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Biomedical subjects

G M Fraser

Publications and source records attributed to G M Fraser.

At least 19 recordsLinked to original sources
PubMed2003

Cystic fibrosis transmembrane conductance regulator and Na+ channel subunits mRNA transcripts, and Cl- efflux, show a different distribution in rat duodenum and colon.

AIM: We compared the distribution and putative association of Cl- channel transport, CFTR mRNA transcripts, and Na+ channel (ENaC) alpha- and beta-subunit mRNA transcripts in villus and crypt epithelial cells of duodenum, with corresponding surface and crypt cells of colon from sodium-depleted rats. METHODS: Cells were loaded with 36Cl- and forskolin-stimulated efflux was determined. RT-PCR was performed for CFTR mRNA transcripts and ENaC alpha- and beta-subunit mRNA. Duodenal epithelial cell response to VIP was assessed by measuring intracellular cAMP. RESULTS: Forskolin-stimulated Cl- efflux occurred with decreasing magnitude in duodenal crypt, duodenal villus, colonic crypt and colonic surface cells in Na(+)-depleted animals. CFTR expression was correlated directly with Cl- efflux (r=0.91, P<0.01). Na+ channel alpha-subunit was expressed in colon and duodenum in animals fed diets with a high or low sodium content. While the beta-subunit mRNA was detected in the colon of sodium-restricted rats, it was absent in the duodenum under control conditions and after Na+ restriction. There was an inverse correlation between mRNA transcripts for CFTR and the ENaC alpha-subunit (r=-0.93, P<0.003) and beta-subunit (r=-0.91, P<0.004) in colon. VIP-stimulated cAMP in duodenal epithelial cells was greater in crypt than villus (P<0.05). CONCLUSION: Cl- efflux, CFTR transcription and forskolin-stimulated cAMP activity occur in both crypt and villus epithelial cells in duodenum. Possible interaction between CFTR and Na+ channels is apparently limited to parts of the colonic crypt. Lack of duodenal beta-subunit expression makes ENaC activity unlikely.

Animals↗
PubMed2003

Colorectal cancer in the south of Israel; comparison of the clinical characteristics and survival between two periods, 1981-2 and 1986-7.

BACKGROUND: Colorectal cancer has the highest incidence of all malignant tumours in men and women in Israel. The public was introduced to the concept of screening in the early 1980s, and full programs began in 1983. OBJECTIVES: The study compares patients with colorectal cancer (CRC) who were diagnosed before screening and five years later, for stage differences and survival. METHODS: All patients with CRC who were diagnosed from 1981 to 1982 (period I) and 1986-87 (period II) at Soroka Medical Centre and who were residents of the Negev area were eligible for the study. Data were collected retrospectively from the Israel Cancer Registry and patient files and endoscopic, histological and surgical reports from the Departments of Pathology, Gastroenterology, Oncology and Surgery at Soroka Medical Centre. RESULTS: The study groups included 207 patients with CRC, 85-from period I and 122-from period II. The mean annual incidence of CRC for these 2 periods was 18 and 24.8 cases per 100, 000, respectively, for an increase of 37% (P < 0.001). Five-year-survival in period I was 53.3% and in period II, 39.6% (P = 0.025). Survival did not differ by origin or gender. Dukes' stage, well and moderately differentiated tumours, and left-sided tumours were associated with better prognosis (P = 0.03). Forty-two percent of the cases were less than 64-year-old-at diagnosis, compared with 27% of 2069 Israeli patients in whom CRC was diagnosed in 1991 (P < 0.001). CONCLUSIONS: Before a nation wide decision is made with regard to public screening for CRC with fecal occult blood tests or sigmoidoscopy, the available data should be thoroughly evaluated, and further in-depth investigations performed to determine trends in diagnosis and prognosis.

Adenocarcinoma↗
PubMed2002

Association between gastric acid and mucin secretion in dyspeptic patients.

