The 5-HTTLPR polymorphism of the serotonin transporter gene and short term behavioral response to methylphenidate in children with ADHD

<p>Abstract</p> <p>Background</p> <p>Animal models of ADHD suggest that the paradoxical calming effect of methylphenidate on motor activity could be mediated through its action on serotonin transmission. In this study, we have investigated the relationship between the 5-HTTLPR polymorphism in the serotonin transporter gene (<it>SLC6A4</it>) and the response of ADHD relevant behaviors with methylphenidate treatment.</p> <p>Methods</p> <p>Patients between ages 6-12 (n = 157) were assessed with regard to their behavioral response to methylphenidate (0.5 mg/kg/day) using a 2-week prospective within-subject, placebo-controlled (crossover) trial. The children were then genotyped with regard to the triallelic 5-HTTLPR polymorphism in the <it>SLC6A4 </it>gene. Main outcome measure: Conners' Global Index for parents (CGI-Parents) and teachers (CGI-Teachers) at baseline and at the end of each week of treatment with placebo and methylphenidate. For both outcome measurements, we used a mixed model analysis of variance to determine gene, treatment and gene × treatment interaction effects.</p> <p>Results</p> <p>Mixed model analysis of variance revealed a gene × treatment interaction for CGI-Parents but not for CGI-Teachers. Children homozygous for the lower expressing alleles (<it>s+l_G= s'</it>) responded well to placebo and did not derive additional improvement with methylphenidate compared to children carrying a higher expressing allele (<it>l_A</it>). No genotype main effects on either CGI-Parents or CGI-teachers were observed.</p> <p>Conclusions</p> <p>A double blind placebo-controlled design was used to assess the behavioral effects of methylphenidate in relation to the triallelic 5-HTTLPR polymorphism of the <it>SLC6A4 </it>gene in children with ADHD. This polymorphism appears to modulate the behavioral response to methylphenidate in children with ADHD as assessed in the home environment by parents. Further investigation is needed to assess the clinical implications of this finding.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NCT00483106</p

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

Tissue oxygen saturation changes during intramedullary nailing of lower-limb fractures

BACKGROUND: The systemic complications of acute intramedullary nailing (IMN) in trauma patients are well known. There are no reliable methods available to predict these adverse outcomes. Noninvasive near-infrared spectroscopy (NIRS) allows measurement of oxygen saturation within muscle tissue (StO2) and quantification of the potential metabolic and microcirculatory effects of IMN in real time. The aim of this study was to characterize tissue oxygenation changes occurring during reamed IMN. METHODS: Patients undergoing reamed IMN for fixation of a tibia or femur fracture and patients having an open reduction and internal fixation of the ankle (to control for potential effects of anesthesia) had a noninvasive NIRS probe attached to the thenar eminence of the hand. Tissue oxygenation was monitored continuously throughout the operation and digitally recorded for later analysis. Vascular occlusion tests, an established technique with the NIRS device, were performed before canal opening and after nail insertion (at equivalent times in the control group), to establish the presence and nature of changes in systemic microcirculation occurring during the duration of the operation. RESULTS: Tissue oxygenation data were collected on 23 patients undergoing 26 IMN. (mean [SD] age, 36 [19] years; median Injury Severity Score [ISS], 9; interquartile range, 9–12). The control group consisted of 19 patients (mean [SD] age, 41 [18] years; ISS, 4). Remote muscle tissue desaturated significantly faster after IMN compared with the control operation (mean [SD] difference in IMN desaturation rate, 1.8% per minute [2.6% per minute]; mean [SD] difference in control group desaturation rate, -0.6% per minute [1.5% per minute]; p = 0.014). Near infrared-derived muscle oxygen consumption (NIR VO₂) was significantly increased during the course of IMN compared with the control (mean [SD] difference in IMN NIR VO₂, 19.9 [32.1]; mean [SD] difference in control NIR VO₂, -4.2 [17.9]; p = 0.041). CONCLUSION: IMN causes significant remote microcirculatory changes. The responsiveness of the microcirculation could be a predictor of secondary organ dysfunction. LEVEL OF EVIDENCE: Epidemiologic study, level III

Clinical implications and pathological associations of circulating mitochondrial DNA

