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Abstract Objectives Neurogenic muscle hypertrophy (NMH) is a rare condition characterized by focal muscle hypertrophy caused by chronic partial nervous injury. Given its infrequency, underlying mechanisms remain poorly understood. Inspired by two clinical cases, we conducted a systematic review to gain insights into the different aspects of NMH. Methods We systematically searched online databases up until May 30, 2023, for reports of muscle hypertrophy attributed to acquired neurogenic factors. We conducted an exploratory analysis to identify commonly associated features. We also report two representative clinical cases. Results Our search identified 63 reports, describing 93 NMH cases, to which we added our two cases. NMH predominantly affects patients with compressive radiculopathy (68.4%), negligible muscular weakness (93.3%), and a chronic increase in muscle bulk. A striking finding in most neurophysiological studies (60.0%) is profuse spontaneous discharges, often hindering the analysis of voluntary traces. Some patients exhibited features consistent with more significant muscle damage, including higher creatine phosphokinase levels, muscle pain, and inflammatory muscle infiltration. These patients are sometimes referred to in literature as “focal myositis.” Treatment encompassed corticosteroid, Botulinum Toxin A, decompressive surgery, antiepileptic medications, and nerve blocks, demonstrating varying degrees of efficacy. Botulinum Toxin A yielded the most favorable response in terms of reducing spontaneous discharges. Interpretation This systematic review aims to provide a clear description and categorization of this uncommon presentation of an often‐overlooked neurological disorder. Though questions remain about the underlying mechanism, evidence suggests that aberrant fiber overstimulation along with increased workload that promotes focal damage may result in muscle hypertrophy. This may serve as a guide for therapeutic interventions.

Abstract Background The COVID-19 pandemic substantially affected the lives of persons with inherited neuromuscular disorders (INMD), causing disruption in clinical and support services. While several studies have investigated mental health, distress and psychosocial resources in the general population during the pandemic, little is known about the experience of persons with INMD. Methods This study was aimed to fill this gap by jointly investigating both psychopathological symptoms and psychosocial resources – specifically, resilience and perceived social support – among persons with INMD during the pandemic, taking into account demographic and clinical factors. Between April and December 2020, 59 participants with INMD (aged 15–59, 71.2% M) completed a questionnaire collecting demographic and clinical data, the Multidimensional Scale of Perceived Social Support, the Resilience Scale for Adults, and the Achenbach System of Empirically Based Assessment. Results Overall, participants showed good levels of resilience and perceived social support. A minority of participants reported clinically relevant psychopathological symptoms, 28.81% for anxiety and depression. Most psychopathological symptoms were negatively correlated with resilience (-0.347

A one-year-old female miniature goat was presented to an emergency service after calving a dead goatling. Physical and ultrasonographic examination revealed the presence of a viable fetus; therefore, the goat was submitted to an emergency cesarean section. In the postoperative period, the animal had septic peritonitis caused by Enterococcus faecium and Enterococcus casseliflavus. Both bacterial strains showed contrasting antimicrobial resistance profiles. Laparohysterectomy and abdominal cavity lavage were performed, but, once the animal had adhesions and necrotic lesions in abdominal organs, euthanasia was executed. A post-mortem examination revealed fibrino-necrotic septic peritonitis secondary to uterine rupture. To the authors’ knowledge, this is the first detailed report of polymicrobial septic peritonitis in a miniature goat and the first report of septic peritonitis caused by E. faecium and E. casseliflavus.

Abstract Mass movements constitute major natural hazards in the Alpine realm. When triggered on slopes adjacent to lakes, these mass movements can generate tsunami-like waves that may cause additional damage along the shore. For hazard assessment, knowledge about the occurrence, the trigger and the geomechanical and hydrogeological mechanisms of these mass movements is necessary. For reconstructing mass movements that occurred in or adjacent to lakes, the lakes’s sedimentary record can be used as an archive. Here, we present a prehistorical mass-movement event, of which the traces were found in an alpine lake, Lake Thun, in central Switzerland. The mass movement is identified by large blocks on the bathymetric map, a chaotic to transparent facies on the reflection seismic profiles, and by a mixture of deformed lake sediments and sandy organic-rich layers in the sediment-core record. The event is dated at 2642–2407 cal year BP. With an estimated volume of ~ 20 × 106 m3 it might have generated a wave with an initial amplitude of > 30 m. In addition to this prehistorical event, two younger deposits were identified in the sedimentary record. One could be dated at 1523–1361 cal year BP and thus can be potentially related to an event in 598/599 AD documented in historical reports. The youngest deposit is dated at 304–151 cal year BP (1646–1799 AD) and is interpreted to be related to the artificial Kander river deviation into Lake Thun (1714 AD).

