Effects of methylphenidate on cognition and behaviour in children with neurofibromatosis type 1:a study protocol for a randomised placebo-controlled crossover trial

INTRODUCTION: Dopamine dysregulation has been identified as a key modulator of behavioural impairment in neurofibromatosis type 1 (NF1) and a potential therapeutic target. Preclinical research demonstrates reduced dopamine in the brains of genetically engineered NF1 mouse strains is associated with reduced spatial-learning and attentional dysfunction. Methylphenidate, a stimulant medication that increases dopaminergic and noradrenergic neurotransmission, rescued the behavioural and dopamine abnormalities. Although preliminary clinical trials have demonstrated that methylphenidate is effective in treating attention deficit hyperactivity disorder (ADHD) symptoms in children with NF1, its therapeutic effect on cognitive performance is unclear. The primary aim of this clinical trial is to assess the efficacy of methylphenidate for reducing attention deficits, spatial working memory impairments and ADHD symptoms in children with NF1.METHODS AND ANALYSIS: A randomised, double-blind, placebo-controlled trial of methylphenidate with a two period crossover design. Thirty-six participants with NF1 aged 7-16 years will be randomised to one of two treatment sequences: 6 weeks of methylphenidate followed by 6 weeks of placebo or; 6 weeks of placebo followed by 6 weeks of methylphenidate. Neurocognitive and behavioural outcomes as well as neuroimaging measures will be completed at baseline and repeated at the end of each treatment condition (week 6, week 12). Primary outcome measures are omission errors on the Conners Continuous Performance Test-II (attention), between-search errors on the Spatial Working Memory task from the Cambridge Neuropsychological Test Automated Battery (spatial working memory) and the Inattentive and Hyperactivity/Impulsivity Symptom Scales on the Conners 3-Parent. Secondary outcomes will examine the effect of methylphenidate on executive functions, attention, visuospatial skills, behaviour, fine-motor skills, language, social skills and quality of life.ETHICS AND DISSEMINATION: This trial has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.TRIAL REGISTRATION NUMBER: ACTRN12611000765921.</p

Modeling Urban Hydrology and Green Infrastructure Using the AGWA Urban Tool and the KINEROS2 Model

Urban hydrology and green infrastructure (GI) can be modeled using the Automated Geospatial Watershed Assessment (AGWA) Urban tool and the Kinematic Runoff and Erosion (KINEROS2) model. The KINEROS2 model provides an urban modeling element with nine overland flow components that can be used to represent various land cover types commonly found in the built environment while treating runoff-runon and infiltration processes in a physically based manner. The AGWA Urban tool utilizes a Geographic Information System (GIS) framework to prepare parameters required for KINEROS2, executes the model, and imports results for visualization in the GIS. The AGWA Urban tool was validated on a residential subdivision in Arizona, USA, using 47 rainfall events (June 2005 to September 2006) to compare observed runoff volumes and peak flow rates with simulated results. Comparison of simulated and observed runoff volumes resulted in a slope of 1.00 for the regression equation with an R2 value of 0.80. Comparison of observed and simulated peak flows had a slope of 1.12 with an R2 value of 0.83. A roof runoff analysis was simulated for 787 events, from January 2006 through December 2015, to analyze the water availability from roof runoff capture. Simulation results indicated a 15% capture of the average monthly rainfall volume on the watershed. Additionally, rainwater captured from roofs has the potential to provide for up to 70% of the domestic annual per capita water use in this region. Five different scenarios (S1 - base, S2 - with retention basins, S3 - with permeable driveways, S4 - with rainwater harvesting cisterns, and S5 - all GI practices from S2, S3, and S4) were simulated over the same period to compare the effectiveness of GI implementation at the parcel level on runoff and peak flows at the watershed outlet. Simulation results indicate a higher runoff volume reduction for S2 (53.41 m3 average capacity, average 30% reduction) as compared to S3 (average 14% reduction), or S4 (3.78 m3 capacity, average 6% reduction). Analysis of peak flows reveal larger peak flow reduction for S2. S3 showed more reduction of smaller peak flows as compared to S4

Evolution of metabolic divergence in <i>Pseudomonas aeruginosa</i> during long-term infection facilitates a proto-cooperative interspecies interaction

The effect of polymicrobial interactions on pathogen physiology and how it can act either to limit pathogen colonization or to potentiate pathogen expansion and virulence are not well understood. Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens commonly found together in polymicrobial human infections. However, we have previously shown that the interactions between these two bacterial species are strain dependent. Whereas P. aeruginosa PAO1, a commonly used laboratory strain, effectively suppressed S. aureus growth, we observed a commensal-like interaction between the human host-adapted strain, DK2-P2M24-2003, and S. aureus. In this study, characterization by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) imaging mass spectrometry (IMS) and mass spectral (MS) molecular networking revealed a significant metabolic divergence between P. aeruginosa PAO1 and DK2-P2M24-2003, which comprised several virulence factors and signaling 4-hydroxy-2-alkylquinoline (HAQ) molecules. Strikingly, a further modulation of the HAQ profile was observed in DK2-P2M24-2003 during interaction with S. aureus, resulting in an area with thickened colony morphology at the P. aeruginosa–S. aureus interface. In addition, we found an HAQ-mediated protection of S. aureus by DK2-P2M24-2003 from the killing effect of tobramycin. Our findings suggest a model where the metabolic divergence manifested in human host-adapted P. aeruginosa is further modulated during interaction with S. aureus and facilitate a proto-cooperative P. aeruginosa–S. aureus relationship

