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Biomedical subjects

J Cook

Publications and source records attributed to J Cook.

At least 91 records · Page 5Linked to original sources
PubMed1998

Once-weekly fluconazole (450 mg) for 4, 6, or 9 months of treatment for distal subungual onychomycosis of the toenail.

BACKGROUND: Fluconazole is a bis-triazole antifungal agent approved for the treatment of oropharyngeal, esophageal, and vaginal candidiasis, serious systemic candidal infections, and cryptococcal meningitis. OBJECTIVE: The purpose of this study was to evaluate three different durations of once-weekly fluconazole for the treatment of onychomycosis of the toenail caused by dermatophytes. METHODS: In a multicenter, randomized, double-blind, parallel, placebo-controlled trial, 384 patients with distal subungual onychomycosis of the toenail received fluconazole, 450 mg once weekly, or placebo for 4, 6, or 9 months. For inclusion, patients were required to have mycologically confirmed distal subungual onychomycosis of the toenail with a large toenail at least 25% clinically affected but having at least 2 mm of healthy nail between the nail fold and the proximal onychomycotic border. Efficacy was assessed by clinical and mycologic (microscopic and microbiologic) measures at screening, at every treatment visit starting at month 3, and at months 2, 4, and 6 after therapy. Observed or volunteered adverse events were recorded and classified at all visits. RESULTS: At the end of treatment, very significantly superior clinical and mycologic results were achieved in all fluconazole groups compared with placebo (p=0.0001). This superiority was largely maintained over 6 months of follow-up. The clinical and mycologic responses of the 9-month treatment duration were significantly superior to the 4- and 6-month durations. Similar percentages of patients in the fluconazole and placebo groups reported adverse experiences for all three durations of the study. CONCLUSION: Results of this study support the efficacy and safety of fluconazole in the treatment of distal subungual onychomycosis of the toenail.

Adolescent↗
PubMed1998

Suppressed thromboxane production in endotoxin-desensitized THP-1 cells is not a result of decreased prostaglandin H synthase activity.

Pre-exposure of THP-1 cells to low concentrations of endotoxin (lipopolysaccharide, LPS) down-regulates thromboxane (Tx) A2, an arachidonic acid (AA) metabolite, production in response to a subsequent LPS stimulation. To further delineate the mechanisms of LPS-induced down-regulation of TxA2, we examined expression of prostaglandin H synthase (PGHS)-2 mRNA, changes in PGHS activity, and content of PGHS-1 and -2. Pre-exposure to LPS (1 microg/mL for 18 h to desensitize cells) inhibits production of TxB2, the stable metabolite of TxA2, in response to secondary stimulation of LPS (10 microg/mL), when compared with LPS-stimulated naive cells (p < .05, n=5). LPS (10 microg/mL) induced expression of PGHS-2 mRNA at 1 and 2 h in naive cells, but this expression was decreased in the LPS-desensitized cells. However, exogenous AA (16 microM) or phorbol myristic acid (PMA), 3 microM) stimulated greater TxB2 production in the LPS-desensitized cells than in the naive cells (p < .05). Protein content of PGHS-1 and -2 were examined by Western blot analysis, using antibodies specific for PGHS-1 and PGHS-2. Densitometric analysis demonstrated a significant increase in PGHS-2 induction in LPS-stimulated naive cells (405+/-174%) over its respective basal group (p < .05, n=5). PGHS-1 was constitutively present, but there was no significant difference in quantity between naive and LPS-desensitized basal or LPS-stimulated groups. Thus, despite the reduction in expression of PGHS-2 mRNA, these composite data demonstrate that down-regulation of PGHS activity (assessed with exogenous AA or PMA) cannot be responsible for the inhibition of AA metabolism observed in LPS desensitization.

Arachidonic Acid↗
PubMed1998

Retroviral diversity and distribution in vertebrates.

