Are Geriatrics-Focused Primary Care Clinics Better at Diagnosing Dementia Than Traditional Clinics? A Matched Cohort Study.

BACKGROUND: Dementia and mild cognitive impairment (MCI) are prevalent but underdiagnosed. OBJECTIVE: To compare new dementia/MCI diagnosis rates in geriatrics-focused primary care clinics and traditional primary care clinics. DESIGN: Secondary analysis of a prospective matched cohort study that spanned 2017-2021. PARTICIPANTS: Community-dwelling Veterans over 65 receiving primary care in a geriatrics-focused medical home (GeriPACT) or traditional primary care home (PACT) at one of 57 Veterans Affairs sites. We excluded individuals with a documented diagnosis of dementia or MCI in the year prior to enrollment. MAIN MEASURES: Diagnoses obtained from EHR. Cognitive status was assessed using modified Telephone Interview for Cognitive Status (mTICS) tool. KEY RESULTS: The 470 participants included in this analysis were predominantly white, non-Hispanic males with an average age of 80.3 years. 9.4% of participants received a diagnosis of dementia/MCI after 24 months: 11.5% in GeriPACT and 7.2% in PACT. Adjusted OR for dementia/MCI diagnosis based on GeriPACT exposure was 1.47 (95% CI 0.65-3.29). Low mTICS score (≤ 27) (OR 4.89, 95% CI 2.36-10.13) and marital status (married/partnered) (OR 1.89, CI 0.99-3.59) were independent predictors of dementia/MCI diagnosis. When stratified by cognitive status: diagnosis rates were 20.8% in GeriPACT and 16.7% in PACT among those who scored lower on the cognitive assessment (mTICS ≤ 27); 7.4% in GeriPACT and 3.6% in PACT among those who scored higher (mTICS > 27). The OR for new dementia/MCI diagnosis in GeriPACT was 1.19 (95% CI 0.49-2.91) among those with a low mTICS score and 1.85 (95% CI 0.70-4.88) among those with a higher mTICS score. CONCLUSIONS: Observed rates of new dementia/MCI diagnosis were higher in GeriPACT, but with considerable uncertainty around estimates. Geriatrics-focused primary care clinics may be a promising avenue for improving the detection of dementia in older adults, but further larger studies are needed to confirm this relationship.

Erythropoietin or darbepoetin for patients with cancer.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (Epo), darbepoetin (Darbepo) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effects of Epo or Darbepo to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE and EMBASE and other data bases. Searches were done for the periods 01/1985 to 12/2001 for the first review and 1/2002 to 04/2005 for the update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients that compared the use of Epo/Darbepo (plus transfusion if needed) with observation until red blood cell transfusion was required. DATA COLLECTION AND ANALYSIS: Several reviewers independently assessed trial quality and extracted data. MAIN RESULTS: This update of the systematic review included a total of 57 trials with 9,353 patients. Of these, 27 trials with 3,287 adults were also included in the first Cochrane Review. Thirty trials with 6,066 patients were added during the update process. Use of Epo/Darbepo significantly reduced the relative risk of red blood cell transfusions (RR 0.64; 95% CI 0.60 to 0.68, 42 trials, n = 6,510). On average participants in the Epo/Darbepo group received one unit of blood less than the control group (WMD -1.05; 95% CI -1.32 to -0.78, 14 trials, n = 2,353). For participants with baseline haemoglobin below 12 g/dL haematological response was observed more often in participants receiving Epo/Darbepo (RR 3.43; 95% CI 3.07 to 3.84, 22 trials, n = 4,307). There was suggestive evidence that Epo/Darbepo may improve Quality of Life (QoL). The relative risk for thrombo embolic complications was increased in patients receiving Epo/Darbepo compared to controls (RR 1.67, 95% CI 1.35 to 2.06; 35 trials, n = 6,769). Uncertainties remain whether and how Epo/Darbepo effects tumour response (fixed effect RR 1.12; 95% CI 1.01 to 1.23, 13 trials, n = 2,833; random effects: RR 1.09; 95% CI 0.94 to 1.26) or overall survival (unadjusted and adjusted data: HR 1.08; 95% CI 0.99 to 1.18; 42 trials, n = 8,167). AUTHORS' CONCLUSIONS: There is consistent evidence that administration of Epo/Darbepo reduces the relative risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 12 g/dL (mild anaemia) there is strong evidence that Epo/Darbepo improves haematological response. There is suggestive evidence that Epo/Darbepo may improve QoL. However, there is strong evidence that Epo/Darbepo increases the relative risk for thrombo embolic complications. Whether and how Epo/Darbepo effects tumour response and overall survival remains uncertain.

