The move towards evidence-based medicine.
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Humans↗
Biomedical subjects
M Robinson
Publications and source records attributed to M Robinson.
Prokinetic therapy for gastroesophageal reflux disease.
Prokinetic drugs theoretically have the ability to correct the pathophysiologic abnormalities of gastrointestinal motility that lead to gastroesophageal reflux disease. However, the prokinetic agents bethanechol and metoclopramide have been associated with central nervous system and other side effects, as well as uncertain efficacy. In addition, erythromycin seems unsuitable for use as an oral prokinetic agent. A recently introduced prokinetic agent, cisapride, has a minimum incidence of side effects and is effective in the treatment of reflux symptoms, but trials in the United States have not confirmed the symptomatic improvement or healing of erosive esophagitis that has been demonstrated in studies abroad. An expanded role may unfold for cisapride and additional new prokinetic drugs as primary therapy for reflux in some patients, as adjunctive treatment with an antisecretory agent, or as maintenance treatment for a subset of patients with gastroesophageal reflux. Therapy tailored to individual pathophysiology is appropriate and may offer cost savings and improved clinical outcome.
Bethanechol↗
The rationale for continuous maintenance treatment of reflux esophagitis.
Reflux esophagitis is a chronic process associated with frequent episodes of relapse in many patients. In addition, the disease may be progressive in at least some patients. Erosion of the esophageal mucosa precedes the development of some of the complications of the condition. There is accumulating evidence that continuous treatment of patients with erosive esophagitis effectively maintains symptomatic remission and absence of esophageal erosions. Whether such treatment will prevent the development of complications has not yet been demonstrated. We investigated a number of questions concerning the natural history and complications of erosive esophagitis and the need for maintenance treatment for patients with severe manifestations of disease as well as the impact of continuous maintenance treatment on the natural history of reflux esophagitis and its complications.
Chronic Disease↗
Perspectives. Perestroika at Hopkins: new environment in microcosm.
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Academic Medical Centers↗
Growth-dependent accumulation of monoalkylglycerol in Madin-Darby canine kidney cells. Evidence for a role in the regulation of protein kinase C.
1-O-Alkyl-sn-glycerol (alkylglycerol) forms the backbone of complex ether-linked glycerolipids, including biologically active lipids such as platelet-activating factor. Synthetic alkylglycerol itself possesses several potent pharmacological activities and has been shown to inhibit protein kinase C (PKC) in vitro. In spite of these properties, free alkylglycerol has been regarded only as a potential product of the inflammatory degradation of complex ether lipids rather than a natural cell constituent. To explore the possibility that endogenous alkylglycerol functions as a physiological regulator in normal cells, we measured its content, along with related monoglycerides and diglycerides, by high performance liquid chromatography and gas-liquid chromatography in Madin-Darby canine kidney (MDCK) cells. The content of free alkylglycerol increased up to 20-fold during the growth of MDCK cell cultures to a confluent density. The increase was greatest during the log phase of growth, in which the content of alkylglycerol rose from 6.0 +/- 1.3 nmol/10(8) cells in preconfluent cultures to 23.6 +/- 3.4 nmol/10(8) cells in confluent cultures. Analysis of the molecular species of alkylglycerol showed that the higher content in quiescent MDCK cells was due primarily to an increase in 1-O-octadecyl-sn-glycerol. In contrast, the levels of monoacylglycerol and the PKC activator diacylglycerol were lower in confluent, quiescent cultures than in preconfluent, proliferating cultures. A similar pattern of changes in the monoglyceride and diglyceride content was observed in interleukin-3-dependent CFTL-12 mast cells when cell proliferation was blocked by growth factor withdrawal. Growth of MDCK cells to a confluent density resulted in a decrease in particulate PKC enzyme activity to a level that was only 6% of that in proliferating cells. To explore whether the accumulation of cellular alkylglycerol contributes to growth-dependent changes in PKC activity, we examined the effects of adding alkylglycerol to the activity and subcellular distribution of the enzyme in MDCK cells. Treatment of cells with 1-O-dodecyl-sn-glycerol resulted in a decrease in the activity of membrane-associated PKC activity and inhibited 12-O-tetradecanoylphorbol-13-acetate-stimulated translocation of PKC from the cytosol to the membrane fraction. Alkylglycerol was also shown to inhibit the activity of purified PKC in vitro when present at levels similar to that of the diacylglycerol activator. We propose that the accumulation of alkylglycerol during the growth of MDCK cells to a confluent density contributes to the decrease in PKC activity. The control of cellular alkylglycerol levels may be a novel mechanism for the regulation of cellular physiology.
