Search PubMed⌕ Search

Biomedical subjects

J E Godwin

Publications and source records attributed to J E Godwin.

16 recordsLinked to original sources
PubMed1995

Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases.

Resistance to chemotherapy is a major factor limiting successful treatment of acute myeloid leukemia (AML); one of the best characterized drug resistance mechanisms is extrusion of drugs by the energy-dependent multidrug resistance (MDR1) transport protein. Expression of MDR1 is common in AML and has been linked to lower remission induction rates and decreased remission durations. Because MDR1 efflux function may be modified by drugs such as cyclosporin A, accurate identification of MDR1+/efflux+ AML cases will be critical to identify patients who may benefit from therapies that contain such MDR1 modulators. We have optimized single and multiparameter flow cytometric assays to detect efflux of drugs or fluorescent dyes by previously cryopreserved AML blasts. These assays allowed precise identification of efflux by leukemic blasts, and correlation with CD34 and MDR1 expression. We subsequently studied a series of 60 previously untreated AML cases. Functional efflux was identified in 39 cases and was significantly correlated with MDR1 expression (P = .0002). However, discrepant cases were identified; 10 cases were efflux+ without significant MDR1 expression, whereas 6 MDR1+ cases were efflux-. There was also a highly significant correlation of efflux with CD34; 31 (79%) of the 39 efflux+ cases were CD34+ in comparison with only 5 (24%) of the 21 efflux- cases (P < .0001). Multivariate analysis showed that efflux was significantly associated with independent effects of both CD34 (P = .0011) and MDR1 expression (P = .034); the majority of efflux+ cases were CD34+, whereas 5 of the 6 MDR1+ efflux- cases lacked CD34 expression. Cyclosporin A blocked efflux in all but 2 cases regardless of MDR1 expression. Functional efflux in AML is frequently detected without the classic MDR1+ phenotype indicating that alternate non-MDR1-mediated efflux mechanisms may be important. Efflux assays may better identify patients who would benefit from therapies that include efflux modulators.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

A phase I/II study of sequential interleukin-3 and granulocyte-macrophage colony-stimulating factor in myelodysplastic syndromes.

In this phase I/II study, 9 patients with myelodysplastic syndromes (MDS) were treated with interleukin-3 (IL-3) followed by granulocyte-macrophage colony-stimulating factor (GM-CSF). Each treatment cycle was 28 days long and administered as follows: 1 microgram/kg/d IL-3 on days 1 through 7 and 3 micrograms/kg/d GM-CSF for days 8 through 21, followed by a 7-day rest period. IL-3 dose escalations were planned, but the dose of GM-CSF was fixed. Three patients had refractory anemia, 4 had refractory anemia with ringed sideroblasts, and 2 had refractory anemia with excess blasts. Six patients were dependent on red blood cell transfusions, 1 on platelet transfusions, and 2 on both. The absolute neutrophil count improved in 7 (77%) patients and the platelet count improved in 3 (33%) patients during therapy. Hemoglobin levels were unchanged. A clinically relevant response was seen in only 1 patient with thrombocytopenia, and he received five cycles of therapy. The neutrophil count decreased in 2 patients and the platelet count decreased in 4 patients during treatment. The toxicity of the treatment was significant. In the first cohort of 3 patients, 1 patient developed supraventricular tachycardia and congestive heart failure. In the second group, 1 patient developed progressive granulocytopenia and died of gram-negative septicemia. Because of the disparate toxicity, 3 more patients were treated at the same dose level. One of these experienced a high fever and bone pain requiring hospitalization. Because of these adverse effects, the IL-3 dose was not escalated and all patients received 1 microgram/kg/d for 7 days. We believe that sequential therapy with IL-3 and GM-CSF at these dose levels causes unacceptable toxicity in patients with MDS. The major toxic events occurred during weeks 4 and 5 after starting treatment and may have been primarily caused by GM-CSF therapy. Although neutrophil counts improve in most patients, the effect on red blood cells and platelets is minimal. At present, this form of therapy remains problematic and appears to have a limited potential in the management of MDS.

