pinecone/core-2020-05-10-deduplication huggingface dataset:
Quality assurance of geometric accuracy based on an electronic portal imaging device and log data analysis for Dynamic WaveArc irradiation

The purpose of this study was to develop a simple verification method for the routine quality assurance (QA) of Dynamic WaveArc (DWA) irradiation using electronic portal imaging device (EPID) images and log data analysis. First, an automatic calibration method utilizing the outermost multileaf collimator (MLC) slits was developed to correct the misalignment between the center of the EPID and the beam axis. Moreover, to verify the detection accuracy of the MLC position according to the EPID images, various positions of the MLC with intentional errors in the range 0.1–1 mm were assessed. Second, to validate the geometric accuracy during DWA irradiation, tests were designed in consideration of three indices. Test 1 evaluated the accuracy of the MLC position. Test 2 assessed dose output consistency with variable dose rate (160–400 MU/min), gantry speed (2.2–6°/s), and ring speed (0.5–2.7°/s). Test 3 validated dose output consistency with variable values of the above parameters plus MLC speed (1.6–4.2 cm/s). All tests were delivered to the EPID and compared with those obtained using a stationary radiation beam with a 0° gantry angle. Irradiation log data were recorded simultaneously. The 0.1‐mm intentional error on the MLC position could be detected by the EPID, which is smaller than the EPID pixel size. In Test 1, the MLC slit widths agreed within 0.20 mm of their exposed values. The averaged root‐mean‐square error (RMSE) of the dose outputs was less than 0.8% in Test 2 and Test 3. Using log data analysis in Test 3, the RMSE between the planned and recorded data was 0.1 mm, 0.12°, and 0.07° for the MLC position, gantry angle, and ring angle, respectively. The proposed method is useful for routine QA of the accuracy of DWA
Baclofen facilitates sleep, neuroplasticity, and recovery after stroke in rats.

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Sleep disruption in the acute phase after stroke has detrimental effects on recovery in both humans and animals. Conversely, the effect of sleep promotion remains unclear. Baclofen (Bac) is a known non-rapid eye movement (NREM) sleep-promoting drug in both humans and animals. The aim of this study was to investigate the effect of Bac on stroke recovery in a rat model of focal cerebral ischemia (isch).\ud
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METHODS\ud
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Rats, assigned to three experimental groups (Bac/isch, saline/isch, or Bac/sham), were injected twice daily for 10 consecutive days with Bac or saline, starting 24 h after induction of stroke. The sleep-wake cycle was assessed by EEG recordings and functional motor recovery by single pellet reaching test (SPR). In order to identify potential neuroplasticity mechanisms, axonal sprouting and neurogenesis were evaluated. Brain damage was assessed by Nissl staining.\ud
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RESULTS\ud
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Repeated Bac treatment after ischemia affected sleep, motor function, and neuroplasticity, but not the size of brain damage. NREM sleep amount was increased significantly during the dark phase in Bac/isch compared to the saline/isch group. SPR performance dropped to 0 immediately after stroke and was recovered slowly thereafter in both ischemic groups. However, Bac-treated ischemic rats performed significantly better than saline-treated animals. Axonal sprouting in the ipsilesional motor cortex and striatum, and neurogenesis in the peri-infarct region were significantly increased in Bac/isch group.\ud
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CONCLUSION\ud
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Delayed repeated Bac treatment after stroke increased NREM sleep and promoted both neuroplasticity and functional outcome. These data support the hypothesis of the role of sleep as a modulator of poststroke recovery
Hyperglycemia‐ and neuropathy‐induced changes in mitochondria within sensory nerves

