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Biomedical subjects

S E Gabriel

Publications and source records attributed to S E Gabriel.

At least 109 records · Page 6Linked to original sources
PubMed1993

Patient preferences for nonsteroidal antiinflammatory drug related gastrointestinal complications and their prophylaxis.

We conducted a pilot study examining the relative preferences for various nonsteroidal antiinflammatory drug associated adverse gastrointestinal events and misoprostol prophylaxis for these events. Thirty patients with rheumatoid arthritis volunteered to participate. A trained nurse interviewer administered the structured pretested interview. Respondents rated 18 hypothetical health states on a category rating scale with anchors at 0 (immediate death) and 100 (full health for life). Linear contrasts were created to test the null hypotheses of equal preferences, using t tests for correlated means. Our results suggest that respondents place a high value on the avoidance of (in order of decreasing importance) surgery, hospitalization, prophylaxis induced diarrhea and uncomplicated ulcer requiring outpatient treatment. The avoidance of ulcer symptoms (primarily dyspepsia) and the inconvenience of an additional medication taken 4 times daily (in the absence of diarrhea) appeared to be substantially less important from these patients' perspective. Further work is underway to confirm these preliminary findings.

Adult↗
PubMed1992

Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an adenosine 3',5'-monophosphate (cyclic AMP)-activated chloride channel. In cystic fibrosis (CF) patients, loss of CFTR function because of a genetic mutation results in defective cyclic AMP-mediated chloride secretion across epithelia. Because of their potential role as an animal model for CF, mice with targeted disruption of the murine CFTR gene [CFTR(-/-)] were tested for abnormalities in epithelial chloride transport. In both freshly excised tissue from the intestine and in cultured epithelia from the proximal airways, the cyclic AMP-activated chloride secretory response was absent in CFTR(-/-) mice as compared to littermate controls. Thus, disruption of the murine CFTR gene results in the chloride transport abnormalities predicted from studies of human CF epithelia.

Amiloride↗
PubMed1992

Inhibition of ileal brush-border chloride conductance by specific antibody.

Antibody raised in mice was used in attempting to identify proteins responsible for the conductive chloride transport that can be measured in porcine ileal brush border membrane vesicles. Ileal brush-border membrane vesicle protein from pig was separated into five different molecular mass fractions by preparative SDS polyacrylamide disc gel electrophoresis. Separated protein fractions were used to immunize mice. Antibody was screened for reactivity with antigen by Western blotting, and for effects on conductive chloride transport in ileal brush border membrane vesicles. Immunization with brush-border protein from fraction I proteins (> 110 kDa) produced polyclonal antisera which specifically inhibited the conductive component of chloride uptake by ileal brush border vesicle preparations. Western blotting of the antigen showed the presence of several protein species of molecular mass > 100 kDa that were recognized by immune serum. Spleen cells from a mouse producing antiserum that inhibited conductive chloride transport were fused with a myeloma cell line. The resulting hybridoma colonies produced antibody that reacted with at least seven distinct protein bands by Western blot assay and inhibited chloride conductance in brush-border membrane vesicles.

Animals↗
PubMed1992

Trends in the utilization of non-steroidal anti-inflammatory drugs in the United States, 1986-1990.

National estimates of NSAID utilization were obtained from two databases available from IMS America. These data illustrate that in contrast to the rapid rise in NSAID prescriptions from 1973 (27.5 million) to 1983 (66.7 million), NSAID prescriptions have recently been remarkably stable. Over the same time period, a 46 fold increase in the use of gastro-protective and/or anti-ulcer drugs concomitantly with NSAID was demonstrated. It is hypothesized that the stabilization of NSAID prescription usage coupled with the dramatic increase in usage of concomitant anti-ulcer and gastro-protective agents has occurred due to physician awareness of the increased relative risk for adverse gastrointestinal events among NSAID users compared to non-users.

Adult↗
PubMed1992

Small linear chloride channels are endogenous to nonepithelial cells.

