Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study.

BACKGROUND & AIM: Brain metastases are frequent in patients with metastatic melanoma, indicating poor prognosis. We investigated the BRAF kinase inhibitor vemurafenib in patients with advanced melanoma with symptomatic brain metastases. METHODS: This open-label trial assessed vemurafenib (960mg twice a day) in patients with BRAF(V600) mutation-positive metastatic melanoma with non-resectable, previously treated brain metastases. The primary end-point was safety. Secondary end-points included best overall response rate, and progression-free and overall survival. RESULTS: Twenty-four patients received vemurafenib for a median treatment duration of 3.8 (0.1-11.3) months. The majority of discontinuations were due to disease progression (n=22). Twenty-three of 24 patients reported at least one adverse event (AE). Grade 3 AEs were reported in four (17%; 95% confidence interval [CI], 4.7-37.4%) patients and included cutaneous squamous cell carcinoma in four patients. Median progression-free survival was 3.9 (95% CI, 3.0-5.5) months, and median survival was 5.3 (95% CI, 3.9-6.6) months. An overall partial response (PR) at both intracranial and extracranial sites was achieved in 10 of 24 (42%; 95% CI, 22.1-63.4) evaluable patients, with stable disease in nine (38%; 95% CI, 18.8-59.4) patients. Of 19 patients with measurable intracranial disease, seven (37%) achieved >30% intracranial tumour regression, and three (16%; 95% CI, 3.4-39.6%) achieved a confirmed PR. Other signs of improvement included reduced need for corticosteroids and enhanced performance status. CONCLUSIONS: Vemurafenib can be safely used in patients with advanced symptomatic melanoma that has metastasised to the brain and can result in meaningful tumour regression.

Le multiple evanescent white dot syndrome: une prédisposition génétique [Multiple evanescent white dot syndrome: a genetic predisposition?]

BACKGROUND: Multiple evanescent white dot syndrome (MEWDS) is a benign acquired isolated chorioretinal disorder. Symptoms include photopsia, visual blur and scotomas. Ocular examination reveals multiple white dots at the level of the deep retina. A parainfectious disorder was suggested but the exact mechanism of MEWDS is still unknown. Postulating that MEWDS might be an antigen driven inflammatory reaction, we analyzed HLA subtypes in patients with MEWDS. PATIENTS AND METHODS: Sixteen patients were diagnosed with MEWDS in Lausanne from 1985 to 1994. Blood was withdrawn in 9/16 patients. HLA-A, -B and -DR were sought. RESULTS: HLA-B51 was detected in 4/9 patients (44.4%). Other HLA subtypes were detected sporadically. CONCLUSIONS: The frequency of HLA-B51 haplotype was found to be 3.7 times more elevated than in a normal control caucasian group. This suggests the possibility that MEWDS might be a genetically determined disorder as it is the case for other ocular diseases like Birdshot chorioretinopathy (HLA-A29), Harada's disease (HLA-DRMT3), acute anterior uveitis (HLA-B27) or Behçet's disease (HLA-B51). We have no explanation for the presence of HLA-B51 in both Behçet's disease and MEWDS. The association of HLA-B51 and MEWDS needs confirmation by further testing.

Adherence to statin treatment and associated factors in female users from the Unified Health System (SUS)

Objective: To identify the adherence rate of a statin treatment and possible related factors in female users from the Unified Health System. Method: Seventy-one women were evaluated (64.2 ± 11.0 years) regarding the socio-economic level, comorbidities, current medications, level of physical activity, self-report of muscular pain, adherence to the medical prescription, body composition and biochemical profile. The data were analyzed as frequencies, Chi-Squared test, and Mann Whitney test (p<0.05). Results: 15.5% of women did not adhere to the medical prescription for the statin treatment, whose had less comorbidities (p=0.01), consumed less quantities of medications (p=0.00), and tended to be younger (p=0.06). Those patients also presented higher values of lipid profile (CT: p=0.01; LDL-c: p=0.02). Musculoskeletal complains were not associated to the adherence rate to the medication. Conclusion: The associated factors to adherence of dyslipidemic women to statin medical prescription were age, quantity of comorbidities and quantity of current medication.


