Circulating Glucocorticoid Bioactivity and Serum Glucocorticoid-Responsive Biomarkers during Steroid Therapy in Children and Adolescents with Inflammatory Bowel Disease

Objective: Glucocorticoid therapy is used worldwide to treat various inflammatory and immune conditions, including inflammatory bowel disease (IBD). In IBD, 80% of the patients obtain a positive response to the therapy; however the development of glucocorticoid-related side-effects is common. Our aim was therefore to study the possibility of optimizing glucocorticoid therapy in children and adolescents with IBD by measuring circulating glucocorticoid bioactivity (GBA) and serum glucocorticoid-responsive biomarkers in patients receiving steroid treatment for active disease. Methods: A total of sixty-nine paediatric IBD patients from the Paediatric Outpatient Clinics of the University Hospitals of Helsinki and Tampere participated in the studies. Control patients included 101 non-IBD patients and 41 disease controls in remission. In patients with active disease, blood samples were withdrawn before the glucocorticoid therapy was started, at 2-4 weeks after the initiation of the steroid and at 1-month intervals thereafter. Clinical response to glucocorticoid treatment and the development of steroid adverse events was carefully registered. GBA was analyzed with a COS-1 cell bioassay. The measured glucocorticoid therapy-responsive biomarkers included adipocyte-derived adiponectin and leptin, bone turnover-related collagen markers amino-terminal type I procollagen propeptide (PINP) and carboxyterminal telopeptide of type I collagen (ICTP) as well as insulin-like growth factor 1 (IGF-1) and sex hormone-binding globulin (SHBG), and inflammatory marker high-sensitivity C-reactive protein (hs-CRP). Results: The most promising marker for glucocorticoid sensitivity was serum adiponectin that associated with steroid therapy–related adverse events. Serum leptin indicated a similar trend. In contrast, circulating GBA rose in all subjects receiving glucocorticoid treatment but did not associate with the clinical response to steroids or with glucocorticoid therapy-related side-effects. Of notice, young patients (<10 years) showed similar GBA levels than older patients, despite receiving higher weight-adjusted doses of glucocorticoid. Markers of bone formation were lower in children with active IBD than in the control patients, probably reflecting the suppressive effect of the active inflammation. The onset of the glucocorticoid therapy further suppressed bone turnover. Inflammatory marker hs-CRP decreased readily after the initiation of the steroid, however the decrease did not associate with the clinical response to glucocorticoids. Conclusions: This is the first study to show that adipocyte-derived adiponectin associates with steroid therapy-induced side-effects. Further studies are needed, but it is possible that the adiponectin measurement could aid the recognition of glucocorticoid-sensitive patients in the future. GBA and the other markers reflecting glucocorticoid activity in different tissues changed during the treatment, however their change did not correlate with the therapeutic response to steroids or with the development of glucocorticoid-related side effects and therefore cannot guide the therapy in these patients. Studies such as as the present one that combine clinical data with newly developed biomolecular technology are needed to step-by-step build a general picture of the glucocorticoid actions in different tissues.

Qualidade de vida em pacientes com más oclusões de Classe III tratados com o protocolo do benefício antecipado

O protocolo do benefício antecipado é uma modalidade de tratamento ortocirúrgico que não envolve o preparo ortodôntico prévio. De acordo com os preceitos da Odontologia baseada em evidências, é essencial que se conheça o impacto dessa modalidade de tratamento na vida diária dos pacientes, uma vez que, para ser considerada viável, deve-se comprovar que ela oferece benefícios significativos para a qualidade de vida. Esse estudo objetivou conhecer os efeitos do tratamento ortocirúrgico com o protocolo do benefício antecipado na qualidade de vida e na autopercepção estética dos pacientes, durante dois anos de acompanhamento, e compará-los com os percebidos pelos pacientes tratados pela técnica tradicional. A amostra foi constituída por dezesseis pacientes, sendo oito no grupo tratado com o benefício antecipado (GBA) e oito no grupo tratado com a técnica ortocirúrgica tradicional. A qualidade de vida dos pacientes foi avaliada com três questionários: o OQLQ (Orthognathic Quality of Life Questionnaire), o OHIP-14 (Oral Health Impact Profile Short Version) e o SF-36 (Medical Outcomes Study 36 Item Short-Form Health Survey), em suas versões traduzidas e validadas para o português, e a autopercepção estética e a gravidade da má oclusão foram avaliadas com o Índice de Necessidade de Tratamento Ortodôntico (IOTN). Os exames foram repetidos em sete momentos de avaliação dos participantes: no exame inicial (T0), um mês depois do início do tratamento (T1), três meses depois do início do tratamento (T2), seis meses depois do início do tratamento (T3), um ano depois do início do tratamento e dois anos após o início do tratamento ou no término do tratamento ortocirúrgico (T5). Para ambos os grupos, houve um tempo pós-operatório (TPO) que foi realizado entre duas e três semanas após a cirurgia ortognática. A análise dos dados foi realizada com os testes de Mann-Whitney e de Friedman. Os pacientes do grupo GBA tiveram uma redução significativa no OQLQ (p<0,001) e no OHIP-14 (p<0,001) após dois anos de avaliação. Essa melhora foi progressiva e iniciada após a realização da cirurgia ortognática. O SF-36 apresentou melhoras significativas nas dimensões de capacidade funcional, limitação por aspectos físicos e aspectos sociais (p<0,001). A autopercepção estética comportou-se de maneira similar, com uma melhora progressiva e significativa (p<0,001), acompanhada de uma melhora significativa na gravidade da má oclusão (p<0,001). Porém os indivíduos que removeram o aparelho tiveram OHRQoL e autopercepção estética melhores em relação aos pacientes que não finalizaram o tratamento no período de dois anos no grupo GBA (N=4). No grupo GTT nenhum paciente foi operado após os dois anos de acompanhamento, e pioras significativas foram observadas no OQLQ (p<0,001) e no OHIP-14 (p<0,001) e na autopercepção estética (p<0,001). O CPO-D não teve alteração significativa para nenhum dos dois grupos. Concluiu-se que o tratamento ortocirúrgico com o protocolo do benefício antecipado gerou efeitos mais positivos na qualidade de vida, na autopercepção estética e na gravidade da má oclusão do que o tratamento ortocirúrgico tradicional após dois anos.