Objective  This study focused on altered mitochondrial dynamics as a potential mechanism for diabetic peripheral neuropathy ( DPN ). We employed both an in vitro sensory neuron model and an in situ analysis of human intraepidermal nerve fibers ( IENF s) from cutaneous biopsies to measure alterations in the size distribution of mitochondria as a result of hyperglycemia and diabetes, respectively.    Methods  Neurite‐ and nerve‐specific mitochondrial signals within cultured rodent sensory neurons and human  IENF s were measured by employing a three‐dimensional visualization and quantification technique. Skin biopsies from distal thigh (DT) and distal leg (DL) were analyzed from three groups of patients; patients with diabetes and no  DPN , patients with diabetes and confirmed  DPN , and healthy controls.    Results  This analysis demonstrated an increase in mitochondria distributed within the neurites of cultured sensory neurons exposed to hyperglycemic conditions. Similar changes were observed within  IENF s of the DT in  DPN  patients compared to controls. This change was represented by a significant shift in the size frequency distribution of mitochondria toward larger mitochondria volumes within DT nerves of  DPN  patients. There was a length‐dependent difference in mitochondria within  IENF s. Distal leg  IENF s from control patients had a significant shift toward larger volumes of mitochondrial signal compared to DT  IENF s.    Interpretation  The results of this study support the hypothesis that altered mitochondrial dynamics may contribute to  DPN  pathogenesis. Future studies will examine the potential mechanisms that are responsible for mitochondrial changes within  IENF s and its effect on  DPN  pathogenesis
Systemic chemotherapy decreases brain glucose metabolism

Objective: Cancer patients may experience neurologic adverse effects, such as alterations in neurocognitive function, as a consequence of chemotherapy. The mechanisms underlying such neurotoxic syndromes remain poorly understood. We here describe the temporal and regional effects of systemically administered platinum-based chemotherapy on glucose metabolism in the brain of cancer patients. Methods: Using sequential FDG-PET/CT imaging prior to and after administration of chemotherapy, we retrospectively characterized the effects of intravenously administered chemotherapy on brain glucose metabolism in a total of 24 brain regions in a homogenous cohort of 10 patients with newly diagnosed non-small-cell lung cancer. Results: Significant alterations of glucose metabolism were found in response to chemotherapy in all gray matter structures, including cortical structures, deep nuclei, hippocampi, and cerebellum. Metabolic changes were also notable in frontotemporal white matter (WM) network systems, including the corpus callosum, subcortical, and periventricular WM tracts. Interpretation Our data demonstrate a decrease in glucose metabolism in both gray and white matter structures associated with chemotherapy. Among the affected regions are those relevant to the maintenance of brain plasticity and global neurologic function. This study potentially offers novel insights into the spatial and temporal effects of systemic chemotherapy on brain metabolism in cancer patients
Decoding upper limb residual muscle activity in severe chronic stroke

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                  135633.pdf (publisher's version ) (Open Access)Objective: Stroke is a leading cause of long-term motor disability. Stroke patients with severe hand weakness do not profit from rehabilitative treatments. Recently, brain-controlled robotics and sequential functional electrical stimulation allowed some improvement. However, for such therapies to succeed, it is required to decode patients' intentions for different arm movements. Here, we evaluated whether residual muscle activity could be used to predict movements from paralyzed joints in severely impaired chronic stroke patients.
Methods: Muscle activity was recorded with surface-electromyography (EMG) in 41 patients, with severe hand weakness (Fugl-Meyer Assessment [FMA] hand subscores of 2.93 ± 2.7), in order to decode their intention to perform six different motions of the affected arm, required for voluntary muscle activity and to control neuroprostheses. Decoding of paretic and nonparetic muscle activity was performed using a feed-forward neural network classifier. The contribution of each muscle to the intended movement was determined.
Results: Decoding of up to six arm movements was accurate (>65%) in more than 97% of nonparetic and 46% of paretic muscles.
Interpretation: These results demonstrate that some level of neuronal innervation to the paretic muscle remains preserved and can be used to implement neurorehabilitative treatments in 46% of patients with severe paralysis and extensive cortical and/or subcortical lesions. Such decoding may allow these patients for the first time after stroke to control different motions of arm prostheses through muscle-triggered rehabilitative treatments.12 p
MRI features of Binswanger's disease predict prognosis and associated pathology

