The genomics of visuospatial neurocognition in obsessive-compulsive disorder: A preliminary GWAS.

BACKGROUND: The study of Obsessive-Compulsive Disorder (OCD) genomics has primarily been tackled by Genome-wide association studies (GWAS), which have encountered troubles in identifying replicable single nucleotide polymorphisms (SNPs). Endophenotypes have emerged as a promising avenue of study in trying to elucidate the genomic bases of complex traits such as OCD. METHODS: We analyzed the association of SNPs across the whole genome with the construction of visuospatial information and executive performance through four neurocognitive variables assessed by the Rey-Osterrieth Complex Figure Test (ROCFT) in a sample of 133 OCD probands. Analyses were performed at SNP- and gene-level. RESULTS: No SNP reached genome-wide significance, although there was one SNP almost reaching significant association with copy organization (rs60360940; P = 9.98E-08). Suggestive signals were found for the four variables at both SNP- (P < 1E-05) and gene-levels (P < 1E-04). Most of the suggestive signals pointed to genes and genomic regions previously associated with neurological function and neuropsychological traits. LIMITATIONS: Our main limitations were the sample size, which was limited to identify associated signals at a genome-wide level, and the composition of the sample, more representative of rather severe OCD cases than a population-based OCD sample with a broad severity spectrum. CONCLUSIONS: Our results suggest that studying neurocognitive variables in GWAS would be more informative on the genetic basis of OCD than the classical case/control GWAS, facilitating the genetic characterization of OCD and its different clinical profiles, the development of individualized treatment approaches, and the improvement of prognosis and treatment response.

Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

High-Brightness Continuous-Wave Electron Beams from Superconducting Radio-Frequency Photoemission Gun.

Continuous-wave photoinjectors operating at high accelerating gradients promise to revolutionize many areas of science and applications. They can establish the basis for a new generation of monochromatic x-ray free electron lasers, high-brightness hadron beams, or a new generation of microchip production. In this Letter we report on the record-performing superconducting rf electron gun with CsK_{2}Sb photocathode. The gun is generating high charge electron bunches (up to 10 nC/bunch) and low transverse emittances, while operating for months with a single photocathode. This achievement opens a new era in generating high-power beams with a very high average brightness.

Anaerobic degradation of glycol ether-ethanol mixtures using EGSB and hybrid reactors: Performance comparison and ether cleavage pathway.

The anaerobic biodegradation of ethanol-glycol ether mixtures as 1-ethoxy-2-propanol (E2P) and 1-methoxy-2-propanol (M2P), widely used in printing facilities, was investigated by means of two laboratory-scale anaerobic bioreactors at 25oC: an expanded granular sludge bed (EGSB) reactor and an anaerobic hybrid reactor (AHR), which incorporated a packed bed to improve biomass retention. Despite AHR showed almost half of solid leakages compared to EGSB, both reactors obtained practically the same performance for the operating conditions studied with global removal efficiencies (REs) higher than 92% for organic loading rates (OLRs) as high as 54 kg of chemical oxygen demand (COD) m-3 d-1 (REs of 70% and 100% for OLRs of 10.6 and 8.3 kg COD m-3 d-1 for E2P and M2P, respectively). Identified byproducts allowed clarifying the anaerobic degradation pathways of these glycol ethers. Thus, this study shows that anaerobic scrubber can be a feasible treatment for printing emissions.

A high migratory capacity of donor T-cells in response to the lymph node homing receptor CCR7 increases the incidence and severity of GvHD.

