Population Pharmacokinetic Analysis of Perampanel in Portuguese Patients Diagnosed with Refractory Epilepsy.

Perampanel is a promising antiepileptic drug (AED) for refractory epilepsy treatment due to its innovative mechanism of action. This study aimed to develop a population pharmacokinetic (PopPK) model to be further used in initial dose optimization of perampanel in patients diagnosed with refractory epilepsy. A total of seventy-two plasma concentrations of perampanel obtained from forty-four patients were analyzed through a population pharmacokinetic approach by means of nonlinear mixed effects modeling (NONMEM). A one-compartment model with first-order elimination best described the pharmacokinetic profiles of perampanel. Interpatient variability (IPV) was entered on clearance (CL), while the residual error (RE) was modeled as proportional. The presence of enzyme-inducing AEDs (EIAEDs) and body mass index (BMI) were found as significant covariates for CL and volume of distribution (V), respectively. The mean (relative standard error) estimates for CL and V of the final model were 0.419 L/h (5.56%) and 29.50 (6.41%), respectively. IPV was 30.84% and the proportional RE was 6.44%. Internal validation demonstrated an acceptable predictive performance of the final model. A reliable population pharmacokinetic model was successfully developed, and it is the first enrolling real-life adults diagnosed with refractory epilepsy.

Predicted Environmental Risk Assessment of Antimicrobials with Increased Consumption in Portugal during the COVID-19 Pandemic; The Groundwork for the Forthcoming Water Quality Survey.

The environmental release of antimicrobial pharmaceuticals is an imminent threat due to ecological impacts and microbial resistance phenomena. The recent COVID-19 outbreak will likely lead to greater loads of antimicrobials in the environment. Thus, identifying the most used antimicrobials likely to pose environmental risks would be valuable. For that, the ambulatory and hospital consumption patterns of antimicrobials in Portugal during the COVID-19 pandemic (2020-2021) were compared with those of 2019. A predicted risk assessment screening approach based on exposure and hazard in the surface water was conducted, combining consumption, excretion rates, and ecotoxicological/microbiological endpoints in five different regions of Portugal. Among the 22 selected substances, only rifaximin and atovaquone demonstrated predicted potential ecotoxicological risks for aquatic organisms. Flucloxacillin, piperacillin, tazobactam, meropenem, ceftriaxone, fosfomycin, and metronidazole showed the most significant potential for antibiotic resistance in all analysed regions. Regarding the current screening approach and the lack of environmental data, it is advisable to consider rifaximin and atovaquone in subsequent water quality surveys. These results might support the forthcoming monitorisation of surface water quality in a post-pandemic survey.

Mycotoxins in Rice Correlate with Other Contaminants? A Pilot Study of the Portuguese Scenario and Human Risk Assessment.

Rice is the second most important cereal crop and is vital for the diet of billions of people. However, its consumption can increase human exposure to chemical contaminants, namely mycotoxins and metalloids. Our goal was to evaluate the occurrence and human exposure of aflatoxin B1 (AFB1), ochratoxin A (OTA), zearalenone (ZEN), and inorganic arsenic (InAs) in 36 rice samples produced and commercialized in Portugal and evaluate their correlation. The analysis of mycotoxins involved ELISA, with limits of detection (LODs) of 0.8, 1 and 1.75 µg kg-1 for OTA, AFB1, and ZEN, respectively. InAs analysis was carried out by inductively coupled plasma mass spectrometry (ICP-MS; LOD = 3.3 µg kg-1). No sample showed contamination by OTA. AFB1 was present in 2 (4.8%) samples (1.96 and 2.20 µg kg-1), doubling the European maximum permitted level (MPL). Concerning ZEN, 88.89% of the rice samples presented levels above the LOD up to 14.25 µg kg-1 (average of 2.75 µg kg-1). Regarding InAs, every sample presented concentration values above the LOD up to 100.0 µg kg-1 (average of 35.3 µg kg-1), although none surpassed the MPL (200 µg kg-1). No correlation was observed between mycotoxins and InAs contamination. As for human exposure, only AFB1 surpassed the provisional maximum tolerable daily intake. Children were recognized as the most susceptible group.

