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Recently, some drugs were approved to control Monkeypox (MPX), among them tecovirimat. This was recently approved by regulatory agencies around the world, the paper of Zovi et al entitled Pharmacological Agents with Antiviral Activity against Monkeypox Infection highlight it as safe and effective, although the safety data are still not very robust. In this Comment, we present some theoretical evaluations of its safety, considering that for use in humans it is essential to have a rich scientific literature in the area. After a series of analyses, a potential risk of liver, respiratory and kidney damage was found in addition to carcinogenic potential. Thus, while we agree that there is a need for rapid responses to infection, we reinforce that well-designed and adequately powered studies should not only focus on investigating the pharmacological efficacy of tecovirimat but also demonstrate its safety in humans. Therefore, in this Comment, we present some concerns that may help in formulating a safer treatment for patients infected with Monkeypox virus (MPXV).

Introduction Pyruvate dehydrogenase complex (PDH) deficiency (Online Mendelian Inheritance in Man # 312170) is a relatively common mitochondrial disorder, caused by mutations in the X-linked PDHA1 gene and presenting with a variable phenotypic spectrum, ranging from severe infantile encephalopathy to milder chronic neurological disorders.Isolated peripheral neuropathy as predominant clinical presentation is uncommon. Results We report on a patient, now 21 years old, presenting at the age of 2 years with recurrent symmetric weakness as first symptom of a PDH deficiency. Neurophysiological evaluation proving a sensory-motor polyneuropathy with conduction blocks and presence of elevated cerebrospinal fluid proteins, suggested a chronic inflammatory demyelinating polyneuropathy. The evidence of high serum lactate and the alterations in oxidative metabolism in muscle biopsy pointed toward the final diagnosis. After starting nutritional supplements, no further episodes occurred. A hemizygous mutation in PDHA1 (p.Arg88Cys) was identified. This mutation has been previously described in five patients with a similar phenotype. A three-dimensional reconstruction demonstrated that mutations affecting this arginine destabilize the interactions between the subunits of the E1 complex. Conclusion We summarize the clinical and genetic characteristics of one patient with PDH deficiency presenting isolated peripheral nervous system involvement. This study highlights that the diagnosis of PDH deficiency should be considered in children with unexplained peripheral neuropathy, even with features suggestive of acquired forms, especially in case of early onset and limited response to treatment. A simple analysis of lactic acid could help to target the diagnosis.In addition, we suggest that the residue Arg88 is the most frequently involved in this specific phenotype of PDH deficiency.

A human Mars mission is more challenging to astronauts than the Apollo mission because of travel time, life support requirements, and the space environment. Although plans for Mars exploration by NASA and SpaceX based on conventional rockets have been presented, there are considerations that suggest alternatives for the mid- or long-term. The purpose of this paper is to outline a fast mission enabled by advanced (nuclear) propulsion and by internationally shared technology. Whether the destination is the Mars surface or Phobos, for a chemical powered spacecraft, the round trip takes about 990 days, including a 480-day surface stay, compared to only 370 days, including a 41-day surface stay, for the nuclear-powered spacecraft assumed here. Since nuclear propulsion can provide higher speed than chemical, the radiation dose can be drastically reduced. The logistics of such a mission involve one or more cargo craft that must precede the astronauts. Ballistic entry into Mars’ atmosphere depends on accurate knowledge of its features, to date poorly known, that may result in uncertainty in landing coordinates. For a single vehicle, this is not critical, but for a human crew ballistic landing kilometers away from cargo is unacceptable: walking for anything but the shortest distance cannot be afforded with current space suits. In this context, the concept of a modest L/D maneuvering cargo glider based on the past Russian “Kliper” is recommended and developed to ensure landing within a hundred meters of each spacecraft. The crewed lander vehicle is based on the high L/D, inherently stable USAF FDL-7C/D hypersonic glider experience. In a similar approach, an exploration vehicle powered by in situ manufactured CO2 and silane is described that can explore the Martian surface much faster and efficiently than with rovers or rocket-powered ‘hoppers’.

Emery-Dreifuss muscular dystrophy (EDMD) is a rare disease characterized by early contractures, progressive muscle weakness, and cardiac abnormalities. Different subtypes of EDMD have been described, with the two most common forms represented by the X-linked EDMD1, caused by mutations in the EMD gene encoding emerin, and the autosomal EDMD2, due to mutations in the LMNA gene encoding lamin A/C. A clear definition of the magnetic resonance imaging (MRI) pattern in the two forms, and especially in the rarer EDMD1, is still lacking, although a preferential involvement of the medial head of the gastrocnemius has been suggested in EDMD2. We report a 13-year-old boy with mild limb girdle muscle weakness, elbow and ankle contractures, with absence of emerin at muscle biopsy, carrying a hemizygous frameshift mutation on the EMD gene (c.153dupC/p.Ser52Glufs*9) of maternal inheritance. Minor cardiac rhythm abnormalities were detected at 24-hour Holter electrocardiogram and required β-blocker therapy. MRI scan of the thighs showed a mild diffuse involvement, while tibialis anterior, extensor digitorum longus, peroneus longus, and medial gastrocnemius were the most affected muscles in the leg. We also provide a review of the muscular MRI data in EDMD patients and highlight the relative heterogeneity of the MRI patterns found in EDMDs, suggesting that muscle MRI should be studied in larger EDMD cohorts to better define disease patterns and to cover the wide disease spectrum.

Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was −0.67 (2.80), −1.15 (3.98), −1.46 (3.37) and −1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was −1.47 (3.73), −2.78 (5.86), −2.95 (4.56) and −4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p < 0.001), the shoulder (p = 0.01) and the elbow domain (p < 0.001), with patients amenable to skipping exon 44 having smaller changes compared to those amenable to skipping exon 53. There was no difference within ambulant or non-ambulant cohorts when subdivided by exon skip class for the total and subdomains score (p > 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients.

