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The invasion of Ukraine by Russia in February 2022 has resulted in destruction of healthcare infrastructure and triggered the largest wave of internally displaced populations and refugees since World War Two. Conflicts in transitioned countries such as Ukraine create new non-communicable disease (NCD) challenges, especially for cancer care for refugees and humanitarian assistance in host countries. In the early days, rapid attempts were made to model possible impacts. By evaluating open source intelligence used in the first three months of the conflict through snowball search methods, we aimed to address: (i) burden of cancer in Ukrainian population, specifically considering translating to the refugees population, and its cancer care capacity; ii) baseline capacity/strengths of cancer systems in initial host countries. Moreover, using a baseline scenario based on crude cancer incidence in Ukraine, and considering data from UNHCR, we estimated how cancer cases would be distributed across host countries. Finally, a surveillance assessment instrument was created, intersecting health system's capacity and influx of internally displaced populations and refugees. The total new cancer patients per month in pre-conflict Ukraine was estimated as 13,106, of which < 1 % are paediatric cases. The estimated cancer cases in the refugee population (combining prevalent and incident), assuming 7.5 million refugees by July 2022 and a female:male ratio of 9:1, was 33,121 individuals (Poland: 19284; Hungary: 3484; Moldova: 2651; Slovakia: 2421; Romania: 5281). According to our assessments, Poland is the only neighbouring country classified as green/yellow for cancer capacity, i.e. sufficient ablility to absorb additional burden into national health system; Slovakia we graded as yellow, Hungary and Romania as yellow/red and Moldova as red.

Objectives The aims of the study were (1) to analyze the etiology and clinical management of headaches in children in the emergency department and (2) to analyze the treatment used in children diagnosed with headaches and with migraines. Methods Retrospective study of all the patients who were admitted to the pediatric emergency department of Hospital Professor Doutor Fernando Fonseca, Lisbon, in 2014, with a chief complaint of headaches or the primary discharge diagnosis was headache/migraine. Results Headache related cases represented 3.8% of all the visits, a total of 2354 subjects. The median age was 10 years and 52.6% were female. The most frequent diagnoses were as follow: headaches (21.3%), upper respiratory infections (18.4%), and migraines (6.1%). There were 4 cases of meningitis, 6,5% of all patients underwent computed tomography which was mostly requested in school-age children and adolescents. The average time from the first medical observation until discharge was 85 minutes. Fifty-five percent did not take any pain relief medication, 17.2% took acetaminophen, and 11.1% took ibuprofen. Patients who received ondansetron had less revisits (P = 0.000). Subjects with mild-moderate pain treated with acetaminophen or no medication had more revisits (P = 0.000). Conclusions Secondary benign headaches were the most common and very rarely headache as a symptom was associated with life-threatening situations. Antiemetics seem to be efficient ally in the treatment of primary headaches, but it is important to consider alternative pharmacological regimes in patients who present with higher pain scores.

© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2022, Purpose: The aim of the study was to assess the prevalence and characteristics of spinal cord cavernous malformations (SCCM) and intraosseous spinal vascular malformations (ISVM) in a pediatric familial cerebral cavernous malformation (FCCM) cohort and evaluate clinico-radiological differences between children with (SCCM +) and without (SCCM-) SCCM. Methods: All patients with a pediatric diagnosis of FCCM evaluated at three tertiary pediatric hospitals between January 2010 and August 2021 with [Formula: see text] 1 whole spine MR available were included. Brain and spine MR studies were retrospectively evaluated, and clinical and genetic data collected. Comparisons between SCCM + and SCCM- groups were performed using student-t/Mann-Whitney or Fisher exact tests, as appropriate. Results: Thirty-one children (55% boys) were included. Baseline spine MR was performed (mean age = 9.7 years) following clinical manifestations in one subject (3%) and as a screening strategy in the remainder. Six SCCM were detected in five patients (16%), in the cervico-medullary junction (n = 1), cervical (n = 3), and high thoracic (n = 2) regions, with one appearing during follow-up. A tendency towards an older age at first spine MR (P = 0.14) and [Formula: see text] 1 posterior fossa lesion (P = 0.13) was observed in SCCM + patients, lacking statistical significance. No subject demonstrated ISVM. Conclusion: Although rarely symptomatic, SCCM can be detected in up to 16% of pediatric FCCM patients using diverse spine MR protocols and may appear de novo. ISVM were instead absent in our cohort. Given the relative commonality of asymptomatic SCCM, serial screening spine MR should be considered in FCCM starting in childhood.

BACKGROUND AND PURPOSE: Pathogenic somatic variants affecting the genes Histone 3 Family 3A and 3B (H3F3) are extensively linked to the process of oncogenesis, in particular related to central nervous system tumors in children. Recently, H3F3 germline missense variants were described as the cause of a novel pediatric neurodevelopmental disorder. We aimed to investigate patterns of brain MR imaging of individuals carrying H3F3 germline variants. MATERIALS AND METHODS: In this retrospective study, we included individuals with proved H3F3 causative genetic variants and available brain MR imaging scans. Clinical and demographic data were retrieved from available medical records. Molecular genetic testing results were classified using the American College of Medical Genetics criteria for variant curation. Brain MR imaging abnormalities were analyzed according to their location, signal intensity, and associated clinical symptoms. Numeric variables were described according to their distribution, with median and interquartile range. RESULTS: Eighteen individuals (10 males, 56%) with H3F3 germline variants were included. Thirteen of 18 individuals (72%) presented with a small posterior fossa. Six individuals (33%) presented with reduced size and an internal rotational appearance of the heads of the caudate nuclei along with an enlarged and squared appearance of the frontal horns of the lateral ventricles. Five individuals (28%) presented with dysgenesis of the splenium of the corpus callosum. Cortical developmental abnormalities were noted in 8 individuals (44%), with dysgyria and hypoplastic temporal poles being the most frequent presentation. CONCLUSIONS: Imaging phenotypes in germline H3F3-affected individuals are related to brain features, including a small posterior fossa as well as dysgenesis of the corpus callosum, cortical developmental abnormalities, and deformity of lateral ventricles.

Made available in DSpace on 2022-04-29T08:37:35Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Brazil is the largest exporter of beef in the world, and most of that beef derives from Nellore cattle. Although considered a zebu breed (Bos indicus), the history of Nellore cattle in Brazil is marked by the importation of bulls from India, the use of a Creole taurine (Bos taurus) maternal lineage to quickly expand the herds and backcrossing to Nellore bulls to recover zebu ancestry. As a consequence, the current Brazilian Nellore population carries an average taurine ancestry of approximately 1%. Although that percentage seems small, some taurine variants deviate substantially from that average, with the better-known cases being the PLAG1-Q haplotype involved with body size variation and the Guarani (PG) polled variant producing hornless animals. Here, we report taurine haplotypes in 9074 Nellore animals genotyped for 539 657 imputed SNP markers. Apart from PLAG1-Q and PG, our analysis further revealed common taurine haplotypes (>3%) spanning genes related to immunity, growth, reproduction and hair and skin phenotypes. Using data from 22 economically important traits, we showed that many of the major QTL previously reported in the breed are at least partially driven by taurine haplotypes. As B. taurus and B. indicus haplotypes are highly divergent, presenting widely different sets of functional variants, our results provide promising targets for future scrutiny in Nellore cattle. Department of Production and Animal Health School of Veterinary Medicine of Araçatuba São Paulo State University, 16050-680 R. Clovis Pestana 793 – Dona Amelia, SP International Atomic Energy Agency Collaborating Centre on Animal Genomics and Bioinformatics, 16050-680 R. Clovis Pestana 793 – Dona Amelia, SP AgroPartners Consulting. R. Floriano Peixoto, 120 – Sala 43A – Centro, SP Personal-PEC. R. Sebastião Lima, 1336 – Centro, MS Department for Innovation in Biological Agro-Food and Forest Systems Università Della Tuscia, Via S. Camillo de Lellis snc Acceligen Department of Preventive Veterinary Medicine and Animal Reproduction School of Agricultural and Veterinarian Sciences São Paulo State University, 14884-900 Via de Acesso Prof. Paulo Donato Castellane s/n, SP Department of Production and Animal Health School of Veterinary Medicine of Araçatuba São Paulo State University, 16050-680 R. Clovis Pestana 793 – Dona Amelia, SP Department of Preventive Veterinary Medicine and Animal Reproduction School of Agricultural and Veterinarian Sciences São Paulo State University, 14884-900 Via de Acesso Prof. Paulo Donato Castellane s/n, SP CAPES: 001 FAPESP: 2010/52030-2 CNPq: 483590/2010-0 CNPq: 560922/2010-8

Summary Background Paediatric Early Warning Scores (PEWSs) are being used increasingly in hospital wards to identify children at risk of clinical deterioration, but few scores exist that were designed for use in emergency care settings. To improve the prioritisation of children in the emergency department (ED), we developed and validated an ED-PEWS. Methods The TrIAGE project is a prospective European observational study based on electronic health record data collected between Jan 1, 2012, and Nov 1, 2015, from five diverse EDs in four European countries (Netherlands, the UK, Austria, and Portugal). This study included data from all consecutive ED visits of children under age 16 years. The main outcome measure was a three-category reference standard (high, intermediate, low urgency) that was developed as part of the TrIAGE project as a proxy for true patient urgency. The ED-PEWS was developed based on an ordinal logistic regression model, with cross-validation by setting. After completing the study, we fully externally validated the ED-PEWS in an independent cohort of febrile children from a different ED (Greece). Findings Of 119 209 children, 2007 (1·7%) were of high urgency and 29 127 (24·4%) of intermediate urgency, according to our reference standard. We developed an ED-PEWS consisting of age and the predictors heart rate, respiratory rate, oxygen saturation, consciousness, capillary refill time, and work of breathing. The ED-PEWS showed a cross-validated c-statistic of 0·86 (95% prediction interval 0·82–0·90) for high-urgency patients and 0·67 (0·61–0·73) for high-urgency or intermediate-urgency patients. A cutoff of score of at least 15 was useful for identifying high-urgency patients with a specificity of 0·90 (95% CI 0·87–0·92) while a cutoff score of less than 6 was useful for identifying low-urgency patients with a sensitivity of 0·83 (0·81–0·85). Interpretation The proposed ED-PEWS can assist in identifying high-urgency and low-urgency patients in the ED, and improves prioritisation compared with existing PEWSs. Funding Stichting de Drie Lichten, Stichting Sophia Kinderziekenhuis Fonds, and the European Union's Horizon 2020 research and innovation programme.