Quality of records in clinical forms of childbirth in the Maternity Hospital of Lubango, Angola / Calidad de los registros en las formas clínicas del parto en el Hospital Maternidad de Lubango, Angola

Objective: To describe the quality of clinical records of deliveries and births by quantitative assessing the unfilled variables in birth data collection forms and their implications at Maternity Hospital, in the municipality of Lubango, Angola. Method: The study was conducted from January to August 2018. It adopted a quantitative research design, analysed variables not filled in a total of 202 birth record forms collected for 3 months (secondary data). Results: The findings revealed that 80% of the sections of the entire set of information about obstetrical history were not filled in. This occurred with a relatively high frequency resulting in some of the relevant variables being left blank, such as antenatal diagnosis (94%) and the number of last menstruation (91%). Conclusions: The rate of missing fundamental information from the clinical birth record are high. This result has important implications in evaluating the quality of data and may, consequently, jeopardize: 1) the evaluation of the prenatal assistance, 2) the clinical assistance at delivery, and 3) decision-making for preventive and intervening procedures. (AU)

Objetivo: Describir la calidad de los registros clínicos de partos y nacimientos mediante la evaluación cuantitativa de las variables no cumplimentadas en los formularios de recolección de datos de nacimiento y sus implicaciones en el Hospital de Maternidad de Lubango, Angola. Método: El estudio se realizó de enero a agosto de 2018. Adoptó un diseño de investigación cuantitativa y analizó variables no cumplimentadas en un total de 202 registros de nacimiento recolectados durante 3 meses (datos secundarios). Resultados: Los hallazgos revelaron que el 80% de las secciones de todo el conjunto de información sobre la historia obstétrica no se completaron. Esto ocurrió con una frecuencia relativamente alta, lo que provocó que algunas de las variables relevantes se dejaran en blanco, como el diagnóstico prenatal (94%) y el número de la última menstruación (91%). Conclusiones: La tasa de falta de información fundamental en el registro clínico de nacimientos es alta. Estos resultados tienen implicaciones importantes en la evaluación de la calidad de los datos y, en consecuencia, pueden poner en peligro: 1) la evaluación de la asistencia prenatal, 2) la asistencia clínica al parto y 3) la toma de decisiones para los procedimientos preventivos e intervinientes. (AU)

Clinical Application of Pharmacokinetics to Appraise Adherence to Levetiracetam in Portuguese Epileptic Patients.

Adherence to antiseizure drug treatment determines its effectiveness and safety, and consequently affects patients' quality of life. Herein, we assessed adherence to levetiracetam in Portuguese patients with refractory epilepsy (n = 115), with resort to a pharmacokinetic drug monitoring approach. The pharmacokinetic parameters of levetiracetam in each patient were determined in steady-state while admitted to the hospital. Then, adherence was assessed by comparing the plasma concentration of the drug observed on the first day of hospitalization with the predicted plasma concentration, considering previously determined pharmacokinetic parameters. The rate of adherence was assessed according to gender, age, diagnosis, and antiseizure drug regimen. Among 115 enrolled patients, 49 (42.6%) were identified as non-adherent, 30 (26.1%) classified as under-consumers, and 19 (16.5%) as over-consumers. A relationship between adherence, daily dose and plasma concentrations was herein reported for the first time. Adherent patients received higher daily doses of levetiracetam [2500 (2000-3000) mg] than non-adherent over-consumers [1500 (1000-2000) mg] and non-adherent under-consumers [2000 (1500-3000) mg]. Higher average steady-state plasma concentrations of levetiracetam were found in non-adherent under-consumers [27.28 (15.33-36.36) mg/L], followed by adherent patients [22.05 (16.62-29.81) mg/L] and non-adherent over-consumers [17.50 (10.69-24.37) mg/L]. This study demonstrates that adherence (or lack thereof) influences the plasma concentrations of levetiracetam in steady-state and its pharmacological effects. Moreover, it emphasizes the importance of educating patients to encourage adherence to therapy. Otherwise, the risk of developing toxic and subtherapeutic concentrations is undeniable, compromising the therapeutic effect and safety of treatment.

