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PubMed1995

Self-Directed Treatment of Intermittent Heartburn: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Evaluation of Antacid and Low Doses of an H(2)-Receptor Antagonist (Famotidine).

BACKGROUND: Heartburn, a common symptom, is self-treated with oral antacids. Efficacy of antacids has not been demonstrated for individual, spontaneous heartburn episodes. METHODS: We conducted a double-blind, randomized, placebo-controlled, parallel-group study of self-directed treatment for episodic heartburn comparing famotidine (FAM) 5, 10, or 20 mg and antacid (11 mEq ANC) to placebo (PBO) during a 4-week period. Twenty-nine US investigators enrolled a total of 565 outpatients, ages 18--81 years (mean 44.1 years) with heartburn but not seeking care for heartburn. Treatment of spontaneous heartburn episodes was permitted as needed, up to twice daily, with self-administered test drug. An open-label, backup antacid was provided to use if test drug did not provide adequate relief. Patients assessed heartburn relief hourly and recorded use of backup antacid. Relief was defined as complete relief of symptoms without the use of backup antacid. RESULTS: The media proportion of episodes relieved was: PBO, 41%; FAM 5 mg, 59%, 0.05 less-than-or-equal p < 0.10; FAM 10 mg, 70%, p < 0.001; FAM 20 mg, 69%, p < 0.001; antacid, 62%, p < 0.05 (p-values versus PBO). Supplemental analyses incorporating time to relief confirmed that famotidine and antacid provided more rapid and more frequent relief than placebo (odds ratio for relief relative to PBO: FAM 5 mg, 1.55, p = 0.003; FAM 10 mg, 1.94, p < 0.001; FAM 20 mg, 2.13, p < 0.001; antacid 1.57, p = 0.003). The tolerability profile was similar with famotidine, antacid, and placebo. CONCLUSIONS: The positive results with antacid demonstrated for the first time the efficacy of antacid in self-treatment of individual heartburn episodes and provided internal validation of this study paradigm. Patients in this study self-medicated effectively using low doses of famotidine on an as needed basis for spontaneous episodes of heartburn.

Journal Article↗

PubMed2002

The effect of low-intensity pulsed ultrasound therapy on time to fracture healing: a meta-analysis.

BACKGROUND: The effect of low-intensity ultrasonography on fracture healing is controversial, and current management of fractures does not generally involve the use of ultrasound therapy. We describe a systematic review and meta-analysis of randomized controlled trials of low-intensity pulsed ultrasound therapy for healing of fractures. METHODS: We searched 5 electronic databases (MEDLINE, EMBASE, Cochrane Database of Randomised Clinical Trials, HealthSTAR and CINAHL) for trials of ultrasonography and fracture healing, in any language, published from 1966 to December 2000. In addition, selected journals published from 1996 to December 2000 were searched by hand for relevant articles, and attempts were made to contact content experts in the area of ultrasound therapy and fracture healing as well as primary authors of reviewed trials. Trials selected for review met the following criteria: random allocation of treatments; inclusion of skeletally mature patients of either sex with 1 or more fractures; blinding of both the patient and the assessor(s) as to fracture healing; administration of low-intensity pulsed ultrasound treatments to at least 1 of the treatment groups; and assessment of time to fracture healing, as determined radiographically by bridging of 3 or 4 cortices. Two reviewers independently applied selection criteria to blinded articles, and selected articles were scored for methodologic quality. The internal validity of each trial was assessed with the use of a 5-point scale that evaluates the quality of trial method on the basis of description and appropriateness of randomization and double-blinding, and assessment of study withdrawals and likelihood of bias. RESULTS: We identified 138 potentially eligible studies, of which 6 met our inclusion criteria. Agreement beyond chance of quality assessments of the 6 trials was good (intraclass correlation coefficient 0.77, p = 0.03). One trial was a repeat analysis of previously reported data, and 2 trials appeared to report on a shared group of subjects. Three trials, representing 158 fractures, were of sufficient homogeneity for pooling. The pooled results showed that time to fracture healing was significantly shorter in the groups receiving low-intensity ultrasound therapy than in the control groups. The weighted average effect size was 6.41 (95% confidence interval 1.01-11.81), which converts to a mean difference in healing time of 64 days between the treatment and control groups. INTERPRETATION: There is evidence from randomized trials that low-intensity pulsed ultrasound treatment may significantly reduce the time to fracture healing for fractures treated nonoperatively. There does not appear to be any additional benefit to ultrasound treatment following intramedullary nailing with prior reaming. Larger trials are needed to resolve this issue.