BACKGROUND AND AIMS: The maintenance of an intact gastric mucosa implies a balance between aggressive, such as acid, and protective factors such as mucin. We examined gastric aspirates to determine a possible correlation between gastric acid and mucin contents. METHODS: Gastric contents were aspirated at gastroscopy in 14 patients. Acid content was evaluated by titration, and mucin content by gel filtration. In 4 other patients these measurements were also performed for 1-hour basal gastric secretion, and after pentagastrin stimulation. Western blot and dot blot for mucin protein were performed with polyclonal antibodies to the protein of MUC 5AC and MUC 6. RESULTS: A positive correlation was demonstrated between acid and mucin content in 14 patients, r = 0.77. In 4 other patients mucin secretion, after pentagastrin injection, increased by 3-46 fold in comparison with basal secretion. A positive correlation was demonstrated between basal acid and mucin secretion, and stimulated acid and mucin secretion. In dot blot experiments, MUC 5AC had a significant higher dot blot intensity than MUC 6. CONCLUSIONS: There is a correlation between acid and mucin secretion rates. Secretagogue that causes acid secretion may also cause secretion of protective mucin.

Aged↗
PubMed2001

Flagellin polymerisation control by a cytosolic export chaperone.

Assembly of the long helical filament of the bacterial flagellum requires polymerisation of ca 20,000 flagellin (FliC) monomeric subunits into the growing structure extending from the cell surface. Here, we show that export of Salmonella flagellin is facilitated specifically by a cytosolic protein, FliS, and that FliS binds to the FliC C-terminal helical domain, which contributes to stabilisation of flagellin subunit interactions during polymerisation. Stable complexes of FliS with flagellin were assembled efficiently in vitro, apparently by FliS homodimers binding to FliC monomers. The data suggest that FliS acts as a substrate-specific chaperone, preventing premature interaction of newly synthesised flagellin subunits in the cytosol. Compatible with this view, FliS was able to prevent in vitro polymerisation of FliC into filaments.

Bacterial Proteins↗
PubMed2001

Substrate complexes and domain organization of the Salmonella flagellar export chaperones FlgN and FliT.

The flagellar proteins FlgN and FliT have been proposed to act as substrate-specific export chaperones, facilitating incorporation of the enterobacterial hook-associated axial proteins (HAPs) FlgK/FlgL and FliD into the growing flagellum. In Salmonella typhimurium flgN and fliT mutants, the export of target HAPs was reduced, concomitant with loss of unincorporated flagellin into the surrounding medium. Gel filtration chromatography of wild-type S. typhimurium cell extracts identified stable pools of FlgN and FliT homodimers in the cytosol, but no chaperone-substrate complexes were evident. Nevertheless, stable unique complexes were assembled efficiently in vitro by co-incubation of FlgN and FliT with target HAPs purified from recombinant Escherichia coli. The sizes of the chaperone-substrate complexes indicated that, in each case, a chaperone homodimer binds to a substrate monomer. FlgN prevented in vitro aggregation of FlgK monomers, generating a soluble form of the HAP. Recombinant polypeptides spanning the potentially amphipathic C-terminal regions of FlgN or FliT could not complement in trans the chaperone deficiency of the respective flgN and fliT mutants, but efficient flagellar assembly was restored by homodimeric translational fusions of these domains to glutathione S-transferase, which bound FlgK and FlgL like the wild-type FlgN. These data provide further evidence for the substrate-specific chaperone function of FlgN and FliT and indicate that these chaperones comprise common N- and C-terminal domains mediating homodimerization and HAP substrate binding respectively. In support of this view, the flgN mutation was specifically complemented by a hybrid chaperone comprising the N-terminal half of FliT and the C-terminal half of FlgN.

Bacterial Proteins↗
PubMed2001

Abolition of pentagastrin-stimulated alkaline tide using the carbonic anhydrase inhibitor acetazolamide.

