Search

Spinal cord injury represents a great health and economic burden for patients and society, and a major challenge for both the physician and the researcher. Following a lesion, a series of anatomopathological changes (glial scar formation, neuroinflammatory reactions, and cell death) occurs, associated with the poor capability of the adult CNS to restore its connectivity owing to an environment that inhibits axonal growth and the subsequent inactivation of the growth program. Some reorganization of local neural circuits and sprouting of axons can occur, and different therapeutic approaches are being tested in the early and delayed phases of disease by preventing glial scar formation, removing inhibitory molecules, or stimulating axonal growth by trophic factors, inducing physical exercise. In addition, cell therapy may be used to replace and restore lost neural circuits or to modulate the environment, as well as different types of scaffold. Finally, gene therapy could enhance axonal growth.

Several cases of deep venous thrombosis in people who had recently received Vaxzevria (previously known as COVID-19 Vaccine AstraZeneca) have recently been reported, mainly presenting as cerebral vein/cerebral venous sinus thrombosis. This syndrome has been termed "vaccine-induced immune thrombotic thrombocytopenia (VITT)". Acute spleno-porto-mesenteric vein thrombosis is an uncommon but serious condition with potential sequelae, such as small-bowel gangrene and end-stage liver failure. We describe a case of concomitant thrombosis of portal, superior mesenteric and splenic veins in a young female patient with no other risk factors who received Vaxzevria (previously ChAdOx1 nCoV-19 vaccine, AstraZeneca) 17 days before. The diagnostic workup and the successful endovascular treatment and systemic anticoagulation management is reported.

Environmental, maternal and early life microbial/immune networks program human developmental trajectories and health outcomes and strongly modify allergic disease risk. The effects of environmental microbiota are illustrated by the 'farm effect' (the protection against asthma and allergy conferred by growing up on a traditional farm) and other natural experiments in populations exposed to microbe-rich environments. The role of gut microbiome maturation in the asthma/allergy trajectory is demonstrated by the most recent farm studies, which identified microbial metabolites specifically associated with asthma protection, and studies in other cohorts, which defined dynamic microbial community profiles associated with allergic disease phenotypes. Current and future studies in germ-free mice associated with gut microbiota from human disease states are providing novel mechanistic insights into the role of microbiota in shaping immune function and allergic disease susceptibility.

Purpose To assess differences in referral and pathologic outcomes for uro-oncology cases prior to and during the COVID pandemic, comparing clinical and pathological data of cancer surgeries performed at an academic referral center between 2019 and 2020. Methods We collected data of 880 prostate biopsies, 393 robot-assisted radical prostatectomies (RARP) for prostate cancer (PCa), 767 trans-urethral resections of bladder tumor (TURB) and 134 radical cystectomies (RC) for bladder cancer (BCa), 29 radical nephro-ureterectomies (RNU) for upper tract urothelial carcinoma, 130 partial nephrectomies (PN) and 12 radical nephrectomies (RN) for renal cancer, and 41 orchifunicolectomies for testicular cancer. Data of patients treated in 2019 (before COVID-19 pandemic) were compared to patients treated in 2020 (during pandemic). Results No significant decline in uro-oncological surgical activity was seen between 2019 and 2020. No significant increase in time between diagnosis and surgery was observed for all considered cancers. No differences in terms of main pathologic features were observed in patients undergoing RARP, TURB, RNU, RN/PN, or orchifunicolectomy. A higher proportion of ISUP grade 3 and 4 PCa were diagnosed in 2020 at biopsy (p = 0.001), but this did not translate into worse pathological grade/stage at RARP. In 2020, more advanced disease features were seen after RC, including lymph node involvement (p = 0.01) and non-organ confined disease (p = 0.02). Conclusion Neither decline in uro-oncologic activity nor delay between diagnosis and treatment was observed at our institution during the first year of COVID-19 pandemic. No significant worsening of cancer disease features was found in 2020 except for muscle-invasive BCa. Supplementary Information The online version contains supplementary material available at 10.1007/s00345-021-03842-y.

A growing number of individuals live with an opioid use disorder (OUD). While many go on to recover from such disorders, certainly, there will be individuals in palliative care (PC) at some point who still suffer with OUD. One of the major barriers to PC for individuals recovering and currently suffering from an OUD is the stigma related to having an OUD. Therefore, in the context of PC, it is important to understand the relationship that exists between PC, OUDs, and how stereotypes related to substance use disorders affect patient engagement in PC. For this paper, the focus will be on how stereotypes affect pain management in PC for persons with an OUD. A review of current literature regarding OUDs and pain management indicates a need for care specific to the needs of those in PC who formerly and/or currently suffer from an OUD in order to avoid relapse or worsening of their affliction while still managing their pain. The striking lack of knowledge and resources regarding OUDs and their treatment indicates a need to strengthen/increase resources for physicians to educate on treating OUDs as well as alternatives for pain management. This article presents dignity-enhancing care as a gateway to fairly treat individuals with an OUD and to get rid of the stigma associated with OUD patients.

Background Double J (DJ) ureteral stents are commonly inserted after ureteroscopy (URS) procedures for stone treatment. However, stent-related symptoms are still a major issue. Objective To determine whether a commercially available pigtail suture stent (PSS) can reduce stent-related symptoms compared to a conventional DJ stent after uncomplicated URS. Design, setting, and participants We designed a randomized, single-blind, parallel-group trial from January to November 2020. The inclusion criteria were stone-free URS without intraprocedural complications. Patients with distal ureteral stones were excluded. Intervention Insertion of a PSS or DJ stent after URS. Outcome measurements and statistical analysis The primary endpoint was the Urinary Symptom Index score on the Ureteral Stent Symptoms Questionnaire (USSQ) 2 wk after URS. Secondary endpoints were USSQ domain scores and responses to individual USSQ questions at 2 d and 2 wk after surgery. Results and limitations A total of 78 patients were randomized and treated according to protocol. The Urinary Symptom Index score (p = 0.004), overall Visual Analogue Scale (VAS) score (p = 0.022), and the percentage of patients complaining of pain (63.9% vs 86.1%, p = 0.029) were significantly in favor of PSS at both 2 d and 2 wk after URS. At 2 d, the VAS score among patients with pain (p = 0.025) and the General Health Index score (p = 0.036) were significantly better in the PSS group. No severe complications occurred in either group. Study limitations are the exclusion of patients with distal ureteral stones and the limited sample size. Conclusions PSS significantly reduced stent-related symptoms after URS, in particular urinary symptoms and pain, compared to conventional DJ stents, and showed a good safety profile. Patient summary Stents are hollow tubes placed in the passage between the kidney and the bladder (ureter). The standard stent has two coiled ends (double J stent) to keep it in place in both the kidney and the bladder. We tested a commercial stent with two strings at the bladder end (pigtail suture stent) after procedures to remove stones from the upper urinary tract and found that it caused less stent-related symptoms compared to a double J stent. This trial is registered at Clinicaltrials.gov as NCT03344120., Take Home Message A pigtail suture stent significantly reduced stent-related symptoms compared to a conventional double J stent, in particular urinary symptoms and pain. We suggest the use of a pigtail suture stent rather than a double J stent after uncomplicated ureteroscopy performed for renal or proximal to mid-ureteral stones.

International audience; Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF β2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF β2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery-Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF β2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF β2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF β2-dependent mechanisms were also determined in laminopathic cells, where TGF β2 activated AKT/mTOR phosphorylation. These data show that TGF β2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF β2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies.

