Comparison of the clinical efficacy of twice-daily Ritalin and once-daily Equasym XL with placebo in children with Attention Deficit/Hyperactivity Disorder

Objective To compare the efficacy and safety of two methylphenidate (MPH) formulations—once-daily modified-release MPH (EqXL, Equasym™ XL) and twice-daily immediate-release methylphenidate (MPH-IR, Ritalin®)—and placebo in children with Attention Deficit/Hyperactivity Disorder (ADHD). Methods Children aged 6–12 years on a stable dose of MPH were randomized into a double-blind, three-arm, parallel-group, multi-center study and received 3 weeks of EqXL (20, 40, or 60 mg qd), MPH-IR (10, 20, or 30 mg bid) or placebo. Non-inferiority of EqXL to MPH-IR was assessed by the difference in the inattention/overactivity component of the overall teacher’s IOWA Conners’ Rating Scale on the last week of treatment (per protocol population). Safety was monitored by adverse events, laboratory parameters, vital signs, physical exam, and a Side Effect Rating Scale. Results The lower 97.5% confidence interval bound of the difference between MPH groups fell above the non-inferiority margin (−1.5 points) not only during the last week of treatment but during all three treatment weeks. Both MPH-treatment groups experienced superior benefit when compared to placebo during all treatment weeks (P < 0.001). All treatments were well tolerated. Conclusions EqXL given once-daily was non-inferior to MPH-IR given twice-daily. Both treatments were superior to placebo in reducing ADHD symptoms.

Early identification of stimulant treatment responders, partial responders and non-responders using objective measures in children and adolescents with hyperkinetic disorder

Background: The aim of this study was to evaluate stimulant medication response following a single dose of methylphenidate (MPH) in children and young people with hyperkinetic disorder using infrared motion analysis combined with a continuous performance task (QbTest system) as objective measures. The hypothesis was put forward that a moderate testdose of stimulant medication could determine a robust treatment response, partial response and non-response in relation to activity, attention and impulse control measures. Methods: The study included 44 children and young people between the ages of 7-18 years with a diagnosis of hyperkinetic disorder (F90 & F90.1). A single dose-protocol incorporated the time course effects of both immediate release MPH and extended release MPH (Concerta XL, Equasym XL) to determine comparable peak efficacy periods post intake. Results: A robust treatment response with objective measures reverting to the population mean was found in 37 participants (84%). Three participants (7%) demonstrated a partial response to MPH and four participants (9%) were determined as non-responders due to deteriorating activity measures together with no improvements in attention and impulse control measures. Conclusion: Objective measures provide early into prescribing the opportunity to measure treatment response and monitor adverse reactions to stimulant medication. Most treatment responders demonstrated an effective response to MPH on a moderate testdose facilitating a swift and more optimal titration process.

Sim-xl: A Powerful And User-friendly Tool For Peptide Cross-linking Analysis.

Chemical cross-linking has emerged as a powerful approach for the structural characterization of proteins and protein complexes. However, the correct identification of covalently linked (cross-linked or XL) peptides analyzed by tandem mass spectrometry is still an open challenge. Here we present SIM-XL, a software tool that can analyze data generated through commonly used cross-linkers (e.g., BS3/DSS). Our software introduces a new paradigm for search-space reduction, which ultimately accounts for its increase in speed and sensitivity. Moreover, our search engine is the first to capitalize on reporter ions for selecting tandem mass spectra derived from cross-linked peptides. It also makes available a 2D interaction map and a spectrum-annotation tool unmatched by any of its kind. We show SIM-XL to be more sensitive and faster than a competing tool when analyzing a data set obtained from the human HSP90. The software is freely available for academic use at http://patternlabforproteomics.org/sim-xl. A video demonstrating the tool is available at http://patternlabforproteomics.org/sim-xl/video. SIM-XL is the first tool to support XL data in the mzIdentML format; all data are thus available from the ProteomeXchange consortium (identifier PXD001677).

