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Biomedical subjects

D Powell

Publications and source records attributed to D Powell.

At least 55 records · Page 3Linked to original sources
PubMed1996

alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6,7-dimethoxy-alpha- [(4-methylphenyl)thio]-2(1H)-isoquinolineheptanenitrile (CL 329,753): a novel chemosensitizing agent for P-glycoprotein-mediated resistance with improved biological properties compared with verapamil and cyclosporine A.

Agents that inhibit P-glycoprotein may restore sensitivity to some antitumor drugs in cancer patients. Optimization of the specificity and potency of one class of chemosensitizing agents related to verapamil has led to the identification of alpha-(3,4-dimethyoxyphenyl)-3,4-dihydro-6, 7-dimethoxy-alpha-[(4-methylphenyl) thio]-2(1H)-isoquinolineheptanenitrile, designated CL 329,753. In vitro, 0.1 to 2.0 microM CL 329,753 restored sensitivity to drugs in the multidrug resistance (MDR) phenotype in cell lines that overexpress P-glycoprotein. CL 329,753 was greater than 10-fold more potent and efficacious than cyclosporine A or verapamil in vitro, particularly in cells that express high levels of P-glycoprotein. The enhanced activity of CL 329,753 may be related to its inability to be transported by P-glycoprotein, since low drug accumulation of cyclosporine or verapamil but not CL 329,753 was found in P-glycoprotein-containing cells, yet all three agents inhibited vinblastine binding to membranes containing P-glycoprotein and inhibited photoaffinity labeling of P-glycoprotein. In vivo, CL 329,753 resensitized drug-resistant tumors to vinblastine or doxorubicin in an ascitic or solid tumor model, respectively. No alteration in the plasma pharmacokinetic profile of doxorubicin by CL 329,753 has been found. Furthermore, the compound had 70-fold less calcium channel antagonistic activity compared with verapamil.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Biocompatible dialysis membranes and acute renal failure: a study in post-operative acute tubular necrosis in cadaveric renal transplant recipients.

Previous experimental and human data suggests a detrimental effect on the course of acute renal failure related to exposure of blood to artificial dialysis membranes of poor biocompatibility. We performed a 2.5-year prospective randomized trial to compare the clinical course of acute renal failure (post-operative ischemic acute tubular necrosis, ATN) in patients receiving a cadaveric renal transplant requiring supportive hemodialysis in the immediate post-transplant setting. Patients were randomized to either a cuprophane or polymethylmethacrylate (PMMA) conventional hollow fiber dialyzer. All patients received a standard immunosuppressive regimen which included induction therapy with either horse anti-thymocyte gamma globulin (ATGAM) or the murine anti-CD3 monoclonal antibody (OKT3). Of 53 patients randomized, 17 were excluded (2 for intervening biopsy-proven rejection prior to recovery from ATN, 10 for primary graft nonfunction and 5 for other reasons), leaving 36 evaluable cases of uncomplicated ATN, 18 in each group. There was no difference by age, race, gender, cause of ESRD, immunosuppressive regimen, cold or warm ischemia time, use of pre-transplant dialysis, percent oliguria or the incidence of intra-dialytic hypotension between the 2 groups. There was no difference in the mean time to recovery from ATN posttransplant (8.9 days in the cuprophane group vs 9.5 days in the PMMA group, p = NS) or in the average number of hemodialysis treatments required (3.6 in both groups, p = NS). There was also no difference in long term allograft outcome in terms of the nadir serum creatinine, the number of episodes of subsequent acute rejection or in the development of chronic rejection. An intent-to-treat analysis of all 53 originally randomized patients similarly yielded no significant differences. A subsequent, non-randomized study using a membrane of intermediate biocompatibility (Hemophan) also showed no difference in recovery time from ATN. Bioincompatible membranes do not seem to have a significant clinical impact on the course of recovery of this form of acute renal failure. The striking benefits of biocompatibility in the course of ARF seen in other human trials may relate more to the non-renal systemic toxic effects of bioincompatibility.

Adult↗
PubMed1995

Molecular activation-deactivation of xanthine oxidase in human milk.