Acylation↗
Heligmosomoides polygyrus adult worm homogenate superantigen: presentation to T cells requires MHC class I positive accessory cells.
A series of experiments were carried out to further characterize the previously discovered Heligmosomoides polygyrus, adult worm homogenate (AWH), superantigen. AWH, in contrast to staphylococcal enterotoxin B (SEB) superantigen, was totally unable to stimulate naive thymocytes, in either the presence or the absence of exogenous accessory cells (AC). Experiments using AC from B10 congenic mice failed to indicate a requirement for a specific MHC haplotype for successful presentation of the AWH superantigen and also indicated that the presence or absence of the H-2,E molecule on AC did not affect AWH stimulation of T cell hybridomas. Furthermore, AWH was found to require the presence of MHC class I-positive AC in order to stimulate T cell hybridomas, while, in contrast, the absence of MHC Class II on AC did not affect the superantigenic properties of AWH. Initial characterization of the T cell hybridomas stimulated by the AWH superantigen, indicated that all were CD4-positive and that three of them expressed TCR V beta 8.1. Hence AWH superantigen can stimulate TCR V beta 8.1/CD4-positive T cells only in the presence of MHC Class I-positive AC.
Animals↗
Inhibition of phorbol ester-stimulated arachidonic acid release by alkylglycerols.
Although synthetic analogs of alkylglycerol (AG), such as dodecylglycerol, possess potent biological activities, their mechanism of action has not been determined. We recently detected substantial amounts of AG in unstimulated MDCK cells (Warne, T.R. and Robinson, M. (1991) Anal. Biochem. 198, 302-307) raising the possibility that the endogenous compound may act as a biological mediator. In this study, we examined the effects of synthetic AG on the release of arachidonic acid and arachidonate metabolites (AA) from Madin Darby canine kidney (MDCK) cells in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) in order to characterize its effects on this signalling pathway. Treatment of MDCK with AG potently inhibited the release of AA during subsequent stimulation with TPA. Dodecylglycerol, the most effective of a series of alkyglycerols tested, was active at concentrations as low as 3 microM. The sn-1 and sn-3 forms of AG were found to be equally potent inhibitors. The effects of AG on AA release were not the result of arachidonic acid redistribution among cellular lipids and were independent of the phospholipid source of the released AA. AG did not inhibit the release of AA from MDCK cells when bradykinin was used as a stimulus, indicating selectivity for the effects produced by phorbol esters. These results show that AG can function as a potent and specific inhibitor of TPA-mediated AA release. The ability of AG to regulate this signalling pathway in intact MDCK cells, together with its natural occurrence, suggests a potential bioregulatory role for the endogenous compound as an inhibitor of protein kinase C.
Animals↗
Quality-of-life results of double-blind, placebo-controlled trial of mesalamine in patients with Crohn's disease.
Seven quality-of-life parameters were assessed in a trial of mesalamine in Crohn's disease. The results with regard to efficacy and safety have been previously published. A total of 310 patients were enrolled in this double-blind, parallel trial and randomized to receive placebo, or 1, 2, or 4 g/day of mesalamine in controlled-release capsules for 16 weeks. Results revealed that mesalamine at the dose of 4 g/day resulted in significant (P < 0.03) improvements from baseline in all quality-of-life parameters. A significant (P < 0.02) linear trend between increasing doses of mesalamine and increasing response was also noted. The 1- and 2-g/day doses of mesalamine also resulted in an improvement in quality of life, however, with the exception of 2 g/day of mesalamine on the hobby and recreational activities parameter, these changes were not significantly different from placebo.
Adult↗
Treatment of erosive reflux esophagitis resistant to H2-receptor antagonist therapy. Lansoprazole, a new proton pump inhibitor.
Fifty-four patients with endoscopically documented therapy-resistant erosive reflux esophagitis were treated with lansoprazole, a new proton pump inhibitor, for up to 12 weeks. Prior to entry, all had remained unhealed after treatment with at least two histamine2-receptor antagonists, at therapeutic doses or higher, for at least 12 weeks. Patients were randomized to receive either 30 or 60 mg lansoprazole once daily. Endoscopy was performed and symptoms assessed at weeks 2,4,6,8 and 12. Fifty-nine percent of the 50 evaluable patients were healed (ie, no evidence of erosions) after only two weeks of lansoprazole. Cumulative endoscopic healing rates were 82% and 92% by week 4 and week 8, respectively, and the two doses were equally effective in healing. The 30- and 60-mg doses effected a decrease in the overall symptom score from 5.30 and 4.85 to 2.35 and 1.67, respectively, by the final treatment visit (P = 0.001). No clinically significant adverse events or changes in laboratory parameters were observed, and no patients withdrew prematurely from the study. This study demonstrates that lansoprazole therapy is highly effective in healing erosive reflux esophagitis resistant to therapy with histamine H2-receptor antagonists.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Safety and efficacy of controlled-release mesalamine for maintenance of remission in ulcerative colitis. Pentasa UC Maintenance Study Group.
