Z. Ahmed, Y. T. Asi, A. Sailer, A. J. Lees, H. Houlden, T. Revesz and J. L. Holton (2012) Neuropathology and Applied Neurobiology38, 4–24
The neuropathology, pathophysiology and genetics of multiple ...system atrophy
Multiple system atrophy (MSA) is an unrelenting, sporadic, adult‐onset, neurodegenerative disease of unknown aetiology. Its clinically progressive course is characterized by a variable combination of parkinsonism, cerebellar ataxia and/or autonomic dysfunction. Neuropathological examination often reveals gross abnormalities of the striatonigral and/or olivopontocerebellar systems, which upon microscopic examination are associated with severe neuronal loss, gliosis, myelin pallor and axonal degeneration. MSA is a member of a diverse group of neurodegenerative disorders termed α‐synucleinopathies, due to the presence of abnormal α‐synuclein positive cytoplasmic inclusions in oligodendrocytes, termed glial cytoplasmic inclusions. These are the hallmark neuropathological lesion of MSA and are thought to play a central role in the pathogenesis of the disease. In this review, neuropathological features of MSA are described in detail, along with recent advances in the pathophysiology and genetics of the disease. Our current knowledge of the expression and accumulation of α‐synuclein, and efforts to model the disease in vitro and in vivo, are emphasized in this paper and have helped formulate a working hypothesis for the pathogenesis of MSA.
The impact of synchrotron radiation at the Compact Linear Collider Arominski, D.; Sailer, A.; Latina, A. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
12/2020, Letnik:
983, Številka:
C
Journal Article
Recenzirano
Odprti dostop
Synchrotron radiation (SR) emission and interactions with the vacuum chamber walls have the potential to negatively impact the performance of future electron–positron colliders. The Beam Delivery ...System (BDS) of the Compact Linear Collider (CLIC) contains weak bending and multipole magnets that lead to less intense emissions than at circular colliders with similar centre-of-mass energies. However, the linear geometry more easily allows for multiple reflections of SR photons, that can travel further downstream in the accelerator and impact the detector region. In this study, the results of PLACET and Synrad+ simulations of photon emissions and reflections in the CLIC BDS at two energy stages of 380GeV and 3TeV are presented. Estimates are given for heating and outgassing caused by SR photons interacting with the vacuum chamber in the BDS. The occupancy levels in the tracking detectors coming from full-detector simulations in Geant4 are presented. Optimised beam pipe apertures are proposed for the forward detector region, as well as mitigation methods to ensure the safety and best possible performance of the detector.
Abstract Perturbation of steroids pathways is linked to inflammation and chronic diseases, however the underlying mechanism remains unclear. Oxysterols, oxidized forms of cholesterol, are not only ...essential for bile synthesis and sterol transportation but have recently been shown to contribute to the immune response. In addition, serum oxysterols levels have been proposed as suitable candidate biomarkers for neurological diseases such as multiple sclerosis (MS). However how oxysterols modulate adaptive immunity is unknown and their functions in autoimmunity have not been investigated. The enzyme cholesterol 25 hydroxylase (Ch25h) is the rate limiting step to synthesize the oxysterol 7α,25-dihydroxycholesterol (7α,25-OHC) from cholesterol. We here report, using the MS murine model experimental autoimmune encephalomyelitis (EAE), that Ch25h deletion significantly attenuated EAE disease course by limiting trafficking of pathogenic CD4+ T lymphocytes to the central nervous system (CNS). Mechanistically, we show a critical involvement for oxysterols in recruiting leukocytes into inflamed tissues and propose that 7α,25-OHC preferentially promotes the migration of activated CD44+ CD4+ T cells by binding the G protein-coupled receptor called Epstein-Barr virus induced gene 2 (EBI2). Collectively, our results support a pro-inflammatory role for oxysterols during EAE and identify oxysterols as a potential therapeutic target to treat autoimmune diseases.
Cross-sectional survey.
To investigate annual rates and geographic variation of health care utilization in persons with spinal cord injury (SCI), and to identify factors associated with health care ...utilization.
Community setting, entire country of Switzerland.
Annual rates of planned and emergency visits to the general practitioner (GP), planned and emergency outpatient clinic visits and in-patient hospitalizations were compared between individuals with chronic SCI, over 16 years of age residing in Switzerland between late 2011 and early 2013 and a population sample (2012) of the Swiss general population. Risk factors for increased health service utilization were identified by means of regression models adjusted for spatial variation.