Enzymic activity and protein levels of xanthine oxidase were measured in serial samples of breast milk donated by each of 14 mothers, starting, in all but two cases, within 7 days following parturition. Enzyme activity varied widely, usually reaching peak values during the first 15 days and falling thereafter, by as much as 98%, to basal levels that were subsequently largely maintained. Corresponding changes in xanthine oxidase protein levels were not observed and, consequently, the specific activity of xanthine oxidase followed the above pattern. The capacity of human xanthine oxidase to undergo activation-deactivation cycles at the molecular level has important implications, not only for its role in breast milk, but also for its potential as a source of reactive oxygen species in other human tissues.

Enzyme Activation↗
PubMed1995

Endotoxin receptors (CD14) are found with CD16 (Fc gamma RIII) in an intracellular compartment of neutrophils that contains alkaline phosphatase.

CD14 is a glycosylphosphatidylinositol (GPI)-anchored protein on the surfaces of monocytes and polymorphonuclear leukocytes (PMN) that binds and initiates cellular responses to bacterial LPS. PMN also contain an intracellular pool of CD14 that can be deployed rapidly to the cell surface in response to stimulation with a variety of agonists. To determine which of the well-characterized subcellular compartments of PMN contains CD14, cells were cavitated and fractionated on Percoll gradients. The gradient fractions were assayed for CD14 by ELISA and Western blot and for the marker proteins beta-glucuronidase (azurophil granules), vitamin B12 binding protein (specific granules), alkaline phosphatase (secretory vesicles and plasma membrane), and HLA (plasma membrane). Approximately one-half of the CD14 ran with plasma membrane fractions and one-half with intracellular membranes of light density. Both intracellular and cell surface CD14 were associated tightly with membrane, and both forms showed identical electrophoretic mobility. The intracellular CD14 was clearly not present in azurophil granules or specific granules, but ran precisely with alkaline phosphatase, a marker for secretory vesicles. Parallel studies showed that an additional GPI-linked protein, Fc gamma RIII (CD16), also fractionated precisely with CD14 and alkaline phosphatase. Association of CD14 with secretory vesicles were confirmed by studies on cells stimulated with the formyl peptide fNLLP for 20 min at 37 degrees C before fractionation. This treatment caused translocation of CD14 from intracellular fractions to plasma membrane fractions. No release of the specific granule marker vitamin B12 binding protein was observed under these conditions, whereas two other GPI-anchored proteins, alkaline phosphatase and CD16, moved coincidentally with CD14 to comigrate with the plasma membrane. Time course studies of CD14 and CD16 surface expression confirmed the rapid and coordinate up-regulation of these proteins. Thus, the intracellular compartment containing CD14 and CD16 had the properties of secretory vesicles. These vesicles may represent a specialized membrane domain of PMN enriched in GPI-anchored proteins.

Alkaline Phosphatase↗
PubMed1995

Genome organisation in the murine sperm nucleus.

The organisation of DNA sequences in the murine sperm nucleus was studied using in situ hybridisation of biotinylated DNA probes. The efficiency of this reaction was assessed using a dispersed repetitive DNA probe. Telomeric DNA was distributed around the nucleus. Centromeric and ribosomal DNA sequences occupied restricted domains in the sperm nucleus. DNA sequences for a transgene and a cluster of homeogenes occupied different, and rather less defined, domains. Together these results imply that both repetitive and protein-coding sequences are arranged in the nucleus in an ordered fashion.

Animals↗
PubMed1994

Mechanistic studies of sterol carrier protein-2 effects on L-cell fibroblast plasma membrane sterol domains.

The factors which regulate intermembrane sterol domains and exchange in biomembranes are not well understood. A new fluorescent sterol exchange assay allowed correlation of changes in polarization to sterol transfer. Analysis of spontaneous sterol exchange between L-cell plasma membranes indicated two exchangeable and one very slowly or nonexchangeable sterol domain. The exchangeable domains exhibited half-times of 23 and 140 min with fractional contributions of 5 and 30%, respectively. Sterol carrier protein-2 (SCP-2) enhanced sterol exchange between L-cell plasma membranes and altered sterol domain size in a concentration dependent manner. Previous model membrane studies indicate that SCP-2 alters sterol domains and exchange through interaction with anionic phospholipids. In contrast to these observations, the ionic shielding agents KCl, low pH, or neomycin were either totally or partially ineffective inhibitors of SCP-2 action in L-cell plasma membrane exchanges. Thus the mechanism of SCP-2 in sterol transfer appears to be less charge dependent in L-cell plasma membranes than in model membranes. The cholesterol lowering drug probucol was also capable of altering the sterol exchange kinetics.