Quality of records in clinical forms of childbirth in the Maternity Hospital of Lubango, Angola.

OBJECTIVE: To describe the quality of clinical records of deliveries and births by quantitative assessing the unfilled variables in birth data collection forms and their implications at Maternity Hospital, in the municipality of Lubango, Angola. METHOD: The study was conducted from January to August 2018. It adopted a quantitative research design, analysed variables not filled in a total of 202 birth record forms collected for 3 months (secondary data). RESULTS: The findings revealed that 80% of the sections of the entire set of information about obstetrical history were not filled in. This occurred with a relatively high frequency resulting in some of the relevant variables being left blank, such as antenatal diagnosis (94%) and the number of last menstruation (91%). CONCLUSIONS: The rate of missing fundamental information from the clinical birth record are high. This result has important implications in evaluating the quality of data and may, consequently, jeopardize: 1) the evaluation of the prenatal assistance, 2) the clinical assistance at delivery, and 3) decision-making for preventive and intervening procedures.

Assessing the Use of Hospital Information Systems (HIS) to Support Decision-Making: A Cross-Sectional Study in Public Hospitals in the Huíla Health Region of Southern Angola.

Hospital information systems could be relevant tools to inform hospital managers, support better management decisions in healthcare, and increase efficiency. Nonetheless, hospital managers' effective use of these systems to support decision-making in Angola is unknown. Our study aimed to analyse the use of hospital information systems as a tool to support decision-making by hospital managers in Huíla, Angola. It was a descriptive, cross-sectional study inducted between July and September 2017 in seven hospitals in Huíla Province, Angola, specifically in the cities of Lubango and Matala. Thirty-six members of the hospital boards filled out a self-questionnaire that consisted of twenty questions based on the following issues: Characterisation of the interviewee's profile; availability of information in the institution; and quality and usefulness of the available operational information. At least two thirds of the participants reported being unsatisfied or relatively satisfied with each assessed hospital information systems-specific feature. More than 50% have rarely or never used the health information system to support decision-making. Most managers do not use hospital information systems to support management-related decision-making in Angola. Improving the ability of hospital information systems to compute adequate indicators and training for hospital managers could be targets for future interventions to support better management-related decision-making in Angolan healthcare.

Mycotoxins Exposure in Cabinda, Angola-A Pilot Biomonitoring Survey of Breastmilk.

Breast milk is considered the ideal form of nutrition for newborns and infants. However, it can carry over contaminants, namely mycotoxins, with biological effects to which this population is particularly vulnerable. Human biomonitoring and surveillance programs are particularly scarce in low-income countries, where food security is a more urgent priority in comparison with food safety. This pilot survey aims to assess exposure of breastfed infants to aflatoxin M1 (AFM1), zearalenone (ZEN), and ochratoxin A (OTA) in Angola, and to evaluate the main socio-demographical and food consumption determinants of lactating mothers. All 37 breast milk samples analyzed are found to be contaminated with ZEN and OTA, although none are found contaminated with AFM1. Contamination levels are lower than previously reported for ZEN but higher in the case of OTA. A significant association between ZEN levels in breast milk and the consumption of cookies by the lactating mothers is found. As for OTA, higher levels are observed in the milk from mothers with younger infants, for which high estimated daily intake (EDI) is determined. As far as the authors are aware, this is the first survey of the occurrence of mycotoxins in breast milk in Angola, so further human biomonitoring works should follow, given that mycotoxins are a global health issue that directly impact the health of populations.

Identification of Antibiotics in Surface-Groundwater. A Tool towards the Ecopharmacovigilance Approach: A Portuguese Case-Study.

