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Biomedical subjects

G Gordon

Publications and source records attributed to G Gordon.

At least 37 records · Page 2Linked to original sources
PubMed1996

Evidence that the 42- and 40-amino acid forms of amyloid beta protein are generated from the beta-amyloid precursor protein by different protease activities.

Cerebral deposition of the amyloid beta protein (A beta) is an early and invariant feature of Alzheimer disease (AD). Whereas the 40-amino acid form of A beta (A beta 40) accounts for approximately 90% of all A beta normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidogenic 42-residue form (A beta 42), accounting for only approximately 10% of secreted A beta, is deposited in the earliest phase of AD and remains the major constituent of most amyloid plaques throughout the disease. Moreover, its levels have been shown to be increased in all known forms of early-onset familial AD. Thus, inhibition of A beta 42 production is a prime therapeutic goal. The same protease, gamma-secretase, is assumed to generate the C termini of both A beta 40 and A beta 42. Herein, we analyze the effect of the compound MDL 28170, previously suggested to inhibit gamma-secretase, on beta-amyloid precursor protein processing. By immunoprecipitating conditioned medium of different cell lines with various A beta 40- and A beta 42-specific antibodies, we demonstrate a much stronger inhibition of the gamma-secretase cleavage at residue 40 than of that at residue 42. These data suggest that different proteases generate the A beta 40 and A beta 42 C termini. Further, they raise the possibility of identifying compounds that do not interfere with general beta-amyloid precursor protein metabolism, including A beta 40 production, but specifically block the generation of the pathogenic A beta 42 peptide.

Amino Acid Sequence↗
PubMed1996

Dose-range and dose-frequency study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis. The IL-1Ra Arthritis Study Group.

OBJECTIVE: To preliminarily evaluate the safety and efficacy of different dose levels and dosing frequencies of recombinant human interleukin-1 receptor antagonist (rHuIL-1Ra) in the treatment of patients with rheumatoid arthritis (RA). METHODS: One hundred seventy-five patients with active RA were enrolled in a randomized, double-blind trial of rHuIL-1Ra administered by subcutaneous injection. There were 9 treatment groups in the trial. During the initial 3-week treatment phase, patients were treated with 20, 70, or 200 mg rHuIL-1Ra, administered either once, 3 times, or 7 times per week, followed by a 4-week maintenance phase, during which all patients received the treatment-phase dose once per week. To maintain the blindness of the study, patients received daily injections of either rHulL-1Ra or placebo on the days rHuIL-1Ra was not administered. RESULTS: Recombinant HuIL-1Ra was well tolerated. The most frequent adverse event was injection-site reactions, which were reported in 62% of patients and caused 8 patients (5%) to withdraw prematurely from the study. Five patients (3%) developed serious adverse reactions unrelated to dose or dosing frequency. Due to the lack of a placebo arm and to the multiple small treatment groups, a definitive statement regarding efficacy could not be made. However, by the end of the 3-week treatment phase, daily dosing appeared more effective than weekly dosing when assessed by the number of swollen joints, the investigator and patient assessments of disease activity, pain score, and C-reactive protein levels. CONCLUSION: These preliminary data suggest that rHuIL-1Ra may be safely administered by subcutaneous injection to RA patients. The frequency of dosing appears to be important in determining clinical response, with daily administration providing the most benefit. A placebo-controlled trial is in progress to further assess the clinical usefulness and to better define appropriate doses of rHuIL-1Ra in patients with RA.

Antibodies↗
PubMed1996

Evidence for a prolonged role of alpha 4 integrin throughout active experimental allergic encephalomyelitis.

The leukocyte integrin receptor, alpha 4 beta 1, and its endothelial cell ligand, vascular cell adhesion molecule 1, appear to be of critical importance in the leukocyte trafficking that accompanies CNS damage in experimental allergic encephalomyelitis (EAE). In this study, the persistence of the role for alpha 4 beta 1/VCAM-1 in EAE was established by observing antibody-mediated disease reversal up to 1 month following disease onset. Limited treatment with a monoclonal antibody against alpha 4 integrin, GG5/3, resulted in a significant decrease in both clinical and histopathologic signs. This was not observed in isotype control experiments. In the latter phase of progressive disease, widespread demyelination occurred in the animals that did not respond to 6 days of anti-alpha 4 treatment. These results demonstrate an essential role for alpha 4 beta 1 interactions throughout active EAE and illustrate the difference between reversible clinical deficits caused by edema and irreversible deficits associated with demyelination.

