Ferran Torres

Abstract: Establishing valid and reliable methods of assessing night eating symptoms is an important goal to maximize identification and treatment of the night eating syndrome (NES). The 14-item Night Eating Questionnaire (NEQ) is the only published and validated assessment instrument but is not yet adapted to Spanish.

Abstract: Polymorphisms of the ITPA gene have been associated with anemia during combination therapy in hepatitis C virus (HCV)-monoinfected patients. Our aim was to confirm this association in HIV/HCV-coinfected patients. In this prospective, observational study, 73 HIV/HCV-coinfected patients treated with pegylated interferon plus ribavirin (RBV) were enrolled. Two single nucleotide polymorphisms within or adjacent to the ITPA gene (rs1127354 and rs7270101) were genotyped. The associations between the ITPA genotype and anemia or treatment outcome were examined. Fifty-nine patients (80.8%) had CC at rs1127354, whereas 14 (19.2%) had a CA/AA ITPA genotype. Percent decreases from baseline hemoglobin level were significantly greater in patients with the CC genotype than in those with the CA/AA genotype at week 4 (P = 0.0003), week 12 (P < 0.0001), and week 36 (P = 0.0102) but not at the end of treatment. RBV dose reduction was more often needed in patients with the CC genotype than in those with the CA/AA genotype (odds ratio [OR] = 11.81; 95% confidence interval [CI] = 1.45 to 256.17; P = 0.0039), as was erythropoietin therapy (OR = 8.28; 95% CI = 1.04 to 371.12; P = 0.0057). Risk factors independently associated with percent hemoglobin nadir decrease were RBV dose reduction (OR = 11.72; 95% CI = 6.82 to 16.63; P < 0.001), baseline hemoglobin (OR = 1.69; 95% CI = 0.23 to 3.15; P = 0.024), and body mass index (OR = -0.7; 95% CI = -1.43 to 0.03; P = 0.061). ITPA polymorphism was not an independent predictor of sustained virological response. Polymorphisms at rs1127354 in the ITPA gene influence hemoglobin levels during combination HCV therapy and the need for RBV dose reduction and erythropoietin use in HIV/HCV-coinfected patients.

Abstract: Analysis of total tissue composition and, particularly, body fat measurements has become progressively important in the diagnosis and follow-up of patients with different clinical conditions. Dual-energy X-ray absorptiometry (DXA) fan-beam scanners are widely used to measure body composition, but the development of translational equations to be able to compare data of different scanning systems is necessary. The aim of this study was to assess the extent of agreement for regional measurements of body composition among the following 3 fan-beam DXA scanners: (1) Hologic Discovery (Hologic, Inc., Waltham, MA), (2) Lunar iDXA (GE Healthcare, Madison, WI), and (3) Lunar Prodigy Advance (GE Healthcare, Madison, WI). The study population consisted of 91 adult healthy volunteers (40 males and 51 females; mean age 48.5±14.4yr) who underwent DXA evaluation of the lumbar spine, hip, and whole body in each machine on the same day. Agreement among the 3 scanners was evaluated according to the Bland-Altman method and Lin's concordance correlation coefficient. Results showed a better agreement and concordance for the Lunar iDXA scanner than for any of them with the Hologic scanner. Differences were higher for any tissue or region than for the whole tissue mass. Translational equations were developed to ensure comparability of body composition measurements obtained with each of these 3 scanners.

Abstract: Cocoa, mixed with other food ingredients, intake can have beneficial effects on cardiovascular disease (CVD) biomarkers. We compared the effects of 4 cocoa cream products on some of these biomarkers.

Abstract: The 23-valent pneumococcal vaccine has unequal effectiveness in splenectomised patients. We performed a longitudinal study (2005-2008) whose main objective was to characterize the profile of non-responders among splenectomised patients treated at our institution and identify potential predictive indicators of the response to the vaccine. The immune response was evaluated in 96 subjects. The proportion of responders was 70% (95% CI: 60-78%). Immunosuppression (OR=3.19, 95% CI 1.04-9.73) and the reason for splenectomy (hematologic neoplasia versus non-malignant hematologic diseases, OR=7.37, 95% CI 1.71-31.7) were independent predictors of non-response to vaccination. However, the positive predictive value of the model and the likelihood ratio for a positive result were low (PPV=76.6%, 95% CI 66.2-84.4%, LR(+)=1.41, 95% CI 1.08-1.86). We recommend determining the response to pneumococcal vaccine in these patients when possible.

Abstract: One bioequivalence study was carried out in healthy volunteers in order to compare the rate and extent of absorption of two oral formulations of quetiapine fumarate (CAS 111974-72-2) 25 mg film-coated tablet. Thirty subjects were administered quetiapine fumarate film-coated tablet of test and reference formulation in an open-label, randomised, fasting, two-period, two-sequence, crossover study. Blood samples were taken before and within 48 h after drug administration. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUC and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). Tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUCo-t, and Cmax were within the bioequivalence acceptance range of 80-125%. It may be therefore concluded that the test formulation of quetiapine fumarate 25 mg film-coated tablet is bioequivalent to the reference product and can be prescribed interchangeably.

Abstract: The antiviral activity and toxicity of stavudine (d4T) depend on its triphosphate metabolite, stavudine triphosphate (d4T-TP). Therefore, modifications in intracellular levels of d4T-TP may change the toxicity profile of stavudine. d4T-TP intracellular levels in peripheral blood mononuclear cells were determined with a prominence liquid chromatograph connected to a triple-quadruple mass spectrometer. Polymorphisms in the thymidylate synthase (TS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), reduced folate carrier 1 (RFC1; SLC19A1), and cyclin D1 (CCND1) genes were determined by direct sequencing using an ABI Prism 3100 genetic analyzer or Fluidigm's Biomark system. The Mann-Whitney test, rank analysis of variance (with Bonferroni's adjusted post hoc comparisons), and logistic regression were used for the inferential analyses. Thirty-three stavudine-treated patients were enrolled in this cross-sectional study. d4T-TP intracellular levels were 11.50 fmol/10(6) cells (interquartile range [IQR] = 8.12 to 13.87 fmol/10(6) cells) in patients with a high-expression TS genotype (2/3G, 3C/3G, and 3G/3G), whereas in those with a low-expression TS genotype (2/2, 2/3C, and 3C/3C), they were 21.40 fmol/10(6) cells (IQR = 18.90 to 27.0 fmol/10(6) cells) (P < 0.0001). Polymorphisms in the MTHFR, DHFR, RFC1, and CCND1 genes did not influence the intracellular concentration of d4T-TP. d4T-TP levels were independently associated with the TS genotype (low versus high expression; odds ratio [OR] = 86.22; 95% confidence interval [CI] = 8.48 to nonestimable; P = 0.0023). The low-expression TS genotype was associated with the development of HIV/highly active antiretroviral therapy-associated lypodystrophy syndrome (HALS) (OR = 14.0; 95% CI = 2.09 to 108.0; P = 0.0032). Our preliminary data show that polymorphisms in the thymidylate synthase gene are strongly associated with d4T-TP intracellular levels and with development of HALS.

Abstract: The prevalence of obesity in Spain is on the rise with the consequent increase in bariatric surgery. Studies in non-Mediterranean populations have shown that micronutrient deficits are present before surgery. However, there is no data on this topic in a Spanish population.

Abstract: Uric acid (UA) is a neuroprotective antioxidant that improves the benefits of alteplase in experimental ischemia. However, it is unknown whether endogenous UA also influences the response to thrombolysis in patients with stroke.

Abstract: Tuberous sclerosis (TS) is a systemic disease, with an autosomal dominant pattern of inheritance caused by mutations in two genes (TSC1 and TSC2) that cause tumours (angiomyolipomas [AML], angiofibromas, astrocytomas). Constant and inadequate proliferation occurring in TS may be blocked by mTOR inhibitors (mammalian target of rapamycin), such as rapamycin.

Abstract: Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

Abstract: ARDS can produce a loss of lung function with persistent sequelae. This study aimed to evaluate health-related quality of life (HRQL) in survivors of ARDS compared with a healthy reference population and to determine the middle/long-term radiographic abnormalities and functional status, as well as their relation to observed HRQL, in these patients.

Abstract: A recent survey has shown that data management in clinical trials performed by academic trial units still faces many difficulties (e.g. heterogeneity of software products, deficits in quality management, limited human and financial resources and the complexity of running a local computer centre). Unfortunately, no specific, practical and open standard for both GCP-compliant data management and the underlying IT-infrastructure is available to improve the situation. For that reason the "Working Group on Data Centres" of the European Clinical Research Infrastructures Network (ECRIN) has developed a standard specifying the requirements for high quality GCP-compliant data management in multinational clinical trials.

Abstract: The value of multimodal CT to assist thrombolysis has received little attention in stroke.

Abstract: Two bioequivalence studies were carried out in healthy volunteers in order to compare the rate and extent of absorption of two dosage forms (film-coated tablet and orodispersible tablet) of oral olanzapine (CAS 132539-06-1) 10 mg test formulations and the respective brand formulations as reference. Twenty and twenty-six subjects were administered olanzapine film-coated tablet or orodispersible tablet of test and reference formulations in an open-label, randomised, fasting, two-period, two-sequence, crossover study. Blood samples were taken before and within 240 h after drug administration. Plasma concentrations were determined by LC/MS/MS. Log-transformed AUC and Cmax values were tested for bioequivalence based on the ratios of the geometric means (test/reference). tmax was analysed nonparametrically. The 90% confidence intervals of the geometric mean values for the test/reference ratios for AUC(0-t) and Cmax were within the bioequivalence acceptance range of 80-125%. It may be therefore concluded that the test formulations of olanzapine 10 mg film-coated tablet and orodispersible tablet are bioequivalent to the reference products and can be prescribed interchangeably.

Abstract: The complement system is a major effector of innate immunity that has been involved in stroke brain damage. Complement activation occurs through the classical, alternative and lectin pathways. The latter is initiated by mannose-binding lectin (MBL) and MBL-associated serine proteases (MASPs). Here we investigated whether the lectin pathway contributes to stroke outcome in mice and humans.

Abstract: Triflusal (CAS 322-79-2) is an antiplatelet agent that irreversibly acetylates cyclooxygenase isoform 1 (COX-1) and therefore inhibits thromboxane biosynthesis. The main metabolite of triflusal, 2-hydroxy-4-trifluoromethyl benzoic acid (HTB), possesses also antiaggregant activity. Recently a new oral 600 mg (10 ml) solution form of triflusal has been developed. The purpose of this clinical trial was to study the relative bioavailability of the new oral solution of triflusal versus the capsules formulation, both administered as a single dose. This was a randomized, two-way, cross-over, open-label, single-site phase I clinical trial, in 24 healthy volunteers who received triflusal as 600 mg oral solution and as two 300 mg capsules in a single administration separated by a washout period of at least 17 days. Blood samples were collected and plasma concentrations of HTB were measured. Pharmacokinetic parameters used for bioequivalence assessment included AUC(0-t), AUC(0-inf) and Cmax. The formulations were considered bioequivalent if the geometric mean ratios of AUC(0-t), AUC(0-inf) and Cmax were within the predetermined equivalence range (80% to 125%). Tolerability was based on the recording of adverse events (AEs), physical examination, electrocardiogram (ECG) and laboratory tests. The parameters for bioequivalence, mean [SD] values were as follows: AUC(0-t) (microg x h/ml): 3574.08 [628.17] for triflusal oral solution and 3901.78 [698.43] for triflusal capsules; AUC(0-infinity) (microg x h/ml): 4089.21 [842.54] for triflusal oral solution and 4471.33 [905.93] for triflusal capsules; Cmax, (microg/ml): 91.24 [12.88] for triflusal oral solution and 88.61 [13.46] for triflusal capsules; Cmax/AUC(0-infinity) (h(-1)): 0.03 (0.00) for triflusal oral solution and 0.02 (0.00) for triflusal capsules. The 90% confidence intervals for the ratio experimental/control by analysis of variance after log transformed AUC(0-infinity), AUC(0-t), and Cmax were within 80% to 125%. Similar results were found for the data without log transformation. All adverse events were of mild or moderate intensity and all subjects recovered. Nine and 12 subjects reported at least one adverse event during treatment with triflusal oral solution and with triflusal capsules, respectively. The most frequently reported adverse events were headache and dizziness. It was concluded that the 600-mg solution of triflusal appeared to be bioequivalent to the reference formulation capsules. Both formulations were well tolerated.