Mitochondria are membrane-enclosed organelles, the energy-producing centers in almost all eukaryotic cells. The evolutionary emergence of mitochondria is a result of the endocytosis of a-proteobacteria. There are several characteristic features which refer to its prokaryotic ancestors including its independent sets of double-stranded mitochondrial DNA, which is uniquely circular in form and contains a significant amount of unmethylated DNA as CpG islands. Resent research has proven that free mitochondrial DNA found in blood was associated with innate immunomodulation in a broad-range of clinical conditions. Upon release, mitochondrial DNA acts as a danger-associated molecular pattern in the circulation, it is recognized by pattern recognition receptors and it facilitates inflammatory responses. Besides its high receptor activation potential, mitochondrial DNA is likely to perform direct crosstalk with activated leukocytes and to be contributed to other anti-microbial activities. Here we highlight the pathological conditions where cell free mtDNA is involved, describe the potential sources and mechanisms of extracellular mtDNA release and explore evidence for its mechanism of action after being excreted and potential therapeutic strategies

Biomarkers to Guide the Timing of Surgery: Neutrophil and Monocyte L-Selectin Predict Postoperative Sepsis in Orthopaedic Trauma Patients

Deciding whether to delay non-lifesaving orthopaedic trauma surgery to prevent multiple organ failure (MOF) or sepsis is frequently disputed and largely based on expert opinion. We hypothesise that neutrophils and monocytes differentially express activation markers prior to patients developing these complications. Peripheral blood from 20 healthy controls and 162 patients requiring major orthopaedic intervention was collected perioperatively. Neutrophil and monocyte L-selectin, CD64, CD11, CD18, and CXCR1 expression were measured using flow cytometry. The predictive ability for MOF and sepsis was assessed using the Receiver Operating Characteristic (ROC) comparing to C-reactive protein (CRP). Neutrophil and monocyte L-selectin were significantly higher in patients who developed sepsis. Neutrophil L-selectin (AUC 0.692 [95%CI 0.574–0.810]) and monocyte L-selectin (AUC 0.761 [95%CI 0.632–0.891]) were significant predictors of sepsis and were not significantly different to CRP (AUC 0.772 [95%CI 0.650–0.853]). Monocyte L-selectin was predictive of MOF preoperatively and postoperatively (preop AUC 0.790 [95%CI 0.622–0.958]). CD64 and CRP were predictive of MOF at one-day postop (AUC 0.808 [95%CI 0.643–0.974] and AUC 0.809 [95%CI 0.662–0.956], respectively). In the perioperative period, elevated neutrophil and monocyte L-selectin are predictors of postoperative sepsis. Larger validation studies should focus on these biomarkers for deciding the timing of long bone/pelvic fracture fixation

Cell necrosis-independent sustained mitochondrial and nuclear DNA release following trauma surgery

Background: Mitochondrial DNA (mtDNA), a potent proinflammatory damage-associated molecular pattern, is released in large titers following trauma. The effect of trauma surgery on mtDNA concentration is unknown. We hypothesized that mtDNA and nuclear DNA (nDNA) levels would increase proportionately with the magnitude of surgery and both would then decrease rapidly. Methods: In this prospective pilot, plasma was sampled from 35 trauma patients requiring orthopedic surgical intervention at six perioperative time points. Healthy control subjects (n = 20) were sampled.DNAwas extracted, and the mtDNA and nDNAwere assessed using quantitative polymerase chain reaction. Markers of cell necrosis were also assayed (creatine kinase, lactate dehydrogenase, and aspartate aminotransferase). Results: The free plasma mtDNA and nDNA levels (ng/mL) were increased in trauma patients compared with healthy controls at all time points (mtDNA: preoperative period, 108 [46-284]; postoperative period, 96 [29-200]; 7 hours postoperatively, 88 [43-178]; 24 hours, 79 [36-172]; 3 days, 136 [65-263]; 5 days, 166 [101-434] [healthy controls, 11 (5-19)]) (nDNA: preoperative period, 52 [25-130]; postoperative period, 100 [35-208]; 7 hours postoperatively, 75 [36-139]; 24 hours postoperatively, 85 [47-133]; 3 days, 79 [48-117]; 5 days, 99 [41-154] [healthy controls, 29 (16-54)]). Elevated DNA levels did not correlate with markers of cellular necrosis. mtDNA was significantly elevated compared with nDNA at preoperative period (<i>p</i> = 0.003), 3 days (<i>p</i> = 0.003), and 5 days (<i>p</i> = 0.0014). Preoperative mtDNA levelswere greater with shorter time from injury to surgery (<i>p</i> = 0.0085). Postoperative mtDNA level negatively correlated with intraoperative crystalloid infusion (<i>p</i> = 0.0017). Major pelvic surgery (vs. minor) was associated with greater mtDNA release 5 days postoperatively (<i>p</i> < 0.05). Conclusion: This pilot of heterogeneous orthopedic trauma patients showed that the release of mtDNA and nDNA is sustained for 5 days following orthopedic trauma surgery. Postoperative, circulating DNA is not associated with markers of tissue necrosis but is associated with surgical invasiveness and is inversely related to intraoperative fluid administration. Sustained elevation of mtDNA levels could be of inflammatory origin and may contribute to postinjury dysfunctional inflammation

