is indicated by the presence in three of the tumors of a CC----TT double-base change, which is only known to be induced by UV. UV is also implicated by a UV-like occurrence of mutations exclusively at dipyrimidine sites, including a high frequency of C----T substitutions. p53 mutations in internal malignancies do not show these UV-specific mutations. The dipyrimidine specificity also implicates dipyrimidine photoproducts containing cytosine as oncogenic photoproducts. We believe these results identify a carcinogen-related step in a gene involved in the subsequent human cancer.

A survey of attitudes concerning contraception and the resolution of teenage pregnancy.

This study reports the results of a survey of 498 respondents in a large midwestern community concerning their attitudes toward making contraceptive services available to teenagers and the manner in which a teenage pregnancy should be resolved. The results indicated that the large majority of respondents approved of the practice of making contraceptives available to teenagers but there were also significant differences in attitudes expressed which were dependent upon demographic characteristics of the respondent. There was also considerable variability in the attitudes expressed concerning the resolution of a teenage pregnancy. The preferred method of resolution depended again on the demographic characteristics of the respondent. Keeping the baby and placing the baby for adoption were the most frequent choices. These results are discussed with relation to the present strong political conservative movement in the nation.

PIP: This study reports the results of a survey of 498 respondents in a large mid-western community concerning their attitudes toward making contraceptive services available to teenagers (only 30% of sexually active adolescents make consistent use of contraception), and the manner in which a teenage pregnancy should be resolved. 80.4% of the respondents were in favor of making contraceptives available to teenagers. However, significant differences were found among the different ages and the educational level of those surveyed, as age increased, support of availability decreased, but as education increased, support also increased. Persons without children were also more likely to approve contraceptive services in schools. 70.8% of the respondents felt that it was not necessary to require parental consent. There was considerable variability in the attitudes expressed concerning the resolution of a teenage pregnancy; 26.6% chose adoption, 16.7% picked abortion; 9.3% chose marriage, and 35.2% chose keeping the baby. Significant differences were found between white and black respondents and the single and separated. When attitudes were analyzed by age, the older the respondent, the more likely he/she was to feel that the pregnant teenager should not keep her baby. The same attitudes was evinced by those with higher levels of educational attainment. 40% of the respondents favored abortion, 52.4% were opposed, and 7% were either uncertain or favored abortion only under certain circumstances. Again there were significant differences by race, marital status, age, and educational level. Despite personal reservation concerning abortion, a clear majority of the respondents favored women having the choice, a finding that was consistent across all ages, races, and the majority of educational groups. The results of the survey are discussed in relation to the present strong political conservative movement in the nation.