BACKGROUND: Alkaline tide is the transient increase in blood and urine pH following stimulation of gastric acid secretion. It is attributed to HCO3- release from parietal cells in parallel with H+ secretion. The enzyme carbonic anhydrase is thought to be responsible for HCO3- production from CO2 and OH- in the parietal cell. OBJECTIVE: To examine the effect of pretreatment with the carbonic anhydrase inhibitor, acetazolamide, on the alkaline tide phenomenon. METHODS: Ten patients with dyspepsia and demonstrable alkaline tide were tested on three separate days. The pH and base excess were determined in arterialized venous blood before and 45 minutes after an intramuscular injection of pentagastrin. The pH of the urine was measured before and 120 min after pentagastrin injection. Measurements were performed after pentagastrin alone on day 1, following pretreatment with acetazolamide 60 min before pentagastrin on day 2, and after the administration of acetazolamide alone on day 3. RESULTS: Following the administration of pentagastrin alone, the blood base excess increased by 1.61 +/- 0.2 mEq/L (mean +/- standard deviation) and the calculated alkaline tide at 45 min was 33.99 +/- 4.49 mEq. On day 2 with prior administration of acetazolamide, base excess decreased by 0.21 +/- 0.39 mEq/L, and the calculated alkaline tide was -3.28 +/- 7.57 mEq, which was significantly lower than on day 1 (P = 0.0001). On day 3, following acetazolamide alone, the base excess values decreased by 0.53 +/- 0.2 mEq/L and the alkaline tide was -10.05 +/- 3.33 mEq; there was no significant difference compared with day 2 (P = 0.44). CONCLUSION: Pretreatment with acetazolamide abolished the alkaline tide induced by pentagastrin. This finding supports the view that carbonic anhydrase has a major role in the alkaline tide phenomenon.

Acetazolamide↗
PubMed2000

Pernicious anemia, gastric carcinoid, and autoimmune thrombocytopenia in a young woman.

The association between gastric carcinoid tumors and pernicious anemia is well recognized. Such tumors occur in the presence of achlorhydria, chronic atrophic gastritis, hypergastrinemia, and enterochromaffin-like cell hyperplasia. In this case report, a 29-year-old woman with pernicious anemia and autoimmune thrombocytopenia who developed gastric carcinoid tumors of the gastric body is described. This is the second description of pernicious anemia associated with autoimmune thrombocytopenia. This association in a young woman together with the therapeutic options and decisions that were taken in the treatment of the patient are discussed.

Adult↗
PubMed2000

Percutaneous endoscopic gastrostomy: high mortality rates in hospitalized patients.

OBJECTIVE: Percutaneous endoscopic gastrostomy (PEG) is a widely used method for insertion of a gastrostomy tube in patients who are unable to eat but have a normally functioning gut. Complications have been described, especially in fragile, debilitated patients, and 30-day mortality rates of 4.1-26% have been reported. We assessed the outcome of PEG tube placement for inpatients and outpatients, based on morbidity, mortality, and long-term survival. METHODS: We reviewed the medical records of all patients who underwent PEG at our institution between January 1, 1995 and December 31, 1996. Four groups of patients were compared: Group 1, patients from nursing homes; Group 2, hospitalized patients; Group 3, hospitalized patients matched to Group 2 for diseases, except mental disorder, and not treated with PEG; and Group 4, the general hospital population matched for age. RESULTS: A total of 114 PEG tubes were inserted in 114 patients, 47 from Group 1, 67 from Group 2. Eighty-seven percent of patients in Group 1 underwent PEG because of dementia, versus 46% of Group 2 (p<0.001). The mortality rate was five times higher in Group 2 than in Group 3 (p<0.001). The 30-day mortality was seven times higher in Group 2 than in Group 1, twice that in Group 3, and five times higher than in Group 4 (p = 0.002 and p<0.001, respectively). When intention-to-treat analyses were applied to the data, 19/48 patients died (39.5%) in Group 1, and 60/83 (72.0%) died in Group 2, (p<0.001). CONCLUSIONS: Patients hospitalized with acute illness are at high risk for serious adverse events after PEG insertion and this procedure should be avoided.

Aged↗
PubMed2000

Epidemiology of ulcerative colitis in Israel: a survey of Israeli kibbutz settlements.

