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Purpose Methods Results Conclusions Level of Evidence This study investigated the effect of different fluoroscopy settings on the accuracy of locating Schottle's point during medial patellofemoral ligament (MPFL) reconstruction.The centre of the MPFL femoral footprint was identified and marked on 44 dry femurs. Two standard true lateral knee fluoroscopic images were obtained: (1) medial to lateral (ML) and (2) lateral to medial (LM). The deviation between the anatomically determined MPFL femoral footprint and the fluoroscopically identified point was measured on both fluoroscopic images. An ‘acceptable tunnel location’ was defined as within a 5‐ or 7‐mm margin of error from the anatomic MPFL footprint. Distal femoral morphometric dimensions were also measured using digital calipers. Statistical analysis determined discrepancies between techniques and their relation to femoral morphometry.The LM view yielded a significantly smaller distance between the anatomical MPFL footprint and Schottle's point compared to the ML view (3.2 ± 1.5 vs. 4.5 ± 2.1 mm, p < 0.001). The LM view achieved acceptable tunnel locations, meeting the 5‐mm error criterion in 90.9% of cases, while the ML view achieved 65.9% (p < 0.001). Both views yielded acceptable tunnel locations at similar rates using the 7‐mm error criterion (n.s.). The anatomic MPFL footprint was displaced towards the anterior and proximal location in the ML view in reference to the Schottle point. No correlation was observed between any of the morphometric measurements and the deviations.This study demonstrated that using the LM fluoroscopic view improves the accuracy of femoral tunnel placement when identifying the MPFL footprint via the Schottle technique. Adopting the LM view in surgical practice will help surgeons locate the anatomical femoral footprint accurately, replicating the native MPFL and enhancing clinical outcomes.Level 4, cadaveric study. [ABSTRACT FROM AUTHOR]

Purpose: The success of medial patellofemoral ligament (MPFL) reconstruction is closely linked to the precise positioning of the femoral tunnel. Intraoperative fluoroscopy is commonly utilized to identify the MPFL footprint. This study aimed to ascertain the most accurate fluoroscopic method among the five previously described methods used to determine the MPFL femoral footprint. Materials and methods: Using 44 well-preserved dry femur bones, the MPFL femoral insertion site was demarcated using anatomical bony landmarks, namely the center of the saddle sulcus between the medial epicondyle, adductor tubercle and gastrocnemius tubercle. Fluoroscopic true lateral knee images were acquired and measurements taken, referencing established methods by Schottle et al., Redfern et al., Wijdicks et al., Barnett et al., and Kaipel et al. The distance between anatomic and fluoroscopic MPFL footprints was then measured on digital fluoroscopic images. The accuracy of the locations was compared using a margin of error of 5 and 7 mm. Results: The Schottle method consistently emerged superior, showcasing the smallest mean distance (3.2 ± 1.2 mm) between the anatomic and radiographic MPFL footprints and a high in-point detection rate of 90.9% under 5 mm criteria. While the Redfern method displayed perfect accuracy (100%) within the 7 mm criteria, the Schottle method also performed 97.7% accuracy. Conclusions: For intraoperative identification of the MPFL footprint using fluoroscopy, the Schottle method is the most consistent and accurate among the assessed methods. Thus, its accuracy in detecting the MPFL footprint makes it recommended for MPFLR to ensure optimal outcomes. Level of evidence: Level IV, cadaveric study. [ABSTRACT FROM AUTHOR]

MEMS (micro-electromechanical system) vibratory gyroscopes have attracted a lot of interest recently and these gyroscopes made their way through portable devices and smart phones. However, their performance is not enough to cope with the demanding requirements of applications such as dead reckoning. Mode-matched gyroscopes can be a solution for this problem. Various mode-matched gyroscope architectures have been proposed and their noise performances have been analyzed in detail. However, in most of these analyses zero-rate output was considered and the noise analysis for dynamic cases were ignored. In this paper, we demonstrate the noise analysis of mode-matched vibratory gyroscope using the power spectral density (PSD) and the Allan deviation methods while in rotation. We show that for mode-matched gyros the noise performance of a rotating gyro can be significantly different from that of a gyro that does not experience any rotation. We also show that this difference is due to the coupling between the drive and sense systems via Coriolis force. This sets a fundamental limit for the noise performance of mode-matched vibratory gyroscopes where ARW (angle random walk) increases proportionally with the rotation rate for the open loop and the force to rebalance operation modes. [ABSTRACT FROM AUTHOR]

Acoustic manipulation of microparticles and cells, called acoustophoresis, inside microfluidic systems has significant potential in biomedical applications. In particular, using acoustic radiation force to push microscopic objects toward the wall surfaces has an important role in enhancing immunoassays, particle sensors, and recently microrobotics. In this paper, we report a flexural-wave based acoustofluidic system for trapping micron-sized particles and cells at the soft wall boundaries. By exciting a standard microscope glass slide (1 mm thick) at its resonance frequencies <200 kHz, we show the wall-trapping action in sub-millimeter-size rectangular and circular cross-sectional channels. For such low-frequency excitation, the acoustic wavelength can range from 10–150 times the microchannel width, enabling a wide design space for choosing the channel width and position on the substrate. Using the system-level acousto-structural simulations, we confirm the acoustophoretic motion of particles near the walls, which is governed by the competing acoustic radiation and streaming forces. Finally, we investigate the performance of the wall-trapping acoustofluidic setup in attracting the motile cells, such as Chlamydomonas reinhardtii microalgae, toward the soft boundaries. Furthermore, the rotation of microalgae at the sidewalls and trap-escape events under pulsed ultrasound are demonstrated. The flexural-wave driven acoustofluidic system described here provides a biocompatible, versatile, and label-free approach to attract particles and cells toward the soft walls. [ABSTRACT FROM AUTHOR]

The use of proton pump inhibitors (PPIs) has been proposed as a potential risk factor for neurodegenerative diseases, but little is known regarding its role in amyotrophic lateral sclerosis (ALS). We therefore aimed to assess the association of PPI use with the subsequent risk of ALS, and performed a register-based nationwide nested case–control study, including 2,484 ALS cases diagnosed during July 2006–December 2013 in Sweden and 10 population controls per case that were individually matched to the case by sex, age, and area of residence. Dispenses and cumulative defined daily doses (cDDDs) of PPIs were extracted from the Swedish Prescribed Drug Register. The association of PPI use with the risk of ALS was assessed using conditional logistic regression, after applying different lag windows to avoid reverse causation. ALS patients were more likely to be dispensed with PPIs before diagnosis than controls. However, previous PPI use was not associated with an increased risk of ALS (OR = 1.08, 95% CI 0.97–1.19), and there was no dose–response relationship between cDDDs of PPIs and ALS risk (p = 0.0874), after excluding dispenses during the year before ALS diagnosis. The results were similar after excluding dispenses during the 2 or 3 years before ALS diagnosis. [ABSTRACT FROM AUTHOR]