The pathogenesis of GvHD involves migration of donor T-cells into the secondary lymphoid organs in the recipient, which is steered by two homing molecules, CD62L and CCR7. Therefore, we investigated whether the migratory capacity of donor T-cells is associated with GvHD. This single center prospective study included 85 donor-recipient pairs. In vitro chemotaxis assays of the lymphocytes of the apheresis product were performed in parallel to the analysis of CD62L and CCR7 by flow cytometry. The migratory index to the CCR7 ligands, CCL19 and CCL21, was higher in T-cells from donors whose recipients will develop GvHD. Similarly, the acute GvHD (aGvHD) group received higher percentage of CD4+CCR7+ T-cells, whereas chronic GvHD (cGvHD) patients were transplanted with higher percentages of CD8+CCR7+ T-cells compared with the non-GvHD group. These results were confirmed when patients were subdivided according to degrees of severity. Further, multivariate analysis confirmed that the proportions of CCR7+ CD4+ and CCR7+ CD8+ T-cells are risk factors for the development and severity of aGvHD and cGvHD, respectively. Functional experiments demonstrated that CCR7+ T-cells exhibited higher potential for activation than CCR7- T-cells did. We therefore propose that the selective depletion of CCR7-expressing T-cells may be an effective preventive therapy for GvHD.

Utilidad de la enterotomografía en la hemorragía digestiva de origen oscuro / CT enterography in the management of obscure gastrointestinal bleeding

Nuestro objetivo es describir la técnica y los hallazgos de la enterotomografía (ETC) en la hemorragia digestiva de origen oscuro (HDOO). Esta entidad constituye un sangrado digestivoque persiste o recurre sin una causa identificable tras la realización de una videoendoscopia digestiva alta (VEDA) y una colonoscopia convencional (CC). Se subclasifica en evidente (HDOOE)u oculta (HDOO-O), según la presencia o ausencia de sangrado visible en la materia fecal. En el 40-70% de los casos el sitio de la hemorragia se encuentra en el intestino delgado. En los jóvenes prevalecen los tumores como etiología, mientras que en los de mayor edad predominan las angiodisplasias intestinales. La ETC consiste en la administración de contraste neutro de alta viscosidad por vía oralpara lograr la correcta distensión de las asas del intestino delgado y/o el colon. El contraste endovenoso permite una correcta valoración y caracterización de las alteraciones con asientoen la mucosa y pared del intestino. La capacidad diagnóstica de la ETC es de aproximadamenteel 40%...

Dose Modification in Biologic Therapy for Moderate to Severe Psoriasis: A Descriptive Analysis in a Clinical Practice Setting.

INTRODUCTION: In biologic therapy, dose modification in carefully selected patients when psoriasis is in remission could reduce treatment costs and the risks associated with drug exposure. MATERIAL AND METHODS: Observational, descriptive, crosssectional study, performed in January 2014, of 112 patients with moderate to severe psoriasis who had been on biologic therapy for at least 6 months. The therapeutic objective in all cases was to achieve and maintain a 75% reduction in Psoriasis Area and Severity Index (PASI 75). All the patients had started treatment with the standard regimen. During treatment, the dose had been reduced in patients who achieved the therapeutic objective and escalated in those who failed to respond adequately to standard doses. RESULTS: At the time of the study, 42.9% of the patients were receiving the standard dose, 50% were on a reduced dose, and 7.1% were on an escalated regimen. The agent with which the dose was most often reduced was adalimumab (57.7%), and the agents with which therapy was most often escalated were ustekinumab (17.9%) and infliximab (12.5%). Patients who received reduced doses had significantly longer-standing disease (P=.049) and longer treatment duration with the same biologic agent (P=.009). In the group that did not fulfill the criteria for dose reduction, the proportion of patients with psoriatic arthritis was significantly higher (P=.023). Cost savings were as follows: 21.5% with adalimumab, 13.8% with etanercept, .9% with ustekinumab, and .55% with infliximab. CONCLUSIONS: Patients with longer-standing disease and longer treatment duration with the same biologic agent were significantly more likely to be candidates for dose reduction. The proportion of patients with psoriatic arthritis was greater in the group of patients who did not fulfill the conditions for dose reduction. The overall cost saving achieved using the dose modification algorithm described in this study was 13%. Controlled studies are needed to define the profile of the patients best suited for dose reduction strategies without loss of treatment efficacy.

Results of allogeneic stem cell transplantation in the Spanish MDS registry: prognostic factors for low risk patients.

