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Biomedical subjects

S M Graham

Publications and source records attributed to S M Graham.

At least 91 records · Page 5Linked to original sources
PubMed1995

Guanine nucleotide exchange factors: activators of Ras superfamily proteins.

Members of the Ras superfamily of proteins function as regulated GDP/GTP switches that cycle between active GTP-complexed and inactive GDP-complexed states. Guanine nucleotide exchange factors (GEFs) stimulate formation of the GTP-bound state, whereas GTPase activating proteins (GAPs) catalyze the formation of the GDP-bound state. We describe three studies that evaluate the mechanism of action of GEFs for Ras (SOS1 and RasGRF/CDC25) or Ras-related Rho (Dbl and Vav) proteins. Growth factor-mediated activation of Ras is believed to be mediated by activation of Ras GEFs (CDC25/GRF and SOS1/2). Although the mechanisms of Ras GEF regulation are unclear, recent studies suggest that translocation of SOS1 to the plasma membrane, where Ras is located, might be responsible for Ras activation. Our observation that the addition of the Ras plasma membrane-targeting sequence to the catalytic domains of CDC25 and SOS1 greatly enhanced their transforming and transactivation activities (10-50 fold and 5-10 fold, respectively) suggests that membrane translocation alone is sufficient to potentiate GEF activation of Ras. We have determined that two Ras-related proteins, designated R-Ras and R-Ras2/TC21, can trigger the malignant transformation of NIH 3T3 cells via activation of the Ras signal transduction pathway. Furthermore, like Ras and R-Ras, we observed that TC21 GTPase activity was stimulated by Ras GAPs. However, we observed that both SOS1 and CDC25 were activators of normal TC21, but not R-Ras, transforming activities. Therefore, TC21, but not R-Ras, may be activated by the same extracellular signaling events that activate Ras proteins. Dbl family proteins are believed to function as GEFs and activators of the Ras-related Rho family of proteins. However, one Dbl family oncogene, designated Vav, has been reported to be a GEF for Ras proteins. Therefore we were interested in determining whether Dbl family oncogenes cause transformation by triggering the constitutive activation of Rho or Ras proteins. Our results suggest that Dbl oncogenes cause transformation via a Ras-independent activation of MAP kinases and Rho family proteins.

Amino Acid Sequence↗
PubMed1995

Opportunistic upper gastrointestinal infection in transplant recipients.

Opportunistic infection of the upper gastrointestinal tract by cytomegalovirus (CMV) or invasive fungal infection was studied in 219 consecutive kidney and kidney/pancreas transplant recipients with regard to incidence, presentation, and clinical outcome. Prompt upper endoscopy was done in all patients with these symptoms: dyspepsia, dysphagia, or bleeding. Multiple biopsies were obtained for fungal culture, CMV culture, CMV assay, and histologic examination for fungal invasion. Between April 1991 and July 1993, 57/219 (26%) transplant patients developed upper gastrointestinal symptoms. At endoscopy, gross mucosal abnormality was evident in 48/57 (84%). Opportunistic infection was found in 21/48 (44%); however, CMV infection was also detected in 2/9 (22%) who had a normal study. Overall, CMV was present in 15/57 (26%) and invasive fungal infection in 8/57 (14%). All 23 infections were successfully eradicated. Opportunistic infection occurred in 12/31 (39%) with dyspepsia, 9/14 (64%) with dysphagia, and 2/12 (17%) with bleeding. Graft loss occurred in 5/23 (22%) with opportunistic infection vs 23/196 (12%) other recipients. Upper gastrointestinal symptoms are indicative of serious opportunistic infection in a significant number of transplant recipients. As opportunistic infection may jeopardize allograft function, all patients with upper gastrointestinal tract symptoms require prompt endoscopy and biopsy to effect appropriate therapy. Random biopsy is also recommended in the face of a normal endoscopic examination.

Adult↗
PubMed1995

The utility of prophylactic laparoscopic cholecystectomy in transplant candidates.