Aim of the study: We conducted a systematic review on existing literature in humans and animals, linking the gut microbiome with amyotrophic lateral sclerosis (ALS). Additionally, we sought to explore the role of the bacterially produced metabolite butyrate as well as of proton pump inhibitors (PPIs) in these associations. Materials and methods: Following PRISMA guidelines for systematic literature reviews, four databases (Medline, Scopus, Embase and Web of Science) were searched and screened by two independent reviewers against defined inclusion criteria. Six studies in humans and six animal studies were identified, summarized and reviewed. Results: Overall, the evidence accrued to date is supportive of changes in the gut microbiome being associated with ALS risk, and potentially progression, though observational studies are small (describing a total of 145 patients with ALS across all published studies), and not entirely conclusive. Conclusions: With emerging studies beginning to apply metagenome sequencing, more clarity regarding the importance and promise of the gut microbiome in ALS can be expected. Future studies may also help establish the therapeutic potential of butyrate, and the role of PPIs in these associations. [ABSTRACT FROM AUTHOR]

Charge selectivity forms the basis of cellular excitation or inhibition by Cys-loop ligand-gated ion channels (LGICs), and is essential for physiological receptor function. There are no reports of naturally occurring mutations in LGICs associated with the conversion of charge selectivity. Here, we report on a CHRNA1 mutation (α1Leu251Arg) in a patient with congenital myasthenic syndrome associated with transformation of the muscle acetylcholine receptor (AChR) into an inhibitory channel. Performing patch-clamp experiments, the AChR was found to be converted into chloride conductance at positive potentials, whereas whole-cell currents at negative potentials, although markedly reduced, were still carried by sodium. Umbrella sampling molecular dynamics simulations revealed constriction of the channel pore radius to 2.4 Å as a result of the mutation, which required partial desolvation of the ions in order to permeate the pore. Ion desolvation was associated with an energetic penalty that was compensated for by the favorable electrostatic interaction of the positively charged arginines with chloride. These findings reveal a mechanism for the transformation of the muscle AChR into an inhibitory channel in a clinical context. [ABSTRACT FROM AUTHOR]

Key points: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied.Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform.Recovery from desensitization is determined by the AChR isoform‐specific cytoplasmic M3–M4 domain.The co‐expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering.These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. The neuromuscular junction (NMJ) is the site of a number of autoimmune and genetic disorders, many involving the muscle‐type nicotinic acetylcholine receptor (AChR), although there are aspects of normal NMJ development and function that need to be better understood. In particular, there are still questions regarding the implications of the developmental switch from fetal to adult AChRs, as well as how their functions might be modified by rapsyn that clusters the AChRs. Desensitization of human muscle AChRs was investigated using the patch clamp technique to measure whole‐cell currents in muscle‐type (TE671/CN21) and non‐muscle (HEK293) cell lines expressing either fetal or adult AChRs. Desensitization time constants were similar with both AChR isoforms but recovery time constants were shorter in cells expressing adult compared to fetal AChRs (P < 0.0001). Chimeric experiments showed that recovery from desensitization was determined by the M3–M4 cytoplasmic loops of the γ‐ and ε‐subunits. Expression of rapsyn in TE671/CN21 cells induced AChR aggregation and also, surprisingly, shortened recovery time constants in both fetal and adult AChRs. However, this was not dependent on clustering because rapsyn also facilitated recovery from desensitization in HEK293 cells expressing a δ‐R375H AChR mutant that did not form clusters in C2C12 myotubes. Thus, rapsyn interactions with AChRs lead not only to clustering, but also to a clustering independent faster recovery from desensitization. Both effects of rapsyn could be a necessary adjustment to the motor neuron firing rates that increase around the time of birth. Key points: The physiological significance of the developmental switch from fetal to adult acetylcholine receptors in muscle (AChRs) and the functional impact of AChR clustering by rapsyn are not well studied.Using patch clamp experiments, we show that recovery from desensitization is faster in the adult AChR isoform.Recovery from desensitization is determined by the AChR isoform‐specific cytoplasmic M3–M4 domain.The co‐expression of rapsyn in muscle cells induced AChR clustering and facilitated recovery from desensitization in both fetal and adult AChRs. In fetal AChRs, facilitation of recovery kinetics by rapsyn was independent of AChR clustering.These effects could be crucial adaptations to motor neuron firing rates, which, in rodents, have been shown to increase around the time of birth when AChRs cluster at the developing neuromuscular junctions. [ABSTRACT FROM AUTHOR]

Autoimmune myasthenic syndromes are antibody-mediated disorders of the neuromuscular junction. Common antigenic targets are the acetylcholine receptor or muscle specific kinase (MuSK) in myasthenia gravis (MG) and the voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. There is evidence that antibodies directed against other antigens such as low-density lipoprotein receptor-related protein 4 (LRP4) are also involved in MG. The mechanisms by which various antibodies exert their pathogenic effect depend on the IgG subclass and also the epitope location on the antigens. These mechanisms are partly heterogeneous and include antigen degradation, complement activation, direct functional blocking, or disruption of protein-protein interactions. The neuromuscular junction is characterized by a structural and functional plasticity that is able to compensate for some of the neuromuscular junction defects. Here, we discuss the underlying pathogenic mechanisms of the different autoantibodies and correlate them with phenotypic features. The understanding of these elements should help guide the clinical management of patients with autoimmune myasthenic syndromes. [ABSTRACT FROM AUTHOR]

Objective: The effects of antipsychotic drugs, of whose different classes can be used in the treatment of patients with resistant to schizophrenia, on the fetus and the benefits of the treatment to the mother should be taken into consideration before making a decision about initiating treatment. This study aimed to examine the effects of prenatal exposure to various antipsychotic agents on learning and memory in adult rats. Method: In this study, antipsychotic drugs from different chemical classes (2 mg/kg haloperidol, 100 mg/kg thioridazine, 200 mg/kg sulpiride, 20 mg/kg chlorprothixene, 40 mg/kg clozapine, 10 mg/kg fluphenazine, 20 mg/kg chlorpromazine) and water for the control group were administered to pregnant Sprague-Dawley dams through gavage during the pregnancy period. In total, 16 groups were created and tested in the Morris water maze by dividing offspring of eight mother rats into male and female rat groups (n=10) on postpartum day 60. Learning was tested with hidden platform task and memory was tested with probe test. Results: It has been observed that learning was impaired in the male and female groups that received haloperidol, sulpiride, chlorprothixene, clozapine, and chlorpromazine, as well as in the female groups receiving fluphenazine and thioridazine. Thigmotaxis is the time spent on 10 cm perimeter of the walls of the pool. Thigmotaxis values of all groups were still higher except for the male group of thioridazine on fifth day. Conclusion: These results show that when prenatal exposure to antipsychotics occurs, it causes impairment in the realization of task of finding escape platform properly, rather than affecting learning and memory functions, specifically in their adulthood so that high thigmotaxis may be the reason for deterioration in escape latency parameter. [ABSTRACT FROM AUTHOR]