How well do we understand the clusters found in microarray data?

Clare, A. and King R.D. (2002) How well do we understand the clusters found in microarray data? In In Silico Biol. 2, 0046

Recherche des facteurs génétiques à l’origine de la maladie de Parkinson dans la population canadienne-française du Québec

La maladie de Parkinson (MP) est une affection neurodégénérative invalidante et incurable. Il est maintenant clairement établi que d’importants déterminants génétiques prédisposent à son apparition. La recherche génétique sur des formes familiales de la MP a mené à la découverte d’un minimum de six gènes causatifs (SNCA, LRRK2, Parkin, PINK1, DJ-1 and GBA) et certains, par exemple LRRK2, contiennent des variations génétiques qui prédisposent également aux formes sporadiques. La caractérisation des protéines codées par ces gènes a mené à une meilleure compréhension des mécanismes moléculaires sousjacents. Toutefois, en dépit de ces efforts, les causes menant à l’apparition de la MP restent inconnues pour la majorité des patients. L’objectif général des présents travaux était d’identifier des mutations prédisposant à la MP dans la population canadienne-française du Québec à partir d’une cohorte composée principalement de patients sporadiques. Le premier volet de ce projet consistait à déterminer la présence de mutations de LRRK2 dans notre cohorte en séquençant directement les exons contenant la majorité des mutations pathogéniques et en effectuant une étude d’association. Nous n’avons identifié aucune mutation et l’étude d’association s’est avérée négative, suggérant ainsi que LRRK2 n’est pas une cause significative de la MP dans la population canadienne-française. La deuxième partie du projet avait pour objectif d’identifier de nouveaux gènes causatifs en séquençant directement des gènes candidats choisis à cause de leurs implications dans différents mécanismes moléculaires sous-tendant la MP. Notre hypothèse de recherche était basée sur l’idée que la MP est principalement due à des mutations individuellement rares dans un grand nombre de gènes différents. Nous avons identifié des mutations rares dans les gènes PICK1 et MFN1. Le premier code pour une protéine impliquée dans la régulation de la transmission du glutamate tandis que le second est un des acteurs-clés du processus de fusion mitochondriale. Nos résultats, qui devront être répliqués, suggèrent que le séquençage à grande échelle pourrait être une méthode prometteuse d’élucidation des facteurs de prédisposition génétiques à la MP ; ils soulignent l’intérêt d’utiliser une population fondatrice comme les canadiens-français pour ce type d’étude et devraient permettre d’approfondir les connaissances sur la pathogénèse moléculaire de la MP.

¿A quiénes afecta el desempleo? análisis de la tasa de incidencia en Colombia

El análisis de la dimensión de riesgo en el estudio del desempleo, complementa el estudio de aspectos como su tipología, la importancia de la intermediación laboral o la vulnerabilidad de ciertos grupos. En este sentido, la tasa de incidencia representa un indicador compuesto que tiene en cuenta el volumen de desempleados y la persistencia en este estado mediante la incorporación de la duración media del desempleo. El análisis de la tasa de incidencia permite caracterizar de manera más completa a quienes tienen una mayor probabilidad de entrar en el desempleo o permanecer en esta situación. Se encuentra que en Colombia existen diferencias significativas entre la tasa de desempleo y la tasa de incidencia, lo que implica que la situación del mercado de trabajo no sólo se explica por el efecto que los choques económicos tienen sobre la composición de la oferta y demanda de trabajo sino también por los fenómenos de duración en los diferentes estados laborales. Estos eventos se pueden considerar igualmente importantes para explicar la dinámica de corto y mediano plazo del mercado laboral.

