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Biomedical subjects

J L Goldstein

Publications and source records attributed to J L Goldstein.

At least 37 records · Page 2Linked to original sources
PubMed2001

Comparison of novel and existing methods for detection of linkage disequilibrium using parent-child trios in the GAW12 genetic isolate simulated data.

A novel method for joint detection of association caused by linkage disequilibrium (LD) and estimation of both recombination fraction and linkage disequilibrium parameters was compared to several existing implementations of the transmission/disequilibrium test (TDT) and modifications of the TDT in the simulated genetic isolate data from Genetic Analysis Workshop 12. The first completely genotyped trio of affected child and parents was selected from each family in each replicate so that the TDT tests are valid tests of linkage and association, rather than being only valid as tests for linkage. In general, power to detect LD using the genome-wide scan markers was inadequate in the individual replicate samples, but the power was better when analyzing several SNP markers in candidate gene 1.

Adult↗
PubMed2001

Enteroscopy.

Explore the source record for details and available documents.

Endoscopy, Gastrointestinal↗
PubMed2001

Upper gastrointestinal safety evaluation of parecoxib sodium, a new parenteral cyclooxygenase-2-specific inhibitor, compared with ketorolac, naproxen, and placebo.

BACKGROUND: Conventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with an increased risk of ulcers and upper gastrointestinal (GI) ulcer complications, which has been attributed to the inhibition of cyclooxygenase-1. These risks are usually increased in elderly populations. Parecoxib sodium is an injectable prodrug of the cyclooxygenase-2-specific inhibitor valdecoxib that has exhibited analgesic activity in previous trials. OBJECTIVE: The purpose of this study was to compare the GI safety and tolerability profile of parecoxib sodium with that of ketorolac, naproxen, and placebo in a 7-day endoscopic trial in elderly subjects. METHODS: This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. After a normal baseline endoscopy, healthy elderly subjects aged 66 to 75 years were randomized to receive i.v. parecoxib sodium (10 mg BID), oral naproxen (500 mg BID), or placebo for 7 days, or placebo for 2 days followed by i.v. ketorolac (15 mg QID) for 5 days. Endoscopy was performed again after 7 days. RESULTS: Among the first 17 subjects enrolled, ulcers were observed in all treatment groups except the parecoxib sodium group (ketorolac, 4/4 subjects; naproxen, 2/4 subjects; and placebo, 2/5 subjects). Four subjects in the ketorolac group and 1 subject in the naproxen group had multiple gastric ulcers or combined gastric and duodenal ulcers. Because of the unexpectedly high incidence of gastroduodenal ulcers observed, the study was terminated early and the randomization blind broken. CONCLUSION: These findings suggest that elderly patients may be at risk for GI ulceration even after short-term use of the conventional NSAIDs ketorolac and naproxen.

Aged↗
PubMed2001

Esomeprazole once daily for 6 months is effective therapy for maintaining healed erosive esophagitis and for controlling gastroesophageal reflux disease symptoms: a randomized, double-blind, placebo-controlled study of efficacy and safety.

OBJECTIVE: Esomeprazole, the S-isomer of omeprazole, achieves a significantly greater healing rate and symptom resolution of erosive esophagitis than that achieved by omeprazole. The objective of this study is to assess the efficacy of the new proton pump inhibitor esomeprazole in preventing relapse over a prolonged period in patients with healed erosive esophagitis. METHODS: A total of 318 gastroesophageal reflux patients whose erosive esophagitis was healed in a comparative study of esomeprazole 40 mg, 20 mg, or omeprazole 20 mg, were randomized to maintenance therapy with once daily esomeprazole 40 mg, 20 mg, or 10 mg, or placebo in a U.S., double-blind multicenter trial. RESULTS: After 6 months, healing was maintained (cumulative life table rates) in 93.6% (95% CI 87.4-99.7) of patients treated with esomeprazole 40 mg, 93.2% (95% CI 87.4-99.0) treated with esomeprazole 20 mg, and 57.1% (95% CI 45.2-69) treated with esomeprazole 10 mg; p < 0.001 vs placebo (29.1%; 95% CI 17.7-40.3). Of patients relapsing, mean time to first recurrence of esophagitis increased with dose, from 34 days (placebo) to 78 days (10 mg), 115 days (20 mg), and 163 days (40 mg). Patients treated with esomeprazole had less frequent and less severe heartburn than those treated with placebo. At month 6, more than 70% of patients being treated with esomeprazole remained symptom-free. CONCLUSIONS: Esomeprazole is effective and well tolerated in the maintenance of a healing erosive esophagitis. Esomeprazole 40 mg and 20 mg maintain healing in over 90% of patients while providing effective control of heartburn symptoms.

Administration, Oral↗
PubMed2001

Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis.