Apoptosis and Expression of Bcl-2, Bcl-XL, and Bax in Renal Cell Carcinomas

There are at present disparate published results with regard to the relevance of the Bcl-2 gene family, levels of apoptosis, and cell proliferation in the development and progression of renal cell carcinoma (RCC). The present study v analyses the interrelationship between the expression of representatives of the anti-apoptotic (Bcl-2, Bcl-X-L) or pro-apoptotic (Bax) Bcl-2 proteins, incidence of apoptosis, and mitosis in a selected small group of 22 graded RCCs that had paired normal renal tissue, or non-neoplastic tissue in the renal biopsy specimen. The cases were chosen to determine the feasibility of measuring these parameters as potential surrogate markers of progression or treatment failure of the cancers. The results showed that in approximately 50% of the RCCs, where Bcl-2 and/or Bcl-X-L expression was high, apoptosis it-as not detected, and when expression of these proteins was low or not found, increased levels of apoptosis were seen. In most of the remaining 50% of samples, high levels of Bcl-X-L but not Bcl-2 were negatively correlated with low levels of apoptosis (Bcl-X-L: r = -0.437, P = 0.07 and Bcl-2: r = + 0.560, P = 0.02). For the same group of samples, high Bax expression was found in association with apoptosis (r = + 0.578, P = 0,02). A novel finding was an association between low expression of Bcl-2 an/or Bcl-X-L in normal tissue and the level of expression of these proteins in the RCCs, an intrinsic variation that may be an individual patient factor. The results indicate that, in RCCs with increased expression of Bcl-2 and/or Bcl-X-L, levels of apoptosis are minimal and these combined factors may assist in progression of the cancers and resistance to treatments.

O Projecto XL – Pensar em grande = A propos du projet XL

RESUMO: Este trabalho descreve pormenorizadamente as valências do projecto «XL» da Associação Solidariedade e Desenvolvimento do Laranjeiro direccionado para a população jovem, multiétnica e multicultural, bem como as diversas actividades e parcerias. Em forma de conclusão apresentamos o caso de sucesso de um jovem entrevistado por um dos técnicos do «XL». ABSTRACT:This work describes on details about the «XL» project of the Associação Solidariedade e Desenvolvimento do Laranjeiro, directed for multiethnic and multicultural teenagers. It’s about their activities and partnerships, followed with the interview conducted by a «XL» worker of a young man, a successful case of this project.

Nutrição mineral de hortaliças. XL. concentração e acúmulo de micronutrientes em alface (Lactuca sativa L.) Cv. Brasil 48 e Clause's Aurélia

Com os objetivos de: - Determinar a concentração e acumulação de B, Cu, Fe, Mn e Zn nos cultivares Brasil 48 e Clause's Aurélia em função da idade. Foi conduzido um ensaio de campo em Piracicaba, São Paulo sobre o solo Terra Roxa Estruturada, série "Luiz de Queiroz" que vem sendo cultivado com hortaliças há mais de 50 anos. Mudas com 20 dias foram transplantadas para um espaçamento de 0,30 x 0,25 m. A adubação constou em aplicação de 200 g por metro quadrado da fórmula 4-14-10. Aos 20 e 40 dias após o transplante foi aplicado 5 g de sulfato de amônio por planta. A cultura foi irrigada sempre que necessário. As amostragens foram feitas por ocasião do transplante e depois a intervalos de dez dias aproximadamente. As plantas foram cortadas rente ao solo, lavadas, secas e analisadas para B, Cu, Fe, Mn e Zn de acordo com as instruções contidas em SARRUGE & HAAG (1974). Houve diferenças na concentração de nutrientes, mostrando-se o cultivar Brasil 48 mais exigente. Os cultivares Brasil 48 e Clause's Aurélia acumularam ao final do ciclo respectivamente, 896 g e 958 µg de B, 196µg e 168 µg de Cu, 6800 µg de Fe, 3534 µg e 1025 µg de Mn, 4462 µg e 2425 µg de Zn.

Estudos sobre a nutrição mineral do cafeeiro: XL. Fitomassa e conteúdo de macro e micronutrientes no material podado

Foi conduzido um ensaio numa plantação comercial de café de variedade Mundo Novo de 9 anos de idade, com uma população de 1904 covas/ha, destinada a avaliar a quantidade de biomassa e de nutrientes removidas por diferentes tipos de poda: recepa a 0,40m; decote a 1,00, 1,50 e 2,00 m; decote a 1,50m com esqueletamento. A análise do material e dos dados permitiu tirar-se as seguintes conclusões: (1) a biomassa removida pela poda foi maior na recepa (24,3 t de matéria fresca e 11,9 de matéria seca) e no decote a 1,00 m (20,6 e 10,1 t, respectivamente); seguia-se o decote a 1,50 m com esqueletamento que deu 19,4 e 8,3 t de matéria fresca e seca por hectare; os pesos da matéria fresca e seca correspondentes aos decotes a 1,50 m e 2,00 m foram: 12,1 e 5,4; 5,6 e 2,5 t/ha; (2) a relação existente entre a altura de poda e quantidade de fitomassa removida é descrita por equações de regressão simples; (3) as quantidades de nutrientes removidas são proporcionais as quantidades de material podado sendo as seguintes de acordo com a ordem dos tratamentos dado, em kg/ha: N - 320, 294, 162, 80 e 261; P - 18, 15, 10, 44 e 16; K - 286, 266, 168, 78 e 273; Ca - 149, 139, 63, 33 e 101: Mg - 30, 33, 16, 8 e 26; S - 10, 7,6, 3 e 10; as quantidades de micronutrientes removidas foram, em g/ha: B - 306, 337, 163, 83 e 268; Cu - 229, 219, 121, 51 e 191; Fe - 2783, 2328, 1367, 544 e 2,088; Mn - 437, 779, 264, 142 e 412; Zn - 174, 152, 74, 28 e 121; (3) foram derivadas equações de regressão simples que relacionam quantidade extraídas e altura da poda; (4) a reciclagem de fitomassa contribui com economia substancial de fertilizantes para a nova vegetação. Cerca de dois terços e três quartos de nutrientes, entretanto, estão contidos no material lenhoso de caules e ramos o que deve fazer que a sua disponibilidade seja mais lenta.