We used the PCR to screen for the presence of endogenous retroviruses within the genomes of 18 vertebrate orders across eight classes, concentrating on reptilian, amphibian, and piscine hosts. Thirty novel retroviral sequences were isolated and characterized by sequencing approximately 1 kb of their encoded protease and reverse transcriptase genes. Isolation of novel viruses from so many disparate hosts suggests that retroviruses are likely to be ubiquitous within all but the most basal vertebrate classes and, furthermore, gives a good indication of the overall retroviral diversity within vertebrates. Phylogenetic analysis demonstrated that viruses clustering with (but not necessarily closely related to) the spumaviruses and murine leukemia viruses are widespread and abundant in vertebrate genomes. In contrast, we were unable to identify any viruses from hosts outside of mammals and birds which grouped with the other five currently recognized retroviral genera: the lentiviruses, human T-cell leukemia-related viruses, avian leukemia virus-related retroviruses, type D retroviruses, and mammalian type B retroviruses. There was also some indication that viruses isolated from individual vertebrate classes tended to cluster together in phylogenetic reconstructions. This implies that the horizontal transmission of at least some retroviruses, between some vertebrate classes, occurs relatively infrequently. It is likely that many of the retroviral sequences described here are distinct enough from those of previously characterized viruses to represent novel retroviral genera.

Amino Acid Sequence↗
PubMed1998

Phase I study of paclitaxel as a radiation sensitizer in the treatment of mesothelioma and non-small-cell lung cancer.

PURPOSE: To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel with concurrent thoracic irradiation in patients with malignant pleural mesothelioma and locally advanced non-small-cell lung cancer (NSCLC) using a 120-hour continuous infusion regimen. A secondary objective was to assess the effect of paclitaxel on the cell cycle through serial tumor biopsies. PATIENTS AND METHODS: Paclitaxel was administered as a 120-hour (5-day) continuous infusion repeated every 3 weeks during the course of radiation therapy. The starting dose of paclitaxel was 90 mg/m2. Doses were escalated at 15-mg/m2 increments in successive cohorts of three patients. In NSCLC patients, radiation was delivered to the primary tumor and regional lymph nodes for a total tumor dose of 6,120 cGy. In mesothelioma patients, hemithoracic irradiation was delivered as the initial treatment field with a conedown to the tumor volume for a total dose of 5,760 to 6,300 cGy. Tumor biopsies were obtained, if possible, before and during paclitaxel treatment. RESULTS: Thirty patients were entered onto this study through three dose levels (from 90 mg/m2 to 120 mg/m2). The MTD was determined to be 105 mg/m2. The dose-limiting toxicity was grade 4 neutropenia (two patients). Grade 2 gastrointestinal (GI) toxicity (nausea and vomiting) was also observed at 120 mg/m2. Three of 30 patients developed a hypersensitivity reaction. Six patients had grade 2 lung injury manifested by a persistent cough that required antitussives. Five patients underwent tumor biopsies. None of the patients showed a significant block of cells in mitosis (G2/M) after paclitaxel infusion. CONCLUSION: The MTD of paclitaxel, when administered as a 120-hour continuous infusion with concurrent radiotherapy, was determined to be 105 mg/m2. The dose-limiting toxicity was neutropenia. Continuous infusion paclitaxel administered with large field irradiation of the lung is well tolerated and deserves continued evaluation.

Adult↗
PubMed1998

Modifying effects of amlodipine on cyclosporin A-induced changes in renal function in patients with psoriasis.

OBJECTIVE: To assess the benefit of amlodipine, a calcium channel blocker, on renal function and vasoactive hormones in individuals with normal kidneys and blood pressure and who were being treated with cyclosporin A for refractory psoriasis. DESIGN: An open-label, two-stage, longitudinal study was employed. METHODS: Patients were divided into two groups: Group I received cyclosporin A, 5 mg/kg per day for 6 months titrated down to 2.5-3.5 mg/kg per day for 6 months, then concomitant amlodipine 5 mg/day for 6 months; and Group II received concomitant cyclosporin A, 5 mg/kg per day, and amlodipine, 5 mg/day, for 6 months. Blood pressure, serum creatinine, glomerular filtration rate, urinary magnesium, plasma renin activity and urinary kallikrein excretion were measured before and after treatment. RESULTS: Eighteen patients were enrolled, and 12 completed the study. In Group I (n = 7), 12 months of cyclosporin A therapy significantly increased systolic blood pressure and significantly decreased glomerular filtration rate, plasma renin activity and active urinary kallikrein. Amlodipine reversed these changes. In Group II (n = 5), 6 months of concomitant cyclosporin A and amlodipine significantly reduced active urinary kallikrein levels. No significant changes occurred in the other measured parameters in either group. CONCLUSIONS: Cyclosporin A produces a sustained and significant fall in glomerular filtration rate and urinary kallikrein excretion, even in patients with normal kidneys and blood pressure. Amlodipine is potentially capable of reversing these nephrotoxic effects.

