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PubMed2003

Trends in clinical trials reports in common cancers between 1989 and 2000.

PURPOSE: Cancer clinical trials can be dichotomized into pilot (phase I and phase II) and randomized controlled clinical trials (RCTs). The best data source for evidence-based medicine is from RCTs. However, many patients prefer to enroll onto pilot trials, and many investigators prefer to conduct or refer their patients to pilot trials. This exploratory study sought to describe the epidemiologic patterns of clinical trial reports in common cancers. METHODS: A structured review was conducted of MEDLINE citations of all English clinical trials reports published between 1989 and 2000 in breast, lung, colorectal, prostate, and female genital cancers, plus leukemias and lymphomas. Each report was classified by design (RCT, pilot, or other) and country. The abstracts of RCTs were reviewed for sample size. Reports addressing screening or prevention were excluded. RESULTS: A total of 12,035 reports, of which 3,560 were from RCTs, were found. The annual growth in RCT reports in breast, colorectal, and prostate cancer was significant (range, 4.8% to 8.5% per year) but was insignificant in leukemias, lymphomas, and female genital and lung cancers (range, 0.1% to 4.3% per year). Within each cancer, the average sample size per report did not change during the 12 years. Nonrandomized trial reports increased on average 15.1% per year (range, 10.1% to 23.2%). The United States accounted for 30% of all RCT reports and 45% of pilot trial reports. CONCLUSION: The faster growth in nonrandomized compared with RCT reports may reflect rapid advances in cancer biology or different structural, commercial, and financial incentives, especially in the United States compared with Europe. Unless additional studies show evidence of an increase in their quality, the modest growth in RCT reports may limit future evidence-based cancer care.

Clinical Trials as Topic↗
PubMed1989

Rat calvarial cell lines immortalized with SV-40 large T antigen: constitutive and retinoic acid-inducible expression of osteoblastic features.

Two new bone cell lines were established by immortalizing cells derived from embryonic rat calvariae with a recombinant retrovirus containing the cDNA for SV-40 large T antigen and the neomycin resistance gene. One cell line, RCT-1, isolated from early digest cells, a population which typically does not express osteoblastic features, displayed osteoblastic characteristics only after 3 days of treatment with 1 microM retinoic acid: alkaline phosphatase activity increased from 0.003 to 0.25 mumol/min.mg protein, the steady state level of type I procollagen mRNA increased 4-fold, and the cells acquired a PTH-stimulatable adenylate cyclase (EC50, 10 nM). mRNA for osteopontin, an abundant bone matrix protein, was induced in RCT-1 cells by 1,25-dihydroxyvitamin D3 (10 nM). The second cell line, RCT-3, isolated from late digest cells, a population previously shown to be enriched with differentiated osteoblasts, expressed constitutively the properties described above. In addition, RCT-3 cells responded to interleukin-1 by increased prostaglandin production (EC50, 20 pM) and to prostaglandin E2 by enhanced cAMP accumulation, features exhibited by calvarial cells in organ culture. Thus, the SV-40 immortalized cell lines we describe retained many of the characteristics of osteoblasts in primary culture, including hormonal regulation of phenotype-related genes. In RCT-1 cells the coordinate induction of several properties by retinoic acid offers a new model for the study of differentiation-related gene expression in bone cells.

1-Methyl-3-isobutylxanthine↗
PubMed1989

Estradiol effects on proliferation, messenger ribonucleic acid for collagen and insulin-like growth factor-I, and parathyroid hormone-stimulated adenylate cyclase activity in osteoblastic cells from calvariae and long bones.