Loss-of-function variants in AP3D1 have been linked to Hermansky–Pudlak syndrome (HPS) 10, a severe multisystem disorder characterized by oculocutaneous albinism, immunodeficiency, neurodevelopmental delay, hearing loss (HL), and neurological abnormalities, fatal in early childhood. Here, we report a consanguineous family who presented with presumably isolated autosomal recessive (AR) HL. Whole-exome sequencing was performed on all core family members, and selected patients were screened using array-based copy-number analysis and karyotyping. Candidate variants were validated by Sanger sequencing and assessed in silico. A homozygous, likely pathogenic p.V711I missense variant in AP3D1 segregated with the HL. The family was characterized by thorough medical and laboratory examination. The HL was consistent across patients and accompanied by neurological manifestations in two brothers. The sole female patient was diagnosed with premature ovarian failure. Further findings, including mild neutropenia and reduced NK-cell cytotoxicity in some as well as brain alterations in all homozygous patients, were reminiscent of HPS10, though milder and lacking the characteristic albinism. Previously unrecognized, milder, isolated HL was identified in all heterozygous carriers. A protein model indicates that the variant interferes with protein–protein interactions. These results suggest that a missense variant alters inner-ear-specific functions leading to HL with mild HPS10-like symptoms of variable penetrance. Milder HL in heterozygous carriers may point towards semi-dominant inheritance of this trait. Since all previously reported HPS10 cases were pediatric, it is unknown whether the observed primary ovarian insufficiency recapitulates the subfertility in Ap3d1-deficient mice. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate associations between co-medications and survival of patients with amyotrophic lateral sclerosis (ALS). Prescription databases of the Austrian sickness funds covering more than 5 million people formed the basis of this study. ALS cases were deduced from riluzole prescriptions during the study period from January 1, 2008, to June 30, 2012. After adjusting for potential confounding factors associations between co-medications and ALS survival were analyzed. A total of 522 ALS patients could be identified during the study period. Sixteen of the most frequently used drug classes were considered for the survival analyses of which two were nominally associated with ALS survival. Proton pump inhibitors (PPI) were negatively correlated with survival (HR 1.34, 95 % CI 1.04-1.73) and centrally acting muscle relaxants (CAMR) showed a positive association (HR 0.56, 95 % CI 0.39-0.81). After correcting for multiple testing, the association between CAMR and ALS survival remained significant ( p = 0.03). In conclusion, this is the first study systematically evaluating potential associations between commonly used drugs and ALS disease course. We report a positive association between CAMR use and survival, which may have derived from an indication bias representing the better prognosis of the upper motor neuron predominant disease variant. However, this is still interesting since it demonstrates the sensitivity of our study design to pick up survival effects. The use of large prescription registries could thus provide a valuable basis to find clues to underlying pathophysiological mechanisms in ALS. [ABSTRACT FROM AUTHOR]

Elevated plasma asymmetric dimethylarginine (ADMA) levels have been implicated in many cardiovascular and metabolic disorders. In the current work, we investigated the hypothesis that peripheral ADMA is an important contributor to opioid tolerance and dependence, by determining plasma ADMA levels during the development of tolerance and dependence to morphine in mice. Tolerance to and dependence on morphine were induced by repeated injections of morphine (10 mg/kg, s.c.) twice daily to male mice, divided into groups of 3-, 6-, 9- and 10-day injection duration. The loss of antinociceptive effect of morphine in the tail flick test was used for evaluating the degree of tolerance. Physical dependence was assessed following the administration of a 5 mg/kg dose of naloxone, by counting the occurrence of withdrawal jumps and forepaw tremors for 20 min. At the end of each period, animals were anesthetized and blood samples were collected from carotid artery. The plasma levels of ADMA, symmetric dimethylarginine (SDMA), l-homoarginine and l-arginine in morphine-tolerant and -dependent mice were not different from duration-matched control mice. Similarly, no difference was observed in plasma ADMA and the other molecules concentrations between groups of mice with different stages of development of tolerance and dependence. Our results suggest that endogenous plasma ADMA, SDMA, l-homoarginine and l-arginine levels remain unchanged during the development of morphine tolerance and dependence, and are not associated with these phenomena. [ABSTRACT FROM AUTHOR]

Vibration analysis of rods that are subjected to rotation is presented. It is shown that flexural-flexural, longitudinal-flexural and torsional-flexural wave coupling occur due to the Coriolis Effect. First, we carried out our analysis for thin rods where the wavelength is much larger than the radius. It is shown that the wavenumbers change due to the Coriolis Effect. Then, we characterize the 3-D wave propagation in rotating rods by using the Finite Element Method (FEM) in order to determine the corresponding wavenumber shifts for each type of wave. We show that for different drive frequency (ω 0) and rotation rate (Ω), wave couplings exhibit different characteristics. For flexural-flexural wave coupling, the wavenumber increases for the primary flexural wave whereas the wave number decreases for the coupled flexural wave where Ω < ω 0. For the Coriolis coupling between flexural-longitudinal waves, the wavenumber increases for the flexural wave and decreases for the longitudinal wave where Ω < ω 0. For the Coriolis coupling between flexural-torsional waves, the wavenumber increases for both flexural and torsional waves. [ABSTRACT FROM AUTHOR]

