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Biomedical subjects

M Green

Publications and source records attributed to M Green.

At least 199 records · Page 11Linked to original sources
PubMed1998

Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy. RESULTS: Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts. CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.

Adult↗
PubMed1998

Preclinical and phase I clinical studies with the nonclassical antifolate thymidylate synthase inhibitor nolatrexed dihydrochloride given by prolonged administration in patients with solid tumors.

PURPOSE: A phase I, multicenter trial of the thymidylate synthase (TS) inhibitor THYMITAQ (nolatrexed dihydrochloride; Agouron Pharmaceuticals, Inc, San Diego, CA) given by 5-day continuous infusion was performed to establish the maximum-tolerated dose (MTD) and to investigate pharmacokinetics, pharmacodynamics, and antitumor effects. METHODS: In vitro and in vivo preclinical studies demonstrated increased activity with prolonged nolatrexed exposure. In 32 patients, nolatrexed was given as a 5-day infusion at 96 to 1,040 mg/m2/d for 5 days. Pharmacokinetics were determined from high-performance liquid chromatography (HPLC) analyses of plasma and urine. In addition to studying toxicity, plasma deoxyuridine (UdR) elevations were measured as a marker of TS inhibition. RESULTS: The MTD was 904 mg/m2/d for 5 days and the recommended phase II dose is 800 mg/m2/d for 5 days. The dose-limiting toxicity was neutropenia with clinically significant thrombocytopenia and mucositis. These antiproliferative toxicities of nolatrexed were predictable and reversible. A partial response that lasted 3 months occurred in a patient with metastatic colorectal cancer. Pharmacokinetics were nonlinear, with the median plasma clearance (CI) decreasing from 151 mL/min/m2 (range, 124 to 211) at 96 mg/m2/d for 5 days to 49 mL/min/m2 (range, 30 to 84) at 768 mg/ m2/d for 5 days. The half-life (t1/2) was 173 minutes (range, 43 to 784) and 18% (range, 9% to 35%) of the dose was excreted unchanged in the urine. Plasma UdR increased, but returned to pretreatment levels after the end of infusion. Hematologic toxicity was significantly related to nolatrexed plasma concentrations and dose. CONCLUSION: Nolatrexed can be safely administered to patients at a dose of 800 mg/m2/d over 5 days by continuous intravenous infusion and this schedule is associated with antitumor effects. The phase II evaluation of nolatrexed is ongoing.

Adult↗
PubMed1998

Monitoring for mefloquine-resistant Plasmodium falciparum in Africa: implications for travelers' health.

The effectiveness of mefloquine to prevent malaria caused by Plasmodium falciparum is influenced by the sensitivity of the malaria parasites to this drug. Concern has been raised that resistance to mefloquine may develop in sub-Saharan Africa as has been observed in Southeast Asia. Case reports, along with blood smears to confirm the diagnosis and blood samples to determine the mefloquine concentration, were provided on any Peace Corps volunteer serving in sub-Saharan Africa who was diagnosed with malaria. We defined prophylaxis failures probably due to mefloquine resistance as patients with P. falciparum malaria confirmed at the Centers for Disease Control and Prevention, reported compliance with prophylaxis, no ingestion of mefloquine between date of illness onset and date of blood drawing, and a mefloquine level > or = 620 ng/ml in blood drawn within five days of onset of illness. Between January 1, 1991 and September 6, 1996, 44 (31%) of 140 volunteers with confirmed P. falciparum had blood drawn within five days of onset of illness. Twenty-nine (66%) had not fully complied with prophylaxis. Five of 15 prophylaxis failures in four countries had mefloquine levels > or = 620 ng/ml. Failure of mefloquine prophylaxis is primarily due to noncompliance. Evidence of probable resistance to mefloquine among strains of P. falciparum was found in five Peace Corps volunteers in sub-Saharan Africa. Clusters of well-documented prophylaxis failures need to be followed-up by therapeutic in vivo studies to document parasite resistance to mefloquine. Reduced sensitivity to mefloquine does not (yet) appear to be a significant problem in sub-Saharan Africa.

Adult↗
PubMed1998

Recovery of ceftazidime-resistant Klebsiella pneumoniae from pediatric liver and intestinal transplant recipients.