Abstract: To compare the comfort of oxygen therapy via high-flow nasal cannula (HFNC) versus via conventional face mask in patients with acute respiratory failure. Acute respiratory failure was defined as blood oxygen saturation < 96% while receiving a fraction of inspired oxygen > or = 0.50 via face mask.

Abstract: Background: Altered renal sodium handling has a major pathogenic role in salt-sensitive hypertension. Renal sodium transporters are present in urinary exosomes. We hypothesized that sodium transporters would be excreted into the urine in different amounts in response to sodium intake in salt-sensitive versus salt-resistant patients. Methods: Urinary exosomes were isolated by ultracentrifugation, and their content of Na-K-2Cl cotransporter (NKCC2) and Na-Cl cotransporter (NCC) was analyzed by immunoblotting. Animal studies: NKCC2 and NCC excretion was measured in 2 rat models to test whether changes in sodium transporter excretion are indicative of regulated changes in the kidney tissue. Human studies: in hypertensive patients (n = 41), we investigated: (1) a possible correlation between sodium reabsorption and urinary exosomal excretion of sodium transporters, and (2) the profile of sodium transporter excretion related to blood pressure (BP) changes with salt intake. A 24-hour ambulatory BP monitoring and a 24-hour urine collection were performed after 1 week on a low- and 1 week on a high-salt diet. Results: Animal studies: urinary NKCC2 and NCC excretion rates correlated well with their abundance in the kidney. Human studies:6 patients (15%) were classified as salt sensitive. The NKCC2 and NCC abundance did not decrease after the high-salt period, when the urinary sodium reabsorption decreased from 99.7 to 99.0%. In addition, the changes in BP with salt intake were not associated with a specific profile of exosomal excretion. Conclusions: Our results do not support the idea that excretion levels of NKCC2 and NCC via urinary exosomes are markers of tubular sodium reabsorption in hypertensive patients.

Abstract: Randomized, controlled trials have demonstrated efficacy for second-generation antipsychotics in the treatment of acute mania in bipolar disorder. Despite depression being considered the hallmark of bipolar disorder, there are no published systematic reviews or meta-analyses to evaluate the efficacy of modern atypical antipsychotics in bipolar depression. We systematically reviewed published or registered randomized, double-blind, placebo-controlled trials (RCTs) of modern antipsychotics in adult bipolar I and/or II depressive patients (DSM-IV criteria). Efficacy outcomes were assessed based on changes in the Montgomery-Asberg Depression Rating Scale (MADRS) during an 8-wk period. Data were combined through meta-analysis using risk ratio as an effect size with a 95% confidence interval (95% CI) and with a level of statistical significance of 5% (p<0.05). We identified five RCTs; four involved antipsychotic monotherapy and one addressed both monotherapy and combination with an antidepressant. The two quetiapine trials analysed the safety and efficacy of two doses: 300 and 600 mg/d. The only olanzapine trial assessed olanzapine monotherapy within a range of 5-20 mg/d and olanzapine-fluoxetine combination within a range of 5-20 mg/d and 6-12 mg/d, respectively. The two aripiprazole placebo-controlled trials assessed doses of 5-30 mg/d. Quetiapine and olanzapine trials (3/5, 60%) demonstrated superiority over placebo (p<0.001). Only 2/5 (40%) (both aripiprazole trials) failed in the primary efficacy measure after the first 6 wk. Some modern antipsychotics (quetiapine and olanzapine) have demonstrated efficacy in bipolar depressive patients from week 1 onwards. Rapid onset of action seems to be a common feature of atypical antipsychotics in bipolar depression.

Abstract: The use of Clinical Data Management Systems (CDMS) has become essential in clinical trials to handle the increasing amount of data that must be collected and analyzed. With a CDMS trial data are captured at investigator sites with "electronic Case Report Forms". Although more and more of these electronic data management systems are used in academic research centres an overview of CDMS products and of available data management and quality management resources for academic clinical trials in Europe is missing.

Abstract: The objective was to evaluate whether the soluble fibre Plantago ovata (Po)-husk improves cardiovascular disease (CVD) risk biomarkers including low-density lipoprotein cholesterol (LDL-C).

Abstract: To determine the short- and long-term benefits of noninvasive home mechanical ventilation (NIHMV) in patients aged 65 and older who were eligible for this treatment.

Abstract: Significant liver fibrosis (F >or= 2) and portal hypertension (hepatic venous pressure gradient [HVPG] >or= 6 mmHg) at 1 year after liver transplantation (LT) identify patients with severe hepatitis C recurrence. We evaluated whether repeated liver stiffness measurements (LSM) following LT can discriminate between slow and rapid "fibrosers" (fibrosis stage F2-F4 at 1 year after LT). Eighty-four patients who had undergone LT and who were infected with hepatitis C virus (HCV) and 19 LT controls who were not infected with HCV underwent LSM at 3, 6, 9, and 12 months after LT. All HCV-infected patients underwent liver biopsy 12 months after LT (paired HVPG measurements in 74); 31 (37%) were rapid fibrosers. Median LSM (in kilopascal) at months 6, 9, and 12 were significantly higher in rapid fibrosers (9.9, 9.5, 12.1) than in slow fibrosers (6.9, 7.5, 6.6) (P < 0.01 all time points). The slope of liver stiffness progression (kPa x month) in rapid fibrosers (0.42) was significantly greater than in slow fibrosers (0.05) (P < 0.001), suggesting two different speeds of liver fibrosis progression. Figures were almost identical for patients with HVPG >or= 6 mmHg or HVPG < 6 mmHg at 1 year after LT. Multivariate analysis identified donor age, bilirubin level, and LSM as independent predictors of fibrosis progression and portal hypertension in the estimation group (n = 50) and were validated in a second group of 34 patients. The areas under the receiver operating characteristic curve that could identify rapid fibrosers and patients with portal hypertension as early as 6 months after LT were 0.83 and 0.87, respectively, in the estimation group and 0.75 and 0.80, respectively, in the validation group. CONCLUSION: Early and repeated LSM following hepatitis C recurrence in combination with clinical variables discriminates between rapid and slow fibrosers after LT.

Abstract: A Phase I interventional Clinical Trial was performed with a potential tuberculosis vaccine, based on detoxified cellular fragments of M. tuberculosis, named RUTI. The objective was to evaluate the safety profile and T-cell immune responses over a 6-month period following subcutaneous inoculation. The double-blind, randomized and placebo-controlled trial was conducted in healthy volunteers, all recruited at one site. RUTI, at each of the four tested doses, starting from 5microg and going up to 200microg, and placebo were inoculated to groups of 4 and 2 volunteers respectively, consecutively. RUTI appeared to be well tolerated as judged by local and systemic clinical evaluation, though vaccine dose dependent local adverse reactions were recorded. T-cell responses of blood lymphocytes to PPD and a number of antigen subunits were elevated, when compared with controls subjects. These results support the feasibility of future evaluation, to be targeted at subjects with latent tuberculosis infection (LTBI).

Abstract: Cystatin C (Cys C) is an endogenous marker of glomerular filtration rate (GFR) unaffected by body composition. The aim of the present study was to assess the utility of Cys C-based GFR prediction equations (Hoek, Larsson and Stevens) and creatinine (modification of diet in renal disease-isotope dilution mass spectrometry--MDRD-IDMS, and Cockcroft-Gault--CG) compared with 51Cr-EDTA.

Abstract: Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.

Abstract: Recently, new concerns on the safety profile of nonsteroidal anti-inflammatory drugs (NSAIDs) have been raised by the European Medicines Agency (EMEA) and other regulatory authorities. The safety profile of oral dexketoprofen trometamol for the treatment of acute mild to moderate pain of different causes in actual conditions of use in the primary care setting was assessed. A prospective cohort study was designed to evaluate the tolerability of dexketoprofen compared with other commonly prescribed analgesics. Medications were given according to specifications in the summary of product characteristics. The intensity of pain was assessed at baseline and at days 1 and 7 of drug treatment using a 100-mm visual analog scale (VAS). Adverse events (AEs) were recorded. A total of 7,337 patients (median age [IQR] = 46 [33-61] years) were included in the study comparing dexketoprofen (n = 5,429), diclofenac (n = 485), ibuprofen (n = 479), paracetamol (n = 459), metamizole (n = 207), aceclofenac (n = 103), naproxen (n = 74), piroxicam (n = 69) and dexibuprofen (n = 32). The reasons for use were: musculoskeletal disorders, headache, dysmenorrhea and odontalgia. Treatment compliance was very high. Metamizole-paracetamol and dexketoprofen showed the lowest prevalence of AEs (2.7% and 3.6%, respectively), while aceclofenac-diclofenac showed the highest prevalence (8.2%) (P < 0.0001). AEs most frequently observed during NSAID treatment were those related to the gastrointestinal tract (3.5% of subjects, 84% of all AEs), followed by AEs related to the nervous system (0.4%) and skin (0.1%). Most of the reported AEs (91.3%) were of mild to moderate intensity (303 of 332) and only 3.3% of them were considered severe (11 of 332). Risks for gastrointestinal AEs were adjusted for age, gender, history of previous NSAID intake, gastroprotective drugs and reason for prescription. Taking metamizole-paracetamol as the reference group, the odds ratios (OR, 95%) were: 1.30 (0.77-2.19) for dexketoprofen, 1.57 (0.79-3.13) for ibuprofen and dexibuprofen, 2.31 (0.64-8.27) for naproxen, 2.63 (0.85-8.15) for piroxicam and 3.37 (1.87-6.06) for aceclofenac-diclofenac. These results confirm the safety of oral treatment with dexketoprofen in patients with acute pain of various etiologies observed in previous studies and support the use of dexketoprofen as a first-line drug for the approved therapeutic indications.

Abstract: Complications and technical problems of paracentesis in cirrhotic patients are infrequent. However, the severity and the incidence of these events and their risk factors have not been assessed prospectively.

Abstract: The aim of this study was to investigate whether hyponatremia is a risk factor of overt hepatic encephalopathy (HE) in cirrhosis.

Abstract: The burden that spontaneous bacterial meningitis (SBM) currently represents among HIV-1-infected patients is poorly known.

Abstract: Total tear IgE has been considered to play an important role in allergic conjunctivitis, and measurement has been considered useful for diagnosis. The aim of this study was to ascertain whether Lacrytest(®), a new commercialised method to detect IgE levels in lacrimal fluid, could constitute a screening test for the diagnosis of allergic conjunctivitis. This was a cross-sectional study. Patients with seasonal and perennial allergic conjunctivitis, vernal keratoconjunctivitis and a control group were included. Clinical history, ophthalmic examination, skin prick test and conjunctival provocation test were obtained. Lacrytest(®) was later performed in all groups. Fifty-four patients were enrolled: thirty with IgE-mediated conjunctivitis and, nine with vernal keratoconjunctivitis and fifteen controls. Lacrytest(®) was negative in all controls, positive in 20% of the IgE-mediated conjunctivitis group and in 88.9% of the vernal keratoconjunctivitis group. Global statistically-significant differences were found among the three groups (P = .003). Sensitivity of the test in the IgE-mediated conjunctivitis group was 20%, specificity 100%, positive predictive value 100%, and negative predictive value 38.46%, while in VKC sensitivity was 88.88%, specificity 100%, positive predictive value 100%, and negative predictive value 93.75%. Our data confirm that this test is not useful for screening allergic conjunctivitis. Lacrytest(®), while not providing any useful information to an allergist, could be helpful for ophthalmologists to confirm an IgE-mediated or VKC conjunctivitis.

