Methotrexate Withdrawal at 6 vs 12 Months in Juvenile Idiopathic Arthritis in Remission A Randomized Clinical Trial

Context Novel therapies have improved the remission rate in chronic inflammatory disorders including juvenile idiopathic arthritis (JIA). Therefore, strategies of tapering therapy and reliable parameters for detecting subclinical inflammation have now become challenging questions. Objectives To analyze whether longer methotrexate treatment during remission of JIA prevents flares after withdrawal of medication and whether specific biomarkers identify patients at risk for flares. Design, Setting, and Patients Prospective, open, multicenter, medication-withdrawal randomized clinical trial including 364 patients (median age, 11.0 years) with JIA recruited in 61 centers from 29 countries between February 2005 and June 2006. Patients were included at first confirmation of clinical remission while continuing medication. At the time of therapy withdrawal, levels of the phagocyte activation marker myeloid-related proteins 8 and 14 heterocomplex (MRP8/14) were determined. Intervention Patients were randomly assigned to continue with methotrexate therapy for either 6 months (group 1 [n = 183]) or 12 months (group 2 [n = 181]) after induction of disease remission. Main Outcome Measures Primary outcome was relapse rate in the 2 treatment groups; secondary outcome was time to relapse. In a prespecified cohort analysis, the prognostic accuracy of MRP8/14 concentrations for the risk of flares was assessed. Results Intention-to-treat analysis of the primary outcome revealed relapse within 24 months after the inclusion into the study in 98 of 183 patients (relapse rate, 56.7%) in group 1 and 94 of 181 (55.6%) in group 2. The odds ratio for group 1 vs group 2 was 1.02 (95% CI, 0.82-1.27; P=.86). The median relapse-free interval after inclusion was 21.0 months in group 1 and 23.0 months in group 2. The hazard ratio for group 1 vs group 2 was 1.07 (95% CI, 0.82-1.41; P=.61). Median follow-up duration after inclusion was 34.2 and 34.3 months in groups 1 and 2, respectively. Levels of MRP8/14 during remission were significantly higher in patients who subsequently developed flares (median, 715 [IQR, 320-1110] ng/mL) compared with patients maintaining stable remission (400 [IQR, 220-800] ng/mL; P=.003). Low MRP8/14 levels indicated a low risk of flares within the next 3 months following the biomarker test (area under the receiver operating characteristic curve, 0.76; 95% CI, 0.62-0.90). Conclusions In patients with JIA in remission, a 12-month vs 6-month withdrawal of methotrexate did not reduce the relapse rate. Higher MRP8/14 concentrations were associated with risk of relapse after discontinuing methotrexate.

Peripheral withdrawal recruits distinct central nuclei in morphine-dependent rats

This study examined if brain pathways in morphine-dependent rats are activated by opioid withdrawal precipitated outside the central nervous system. Withdrawal precipitated with a peripherally acting quaternary opioid antagonist (naloxone methiodide) increased Fos expression but caused a more restricted pattern of neuronal activation than systemic withdrawal (precipitated with naloxone which enters the brain). There was no effect on locus coeruleus and significantly smaller increases in Fos neurons were produced in most other areas. However in the ventrolateral medulla (A1/C1 catecholamine neurons), nucleus of the solitary tract (A2/C2 catecholamine neurons), lateral parabrachial nucleus, supramamillary nucleus, bed nucleus of the stria terminalis. accumbens core and medial prefrontal cortex no differences in the withdrawal treatments were detected. We have shown that peripheral opioid withdrawal can affect central nervous system pathways. Crown Copyright (C) 2001 Published by Elsevier Science Ltd. All rights reserved.