Adult↗

PubMed2001

[Maternal mortality in France: frequency, trends and causes].

Ten years ago the first epidemiological surveys on maternal mortality in France were carried out on the national level. In 1995, a National Committee of Medical Experts was created to conduct confidential inquiries into maternal deaths. It is thus useful to examine the general picture of maternal mortality in France drawn by the routinely and permanently collected data. These statistics are collected independently of the procedure adopted by the National Committee on confidential inquiries into maternal deaths. National death and cause-of-death registries have recorded maternal death rates for several years with data by age, area of residence, nationality, and direct or indirect obstetric causes. The low and underestimated rate of 8.5 maternal deaths per 100,000 live births recorded in 1989 increased regularly up to 1992. Currently the rates have been around 9 to 13 with no evidence of a declining trend. The larger urban area around Paris (Ile-de-France) has shown a statistically significant higher rate over the last several years. Post-partum hemorrhage remains the leading cause of maternal death. Compared with other European countries, maternal mortality in France is in an average position, similar to Great Britain (12 per 100,000), but higher than in Scandinavian countries. The elevated mean age of mothers at delivery is one explanation for the lack of a decline in the rate of maternal deaths expected until 2005 although further actions should be implemented to attempt to lower the rate to that observed in Scandinavian countries. A pertinent classification of causes of maternal deaths allowing valid international comparisons would be useful for helping answer the questions raised by clinicians.

Cause of Death↗

PubMed2001

Methodological issues using household budget survey expenditure data for individual food availability estimation: Irish experience in the DAFNE pan-European project. DAta Food NEtworking.

OBJECTIVE: Irish participation in the EU-supported DAta Food NEtworking (DAFNE) project required compliance with the overall aims and objectives. The Irish Household Budget Survey (HBS) expenditure data had to be transformed into a format compatible with the collaborative effort, by converting them into quantities of foodstuffs available per person per day. SETTING: The Irish 1987 HBS expenditure data on all commodities for 7705 households in the Republic of Ireland, collected using a 14-day diary kept by all members of the household aged 15 years and over. DESIGN: Following identification of 188 food items in the HBS dataset, retail prices per unit weight were sought for each food. Adjustment of prices, collected from a number of different sources, was made to those of 1987 using the Consumer Price Index. Simple models were used to estimate household food availability through application of the adjusted retail prices per unit weight to the expenditure data. The household level data were converted to food availability per person per day. An internal validation of quantities estimated using the retail prices was made using the 12 foodstuffs for which the Irish HBS collects expenses and quantities. RESULTS: The comparison of quantities published by the Irish Central Statistics Office for 12 foodstuffs in the Irish 1987 Household Budget Survey with the quantities estimated using equivalent expenditure data and corresponding retail prices showed agreement, with less than a 10% margin of error for 10 of the foods. CONCLUSION: In spite some difficulty in converting HBS food expenditure data into food availability per person per day, the DAFNE approach is potentially useful for Irish nutrition surveillance purposes and for facilitating comparisons of the Irish HBS food data with those of other European countries.

Adolescent↗

PubMed2002

[Improving the embryonic stem cell test (EST) by establishing molecular endpoints of tissue specific development using murine embryonic stem cells (D3 cells)].

