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Biomedical subjects

R Fisher

Publications and source records attributed to R Fisher.

At least 73 records · Page 4Linked to original sources
PubMed1997

Adenosine A1 receptor promotion of multinucleated giant cell formation by human monocytes: a mechanism for methotrexate-induced nodulosis in rheumatoid arthritis.

OBJECTIVE: To determine why methotrexate (MTX) exacerbates rheumatoid nodules in some patients, despite the effective suppression of synovial inflammation. METHODS: Phorbol myristate acetate (PMA)-induced differentiation of monocytes into multinucleated giant cells was used as an in vitro model to study the effects of adenosine on nodulosis. RESULTS: MTX at 200-2,000 nM or the adenosine A1 agonist N5-cyclopentyl adenosine (CPA) (10(-12) to 10(-9) M) or the A2 antagonist 3,7-dimethyl-1-propargylxanthine markedly enhanced giant cell formation, whereas the adenosine A1 antagonist 8-cyclopentyl-dipropylxanthine completely reversed these effects. PMA, CPA, and MTX induced adenosine release by cultured monocytes at concentrations consistent with those associated with predominantly A1 effects. Furthermore, surface expression of A1 receptors was found to remain unchanged on the differentiating cells throughout the culture period. CONCLUSION: Agents that inhibit adenosine A1 receptors might be useful in the treatment of MTX-induced rheumatoid nodulosis, while still potentiating the A2-mediated antiinflammatory effects of MTX on synovitis.

Adenosine↗
PubMed1997

Prenatal ultrasound diagnosis of gastrointestinal malformations.

Prenatal ultrasonography is commonly used to detect fetal structural abnormalities. The aim of this study was to evaluate the reliability of fetal sonography in the detection of congenital gastrointestinal malformations (GIM). From a prospective database of all major structural fetal anomalies detected by ultrasound over 3 years in a region with a population of 3.5 million and an annual birth rate of 52,000, 294 reports of GIM were identified and reviewed. There were 220 confirmed cases of GIM, of which only 35 (16%) had been correctly identified prenatally. Of 84 prenatal diagnoses of GIM, only 35 (42%) were confirmed postnatally. Prenatal ultrasound was most reliable in the detection of duodenal obstruction (55% confirmed cases identified prenatally) and least reliable in malformations of the hindgut. Of 44 cases of nonspecific sonographic bowel abnormality (eg, echogenic bowel) with adequate follow-up, only 12 (27%) had a confirmed GIM after delivery. This study demonstrates that the prenatal ultrasound scan is still unreliable in the detection or exclusion of fetal GIM, and consequently clinicians involved in prenatal sonography or counselling should exercise caution in making such diagnoses.

Digestive System Abnormalities↗
PubMed1997

Alterations in the spontaneous release of dopamine and the density of the DA D2 receptor mRNA after chronic postnatal exposure to cocaine.

The influence of cocaine administration on dopamine (DA) release and D2 dopamine receptor mRNA levels was examined in developing rat brain. In the rat pup, cocaine (25 mg/ kg SC) was administered daily from postnatal days 1-9 and extracellular DA measured 24 h after the last injection of cocaine, using in vivo micro dialysis. Twenty-four hours after discontinuing cocaine administration, a decrease in the extracellular concentration of DA of more than 100% was found in treated pups compared to control pups. Pups were tested on postnatal days 10-12, 20-21, or 35-36. After 1 month, basal release of DA returned to control levels. To examine the structural basis of the alteration in basal release of DA, in situ hybridization studies were performed to access the effect of chronic administration of cocaine on the mRNA encoding the D2 DA receptor. These preliminary studies, on postnatal day 10, indicate that drug treatment alters the developmental pattern of D2 mRNA. The changes in D2 mRNA expression were accompanied by delayed disaggregation of neostriatal cells and diminished growth of neostriatal neurons. These structural changes may lead to functional impairment in the development of dopamine target cells, thus altering the balance of synaptic and trophic effects of DA.