OBJECTIVE To characterize the bulbospongiosus muscle (BSM) in patients with bulbar urethral strictures. MATERIALS AND METHODS We studied 21 patients divided into 2 groups: Stricture Group (n = 14; mean age = 62.00 years) with bulbar stricture submitted to open urethroplasty; and Control Group (n = 7; mean age = 60.14 years) with penile strictures (hypospadias cripples, penile cancer and/or penile infection) who were submitted to perineal urethrostomy. Samples of the BSM were dissected and histologic sections were stained by histochemical and immunohistochemical techniques. Histomorphometric analyzes were performed on photomicrographs. Means were statistically compared using the unpaired Student t test and the Mann-Whitney test (P RESULTS The etiology of bulbar urethral stricture was idiopathic in 2 cases (14.29%), post-TURP in 6 (42.86%), post open radical prostatectomy in 5 (35.71%) and post open prostatectomy in 1 case (7.14%). The average length of the stricture was 2.08 cm. The only parameter analyzed with significant difference between the groups was the vessels (significant difference between the control group: 5.11 ± 1.98% and stricture group: 3.57 ± 1.32%, P = .0460). The quantitative analysis of collagen (Control Group: 10.63 ± 5.37% and Stricture Group: 10.83 ± 4.55%, P = .9296); diameter of BSM muscle fibers (Control Group: 41.71 ± 14.63 µm and Stricture Group: 40.11 ± 8.59 µm, P = .76 and elastic system fibers (Control Group; 3.83 ± 1.54% and Stricture Group: 5.43 ± 2.90%, P = .2601) showed no significant difference. CONCLUSIONS Histologic analysis showed a significant decrease of the BSM vessels in urethral stricture, without changes in elastic fibers, collagen, nerves, and muscle fiber diameter. These findings show that the bulbar urethral stricture causes minimal alterations in the structure of the BSM.

Malignant hyperthermia (MH) is a hypermetabolic disorder that can occur in genetically susceptible individuals exposed to halogenated anesthetics and succinylcholine. Spinal cord injury (SCI) above the sixth thoracic vertebra is associated with dysfunction of the sympathetic/parasympathetic nervous pathways, including thermoregulatory dysfunction, presenting as hypothermia in cold environments because of vasodilation and heat loss. This effect could mitigate or obscure an MH episode. Here, we describe development of a fatal MH crisis in a patient with SCI.A 27-yr-old male patient with an SCI after fracture of the sixth cervical vertebra was admitted for spinal arthrodesis. Anesthetic medications included remifentanil, propofol, succinylcholine, rocuronium, and isoflurane. After the start of the surgery, muscular contractures resembling myoclonus were noted, which resolved with pancuronium administration. Four hours after the start of anesthesia, the patient presented with hyperthermia, hypercarbia, hypotension, muscle rigidity, arrhythmia, and cardiogenic shock, with metabolic/respiratory acidosis. Malignant hyperthermia was suspected and the treatment was started, but he developed cardiopulmonary arrest and died an hour and a half after the first cardiac arrest. Both parents were investigated and were found to have normal creatine kinase levels and positive in vitro contracture tests. His mother carried a variant in the ryanodine receptor type 1 (RYR1) gene (c.14918CT), which is associated with MH.Spinal cord injury-induced thermoregulatory dysfunction may obscure the early diagnosis of MH and lead to fatal outcome.RéSUMé: OBJECTIF: L’hyperthermie maligne est un trouble hypermétabolique qui peut survenir chez les personnes génétiquement susceptibles exposées à des anesthésiques volatils et à la succinylcholine. Les lésions médullaires situées au-dessus de la sixième vertèbre thoracique sont associées à un dysfonctionnement des voies nerveuses sympathiques / parasympathiques, y compris un trouble de la thermorégulation, et se présentent sous forme d’hypothermie dans des environnements froids en raison de la vasodilatation et de la perte de chaleur. Cet effet pourrait atténuer ou occulter un épisode d’hyperthermie maligne. Nous décrivons ici l’apparition d’une crise mortelle d’hyperthermie maligne chez un patient atteint de lésion médullaire. CARACTéRISTIQUES CLINIQUES: Un patient de 27 ans atteint d’une lésion médullaire après une fracture de la sixième vertèbre cervicale a été admis pour une arthrodèse rachidienne. Les médicaments anesthésiques comprenaient du rémifentanil, du propofol, de la succinylcholine, du rocuronium et de l’isoflurane. Après le début de la chirurgie, des contractures musculaires ressemblant à une myoclonie ont été notées, lesquelles se sont résolues avec l’administration de pancuronium. Quatre heures après l’induction d’anesthésie, le patient a présenté une hyperthermie, une hypercarbie, une hypotension, une rigidité musculaire, une arythmie et un choc cardiogénique, avec acidose métabolique / respiratoire. Une hyperthermie maligne a été suspectée et le traitement a été amorcé, mais le patient a subi un arrêt cardiorespiratoire et est décédé une heure et demie après le premier arrêt cardiaque. Les deux parents ont passés des tests et se sont avérés avoir des taux normaux de créatine kinase et des tests de contracture in vitro positifs. La mère du patient était porteuse d’un variant du gène récepteur de ryanodine de type 1 (RYR1) (c.14918CT), lequel est associé à l’hyperthermie maligne. CONCLUSION: Un trouble de la thermorégulation induit par une lésion médullaire peut masquer un diagnostic précoce d’hyperthermie maligne et entraîner une issue fatale.

Background To develop a clinical prediction model to identify children at risk for revisits with serious illness to the emergency department. Methods and findings A secondary analysis of a prospective multicentre observational study in five European EDs (the TRIAGE study), including consecutive children aged = 3%, which was useful for ruling in a revisit with serious illness, with positive likelihood ratio 4.41 (95% CI 3.87–5.01) and specificity 0.96 (95% CI 0.95–0.96). 37,546 (39%) had a risk Conclusion We developed a prediction model and a digital calculator which can aid physicians identifying those children at highest and lowest risks for developing a serious illness after initial discharge from the ED, allowing for more targeted safety netting advice and follow-up.

Objective Our aim was to describe variability in resource use and hospitalization in children presenting with shortness of breath to different European Emergency Departments (EDs) and to explore possible explanations for variability. Design The TrIAGE project, a prospective observational study based on electronic health record data. Patients and setting Consecutive paediatric emergency department visits for shortness of breath in five European hospitals in four countries (Austria, Netherlands, Portugal, United Kingdom) during a study period of 9–36 months (2012–2014). Main outcome measures We assessed diversity between EDs regarding resource use (diagnostic tests, therapy) and hospital admission using multivariable logistic regression analyses adjusting for potential confounding variables. Results In total, 13,552 children were included. Of those, 7,379 were categorized as immediate/very urgent, ranging from 13–80% in the participating hospitals. Laboratory tests and X-rays were performed in 8–33% of the cases and 21–61% was treated with inhalation medication. Admission rates varied between 8–47% and PICU admission rates varied between 0.1–9%. Patient characteristics and markers of disease severity (age, sex, comorbidity, urgency, vital signs) could explain part of the observed variability in resource use and hospitalization. However, after adjusting for these characteristics, we still observed substantial variability between settings. Conclusion European EDs differ substantially regarding the resource use and hospitalization in children with shortness of breath, even when adjusting for patient characteristics. Possible explanations for this variability might be unmeasured patient characteristics such as underlying disease, differences in guideline use and adherence or different local practice patterns.