Abstract: OBJECTIVE: The objective of the study was to evaluate bioequivalence of two strengths (1 and 2 mg) of oral risperidone tablet formulations (test product manufactured by Vita-Invest, S.A., Barcelona, Spain, reference product manufactured by Janssen-Cilag Ltd., UK). SUBJECTS AND METHODS: In each of the 2 studies, 30 healthy volunteers were administered 1 or 2 mg, respectively, of test or reference formulation under fasting conditions in an open, two-way crossover, controlled, randomized and single-site fashion. Blood withdrawal was performed prior to dosing as well as 15 min, 30 min, 1 h, 1.5 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h, 48 h, 72 h, and 96 h after drug administration. Plasma concentrations of risperidone and its metabolite 9-hydroxy-risperidone were analyzed using LC/MS/MS. Descriptive data of AUC0-t, AUC0- yen, Cmax, and Cmax/AUC0- yen were log-transformed to evaluate bioequivalence based on the ratios of the geometric means of test and reference formulations. tmax was analyzed using nonparametric methods. RESULTS: The results show that in both studies, 1 and 2 mg formulations, the 90% confidence intervals for the geometric means ratios of the test and reference products for both the parent compound risperidone and its metabolite 9-hydroxy-risperidone were all within the bioequivalence acceptance criteria of 0.80 - 1.25 of the European CPMP and the US FDA guidelines, with the exception of tmax for risperidone parent compound in the 2 mg formulation, which was slightly suprabioequivalent for test formulation. CONCLUSION: This study demonstrated the bioequivalence between the test and the reference product of risperidone of both 1 and 2 mg formulations. Both formulations of each strength may, therefore, be prescribed interchangeably.

Abstract: The present study aimed to assess whether arterial carbon dioxide pressure (Pa,CO(2)) has an impact on agreement between oxygen saturation measured with pulse oximetry (Sp,O(2)) or arterial blood gas co-oximetry (Sa,O(2)). Sa,O(2) and Sp,O(2) determinations were obtained simultaneously from 846 patients under assessment for long-term home oxygen therapy in a specialised outpatient clinic. Both measurements were taken with patients seated and breathing room air. Agreement between Sa,O(2) and Sp,O(2) results was analysed by the Bland-Altman method and the Lin concordance coefficient. In addition, potential interactions of arterial oxygen tension (Pa,O(2)) or Pa,CO(2) on agreement were analysed by adjusted multivariate analysis. Upon comparison of Sa,O(2) and Sp,O(2) results, the Bland-Altman technique yielded a bias (95% confidence interval (CI)) of -1.24 (-6.86-4.38) and -1.32 (-7.78-5.15) when Pa,CO(2) >48 mmHg (6.39 kPa) or Pa,O(2) <54 mmHg (7.20 kPa), respectively. Estimate by Lin's coefficient (95% CI) in these cases was 0.88 (0.85-0.90) and 0.81 (0.77-0.85). Adjusted multivariate analysis, performed to assess the impact of pH, Pa,O(2), Pa,CO(2) and bicarbonate on bias, showed that Pa,O(2), Pa,CO(2) and their interaction terms were the most important predictors of the bias (standardised estimates of -0.54, -0.94, and 0.85, respectively). The effect of pH, although statistically significant, was small, and bicarbonate had no significant effect. Arterial carbon dioxide pressure status can contribute to impaired agreement between arterial oxygen saturation and arterial oxygen saturation measured with pulse oximetry, particularly in patients with hypercapnia.

Abstract: The aim of the study was to compare the effect of the administration of a mixture of fibres on body weight-loss, satiety, lipid profile and glucose metabolism. We included 200 overweight or obese patients in a parallel, double-blind, placebo-controlled clinical trial, who were randomised to receive, in the context of an energy-restricted diet for a period of 16 weeks, a mixed fibre dose (3 g Plantago ovata husk and 1 g glucomannan) twice (b.i.d. group) or three times daily (t.i.d. group) or placebo. Weight change was the primary efficacy endpoint. Satiety, dietary compliance, lipid profile, glucose tolerance, insulin resistance and high-sensitivity C-reactive protein were secondary endpoints. Weight loss tended to be higher after both doses of fibre (-4.52 (SD 0.56) and -4.60 (SD 0.55) kg) than placebo (-0.79 (SD 0.58) kg); the differences in changes between groups were not statistically significant. Postprandial satiety increased in both fibre groups compared to the placebo. The differences between groups in LDL-cholesterol levels were significant (P = 0.03), with greater reductions in the two fibre-supplemented groups (-0.38 (SD 0.10) and -0.24 (SD 0.09) mmol/l in the b.i.d. and t.i.d. groups v. -0.06 (SD 0.09) mmol/l in placebo group). A similar pattern was observed for changes in total cholesterol:HDL-cholesterol and HDL-cholesterol:LDL-cholesterol ratios. Interventions were well tolerated and had no effects on HDL-cholesterol, glucose and insulin concentrations, glucose tolerance or high-sensitivity C-reactive protein. In conclusion, a 16-week dietary supplement of soluble fibre in overweight or obese patients was well tolerated, induced satiety and had beneficial effects on some CVD risk factors, the most important of which was a significant decrease in plasma LDL-cholesterol concentrations.

Abstract: There is increasing evidence that metabolic adverse effects associated with antiretroviral therapy may translate into an increased cardiovascular risk in HIV-1-infected patients.

Abstract: Human seminal plasma (HSP) allergy is uncommon, with symptoms ranging from vulvovaginal pruritus to life-threatening anaphylaxis. Although several seminal plasma allergens have been reported and their molecular masses have been estimated to range between 12 and 75 kd, the prostate-specific antigen (PSA) has recently been identified as a causative allergen. Given that in a large number of cases symptoms appeared during or after the first intercourse, a cross-reactivity phenomenon might be implicated.

Abstract: BACKGROUND: To compare the analgesic efficacy of epidural infusions of levobupivacaine, bupivacaine and ropivacaine in labor. METHODS: 102 nulliparous parturients in early labor were enrolled in this randomized, double-blind clinical trial. They were randomly assigned to receive one of three continuous epidural infusion regimens: levobupivacaine 0.125%, bupivacaine 0.125% or ropivacaine 0.2%, all with fentanyl 1 microg/mL at 8 mL/h. Supplementary analgesia was provided with an 8-mL epidural bolus of the study solution if visual analogue scale (VAS) score for pain was 40 (0-100 mm). Pain and motor and sensory block were measured at 0, 15 and 30 min, 1, 2, 3 and 4h and full cervical dilatation. RESULTS: Analgesia was satisfactory in all three groups, with VAS score <40 mm at all measurements. VAS scores were greater in those receiving levobupivacaine (P<0.005). Motor block was greater with bupivacaine than levobupivacaine (P<0.01). There were no differences in motor block between levobupivacaine and ropivacaine. There were no other differences between groups. CONCLUSION: All three regimens were effective during first stage of labor although pain scores were higher in those receiving levobupivacaine. Motor block was greater with bupivacaine than with levobupivacaine.

Abstract: Efavirenz and lopinavir/ritonavir are both recommended antiretroviral agents for combination first-line therapy, although information on direct comparisons between them is scarce. A retrospective longitudinal study from the VACH cohort comparing both regimens was performed.

Abstract: To test the Mayo Clinic Quadratic (MCQ) equation against isotopic glomerular filtration rate, compared with the Modification of Diet in Renal Disease (MDRD) and the Cockcroft-Gault formulas, in type 2 diabetes.

Abstract: Amnestic mild cognitive impairment represents, in many cases, the earliest clinical phases of Alzheimer disease. Anti-inflammatory agents have epidemiologic support as drugs potentially beneficial in Alzheimer disease. In vivo studies have shown that Triflusal and its active metabolite 2-hydroxy-4-trifluoromethyl-benzoic acid have potent anti-inflammatory actions in the central nervous system.

Abstract: BACKGROUND: Hypertension induced by cyclosporine is associated with renal sodium and water retention. Using immunoblotting of kidney homogenates, we investigated the regulation of sodium and water transport proteins in a rat model of cyclosporine-induced hypertension. METHODS: Rats were treated with cyclosporine (25 mg/kg/day intraperitoneally) during 7 days. Control rats received vehicle. RESULTS: Cyclosporine-treated rats had an increase in blood pressure with a decrease in renal sodium excretion compared with control rats. There were no differences either in sodium intake or in plasma creatinine levels between the two groups of rats. These data suggest that the decrease in sodium excretion in the cyclosporine-treated rats was due to an increase in renal sodium absorption. The densitometric analysis of the renal immunoblot showed an increase in the Na-K-2Cl cotransporter of the loop of Henle (NKCC2) in cyclosporine-treated rats (178% +/- 36) compared with control rats (100% +/- 18; P < 0.05*). This protein rise was associated with an increase in the NKCC2 mRNA pointing to a transcriptional regulation of this sodium transporter. There were no statistically significant changes in the sodium proton exchange (NHE-3) of the proximal tubule although in this renal segment, aquaporin-1 was increased in cyclosporine-treated rats compared with control rats (control 100% +/- 6 vs cyclosporine 119% +/- 6; P < 0.05*). CONCLUSIONS: Our results pointed to the thick ascending limb of the loop of Henle as an important site of sodium retention in cyclosporine-induced hypertension. This data may have potential clinical implications for the treatment of hypertension induced by cyclosporine

Abstract: Hypertension induced by cyclosporine is associated with renal sodium and water retention. Using immunoblotting of kidney homogenates, we investigated the regulation of sodium and water transport proteins in a rat model of cyclosporine-induced hypertension.

Abstract: Experimental studies have recently suggested that acute ischemia may facilitate the appearance of fatal infections as part of a brain-induced immunodepression syndrome. However, the mechanisms and neurological consequences of infections complicating acute ischemic stroke have received much less attention at the bedside. The incidence of infection and death after non-septic stroke was compared in this prospective study with longitudinal changes of cytokines, leukocytes, normetanephrine (NMN) and metanephrine (MN) in 75 consecutive patients. In multivariate analysis, infection, n = 13 (17%), was associated with the upper quartile of MN (OR 3.51, 95% Cl 1.30-9.51), neurological impairment (NIHSS) on admission (OR 3.99, 95% Cl 1.34-11.8), monocyte count (OR 1.78, 95% Cl 1.13-2.79), and increased interleukin (IL)- 10 (OR 1.54, 95% CI 1.00-2.38). Mortality at 3 months, n 16 (21 %), was associated with increased levels of NMN on admission (OR 2.34 95% CI 1.15-4.76), NIHSS score (OR 2.57, 95% CI 1.29-5.11), and higher IL-6 levels (OR 1.29, 95% 1.00-1.67). These findings suggest that acute ischemic stroke is associated with an early activation of the sympathetic adrenomedullar pathway that lowers the threshold of infection and increases the risk of death. Moreover, these findings are independent of the blood borne effects of pro- and anti-inflammatory cytokines, and circulating leukocytes. (c) 2006 Elsevier B.V. All rights reserved

Abstract: Experimental studies have recently suggested that acute ischemia may facilitate the appearance of fatal infections as part of a brain-induced immunodepression syndrome. However, the mechanisms and neurological consequences of infections complicating acute ischemic stroke have received much less attention at the bedside. The incidence of infection and death after non-septic stroke was compared in this prospective study with longitudinal changes of cytokines, leukocytes, normetanephrine (NMN) and metanephrine (MN) in 75 consecutive patients. In multivariate analysis, infection, n = 13 (17%), was associated with the upper quartile of MN (OR 3.51, 95% CI 1.30-9.51), neurological impairment (NIHSS) on admission (OR 3.99, 95% CI 1.34-11.8), monocyte count (OR 1.78, 95% CI 1.13-2.79), and increased interleukin (IL)-10 (OR 1.54, 95% CI 1.00-2.38). Mortality at 3 months, n = 16 (21%), was associated with increased levels of NMN on admission (OR 2.34 95% CI 1.15-4.76), NIHSS score (OR 2.57, 95% CI 1.29-5.11), and higher IL-6 levels (OR 1.29, 95% 1.00-1.67). These findings suggest that acute ischemic stroke is associated with an early activation of the sympathetic adrenomedullar pathway that lowers the threshold of infection and increases the risk of death. Moreover, these findings are independent of the blood borne effects of pro- and anti-inflammatory cytokines, and circulating leukocytes.