Erythropoietin for patients with malignant disease.

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoietin (EPO) and red blood cell transfusions. OBJECTIVES: The aim of this systematic review was to assess the effect of erythropoietin to either prevent or treat anaemia in cancer patients. SEARCH STRATEGY: We searched the Central Register of Controlled Trials, MEDLINE (01/1985 to 12/2001), EMBASE (01/1985 to 12/2001), other databases and reference lists of articles. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials comparing the use of recombinant human erythropoietin (plus transfusion if needed) with red blood cell transfusions alone for the treatment or prevention of anaemia in cancer patients. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality and extracted data. All authors from included studies were contacted for additional information. MAIN RESULTS: Twenty seven trials with 3,287 adults were included. Use of erythropoietin significantly reduced the relative risk of red blood cell transfusions (RR 0.67; 95% CI 0.62 to 0.73, 25 trials, n = 3,069). On average participants in the erythropoietin group received one unit of blood less than the control group (WMD -1.00; 95% CI-1.31 to -0.70, 13 trials, n = 2,056). For participants with baseline haemoglobin below 10 g/dL haematological response was observed more often in participants receiving EPO (RR 3.60; 95% CI 3.07 to 4.23, 14 trials, n = 2,347). There was inconclusive evidence whether EPO improves tumour response (fixed effect RR 1.36; 95% CI 1.07 to 1.72, seven trials, n = 1,150; random effects: RR 1.21; 95% CI 0.92 to 1.59) and overall survival (adjusted data: HR 0.81; 95% CI 0.67 to 0.99; unadjusted data: HR 0.84; 95% CI 0.69 to 1.02, 19 trials, n = 2,865). There were no statistically significant adverse effects. Evidence was inconclusive with respect to quality of life and fatigue. REVIEWERS' CONCLUSIONS: There is consistent evidence that the administration of erythropoietin reduces the risk for blood transfusions and the number of units transfused in cancer patients. For patients with baseline haemoglobin below 10 g/dL there is strong evidence that erythropoietin improves haematological response. There is inconclusive evidence whether erythropoietin improves tumour response and overall survival. Research on side effects is inconclusive.

Erythropoietin: a paradigm for the development of practice guidelines.

Erythropoietin (EPO) is an endogenous hormone produced in the kidney that regulates red blood cell production within the body. Since the cloning and first clinical introduction of recombinant erythropoietin (epoetin) in the late 1980s indications and usage of epoetin have expanded significantly. It is estimated that as many as one third of patients with substantial anemia (hemoglobin less than 10.0 g/dL) resulting from chemotherapy for cancer are treated with epoetin. Though use of epoetin may avoid the inconvenience and infectious risk of blood transfusions, it is expensive and its benefit in some clinical scenarios has been modest. Like many new technologies, strong evidence suggesting situations where the benefit is high has lagged behind its adoption by patients and practitioners. As well, epoetin is expensive and third party payers do not always reimburse it. Research suggests there is considerable variation in epoetin usage in practice. To provide guidance to hematology/oncology specialists regarding use of epoetin, the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) proposed that the Agency for Healthcare Research and Quality (AHRQ) fund an evidence review by one of the Evidence-based Practice Centers (EPC) that would be used to develop evidence-based guidelines for members of the society. This review highlights principles of evidence-based medicine, distills and appraises the evidence in the published literature that supports the use of epoetin, and presents evidence-based recommendations for use of epoetin in situations where benefit is substantiated by high-quality studies. As well, this review addresses some of the difficulties of performing clinical research in this area, provocative research findings that will require further study, and suggestions regarding epoetin in those areas where further strong evidence has yet to be developed.

Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the meta-analysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval [CI] = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemia-related symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/dL.

Maximal androgen blockade for advanced prostate cancer.

OBJECTIVES: This systematic review assessed the effect of maximal androgen blockade (MAB) on survival when compared to castration (medical or surgical) alone for patients with advanced prostate cancer. SEARCH STRATEGY: Randomized controlled trials were searched in general and specialized databases (MEDLINE, EMBASE, Cancerlit, Cochrane Library, VA Cochrane Prostate Disease register) and by reviewing bibliographies. SELECTION CRITERIA: All published randomized trials were eligible for inclusion provided they (1) randomized men with advanced prostate cancer to receive a non-steroidal anti-androgen (NSAA) medication in addition to castration (medical or surgical) or to castration alone, and (2) reported overall survival, progression-free survival, cancer-specific survival, and/or adverse events. Eligibility was assessed by two independent reviewers. DATA COLLECTION AND ANALYSIS: Information on patients, interventions, and outcomes were extracted by two independent reviewers using a standardized form. The main outcome measure for comparing effectiveness was overall survival at 1, 2, and 5 years. Secondary outcome measures included progression-free survival and cancer-specific survival. The relationship of specific NSAA on outcome was evaluated. Additionally, the incidence of adverse effects was measured. MAIN RESULTS: Twenty trials enrolling 6,320 patients were included. The pooled OR for overall survival was 1.03 (95% CI:0.85 to 1.25), 1.16 (95% CI:1.00 to 1.33), and 1.29 (95% CI:1.11 to 1.50) at 1, 2, and 5 years respectively. Overall survival was only significant at 5 years. The risk difference at 5 years was 0.048 (95% CI:0.02 to 0.077) and NNT at 5 years 20.8. Progression-free survival was improved only at 1 year follow-up (OR=1.38) and cancer-free survival was improved only at 5 years (OR=1.22). Adverse events occurred more frequently in those assigned to MAB and resulted in withdrawal in 10%. Quality of life was measured in only one study favored orchiectomy alone (less diarrhea and better emotional functioning in the first 6 months). REVIEWER'S CONCLUSIONS: MAB produces a modest overall and cancer-specific survival at 5 years but is associated with increased adverse events and reduced quality of life.

Single-therapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis.

PURPOSE: To compare luteinizing hormone-releasing hormone (LHRH) agonists with orchiectomy or diethylstilbestrol, and to compare antiandrogens with any of these three alternatives. DATA SOURCES: A search of the MEDLINE, Cancerlit, EMBASE, and Cochrane Library databases from 1966 to March 1998 and Current Contents to 24 August 1998 for articles comparing the outcomes of the specified treatments. The search was limited to studies on prostatic neoplasms in humans. Total yield was 1477 studies. STUDY SELECTION: Reports of efficacy outcomes were limited to randomized, controlled trials. Twenty-four trials involving more than 6600 patients, phase II studies that reported on withdrawals from therapy (the most reliable indicator of adverse effects), and all studies reporting on quality of life were abstracted. DATA EXTRACTION: Two independent reviewers abstracted each article by following a prospectively designed protocol. The meta-analysis combined data on 2-year overall survival by using a random-effects model and; reported results as a hazard ratio relative to orchiectomy. DATA SYNTHESIS: Ten trials of LHRH agonists involving 1908 patients reported no significant difference in overall survival. The hazard ratio showed LHRH agonists to be essentially equivalent to orchiectomy (hazard ratio, 1.1262 [corrected] [95% CI, 0.915 to 1.386]). There was no evidence of difference in overall survival among the LHRH agonists, although CIs were wider for leuprolide (hazard ratio, 1.0994 [CI, 0.207 to 5.835]) and buserelin (hazard ratio, 1.1315 [CI, 0.533 to 2.404]) than for goserelin (hazard ratio, 1.1172 [CI, 0.898 to 1.390]). Evidence from 8 trials involving 2717 patients suggests that nonsteroidal antiandrogens were associated with lower overall survival. The CI for the hazard ratio approached statistical significance (hazard ratio, 1.2158 [CI, 0.988 to 1.496]). Treatment withdrawals were less frequent with LHRH agonists (0% to 4%) than with nonsteroidal antiandrogens (4% to 10%). CONCLUSIONS: Survival after therapy with an LHRH agonist was equivalent to that after orchiectomy. No evidence shows a difference in effectiveness among the LHRH agonists. Survival rates may be somewhat lower if a nonsteroidal antiandrogen is used as monotherapy.

Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer.

OBJECTIVES: With 184,500 new cases and 39,200 deaths anticipated in 1998, prostate cancer is second only to lung cancer in cancer mortality for men. This report is a systematic review of the evidence from randomized controlled trials on the relative effectiveness of alternative strategies for androgen suppression as treatment of advanced prostate cancer. Three key issues are addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone-releasing hormone [LHRH] agonists, and antiandrogens), (2) the effectiveness of combined androgen blockade compared to monotherapy, and (3) the effectiveness of immediate androgen suppression compared to androgen suppression deferred until clinical progression. Outcomes of interest are overall, cancer-specific, and progression-free survival; time to treatment failure; adverse effects; and quality of life. Two supplementary analyses were conducted for each key question: (1) meta-analysis of overall survival at 2 years (questions 1 and 2) and 5 years (questions 2 and 3), and (2) cost-effectiveness analysis. SEARCH STRATEGY: The MEDLINE, CANCERLIT, and EMBASE databases were searched from 1966 to March 1998, and Current Contents to August 24, 1998, for the terms: leuprolide (Lupron); goserelin (Zoladex); buserelin (Suprefact); flutamide (Eulexin); nilutamide (Anandron, Nilandron); bicalutamide (Casodex); cyproterone acetate (Androcur); diethylstilbestrol (DES); and orchiectomy (castration, orchidectomy). The search was then limited to human studies indexed under the MeSH term "prostatic neoplasms" and by the UK Cochrane Center search strategy for randomized controlled trials. Total yield was 1,477 references. SELECTION CRITERIA: We Reports of efficacy outcomes were limited to randomized controlled trials. Phase II studies that reported on withdrawals from therapy and all studies reporting on quality of life were also included. DATA COLLECTION AND ANALYSIS: The systematic review used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis combined data on overall survival using a random effects model. The cost-effectiveness analysis used a decision analysis model of advanced prostate cancer with health states and transitions derived from the literature and estimates of effectiveness derived from the meta-analysis. The cost-effectiveness analysis is conducted from a societal perspective, consistent with the guidelines of the U.S. Public Health Service Panel on Cost-Effectiveness in Health and Medicine. MAIN RESULTS: Survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy. The available LHRH agonists are equally effective, and no LHRH agonist is superior to the other when adverse effects are considered. Survival may be somewhat lower with use of a nonsteroidal antiandrogen. There is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy. Meta-analysis of the limited data available shows a statistically significant difference in survival at 5 years that favors combined androgen blockade. However, the magnitude of this difference is of questionable clinical significance. For the subgroup of patients with good prognosis, there is no statistically significant difference in survival. Adverse effects leading to withdrawal from therapy occurred more often with combined androgen blockade. No evidence is yet available from randomized controlled trials of androgen suppression initiated at prostate-specific antigen (PSA) rise after definitive therapy for clinically localized disease. For patients who are newly diagnosed with locally advanced or asymptomatic metastatic disease, the evidence is insufficient to determine whether primary androgen suppression initiated at diagnosis improves outcomes. (ABSTRACT TRUNCATED)

Effects of prolonged controlled mechanical ventilation on diaphragmatic function in healthy adult baboons.