OBJECTIVE: The incidence of ulcerative colitis ranges from 3 to 15 cases per 100,000 persons per year with a prevalence of 50-80 cases per 100,000, and the disease is 3-5 times more common among Jews. In Israel, Ashkenazi Jews have a higher incidence than Sephardi Jews, but a lower incidence than Ashkenazi Jews in the United States or Northern Europe. The aim of this study was to examine the prevalence, mean annual incidence, and clinical patterns of ulcerative colitis in a stable population of communal settlements (kibbutz). METHODS: We repeated a community-based survey in 124,400 kibbutz residents, 10 yr after our first study. This population represents 2.5% of the Jewish population of Israel. All ulcerative colitis patients were located by contacting the kibbutz clinics of the 269 kibbutz settlements (100% compliance). Data were updated to December 31st, 1997, which was designated the point prevalence date, and included information on gender, age, origin, education, profession, extent of the inflammatory process, clinical spectrum of the disease, therapy, complications of the disease, and treatment. The mean annual incidence for the 10 yr was calculated from the prevalence data. Only cases with a definite diagnosis of ulcerative colitis made in a recognized gastroenterology unit were accepted into the study. RESULTS: There were 208 confirmed cases of ulcerative colitis disease, 113 women and 95 men (female:male ratio = 1.19). The prevalence rate rose from 121.0/100,000 in 1987 to 167.2/100,000 in 1997 (p < 0.001). The prevalence rates were higher in women than men. Prevalence was highest in Israeli-born members in 1987 but in European/American-born members in 1997. The average annual incidence rate for the 10-yr period was 5.04/100,000/yr. In 1987, 146 cases of ulcerative colitis were collected. During 10 yr of surveillance 17 patients left the kibbutz, 12 died, and 62 new cases were added. The mean age at presentation of the disease was lower in 1987 than in 1997, 46.14 +/- 11.10 and 51.43 +/- 16.67 yr, respectively. Prevalence was highest in men with >16 yr and in women with 9-10 yr of education, 259.3 and 242.9/100,000, respectively. CONCLUSIONS: The prevalence of ulcerative colitis in this Israeli population increased and has reached the upper range for European and American populations. The mean annual incidence rate of ulcerative colitis is in the lower range of that reported for the Western countries.

Adolescent↗
PubMed2000

Portal hypertension induces sodium channel expression in colonocytes from the distal colon of the rat.

Cellular mechanisms for Na(+) retention in portal hypertension are undefined, but epithelial Na(+) channels (ENaC) may be involved. Under high-salt diet, ENaC are absent from distal colon of rat but can be induced by mineralocorticoids such as aldosterone. Presence of rat ENaC was determined by amiloride inhibition of (22)Na(+) uptake in surface colonocytes 7 and 14 days after partial portal vein ligation (PVL) or sham surgery. At both times, uptake inhibition was significantly increased in PVL rats. Presence of mRNA transcripts, determined by RT-PCR, demonstrated that channel alpha- and gamma-subunits were similarly expressed in both groups but that beta-subunit mRNA was increased in PVL rats. This confirms that there was induction of rat ENaC and indicates that beta-subunit has a regulatory role. Urinary Na(+) was decreased for 3 days after PVL but was not different at other times, and serum aldosterone levels were elevated at 7 days, at a time when urinary Na(+) output was similar to that of sham-operated rats. We conclude that PVL leads to induction of ENaC in rat distal colon. An increase in aldosterone levels may prevent natiuresis and is probably one of several control mechanisms involved in Na(+) retention in portal hypertension.

Aldosterone↗
PubMed1999

Swarming motility.

Swarming involves differentiation of vegetative cells into hyperflagellated swarm cells that undergo rapid and coordinated population migration across solid surfaces. Cell density, surface contact, and physiological signals all provide critical stimuli, and close cell alignment and the production of secreted migration factors facilitate mass translocation. Flagella biogenesis is central to swarming, and the flhDC flagellar master operon is the focal point of a regulatory network governing differentiation and migration.

Flagella↗
PubMed1999

Substrate-specific binding of hook-associated proteins by FlgN and FliT, putative chaperones for flagellum assembly.