OBJECTIVE: Nonsteroidal anti-inflammatory drugs (NSAIDs) block prostaglandin production by inhibiting cyclooxygenase (COX); they are believed to cause gastroduodenal damage by inhibiting the COX-1 isoform and to have analgesic and anti-inflammatory effects by inhibiting the COX-2 isoform. As compared to conventional NSAIDs, celecoxib, a COX-2 specific inhibitor, has been shown in previous single posttreatment endoscopy studies to be associated with lower gastroduodenal ulcer rates. In response to concerns that such studies may under-represent ulceration rates, the present serial endoscopy study was designed to compare cumulative gastroduodenal ulcer rates associated with the use of celecoxib to those of naproxen, a conventional NSAID. METHODS: In this double-blind, parallel-group, multicenter study, 537 patients with osteoarthritis (OA) or rheumatoid arthritis (RA) were randomized to treatment with celecoxib 200 mg b.i.d. (n = 270) or naproxen 500 mg b.i.d. (n = 267) for 12 wk. Gastroduodenal damage was determined from esophagogastroduodenoscopy after 4, 8, and 12 wk of therapy. Arthritis efficacy was evaluated with Patient's and Physician's Global Assessments. RESULTS: Gastroduodenal ulcer rates after celecoxib and naproxen treatment were 4% versus 19% in the 0-4 wk interval (p < 0.001), 2% versus 14% in the 4-8 wk interval (p < 0.001), and 2% versus 10% in the 8-12 wk interval (p < 0.001), respectively. After 12 wk of treatment, the cumulative incidence of gastroduodenal ulcers was 9% with celecoxib and 41% with naproxen. In the celecoxib group, gastroduodenal ulcers were significantly associated with Helicobacter pylori status (p < 0.05), concurrent aspirin usage (p = 0.001), and a history of ulcer (p = 0.010), but not with disease type (OA/RA), age, gender, other relevant medical histories, or concurrent corticosteroid or disease-modifying antirheumatic drugs usage (p > 0.05). Celecoxib produced a significantly lower incidence rate of both gastric (p < 0.001) and duodenal (p < 0.030) ulcers. The two agents produced similar improvements in Patient's and Physician's Global Assessments of arthritis efficacy. The incidence of adverse events and withdrawal rates did not differ significantly between treatments. CONCLUSIONS: As compared to naproxen (500 mg b.i.d.), use of celecoxib (200 mg b.i.d.), a COX-2 specific agent, at the recommended RA dose and twice the most frequently prescribed OA dose, was associated with lower rates of gastric, duodenal, and gastroduodenal ulcers but had comparable efficacy, in patients with OA and RA.

Adult↗
PubMed2001

Low molecular weight heparin versus unfractionated heparin in the colonoscopy peri-procedure period: a cost modeling study.

OBJECTIVE: The aim of this study was to compare the economic outcomes of peri-procedure anticoagulation approaches for elective colonoscopy. METHODS: Decision analysis was used to model the economic outcomes of five peri-procedure anticoagulation options: outpatient low molecular weight heparin (LMWH), inpatient unfractionated heparin infusion (UFHi), continuous warfarin (with probability of a repeat procedure using LMWH or UFHi), and discontinuation of anticoagulation therapy. The model's base-case scenario assumed drug therapy options for high-risk patients were equally effective in preventing a thromboembolic event (0.1% risk), with a higher probability for the no anticoagulation strategy (0.4%); event costs were based on published data and adjusted to 1997 dollars. Drug costs reflected 1997 average wholesale price. Medical costs for other variables were estimated based on local hospital charges. Indirect costs were not considered. Risk probabilities and LMWH drug cost were tested in sensitivity analysis. RESULTS: In the base-case scenario, costs for the options evaluated were $1436/patient, $1792/patient, $1848/patient, $2629/patient, and $5196/patient for no anticoagulation, continuous warfarin/repeat LMWH, LMWH as outpatient, continuous warfarin/repeat UFHi, and UFHi as inpatient respectively ($1997). Discontinuing anticoagulation was the least costly approach but involved the greatest thromboembolic risk. The cost of continued warfarin anticoagulation/repeat LMWH was minimally less than the LMWH option, but assumes 25% of patients would require a second procedure. The traditional approach (UFHi) requires an extended hospitalization and is the most costly option. Varying risk category or LMWH cost in sensitivity analysis had a negligible impact on overall costs. CONCLUSION: Within the model's assumptions, LMWH offers a novel, convenient, and economical solution to the problem of peri-procedure anticoagulation for elective colonoscopy.

Ambulatory Care↗
PubMed2001

Recurrence and malignancy rates in a benign colorectal neoplasm patient cohort: results of a 5-year analysis in a managed care environment.