Estradiol (E2) replacement therapy effectively prevents or delays postmenopausal bone loss, but the mode of E2 action on bone is still unknown. Recently, the presence of E2 receptors was described for bone-derived cells. In this study we examined the estrogen responsiveness of osteoblastic cells using the experimentally immortalized calvarial cell lines RCT-1 and RCT-3 as well as primary cultures of calvarial and trabecular bone cells. E2 treatment reduced PTH-stimulated adenylate cyclase activity by 20-30% in RCT cells; the maximum effect was observed after treatment with 1 nM E2 for 4 h or longer. In trabecular cells E2 decreased PTH-stimulated adenylate cyclase activity by 60-80%. After a lag period of at least 48 h, E2 treatment (0.01-10 nM) increased cell number and [3H]thymidine incorporation in both RCT-3 cells and primary cultures of trabecular cells to 20-60% above control values. Half-maximal effects were observed at about 1 nM E2. Antibodies against insulin-like growth factor-I (IGF-I) inhibited the E2-induced proliferation in a dose-dependent manner without affecting basal growth. Furthermore, E2 treatment increased the steady state levels of IGF-I mRNA 2- to 2.5-fold in calvarial and RCT-3 cells compared to control levels. In addition, E2 (10 nM) increased the level of collagen mRNA more than 2-fold and opposed the suppression of collagen mRNA produced by PTH treatment. The E2 effects were specific to 17 beta-E2, since they were not observed with the biologically less active stereoisomer 17 alpha-E2 and were blocked by the E2 antagonist tamoxifen (1 microM). Thus, for osteoblastic cells in culture, E2 can directly stimulate proliferation as well as collagen and IGF-I mRNA while decreasing PTH responsiveness; these effects could explain the anabolic and anticatabolic effects of E2 on bone.

Adenylyl Cyclases↗
PubMed2006

Is cardiorespiratory fitness related to quality of life in survivors of breast cancer?

The purpose of this study was to investigate whether indices of cardiorespiratory fitness are related to quality of life (QOL) in women survivors of breast cancer. Using the European Organization for Research and Treatment of Cancer QLQ-30 questionnaire, we assessed the QOL of 16 participants (age, 50 +/- 9 years; body mass, 66.6 +/- 9.6 kg). All participants performed incremental cycle ergometer exercise to determine several indices of cardiorespiratory fitness (e.g., peak oxygen uptake [.V(O2)peak, in L.min(-1), ml.kg(-1).min(-1)]), peak power output (PPO, in W), PPO/ body mass (W.kg(-1), peak heart rate (HRpeak, b.min(-1), peak ventilation (VEpeak), and .V(O2) and heart rate (HR) at the ventilatory (VT) and respiratory compensation (RCT) thresholds. Relationships between QOL and variables were assessed using Spearman rank-difference correlation tests. A significant inverse relationship (p < 0.05) was found for QOL scores and values for age (years) and body mass (kg) ( = -0.53), %HRpeak@VT ( = -0.59) and %VEpeak@VT ( = -0.61). A significant positive relationship (p < 0.05) was found for QOL and PPO/body mass ( = 0.59) and HRpeak ( = 0.78), .V(O2)@RCT (ml.kg(-1.min(-1) ( = 0.51), power output (PO, expressed as either W or W.kg(-1) at RCT, and HR at RCT ( = 0.54). No other significant relationship was found between QOL and variables obtained from the tests. In conclusion, these findings highlight possible relationships between cardiorespiratory fitness and well-being in survivors of breast cancer. From a practical point of view, our data emphasize the need for this population to engage in programmed cardiorespiratory exercise training, mainly designed to improve VT and RCT. The improvement of both submaximal indices can have a beneficial effect on QOL.

Age Factors↗
PubMed2006

Role of blood pressure targets and specific antihypertensive agents used to prevent diabetic nephropathy and delay its progression.