BACKGROUND: This study addresses the impact of laparoscopic cholecystectomy prior to kidney or pancreas transplant. PATIENTS AND METHODS: Between January 1991 and July 1993, 551 patients were listed for transplant. Gallbladder ultrasound became part of the standard evaluation for all transplant candidates in October 1991. Pretransplant laparoscopic cholecystectomy was recommended for all patients found to have gallstones. To assess the benefit of this policy, patients transplanted prior to routine ultrasound (Group I; n = 88) were compared to those listed or transplanted after routine ultrasound (Group II; n = 406). RESULTS: In Group I, 18% developed gallstone complications requiring surgery. Surgical morbidity occurred in 14% and mortality in 7% of these operations. Graft loss occurred in 20% having biliary complications versus 7% among other recipients. In Group II, gallstones were detected in 10%, and 9% subsequently had laparoscopic cholecystectomy with no morbidity or mortality. CONCLUSIONS: Transplant recipients with unsuspected gallstones were found to have a high incidence of acute biliary complications. Urgent biliary surgery carried significant morbidity and mortality in these immunosuppressed patients and appeared to increase the risk of graft failure as well. A policy of screening gallbladder ultrasound and pretransplant laparoscopic cholecystectomy seems to reduce these concerns and is recommended for all transplant candidates.

Adolescent↗
PubMed1995

Biological assays for Ras transformation.

The rodent fibroblast systems described above have provided sensitive and rapid biological assays to characterize the properties of normal and mutated Ras proteins. Furthermore, these assays have provided in vitro systems to measure the ability of other cellular components to modulate Ras signal transduction and transformation. However, while these assays provide an excellent measure of Ras-transforming activity, the fact that these cells are of fibroblastic origin, and can be transformed by a single hit, indicates that caution should be used in extrapolating observations from NIH 3T3 transformation assays to the situation in human tumors. Therefore, using human epithelial cell-based assays that more closely approximate the cell types where mutated ras alleles are most frequently detected may provide more realistic assays for examining the biochemical and biological consequences of aberrant Ras function in human tumors. Nevertheless, despite these cautions, these rodent transformation assays will continue to be the best and most widely applied assays for Ras biological activity.

3T3 Cells↗
PubMed1995

Evaluation of temporal and facial osteomyelitis by simultaneous In-WBC/Tc-99m-MDP bone SPECT scintigraphy and computed tomography scan.

A reliable imaging technique is needed for follow-up of patients with temporal and facial osteomyelitis. Clinical outcome in 20 patients with suspected osteomyelitis of the temporal/mastoid, calvarium, and mandible facial bones was evaluated with 30 combined In-WBC/Tc-99m MDP bone single photon emission computed tomographic (SPECT) scans and 27 computed tomographic scans. Simultaneous dual-tracer 25-minute SPECT scans were acquired 18 to 20 hours after radiotracer injection by use of a three-detector system. Diagnosis of the 20 patients (age range, 3 to 74 years) included 8 with facial osteomyelitis, 6 with malignant otitis externa, 3 with mandibular osteomyelitis, and 3 with calvarial osteomyelitis. Diagnosis was confirmed by biopsy/culture results in 18 patients and by endoscopic and clinical evaluation in 2 patients with initial negative scans. Of the 30 In-WBC/MDP scans, 15 were true-positive, 13 true-negative, 1 false-negative, and 1 equivocal. Of a total of 27 CT scans, 9 were true-positive, 5 false-negative, and 1 equivocal in patients with biopsy-proven osteomyelitis. Three computed tomographic scans were false-positive and 1 was equivocal in patients without osteomyelitis, because of concurrent postoperative bone abnormalities. Additionally, 8 computed tomographic scans were true-negative. These results suggest that dual In-WBC/Tc-99m MDP bone SPECT scintigraphy provides an accurate imaging modality for diagnosis and follow-up of temporal and facial osteomyelitis when existing clinical or postoperative bone changes make it difficult to detect active osteomyelitis by computed tomographic scan.