To present the step-by-step description of an ejaculation-sparing anatomic photo-selective vaporization of the prostate (PVP) technique. To report the results of a series of ejaculation-sparing versus non-ejaculation-sparing anatomic PVPs. Sexually active, benign prostatic hyperplasia (BPH) patients undergoing an anatomic PVP between 11/2018 and 2/2020 were included. Patients were divided into group A (ejaculation-sparing surgery) and group B (control group). Baseline, peri-operative and 6-months follow-up data were evaluated. Lower urinary tract symptoms (LUTS) and sexual function were assessed through internationally validated questionnaires. Groups were matched by an inverse probability of treatment weighting (IPTW) analysis. Logistic univariable regression analysis was performed to detect predictors of antegrade ejaculation preservation. Overall, 76 patients were included, among which 15 in group A and 61 in group B. Median (inter-quartile range, IQR) age was 72 (66.5–77) years, median (IQR) prostate volume 63.5 (54.5–98.5) cc. No differences about peri-operative outcomes were detected, included high-grade complications. At 6-months follow-up, no differences in urinary or erectile function were detected between groups, while ejaculation-sparing patients showed better Male Sexual Health Questionnaire (MSHQ) scores [7 (1–13) vs. 1 (1–1), p

Over the last few years, antimicrobial shampoo therapy has been increasingly used to treat skin infections in order to reduce systemic use of antibiotics. This study was aimed to compare the In vitro bactericidal effect of a black currant oil based shampoo (S1) to a chlorhexidine 4% shampoo (S2) against methicillin-sensitive Staphylococcus pseudintermedius (MSSP), methicillin-resistant Staphylococcus pseudintermedius (MRSP), Staphylococcus aureus (SA), Escherichia coli (EC) and Pseudomonas aeruginosa (PA) isolates. A collection of 50 bacterial strains from skin swabs of dogs with superficial recurrent pyoderma was selected: 10 MSSP, 10 MRSP, 10 SA, 10 EC and 10 PA. The two shampoos were blindly tested in duplicate with a microdilution plate method, with scalar concentrations from 1:2 to 1: 256. The MBC was performed for each dilution. A linear regression was used to detect a statistically significance between the two shampoos. All isolates were completely killed at 1:2 up to 1:16 dilution of the two antiseptic products. At the 1:32 dilution the first bacterial growths were observed, in particular for 2 and 4 strains of MRSP by S1 and S2 respectively. The first lethal dilution for SA was at 1:64 for S1/S2 and only for S2 against SP. No significant difference was observed between the two shampoos according to the results of linear regression significant for: i) MRSP, PA and EC (p < 0.05); ii) MSSP and SA (p < 0.1). This study showed that both black currant oil based shampoo and chlorhexidine 4% shampoo have a similar In vitro bactericidal activity.

A 10-year-old canine with chronic unilateral otitis and a history of unsuccessful systemic and topical antibiotic treatments was referred. A computer tomography scan (CT scan) revealed unilateral chronic otitis with calcification of the ear canal, abscessation and fistula. On bacterial culture a Staphylococcus pseudintermedius sensitive to pradofloxacin was isolated. Systemic treatment with pradofloxacin, 3 mg/kg per os once daily, improved the infection and the dog had total ear canal ablation and bulla osteotomy performed. After one month, despite antibiotic treatment new fistulas developed in the same area. Bacterial culture revealed an drug-resistant S. pseudintermedius sensitive only to rifampicin. Under general anesthesia, the area was cleaned with 0.5% saline solution and 1 mL of indocyanine green (Emundo®, A.R.C.) was injected into the fistulas. A treatment with diode laser (A.R.C. Laser 810 nm, GmbH, Nurnberg, Germany) of four cycles 500 mw for 30 s, with a dosage of 50 J/cm2 in the effected area was performed. No antibiotic was administered and one week later, 50% of the fistulas were closed with a significant improvement of the patient's clinical condition. Cytology and bacterial culture were negative 72 h after the treatment. Total recovery occurred after two weeks. Photodynamic Therapy(PDT) is a promising antibacterial technique in case of localized refractory bacterial infections.

Objective To compare stent-related symptoms (SRS) of loop-tail (LT) and conventional double J (DJ) stents after uncomplicated flexible ureterorenoscopy (fURS), in a prospective randomised controlled single-blind parallel-group study. Patients and methods Patients undergoing fURS were randomised into two groups: the LT Group received LT stents (Polaris™ Loop) and the DJ Group received conventional DJ stents (Vortek® ). The stent was removed after 4 weeks. The Ureteric Stent Symptom Questionnaire (USSQ) was administered at 2 days, 4 and 8 weeks (baseline evaluation) after stent insertion. The primary endpoint was to compare the Urinary Symptom Index Score of the LT vs DJ groups at 4 weeks after stent insertion. The secondary endpoints were to compare the USSQ domains' subscores at 2 days and 4 weeks after stent insertion, USSQ single answers at 4 weeks, and the 4-week USSQ domains' subscores adjusted for baseline. Results A total of 68 patients were randomised (34 LT and 34 DJ). The answers given at 4 weeks were not significantly different between the two groups for the Urinary Symptom Index Score (P = 0.982), Pain Index Score (P = 0.169), visual analogue scale (P = 0.276), and all the other domains of the USSQ. At 4 weeks, the single-answer analysis did not find any differences between the groups; the urinary symptoms were all comparable, as was the requirement for pain painkillers (P = 0.684) and pain during sex (P = 0.496). There were also no significant differences for every single domain score for the responses given at 2 days. The same applied to USSQ subscores at 4 weeks adjusted for the 8-week baseline results, which were also comparable. Conclusions The study found no differences in terms of SRS between the LT and DJ groups, either at 2 days or 4 weeks after stent insertion, with or without baseline correction.

Background Early diagnosis of breast, colon, rectum and prostate cancers improves health outcomes. Low socioeconomic status (SES) is related to advanced stages at diagnosis; inequalities could explain differences in outcomes by age. The influence of SES, age and residence area on staging was explored in the Umbrian population. Methods 2001-2010 cases were geo-coded by census tract of residence. Stage distribution or Gleason score were analyzed by multilevel multinomial logistic regression with age and SES as the fixed effects and census tract as the random-effect. Results For breast and colorectal cancers, the screening age class was advantaged. For breast, age effect was modulated by deprivation and census tract. In the elderly, the richest were advantaged, the poorest disadvantaged; issues emerged for the young. For colon, age effect is modulated by census tract in early stages and deprivation in late stages. The elderly were disadvantaged; the young and the deprived had more stages IV. About rectum, age effect was modulated by deprivation in the late stages. The elderly were disadvantaged; the young and the deprived presented more stages IV. For prostate, age effect was modulated by deprivation and census tract. The intermediate age class was advantaged, the elderly disadvantaged. Conclusion Age was not always the determinant of a delayed staging when SES was considered. For breast and colorectal cancers, issues of delayed diagnosis emerged in the young. If the care center was near the residence, the census tract modified the stage at diagnosis. These results are useful to reduce SES barriers by specific programs adapted to the age of the patient and area of residence.

A 3-months-old male domestic kitten was referred for repeated seizures. Analysis revealed Cryptococcus neoformans. Levetiracetam and fluconazole were administered without significant clinical improvements and without negativization. Hypothesizing resistance, therapy was switched to amphotericin B. Seizure disappeared. Haematological controls highlighted transitory increasing of CK, BUN, ALP and cholesterol. PCR repeated two weeks after the treatment was negative for Cryptococcus neoformans. Nowadays the cat is 5 years old, and no seizures occurred since the age of 5 months.

The aim of this study was to investigate the reliability and validity of the Trunk Control Measurement Scale (TCMS) among children with cerebral palsy (CP) who were living in Tanzania. Two physiotherapy trainees, each blinded to the other’s test findings, independently administered the TCMS to 38 children with CP (16 female; M age = 7.2, SD = 4.8 years) twice over sessions separated by a 30-day interval. We assessed internal consistency and intra/inter-rater reliability using Cronbach’s alpha and the Intraclass Correlation Coefficient (ICC), respectively. We examined measurement error through Standard Error of Measurement (SEM) and Minimal Detectable Change (MDC). We assessed construct validity with Spearman's correlation coefficient between the TCMS and both the Gross Motor Function Classification System (GMFCS) and the Manual Ability Classification System (MACS). We found a frank floor effect. Internal consistency (α = 0.945) and reliability indices were excellent for the total scale (ICC for intra-rater reliability = 0.985, inter- reliability = 0.997) and for each sub-scale score. We found low values of SEM (1.7 points) and MDC (4.8 points). Construct validity was supported by moderate and strong correlations between the TCMS and the GMFCS and MACS in this sample. We conclude that the psychometric properties of the TMCS support its clinical and research use for youth with CP in low-income settings.

