G16 as a universal G protein adapter: implications for agonist screening strategies.
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Biomedical subjects
Publications and source records attributed to F Marshall.
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Effects of the cyclic AMP second messenger system were studied on the retraction of neurites elicited by the phospholipid mediator lysophosphatidic acid (LPA) in PC12 cells. LPA stimulation inhibited adenylyl cyclase, indicating that the LPA receptor couples to the heterotrimeric Gi proteins. However, pertussis toxin or expression of dominant negative Ras did not prevent neurite retraction. In contrast, cholera toxin, forskolin, and application of dibutyryl-cyclic AMP prevented neurite retraction. The neurite-protective effect of forskolin was blocked by Rp-adenosine 3',5'-phosphorothioate. Forskolin and dibutyryl-cyclic AMP both failed to protect neurites in A126-1B2 and 123.7 cells, which lack cyclic AMP-activated protein kinase. Data indicate that elevation of cyclic AMP levels triggers a cyclic AMP-activated protein kinase-dependent mechanism that opposes the functioning of the morphoregulatory signaling activated by LPA. ADP-ribosylation of Rho by the Clostridium botulinum C-3 toxin in 123.7 cells caused neuronal differentiation, indicated by neurite extension, and blocked LPA-induced neurite retraction. LPA activates Gq- and Gi-linked signaling in parallel; therefore, a morphoregulatory signaling network hypothesis is proposed versus the simplistic approach of a signaling pathway. The signaling network integrates the receptor-activated individual, sequential, and parallel signaling events into an interactive network whose individual components may fulfill required and permissive functions encoding the cellular response.
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Although bladder cancers are very common, little is known about their molecular pathogenesis. In this study, invasive bladder cancers were evaluated for the presence of gene mutations in the p53 suppressor gene. Of 18 tumors evaluated, 11 (61 percent) were found to have genetic alterations of p53. The alterations included ten point mutations resulting in single amino acid substitutions, and one 24-base pair deletion. In all but one case, the mutations were associated with chromosome 17p allelic deletions, leaving the cells with only mutant forms of the p53 gene products. Through the use of the polymerase chain reaction and oligomer-specific hybridization, p53 mutations were identified in 1 to 7 percent of the cells within the urine sediment of each of three patients tested. The p53 mutations are the first genetic alterations demonstrated to occur in a high proportion of primary invasive bladder cancers. Detection of such mutations ex vivo has clinical implications for monitoring individuals whose tumor cells are shed extracorporeally.
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We used a modified acid-fast stain to detect Cryptosporidium oocysts in unconcentrated stools from 824 Haitian children less than 2 years of age with acute diarrhea. Oocysts were identified in stools from 17.5% of 291 children seen at a rural dispensary and in 16.3% of stools from 533 children in an urban hospital. Children with cryptosporidiosis were identified throughout a 22-month period from October 1982 to July 1984, without seasonal predilection. Cryptosporidiosis was twice as common in infants greater than 6 months of age than in younger infants. Cryptosporidium oocysts were rarely found in stools of infants receiving only breast milk. The clinical presentation of children with cryptosporidiosis was similar to other patients with diarrhea who did not have cryptosporidiosis. No asymptomatic Cryptosporidium infections were detected among 71 family members of 31 children with cryptosporidiosis. Three of the 71 family members less than 3 years of age were found to have diarrhea and Cryptosporidium oocysts. In follow-up studies of 31 patients, oocysts persisted in stools for a mean of 14 days (range 5-31 days). Duration of oocyst excretion was directly correlated with duration of diarrhea. These findings suggest that Cryptosporidium is an important cause of acute self-limited diarrheal illness to Haitian children.
Cardiorespiratory and transcutaneous oxygen monitors were used on 13 preterm neonates to examine physiologic changes during ductus arteriosus ligation. Transcutaneous oxygen decreased 30 seconds after left lung deflation; all infants required increases in inspired oxygen and ventilation to correct abnormal values after the left lung was compressed. Transcutaneous oxygen decreased 30 seconds after ductus arteriosus ligation (mean delta tcPO2 = -17 mm Hg +/- 11.4) but increased 150 seconds after left lung inflation (mean delta tcPO2 = 46.9 mm Hg +/- 28.8). Arterial blood pressure increased (mean delta systolic BP = 17.9 mm Hg +/- 9.5) and heart rate decreased 10 seconds after ductus arteriosus ligation. In five neonates, gradual closure of the ductus arteriosus over 40 to 75 seconds resulted in a more gradual increase in blood pressure. Intraventricular hemorrhage was confirmed in two patients after surgery. Ligation of the ductus arteriosus results in an abrupt increase in blood pressure, which may be related to the pathogenesis of intraventricular hemorrhage. We suggest that the ductus arteriosus be closed gradually to allow a more gradual increase in blood pressure.
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In 1967, care of esophageal burns from caustic substances was altered to include immediate esophagoscopy, high doses of steroid, and follow-up dilatations plus cine-esophagograms as needed. Previously, this area averaged six repairs of esophageal stricutre each year. Since 1967, there have been no esophageal strictures in 100 patients.
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785 combined diagnostic procedures are reported which were carried out on 353 patients with microscopically proven carcinoma of the prostate in order to detect metastases. X-ray films of the thorax, spine and pelvis were taken. Also bone-scintigraphy was done with 87MSr or 99MTc-polyphosphate. Additionally the alcaline, acid and prostate phosphatases were determined. A diagnostic coincidence between radiological results and bone-scan was found in 95.1% of cases. The bone-scan was false negative in 3.7%. Only in 1.2% metastases were detected earlier by the bone-scan than by x-ray examinations. Referring to the number of studies identical results were found. In roentgenologically detected metastases an increased serum level of the alcaline phosphatase was found in 61%, of the acid phosphatase in 31% and of the prostate-phosphatase in 25%.
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