Water chemistry and isotope composition of the Acquarossa thermal system, Ticino, Switzerland

The thermal springs of Acquarossa and the nearby mineral springs of Soia have outlet temperatures of 12 degrees to 25 degrees C, TDS of 2290 to 3000 mg/kg and Ca-SO4 to Ca-SO4-HCO3 composition. Chemical geothermometers suggest reservoir temperatures close to 60 degrees C. P-CO2 values at depth are estimated to range from 0.3 to 2 bar. delta D and delta(18)O values indicate a meteoric origin and recharge elevations of 1600 +/- 150 m above sea level (a.s.l.) for these thermal and mineral waters. All these waters discharge from the overturned limb of the Simano nappe, probably dose to the contact between basement and underlying cover rocks. They therefore represent rain waters that descend slowly, heat at depth and locally rise relatively quickly to the surface, preserving part of their physical and chemical characteristics. (C) 1999 CNR. Published by Elsevier Science Ltd. All rights reserved.

Longitudinal and cross-sectional changes in active commuting to school among Brazilian schoolchildren.

OBJECTIVE: The objective of the study is to evaluate cross-sectional and longitudinal changes in children's commuting to school in a representative sample of a Brazilian city. METHODS: Two school-based studies were carried out in 2002 (n=2936; 7-10years old) and 2007 (n=1232; 7-15years old) in Florianopolis, Brazil. Cross-sectional data were collected from children aged 7 to 10years in 2002 and 2007. Longitudinal analyses were performed with data from 733 children participating in both surveys. Children self-reported their mode of transportation to school using a validated illustrated questionnaire. Changes were tested with chi square statistics and McNemar's test. RESULTS: Cross-sectional data showed a 17% decline in active commuting; a decrease from 49% in 2002 to 41% in 2007. On the other hand, active commuting among the 733 children increased as they entered adolescence 5years later, rising from 40% to 49%. CONCLUSION: Active commuting to school decreased in Brazilian children aged 7-10years over a five year period; whereas, it increased among children entering adolescence. Policies should focus on safety and environmental determinants to increase active commuting.

Genome-wide association analyses identify 18 new loci associated with serum urate concentrations.

Elevated serum urate concentrations can cause gout, a prevalent and painful inflammatory arthritis. By combining data from >140,000 individuals of European ancestry within the Global Urate Genetics Consortium (GUGC), we identified and replicated 28 genome-wide significant loci in association with serum urate concentrations (18 new regions in or near TRIM46, INHBB, SFMBT1, TMEM171, VEGFA, BAZ1B, PRKAG2, STC1, HNF4G, A1CF, ATXN2, UBE2Q2, IGF1R, NFAT5, MAF, HLF, ACVR1B-ACVRL1 and B3GNT4). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. We further characterized these loci for associations with gout, transcript expression and the fractional excretion of urate. Network analyses implicate the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. New candidate genes for serum urate concentration highlight the importance of metabolic control of urate production and excretion, which may have implications for the treatment and prevention of gout.

Fluctuaciones en la abundancia aparente del stock de anchoveta en 1959-1962

Se han analizado los efectos del tamaño de la embarcación, tamaño del boliche y uso del equipo auxiliar sobre el poder de pesca definiéndose una unidad estándar de esfuerzo. El Indice de abundancia se derivó incorporando además el efecto estimado de la saturación de las embarcaciones, y se han discutido las variaciones en la disponibilidad o abundancia. Los datos usados comprendieron una cubierta casi completa de los desembarques individuales para embarcaciones bolicheras identificadas desde 1959 hasta 1962. Se presentan los datos no corregidos de captura por embarcación de las embarcaciones clasificadas por grupos de longitud, pero debido a cambios en el tamaño de las embarcaciones, tamaño de redes y uso de equipo auxiliar fue necesario definir una unidad estándar de esfuerzo. Una correlación alta y positiva se encontró entre el éxito de pesca y tamaño de la embarcación medido en toneladas de registro grueso y se decidió usar Mes por GRT como unidad de tiempo y esfuerzo. El. efecto del tamaño del boliche-sobre el poder de pesca se estudió por un análisis de correlación parcial y esta correlación resultó significante pero relativamente baja. El efecto del incremento promedio de 20-30 brazas en la longitud de las redes entre 1959 y 1962 se estimó en capturas más altas en cerca de 10%. Se piensa que el uso de jaladores hidráulicos tiene influencia significante en el poder de pesca y su efecto es evaluado de algunos datos del tiempo ahorrado cuando se usan estos aparejos. Finalmente se ha discutido el fenómeno de saturación de la pesquería. La relación entre captura por unidad de esfuerzo y la ocurrencia de saturación de las embarcaciones indica que a altos niveles de abundancia de peces, la saturación trae como consecuencia una depresión relativa de la c. p. u. e. Se ha derivado una relación entre abundancia y c. p. u. e. asumiendo que el efecto es proporcional al porcentaje de saturación. Se han usado los índices de abundancia aparente para estudiar las fluctuaciones estacionales de la pesquería, las cuales tienen un tipo muy regular, y las variaciones entre estaciones indican cambios considerables en la abundancia o disponibilidad de año a año.

