Altered adrenal and gonadal steroids biosynthesis in patients with burn injury

Peer reviewe

Noisy galvanic vestibular stimulation promotes GABA release in the substantia nigra and improves locomotion in hemiparkinsonian rats

Dopamine related disorders usually respond to dopaminergic drugs, but not all symptoms are equally responsive. In Parkinson’s disease (PD) in particular, axial symptoms resulting in impaired gait and postural control are difficult to treat. Stochastic vestibular stimulation (SVS) has been put forward as a method to improve CNS function in dopamine related disorders, but the mechanisms of action are not well understood. This thesis aimed to investigate the effects of SVS on neuronal brain activity and to evaluate the possible enhancing effect of SVS on motor control in PD and on cognitive functions and motor learning in Attention deficit hyperactivity disorder (ADHD). Behavioural tests were conducted in the 6-OHDA rat model of PD using the accelerating Rotarod and the Montoya skilled reach test to evaluate the effect of SVS on motor control. The effect of SVS on brain activity was assessed using in vivo microdialysis and immunohistochemistry. We evaluated the effect of SVS on postural control and Parkinsonism in patients with PD and the effect of SVS on cognitive function in people with ADHD. The behavioural animal studies indicate that SVS may have an enhancing effect on locomotion, but not skilled forepaw function. SVS increased GABA transmission in the ipsilesional substantia nigra (SN) and may have a rebalancing effect on dysfunctional brain activity. SVS increased c-Fos activity more than levodopa and saline in the vestibular nucleus of all animals. c-Fos expression was also higher in this region in the 6-OHDA lesioned than in shamlesioned animals, supporting the theory that SVS may have larger effects in the dopamine depleted brain. SVS increased c-Fos expression in the habenula nucleus substantially more than levodopa did. Furthermore, SVS and levodopa had similar effects on many brain regions, including the striatum, where saline had no effect. The clinical studies revealed improvement of postural control in PD during SVS. There was a trend towards reduced Parkinsonism during SVS when off levodopa. No substantial effects were found on cognitive performance in ADHD. In PD, SVS may improve motor control by inhibiting the overactive SN, possibly through a non-dopaminergic modulatory pathway involving increased neurotransmission in the habenula nucleus. SVS could be trialled in larger studies to evaluate long-term effects on treatment resistant axial symptoms associated with PD

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

Background The Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function. Results Here, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory. Conclusion We conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.Peer reviewe

Matrix Metalloproteinases-8 and-9 and Tissue Inhibitor of Metalloproteinase-1 in Burn Patients. A Prospective Observational Study

Introduction Matrix metalloproteinases (MMPs) -8 and -9 are released from neutrophils in acute inflammation and may contribute to permeability changes in burn injury. In retrospective studies on sepsis, levels of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 (TIMP-1) differed from those of healthy controls, and TIMP-1 showed an association with outcome. Our objective was to investigate the relationship between these proteins and disease severity and outcome in burn patients. Methods In this prospective, observational, two-center study, we collected plasma samples from admission to day 21 post-burn, and burn blister fluid samples on admission. We compared MMP-8, -9, and TIMP-1 levels between TBSA20% (N = 30) injured patients and healthy controls, and between 90-day survivors and non-survivors. MMP-8, -9, and TIMP-1 levels at 24-48 hours from injury, their maximal levels, and their time-adjusted means were compared between groups. Correlations with clinical parameters and the extent of burn were analyzed. MMP-8, -9, and TIMP-1 levels in burn blister fluids were also studied. Results Plasma MMP-8 and -9 were higher in patients than in healthy controls (P20% groups. MMP-8 and -9 were not associated with clinical severity or outcome measures. TIMP-1 differed significantly between patients and controls (P20% groups (PPeer reviewe

The CAFA challenge reports improved protein function prediction and new functional annotations for hundreds of genes through experimental screens