High-Resolution Bulgeless Liquid-Cell Electron Microscopy

Liquid cell electron microscopy (LCEM) has long suffered from irreproducibility and its inability to confer high-quality images over a wide field of view. LCEM demands the encapsulation of the in-liquid sample between two ultrathin membranes (windows). In the vacuum environment of the electron microscope, the windows bulge, drastically reducing the achievable resolution and the usable viewing region. Herein, we introduce a shape-engineered nanofluidic cell architecture and an air-free drop-casting sample loading technique, which combined, provide robust bulgeless imaging conditions. We demonstrate the capabilities of our approach through the study of in-liquid model samples and quantitative measurements of the liquid layer thickness. The presented LCEM method confers high throughput, lattice resolution across the complete viewing window, and sufficient contrast for the observation of unstained liposomes, paving the way to high-resolution movies of biospecimens in their near native environment

Effect of Kinesio®tape on Scapular Kinematics of the Asymptomatic Shoulder in Healthy Younger Adults

Introduction Limited scapular upward rotation and posterior tilting during upper extremity elevation are correlated with subacromial impingement syndrome (SAIS) Previous research found significant increases in scapular posterior tilting with Kinesio®tape (KT) application Purpose: To find a taping method that increases scapular upward rotation and posterior tilting Hypothesis: KT application for mechanical facilitation will increase scapular upward rotation during upper extremity elevation Objective Investigate the effects of KT on scapular kinematics during upper extremity elevation Participants Twenty asymptomatic participants aged 23-36 years old (mean 25.45) No cervical, thoracic, or shoulder conditions affecting shoulder ROM Right hand dominant Methods Kinesio ® tape was applied to the dominant upper extremity 3D motion of the humerus and scapula were measured using the G4 electromagnetic motion capture system and MotionMonitor software Upper extremely elevation was performed in the sagittal, frontal, and scapular planes without tape and with tape. The non-tape condition was repeated Repeated measures ANOVA utilizing SPSS v 28 for statistical analysis Results No statistically significant difference in scapular upward rotation with upper extremity elevation between KT, non-KT, and repeated non-KT conditions (p=0.603) No statistically significant difference in scapular posterior tilting with upper extremity elevation between KT, non-KT, and repeated non-KT conditions (p=0.376) Results are outlined in figure 2. Conclusion It is hypothesized that KT can alter the kinematics of the scapula and could be used to help treat individuals with SAIS The current literature has not reached a consensus as to whether or not KT has the ability to alter the kinematics of the scapula Current study found no change in either scapular posterior tilting or upward rotation Further research is needed to see if this taping method would be effective at reducing pain in individuals with symptomatic SAIS Clinical Relevance Increasing posterior tilt and upward rotation of the scapula may improve SAIS symptoms Kinesiotape may provide improvements in scapular motion during UE elevatio

Mitochondrial DNA neutrophil extracellular traps are formed after trauma and subsequent surgery

Introduction: Neutrophil extracellular traps (NETs) have not been demonstrated after trauma and subsequent surgery. Neutrophil extracellular traps are formed from pure mitochondrial DNA (mtDNA) under certain conditions, which is potently proinflammatory. We hypothesized that injury and orthopedic trauma surgery would induce NET production with mtDNA as a structural component. Methods: Neutrophils were isolated 8 trauma patients requiring orthopedic surgery postinjury and up to 5 days postoperatively. Four healthy volunteers provided positive and negative controls. Total hip replacement patients acted as an uninjured surgical control group. Neutrophil extracellular traps were visualized with DNA (Hoechst 33342TM/Sytox Green/MitoSox/MitoTracker) stains using live cell fluorescence microscopy with downstream quantitative polymerase chain reaction analysis of DNA composition. Results: Neutrophil extracellular traps were present after injury in all 8 trauma patients. They persisted for 5 days postoperatively. Delayed surgery resulted in NET resolution, but they reformed postoperatively. Total hip replacement patients developed NETs postoperatively, which resolved by day 5. Quantitative polymerase chain reaction analysis of NET-DNA composition revealed that NETs formed after injury and surgery were made of mtDNA with no detectable nuclear DNA component. Conclusions: Neutrophil extracellular traps formed after major trauma and subsequent surgery contain mtDNA and represent a novel marker of heightened innate immune activation. They could be considered when timing surgery after trauma to prevent systemic NET-induced inflammatory complications