This study evaluated the comparative effects of antihypertensive agents in patients with diabetes and normoalbuminuria and the evidence supporting equivalent use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with diabetes and micro- or macroalbuminuria. A systematic review was conducted by searching for randomized controlled trials (RCT) of antihypertensive agent versus placebo or another agent in hypertensive or normotensive patients with diabetes and no nephropathy and RCT of ACEi or ARB in patients with diabetic nephropathy. Medline, Embase, the Cochrane Controlled Trials Register, conference proceedings, and contact with investigators were used to identify available evidence. Two investigators independently extracted data and assessed quality of trials. Sixteen RCT (7603 patients) of antihypertensive agents conducted in patients with diabetes and no nephropathy and 43 (7739 patients) of ACEi or ARB in patients with diabetic nephropathy were identified. A significant reduction in the risk for developing microalbuminuria in patients who had diabetes with no nephropathy was demonstrated for ACEi only (six trials, 3840 patients; relative risk [RR] 0.60; 95% confidence interval [CI] 0.43 to 0.84), and in patients with diabetic nephropathy, existing RCT have shown a survival benefit of ACEi (20 trials, 2383 patients; RR 0.79; 95% CI 0.63 to 0.99; P = 0.04) but not ARB (four trials, 3329 patients; RR 0.99; 95% CI 0.85 to 1.17). On the basis of available RCT evidence, ACEi are the only agents with proven renal benefit in patients who have diabetes with no nephropathy and the only agents with proven survival benefit in patients who have diabetes with nephropathy.

Albuminuria↗
PubMed2005

Barriers to Australian physicians' and paediatricians' involvement in randomised controlled trials.

OBJECTIVE: To compare attitudes of Australian physicians and paediatricians about treatment and randomised controlled trial (RCT) participation. DESIGN AND PARTICIPANTS: A cross-sectional survey using the validated "Physician Orientation Profile" (POP), with 250 physicians and 250 paediatricians surveyed. OUTCOME MEASURES: Five indices - primary allegiance, decision making under uncertainty, professional activities, perceived rewards, and peer-group influence - with scores for each participant ranging along a continuum from clinician-oriented to research-oriented and expressed as a number between 0 and 1. RESULTS: Overall response rate was 60%, with 135 physicians (54%) and 165 paediatricians (66%) responding. Paediatricians and physicians were similar in their attitudes to RCT participation, being generally clinician-oriented rather than research-oriented and less inclined to participate in RCTs when there is uncertainty about the best treatment. Most assign limited time to research, with 26.9% not currently involved in research and 31.5% having no experience of RCT participation. Doctors perceive few rewards and little peer-group influence regarding trial participation. Independent predictors of favourable attitudes to trial participation (based on POP scores) were the presence of allocated research time (0.37 for no allocated research time v 0.61 for > 70% research time; P < 0.0001), previous experience enrolling a patient in an RCT (0.40 for no experience v 0.46 for experience; P < 0.0001), and articles published in the past 12 months (0.40 for no publications v 0.55 for > 3 publications; P < 0.0001). CONCLUSIONS: This study highlights the minor importance of research for most Australian physicians. Research plays only a small role in their professional activities, and the importance of research participation is not recognised. They are clinician-oriented in their attitudes to RCT participation. To encourage greater involvement in trials among physicians in Australia, clinical research needs to be restructured in a primarily clinically oriented setting with dedicated research time.

Adult↗
PubMed2000

Using routine data to complement and enhance the results of randomised controlled trials.