Blastocyst-derived pluripotent embryonic stem (ES) cells of the mouse can be induced to differentiate in culture into a variety of cell types, including cardiac muscle cells. In the embryonic stem cell test (EST) the capacity of ES cells of the mouse cell line D3 to differentiate into contracting cardiomyocytes is used to assess the embryotoxic potential of test compounds and in addition, the effects on the viability of ES cells and differentiated mouse fibroblasts (cell line 3T3) are compared. The three endpoints are used to classify the embryotoxic potential of chemicals after 10 days of exposure: (i) the inhibition of differentiation of ES cells into cardiomyocytes (ID50) and (ii) the decrease of viability of 3T3 cells (IC503T3) and (iii) ES cells (IC50D3) in a MTT cytotoxicity test. Applying linear analysis of discriminance, a biostatistical prediction model (PM) was developed to assign test chemicals to three classes of embryotoxicity. In an international validation study funded by ECVAM it could be demonstrated that the EST can predict the embryotoxic potential of a test compound as good as frequently used mammalian systems based on pregnant animals. In a joint project with major German pharmaceutical companies we are attempting to improve the EST by establishing molecular endpoints of differentiation (e.g. cardiac, neuronal, chondrogenic) in cultured ES cells. We have studied the expression of tissue specific proteins in ES cell cultures in the presence of embryotoxic chemicals by immunofluorescent antibody techniques, e.g. FACS analysis. The other groups are focusing on endogenous gene expression in early development by RT-PCR methods or the DNA microarray technique. The results obtained recently using molecular markers specific for cardiac differentiation and employing intracellular flow cytometry for quantification will be presented. Molecular endpoints will allow improvement of the EST by measuring gene expression patterns in a small number of murine ES cells.

3T3 Cells↗

PubMed2002

Beneficial effect of climatic therapy on inflammatory arthritis at Tiberias Hot Springs.

OBJECTIVE: To examine the beneficial effect of climatic therapy at the Tiberias Hot Springs on patients with inflammatory arthritis. METHODS: Patients from Sweden with inflammatory arthritis underwent climatic therapy for 4 weeks at the Tiberias Hot Springs in Israel. Patients were examined at the beginning and end of the therapy and were evaluated as responders according to internationally validated criteria. RESULTS: One hundred-thirty-six patients were evaluated, 83 with a clinical course of rheumatoid arthritis (RA) and 53 with ankylosing spondylitis (AS). Forty-seven (57%) of the RA patients and 32 (60%) of the AS patients were considered responders. Shorter disease duration and more active disease were associated with a greater response in RA, while in AS males responded more often than females. CONCLUSION: Most patients benefited significantly from climatic therapy. Long-term follow-up is necessary to see whether improvement is sustained and if work ability and hospitalizations are also improved.

Adult↗

PubMed2002

[Smoking cessation: practice guidelines].

Smoking is a habit sustained and amplified by dependency on nicotine. Despite knowing the risks to their health, smokers have great difficulty in stopping. The syndrome of nicotine withdrawal and the related complications when stopping smoking: depression, weight gain, are adequate justifications of the many failures to stop smoking. However, we have now come out of the empiricism, effective treatment is available and scientifically validated international recommendations have been established. They involve: the practice of minimal advice which consists of questioning every patient about smoking habits and encouraging them to stop; the treatments of nicotine substitution, patch, chewing gum, tablets or inhaler, used at effective dosage and sometimes in association with each other; more recently, Bupropion (Zyban, LP), a psychotropic inhibitor of Dobutamine and Noradrenalin recapture; behavioural and cognitive therapies, alone or in association with pharmacological therapy. The measurement of the score of tobacco dependency with the Fagerström test enables definition of a therapeutic strategy. Of course, these treatments are only effective in smokers motivated to stop smoking. The decision to stop smoking should only be taken after a period of reflection during which the role of information and advice given by all health professionals is primordial. Also, the long-term follow-up and counsel are essential to prevent relapse, especially during the first year.

Counseling↗

PubMedDate not supplied

[Accuracy and diagnostic utility of the Hospital Anxiety and Depression Scale (HAD) in a sample of obese Mexican patients].