OBJECTIVE: To study diaphragmatic strength and endurance after a prolonged period of mechanical ventilation. DESIGN: Prospective animal study. SETTING: Animal research laboratory. SUBJECTS: Seven uninjured adult baboons (Papio cynocephalus) were anesthetized with ketamine, sedated, paralyzed, and mechanically ventilated. Animals were monitored with pulmonary arterial and peripheral arterial catheters. INTERVENTIONS: Mechanical ventilation was provided for 11 days with an FIO2 of 0.21 and tidal volume of 15 mL/kg. Pulmonary function tests, including lung volumes, arterial blood gases, and chest radiographs were also monitored. Nursing care procedures included frequent turning, chest physiotherapy, and endotracheal suction. Antacids and prophylactic antibiotics (intravenous penicillin, topical polymyxin B, and gentamicin sulfate) were administered. In three animals, fishhook electrodes were surgically placed around both phrenic nerves on both day 0 and after 11 days of mechanical ventilation for diaphragmatic stimulation. On day 0, the electrodes were removed after phrenic nerve stimulation studies were performed. After 11 days of mechanical ventilation, animals were electively killed and full autopsy performed. MEASUREMENTS AND MAIN RESULTS: Hemodynamic and pulmonary function parameters were measured at baseline and every day during the 11 days of mechanical ventilation. Diaphragmatic strength and endurance were measured on days 0 and 11. Diaphragmatic endurance was determined by an inspiratory resistive loading protocol. There were no significant changes in hemodynamics, lung volumes, or gas exchange during the period of mechanical ventilation. On day 7, the chest radiographs showed patchy lobar atelectasis in six animals, which cleared by day 11 in all but two of the animals. Lung pathology showed mild, focal pneumonitis. By day 11, maximum transdiaphragmatic pressure had decreased by 25% from day 0 and diaphragmatic endurance had decreased by 36%. CONCLUSIONS: Eleven days of mechanical ventilation and neuromuscular blockade in healthy baboons resulted in nonsignificant changes in hemodynamics, oxygenation, and/or lung function. However, significant impairment in diaphragmatic endurance and strength were seen. Based on these results, it is likely that prolonged mechanical ventilation by itself impairs diaphragmatic function independent of underlying lung disease.

Selective activation of human heat shock gene transcription by nitrosourea antitumor drugs mediated by isocyanate-induced damage and activation of heat shock transcription factor.

Treatment of cultured human tumor cells with the chloroethylnitrosourea antitumor drug 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) selectively induces transcription and protein synthesis of a subset of the human heat shock or stress-induced genes (HSP90 and HSP70) with little effect on other stress genes or on expression of the c-fos, c-myc, or beta-actin genes. The active component of BCNU and related compounds appears to be the isocyanate moiety that causes carbamoylation of proteins and nucleic acids. Transcriptional activation of the human HSP70 gene by BCNU is dependent on the heat shock element and correlates with the level of heat shock transcription factor and its binding to the heat shock element in vivo. Unlike activation by heat or heavy metals, BCNU-mediated activation is strongly dependent upon new protein synthesis. This suggests that BCNU-induced, isocyanate-mediated damage to newly synthesized protein(s) may be responsible for activation of the heat shock transcription factor and increased transcription of the HSP90 and HSP70 genes.

Alpha-difluoromethylornithine inhibits bone resorption in vitro without decreasing beta-glucuronidase release.