Introduction and objective: To evaluate changes in verumontanum anatomy in patients with benign prostatic hyperplasia (BPH) who used 5-alpha reductase inhibitors (5-ARIs) and to propose an anatomical classification of the verumontanum. Materials and Methods: We studied 86 patients with BPH and 7 patients without the disease (age under 40 years-old who underwent kidney or ureteral lithotripsy). Of the patients with BPH, 34 (mean age=67.26) had 5-ARIs use and 52 (mean age=62.69) did not use the drug. During surgeries, photographs of the seminal colliculus were taken and later, with the aid of software (Image J), the length (longitudinal diameter) and width (transverse diameter) of the verumontanum were measured in all patients. During the procedure, we evaluated the different types of verumontanum. For statistical analysis, the R-Project software was used. Results: In the group of patients with BPH who were taking medication (group 1), the mean measures of length and width of the verumontanum were 4.69mm and 2.94mm respectively. In the group of patients with BPH who did not use the drug (group 2), the mean diameters were 4.54mm and 3.20mm respectively. In the control group (group 3), the average length and width were 5.63mm and 4.11mm respectively. There was an increase in longitudinal and transverse measurements of the control group with an increase in body mass index (BMI) (p=0.0001 and p=0.035 respectively). In addition, there was a reduction in transverse diameter in the group of BPH using 5-ARI with increased prostate volume (p=0.010). We found five different verumontanum types: “volcano” (51.61%), “lighthouse” (24.73%), “whale tail” (12.90%), “hood” (5.38%) and “castle door” (5.38%), which we propose as an anatomical classification. Conclusion: Veromontanum has smaller measurements in patients with BPH regardless of treatment. In the control group, there was an increase in verumontanum diameters with an increase in BMI. The volcano type of verumontanum was the most frequent regardless of groups and BMI.

Background Vital signs are used in emergency care settings in the first assessment of children to identify those that need immediate attention. We aimed to develop and validate vital sign based Manchester Triage System (MTS) discriminators to improve triage of children at the emergency department. Methods and findings The TrIAGE project is a prospective observational study based on electronic health record data from five European EDs (Netherlands (n = 2), United Kingdom, Austria, and Portugal). In the current study, we included 117,438 consecutive children 2 0.199 versus 0.204). Conclusions Six new discriminators based on vital signs lead to a small but relevant increase in performance and should be implemented in the MTS.

Adrenocortical tumors (ACT) in the adult and pediatric population are generally considered distinct entities due to differences in molecular events related to tumorigenesis, clinical presentation, and outcome. Furthermore, pathological criteria used for diagnosis and prognostication of ACT in adults are usually inadequate for predicting the biological behavior of ACT in children. Here, we analyzed 146 adult and 44 pediatric ( 15y/o) ACT with long-term clinical follow-up and furthered current evidence on the clinical and pathological differences between pediatric and adult tumors. Predilection for female over male gender was observed in both cohorts, but more so in adults (84% vs. 61%, p = 0.003). Cushing syndrome was more frequent in adults (p 0.001), whereas virilization, either isolated (p 0.001) or combined to Cushing (p = 0.047), was more common in children. The Ki67 labelling index (LI) of pediatric adenomas and carcinomas was much higher than their corresponding tumors in adults (p 0.001). Despite these differences, pathological analyses including the evaluation of Ki67 greatly improved patient prognostication in both age cohorts. Indeed, increased Weiss scores and Ki67 indexes correlated with poor overall- and disease-free survival in adult patients with carcinoma. Among the proliferative indexes tested, Ki67 LI ≥ 10% showed the highest hazard ratio (HR) for recurrence and the Ki67 LI ≥ 3% showed the highest HR for survival. In pediatric tumors, the Wieneke score (p 0.001) and the Ki67 LI (p 0.001) showed high accuracy for predicting biological behavior, and increased scores/indexes correlated with worse overall and disease-free survival. In this age cohort, Ki67 LI 10% was able to rule out malignant behavior, whereas Ki67 LI ≥ 15% may be used to predict the patients with higher risks of recurrence and/or poor outcome.

Made available in DSpace on 2020-12-12T01:33:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2020-11-15 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG) Insular cortex is a brain structure involved in the modulation of autonomic activity and cardiovascular function. The nitric oxide/cyclic guanosine-3′,5′-monophosphate pathway is a prominent signaling mechanism in the central nervous system, controlling behavioral and physiological responses. Nevertheless, despite evidence regarding the presence of nitric oxide-synthesizing neurons in the insular cortex, its role in the control of autonomic and cardiovascular function has never been reported. Thus, the present study aimed to investigate the involvement of nitric oxide/cyclic guanosine-3′,5′-monophosphate pathway mediated by neuronal nitric oxide synthase (nNOS) activation within the insular cortex in the modulation of baroreflex responses in unanesthetized rats. For this, we evaluated the effect of bilateral microinjection of either the nitric oxide scavenger carboxy-PTIO, the selective neuronal nitric oxide synthase inhibitor Nω-Propyl-L-arginine or the soluble guanylate cyclase inhibitor ODQ into the insular cortex on the bradycardia evoked by blood pressure increases in response to intravenous infusion of phenylephrine, and the tachycardia caused by blood pressure decreases evoked by intravenous infusion of sodium nitroprusside. Bilateral microinjection of either NPLA or carboxy-PTIO into the insular cortex increased the reflex bradycardic response, whereas the reflex tachycardia was decreased by these treatments. Bilateral microinjection of the soluble guanylate cyclase inhibitor into the insular cortex did not affect any parameter of baroreflex function evaluated. Overall, our findings provide evidence that insular cortex nitrergic signaling, acting via neuronal nitric oxide synthase, plays a prominent role in control of baroreflex function. However, control of reflex responses seems to be independent of soluble guanylate cyclase activation. Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo Laboratory of Pharmacology School of Pharmaceutical Sciences São Paulo State University (UNESP) Department of Health Sciences Faculty of Medicine – Federal University of Lavras Laboratory of Pharmacology School of Pharmaceutical Sciences São Paulo State University (UNESP) CNPq: 141992/2016-6 FAPESP: 2015/05922-9 CNPq: 456405/2014-3 FAPEMIG: APQ-01316-16

The aim of the study was to raise the awareness of atrial fibrillation (AF) and the importance of pulse check in Czech pharmacies as well as to point out further possibilities of developing consulting activities in pharmacies.Our project was performed as part of a worldwide campaign during three weeks: Heart Rhythm Week (06/2017) and Atrial Fibrillation Awareness Week (11/2017, 11/2018). Pharmacies actively providing indi-vidual counselling offered manual pulse check to patients aged 40 years without chronic anticoagulant therapy. Whenever high risk of AF was observed, patients were referred to a physician for further evaluation.Pharmacists undertook pulse checks in 187 patients (mean age 59.0 ± 12.3 years; 70.6% women) in 14 participating pharmacies. The most common symptoms were fatigue (42.2%) and palpitations (20.9%), however, 40.6% of patients were asymptomatic. The mean heart rate was 73.2 ± 11.3 beats per minute (min. 51; max. 135) and irregular pulse was observed in 4.3% patients. The average CHA2DS2-VASc score was 2.0 ± 1.3. Eight (4.3%) patients were referred to a physician and in 5 patients (2.7%) the arrhythmia was diagnosed.Czech pharmacies have successfully adopted this campaign, are interested in continuity of the project and may thus contribute to raise awareness of AF.

ObjectiveTo assess the role of sex in the presentation and management of children attending the emergency department (ED).DesignThe TrIAGE project (TRiage Improvements Across General Emergency departments), a prospective observational study based on curated electronic health record data.SettingFive diverse European hospitals in four countries (Austria, The Netherlands, Portugal, UK).ParticipantsAll consecutive paediatric ED visits of children under the age of 16 during the study period (8–36 months between 2012 and 2015).Main outcome measuresThe association between sex (male of female) and diagnostic tests and disease management in general paediatric ED visits and in subgroups presenting with trauma or musculoskeletal, gastrointestinal and respiratory problems and fever. Results from the different hospitals were pooled in a random effects meta-analysis.Results116 172 ED visits were included of which 63 042 (54%) by boys and 53 715 (46%) by girls. Boys accounted for the majority of ED visits in childhood, and girls in adolescence. After adjusting for age, triage urgency and clinical presentation, girls had more laboratory tests compared with boys (pooled OR 1.10, 95% CI 1.05 to 1.15). Additionally, girls had more laboratory tests in ED visits for respiratory problems (pooled OR 1.15, 95% CI 1.04 to 1.26) and more imaging in visits for trauma or musculoskeletal problems (pooled OR 1.10, 95% CI 1.01 to 1.20) and respiratory conditions (pooled OR 1.14, 95% CI 1.05 to 1.24). Girls with respiratory problems were less often treated with inhalation medication (pooled OR 0.76, 95% CI 0.70 to 0.83). There was no difference in hospital admission between the sexes (pooled OR 0.99, 95% CI 0.95 to 1.04).ConclusionIn childhood, boys represent the majority of ED visits and they receive more inhalation medication. Unexpectedly, girls receive more diagnostic tests compared with boys. Further research is needed to investigate whether this is due to pathophysiological differences and differences in disease course, whether girls present signs and symptoms differently, or whether sociocultural factors are responsible.