Background: Four main clinical phenotypes have been traditionally described in patients mutated in SCN4A, including sodium-channel myotonia (SCM), paramyotonia congenita (PMC), Hypokaliemic type II (HypoPP2), and Hyperkaliemic/Normokaliemic periodic paralysis (HyperPP/NormoPP); in addition, rare phenotypes associated with mutations in SCN4A are congenital myasthenic syndrome and congenital myopathy. However, only scarce data have been reported in literature on large patient cohorts including phenotypes characterized by myotonia and episodes of paralysis.Methods: We retrospectively investigated clinical and molecular features of 80 patients fulfilling the following criteria: (1) clinical and neurophysiological diagnosis of myotonia, or clinical diagnosis of PP, and (2) presence of a pathogenic SCN4A gene variant. Patients presenting at birth with episodic laryngospasm or congenital myopathy-like phenotype with later onset of myotonia were considered as neonatal SCN4A.Results: PMC was observed in 36 (45%) patients, SCM in 30 (37.5%), Hyper/NormoPP in 7 (8.7%), HypoPP2 in 3 (3.7%), and neonatal SCN4A in 4 (5%). The median age at onset was significantly earlier in PMC than in SCM (p < 0.01) and in Hyper/NormoPP than in HypoPP2 (p = 0.02). Cold-induced myotonia was more frequently observed in PMC (n = 34) than in SCM (n = 23) (p = 0.04). No significant difference was found in age at onset of episodes of paralysis among PMC and PP or in frequency of permanent weakness between PP (n = 4), SCM (n = 5), and PMC (n = 10). PP was more frequently associated with mutations in the S4 region of the NaV1.4 channel protein compared to SCM and PMC (p < 0.01); mutations causing PMC were concentrated in the C-terminal region of the protein, while SCM-associated mutations were detected in all the protein domains.Conclusions: Our data suggest that skeletal muscle channelopathies associated with mutations in SCN4A represent a continuum in the clinical spectrum.

PURPOSE: We studied microRNAs as potential biomarkers for Pompe disease. METHODS: We analyzed microRNA expression by small RNA-seq in tissues from the disease murine model at two different ages (3 and 9 months), and in plasma from Pompe patients. RESULTS: In the mouse model we found 211 microRNAs that were differentially expressed in gastrocnemii and 66 in heart, with a different pattern of expression at different ages. In a preliminary analysis in plasma from six patients 55 microRNAs were differentially expressed. Sixteen of these microRNAs were common to those dysregulated in mouse tissues. These microRNAs are known to modulate the expression of genes involved in relevant pathways for Pompe disease pathophysiology (autophagy, muscle regeneration, muscle atrophy). One of these microRNAs, miR-133a, was selected for further quantitative real-time polymerase chain reaction analysis in plasma samples from 52 patients, obtained from seven Italian and Dutch biobanks. miR-133a levels were significantly higher in Pompe disease patients than in controls and correlated with phenotype severity, with higher levels in infantile compared with late-onset patients. In three infantile patients miR-133a decreased after start of enzyme replacement therapy and evidence of clinical improvement. CONCLUSION: Circulating microRNAs may represent additional biomarkers of Pompe disease severity and of response to therapy.

Myotonia congenita (MC) is a skeletal-muscle hyperexcitability disorder caused by loss-of-function mutations in the ClC-1 chloride channel. Mutations are scattered over the entire sequence of the channel protein, with more than 30 mutations located in the poorly characterized cytosolic C-terminal domain. In this study, we characterized, through patch clamp, seven ClC-1 mutations identified in patients affected by MC of various severities and located in the C-terminal region. The p.Val829Met, p.Thr832Ile, p.Val851Met, p.Gly859Val, and p.Leu861Pro mutations reside in the CBS2 domain, while p.Pro883Thr and p.Val947Glu are in the C-terminal peptide. We showed that the functional properties of mutant channels correlated with the clinical phenotypes of affected individuals. In addition, we defined clusters of ClC-1 mutations within CBS2 and C-terminal peptide subdomains that share the same functional defect: mutations between 829 and 835 residues and in residue 883 induced an alteration of voltage dependence, mutations between 851 and 859 residues, and in residue 947 induced a reduction of chloride currents, whereas mutations on 861 residue showed no obvious change in ClC-1 function. This study improves our understanding of the mechanisms underlying MC, sheds light on the role of the C-terminal region in ClC-1 function, and provides information to develop new antimyotonic drugs.

Spinal muscular atrophy (SMA) is a severe neuromuscular disease affecting children, due to mutation/deletion of survival motor neuron 1 (SMN1) gene. The lack of functional protein SMN determines motor neuron (MN) degeneration and skeletal muscle atrophy, leading to premature death due to respiratory failure. Nowadays, the Food and Drug Administration approved the administration of three drugs, aiming at increasing the SMN production: although assuring noteworthy results, all these therapies show some non-negligible limitations, making essential the identification of alternative/synergistic therapeutic strategies. To offer a valuable in vitro experimental model for easily performing preliminary screenings of alternative promising treatments, we optimized an organotypic spinal cord culture (derived from murine spinal cord slices), which well recapitulates the pathogenetic features of SMA. Then, to validate the model, we tested the effects of human Mesenchymal Stem Cells (hMSCs) or murine C2C12 cells (a mouse skeletal myoblast cell line) conditioned media: 1/3 of conditioned medium (obtained from either hMSCs or C2C12 cells) was added to the conventional medium of the organotypic culture and maintained for 7 days. Then the slices were fixed and immunoreacted to evaluate the MN survival. In particular we observed that the C2C12 and hMSCs conditioned media positively influenced the MN soma size and the axonal length respectively, without modulating the glial activation. These data suggest that trophic factors released by MSCs or muscular cells can exert beneficial effects, by acting on different targets, and confirm the reliability of the model. Overall, we propose the organotypic spinal cord culture as an excellent tool to preliminarily screen molecules and drugs before moving to in vivo models, in this way partly reducing the use of animals and the costs.

Spinal cord injury (SCI) is a devastating lesion to the spinal cord, which determines the interruption of ascending/descending axonal tracts, the loss of supraspinal control of sensory-motor functions below the injured site, and severe autonomic dysfunctions, dramatically impacting the quality of life of the patients. After the acute inflammatory phase, the progressive formation of the astrocytic glial scar characterizes the acute-chronic phase: such scar represents one of the main obstacles to the axonal regeneration that, as known, is very limited in the central nervous system (CNS). Unfortunately, a cure for SCI is still lacking: the current clinical approaches are mainly based on early vertebral column stabilization, anti-inflammatory drug administration, and rehabilitation programs. However, new experimental therapeutic strategies are under investigation, one of which is to stimulate axonal regrowth and bypass the glial scar. One major issue in axonal regrowth consists of the different genetic programs, which characterize axonal development and maturation. Here, we will review the main hurdles that in adulthood limit axonal regeneration after SCI, describing the key genes, transcription factors, and miRNAs involved in these processes (seen their reciprocal influencing action), with particular attention to corticospinal motor neurons located in the sensory-motor cortex and subjected to axotomy in case of SCI. We will highlight the functional complexity of the neural regeneration programs. We will also discuss if specific axon growth programs, that undergo a physiological downregulation during CNS development, could be reactivated after a spinal cord trauma to sustain regrowth, representing a new potential therapeutic approach.

We report the case of a 62-year-old male patient fully vaccinated for COVID-19, admitted to our emergency room for persistent fever associated with exertional dyspnoea, skin lesions, diffuse myalgias and arthralgias not responsive to broad-spectrum antibiotic and antiviral therapy, who developed a rapidly progressive refractory to treatment interstitial lung disease due to anti-melanoma differentiation-associated gene 5 (MDA5) antibodies, that required mechanical ventilation and ECMO. Here, we highlight the importance of always considering alternative diagnoses, i.e. viral and autoimmune diseases, including anti-MDA5 antibody screening, when dealing with patients with a skin rash, seronegative polyarthralgias and interstitial pneumonia, or acute respiratory distress syndrome of unknown origin. LEARNING POINTS: MDA5-associated dermatomyositis is a rare systemic syndrome associated with rapidly progressive and treatment-refractory interstitial lung disease. The anti-MDA5 antibody is the key biomarker for the diagnosis. Early diagnosis is crucial to promptly start aggressive immunosuppressive therapy with the aims of improving prognosis and reducing mortality.