Abstract: The aim of this study was to compare the accuracy of prediction equations [modification of diet in renal disease (MDRD), simplified MDRD, Cockcroft-Gault (CG), reciprocal of creatinine and creatinine clearance] in a cohort of patients with type 2 diabetes.

Abstract: Background and Purpose-It is unsettled whether stroke-associated infection (SAI) is an independent prognostic factor, and a recent clinical trial failed to show that antibiotic prophylaxis prevented SAI. Contrarily, this trial suggested that antibiotic prophylaxis impaired clinical recovery. We sought to evaluate the predisposing factors and clinical consequences of SAI to gather additional insight on the need of exploring other antibiotics in acute stroke. Methods-Between March 2001 and April 2002, 229 consecutive patients were admitted into the neurological wards within 24 hours of stroke onset. Demographics, risk factors, National Institutes of Health Stroke Scale (NIHSS) score, vital data, imaging, and laboratory findings were prospectively evaluated. SAI was treated as early as possible. Multivariate regression analyses assessed predisposing factors of SAI and the independent association between SAI and poor stroke outcome at day 7 (Rankin >2). Results-Sixty (26%) patients developed SAI, most frequently chest infections, and within 3 days of stroke onset. Tube feeding (odds ratio [OR], 3.2; 95% CI, 1.3, 7.8) was the strongest predisposing factor of SAI. Poor outcome at hospital discharge was associated to baseline NIHSS score (OR, 10.0; 95% CI, 1.5, 100) and tube feeding (OR, 16.6; 95% CI, 2.9, 100.0), adjusted for confounders including antibiotic use. SAI was not independently associated to poor outcome (OR, 0.9; 95% CI, 0.9, 1.0). Conclusions-SAI is a marker of the severity of stroke without an independent outcome effect when it is promptly treated. These results support current stroke guidelines that advise prompt treatment of infection and warn against antibiotic prophylaxis. Yet, these recommendations should not prevent the performance of acute stroke trials assessing the value of antibiotics with acknowledged neuroprotective properties

Abstract: The accuracy of prediction equations has not been validated in adult patients with chronic kidney disease (CKD) stages 4-5 in extreme situations of nutritional status and age.

Abstract: Study objective: Two modes of noninvasive home mechanical ventilation (NIHMV) with volumetric ventilators were compared in patients with chronic respiratory failure. Design: Retrospective, parallel-group, comparative study. Setting: Third-level teaching Hospital in Barcelona (Spain). Patients and methods: We studied 110 patients with chronic hypercapnic respiratory failure secondary to neuromuscular disease, kyphoscoliosis or post-tuberculosis sequelae, starting NIHMV with volumetric ventilators. The assist/control (A/C) ventilation mode was used in 45 patients and the control (C) mode in 65 patients. Clinical characteristics, pulmonary function results and arterial blood gas findings were assessed in each patient before establishing ventilation and at 6 and 12 months after. The patient's satisfaction with ventilation, the time required for adaptation, and compliance with the prescription were also assessed. Measurements and results: Significant improvements in PaO2 and PaCO2 (P < 0.001) were found at 6 and 12 months with both modes of mechanical ventilation. There were no significant differences between the two modes for pulmonary function or blood gas parameters with the exception of maximum inspiratory pressure (MIP) in patients receiving the C mode, which was significantly different as compared to the baseline value after 12 months of use (mean +/- SD: 36.6 +/- 14.8 and 44.7 +/- 24.2 cmH(2)O, respectively; P = 0.010). No significant differences were found in adaptation, compliance with ventilation or patient satisfaction between the two modes studied. Conclusions: According to several factors analysed, results with the A/C or C mode used with volumetric ventilators appear to be comparable in patients with chronic respiratory disease receiving NIHMV. Choice of mode will depend on the acquired experience of the prescribing physicians in each centre. (c) 2005 Elsevier Ltd. All rights reserved

Abstract: BACKGROUND: The D:A:D (Data Collection on Adverse Events of Anti-HIV Drugs) Study, a prospective observational study on a cohort of 23 468 patients with HIV infection, indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). However, it remains unclear whether the observed increase in the rate of MI in this population can be attributed to changes in conventional cardiovascular risk factors. OBJECTIVE: To compare the number of MIs observed among participants in the D:A:D Study with the number predicted by assuming that conventional cardiovascular risk equations apply to patients with HIV infection. METHODS: The Framingham equation, a conventional cardiovascular risk algorithm, was applied to individual patient data in the D:A:D Study to predict rates of MI by duration of CART. A series of sensitivity analyses were performed to assess the effect of model and data assumptions. Predictions were extrapolated to provide 10-year risk estimates, and various scenarios were modelled to assess the expected effect of different interventions. RESULTS: In patients receiving CART, the observed numbers of MIs during D:A:D follow up were similar to or somewhat higher than predicted numbers: 9 observed vs 5.5 events predicted, 14 vs 9.8, 22 vs 14.9, 31 vs 23.2 and 47 vs 37.0 for<1 year, 1-2 years, 2-3 years, 3-4 years and >4 years CART exposure, respectively. In patients who had not received CART, the observed number of MIs was fewer than predicted (3 observed vs 7.6 predicted). Nine per cent of the study population have a predicted 10-year risk of MI above 10%, a level usually associated with initiation of intervention on risk factors. CONCLUSIONS: A consistent feature of all analyses was that observed and predicted rates of MI increased in a parallel fashion with increased CART duration, suggesting that the observed increase in risk of MI may at least in part be explained by CART-induced changes in conventional risk factors. These findings provide guidance in terms of choosing lifestyle or therapeutic interventions to decrease those risk factors in much the same way as in persons without HIV infection

Abstract: Background and purpose: The pathophysiology of stroke-associated infection (SAI) is uncertain. The cytokine profile and peripheral white cell response were assessed in patients with or without SAI. Methods: The incidence of SAI was assessed in 110 patients with ischaemic stroke allocated antibiotic prophylaxis or placebo within 24 h of clinical onset. Peripheral white cell counts, interleukin (IL)6, tumour necrosis factor (TNF)alpha and IL10 were measured in plasma. Results: 17 (15%) patients developed infection and showed time-dependent increases of total white cell count, neutrophils, monocytes, lymphocytes, IL6 and IL10, whereas TNF alpha and the TNF alpha/IL10 ratio decreased. In logistic regression, IL10 (odds ratio (OR) 1.08, 95% confidence interval (CI) 1.01 to 1.16), monocyte count (OR 1.42, 95% CI 1.08 to 1.87) and National Institute for Health Stroke Survey score on admission (OR 1.17, 95% CI 1.05 to 1.31) were independent predictors of systemic infection. Conclusions: SAI is associated with stroke severity, excessive IL10-mediated response and an increased number of circulating monocytes. These results support the finding that acute ischaemic brain injury triggers a blood-borne anti-inflammatory response that decreases the antimicrobial drive of the immune system

Abstract: Background. The aim of this study was to compare the accuracy of prediction equations [modification of diet in renal disease (MDRD), simplified MDRD, Cockcroft-Gault (CG), reciprocal of creatinine and creatinine clearance] in a cohort of patients with type 2 diabetes. Methods. A total of 525 glomerular filtration rates (GFRs) using I-125-iothalamate were carried out over 10 years in 87 type 2 diabetic patients. Accuracy was evaluated at three levels of renal function according to the baseline values obtained with the isotopic method: hyperfiltration (GFR: > 140 ml/min/1.73 m(2); 140 isotopic determinations in 27 patients), normal renal function (GFR: 140-90 ml/min/1.73 m(2); 294 isotopic determinations in 47 patients) and chronic kidney disease (CKD) stages 2-3 (GFR: 30-89 ml/min/1.73 m(2); 87 isotopic determinations in 13 patients). The annual slope for GFR (change in GFR expressed as ml/min/year) was considered to ascertain the variability in the equations compared with the isotopic method during follow-up. Student's t-test was used to determine the existence of significant differences between prediction equations and the isotopic method (P < 0.05 with Bonferroni adjusted for five contrast tests). Results. In the subgroup of patients with hyperfiltration, a GFR slope calculated with I-125-iothalamate -4.8 +/- 4.7 ml/min/year was obtained. GFR slope in patients with normal renal function was -3.0 +/- 2.3 ml/min/year. In both situations, all equations presented a significant underestimation compared with the isotopic GFR (P < 0.01; P < 0.05). In the subgroup of CKD stages 2-3, the slope for GFR with I-125-iothalamate was -1.4 +/- 1.8 ml/min/year. The best prediction equation compared with the isotopic method proved to be MDRD with a slope for GFR of -1.4 +/- 1.3 ml/min/year (P: NS) compared with the CG formula -1.0 +/- 0.9 ml/min/year (P: NS). Creatinine clearance presented the greatest variability in estimation (P < 0.001). Conclusions. In the normal renal function and hyperfiltration groups, none of the prediction equations demonstrated acceptable accuracy owing to excessive underestimation of renal function. In CKD stages 2-3, with mean serum creatinine >= 133 mu mol/l (1.5 mg/dl), the MDRD equation can be used to estimate GFR during the monitoring and follow-up of patients with type 2 diabetes receiving insulin, anti-diabetic drugs or both

Abstract: Background: The accuracy of prediction equations has not been validated in adult patients with chronic kidney disease (CKD) stages 4-5 in extreme situations of nutritional status and age. Objective and Methods: The significance of nutritional status, calculated with the creatinine production (CP) formula, and age (<= 64 years and 1 64 years) in the application of different prediction equations-modification of diet in renal disease (MDRD), simplified MDRD (sMDRD), Cockcroft-Gault (CG)-and the mean of urea and creatinine clearance (Cr-Ur) compared with the isotopic glomerular filtration rate (GFR) estimation calculated by 51Cr-EDTA was studied in 87 Caucasian adults with CKD stages 4-5 (GFR: 30 - 8ml/min/1.73 m(2)). The Bland-Altman method and Lin's concordance coefficient (Rc) were used to study accuracy (bias) and precision. Results: The GFR calculated with Cr-51-EDTA in the study group was 22.2 +/- 6.9 ml/min/1.73 m(2) (range: 8 - 30). CG and sMDRD were the best prediction equations with bias of -1.1 and - 3.8 ml/min/1.73 m(2) and Rc of 0.52-0.50. In this situation, the mean Cr-Ur proved the most inaccurate equation compared with the isotopic technique with bias of -5.4 ml/min/1.73m(2) and Rc of 0.32. In the analysis of patients with higher CP (> 0.90; n = 44), CG and sMDRD obtained the best bias of 1.2 and -2.7 ml/min/1.73m(2) and Rc of 0.54-0.53. In patients aged <= 64 ( n = 44), these equations obtained a bias of 1.1 and -3.6 ml/min/1.73m(2) and Rc 0.5-0.49. Both in lower CP (> 0.90; n = 43) and older age (> 64 years; n = 43), all the equations underestimated the value obtained with isotopic GFR. In these situations, the results obtained with CG had a bias of -2.2 and -3.6ml/min/1.73m(2) (Rc 0.29-0.56) and with sMDRD -4.0 and -4.1 ml/min/1.73m(2) (Rc 0.39-0.51). In these circumstances, Cr-Ur was the most inaccurate equation, obtaining a bias of -10.1 and -13.2 ml/min/1.73m(2) (Rc 0.14-0.16). Conclusions: In the group with higher CP and age <= 64 years, results of the presented data yielded no evidence for superiority of the MDRD equation over CG formula in patients with advanced renal failure. On the basis of our results, we do not recommend the use of the Cr-Ur adjusted to 1.73 m(2) of body surface area, which was the most imprecise equation. Application of all the equations proved inaccurate in lower CP patients with or without advanced age, implying the premature start of substitution renal treatment. In these circumstances, ambulatory GFR determination by isotopic techniques would be indicated. Copyright (c) 2006 S. Karger AG,

Abstract:

Abstract: We assessed the in vitro toxicity of tenofovir (TFV) and compared it with those of zidovudine (AZT), didanosine (ddI), ritonavir (RTV), and lopinavir (LPV) alone and in combination in human renal proximal tubule epithelial cells (RPTECs). The cells were treated with various concentrations and combinations of the tested antiretrovirals for up to 22 days, and cytotoxicity was determined. In addition, we assessed the levels of mitochondrial DNA (mtDNA) and cytochrome oxidase II (COII) mRNA in RPTECs treated with reverse transcriptase inhibitors. TFV alone was not associated with significant cytotoxicity. ddI showed pronounced cytotoxicity that was greater than those of AZT (P = 0.002) and TFV (P = 0.0001). The combination of 10 muM RTV and 40 muM LPV significantly reduced RPTEC viability (P < 0.0001), and TFV tended to partially reduce this effect. TFV alone affected neither mtDNA nor COII mRNA levels, whereas ddI caused a profound depletion of mtDNA and a parallel reduction in COII mRNA expression. The effects of ddI, but not those of AZT, on mtDNA and COII mRNA were further enhanced in the presence of TFV, a finding consistent with the inhibition of ddI clearance by TFV. The addition of TFV to ddI or AZT appeared to slightly increase the COII mRNA/mtDNA ratio relative to that in cells treated with ddI or AZT alone. Together, these in vitro results indicate that combination with other antiretrovirals does not significantly increase the toxic potential of TFV in RPTECs.