Although new agents have been approved for the treatment of MDS, the only curative approach is allogeneic hematopoietic stem cell transplantation (HSCT) and thus, in particular circumstances this procedure has been proposed as a treatment option for low risk patients. We have retrospectively analyzed the results of HSCT in 291 patients from the Spanish MDS registry with special attention to low risk MDS (LR-MDS) in order to define the variables that could impact their clinical evolution after transplantation. At 2 years OS was 51% and EFS was 50% (95% CI 0.7-4.5 years for OS and 95% CI 0.1-3.9 years for EFS). Among 43 LR-MDS, transplant-related mortality was 28%. At 3 years, OS was 67% (95% CI 264.7-8927.2 days for OS) and EFS was 64% (95% CI 0-9697.2 days for EFS). In the multivariate analysis only cytogenetics retained statistical significant effect on both OS (p=.047) and EFS (p=.046). Conditioning regimen could improve outcome among this subset of patients (OS 86% and RFS 100% for patients receiving RIC regimen). The present study confirms that specific disease characteristic as well as transplant characteristics have a significant impact on transplant outcome. Regarding low risk patients a non-myeloablative conditioning would be preferable especially in cases without high-risk cytogenetics.

Cobertura de tobillo con colgajo de hemisóleo de flujo retrógrado. Más allá de su indicación clásica / Ankle's covarage with hemisoleous retrograde flow flap. Beyond its classical indication

Planteamos 5 casos clínicos de fractura expuesta de tobillo con pérdida de cobertura cutánea y una revisión de la vascularización del músculo sóleo. Basándonos en conceptos anatomo-hemodinámicos, realizamos la cobertura de dichos defectos con un colgajo muscular de hemisóleo a pedículo distal y flujo retrógrado. El colgajo se llevó más allá de su indicación clásica a partir de la selección de pacientes según puntuación en base a patología previa y edad. En todos los casos la vitalidad del colgajo fue buena y los resultados anatomo-funcionales obtenidos fueron satisfactorios. La recuperación postoperatoria fue de un promedio de 3 semanas, más rápida que la esperada con otros métodos (AU)

We expose 5 clinical cases of open fracture of ankle with skin coverage loss and a review of soleous vascular anatomy. Based on anatomo-hemodynamics concepts we cover this defect with distally based hemisoleous muscle flap. The flap was performed beyond its classical indication in patients selected according to individual score. In all of the cases the viability of the flap was good, and the functional and anatomic results were satisfactory. The postoperatory recovery was in an average of 3weeks, obtaining a quicker recovery than expected with other methods (AU)

Control of VOC emissions from a flexographic printing facility using an industrial biotrickling filter.

The study of an industrial unit of biotrickling filter for the treatment of the exhaust gases of a flexographic facility was investigated over a 2-year period with the objective to meet the volatile organic compound (VOC) regulatory emission limits. Increasing the water flow rate from 2 to 40 m(3) h(-1) improved the performance of the process, meeting the VOC regulation when 40 m(3) h(-1) were used. An empty bed residence time (EBRT) of 36 s was used when the inlet air temperature was 18.7 °C, and an EBRT as low as 26 s was set when the inlet temperature was 26.8 °C. During this long-term operation, the pressure drop over the column of the bioreactor was completely controlled avoiding clogging problems and the system could perfectly handle the non-working periods without VOC emission, demonstrating its robustness and feasibility to treat the emission of the flexographic sector.

Long-term follow-up of HCV-infected hematopoietic SCT patients and effects of antiviral therapy.

This prospective study was initiated in 1993 with the aim to study late effects and responses to antiviral therapy in a cohort of hepatitis C virus (HCV)-infected patients. A total of 195 patients were included from 12 centers. In all, 134 patients had undergone allogeneic and 61 autologous hematopoietic SCT (HSCT). The median follow-up from HSCT is currently 16.8 years and the maximum 27.2 years. Overall 33 of 195 patients have died of which 6 died from liver complications. The survival probability was 81.6% and the cumulative incidence for death in liver complications was 6.1% at 20 years after HSCT. The cumulative incidence of severe liver complications (death from liver failure, cirrhosis and liver transplantation) was 11.7% at 20 years after HSCT. In all, 85 patients have been treated with IFN; 42 in combination with ribavirin. The sustained response rate was 40%. The rates of severe side effects were comparable to other patient populations and no patient developed significant exacerbations of GVHD. Patients receiving antiviral therapy had a trend toward a decreased risk of severe liver complications (odds ratio=0.33; P=0.058). HCV infection is associated with morbidity and mortality in long-term survivors after HSCT. Antiviral therapy can be given safely and might reduce the risk for severe complications.