Objective: Mutations in the gene encoding for optineurin (OPTN) have been reported in the context of different neurodegenerative diseases including the amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) spectrum. Based on single case reports, neuropathological data in OPTN mutation carriers have revealed transactive response DNA‐binding protein 43 kDa (TDP‐43) pathology, in addition to accumulations of tau and alpha‐synuclein. Herein, we present two siblings from a consanguineous family with a homozygous frameshift mutation in the OPTN gene and different clinical presentations. Methods: Both affected siblings underwent (i) clinical, (ii) neurophysiological, (iii) neuropsychological, (iv) radiological, and (v) laboratory examinations, and (vi) whole‐exome sequencing (WES). Postmortem histopathological examination was conducted in the index patient, who deceased at the age of 41. Results: The index patient developed rapidly progressing clinical features of upper and lower motor neuron dysfunction as well as apathy and cognitive deterioration at the age of 41. Autopsy revealed an ALS‐FTLD pattern associated with prominent neuronal and oligodendroglial TDP‐43 pathology, and an atypical limbic 4‐repeat tau pathology reminiscent of argyrophilic grain disease. The brother of the index patient exhibited behavioral changes and mnestic deficits at the age of 38 and was diagnosed with behavioral FTD 5 years later, without any evidence of motor neuron dysfunction. WES revealed a homozygous frameshift mutation in the OPTN gene in both siblings (NM_001008212.2: c.1078_1079del; p.Lys360ValfsTer18). Interpretation: OPTN mutations can be associated with extensive TDP‐43 pathology and limbic‐predominant tauopathy and present with a heterogeneous clinical phenotype within the ALS‐FTD spectrum within the same family. [ABSTRACT FROM AUTHOR]

Background: Neuromuscular disorders (NMDs) are heterogeneous conditions with a considerable fraction attributed to monogenic defects. Despite the advancements in genomic medicine, many patients remain without a diagnosis. Here, we investigate whether a comprehensive reassessment strategy improves the diagnostic outcomes. Methods: We analyzed 263 patients with NMD phenotypes that underwent diagnostic exome or genome sequencing at our tertiary referral center between 2015 and 2023. We applied a comprehensive reassessment encompassing variant reclassification, re-phenotyping and NGS data reanalysis. Multivariable logistic regression was performed to identify predictive factors associated with a molecular diagnosis. Results: Initially, a molecular diagnosis was identified in 53 cases (20%), while an additional 23 (9%) had findings of uncertain significance. Following comprehensive reassessment, the diagnostic yield increased to 23%, revealing 44 distinct monogenic etiologies. Reasons for newly obtained molecular diagnoses were variant reclassifications in 7 and NGS data reanalysis in 3 cases including one recently described disease-gene association (DNAJB4). Male sex reduced the odds of receiving a molecular diagnosis (OR 0.42; 95%CI 0.21–0.82), while a positive family history (OR 5.46; 95%CI 2.60–11.76) and a myopathy phenotype (OR 2.72; 95%CI 1.11–7.14) increased the likelihood. 7% were resolved through targeted genetic testing or classified as acquired etiologies. Conclusion: Our findings reinforce the use of NGS in NMDs of suspected monogenic origin. We show that a comprehensive reassessment enhances diagnostic accuracy. However, one needs to be aware that genetic diagnoses are often made with uncertainty and can even be downgraded based on new evidence. [ABSTRACT FROM AUTHOR]

Introduction/Aims: The clinical presentation of multifocal motor neuropathy (MMN) may mimic early amyotrophic lateral sclerosis (ALS) with predominant lower motor neuron (LMN) involvement, posing a diagnostic challenge. Both diseases have specific treatments and prognoses, highlighting the importance of early diagnosis. The aim of this study was to assess the diagnostic value of serum neurofilament light chain (NfL) in differentiating MMN from LMN dominant ALS. Methods: NfL was measured in serum in n = 37 patients with MMN and n = 37 age‐ and sex‐matched patients with LMN dominant ALS, to determine the diagnostic accuracy. Clinical and demographic data were obtained at the time of NfL sampling. Results: Serum NfL concentration was significantly lower in MMN patients compared to ALS patients (mean 20.7 pg/mL vs. 59.4 pg/mL, p <.01). NfL demonstrated good diagnostic value in discriminating the two groups (AUC 0.985 [95% CI 0.963–1.000], sensitivity 94.6%, specificity 100%, cut‐off 44.00 pg/mL). Discussion: NfL could be a helpful tool in differentiating MMN from LMN dominant ALS in those patients in whom electrophysiological and clinical examinations remain inconclusive early in the diagnostic process. [ABSTRACT FROM AUTHOR]

Affordable housing plays a key role in well-being and sustainable development. The energy efficiency and sustainability performance of these houses support environmental sustainability and reduce their operational cost and energy consumption. Furthermore, enhanced energy efficiency is a significant factor in affordable houses in the fight against fuel poverty. This paper underlines the importance of sustainable affordable houses for reduced life cycle costs and enhanced welfare and well-being of its residents. Based on an in-depth literature review, considering the entire life cycle of affordable houses, this paper aims to investigate usage of all BIM dimensions and their application areas for enhancing sustainability and affordability of affordable housing as a key for effective housing policies. The integrated usage of Building Information Modelling (BIM) and energy simulation software has the potential to add value to the affordable houses as this integration supports energy savings and enhanced sustainability performance throughout the building's life-cycle. This paper highlights BIM's usage for energy and facility management. Furthermore, this paper emphasises the importance of the policies for effective solutions to the housing problem and recommends holistic policies based on a systematic and interdisciplinary approach to the housing problem. This paper highlights the political economy of affordable housing policies and suggests affordable housing policies request usage of BIM throughout the entire life cycle of affordable houses. [ABSTRACT FROM AUTHOR]

The cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats. [ABSTRACT FROM AUTHOR]

Background and purpose: Dementia prevalence is increasing, with numbers projected to double by 2050. Risk factors for its development include age and cardiovascular comorbidities, which are found more often in patients with dementia and should be treated properly to improve outcomes. In this case–control study, we analysed a large population‐based prescription database to explore the patterns of co‐medication in patients with dementia. Methods: Prescription claims covering >99% of the Austrian population from 2005 to 2016 were obtained. Patients who were treated with an approved antidementia drug (ADD) were included and co‐medication exposure was recorded. A group of people not taking ADDs was matched for age, sex and follow‐up duration as a control. Results: We included 70,799 patients on ADDs who were exposed to a mean of 5.3 co‐medications while control patients were treated with a total of 5.2 co‐medications (p < 0.001). We found that patients on ADDs received less somatic (4.1 vs. 4.5) but more psychiatric medication (1.1 vs. 0.6; p < 0.001 for both). Patients on ADDs were less likely to be treated for pain, cardiovascular conditions or hyperlipidemia. More than 50% of patients on ADDs were treated with antidepressants or antipsychotics. Greater number of co‐medications was associated with markers of more intensive antidementia treatment. Conclusion: Patients on ADDs received more medications overall but were less frequently treated for somatic conditions known to be more prevalent in this group. Together, our data suggest that management of comorbidities in dementia could be improved to optimize outcome and quality of life. [ABSTRACT FROM AUTHOR]