Duchenne muscular dystrophy (DMD) is a severe and progressive myopathy leading to motor and cardiorespiratory impairment. We analyzed samples from patients with DMD and a preclinical rat model of severe DMD and determined that compromised repair capacity of muscle stem cells in DMD is associated with early and progressive muscle stem cell senescence. We also found that extraocular muscles (EOMs), which are spared by the disease in patients, contain muscle stem cells with long-lasting regenerative potential. Using single-cell transcriptomics analysis of muscles from a rat model of DMD, we identified the gene encoding thyroid-stimulating hormone receptor ( Tshr ) as highly expressed in EOM stem cells. Further, TSHR activity was involved in preventing senescence. Forskolin, which activates signaling downstream of TSHR, was found to reduce senescence of skeletal muscle stem cells, increase stem cell regenerative potential, and promote myogenesis, thereby improving muscle function in DMD rats. These findings indicate that stimulation of adenylyl cyclase leads to muscle repair in DMD, potentially providing a therapeutic approach for patients with the disease.

Thanks to advances in gene sequencing, RYR1-related myopathy (RYR1-RM) is now known to manifest itself in vastly heterogeneous forms, whose clinical interpretation is, therefore, highly challenging. We set out to develop a novel unsupervised cluster analysis method in a large patient population. The objective was to analyze the main RYR1-related characteristics to identify distinctive features of RYR1-RM and, thus, offer more precise genotype–phenotype correlations in a group of potentially life-threatening disorders. We studied 600 patients presenting with a suspicion of inherited myopathy, who were investigated using next-generation sequencing. Among them, 73 index cases harbored variants in RYR1. In an attempt to group genetic variants and fully exploit information derived from genetic, morphological, and clinical datasets, we performed unsupervised cluster analysis in 64 probands carrying monoallelic variants. Most of the 73 patients with positive molecular diagnoses were clinically asymptomatic or pauci-symptomatic. Multimodal integration of clinical and histological data, performed using a non-metric multi-dimensional scaling analysis with k-means clustering, grouped the 64 patients into 4 clusters with distinctive patterns of clinical and morphological findings. In addressing the need for more specific genotype–phenotype correlations, we found clustering to overcome the limits of the “single-dimension” paradigm traditionally used to describe genotype–phenotype relationships.

Background Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, but has not been specifically investigated in patients affected by severe and milder forms of spinal muscular atrophy (SMA). Methods In this two-center retrospective study, we investigated signatures of neuroinflammation in forty-eight pediatric male and female SMA1 (n = 18), male and female SMA2 (n = 19), and female SMA3 (n = 11) patients, as well as in a limited number of male and female non-neurological control subjects (n = 4). We employed a Bio-Plex multiplex system based on xMAP technology and performed targeted quantitative analysis of a wide range of pro- and anti-inflammatory cytokines (chemokines, interferons, interleukins, lymphokines and tumor necrosis factors) and neurotrophic factors in the cerebrospinal fluid (CSF) of the study cohort before and after Nusinersen treatment at loading and maintenance stages. Results We find a significant increase in the levels of several pro-inflammatory cytokines (IL-6, IFN-γ, TNF-α, IL-2, IL-8, IL-12, IL-17, MIP-1α, MCP-1, and Eotaxin) and neurotrophic factors (PDGF-BB and VEGF) in the CSF of SMA1 patients relative to SMA2 and SMA3 individuals, who display levels in the range of controls. We also find that treatment with Nusinersen significantly reduces the CSF levels of some but not all of these neuroinflammatory molecules in SMA1 patients. Conversely, Nusinersen increases the CSF levels of proinflammatory G-CSF, IL-8, MCP-1, MIP-1α, and MIP-1β in SMA2 patients and decreases those of anti-inflammatory IL-1ra in SMA3 patients. Conclusions These findings highlight signatures of neuroinflammation that are specifically associated with severe SMA and the neuro-immunomodulatory effects of Nusinersen therapy.

BACKGROUND: Risdiplam is an oral small molecule approved for the treatment of patients with spinal muscular atrophy, with approval for use in patients with type 2 and type 3 spinal muscular atrophy granted on the basis of unpublished data. The drug modifies pre-mRNA splicing of the SMN2 gene to increase production of functional SMN. We aimed to investigate the safety and efficacy of risdiplam in patients with type 2 or non-ambulant type 3 spinal muscular atrophy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled study, patients aged 2-25 years with confirmed 5q autosomal recessive type 2 or type 3 spinal muscular atrophy were recruited from 42 hospitals in 14 countries across Europe, North America, South America, and Asia. Participants were eligible if they were non-ambulant, could sit independently, and had a score of at least 2 in entry item A of the Revised Upper Limb Module. Patients were stratified by age and randomly assigned (2:1) to receive either daily oral risdiplam, at a dose of 5·00 mg (for individuals weighing =20 kg) or 0·25 mg/kg (for individuals weighing

Summary Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov , NCT03461289 (completed). Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p Interpretation STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Funding Novartis Gene Therapies.

Early-onset myopathy, areflexia, respiratory distress, and dysphagia (EMARDD) is caused by homozygous or compound heterozygous mutation in the

SPTLC1-related disorder is a late onset sensory-autonomic neuropathy associated with perturbed sphingolipid homeostasis which can be improved by supplementation with the serine palmitoyl-CoA transferase (SPT) substrate, l-serine. Recently, a juvenile form of motor neuron disease has been linked to SPTLC1 variants. Variants affecting the p.S331 residue of SPTLC1 cause a distinct phenotype, whose pathogenic basis has not been established. This study aims to define the neuropathological and biochemical consequences of the SPTLC1 p.S331 variant, and test response to l-serine in this specific genotype.We report clinical and neurophysiological characterisation of two unrelated children carrying distinct p.S331 SPTLC1 variants. The neuropathology was investigated by analysis of sural nerve and skin innervation. To clarify the biochemical consequences of the p.S331 variant, we performed sphingolipidomic profiling of serum and skin fibroblasts. We also tested the effect of l-serine supplementation in skin fibroblasts of patients with p.S331 mutations.In both patients, we recognised an early onset phenotype with prevalent progressive motor neuron disease. Neuropathology showed severe damage to the sensory and autonomic systems. Sphingolipidomic analysis showed the coexistence of neurotoxic deoxy-sphingolipids with an excess of canonical products of the SPT enzyme. l-serine supplementation in patient fibroblasts reduced production of toxic 1-deoxysphingolipids but further increased the overproduction of sphingolipids.Our findings suggest that p.S331 SPTLC1 variants lead to an overlap phenotype combining features of sensory and motor neuropathies, thus proposing a continuum in the spectrum of SPTLC1-related disorders. l-serine supplementation in these patients may be detrimental.