Optimização das fugas pela boca durante o CPAP nasal: banda submentoniana versus máscara facial

Introdução: O CPAP nasal é o tratamento de eleição para os pacientes com Síndrome da Apneia Obstrutiva do Sono (SAOS). Com a máscara nasal podem ocorrer fugas de ar pela boca, que podem por em causa a aderência do paciente ao tratamento devido muitas vezes ao desconforto que provocam, ao aumento do trabalho respiratório e por afectarem a qualidade do sono. Objectivos: Este estudo tem como principal objectivo verificar a eficácia da banda submentoniana e da máscara facial na correcção das fugas pela boca em pacientes com SAOS. Métodos e Participantes: Uma amostra de conveniência de 15 pacientes (8 homens) com SAOS e a fazerem CPAP com máscara nasal, foi recrutada. Foram divididos em dois grupos A e B, onde no grupo A se colocou a banda submentoniana e no grupo B se alterou a interface para máscara facial. Medidas e Resultados: As variáveis avaliadas neste estudo foram as fugas, o IAH, o percentil 95 da pressão de tratamento, a Sa,O2 e os efeitos adversos das duas intervenções. O nível de fugas reduziu no grupo A de 38±11,27 para 24,55±14,30L/min (p=0,002) e no grupo B de 34,34±16,50 para 18,51±16,22L/min (p=0,008). O IAH aumentou no grupo B de 2,60±2,13 para 4,41±3,88 (p=0,016). Relativamente ao percentil 95 da pressão de tratamento aumentou nos dois grupos (Grupo A de 10,15±2,63 para 12,08±2,45cmH2O (p=0,008) e no Grupo B 10,51±1,88 para 12,64±1,29cmH2O (p=0,008)). A Sa,O2 mínima aumentou e o tempo<90% diminui no grupo A com p=0,008, p=0,031, respectivamente. Quanto ao uso auto-reportado verificaram-se poucos efeitos adversos, salientando-se apenas a facilidade de colocação da banda submentoniana, a secura da boca nos dois grupos, a pressão no queixo provocada pela banda e a dor no dorso do nariz provocada pela máscara facial. Conclusão: Ambas as estratégias provaram ser mais eficazes a reduzir a fuga que a máscara nasal. Foram bem toleradas e com poucos efeitos adversos.

Withdrawal of maintenance therapy for cytomegalovirus retinitis in AIDS patients exhibiting immunological response to HAART

BACKGROUND: Before the introduction of highly active antiretroviral therapy (HAART), CMV retinitis was a common complication in patients with advanced HIV disease and the therapy was well established; it consisted of an induction phase to control the infection with ganciclovir, followed by a lifelong maintenance phase to avoid or delay relapses. METHODS: To determine the safety of CMV maintenance therapy withdrawal in patients with immune recovery after HAART, 35 patients with treated CMV retinitis, on maintenance therapy, with CD4+ cell count greater than 100 cells/mm³ for at least three months, but almost all patients presented these values for more than six months and viral load < 30000 copies/mL, were prospectively evaluated for the recurrence of CMV disease. Maintenance therapy was withdrawal at inclusion, and patients were monitored for at least 48 weeks by clinical and ophthalmologic evaluations, and by determination of CMV viremia markers (antigenemia-pp65), CD4+/CD8+ counts and plasma HIV RNA levels. Lymphoproliferative assays were performed on 26/35 patients. RESULTS: From 35 patients included, only one had confirmed reactivation of CMV retinitis, at day 120 of follow-up. No patient returned positive antigenemia tests. No correlation between lymphoproliferative assays and CD4+ counts was observed. CONCLUSION: CMV retinitis maintenance therapy discontinuation is safe for those patients with quantitative immune recovery after HAART.

Impact of alcohol intoxication and withdrawal syndrome on social phobia and panic disorder in alcoholic inpatients

PURPOSE: To investigate the impact of alcohol intoxication and withdrawal on the course of social phobia and panic disorder. METHOD: A group of 41 alcoholic inpatients undergoing detoxification therapy were interviewed using the SCID-I (DSM-IV) and questions to detect fluctuations in the course of social phobia and panic disorder as a function of the different phases in alcohol dependence (intoxication, withdrawal, and lucid interval). RESULTS: Only 1 (2.4%) patient presented panic disorder throughout life, and 9 (21.9%) had panic attacks during alcohol intoxication or during the withdrawal syndrome. Sixteen (39%) alcoholic patients showed social phobia with onset prior to drug use. However, drinking eventually became unable to alleviate social phobia symptoms or worsened such symptoms in 31.2% of social-phobic patients. While patients with social phobia reported a significant improvement in psychiatric symptoms during alcohol intoxication, patients experiencing panic attacks worsened significantly during intoxication. In the withdrawal phase, patients with social phobia tended to have more and more intense phobic symptoms. CONCLUSION: Our findings indicate that the impact of alcohol intoxication is different for social phobia as compared to panic disorder, at first decreasing the social-phobic symptoms but later aggravating them. In panic disorder, the impact of intoxication by alcohol is more harmful, at least in the short term.