This study evaluated clinical and pathological aspects of patients with hepatocellular carcinoma (HCC) secondary to non-alcoholic fatty liver disease (NAFLD) and related these factors to immunohistochemical markers representative of the proliferative class.We evaluated 35 HCC nodules from 21 patients diagnosed with NAFLD undergoing liver resection (n=12) or liver transplantation (n=8) or both (n=1). Demographic, clinical and biochemical data were compared to histological features and to immunohistochemical reactivity for K19 and Ki-67.Cirrhosis was present in 58% of patients. Ages ranged from 50 to 77 years. Sixteen patients (76%) were male and had type 2 diabetes mellitus, 81% had arterial hypertension, and 90% had BMI above 25 kg/m². Alpha-fetoprotein levels were normal in 62% of patients. Twenty-five (70%) nodules were diagnosed as "steatohepatitic HCC". Only 32% of the nodules presented high levels of Ki-67 (10%) and/or K19 (5%), although 63% were poorly differentiated (G.3/G.4) according to EdmondsonSteiner grading system. K19 positivity (5%) was associated with higher degree of intratumoral inflammation (G.2/G.3), and with fibrosis, both at the center of the tumor and at the tumor front, whereas Ki-67 positivity (10%) was associated with ballooning of neoplastic cells and occurred in more than 70% in non-cirrhotic patients.NAFLD-related HCC was found in non-cirrhotic patients in 42% of cases, alpha-fetoprotein level was normal in 63% and "steatohepatitic HCC" was the predominant histological type. Immunoexpression of K19 and/or Ki-67 occurred in 32% of the nodules and were associated with intratumoral inflammation and ballooning, suggesting that HCC in MtS may be preferentially "an inflammatory, non-proliferative subtype of HCC".

The medial preoptic area (mPOA) participates in the temperature and cardiovascular control. The mPOA receives inputs from limbic structures and sends projections to hypothalamus and brainstem. Moreover, stress elicits pronounced neuronal activation in mPOA, suggesting its involvement in central neural pathway mediating stress responses. In the present study, we report the effect of acute mPOA neurotransmission inhibition using cobalt chloride (CoCl2-nonselective synapse blocker) on the mean arterial pressure (MAP), heart rate (HR), body and tail temperature (Tbody and Ttail, respectively), as well as on the HR component of baroreflex. We also verified the participation of mPOA in the autonomic changes evoked by acute restraint stress (RS). Our results demonstrated that microinjection of CoCl2 into mPOA caused tachycardia, hyperthermia and a Ttail decrease, without altering MAP. The inhibition of mPOA with CoCl2 increased the sympathetic component of cardiac baroreflex when assessed 10min after its administration. In addition, pretreatment of mPOA with CoCl2 increased RS-evoked tachycardic and hyperthermic responses evoked by RS when compared with aCSF-treated animals, without affecting the RS-evoked pressor response and the fall in Ttail. In summary, our results suggest that mPOA exerts a tonic inhibitory influence on the sympathetic cardiac tone under both rest and stress conditions, modulating negatively the sympathetic component of baroreflex. Results also confirm the mPOA involvement in the control of body temperature because its inhibition was followed by a sustained increase in body temperature and vasoconstriction in the tail artery territory.

Brazilian propolis is popularly used as treatment for different diseases including the ones with inflammatory origin. Brazilian red propolis chemical profile and its anti-inflammatory properties were recently described however, its mechanism of action has not been investigated yet.Elucidate Brazilian red propolis major pathways of action on the modulation of neutrophil migration during the inflammatory process.The ethanolic extract of propolis (EEP) activity was investigated for neutrophil migration into the peritoneal cavity, intravital microscopy (rolling and adhesion of leukocytes), quantification of cytokines TNF-α, IL-1β and chemokines CXCL1/KC, CXCL2/MIP-2, neutrophil chemotaxis induced by CXCL2/MIP-2, calcium influx and CXCR2 expression on neutrophils.EEP at 10mg/kg prevented neutrophil migration into peritoneal cavity (p 0.05), reduced leukocyte rolling and adhesion on the mesenteric microcirculation (p 0.05) and inhibited the release TNF-α, IL-1β, CXCL1/KC and CXCL2/MIP-2 (p 0.05). EEP at 0.01, 0.1 and 1µg/ml reduced the CXCL2/MIP-2-induced neutrophils chemotaxis (p 0.05) without affect cell viability (p 0.05).EEP at 1µg/ml decreased the calcium influx induced by CXCL2/MIP-2 (p0.05). On the other hand, none of EEP concentrations tested altered CXCR2 expression by neutrophils (p0.05).Brazilian red propolis appears as a promising anti-inflammatory natural product which mechanism seems to be by reducing leukocyte rolling and adhesion; TNF-α, IL-1β, CXCL1/KC and CXCL2/MIP-2 release; CXCL2/MIP-2-induced chemotaxis and calcium influx.

The aim of this study was to analyze the effect of reduced glutathione (GR) and adenosine triphosphate (ATP) in cryopreserved sperm tambaqui, Colossoma macropomum..Semen samples were frozen at different concentrations of GR (2, 4, and 6 mM) and ATP (7.5, 15, 30 mM) evaluated separately.Different concentrations of GR and ATP were added to the diluent Beltsville Thawing Solution 10 % of DMSO (extender control). The thawed sperm was evaluated as the kinetic parameters for Computer Assisted Semen Analysis (CASA) and cell feature parameters by flow cytometry.All concentrations of GR and ATP had gradual reduction in the production of reactive oxygen species, mainly ATP 15; 22.5 mM and 30 mM, which decreased by 50% or more when compared to the control. All concentrations of GR and ATP did not change (P0.05) DNA fragmentation and lipid peroxidation. The membrane fluidity GR in concentrations 4 and 6 mM were better than control; and the concentrations of 2 and 4 mM maintained more efficiently to motility period, total and progressive motility.Thus, it is indicated the use of BTS extender with 10% DMSO added 4 mM GR thawed sperm Tambaqui C. macropomum.

The most widely used data for cardiorespiratory fitness (CRF) referrals are from the Cooper Clinic, which uses calculated maximal oxygen uptake (VO2max) values.To develop CRF values from cardiopulmonary exercise testing (CPX) in a Brazilian population with high socioeconomic level and free of structural heart disease. VO2max testing results were compared with the Cooper Clinic and FRIEND Registry data.CPX data from consecutive individuals between January 1,2000, and May 31,2016 were used in this study. Inclusion criteria were: VO2max by a pre-specified definition. We built a CRF chart according to VO2max percentiles: very poor (≤20%), poor (20-40%), fair (40-60%), good (60-80%), excellent (80-90%), and superior (≥90%). Kappa correlation was used to analyze our data in comparison with that of the other two databases. Statistical tests with p0.005 were considered significant.Final cohort included 18,186 tests: 12,552 men, 5,634 women (7-84 years). The most recurrent response was "good" (20.2%). There was a mean difference in weight, height, body mass index (BMI), and age in the CRF chart. An inverse correlation existed between VO2max and age, weight, and BMI. Using a linear regression and these variables, a predictive equation was developed for VO2max. Our findings differed from that of the other databases.We developed a classification for CRF and found higher values in all classification ranges of functional capacity in contrast to the Cooper Clinic and FRIEND Registry. Our findings offer a more accurate interpretation of ACR in this large Brazilian population sample when compared to previous standards based on the estimated VO2max. (Arq Bras Cardiol. 2020; 115(3):468-477).Os dados mais utilizados como referência de aptidão cardiorrespiratória (ACR) são os de Cooper, que utiliza valores calculados de captação máxima de oxigênio (VO2máx).Desenvolver valores de ACR a partir do teste cardiopulmonar de exercício (TCPE) em uma população brasileira com alto nível socioeconômico e livre de cardiopatia estrutural. Os resultados dos testes de VO2max foram comparados aos dados de Cooper e do FRIEND Registry.Foram utilizados neste estudo dados de TCPE de indivíduos consecutivos entre 1º de janeiro de 2000 e 31 de maio de 2016. Os critérios de inclusão foram: VO2máx pré-definido. Foi construído um gráfico de ACR de acordo com os percentuais do VO2máx: muito ruim (≤20%), ruim (20-40%), regular (40-60%), boa (60-80%), excelente (80-90%), e superior (≥90%). A correlação Kappa foi usada para analisar nossos dados em comparação aos dados dos outros dois bancos de dados. Os testes estatísticos com p0,005 foram considerados significativos.A coorte final incluiu 18.186 testes: 12.552 homens, 5.634 mulheres (7 a 84 anos). A resposta mais recorrente foi “boa” (20,2%). Houve diferença média de peso, altura, índice de massa corporal (IMC) e idade no gráfico da ACR. Houve correlação inversa entre VO2máx e idade, peso e IMC. Usando uma regressão linear e essas variáveis, uma equação preditiva foi desenvolvida para o VO2máx. Nossas descobertas diferiram das dos outros bancos de dados.Desenvolvemos uma classificação para a ACR e encontramos valores mais altos em todas as faixas de classificação de capacidade funcional, em contraste com os dados de Cooper e do FRIEND Registry. Nossos achados oferecem uma interpretação mais precisa da ACR nessa grande amostra populacional brasileira, quando comparados aos padrões anteriores, com base no VO2máx estimado. (Arq Bras Cardiol. 2020; 115(3):468-477).