BACKGROUND: Randomised controlled trials (RCTs) are widely accepted as the best way to assess the outcomes and safety of medical interventions, but are sometimes not ethical, not feasible, or limited in the generalisability of their results. In such circumstances, routinely available data could help in several ways. Routine data could be used, for example, to conduct 'pseudo-trials', to estimate likely outcomes and required sample size to help design and conduct trials, or to examine whether the expected outcomes observed in an RCT will be realised in the general population. OBJECTIVES: The project was undertaken to explore how routinely assembled hospital data might complement or supplement RCTs to evaluate medical interventions: in contexts where RCTs are not feasible for defining the context and design of an RCT for assessing whether the benefits indicated by RCTs are achieved in wider clinical practice. METHODS: The project was based on the system of linked Scottish morbidity records, which cover 100% of acute hospital care episodes and statutory death records from 1981 to 1995. Three case studies were undertaken as a way of investigating the utility of these records in different applications. First, an attempt was made to analyse the link between the timing of surgery for subarachnoid haemorrhage (SAH) and subsequent outcomes (a question not easily susceptible to RCT design). A subsample was derived by excluding patients for which a diagnosis of SAH may not have been established or that may not have been admitted to a neurosurgical unit, and the data were assessed to attempt to inform the design of a trial of early versus late surgery. Transurethral prostatectomy (TURP), the second case study, has become the surgery of choice for benign prostatic hyperplasia without systematic assessment of its effectiveness and safety, and an RCT would now be considered unethical. However, there is a need to investigate long-term effects and the influence of co-morbidities on outcomes. A retrospective comparison of mortality and re-operation following either open prostatectomy (OPEN) or TURP was, therefore, undertaken. Patients for whom it was not possible to establish the initial procedure were excluded. The third case study compared coronary artery bypass grafting (CABG) with percutaneous transluminal angioplasty (PTCA) for coronary revascularisation. RCTs have been conducted in limited patient subgroups with short follow-up periods. A meta-analysis of RCTs could be augmented by routine data, which are available for large populations. This would allow assessment of subgroup effects, and outcomes over a long period. A subgroup of patients was therefore constructed for whom relevant routine data were available and who reflected the entry criteria for major RCTs, thus enabling a comparison between the results expected from this subgroup and those of the general population. RESULTS AND CONCLUSIONS: The uses of routine data in these contexts had strengths and weaknesses. The SAH study suggested a means of assessing outcomes and survival rates following haemorrhage, which could have value in informing the design of more precise trials and in evaluating changes in outcome following the introduction of new treatments such as embolisation. However, the potential of the data was not realised because their scope and content were insufficient. For example, lack of data on the time of onset of symptoms and patients' conditions at hospital admission made it difficult to establish the link between timing of surgery and the outcome, and there was insufficient information on patients' conditions at discharge to enable a comparison of outcomes. The prostatectomy study was able to address questions not answered by RCT literature because the large number of cases it included allowed exploration of subgroup effects. (ABSTRACT TRUNCATED)

Adult↗
PubMed2000

A systematic review of comparisons of effect sizes derived from randomised and non-randomised studies.

BACKGROUND: There is controversy about the value of evidence about the effectiveness of healthcare interventions from non-randomised study designs. Advocates for quasi-experimental and observational (QEO) studies argue that evidence from randomised controlled trials (RCTs) is often difficult or impossible to obtain, or is inadequate to answer the question of interest. Advocates for RCTs point out that QEO studies are more susceptible to bias and refer to published comparisons that suggest QEO estimates tend to find a greater benefit than RCT estimates. However, comparisons from the literature are often cited selectively, may be unsystematic and may have failed to distinguish between different explanations for any discrepancies observed. OBJECTIVES: The aim was to investigate the association between methodological quality and the magnitude of estimates of effectiveness by comparing systematically estimates of effectiveness derived from RCTs and QEO studies. Quantifying any such association should help healthcare decision-makers to judge the strength of evidence from non-randomised studies. Two strategies were used to minimise the influence of differences in external validity between RCTs and QEO studies: a comparison of the RCT and QEO study estimates of effectiveness of any intervention, where both estimates were reported in a single paper a comparison of the RCT and QEO study estimates of effectiveness for specified interventions, where the estimates were reported in different papers. The authors also sought to identify study designs that have been proposed to address one or more of the problems often found with conventional RCTs. METHODS DATA SOURCES: Relevant literature was identified from: The Cochrane Library, MEDLINE, EMBASE, DARE, and the Science Citation Index. References of relevant papers already identified experts. Electronic searches were very difficult to design and yielded few papers for the first strategy and when identifying study designs. CHOICE OF INTERVENTIONS TO REVIEW FOR STRATEGIES 1 AND 2: For strategy 1, any intervention was eligible. For strategy 2, interventions for which the population, intervention and outcome investigated were anticipated to be homogeneous across studies were selected for review: Mammographic screening (MSBC) of women to reduce mortality from breast cancer. Folic acid supplementation (FAS) to prevent neural tube defects in women trying to conceive. DATA EXTRACTION AND QUALITY ASSESSMENT: Data were extracted by the first author and checked by the second author. Disagreements were negotiated with reference to the paper concerned. For strategy 1, study quality was scored using a checklist to assess whether the RCT and QEO study estimates were derived from the same populations, whether the assessment of outcomes was 'blinded', and the extent to which the QEO study estimate took account of possible confounding. For strategy 2, a more detailed instrument was used to assess study quality on four dimensions: the quality of reporting, the generalisability of the results, and the extent to which estimates of effectiveness may have been subject to bias or confounding. All quality assessments were carried out by three people. DATA SYNTHESIS AND ANALYSIS: For strategy 1, pairs of comparisons between RCT and QEO study estimates were classified as high or low quality. Seven indices of the size of discrepancies between estimates of effect size and outcome frequency were calculated, where possible, for each comparison. Distributions of the size and direction of discrepancies were compared for high- and low-quality comparisons. FOR STRATEGY 2, THREE ANALYSES WERE CARRIED OUT: Attributes of the instrument were described by k statistics, percentage agreement, and Cronbach's a values. Regression analyses were used to investigate -variations in study quality. (ABSTRACT TRUNCATED)