Costos metabólicos de Engraulis ringens y Sardinops sagax en relación al peso, temperatura y el nivel de actividad

El metabolismo estándar de la anchoveta es más alto que el de la sardina; en .las larvas por un factor promedio de 2.3 y por 2.1 en juveniles y adultos en el rango de temperaturas de 14-20ºC. Lo opuesto sucede en el metabolismo activo: para una velocidad de natación de un cuerpo por segundo( =metabolismo de rutina), la anchoveta adulta con un peso mayor de 20 g a 20ºC y mayor de 50 g a 14ºC gasta menos energía que la sardina de tamaños similares; incrementándose la velocidad a 3 c.p .seg a 17°C.todos los tamaños mayores de 1.5 g de Sardina necesitan más energía que las anchovetas de pesos similares (una sardina de 5 g 1.5 veces y una de 25 g 3.8 veces más). Un cambio de temperatura de 6ºc (de 14° C a 20°c) afecta a ambas especies en una forma diferente : asumiendo una velocidad de natación de 1 cuerpo por segundo, una larva de anchoveta( 0.1 g) tiene que incrementar sus gastos metabólicos dos veces más que la larva de sardina, pero una anchoveta adulta( 40 g)necesita solo un 60% de lo que requiere una sardina del mismo tamaño .

Autosomal Recessive Posterior Microphthalmos/Nanophthalmos is Caused by Loss-of-function Mutations in LOC646960, a Novel Gene Encoding a Trypsin-like Serine Protease

Purpose: Posterior microphthalmos (MCOP)/nanophthalmos (NNO) is a developmental anomaly characterized by extreme hyperopia due to short axial length. The population of the Faroe Islands shows a high prevalence of an autosomal recessive form (arMCOP). The gene mutated in arMCOP is not yet known.Methods: Genetic mapping by linkage analysis using microsatellite and single nucleotide polymorphisms, mutation analysis by PCR and sequencing, molecular modellingResults: Having refined the position of the disease locus (MCOP6) in an interval of 250 kb in chromosome 2q37.1 in Faroese families, we detected 3 mutations in a novel gene, LOC646960: Patients of 10 different Faroese families were either homozygous (n=22) for c.926G>C (p.Trp309Ser) or compound heterozygous (n=6) for c.926G>C and c.526C&gt;G (p.Arg176Gly), whereas a homozygous 1 bp duplication (c.1066dupC) was identified in patients with arNNO from a Tunisian family. In two unrelated patients with MCOP, no LOC646960 mutation was found. LOC646960 is expressed in the human adult retina and RPE. The expression of the mouse homologue in the eye can be first detected at E17 and is highest in adults. The predicted protein is a 603 amino acid long secreted trypsin-like serine peptidase. c.1066dupC should result in a functional null allele. Molecular modelling of the p.Trp309Ser mutant suggests that both affinity and reactivity of the enzyme towards in vivo substrates are substantially reduced.Conclusions: Postnatal growth of the eye is important for proper development of the refractive components (emmetropization), and is mainly due to elongation of the posterior segment from 10-11 mm at birth to 15-16 mm at the age of 13 years. Optical defocus leads to changes in axial length by moving the retina towards the image plane. arMCOP may theoretically be explained, in line with the expression pattern of LOC646960, by a postnatal growth retardation of the posterior segment.

A Institucionalização das Crianças e Adolescentes no Centro Protecção Social Lém Cachorro – Uma resposta do sistema de protecção a violação dos direitos das crianças na cidade da Praia. Estudo de caso no Centro Protecção social Lém Cachorro.