Influence of ground tire rubber on the transient loading response of a peat biofilter.

The effect of using ground tire rubber (GTR) as an adsorptive material in the removal of a 2:1:1 weight mixture of n-butyl acetate, toluene and m-xylene by using a peat biofilter under different intermittent conditions was investigated. The performance of two identical size biofilters, one packed with fibrous peat alone and the other with a 3:1 (vol) fibrous peat and GTR mixture, was examined for a period of four months. Partition coefficients of both materials were measured. Values of 53, 118 and 402 L kg(-1) were determined for n-butyl acetate, toluene and m-xylene in peat, respectively; and values of 40, 609 and 3035 L kg(-1) were measured for the same compounds in GTR. Intermittent load feeding of 16 h per day, 5 days per week working at an EBRT of 60 s and an inlet VOC concentration of 0.3 g C m(-1), resulted in removal efficiencies higher than 90% for both biofilters, indicating that the addition of GTR did not adversely affect the behavior of the bioreactor. Full removal of n-butyl acetate was obtained for both biofilters. GTR improved the removal of the aromatics in the first part of the biofilter, facilitating lower penetration of the toluene and m-xylene into the bed. A 31-day starvation period was applied and intermittent operation subsequently restarted. In both biofilters, high removal efficiencies after a re-acclimation period of two days were achieved. A shock loading test related to 1-h peaks of three- and four-fold increases in its baseline concentration (0.30 g C m(-3)) was applied in both biofilters. For the biofilter packed with the peat and GTR mixture, attenuation greater than 60% was observed in the maximum outlet concentration when compared to the biofilter packed with peat alone.

A haplotype of glycogen synthase kinase 3ß is associated with early onset of unipolar major depression.

Recent findings suggest that glycogen synthase kinase 3ß (GSK3ß) may play a role in the pathophysiology and treatment of mood disorders. Various genetic studies have shown the association of GSK3ß polymorphisms with different mood disorder phenotypes. We hypothesized that genetic variants in the GSK3ß gene could partially underlie the susceptibility to mood disorders. We performed a genetic case-control study of 440 psychiatrically screened control subjects and 445 mood disorder patients [256 unipolar major depressive disorder (MDD) and 189 bipolar disorder (BD)]. We genotyped a set of 11 single nucleotide polymorphisms (SNPs) and determined the relative frequency of a known copy number variant (CNV) overlapping the GSK3ß by quantitative real-time polymerase chain reaction (PCR). We found no evidence of association with MDD or BD diagnosis, and we further investigated the age at onset (AAO) of the disorder and severity of depressive index episode. We found that rs334555, located in intron 1 of GSK3ß, was nominally associated with an earlier AAO of the disease in MDD (P = 0.001). We also identified a haplotype containing three SNPs (rs334555, rs119258668 and rs11927974) associated with AAO of the disorder (permutated P = 0.0025). We detected variability for the CNV, but we could not detect differences between patients and controls for any of the explored phenotypes. This study presents further evidence of the contribution of GSK3ß to mood disorders, implicating a specific SNP and a haplotype with an earlier onset of the disorder in a group of well-characterized patients with unipolar MDD. Further replication studies in patients with the same phenotypic characteristics should confirm the results reported here.

[Circadian rhythms and depression]. / Ritmos circadianos y depresión.