The Hospital Anxiety and Depression Scale (HAD) have been used in Mexico in drug abusers, burned patients, older people, with renal insufficiency and high-risk pregnant women. The aim of this study was to determine reproducibility and accuracy of the questionnaire in a sample of obese subjects. A group of 75 obese patients (BMI > 27) without diabetes mellitus were invited to participated in the study. Diagnosis of anxiety or depression was made by an structured interview based on the DSM-IV criteria, and they were requested to complete the HAD. All subjects were randomized for the manoeuvre sequence. Sensibility specificity, positive predictive value and negative value, and unweighted kappa coefficient (for concordance) were calculated for the two procedures. The questionnaire reproducibility was assessed buy test-retest with other 25 independent subjects. Internal validity was estimated by alpha Cronbach, Guttman and intraclass correlation coefficients. Mean age was 39.7 +/- 11.5 years and BMI 39.1 +/- 9.6. The best cut off point for anxiety was 8 points (Kappa 0.68) and for depression 7 points (Kappa 0.73). Mean age for test-retest was 39.2 +/- 14.5 years and BMI 45.3 +/- 14.6. The alpha-Cronbach was 0.84 for the first tes. and 0.86 for the second. Intraclass coefficient correlation was 0.946. The HAD is applicable for obese subjects, it is reproducible and concordant with a structured interview.

Adult↗

PubMed2003

Evaluating health plan quality 3: survey measurement properties.

OBJECTIVE: To assess the measurement and scaling properties of survey items designed to measure health plan quality from a physician's perspective. STUDY DESIGN: Prospective survey design with multivariate regression analysis. METHODS: Data were from 3798 physicians representing 23 health plans in 5 regions: Florida, New York, Colorado, Pennsylvania, and Washington. Scale reliability was assessed by using the Cronbach alpha. Generalist and specialist scales were compared with structural equation modeling. Multivariate analysis was used to examine internal validity by testing theoretically based hypotheses. RESULTS: Scales constructed from the data were reliable, were stable across both generalist and specialist physicians, and demonstrated construct validity. Hypotheses about the relationship between physician experiences with a health plan and physician recommendations of the plan were confirmed, supporting construct validity. CONCLUSION: The items on the survey instrument can be used with confidence to measure health plan quality from a physician perspective.

Attitude of Health Personnel↗

PubMed2003

[Is it still ethical to conduct clinical trials against a placebo? A review of the ethical and methodological controversy].

UNLABELLED: A DEVELOPING CONTROVERSY: The marketing authorization for new drugs from the regulatory authorities'and ethical point of view, is only possible following convincing proof of their efficacy and safety. Between the drug registration authorities, who underline the necessity of early assessment against a placebo, on the one hand, and the ethical and consumer committees that disapprove of the use, the controversy has developed. FOR METHODOLOGISTS: Comparisons with reference drugs provide less credible results that comparisons versus a placebo. This is why their exclusive use may have deleterious effects on the reliable assessment of products to be launched on the market, in terms of efficacy and safety. Equivalence trials do not provide the expected solution since their internal validation requires a placebo arm. RETICENCE BUT NO PROHIBITION: The fifth revision of the declaration of Helsinki by the World medical association in the year 2000, which led to violent controversy regarding the drawing-up of section 29 and its clarification note, does not really help the debate progress: the authors of the texts confirm their reticence to the use of a placebo, but do not prohibit it. They have chosen a "middle of the road" solution. IN PRACTICE: The decision to conduct or not a placebo-controlled study should take into account the aims of the study (within the context or not of a marketing authorization submittal by an industrial), the early stage of the development of the drug or not and, above all, the level of efficacy and safety of the drugs already available versus the anticipated effects of the new product.

Clinical Trials as Topic↗

PubMed1992

Canadian National Breast Screening Study: 1. Breast cancer detection and death rates among women aged 40 to 49 years.