Adolescent↗
PubMed1995

Salivary sampling for hepatitis B surface antigen carriage: a sensitive technique suitable for epidemiological studies.

Vertical transmission from mothers to infants of hepatitis B infection result in a high incidence of carriage in children with long-term consequences, and is the focus of current immunization strategies. The use of saliva for hepatitis B surface antigen (HBsAg) screening in a country with an intermediate to high prevalence of chronic carriage was investigated. We recruited 88 Thai women with known HBsAg status (44 positive, 44 negative) who were attending an antenatal clinic. The collection of saliva was acceptable to all patients. Aspects of technique regarding collection and handling in a tropical setting are discussed. Comparing the detection of HBsAg in saliva to serum using a commercially available serological test kit without modification, the sensitivity was 92.0% (95% CI 84.8-99.5) and the specificity was 86.8% (95% CI 76.0-97.6). Population acceptability and safety advantages along with a high sensitivity strongly support the use of salivary sampling for epidemiological surveillance of hepatitis B virus.

Adolescent↗
PubMed1995

Lactobacillus GG promotes recovery from acute nonbloody diarrhea in Pakistan.

A prospective, placebo-controlled, triple blind clinical trial was carried out in Pakistan to determine the effect of Lactobacillus GG on the course of acute diarrhea in hospitalized children. Forty children (mean age, 13 months) were enrolled and after rehydration received either oral Lactobacillus GG (n = 21) or placebo (n = 19) twice daily for 2 days, in addition to the usual diet. The clinical course of diarrhea was followed during the treatment period. Features on admission into the study groups were similar and were characterized by severe diarrhea, malnutrition and inappropriate management before presentation. Response was evident on Day 2 when the frequency of both vomiting and diarrhea was less in the Lactobacillus group. In those who had presented with acute nonbloody diarrhea (n = 32), the percentage of children with persistent watery diarrhea at 48 hours was significantly less in the Lactobacillus group: 31% vs. 75% (P < 0.01). No significant difference was observed by 48 hours in those presenting with bloody diarrhea. The relevance of this finding to the management of diarrhea in the tropics is discussed.

Acute Disease↗
PubMed1995

Evaluation of maxillary sinus aspiration in patients with fever of unknown origin.

The value of diagnostic maxillary sinus aspiration in patients with abnormal findings on sinus radiographs and fever of unknown origin is unclear. To better define indications for this procedure, the results of 51 sinus aspirations in 34 patients with fevers of unknown origin and abnormal findings on sinus radiographs were analyzed retrospectively. Results of aerobic and anaerobic cultures were evaluated in the context of clinical signs and symptoms at the time of the maxillary sinus puncture. Typical symptoms of paranasal sinus disease were found to be the best predictor of a positive culture. Of patients with sinusitis complaints, 86.4% had culture-positive aspirations, whereas only 8.3% of patients without clinical symptoms of sinusitis had culture-positive aspirations. This study indicates that symptoms of sinus disease play an important role in determining the benefit of sinus aspiration in this group of patients.

Adolescent↗
PubMed1995

Tumefactive fibroinflammatory lesion of the head and neck: a management strategy.

Tumefactive fibroinflammatory lesions are rare, benign, fibrosclerosing masses in the head and neck that appear clinically as malignancies. Twenty-one cases have been described since first reported in 1975. While all authors agree on the lesion's histopathologic characteristics, multiple variations in appearance, treatment, and results have been reported. We review a case and compile all previously reported cases. Common sites of involvement were sinonasal tract (41%), neck (37%), and parotid (23%). Symptoms frequently reported were pain (50%) and hard mass (55%). Five patients (23%) eventually developed extra-head and neck fibrosclerosing lesions. Treatments have included surgery, radiation, and corticosteroids, occasionally in combination. Results have varied depending on size and location of lesion. Based on this review, a discussion of this rare disease and recommendations regarding diagnosis and treatment are given.