Animals↗
PubMed1997

Middle cerebral artery blood velocity, embolisation, and neurological outcome during carotid endarterectomy: a prospective comparison of the Javid and the Pruitt-Inahara shunts.

OBJECTIVES: To investigate the in vivo haemodynamic performance and neurological outcome of two types of carotid shunt. DESIGN: Randomised single surgeon study of consecutive symptomatic patients. SETTING: 163 consecutive patients undergoing carotid endarterectomy for symptomatic carotid disease were randomised to the Javid or Pruitt shunt. CHIEF OUTCOME MEASURES: Middle cerebral artery velocity (MCAV), preoperatively, during clamping, during shunting and post-restoration of flow, embolic episodes, neurological outcome. MAIN RESULTS: The MCAV preoperatively, at carotid clamping, and postoperatively was the same for both groups (p > 0.15). During shunting the MCAV was significantly lower in the Pruitt group, p < 0.005, 59% of the Javid and 34% of the Pruitt shunts maintained MCAV at preoperative levels p < 0.005, chi 2 = 8.92. The Javid shunt produced significantly more emboli (73% of cases) at declamping than the Pruitt (41%), p < 0.0002, chi 2 = 14.7. Four Javid patients and one Pruitt had disabling thromboembolic strokes; overall thromboembolic stroke rate 3.7%. The difference in stroke rates was not statistically significant (p = 0.14). CONCLUSIONS: The Pruitt shunt was unable to maintain preoperative MCAV in 66% of cases, the Javid shunt had a higher incidence of emboli on declamping. These factors may lead to an increased risk of stroke; however, the numbers required for statistical confirmation would be large.

Adult↗
PubMed1997

Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice.

Dystrophin-deficient mice (mdx) expressing a truncated (trc) utrophin transgene show amelioration of the dystrophic phenotype. Here we report a multifunctional study demonstrating that trcutrophin expression leads to major improvements of the mechanical performance of muscle (that is, force development, mechanical resistance to forced lengthenings and maximal spontaneous activity) and of the maintenance of the intracellular calcium homeostasis. These are two essential functions of muscle fibers, known to be impaired in mdx mouse muscles and Duchenne muscular dystrophy (DMD) patients. Our results bring strong support to the hypothesis that muscle wasting in dystrophin-deficient DMD patients could be prevented by upregulation of utrophin.

Animals↗
PubMed1997

Development of safe and efficient retroviral vectors for Gaucher disease.

We have generated amphotropic and Gibbon ape leukemia (GaLV) viruses carrying either a full-length (IG-GC2) or a shortened glucocerebrosidase cDNA (IG-GC4). For all recombinant retroviruses, a single infection was sufficient to augment glucocerebrosidase activity in unselected Gaucher type I and type II fibroblasts to levels which can be considered therapeutic. Transfer efficiency of the glucocerebrosidase cDNA into normal human and Gaucher type I CD34+ cells, using supernatant transduction, ranged from 4 to 50% as established on vector-positive CFU-GM. In these experiments, GaLV and amphotropic virus were equally efficient in transducing early human progenitors. Importantly, mixing amphotropic and GaLV pseudotyped retroviruses resulted in significantly higher transduction efficiencies as compared with single infections, up to 70% vector-positive CFU-GM. Glucocerebrosidase activity, measured in the progeny of human CD34+ cells, increased up to 460% compared with mock-infected CD34+ cells. Upon transduction of Gaucher CD34+ bone marrow cells the glucocerebrosidase deficiency was reversed.

Antigens, CD34↗
PubMed1997

Genomic regions regulating imprinting and insulin-like growth factor-II promoter 3 activity in transgenics: novel enhancer and silencer elements.