OBJECTIVES: To evaluate the efficacy of the combination of annual screening with mammography, physical examination of the breasts and the teaching of breast self-examination in reducing the rate of death from breast cancer among women aged 40 to 49 years on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or usual care after an initial physical examination (UC group). The 50,430 women enrolled from January 1980 through March 1985 were followed for a mean of 8.5 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size, and rates of death from all causes and from breast cancer. RESULTS: Over 90% of the women in each group attended the screening sessions or returned the annual questionnaires, or both, over years 2 to 5. The characteristics of the women in the two groups were similar. Compared with the Canadian population, the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 3.89 per 1000 in the MP group and 2.46 per 1000 in the UC group; more node-positive tumours were found in the MP group than in the UC group. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.26 in the MP group and 1.02 in the UC group. Of the women with invasive breast cancer through to 7 years, 191 and 157 women in the MP and UC groups respectively had no node involvement, 55 and 43 had one to three nodes involved, 47 and 23 had four or more nodes involved, and 38 and 49 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 28 in the UC group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 1.36 (95% confidence interval 0.84 to 2.21). The survival rates were similar in the two groups. The highest survival rate occurred among women whose cancer had been detected by mammography alone. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography and physical examination of the breasts detected considerably more node-negative, small tumours than usual care, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.

Adult↗

PubMed1992

Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years.

OBJECTIVE: To evaluate the efficacy of annual mammography over and above annual physical examination of the breasts and the teaching of breast self-examination among women aged 50 to 59 on entry. DESIGN: Individually randomized controlled trial. SETTING: Fifteen urban centres in Canada with expertise in the diagnosis and treatment of breast cancer. PARTICIPANTS: Women with no history of breast cancer and no mammography in the previous 12 months were randomly assigned to undergo either annual mammography and physical examination (MP group) or annual physical examination only (PO group). The 39,405 women enrolled from January 1980 through March 1985 were followed for a mean of 8.3 years. DATA COLLECTION: Derived from the participants by initial and annual self-administered questionnaires, from the screening examinations, from the patients' physicians, from the provincial cancer registries and by record linkage to the Canadian National Mortality Data Base. Expert panels evaluated histologic and death data. MAIN OUTCOME MEASURES: Rates of referral from screening, rates of detection of breast cancer from screening and from community care, nodal status, tumour size and rates of death from all causes and from breast cancer. RESULTS: Over 85% of the women in each group attended the screening sessions after screen 1. The characteristics of the women in the two groups were similar. Compared with the Canadian population the participants were more likely to be married, have fewer children, have more education, be in a professional occupation, smoke less and have been born in North America. The rate of screen-detected breast cancer on first examination was 7.20 per 1000 in the MP group and 3.45 per 1000 in the PO group, more node-positive tumours were found in the MP group than in the PO group. At subsequent screens the detection rates were a little less than half the rates at screen 1. During years 2 through 5 the ratios of observed to expected cases of invasive breast cancer were 1.28 in the MP group and 1.18 in the PO group. Of the women with invasive breast cancer through to 7 years, 217 in the MP group and 184 in the PO group had no node involvement, 66 and 56 had one to three nodes involved, 32 and 34 had four or more nodes involved, and 55 and 46 had an unknown nodal status. There were 38 deaths from breast cancer in the MP group and 39 in the PO group. The ratio of the proportions of death from breast cancer in the MP group compared with those in the UC group was 0.97 (95% confidence interval 0.62 to 1.52). The survival rates were similar in the two groups. Women whose cancer had been detected by mammography alone had the highest survival rate. CONCLUSION: The study was internally valid, and there was no evidence of randomization bias. Screening with yearly mammography in addition to physical examination of the breasts detected considerably more node-negative, small tumours than screening with physical examination alone, but it had no impact on the rate of death from breast cancer up to 7 years' follow-up from entry.

Breast Neoplasms↗

PubMed1992

A multivariant study of pituitary adenoma, obtainment of two logistic regression equations as an auxiliary support in the diagnosis of these tumors.

A multivariant analysis was carried out in 120 patients with pituitary adenoma (prolactinoma, HGH-secreting adenoma and nonfunctional adenoma) and an equation was obtained concerning the prolactinoma (whose independent variables were age, galactorrhea, impotence, stage, and pretreatment secretion of ACTH) and another one concerning the nonfunctional adenoma (with age evolution time, visual disturbance evolution and galactorrhea as independent variables). These equations are useful in the differential diagnosis. The internal validity of both equations was obtained by calculating the ROC curve and determining sensibility, specificity and predictive values at the "optimum point" of this curve.