BackgroundFor centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.ObjectiveThe goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.Material and methodsScratching behaviour was induced by intradermal injection of serotonin (50 µg/50 µl/mouse) to Balb/c mice. The neurotoxins 5,7-dihydroxytryptamine (5,7-DHT, 50 μg/mouse) and 6-hydroxydopamine (6-OHDA, 20 μg/mouse) are applied intrathecally to deplete serotonin and noradrenaline in the spinal cord. WIN 55,212-2 (1, 3, 10 mg/kg, i.p.) dose-dependently attenuated serotonin-induced scratches. Neurotoxic destruction of neither the serotonergic nor the noradrenergic systems by 5,7-DHT and 6-OHDA, respectively, had any effect on the antipruritic action of WIN 55,212-2.ConclusionOur findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect. [ABSTRACT FROM AUTHOR]

Repetitive nerve stimulation (RNS) is a standard test for the diagnosis of myasthenia gravis (MG), where decrement of compound muscle action potentials (CMAP) corresponds to clinical muscle fatigability. Our aim was to ascertain the diagnostic and prognostic utility of RNS in MG patients. This study included MG patients treated between 01/2000 and 12/2016, with an observational period of at least one year and a minimum of two neurological examinations. Clinical and electrophysiological data were retrospectively gathered from patient records, and CMAP decrement was correlated with autoantibody titers and clinical disease severity at different time points. Ninety-four patients were included, with 88.3% of the cohort testing positive for acetylcholine receptor autoantibodies (AChR-Abs). RNS sensitivity was higher in patients with generalized disease (71.6%) than in purely ocular MG (38.5%). CMAP decrement did not significantly correlate with AChR-Ab titers, nor with clinical symptom severity at the time of testing or last follow up. However, there was a significant correlation between CMAP decrement and the worst recorded clinical status on a group level. RNS testing is more sensitive in generalized disease and AChR-Ab positive patients, but our data do not support RNS as a tool for long-term outcome prediction. Future studies with a prospective study design could help to overcome a number of limiting factors discussed in our study. [ABSTRACT FROM AUTHOR]

We report the case of a 22-year-old woman presenting with an acute onset of dizziness, gait dysbalance and blurred vision. Magnetic resonance imaging included 3 Tesla and 7 Tesla imaging and revealed a T2-hyperintense, T1-hypointense, non-contrast-enhancing lesion strictly confined to the white matter affecting the right optic radiation. An extensive ophthalmologic examination yielded mild quadrantanopia but no signs of optic neuropathy. The lesion was biopsied. The neuropathological evaluation revealed a demyelinating lesion with marked tissue vacuolization and granular myelin disintegration accompanied by mild T cell infiltration and a notable absence of myelin uptake by macrophages. Oligodendrocytes were strikingly enlarged, displaying oncocytic characteristics and showed cytoplasmic accumulation of mitochondria, which had mildly abnormal morphology on electron microscopy. The diagnosis of multiple sclerosis was excluded. Harding's disease, a variant of Leber's hereditary optic neuropathy, was then suspected. However, neither PCR for relevant mutations nor whole exome sequencing yielded known pathogenetic mutations in the patient's genome. We present a pattern of demyelinating tissue injury of unknown etiology with an oncocytic change of oligodendrocytes and a lack of adequate phagocytic response by macrophages, which to the best of our knowledge, has not been described before. [ABSTRACT FROM AUTHOR]

Background: Pediatric investigation plans (PIPs) describe how adult drugs can be studied in children. In 2015, PIPs for Amyotrophic Lateral Sclerosis (ALS) became mandatory for European marketing-authorization of adult treatments, unless a waiver is granted by the European Medicines Agency (EMA). Objective: To assess the feasibility of clinical studies on the effect of therapy in children (<18 years) with ALS in Europe. Methods: The EMA database was searched for submitted PIPs in ALS. A questionnaire was sent to 58 European ALS centers to collect the prevalence of pediatric ALS during the past ten years, the recruitment potential for future pediatric trials, and opinions of ALS experts concerning a waiver for ALS. Results: Four PIPs were identified; two were waived and two are planned for the future. In total, 49 (84.5%) centers responded to the questionnaire. The diagnosis of 44,858 patients with ALS was reported by 46 sites; 39 of the patients had an onset < 18 years (prevalence of 0.008 cases per 100,000 or 0.087% of all diagnosed patients). The estimated recruitment potential (47 sites) was 26 pediatric patients within five years. A majority of ALS experts (75.5%) recommend a waiver should apply for ALS due to the low prevalence of pediatric ALS. Conclusions: ALS with an onset before 18 years is extremely rare and may be a distinct entity from adult ALS. Conducting studies on the effect of disease-modifying therapy in pediatric ALS may involve lengthy recruitment periods, high costs, ethical/legal implications, challenges in trial design and limited information. [ABSTRACT FROM AUTHOR]

Background and purpose: This study was undertaken to investigate short‐ and long‐term outcome following thymectomy in patients with acetylcholine receptor antibody (AChR‐Ab)‐positive myasthenia gravis (MG). Methods: Rates of clinical response (defined as minimal manifestation, pharmacological remission, or complete stable remission) lasting for at least 1 year were retrospectively analyzed using Cox proportional hazard models. The occurrence of relapses was recorded during follow‐up. Clinical factors associated with achieving an initial or a sustained response were analyzed. Results: Ninety‐four patients with a median age of 33 years (interquartile range [IQR] = 22–51), 68% with nonthymomatous MG and 32% with thymoma‐associated MG, were included. An initial clinical response was reached in 72% (68/94). Neither sex, age at onset, thymus histology, delay to surgery after disease onset, surgical approach, corticosteroid treatment, nor clinical severity before thymectomy was significantly associated with achieving this endpoint. During long‐term follow‐up (median = 89.5 months, IQR = 46–189.5), only half of the patients with an initial response (34/68) had a sustained response without relapses. No clinical factors predicted whether the response would become sustained. In patients without immunosuppressive treatment before thymectomy (n = 24), a high AChR‐Ab reduction rate after thymectomy was associated with a higher likelihood of achieving an initial response (p = 0.03). Conclusions: Sustained long‐term clinical response of MG patients after thymectomy is significantly lower than the initial response rates would suggest. The observation that none of the evaluated clinical factors was associated with a worse outcome supports the current clinical practice of patient selection for thymectomy. The relative decline of AChR‐Abs after surgery appears to be a promising prognostic marker. [ABSTRACT FROM AUTHOR]