Our previous studies suggested that the ornithine decarboxylase inhibitor alpha-difluoromethylornithine (DFMO) inhibits bone resorption by mechanisms that are independent of polyamine depletion. To determine whether DFMO prevents calcitriol-stimulated bone resorption by acting at a step before or after osteoclast activation, we compared the effects of DFMO on release of calcium and beta-glucuronidase from cultured neonatal mouse calvaria. DFMO, at concentrations of 7.5-20 mM, inhibited release of calcium from calcitriol-stimulated calvaria but failed to inhibit the calcitriol-stimulated increase in beta-glucuronidase secretion. In contrast, ornithine, putrescine, spermidine, and spermine, at concentrations with effects on resorption comparable to those of DFMO, inhibited the effects of calcitriol on both calcium and beta-glucuronidase release. NaF (0.2 mM), like DFMO, inhibited calcitriol-stimulated calcium release without affecting medium beta-glucuronidase activity, whereas elevated phosphate (3 mM) inhibited both activities. The results suggest that DFMO, over the concentration range studied, inhibits calcium release by making the matrix resistant to resorption rather than by acting at a cellular locus.

Elastase activity in bronchoalveolar lavage fluid from oxygen-exposed, Pseudomonas-infected baboons.

The adult respiratory distress syndrome is a major cause of morbidity and mortality in critical care patients. Lung injury in this syndrome is frequently associated with lung infection. The combined insults result in an influx of neutrophils and damage to the pulmonary epithelium. We investigated whether active neutrophil elastolytic activity was present in the bronchoalveolar fluid in baboons with mild or moderate hyperoxic lung injury and infection. Group A (N = 7) was exposed for 6 days to FIO2 = 0.8 and then inoculated by intratracheal bolus with Pseudomonas aeruginosa strain DGI-R130 (PA); the FIO2 was reduced to 0.5. Group B (N = 6) was exposed to similar concentrations of inspired oxygen but inoculated with buffered saline. Antibiotics included parenteral penicillin and topical gentamicin and polymyxin B. All 3 were given continuously in group B but stopped 24 h prior to PA inoculation in group A. Bronchoalveolar lavage fluid was collected 1 week before oxygen administration, when the FIO2 was reduced (day 6 or 7) and prior to necropsy (day 11). Hemodynamic, pulmonary function, microbiological, and biochemical variables were studied. Injured, infected animals (group A) had significant elevations of mean pulmonary artery pressure and decreases in total lung capacity and PaO2 compared both to baseline and to group B at day 11. At autopsy, group A had significant increases of bronchoalveolar lavage fluid (BALF) neutrophils and bacterial pathogens. Elastase levels in BALF (equal to 0 at baseline) rose to 136 +/- 98 ng/ml in group A vs. 6 +/- 14 ng/ml in group B. The elastase was inhibited by inhibitors of serine proteases including ones specific for neutrophil elastase. On Sephacryl S-300 chromatography the elastase activity eluted near human alpha 2-macroglobulin and separated from other proteolytic activity. These studies demonstrate a significant level of elastase in BALF from injured, infected baboons compared to injured, uninfected animals.

Acute inhalation toxicity of soman and sarin in baboons.

Adult baboons (Papio sp.; 8-12 kg) were anesthesized with sodium pentobarbital (20 mg/kg iv). The animals were instrumented for measurement of mean blood pressure (MBP), pulmonary artery pressure (PAP), ECG, arterial and mixed venous blood gases, lung volumes, lung pressures, and efferent phrenic nerve activity. Bronchoalveolar lavage (BAL) was performed. Studies were done prior to exposure, at intervals during the first 4 hr postexposure, and at 4 and 28 days after exposure. Control animals received a sham exposure to 2-propanol (N = 5). Soman (pinacolyl methylphosphonofluoridate) at 13.14 micrograms/kg (2 X LD50) was vaporized into the upper airway in a second group of animals (N = 5), and sarin (isopropyl methylphosphonofluoride) 30 micrograms/kg (2 X LD50) was vaporized into a third group of animals (N = 4). Controls showed no change in any parameter either immediately after diluent exposure or during the monitoring period. Soman and sarin produced a decline in MBP and bradyarrhythmias that were reversed with atropine. Apnea occurred in all soman- and sarin-exposed animals within 5 min postexposure, and was associated with absence of phrenic nerve signal. Ventilation was mechanically supported until the animal could maintain normal arterial blood gases during spontaneous breathing. BAL studies revealed an increase in total white cell population and neutrophils at 4 hr in all three groups. There were signs of impaired hemodynamics and persistent lung injury for 4 days that resolved by 28 days after exposure. In conclusion, inhalation of soman and sarin in the baboon is associated with cardiac arrhythmias, development of apnea, and a significant decrease in MBP. Inhalation exposure also resulted in a persistent influx of neutrophils and hypoxemia.