The purpose of this report was to determine the frequency of colonization and bacteremia with ceftazidime-resistant Klebsiella pneumoniae among pediatric candidates for and recipients of liver (LTx) and/or intestinal (ITx) transplantation. Between January and December 1994, surveillance stool cultures obtained from 51 children on the abdominal transplant service were planted on a selective medium containing 2 microg/ml of ceftazidime. Isolates of K. pneumoniae which grew on the selective medium were screened for extended-spectrum beta-lactamase (ESBL) production by the double-disk synergy test and underwent microdilutional susceptibility testing. Strain relatedness of ceftazidime-resistant K. pneumoniae was analyzed by field inversion gel electrophoresis (FIGE). Sixteen of 51 patients had > or = 1 positive stool cultures for ceftazidime-resistant K. pneumoniae; 9 out of 16 on the first culture obtained 1-23 days (median = 5) after admission. All 9 had been in hospital prior to this admission. Four others were positive on their first culture but were in our hospital for > 1 month at the onset of the study. Three patients became colonized after admission. Colonization with ceftazidime-resistant K. pneumoniae was more frequent among recipients of ITx (including combined LTx-ITx) compared to LTx alone (7/13 vs. 7/32, p<0.05). All of the ceftazidime-resistant isolates recovered from surveillance stool cultures had positive double-disk diffusion tests suggesting the presence of ESBL production as the mechanism of resistance. Ceftazidime resistance was identified in 7/8 episodes of bacteremia due to K. pneumoniae in patients on the abdominal transplant service compared with 0/17 episodes in other children in the Children's Hospital of Pittsburgh during the study. During this same time period, 69/312 clinical isolates of K. pneumoniae evaluated in the hospital laboratory were ceftazidime-resistant; 67/69 came from patients on this service. In none of the 312 isolates was resistance to cefotaxime found in the absence of ceftazidime resistance. Unique clones were identified for 10/19 isolates of ceftazidime-resistant strains of K. pneumoniae analyzed by FIGE. Colonization and bacteremia with ceftazidime-resistant K. pneumoniae were commonly identified among recipients of LTx & ITx at the Children's Hospital of Pittsburgh. The mechanism of resistance appeared to be due to the presence of ESBL production by resistant strains. Although resistant strains were frequently recovered from patients on the abdominal transplant service, recovery of ceftazidime-resistant strains from patients outside of this service was rare even in the intensive care setting.

Adolescent↗
PubMed1998

Implantable cardioverter-defibrillators and the pathologist: comment and cautionary notes.

This paper briefly reviews the components of, the clinical uses of, the techniques to place, and the complications related to implantable cardioverter-defibrillators (ICDs). Information useful in the specific identification of ICDs is presented. A series of recommendations for the autopsy examination or postmortem explantation of ICDs by the pathologist is given. Because of the serious risk of injury to the pathologist possible with postmortem discharges of ICDs which have not been deactivated, and because of the risk of device explosion if the ICD is incinerated, a number of cautionary notes are provided. A brief case with occurrence of accidental postmortem discharge of an active ICD is also presented.

Accidents, Occupational↗
PubMed1998

Improving sexually transmitted disease management in the private sector: the Jamaica experience.

OBJECTIVES: To improve the quality of sexually transmitted disease (STD) case management in Jamaica by providing comprehensive continuing medical education to private practitioners who manage 60% of all STDs on the island. METHODS: Six half-day STD seminars were presented at 3-4-month intervals and repeated in three separate geographic locations. All Jamaican practitioners received invitations. The subjects were as follows: urethritis, genital ulcer disease, HIV infection, vaginal discharge syndrome, STDs in children and adolescents, and a review seminar. The program effectiveness was evaluated with a written, self-reported pre-test and a telephone post-test that measured changes in clinical management. RESULTS: Six hundred and twenty eight practitioners attended at least one seminar. Comparing pre- versus post-test scores, there were practitioner improvement trends in all four of the general STD management categories: counseling/education (69.8-73.3%; P > 0.05); diagnostics/screening (57.2-71.0%; P= 0.042); treatment (68.3-74.5%; P> 0.05); and knowledge (66.4-83.2%; P= 0.002). Obtaining syphilis serologies during pregnancy rose from 38.3 to 83.8% (P= 0.001), and providing effective treatment for gonorrhea rose from 57.8 to 81.1 % (P= 0.002), but correct responses on treatment for mucopurulent cervicitis at the post-test was a low 32.4%. CONCLUSION: The introduction of continuing medical education for improved STD care targeting private physicians in Jamaica was successful based on high attendance rates and self-reported STD management practices. However, efforts should continue to address the weaknesses found in STD management and counseling and to reach the providers who did not participate. In the global effort to reduce HIV transmission by improving STD care services, continuing education programs that target the private sector can be successful and should be included as a standard activity to improve care and provide a public/private link to STD/HIV control.

Adolescent↗
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

Behavioural hearing tactics: a controlled trial of a short treatment programme.

Nineteen elderly hearing impaired subjects participated in an experimental treatment study and received either behavioural hearing tactics or served as untreated controls. Treatment was supplied in the form of a self-help treatment manual supplied with telephone contacts during 4 consecutive weeks. The treatment manual included applied relaxation, communication strategies training, advice to relatives, information, and coping skills. Assessments (pre-post) were conducted in a structured interview measuring coping behaviour. In order to evoke behavioural compensation small acoustic provocations were included in the interview. Pre-post assessments also included questionnaires, daily registered hearing problems, and hours of daily hearing aid use. Results showed significant beneficial effects in favour of the treatment in terms of self-assessed problems and behaviour change.