Amino Acid Sequence↗
PubMed1994

Antigenic specificity of antibodies from patients with linear basement membrane deposition of IgA.

We reviewed the immunoreactivity of sera binding to the epidermal side of basement membrane split skin from 13 adults and 8 children with IgA alone, 9 adults with IgA and IgG and 7 adults with IgA and ocular pemphigoid. Immunoblots were done against previously described 45-, 97-, 180- and 230-kD antigens, and reactivity was confirmed by elution of antibody from nitrocellulose and binding to the basement membrane. Ten of 13 adults and 7 of 8 children reacted with the 97-kD antigen. Sera with both IgA and IgG reacted in varying patterns and on occasion with more than 1 antigen. All 7 patients with ocular cicatricial pemphigoid reacted uniquely with a 45-kD antigen.

Adult↗
PubMed1993

'The holiday plug': a temporary solution to the problem of the leaking voice prosthesis.

Tracheo-oesophageal prostheses are commonly inserted in patients following total laryngectomy to improve the quality of the voice. Unfortunately the device eventually fails and requires replacement. A valve change, although well tolerated by patients, necessitates an out-patient visit and delay in its replacement can lead to problems of pneumonia or dehydration. In this short paper we describe a simple temporary solution for a leaking valve and recommend its use in patients who are delayed in returning to the unit for example when on holiday.

Acrylic Resins↗
PubMed1993

A comparison of the effect of isoflurane and propofol on arterial carbon dioxide tensions following intracranial surgery.

Thirty-four adult patients undergoing elective craniotomy were randomly allocated to receive either isoflurane or propofol to supplement nitrous oxide and fentanyl for maintenance of anaesthesia. Arterial blood gases were measured pre-operatively before premedication and at 5, 15, 30 and 60 min after tracheal extubation. The arterial carbon dioxide tension was higher than the preoperative value 5 min after tracheal extubation in both groups (p < 0.01), but there was no difference between the two groups at any time. It is concluded that the degree of postoperative respiratory depression after intracranial surgery is short-lived and minimal following maintenance of anaesthesia with either propofol or isoflurane.

Anesthesia, General↗
PubMed1993

Novel oral combination chemotherapy in the treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin's lymphoma.

PURPOSE: To determine the toxicity, response, and survival rate of orally administered combination chemotherapy in patients with AIDS-related intermediate- and high-grade non-Hodgkin's lymphoma. Secondary objectives included prospective quality-of-life assessment and quantitation of cell-associated p24 antigen (p24 Ag) by flow cytometry. PATIENTS AND METHODS: Eighteen patients with biopsy-proven lymphoma were treated with oral chemotherapy consisting of lomustine (CCNU) 100 mg/m2 on day 1, etoposide 200 mg/m2 on days 1 through 3; cyclophosphamide 100 mg/m2 on days 22 through 31, and procarbazine 100 mg/m2 on days 22 through 31 at 6-week intervals. A variety of clinical assessments were performed: prospective quality-of-life assessment using the Functional Living Index-Cancer (FLIC) and Brief Symptom Inventory (BSI) instruments; indirect immunofluorescence with flow cytometry to measure cell-associated p24 antigen; and price of the oral regimen compared with two other intravenous combination chemotherapy regimens. RESULTS: The overall objective response rate using Eastern Cooperative Oncology Group (ECOG) criteria was 61% (95% confidence interval, 39% to 84%), with seven complete remissions (39%) and four partial remissions (22%). The median survival duration was 7 months, with a range of 11 days to 36 months. The treatment-related mortality rate was 11%. One patient developed CNS progression. Myelosuppression was the most frequent and severe toxicity encountered. Predictor variables of performance status (PS), prior history of thrush, and CD4 lymphocyte count were found to be of prognostic value. In a separate analysis, scores on the three subscales of the BSI were also found to be predictive of complete response. The price of this regimen is several thousand dollars less than that of other intravenous combination chemotherapy regimens. CONCLUSION: This regimen is active in patients with AIDS-related non-Hodgkin's lymphoma. Because it is important to design systemic cytotoxic chemotherapy regimens that are cost-effective, considerate of quality-of-life issues, and efficacious in this patient population, this approach should be compared with standard intravenous combination chemotherapy regimens in randomized controlled clinical trials.