Environmental monitoring, particularly of water, is crucial to screen and preselect potential hazardous substances for policy guidance and risk minimisation strategies. In Portugal, extensive data are missing. This work aimed to perform a qualitative survey of antibiotics in surface- groundwater, reflecting demographic, spatial, consumption and drug profiles during an observational period of three years. A passive sampling technique (POCIS) and high-resolution chromatographic system were used to monitor and analyse the antibiotics. The most frequently detected antibiotics were enrofloxacin/ciprofloxacin and tetracycline in surface-groundwater, while clarithromycin/erythromycin and sulfamethoxazole were identified only in surface water. The detection of enzyme inhibitors (e.g., tazobactam/cilastatin) used exclusively in hospitals and abacavir, a specific human medicine was also noteworthy. North (Guimarães, Santo Tirso and Porto) and South (Faro, Olhão and Portimão) Portugal were the regions with the most significant frequency of substances in surface water. The relatively higher detection downstream of the effluent discharge points compared with a low detection upstream could be attributed to a low efficiency in urban wastewater treatment plants and an increased agricultural pressure. This screening approach is essential to identify substances in order to perform future quantitative risk assessment and establishing water quality standards. The greatest challenge of this survey data is to promote an ecopharmacovigilance framework, implement measures to avoid misuse/overuse of antibiotics and slow down emission and antibiotic resistance.

Urine biomonitoring of glyphosate in children: Exposure and risk assessment.

The use of glyphosate has been increasing over the years, making it one of the most consumed herbicides in the world. Although children are considered a vulnerable population, only four previous published studies determined glyphosate in the urine of non-occupationally exposed children. The paucity of epidemiological data and biomonitoring surveys are considered major gaps, that hinder the implementation of science driven policies in the protection of public health. The aim of the present study was to determine glyphosate in the urine of 41 Portuguese children (2-13 years old) and identify potential determinants of exposure. Glyphosate was detected in 95.1% of the samples (1.77 ± 0.86 µg/L), up to a maximum value of 4.35 µg/L. Glyphosate concentrations were higher in the urine of children aged 7-9 years, living near agricultural areas (<1 km), with a higher percentage of consumption of home-produced foods, and whose parents applied herbicides in the backyard. Risk assessment revealed an exposure representing 1-5.58% of the established Acceptable Daily Intake (ADI) of glyphosate (0.5 mg/kg bw/day). The results should be further analyzed considering the age of the participants, for which no adjusted ADI exists. This was the first published report of glyphosate exposure in the urine of Portuguese children.

Pharmacokinetic Monitoring of Levetiracetam in Portuguese Refractory Epileptic Patients: Effect of Gender, Weight and Concomitant Therapy.

Levetiracetam is a second-generation antiepileptic drug, widely used in the treatment of focal and generalized epilepsy due to its pharmacokinetic and safety profiles. Its pharmacokinetic monitoring is ascribed as useful to personalize its dosing regimen. The aim of the present study was to describe, for the first time, the pharmacokinetics of levetiracetam in Portuguese refractory epileptic patients. Therefore, a retrospective study was carried out on 65 Portuguese refractory epileptic patients (pharmacokinetic study: 48; validation study: 17) admitted to the Refractory Epilepsy Centre of the Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal. The pharmacokinetic parameters of levetiracetam were estimated by applying a one-compartment model with first-order absorption and elimination analysis. Male patients showed higher distribution volume (Vd/F) and oral clearance (CL/F) than female patients (median Vd/F: 52.40 L in males and 38.60 L in females, p = 0.011; median CL/F: 4.71 L/h in males and 3.91 L/h in females, p = 0.028). Higher values of Vd/F (p = 0.026) and CL/F (p = 0.003) were also found in overweight patients relative to normal weight and obese patients. Carbamazepine was the co-administered antiepileptic drug that mostly affected the pharmacokinetics of levetiracetam, increasing both Vd/F (61.30 L with carbamazepine and 39.10 L without carbamazepine, p = 0.007) and CL/F (6.71 L/h with carbamazepine and 3.91 L/h without carbamazepine, p < 0.001). The pharmacokinetics of levetiracetam was affected by gender, body mass index, and co-administration of carbamazepine. This study highlights the impact of several factors on the CL/ and Vd/F of levetiracetam when administered to refractory epileptic patients. The importance of its pharmacokinetic monitoring in clinical pharmacy stands out, thereby enabling the optimization of antiepileptic drug therapy.

Utility assessment of an Enzyme-linked immunosorbent assay for detection of subclinical cases of caseous lymphadenitis in small ruminant flocks.