This 12-month, double-blind, placebo-controlled study randomized 205 ulcerative colitis patients in remission to placebo or controlled-release mesalamine at 4 g/day for 12 months. Patients were stratified to either pancolitis or left-sided disease, based on previous diagnosis. Maintenance of remission was defined as a sigmoidoscopic index of < 5, less than five stools per day, and the absence of rectal bleeding. A significantly greater number of patients maintained remission on mesalamine 4 g/day than on placebo at each of five study visits, following the first one-month visit (P < 0.05). The estimated 12-month remission rates for the mesalamine group were 64% (38% for placebo, P = 0.0004). Baseline subgroups (disease location, time since last flare of active disease, and previous response to oral/rectal steroids or sulfasalazine) did not influence remission rates. Treatment-related adverse events were rare. Controlled-release mesalamine is a safe and efficacious single agent for maintaining remission of ulcerative colitis.
Adult↗
Fecal alpha 1-antitrypsin detection of colorectal neoplasia. An evaluation using HemoQuant.
Fecal alpha 1-antitrypsin measurement may be of value for the detection of colorectal neoplasia and is compared with the HemoQuant test in 119 subjects with either a screen-positive Hemoccult result (N = 78) or iron-deficiency anaemia (N = 41). Nineteen patients were found to have colorectal cancer, 35 had colorectal adenomatous polyps, 5 had inflammatory bowel disease, and 60 had no detected cause of occult blood loss. Of the cancer patients, 63% (12/19) were detected by fecal alpha 1-antitrypsin and 63% (12/19) by HemoQuant. Of the adenomas > 1 cm in diameter 33% (7/23) were detected by fecal alpha 1-antitrypsin and 26% (6/23) by HemoQuant. There was a poor correlation between fecal alpha 1-antitrypsin and HemoQuant results for colorectal cancers (r = 0.37, P > 0.05), and combining the tests, the sensitivity for colorectal cancer was increased to 84% (16/19). Fecal protein loss, as measured using alpha 1-antitrypsin, appears to involve largely different mechanisms from that of blood loss from colorectal cancers.
Adenomatous Polyps↗
A comparison of lansoprazole and ranitidine in the treatment of erosive oesophagitis. Multicentre Investigational Group.
BACKGROUND: Lansoprazole is a new proton pump inhibitor which produces prolonged decrease of gastric acidity. The aim of this study was to compare lansoprazole to a standard dose of ranitidine in the treatment of patients with reflux oesophagitis. METHODS: Two hundred and forty-seven patients with erosive oesophagitis were randomly assigned to 8 weeks of treatment with either 30 mg lansoprazole once daily or 150 mg ranitidine twice daily. RESULTS: Two hundred and forty-two patients were included in the analysis. Lansoprazole (30 mg) daily, healed oesophagitis in 92.1% of patients after 8 weeks of treatment. This was significantly superior to 150 mg ranitidine b.d.s. which healed oesophagitis in 69.9% of patients (P < 0.001). Relief of reflux symptoms was superior with lansoprazole to that with ranitidine. Both lansoprazole and ranitidine were well tolerated with no serious drug-related adverse events noted. CONCLUSION: Lansoprazole, 30 mg once daily, is highly effective and safe in the short-term treatment of erosive oesophagitis.
2-Pyridinylmethylsulfinylbenzimidazoles↗
Genetic control of immunity to Heligmosomoides polygyrus: fixed H-2 E positive but not H-2 negative cells can present antigen to a parasite-specific T cell hybridoma.
A number of T cell hybridomas were produced to adult worm homogenate (AWH) antigen of the nematode parasite Heligmosomoides polygyrus. All of the hybridomas were of the H-2d haplotype and could potentially accept antigen in the context of either the Ad or Ed, H-2 molecules. Three types of antigen presentation were observed, with some of the T cell hybridomas accepting antigen in the context of the E and some in the context of the A molecule. A third type of hybridoma responded to antigen presented by paraformaldehyde fixed APC, but only when APCs were E positive. These same hybridomas, were however, stimulated by AWH, when the antigen was presented by syngeneic but unfixed, E positive or E negative APC. Therefore these data indicate that certain H. polygyrus-specific T cell hybridomas can accept parasite antigen when presented in the context of either the H-2 A or E molecule, but the presentation of antigen by the two different MHC Class II molecules, can apparently utilize differing processing mechanisms.