Disseny i construcció d'un motor 3D en temps real per la Gameboy Advance

El projecte desenvolupat ha tractat l’estudi i disseny d’un motor 3D interactiu a la consola Game Boy Advance (GBA). La GBA disposa d’un processador ARM7TDMI a 16’78 Mhz i no disposa de operacions 3D per-hardware, és una consola lenta en comparació les que podem trobar al mercat d’avui en dia. Aquest treball, va partir de la construcció d’un prototipus ray-casting per-columna. Després, vàrem adaptar-lo a una estructura de portals i sectors. Més tard, es va introduir el mapeig de sostre/terra i de paisatges. Per últim, vàrem introduir efectes a la renderització per donar més realisme al recorregut del món, com il·luminació, objectes, etc. Tot i que es va estudiar l’arquitectura d’un motor eficient, no es tenia prou per arribar a tenir un motor interactiu. Una de les tasques més difícils va ser la part de optimització. Per aconseguir-ho s’ha hagut de substituir operacions a temps real costoses a temps de execució, replantejar parts de l’algorisme per fer-lo més eficient, entre altres

Multicenter Analysis of Glucocerebrosidase Mutations in Parkinson`s Disease

Background Recent studies indicate an increased frequency of mutations in the gene encoding glucocerebrosidase (GBA), a deficiency of which causes Gaucher`s disease, among patients with Parkinson`s disease. We aimed to ascertain the frequency of GBA mutations in an ethnically diverse group of patients with Parkinson`s disease. Methods Sixteen centers participated in our international, collaborative study: five from the Americas, six from Europe, two from Israel, and three from Asia. Each center genotyped a standard DNA panel to permit comparison of the genotyping results across centers. Genotypes and phenotypic data from a total of 5691 patients with Parkinson`s disease (780 Ashkenazi Jews) and 4898 controls (387 Ashkenazi Jews) were analyzed, with multivariate logistic-regression models and the Mantel-Haenszel procedure used to estimate odds ratios across centers. Results All 16 centers could detect two GBA mutations, L444P and N370S. Among Ashkenazi Jewish subjects, either mutation was found in 15% of patients and 3% of controls, and among non-Ashkenazi Jewish subjects, either mutation was found in 3% of patients and less than 1% of controls. GBA was fully sequenced for 1883 non-Ashkenazi Jewish patients, and mutations were identified in 7%, showing that limited mutation screening can miss half the mutant alleles. The odds ratio for any GBA mutation in patients versus controls was 5.43 across centers. As compared with patients who did not carry a GBA mutation, those with a GBA mutation presented earlier with the disease, were more likely to have affected relatives, and were more likely to have atypical clinical manifestations. Conclusions Data collected from 16 centers demonstrate that there is a strong association between GBA mutations and Parkinson`s disease.

Perspectives for Novel Mixed Diruthenium-Organic Drugs as Metallopharmaceuticals in Cancer Therapy

Ruthenium compounds have been actively studied as metallodrugs for cancer therapy. Representatives of ruthenium-based antitumor drugs are the classes of ruthenium(III)-chlorido-(N-ligand)complexes, including the drugs namely NAMI-A and KP1019 in clinical trials, and ruthenium(II)-arene organometallics, with some compounds currently undergoing advanced preclinical testing. An alternative approach for tumor-inhibiting metallodrugs is the coordination of metal ions to organic pharmaceuticals. The combination of antitumor-active ruthenium ion with biologically-active pro-ligands in single compounds can result in the enhancement of activity, for example through synergistic effects. In the present article, some developments in the ruthenium-based antitumor drugs field are briefly highlighted and recent studies on mixed diruthenium-organic drugs as metallopharmaceuticals in cancer therapy are described. Novel organic pharmaceuticals-containing diruthenium(II, III)complexes have shown promising antitumor activity for C6 rat glioma - a model for glioblastoma multiforme (GBA).