We used both single-channel and whole cell patch-clamp techniques to characterize chloride channels and currents endogenous to Sf9 cells, 3T3 fibroblasts, and Chinese hamster ovary cells. In cell-attached patches from these cell types, anion channels were observed with low ohmic conductance (4-11 ps), linear current-voltage relationships, and little time- or voltage-dependent behavior. These channels are very similar to the Cl- channels reported to appear concomitant with the expression of cystic fibrosis transmembrane conductance regulator (CFTR) in these cell lines. The presence of such endogenous channels suggests either that low levels of CFTR are present in all of these cell lines prior to transfection or that an endogenous non-CFTR channel is present in these cell types. Our results suggest that at least some of the channel behaviors attributed to expressed, recombinant CFTR in previous studies may have been due to these endogenous Cl- channels.

3T3 Cells↗
PubMed1991

Risk for serious gastrointestinal complications related to use of nonsteroidal anti-inflammatory drugs. A meta-analysis.

OBJECTIVE: To describe the relative risk for serious gastrointestinal complications due to non-aspirin nonsteroidal anti-inflammatory drug (NSAID) exposure among NSAID users as well as in selected subgroups. DESIGN: Overview and meta-analysis. DATA IDENTIFICATION: A literature search of English-language studies examining the association between NSAIDs and adverse gastrointestinal events for the period 1975 to 1990 identified using MEDLINE and communicating with three internationally recognized experts. DATA ANALYSIS: A qualitative summary of study characteristics and a critical appraisal of study quality were done. The results of 16 primary studies were selected and combined statistically. Summary estimates were weighted by sample size and quality score. MAIN RESULTS: The overall odds ratio of the risk for adverse gastrointestinal events related to NSAID use, summarized from 16 studies (9 case-control and 7 cohort) was 2.74 (95% Cl, 2.54 to 2.97). The summary odds ratios were as follows: elderly patients, (aged greater than or equal to 60 years), 5.52 (Cl, 4.63 to 6.60); patients under 65 years of age, 1.65 (Cl, 1.08 to 2.53); women, 2.32 (Cl, 1.91 to 2.82); and men, 2.40 (Cl, 1.85 to 3.11). The summary odds ratio for NSAID users receiving concomitant corticosteroids compared with NSAID users not receiving corticosteroids was 1.83 (Cl, 1.20 to 2.78). The summary odds ratio for the first gastrointestinal event was 2.39 (Cl, 2.16 to 2.65). The relative risk for a subsequent or unspecified gastrointestinal event was 4.76 (Cl, 4.05 to 5.59). The summary odds ratio for less than 1 month of NSAID exposure was 8.00 (Cl, 6.37 to 10.06); for more than 1 month but less than 3 months of exposure, the summary odds ratio was 3.31 (Cl, 2.27 to 4.82); and for more than 3 months of exposure, the summary odds ratio was 1.92 (Cl, 1.19 to 3.13). CONCLUSIONS: Users of NSAIDs are at approximately three times greater relative risk for developing serious adverse gastrointestinal events than are nonusers. Additional risk factors include age greater than 60 years, previous history of gastrointestinal events, and concomitant corticosteroid use. Another possible risk factor is the first 3 months of NSAID therapy. The risk for serious gastrointestinal events appears to be equal among men and women. These data represent summary statistics from 16 studies and cannot be considered generalizable to all NSAID users.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1991

Candidate proteins for conductive chloride transport in porcine ileal brush-border membrane.

Conductive transport of chloride ion is important in controlling ion and fluid secretion by exocrine tissues. The current study was directed at identifying proteins in the intestinal brush-border membrane that may be involved with conductive chloride transport. Reaction of total brush-border membrane protein with phenyl-isothiocyanate inhibited conductive chloride transport into brush-border membrane vesicles. The conductive transport process was protected from this inhibition by including the ligands Cl- and alpha-phenylcinnamate in the reaction mixture. Brush-border membrane protein protected by this procedure and labeled with fluorescein had an apparent molecular mass in the region of 130 and 23 kDa on separation by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Phosphorylation of brush-border membrane protein with [gamma-32P] ATP and endogenous protein kinase under conditions causing activation of chloride conductance in membrane vesicles caused the transfer of 32P to several proteins, including ones in the same molecular size range (130 and 23 kDa) as those identified by the fluorescein labeling procedure. Conductive chloride transport in porcine intestinal brush-border vesicles may occur via proteins identified by this differential labeling procedure.