Management of patients with thoracoabdominal penetrating injuries is challenging. Thoracoabdominal penetrating trauma may harbor hollow viscus injuries in both thoracic and abdominal cavities and occult diaphragmatic lesions. While radiological tests show poor diagnostic performance in these situations, evaluation by laparoscopy is highly sensitive and specific. Furthermore, minimally invasive surgery may avoid unnecessary laparotomies, despite concerns regarding complication and missed injury rates. The objective of the present study is to evaluate the diagnostic and therapeutic performance of laparoscopy in stable patients with thoracoabdominal penetrating injuries. Retrospective analysis of hemodynamically stable patients with thoracoabdominal penetrating wounds was managed by laparoscopy. We collected data regarding the profile of the patients, the presence of diaphragmatic injury, perioperative complications, and the conversion rate. Preoperative imaging tests were compared to laparoscopy in terms of diagnostic accuracy. Thirty-one patients were included, and 26 (84%) were victims of a stab wound. Mean age was 32 years. Ninety-three percent were male. Diaphragmatic lesions were present in 18 patients (58%), and 13 (42%) had associated injuries. There were no missed injuries and no conversions. Radiography and computerized tomography yielded an accuracy of 52% and 75%, respectively. Laparoscopy is a safe diagnostic and therapeutic procedure in stable patients with thoracoabdominal penetrating wound, with low complication rate, and may avoid unnecessary laparotomies. The poor diagnostic performance of preoperative imaging exams supports routine laparoscopic evaluation of the diaphragm to exclude injuries in these patients.

Snakebites inflicted by the arboreal viperid snake Bothriechis schlegelii in humans are characterized by pain, edema, and ecchymosis at the site of the bite, rarely with blisters, local necrosis, or defibrination. Herein, a comparative study of Bothriechis schlegelii snake venoms from Colombia (BsCo) and Costa Rica (BsCR) was carried out in order to compare their main activities and to verify the efficacy of Bothrops antivenom produced in Brazil to neutralize them. Biochemical (SDS-PAGE and zymography) and biological parameters (edematogenic, lethal, hemorrhagic, nociceptive, and phospholipase A2 activities) induced by BsCo and BsCR snake venoms were evaluated. The presence of antibodies in Bothrops antivenom that recognize BsCo and BsCR snake venoms by enzyme-linked immunosorbent assay and Western blotting, as well as the ability of this antivenom to neutralize the toxic activities were also verified. SDS-PAGE showed differences between venoms. Distinctive caseinolytic and hyaluronidase patterns were detected by zymography. BsCo and BsCR showed similar phospholipase A2 activity. Strong cross-reactivity between BsCo and BsCR was detected using Bothrops antivenom with many components located between 150 and 35 kDa. BsCR was more edematogenic and almost fourfold more hemorrhagic than BsCo, and both venoms induced nociception. BsCR (LD50 5.60 mg/kg) was more lethal to mice than BsCo (LD50 9.24 mg/kg). Bothrops antivenom was effective in the neutralization of lethal and hemorrhagic activities of BsCo and BsCR and was partially effective in the neutralization of edematogenic and nociceptive activities. In conclusion, geographic distribution influences the composition and activities of Bothriechis schlegelii venoms. Bothrops antivenom cross-reacted with these venoms and was partially effective in neutralizing some toxic activities of BsCo and BsCR.

BACKGROUND Transforming growth factor β1 (TGF-β1) and tumour necrosis factor (TNF) have been implicated in Chagas disease pathophysiology and may correlate with left ventricular (LV) function. OBJECTIVES We determined whether TGF-β1 and TNF serum levels correlate with LV systolic and diastolic functions and brain natriuretic peptide (BNP) serum levels in chronic Chagas disease. METHODS This cross-sectional study included 152 patients with Chagas disease (43% men; 57 ± 12 years old), classified as 53 patients with indeterminate form and 99 patients with cardiac form (stage A: 24, stage B: 25, stage C: 44, stage D: 6). TGF-β1, TNF, and BNP were determined by enzyme-linked immunosorbent assay ELISA. Echocardiogram was used to determine left atrial and LV diameters, as well as LV ejection fraction and diastolic function. FINDINGS TGF-b1 serum levels were lower in stages B, C, and D, while TNF serum levels were higher in stages C and D of the cardiac form. TGF-β1 presented a weak correlation with LV diastolic function and LV ejection fraction. TNF presented a weak correlation with left atrial and LV diameters and LV ejection fraction. CONCLUSIONS TNF is increased, while TGF-β1 is decreased in the cardiac form of chronic Chagas disease. TNF and TGF-β1 serum levels present a weak correlation with LV systolic and diastolic function in Chagas disease patients.

In order to evaluate aspects of reproductive biology of the “pequira” ( Bryconamericus stramineus) in the elevator of the Funil Dam - MG, fish capture was carried out from November 2008 to January 2009 and 317 individuals were collected. The mean standard length (SL) of the population was 4.96 cm and mean weight 1.80 g. The females had SL of 5.0 cm, while males had a SL of 4.6 cm. A sex ratio of 2.20: 1 (females: male) was observed. Our results show that 73% of the individuals analyzed were considered adults. The species presented low fecundity, mean of 470.9 oocytes per female and a mean diameter of 221.08 μm, with an increase in oocyte diameter over the evaluation period. The length of the first gonadal maturation was estimated at 5.0 cm. The results obtained in this work suggest that the reproductive cycle of the species occurs in the analyzed period. Although this species does not have migratory reproductive habits, the presence of adults in the reproductive stage was observed in the transposition area, which suggests a search for new environments for spawning. Resumo Com o objetivo de avaliar aspectos da biologia reprodutiva da pequira Bryconamericus stramineus no elevador da represa do Funil - MG foram realizadas capturas entre os meses de novembro de 2008 a janeiro de 2009, sendo coletados 317 indivíduos. O comprimento padrão (CP) médio da população foi de 4,96 cm e peso médio de 1,80 g. As fêmeas apresentaram CP de 5,0 cm, enquanto que os machos obtiveram um CP de 4,6 cm. Foi observada proporção sexual de 2,20:1(fêmeas:macho). Dos indivíduos analisados, 73% foram considerados adultos. A espécie apresentou baixa fecundidade, com média de 470,9 ovócitos por fêmea e diâmetro médio de 221,08 μm, ocorrendo aumento no diâmetro de ovócitos com o decorrer do tempo no período avaliado. O comprimento de primeira maturação gonadal foi estimado em 5,0 cm. Os resultados obtidos neste trabalho sugerem que o ciclo reprodutivo da espécie ocorre no período analisado. Embora esta espécie não tenha hábitos reprodutivos migratórios, a presença de adultos no estágio reprodutivo foi observada na área de transposição, o que sugere a busca de novos ambientes para a reprodução.

BACKGROUND McNeal divided the human prostate into three major anatomical areas: the peripheral zone (PZ), the central zone (CZ), and the transition zone (TZ). Each of these areas is biologically and histologically distinct. The PZ and TZ have clinical significance and are associated with prostate cancer (PC) and benign prostatic hyperplasia (BPH), respectively. Therefore, the objective of the present study was to quantitatively and qualitatively analyze the parenchymal and stromal components that constitute the different prostate zones. METHODS We assessed 19 samples from each prostate zone. The samples were obtained from necropsies of young people between 18 and 32 years of age with intact urogenital tracts. The samples were fixed in 4% buffered formalin and processed for paraffin embedding. Sections with a thickness of five micrometres were obtained from each sample. The sections were stained using histochemical and immunohistochemical techniques to identify the acinar and stromal components of each zone. Photomicrographs were obtained for morphometric analysis using an algorithm based on color segmentation. Data were analyzed using one-way analysis of variance (ANOVA) with the Bonferroni post-test. Differences with P

This study focused on cognitive representations of low back pain patients receiving chiropractic (n = 213) versus physiotherapy treatment (n = 125). Variables assessed included satisfaction with care, illness perceptions, beliefs about pain and medicines, attitudes towards doctors and medicine, suffering, adherence and functional incapacity. In the chiropractic treatment, functional incapacity was predicted by painful symptoms, suffering and personal control, and in the physiotherapy treatment by age, pain intensity, positive suffering, care satisfaction, illness identity and medication adherence. The groups differed on all cognitive variables assessed. Interventions should take into consideration cognitive dimensions, across treatment modalities., info:eu-repo/semantics/submittedVersion

American visceral leishmaniasis is a zoonosis of the New World. Dogs are the main reservoir of the disease and there is much interest in the understanding of mechanisms implicated in protection against canine infection. Nevertheless, most studies in dogs have not been carried out in organs that are targets of infection. This work is first to report the profile of cytokines and parasite burdens, as determined by real-time PCR, in the lymph nodes of dogs naturally infected with Leishmania chagasi. With this purpose, 18 mongrel dogs were divided in three groups: control non-infected dogs (n=6) and naturally infected animals with L. chagasi, asymptomatic (n=6) and symptomatic (n=6). Parasite burden in lymph nodes was 73-fold greater in symptomatic than asymptomatic animals. Prescapular lymph nodes of asymptomatic dogs had the highest expression of IFN-gamma and TNF-alpha and low parasite burden, indicating that these cytokines play a role in protection against infection. Highest expression of IL-10 and TGF-beta and high parasite burden were observed in symptomatic dogs, suggesting a role for these cytokines in the progression of disease. Hence, the balance of expression of IFN-gamma and TNF-alpha (protective) and IL-10 and TGF-beta (disease progression) in lymph nodes determine parasite burden and clinical expression in naturally infected dogs.