Rastreamento populacional para Doença de Gaucher em Tabuleiro do Norte-CE

Background. Gaucher Disease (GD) is a hereditary lysosomal storage disorder characterized by the accumulation of glucosylceramide, mainly in the cells of the reticuloendothelial system, due to a deficiency of the enzyme acid β-glucosidase (GBA). Diagnosis is usually based on measurement of GBA activity in peripheral leukocytes. The purpose of this study was to evaluate the ability of screening for GBA and chitotriosidase activity using Dried Blood Spots on Filter Paper (DBS-FP) to identify individuals at high risk for GD in high-risk populations such as that of Tabuleiro do Norte, a small town in Northeastern Brazil. Methods. Between June 1, 2007 and May 31, 2008, 740 consented residents and descendants of traditional families from Tabuleiro do Norte were submitted to screening with DBS-FP. Subjects with GBA activity <2.19 nmol/h/mL were referred to analysis of GBA and chitotriosidase activity in peripheral leukocytes and in plasma, respectively. Subjects at highest risk for GD (GBA activity in peripheral leukocytes <5.6 nmol/h/mg protein) were submitted to molecular analysis to confirm diagnosis. Results. Screening with DBS-FP identified 135 subjects (18.2%) with GBA activity <2.19 nmol/h/mL, 131 of whom remained in the study. In 10 of these (7.6%), GBA activity in leukocytes was 2.6 5.5 nmol/h/mg protein. Subsequent molecular analysis confirmed 6 cases of heterozygosity and 4 normals for GD. Conclusion. DBS-FP assay was shown to be an effective initial GD screening strategy for high-prevalence populations in developing regions. Diagnosis could not be established from GBA activity in leukocytes alone, but required confirmation with molecular analysis

Influência da aptidão aeróbia no running anaerobic sprint test (RAST)

The aim of this study was to investigate the possible influence of different levels of aerobic fitness (VO2MAX) on the parameters of the running anaerobic sprint test (RAST). Thirty-eight subjects (Age = 18.1 ± 2.5 years, Height = 173 ± 1 cm and Body mass = 65.1 ± 6.5 kg) were classified into two groups, low and high aerobic fitness (LAF: n = 22 and HAF: n = 16). The VO2MAX was determined by an incremental exercise performed until exhaustion. The RAST was composed of six maximal efforts of 35m separated by 10s passive recovery. The VO2MAX was significantly different between groups (LAF = 51.7 ± 1.9 mL.kg -1.min-1; HAF = 58.6 ± 3.1 mL.kg -1.min-1). The mean power (MP) was significantly higher in the LAF (552.7 ± 132.1 W) in relation to the HAF group (463.6 ± 132.8 W). The impulse (ImP) was significantly correlated with the VO 2MAX in HAF. It can be concluded that there is an indication that the aerobic metabolism exerts an influence on the completion of RAST.

Caratterizzazione dei sintomi neurovegetativi e neuropsicologici nella malattia di Parkinson associata a mutazioni del gene glucocerebrosidasi

Pochi studi hanno indagato il profilo dei sintomi non-motori nella malattia di Parkinson associata al gene glucocerebrosidasi (GBA). Questo studio è mirato alla caratterizzazione dei sintomi non-motori, con particolare attenzione alla valutazione delle funzioni neurovegetativa, cognitiva e comportamentale, nel parkinsonismo associato a mutazione del gene GBA con la finalità di verificare se tali sintomi non-motori siano parte dello spettro clinico di questi pazienti. E’ stato condotto su una coorte di pazienti affetti da malattia di Parkinson che erano stati tutti sottoposti ad una analisi genetica per la ricerca di mutazioni in uno dei geni finora associati alla malattia di Parkinson. All’interno di questa coorte omogenea sono stati identificati due gruppi diversi in relazione al genotipo (pazienti portatori della mutazione GBA e pazienti non portatori di nessuna mutazione) e le caratteristiche non-motorie sono state confrontate nei due gruppi. Sono state pertanto indagati il sistema nervoso autonomo, mediante studio dei riflessi cardiovascolari e analisi dei sintomi disautonomici, e le funzioni cognitivo-comportamentali in pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA. I risultati sono stati messi a confronto con il gruppo di controllo. Lo studio ha mostrato che i pazienti affetti da malattia di Parkinson associata a mutazione del gene GBA presentavano maggiore frequenza di disfunzioni ortosimpatiche, depressione, ansia, apatia, impulsività, oltre che di disturbi del controllo degli impulsi rispetto ai pazienti non portatori. In conclusione, i pazienti GBA positivi possono esprimere una sintomatologia non-motoria multidominio con sintomi autonomici, cognitivi e comportamentali in primo piano. Pertanto l’impostazione terapeutica in questi pazienti dovrebbe includere una accurata valutazione dei sintomi non-motori e un loro monitoraggio nel follow up clinico, allo scopo di ottimizzare i risultati e ridurre i rischi di complicazioni.

Decreto 1282/2003: reglamentación de la Ley Nº 25.673. Programa Nacional de Salud Sexual y Procreación Responsable

Se reglamenta la Ley 25673 Sobre el Programa de Salud Sexual y Procreación Responsable.