Abstract: BACKGROUND: An increasing proportion of deaths among human immunodeficiency virus (HIV)-infected persons with access to combination antiretroviral therapy (cART) are due to complications of liver diseases. METHODS: We investigated the frequency of and risk factors associated with liver-related deaths in the Data Collection on Adverse Events of Anti-HIV Drugs study, which prospectively evaluated 76 893 person-years of follow-up in 23 441 HIV-infected persons. Multivariable Poisson regression analyses identified factors associated with liver-related, AIDS-related, and other causes of death. RESULTS: There were 1246 deaths (5.3%; 1.6 per 100 person-years); 14.5% were from liver-related causes. Of these, 16.9% had active hepatitis B virus (HBV), 66.1% had hepatitis C virus (HCV), and 7.1% had dual viral hepatitis co-infections. Predictors of liver-related deaths were latest CD4 cell count (adjusted relative rate [RR], 16.1; 95% confidence interval [CI], 8.1-31.7 for <50 vs > or =500/microL), age (RR, 1.3; 95% CI, 1.2-1.4 per 5 years older), intravenous drug use (RR, 2.0; 95% CI, 1.2-3.4), HCV infection (RR, 6.7; 95% CI, 4.0-11.2), and active HBV infection (RR, 3.7; 95% CI, 2.4-5.9). Univariable analyses showed no relationship between cumulative years patients were receiving cART and liver-related death (RR, 1.00; 95% CI, 0.93-1.07). Adjustment for the most recent CD4 cell count and patient characteristics resulted in an increased risk of liver-related mortality per year of mono or dual antiretroviral therapy before cART (RR, 1.09; 95% CI, 1.02-1.16; P = .008) and per year of cART (RR, 1.11; 95% CI, 1.02-1.21; P = .02). CONCLUSIONS: Liver-related death was the most frequent cause of non-AIDS-related death. We found a strong association between immunodeficiency and risk of liver-related death. Longer follow-up is required to investigate whether clinically significant treatment-associated liver-related mortality will develop

Abstract: Objective: To evaluate the level of compliance with the 2002 consensus document (Spanish Society of Nephrology) on guidelines for the detection, prevention and treatment of diabetic nephropathy in Catalonia. Subjects and methods: Multicenter (23 hospitals), observational, cross-sectional, descriptive study conducted in 413 diabetic patients (61.7% men, 38.3% women) with a median age of 66.2 +/- 11.5 years (26-93 years). The ANOVA test (post-hoc analysis; p value < 0.05) was used to study the relationships between the stages of diabetic nephropathy and different variables. Results: 90.3% of the patients had type 2 DM. The following anthropometric parameters were observed: BMI 29.8 +/- 5 kg/m(2) (BMI > 30 kg/m(2): 48.7%) and waist circumference 104.1 +/- 14 cm (48.6% men > 102 cm and 78.9% women > 88 cm). Serum creatinine 1.9 +/- 1.3 mg/dl and simplified MDRD equation 45.3 +/- 25.0 ml/minl/1.73 m(2) [65.8% with CKD stages 3 and 4]. 80% of patients had ophthalmologic examination and 52.8% antiplatelet treatment. Hb A1c was 7.3 +/- 1.3 %, but the percentage of patients with glycated hemoglobin > 7% and 8% was 54.9 and 28.6% [only 50.2% had been seen by an endocrinologist in the last 6 months]. 52.8% of patients were treated with insulin and 44.1% with anti-diabetic drugs, although only 19.6% used the new anti-diabetic drugs. 61% of patients had an LDLc > 100 mg/dl (61% treated) and 44% had triglycerides (TG) > 150 mg/dl (72% treated). 95% of patients presented with hypertension (BP >= 130/80 mmHg), 91% were undergoing antihypertensive treatment (79.7% with angiotensin-converting enzyme inhibitors and / or angiotensin receptor blockers). 81% with microalbuminuria and 78% with established proteinuria were receiving antiproteinuric treatment. Of the patients considered to be refractory to BP (> 3 drugs), only 28.9% underwent ambulatory BP monitoring. Significant differences were observed between stages of diabetic nephropathy and glycated hemoglobin (HBA1c; p = 0.048), systolic blood pressure (SBP; p = 0.024), lipidic control (HDLc, p = 0.015 and TG; p = 0.034), anemia (Hb; p = 0.070) and CKD (creatinine and sMDRD, p = 0.000). The levels of compliance with the therapeutic objectives regarding lipid control (LDL <= 100 mg/dl and TG <= 150 mg/dl), BP <= 130/80 mmHg and HbA1c <= 7% were 1 objective: 68%, 2 objectives: 21.8% and 3 objectives: only 4% of patients. Conclusions: According to the results of our study, only a reduced proportion of patients fulfilled the different therapeutic end-points indicated. Future measures will be directed at improving physician-patient relationships with the main aim of intensifying the therapeutic measures to attain better metabolic and blood pressure control, nephroprotection and prevention in the appearance of cardiovascular events

Abstract: Two modes of noninvasive home mechanical ventilation (NIHMV) with volumetric ventilators were compared in patients with chronic respiratory failure.

Abstract: It is unsettled whether stroke-associated infection (SAI) is an independent prognostic factor, and a recent clinical trial failed to show that antibiotic prophylaxis prevented SAI. Contrarily, this trial suggested that antibiotic prophylaxis impaired clinical recovery. We sought to evaluate the predisposing factors and clinical consequences of SAI to gather additional insight on the need of exploring other antibiotics in acute stroke.

Abstract:

Abstract: The culture of bronchial secretions from the lower airway has been reported to be positive for potentially pathogenic microorganisms (PPMs) in patients with stable chronic obstructive pulmonary disease (COPD), but the determinants and effects of this bacterial load in the airway are not established.

Abstract: Background The pathogenesis of fat redistribution syndromes (FRS) observed in the setting of highly active antiretroviral therapy (HAART) for the treatment of HIV-1-infection remains elusive. A dysregulation of the tumour necrosis factor alpha (TNF-alpha) system occurs in HIV-infected patients with FRS. Materials and methods The study looked at both the in vivo and in vitro relationship between TNF-alpha and the degree of subcutaneous adipocyte apoptosis in 60 HIV-1-infected patients on HAART with FRS, another 60 HIV-1-infected patients on HAART without FRS and 60 uninfected control patients. Apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP (deoxyuridine 5'-triphosphate)-digoxigenin Nick End Labelling (TUNEL) method. Soluble receptors of TNF-alpha were determined by the sandwich enzyme immunoassay technique. The in vitro viability was assessed by staining with 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) and apoptosis by TUNEL. Results HIV-1-infected patients with FRS had significantly higher degrees of subcutaneous adipocyte apoptosis than those without FRS (P = 0.0001) and uninfected controls (P < 0.0001). There was a statistically significant association between serum levels of soluble TNF-alpha receptors #1 and #2 and the degree of subcutaneous adipocyte apoptosis in patients with and without FRS (P < 0.0001 for both receptors). In vitro, the addition of TNF-alpha (10 ng mL(-1)) to an adipocyte culture embedded with indinavir, either alone or in clinically relevant combinations with stavudine (d4T) and lamivudine (3TC), significantly decreased adipocyte viability (P = 0.0001) and increased adipocyte apoptosis (P < 0.0001) with respect to that observed with the addition of antiretrovirals alone. Conclusions TNF-alpha plays a significant role in subcutaneous adipocyte apoptosis, which occurs in the setting of FRS in HIV-1-infected patients on highly active antiretroviral therapy

Abstract: OBJECTIVE: We assessed predictors of changes in systolic (SBP) and diastolic (DBP) blood pressure during follow-up and of the development of hypertension in HIV-infected individuals. METHODS: International cohort collaborative study (D:A:D) of established prospective cohorts of HIV-1-infected patients. Longitudinal analysis of changes in blood pressure (BP) was performed using mixed effects models in 17170 patients. Predictors of development of hypertension during follow-up (systolic BP > or =140 and/or diastolic BP > or =90 mmHg or initiation of antihypertensive treatment) were assessed using Cox models in 8 984 patients with a normal BP level at baseline. RESULTS: 73548 BP measurements with a median of 4 per patient (interquartile range [IQR]: 2-6) were recorded over a median follow-up of 2.3 years (IQR: 1.5-2.6). Risk factors significantly associated with a development of higher systolic BP and diastolic BP (differences > or =5 mmHg and P-values <0.001) during follow-up were: older age, male sex, higher body mass index (BMI) and use of BP-lowering drugs. In patients with normal BP at baseline, 1186 developed hypertension for an incidence of 72.1 per 1000 person-years (95% confidence interval: 68.2-76.0). Factors associated with development of hypertension were: male sex, higher BMI, older age, higher BP at baseline, high total cholesterol and clinical lipodystrophy. Cumulative duration of exposure to nucleoside reverse transcriptase inhibitors (P=0.75), protease inhibitors (P=0.92) as well as type of antiretroviral treatment at baseline (P=0.18) were not associated with a higher risk of hypertension. Cumulative duration of exposure to non-nucleoside reverse transcriptase inhibitors (NNRTIs) was significantly associated with lower risk of hypertension (hazard ratio=0.78 and 0.67 for those treated < or =10 months and >10 months compared with no exposure; P=0.005). CONCLUSIONS: Increased blood pressure in HIV-infected individuals is associated with established risk factors for hypertension. There was no evidence for an independent deleterious effect of any class of antiretroviral drugs on BP, although the use of NNRTIs was associated with a lower risk of development of hypertension

Abstract: BACKGROUND AND PURPOSE: Early infection after stroke is frequent but the clinical value of antibiotic prophylaxis in acute stroke has never been explored. OBJECTIVE AND METHODS: The Early Systemic Prophylaxis of Infection After Stroke (ESPIAS) is a randomized, double-blind, placebo-controlled study of antibiotic prophylaxis in patients older than 18 years with nonseptic ischemic or hemorrhagic stroke enrolled within 24 hours from clinical onset. Interventions included intravenous levofloxacin (500 mg/100 mL/d, for 3 days) or placebo (0.9% physiological serum) in addition to optimal care. A sample size of 240 patients was calculated to identify a 15% absolute risk reduction of the primary outcome measure, which was the incidence of infection at day 7 after stroke. Secondary outcome measures were neurological outcome and mortality at day 90. RESULTS: Based on a preplanned futility analysis, the study was interrupted prematurely when 136 patients had been included. Levofloxacin and placebo patients had a cumulative rate of infection of 6% and 6% (P=0.96) at day 1; 10% and 12% (P=0.83) at day 2; 12% and 15% (P=0.66) at day 3; 16% and 19% (P=0.82) at day 7; and 30% and 33% (P=0.70), at day 90. Using logistic regression, favorable outcome at day 90 was inversely associated with baseline National Institutes of Health Stroke Scale (OR, 0.72; 95% CI, 0.59 to 0.89; P=0.002) and allocation to levofloxacin (OR, 0.19; 95% CI, 0.04 to 0.87; P=0.03). CONCLUSIONS: Prophylactic administration of levofloxacin (500 mg/100 mL/day for 3 days) is not better than optimal care for the prevention of infections in patients with acute stroke

Abstract: The suitability of new drugs for use in the general population in terms of risk and benefit is assessed by the health authorities through their drug agencies. These agencies regulate the entry of drugs on the market and their conditions for use according to strict criteria of quality, safety and efficacy. To preserve the principle of transparency, the requirements are previously published as guidelines, which are freely available on the Internet. All these guidelines have the following basic recommendations in common: (a) appropriate methodology for the objective, defined in detail a priori, (b) traceability, (c) verification of the appropriateness of the methodology applied, (d) justification of any deviation from the initial plan and (e) demonstration of the robustness of the results in distinct scenarios. Regulatory guidelines differ from other methodological references in their emphasis on the practical issues of the design and performance of studies, accepted methodological principles, and systems to ensure quality assurance in research. Although these requirements might not be universally applied to all types of research, the guidelines are freely available and are a good reference for the authorship, review and publication of clinical trials. The present article aims to review some of the guidelines that could be especially useful.