Breast Neoplasms↗
PubMed2002

[Comparative clinical studies for head and neck cancer in Japan].

Very few large multi-institutional comparative clinical studies for head and neck cancer are reported in Japan. Many studies for organ-preservation with better QOL have been reported around the world, and comparative clinical studies are also necessary in Japan to evaluate organ-preservation treatment. I reviewed comparative clinical studies for head and neck cancer in Japan. Inuyama et al. reported a multi-institutional randomized clinical trial (RCT) that compared the efficacy of CBDCA + PEP and CDDP + PEP. Comparative clinical studies for combination chemotherapy, CDDP + PEP + MTX (PPM) vs. CDDP + PEP + 5-FU (PPF), and PPM vs. CDDP + PEP (PP) are reported. Effects and toxicity are different with each regimen, but the differences are not statistically significant. An RCT of neoadjuvant chemotherapy (NAC) for nasopharyngeal cancer with a small sample size was reported. Three-year survival was significantly better for the NAC group. An RCT of concurrent chemo-radiotherapy with CDDP vs. CBDCA was also reported. CBDCA with radiation was significantly better in terms of 2- and 5-year survival. This result is interesting but the low-dose CDDP with radiation 4 times per week is not standard. A large nationwide RCT with 560 cases investigating adjuvant chemotherapy with UFT was conducted in 1987. The differences in 3-year survival and 3-year disease-free survival with or without UFT adjuvant were not statistically significant, but the incidence of distant metastasis was significantly lower in the UFT adjuvant group. Comparative clinical studies of 5-HT3 antagonists for chemotherapy including CDDP are reported. We conducted a crossover comparative clinical study on the combination of azasetron and dexamethasone. The combination with dexamethasone significantly prevented acute emesis induced by CDDP. Comparative clinical studies of head and neck cancer have not provided good evidence, with the exception of an RCT of adjuvant chemotherapy with UFT, in the past. Well-designed comparative clinical studies with the cooperation of head and neck surgeons, radio-oncologists, and medical oncologists should be considered in order to acquire high-level evidence.

Antineoplastic Agents↗
PubMed2003

Decreased activity of lecithin:cholesterol acyltransferase and hepatic lipase in chronic hypothyroid rats: implications for reverse cholesterol transport.

Chronic hypothyroidism is frequently associated with atherosclerosis due to increased cholesterol plasma levels; nevertheless, the contribution of impaired reverse cholesterol transport (RCT) in this process has not been completely elucidated. The aim of this study was to evaluate the effect of thyroidectomy (Htx) upon the main stages of RCT in rats. Plasma lipid alterations induced by thyroidectomy showed a slight, but significant, reduction of total plasma triglycerides, a 300% increase of LDL-cholesterol and a 25% decrease in HDL-cholesterol compared to control rats. We evaluated the first stage of RCT determining 3H-cholesterol efflux in Fu5AH cells. The capacity of HDL obtained from Htx rats to promote cholesterol efflux was similar to that of controls. Lecithin:cholesterol acyltransferase (LCAT) activity, the second stage and the driving force of RCT was 30% lower in Htx animals compared to controls, as determined by reconstituted HDL used as an external substrate. Lipoproteins are remodeled by hepatic lipase; the mean activity of this enzyme in postheparin plasma of Htx animals was reduced by 30% compared to controls, thus suggesting an impaired HDL remodeling by this enzyme in the hypothyroid status. In contrast, lipoprotein lipase activity in the Htx group was unchanged. In summary, this study demonstrates that chronic hypothyroidism in the rat induced an impaired RCT mainly at the cholesterol esterification, and HDL remodeling mediated by hepatic lipase. The latter probably results in an abnormal HDL structure, i.e. phospholipid enrichment, which contributes to decrease HDL-apo AI fractional catabolic rates.