BackgroundThe Critical Assessment of Functional Annotation (CAFA) is an ongoing, global, community-driven effort to evaluate and improve the computational annotation of protein function.ResultsHere, we report on the results of the third CAFA challenge, CAFA3, that featured an expanded analysis over the previous CAFA rounds, both in terms of volume of data analyzed and the types of analysis performed. In a novel and major new development, computational predictions and assessment goals drove some of the experimental assays, resulting in new functional annotations for more than 1000 genes. Specifically, we performed experimental whole-genome mutation screening in Candida albicans and Pseudomonas aureginosa genomes, which provided us with genome-wide experimental data for genes associated with biofilm formation and motility. We further performed targeted assays on selected genes in Drosophila melanogaster, which we suspected of being involved in long-term memory.ConclusionWe conclude that while predictions of the molecular function and biological process annotations have slightly improved over time, those of the cellular component have not. Term-centric prediction of experimental annotations remains equally challenging; although the performance of the top methods is significantly better than the expectations set by baseline methods in C. albicans and D. melanogaster, it leaves considerable room and need for improvement. Finally, we report that the CAFA community now involves a broad range of participants with expertise in bioinformatics, biological experimentation, biocuration, and bio-ontologies, working together to improve functional annotation, computational function prediction, and our ability to manage big data in the era of large experimental screens.</p

On the mechanisms and physiological function of somatodendritic dopamine release in substantia nigra

Somatodendritic release of neurotransmitters is a neuronal function that is poorly understood in comparison with the more abundant terminal release. This study aimed at characterising somatodendritic dopamine release in substantia nigra in terms of release mechanisms and possible physiological function in motor control.In vivo microdialysis in conscious rats was used to identify the calcium channels involved in somatodendritic and terminal dopamine release in substantia nigra and striatum, respectively. Microdialysis probes were modified to allow local application of high molecular weight compounds like clostridial toxins, which were used to characterise the SNAP-receptor dependency of somatodendritic and terminal dopamine release. Finally, a novel method with combined dual probe microdialysis and simultaneous motor performance testing on an accelerating rod was developed to investigate the physiological role of somatodendritic dopamine release in motor control.The results indicate that a major portion of somatodendritic dopamine release is calcium dependent. Local treatment with selective and non-selective calcium channel blockers confirmed that N-, and P/Q-type voltage sensitive calcium channels (VSCC) mediate most of the calcium dependency of terminal dopamine release, but revealed that somatodendritic dopamine release is only inhibited by unselective VSCC blockers, or the Cav2.3 (R-type VSCC) blocker SNX-482. Local treatments with clostridial toxins showed that striatal and nigral dopamine release were equally sensitive to SNAP-25 destruction. The VAMP-cleaving botulinum toxin B inhibited striatal, but not nigral, dopamine release. A role for somatodendritic dopamine release in the physiological regulation of motor control was supported by: 1) increases in nigral dopamine release related to physical activity; 2) a modulation of motor performance induced by nigral application of D1-like, or D2-like receptor antagonists; and 3) a partial restoration of motor performance in 6-hydroxydopamine lesioned rats during nigral treatment with the dopamine agonist apomorphine.It is suggested that somatodendritic and terminal dopamine release are mediated by different release mechanisms, in particular different VSCC-types and different vesicle associated membrane protein (VAMP) isoforms. The study also presents evidence for a physiological role of somatodendritic dopamine release in substantia nigra in normal motor control. Nigral dopamine release should therefore be considered in future treatment strategies for Parkinson's disease

Optimizing Treatment of Parkinson's Disease

The holy grail of therapy in Parkinson’s disease (PD) is treatment that would halt the disease process or restore the degenerated neuronal circuits [...