Septic shock, which is triggered by microbial products, is mainly characterised by inadequate tissue perfusion, which can lead to multiple organ dysfunction and death. An intense release of vasoconstrictors agents occurs in the early stages of shock, which can lead to ischemic injury. In this scenario, cGMP could play a key role in counterbalancing these agents and preventing tissue damage. Sildenafil, which is a phosphodiesterase-5 inhibitor, increases cGMP in smooth muscle cells and promotes vasodilation. Thus, the purpose of this study was to investigate the effect of treatment with sildenafil in the early stages of sepsis. Male rats were submitted to either cecal ligation and puncture (CLP) or a sham procedure. Eight h after the procedure, the CLP and sham groups were randomly assigned to receive sildenafil (10mg/kg, gavage) or vehicle, and twelve or twenty-four h later the inflammatory, biochemical and haemodynamic parameters were evaluated. Sepsis significantly increased levels of plasma nitrate/nitrite (NOx), aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, creatine kinase and lactate. Additionally, sepsis led to hypotension, hyporesponsiveness to vasoconstrictor, renal blood flow reduction and also increased lung and kidney myeloperoxidase. Sildenafil increased renal blood flow and reduced the plasma levels of creatinine, lactate and creatine kinase, as well as reducing lung myeloperoxidase. Thus, phosphodiesterase inhibition may be a useful therapeutic strategy if administered at the proper time.

Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-27T11:29:38Z No. of bitstreams: 0 Made available in DSpace on 2014-05-27T11:29:38Z (GMT). No. of bitstreams: 0 Previous issue date: 2013-06-03 Dynamic exercise evokes sustained cardiovascular responses, which are characterized by arterial pressure and heart rate increases. Although it is well accepted that there is central nervous system mediation of cardiovascular adjustments during exercise, information on the role of neural pathways and signaling mechanisms is limited. It has been reported that glutamate, by acting on NMDA receptors, evokes the release of nitric oxide through activation of neuronal nitric oxide synthase (nNOS) in the brain. In the present study, we tested the hypothesis that NMDA receptors and nNOS are involved in cardiovascular responses evoked by an acute bout of exercise on a rodent treadmill. Moreover, we investigated possible central sites mediating control of responses to exercise through the NMDA receptor-nitric oxide pathway. Intraperitoneal administration of the selective NMDA glutamate receptor antagonist dizocilpine maleate (MK-801) reduced both the arterial pressure and heart rate increase evoked by dynamic exercise. Intraperitoneal treatment with the preferential nNOS inhibitor 7-nitroindazole reduced exercise-evoked tachycardiac response without affecting the pressor response. Moreover, treadmill running increased NO formation in the medial prefrontal cortex (MPFC), bed nucleus of the stria teminalis (BNST) and periaqueductal gray (PAG), and this effect was inhibited by systemic pretreatment with MK-801. Our findings demonstrate that NMDA receptors and nNOS mediate the tachycardiac response to dynamic exercise, possibly through an NMDA receptor-NO signaling mechanism. However, NMDA receptors, but not nNOS, mediate the exercise-evoked pressor response. The present results also provide evidence that MPFC, BNST and PAG may modulate physiological adjustments during dynamic exercise through NMDA receptor-NO signaling. © 2013 Elsevier B.V. Department of Natural Active Principles and Toxicology School of Pharmaceutical Sciences São Paulo State University, Rodovia Araraquara-Jau Km 01, Caixa Postal 502, Araraquara, SP, 14801-902 Department of Pharmacology School of Medicine of Ribeirão Preto University of São Paulo, Ribeirão Preto, SP, 14049-900 Department of Natural Active Principles and Toxicology School of Pharmaceutical Sciences São Paulo State University, Rodovia Araraquara-Jau Km 01, Caixa Postal 502, Araraquara, SP, 14801-902

The insular cortex (IC) has been reported to be involved in the modulation of memory and autonomic and defensive responses. However, there is conflicting evidence about the role of the IC in fear conditioning. To explore the IC involvement in both behavioral and autonomic responses induced by contextual fear conditioning, we evaluated the effects of the reversible inhibition of the IC neurotransmission through bilateral microinjections of the non-selective synapse blocker CoCl2 (1 mm) 10 min before or immediately after the conditioning session or 10 min before re-exposure to the aversive context. In the conditioning session, rats were exposed to a footshock chamber (context) and footshocks were used as the unconditioned stimulus. Forty-eight hours later, the animals were re-exposed to the aversive context for 10 min, but no shock was given. Behavioral (freezing) as well as cardiovascular (arterial pressure and heart rate increases) responses induced by re-exposure to the aversive context were analysed. It was observed that the local IC neurotransmission inhibition attenuated freezing and the mean arterial pressure and heart rate increase of the groups that received the CoCl2 either immediately after conditioning or 10 min before re-exposure to the aversive context, but not when the CoCl2 was injected before the conditioning session. These findings suggest the involvement of the IC in the consolidation and expression of contextual aversive memory. However, the IC does not seem to be essential for the acquisition of memory associated with aversive context.

Physical exercise can improve health and may lead to changes in the functionality of the immune system. Moderate intensity exercise can reduce the risk of infection by shifting the overall immune response towards a T helper type 1 pattern. This study investigates the effect of 12 weeks of swimming on the cytokine profile of lymph node cells and macrophages and of the nitric oxide production by these cells. BALB/c mice were divided into 2 groups. The exercise group was subjected to swimming exercise. Lymph node cells culture showed that concentrations of interferon-γ and tumour necrosis factor-α were higher in the exercised group, while levels of interleukine-4 and interleukine-10 were significantly decreased in this group. The interleukine-10/interferon-γ ratio tended towards a T helper type 1 profile. Moreover, macrophages isolated from exercised mice produced more interleukine-12 and tumour necrosis factor-α following lipopolysaccharide stimulus. Challenging these macrophages with Leishmania major resulted in higher interleukine-12 production than was observed with macrophages from the control group. Nitric oxide production was increased in macrophages isolated from exercised group following lipopolysaccharide stimulus but not following infection with Leishmania major. These data suggest that exercise biases the immune system towards a T helper type 1 response profile.

In mice, along with the assessment of eosinophils, lung function measurements, most commonly carried out by plethysmography, are essential to monitor the course of allergic airway inflammation, to examine therapy efficacy and to correlate animal with patient data. To date, plethysmography techniques either use intubation and/or restraining of the mice and are thus invasive, or are limited in their sensitivity. We present a novel unrestrained lung function method based on low-dose planar cinematic x-ray imaging (X-Ray Lung Function, XLF) and demonstrate its performance in monitoring OVA induced experimental allergic airway inflammation in mice and an improved assessment of the efficacy of the common treatment dexamethasone. We further show that XLF is more sensitive than unrestrained whole body plethysmography (UWBP) and that conventional broncho-alveolar lavage and histology provide only limited information of the efficacy of a treatment when compared to XLF. Our results highlight the fact that a multi-parametric imaging approach as delivered by XLF is needed to address the combined cellular, anatomical and functional effects that occur during the course of asthma and in response to therapy.

In several patients, intellectual disability and/or congenital malformation may be attributed to chromosomal changes. In this study, we conducted an array-CGH test of 200 patients from the Northeast of Brazil with intellectual disability and/or congenital malformation. Blood samples were collected from the proband and from their parents when possible. DNA was extracted and investigated using the array-CGH test. Findings were evaluated for the pathogenicity in databases of benign and pathogenic changes (ISCA, UCSC, DGV, and DECIPHER). Forty-seven copy number variations (CNVs) were identified in 43/200 (21.5%) patients, including 25/98 (25.5%) in males and 22/102 (21.57%) in females. We considered 33 of these to be clinically significant, reaching a diagnosis rate of 16.5%. The sizes of the CNVs varied from 102 kb to 24 Mb in deletions and from 115 kb to 140 Mb in duplications. In 10/47 (21.3%) patients, the rearrangement involved a sex chromosome. Thirty-nine patients had one chromosomal aberration, while 2 concomitant abnormalities were detected in 4 patients. Ten of 47 CNVs (21.3%) were > 5Mb in size. Fifteen patients had CNVs related to known syndromes. This research highlights the contribution of submicroscopic chromosomal changes to the etiology of intellectual disability and/or congenital malformation, particularly the implication of chromosomal abnormalities detected using an array-CGH test, with a high rate of 16.5%. Thus, our results support the use of array-CGH replacing standard karyotype as the first-tier cytogenetic diagnostic test for patients with multiple congenital anomalies and/or intellectual disability.

The objectives of this study were to describe and compare the displacement patterns and the tactical performance of the players in the first to the second game time and verify possible associations between indirect markers of muscle damage with displacement patterns in a simulated game played by young soccer players.Eighteen young soccer players were submitted to a simulated game and two blood collections, one before and another 30 minutes post-game to analyze the behavior of creatine kinase and lactate dehydrogenase enzymes. The patterns of displacement and tactics variables were obtained through functions developed in MATLAB environment (MathWorks, Inc., Natick, MA, USA).It is observed a significant increase in average speed (P=0.05), number of sprints (P0.001), the percentage the total distance covered at high intensity (P0.001) and tactical variables (team surface area: P=0.002; spreading: P=0.001) in the second period of the simulated game. In addition, there was significant reduction in the percentage of the total distance at low intensity (P≤0.05) in the second period, and there was a strong association between the percentage of change delta of creatine kinase and lactate dehydrogenase with the displacement patterns in the simulated game.The results show that indirect markers of muscle damage have great association with displacement patterns in game performed in training conditions for young soccer players, evidencing a need for reflection on the post-training recovery sessions strategies, contributing to better planning of sessions throughout the macrocycle.