Animals↗
PubMed1996

Tenidap in patients with rheumatoid arthritis. A 4-week, placebo-controlled study.

The present double-blind, placebo-controlled study was conducted to compare the safety and efficacy of tenidap in patients with rheumatoid arthritis (RA). Patients with flare of active RA following NSAID withdrawal were randomized to receive either placebo (n = 67) or tenidap (n = 131; 40-200 mg/day). The mean changes from baseline in efficacy and biochemical variables were compared between treatment groups at endpoint (4 weeks). The improvements in four of the five primary efficacy variables were significantly greater in the tenidap group compared with the placebo group (p < 0.01). Tenidap was also associated with an 18% reduction in erythrocyte sedimentation rate (ESR) and a marked, 51%, reduction in serum C-reactive protein (CRP) level, both of which were significantly greater than the changes in the placebo group (p < 0.05). The percentage of patients who discontinued because of side effects was the same in both groups (3%). In conclusion, tenidap 40-200 mg/day was effective and well tolerated in the treatment of patients with RA for 4 weeks.

Administration, Oral↗
PubMed1996

Developing a cost accounting system for a physician group practice.

Physicians in group practices must gain a competitive edge to survive in a healthcare environment in which cost efficiency has become critical to success. One tool that can help them is a cost accounting system that yields reliable, detailed data on the costs of delivering care. Such a system not only can enable physicians and group administrators to manage their operations more cost-effectively, but also can help them accurately assess the potential profitability of prospective managed care plans. An otolaryngology practice located in Mississippi provides a model for developing a cost accounting system that can be applied to physician group practices.

Accounting↗
PubMed1996

Lack of persistence of E1- recombinant adenoviral vectors containing a temperature-sensitive E2A mutation in immunocompetent mice and hemophilia B dogs.

Two recombinant adenoviruses expressing either human alpha 1-antitrypsin (hAAT) or canine factor IX (cFIX) were modified so that they also contained a temperature-sensitive mutation (ts125) in the DNA binding protein encoded within the viral E2A region. The effects of the inclusion of the ts125 mutation on transgene expression in vivo were evaluated in Balb/c mice and hemophilia B dogs by comparison with adenoviral vectors containing the same transgene but lacking the ts125 mutation. No significant differences in the duration of transgene expression were observed in either animal model. Insufficiency of the ts125 mutation in the prolongation of transgene expression in these two animal models suggests that further modification of the vector backbone may be required to achieve long-term gene expression in a wide variety of applications. Additionally, humoral immune response to transgene products has been demonstrated in immunocompetent animal models, which will also need to be surmounted for long-term efficacy in disease treatment by gene therapy.

Adenoviridae↗
PubMed1995

Effects of variations in flow on aortic valve area in aortic stenosis based on in vivo planimetry of aortic valve area by multiplane transesophageal echocardiography.

This study provides evidence that acute changes in stroke volume and cardiac output do not result in significant alterations in the anatomic AVA measured with multiplane TEE in patients with AS of moderate or severe degree. Thus, TEE could be useful in the assessment of severity of AS in both low- and high-output states.

Adult↗
PubMed1995

On the mechanism of interaction of steroids with human glucose 6-phosphate dehydrogenase.

Previous studies have demonstrated that certain 17- and 20-ketosteroids are potent inhibitors of the NADP-linked oxidation of glucose 6-phosphate by mammalian glucose 6-phosphate dehydrogenases. This inhibition is uncompetitive with respect to both NADP+ and glucose 6-phosphate. In order to elucidate the detailed mechanism of this rare type of inhibition, we examined the effects of steroids on human glucose 6-phosphate dehydrogenase catalyzing the reverse reaction, i.e., the reduction of the gluconolactone by NADPH. To circumvent problems associated with the known instability of 6-phospho-delta-gluconolactone, the natural product of glucose 6-phosphate oxidation, the more stable 6-phospho-gamma-gluconolactone was used. Dehydroepiandrosterone, epiandrosterone, 16 alpha-bromoepiandrosterone, and dehydroepiandrosterone sulfate all inhibited the reverse reaction uncompetitively with respect to both NADPH and the gamma-lactone. The Ki values for each of these steroids, determined by varying either coenzyme or substrate in both the forward and the reverse reactions, are very similar. These results demonstrate that steroids inhibit glucose 6-phosphate dehydrogenase by binding to the ternary enzyme-coenzyme-substrate ternary complex(es). This is the first direct demonstration that uncompetitive inhibition of a two-substrate enzyme, by compounds other than its substrates or products, can occur by binding of the inhibitor to a ternary enzyme complex.