OBJECTIVE: To identify the prevalence of MRI features of Binswanger's disease (BD), specifically MRI with diffuse white matter lesions and scattered multiple lacunes (BD-MRI), and to describe neurological features and pathological outcomes of a community-based cohort study.\ud
METHODS: Of 697 participants (all 75 years old), 503 completed neurological examinations at baseline and were followed-up every 30 months thereafter with MRIs, the mini-mental state examination (MMSE) and the Unified Parkinson Disease Rating Scale-Motor Section (UPDRSM). Data from participants with BD-MRI were compared with those from participants with predominant white matter lesions (WML-MRI), scattered multiple lacunes (ML-MRI), or normal MRIs.\ud
RESULTS: Fourteen BD-MRI patients (2.8%) were detected at baseline. The mean MMSE scores in the BD-MRI, WML-MRI, ML-MRI, and normal MRIs groups were 26.4, 28.2, 28.4, and 28.5, respectively, and the mean UPDRSM scores were 9.1, 1.3, 3.1, and 1.7, respectively. At the 30-month follow-up, mortality rates in the normal MRIs, WML-MRI and ML-MRI were 4%, 9.1%, and 22.2%, respectively, and follow-up MRIs were available for 80%, 82%, and 61% of the participants, respectively. In the BD-MRI, however, five patients were deceased, and only five follow-up individual MRIs were available (33.3%). Autopsies were performed on six of eight BD-MRI brains, and these brains fulfilled the pathological criteria for BD independent of Alzheimer disease pathology. All these six individuals also showed systemic atherosclerosis and renal arterio-arteriolosclerosis.\ud
INTERPRETATION: The BD-MRI participants had poor prognoses and showed pure BD pathology with advanced systemic vascular disease. BD-MRI appears to be a predictor of vascular neurocognitive impairment
Degree of corticospinal tract damage correlates with motor function after stroke

Objectives: Direct injury to the corticospinal tract (CST) is a major factor defining motor impairment after stroke. Diffusion tensor imaging (DTI) tractography allows definition of the CST. We sought to determine whether DTI-based assessment of the degree of CST damage correlates with motor impairment at each phase of ischemic stroke. Methods: We evaluated patients at the acute (3–7 days), subacute (30 days), and chronic (90 days) phases of ischemic stroke with DTI and clinical motor scores (upper extremity Fugl-Myer test [UE-FM], motor items of the National Institutes of Health Stroke Scale [mNIHSS]). The CST was identified and virtual fiber numbers (FN) were calculated for the affected and contralateral CST. We used Spearman correlation to study the relationship of FN ratio (FNr) (affected/unaffected CST) with motor scores at each time point, and the regression model to study the association of the acute parameters with chronic motor scores. Results: We studied 23 patients. Mean age was 66.7 (±12) years. FNr correlated with UE-FM score in the acute (r = 0.50, P = 0.032), subacute (r = 0.57, P = 0.007), and chronic (r = 0.67, P = 0.0008) phase, and with mNIHSS in the acute (r = −0.48, P = 0.043), subacute (r = −0.58, P = 0.006), and chronic (r = −0.75, P = 0.0001) phase. The combination of acute NIHSS and FNr significantly predicted chronic UE-FM score (r = 0.74, P = 0.0001). Interpretation DTI-defined degree of CST injury correlates with motor impairment at each phase of ischemic stroke. The combination of baseline FNr and NIHSS predicts motor outcome. DTI-derived CST assessment could become a surrogate marker of motor impairment in the design of neurorestorative clinical trials
Analysis of graft survival in a trial of stem cell transplant in ALS