Ethnopharmacological relevance Medicinal applications of Pimenta pseudocaryophyllus infusion as a diuretic and aphrodisiac agent as well as tranquilizer in the form of tea for the treatment of emotional tension in Brazilian folk medicine has been in practice since time immemorial. Despite its popular therapeutic acceptance and claims, there are scanty scientific reports to corroborate its central biological activities. Aim To characterize anxiolytic-like effect of the dichloromethane fraction (DF) obtained from ethanolic leaf extract of the Pimenta pseudocaryophyllus and identify mechanisms of action involved while seeking to support its popular use as a soothing agent. Material and methods Mice (25–35 g) were treated orally with DF obtained from ethanolic leaf extract of Pimenta pseudocaryophyllus and were submitted to light-dark box (LDB) and elevated plus maze (EPM) tests. Different groups of mice were treated with flumazenil and NAN-190 to identify mechanisms of action involved in the anxiolytic-like effect of DF. Results Treatment with DF increased number of transitions and time spent in the light compartment of the LDB while the time spent and numbers of entries in the open arm of the LCE were significantly increased. Pre-treatment of the animal with flumazenil (2 mg/kg, i.p. – competitive antagonist of benzodiazepine site of GABA A receptor) did not block this effect, thereby excluding participation of benzodiazepine site of the GABA A receptor. However, anxiolytic-like effect of DF was reversed by pre-treatment with NAN-190 (0.5 mg/kg, i.p. – an antagonist of the 5-HT 1A receptor) thereby suggesting involvement of 5-HT 1A receptor. The thin layer chromatography and high-performance liquid chromatography analysis indicated the predominance of (E)-methyl isoeugenol and oleanolic acid in DF. Conclusion These results support the popular use of Pimenta pseudocaryophyllus as a calming agent and suggest the involvement of 5-HT 1A receptor.

Neural reflex mechanisms, such as the baroreflex, are involved in the regulation of cardiovascular system activity. Previous results from our group (Resstel LB, Correa FM. Medial prefrontal cortex NMDA receptors and nitric oxide modulate the parasympathetic component of the baroreflex. Eur J Neurosci 23: 481–488, 2006) have shown that glutamatergic synapses in the ventral portion of the medial prefrontal cortex (vMPFC) modulate baroreflex activity. Moreover, glutamatergic neurotransmission in the vMPFC can be modulated by the endocannabinoids system (eCBs), particularly the endocannabinoid anandamide, through presynaptic CB1receptor activation. Therefore, in the present study, we investigated eCBs receptors that are present in the vMPFC, and more specifically whether CB1receptors modulate baroreflex activity. We found that bilateral microinjection of the CB1receptor antagonist AM251 (100 or 300 pmol/200 nl) into the vMPFC increased baroreflex activity in unanesthetized rats. Moreover, bilateral microinjection of either the anandamide transporter inhibitor AM404 (100 pmol/200 nl) or the inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, URB597 (100 pmol/200 nl), into the MPFC decreased baroreflex activity. Finally, pretreatment of the vMPFC with an ineffective dose of AM251 (10 pmol/200 nl) was able to block baroreflex effects of both AM404 and URB597. Taken together, our results support the view that the eCBs in the vMPFC is involved in the modulation of baroreflex activity through the activation of CB1receptors, which modulate local glutamate release.

We evaluate the immunomodulation of Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists 15d-PGJ(2) and rosiglitazone (RGZ) in a model of chronic eosinophilia. 15d-PGJ(2) and RGZ significantly reduce eosinophil migration into the peritoneal cavity and down-regulate the eosinopoiesis. The synthesis of IL-5 was decreased after the treatment with 15d-PGJ(2) and RGZ corroborating with the eosinophil migration inhibition. However, IgE was decreased only after the administration of 15d-PGJ(2) in part due to B-cell inhibition. We also observed a decrease in the synthesis of IL-33, IL-17 and IL-23, suggesting that besides the modulation of Th2 pattern, there is a modulation via IL-23 and IL-17 suggesting a role of these cytokines in the eosinophil recruitment. In fact IL-17(-/-) mice failed to develop an eosinophilic response. Altogether, the results showed that PPAR-γ agonists mainly 15d-PGJ(2), have therapeutic efficacy in eosinophil-induced diseases with an alternative mechanism of control, via IL-23/IL-17 and IL-33.

In the present study, we investigated the role played by the hypothalamic paraventricular nucleus (PVN) in the modulation of cardiac baroreflex activity in unanesthetized rats. Bilateral microinjections of the nonselective neurotransmission blocker CoCl(2) into the PVN decreased the reflex bradycardic response evoked by blood pressure increases, but had no effect on reflex tachycardia evoked by blood pressure decreases. Bilateral microinjections of the selective NMDA glutamate receptor antagonist LY235959 into the PVN caused effects that were similar to those observed after microinjections of CoCl(2), decreasing reflex bradycardia without affecting tachycardic response. The microinjection of the selective non-NMDA glutamate receptor antagonist NBQX into the PVN did not affect the baroreflex activity. Also, the microinjection of L-glutamate into the PVN increased the reflex bradycardia, an effect opposed to that observed after PVN treatment with CoCl(2) or LY235959, and this effect of L-glutamate was blocked by PVN pretreatment with LY235959. LY235959 injected into the PVN after i.v. treatment with the selective beta(1)-adrenoceptor antagonist atenolol still decreased the reflex bradycardia. Taken together, our results suggest a facilitatory influence of the PVN on the bradycardic response of the baroreflex through activation of local NMDA glutamate receptors and a modulation of the cardiac parasympathetic activity.

We conducted a four-year (2003-2006) retrospective study of yeasts recovered in a hospital laboratory in the centre of Portugal to evaluate the epidemiology of yeast infections. Clinical isolates and data were gathered from 751 patients corresponding to 906 episodes of yeast infection. The isolates were first identified using classical and commercial methods, routinely employed at the hospital laboratory. We then re-identified the same isolates using RFLP of the ITS 5.8S rRNA gene and sequence of the D1/D2 domain of the 26S rRNA gene. Candida parapsilosis isolates were re-identified using the Ban I digestion of the SADH gene. C. albicans was the most frequently isolated of the yeasts found in the analysed specimens, with an overall incidence of 69.6% and then in decreasing order, C. glabrata, C. tropicalis, C. parapsilosis and C. krusei. C. parapsilosis was most frequently recovered from younger patients, decreasing with age, while C. glabrata occurrence increased with age. We found an increased number of cases of fungemia per 100,000 people per year, reaching a maximum of 4.4 during 2006.

Summary 1 In the present study, we investigated the effects of inhibition of the lateral hypothalamus (LH) neurotransmission with bilateral microinjection of CoCl2, a non-selective blocker of neurotransmission, on modulation of cardiac baroreflex responses in conscious rats as well as the involvement of LH glutamatergic neurotransmission in this modulation. 2 Reflex bradycardiac and tachycardiac responses to blood pressure increases (following i.v. infusion of phenylephrine) or decreases (following i.v. infusion of sodium nitroprusside) were investigated in conscious male Wistar rats. Responses were evaluated before and after microinjection of 1 nmol/100 nL CoCl2, 2 nmol/100 nL 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzoquinoxaline-7-sulphonamide (NBQX; a selective non-N-methyl-d-aspartate (NMDA) glutamate receptor antagonist) or different doses (2, 4 or 8 nmol/100 nL) of the selective NMDA glutamate receptor antagonist LY235959. 3 Microinjection of CoCl2 into the LH had no effect on the tachycardiac baroreflex response, but did evoke a decrease in the reflex bradycardia caused by increases in blood pressure. Microinjection of NBQX into the LH had a similar effect on reflex bradycardia as CoCl2, but had no effect on the tachycardiac response. Microinjection of increasing doses of LY235959 into the LH had no effect on the cardiac baroreflex response. 4 In conclusion, the data suggest that the LH has a tonic facilitatory influence on the parasympathetic component of the baroreflex. The results also indicate that this facilitatory influence is mediated by local LH glutamatergic neurotransmission through non-NMDA glutamatergic receptors.

In the present report, we describe the first case of a phaeohyphomycotic brain abscess in a 5-year-old boy with chronic granulomatous disease (CGD) admitted to hospital with seizures. A computed tomography (CT) scan revealed a cerebral abscess and the microbiology study showed a dark, melanin-pigmented fungus, exhibiting only sterile hyphae. This fungus was identified by the amplification and sequencing of the 5.8S RNA gene and of the adjacent internal transcriber spacer domains, ITS1 and ITS2, as Alternaria infectoria. Due to the impossibility of a surgical excision, and although several therapeutic strategies were attempted, the patient died. Limitations in the routine identification procedures and therapeutic options of this emerging opportunistic agent are highlighted in this report.