Adolescent↗
PubMed1994

Symptomatic double-channel pylorus. Successful treatment with a biliary sphincterotome.

A patient with a previous vagotomy and pyloroplasty was evaluated for symptoms of gastric outlet obstruction. Endoscopy revealed a thick, fibrous bridge that created a dual-channel pylorus. Symptomatic improvement was not achieved with balloon dilatation. Surgery was avoided by dividing the tissue bridge endoscopically with a sphincterotome. Since reestablishing a normal pyloric aperture, the patient's symptoms have been alleviated. This is the first description of this minimally invasive technique in the management of a symptomatic double-channel pylorus.

Endoscopy, Digestive System↗
PubMed1994

Safety and efficacy of repetitive adenovirus-mediated transfer of CFTR cDNA to airway epithelia of primates and cotton rats.

Gene therapy for cystic fibrosis (CF) will require the safe transfer of CFTR cDNA to airway epithelia in vivo. We showed previously that a recombinant adenovirus, Ad2/CFTR-1, expresses CFTR in vitro. As adenovirus rarely integrates, treatment will require repeated vector administration. We applied Ad2/CFTR-1 to intrapulmonary airway epithelia of cotton rats and nasal epithelia of Rhesus monkeys. In both species we detected CFTR mRNA and protein after repeated administration and in monkeys, protein was detected six weeks after repeat administration. The vector did not replicate and was rapidly cleared. Despite an antibody response, there was no evidence of a local or systemic inflammatory response after repeat administration. These data indicate that repetitive administration of Ad2/CFTR-1 is both safe and efficacious.

Adenoviridae↗
PubMed1994

Aberrant function of the Ras-related protein TC21/R-Ras2 triggers malignant transformation.

Although the human Ras proteins are members of a large superfamily of Ras-related proteins, to date, only the proteins encoded by the three mammalian ras genes have been found to possess oncogenic potential. Among the known Ras-related proteins, TC21/R-Ras2 exhibits the most significant amino acid identity (55%) to Ras proteins. We have generated mutant forms of TC21 that possess amino acid substitutions analogous to those that activate Ras oncogenic potential [designated TC21(22V) and TC21(71L)] and compared the biological properties of TC21 with those of Ras proteins in NIH 3T3 and Rat-1 transformation assays. Whereas wild-type TC21 did not show any transforming potential in vitro, both TC21(22V) and TC21(71L) displayed surprisingly potent transforming activities that were comparable to the strong transforming activity of oncogenic Ras proteins. Like Ras-transformed cells, NIH 3T3 cells expressing mutant TC21 proteins formed foci of morphologically transformed cells in monolayer cultures, proliferated in low serum, formed colonies in soft agar, and developed progressive tumors in nude mice. Thus, TC21 is the first Ras-related protein to exhibit potent transforming activity equivalent to that of Ras. Furthermore, mutant TC21 proteins also stimulated constitutive activation of mitogen-activated protein kinases as well as transcriptional activation from Ras-responsive promoter elements (Ets/AP-1 and NF-kappa B). We conclude that aberrant TC21 function may trigger cellular transformation via a signal transduction pathway similar to that of oncogenic Ras and suggest that deregulated TC21 activity may contribute significantly to human oncogenesis.

3T3 Cells↗
PubMed1993

Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis.

To evaluate the potential of direct transfer of cystic fibrosis transmembrane conductance regulator (CFTR) cDNA for the treatment of cystic fibrosis (CF), we administered an E1-deficient adenovirus, encoding CFTR, to a defined area of nasal airway epithelium of three individuals with CF. This treatment corrected the Cl- transport defect that is characteristic of CF-affected epithelia. After treatment, there was a decrease in the elevated basal transepithelial voltage, and the normal response to a cAMP agonist was restored. We found no evidence of viral replication or virus-associated adverse effects, even at the highest dose tested (25 MOI). These data represent a small step in achieving long-term improvement of CF lung function by gene therapy.

Adenoviridae↗