Objective  The first  US  Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis ( ALS ) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells ( HSSC s) transplanted into the spinal cord in patients with  ALS .    Methods  Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real‐time PCR methods ( qPCR ). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells.    Results  Genomic  DNA  from donor  HSSC s was identified in all cases, comprising 0.67–5.4% of total tissue  DNA  in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were  XY ‐positive by  FISH , confirming donor origin. A subset of  XY ‐positive cells labeled for the neuronal marker NeuN and stem cell marker  SOX 2.    Interpretation  This is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted  HSSC s survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of  ALS  patients
Platelet mitochondrial membrane potential in Parkinson's disease

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                  153662.pdf (publisher's version ) (Open Access)OBJECTIVE: Mitochondrial dysfunction is a hallmark of idiopathic Parkinson's disease (IPD), which has been reported not to be restricted to striatal neurons. However, studies that analyzed mitochondrial function at the level of selected enzymatic activities in peripheral tissues have produced conflicting data. We considered the electron transport chain as a complex system with mitochondrial membrane potential as an integrative indicator for mitochondrial fitness. METHODS: Twenty-five IPD patients (nine females; mean disease duration, 6.2 years) and 16 healthy age-matched controls (12 females) were recruited. Live platelets were purified using magnetic-activated cell sorting (MACS) and single-cell data on mitochondrial membrane potential (Deltapsi) were measured by cytometry and challenged with a protonophore agent. RESULTS: Functional mitochondrial membrane potential was detected in all participants. The challenge test reduced the membrane potential in all IPD patients and controls (P < 0.001). However, the response to the challenge was not significantly different between patients and controls. INTERPRETATION: While the reported protonophore challenge assay is a valid marker of overall mitochondrial function in live platelets, intact mitochondrial membrane potential in platelets derived from IPD patients suggests that presumed mitochondrial enzymatic deficiencies are compensable in this cell type. In consequence, mitochondrial membrane potential in platelets cannot be used as a diagnostic biomarker for nonstratified IPD but should be further explored in potential Parkinson's disease subtypes and tissues with higher energy demands
Eye-Search: A web-based therapy that improves visual search in hemianopia

Persisting hemianopia frequently complicates lesions of the posterior cerebral hemispheres, leaving patients impaired on a range of key activities of daily living. Practice-based therapies designed to induce compensatory eye movements can improve hemianopic patients' visual function, but are not readily available. We used a web-based therapy (Eye-Search) that retrains visual search saccades into patients' blind hemifield. A group of 78 suitable hemianopic patients took part. After therapy (800 trials over 11 days), search times into their impaired hemifield improved by an average of 24%. Patients also reported improvements in a subset of visually guided everyday activities, suggesting that Eye-Search therapy affects real-world outcomes
Variants associated with Gaucher disease in multiple system atrophy

ObjectiveGlucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case–control series.MethodsWe sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher‐disease‐causing GBA variants.ResultsIn the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel–Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14–5.21) and a P‐value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15–5.37) and a P‐value of 0.022. Subtype analysis showed that Gaucher‐disease‐causing GBA variants are significantly associated with MSA cerebellar subtype (MSA‐C) patients (P = 7.3 × 10−3).InterpretationThe findings indicate that, as in PD and DLB, Gaucher‐disease‐causing GBA variants are associated with MSA
Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement.

OBJECTIVE\ud
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Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.\ud
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METHODS\ud
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Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.\ud
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RESULTS\ud
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Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial β-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.\ud
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INTERPRETATION\ud
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In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the β-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches
Selective ROCK2 inhibition in focal cerebral ischemia

Objective: Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known. Methods: We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective ROCK2 inhibitor KD025 (formerly SLx-2119) in focal cerebral ischemia models in mice. Results: KD025 dose-dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 h from stroke onset, and the efficacy was sustained for at least 4 weeks. KD025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic. KD025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection, KD025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform-nonselective ROCK inhibitors, KD025 did not cause significant hypotension, a dose-limiting side effect in acute ischemic stroke. Interpretation Altogether, these data show that KD025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating ROCK2 as the relevant isoform in acute ischemic stroke. Data suggest that selective ROCK2 inhibition has a favorable safety profile to facilitate clinical translation