Background Microbial interventions against allergic asthma have robust epidemiologic underpinnings and the potential to recalibrate disease-inducing immune responses. Oral administration of OM-85, a standardized lysate of human airways bacteria, is widely used empirically to prevent respiratory infections and a clinical trial is testing its ability to prevent asthma in high-risk children. We previously showed that intranasal administration of microbial products from farm environments abrogates experimental allergic asthma. Objectives We sought to investigate whether direct administration of OM-85 to the airway compartment protects against experimental allergic asthma; and to identify protective cellular and molecular mechanisms activated through this natural route. Methods Different strains of mice sensitized and challenged with ovalbumin or Alternaria received OM-85 intranasally, and cardinal cellular and molecular asthma phenotypes were measured. Airway transfer experiments assessed whether OM-85–treated dendritic cells protect allergen-sensitized, OM-85–naive mice against asthma. Results Airway OM-85 administration suppressed allergic asthma in all models acting on multiple innate and adaptive immune targets: the airway epithelium/IL-33/ILC2 axis, lung allergen–induced type 2 responses, and dendritic cells whose Myd88/Trif-dependent tolerogenic reprogramming was sufficient to transfer OM-85–induced asthma protection. Conclusions We provide the first demonstration that administering a standardized bacterial lysate to the airway compartment protects from experimental allergic asthma by engaging multiple immune pathways. Because protection required a cumulative dose 27- to 46-fold lower than the one reportedly active through the oral route, the efficacy of intranasal OM-85 administration may reflect its direct access to the airway mucosal networks controlling the initiation and development of allergic asthma.

We describe the case of a 68-year-old man with a known history of hypertension and diabetes mellitus presented to our Emergency Department, complaining of hematuria and vomiting in the last 12 hours, stypsis and urinary incontinence in the last week, and worsening hyporexia in the last 6 months. Bedside ultrasound documented a slight right pleural effusion with B lines in the middle and basal right field, gastrectasis, dilated fluid-filled bowel loops, potential signs of gas in the upper right quadrant, grade 3 bilateral hydronephrosis, and bladder globe. Abdominal CT scan confirmed the bilateral hydroureteronephrosis and showed the right kidney with Emphysematous Pyelonephritis (EPN) with extension into the perinephric and muscular planes for 24 cm, and initial EPN in the left kidney. A RT-PCR nasopharyngeal swab for SARS CoV-2 was negative. A diagnosis of ileum paretic, acute renal failure and urosepsis due to EPN was made.

INTRODUCTION AND OBJECTIVE:Ejaculatory Dysfunction (EjD) is common after traditional surgeries for Benign Prostatic Hyperplasia (BPH), causing significant bother to younger and sexually active pati...

Ultrasonography of the optic nerve sheath diameter (ONSD) is used for the non-invasive assessment of increased intracranial pressure (ICP). ONSD values are usually obtained by averaging the measurements of the two eyes, but asymmetric ONSD dilation is possible, leading to potentially inaccurate ICP estimation when using binocular averaging. In addition, few data are available about the asymmetry of the ONSD and the use of the maximum ONSD value between eyes for raised ICP detection. The aim of the study was to evaluate the interocular ONSD asymmetry in healthy subjects and patients with intracranial hypertension (IH) by ultrasonography and to investigate whether the maximum ONSD could be as useful as the binocular assessment. Forty healthy subjects and 40 patients with IH (20 with idiopathic intracranial hypertension and 20 with intracerebral hemorrhage) who underwent transorbital sonography were retrospectively enrolled. The prevalence and degree of ONSD asymmetry were compared among groups; ONSD median binocular and maximum values were compared. Forty-two out of 80 subjects (52.5%) showed significant ONSD asymmetry, without significant differences in prevalence among groups (p = 0.28). The median asymmetry was higher in patients than in healthy subjects (0.45 mm vs 0.23 mm; p = 0.007), without significant differences between the two pathologies (p = 0.58). Both binocular and maximum ONSD measurements were significantly higher in patients with IH than in controls (p

Introduction: Genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood. Recently, advanced technologie...

Esta pesquisa-intervenção parte dos seguintes questionamentos: “O que o professor de educação infantil entende por daltonismo?”, “Os docentes reconhecem a necessidade de formação continuada para a contextualização e reflexão das práticas pedagógicas inclusivas, a fim de atenderem crianças daltônicas?”, “É possível planejar um trabalho de rastreio e inclusão dessas crianças na educação infantil?”. O objetivo neste estudo foi sensibilizar os professores para que possam entender as dificuldades enfrentadas pela criança daltônica. O universo da pesquisa foi composto por um Centro de Educação Infantil (CEI), que atende crianças de zero a três anos e 11 meses, e uma Escola de Educação Infantil (Emei), que recebe crianças de quatro a cinco anos e 11 meses, ambas localizadas no município de São Paulo. Os sujeitos foram 22 professoras, 2 coordenadoras pedagógicas, 2 diretoras, 2 agentes de apoio e 2 auxiliares técnicos de educação (ATE). A metodologia utilizada foi a de cunho qualitativo, do tipo intervenção pautada na pesquisa-ação, e os instrumentos de coleta de dados foram: observação da vivência durante o uso dos brinquedos, depoimento escrito e entrevista. A pesquisa se fundamentou nos seguintes autores: Mantoan, Santos, Farina e Oliveira. Os resultados indicam que os profissionais de educação infantil participantes da pesquisa não têm clareza sobre o que é daltonismo, como se constitui geneticamente, quais dificuldades uma criança daltônica enfrenta dentro dos espaços escolares e como planejar um trabalho pedagógico inclusivo diante da presença de uma criança daltônica em sala.

Investigations about ventral hernia repair are focused on improving the quality, resistance, and biocompatibility of mesh. This study compared plain polypropylene mesh with a pectin-honey hydrogel-coated polypropylene mesh in an acute hernia model in rats. Forty Wistar rats, randomly assigned to two groups, were submitted to laparotomy, and a 1 cm × 2 cm fascial defect was created, centered on the midline. Uncoated (group C) or coated mesh (group T) was inserted in an inlay fashion to repair the defect. After 30 days, the rats were euthanized, and the presence of adhesions to the mesh was macroscopically evaluated. Histology and measurement of COX-2 as tissue inflammation markers were used to assess fascia tissue healing. Grades of adhesion were not different between groups. Histological score and COX-2 expression were not significantly different between groups, except for the higher inflammatory response demonstrated in group T. The pectin-hydrogel coated mesh could not reduce adhesion formation compared to uncoated polypropylene mesh but improved peritoneal regeneration and tissue healing.

In the COVID-19 era the real challenge for the Emergency Departments (ED) is to avoid the spread of the viral infection within the so called “clean area” of the emergency room and the hospital. Different protocols have been proposed and adopted in the EDs to quickly identify suspected COVID-19 patients and to correctly manage these patients, all based on clinical and epidemiological criteria. To the best of our knowledge, our pre-triage decisional making-process first integrates the pre-triage interview with pointof- care Lung Ultrasound (LUS) performed in the triage area. The aim of our study is to assess the sensitivity and specificity of our screening clinical and/or epidemiological criteria, and to investigate the role of LUS in the triage decision-making process during the “phase 2” of the COVID-19 Italian epidemic. Our study confirms the pivotal role of the triage in the decision-making process and the management of the entire ED, and it demonstrates that further studies are necessary to validate the role of LUS as tool to promptly identify COVID-19 patients, if combined with a correct pre-triage interview.

Simple Summary Equine-assisted interventions (EAIs) are gaining increasing attention as complementary practices in autism spectrum disorders (ASD) as they can provide physical and psychological enrichment to children. However, ASD children could manifest inappropriate behaviours, potentially affecting the welfare of horses. This multicentre study aimed to investigate behavioural and physiological indices of stress in horses involved in EAI standardised sessions with children with ASD compared to sessions involving typically developing (TD) children. It followed a controlled within-subject design with repeated measurements involving 19 horses and 38 children. We compared behavioural and physiological responses of horses between sessions and among session phases. Results indicate a lower sympathetic tone in horses involved in ASD sessions, while in the mounting and dismounting phases, the horses displayed behavioural signs of stress, independently from children’s behaviour. Results from this study indicate that professionals should increase their awareness of horse’s welfare and refine methodologies used in EAIs. Abstract Equine-assisted interventions (EAIs) are well-known complementary practices combining physical activity with emotional/cognitive stimulation. They are especially suited for children with autism spectrum disorders (ASD) who need a high degree of physical and psychological enrichment. Even though EAIs have become a common practice, stress responses in horses interacting with individuals that can manifest inappropriate behaviours, such as ASD children, have not been thoroughly investigated. Our multicentre study aimed to investigate behavioural and physiological indices of stress in horses involved in EAI standardised sessions with children with ASD compared to typically developing (TD) children. A controlled within-subject design with repeated measurements involving 19 horses and 38 children was adopted. Stress-related behaviours, heart rate, heart rate variability, and eye temperature were recorded during the riding sessions. Moreover, blood samples were collected from horses before and after each session to monitor changes in blood adrenocorticotropic hormone (ACTH), cortisol, and catecholamines. Results indicate that, in general, stress responses in horses involved in EAIs did not differ as a function of the horse being ridden by children with ASD or TD. A lower sympathetic tone in horses involved in ASD sessions was found, while in the mounting and dismounting phases, horses displayed behavioural signs of stress, independently from children’s behaviour. We conclude that professionals working in EAI should increase their awareness of animal welfare and refine riding practices, taking into account horse’s needs.