Animals↗
Multiple sclerosis: it epidemiological, genetic, and health care impact.
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Delivery of Health Care↗
After the bomb. Oklahoma City rescuers talk about their experiences.
Rather than trying to write a second-hand description of the response to the April 19 bombing of the Federal Building in Oklahoma City, we thought we'd let some of the people who were there caring for patients and searching for victims share their experiences in their own words. Marion Angell Garza, JEMS editorial/news coordinator, spoke at length with six responders, including paramedics, the triage and treatment officer, a firefighter/EMT-1 and an emergency physician. The following excerpts are from those interviews.
Anecdotes as Topic↗
Benchmarking critical pathways--a method for achieving best practice.
This article outlines the processes for the development and implementation of critical pathways to achieve best practice by two health organisations funded under the Commonwealth Government's Best Practice in the Health Sector Program. Each organisation is using a slightly different approach to using benchmarking as a tool to ensure best practice is achieved, however, they are similar in that they each demonstrate customer focus and a multidisciplinary, participative change management style.
Australia↗
Survival of newly postmitotic motoneurons is transiently independent of exogenous trophic support.
We compared the survival requirements of early- and late-born motoneurons from E5 chicken spinal cord. Density gradient centrifugation followed by immunopanning using SC1 antibody allowed us to purify two size classes of motoneuron. Large motoneurons retained by 6.8% metrizamide were shown by BrdU labeling in ovo to be born on average 1.5 d earlier than the small motoneurons recovered from the metrizamide pellet. Large motoneurons were both biochemically and functionally more mature: they expressed higher levels of choline acetyltransferase and low-affinity neurotrophin receptor, and had an acute requirement for trophic support from muscle-derived factors. After 24 hr in culture in basal medium, all early-born motoneurons died, whereas 60% of late-born motoneurons survived. Small motoneurons can develop into large motoneurons in ovo, suggesting that they represent a general transitional stage in motoneuron development. Our results suggest that a defined period elapses between birth of a motoneuron and its acquisition of trophic dependence, possibly corresponding to the time required for target innervation. This property may have important consequences for the timing and regulation of developmental motoneuron death.
Animals↗
Accumulation of fatty alcohol in MCF-7 breast cancer cells.
The MCF-7 cell line (human breast epithelial cells) accumulates fatty alcohols. The fatty alcohols were identified as C16:0, C18:0, and C18:1 alcohols by thin-layer chromatography and gas chromatography/mass spectrometry. This accumulation of alcohols in MCF-7 was found in cultures of MCF-7 cells obtained from other laboratories but not in a variety of unrelated cell lines. The presence of the alcohols suggested an aberrant ether lipid metabolism in the MCF-7 cells. Therefore, the capacity for either lipid biosynthesis was evaluated using cells incubated with either [14C]stearyl alcohol or [14C]stearic acid. MCF-7 cells incorporated less than 0.4% of the [14C]alcohol into ether-linked phospholipids, whereas the AB589 breast epithelial cells, used as a "normal control" for comparisons, did not accumulate fatty alcohol and incorporated approximately 20% of the radiolabeled alcohol into phospholipids containing ether linkages. Although the MCF-7 cells were unable to effectively incorporate the fatty alcohol into ether linkages, the cells were able to oxidize the alcohol to fatty acid. When incubated with [14C]stearic acid, the conversion to radiolabeled fatty alcohol in MCF-7 cells was approximately four times higher than the alcohol levels found in AB589 cells. While deficient in the ability to synthesize ether linkages, the MCF-7 cells did incorporate radiolabeled hexadecylglycerol, a precursor containing an ether linkage, into phospholipids. Collectively, the data indicate that the MCF-7 cells possess a deficiency in the alkyl DHAP synthase activity. A near absence of ether-linked lipids in the MCF-7 cells was indicated by the radiolabeling studies, and this finding was corroborated by results from HPLC analysis. Analyses of the partial glycerides, obtained from the enzymatic hydrolysis of cellular phospholipids, found only trace levels of ether lipids in the MCF-7 cells. The aberration in ether lipid biosynthesis did not correlate with the expression of the multidrug resistance phenotype in a series multidrug resistant MCF-7 variants. The results are discussed relative to the use of the MCF-7 cells as a model for investigations of ether lipid biosynthesis and the cellular physiology of ether lipids.
Breast Neoplasms↗