Abstract The modern, over 250-m-deep basin of Lake Constance represents the underfilled northern part of an over 400-m-deep, glacially overdeepened trough, which reaches well into the Alps at its southern end. The overdeepening was formed by repeated glacial advance-retreat cycles of the Rhine Glacier throughout the Middle to Late Pleistocene. A seismic survey of Lake Constance revealed a Quaternary sediment fill of more than 150 m thickness representing at least the last glacial cycle. The stratified sedimentary fill consists at the base of ice-contact deposits on top of the molasse bedrock, overlain by glaciolacustrine to lacustrine sediments. During the successful field test of a newly developed, mid-size coring system ("HIPERCORIG"), the longest core (HIBO19) ever taken in Lake Constance was retrieved with an overall length of 24 m. The sediments recovered consist of a nearly continuous succession of lacustrine silts and sands including more than 12 m of Late Glacial sediment at the base. 14 lithotypes were identified through petrophysical and geochemical analyses. In combination with a 14C- and OSL-based age-depth model, the core was divided into three main chronostratigraphic units. The basal age of ~ 13.7 ka BP dates the base of the succession back to the Bølling-Allerød interstadial, with overlying strata representing a complete and thick Younger-Dryas to Holocene succession. The sediments offer a high-resolution insight into the evolution of paleo-Lake Constance from a cold, postglacial to a more productive and warmer Holocene lake. The Late Glacial succession is dominated by massive, m-thick sand beds reflecting episodic sedimentation pulses. They are most likely linked to a subaquatic channel system originating in the river Seefelder Aach, which is, despite the Holocene drape, still apparent in today’s lake bathymetry. The overlying Holocene succession reveals a prominent, several cm-thick, double-turbiditic event layer representing the most distal impact of the Flimser Bergsturz, the largest known rockslide of the Alps that occurred over 100 km upstream the river Rhine at ~ 9.5 ka BP. Furthermore, lithologic variations in the Holocene succession document the varying sediment loads of the river Rhine and the endogenic production representing a multitude of environmental changes.

In the original publication [...]

In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.

Abstract Non-invasive techniques such as seismic investigations and high-resolution multibeam sonars immensely improved our understanding of the geomorphology and sediment regimes in both the lacustrine and the marine domain. However, only few studies provide quantifications of basin wide-sediment budgets in lakes. Here, we use the combination of high-resolution bathymetric mapping and seismic reflection data to quantify the sediment budget in an alpine lake. The new bathymetric data of Lake Brienz reveal three distinct geomorphological areas: slopes with intercalated terraces, a flat basin plain, and delta areas with subaquatic channel systems. Quasi-4D seismic reflection data allow sediment budgeting of the lake with a total sediment input of 5.54 × 106 t sediment over 15 years of which three-quarter were deposited in the basin plain. Lake Brienz yields extraordinarily high sedimentation rates of 3.0 cm/yr in the basin plain, much more than in other Swiss lakes. This can be explained by (i) its role as first sedimentary sink in a high-alpine catchment, and by (ii) its morphology with subaquatic channel-complexes allowing an efficient sediment transfer from proximal to distal areas of the lake.

Abstract 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.

Oligodendrocytes are the primary target of demyelinating disorders, and progressive neurodegenerative changes may evolve in the CNS. DNA damage and oxidative stress are considered key pathogenic events, but the underlying molecular mechanisms remain unclear. Moreover, animal models do not fully recapitulate human diseases, complicating the path to effective treatments. Here we report that mice with cell-autonomous deletion of the nuclear COP9 signalosome component CSN5 (JAB1) in oligodendrocytes develop DNA damage and defective DNA repair in myelinating glial cells. Interestingly, oligodendrocytes lacking JAB1 expression underwent a senescence-like phenotype that fostered chronic inflammation and oxidative stress. These mutants developed progressive CNS demyelination, microglia inflammation, and neurodegeneration, with severe motor deficits and premature death. Notably, blocking microglia inflammation did not prevent neurodegeneration, whereas the deletion of p21CIP1 but not p16INK4a pathway ameliorated the disease. We suggest that senescence is key to sustaining neurodegeneration in demyelinating disorders and may be considered a potential therapeutic target.

The aim of this study was to establish the possible effect of age, corticosteroid treatment and brain dystrophin involvement on motor function in young boys affected by Duchenne Muscular Dystrophy who were assessed using the North Star Ambulatory Assessment between the age of 4 and 7 years. The study includes 951 North Star assessments from 226 patients. Patients were subdivided according to age, to the site of mutation and therefore to the involvement of different brain dystrophin isoforms and to corticosteroids duration. There was a difference in the maximum North Star score achieved among patients with different brain dystrophin isoforms (p = 0.007). Patients with the involvement of Dp427, Dp140 and Dp71, had lower maximum NSAA scores when compared to those with involvement of Dp427 and Dp140 or of Dp427 only. The difference in the age when the maximum score was achieved in the different subgroups did not reach statistical significance. Using a linear regression model on all assessments we found that each of the three variables, age, site of mutation and corticosteroid treatment had an influence on the NSAA values and their progression over time. A second analysis, looking at 12-month changes showed that within this time interval the magnitude of changes was related to corticosteroid treatment but not to site of mutation. Our findings suggest that each of the considered variables appear to play a role in the progression of North Star scores in patients between the age of 4 and 7 years and that these should be carefully considered in the trial design of boys in this age range.