Mecanismos neurobiologicos involucrados en la sensibilizacion emocional inducida por abstinencia a drogas de abuso y estrés. Neurobiological mechanisms involved in emotional sensitization induced by withdrawal from drugs of abuse and stress.

El objetivo principal de este proyecto es estudiar los mecanismos neurobiológicos involucrados en el proceso de sensibilización emocional inducido por la abstinencia a drogas de abuso o por la exposición a un estímulo estresante de caracteristicas incontrolables. El modelo animal de sensibilización a utilizar en este proyecto es la facilitación en la formación de memoria de miedo producida por dichos tratamientos. Nuestra hipótesis sugiere que este proceso es el resultado de un mecanismo desinhibitorio de las interneuronas GABAérgicas del complejo basolateral de la amigdala. Por lo tanto se proponen los siguientes experimentos: 1) El estudio del curso temporal del efecto facilitador sobre la formación de una nueva memoria de miedo luego de la abstinencia a drogas o la exposición a un estímulo estresante (inmovilización). 2) La evaluación de la liberación"in vivo" de dopamina del complejo basolateral de la amigdala durante la adquisición y la expresión de la memoria de miedo en animales previamente expuestos a la abstinencia o al estres. 3) El estudio de la infusión local de antagonistas de receptores dopaminérgicos en el complejo basolateral de la amígdala (BLA) o en el nucleo central de la amígdala (CeA) antes del estrés sobre la adquisición y la expresión de una memoria de miedo. 4) La determinación de la actividad de ERK 1/2 y CREB en el complejo basolateral de la amigdala o en el nucleo central de la amígdala durante la adquisición y la expresión de una memoria de miedo en animales abstinentes o estresados. 5)El estudio de la infusión local de inhibidores de la MEK 1/2 en el complejo basolateral de la amigdala o en el nucleo central de la amígdala antes del estrés sobre la adquisición y la expresión de una memoria de miedo. La facilitación para generar memorias de miedo podría ser un componente crítico del síndrome de abstinencia al etanol responsable de las altas tasas de recurrencia asociadas con el alcoholismo. Por lo tanto se investigará el efecto de la evocación de la memoria de miedo sobre la autoadministración de etanol utilizando un paradigma de libre elección entre agua y soluciones de concentración creciente de etanol en animales en abstinencia al etanol. Con el objeto de investigar si las propiedades reforzantes del etanol están involucradas en el potencial aumento de la ingesta de etanol inducido por la evocación de una memoria de miedo, se evaluará el efecto reforzante de etanol utilizando el paradigma de preferencia por un contexto asociado al etanol.

Procesos de plasticidad sináptica en gyrus dentado hipocampal durante la administración crónica y el síndrome de abstinencia a cocaína. Synaptic plasticity in hippocampal dentate gyrus during chronic administration and withdrawal from cocaine.