The diagonal band of Broca (DBB) is involved in cardiovascular control in rats. In the present study, we report the effect of acute and reversible neurotransmission inhibition in the DBB by bilateral microinjection of the nonselective neurotransmission blocker CoCl(2) (1mM, 100 nL) on the cardiac baroreflex response in unanesthetized rats. Local DBB neurotransmission inhibition did not affect baseline values of either blood pressure or heart rate, suggesting no tonic DBB influence on cardiovascular system activity. However, CoCl(2) microinjections enhanced both the reflex bradycardia associated with blood pressure increases caused by i.v. infusion of phenylephrine and tachycardiac response evoked by blood pressure decreases caused by i.v. infusion of sodium nitroprusside. An increase in baroreflex gain was also observed. Baroreflex returned to control values 60 min after CoCl(2) microinjections, confirming its reversible effect. In conclusion, our data suggest that synapses within DBB have a tonic inhibitory influence on both the cardiac parasympathetic and sympathetic components of the baroreflex.

The bed nucleus of stria terminalis (BST) has a tonic modulating role on the baroreflex parasympathetic component. In the present study, we verified that local BST-adrenoceptors modulate baroreflex-evoked bradycardiac responses in unanesthetized rats. Bilateral microinjection of the selective alpha(1)-adrenoceptor antagonist WB4101 (15 nmol/100 nL) into the BST increased the gain of reflex bradycardia in response to mean arterial pressure increases caused by intravenous (i.v.) infusion of phenylephrine, suggesting that BST alpha(1)-adrenoceptors modulate baroreflex bradycardiac response. Bilateral microinjection of either the selective alpha(2)-adrenoceptor antagonist RX821002 (15 nmol/100 nL) or the non-selective beta-adrenoceptor antagonist propranolol (15 nmol/100 nL) into the BST had not affected baroreflex bradycardia. Animals were pretreated intravenously with the cholinergic muscarinic receptor antagonist homatropine methyl bromide (HMB, 1.5 mg/Kg) to test the hypothesis that activation of alpha(1)-adrenoceptors in the BST would modulate the baroreflex parasympathetic component. Baroreflex bradycardiac responses evoked before and after BST treatment with WB4101 were no longer different when rats were pretreated with HMB. These results suggest that parasympathetic activation accounts for the effects saw after BST pharmacological manipulation and ruling out the possibility of a sympathetic withdraw. In conclusion, our data point out that local alpha(1)-adrenoceptors mediate the BST tonic influence on the baroreflex bradycardiac response modulating parasympathetic cardiac activity.

Lance-headed snakes are found in Central and South America, and they account for most snakebites in Brazil. The phylogeny of South American pitvipers has been reviewed, and the presence of natural and non-natural hybrids between different species of Bothrops snakes demonstrates that reproductive isolation of several species is still incomplete. The present study aimed to analyze the biological features, particularly the thrombin-like activity, of venoms from hybrids born in captivity, from the mating of a female Bothrops erythromelas and a male Bothrops neuwiedi, two species whose venoms are known to display ontogenetic variation. Proteolytic activity on azocoll and amidolytic activity on N-benzoyl-DL-arginine-p-nitroanilide hydrochloride (BAPNA) were lowest when hybrids were 3 months old, and increased over body growth, reaching values similar to those of the father when hybrids were 12 months old. The clotting activity on plasma diminished as hybrids grew; venoms from 3- and 6-months old hybrids showed low clotting activity on fibrinogen (i.e., thrombin-like activity), like the mother venom, and such activity was detected only when hybrids were older than 1 year of age. Altogether, these results point out that venom features in hybrid snakes are genetically controlled during the ontogenetic development. Despite the presence of the thrombin-like enzyme gene(s) in hybrid snakes, they are silenced during the first six months of life.

Background American tegumentary leishmaniasis (ATL) is endemic in Latin America, where Brazil has over 27 thousand cases per year. The aim of the present study was to develop an immunohistochemical method (IHC) for ATL diagnosis. For this purpose, we used serum from a dog naturally infected with Leishmania (L) infantum (canine hyperimmune serum) as the primary antibody, followed by a detection system with a secondary biotinylated antibody. Methodology Skin samples were obtained from 73 patients in an endemic area of Caratinga, Minas Gerais (MG) State, Brazil all testing positive for ATL with the Montenegro skin test, microscopy, and PCR. Canine hyperimmune serum of a dog naturally infected with Leishmania (L.) infantum was employed as a primary antibody in an immunohistochemical diagnostic method using streptavidin-biotin peroxidase. To assess the specificity of this reaction, IHC assays employing two monoclonal antibodies were carried out. As the polymer-based technology is less time-consuming and labor intensive than the IHC labeled streptavidin-biotin peroxidase method, we compared the two methods for all samples. Results The IHC method detected ATL in 67 of the 73 cases (91.8%). Immunolabeled parasites were primarily detected inside macrophages either in the superficial or the deep dermis. Detection was facilitated by the high contrast staining of amastigotes (dark brown) against the light blue background. A lower detection rate (71.2%) was observed with the both of the monoclonal Leishmania antibodies compared to the canine hyperimmune serum. This may have been due to a non-specific background staining observed in all histological samples rendering positive detection more difficult. The higher efficacy of the canine hyperimmune serum in the IHC method was confirmed by the method using streptavidin-biotin peroxidase as well as that with the polymer-based technology (biotin-avidin-free system). Conclusions The data are encouraging with regard to validating IHC as a standard alternative method for ATL diagnosis.

In the present study, we report the effect of bed nucleus of stria terminalis (bed nucleus) ablation caused by bilateral microinjections of the nonselective synapse blocker CoCl2 on the baroreflex response in rats. Reversible ablation of the bed nucleus by bilateral microinjection of CoCl2 did not affect baseline blood pressure or heart rate, suggesting no tonic influence of bed nucleus on the cardiovascular system. Pretreatment with CoCl2 did not affect the tachycardic response to blood pressure decreases caused by intravenous infusion of sodium nitroprusside, but enhanced bradycardic responses evoked by blood pressure increases caused by intravenous infusion of phenylephrine. Present data suggest that synapses within the bed nucleus have a tonic inhibitory influence on the baroreflex parasympathetic component.

Volunteers living in an area where schistosomiasis mansoni is endemic were subjected to ultrasound examination and classified into groups according to the levels of fibrosis diagnosed, namely, absence of indications of fibrosis (group 0), incipient fibrosis (group 1), and moderate/severe fibrosis (group 2). Peripheral blood mononuclear cells (PBMC) collected from the volunteers were stimulated with soluble antigens from adult schistosomes or from schistosome eggs, and the production of the cytokines gamma interferon, tumor necrosis factor alpha, transforming growth factor β (TGF-β), interleukin-4 (IL-4), IL-10, and IL-13 was determined. Potential associations of the level of fibrosis with age, sex, intensity of infection, and cytokine production were investigated between the three groups. Univariate analysis identified associations of age (>50), gender (male), and absence of eggs/g of feces with moderate/severe fibrosis and an association of intensity of infection (>100 eggs) with incipient fibrosis. When cytokine production in PBMC cultures stimulated by soluble egg antigens was categorized as low or high, significant differences in the distribution of IL-13 levels were established between groups 0 and 2. No significant differences were detected between the groups in the cytokines produced by PBMC cultures stimulated with soluble antigens from adult schistosomes. When all variables were tested in multivariate analyses, only IL-13 was strongly associated with fibrosis (odds ratio = 5.8; 95% confidence interval [CI] = 1.1 to 30.5). While high levels of TGF-β appeared to be associated with protection against fibrosis, the strength of the association was low.

Percutaneous ethanol injection (PEI) is a well-established therapeutic option in patients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI.79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up.The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI.

New cyclosporine A (CsA) formulations must prove their bioequivalence to Neoral, the reference CsA formulation, to allow free prescription for the patients. The aim of this study was to compare the pharmacokinetics (PK) of a new CsA formulation (Zinograf-ME), produced by Strides-Arcolab, to Neoral and to demonstrate their interchangeability in stable renal transplant recipients. Twelve-hour PK studies were obtained from 18 (13 M/5 F) adult patients (mean age 44.7 +/- 12 years). They received their renal allografts from 13 cadaver and 5 living donors. Before enrollment, all patients were receiving a third generic CsA for a mean of 48 months. Nine patients were also under azathioprine and 9 under mycophenolate mofetil; 17 received prednisone. A single oral dose of either Zinograf or Neoral was administered. The first PK study was performed with one formulation, and 1 week later, a second PK was done with the other formulation. During the washout period, patients continued taking the third CsA formulation. The drug substitution was done milligram-for-milligram. The CsA whole-blood level was measured by TDx immunoassay. Mean +/- SD of area under the curve (AUC), maximum concentration (C(max)), and concentration at the second hour (C2) of Zinograf were not statistically different from those with Neoral (4019 +/- 1466 vs 3971 +/- 1325 ng x h/mL, 998 +/- 376 vs 1021 +/- 356 ng/mL, and 707 +/- 254 vs 734 +/- 229 ng/mL, respectively). In the same way, the Zinograf 90% confidence interval for either C(max) (-123, +77 ng/mL) or AUC (-214, +311 ng.mL/h) were within the Neoral bioequivalence interval for the same parameters (+/-204 ng/mL and +/-794 ng x mL/h, respectively). These data demonstrate that the ZinografME CsA formulation is bioequivalent to Neoral.