Autoimmune diseases caused by pathogenic IgG4 subclass autoantibodies (IgG4-AID) include diseases like MuSK myasthenia gravis, pemphigus vulgaris or thrombotic thrombocytopenic purpura. Their etiology is still unknown. Polymorphisms in the human leukocyte antigen (HLA) gene locus, particularly in HLA-DRB1, are known genetic susceptibility factors for autoimmune diseases. We hypothesized a similar role for HLA polymorphisms in IgG4-AID and conducted a systematic review and meta-analysis with case–control studies on IgG4-AID based on MOOSE/ HuGENet guidelines. Genotype (G) and allele (A) frequencies of HLA-DQB1*05 (G: OR 3.8; 95% CI 2.44–5.9; p < 0.00001; A: OR 2.54; 95% CI 1.82–3.55; p < 0.00001) and HLA-DRB1*14 (G: OR 4.31; 95% CI 2.82–6.59; p < 0.00001; A: OR 4.78; 95% CI 3.52–6.49; p < 0.00001) and the HLA-DRB1*14-DQB1*05 haplotype (OR 6.3; 95% CI 3.28–12.09; p < 0.00001/OR 4.98; 95% CI 3.8–6.53; p < 0.00001) were increased while HLA-DRB1*13 (G: OR 0.48; 95% CI 0.34–0.68; p < 0.0001; A: OR 0.46; 95% CI 0.34–0.62; p < 0.00001) was decreased in IgG4-AID patients. In conclusion, the HLA-DQB1*05, HLA-DRB1*14 alleles and the HLA-DQB1*05-DRB1*14 haplotype could be genetic risk factors that predispose for the production of pathogenic IgG4 autoantibodies and the HLA-DRB1*13 allele may protect from IgG4 autoimmunity. [ABSTRACT FROM AUTHOR]

The significance of muscle biopsy as a diagnostic tool in idiopathic inflammatory myopathies (IIM) remains elusive. We aimed to determine the diagnostic weight that has been given to muscle biopsy in patients with suspected IIM, particularly in terms of clinical diagnosis and therapeutic decisions. In this retrospective multicentric study, we analyzed muscle biopsy results of adult patients with suspected IIM referred to a tertiary center between January 1, 2007, and October 31, 2021. Information regarding referral department, suspected diagnosis, biopsy site, demographic, clinical, laboratory data, and imaging results were extracted. Statistical analyses included the level of agreement between suspected and histological diagnosis and calculation of diagnostic performance (positive and negative predictive values, positive and negative likelihood ratios, sensitivity, and specificity of muscle biopsy in relation to clinical diagnosis and/or treatment initiation). Performance was tested in different strata based on clinical pre-test probability. Among 758 muscle biopsies, IIM was histologically compatible in 357/758 (47.1%) cases. Proportion of IIM was higher if there was a solid clinical pre-test probability (64.3% vs. 42.4% vs. 48% for high, medium and low pre-test probability). Sensitivity and specificity of muscle biopsy were highest (82%) when the diagnosis by the clinician was used as outcome scenario. Negative predictive value was only moderate (between 63% and 80%) and lowest if autoantibodies were positive (35%). In patients with clinically suspected IIM, approximately 50% of biopsies revealed features indicative of IIM. Diagnostic performance of muscle biopsy was moderate to high depending on clinical pre-test probability. • In case of suspected IIM, muscle biopsy is a reliable tool for confirming diagnosis. • Symptoms, elevated CK-levels and changes in EMG are indicative for IIM in biopsy. • Detection of MAA or MSA are highly relevant to establish clinical diagnosis. [ABSTRACT FROM AUTHOR]

• Rhabdomyolysis was most common in myopathies, epilepsy and stroke. • Rhabdomyolysis-associated acute kidney injury was rare in neurological patients. • Serum CK half-life was 1.5 days and similar between neurological disease entities. The objective of this retrospective cohort study was to evaluate demographic, clinical and laboratory characteristics of patients with rhabdomyolysis as defined by a serum creatine kinase (sCK) activity > 950 U/L. A total of 248 patients were recruited from the Department of Neurology, Medical University of Vienna, between 01/2000 and 12/2017, with a median sCK activity of 2,160 U/l (IQR 1,342–4,786). Seizures (31.9%), illicit drugs/alcohol (9.7%) and exercise (8.5%) were the most common trigger factors. Rhabdomyolysis incidence rates in specific neurological diseases as estimated by the ratio between rhabdomyolysis cases and the total number of cases with the corresponding disease were highest in myopathies (49.8/1,000 person-years, 95% CI 32.3–67.4), followed by epilepsy (16.4/1,000 person-years, 95% CI 12.8–20.0) and stroke (11.9/1,000 person-years, 95% CI 8.4–15.4). The half-life of sCK activity was 1.5 days in the total cohort. In myopathies, sCK activity was significantly higher as compared to other disease entities 7 days after the peak measurement (p = 0.0023). Acute kidney injury (AKI) developed in 18 patients (7.3%) with no AKI-related deaths during the study period. In conclusion, rhabdomyolysis occurred in a broad range of neurological entities but was associated with a favorable prognosis in most cases rarely resulting in AKI and death. [ABSTRACT FROM AUTHOR]

This study investigated treatment characteristics of Guillain-Barré syndrome (GBS) in a real-world setting between 2000 and 2019. We analyzed clinical improvement between nadir and last follow-up in patients with severe GBS (defined as having a GBS disability scale > 2 at nadir) and aimed to detect clinical factors associated with multiple treatments. We included 121 patients (74 male; median age 48 [IQR 35–60]) with sensorimotor (63%), pure motor (15%), pure sensory (10%) and localized GBS (6%) as well as Miller Fisher syndrome (6%). 44% of patients were severely affected. All but one patient received at least one immunomodulatory treatment with initially either intravenous immunoglobulins (88%), plasma exchange (10%) or corticosteroids (1%), and 25% of patients received more than one treatment. Severe GBS but not age, sex, GBS subtype or date of diagnosis was associated with higher odds to receive more than one treatment (OR 4.22; 95%CI 1.36–13.10; p = 0.01). Receiving multiple treatments had no adjusted effect (OR 1.30, 95%CI 0.31–5.40, p = 0.72) on clinical improvement between nadir and last follow-up in patients with severe GBS. This treatment practice did not change over the last 20 years. [ABSTRACT FROM AUTHOR]