Adaptation, Psychological↗
PubMed1997

A sub-unit vaccine elicits IgG in serum, spleen cell cultures and bronchial washings and protects immunized animals against pneumonic plague.

In this study, the protection afforded against aerosolized Yersinia pestis by injection of an alhydrogel-adsorbed sub-unit vaccine has been compared with that given by an existing killed whole cell vaccine licensed for human use. The sub-unit vaccine protected mice against exposure to > 10(4) colony-forming units (c.f.u.) of virulent plague organisms (100 LD50 doses), whereas the whole cell vaccine provided only 50% protection against 1.8 x 10(3) c.f.u. In sub-unit vaccinees, IgG to each of the F1 and V antigens contained in the vaccine, was detected in serum, on direct secretion by spleen cells and in broncho-alveolar washings (BAL). In killed whole cell vaccinees, physiologically significant levels of IgG to F1 only were detectable in equivalent samples. Levels of F1-specific IgG in serum, secreted from spleen cells and in BAL were significantly higher (P < 0.01) in sub-unit compared with killed whole cell vaccinees. IgA was not detected in BAL from intra-muscularly dosed sub-unit vaccinees and thus the protection achieved against inhalational challenge with Yersinia pestis is attributed to the induction of systemic immunity to both the F1 and V antigens in the sub-unit vaccine. The enhanced protective efficacy of this sub-unit vaccine over an existing vaccine has been demonstrated in an animal model of pneumonic plague.

Animals↗
PubMed1997

Cytomegalovirus infection after intestinal transplantation in children.

Sixteen episodes of cytomegalovirus (CMV) disease occurred in 10 of 41 children undergoing intestinal transplantation from 1990 to 1995. Stratification of CMV disease by donor (D)/recipient (R) serological status was as follows: 3 of 8, D+/R-; 3 of 9, D+/R+; 4 of 9, D-/R+; and 0 of 15, D-/R-. Treatment resulted in resolution of CMV disease in 93.3% of episodes. No deaths attributable to CMV disease occurred in this series. CMV in D+/R- children resulted in more extensive and persistent disease. However, patient and graft survival rates were similar in the different D/R subgroups and between children with and without CMV disease. Cumulative dose of steroid boluses (relative risk [RR], 1.59; 95% confidence interval [CI], 1.14-2.21) and history of steroid recycles (RR, 2.72; 95% CI, 1.21-6.13) were associated with CMV disease. These results suggest that although CMV-associated morbidity in pediatric intestinal transplant recipients was substantial, it was not associated with an increased rate of mortality or graft loss, even among high-risk D+/R- patients.

Adolescent↗
PubMed1997

Comparison of intravenous ganciclovir followed by oral acyclovir with intravenous ganciclovir alone for prevention of cytomegalovirus and Epstein-Barr virus disease after liver transplantation in children.

A randomized trial was performed to compare the sequential use of 2 weeks of intravenous ganciclovir (10 mg/[kg.d]) followed by 50 weeks of high-dose oral acyclovir (800 mg/m2 four times daily) with 2 weeks of intravenous ganciclovir alone as prophylaxis for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) disease after pediatric liver transplantation. CMV disease was diagnosed for seven of 24 patients treated with ganciclovir followed by high-dose oral acyclovir compared with two of 24 children treated with ganciclovir alone (P = .048). Similarly, the rate of CMV disease among high-risk patients (CMV-positive donor/CMV-negative recipient) treated with the combination regimen was higher than that among high-risk patients treated with ganciclovir alone (four [57%] of seven vs. zero of five, respectively; vs P < .05). The rate of EBV disease among patients treated with the combination regimen (eight [33%] of 24) was similar to that among patients treated with ganciclovir alone (five [21%] of 24; P = not significant). We conclude that sequential prophylaxis with 2 weeks of intravenous ganciclovir followed by 50 weeks of high-dose oral acyclovir did not decrease the frequency of CMV or EBV disease after pediatric liver transplantation when compared with 2 weeks of intravenous ganciclovir alone.

Acyclovir↗
PubMed1997

A non-invasive system to evaluate diaphragmatic strength in ventilated patients.

In this paper we describe a system that allows an indicator of diaphragmatic strength to be determined non-invasively in mechanically ventilated patients. The system is comprised of an occlusion device that can be incorporated into the ventilator tubing and an occlusion control unit to operate the occlusion. The system electronically coordinates the timing of airway occlusion at the mouthpiece, application of a magnetic phrenic nerve stimulus and rapid removal of the occlusion once the measurement has been made. The system therefore permits measurement of the change in airway pressure produced by a stimulated diaphragm contraction, without disconnection from the ventilator. Other important respiratory measurements such as twitch mouth pressure, simulated cough and P0.1 can also be performed on non-ventilated patients in a repeatable and systematic manner.

Air Pressure↗