O gênero Acinetobacter sp. tem sido cada vez mais reportado como causador de infecções, sobretudo em hospitais, e se destaca por causar infecções graves e ser de difícil tratamento. Compreender a prevalência bem como a sazonalidade das infecções por este patógeno é importante, visto que a partir dessas análises, podem-se estabelecer intervenções de controle de infecção hospitalar. Assim, esse estudo tem como objetivo pesquisar a prevalência e a sazonalidade de infecções por Acinetobacter sp. em hospitais da cidade do Natal-RN. Os dados referentes aos isolados clínicos de Acinetobacter sp. foram colhidos junto ao serviço de Controle de Infecção Hospitalar de quatro hospitais envolvidos no estudo, no período de março de 2013 a março de 2014; enquanto que o perfil de resistência aos antimicrobianos foi realizada pelo nosso grupo de pesquisa. Observou-se que este gênero bacteriano foi o quarto microrganismo mais isolado nesse período. A prevalência de Acinetobacter no hospital A foi de 12,6% com 72 amostras isoladas no período; no hospital B, 4,3%, com 37 amostras ; no hospital C, 9,7%, 20 e no hospital D foi de 4,1%, 26 com uma média de isolamento ao longo do período estudado de 7,6%(±2). A maioria dos isolados, 59,4%, foi detectada nos meses mais quentes. O gênero Acinetobacter foi mais frequentemente isolado a partir de secreção traqueal, hemoculturas e secreção de feridas. As infecções em pacientes do sexo masculino corresponderam a 56,1% (87 isolados). A maioria (58,2%) das amostras recolhidas foram provenientes de pacientes internados em UTIs. A mortalidade foi de 42,7% com a presença de multirresistência observada na maioria (106 ou 68,4%) dos isolados. Os pacientes que tinham 63 anos ou mais, correspondiam à 75%. Esse estudofornece evidências da prevalência e sazonalidade das infecções por Acinetobacter e pode embasar tanto as estratégias de controle de infecção por essa bactéria, como a política de uso de antimicrobianos, direcionando a terapia empírica.

Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.

ObjectiveTo describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).MethodsThis was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy.ResultsThere were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8–16.6) and 15.1 (13.8–16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes.ConclusionsIn SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

OBJECTIVE: We report natural history data in a large cohort of 199 patients with spinal muscular atrophy (SMA) type III assessed using the Hammersmith Functional Motor Scale Expanded (HFMSE). The aim of the study was to establish the annual rate and possible patterns of progression according to a number of variables, such as age of onset, age at assessment, SMN2 copy number, and functional status. METHODS: HFMSE longitudinal changes were assessed using piecewise linear mixed-effects models. The dependency in the data due to repeated measures was accounted for by a random intercept per individual and an unstructured covariance R matrix was used as correlation structure. An additional descriptive analysis was performed for 123 patients, for a total of 375 12-month assessments. RESULTS: A break point at age 7 years was set for the whole cohort and for SMA IIIA and IIIB. Age, SMA type, and ambulatory status were significantly associated with changes in mean HFMSE score, whereas gender and SMN2 copy number were not. The increase in response before the break point of age 7 years is significant only for SMA IIIA (ß = 1.79, p < 0.0001). After the break point, the change in the rate of HFMSE score significantly decrease for both SMA IIIA (ß = -1.15, p < 0.0001) and IIIB (ß = -0.69, p = 0.002). INTERPRETATION: Our findings contribute to the understanding of the natural history of SMA type III and will be helpful in the interpretation of the real-world data of patients treated with commercially available drugs. ANN NEUROL 2020;88:1109-1117.

Background Sengers syndrome is characterized by congenital cataract, hypertrophic cardiomyopathy, mitochondrial myopathy, and lactic acidosis associated with mutations in AGK gene. Clinical course ranges from a severe fatal neonatal form, to a more benign form allowing survival into adulthood, to an isolated form of congenital cataract. Thus far few reported cases have survived the second decade at their latest examination, and no natural history data are available for the disease. Case presentation Here we provide a 20-year follow-up in two siblings with a benign form of Sengers syndrome, expanding the phenotypical spectrum of the disease by reporting a condition of ovarian agenesis. Conclusion To our knowledge, this report provides the first longitudinal data of Sengers syndrome patients.

Mutations in the RYR1 gene, encoding ryanodine receptor 1 (RyR1), are a well-known cause of Central Core Disease (CCD) and Multi-minicore Disease (MmD). We screened a cohort of 153 patients carrying an histopathological diagnosis of core myopathy (cores and minicores) for RYR1 mutation. At least one RYR1 mutation was identified in 69 of them and these patients were further studied. Clinical and histopathological features were collected. Clinical phenotype was highly heterogeneous ranging from asymptomatic or paucisymptomatic hyperCKemia to severe muscle weakness and skeletal deformity with loss of ambulation. Sixty-eight RYR1 mutations, generally missense, were identified, of which 16 were novel. The combined analysis of the clinical presentation, disease progression and the structural bioinformatic analyses of RYR1 allowed to associate some phenotypes to mutations in specific domains. In addition, this study highlighted the structural bioinformatics potential in the prediction of the pathogenicity of RYR1 mutations. Further improvement in the comprehension of genotype–phenotype relationship of core myopathies can be expected in the next future: the actual lack of the human RyR1 crystal structure paired with the presence of large intrinsically disordered regions in RyR1, and the frequent presence of more than one RYR1 mutation in core myopathy patients, require designing novel investigation strategies to completely address RyR1 mutation effect.