Animals↗
PubMed1990

Effects of chloride conductance inhibitors on fluid secretion into ligated ileal and jejunal loops in pigs.

Compounds that prevent chloride transport in membrane vesicles have been tested for in vivo activity against the effects of intestinal secretory agents. Chloride channel blockers including diphenylamine-2-carboxylate, 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate, 5-nitro-2-(2-phenylethylamino)benzoic acid, and alpha-phenylcinnamic acid were tested for effects on jejunal or ileal secretion in weanling pigs. Secretion was studied in ligated intestinal loops in a control state, during exposure to secretory concentrations of theophylline, and after prior treatment with cholera toxin. Increases in net fluid flux induced by either theophylline or cholera toxin were not prevented by adding chloride channel blockers into the intestinal lumen. Channel blocker concentrations that reduced chloride transport by greater than 50% in pig jejunal brush border vesicles did not cause significant changes in unidirectional blood to lumen chloride flux measured in situ. Several routes of administration of the specific chloride channel blocker alpha-phenylcinnamate failed to reduce fluid secretion induced by theophylline. Chloride channel blocker effectiveness appears to be significantly different between in vitro and in vivo experimental models. In contrast to the chloride channel blockers, loperamide significantly reduced net fluid and chloride flux in ileal loops secreting fluid in response to theophylline. Antagonism of the production or actions of second messenger by loperamide was more effective than the chloride channel blockers in reducing conductive chloride transport associated with intestinal secretion.

4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfo↗
PubMed1990

Rifampin therapy in rheumatoid arthritis.

Several second-line antirheumatic agents possess both immunosuppressive and antimicrobial properties. Rifampin is an antimicrobial agent recently found to exhibit immunosuppressive activity in both animal and human studies. Intraarticular rifamycin SV, a rifampin derivative, has been reported to cause dramatic improvement in gonarthritis in 15 patients with rheumatoid arthritis (RA). These reports along with the personal observation of spontaneous improvement of arthritic symptoms in 2 patients with RA treated with rifampin at our institution, prompted us to conduct a pilot study using oral rifampin at 600-1200 mg daily in 8 patients with active, adult onset, seropositive RA. Although, no clinically important or statistically significant improvement occurred in any of the outcome variables measured (p greater than 0.12), the power of this study to detect such differences was limited. Alkaline phosphatase increased modestly in 7 patients. One patient developed an acute, drug induced, flu-like syndrome with marked elevation of liver enzymes which resolved promptly with drug withdrawal. We conclude that the potential effectiveness of oral rifampin therapy in RA is doubtful.

Administration, Oral↗
PubMed1989

Inhibiting conductive Cl uptake in membrane vesicles: specificity of alpha-phenylcinnamate.

alpha-Phenylcinnamate has been investigated in comparison to other inhibitors of chloride ion transport into porcine jejunal brush-border membrane vesicles. The transport modes studied included uptake driven only by a chemical Cl gradient, Cl uptake dependent on a transmembrane potential, self-exchange of Cl with no chemical or potential gradient, and Cl uptake dependent on a chemical gradient for bicarbonate. Uptake driven by the chemical gradient for Cl was strongly inhibited by millimolar concentrations of diphenylamine-2-carboxylate, 5-nitro-2-(2-phenylethylamino)benzoate (NPEB), and to a lesser extent by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulfonate (SITS). Similar concentrations of alpha-phenylcinnamate did not reduce this mode of Cl uptake. Conductive Cl uptake driven by a potassium gradient was inhibited by approx. 50% at 2.5 mM alpha-phenylcinnamate. alpha-Phenylcinnamate was equally effective in reducing the initial rate of conductive chloride accumulation in vesicles with naturally opened Cl channels (conductance activation by cyclic AMP and Ca2+), or with Cl channels opened by exposure to tetramethylammonium (TMA) buffer. In comparison with diphenylamine-2-carboxylate, NPEB and SITS, alpha-phenylcinnamate had the least effect on Cl-HCO3 exchange at inhibitor concentrations which reduced conductance activity. Self-exchange rates of physiological concentrations of Cl were also relatively unaffected by low mM concentrations of alpha-phenylcinnamate. Kinetic analysis indicated that alpha-phenylcinnamate was an uncompetitive inhibitor, requiring the presence of the normal Cl ligand for binding to, and inhibition of, conductive Cl transport by pig intestinal brush-border vesicles.