Transgenic lines (89) were made with constructs containing eight different combinations of candidate regulatory elements from the insulin-like growth factor-II (Igf2)-H19 region of mouse chromosome 7. In all constructs, promoter 3 of Igf2 was attached to a firefly luciferase reporter gene. Promoter 3 was the common element that imposed a decrease in reporter activity similar to that of endogenous Igf2 after birth. The specific activity of the reporter was measured on the day of birth in the liver and the brain, after each transgene had been transmitted by either the father or the mother. This procedure demonstrated that the quantity and organ distribution of expression from this promoter can be regulated by each element. The following new information was obtained. (a) The 5' differentially methylated region of Igf2 inhibits promoter 3 in the liver. (b) The conserved DNase I-hypersensitive Middle region between Igf2 and H19 is an enhancer of promoter 3 in the brain. (c) The H19 promoter inhibits Igf2 promoter 3 in the brain. The results confirmed that the H19 enhancer is a strong enhancer of promoter 3 in the liver. A new finding was that one genomic region regularly imposed imprinted gene expression. This was the H19 enhancer, and this region was sufficient to give higher expression on maternal transmission in the majority of transgenic lines. The full data are reported in Supplementary Publication SUP 50180 (8 pages), which has been deposited at the British Library Document Supply Centre, Boston Spa, Wetherby, West Yorkshire LS23 7BQ, U.K., from whom copies can be obtained on the terms indicated in Biochem. J. (1997) 21, 8-10.

Animals↗
PubMed1997

Ultrasound as a screening study for gastro-oesophageal reflux in children.

A comparison of the abilities of ultrasound and scintigraphy to detect gastro-oesophageal reflux was made in 110 children (mean age 24.5 months) who were divided into groups A (n = 49) and B (n = 61). The former had scintigraphy first followed by ultrasound within about 30 min. For group B scintigraphy was also performed first, but the delay before ultrasound ranged between 1 and 30 days. In most patients (91/110) concordant results were obtained by the two modalities. The 19/110 discordant results can be explained by several plausible mechanisms. It is concluded that ultrasound should be employed much more frequently as an initial investigation when pathological reflux is suspected in children.

Age Distribution↗
PubMed1997

Sucralfate cream in the management of moist desquamation during radiotherapy.

Randomized trials have shown that sucralfate is effective in the management of acute radiation reactions such as oesophagitis, mucositis and proctitis. However, at the time of commencement of the present trial, it had never been used in the management of moist desquamation of the skin. The purpose of the present study was to assess the value of sucralfate cream in the management of moist desquamation during radiotherapy. Patients who developed moist desquamation during radiation were eligible. Patients were stratified by site of radiotherapy into three groups: (i) the head and neck; (ii) the breast; and (iii) other sites. Patients were randomized to receive 10% sucralfate in sorbolene cream or sorbolene alone. Patients' pain and skin healing were assessed by using linear analogue self-assessment (LASA) scales and by serial measurement of the desquamated area. Due to poor patient accrual, the trial was terminated after 2 years and 39 patients. No statistically significant difference was found between the two arms in either time from randomization to healing or improvement in pain score. Twenty patients in the sucralfate arm took a geometric mean of 14.8 days to heal whereas 19 patients receiving sorbolene alone took a geometric mean of 14.2 days. The ratio of mean times of healing, 1.043, is not statistically different from 1 (P = 0.86; 95% CI = 0.65, 1.67). A total of 75% of the patients reported pain relief on application of either cream. Mean LASA scores for pain for each day after randomization were compared by treatment arm and there was no statistically significant difference (P = 0.32). The present trial was unable to show a difference in terms of time to healing or pain relief in the treatment of moist desquamation. The small number of patients in the trial gave a wide confidence interval for treatment difference, implying that an important effect of sucralfate has not been excluded. Given the poor accrual in the present, single-institution study, future studies may need to be multi-institutional and we encourage other centres to perform randomized trials in the management of moist desquamation.