Of 492 participants (86.2% response rate), 94.1% visited a health care provider in the preceding year, with most persons visiting GPs (88.4%) followed by outpatient clinics (53.1%) and in-patient hospitals (35.9%). The increase in utilization as compared with the general population was 1.3-, 4.0- and 2.9-fold for GP, outpatient clinic and in-patient hospital visit, respectively. GP utilization was highest in persons with low income (incidence rate ratio (IRR) 1.85) and old age (IRR 2.62). In the first 2 years post injury, health service visits were 1.7 (GP visits) to 5.8 times (emergency outpatient clinic visits) more likely compared with those later post injury.
People with SCI more frequently use health services as compared with the general population, across all types of medical service institutions. GP services were used most often in areas where availability of specialized outpatient clinic services was low.
Objectives To evaluate the effect of intraoperative guidance by means of live fluoroscopy image fusion with computed tomography angiography (CTA) on iodinated contrast material volume, procedure ...time, and fluoroscopy time in endovascular thoraco-abdominal aortic repair. Methods CTA with fluoroscopy image fusion road-mapping was prospectively evaluated in patients with complex aortic aneurysms who underwent fenestrated and/or branched endovascular repair (FEVAR/BEVAR). Total iodinated contrast material volume, overall procedure time, and fluoroscopy time were compared between the fusion group ( n = 31) and case controls ( n = 31). Reasons for potential fusion image inaccuracy were analyzed. Results Fusion imaging was feasible in all patients. Fusion image road-mapping was used for navigation and positioning of the devices and catheter guidance during access to target vessels. Iodinated contrast material volume and procedure time were significantly lower in the fusion group than in case controls (159 mL 95% CI 132–186 mL vs. 199 mL 95% CI 170–229 mL, p = .037 and 5.2 hours 95% CI 4.5–5.9 hours vs. 6.3 hours (95% CI 5.4–7.2 hours), p = .022). No significant differences in fluoroscopy time were observed ( p = .38). Respiration-related vessel displacement, vessel elongation, and displacement by stiff devices as well as patient movement were identified as reasons for fusion image inaccuracy. Conclusion Image fusion guidance provides added value in complex endovascular interventions. The technology significantly reduces iodinated contrast material dose and procedure time.
Large-conductance calcium- and voltage-activated potassium channels (BKCa) are dually activated by membrane depolarization and elevation of cytosolic calcium ions (Ca²⁺). Under normal cellular ...conditions, BKCa channel activation requires Ca²⁺ concentrations that typically occur in close proximity to Ca²⁺ sources. We show that BKCa channels affinity-purified from rat brain are assembled into macromolecular complexes with the voltage-gated calcium channels Cav1.2 (L-type), Cav2.1 (P/Q-type), and Cav2.2 (N-type). Heterologously expressed BKCa-Cav complexes reconstitute a functional "Ca²⁺ nanodomain" where Ca²⁺ influx through the Cav channel activates BKCa in the physiological voltage range with submillisecond kinetics. Complex formation with distinct Cav channels enables BKCa-mediated membrane hyperpolarization that controls neuronal firing pattern and release of hormones and transmitters in the central nervous system.
Interleukin-6 (IL-6) is a key mediator of inflammation. Inhibitors of IL-6 or of its signal transducing receptor gp130 constitute a novel class of anti-inflammatory drugs, which raise great hopes for ...improved treatments of painful inflammatory diseases such as rheumatoid arthritis. IL-6 and gp130 may enhance pain not only indirectly through their proinflammatory actions but also through a direct action on nociceptors (i.e., on neurons activated by painful stimuli). We found indeed that the IL-6/gp130 ligand-receptor complex induced heat hypersensitivity both in vitro and in vivo. This process was mediated by activation of PKC-delta via Gab1/2/PI(3)K and subsequent regulation of TRPV1, a member of the transient receptor potential (TRP) family of ion channels. To assess the relevance of this direct pain promoting effect of IL-6, we generated conditional knock-out mice, which lack gp130 specifically in nociceptors, and tested them in models of inflammatory and tumor-induced pain. These mice showed significantly reduced levels of inflammatory and tumor-induced pain but no changes in immune reactions or tumor growth. Our results uncover the significance of gp130 expressed in peripheral pain sensing neurons in the pathophysiology of major clinical pain disorders and suggest their use as novel pain relieving agents in inflammatory and tumor pain.
This was a prospective cohort study.
The objective was to describe the incidence, prevalence, characteristics of pressure ulcers (PUs) and the association with specific patient characteristics in a ...consecutive sample of in-patients with a spinal cord injury (SCI).