Utilization and control of ecological interactions in polymicrobial infections and community-based microbial cell factories

Microbial activities are most often shaped by interactions between co-existing microbes within mixed-species communities. Dissection of the molecular mechanisms of species interactions within communities is a central issue in microbial ecology, and our ability to engineer and control microbial communities depends, to a large extent, on our knowledge of these interactions. This review highlights the recent advances regarding molecular characterization of microbe-microbe interactions that modulate community structure, activity, and stability, and aims to illustrate how these findings have helped us reach an engineering-level understanding of microbial communities in relation to both human health and industrial biotechnology

Delivering the Thinking Healthy Programme for perinatal depression through peers: an individually randomised controlled trial in India

Background The Thinking Healthy Programme (THP) is a psychological intervention recommended for the treatment of perinatal depression. However, efforts to integrate the intervention at scale into the routines of community health workers who delivered the THP when it was first evaluated were compromised by the competing responsibilities of community health workers. We aimed to assess the effectiveness and cost-effectiveness of THP peer-delivered (THPP) in Goa, India. Methods In this single-blind, individually randomised controlled trial, we recruited pregnant women aged 18 years or older who scored at least 10 on the Patient Health Questionnaire-9 (PHQ-9) from antenatal clinics in Goa. Participants were randomly allocated (1:1) to receive enhanced usual care (EUC; so-called because, in India, perinatal depression is not typically treated) only (control group) or THPP in addition to EUC (intervention group) in randomly sized blocks that were stratified by area of residence (urban or rural). Group allocations were concealed from participants and researchers before assignments were made by use of sequentially numbered opaque envelopes. The primary outcomes were the severity of depressive symptoms (assessed by PHQ-9 score) and the prevalence of remission (defined as a PHQ-9 score of less than 5) in participants with available data 6 months after childbirth, which was assessed by researchers who were masked to treatment allocations. We analysed outcomes by intention to treat, adjusting for covariates that were defined a priori or that showed imbalance at baseline. The trial is registered with ClinicalTrials.gov, number NCT02104232. Findings Between Oct 24, 2014, and June 24, 2016, we assessed 118 260 women for their eligibility for screening, of whom 111 851 (94·6%) women were ineligible. 6409 (5·4%) women were eligible for screening and 6369 (99·4%) of these women consented to be screened with the PHQ-9 (40 women did not consent), of whom 333 (5·2%) screened positive for depression (defined as a PHQ-9 score of at least 10). We enrolled 280 (84·1%) women with perinatal depression; 140 women were assigned to the THPP and EUC group and 140 women to the EUC only group. The final treatment was given on May 27, 2017. The final 6-month outcome assessment was completed on June 9, 2017. At 6 months after birth, 122 (87%) women in the THPP and EUC group and 129 (92%) women in the EUC only group were assessed for the primary outcome. There was a higher prevalence of remission at 6 months after birth in the THPP and EUC group compared with the EUC only group (89 [73%] women in the intervention group vs 77 [60%] women in the control group; prevalence ratio 1·21, 95% CI 1·01 to 1·45; p=0·04), but there was no evidence of a difference in symptom severity between the groups (mean PHQ-9 score 3·47 [SD 4·49] in the intervention group vs 4·48 [5·11] in the control group; standardised mean difference −0·18, 95% CI −0·43 to 0·07; p=0·16). There was no evidence of significant differences in serious adverse events between the groups. Interpretation THPP had a moderate effect on remission from perinatal depression over the 6-month postnatal period. THPP is relatively cheap to deliver and is cost-saving through reduced health-care, time and productivity costs

ARF-BP1 as a potential therapeutic target

In this review, we discuss the recent identification of ARF-BP1 (also known as Mule, UREB1, E3histone, LASU1, and HectH9). ARF-BP1, a HECT domain-containing E3 ubiquitin ligase, interacts with ARF and p53. Its ubiquitin ligase activity is inhibited by ARF. Inactivation of ARF-BP1 stabilised p53 and induced apoptosis. Notably, inactivation of ARF-BP1 also caused cell growth repression in p53-null cells and breast cancer cells with mutant p53. Thus, ARF-BP1 emerges as a novel therapeutic target against cancer regardless of p53 status

Subcortical volume and white matter integrity abnormalities in major depressive disorder:Findings from UK Biobank imaging data

Previous reports of altered grey and white matter structure in Major Depressive Disorder (MDD) have been inconsistent. Recent meta-analyses have, however, reported reduced hippocampal grey matter volume in MDD and reduced white matter integrity in several brain regions. The use of different diagnostic criteria, scanners and imaging sequences may, however, obscure further anatomical differences. In this study, we tested for differences in subcortical grey matter volume (n = 1157) and white matter integrity (n = 1089) between depressed individuals and controls in the subset of 8590 UK Biobank Imaging study participants who had undergone depression assessments. Whilst we found no significant differences in subcortical volumes, significant reductions were found in depressed individuals versus controls in global white matter integrity, as measured by fractional anisotropy (FA) (β = −0.182, p = 0.005). We also found reductions in FA in association/commissural fibres (β = −0.184, pcorrected = 0.010) and thalamic radiations (β = −0.159, pcorrected = 0.020). Tract-specific FA reductions were also found in the left superior longitudinal fasciculus (β = −0.194, pcorrected = 0.025), superior thalamic radiation (β = −0.224, pcorrected = 0.009) and forceps major (β = −0.193, pcorrected = 0.025) in depression (all betas standardised). Our findings provide further evidence for disrupted white matter integrity in MDD