Administration, Topical↗
PubMed1997

The efficacy of treatment for malignant epidural spinal cord compression.

The aims of this study were to document the efficacy of treatment and to identify factors that were predictive of the outcome in malignant epidural spinal; cord compression. The medical records of patients treated at the Prince Henry and Prince of Wales Hospitals in the period 1980-1989 with a diagnosis of malignant epidural spinal cord compression were reviewed. A total of 94 patients were eligible for the study and were treated by radiotherapy alone (37), surgery alone (19) and surgery followed by radiotherapy (38). Efficacy was determined by measuring complete resolution of symptoms and signs at 1 month after presentation, and also by using an overall functional improvement score (FIS). Complete resolution of individual pre-treatment symptoms that were measured 1 month after treatment occurred as follows: pain (30/88), sensory disturbance (12/61), weakness (8/17), bladder dysfunction (10/42), and bowel dysfunction (10/36). Complete resolution of motor deficit occurred in 7/82 and of sensory deficit in 9/73. The ability to walk was regained in 19/51 previously non-ambulatory patients, and bladder function improved sufficiently to remove an indwelling catheter in 9/32 previously catheterized patients. As judged by FIS, 67 patients improved, 15 patients remained stable and 12 patients deteriorated. Of the treatments given, a combination of surgery followed by radiotherapy was associated with the greatest functional improvement (P = 0.001). The coexistence of 'liver failure' was the only patient-related factor identified which was associated with outcome (P = 0.041). The treatment of malignant spinal cord compression appears to be worthwhile; however, the outcome of treatment is not easy to predict from pretreatment factors. A 'functional improvement score' may be useful in assessing treatment efficacy.

Activities of Daily Living↗
PubMed1997

Elderly care. A pilot project on opportunistic geriatric assessments in general practice.

OBJECTIVES: To develop a pilot program for systematic assessment of functional status of the elderly in general practice. METHOD: The program was developed in consultation with local GPs and aged care services and introduced to GPs at a workshop. The program was piloted for seven general practitioners with 41 patients, 70 years or older. RESULTS: While many problems had been previously identified by GPs additional problems with: home and social life; activities of daily living and mobility; cognition and depression; general health and medication problems were found in up to 2.5% of patients. CONCLUSION: Opportunistic health assessment of the elderly in general practice is practical and useful in detecting health problems.

Activities of Daily Living↗
PubMed1997

A patient classification system for ambulatory care.

Patient classification systems (PCSs) for ambulatory care are difficult to develop because there are so few similarities among groups of patients and/or diagnoses in relation to the required nursing activities. In addition, the nursing activities required for specific patients and/or diagnoses also are dissimilar in relation to nursing time required. Therefore, a PCS was developed to assess staffing needs. This outpatient classification system reflects actual nursing time spent with each patient.

Ambulatory Care↗
PubMed1997

Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine Working Group experience, 1989-1997.