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Abstract: The suitability of new drugs for use in the general population in terms of risk and benefit is assessed by the health authorities through their drug agencies. These agencies regulate the entry of drugs on the market and their conditions for use according to strict criteria of quality, safety and efficacy. To preserve the principle of transparency, the requirements are previously published as guidelines, which are freely available on the Internet. All these guidelines have the following basic recommendations in common: (a) appropriate methodology for the objective, defined in detail a priori, (b) traceability, (c) verification of the appropriateness of the methodology applied, (d) justification of any deviation from the initial plan and (e) demonstration of the robustness of the results in distinct scenarios. Regulatory guidelines differ from other methodological references in their emphasis on the practical issues of the design and performance of studies, accepted methodological principles, and systems to ensure quality assurance in research. Although these requirements might not be universally applied to all types of research, the guidelines are freely available and are a good reference for the authorship, review and publication of clinical trials. The present article aims to review some of the guidelines that could be especially useful

Abstract: Background Aspirin is the standard treatment for secondary prevention of stroke and other vascular events. Several studies suggest that triflusal may have a better safety profile. Objectives To determine in people at high risk of vascular events whether triflusal is an effective and safe treatment for primary and secondary prevention of serious vascular events. Search strategy We searched the trials registers of the following Cochrane Review Groups: Stroke Group ( last searched October 2004), Heart Group, Peripheral Vascular Diseases Group and Metabolic and Endocrine Disorders Group ( last searched May 2003). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2, 2003), MEDLINE (1977 to 2003) and EMBASE ( 1980 to 2003). We searched reference lists and contacted researchers in the field, authors of relevant trials and the drug manufacturer. Selection criteria Randomised and quasi-randomised studies comparing triflusal with placebo or aspirin in people at high risk of vascular events. Data collection and analysis Two authors independently assessed trial quality and extracted data. The primary outcome was a serious vascular event (non-fatal acute myocardial infarction ( AMI), non-fatal ischemic or hemorrhagic stroke, or vascular death). Other efficacy and safety measures collected were frequency of different vascular events, adverse events, minor and major hemorrhages. Main results ( 1) Aspirin versus triflusal: five studies enrolled patients with stroke or transient ischemic attack (TIA) ( 4 trials; 2944 patients; followed for 6 to 47 months) or AMI ( one trial; 2275 patients; followed for 35 days). Entry criteria were similar within each subgroup of patients. Patient groups were appropriately selected and well matched. The primary outcome in all trials was a composite outcome of vascular events. Trials had no important bias except in one study ( 217 patients). For the primary outcome of a serious vascular event there was no significant difference between triflusal and aspirin; the odds ratio ( OR) was 1.04 (95% confidence interval (CI) 0.87 to 1.23). Significant differences were found for frequency of hemorrhages, both minor (OR 1.60, 95% CI 1.31 to 1.95) and major (OR 2.34, 95% CI 1.58 to 3.46) and for non-hemorrhagic gastrointestinal adverse events (OR 0.84, 95% CI 0.75 to 0.95). Sensitivity analysis of well versus poorly allocated trials showed no significant differences. (2) Triflusal versus placebo: two trials enrolled patients with unstable angina ( 281 patients) or peripheral arteriopathy ( 122 patients), who were followed for 6 months. Triflusal was associated with a reduction in serious vascular events ( OR 2.29, 95% CI 1.01 to 5.19; OR greater than 1 favours triflusal) and with a higher frequency of adverse events (OR 1.68, 95% CI 1.00 to 2.80). Authors' conclusions No significant differences were found between triflusal and aspirin for secondary prevention of serious vascular events in patients with stroke or TIA and AMI. However, our review cannot exclude moderate differences in efficacy. Triflusal was associated with a lower risk of hemorrhagic complications

Abstract: Background: The significant value of tests used to certify the diagnosis of occupational asthma due to persulphate salts remains uncertain. Aims: To validate the specific inhalation challenge ( SIC) test for the diagnosis of occupational asthma. Methods: Eight patients with occupational asthma due to persulphate salts, eight patients with bronchial asthma who were never exposed to persulphate salts, and ten healthy subjects were studied. Clinical history taking, spirometry, bronchial challenge with methacholine, skin prick testing to common inhalant allergens and persulphate salts, total IgE levels, and SIC to potassium persulphate were carried out in all subjects. The SIC used increasing concentrations of potassium persulphate ( 5, 10, 15, and 30 g) mixed with 150 g of lactose. Patients tipped the mixture from one tray to another at a distance of 30 cm from the face for 10 minutes in a challenge booth. Results: The SIC was positive in all subjects with persulphate induced asthma and in one patient with bronchial asthma who had never been exposed to persulphate salts. Sensitivity was 100% (95% CI 67.6 to 100) and specificity was 87.5% ( 95% CI 52.9 - 97.8) when patients with occupational asthma due to persulphate salts were compared with those with bronchial asthma never exposed to persulphate salts. Conclusions: SIC to persulphate salts performed according to the protocol described appears to be useful for the diagnosis of occupational asthma secondary to inhalation of this substance

Abstract: Objective: Recent results from the D:A:D Study indicated that the incidence of myocardial infarction (MI) increased by 26% per year of exposure to combination antiretroviral treatment (CART). The present study was performed to investigate whether this risk was similar when including other cardio- and cerebro-vascular disease events (CCVE). Design: D:A:D is an international collaboration of 11 cohorts, following 23 468 HIV-infected patients prospectively at 188 clinics in 21 countries situated in Europe, USA and Australia. Methods: The end-point was the occurrence of a first CCVE during prospective follow-up, defined as the first of: acute MI, invasive cardiovascular procedures, stroke, or death from other cardiovascular disease. Relative rates (RR) for CCVE from Poisson regression models and 95% confidence intervals (CI) are reported. All models are adjusted for other risk factors for CCVE, including age, gender, ethnicity, family history, body mass index, and smoking status as well as cohort and HIV transmission group. Results: Over 36 145 person-years of follow-up, 207 patients experienced at least one CCVE (23.7% fatal). The first event was MI in 126 patients, invasive cardiovascular procedure in 39 patients, stroke in 38 patients, and death from other cardiovascular disease in four patients. The incidence of first CCVE was 5.7 per 1000 person-years [95% confidence interval (CI) 5.0-6.5] and increased with longer exposure to CART (RR per year of exposure, 1.26; 95% CI, 1.14-1.38; P < 0.0001). Conclusion: CART increases the risk of CCVD, and this increase is comparable with how CART affects the risk of MI. This finding is consistent with the hypothesis that atherosclerosis is a side-effect of CART. (C) 2004 Lippincott Williams Wilkins

Abstract: Background: It remains controversial whether exposure to combination antiretroviral treatment increases the risk of myocardial infarction. Methods: In this prospective observational study, we enrolled 23,468 patients from 11 previously established cohorts from December 1999 to April 2001 and collected follow-up data until February 2002. Data were collected on infection with the human immunodeficiency virus and on risk factors for and the incidence of myocardial infarction. Relative rates were calculated with Poisson regression models. Combination antiretroviral therapy was defined as any combination regimen of antiretroviral drugs that included a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Results: Over a period of 36,199 person-years, 126 patients had a myocardial infarction. The incidence of myocardial infarction increased with longer exposure to combination antiretroviral therapy (adjusted relative rate per year of exposure, 1.26 [95 percent confidence interval, 1.12 to 1.41]; P<0.001). Other factors significantly associated with myocardial infarction were older age, current or former smoking, previous cardiovascular disease, and male sex, but not a family history of coronary heart disease. A higher total serum cholesterol level, a higher triglyceride level, and the presence of diabetes were also associated with an increased incidence of myocardial infarction. Conclusions: Combination antiretroviral therapy was independently associated with a 26 percent relative increase in the rate of myocardial infarction per year of exposure during the first four to six years of use. However, the absolute risk of myocardial infarction was low and must be balanced against the marked benefits from antiretroviral treatment

Abstract: BACKGROUND AND PURPOSE: The efficacy of the antiplatelet agent triflusal for prevention of vascular events after stroke has been reported in a pilot study. However, there is a need to confirm those results in a larger study. METHODS: We performed a randomized, double-blind, multicenter study to test the efficacy of triflusal (600 mg/d) versus aspirin (325 mg/d) for prevention of vascular events in patients with stroke or transient ischemic attack (Triflusal versus Aspirin in Cerebral Infarction Prevention [TACIP]). We assessed a combined end point (incidence of nonfatal ischemic stroke, nonfatal acute myocardial infarction, or vascular death) as well as the incidence of these events separately and the incidence of major hemorrhage. RESULTS: Of 2113 patients, 1058 received triflusal and 1055 aspirin. The mean follow-up period was 30.1 months. The incidence of combined end point (13.1% for triflusal, 12.4% for aspirin) as well the survival analysis (hazard ratio [HR] for triflusal versus aspirin, 1.09; 95% CI, 0.85 to 1.38) showed no differences between groups. The incidence of nonfatal stroke (HR, 1.09; 95% CI, 0.82 to 1.44), nonfatal acute myocardial infarction (HR, 0.95; 95% CI, 0.46 to 1.98,) and vascular death (HR, 1.22; 95% CI, 0.75 to 1.96) was also similar. A significantly higher incidence of major hemorrhages in the aspirin group was recorded (HR, 0.48; 95% CI, 0.28 to 0.82). The overall incidence of hemorrhage was significantly lower in the triflusal group (16.7% versus 25.2%) (odds ratio, 0.76; 95% CI, 0.67 to 0.86; P<0.001). CONCLUSIONS: This study failed to show significantly superior efficacy of triflusal over aspirin in the long-term prevention of vascular events after stroke, but triflusal was associated with a significantly lower rate of hemorrhagic complications

Abstract: OBJECTIVES: To estimate the 3-year risk of myocardial infarction (MI) among participants in the Data Collection on Adverse Events of Anti-HIV Drugs (DAD) study. METHODS: Conventional cardiovascular risk equations were applied to baseline data from the DAD study to estimate the 3-year risk of MI. Best estimates were obtained by simply applying the risk equations, with upper and lower limits based on worst case and optimistic case scenarios. Three-year risks of AIDS or death were also estimated based on a prognostic scoring system for patients receiving antiretroviral (ARV) treatment, and on estimated AIDS rates in untreated people with HIV for those patients not on ARVs or if they were to cease ARVs. RESULTS: Analyses were based on 17 600 patients (24.3% female) recruited into the DAD study with baseline data and no previous MI. The overall 3-year risk of MI was estimated to be 0.72% (lower limit 0.35, upper limit 1.12%), corresponding to a total predicted 127 (65-197) MIs over a 3-year follow-up period. The risk was much greater for men than women (0.92% vs. 0.07%), with only three (2-8) MIs predicted in women. The 3-year risk of MI was estimated to increase from 0.30% (0.20-0.38%) in ARV naive patients to 1.07% (0.43-1.77%) in patients receiving ARVs from all three drug classes. The estimated 3-year risk of AIDS or death was in the range 6.2% to 11.1% in patients receiving ARVs if they continued treatment, and 22.5% to 29.4% if they ceased ARVs. DISCUSSION: These models suggest that although the increase in relative risk of MI as a result of ARV treatment may be as high as threefold in a worst case scenario, the absolute risk is modest with a best estimate of 3-year risk less than or equal to 1% in all groups of patients, and is outweighed by the benefits of ARV treatment in terms of reduced risk of AIDS and death in most patients. As estimates are based on models not validated for people receiving ARV drugs, all estimates should be interpreted cautiously

Abstract: The efficacy of the antiplatelet agent triflusal for prevention of vascular events after stroke has been reported in a pilot study. However, there is a need to confirm those results in a larger study.