RNF5, an endoplasmic reticulum (ER) E3 ubiquitin ligase, participates to the ER-associated protein degradation guaranteeing the protein homeostasis. Depending on tumor model tested, RNF5 exerts pro- or anti-tumor activity. The aim of this study was to elucidate the controversial role of RNF5 in neuroblastoma and melanoma, two neuroectodermal tumors of infancy and adulthood, respectively. RNF5 gene levels are evaluated in publicly available datasets reporting the gene expression profile of melanoma and neuroblastoma primary tumors at diagnosis. The therapeutic effect of Analog-1, an RNF5 pharmacological activator, was investigated on in vitro and in vivo neuroblastoma and melanoma models. In both neuroblastoma and melanoma patients the high expression of RNF5 correlated with a better prognostic outcome. Treatment of neuroblastoma and melanoma cell lines with Analog-1 reduced cell viability by impairing the glutamine availability and energy metabolism through inhibition of F1Fo ATP-synthase activity. This latter event led to a marked increase in oxidative stress, which, in turn, caused cell death. Similarly, neuroblastoma- and melanoma-bearing mice treated with Analog-1 showed a significant delay of tumor growth in comparison to those treated with vehicle only. These findings validate RNF5 as an innovative drug target and support the development of Analog-1 in early phase clinical trials for neuroblastoma and melanoma patients.

Background: Risdiplam is an orally administered therapy that modifies pre-mRNA splicing of the survival of motor neuron 2 (SMN2) gene and is approved for the treatment of spinal muscular atrophy. The FIREFISH study is investigating the safety and efficacy of risdiplam in treated infants with type 1 spinal muscular atrophy versus historical controls. The primary endpoint of part 2 of the FIREFISH study showed that infants with type 1 spinal muscular atrophy attained the ability to sit without support for at least 5 s after 12 months of treatment. Here, we report on the safety and efficacy of risdiplam in FIREFISH part 2 over 24 months of treatment. Methods: FIREFISH is an ongoing, multicentre, open-label, two-part study. In FIREFISH part 2, eligible infants (aged 1-7 months at enrolment, with a genetically confirmed diagnosis of spinal muscular atrophy, and two SMN2 gene copies) were enrolled in 14 hospitals in ten countries across Europe, North America, South America, and Asia. Risdiplam was orally administered once daily at 0·2 mg/kg for infants between 5 months and 2 years of age; once an infant reached 2 years of age, the dose was increased to 0·25 mg/kg. Infants younger than 5 months started at 0·04 mg/kg (infants between 1 month and 3 months old) or 0·08 mg/kg (infants between 3 months and 5 months old), and this starting dose was adjusted to 0·2 mg/kg once pharmacokinetic data were available for each infant. The primary and secondary endpoints included in the statistical hierarchy and assessed at month 12 have been reported previously. Here we present the remainder of the secondary efficacy endpoints that were included in the statistical hierarchy at month 24: the ability to sit without support for at least 30 s, to stand alone, and to walk alone, as assessed by the Bayley Scales of Infant and Toddler Development, third edition gross motor subscale. These three endpoints were compared with a performance criterion of 5% that was defined based on the natural history of type 1 spinal muscular atrophy; the results were considered statistically significant if the lower limit of the two-sided 90% CI was above the 5% threshold. FIREFISH is registered with ClinicalTrials.gov, NCT02913482. Recruitment is closed; the 36-month extension period of the study is ongoing. Findings: Between March 13 and Nov 19, 2018, 41 infants were enrolled in FIREFISH part 2. After 24 months of treatment, 38 infants were ongoing in the study and 18 infants (44% [90% CI 31-58]) were able to sit without support for at least 30 s (p

Genetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations.

INTRODUCTION/AIMS: Currently, there are no straightforward guidelines for the clinical and diagnostic management of hyperCKemia, a frequent and nonspecific presentation in muscle diseases. Therefore, we aimed to describe our diagnostic workflow for evaluating patients with this condition. METHODS: We selected 83 asymptomatic or minimally symptomatic patients with persistent hyperCKemia for participation in this Italian multicenter study. Patients with facial involvement and distal or congenital myopathies were excluded, as were patients with suspected inflammatory myopathies or predominant respiratory or cardiac involvement. All patients underwent a neurological examination and nerve conduction and electromyography studies. The first step of the investigation included a screening for Pompe disease. We then evaluated the patients for myotonic dystrophy type II-related CCTG expansion and excluded patients with copy number variations in the DMD gene. Subsequently, the undiagnosed patients were investigated using a target gene panel that included 20 genes associated with isolated hyperCKemia. RESULTS: Using this approach, we established a definitive diagnosis in one third of the patients. The detection rate was higher in patients with severe hyperCKemia and abnormal electromyographic findings. DISCUSSION: We have described our diagnostic workflow for isolated hyperCKemia, which is based on electrodiagnostic data, biochemical screening, and first-line genetic investigations, followed by successive targeted sequencing panels. Both clinical signs and electromyographic abnormalities are associated with increased diagnostic yields. This article is protected by copyright. All rights reserved.

The aim of the study was to establish 24-month changes in a large cohort of type II and III spinal muscular atrophy (SMA) patients assessed with the Revised Upper Limb Module (RULM), a tool specifically developed to assess upper limb function in SMA. We included 107 patients (54 type II and 53 type III) with at least 24-months follow up. The overall RULM 24-month changes showed a mean decline of -0.79 points. The difference between baseline and 24 months was significant in type II but not in type III patients. There was also a difference among functional subgroups but not in relation to age. Most patients had 24-month mean changes within 2 points, with 23% decreasing more than 2 points and 7% improving by >2 points. Our results suggest an overall progressive decline in upper limb function over 24 months. The negative changes were most notable in type II, in non-ambulant type III and with a different pattern of progression, also in non-sitter type II. In contrast, ambulant type III showed relative stability within the 24-month follow up. These findings will help in the interpretation of the real world data collected following the availability of new therapeutic approaches.