The actual prevalence of CLA (caseous lymphadenitis) in small ruminant flocks is underestimated in many countries, and because it is not a notifiable disease, it will continue to spread without data and information about its real economic impact. The difficulty in the accurate identification of the causative agent in internal subclinical cases allows the disease to spread within and between flocks. This research intends to assess the utility of an ELISA (enzyme-linked immunosorbent assay) test in the detection of internal subclinical cases of CLA in farms and to simultaneously add data on the seroprevalence of the disease in Portugal. Sera from 756 small ruminants, 70% sheep (528/756) and 30% goats (228/756) were screened for antibodies against Corynebacterium pseudotuberculosis using the ELISA technique based on a recombinant phospholipase D (ELITEST CLA # CK105A® ). The animals showing internal lesions (n êžŠ 58) were sampled for the identification of the aetiological agent. In this investigation, the prevalence of CLA was 34% (258/756), with the ELISA test showing a low specificity (78%) and high sensitivity (100%). The proof was able to detect 57% (13/23) of subclinical cases of CLA confirmed by postmortem examination and conventional PCR (polymerase chain reaction). The results also reveal that goats have a higher propensity for the disease, and dairy farms and non-extensive production units appear to be more susceptible to CLA. This research clarifies an actual problem and pointed out the importance of CLA in small ruminant herds in Portugal. Finally seems to demonstrate that the ELISA test is a good diagnostic tool for use in CLA eradication programmes.

Sleep-wake patterns reported by parents in hyperactive children diagnosed according to ICD-10, as compared to paired controls.

This study aimed primarily to compare the parent-reported sleep of children with ICD-10 hyperkinetic disorder (HKD) versus community children. Thirty children aged 5-13 years (83.3% boys) diagnosed with HKD by their child and adolescent psychiatrists took part in this study, plus 30 community children, matched for sex, age, and school year. Compared to the controls, the HKD children showed significantly later bedtimes, stronger bedtime resistance, longer sleep latency, shorter sleep; more frequent behaviors and symptoms concerning falling asleep into parents bed, needing something special to initiate sleep, nightmares, sleep talking, sleep bruxism, fear from darkness, bedwetting, and, most notably, loud snoring (26.7%); they also tended to show higher daytime somnolence. Attention deficit/hyperactivity disorder (ADHD)/HKD children may thus have more sleep-related problems than typically developing children. Alternatively, our results may reflect misdiagnoses; thus, special attention should be directed to comorbidity and differential diagnosis issues between sleep disturbances and ADHD/HKD.

A chiral liquid chromatography method for the simultaneous determination of oxcarbazepine, eslicarbazepine, R-licarbazepine and other new chemical derivatives BIA 2-024, BIA 2-059 and BIA 2-265, in mouse plasma and brain.

Recently, in silico models have been developed to predict drug pharmacokinetics. However, before application, they must be validated and, for that, information about structurally similar reference compounds is required. A chiral liquid chromatography method with ultraviolet detection (LC-UV) was developed and validated for the simultaneous quantification of BIA 2-024, BIA 2-059, BIA 2-265, oxcarbazepine, eslicarbazepine (S-licarbazepine) and R-licarbazepine in mouse plasma and brain. Compounds were extracted by a selective solid-phase extraction procedure and their chromatographic separation was achieved on a LiChroCART 250-4 ChiraDex column using a mobile phase of water-methanol (92:8, v/v) pumped at 0.7 mL/min. The UV detector was set at 235 nm. Calibration curves were linear (r(2) ≥ 0.996) over the concentration ranges of 0.2-30 µg/mL for oxcarbazepine, eslicarbazepine and R-licarbazepine; 0.2-60 µg/mL for the remaining compounds in plasma; and 0.06-15 µg/mL for all the analytes in brain homogenate. Taking into account all analytes at these concentration ranges in both matrices, the overall precision did not exceed 9.09%, and the accuracy was within ±14.3%. This LC-UV method is suitable for carrying out pharmacokinetic studies with these compounds in mouse in order to obtain a better picture of their metabolic pathways and biodistribution.