Abstract: The aim of this study was to determine mortality in patients with sleep apnoea/hypopnoea syndrome (SANS) according to the treatments employed and comorbidity. An historical cohort of patients with SANS diagnosed at a university hospital between 1982 and 1992 and followed until 1996 was studied. From a total of 475 SANS patients, 444 (94%), with a mean+/-SD apnoea/hypopnoea index at diagnosis of 55+/-27, were located and included in the study. SANS treatments employed were: surgery (88), weight loss (134), continuous positive airway pressure (124) and 98 patients were not treated. By the end of follow-up, 49 patients had died. According to Cox regression analysis, mortality in treated patients was lower than in those not treated, but higher in those with a history of severe chronic obstructive pulmonary disease. Mortality in nontreated patients compared with that of the general population, adjusted for age and sex, showed excessive mortality, which decreased in treated patients. Stratification by age showed a greater mortality rate ratio in patients <50 yrs. These findings were maintained when mortality from cardiovascular causes was compared. In conclusion, a rise in mortality was found in nontreated sleep apnoea/hypopnoea syndrome patients compared with the general population, whereas mortality in those treated for sleep apnoea/hypopnoea syndrome did not differ significantly from that of the general population

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Abstract: Hypertension is an important cardiovascular risk factor and the goal of its pharmacologic treatment is to reduce morbidity and mortality. Treatment is usually initiated with a low dose of a single agent and titrated to a higher dose as required. As many as 50% of patients require the addition of a second agent to achieve satisfactory blood pressure control. The aim of this study was to assess the dose-response relationship of nitrendipine and enalapril alone or in fixed combination in the treatment of mild to moderate hypertension. A total of 496 patients were enrolled in a multicenter. randomized. double-blind, factorial-design, parallel-group clinical trial comparing placebo, nitrendipine (5, 10, and 20 mg) and enalapril (5, 10, and 20 mg) alone or in combination. After a single-blind, 2-week placebo run-in period, 414 patients whose diastolic blood pressure ranged between 90-109 mm Hg were randomly assigned to a treatment group. The combination of nitrendipine and enalapril, particularly regimens including nitrendipine 20 mg and enalapril 5 or 10 mg, were significantly superior to both monotherapies; mean diastolic blood pressure reductions from baseline to last visit were -12.5 and -14.3 mm Hg, respectively. Response surface analysis provided further evidence that these combinations were optimal in terms of anti-hypertensive efficacy. All treatments were well tolerated and the incidence of adverse events did not differ significantly between groups. In summary, the anti-hypertensive efficacy of the combination was found to be superior to both monotherapies at any doses. The dose combination achieving the greatest blood pressure reduction was nitrendipine 20 mg and enalapril 10 mg

Abstract: Hypertension is an important cardiovascular risk factor and the goal of its pharmacologic treatment is to reduce morbidity and mortality. Treatment is usually initiated with a low dose of a single agent and titrated to a higher dose as required. As many as 50% of patients require the addition of a second agent to achieve satisfactory blood pressure control. The aim of this study was to assess the dose-response relationship of nitrendipine and enalapril alone or in fixed combination in the treatment of mild to moderate hypertension. A total of 496 patients were enrolled in a multicenter, randomized, double-blind, factorial-design, parallel-group clinical trial comparing placebo, nitrendipine (5, 10, and 20 mg) and enalapril (5, 10, and 20 mg) alone or in combination. After a single-blind, 2-week placebo run-in period, 414 patients whose diastolic blood pressure ranged between 90-109 mm Hg were randomly assigned to a treatment group. The combination of nitrendipine and enalapril, particularly regimens including nitrendipine 20 mg and enalapril 5 or 10 mg, were significantly superior to both monotherapies; mean diastolic blood pressure reductions from baseline to last visit were -12.5 and -14.3 mm Hg, respectively. Response surface analysis provided further evidence that these combinations were optimal in terms of anti-hypertensive efficacy. All treatments were well tolerated and the incidence of adverse events did not differ significantly between groups. In summary, the anti-hypertensive efficacy of the combination was found to be superior to both monotherapies at any doses. The dose combination achieving the greatest blood pressure reduction was nitrendipine 20 mg and enalapril 10 mg.

Abstract: Aims To compare the efficacy and tolerability of the antiplatelet agent triflusal with aspirin in the prevention of cardiovascular events following acute myocardial infarction. Methods and Results In this double-blind, multicentre, sequential design study, patients were randomized within 24h of acute myocardial infarction symptom onset to receive triflusal 600 mg or aspirin 300 mg once daily for 35 days. The primary end-point was death, non-fatal myocardial reinfarction or a non-fatal cerebrovascular event. The incidences of these individual outcomes and urgent revascularization were secondary end-points. The null hypothesis of no difference between treatments in the primary combined end-point was accepted with 80% power after recruiting 2124 validated patients (odds ratio (OR) for failure [95% confidence interval (CI)]: 0.882 [0.634-1227]). Non-fatal cerebrovascular events were significantly less frequent with triflusal (OR [95% CI]: 0.364 [0.146-0.908]; P=0.030). There was no significant difference between treatments for death (OR [95% CI]: 0.816 [0.563-1.179]; P=0.278), non-fatal reinfarction (OR [95% CI]: 1.577 [0.873-2.848]; P=0.131) or revascularization (OR [95% CI]: 0.864 [0.644-1.161]; P=0.334). Overall, both drugs were well tolerated, although there was a trend towards fewer bleeding episodes with triflusal; significantly fewer central nervous system bleeding episodes were observed in triflusal-treated patients (0.27% vs 0.97%; P=0.033). Conclusion Triflusal and aspirin have similar efficacy in preventing further cardiovascular events after acute myocardial infarction, but triflusal showed a more favourable safety profile. Triflusal significantly reduced the incidence of non-fatal cerebrovascular events compared with aspirin. (C) 2000 The European Society of Cardiology

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Abstract: Background: Dexketoprofen trometamol (DKP.TRIS) is the tromethamine salt of dexketoprofen, the S-enantiomer responsible for the pharmacological activity of ketoprofen. DKP.TRIS has rapid absorption and onset of action in pain relief. Objective: To compare the efficacy and tolerability of DKP.TRIS and diclofenac, a nonsteroidal anti-inflammatory drug widely accepted as reference therapy for symptomatic treatment of osteoarthritis, in patients with chronic pain due to knee osteoarthritis. Design: This was a multicentre, randomised, comparative, double-blind study. Methods: Radiological evidence of osteoarthritis, shown by the presence of Kellgren grade 2 to 4 changes, was required. Patients were evaluated before and after a washout period of 7 to 14 days and after 1 and 2 weeks of treatment with DKP.TRIS 25mg three times daily orally or diclofenac 50mg three times daily orally. Primary end-points were reduction of pain measured on a visual analogue scale (VAS, 0 to 100mm) and disability measured by the Lequesne index of severity for knee osteoarthritis (ISK). Tolerability was evaluated by laboratory parameters and frequency and nature of adverse events. Results: Of 117 patients recruited to the study, 115 were treated (61 with DKP.TRIS, 54 with diclofenac) and 99 (54/45) completed the 2-week treatment period. Patient characteristics were homogenous between groups. Pain measured on the VAS decreased by 43% from 61.7 +/- 18.5mm (mean +/- SD) at baseline to 34.7 +/- 22.3mm at the end of treatment with DKP.TRIS compared with a 29% decrease from 62.1 +/- 22..7mm to 40.6 +/- 22.2mm for diclofenac [p = 0.027; 95% confidence interval (CI) for the difference between treatments: 1.7, 27.9]. Median [SK scores improved from 11 (range 9 to 12 to 8 (6 to 10) in the DKP.TRIS group versus 10.75 (9 to 12.5) to 8.5 (6 to 10.5) in the diclofenac group. There were no group differences for secondary end-points. Adverse events were comparable overall between groups. Conclusion: Oral DKP.TRIS 25 mg three times daily is at least as effective as diclofenac 50mg three times daily for the short term treatment of pain in patients with osteoarthritis of the knee

Abstract: AIMS: To compare the efficacy and tolerability of the antiplatelet agent triflusal with aspirin in the prevention of cardiovascular events following acute myocardial infarction. METHODS AND RESULTS: In this double-blind, multicentre, sequential design study, patients were randomized within 24 h of acute myocardial infarction symptom onset to receive triflusal 600 mg or aspirin 300 mg once daily for 35 days. The primary end-point was death, non-fatal myocardial reinfarction or a non-fatal cerebrovascular event. The incidences of these individual outcomes and urgent revascularization were secondary end-points. The null hypothesis of no difference between treatments in the primary combined end-point was accepted with 80% power after recruiting 2124 validated patients (odds ratio (OR) for failure [95% confidence interval (CI)]: 0.882 [0.634-1.227]). Non-fatal cerebrovascular events were significantly less frequent with triflusal (OR [95% CI]: 0.364 [0.146-0.908]; P = 0.030). There was no significant difference between treatments for death (OR [95% CI]: 0.816 [0.564-1.179]; P = 0.278), non-fatal reinfarction (OR [95% CI]: 1.577 [0.873-2.848]; P = 0.131) or revascularization (OR [95% CI]: 0.864 [0.644-1.161]; P = 0.334). Overall, both drugs were well tolerated, although there was a trend towards fewer bleeding episodes with triflusal; significantly fewer central nervous system bleeding episodes were observed in triflusal-treated patients (0.27% vs. 0.97%; P = 0.033). CONCLUSION:Triflusal and aspirin have similar efficacy in preventing further cardiovascular events after acute myocardial infarction, but triflusal showed a more favourable safety profile. Triflusal significantly reduced the incidence of non-fatal cerebrovascular events compared with aspirin.

Abstract: Dexketoprofen, the active enantiomer of the racemic compound ketoprofen, is a new nonsteroidal antiinflammatory drug (NSAID) of the arylpropionate family. The efficacy and safety of dexketoprofen trometamol were compared with the equivalent enantiomeric dose of ketoprofen in a multicenter, randomized, double-blind 3-week trial of adult outpatients with pain due to osteoarthritis of the knee. After a washout period of 7-15 days, patients were randomly assigned to receive either dexketoprofen trometamol 25 mg tid (N = 89) or ketoprofen 50 mg tid (N = 94). Of the 183 patients enrolled, two were lost to follow up. At the end of treatment (3 weeks), the main efficacy outcome measures were significantly better in the dexketoprofen trometamol group than in the ketoprofen group. In addition, overall physician assessment indicated that 75% of the dexketoprofen group had improved compared with 50% of the ketoprofen patients. There were fewer adverse events in the dexketoprofen treatment group, but the difference did not reach statistical significance. These results demonstrate that dexketoprofen trometamol 25 mg tid is more effective than ketoprofen 50 mg tid in shortterm symptomatic treatment of knee osteoarthritis and suggest that the tolerability of dexketoprofen trometamol is more favorable than ketoprofen. Therefore, the substitution of dexketoprofen for racemic ketoprofen may be advantageous in clinical practice. Journal of Clinical Pharmacology, 1998;38:74S-80S (C) 1998 The American College of Clinical Pharmacology

Abstract: Dexketoprofen, the pure S(+)-enantiomer of ketoprofen, is a promising new analgesic, but few clinical trials have yet examined its efficacy and tolerability. In this study, patients with a history of primary dysmenorrhea were treated with dexketoprofen doses of 12.5 and 25 mg, ketoprofen 50 mg, and placebo using a randomized, four-way crossover design. Efficacy analyses showed that dexketoprofen 12.5 and 25 mg and racemic ketoprofen 50 mg significantly reduced pain intensity compared with placebo from 1 h after dose to 4-6 h after dose. Interestingly, dexketoprofen at 12.5 mg was significantly superior to placebo at 30 min after dose. Mean pain relief scores also demonstrated that both doses of dexketoprofen and racemic ketoprofen were significantly superior to placebo at 1-6 h after the first dose. No indices of analgesic efficacy showed any significant differences between the two doses of dexketoprofen or between dexketoprofen and ketoprofen. After repeated dose administration, similar results were obtained. There were no significant effects of any treatment on activities of daily living, menstrual flow, or associated symptoms. Dexketoprofen was effective, well tolerated, and had no difference in the incidence of adverse events compared to ketoprofen or placebo.