O trabalho da memória que ora apresentamos incide sobre a temática da institucionalizaçãocomo resposta do sistema de protecção, a violação dos direitos das crianças na cidade da Praiaseguindo o formato de um estudo de caso, o trabalho teve como campo empírico o CentroProtecção Social Lém Cachorro na Cidade da Praia. Todas as crianças deveriam ter oportunidade de viver uma infância feliz e no seio da sua família, construindo assim o acesso a um desenvolvimento equilibrado. No entanto a existência de certos condicionalismos vem destruir essa possibilidade. As várias formas de violência principalmente as ocorridas no espaço familiar, onde deveria ser um espaço de protecção e garantia máxima dos seus direitos são disso um exemplo, causando sofrimento a estas crianças que se vêem numa situação de desamparo tanto a nível afectivo como na prestação dos cuidados essenciais para a sua sobrevivência. Sendo assim torna-se necessária a procura incessante de uma solução capaz de as proteger e as colocar numa situação mais favorável, para que se desenvolvem de forma adequada. Neste sentido a institucionalização, aparece como sendo uma das medidas de garantia da convivência, de maneira provisória e excepcional, quando a família ou os responsáveis pela criança/adolescente não conseguem efectivar o direito essencial a formação e ao desenvolvimento das crianças/adolescentes ou quando o Estado não actua eficazmente mediante as políticas públicas e sociais na garantia a protecção social da família. Com o objectivo de analisar e compreender o processo de institucionalização das crianças/adolescentes no C.P.S.L.C, como factor de mudança das suas condições de vida, realizou se uma investigação que incidiu sobre um grupo de crianças institucionalizadas no C.P.S.L.C. Este grupo foi constituída por crianças/adolescentes (do sexo masculino e do sexo feminino) com idades compreendidas entre os 9 aos 17 anos de idade e suas respectivas famílias. Para a recolha de dados junto destas crianças/adolescentes recorremos a metodologia qualitativa e quantitativa, uma vez que estas apresentaram formas mais eficazes para a obtenção de informações, foi aplicada a técnica da entrevista a coordenadora do centro, e o inquérito por questionário as crianças/adolescentes institucionalizadas no C.P.S.L.C e suas respectivas famílias. Para a análise e comentários dos dados dos inquéritos aplicados aos sujeitos da pesquisa, fez-se o tratamento dos mesmos com base no programa informático SPSS versão 15. Ainda, foram analisadas e comentadas as informações das entrevistas aplicadas aos sujeitos de pesquisa. Com a realização deste trabalho, chegou-se a conclusão que, o Centro Protecção Social Lém Cachorro, através das suas acções desenvolvidas, tem vindo a contribuir para a melhoria das condições de vidas das crianças/ adolescentes institucionalizadas, deforma activa, e articulada com outras organizações e instituições que trabalham directa ou indirectamente nessa área, intervindo no próprio microssistema, que na maioria das vezes condiciona o desenvolvimento saudável destas crianças, devido a condição social e económica.

Distinct genetic structure in populations of Chrysoperla externa (Hagen) (Neuroptera, Chrysopidae) shown by genetic markers ISSR and COI gene

Distinct genetic structure in populations of Chrysoperla externa (Hagen) (Neuroptera, Chrysopidae) shown by genetic markers ISSR and COI gene. Green lacewings are generalist predators, and the species Chrysoperla externa presents a great potential for use in biological control of agricultural pests due to its high predation and reproduction capacities, as well as its easy mass rearing in the laboratory. The adaptive success of a species is related to genetic variability, so that population genetic studies are extremely important in order to maximize success of the biological control. Thus, the present study used nuclear (Inter Simple Sequence Repeat - ISSR) and mitochondrial (Cytochrome Oxidase I - COI) molecular markers to estimate the genetic variability of 12 populations in the São Paulo State, Brazil, as well as the genetic relationships between populations. High levels of genetic diversity were observed for both markers, and the highest values of genetic diversity appear associated with municipalities that have the greatest areas of native vegetation. There was high haplotype sharing, and there was no correlation between the markers and the geographic distribution of the populations. The AMOVA indicated absence of genetic structure for the COI gene, suggesting that the sampled areas formed a single population unit. However, the great genetic differentiation among populations showed by ISSR demonstrates that these have been under differentiation after their expansion or may also reflect distinct dispersal behavior between males and females.