[Mental health of students of medicine: exploraty study in the Universidade da Beira Interior]. / A saúde mental de estudantes de medicina: estudo exploratório na Universidade da Beira Interior.

The objective of the present study was to investigate the relations between levels of mental health of medical students of the Universidade da Beira Interior, from a positive and negative point of view (psychological well-being and psychological distress) with sociodemographic factors, year of course and psychological support from an health professional. The cross-sectional and anonymous study consisted in an online application questionnaire, available between February and March of the year 2009, constituted of three sections: a) Socio-demographic data b) Mental Health Inventory (MHI) c) Psychological support. The results were analyzed on the statistical program SPSS version 17 for Windows and the significant results for p <0,05 had been considered. A total of 272 (49.3%) students answered the questionnaire, of which 215 were female. The basic cycle had significant low differences in psychological well-being. The females and the third-year of course had large independent and significant negative effects on psychological well-being and psychological distress. This study shows that 8.6% of the students with levels of mental health below the mean are followed by health professionals and 6% do pharmaceutical treatment. About 10% of all students already had self-medicated for symptoms related with mental health and these had significantly low scores in global Mental Health Inventory. This research shows that symptoms of distress appear to be particular important in female students and in the 1st and 3rd years and it is necessary to understand the causes and the consequences of this situation. Targeted interventions that promote psychological well-being during the medical formation, teaching students to recognize and deal with symptoms of distress and help them to understand when they need aid may be an effective way of dealing with this problem.

Recombinant human erythropoietin treatment protects the cardio-renal axis in a model of moderate chronic renal failure.

Chronic kidney disease (CKD) patients develop anemia because of the low kidney erythropoietin (EPO) production, thus promoting cardiovascular complications. The degree of renal insufficiency might determine the moment to start recombinant human erythropoietin (rhEPO) therapy, but the molecular basis for these options deserves better elucidation. This study aimed to clarify the cardio-renal effects of earlier rhEPO therapy in rats with moderate chronic renal failure (CRF). Four groups of rats were evaluated for 15 weeks (control; rhEPO - 50 IU/kg/week; CRF - 3/4 nephrectomy; CRF + rhEPO) to assess renal and hematology data, EPO levels, blood pressure, heart rate, peripheral catecholamines contents, serum-transforming growth factor-ß1 (TGF-ß1), kidney gene expression of EPO, Caspase 9 (Casp9), and vascular endothelial growth factor (Vegf). This model of moderate CRF showed moderate and corrected anemia, hypertension, tachycardia, sympathetic overactivity, and increased serum TGF-ß1 content. The remnant kidney showed a proliferative profile, with hypertrophy, downregulated gene expression of EPO, and upregulated gene expression of Vegf and Casp9. rhEPO treatment promoted erythrocytosis and prevented tachycardia and catecholamines increment, with a rise of serum TGF-ß1. Furthermore, the decreased kidney gene expression of EPO and the overexpression of Casp9 were prevented, demonstrating a renoprotective action on the remnant kidney. In conclusion, rhEPO therapy promotes a protective effect on the cardio-renal axis, which might be mainly attributed to its pro-proliferative and anti-apoptotic properties. These findings might recommend its use in earlier stages of CRF, acting as an erythropoiesis stimulating agent, to efficiently correct not only the anemia, one of the major complications in these patients, but also the succeeding adverse cardio-renal effects.

Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: no interference with carbamazepine and its metabolites.

As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

Frequency and functional activity of Th17, Tc17 and other T-cell subsets in Systemic Lupus Erythematosus.

To compare frequency and functional activity of peripheral blood (PB) Th(c)17, Th(c)1 and Treg cells and the amount of type 2 cytokines mRNA we recruited SLE patients in active (n=15) and inactive disease (n=19) and healthy age- and gender-matched controls (n=15). The study of Th(c)17, Th(c)1 and Treg cells was done by flow cytometry and cytokine mRNA by real-time PCR. Compared to NC, SLE patients present an increased proportion of Th(c)17 cells, but with lower amounts of IL-17 per cell and also a decreased frequency of Treg, but with increased production of TGF-beta and FoxP3 mRNA. Iotan active compared to inactive SLE, there is a marked decreased in frequency of Th(c)1 cells, an increased production of type 2 cytokines mRNA and a distinct functional profile of Th(c)17 cells. Our findings suggest a functional disequilibrium of T-cell subsets in SLE which may contribute to the inflammatory process and disease pathogenesis.