An acute care and rehabilitation clinic specialized in SCIs in Switzerland.
The presence and characteristics of PUs for all adult patients with a SCI admitted to the clinic from 1 September 2009 to 28 February 2010 were recorded on a daily basis during their complete hospitalization. Risk factors were analyzed in univariate and multivariate logistic regression models.
A total of 185 patients were included in the study and observed for the entirety of their hospitalization. The prevalence of at least one PU was 49.2% in all patients, compared with 25.4% in the group of patients admitted without PUs. The incidence was 2.2 per person and year. In 91 patients, a total of 219 PUs were observed. PUs were most frequently located on the foot (36.1%), and the coccyx/sacrum (15.1%). The risk for occurrence of a PU increased with age (odds ratio (OR)=1.04) and post SCI (OR=1.03). In the multivariate analyses, the risk for PUs was lower for patients with the American Spinal Injury Association (ASIA) Impairment Scale (AIS) of C or D (ORC=0.25, ORD=0.28) compared with patients with an AIS of A.
Using a daily documentation system, PUs were detected as a frequent complication of SCIs. Completeness of injury, age and time since injury were significant risk factors for PUs. The foot was a region at high risk for PUs.
Sensory abnormalities have been reported in Parkinson’s disease and may contribute to the motor deficits. Peripheral sensory stimulation inhibits the motor cortex, and the effects depend on the ...interstimulus interval (ISI) between the sensory stimulus and transcranial magnetic stimulation (TMS) to the motor cortex. Short latency afferent inhibition (SAI) occurs at an ISI of ∼20 ms, and long latency afferent inhibition (LAI) at an ISI of ∼200 ms. We studied SAI and LAI in 10 Parkinson’s disease patients with the aim of assessing whether sensorimotor processing is altered in Parkinson’s disease. Patients were studied on and off medication, and the findings were compared with 10 age‐matched controls. Median nerve and middle finger stimulation were delivered 20–600 ms before TMS to the contralateral motor cortex. The motor evoked potentials were recorded from the relaxed first dorsal interosseous (FDI) muscle. SAI was normal in Parkinson’s disease patients off dopaminergic medications, but it was reduced on the more affected side in Parkinson’s disease patients on medication. LAI was reduced in Parkinson’s disease patients compared with controls independent of their medication status. LAI reduced long interval intracortical inhibition in normal subjects but not in Parkinson’s disease patients. The different results for SAI and LAI indicate that it is likely that separate mechanisms mediate these two forms of afferent inhibition. SAI probably represents the direct interaction of a sensory signal with the motor cortex. This pathway is unaffected by Parkinson’s disease but is altered by dopaminergic medication in Parkinson’s disease patients and may contribute to the side effects of dopaminergic drugs. LAI probably involves other pathways such as the basal ganglia or cortical association areas. This defective sensorimotor integration may be a non‐dopaminergic manifestation of Parkinson’s disease.
Prospective controlled before-and-after study.
To investigate the effects of antimuscarinic treatment of neurogenic lower urinary tract dysfunction on the cognition of individuals with spinal cord ...injury (SCI) during the early post-acute phase.
Single SCI rehabilitation center.
Patients with acute traumatic SCI admitted for primary rehabilitation from 2011 to 2015 were screened for study enrollment. Study participants underwent baseline neuropsychological assessments prior to their first urodynamic evaluation (6-8 weeks after SCI). Individuals suffering from neurogenic detrusor overactivity received antimuscarinic treatment, and those not requiring antimuscarinic treatment constituted the control group. The neuropsychological follow-up assessment was carried out 3 months after the baseline assessment. The effects of group and time on the neuropsychological parameters were investigated.
The data of 29 individuals were evaluated (control group 19, antimuscarinic group 10). The group had a significant (P≤0.033) effect on immediate recall, attention ability and perseveration. In the control group, individuals performed significantly (P≤0.05) better in immediate recall both at baseline (percentile rank 40, 95% CI 21-86 versus 17, 95% CI 4-74) and follow-up (percentile rank 40, 95% CI 27-74 versus 16, 95% CI 2-74). The time had a significant (P≤0.04) effect on attention ability, processing speed, word fluency and visuospatial performance. The individuals in both groups performed better at the follow-up compared to the baseline assessment.
Even though, we did not observe cognitive deterioration in the investigated, cognitively intact SCI individuals during the first 3 treatment months, the concerns regarding deleterious effects of antimuscarinics on cognition remain.
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