Adult↗
PubMed1993

Dexamethasone stimulates expression of insulin-like growth factor binding protein-1 in HEP G2 human hepatoma cells.

Insulin-like growth factor binding protein-1 (IGFBP-1) serum levels are increased by glucocorticoids and glucagon, and are decreased by insulin; these effects seem to reflect changes in hepatic IGFBP-1 expression. Human HEP G2 hepatoma cells respond to cAMP or insulin with stimulation or inhibition of IGFBP-1 expression, respectively; however, dexamethasone alone does not stimulate IGFBP-1 expression. Studies presented here show that in the presence of cAMP and theophylline, nontransfected HEP G2 cells respond to further addition of dexamethasone with a approximately 70% rise in IGFBP-1 mRNA levels, and HEP G2 cells transfected with IGFBP-1 promoter constructs respond to further addition of dexamethasone with a approximately 70% rise in IGFBP-1 protein levels and a approximately 9-fold rise in IGFBP-1 promoter activity. The stimulatory effect of dexamethasone and cAMP, conferred to the IGFBP-1 promoter between 357 and 103 base pairs 5' to the mRNA cap site, is inhibited by insulin. Thus, the cis elements necessary to confer multihormonal regulation of IGFBP-1 expression appear to reside in a short stretch of DNA just upstream from the IGFBP-1 transcription start site.

Animals↗
PubMed1993

Mesangial IgG in childhood minimal change disease: clinical relevance.

The clinical courses of five children with the nephrotic syndrome and renal biopsies diagnosed as minimal change disease (MCD) by light microscopy but with mesangial immune deposits of IgG (> or = 2+) and no dominant or codominant IgA were reviewed retrospectively to determine if the presence of significant mesangial deposits of IgG has prognostic implications and to evaluate the treatment these patients received. All five of the children were steroid dependent or resistant initially, and four received cyclosporine or cytotoxic agents later. After a mean follow-up period of 2.9 years for four and 20 years for one, all are in remission. All have normal renal function with no hypertension. These results suggest that the deposition of IgG in the mesangium of biopsies from patients with MCD by light microscopy may predict a more difficult course initially and may require more aggressive treatment to achieve permanent remission.

Biopsy↗
PubMed1992

Progression from partial to generalised lipodystrophy--a case report.

Lipodystrophies are rare disorders of adipose tissue metabolism. Two forms are recognised--partial or generalised. Though loss of body fat is a common feature these have been considered mutually exclusive clinical entities making any unifying pathophysiological concept difficult. We report, for the first time, a case of partial lipodystrophy affecting the face which progressed to become generalised.

Adult↗
PubMed1992

Predictive value of specimen histology after preoperative radiotherapy in the treatment of bulky/barrel carcinoma of the cervix.

One hundred thirty-four patients with bulky and barrel-shaped cervix cancers were treated with preoperative radiation to 40-45 Gy, intracavitary therapy using Cs-137 or Cf-252 and extrafascial total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAHBSO) 4-6 weeks after radiotherapy. Outcome of therapy was traced for patients with residual tumor (positive) in the hysterectomy specimen and those who had no residual tumor (negative) in the specimens. All specimens were studied by a set protocol to carefully evaluate the TAHBSO specimen for gross or residual tumor. Ninety-two percent of the patients with negative specimens survived 5 years, but this dropped to 71% if the specimen was positive. These findings were observed in both the Cs-137- and Cf-252-treated patients. Patients with negative specimens failed mainly in distant sites, whereas those with positive specimens failed locally and distantly. Patient survival was less in patients with positive specimens. There was no difference in outcomes for adenocarcinoma and squamous cell carcinomas. The specimen histological findings have predictive value in patients treated with preoperative radiation and surgery.

Actuarial Analysis↗
PubMed1992

Growth hormone therapy in Turner's syndrome.

Girls with Turner's Syndrome respond to growth hormone therapy. In combination with anabolic steroids, studies show a synergistic effect that does not cause an undue increase in bone age. As studies progress, patients are growing taller than their predicted final heights. Whether the increase in linear growth velocity will be sufficient to bring the Turner's Syndrome patient in to the normal range (greater than 150cms) and remove short stature as a necessary stigma for these unfortunate patients remains to be seen.

Body Height↗