Background: Albuminocytologic dissociation in cerebrospinal fluid (CSF) is a diagnostic hallmark of Guillain–Barré syndrome (GBS). Compared to CSF total protein (TP), the CSF/serum albumin quotient (Qalb) has the advantage of method-independent reference ranges. Whether the diagnostic yield differs between Qalb and CSF-TP is currently unknown. Methods: We retrospectively analyzed the diagnostic yield (i.e., a value above the URL indicating blood–nerve barrier dysfunction) of Qalb and CSF-TP levels in patients with GBS. We evaluated two different equations (Reiber's and Hegen's) for age-adjusted URLs of Qalb and compared results to CSF-TP using the standard URL of 0.45 g/L as well as age-adjusted URLs (by decade of age). Additionally, multivariable logistic regression analysis was used to assess the effect of clinical factors on the diagnostic yield. Results: We analyzed 110 patients [62% males; median age 48 (IQR 35–58)] with sensorimotor (68), motor (16), sensory (12) and localized (8) GBS as well as Miller Fisher syndrome (6). Qalb and CSF-TP were highly correlated (r = 0.95, p < 0.001). The diagnostic yield of Qalb was 65% with Reiber's and 47% with Hegen's age-adjusted URLs compared to 66% with the fixed CSF-TP URL of 0.45 g/L and 49% with age-adjusted CSF-TP URLs. A longer duration from clinical onset to lumbar puncture was associated with a higher diagnostic yield. Conclusion: Qalb strongly correlates with CSF-TP in patients with GBS with a similar diagnostic yield for the detection of a blood–nerve barrier dysfunction. However, the diagnostic yield of both values is lower when using more recent age-adjusted URLs and at earlier timepoints. [ABSTRACT FROM AUTHOR]

Background: To investigate the frequency and characterize the clinical features of treatment-refractory myasthenia gravis in an Austrian cohort. Methods: Patient charts of 126 patients with generalized myasthenia gravis and onset between 2000 and 2016 were analyzed retrospectively. Patients were classified as treatment-refractory according to strict, predefined criteria. These mandated patients being at least moderately symptomatic (i.e., MGFA class III) or needing either maintenance immunoglobulins or plasma exchange therapy for at least 1 year in spite of two adequately dosed immunosuppressive drugs. Clinical features and outcome at last follow-up were compared to treatment-responsive patients. Results: 14 out of 126 patients (11.1%) met these criteria of treatment-refractory myasthenia gravis. Treatment-refractory patients had more frequent clinical exacerbations and more often received rescue treatments or a further escalation of immunosuppressive therapies. They also remained more severely affected at last follow-up. An early onset of myasthenia gravis was associated with a higher risk for a refractory course. Conclusion: A small subgroup of patients with generalized myasthenia gravis do not respond sufficiently to standard therapies. Refractory disease has considerable implications for both patients and health care providers and highlights an unmet need for new treatment options. [ABSTRACT FROM AUTHOR]

In recent years, it has been pointed out that epigenetic changes affect learning and memory formation. Particularly, it has been shown that histone acetylation and DNA methylation work in concert to regulate learning and memory formation. We aimed to examine whether acetylation of H2B within the rat hippocampus alters by trainings in the Morris water maze test. Male, 2–3 months old, Sprague Dawley rats were trained in Morris water maze task. Animals were given four trials per day for five consecutive days to locate a hidden platform. On the sixth day, the platform was removed and the animals were swum for 60 s. The effects of sodium butyrate, histone deacetylase inhibitor, were tested on normal and scopolamine‐induced memory‐impaired rats. The histone deacetylase inhibitor, sodium butyrate, increased histone H2B acetylation in normal rats. Sodium butyrate had no effect on learning and memory performance of normal rats; however, it partially ameliorated learning and memory disruption induced by scopolamine. So, the histone deacetylase inhibitors can be new treatment agent for cognitive disorders. [ABSTRACT FROM AUTHOR]

Acetylcholine receptor deficiency is the most common form of the congenital myasthenic syndromes, a heterogeneous collection of genetic disorders of neuromuscular transmission characterized by fatiguable muscle weakness. Most patients with acetylcholine receptor deficiency respond well to acetylcholinesterase inhibitors; however, in some cases the efficacy of acetylcholinesterase inhibitors diminishes over time. Patients with acetylcholine receptor deficiency can also benefit from the addition of a β2-adrenergic receptor agonist to their medication. The working mechanism of β2-adrenergic agonists in myasthenic patients is not fully understood. Here, we report the long-term follow-up for the addition of β2-adrenergic agonists for a cohort of patients with acetylcholine receptor deficiency on anticholinesterase medication that demonstrates a sustained quantitative improvement. Coincidently we used a disease model to mirror the treatment of acetylcholine receptor deficiency, and demonstrate improved muscle fatigue, improved neuromuscular transmission and improved synaptic structure resulting from the addition of the β2-adrenergic agonist salbutamol to the anticholinesterase medication pyridostigmine. Following an initial improvement in muscle fatiguability, a gradual decline in the effect of pyridostigmine was observed in mice treated with pyridostigmine alone (P < 0.001). Combination therapy with pyridostigmine and salbutamol counteracted this decline (P < 0.001). Studies of compound muscle action potential decrement at high nerve stimulation frequencies (P < 0.05) and miniature end-plate potential amplitude analysis (P < 0.01) showed an improvement in mice following combination therapy, compared to pyridostigmine monotherapy. Pyridostigmine alone reduced postsynaptic areas (P < 0.001) and postsynaptic folding (P < 0.01). Combination therapy increased postsynaptic area (P < 0.001) and promoted the formation of postsynaptic junctional folds (P < 0.001), in particular in fast-twitch muscles. In conclusion, we demonstrate for the first time how the improvement seen in patients from adding salbutamol to their medication can be explained in an experimental model of acetylcholine receptor deficiency, the most common form of congenital myasthenic syndrome. Salbutamol enhances neuromuscular junction synaptic structure by counteracting the detrimental effects of long-term acetylcholinesterase inhibitors on the postsynaptic neuromuscular junction. The results have implications for both autoimmune and genetic myasthenias where anticholinesterase medication is a standard treatment. [ABSTRACT FROM AUTHOR]

Background and objectives: Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature.Methods: Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed.Results: 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment.Discussion: The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time. [ABSTRACT FROM AUTHOR]

Abstract: Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10–20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle‐specific kinase (MuSK). The use of cell‐based assays has extended the repertoire of antibody tests to clustered AChRs, low‐density lipoprotein receptor–related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed. [ABSTRACT FROM AUTHOR]

Currently, it has not been satisfactorily established, whether modern low-osmolality iodinated contrast agents (ICAs) used in computed tomography (CT) studies are a risk factor for exacerbation of myasthenic symptoms. The rate of acute adverse events as well as delayed clinical worsening up to 30 days were analyzed in 73 patients with confirmed myasthenia gravis (MG) who underwent contrast-enhanced CT studies and compared to 52 patients who underwent unenhanced CT studies. One acute adverse event was documented. 12.3% of MG patients experienced a delayed exacerbation of symptoms after ICA administration. The rate of delayed severe exacerbation was higher in the contrast-enhanced group. Alternative causes for the exacerbation of MG-related symptoms were more likely than ICA administration in all cases. ICA administration for CT studies in MG patients should not be withheld if indicated, but patients particularly those with concomitant acute diseases should be carefully monitored for exacerbation of symptoms. [ABSTRACT FROM AUTHOR]