The aim of this study is to retrospectively assess onset and progression of scoliosis in type II SMA patients not treated with the approved disease modifying treatments. Scoliosis was evaluated by measuring the scoliosis angle on X-ray obtained in the anteroposterior view in sitting position (Cobb's angle method). Eighty-four patients had at least one assessment of scoliosis angle (287 assessments). There was a positive correlation between age and scoliosis angles (p0.001) with a progressive increase of scoliosis with age. When subdividing the population by HFMSE score (10; 11-22;22), there was a progressive increase in scoliosis angles with decreasing HFMSE scores. The difference between HFMSE categories was significant (p0.001). Fifty-four patients had at least two assessments at 6-month distance and were retained for the longitudinal analysis. Using a mixed model, age, functional status and scoliosis angle at baseline were predictive on scoliosis progression. The mean annual rate of increase of scoliosis angle was 5.63 (95%CI: 4.74-6.52). Our results confirm the progression of scoliosis in untreated type II SMA providing details of the progression in relation to different variables. With different therapeutical options being available in many countries, our findings will provide reference data for establishing possible differences in the trajectories of progression with treated type II individuals.

Intrathecal delivery of Nusinersen–an antisense oligonucleotide that promotes survival motor neuron (SMN) protein induction–is an approved therapy for spinal muscular atrophy (SMA). Here, we employed nuclear magnetic resonance (NMR) spectroscopy to longitudinally characterize the unknown metabolic effects of Nusinersen in the cerebrospinal fluid (CSF) of SMA patients across disease severity. Modulation of amino acid metabolism is a common denominator of biochemical changes induced by Nusinersen, with distinct downstream metabolic effects according to disease severity. In severe SMA1 patients, Nusinersen stimulates energy-related glucose metabolism. In intermediate SMA2 patients, Nusinersen effects are also related to energy homeostasis but involve ketone body and fatty acid biosynthesis. In milder SMA3 patients, Nusinersen mainly modulates amino acid metabolism. Moreover, Nusinersen modifies the CSF metabolome of a more severe clinical group towards the profile of untreated SMA patients with milder disease. These findings reveal disease severity-specific neurometabolic signatures of Nusinersen treatment, suggesting a selective modulation of peripheral organ metabolism by this CNS-directed therapy in severe SMA patients.

To describe the use of surgical repair (One-step resective-conservative surgery) in all cases of placenta accreta spectrum.Multicentre retrospective case series from tertiary referral hospitals in Argentina. A total of 452 patients were accepted from 12 hospitals presenting suspicion of invasive placenta by auxiliary methods (ultrasound, Doppler and MRI). At the time of the surgery, placenta accreta spectrum was classified according to invasion topography (specific blood supply) and local features (proximity to other structures, adhesion process, and multiple anastomotic blood vessels). Type 1: upper posterior bladder; type 2: parametrial; type 3: low posterior bladder; and type 4: low posterior bladder and fibrosis. After the ligature of newly formed vessels between the uterus and pelvic organs, the fetus was delivered through an upper segmental hysterotomy. Hemostasis was achieved by selective ligature of vesical-uterine and colpo-uterine vessels. Then, the invaded myometrium and the entire placenta were removed totally in bloc and until detected healthy tissue in both edges, to guarantee the most physiological hysterotomy in the uterine segment. The uterus was closed with a polyglactin suture, double-layer technique. The main outcome measurements were the uterine conservation, the blood loss and other complications classified according to intrasurgical classification.From 452 accepted patients, 326 patients had a confirmed diagnosis of placenta accreta spectrum by histology analysis and surgical-clinical findings. In 126 cases, placenta accreta spectrum was excluded used the same diagnostic criteria (Type 0 or false positive PAS). They were identified 248 cases as type 1, 44 as type 2, 23 as type 3 and 11 as type 4. Uterine conservation was possible in the 81% of type 1 invasion with 500 mL of blood loss (interquartile range, IQR = Q3 - Q1). The modified Pfannenstiel was the most commonly used incision, while midline incision was chosen in all emergencies or in patients with a previous midline incision. Hysterotomy made in the upper part of the uterine segment presented normally attached placentas and not accreta. Selective vessel ligature, also named custom-made hemostasis method (CMHM) was effective at stopping or preventing bleeding associated with PAS. The entire placenta and the invaded area are removed in block, to guarantee to perform the uterine repair with healthy tissue and to avoid a recurrence in the subsequent cesarean. The uterine-ovary artery axis is never occluded or obliterate to guarantee the uterine-endometrial and ovary blood supply as before surgery. No significant differences existed according to the population; however, the presence of total occlusive placenta previa was more frequent in types 3 and 4, which were also associated with older mothers and age-related collagen changes. Lateral and lower segment invasions (types 2 and 3) were most commonly associated with previous terminations of pregnancy, curettage, and manual removal of the placenta. Blood loss and technical difficulty were clearly associated to the invaded area, while invasion degree was a poor marker to predicting bleeding or complications in all locations Uterine conservation was possible in 202/248 (81.5%) of type 1, 21/44 (47.7%) of type 2, 5/23 (21.8%) of type 3 and 0/11 (0%) of type four cases. Type 0 (false positive) were excluded of statistical analysis, and the uterus was preserved in 100% of cases. In a separate report, we will describe the maternal and fetal outcomes as well as 204 subsequent pregnancies after the use of one-step resective reconstructive technique.Using the resective-reconstructive approach (one-step conservative surgery) to the management of invasive placenta, the uterus can be preserved with minimal morbidity and reduced blood loss in almost 80% of cases. Précis preventing hysterectomy in 80% of placenta accreta spectrum.