Some core symptoms of major depression show a circadian rhythm in their clinical manifestations or are intimately linked to the circadian system functioning, such as sleep-wake cycle. Moreover, abnormalities in circadian rhythms of core body temperature and some endocrine-metabolic parameters have been detected in depressive patients compared to healthy controls. The circadian rhythm disturbances described in depressive states as well as the efficacy and fast onset of action of chronobiological based treatments point out the circadian system as an therapeutic target in the treatment of depression. The aim of this work is to review the biological and clinical data that link major depression to circadian rhythm abnormalities, the mechanisms that may underlie the abnormalities of circadian rhythm physiology seen in depressive states and the different therapeutic approaches to depression that involve the circadian system in their mechanisms of action.

Evaluación y mejora del manejo del consentimiento informado en urgencias / Evaluation and improvement of the management of informed consent in the emergency department

Objetivo: Evaluar la preparación preoperatoria del paciente quirúrgico en urgencias y mejorar así la calidad de la atención prestada a estos pacientes. Material y métodos: Para detectar las causas de incumplimiento se utilizó el diagrama de causa-efecto de Ishikawa, de forma que se elaboraron 8 criterios (C) de evaluación de la preparación preoperatoria en urgencias. La primera evaluación incluyó una muestra de 120 pacientes intervenidos de urgencia desde enero a abril de 2007. Se establecieron medidas correctoras consistentes en reuniones y charlas informativas con personal facultativo y enfermería, recordando la importancia del consentimiento informado (CI) como documento legal que debe ser firmado por el paciente y la obligación de proporcionar una copia de éste al paciente o a los familiares. La segunda evaluación incluye el período comprendido entre julio y octubre (n=120). Resultados: Se detectó un incumplimiento importante de la firma del CI de cirugía del C1 (C1: todo paciente deberá tener firmado el CI de cirugía correspondiente a la intervención realizada [27,5%]) y la entrega de la copia del consentimiento tanto por cirugía del C2 (C2: todo paciente debe haber recibido una copia del CI de cirugía correspondiente a la intervención realizada [72,5%]) como por parte de anestesia del C4 (C4: todo paciente debe haber recibido una copia del CI de anestesia correspondiente a la intervención realizada [90%]). Tras implantar las medidas correctoras se observó una mejora significativa en el cumplimiento del C2 y del C4. En el C1 se apreció mejora, pero sin significación estadística. Conclusiones: La realización de un ciclo de mejora ha permitido alcanzar el propósito fundamental de este trabajo: mejorar en un aspecto importante de nuestra actividad clínica como es el uso de los documentos del CI y, lo que es más importante, proporcionar una adecuada atención e información a nuestros pacientes (AU)

Objective: To assess the preoperative management in our emergency surgical service and to improve the quality of the care provided to patients. Material and methods: In order to find the causes of non-compliance, the Ishikawa Fishbone diagram was used and eight assessment criteria were chosen. The first assessment includes 120 patients operated on from January to April 2007. Corrective measures were implemented, which consisted of meetings and conferences with doctors and nurses, insisting on the importance of the informed consent as a legal document which must be signed by patients, and the obligation of giving a copy to patients or relatives. The second assessment includes the period from July to October 2007 (n=120). Results: We observed a high non-compliance of C1 signing of surgical consent (CRITERION 1: all patients or relatives have to sign the surgical informed consent for the operation to be performed [27.5%]) and C2 giving a copy of the surgical consent (CRITERION 2: all patients or relatives must have received a copy of the surgical informed consent for the Surgery to be performed [72.5%]) and C4 anaesthetic consent copy (CRITERION 4: all patients or relatives must have received a copy of the Anaesthesia informed consent corresponding to the operation performed [90%]). After implementing corrective measures a significant improvement was observed in the compliance of C2 and C4. In C1 there was an improvement without statistical significance. Conclusions: The carrying out of an improvement cycle enabled the main objective of this paper to be achieved: to improve the management of informed consent and the quality of the care and information provided to our patients (AU)

[Evaluation and improvement of the management of informed consent in the emergency department]. / Evaluación y mejora del manejo del consentimiento informado en urgencias.