Comparative abundance and diversity of Dryininae (Hymenoptera, Dryinidae) in three savannah phytophysiognomies in southeastern Brazil, under three sampling methods

Comparative abundance and diversity of Dryininae (Hymenoptera, Dryinidae) in three savannah phytophysiognomies in southeastern Brazil, under three sampling methods. This study aimed to assess the abundance and diversity of Dryininae in riparian vegetation, Brazilian savannah, and savannah woodland vegetation at the Estação Ecológica de Jataí, in Luiz Antônio, State of São Paulo, Brazil, by using Moericke, Malaise, and light traps. The sampling was carried out from December 2006 to November 2009, and 371 specimens of Dryininae were caught, with the highest frequencies in spring and summer. Fourteen species of Dryinus Latreille, 1804 and one of Thaumatodryinus Perkins, 1905 were identified. The highest frequencies of Dryinus in the riparian vegetation differed significantly from those obtained in the Brazilian savannah and savannah woodland vegetation. In the riparian vegetation, the highest number of Dryinus was collected using light traps and the interactions between abundance and the collection method used were significant. The number of specimens of Dryinus collected in the Brazilian savannah and savannah woodland vegetation using Malaise traps did not differ significantly from those obtained using Moericke traps. Males significantly outnumbered females in the sex ratio of Dryinus. The species diversity of Dryinus based on females collected using Malaise traps was high in the Brazilian savannah. Furthermore, high species richness of female Dryinus was observed in riparian vegetation (six species) and Brazilian savannah (five). The light trap was the most successful method for sampling diversity of Dryininae.

Parenteral nutrition in the intensive care unit: cautious use improves outcome.

Critical illness is characterised by nutritional and metabolic disorders, resulting in increased muscle catabolism, fat-free mass loss, and hyperglycaemia. The objective of the nutritional support is to limit fat-free mass loss, which has negative consequences on clinical outcome and recovery. Early enteral nutrition is recommended by current guidelines as the first choice feeding route in ICU patients. However, enteral nutrition alone is frequently associated with insufficient coverage of the energy requirements, and subsequently energy deficit is correlated to worsened clinical outcome. Controlled trials have demonstrated that, in case of failure or contraindications to full enteral nutrition, parenteral nutrition administration on top of insufficient enteral nutrition within the first four days after admission could improve the clinical outcome, and may attenuate fat-free mass loss. Parenteral nutrition is cautious if all-in-one solutions are used, glycaemia controlled, and overnutrition avoided. Conversely, the systematic use of parenteral nutrition in the ICU patients without clear indication is not recommended during the first 48 hours. Specific methods, such as thigh ultra-sound imaging, 3rd lumbar vertebra-targeted computerised tomography and bioimpedance electrical analysis, may be helpful in the future to monitor fat-free mass during the ICU stay. Clinical studies are warranted to demonstrate whether an optimal nutritional management during the ICU stay promotes muscle mass and function, the recovery after critical illness and reduces the overall costs.

Influência do alumínio no crescimento e na acumulação de nutrientes em mudas de goiabeira

Durante 110 dias, realizou-se um experimento em solução nutritiva, para avaliar os efeitos do alumínio nas concentrações de 0, 5, 10, 15, 20 e 25 mg L-1, em pH 4,0, sobre o crescimento de mudas de goiabeira, absorção e acumulação de macronutrientes e de Cu, Fe, Mn, Zn e Al. Os sintomas visuais de fitotoxidez, associados às doses 20 e 25 mg L-1 de Al, foram caracterizados pela menor altura das plantas, ausência de ramificação, menor diâmetro do caule e raízes mais escuras; as folhas apresentaram dimensões menores e pecíolos avermelhados. Em doses relativamente baixas, o alumínio promoveu resposta positiva de crescimento, porém, em doses altas, os teores de macronutrientes e de Fe, Mn e Zn nas folhas de diagnose (3º e 4º pares a partir do ápice), bem como o conteúdo mineral nas diversas partes da planta, foram influenciados pelas doses de alumínio. A fitotoxidez afetou, mais acentuadamente, os teores de P, Ca, Mg, Mn e Zn. Cerca de 95% do Al absorvido concentrou-se nas raízes.