Comparisons between sensitive and resistant human tumor cell lines regarding effects of polyamine depletion on chloroethylnitrosourea efficacy.

We have reported that 2-difluoromethylornithine (DFMO)-induced polyamine (PA) depletion sensitized five chloroethylnitrosourea (CENU)-resistant, O6-alkylguanine repair-proficient (Mer+) human tumor cell lines to 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), but failed to alter BCNU efficacy in a single CENU-sensitive, repair-deficient (Mer-) line. Further, alkaline elution assays of DNA interstrand cross-links (ISC) found no BCNU-induced ISC in either PA-depleted or control Mer+ cells, suggesting that targets other than ISC may be involved in the DFMO/BCNU drug interaction. To verify that DFMO-induced enhancement of BCNU action segregates with Mer phenotype, we tested three additional Mer- lines for effects of DFMO pretreatment on BCNU efficacy. We found no potentiation of BCNU by PA depletion in any of our human Mer- lines. We also used streptozotocin (STZ) to deplete the repair capacity of Mer+ cell lines, thus converting their BCNU sensitivity to near that of Mer- cells. Combined pretreatment with DFMO then STZ did enhance BCNU cell kill relative to STZ pretreatment alone. Exogenous putrescine restored BCNU sensitivity of (DFMO plus STZ)-pretreated cells to that of cells pretreated with STZ alone. Measurements of O6-alkylguanine DNA alkyltransferase activity verified that in at least one of the Mer+ lines (HT-29), STZ did deplete repair capacity to below detectable limits. These results suggest that in HT-29 cells, STZ and DFMO probably act via differing mechanisms to potentiate BCNU. Our observations also imply that targets for CENUs may differ between Mer+ and Mer- cells, with importance of ISC possibly limited to Mer- cells. Our data further suggest that PA depletion may potentiate CENUs only at targets critical in Mer+ cells. We also noted that 48-h treatments with DFMO markedly reduced clonogenicity of Mer- cells. Exogenous putrescine restored Mer- cell survival after DFMO to near that of controls. In contrast, Mer+ cells showed little, if any, effect of DFMO treatment on plating efficiency. These results suggest that PA depletion may be cytocidal to some Mer- cells.

Effects of alpha-difluromethylornithine on the development of deeply invasive urinary bladder carcinomas in mice.

alpha-Difluoromethylornithine (DFMO), was examined for its ability to suppress the development of invasive urinary bladder carcinoma in C3H/He male mice. Continuous administration of 0.2% DFMO in water following carcinogen treatment (0.05% N-butyl-N-(4-hydroxybutyl)nitrosamine, BHBN, in drinking water for 8 weeks) was effective in suppressing urinary bladder carcinomas (P less than 0.05) as compared with the control group. However, when comparison was made based on tumors involving the entire urinary tract, protective effects could not be demonstrated. Coadministration of DFMO (0.2%) and BHBN (0.01%) did not alter tumor induction by the latter. These results were in sharp contrast to the protective effects in rats. Since bladder tumors in rats are of low grade and superficial whereas those in mice are of high grade and deeply invasive, our data indicate that DFMO has little to no effects against the development of aggressive forms of bladder carcinoma.