Animals↗
PubMed2004

Trial bank publishing: phase I results.

BACKGROUND: Randomized clinical trials (RCTs) are an important source of evidence for clinical practice, but finding and applying RCT reports to care is time consuming. Publishing RCTs directly into machine-understandable "trial banks" may allow computers to deliver RCT evidence more selectively and effectively to clinicians. METHODS: Authors of eligible RCTs published in JAMA or the Annals of Internal Medicine between January 2002 and July 2003 were invited to co-publish their trial in RCT Bank, an electronic knowledge base containing details of trial design, execution, and summary results. Trial bank staff used Bank-a-Trial, a web-based trial-bank entry tool, to enter information from the manuscript into RCT Bank, obtaining additional information as necessary from the authors. RESULTS: The author participation rate rose from 38% to 76% after the first co-published trial was available as an example. Seven diverse RCTs are now co-published, with 14 in progress. CONCLUSIONS: We have demonstrated proof of concept for co-publishing RCTs with leading journals into a structured knowledge base. Phase II of trial bank publishing will introduce direct author submission to RCT Bank.

Databases as Topic↗
PubMed2005

Understanding participation in a trial comparing cryotherapy and radiation treatment.

BACKGROUND: To date, few two-arm active treatment randomized control trials (RCTs) have compared prostate cancer therapies. OBJECTIVE: To examine the difference and similarities between the reasons for accepting and declining participation in a two-arm active treatment RCT comparing external beam radiation therapy (EBRT) versus cryotherapy. METHODS: Eleven men with prostate cancer, selected purposively, participated in a 30-minute post-treatment semi-structured interview. Interviews were transcribed verbatim, coded and analyzed for patterns with the assistance of the text management (TM) software (NVivo). RESULTS: RCT accepters participated principally with the hope of being randomized into the cryotherapy treatment arm. Consequently, randomization into the EBRT arm was often perceived as receiving the consolation prize. RCT decliners were either pushed away from cryotherapy and/or pulled towards another treatment (surgery, EBRT, brachytherapy). Factors influencing accepters'/decliners' treatment decisions include (1) personal factors such as patient research and treatment preference, cancer survivors, family/friends, and altruism, and (2) physician, trial, and treatment factors such as patient-physician rapport, RCT awareness and understanding, therapy convenience, expected outcome and perceived side effects. CONCLUSIONS: By better understanding patients' views about RCT participation, recruitment rates for prostate cancer RCTs can be improved.

Cryotherapy↗
PubMed1989

Comparison of viscoelastic measures of coagulation after cardiopulmonary bypass.

Postoperative hemorrhage remains a major cause of morbidity after cardiopulmonary bypass (CPB). Treatment remains empiric because of the need for immediate correction and the lack of availability of rapid intraoperative coagulation monitoring (except for ACT) at most institutions. Thrombelastography (TEG) and Sonoclot analysis (SCT) are measures of viscoelastic properties of blood which allow rapid intraoperative evaluation of coagulation factor and platelet activity as well as overall clot integrity from a single blood sample. Routine coagulation tests (RCT) including activated clotting time (ACT), prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level (FIB), and platelet count (PLT) were determined and compared to TEG and SCT to assess which best predicted clinical hemostasis after CPB. Forty-two patients prospectively felt to be at high risk for excessive post-CPB bleeding had blood obtained for RCT, TEG, and SCT analysis before systemic heparinization and 30 min after protamine administration. Nine of 42 patients had excessive chest tube drainage, but no reoperations were required. After CPB, mean values for RCT were normal, but there were abnormalities in TEG and SCT parameters that reflect platelet-fibrin interaction. Both TEG and SCT were 100% accurate in predicting bleeding in these nine patients and, overall, both tests were significantly better predictors of postoperative hemorrhage than RCT. We conclude that viscoelastic determinants of clot strength may be abnormal after CPB and that SCT and TEG are, therefore, more useful than RCT for the detection and management of coagulation defects associated with CPB.