OBJETIVO: Caracterizar o perfil dos pacientes que evoluiram a obito na emergencia psiquiatrica (EP) no periodo de 2009 a 2015 no Hospital de Clinica Gaspar Vianna em Belem do Para, avaliando assim as variaveis demograficas e socioeconomicas e os habitos de vida dos pacientes que evoluiram ao obito, bem como identificar o tempo de doenca psiquiatrica dos pacientes que morreram durante a internacao psiquiatrica, estabelecendo as comorbidades associadas ao quadro clinico psiquiatrico dos usuarios atendidos na EP, alem de comparar os obitos entre os sexos dos individuos na EP. METODO: O estudo caracterizou-se por ser do tipo retrospectivo, transversal com abordagem quantitativa sendo realizado na cidade de Belem, na FHCGV. Foram incluidos no estudo dados dos prontuarios dos usuarios internados na emergencia psiquiatrica que evoluiram ao obito no periodo de 2009 a 1015. RESULTADO: Observou-se que 60% dos pacientes eram do sexo masculino, enquanto que 40% do feminino, fatores como alcoolismo (20%) e tabagismo (60%) tambem foram identificados nos pacientes. A comorbidade mais frequente foi de HAS (33,3%), acerca da internacao, se constatou que 73,3% foram por motivo de agressividade, e os medicamentos mais utilizados foram Haldol (66,7%). Na classificacao CID-10 o F19 ocorreu mais no sexo masculino (44,4%) e o F31 (33,3%) no sexo feminino, sendo que na classificacao geral o F29 apresentou o maior numero (33.3%). Observou-se que em relacao ao sexo masculino o obito ocorreu, em media, antes dos 40 anos, nas mulheres foi, em media, aos 65 anos. CONCLUSAO: Compreende-se que o conhecimento desse perfil dos pacientes proporcionara a equipe de saude da FHCGV realizar um melhor acolhimento dos pacientes dando atencao especial aos que apresentam perfis semelhantes aos que evoluiram ao obito, prevenindo desfechos como obito durante a internacao na EP.

The role of muscle biopsy in the diagnostic workup of floppy infants is controversial. Muscle sampling is invasive, and often, results are not specific. The rapid expansion of genetic approach has made the muscle histopathology analysis less crucial. This study aims to assess the role and efficacy of muscle histopathology in the diagnostic algorithm of hypotonia in early infancy through a retrospective analysis of 197 infants who underwent muscle biopsy in their first 18 months of life. Data analysis revealed that 92/197 (46.7%) of muscle biopsies were non-specific (80) or normal (12), not allowing a specific diagnosis. In 41/197 (20.8%) cases, biopsy suggested a metabolic or mitochondrial myopathy, while in 23/197 cases (11.7%), we found evidence of muscular dystrophy. In 19/197 cases (9.7%), histopathology characteristics of a congenital myopathy were reported. In 22/197 cases (11.7%), the histopathological study indicated presence of a neurogenic damage. Overall, 46 diagnoses were then achieved by oriented genetic tests. Muscle biopsy results were consistent with genetic results in 90% of cases. Diagnostic algorithms for the diagnosis of a floppy infant are largely missing. Muscle biopsy alone can lead to a diagnosis, help the clinician in the choice of a genetic test, or even modify a diagnosis made previously.

Background Leigh syndrome (LS) is a progressive neurodegenerative disorder associated with primary or secondary dysfunction of mitochondrial oxidative phosphorylation and is the most common mitochondrial disease in childhood. Numerous reports on the biochemical and molecular profiles of LS have been published, but there are limited studies on genetically confirmed large series. We reviewed the clinical, imaging, biochemical and molecular data of 122 patients with a diagnosis of LS collected in the Italian Collaborative Network of Mitochondrial Diseases database. Results Clinical picture was characterized by early onset of several neurological signs dominated by central nervous system involvement associated with both supra- and sub-tentorial grey matter at MRI in the majority of cases. Extraneurological organ involvement is less frequent in LS than expected for a mitochondrial disorder. Complex I and IV deficiencies were the most common biochemical diagnoses, mostly associated with mutations in SURF1 or mitochondrial-DNA genes encoding complex I subunits. Our data showed SURF1 as the genotype with the most unfavorable prognosis, differently from other cohorts reported to date. Conclusion We report on a large genetically defined LS cohort, adding new data on phenotype-genotype correlation, prognostic factors and possible suggestions to diagnostic workup.

Background:Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by the degeneration of the second motor neuron. The phenotype ranges from very severe to very mild forms. All patients have the homozygous loss of the SMN1 gene and a variable number of SMN2 (generally 2–4 copies), inversely related to the severity. The amazing results of the available treatments have made compelling the need of prognostic biomarkers to predict the progression trajectories of patients. Besides the SMN2 products, few other biomarkers have been evaluated so far, including some miRs.Methods:We performed whole miRNome analysis of muscle samples of patients and controls (14 biopsies and 9 cultures). The levels of muscle differentially expressed miRs were evaluated in serum samples (51 patients and 37 controls) and integrated with SMN2 copies, SMN2 full-length transcript levels in blood and age (SMA-score).Results:Over 100 miRs were differentially expressed in SMA muscle; 3 of them (hsa-miR-181a-5p, -324-5p, -451a; SMA-miRs) were significantly upregulated in the serum of patients. The severity predicted by the SMA-score was related to that of the clinical classification at a correlation coefficient of 0.87 (p-5).Conclusions:miRNome analyses suggest the primary involvement of skeletal muscle in SMA pathogenesis. The SMA-miRs are likely actively released in the blood flow; their function and target cells require to be elucidated. The accuracy of the SMA-score needs to be verified in replicative studies: if confirmed, its use could be crucial for the routine prognostic assessment, also in presymptomatic patients.Funding:Telethon Italia (grant #GGP12116).