OBJECTIVE: To estimate the apparent recurrence rates of benign neoplasms and the development of malignant colorectal neoplasms over a 5-yr period in a high risk managed care population. METHODS: Using the CPT and ICD-9 CM codes, a cohort of subjects with benign neoplasms were identified with a colonoscopy in 1992 from a longitudinal claims database (MarketScan). Three groups of subjects (benign neoplasms with polypectomy, benign neoplasms without polypectomy, and no neoplasms) were evaluated. Five-year recurrence rates of benign or new malignant colorectal neoplasms were determined for the baseline benign neoplasms with polypectomy and no neoplasm groups. For the benign neoplasm without polypectomy, only rates for malignancy were evaluated. RESULTS: Of 16,293 subjects at baseline, 39.50% were diagnosed with benign and 5.50% with malignant neoplasms. The 5-yr cumulative incidence of benign neoplasms in subjects without an index neoplasm (n = 8,967) was 7.92% compared to the recurrence of 40.93% in subjects with a benign neoplasm and polypectomy (n = 4,046) at baseline (p < 0.001). The 5-yr cumulative incidence rates of malignant colorectal neoplasms in the no neoplasm (n = 8,967) and benign neoplasm groups (n = 6,438) were 1.81% and 2.55%, respectively (p < 0.005). A lower 5-yr malignancy rate was observed in benign neoplasm group with polypectomy (2.17%) compared to the benign neoplasm group without polypectomy (3.18%) (p < 0.05). CONCLUSION: The high recurrence rate of benign colorectal neoplasms and a higher incidence of colorectal cancer in subjects at high risk (history of benign colorectal neoplasm) highlight a healthcare opportunity for surveillance and/or interventions to reduce the morbidity associated with colorectal neoplasms.

Adult↗
PubMed2001

A framework for evaluating the clinical consequences of initial therapy with NSAIDs, NSAIDs plus gastroprotective agents, or celecoxib in the treatment of arthritis.

OBJECTIVE: The purpose of this study is to provide a framework for estimating the economic efficiency of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), concomitant gastroprotective agents (GPAs) to reduce the risk of NSAID toxicity, and celecoxib, a specific cyclo-oxygenase-2 inhibitor. Concomitant GPA therapies considered include one of the following: proton pump inhibitors (PPIs) plus NSAIDs, histamine H2 receptor antagonists (H2RAs) plus NSAIDs, misoprostol plus NSAIDs, and a single tablet formulation of diclofenac/misoprostol. DESIGN: The study employs a decision-tree framework to establish probabilities of upper gastrointestinal (GI) adverse events occurring over a 6-month time frame. Celecoxib clinical trial data are used to establish probabilities of upper GI events for celecoxib and NSAIDs, and published literature is used to predict upper GI events for the other concomitant therapies. Upper GI adverse events included in the decision-tree are as follows: GI discomfort, symptomatic ulcer, serious GI complications (with and without death), and anaemia with occult bleeding. MAIN OUTCOME MEASURES AND RESULTS: Clinical probabilities indicate celecoxib has significant tolerability and safety advantages compared with nonselective NSAIDs. Celecoxib also reduces the risk of GI adverse events to a similar or superior degree when compared with reductions observed with NSAIDs with concomitant GPAs. CONCLUSION: Use of celecoxib is expected to significantly reduce the economic costs of GI toxicity and its associated morbidity.

Anemia↗
PubMed2000

Unsaturated fatty acids down-regulate srebp isoforms 1a and 1c by two mechanisms in HEK-293 cells.

Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that increase the synthesis of fatty acids as well as cholesterol in animal cells. All three SREBP isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their proteolytic release from membranes. Previous data indicate that the SREBPs are also negatively regulated by unsaturated fatty acids, but the mechanism is uncertain. In the current experiments, unsaturated fatty acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic kidney (HEK)-293 cells. The potency of unsaturated fatty acids increased with increasing chain length and degree of unsaturation. Oleate, linoleate, and arachidonate were all effective, but the saturated fatty acids palmitate and stearate were not effective. Down-regulation occurred at two levels. The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteolytic processing of these SREBPs was inhibited. When SREBP-1a was produced by a cDNA expressed from an independent promoter, unsaturated fatty acids reduced nuclear SREBP-1a without affecting the mRNA level. There was no effect when the cDNA encoded a truncated version that was not membrane-bound. When administered together, sterols and unsaturated fatty acids potentiated each other in reducing nuclear SREBP-1. In the absence of fatty acids, sterols did not cause a sustained reduction of nuclear SREBP-1, but they did reduce nuclear SREBP-2. We conclude that unsaturated fatty acids, as well as sterols, can down-regulate nuclear SREBPs and that unsaturated fatty acids have their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas sterols have their greatest inhibitory effects on SREBP-2.

Base Sequence↗
PubMed2000

Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-1c) by oxysterol receptors, LXRalpha and LXRbeta.

The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.

Animals↗