Abstract: Dexketoprofen, the pure S(+)-enantiomer of ketoprofen, is a promising new analgesic, but few clinical trials have yet examined its efficacy and tolerability. In this study, patients with a history of primary dysmenorrhea were treated with dexketoprofen doses of 12.5 and 25 mg, ketoprofen 50 mg, and placebo using a randomized, four-way crossover design. Efficacy analyses showed that dexketoprofen 12.5 and 25 mg and racemic ketoprofen 50 mg significantly reduced pain intensity compared with placebo from 1 h after dose to 4-6 h after dose. Interestingly, dexketoprofen at 12.5 mg was significantly superior to placebo at 30 min after dose. Mean pain relief scores also demonstrated that both doses of dexketoprofen and racemic ketoprofen were significantly superior to placebo at 1-6 h after the first dose. No indices of analgesic efficacy showed any significant differences between the two doses of dexketoprofen or between dexketoprofen and ketoprofen. After repeated dose administration, similar results were obtained. There were no significant effects of any treatment on activities of daily living, menstrual flow, or associated symptoms. Dexketoprofen was effective, well tolerated, and had no difference in the incidence of adverse events compared to ketoprofen or placebo. Journal of Clinical Pharmacology, 1998;38:65S-73S (C) 1998 The American College of Clinical Pharmacology

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Abstract: PURPOSE: To compare the intraoperative complications of planned extracapsular cataract extraction (ECCE) with those of manual nucleofragmentation. SETTING: Hospital de la Esperanza, Universitat Autonoma de Barcelona, Spain. METHODS: This retrospective study comprised 567 eyes; 444 had planned ECCE and 123, manual nucleofragmentation through a scleral tunnel incision. RESULTS: No significant differences between techniques were found in terms of intraoperative complications (P < .05). Manual nucleofragmentation did not increase the risk of intraoperative complications (P < .05). CONCLUSIONS: Although phacoemulsification is the procedure of choice in many cases, manual nucleofragmentation is a safe and valid alternative that achieves the goals of small incision cataract surgery

Abstract: The authors propose a method to perform a combined analysis of matched and unmatched case-control studies that is based on an adaptation of logistic regression and can be performed using standard software. This methodology can be used to do pooled analyses of studies with different designs. Likelihood ratio tests can be performed to assess association, heterogeneity, or trend. The standard errors of the coefficients allow the derivation of a Wald test and the calculation of confidence intervals. Another application is to compare relative risk estimators for the same risk factors studied in different phases of a disease in an effort to explore factors that may be more important in one phase than in another. Interaction terms of risk factors with variables that code the different pooled studies can be used for this purpose. The advantage of using this method is that a formal statistical comparison can be performed in which the regression coefficients of the interaction terms estimate the relative differences in risk (odds ratio ratios) between the studies. This estimation can be adjusted for other confounder factors. Two examples of application using data from case-control studies on cervical cancer and colorectal cancer are presented to illustrate the use of this epidemiologic method.

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Abstract: Purpose: To compare the intraoperative complications of planned extracapsular cataract extraction (ECCE) with those of manual nucleofragmentation. Setting: Hospital de la Esperanza, Universitat Autonoma de Barcelona, Spain, Methods: This retrospective study comprised 567 eyes; 444 had planned ECCE and 123, manual nucleofragmentation through a scleral tunnel incision. Results: No significant differences between techniques were found in terms of intraoperative complications (P < .05). Manual nucleofragmentation did not increase the risk of intraoperative complications (P < .05). Conclusions: Although phacoemulsification is the procedure of choice in many cases, manual nucleofragmentation is a safe and valid alternative that achieves the goals of small incision cataract surgery

Abstract: Dexketoprofen (S(+)-2-(3-benzoylphenyl)propionic acid) is the active enantiomer of ketoprofen, a racemic nonsteroidal anti-inflammatory drug with proven analgesic activity in the treatment of pain, including acute pain after dental surgery. To aim of this randomised, double-blind study was to compare the analgesic efficacy of single oral doses (5, 10 and 20mg) of the tromethamine salt of dexketoprofen (DKP.TRIS) [equivalent to 3.5, 7 and 14mg of dexketoprofen, respectively] with that of placebo in the dental pain model. Ibuprofen (400mg) was used to validate the model. A total of 206 patients experiencing moderate to severe pain after surgical removal of the impacted third molar tooth under local anaesthesia were entered in this trial at 2 centers. Patients rated their pain intensity and pain relief on verbal rating and visual analogue scales at regular intervals during the 6-hour period after drug administration. Patients were also requested to provide a global evaluation of treatment efficacy at the end of the observation period. DKP.TRIS (10 and 20mg) and ibuprofen were superior to placebo as determined by significantly higher values for the sum of the pain intensity difference scores and total pain relief scores from baseline. Furthermore, the time to reduce baseline pain by at least 50% was significantly more rapid in patients treated with DKP.TRIS (10 and 20mg) and ibuprofen than in placebo recipients. The mean time to remedication with rescue analgesia was significantly longer in all active treatment groups compared with placebo. DKP.TRIS was well tolerated, with a reported incidence of adverse events similar to that of placebo. No serious adverse events were reported incidence of adverse events similar to that of placebo. No serious adverse events were reported in any treatment group. The results of this study suggest that DKP.TRIS is an effective analgesic with a favourable tolerability profile for the treatment of acute pain states

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Abstract: The authors propose a method to perform a combined analysis of matched and unmatched case-control studies that is based on an adaptation of logistic regression and can be performed using standard software, This methodology can be used to do pooled analyses of studies with different designs. Likelihood ratio tests can be performed to assess association, heterogeneity, or trend, The standard errors of the coefficients allow the derivation of a Wald test and the calculation of confidence intervals, Another application is to compare relative risk estimators for the same risk factors studied in different phases of a disease in an effort to explore factors that may be more important in one phase than in another. Interaction terms of risk factors with variables that code the different pooled studies can be used for this purpose. The advantage of using this method is that a formal statistical comparison can be performed in which the regression coefficients of the interaction terms estimate the relative differences in risk (odds ratio ratios) between the studies, This estimation can be adjusted for other confounder factors, Two examples of application using data from case-control studies on cervical cancer and colorectal cancer are presented to illustrate the use of this epidemiologic method

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Abstract:

Abstract: 1 Thromboembolic disease (TED) is an important cause of in-hospital morbidity and mortality. Although different prophylactic approaches have been shown to be effective and cost-effective, surveys have suggested that they are underused. The aim of this study was to estimate the prevalence of use of TED prophylaxis in our hospitals. 2 All patients admitted on a specified day to the Internal Medicine and General Surgery wards of seven Spanish university hospitals were included in the study. They were identified cross-sectionally and followed up until discharge or for 15 days. Information about the following variables was collected: risk factors for venous thromboembolism, prophylactic measures used (if any), contraindications to the use of each specific drug or other prophylactic measure, and dosage schedule of the drug used, if any. 3 Nine hundred and thirty-nine patients (53% men) were studied. The most common risk factors for venous thromboembolism were: age greater than or equal to 40 years (802; 85%), major surgery (298; 32%), immobilization greater than or equal to 6 days (285; 30%), obesity (241; 26%), and cancer (202; 22%). 4 Prophylactic measures were used in 320 patients (34%). Of these, 297 (93%) received heparin, mainly as low molecular weight heparins (248, 78%); physical measures were rarely used. 5 Five hundred and eighty-three patients (62%) fulfilled criteria for moderate or high risk of venous thromboembolism; only 275 (47%) of them received any form of prophylaxis. 6 In a multivariate analysis the following variables were associated with the use of prophylaxis: hospital centre (adjusted odds ratios, 1.7 to 23.3, compared with reference hospital), history of venous thrombosis, major surgery, congestive heart failure, inflammatory bowel disease, age, immobilization, dehydration, and obesity. 7 Contraindications to the use of anticoagulant or antiplatelet drugs were present in 234 patients (25%), but no relationship to the use of heparin was found. Of the patients treated with heparin who underwent major surgery, only 55 (36%) had received a preoperative dose. 8 Although prophylaxis of TED was associated with certain risk factors, it was highly underused in moderate and high risk patients. Wide interhospital variability in the use of prophylaxis was recorded; this variability persisted after adjusting for differences in the prevalence of risk factors and for the presence of contraindications in each centre. Low molecular weight heparins are replacing conventional unfractionated heparin for this indication

Abstract: 1. Thromboembolic disease (TED) is an important cause of in-hospital morbidity and mortality. Although different prophylactic approaches have been shown to be effective and cost-effective, surveys have suggested that they are underused. The aim of this study was to estimate the prevalence of use of TED prophylaxis in our hospitals. 2. All patients admitted on a specified day to the Internal Medicine and General Surgery wards of seven Spanish university hospitals were included in the study. They were identified cross-sectionally and followed up until discharge or for 15 days. Information about the following variables was collected: risk factors for venous thromboembolism, prophylactic measures used (if any), contraindications to the use of each specific drug or other prophylactic measure, and dosage schedule of the drug used, if any. 3. Nine hundred and thirty-nine patients (53% men) were studied. The most common risk factors for venous thromboembolism were: age > or = 40 years (802; 85%), major surgery (298; 32%), immobilization > or = 6 days (285; 30%), obesity (241; 26%), and cancer (202; 22%). 4. Prophylactic measures were used in 320 patients (34%). Of these, 297 (93%) received heparin, mainly as low molecular weight heparins (248, 78%); physical measures were rarely used. 5. Five hundred and eighty-three patients (62%) fulfilled criteria for moderate or high risk of venous thromboembolism; only 275 (47%) of them received any form of prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: The case of a patient with acute renal failure and anemia, preceded by anterior uveitis in both eyes, is presented. Renal histopathology showed a predominantly lymphocytic interstitial infiltrate with immunoglobulin G deposits at the basal tubular membrane level A remarkably normal glomerular pattern was present. After a four month course of prednisone therapy, a total recovery of the renal function and the anemia was observed. Uveitis although having relapsing course finally disappeared

Abstract: Cough is one of the possible untoward adverse drug effects of angiotensin converting enzyme inhibitors. We describe the available information on 50 cough episodes attributable to captopril and 18 episodes attributable to enalapril reported to the Spanish Drug Surveillance System. Cough represented 37 % and 39 % of the reports of side effects of captopril and enalapril, respectively. There was a remarkable female predominance among the patients with cough. Cough developed at very low doses (15 mg of captopril and 5 mg of enalapril daily), although the patients on captopril who developed cough were receiving higher doses than those who presented other side effects. A high proportion of patients (29 %) continued with the drug for more than six months after cough had developed, suggesting the need for a wider knowledge of this side effect

Abstract:

Abstract: Cough is one of the possible untoward adverse drug effects of angiotensin converting enzyme inhibitors. We describe the available information on 50 cough episodes attributable to captopril and 18 episodes attributable to enalapril reported to the Spanish Drug Surveillance System. Cough represented 37% and 39% of the reports of side effects of captopril and enalapril, respectively. There was a remarkable female predominance among the patients with cough. Cough developed at very low doses (15 mg of captopril and 5 mg of enalapril daily), although the patients on captopril who developed cough were receiving higher doses than those who presented other side effects. A high proportion of patients (29%) continued with the drug for more than six months after cough had developed, suggesting the need for a wider knowledge of this side effect.