Adult↗
PubMed1997

Synthesis and evaluation of polycyclic pyrazolo[3,4-d]pyrimidines as PDE1 and PDE5 cGMP phosphodiesterase inhibitors.

Polycyclic pyrazolo[3,4-d]pyrimidines (represented by 3 and 4) were synthesized as analogues of the recently reported polycyclic guanine phosphodiesterase (PDE) inhibitors. From the structure-activity relationship (SAR) development of a series of compounds, it was discovered that C-3 benzyl and N-2 methyl disubstitution on the pyrazole ring gave the best combination of potency and selectivity for PDE1 and PDE5 cGMP PDEs as represented by compound 4c: PDE1, IC50 = 60 nM; PDE3, IC50 = 55,000 nM; PDE5, IC50 = 75 nM. These compounds were also evaluated in vivo and found to be good orally active antihypertensives in laboratory animal models. Finally, comparisons were made of the in vitro and in vivo profiles of the pyrazolo-[3,4-d]pyrimidine compound 4c with those of two representative guanine compounds.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Potent tetracyclic guanine inhibitors of PDE1 and PDE5 cyclic guanosine monophosphate phosphodiesterases with oral antihypertensive activity.

Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1997

Recombinant antibodies with conformationally constrained HIV type 1 epitope inserts elicit glycoprotein 160-specific antibody responses in vivo.

Although neutralizing epitopes have been identified on the HIV-1 gp120/gp41 envelope complex, efforts to exploit this information through the construction of synthetic peptide vaccines have been largely unsuccessful. Unfortunately, synthetic peptides tend to be poorly immunogenic, and most often lack the conformational characteristics of the corresponding epitope in the native protein. In an effort to circumvent these difficulties, we have utilized an anti-class II MHC antibody as a molecular scaffold for the construction of two conformationally constrained neutralizing HIV-1 epitopes. Previously we demonstrated that anti-class II MHC antibodies can function as vectors for the induction of adjuvant-independent antibody responses to incorporated epitopes. In this instance, one epitope, IHIGPGRAFYT, is the crown of the V3 loop from gp120, and the other, ELDKWAS, is a neutralizing epitope from gp41. The insertion of these epitopes into a specific loop region of the immunoglobulin heavy chain FR3 was found to preserve the anti-class II MHC-binding activity of these recombinant antibodies, and the inserts were recognized by epitope specific monoclonal antibodies. When utilized as immunogens, each of these epitope insertion antibodies was able to induce high-titer anti-HIV-1 gp160 responses in guinea pigs. These responses were conformation specific in that the anti-gp160 binding was not inhibited by the synthetic peptide corresponding to the epitope in question. These data demonstrate the potential to construct conformationally constrained HIV-1 epitope immunogens, and thus establish an alternative approach to the design of an effective HIV-1 subunit vaccine.

Amino Acid Sequence↗
PubMed1997

Acidic fibroblast growth factor (FGF1) increases survival and haematopoietic recovery in total body irradiated C3H/HeNCr mice.

Basic fibroblast growth factor is known to stimulate the proliferation of bone marrow stem and/or progenitor cells in vitro and in vivo. We examined a similar cytokine, acidic fibroblast growth factor (FGF1), for its in vivo radiomodifying effects. Female C3H/HeNCr mice were given human recombinant FGF1 intravenously at doses ranging from 1 to 24 micrograms. FGF1 was delivered in two equal doses 24 and 4 h before or 24 h after otherwise lethal total body irradiation (TBI). In vivo FGF1 radioprotection of C3H mice was maximized at a total dose of 12 micrograms/mouse given before TBI. The radiomodification was 1.16 +/- 0.03 (+/- 1 SD) with an increase of LD50/30 from 736 +/- 9 to 854 +/- 16 cGy (P < 0.01). Some retroactive radiomodification was observed even when FGF1 was given 24 h after irradiation (P < 0.05). FGF1 radioprotected mice by improving the repopulation of haematopoietic progenitor cells of bone marrow. The radioprotection was not associated with an increase in S-phase fraction or detectable circulating IL-3, TNF-alpha or GM-CSF, suggesting that other mechanisms of protection were responsible.