Ear tip ulcerative dermatitis (ETUD) is an uncommon clinical reaction pattern in canine dermatology. The lesions are suggestive of vascular damage which may be caused by inflammatory or noninflammatory diseases, and often are idiopathic. Therapeutic options for ETUD include topical glucocorticoids or tacrolimus, pentoxifylline, vitamin E, doxycycline, tetracycline and niacinamide, sulfonamides, glucocorticoids, ciclosporin and surgical correction.The aims of this retrospective case series were to describe the clinical features and report response to treatment with oclacitinib in dogs with idiopathic, chronic ETUD.Twenty-five privately owned dogs with unilateral or bilateral ETUD.Cases of ETUD which were poorly responsive to conventional therapy and subsequently treated with oclacitinib, are summarised. All cases were tested for leishmaniosis by serological examination [indirect fluorescent antibody test (IFAT) or enzyme-linked immunosorbent assay (ELISA)]. Histopathological examination was performed in two cases.Serological results were negative for leishmaniosis in all dogs. Histopathological changes consistent with proliferative thrombovascular necrosis of the pinnae were documented in two cases. Oclacitinib, used at the standard dose range recommended for the treatment of canine atopic dermatitis, effectively resolved ETUD in 22 of 25 dogs within one to three months. Several of the dogs required prolonged use of twice daily dosing.Oclacitinib should be included among the therapeutic options for ETUD, once infectious diseases have been ruled out.L'ETUD (Ear Tip Ulcerative Dermatitis) est un patron réactionnel clinique rare en dermatologie canine. Les lésions sont suggestives d'un dommage vasculaire qui peut être causé par des maladies inflammatoires ou non inflammatoires, souvent idiopathiques. Les options thérapeutiques pour ETUD comprennent les corticoïdes topiques, le tacrolimus, la pentoxifylline, la vitamine E, la doxycycline, la tétracycline et niacinamide, les sulfonamides, les corticoïdes, la ciclosporine et la chirurgie. HYPOTHÈSES/OBJECTIFS: Les buts de cette série rétrospective de cas étaient de décrire les données cliniques et rapporter les réponses aux traitements avec l’oclacitinib chez les chiens avec ETUD chronique idiopathique.Vingt-cinq chiens de propriétaire avec ETUD unilatérale ou bilatérale. MATÉRIELS ET MÉTHODES: Les cas d’ETUD qui répondaient mal au traitement conventionnel et ainsi traités avec de l’oclacitinib, ont été résumés. Tous les cas ont été testés pour leishmaniose par examen sérologique [indirect fluorescent antibody test (IFAT) ou enzyme-linked immunosorbent assay (ELISA)]. L’examen histopathologique a été réalisé pour deux cas. RÉSULTATS: Les résultats sérologiques étaient négatifs pour la leishmaniose pour tous les chiens. Les changements histopathologiques consistaient en une nécrose thrombovasculaire proliférative des pavillons, documentés dans deux cas. L’oclacitinib, utilisé à la dose standard recommandée pour le traitement de la dermatite atopique canine, a été efficace pour 22 des 25 chiens en un à trois mois. Plusieurs des chiens ont nécessité un traitement prolongé d’une dose deux fois par jour.L’oclacitinib devrait être incluse dans les options thérapeutiques de l’ETUD, lorsque les infections ont été éliminées.INTRODUCCIÓN: la dermatitis ulcerativa de la punta del oído (ETUD) es un patrón de reacción clínica poco común en la dermatología canina. Las lesiones sugieren daño vascular que puede ser causado por enfermedades inflamatorias o no inflamatorias y, a menudo, son idiopáticas. Las opciones terapéuticas para ETUD incluyen glucocorticoides tópicos o tacrolimus, pentoxifilina, vitamina E, doxiciclina, tetraciclina y niacinamida, sulfonamidas, glucocorticoides, ciclosporina y corrección quirúrgica. HIPÓTESIS/OBJETIVOS: los objetivos de esta serie de casos retrospectivos fueron describir las características clínicas e informar de la respuesta al tratamiento con oclacitinib en perros con ETUD crónica idiopática. ANIMALES: veinticinco perros de propietarios particulares con ETUD unilateral o bilateral. MÉTODOS Y MATERIALES: se resumen los casos de ETUD que respondieron mal a la terapia convencional y posteriormente se trataron con oclacitinib. Todos los casos se analizaron para detectar leishmaniosis mediante examen serológico [prueba de anticuerpos fluorescentes indirecta (IFAT) o ensayo inmunoabsorbente ligado a enzimas (ELISA)]. Se realizó examen histopatológico en dos casos. RESULTADOS: los resultados serológicos fueron negativos para leishmaniosis en todos los perros. En dos casos se documentaron cambios histopatológicos compatibles con necrosis trombovascular proliferativa del pabellón auricular. Oclacitinib, utilizado en el rango de dosis estándar recomendado para el tratamiento de la dermatitis atópica canina, resolvió eficazmente la ETUD en 22 de 25 perros en uno a tres meses. Varios de los perros requirieron el uso prolongado de dosis dos veces al día. CONCLUSIÓN Y RELEVANCIA CLÍNICA: El oclacitinib debe incluirse entre las opciones terapéuticas para la ETUD, una vez descartadas enfermedades infecciosas.Bei der ulzerativen Ohrranddermatitis (ETUD) handelt es sich um ein seltenes klinisches Reaktionsmuster in der Dermatologie des Hundes. Die Läsionen weisen auf Blutgefäßschädigungen hin, die durch entzündliche oder nicht entzündliche Erkrankungen verursacht werden können, oft aber auch idiopathisch auftreten.Die Ziele dieser retrospektiven Fallserie waren die Beschreibung der klinischen Merkmale und ein Bericht über das Ansprechen auf eine Behandlung mit Oclacitinib bei Hunden mit idiopathischer, chronischer ETUD.Fünfundzwanzig Hunde in Privatbesitz mit uni- oder bilateraler ETUD.Fälle von ETUD, die auf eine konventionelle Therapie nur schlecht ansprachen und in der Folge mit Oclacitinib behandelt wurden, sind zusammengefasst. Alle Fälle wurden mittels serologischer Untersuchung [Indirekter Immuno Fluoreszenz Antikörpertest (IFAT) oder Enzym-Linked Immunosorbent Assay (ELISA)] auf Leishmaniose getestet. In zwei Fällen wurde eine histopathologische Untersuchung durchgeführt.Die serologischen Ergebnisse waren bei allen Hunden negativ für Leishmaniose. In zwei Fällen wurden histopathologische Veränderungen passend zu einer proliferativen thrombovaskulären Nekrose der Pinnae dokumentiert. Bei 22 von 25 Hunden konnte mittels Oclacitinib, welches in der empfohlenen Standarddosis zur Behandlung einer atopischen Dermatitis des Hundes eingesetzt wurde, innerhalb von einem bis drei Monaten die ETUD erfolgreich behandelt werden. Einige der Hunde benötigten langfristig eine zweimal tägliche Dosierung.Wenn infektiöse Erkrankungen ausgeschlossen wurden, sollte Oclacitinib in die therapeutischen Optionen für ETUD inkludiert werden.背景: 耳介先端部潰瘍性皮膚炎（ETUD）は、犬の皮膚科では珍しい臨床反応パターンである。炎症性疾患や非炎症性疾患による血管障害を示唆する病変であり、特発性のものも多い。ETUDの治療法としては、グルココルチコイドやタクロリムスの外用、ペントキシフィリン、ビタミンE、ドキシサイクリン、テトラサイクリン、ナイアシンアミド、スルホンアミド、グルココルチコイド、シクロスポリン、外科的矯正などがある。 仮説／目的: この回顧的な症例シリーズの目的は、特発性の慢性ETUDを持つ犬の臨床的特徴を説明し、オクラシチニブによる治療に対する反応を報告することであった。 被験動物: 片側または両側のETUDを有する25頭のオーナー所有犬。 材料と方法: 従来の治療に反応が悪く、その後オクラシチニブで治療したETUDの症例をまとめている。全例、血清学的検査［間接蛍光抗体法（IFAT）または酵素結合免疫吸着法（ELISA）］によりリーシュマニア症の検査を行った。また，2例では病理組織学的検査を行った。 結果: 血清検査の結果、すべての犬でリーシュマニア症は陰性であった。耳介の増殖性血栓性血管性壊死と一致する病理組織学的変化が2例で記録された。オクラシチニブは、犬アトピー性皮膚炎治療に推奨される標準的な用量範囲で使用され、25頭中22頭のETUDを1～3か月以内に効果的に解決した。数頭の犬は、1日2回の投与を長期に渡って行う必要があった。 結論と臨床的妥当性: オクラシチニブは、感染症が除外された後、ETUDの治療オプションに含まれるべきである。.背景: 耳尖溃疡性皮炎(ETUD)是犬皮肤病学中不常见的临床反应模式。病变提示血管损伤，可能由炎性或非炎性疾病引起，通常为特发性。ETUD的治疗选择包括外用糖皮质激素或他克莫司、己酮可可碱、维生素E、多西环素、四环素和烟酰胺、磺胺类药物、糖皮质激素、环孢素和手术矫正。 假设/目的: 本回顾性病例系列的目的是描述特发性、慢性ETUD犬的临床特征，并报告对奥拉替尼治疗的反应。 动物: 25只患有单侧或双侧ETUD的私家犬。 方法和材料: 总结了对常规治疗反应不佳且随后接受奥拉替尼治疗的ETUD病例。所有病例均经血清学检查[间接荧光抗体试验(IFAT)或酶联免疫吸附试验(ELISA)]检测利什曼病。2例进行了组织病理学检查。 结果: 所有犬的利什曼病血清学结果均为阴性。2例组织病理学变化记录为耳廓增生性血栓血管坏死。奥拉替尼使用按照治疗犬特应性皮炎的标准推荐剂量范围，在1-3个月内，22/25只ETUD患犬得到有效缓解。一些犬需要长期使用，且每日两次给药。 结论和临床相关性: 一旦排除感染性疾病，应将奥拉替尼纳入ETUD的治疗备选方案。.A dermatite ulcerativa da borda da orelha (DUBO) é um padrão reacional incomum na dermatologia canina. As lesões são sugestivas de dano vascular, que pode ser causado por doenças inflamatórias ou não inflamatórias, e frequentemente são idiopáticas. As opções terapêuticas para a DUBO incluem glicocorticoides tópicos ou tacrolimus, pentoxifilina, vitamina E, doxiciclina, tetraciclina e niacinamida, sulfonamidas, glicocorticoides e correção cirúrgica. HIPÓTESE/OBJETIVOS: O objetivo dessa série de casos retrospectivos foi descrever as características clínicas e relatar a resposta de cães com DUBO crônica idiopática ao tratamento com oclacitinib.Vinte e cinco cães de propriedade privada com DUBO unilateral ou bilateral. MÉTODOS E MATERIAIS: Os casos de DUBO que apresentaram resposta insatisfatória à terapia convencional e foram subsequentemente tratados com oclacitinib foram descritos neste trabalho. Todos os casos foram testados para leishmaniose por exame sorológico [método de indirect fluorescent antibody test (IFAT) ou de enzyme-linked immunosorbent assay (ELISA)]. Dois casos foram enviados para exame histopatológico.Os testes sorológicos foram negativos para leishmaniose em todos os cães. Achados histopatológicos compatíveis com necrose trombovascular proliferativa do pavilhão auricular foram observados em dois casos. O oclacitinib, utilizado na dose recomendada para o tratamento de dermatite atópica canina, resolveu efetivamente a DUBO em 22 dos 25 casos em um período de um a três meses. Muitos cães necessitaram de tratamento prolongado com a dose de duas vezes ao dia. CONCLUSÃO E RELEVÂNCIA CLÍNICA: O oclacitinib deve ser incluso nas opções terapêuticas para DUBO quando as causas infecciosas forem excluídas.