The aim of this retrospective study was to review body mass index (BMI) in a large cohort of Italian pediatric type 2 spinal muscular atrophy (SMA) patients, aged between 0 and 20 years and to establish possible differences in relation to a number of variables such as ventilation, motor function, and survival motor neuron 2 gene copies. Cross-sectional data were collected from 102 patients for a total of 344 visits. Standard growth charts for height and weight were used as reference, with age adjusted BMI calculated using the Center for Disease and Prevention Children’s BMI Tool. In the 344 visits, weight ranged between 3.90 and 83 kg, and the BMI between 8.4 and 31.6 with a BMI/age z-scores z-scores > + 2SD in 9% of the measurements. The BMI/age z-scores were relatively stable z-scores after the age of 13. A difference on the BMI/age z-scores was found among the different age subgroups (z-scores and gender were significantly contributing to the changes while other variables were not.Conclusion: Our results confirm that careful surveillance of weight and BMI/age z-scores is needed in type 2 SMA. Further studies, including assessments of chewing and swallowing and of lean/fat body mass, will help to better understand the possible mechanisms underlying weight issues. What is Known:• Feeding difficulties have been reported in a few studies and were invariably found in patients with type 1 SMA.• Type 2 SMA patients often have low BMI with a relevant number of patients requiring tube feeding. What is New:• Reduction in BMI/age z-score overtime appeared to depend on baseline BMI/age z-score and gender.• Patients with a low BMI/age z-score were at higher risk of developing further reduction.

Introduction The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. Results The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). Discussion Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. Conclusion Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

Muscular dystrophies (MDs) are a group of genetic diseases characterized by progressive muscle wasting associated to oxidative stress and persistent inflammation. It is essential to deepen our knowledge on the mechanism connecting these two processes because current treatments for MDs have limited efficacy and/or are associated with side effects. Here, we identified the alarmin high-mobility group box 1 (HMGB1) as a functional link between oxidative stress and inflammation in MDs. The oxidation of HMGB1 cysteines switches its extracellular activities from the orchestration of tissue regeneration to the exacerbation of inflammation. Extracellular HMGB1 is present at high amount and undergoes oxidation in patients with MDs and in mouse models of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy 3 (LGMDR3) compared to controls. Genetic ablation of HMGB1 in muscles of DMD mice leads to an amelioration of the dystrophic phenotype as evidenced by the reduced inflammation and muscle degeneration, indicating that HMGB1 oxidation is a detrimental process in MDs. Pharmacological treatment with an engineered nonoxidizable variant of HMGB1, called 3S, improves functional performance, muscle regeneration, and satellite cell engraftment in dystrophic mice while reducing inflammation and fibrosis. Overall, our data demonstrate that the balance between HMGB1 redox isoforms dictates whether skeletal muscle is in an inflamed or regenerating state, and that the nonoxidizable form of HMGB1 is a possible therapeutic approach to counteract the progression of the dystrophic phenotype. Rebalancing the HMGB1 redox isoforms may also be a therapeutic strategy for other disorders characterized by chronic oxidative stress and inflammation.

Purpose: This study evaluated if Toxoplasma gondii infection and the drug-associated infection modifies the brain radiopharmaceutical Ethylene Cystine Diethylester Dihydrochloride (99mTc-ECD) biodistribution in mice.Materials and methods: A total of 18 mice were divided into 3 groups. Control group (C) received distilled water and 99mTc-ECD; Infected group (I) received T. gondii strain and 99mTc-ECD; Infected and Treated group (IT), in addition to infection, received association of Pyrimethamine and Sulfadiazine and 99mTc-ECD. The T. gondii strain used in this study was TgCkRrRN3. Forty minutes after administration of the 99mTc-ECD, all animals were euthanized, and blood and brain samples were isolated. The counting of the radioactivity percentage per gram of tissue (%ATI/g) was calculated, and statistical analysis was performed by t-test, with a level of significance of p < .05.Results: There was a significant increase in %ATI/g between groups C and I on brain (0.35 ± 0.02 and 0.45 ± 0.04; p = .041) and on blood (0.80 ± 0.09 and 1.14 ± 0.31; p = .049). A significant decrease in %ATI/g occurred between groups C and IT on blood (0.80 ± 0.09 and 0.54 ± 0.08; p = .001) and on brain (0.35 ± 0.02 and 0.22 ± 0.04; p = .049).Conclusions: Combined therapy of anti-Toxoplasma drugs in infected mice reduced the uptake of 99mTc-ECD, probably due to its binding to plasma proteins.

The title compound C17H18ClNO3S crystallizes in the monoclinic P21/c space group with unit cell parameters a = 15.040 (3) A, b = 9.151 (6) A, c = 13.868 (7) A, β = 116.38 (5)°. Chlorophenyl and methoxyphenyl ring planes are approximately perpendicular and the two moieties form an angle of 82.2°. The crystal packing is stabilized by π–π and Cl–π interactions, which occur between parallel methoxyphenyl and chlorophenyl moieties. Dipolar intermolecular contacts, mainly involving the oxygen atoms and C–H, also contribute to the crystal network. The title compound is formed in the synthetic route for the production of potent inhibitors of calmodulin. Its crystal structure shows the chlorophenyl and methoxyphenyl moieties forming an angle of 82.2°. The crystal packing is stabilized by π–π, Cl–π and dipolar intermolecular contacts.