Animals↗
PubMed1997

Human endogenous retrovirus type I-related viruses have an apparently widespread distribution within vertebrates.

Retroviruses from lower vertebrate hosts have been poorly characterized to date. Few sequences have been isolated, and those which have been reported are all highly divergent when compared to the retroviruses known to be harbored by mammals and birds. Here we show that retroviruses with significant homology to the human endogenous retrovirus type I (HERV-I) are present within the genomes of fish, reptiles, birds, and mammals and that they may well be widespread within many vertebrates. Phylogenetic analysis of nucleotide sequences strongly supported the inclusion of viruses from each of these vertebrate classes into one monophyletic group. This analysis also demonstrated that the HERV-I-related viruses are more closely related to retroviruses belonging to the murine leukemia virus genus than to members of the other retroviral genera. The presence of HERV-I-related retroviruses in so many disparate vertebrate hosts suggests that other endogenous human retroviruses may also have a much wider distribution than is currently appreciated.

Amino Acid Sequence↗
PubMed1997

Vascular smooth muscle cell cytotoxicity and sustained inhibition of neointimal formation by fibroblast growth factor 2-saporin fusion protein.

Basic fibroblast growth factor (FGF2) is an important mediator of smooth muscle cell (SMC) proliferation following arterial injury that results in neointimal growth. The present study was designed to explore the effects of recombinant FGF2 linked to the ribosome-inactivating protein saporin-6 (rFGF2-SAP) on vascular SMC cytotoxicity and neointimal formation following arterial injury. Cultured rat aortic SMCs were exposed to various concentrations of rFGF2-SAP, FGF2, and saporin-6 (SAP). Incubation with rFGF2-SAP resulted in a decreased number of SMCs beginning at a concentration of 10(-9) mol/L. Significant cytotoxicity was observed with as little as a 30-minute exposure of SMCs to rFGF2-SAP. To evaluate the ability of rFGF2-SAP in an in vivo model to reduce neointimal formation, Sprague-Dawley rats underwent carotid artery balloon denudation and received an intravenous bolus of vehicle or 5, 10, 15, or 20 micrograms/kg rFGF2-SAP on 0, 3, 6, and 9 days after injury. Rats were euthanized at 14 days, and carotid arteries were analyzed by computerized morphometry. The threshold dose for a significant reduction in neointimal area by rFGF2-SAP was 15 micrograms/kg (47% reduction in neointima). When dosing was extended to include days 16, 19, and 22, the neointima was reduced 33% at 28 days (P = .048). rFGF2-SAP reduced neointima without associated medial thinning or arterial wall dilatation. To determine if rFGF2-SAP directly targets SMCs in vivo, rats underwent carotid injury and received either 15 micrograms/kg rFGF2-SAP or vehicle on day 0 and at 72 hours, with euthanasia at 78 hours after balloon denudation. Medial SMC number was reduced 46% in the rFGF2-SAP group. Tissue sections from arteries 3 days after balloon injury demonstrated rFGF2-SAP binding to medial SMCs and adventitial cells. Staining for fibroblast growth factor receptor 1 revealed a high level of expression in ballooned arteries 3 and 14 days after injury. Taken together, these results provide a molecular and cellular basis for the observed specificity. Prolonged delivery of rFGF2-SAP can affect the natural history of arterial repair after injury.

Angioplasty, Balloon↗
PubMed1997

The five Cs of choice. Outcome measures for individuals with severe and persistent mental illness.

In a time when mental health service providers are cutting costs and services, stakeholders need adequate information in the form of outcome measures to evaluate services based on quality. Outcome measures are particularly important for high-risk populations, where severe and persistent mental illness results in serious functional impairment of daily life. A client-oriented method of gauging rehabilitation of real-world behavior over the long-term, as well as the short-term, and which allows for comparison with other programs, must be developed. Lack of agreement on the domains to be measured, however, has hindered the development of common standards, making it difficult to track accountability and service effectiveness. Four authors provide a framework to help organizations choose and develop appropriate outcome measures, as well as core data suggested to measure longitudinal changes in rehabilitation.

Chronic Disease↗