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BACKGROUND: Valosin-containing protein (VCP) disease, caused by mutations in the VCP gene, results in myopathy, Pagets disease of bone (PBD) and frontotemporal dementia (FTD). Natural history and genotype-phenotype correlation data are limited. This study characterises patients with mutations in VCP gene and investigates genotype-phenotype correlations. METHODS: Descriptive retrospective international study collecting clinical and genetic data of patients with mutations in the VCP gene. RESULTS: Two hundred and fifty-five patients (70.0% males) were included in the study. Mean age was 56.8±9.6 years and mean age of onset 45.6±9.3 years. Mean diagnostic delay was 7.7±6 years. Symmetric lower limb weakness was reported in 50% at onset progressing to generalised muscle weakness. Other common symptoms were ventilatory insufficiency 40.3%, PDB 28.2%, dysautonomia 21.4% and FTD 14.3%. Fifty-seven genetic variants were identified, 18 of these no previously reported. c.464G>A (p.Arg155His) was the most frequent variant, identified in the 28%. Full time wheelchair users accounted for 19.1% with a median time from disease onset to been wheelchair user of 8.5 years. Variant c.463C>T (p.Arg155Cys) showed an earlier onset (37.8±7.6 year) and a higher frequency of axial and upper limb weakness, scapular winging and cognitive impairment. Forced vital capacity (FVC) below 50% was as risk factor for being full-time wheelchair user, while FVC

Background and Objectives: Allergic contact dermatitis is a common type IV hypersensitivity reaction characterised by redness, itching, oedema and thickening of the skin. It occurs in about 7% of the population and its incidence is increasing. It has been observed that the preconditioning of tissues by exposing them to transient ischemia increases resistance to subsequent permanent ischemia, and this phenomenon is called ischemic preconditioning. It has been shown that conditioning in one organ can also protect other organs. The protective effect of remote ischemic preconditioning is thought to be based on the induction of anti-inflammatory responses. The aim of this project was to investigate the anti-inflammatory and antipruritic effects of remote ischemic postconditioning in a mouse model of experimental allergic contact dermatitis. Methods: Experimental allergic contact dermatitis was induced with 1-fluoro-2,4-dinitrobenzene. Remote ischemic postconditioning was performed at 3 and 25 h after the challenge. Ear thickness and number of scratches 24 and 48 h after challenge, as well as cytokine levels and the infiltration of mast cells, neutrophils, CD4+ and CD8+ T lymphocytes in serum and ear tissue at 48 h were measured to determine the effect of RIPsC. Results: Remote ischemic postconditioning decreased ear thickness, one of the symptoms of allergic contact dermatitis (p < 0.0001). It had no significant effect on the number of scratches. It reduced serum IL-17 levels (p < 0.01). It alleviated local inflammation by suppressing CD8+ T lymphocyte and neutrophil infiltration. Conclusions: It was concluded that remote ischemic postconditioning may alleviate the symptoms of allergic contact dermatitis by suppressing CD8+ T lymphocyte and neutrophil infiltration and reducing IL-17 secretion.

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]

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]

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]

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 RVM12 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. Key words: dipyrone, endocannabinoid, N-acylethanolamide, paracetamol. On a soupconne que la contribution du systeme cannabinoide participe aux modes d'action de la dipyrone et du paracetamol. Nous avions pour but de mesurer les taux d'endocannabinoides et de N-acylethanolamide localement dans le cerveau et la moelle epiniere de rats a la suite de l'administration de dipyrone et de paracetamol. Nous avons evalue la nociception 1, 5 et 12 heures apres l'injection de medicaments a des rats Wistar, a l'aide des tests de retraction de la queue et de la plaque chauffante. Nous avons observe les effets antinociceptifs de la dipyrone (150, 300 et 600 mg/kg, i.p.) et du paracetamol (30,100 et 300 mg/kg, i.p.). Apres l'administration des doses les plus elevees de paracetamol et de dipyrone, nous avons mesure les taux d'endocannabinoides (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) et de N- acylethanolamines (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) dans la substance grise periaqueducale (GPA), dans la region bulbaire ventromediane (BVM) et dans la moelle epiniere des rats, a l'aide de la methode de spectrometrie de masse en tandem avec la chromatographie liquide. Nous avons observe une hausse des taux de 2-AG dans la GPA et la region BVM apres l'injection de paracetamol; la dypirone n'a eu aucun effet sur les taux de 2-AG. L'administration d'analgesiques a mene a un abaissement des taux d'AEA dans la region BVM et la moelle epiniere; nous avons aussi observe une diminution similaire des taux de PEA et d'OEA dans la region BVM et la moelle epiniere. L'administration de dipyrone et de paracetamol semble exercer des effets complexes sur les taux d'endocannabinnoides et de N-acylethanolamides chez le rat. [Traduit par la Redaction] Mots-cles : dipyrone, endocannabinoide, N-acylethanolamide, paracetamol., Introduction Cannabinoids are a group of compounds including naturally occurring phytocannabinoids found in the cannabis plant, synthetic cannabinoids, and endogenous cannabinoids (endocannabinoids). They exert their effects by interacting with 2 [...]