Laminopathies are a wide and heterogeneous group of rare human diseases caused by mutations of the LMNA gene or related nuclear envelope genes. The variety of clinical phenotypes and the wide spectrum of histopathological changes among patients carrying an identical mutation in the LMNA gene make the prognostic process rather difficult, and classical genetic screens appear to have limited predictive value for disease development. The aim of this study was to evaluate whether a comprehensive profile of circulating cytokines may be a useful tool to differentiate and stratify disease subgroups, support clinical follow-ups and contribute to new therapeutic approaches. Serum levels of 51 pro- and anti-inflammatory molecules, including cytokines, chemokines and growth factors, were quantified by a Luminex multiple immune-assay in 53 patients with muscular laminopathy (Musc-LMNA), 10 with non-muscular laminopathy, 22 with other muscular disorders and in 35 healthy controls. Interleukin-17 (IL-17), granulocyte colony-stimulating factor (G-CSF) and transforming growth factor beta (TGF-&beta, 2) levels significantly discriminated Musc-LMNA from controls, interleukin-1&beta, (IL-1&beta, ), interleukin-4 (IL-4) and interleukin-8 (IL-8) were differentially expressed in Musc-LMNA patients compared to those with non-muscular laminopathies, whereas IL-17 was significantly higher in Musc-LMNA patients with muscular and cardiac involvement. These findings support the hypothesis of a key role of the immune system in Musc-LMNA and emphasize the potential use of cytokines as biomarkers for these disorders.

Objectives: Gross Motor Function Classification System (GMFCS) and Manual Ability Classification System (MACS) are broadly studied in high-income countries, but data concerning their functioning are lacking in developing countries. Therefore, we analyzed their reliability and sensitivity to change in children with cerebral palsy in Tanzania. Methods: GMFCS and MACS are two ordinal grading systems used to assess motor functions while observing children’s performances. Forty-nine children were classified by two independent physiotherapy students at baseline, after one month and after one year. Reliability and sensitivity to change were analyzed using intraclass correlation coefficient (ICC), effect size (ES), standard response mean (SRM), standard error of measurement (SEM), and minimal detectable change (MDC). Results: Inter- (ICC = 0.97/0.95 for GMFCS/MACS) and intra-rater reliability (ICC = 0.98/0.96 GMFCS/MACS) were excellent. Sensitivity to change was small (ES = −0.14/0.11, SRM = −0.24;/0.24 GMFCS/MACS). SEM was 0.2 points, resulting in MDC = 0.5/0.7 for GMFCS/MACS, respectively. Conclusions: GMFCS and MACS demonstrated excellent reliability, but not sensitivity to change.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects both lower and upper motor neurons (MNs) in the central nervous system. ALS etiology is highly multifactorial and multifarious, and an effective treatment is still lacking. Neuroinflammation is a hallmark of ALS and could be targeted to develop new therapeutic approaches. Interestingly, the transcription factor Nurr1 has been demonstrated to have an important role in the inflammatory process in several neurological disorders, such as Parkinson's disease and multiple sclerosis. In the present paper, we demonstrate for the first time that Nurr1 expression levels are upregulated in the peripheral blood of ALS patients. Moreover, we investigated Nurr1 function in the SOD1-G93A mouse model of ALS. Nurr1 was strongly upregulated in the spinal cord during the asymptomatic and early symptomatic phases of the disease, where it promoted the expression of brain-derived neurotrophic factor mRNA and the repression of NFκB pro-inflammatory targets, such as inducible nitric oxide synthase. Therefore, we hypothesize that Nurr1 is activated in an early phase of the disease as a protective endogenous anti-inflammatory mechanism, although not sufficient to reverse disease progression. On the basis of these observations, Nurr1 could represent a potential biomarker for ALS and a promising target for future therapies., Summary: We hypothesize that the transcription factor Nurr1 is activated in the early phase of the neurodegenerative disease amylotrophic lateral sclerosis (ALS), probably as a neuroprotective endogenous mechanism. Nurr1 might represent a promising target for ALS therapy.