Los procesos neuronales adaptativos que se observan como consecuencia de la administración crónica de drogas de abuso, son similares a los procesos plásticos que subyacen al aprendizaje y la memoria. Por otra parte, el hipocampo forma parte del circuito neuronal responsable de los cambios conductuales observados como consecuencia de la administración crónica de diferentes drogas de abuso. De acuerdo con esto, resultados previos de nuestro laboratorio demostraron que la plasticidad sináptica en el hipocampo y las claves contextuales relacionadas con la administración de la droga, son relevantes para el incremento de la plasticidad hipocampal por la administración crónica de diazepam. Específicamente en el gyrus dentado hipocampal se han descripto fenómenos plásticos relacionados con la exposición crónica a psicofármacos, tales como facilitación en la transmisión sináptica, disminución de la proliferación celular y el aumento del factor de transcripción ?Fos B. Debido a la correlación existente entre los mecanismos de plasticidad neuronal, los aprendizaje asociativos y formación de memorias y aquellos responsables de la adicción, el objetivo general de este trabajo es caracterizar los cambios inducidos por la exposición repetida de cocaína y durante el periodo de abstinencia, en la excitabilidad neuronal de las células del gyrus dentado hipocampal, los canales iónicos afectados y los posibles mecanismos bioquímicos involucrados en dichos cambios, que podrían explicar las alteraciones conductuales observadas después de dicho tratamiento. Con este propósito, se estudiará: 1) la plasticidad sináptica (potenciación a largo plazo, LTP y depotenciación a largo plazo, LTD) en el gyrus dentado, mediante registros electrofisiológios multiunitarios; 2)la excitabilidad de las células granulares del gyrus dentado y la actividad de los canales iónicos, utilizando la técnica de patch clamp; 3) las alteraciones en la neurotransmisión glutamatergica, midiendo los niveles del neurotransmisor in vivo, utilizando la técnica de microdiálisis; el tráfico de receptores glutamatérgicos, utilizando la técnica de western-blott, 4) la participación del óxido nítrico en los cambios adaptativos observados como consecuencia de la sensibilización a cocaína. Además, mediante la utilización de técnicas comportamentales (avoidance inhibitorio), se estudiarán las posibles alteraciones de conductas que se sabe dependen de la integridad funcional del hipocampo.En relación a los resultados del presente proyecto se espera obtener un incremento en la plasticidad sináptica, en la excitabilidad neuronal de las células granulares del gyrus dentado de la formación hipocámpica, en la liberación extracelular de glutamato in vivo, como así también en el tráfico de receptores glutamatérgicos. Además se espera obtener un aumento de las vías de señalización activadas por la acción de glutamato, como la de óxido nítrico/GMPc, como consecuencia de la administración crónica de cocaína. Con este aumento global de la plasticidad sináptica hipocampal, las conductas dependientes de esta estructura debieran estar facilitadas, demostrando así una participación activa del hipocampo en los procesos de sensibilización y posiblemente en la adicción a psicoestimulantes. La caracterización del impacto del desarrollo de sensibilización a cocaína en la excitabilidad neuronal en el hipocampo, sobre los sistemas de neurotransmisión y las vías de señalización involucradas contribuirían a dilucidar los mecanismos que contribuyen al desarrollo de sensibilización a cocaína, los cuales podrían representar potenciales blancos terapéuticos para el tratamiento de la adicción, considerando principalmente aspectos específicos de la actividad eléctrica neuronal y la plasticidad sináptica asociada con las diferentes fases del ciclo de la adicción.

O impacto do CPAP na reabilitação cardíaca de pacientes com ICC: relato de caso

A insuficiência cardíaca congestiva é uma patologia que limita a função física do paciente. Neste estudo foi analisada uma paciente, realizando um programa de reabilitação cardíaca associado à pressão positiva contínua nas vias aéreas, aferindo-se antes do estudo e após 6 semanas, o teste de caminhada de 6 minutos (TC6M), questionário de qualidade de vida e ecocardiograma. A paciente aumentou a distância no TC6M de 152,5 m para 520,44 m. O questionário Minnesota reduziu de 62 para 18. A fração de ejeção subiu de 33% para 36%. Na paciente estudada a conduta melhorou o desempenho físico e a qualidade de vida.

Withdrawal, "serosorting" and "strategic positioning": use of risk reduction strategies with casual sex partners in men who have sex with men (MSM) in Switzerland, 2007