PURPOSE: This article reviews long-term follow-up data from three phase II studies conducted by the Cytokine Working Group from 1989 to 1995 that evaluated various recombinant interleukin-2 (rIL-2) -based regimens in patients with metastatic renal cell cancer. Response rates, long-term response duration, and toxicity are compared. PATIENTS AND METHODS: The Cytokine Working Group studies reviewed here investigated the safety and efficacy of two high-dose intravenous rIL-2-based regimens and two moderate-dose outpatient subcutaneous rIL-2-based regimens in patients with progressive metastatic renal cell cancer. A randomized phase II study, initiated in 1989, investigated the safety and efficacy of high-dose intravenous rIL-2 alone and high-dose intravenous rIL-2 plus recombinant interferon-alpha (rIFN-alpha). A second phase II study, initiated in 1992, tested the safety and efficacy of moderate-dose subcutaneous rIL-2 plus subcutaneous rIFN-alpha in the outpatient setting. The third trial, initiated in 1995, investigated a regimen consisting of the previous subcutaneous rIL-2 plus rIFN-alpha regimen alternating with intravenous bolus 5-fluorouracil (5-FU) plus subcutaneous rIFN-alpha. Median follow-up for these studies is 72 months, 48 months, and 24 months, respectively. RESULTS: The overall response rates observed with each of these regimens were similar (17% with high-dose rIL-2 alone, 11% with high-dose rIL-2/rIFN-alpha, 17% with outpatient subcutaneous rIL-2/rIFN-alpha, and 16% with outpatient rIL-2/rIFN-alpha, plus 5-FU/rIFN-alpha). However, the high-dose rIL-2 regimen produced a 7% complete response rate, compared with 0%, 4%, and 4%, respectively, with each of the other regimens. Median response duration was also much longer with high-dose intravenous rIL-2 alone (53 months), compared with 7 months, 12 months, and 9 months, respectively, with each of the other regimens. CONCLUSION: Complete response rate and response duration appear to favor the high-dose intravenous rIL-2 regimen. This will require verification in a randomized study comparing the best high-dose arm (rIL-2 alone) with the best outpatient regimen (rIL-2/IFN-alpha). The Cytokine Working Group is currently conducting such a study.

Adult↗
PubMed1997

Prospective randomized trial of lisofylline for the prevention of toxicities of high-dose interleukin 2 therapy in advanced renal cancer and malignant melanoma.

The therapeutic application of high-dose interleukin (IL) 2 in human malignancy is limited by severe multiorgan toxicities that are mediated, in part, by tumor necrosis factor (TNF) and IL-1. CT1501R (lisofylline; LSF) is one of several methyl xanthine congeners that inhibit the effects of TNF by the interruption of specific signal transduction pathways. This randomized, placebo-controlled trial was designed to assess the activity of LSF in reducing the toxicities of high-dose IL-2 therapy. Fifty-three patients with metastatic renal cancer or malignant melanoma were treated with i.v. bolus IL-2, 600, 000 IU/kg every 8 h for 5 days (14 doses), followed by 9 days of rest and another 5-day course of IL-2. Patients were randomly assigned to LSF, 1.5 mg/kg i.v. bolus, or placebo every 6 h during IL-2 therapy. All patients were to be treated to individual maximum tolerance of IL-2 at the intensive care unit level of support. The end points for statistical analysis were the number of IL-2 doses administered during the first cycle of treatment (maximum, 28) and the toxicities experienced by each group after the first 8 planned IL-2 doses. There was no difference between the LSF and placebo groups in the mean number of IL-2 doses tolerated in the entire first cycle of therapy (19.6 +/- 5.4 versus 19.5 +/- 5.8, P = 0.86) or in the first or second 5-day course of IL-2. The only significant difference in toxicities occurring through the eighth dose of IL-2 was in the maximum elevation of serum creatinine (mean, 1.7 +/- 0.8 for placebo versus 1.5 +/- 0.6 mg/dl for LSF, P = 0.013). A Monte Carlo analysis of major toxicities over the first 14-dose course of therapy showed a statistically significant difference favoring the LSF-treated group (P = 0.025). LSF was well tolerated, associated only with mildly increased nausea (P = 0.006 after eight IL-2 doses, but not significant for the entire first cycle). The antitumor activity was comparable in both groups (objective responses, 2 of 28 with LSF versus 4 of 24 with placebo). The mean peak plasma concentrations of LSF on days 1, 5, and 19 were 6.24, 3.83, and 5.04 micromol/liter, respectively. In conclusion, with this dose and schedule, LSF did not alter the toxicities of high-dose i.v. IL-2 sufficiently to impact the overall dose intensity of IL-2. Successful IL-2 toxicity modulation may require the use of higher doses of LSF, the development of agents with more potent anti-TNF activity, and/or combined modulating agents that function via distinct mechanisms to interrupt cytokine-mediated signaling.