Facioscapulohumeral muscular dystrophy (FSHD) is a myopathy with prevalence of 1 in 20,000. Almost all patients affected by FSHD carry deletions of an integral number of tandem 3.3 kilobase repeats, termed D4Z4, located on chromosome 4q35. Assessment of size of D4Z4 alleles is commonly used for FSHD diagnosis. However, the extended molecular testing has expanded the spectrum of clinical phenotypes. In particular, D4Z4 alleles with 9–10 repeat have been found in healthy individuals, in subjects with FSHD or affected by other myopathies. These findings weakened the strict relationship between observed phenotypes and their underlying genotypes, complicating the interpretation of molecular findings for diagnosis and genetic counseling. In light of the wide clinical variability detected in carriers of D4Z4 alleles with 9–10 repeats, we applied a standardized methodology, the Comprehensive Clinical Evaluation Form (CCEF), to describe and characterize the phenotype of 244 individuals carrying D4Z4 alleles with 9–10 repeats (134 index cases and 110 relatives). The study shows that 54.5% of index cases display a classical FSHD phenotype with typical facial and scapular muscle weakness, whereas 20.1% present incomplete phenotype with facial weakness or scapular girdle weakness, 6.7% display minor signs such as winged scapula or hyperCKemia, without functional motor impairment, and 18.7% of index cases show more complex phenotypes with atypical clinical features. Family studies revealed that 70.9% of relatives carrying 9–10 D4Z4 reduced alleles has no motor impairment, whereas a few relatives (10.0%) display a classical FSHD phenotype. Importantly all relatives of index cases with no FSHD phenotype were healthy carriers. These data establish the low penetrance of D4Z4 alleles with 9–10 repeats. We recommend the use of CCEF for the standardized clinical assessment integrated by family studies and further molecular investigation for appropriate diagnosis and genetic counseling. Especially in presence of atypical phenotypes and/or sporadic cases with all healthy relatives is not possible to perform conclusive diagnosis of FSHD, but all these cases need further studies for a proper diagnosis, to search novel causative genetic defects or investigate environmental factors or co-morbidities that may trigger the pathogenic process. These evidences are also fundamental for the stratification of patients eligible for clinical trials. Our work reinforces the value of large genotype–phenotype studies to define criteria for clinical practice and genetic counseling in rare diseases.

Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS.

The most relevant manifestation of coronavirus disease 2019 (COVID-19) is interstitial pneumonia. Several lung ultrasound (US) protocols for pneumonia diagnosis are used in clinical practice, but none has been proposed for COVID-19 patients' screening in the emergency department. We adopted a simplified 6-scan lung US protocol for COVID-19 pneumonia diagnosis (LUSCOP) and compared its sensitivity with high resolution computed tomography (HRCT) in patients suspected for COVID-19, presenting to one Emergency Department from February 21st to March 15th, 2020, during the outbreak burst in northern Italy. Patients were retrospectively enrolled if both LUSCOP protocol and HRCT were performed in the Emergency Department. The sensitivity of LUSCOP protocol and HRCT were compared. COVID-19 pneumonia's final diagnosis was based on real-time reverse-transcription polymerase chain reaction from nasal-pharyngeal swab and on clinical data. Out of 150 suspected COVID-19 patients, 131 were included in the study, and 130 had a final diagnosis of COVID-19 pneumonia. The most frequent lung ultrasonographic features were: bilateral B-pattern in 101 patients (77%), B-pattern with subpleural consolidations in 26 (19.8%) and lung consolidations in 2 (1.5%). LUSCOP Protocol was consistent with HRCT in correctly screening 130 out of the 131 COVID-19 pneumonia cases (99.2%). In one case COVID-19 pneumonia was excluded by both HRCT and lung US. LUSCOP protocol showed optimal sensitivity and can be proposed as a simple screening tool for COVID-19 pneumonia diagnosis in the context of outbreak burst areas where prompt isolation of suspected patients is crucial for patients' and operators' safety.

Laminopaties; Distròfia muscular; Múscul estriat Laminopatías; Distrofia muscular; Músculo estriado Laminopathies; Muscular dystrophy; Striated muscle Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0–2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8–4.0) and age of ambulation loss (median: 7 years, range: 1.2–38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype–phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations. This work was supported by the AFM-Telethon, the Institut National de la Santé et de la Recherche Médicale (INSERM) and Sorbonne Université (R.B.Y., G.B.), intramural funds of the National Institute of Neurological Disorders and Stroke, National Institutes of Health (C.G.B.), Cure-CMD (A.R., G.B., R.B.Y.), The Andres Marcio Fondation (G.B., R.B.Y). and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular and the Fashion Industries Guild Endowed Fellowship for the Undiagnosed Diseases Program (T.M.P).

Radiculomedullary artery malformations are rare conditions: their rupture usually manifests with subarachnoid hemorrhage. To the best of our knowledge no cases of subdural bleeding have been described in the literature. We present the rare case of a 74 year old woman admitted to our Institute with sudden onset of right lower limb motor deficit and hypoesthesia, with no history of trauma: Magnetic Resonance Imaging of the dorsal spine was performed and a subdural hematoma was detected; subsequent dorsal laminectomy for hematoma evacuation was carried out. As the source of bleeding was not recognized, Digital Subtraction Angiography (DSA) was performed: a new leak of contrast agent from a dilation of a spinal radicular artery at the level of T5 was detected; XperCT imaging (an angiographic acquisition of Computed Tomography-like images) confirmed a new acute subdural bleeding. Urgent repeat surgery was considered the best option to identify and close the malformation. Postoperative DSA confirmed complete exclusion of the radicular artery malformation. This is the first report that describes, with an intraoperative video, a case of radiculomedullary artery pseudoaneurysm, responsible of an acute subdural bleeding and associated neurological deficit.

Spinal cord injury (SCI) affects 6 million people worldwide with no available treatment. Despite research advances, the inherent poor regeneration potential of the central nervous system remains a major hurdle. Small RNAs (sRNAs) 19–33 nucleotides in length are a set of non-coding RNA molecules that regulate gene expression and have emerged as key players in regulating cellular events occurring after SCI. Here we profiled a class of sRNA known as microRNAs (miRNAs) following SCI in the cortex where the cell bodies of corticospinal motor neurons are located. We identified miR-7b-3p as a candidate target given its significant upregulation after SCI in vivo and we screened by miRWalk PTM the genes predicted to be targets of miR-7b-3p (among which we identified Wipf2, a gene regulating neurite extension). Moreover, 16 genes, involved in neural regeneration and potential miR-7b-3p targets, were found to be downregulated in the cortex following SCI. We also analysed miR-7b-3p function during cortical neuron development in vitro: we observed that the overexpression of miR-7b-3p was important (1) to maintain neurons in a more immature and, likely, plastic neuronal developmental phase and (2) to contrast the apoptotic pathway; however, in normal conditions it did not affect the Wipf2 expression. On the contrary, the overexpression of miR-7b-3p upon in vitro oxidative stress condition (mimicking the SCI environment) significantly reduced the expression level of Wipf2, as observed in vivo, confirming it as a direct miR-7b-3p target. Overall, these data suggest a dual role of miR-7b-3p: (i) the induction of a more plastic neuronal condition/phase, possibly at the expense of the axon growth, (ii) the neuroprotective role exerted through the inhibition of the apoptotic cascade. Increasing the miR-7b-3p levels in case of SCI could reactivate in adult neurons silenced developmental programmes, supporting at the same time the survival of the axotomised neurons.