Dehydroepiandrosterone↗
PubMed1995

Gene therapy for hemophilia B: host immunosuppression prolongs the therapeutic effect of adenovirus-mediated factor IX expression.

Hemophilia B is caused by a deficiency of blood clotting factor IX (FIX). Previous studies have shown that the delivery of a recombinant adenoviral vector expressing canine FIX (cFIX) resulted in a complete correction of hemophilia B in FIX-deficient dogs, but that cFIX expression decreased to only about 1-2% of normal levels 3 weeks after treatment. In the present study, therapeutic levels of cFIX expression capable of producing a partial correction of hemophilia B were maintained for at least 6 months after the coadministration of the cFIX-expressing adenovirus and the immunosuppressive agent cyclosporin A (CsA). These findings support a recent report (Yang et al., 1994) that host T-cell-mediated immunity against virally transduced cells is a major contributing factor to the transient nature of adenovirus-mediated gene expression in immunocompetent animals. Although a second administration of the cFIX-expressing adenovirus 6 months after the first infusion had only a minimal effect on plasma FIX levels in a dog that had been continuously treated with CsA, the prolonged expression of the transgene indicates that immunosuppression may be applicable in attaining long-term treatment of clinically relevant disorders.

Adenoviridae↗
PubMed1994

Invasive otitis externa due to Aspergillus species: case report and review.

Aspergillus flavus, an unusual cause of malignant external otitis, was identified in pure culture of tissue from two patients in which histologic examinations demonstrated branching septate hyphae invading the temporal bone. Both patients presented with protracted external ear pain. Multiple attempts at treatment with topical agents (polymyxin B sulfate-neomycin sulfate-hydrocortisone), oral agents (cephalexin and ciprofloxacin), and parenteral agents (ceftazidime and tobramycin) were unsuccessful before definitive diagnosis was made. Treatment with amphotericin B, followed by a more protracted course of itraconazole, resulted in an apparent cure for these patients. Follow-up examination at 15 months after the discontinuation of therapy with itraconazole demonstrated no recurrence of infection. Previously reported cases have predominantly involved immunocompromised persons, and these cases are summarized.

Aged↗
PubMed1993

Transesophageal echocardiography for hemodynamic management of thoracoabdominal aneurysm repair.

Maintenance of cardiovascular stability during thoracoabdominal aneurysm repair remains a formidable challenge. Transesophageal echocardiography (TEE) has been shown to be an excellent method for detecting myocardial ischemia and assessing left ventricular volume. We examined the utility of TEE in a group of 17 patients from an overall series of 33 patients who underwent thoracoabdominal aneurysm resection between 1988 and 1992. The mortality rate was 9%, whereas the incidences of myocardial infarction and paraplegia were 13% and 6%, respectively. Intraoperative management was significantly altered by TEE data in nine patients. Two patients were noted to have mitral valve insufficiency, and one had transient ischemia-induced regional wall abnormalities. In six patients, Swan-Ganz-derived filling data failed to identify severe hemodynamic alterations that were noted on TEE. Five patients were hypovolemic and hyperdynamic, whereas one was in florid congestive heart failure. Further investigation is warranted to prospectively validate this technique.

Adult↗
PubMed1993

A community-based approach to HIV case management: systematizing the unmanageable.

This article presents an analysis and typology of community-based care for a young Hispanic mother with acquired immune deficiency syndrome (AIDS). It develops a conceptual framework that examines retrospectively the needs generated by AIDS over time, the appropriateness of the services, and an assessment of the interventions. Community-based case management can effectively address some of the diverse and changing needs of AIDS patients and their families, such as bridging service gaps and fortifying patient and system strengths while minimizing their weaknesses. Community-based case managers may also be better equipped than hospital case managers to work with difficult patients and coordinate community- and hospital-based care. Conclusions are presented regarding the definition and implementation of community-based, culturally sensitive, family-centered human immunodeficiency virus case management, as well as the importance and difficulty of developing relationships among the family, health care providers, and institutions within the community.

Acquired Immunodeficiency Syndrome↗