Adult↗
PubMed1996

Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene.

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disease that causes cardiac or respiratory failure and results in death at about 20 years of age. Replacement of the missing protein, dystrophin, using myoblast transfer in humans or viral/liposomal delivery in the mouse DMD model is inefficient and short-lived. One alternative approach to treatment would be to upregulate the closely related protein, utrophin, which might be able to compensate for the dystrophin deficiency in all relevant muscles. As a first step to this approach, we have expressed a utrophin transgene at high levels in the dystrophin-deficient mdx mouse. Our results indicate that high expression of the utrophin transgene in skeletal and diaphragm muscle can markedly reduce the dystrophic pathology. These data suggest that systemic upregulation of utrophin in DMD patients may lead to the development of an effective treatment for this devastating disorder.

Animals↗
PubMed1996

Genomic organization and the 5' flanking region of the gamma subunit of the human amiloride-sensitive epithelial sodium channel.

The amiloride-sensitive epithelial sodium channel (ENaC) complex is made up of at least three different subunits alpha, beta, and gamma, which are developmentally regulated, selectively expressed, and variously up-regulated by steroid hormones. To understand mechanisms involved in regulation of the gamma subunit, we have determined the structure of the human gammaENaC gene. By 5' rapid amplification of cDNA ends, primer extension analysis, and nuclease protection assay, we identified transcription start sites in human brain, kidney, and lung. A human genomic library was screened and overlapping cosmid clones that span approximately 50 kilobases and contain the hgammaENaC gene were identified. The 5'-untranslated region is 141 bases long, and the translation start codon is contained within the second exon. The human gene spans at least 35 kilobases. The 5' end of the gene including portions of 5' flanking genomic DNA and the first intron are G + C rich and contain several CpG dinucleotides, consistent with a CpG island. The 5' flanking region contains no CCAAT or TATA-like elements but does contain two GC boxes as well as several putative transcription factor binding sites including AP-2, Sp1, CRE, PEA-3, and NF-IL6. This is the first description of the structural organization and the 5' flanking region of a member of the epithelial sodium channel complex.

Alternative Splicing↗
PubMed1996

Determination of aflatoxin B1 biotransformation and binding to hepatic macromolecules in human precision liver slices.

Although epidemiological studies suggest that aflatoxin B1 (AFB1) is a human carcinogen, at least in the presence of hepatitis B virus infection, animal studies have demonstrated large differences in species sensitivity to AFB1, and the sensitivity of humans relative to experimental animals remains unclear. The purpose of this study was to determine the profile of AFB1 metabolism and the extent of AFB1 binding to cell macromolecules in human liver slices under experimental conditions that would allow direct comparison to similar endpoints in the rat, a species sensitive to the carcinogenic actions of AFB1. Liver slices were prepared from three individual human liver samples with a Krumdieck tissue slicer and incubated with 0.5 microM [3H]AFB1 for 2 hr. Significant interindividual variations were observed in the rates of oxidative metabolite formation and in specific binding to cell macromolecules. The rates of oxidative metabolism of AFB1 to AFQ1, AFP1, and AFM1 in the three human liver samples were similar to those previously observed in rat liver slices. AFB1-GSH conjugate formation was not detected in any of the human liver samples, and yet specific binding of AFB1 to cell macromolecules was considerably lower in the human liver slices relative to that in rat liver slices. AFB1-DNA binding levels ranged from 3 to 26% of control rat and AFB1-RNA binding levels ranged from 25 to 49% of control rat. The AFB1-protein binding level in the one human sample measured was 20% of that observed for control rat. While these results suggest that humans do not form as much AFBO as the rat, they are also consistent with the hypothesis that humans do not possess GST isozyme(s) with high specific activity toward AFBO. Significant individual differences in AFB1 metabolism and binding between humans suggest the presence of genetic and/or environmental factors that may confer large variability in susceptibility to AFB1.

Adult↗