Adult↗
PubMed1994

ProMACE day 1/MOPP day 8 chemotherapy for prolymphocytic leukemia: a case report of prolonged survival.

The treatment result of a case of de novo B-cell prolymphocytic leukemia (B-PLL) is described. The diagnosis was established with histologic, ultrastructural and immunologic studies. The patient was treated with chemotherapy using a total of seven cycles of ProMACE Day 1/MOPP Day 8 lymphoma regimen. Complete remission was achieved after 5 cycles of chemotherapy. The patient remains disease free after a 7-year follow up. This is the first case of PLL being treated with such a regimen and the only case reported achieved such prolonged survival. Results of other treatment modalities are reviewed.

Aged↗
PubMed1993

A phase I trial of combination fludarabine monophosphate and chlorambucil in chronic lymphocytic leukemia: a Southwest Oncology Group study.

Fludarabine monophosphate is a new antimetabolite with demonstrated activity in chronic lymphocytic leukemia (CLL). We have investigated the practicality of utilizing fludarabine in combination with chlorambucil in a disease-specific phase I trial. Twenty-one patients with advanced and previously treated, relapsed or refractory CLL were treated with chlorambucil plus fludarabine. Chlorambucil was given day 1 at 15 or 20 mg/m2 per os and fludarabine days 1-5 at 10, 15, or 20 mg/m2 intravenously, every 28 days. We concluded that with chlorambucil 15 mg/m2, the maximum tolerated dose for fludarabine was 20 mg/m2 in this patient population with this scheduling. Dose-limiting toxicity was thrombocytopenia. A low incidence of peripheral neuropathy, rash, pulmonary fungal infection, and acute tumor lysis syndrome was also encountered. Although responses were observed, it was impossible from this study to determine whether the combination was better than fludarabine alone in this heavily pretreated population. This study does, however, demonstrate the feasibility of exploring the utility of such a combination in previously untreated patients. An intergroup phase III trial utilizing this combination has been initiated.

Administration, Oral↗
PubMed1992

Platelet prevention of oxidant lung oedema is not mediated through scavenging of hydrogen peroxide.

Previous studies have shown that washed human platelets attenuate oxidant oedema in isolated perfused rabbit lungs through mechanisms dependent on platelet glutathione. We hypothesized that the platelet glutathione redox cycle scavenges hydrogen peroxide in this model and thereby protects vascular endothelial cells from oxidant injury. This hypothesis was tested by asking two questions: (1) do glutathione-supplemented platelets demonstrate augmented lung protection compared with control platelets, and (2) does conjugation of platelet glutathione with 1-chloro-2,4-dinitrobenzene or inactivation of catalase with 3-amino-1,2,4-triazole decrease in vitro platelet metabolism of hydrogen peroxide? We incubated washed human platelets with reduced glutathione or glutathione monoester and observed platelet glutathione contents of 181% and 189%, respectively, compared with control values. Incubation of platelets with N-acetylcysteine did not alter platelet glutathione content. Infusion of glutathione-supplemented platelets into isolated lungs injured by purine and xanthine oxidase did not augment platelet protection compared with untreated platelets. We also found that conjugation of platelet glutathione and/or inactivation of platelet catalase did not decrease the rate constant for platelet metabolism of hydrogen peroxide. We conclude that platelets attenuate oxidant lung oedema through glutathione-dependent mechanisms other than direct scavenging of hydrogen peroxide.

Amitrole↗
PubMed1991

Abnormal plasminogen Maywood I.