C9orf72 repeat expansions have been observed in a wide variety of neurodegenerative disorders. The cut-off between normal and pathogenic alleles is not well established as repeat sizing methods are often semi-quantitative. However, intermediate alleles might influence disease prevalence and phenotype, as seen for other repeat expansion disorders. We aimed to further delineate the prevalence of small, intermediate and expanded C9orf72 alleles and elucidate their potential influence on the disease phenotype. DNA derived from patients (n = 1804) and healthy individuals (n = 643) was obtained from multiple collectives in Austria. Genotyping was performed using a two-step PCR assay followed by Southern blotting. 3.4% of clinically diagnosed frontotemporal dementia (FTD; n = 5/147) cases and 0.8% of clinically diagnosed Alzheimer's disease (AD; n = 5/602) cases were carriers of a pathological C9orf72 repeat expansion. A significantly earlier disease onset was detected in expansion carriers compared to non-carriers in the FTD and AD cohorts (median 50 years, range 39–64 vs. median 64 years, range 36–92, p = 0.018 and median 63 years, range 54–71 vs. median 74 years, range 45–92, p = 0.006, respectively). C9orf72 intermediate alleles were significantly associated with cerebellar symptoms (p = 0.0004) and sensory deficits in the dementia cohort (p = 0.01). C9orf72 repeat expansion carriers showed earlier disease onset compared to non-carriers with clinical diagnosis of FTD and AD. Furthermore, C9orf72 intermediate repeats might modify the phenotypic expression in dementia. • C9orf72 expansions were found in clinically diagnosed patients with dementia probably due to AD. • C9orf72 repeat expansion carriers show earlier disease onset compared to non-carriers. • Intermediate C9orf72 alleles act as potential disease modifiers in dementia-subtypes. [ABSTRACT FROM AUTHOR]

Myoglobinuric acute renal failure (mARF) is an uremic syndrome which develops due to damage of skeletal muscle. It was demonstrated that free radicals and nitric oxide (NO) play an important role in pathogenesis of mARE. Our aim was to investigate the effect of losartan, a drug known for its antioxidant effect, on mARF. In our study, a total of 34 male Spraque Dawley rats were divided into four groups. 1st and 2nd groups were injected with saline, 3rd and 4th groups were injected with intramuscular glycerol. One and 24 hours later, 1st and 3rd groups received saline orally and 2nd and 4th groups have taken 10mg/kg losartan. Urine was collected; the blood samples and kidneys of the rats were taken under the anesthesia. The levels of NO, arginine, asymmetric dimethylarginine (ADMA), glutathione (GSH) and malondialdehyde (MDA) were determined, renal functions and histopathological changes examined. In our study, we found that levels of urea, creatinine, and potassium, in serum samples and MDA and ADMA in renal tissue were increased in 3rd group when it's compared with the 1st group. Levels of sodium, arginine in serum samples and arginine in renal tissue were reduced 3rd group when compared with the 1st group. When 3rd and 4th groups were compared, serum creatinine was higher in the latter group whereas ADMA level in renal tissue was lower in the same group. We think that there is no positive effect of losartan on the pathogenesis of mARF. [ABSTRACT FROM AUTHOR]

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action. • Dipyrone elicits antidepressant and anxiolytic effects in CUMS in mice. • Endocannabinoid and N-acylethanolamines levels do not change in amygdala in CUMS model of mice. • CB1 receptors mediate anxiolytic effects of dipyrone in CUMS in mice. • Antidepressant effect of dipyrone may be mediated via TRPV1 receptors in mice exposed to CUMS. [ABSTRACT FROM AUTHOR]

Nerve conduction studies (NCS) are essential to differentiate between demyelinating and axonal subtypes in Guillain-Barré syndrome (GBS). However, it is debated to which extent the delay of NCS after symptom onset and repeated measurements during the disease course influence the diagnostic accuracy. We evaluated NCS in 93 patients with a classical GBS applying two widely used criteria (Hadden's and Rajabally's). The initial measurements after symptom onset were compared to follow-up studies where available (n = 43). We analyzed the influence of NCS timing after symptom onset and clinical severity on fulfilling the electrophysiological criteria for axonal or demyelinating subtypes and evaluated the impact of repeated measurements. We further evaluated the presence of reversible conduction failure. A higher GBS disability scale at nadir correlated with a successful subclassification whereas the delay of the first NCS after symptom onset did not influence the diagnostic yield (75% for Hadden's and 68% for Rajabally's criteria for the first assessment). A second measurement allowed the additional successful classification in 19% and 14% of patients, respectively. On the other hand, a repeated measurement in patients with an initial successful classification resulted in a different subtype in 5% and 7%, respectively. Reversible conduction failure was found in 7% of patients. Clinical severity but not timing of NCS influenced the fulfilment of electrophysiological criteria for either the axonal or demyelinating subtype. Repeated electrophysiological measurements led to a further specification or a change in subtype classification in a relevant proportion of patients. • Clinical severity but not timing of NCS correlates with fulfilling the electrophysiological criteria in GBS. • Repeated NCS increases the rate of successful electrophysiological classifications of either demyelinating or axonal GBS subtype. • A change in GBS subtype classification between the initial and follow-up studies can occur in a minority of patients. • Reversible conduction failure was found in 7% of patients. [ABSTRACT FROM AUTHOR]

The neuromuscular junction (NMJ) is the synapse between motoneurons and skeletal muscle, and is responsible for eliciting muscle contraction. Neurotransmission at synapses depends on the release of synaptic vesicles at sites called active zones (AZs). Various proteins of the extracellular matrix are crucial for NMJ development; however, little is known about the identity and functions of the receptors that mediate their effects. Using genetically modified mice, we find that integrin-a3 (encoded by Itga3), an adhesion receptor at the presynaptic membrane, is involved in the localisation of AZ components and efficient synaptic vesicle release. Integrin-a3 also regulates integrity of the synapse - mutant NMJs present with progressive structural changes and upregulated autophagy, features commonly observed during ageing and in models of neurodegeneration. Unexpectedly, we find instances of nerve terminal detachment from the muscle fibre; to our knowledge, this is the first report of a receptor that is required for the physical anchorage of pre- and postsynaptic elements at the NMJ. These results demonstrate multiple roles of integrin-a3 at the NMJ, and suggest that alterations in its function could underlie defects that occur in neurodegeneration or ageing. [ABSTRACT FROM AUTHOR]