Adult↗
PubMed1989

Promoting effects of unleaded gasoline and 2,2,4-trimethylpentane on the development of atypical cell foci and renal tubular cell tumors in rats exposed to N-ethyl-N-hydroxyethylnitrosamine.

Unleaded gasoline (UG), a nongenotoxic kidney carcinogen in male, but not female, F344 rats or either sex of mice, and 2,2,4-trimethylpentane (TMP), a representative nephrotoxic isoparaffinic component of UG, were tested for potential promoting and cocarcinogenic effects in a kidney initiation-promotion model. The promotion study was conducted with 305 male and 305 female F344 rats fed 170 ppm N-ethyl-N-hydroxyethylnitrosamine in the drinking water for 2 weeks and then inhalation exposed to 0, 10, 70, or 300 ppm UG or 50 ppm TMP for 24 or 59 to 61 weeks. In a sequence reversal study, 390 male F344 rats were inhalation exposed to 0, 10, 70, or 300 ppm UG or 50 ppm TMP for 24 weeks, followed by 170 ppm N-ethyl-N-hydroxyethylnitrosamine in the drinking water during weeks 28 to 30, and killed at weeks 65 to 67. Renal neoplastic lesions were classified as atypical cell foci (ACF) and renal cell tumors (RCT). In the hydrocarbon promotion study, dose related increases were observed in the incidence of ACF in male rats promoted with UG or 50 ppm TMP for 24 or 60 weeks. A significant linear trend in the incidence of RCT was observed in male rats promoted with UG for 24 weeks. The incidence of ACF or RCT was not elevated in female rats promoted with UG or TMP. In the sequence reversal study, a slight increase in ACF was demonstrated in male rats exposed to 300 ppm UG, whereas no increase in RCT was observed in any exposure group. It is concluded that UG and TMP are promoters of ACF and RCT in male, but not female, rats under the conditions of this study. Data from related investigations suggest that the tumor promoting potential of UG and TMP results from reversible binding of metabolites to alpha 2u-globulin, which leads to decreased renal catabolism of this protein, chronic lysosomal overload, cell death, and compensatory cell proliferation.

Animals↗
PubMed1994

Can quality care be planned?

Planning quality care can begin with planning a randomized controlled trial (RCT). Given that health-care services must compete for scarce resources, it is important that RCTs collect data to support an economic evaluation when the RCT ends. Economic data can be collected after an RCT ends; however, translating the clinical findings into clinical practice and health-care policy may be less efficient and less effective. Three types of data--economic, behavioral, and biological outcomes--should be collected during an RCT to conduct an economic evaluation at the end of an RCT. Economic outcomes represent the actual resources consumed by a health service, i.e., economic costs; behavioral outcomes include measures of longevity and health-related quality of life; and biological outcomes measure physiological state, e.g., retinopathy level.

Delivery of Health Care↗
PubMedDate not supplied

[Enzymic spectrum of preneoplastic and neoplastic changes induced by 1,2-dimethylhydrazine in mouse kidneys].