Adenoma↗

PubMed2003

[Favorable effect of sildenafil on erectile dysfunction in patients after radiotherapy for prostate cancer; randomised, double-blind, placebo-controlled crossover study].

OBJECTIVE: To determine the efficacy of sildenafil in patients with erectile dysfunction after external beam radiotherapy for prostate cancer. DESIGN: Randomised, double-blind, placebo-controlled, crossover study. METHOD: A total of 406 patients with erectile dysfunction reported in their medical records who had completed external beam radiotherapy at least 6 months prior to the study, were approached by letter. Sixty patients were included in a study which lasted 12 weeks. They received 50 mg of sildenafil citrate or placebo for two weeks; during week 2 the dose could be increased to 100 mg in the case of unsatisfactory erectile response. At week 6 patients crossed over to the alternative treatment. Data were collected using the validated 'International index of erectile function' (IIEF) questionnaire, and side-effects were recorded. Patients were given the possibility of continuing to a 6-week open-label phase. RESULTS: The mean age of those participating was 68 years. All patients completed the double-blind phase. For the majority f questions in the IIEF questionnaire, there was a significant increase in mean scores from baseline with sildenafil, but of the patients with sildenafil, versus 18% with placebo. Ninety percent of the patients required a dose adjustment to 100 mg sildenafil, and 100% of the patients in the placebo group increased the dose. Side-effects were mild or moderate. Patients who proceeded to the open-label phase reported the same results as in the double-blind phase. CONCLUSION: Sildenafil improved erectile function in about half of the patients with erectile dysfunction after external beam radiotherapy for prostate cancer, and it was well tolerated.

Aged↗

PubMed2003

Stratification of adverse outcomes by preoperative risk factors in coronary artery bypass graft patients: an artificial neural network prediction model.

We constructed and internally validated an artificial neural network (ANN) model for prediction of in-hospital major adverse outcomes (defined as death, cardiac arrest, coma, renal failure, cerebrovascular accident, reinfarction, or prolonged mechanical ventilation) in patients who received "on-pump" coronary artery bypass grafting (CABG) surgery. We retrospectively analyzed a 5-year CABG surgery database with a final study population of 563 patients. Predictive variables were limited to information available before the procedure, and outcome variables were represented only by events that occurred postoperatively. The ANN's ability to discriminate outcomes was assessed using receiver-operating characteristic (ROC) analysis and the results were compared with a multivariate logistic regression (LR) model and the QMMI risk score (RS) model. A major adverse outcome occurred in 12.3% of all patients and 18 predictive variables were identified by the ANN model. Pairwise comparison showed that the ANN model significantly outperformed the RS model (AUC = 0.886 vs.0.752, p = 0.043). However, the other two pairs, ANN vs. LR models (AUC = 0.886 vs. 0.807, p = 0.076) and LR vs. RS models (AUC = 0.807 vs. 0.752, p = 0.453) performed similarly well. ANNs tend to outperform regression models and might be a useful screening tool to stratify CABG candidates preoperatively into high-risk and low-risk groups.

Cardiopulmonary Bypass↗

PubMed2003

[What treatments can reduce the digestive complications of NSAIDs].