Animals↗
PubMed1989

Activation of chloride conductance in pig jejunal brush border vesicles.

Requirements for the activation of Cl- conductance have been investigated in pig jejunal brush border vesicles. The stability of ATP as a substrate for protein kinase activity, the stability of the phosphoprotein product of protein kinase action, and the choice of buffer system used for vesicle preparation were studied as variables which affected the outcome of in vitro activation attempts. Arsenate was selected as the most effective agent in protecting ATP from hydrolysis by the phosphatase activity in this vesicle system. Brush border vesicle protein appeared to prevent the accumulation of phosphoprotein in a cAMP-dependent protein kinase reaction, and vesicle protein only had phosphate acceptor activity when KF was added as a presumptive inhibitor of phosphoprotein phosphatase. A Cl- conductance response to a potassium gradient and valinomycin was present in vesicles prepared in buffers containing tetramethylammonium. Cl- conductance activity was not increased in this system by the addition of ATP, dibutyryl cyclic AMP, and cyclic AMP-dependent protein kinase. There was no Cl conductance response to a potassium gradient in vesicles buffered with imidazolium-acetate. Incorporation of ATP, AsO4(3-), and F- into these nonconductive vesicles by homogenization, followed by addition of dibutyryl cAMP, produced substantial conductance activity. Maximal activation of Cl- conductance was obtained with vesicles prepared in imidazolium-acetate buffering, using precautions to stabilize ATP and phosphoprotein prior to conductance measurements.

Adenosine Triphosphate↗
PubMed1989

A population-based case-control study of temporal arteritis: evidence for an association between temporal arteritis and degenerative vascular disease?

The first population-based incident case-control study of temporal arteritis (TA) in the US was conducted using the unique data resources of the Rochester Epidemiology Project. During the period 1950-1985, 88 newly diagnosed cases of biopsy-proven TA were identified among residents of Olmsted County, Minnesota. Cases were each matched to four Olmsted County community controls on age, sex and duration of community medical record. Odds ratios (OR) were calculated for marital status, education, Quetelet index, pregnancy, age at menopause, thyroid disease, diabetes, smoking, hypertension, angina, myocardial infarction, peripheral vascular disease, and stroke. Multivariable conditional logistic regression analysis identified statistically significant adjusted OR for smoking (2.3, 95% CI = 1.3-4.1). Elevated ORs which were not statistically significant were noted for angina, myocardial infarction, and peripheral vascular disease. These data suggest that TA and arteriosclerosis may share a common causal pathway. Alternatively, histopathological misclassification of temporal artery biopsies may have resulted in the observed association. Due to the limited power of this population-based study, multicentre collaboration should be encouraged to more precisely define the epidemiology of TA.

Aged↗
PubMed1989

Clinical trials in fibrositis: a critical review and future directions.

A critical appraisal of the design of clinical trials which examined the effectiveness of various interventions in fibrositis was conducted. Therapeutic interventions included physical fitness, biofeedback, acupuncture, dothiepin, imipramine, cyclobenzaprine, S-adenosylmethionine and amitriptyline. The design and analysis of the randomized, controlled studies render their results reliable. Major areas for methodologic improvement in future trials were identified. Standardized, validated and reliable diagnostic and outcome criteria need to be established. Factors which could predict response need to be identified to enable the selection of the most appropriate patient population for inclusion in future studies. Finally, the incorporation of measures of patient function will result in more clinically meaningful outcome evaluation.

Fibromyalgia↗
PubMed1988

Rheumatoid arthritis: can the long-term outcome be altered?