Mouse renal cell tumors (RCT) were induced in male CBA male mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH) per kg body weight once a week. After a lag period of two years the kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: Glycogen content, basophilia, and activities of glycogen synthase (SYN), glycogen phosphorylase (PHO), glucose-6-phosphatase (G6Pase), glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), pyruvate kinase (PK), lactate dehydrogenase (LDH), malic enzyme (ME), succinate dehydrogenase (SDH), alkaline phosphatase (ALPase) and glutamyl-transpeptidase (GGT). RCT displayed the same histochemical profile irrespective of their size and growth pattern. In comparison with normal kidney epithelium, the neoplastic cells exhibited elevated activities of enzymes for glycolysis (HK, PK LDH) and the pentose phosphate pathway (G6PDH) while negative G6Pase and low SDH activity were observed in these cells. The majority of RCT showed high PHO activity and weak staining for SYN. Activities of ALPase and GGT were negative in most of the RCT. Giant cells were detected in some large RCT. Higher activities of glycolytic and mitochondrial enzymes and G6PDH were found in giant cells compared with other tumor cells. Tubular preneoplastic lesions were similar to neoplastic lesions in morphological and histochemical characteristics. The present study revealed that a markedly elevated capacity for glycolysis and the pentose phosphate pathway occurred in renal cell tumors in mice. A similar histochemical pattern in the few preneoplastic tubular lesions observed suggests that these metabolic aberrations emerge early in carcinogenesis, but studies on earlier stages of renal carcinogenesis are needed to substantiate this assumption.

1,2-Dimethylhydrazine↗
PubMed1996

Reverse cholesterol transport: its contribution to cholesterol catabolism in normal and disease states.

OBJECTIVES: To review the reverse cholesterol transport (RCT) model and its contribution to cholesterol catabolism in normal and disease states. DATA SOURCES: Pertinent articles were identified through a MEDLINE search of the English language literature from 1983 to 1995, followed by a manual search of the bibliographies of pertinent articles. STUDY SELECTION: Review articles, laboratory and clinical studies and case reports. DATA EXTRACTION: The physiology of the RCT pathway as well as alterations observed in individuals with diseases or lifestyle changes were reviewed. DATA SYNTHESIS: Data were derived mainly from laboratory studies and clinical observations. The RCT model is proposed to explain the removal of excess cholesterol from extrahepatic tissues and its delivery to liver for catabolism. This involves several regulated steps mediated by the plasma apolipoproteins and two key enzymes, lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP). In essence free cholesterol in peripheral tissues is taken up by nascent high density lipoprotein (HDL) particles, converted to cholesteryl esters (by LCAT), and then transferred to apo B-containing lipoproteins (by CETP) for hepatic removal. Altered cholesterol catabolism may occur in individuals with disorders of a genetic or acquired nature as well as lifestyle changes, as a result of alterations in one of several of the putative steps or enzymes involved in RCT. CONCLUSIONS: The proposed antiatherogenic role of RCT remains to be validated as a review of the possible alterations noted in various disorders showed conflicting results in atherogenic propensity.

Apolipoproteins↗
PubMed2002

Association of journal quality indicators with methodological quality of clinical research articles.

CONTEXT: The ability to identify scientific journals that publish high-quality research would help clinicians, scientists, and health-policy analysts to select the most up-to-date medical literature to review. METHODS: To assess whether journal characteristics of (1) peer-review status, (2) citation rate, (3) impact factor, (4) circulation, (5) manuscript acceptance rate, (6) MEDLINE indexing, and (7) Brandon/Hill Library List indexing are predictors of methodological quality of research articles, we conducted a cross-sectional study of 243 original research articles involving human subjects published in general internal medical journals. RESULTS: The mean (SD) quality score of the 243 articles was 1.37 (0.22). All journals reported a peer-review process and were indexed on MEDLINE. In models that controlled for article type (randomized controlled trial [RCT] or non-RCT), journal citation rate was the most statistically significant predictor (0.051 increase per doubling; 95% confidence interval [CI], 0.037-0.065; P<.001). In separate analyses by article type, acceptance rate was the strongest predictor for RCT quality (-0.113 per doubling; 95% CI, -0.148 to -0.078; P<.001), while journal citation rate was the most predictive factor for non-RCT quality (0.051 per doubling; 95% CI, 0.044-0.059; P<.001). CONCLUSIONS: High citation rates, impact factors, and circulation rates, and low manuscript acceptance rates and indexing on Brandon/Hill Library List appear to be predictive of higher methodological quality scores for journal articles.

Biomedical Research↗