[Gastric carcinoma and chronic gastritis: epigenetic regulation of CDH1 (E-Cadherin), CDKN2A (p16INK4A), PTGS2 (COX-2) and EGFR genes through methylation]. / Carcinoma gástrico e gastrite crónica: regulação epigenética por metilação dos genes CDH1 (Caderina-E), CDKN2A (p16INK4A), PTGS2 (COX2) e EGFR.

The genetic and epigenetic alterations are being studied as one of the causes of gastric cancer (GC) progression and development. DNA methylation is an epigenetic alteration which leads to suppressor gene silencing and proto-oncogene activation, playing an important role in carcinogenesis. The histological types of gastric carcinoma have different genetic paths and the knowledge of the molecular bases of tumoral progression leads to diagnostic accuracy and attempted therapy. CDH1 (E-cadherin) and CDKN2A (p16(INK4A)) genes are thought to be tumoral suppressor genes and PTGS2 (COX-2) and genes are involved in tumour regulation and growth. In one hand, gene silencing as an epigenetic phenomenon, and in the other hand, gene expression enhancement due to possible demethylation, simultaneously, can facilitate carcinogénesis and tumoral progression. Our aim was to relate CDH1, p16(INK4A), COX-2 and EGFR genes DNA methylation with the several histological types of gastric carcinoma and chronic gastritis. We studied 55 formalin fixed paraffin embedded gastric biopsies: 35 were GC specimens (12 diffuse type, 15 intestinal type and 8 indeterminate type, according to Laurén's classification) and 20 samples had chronic gastritis (CG). The DNA was treated with sodium bisulfite after extraction and then performed Methylation Specific PCR (MSP). Statistical analysis was based on chi-square test and Exact Fisher's test. CpG island methylation was detected in 94% of the GC samples for CDH1, 91% for COX-2, 80% for p16(INK4A) and no methylation was detected in EGFR gene (0%). In CG, CpG island methylation was found in 100% for CDH1 and COX-2 genes, 90% for p16(INK4A) and 20% for EGFR. These results reveal significant differences in EGFR gene methylation distinguishing GC from CG (p < 0, 01), suggesting that gene demethylation leads to malignant transformation and favours the use of tyrosine-kinase inhibitors in its treatment. Genes COX2 e p16INK4A lower methylation in intestinal and diffuse types of GC, favours their different role in respective histogenesis.

Performance of gentamicin population kinetic parameters in Portuguese neonates.

AIM: To evaluate the performance of eight different sets of gentamicin populational pharmacokinetic parameters, regarding potential implementation in clinical pharmacokinetic software as prior information. METHODS: The study involved 49 patients of 31.3+/-4.1 weeks of gestational age (GA), receiving gentamicin, and for whom peak and trough concentrations were obtained. Accuracy and precision were assessed by mean prediction error (ME), mean squared prediction error (MSE) and root mean squared prediction error (RMSE). Weighted prediction-error analysis was carried out in order to evaluate peak and trough concentrations together (ME(w), MSE(w) and RMSE(w)). RESULTS: The analysis showed CL=0.036 l/h/kg (< 34 weeks GA) or CL=0.051 l/h/kg (> or = 34 weeks GA), and V ( d )=0.5 l/kg (< or = 37 weeks GA) or Vd = 0.4 l/kg (>37 weeks of GA) as the most accurate and precise set of pharmacokinetic parameters (Set 4), presenting the highest percentage of clinically acceptable estimates (Error(Peak)<1 microg/ml, and Error(Trough) <0.375 microg/ml). CONCLUSION: The adoption of the previously mentioned set of parameters as population estimates seems to be the best option, bearing in mind the obtained results. However, we strongly believe that pharmacokinetic parameter determination of gentamicin should be carried out whenever possible in order to improve the rationale and cost-effectiveness of therapy.