Capacitive and resistive electric transfer (CRET) therapy is a physical treatment modality commonly used to treat musculoskeletal pain. It normally uses a longwave radiofrequency of ~0.5 MHz. The system consists of a neutral plate and two different electrodes that can transfer energy in two modalities: capacitive and resistive. The aim of this systematic review was to identify and summarize the available data in the literature on this physical modality. From a search of articles published before December 2019 in MEDLINE and Scopus indexed journals, we retrieved 276 articles, 13 of which met the inclusion criteria for this review. Most articles dealt with musculoskeletal disorders, mainly spine disorders and knee osteoarthritis. More than 75% of the studies used a similar range of frequency (440-600 KHz). Almost all described an improvement in strength and function and reduced pain intensity after the treatment. Although nine of the 13 studies (70%) were randomized controlled trials, only two had a low risk of bias according to the Cochrane library assessment tool. CRET seems to be an effective therapy to decrease pain, and improve the quality of life and disability of patients affected by musculoskeletal disorders. There is no study on symptoms of patients with neurological disorders. Further research is necessary to standardize the therapeutic protocols across different orthopedic diseases, and to assess the benefits of CRET in other fields such as neurological or rheumatologic disorders.

Background SARS-CoV-2 has dramatically changed our world, country, communities and families. There is controversy regarding risk factors for severe COVID-19 disease. It has been suggested that asthma and allergy are not highly represented as co-morbid conditions associated with COVID-19. Objective To extend our work in interleukin (IL)-13 biology to determine if airway epithelial cell expression of two key mediators critical for SARS-CoV-2 infection, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) are modulated by IL-13. Methods We determined effects of IL-13 treatment on ACE2 and TMPRSS2 expression ex vivo in primary airway epithelial cells from participants with and without type 2 asthma obtained by bronchoscopy. We also examined expression of ACE2 and TMPRSS2 in two datasets containing gene expression data from nasal and airway epithelial cells from children and adults with asthma and allergic rhinitis. Results IL-13 significantly reduced ACE2 and increased TMPRSS2 expression ex vivo in airway epithelial cells. In two independent datasets, ACE2 expression was significantly reduced and TMPRSS2 was significantly increased in the nasal and airway epithelial cells in type 2 asthma and allergic rhinitis. ACE2 expression was significantly negatively associated with type 2 cytokines while TMPRSS2 expression was significantly positively associated with type 2 cytokines. Conclusion IL-13 modulates ACE2 and TMPRSS2 expression in airway epithelial cells in asthma. This deserves further study with regard to any effects asthma and atopy may render in the setting of COVID-19 infection., Capsule Summary: ACE2 and TMPRSS2 are required for cell entry by SARS-CoV-2. The expression of ACE2 and TMPRSS2 in asthma and allergy is modulated by IL-13. Whether this affects susceptibility to COVID-19 requires further study.

Onuf’s nucleus is a small group of neurons located in the ventral horns of the sacral spinal cord. The motor neurons (MNs) of Onuf’s nucleus innervate striated voluntary muscles of the pelvic floor and are histologically and biochemically comparable to the other somatic spinal MNs. However, curiously, these neurons also show some autonomic-like features as, for instance, they receive a strong peptidergic innervation. The review provides an overview of the histological, biochemical, metabolic, and gene expression peculiarities of Onuf’s nucleus. Moreover, it describes the aging-related pathologies as well as several traumatic and neurodegenerative disorders in which its neurons are involved: indeed, Onuf’s nucleus is affected in Parkinson’s disease (PD) and Shy-Drager Syndrome (SDS), whereas it is spared in Amyotrophic Lateral Sclerosis (ALS), Spinal Muscular Atrophy (SMA), Duchenne Muscular Dystrophy (DMD). We summarize here the milestone studies that have contributed to clarifying the nature of Onuf’s neurons and in understanding what makes them either vulnerable or resistant to damage. Altogether, these works can offer the possibility to develop new therapeutic strategies for counteracting neurodegeneration.

We describe the case of a male patient admitted to our emergency department during the Italian COVID-19 epidemic, for progressive worsening dyspnoea. A diagnosis of pneumothorax and diffuse interstitial lung involvement was promptly made by lung ultrasound and confirmed by an HRCT scan. A chest CT scan also showed diffuse emphysema, as observed in chronic obstructive pulmonary disease (COPD), and small consolidations in the lower lobes, suggestive for COVID-19 pneumonia. A chest tube was immediately inserted in the emergency room with complete resolution of the dyspnoea. A nasopharyngeal swab for 2019-nCoV was positive. Unfortunately, the patient died from COVID-19-related acute respiratory distress syndrome after 48 days of hospitalization. LEARNING POINTS Coronavirus disease (COVID-19) can cause death from severe acute respiratory distress syndrome (ARDS). Pneumothorax is a common complication of chronic obstructive pulmonary disease (COPD). The combination of COVID-19, COPD and pneumothorax can prove fatal. Keywords: COVID-19, pneumonia, dyspnoea, pneumothorax, COPD, ARDS INTRODUCTION Coronavirus disease 2019 (COVID-19), also called SARS-CoV-2, is caused by 2019 n-CoV, a new type of coronavirus first identified in China at the end of December 2019. It rapidly spread worldwide, causing significant morbidity and mortality, and developed into a global pandemic. Acute respiratory distress syndrome (ARDS) is the most common complication of COVID-19, and the main cause of death. We present the case of an 87-year-old man with a diagnosis of chronic obstructive pulmonary disease (COPD) and COVID-19 pneumonia complicated by pneumothorax.

We describe the case of a young female patient admitted to our emergency department during the Italian COVID-19 epidemic, for fever and dry cough associated with symptoms of gastric reflux over the previous 5 days. Lung ultrasound showed diffuse bilateral B lines with irregular pleural thickening, and consolidation with air bronchogram and slight pleural effusion in the lower left lobe. Chest HRCT and abdominal CT scanning with contrast revealed diaphragmatic rupture with gastric perforation, and atelectasis of the left pulmonary lobe with unilateral pleural effusion, diffuse ground-glass opacities and multiple small consolidations in both lobes. A nasopharyngeal swab for 2019-nCoV was positive. A diagnosis of diaphragmatic rupture and gastric perforation in COVID-19 pneumonia was made. The patient was immediately hospitalized and surgically treated. Treatment for COVID-19 and empiric antibiotic therapy were promptly started. LEARNING POINTS Coronavirus disease (COVID-19) can cause fever, dry cough and acute respiratory failure. Cough can result in several complications, including rupture of the diaphragm and abdominal herniation. CT scanning is the gold standard technique to investigate COVID-19 pneumonia and diaphragmatic rupture.

Mitochondria play a central role in a plethora of processes related to the maintenance of cellular homeostasis and genomic integrity. They contribute to preserving the optimal functioning of cells and protecting them from potential DNA damage which could result in mutations and disease. However, perturbations of the system due to senescence or environmental factors induce alterations of the physiological balance and lead to the impairment of mitochondrial functions. After the description of the crucial roles of mitochondria for cell survival and activity, the core of this review focuses on the “mitochondrial switch” which occurs at the onset of neuronal degeneration. We dissect the pathways related to mitochondrial dysfunctions which are shared among the most frequent or disabling neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Huntington’s, Amyotrophic Lateral Sclerosis, and Spinal Muscular Atrophy. Can mitochondrial dysfunctions (affecting their morphology and activities) represent the early event eliciting the shift towards pathological neurobiological processes? Can mitochondria represent a common target against neurodegeneration? We also review here the drugs that target mitochondria in neurodegenerative diseases.

Background Dexterity impairments caused by carpal tunnel syndrome (CTS) make working and daily activities challenging. We aimed to investigate: i) the relationship between dexterity and nerve conduction studies (NCS) in workers with classic symptoms presentation; ii) the ability of the Functional Dexterity Test (FDT) to discriminate different levels of CTS severity as classified by NCS; iii) the diagnostic accuracy of a clinical battery composed of the FDT, Phalen’s test and Tinel’s sign. Methods In a convenience sample of individuals diagnosed with CTS, we correlated FDT net scores with the NCS-based classification by means of Spearman’s (rho) test. Discriminative ability of the FDT was assessed by ANOVA, and a ROC curve determined cutoff thresholds. Sensitivity, specificity, and likelihood ratios (LRs) were used to investigate the diagnostic accuracy of the clinical battery. Results Data from 180 hands were collected. The FDT was significantly correlated (rho = 0.25, p 95% 0.83–0.99; LR+: 14.49, CI95% 2.09–100.53). Conclusions Sensorimotor impairments related to CTS can affect hand dexterity. The FDT discriminated patients with severe NCS involvement. Positive results on the clinical battery (Phalen, Tinel, and FDT) could help to confirm the CTS diagnosis, showing a very high specificity and LR+. On the contrary, the low sensitivity is not able to rule out CTS in individuals with negative results.