Objective assessment of Parkinson’s disease motor symptoms during leg agility test using motion sensors

Title: Objective assessment of Parkinson’s disease motor symptoms during leg agility test using motion sensors Objective: To develop and evaluate machine learning methods for assessment of Parkinson’s disease (PD) motor symptoms using leg agility (LA) data collected with motion sensors during a single dose experiment. Background: Nineteen advanced PD patients (Gender: 14 males and 5 females, mean age: 71.4, mean years with PD: 9.7, mean years with levodopa: 9.5) were recruited in a single center, open label, single dose clinical trial in Sweden [1]. Methods: The patients performed up to 15 LA tasks while wearing motions sensors on their foot ankle. They performed tests at pre-defined time points starting from baseline, at the time they received a morning dose (150% of their levodopa equivalent morning dose), and at follow-up time points until the medication wore off. The patients were video recorded while performing the motor tasks. and three movement disorder experts rated the observed motor symptoms using 4 items from the Unified PD Rating Scale (UPDRS) motor section including UPDRS #26 (leg agility), UPDRS #27 (Arising from chair), UPDRS #29 (Gait), UPDRS #31 (Body Bradykinesia and Hypokinesia), and dyskinesia scale. In addition, they rated the overall mobility of the patients using Treatment Response Scale (TRS), ranging from -3 (very off) to 3 (very dyskinetic). Sensors data were processed and their quantitative measures were used to develop machine learning methods, which mapped them to the mean ratings of the three raters. The quality of measurements of the machine learning methods was assessed by convergence validity, test-retest reliability and sensitivity to treatment. Results: Results from the 10-fold cross validation showed good convergent validity of the machine learning methods (Support Vector Machines, SVM) with correlation coefficients of 0.81 for TRS, 0.78 for UPDRS #26, 0.69 for UPDRS #27, 0.78 for UPDRS #29, 0.83 for UPDRS #31, and 0.67 for dyskinesia scale (P&lt;0.001). There were good correlations between scores produced by the methods during the first (baseline) and second tests with coefficients ranging from 0.58 to 0.96, indicating good test-retest reliability. The machine learning methods had lower sensitivity than mean clinical ratings (Figure. 1). Conclusions: The presented methodology was able to assess motor symptoms in PD well, comparable to movement disorder experts. The leg agility test did not reflect treatment related changes

Feasibility of a multi-sensor data fusion method for assessment of Parkinson’s disease motor symptoms

Title: Feasibility of a multi-sensor data fusion method for assessment of Parkinson’s disease motor symptoms Objective: To assess the feasibility of measuring Parkinson’s disease (PD) motor symptoms with a multi-sensor data fusion method. More specifically, the aim is to assess validity, reliability and sensitivity to treatment of the methods. Background: Data from 19 advanced PD patients (Gender: 14 males and 5 females, mean age: 71.4, mean years with PD: 9.7, mean years with levodopa: 9.5) were collected in a single center, open label, single dose clinical trial in Sweden [1]. Methods: The patients performed leg agility and 2-5 meter straight walking tests while wearing motion sensors on their limbs. They performed the tests at baseline, at the time they received the morning dose, and at pre-specified time points until the medication wore off. While performing the tests the patients were video recorded. The videos were observed by three movement disorder specialists who rated the symptoms using a treatment response scale (TRS), ranging from -3 (very off) to 3 (very dyskinetic). The sensor data consisted of lower limb data during leg agility, upper limb data during walking, and lower limb data during walking. Time series analysis was performed on the raw sensor data extracted from 17 patients to derive a set of quantitative measures, which were then used during machine learning to be mapped to mean ratings of the three raters on the TRS scale. Combinations of data were tested during the machine learning procedure. Results: Using data from both tests, the Support Vector Machines (SVM) could predict the motor states of the patients on the TRS scale with a good agreement in relation to the mean ratings of the three raters (correlation coefficient = 0.92, root mean square error = 0.42, p&lt;0.001). Additionally, there was good test-retest reliability of the SVM scores during baseline and second tests with intraclass-correlation coefficient of 0.84. Sensitivity to treatment for SVM was good (Figure 1), indicating its ability to detect changes in motor symptoms. The upper limb data during walking was more informative than lower limb data during walking since SVMs had higher correlation coefficient to mean ratings.   Conclusions: The methodology demonstrates good validity, reliability, and sensitivity to treatment. This indicates that it could be useful for individualized optimization of treatments among PD patients, leading to an improvement in health-related quality of life