Bcl-xL is overexpressed in hormone-resistant prostate cancer and promotes survival of LNCaP cells via interaction with proapoptotic Bak.

Androgen-sensitive prostate cancer cells turn androgen resistant through complex mechanisms that involve dysregulation of apoptosis. We investigated the role of antiapoptotic Bcl-xL in the progression of prostate cancer as well as the interactions of Bcl-xL with proapoptotic Bax and Bak in androgen-dependent and -independent prostate cancer cells. Immunohistochemical analysis was used to study the expression of Bcl-xL in a series of 139 prostate carcinomas and its association with Gleason grade and time to hormone resistance. Expression of Bcl-xL was more abundant in prostate carcinomas of higher Gleason grades and significantly associated with the onset of hormone-refractory disease. In vivo interactions of Bcl-xL with Bax or Bak in untreated and camptothecin-treated LNCaP and PC3 cells were investigated by means of coimmunoprecipitation. In the absence of any stimuli, Bcl-xL interacts with Bax and Bak in androgen-independent PC3 cells but only with Bak in androgen-dependent LNCaP cells. Interactions of Bcl-xL with Bax and Bak were also evidenced in lysates from high-grade prostate cancer tissues. In LNCaP cells treated with camptothecin, an inhibitor of topoisomerase I, the interaction between Bcl-xL and Bak was absent after 36 h, Bcl-xL decreased gradually and Bak increased coincidentally with the progress of apoptosis. These results support a model in which Bcl-xL would exert an inhibitory effect over Bak via heterodimerization. We propose that these interactions may provide mechanisms for suppressing the activity of proapoptotic Bax and Bak in prostate cancer cells and that Bcl-xL expression contributes to androgen resistance and progression of prostate cancer.

The Bcl-2/Bcl-XL inhibitor ABT-737 promotes death of retinoblastoma cancer cells.

Purpose: Retinoblastoma is a malignant tumor that usually develops in early childhood. During retinoblastoma spreading, RB1 gene inactivation is followed by additional genomic modifications which progressively lead to resistance of tumor cells to death. Drugs that act at downstream levels of death signaling pathways should therefore be interesting in killing retinoblastoma cells. ABT-737, a BH3 mimetic molecule effective at the mitochondrial level, has been shown to induce apoptosis in different human tumoral cell lines as well as in primary patient-derived cells, and in a mouse xenograph model. Methods: In this report, we analyzed the pro-death effect of ABT-737 on two human retinoblastoma cell lines, Y79 and WERI-Rb, as well as on the mouse photoreceptor cell line 661W. Results: We observed that ABT-737 was very effective as a single agent in inducing human WERI-Rb cells apoptosis without affecting the mouse 661W photoreceptor cells. However human Y79 cells were resistant to ABT-737, as a probable consequence of the absence of Bax. The high sensitivity of WERI-Rb to ABT-737 can be increased by downregulating Mcl-1 using the proteasome inhibitor MG-132. Preliminary analysis in primary mouse retinoblastoma tumoral cell lines predicts high sensitivity to ABT-737. Conclusion: Our data suggest that ABT-737 or related compounds could be a highly effective drug in the treatment of some retinoblastomas.

La Merluza en la Eureka XL, 19-21 de Julio, 1978

Demuestra que durante la Operación Eureka XL, la merluza mostró visiblemente un panorama con características diferentes a los modelos normales de distribución. Este cambio tiene importancia vital en la explotación y en la administración del recurso merluza. Menciona que la flota de altura ha cambiado su área habitual de pesca y otras flotas costeras están capturando la especie en forma no usual.