Maywood I is a dysfunctional plasminogen. It is described in a patient (W.Y.) with a reduced plasma functional activity and with a low normal antigen level. Plasminogen was isolated from the patients plasma by affinity chromatography with L-lysine-substituted Sepharose. The protein yield was 86 mg/l, which was 88% of the plasma Plg antigen level; the specific activity was 24.4 IU/mg protein compared to 28.5 IU/mg protein for the native molecule. The protein was the Glu-form determined by SDS-PAGE and by isoelectric focusing. Six major isoelectric forms were found with isoelectric points between pH's 6.40 and 5.45. Titration of the equimolar plasminogen.streptokinase complex with p-nitrophenyl-p-guanidinobenzoate gave 85% active-sites indicating a homogenous population of molecules; therefore, the propositus is a homozygote. Four different plasminogen activators: a) streptokinase, b) urokinase c) the plasmin-derived light (B) chain-streptokinase complex, and d) tissue plasminogen activator (with soluble fibrin/CNBr-fibrinogen fragments) generated little plasmin from the variant plasminogen (4.5 to 45 nM), 5% or less than that generated from normal plasminogen. At 45 nM plasminogen, the molar ratio of plasminogen:activator was 3.0 for streptokinase, 3.9 for urokinase, 7.1 for the light (B) chain-streptokinase complex, and 155 for tissue plasminogen activator. In the equimolar variant plasminogen.streptokinase complex, the active-site was slowly developed, to a maximum of 85% in 40 min; in the normal complex, 100% active-sites were developed in 15 min. The variant plasminogen forms two equimolar complexes with streptokinase (I and II), with different mobilities in PAGE, in about equal amounts.(ABSTRACT TRUNCATED AT 250 WORDS)

Electrophoresis, Polyacrylamide Gel↗
PubMed1991

Granulocyte-macrophage colony stimulating factor for the treatment of drug induced agranulocytosis.

Drug induced agranulocytosis is an uncommon but potentially fatal complication. In some cases, it may be associated with hypoplasia and depletion of granulocytic precursors in the marrow, leading to prolonged neutropenia. We report on the use of granulocytic-macrophage colony stimulating factor (GM-CSF) in two such cases, at a dose of 10 micrograms per kilogram per day subcutaneously. The absolute neutrophil count rose above 500/mm3 in 3 days in both cases. We believe that GM-CSF expedited the recovery of granulocyte counts in our patients and warrants further study in the management of drug induced neutropenia.

Agranulocytosis↗
PubMed1991

Miliary tuberculosis presenting as hepatic and renal failure.

A 67-year-old man developed hepatic and renal failure over a six-day period. Despite full supportive measures, he died on his 11th day of hospitalization with fulminant DIC and hepatic, renal, and respiratory failure. Postmortem examination revealed acid-fast bacilli in virtually all organ systems. Miliary tuberculosis should be considered as a potentially treatable cause of hepatic failure.

Acute Kidney Injury↗
PubMed1991

Benign thyroid hyperplasia presenting as bilateral vocal cord paralysis. Complete remission following surgery.

A 52-year-old woman developed respiratory arrest on two separate occasions that required mechanical ventilation. Fiberoptic bronchoscopy demonstrated bilateral vocal cord paralysis, and a CT scan of the neck demonstrated a right neck mass. On surgical exploration, the mass was found extending from the thyroid gland and was identified as benign thyroid tissue. Thyroid hyperplasia should be considered in the differential diagnosis of bilateral vocal cord paralysis.

Female↗
PubMed1991

Special critical care considerations in tracheostomy management.

The tracheotomized patient undergoing mechanical ventilation presents numerous challenges to the intensive care team. During the initial phase of respiratory failure, patient instability and risks of multiorgan failure focus efforts on an array of critical care management techniques designed to reverse the underlying process and prevent complications. During the stabilization phase, issues of tracheostomy care become equally important in improving patient outcome. These topics include the proper assistance in patient communication, initiation of enteral nutrition, weaning from airway cannulation, and anticipation of adverse reactions after airway decannulation. Failure in promoting a logically conceived and carefully applied treatment plan in any of these areas frequently delays patient recovery and risks serious complications of airway compromise.

Critical Care↗
PubMed1990

Mechanical ventilation.

Among the many advances made in intensive care therapeutics in recent years, few have rivaled the impact of mechanical ventilators. Their expanded use affects all who practice in the critical care setting. This article reviews the physiologic basis for mechanical ventilation, how ventilators are classified, the various modes, and specific indications. A basic introduction is made into ventilator set up, weaning techniques, adjunctive drug therapy, and complications. The pharmacotherapy specialist who understands interactions between patients and ventilators, and the effects of mechanical ventilation on cardiopulmonary function will be best equipped to individualize drug therapy.