Objective: To identify and describe comparativelythe chemical models of the induction of inflammatory bowel diseases (IBD) in rodents most used and that best mimic the pathogenesis in humans.Methods: Based on an integrative review in the MEDLINE and LILACS databases, it was investigated which experimental induction models were most cited in articles published from 2004 to 2020, with the descriptors "Colitis/CI", "Colitis model ulcerative" and "Intestinal inflammation model."All empirical articles that addressed one or more inflammation models in rats or mice were included.Results: 239 articles were identified; of these, only ten empirical articles were selected.The most used models were colitis induced by TNBS acid, DSS, and colitis induced by acetic acid (AA).Conclusion: It was possible to identify the most used models to promote the induction of intestinal inflammation in rats, and both models proved to be effective according to the limitations observed in the models described, suggesting the need for new works that use more well-defined protocols and that more fully represent the pathophysiological complexity of the disease. Objetivo: Identificar e descrever de forma comparativa os modelos químicos de indução das doenças inflamatórias intestinais (DII) em roedores mais utilizados e que melhor mimetizam a patogênese em humanos. Métodos: a partir de uma revisão integrativa nas bases de dados MEDLINE e LILACS, investigou-se quais os modelos de indução experimental mais citados nos artigos publicados no período de 2004 a 2020, com os descritores “Colite/CI", “Modelo de colite ulcerativa” e “Modelo de inflamação intestinal”. Foram incluídos todos os artigos empíricos que abordassem um ou mais modelos de inflamação em ratos ou camundongos. Resultados: 239 artigos foram identificados; destes, somente dez artigos empíricos foram selecionados. Os modelos mais utilizados foram o de colite induzida por ácido TNBS, por DSS e colite induzida por ácido acético (AA). Conclusão: Foi possivel identificar os modelos mais utilizados para promover a indução da inflamação intestinal em ratos e ambos os modelos se mostraram eficazes de acordo com seu protocolo de indução. Ficaram claras as limitações observadas nos modelos já descritos, sugerindo a necessidade de novos trabalhos que utilizem protocolos mais bem definidos e que representem de forma mais integral a complexidade fisiopatológica da doença.

Background Benign acute childhood myositis (BACM) is a self-limited syndrome associated with viral infections characterized by symmetric lower extremity pain typically affecting school-aged children. Evolution in rhabdomyolysis and kidney damage is rarely reported. Despite this, the acute presentation commonly concerns both parents and health care providers, often leading to unnecessary workup. The aim of the study was to determine the features and outcome of a large series of children with BACM identifying a management pathway for pediatricians in Emergency Department (ED). Methods We conducted a retrospective study of patients with BACM managed in 2 Italian pediatric ED during a period of 8 and a half years. Demographic data, clinical, and laboratory results were extracted from electronic medical records. Recurrence, complications, treatments, and outcomes were also recorded. Descriptive statistics were produced for first-episode patients and for those with recurrence of myositis. A comparison between groups was performed. Results One hundred and thirteen patients with BACM were identified. Ninety-two children (65 males) had a single episode, while ten (nine males) had recurrence. The mean age at presentation was 6.0 years (range 2–13,2). All patients had normal neurological examination and no one developed myoglobinuria, or renal failure. At first evaluation median CK level was 1413 UI/l (normal values Median CK of “recurrent” patients was higher than “non-recurrent” (2330 vs 1150 U/L, p = 0.009). Viral studies were positive in 51/74 cases, with high prevalence of Influenza viruses. Ninety-six patients (85%) were hospitalized with a median of 4 days. No patients had any residual muscular impairment. Conclusions BACM has an excellent prognosis. Severe pathological conditions can be excluded with a complete history and clinical examination and simple blood and urine tests, avoiding unnecessary diagnostic investigations. Most patients may be discharged home from ED recommending hydration, rest, analgesics and careful follow-up.

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5' (upstream) and 3' (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3' adjacent nucleotide ("stop+4 model") was considered (p 0.05) with patients with stop codon TGA and 3' adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.

Previous natural history studies suggest that type II SMA patients remain stable over one year but show some progression over two years. Since nusinersen approval, there has been increasing attention to identify more specific age-related changes. The aim of the study was to establish 12-month changes in a cohort of pediatric type II SMA treated with nusinersen and to establish possible patterns of treatment effect in relation to different variables such as age, baseline value and SMN2 copy number. The Hammersmith Functional Motor Scale Expanded and the Revised Upper Limb Module were performed at T0 and 12 months after treatment (T12). Data in treated patients were compared to available data in untreated patients collected by the same evaluators.Seventy-seven patients of age between 2.64 and 17.88 years (mean:7.47, SD:3.79) were included. On t-test there was an improvement, with increased mean scores between T0 and T12 on both scales (p 0.001). Using multivariate linear regression analysis, age and baseline scores were predictive of changes on both scales (p 0.05) while SMN2 copy number was not. Differences were also found between study cohort and untreated data on both scales (p 0.001). At 12 months, an increase in scores was observed in all the age subgroups at variance with natural history data. Our real-world data confirm the treatment effect of nusinersen in pediatric type II SMA patients and that the data interpretation should take into account different variables. These data confirm and expand the ones already reported in the Cherish study.

Ref: Different trajectories in upper limb and gross motor function in spinal muscular atrophy INTRODUCTION: The Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM) have been widely used in natural history studies and clinical trials. Our aim was to establish how the scales relate to each other at different age points in spinal muscular atrophy (SMA) type 2 and 3, and to describe their coherence over 12 months. METHODS: The study was performed by cross-sectional and longitudinal reanalysis of previously published natural history data. The longitudinal analysis of the 12-month changes also included the analysis of concordance between scales with changes grouped as stable (+2 points), improved (>+2) or declined (>-2). RESULTS: Three hundred sixty-four patients were included in the cross-sectional analysis, showing different trends in score and point of slope change for the two scales. For type 2 the point of slope change was 4.1 years for the HFMSE and 5.8 for the RULM, while for type 3 it was 6 years for the HFMSE and 7.3 for the RULM. One-hundred-twenty-one patients had at least 2 assessments at 12-month. Full concordance was found in 57.3% of the assessments, and in 40.4% one scale remained stable and the other changed. Each scale appeared to be more sensitive to specific age or functional subgroups. DISCUSSION: The two scales, when used in combination, may increase the sensitivity to detect clinically meaningful changes in motor function in patients with SMA types 2 and 3.

Objective The aim of this paper was to report the 2‐year follow‐up in type I patients treated with Nusinersen and to assess whether possible changes in motor function are related to the subtype, age, or SMN2 copy number. Methods Sixty‐eight patients, with ages ranging from 0.20 to 15.92 years (mean: 3.96; standard deviation: +3.90) were enrolled in the study. All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the developmental section of the Hammersmith Infant Neurological Examination (HINE‐2) at the time they started treatment and 12 and 24 months after that. Results For both CHOP and HINE‐2 repeated measures analysis of variance showed a significant difference (P