Although several agents (for example, intramuscularly administered gold, auranofin, D-penicillamine, hydroxychloroquine, and methotrexate) are of clinical benefit in the management of rheumatoid arthritis (RA), their effect on the long-term outcome of the disease is controversial. Assessment of the influence of therapeutic interventions in RA is difficult because the natural history of the disease remains poorly defined and unpredictable, and neither the traditional clinical and laboratory measurements of inflammation nor radiographic analyses of progression of joint destruction provide an accurate estimate of the long-term outcome of RA. Furthermore, there is little evidence that second-line agents yield benefits beyond 3 years. Therefore, adequately tested comprehensive measures should be used in large, long-term, multicenter controlled clinical trials to determine whether the long-term outcome of RA can be altered.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1988

Chloride ion transport into pig jejunal brush-border membrane vesicles.

1. This study was carried out to determine the types and activities of carrier proteins which transport the chloride ion in pig jejunal brush-border membranes, with an emphasis on studying the properties of chloride conductance activity in vesicles prepared from these membranes. 2. Sodium-chloride co-transport activity was not detected in this tissue. A sodium-proton antiport with typical amiloride sensitivity was present. An anion exchanger linking chloride to hydroxyl or bicarbonate ions was also found in the pig jejunal brush-border membrane vesicles. 3. Chloride conductance activity in this system was specifically dependent on the buffering agents used for vesicle preparation. Conductance activity could not be demonstrated in vesicles prepared in imidazolium acetate or in HEPES-Tris buffers. HEPES-tetramethylammonium buffering of vesicles in the chloride uptake system produced a significant conductance response to a potassium gradient plus valinomycin. 4. Chloride conductance showed saturable kinetics with respect to substrate concentration, with a Michaelis-Menten constant (Km) of approximately 116 mM and a maximum velocity (Vmax) of 132 nmol (mg protein)-1 min-1. 5. Preliminary screening of potential inhibitors of chloride conductance showed only minimal inhibitor effects of SITS (4-acetamido-4'-isothiocyanostilbene-2,2'-sulphonic acid), anthracene-9-carboxylate, N-phenylanthranilate and piretanide. 6. The conductance activity in pig jejunal vesicles appears to have stringent buffer requirements, and to be relatively insensitive to the effects of reported conductance inhibitors.

Animals↗
PubMed1988

Scleromyxedema: a scleroderma-like disorder with systemic manifestations.

Scleromyxedema is a rare fibromucinous connective tissue disorder characterized by papular skin lesions associated with sclerosis and a serum monoclonal gammopathy. Little is known about either the natural history or the systemic manifestations of this disease. We reviewed the medical records of 19 patients with biopsy-proven scleromyxedema seen from 1950 to 1985 for evidence of systemic disease. There were 10 males and 9 females with a median age at diagnosis of 53 years. Monoclonal gammopathy was present in 13 patients. Eight patients complained of dysphagia; 3 had proximal esophageal dysfunction and 1 had total esophageal aperistalsis on barium swallow. Proximal muscle weakness was noted in 5, with an inflammatory myopathy in 3. Six patients complained of dyspnea on exertion. Of these, 5 had reduced diffusing capacity, 3 had reduced volumes, and 2 developed cor pulmonale. Pathologic changes characteristic of "scleroderma kidney" were demonstrated in 1 patient at postmortem. One patient had Raynaud's phenomenon and 2 had arthralgias/arthritis with noninflammatory synovial fluids. Although 8 of 12 patients treated with melphalan noted regression of their skin changes, no consistent improvement in the extracutaneous manifestations was demonstrated. Furthermore, 2 patients died of sepsis related to melphalan-induced myelosuppression, and 4 developed hematological malignancies following melphalan therapy. In conclusion, systemic manifestations in scleromyxedema are more prevalent than previously recognized, and can resemble those of scleroderma. Significant toxicity occurred with the use of alkylating agents in these patients, with treatment-related complications developing in 45% of patients treated with melphalan. The lack of definitive data regarding the natural history of this disease complicates the question of optimal therapy, but the use of alkylating agents should be reserved for those patients with severe debilitating skin disease.

Adult↗