During flagellum assembly by motile enterobacteria, flagellar axial proteins destined for polymerization into the cell surface structure are thought to be exported through the 25-30 A flagellum central channel as partially unfolded monomers. How are premature folding and oligomerization in the cytosol prevented? We have shown previously using hyperflagellated Proteus mirabilis and a motile but non-swarming flgN transposon mutant that the apparently cytosolic 16. 5 kDa flagellar protein FlgN facilitates efficient flagellum filament assembly. Here, we investigate further whether FlgN, predicted to contain a C-terminal amphipathic helix typical of type III export chaperones, acts as a chaperone for axial proteins. Incubation of soluble radiolabelled FlgN from Salmonella typhimurium with nitrocellulose-immobilized cell lysates of wild-type S. typhimurium and a non-flagellate class 1 flhDC mutant indicated that FlgN binds to flagellar proteins. Identical affinity blot analysis of culture supernatants from the wild-type and flhDC, flgI, flgK, flgL, fliC or fliD flagellar mutants showed that FlgN binds to the flagellar hook-associated proteins (HAPs) FlgK and FlgL. This was confirmed by blotting artificially expressed individual HAPs in Escherichia coli. Analysis of axial proteins secreted into the culture medium by the original P. mirabilis flgN mutant demonstrated that export of FlgK and FlgL was specifically reduced, with concomitant increased release of unpolymerized flagellin (FliC), the immediately distal component of the flagellum. These data suggest that FlgN functions as an export chaperone for FlgK and FlgL. Parallel experiments showed that FliT, a similarly small (14 kDa), potentially helical flagellar protein, binds specifically to the flagellar filament cap protein, FliD (HAP2), indicating that it too might be an export chaperone. Flagellar axial proteins all contain amphipathic helices at their termini. Removal of the HAP C-terminal helical domains abolished binding by FlgN and FliT in each case, and polypeptides comprising each of the HAP C-termini were specifically bound by FlgN and FliT. We suggest that FlgN and FliT are substrate-specific flagellar chaperones that prevent oligomerization of the HAPs by binding to their helical domains before export.

Bacterial Proteins↗
PubMed1999

Seroprevalence of Helicobacter pylori and length of stay in a nursing home.

BACKGROUND: Helicobacter pylori infection appears to be contracted mainly in childhood, and it is associated with disadvantaged socioeconomic conditions, overcrowding, and living in institutions. In this study we determined the seroprevalence of H. pylori among elderly patients (age > or = 70 years) admitted to a major medical center in Israel, and studied the relationship between seroprevalence of H. pylori and the duration of stay in a nursing home prior to the admission. PATIENTS AND METHODS: Whole blood from 182 consecutive patients hospitalized at the Rabin Medical Center was tested for the presence of anti-H. pylori IgG using Helisal Rapid Blood Test kit (Cortecs Diagnostics). Multivariate logistic regression analysis was used to study the relation between H. pylori seropositivity and possible predictive factors such as age, gender and duration of stay in a nursing home. RESULTS: Of the 182 patients included in the study, 80 (44%) were living in nursing homes (NH) and 102 (56%) were living in their own homes (H) prior to admission. Subjects that stayed in nursing homes for more than 15 months were significantly more likely to be seropositive than subjects with a shorter duration of stay (84% and 63% respectively, p = 0.03). Using a multivariate logistic regression analysis on both the NH group and the whole group, seropositivity was found to be significantly associated with duration of stay in a nursing home (p = 0.03 and p = 0.01 respectively). Seropositivity was not associated with age in either group. CONCLUSIONS: Living in a nursing home is associated with increased risk for H. pylori infection in the elderly. There is a strong correlation between the duration of stay in a nursing home and the prevalence of H. pylori infection.

Age Factors↗
PubMed1999

Mesalamine-induced granulomatous hepatitis.

A 42-yr-old man with ulcerative colitis was admitted for investigation of prolonged fever associated with cholestatic liver tests. Endoscopic retrograde cholangiopancreatography demonstrated a normal biliary tree, and liver biopsy showed granulomata. A clinical diagnosis of drug-induced granulomatous hepatitis was established as the symptoms disappeared after cessation of mesalamine therapy and recurred on rechallenge. Although the differential diagnosis of fever and hepatitis in patients with inflammatory bowel disease is wide, in this case mesalamine is the most likely cause.

Adult↗
PubMed1999

Epidemiology of Crohn's disease in Israel: a survey of Israeli kibbutz settlements.