Critical Care↗
PubMed1990

Sarcoidosis presenting as progressive ascending lower extremity weakness and asymptomatic meningitis with hypoglycorrhachia.

A 26-year-old man developed progressive weakness over a two-month period. His chest radiograph showed diffuse interstitial infiltrates, and transbronchial lung biopsies demonstrated noncaseating granulomas consistent with sarcoidosis. Sarcoid neuropathy should be considered in the differential diagnosis of the patient presenting with an atypical Landry-Guillain-Barré syndrome.

Adult↗
PubMed1988

Hypoplastic myelodysplastic syndrome.

Over a period of 8 years 11 of 64 patients seen at Loyola University Medical Center with the diagnosis of myelodysplastic syndrome (MDS) also exhibited bone marrow hypoplasia (marrow cellularity of 25% or less) at presentation. The other 53 had normocellular or hypercellular marrow. Clinical features, hemograms, chromosome analysis, incidence of progression to acute leukemia or aplastic anemia, and survival in each group were compared. Using the French-American-British (FAB) classification, there were seven patients with refractory anemia (RA), one refractory anemia with ringed sideroblasts (RARS), and three refractory anemia with excess blasts (RAEB) in the hypoplastic MDS group. Those with normocellular or hypercellular marrow included 22 with RA, nine with RARS, 12 with RAEB, three with chronic myelomonocytic leukemia, and four with RAEB in transformation; one had chronic diGuglielmo syndrome and two patients were not classified. Patients with hypoplastic MDS had lower hemoglobin levels (median, 8 g/dl versus 9 g/dl), more severe leucopenia (median 3100/microliter versus 4200/microliter) and thrombocytopenia (median, 28,000/microliter versus 75,000/microliter), and marked macrocytosis (mean corpuscular volume (MCV), 107 mu 3 versus 97 mu 3). Nine patients with hypoplastic MDS had a chromosome analysis of the bone marrow, and all were normal. In those with normocellular or hyperplastic bone marrow, 22 such analyses were done, and seven (23%) were abnormal. One patient (11%) from the hypoplastic group and 11 (23%) from the normocellular or hyperplastic MDS transformed into acute leukemia. None progressed to aplastic anemia. With a mean follow-up time of 33 months in the hypoplastic MDS, eight patients (72%) are alive. In the group with normal or hyperplastic MDS, the mean follow up was 47 months, and 27 patients (50%) have survived. The two groups differ significantly in leukocyte count (P less than 0.0015), platelet count (P less than 0.0001), and MCV (P less than 0.0023). There may be a possible difference between these groups related to abnormal karyotype, but it is not statistically significant (P = 0.06). Therapy with pyridoxine, folic acid, prednisone, anabolic steroids, retinoids, or low-dose cytosine arabinoside was not beneficial in hypoplastic MDS. Hypoplastic MDS appears to be a distinct clinicopathologic entity characterized by marrow hypoplasia, macrocytosis, severe leucopenia and thrombocytopenia, low incidence of progression to acute leukemia, and unresponsiveness to conventional therapy.

Adult↗
PubMedDate not supplied

Is histological subtype a marker for environmental exposures in acute myelogenous leukemia?

The association between occupational and other environmental exposures was evaluated in 60 acute myelogenous leukemia cases and controls. Odds ratios and 95% confidence intervals for prior cytotoxic therapy and benzene exposure, adjusted for age, sex, and race by logistic regression, were 3.7 (0.7, 19.9) and 2.6 (0.4, 15.2), respectively. No other work-related associations, including employment in electrical occupations, were present. Other associations were suggestive but may have been due to biases in control selection or small numbers of subjects. The risks for prior cytotoxic therapy (odds ratio = 10.2) and benzene exposure (odds ratio = 11.4) were concentrated in 13 patients with French-American-British M4 leukemia; no environmental exposures were associated with French-American-British subtypes M1 and M2. These findings support the concept that French-American-British histological subtypes of AML may have different etiologies.

Antineoplastic Agents↗