Introduction: 1) Withdrawal before ejaculation, "serosorting" (to choose a partner of same serostatus) and "strategic positioning" (only insertive vs. only receptive role in anal sex according to serostatus) are known to be used by MSM as alternatives to condom use. 2) Despite their questionable levels of effectiveness they are collectively labelled as "risk reduction strategies" (RRS). Objectives: The aim of this study is to estimate the prevalence and factors related to RRS in men who report unprotected anal intercourse (UAI) with occasional partners in the last 12 months. Methods: 1) In 2007, a module on RRS was included in a repeated national survey conducted among readers of gay newspapers, members of gay organizations and visitors of gay websites (N=2953). 2) Using an anonymous self-completed questionnaire, participants were asked whether, with the aim of avoiding HIV infection, RRS were used with occasional partners. Analysis: 1) Prevalences were calculated in participants who reported UAI with occasional partners in the last 12 months (n=416). 2) A logistic regression was performed, using "at least one RRS" as dependent variable. Number of partners in the last 12 months, HIV-status and usual socio-demographic characteristics were used as independent factors. Result : 1) 70% (292/416) of the participants reporting UAI used at least one RRS when they had unprotected sex with casual partners in the last 12 months (Table 1). 2) Withrawal before ejaculation was the most frequently reported strategy, followed by serosorting and strategic positioning (Table 1). 3) Participants who reported at least one RRS were more likely to be over 30 years and to belong to a gay organisation. HIV-positive and non-tested participants were less likely to report RRS than HIV-negative participants (Table 2). Conclusions: 1) The majority of MSM who reported UAI in the last 12 months tried to reduce risk of HIV transmission by using specific strategies (withdrawal, serosorting, strategic positioning). It is not known, however, to what extent the use of these strategies was systematic. 2) It is necessary to provide MSM with balanced information on these strategies and their respective level of effectiveness. 3) It is important to monitor the use of RRS in HIV behavioural surveillance surveys in MSM.

Aplicación de CPAP vs. BIPAP en pacientes con edema agudo de pulmón

Estudi clínic, prospectiu, randomizat, on d'un total de 59 pacients foren asignats a dos grups de soport ventilatori (CPAP (30) o BIPAP (29)). L' objectiu primari analizat fou la necessitat de IOT. Com objetius secundaris s'estudiaren la milloria de parámetres clínics, gasomètrics, el temps de soport ventilatori i d' estància en UCI, la supervivència a l' alta d' UCI i als 28 dies. No vam trobar diferències en cap dels paràmetres excepte en la pO2/FiO2 després de la primera hora (146,94CPAP vs 198,49BIPAP p=0.037).

Endocannabinoid regulation of acute and protracted nicotine withdrawal: effect of FAAH inhibition.

Evidence shows that the endocannabinoid system modulates the addictive properties of nicotine. In the present study, we hypothesized that spontaneous withdrawal resulting from removal of chronically implanted transdermal nicotine patches is regulated by the endocannabinoid system. A 7-day nicotine dependence procedure (5.2 mg/rat/day) elicited occurrence of reliable nicotine abstinence symptoms in Wistar rats. Somatic and affective withdrawal signs were observed at 16 and 34 hours following removal of nicotine patches, respectively. Further behavioral manifestations including decrease in locomotor activity and increased weight gain also occurred during withdrawal. Expression of spontaneous nicotine withdrawal was accompanied by fluctuation in levels of the endocannabinoid anandamide (AEA) in several brain structures including the amygdala, the hippocampus, the hypothalamus and the prefrontal cortex. Conversely, levels of 2-arachidonoyl-sn-glycerol were not significantly altered. Pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for the intracellular degradation of AEA, by URB597 (0.1 and 0.3 mg/kg, i.p.), reduced withdrawal-induced anxiety as assessed by the elevated plus maze test and the shock-probe defensive burying paradigm, but did not prevent the occurrence of somatic signs. Together, the results indicate that pharmacological strategies aimed at enhancing endocannabinoid signaling may offer therapeutic advantages to treat the negative affective state produced by nicotine withdrawal, which is critical for the maintenance of tobacco use.

Planifier un sevrage aux glucocorticoïdes: stratégie diagnostique et thérapeutique [How to plan glucocorticoid withdrawal: diagnostic and therapeutic strategies]

Glucocorticoïds are widely used in medicine and associated with numerous complications. Whenever possible, dosage reduction or treatment withdrawal should be considered as soon as possible depending on the underlying disease being treated. Administration of glucocorticoids induces a physiologic negative feed-back on the hypothalamic-pituitary-adrenal (HPA) axis and three clinical situations can be distinguished during treatment withdrawal: reactivation of the disease for which the glucocorticoids were prescribed, acute adrenal insufficiency and steroid withdrawal syndrome. Acute adrenal insufficiency is a feared complication but probably rare. It is usually seen during stress situations and can be observed long after steroid withdrawal. There is no good predictive marker to anticipate acute adrenal insufficiency and clinical evaluation of the patient remains a key element in its diagnosis. If adrenal insufficiency is suspected, HPA suppression can be assessed with dynamic tests. During stress situation, steroid administration is then recommended depending on the severity of the stress.