OBJECTIVE: The prevalence of Crohn's disease ranges from 10 to 70 cases per 100,000 population, and is 3-8 times more common among Jews. However, this excess risk is not evident in the Jewish population of Israel. Recently we have described a significant increase in the prevalence and incidence of Crohn's disease in the south of Israel. The aim of this study was to confirm this trend in a stable population found in communal (kibbutz) settlements. METHODS: We repeated a community-based survey in 124,400 kibbutz residents, 10 yr after our first study. This population represents 5% of the Jewish population of Israel. All Crohn's disease patients were located by contacting the kibbutz clinics of the 269 kibbutz settlements (100% compliance). Data was updated to December 31st, 1997, which was designated the point prevalence date, and included information on gender, age, origin, education, profession, extent of the inflammatory process, clinical spectrum of the disease, therapy, complications of the disease, and treatment. The average annual incidence for the 10 yr was calculated from the prevalence data. Only cases with a definite diagnosis of Crohn's disease made in a recognized gastroenterology unit were accepted into the study. RESULTS: There were 81 confirmed cases of Crohn's disease and the prevalence rate rose from 25.5/100,000 in 1987 to 65.1/100,000 in 1997 (p < 0.001). The mean annual incidence rate for this period (1987-1997) is 5.0/100,000/yr. Prevalence rates were higher in women than men, and in those born in Israel or Europe/America than in Asia/Africa. The mean age at presentation of the disease was lower in 1997 than in 1987, 37.4 +/- 17.0 and 45.0 +/- 17.0 yr, respectively (p = 0.041). Prevalence was highest in men with > 16 yr of education, and in women with 11-12 yr education, 119.7 and 100.3/100,000, respectively. CONCLUSIONS: During the decade 1987-1997, the prevalence of Crohn's disease has increased in Israel and is approaching the rates in Europe and America.

Adolescent↗
PubMed1997

Characterization of sodium and chloride conductances in preneoplastic and neoplastic murine colonocytes.

Glucocorticoids, such as dexamethasone, induce amiloride-sensitive Na+ conductances in rat distal colon epithelium. The activity of these conductances diminishes from the surface to the base of the crypt whereas cAMP-stimulated Cl- secretion decreases from the crypt base to the surface. These gradients are likely to be perturbed during carcinogenesis. We therefore determined the magnitude of Na+ and Cl- conductances in colonocytes isolated from normal and carcinogen-treated rats. Colon carcinogenesis was induced by injection of dimethylhydrazine (DMH) (18 mg/kg) for 5 weeks. Before sacrifice animals were treated for 3 days with dexamethasone. Colonocyte populations from the surface to the crypt base (C1-C5) were harvested from the distal colon by a Ca2+-chelating procedure. The activity of Na+ conductances was determined by uptake of 22Na+ by surface and crypt colonocyte populations and by membrane vesicles in the presence and absence of 10 microM amiloride. In control rats Na+ conductance was highest in surface colonocytes and absent in the crypt base. As early as 2 weeks after initiation of DMH treatment amiloride-inhibited Na+ uptake was virtually absent in the upper crypt. Transcriptional assessment of the alpha-, beta- and gamma-subunits that constitute the epithelial Na+ channel revealed that DMH treatment reduces the expression of beta-subunit mRNA. We then examined 36Cl- efflux from isolated colonocytes of normal and carcinogen-treated rats in response to forskolin (0.01 mM). Forskolin induced a marked rise in cAMP in lower crypt cells concomitant with a significant stimulation of 36Cl- efflux. Intracellular cAMP increased in upper crypt cells in response to forskolin without an increase in 36Cl- efflux. By contrast, upper crypt colonocytes from DMH-treated rats showed forskolin-stimulated efflux beginning 4 weeks after initiation of treatment. We conclude that induction of Na+ conductances by glucocorticoids is inhibited during the early stages of chemical carcinogenesis due to lack of induction of the beta-subunit of the channel. By contrast, Cl- transport is stimulated both in surface and lower crypt cell compartments during different stages of chemical carcinogenesis.

Amiloride↗