OBJECTIVE: To assess the preoperative management in our emergency surgical service and to improve the quality of the care provided to patients. MATERIAL AND METHODS: In order to find the causes of non-compliance, the Ishikawa Fishbone diagram was used and eight assessment criteria were chosen. The first assessment includes 120 patients operated on from January to April 2007. Corrective measures were implemented, which consisted of meetings and conferences with doctors and nurses, insisting on the importance of the informed consent as a legal document which must be signed by patients, and the obligation of giving a copy to patients or relatives. The second assessment includes the period from July to October 2007 (n=120). RESULTS: We observed a high non-compliance of C1 signing of surgical consent (CRITERION 1: all patients or relatives have to sign the surgical informed consent for the operation to be performed [27.5%]) and C2 giving a copy of the surgical consent (CRITERION 2: all patients or relatives must have received a copy of the surgical informed consent for the Surgery to be performed [72.5%]) and C4 anaesthetic consent copy (CRITERION 4: all patients or relatives must have received a copy of the Anaesthesia informed consent corresponding to the operation performed [90%]). After implementing corrective measures a significant improvement was observed in the compliance of C2 and C4. In C1 there was an improvement without statistical significance. CONCLUSIONS: The carrying out of an improvement cycle enabled the main objective of this paper to be achieved: to improve the management of informed consent and the quality of the care and information provided to our patients.

Ritmos circadianos y depresión / Circadian rhythms and depression

Determinados síntomas nucleares de la depresión mayor muestran ritmicidad circadiana en su expresión clínica o están íntimamente vinculados al funcionamiento del sistema circadiano, como las alteraciones del ciclo sueño-vigilia. Asimismo, en los sujetos depresivos se han detectado alteraciones en los ritmos circadianos de temperatura corporal y varios parámetros endocrino metabólicos en comparación con individuos sanos. Las anomalías en los ritmos circadianos descritas en los estados depresivos, así como la eficacia y rapidez de acción de tratamientos basados en cronobiología, señalan al sistema circadiano como una importante diana terapéutica en el tratamiento de la depresión. El objetivo del presente trabajo es revisar los datos clinicobiológicos que vinculan a la depresión mayor con alteraciones de los ritmos circadianos, los mecanismos que pueden conducir a las anomalías de la ritmicidad fisiológica descritas en los estados depresivos y los diferentes abordajes terapéuticos de la depresión que implican al sistema circadiano en su mecanismo de acción (AU)

Some core symptoms of major depression show a circadian rhythm in their clinical manifestations or are intimately linked to the circadian system functioning, such as sleep-wake cycle. Moreover, abnormalities in circadian rhythms of core body temperature and some endocrine metabolic parameters have been detected in depressive patients compared to healthy controls. The circadian rhythm disturbances described in depressive states as well as the efficacy and fast onset of action of chronobiological based treatments point out the circadian system as an important therapeutic target in the treatment of depression. The aim of this work is to review the biological and clinical data that link major depression to circadian rhythm abnormalities, the mechanisms that may underlie the abnormalities of circadian rhythm physiology seen in depressive states and the different therapeutic approaches to depression that involve the circadian system in their mechanisms of action (AU)

A brain-derived neurotrophic factor (BDNF) haplotype is associated with antidepressant treatment outcome in mood disorders.

Brain-derived neurotrophic factor (BDNF) has been studied extensively in relation to the susceptibility to mood disorders (MD), although it remains to be clarified whether BDNF is a susceptibility locus for MD phenotypes, including therapeutic response to antidepressants. We have performed a single-marker and haplotype association study of eight TagSNPs polymorphisms in the genomic region containing the BDNF gene in 342 control subjects and 374 patients with MD, and have tested the association with antidepressant treatment outcome. None of the eight single nucleotide polymorphisms (TagSNPs) was significantly associated with MD phenotype after Bonferroni correction. In the single-marker analysis, a SNP was found to be associated with the patient's state of 'remitter' after adequate trial with a single antidepressant phenotype (odds ratio (OR)=2.95; P=0.0025). We also identified a haplotype associated with this phenotype. This study supports the implication of BDNF in antidepressant treatment outcome in MD, with specific association with 5' upstream region of BDNF gene.