OBJECTIVE: The aim is to compile a systematic review of literature data on the efficacy of GI protective agents in the prevention of upper GI lesions in a subject receiving long-term therapy with an NSAID. METHOD: We have selected solely experimental studies which have received a very high score in terms of methodology, whether in internal validity or clinical significance. Thus, 35 randomized, controlled studies have been reviewed. RESULTS: Only one large long-term study examined the prevention of serious GI risks and misoprostol (800 micrograms/day) showed that it was capable of reducing the incidence of ulcer complications (perforations and bleeding) by 40% compared to placebo. No such data are available for PPI and H2-receptor antagonists (H2-RA). In summary Controlled endoscopic study results for patients with joint diseases receiving NSAID therapy for a period greater than 3 weeks demonstrated that misoprostol, PPI and H2-RA at double-dose are effective in reducing the risk both of gastric and duodenal ulcer. The standard doses of H2-RA are not effective in reducing the risk of gastric ulcer. There are very few studies comparing two gastro-intestinal protective agents and they seem to indicate that misoprostol and proton pump inhibitors are comparable in reducing the risk of gastric ulcer and are better than standard doses of H2-RA and that omeprazol is better than misoprostol at reducing the risk of duodenal ulcer. Tolerability of PPI and H2-RA are appreciably better than misoprostol which induces intestinal disorders.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

Trends in improving the embryonic stem cell test (EST): an overview.

The embryonic stem cell test (EST) is an in vitro assay that has been developed to assess the teratogenic and embryotoxic potential of drugs and chemicals. It is based on the capacity of murine ES cells (cell line D3) to differentiate into contracting myocardial cells under specific cell culture conditions. The appearance of beating cardiomyocytes in embryoid body (EB) outgrowths is used as a toxicological endpoint to assess the embryotoxic potential of a test substance. Applying linear analysis of discriminance, a biostatistical prediction model (PM) was developed to assign test chemicals to three classes of embryotoxicity. In an international validation study the EST predicted the embryotoxic potential of chemicals and drugs with the same reliability as two other in vitro embryotoxicity tests, which employed embryonic cells and tissues from pregnant animals. In a joint research project with German pharmaceutical companies we have successfully improved the EST by establishing molecular endpoints of differentiation in cultured ES cells. The quantification of cardiac-specific protein expression by intracellular flow cytometry has been studied in the presence of chemicals of different embryotoxic potential. The results obtained using molecular endpoints specific for differentiated cardiomyocytes employing FACS (fluorescence-activated cell sorting) analysis will be presented in comparison to the validated endpoint - the microscopic analysis of beating areas. FACS analysis provides a more objective endpoint for predicting the embryotoxic potential of chemicals than the validated method. Furthermore, flow cytometry promises to be suitable for high-throughput screening systems (HTS). In addition, our partners from the joint project have improved the EST by developing protocols that stimulate differentiation of ES cells into neural and endothelial cells, chondrocytes and osteoblasts, because some substances might have embryotoxic effects on specific cell-types other than cardiomyocytes. These protocols have been successfully established at ZEBET and in the participating laboratories. Additionally, molecular endpoints have been established for the detection of specific differentiation pathways. Furthermore, new prediction models (PMs) have been developed using single endpoints of the EST.

Animal Testing Alternatives↗

PubMed2004

Practice guidelines for the therapy of essential thrombocythemia. A statement from the Italian Society of Hematology, the Italian Society of Experimental Hematology and the Italian Group for Bone Marrow Transplantation.

BACKGROUND AND OBJECTIVES: The Italian Society of Hematology (SIE) and the two affiliated Societies (SIES and GITMO) commissioned a project to develop guidelines for the therapy of essential thrombocythemia (ET) using evidence-based knowledge and consensus formation techniques. DESIGN AND METHODS: Key questions on the optimal management of ET patients were formulated by an Advisory Council (AC) and approved by an Expert Panel (EP) composed of 7 senior hematologists. The AC systematically reviewed the published literature from 1980 to August 2002, and articles were graded according to their internal validity and quality. Using the Delphi technique, the EP was asked to answer the key questions according to the available evidence. From September 2002 to March 2003, four Consensus Conferences were held in accordance with the Nominal Group Technique with the goal of solving residual disagreement on recommendations. RESULTS: The EP provided recommendations on when to start platelet-lowering therapy, the most appropriate platelet-lowering agent, the use of anti-platelet therapy, and the management of women in childbearing age and of pregnant women. INTERPRETATION AND CONCLUSIONS: By using evidence and consensus, recommendations for the treatment of key problems in ET have been issued. Statements are graded according to the strength of the supporting evidence and uncertainty is explicitly declared.

Acute Disease↗