Cropland expansion is expected to increase across sub-Saharan African (SSA) countries in the next thirty years to meet growing food needs across the continent. These land transformations will have cascading social and ecological impacts that can be monitored using novel Earth observation techniques that produce datasets complementary to national cropland surveys. In this study, we present a flexible Bayesian data synthesis workflow on Google Earth Engine (GEE) that can be used to fuse optical and synthetic aperture radar data and demonstrate its ability to track agricultural change at national scales. We adapted the previously developed Bayesian Updating of Land Cover (Unsupervised) algorithm (BULC-U) by integrating a shapelet and slope thresholding algorithm to identify the locations and dates of cropland expansion and implemented a tiling scheme to allow the processing of large volumes of imagery. We apply this approach to map annual cropland change from 2000 to 2015 for Zambia (750,000 km2), a country that is experiencing rapid growth in agricultural land. We applied our cropland mapping approach to a time series of unsupervised classifications developed from Landsat 5, 7, 8, Sentinel-1, and ALOS PALSAR within 1476 tiles covering Zambia. The annual cropland changes maps reveal active cropland expansion between 2000 to 2015 in Zambia, especially in the Southern, Central, and Eastern provinces. Our accuracy assessment estimates that we have identified 27.5% to 69.6% of the total cropland expansion from 2000 to 2015 in Zambia (commission errors between 6.1% to 37.6%), depending on the slope threshold. Our results demonstrate the usefulness of Bayesian data fusion and shapelet, slope-based thresholding to synthesize optical and synthetic aperture radar for monitoring agricultural changes in situations where training data are scarce. In addition, the annual cropland maps provide one of the first spatially continuous, annually incremented accounts of cropland growth in this region. Our flexible, cloud-based workflow using GEE enables multi-sensor, national-scale agricultural change monitoring at low cost for users.

This article will review myogenic cell transplantation for congenital and acquired diseases of skeletal muscle. There are already a number of excellent reviews on this topic, but they are mostly focused on a specific disease, muscular dystrophies and in particular Duchenne Muscular Dystrophy. There are also recent reviews on cell transplantation for inflammatory myopathies, volumetric muscle loss (VML) (this usually with biomaterials), sarcopenia and sphincter incontinence, mainly urinary but also fecal. We believe it would be useful at this stage, to compare the same strategy as adopted in all these different diseases, in order to outline similarities and differences in cell source, pre-clinical models, administration route, and outcome measures. This in turn may help to understand which common or disease-specific problems have so far limited clinical success of cell transplantation in this area, especially when compared to other fields, such as epithelial cell transplantation. We also hope that this may be useful to people outside the field to get a comprehensive view in a single review. As for any cell transplantation procedure, the choice between autologous and heterologous cells is dictated by a number of criteria, such as cell availability, possibility of in vitro expansion to reach the number required, need for genetic correction for many but not necessarily all muscular dystrophies, and immune reaction, mainly to a heterologous, even if HLA-matched cells and, to a minor extent, to the therapeutic gene product, a possible antigen for the patient. Finally, induced pluripotent stem cell derivatives, that have entered clinical experimentation for other diseases, may in the future offer a bank of immune-privileged cells, available for all patients and after a genetic correction for muscular dystrophies and other myopathies.

Pockmarks are crater-like depressions formed by upward fluid flow (gas and/or liquid) through the unconsolidated sediment column on the floor of oceans and lakes. While pockmarks are well described in the marine realm, they have essentially been overlooked in lacustrine settings, likely due to a lack in economic interest to apply high-resolution hydroacoustic techniques in lakes. A swath-bathymetry survey on Lake Thun, Switzerland, revealed the existence of three pockmark systems. One pockmark (110 m in diameter) was discovered near a big karst system at Beatenberg at a water depth of ~217 m. Its activity is probably associated with episodic groundwater seepage induced by earthquakes, floods and snowmelt. At another site, Daerligen, we detected at ~60 m water depth the presence of multiple smaller pockmarks (~1.5 to 10 m in diameter) that seem to be active, continuously liberating CH4 gas by bubble ebullition. The CH4 displayed a biogenic carbon isotopic signature, however, the exact origin of the gas remains unknown. The third site, Tannmoos (~35 m water depth), comprises two large pockmarks (20–43 m in diameter) connected to a karst system in gypsum-carrying bedrock. One of these pockmarks is constituted of several unit pockmarks (e.g., sub-pockmarks; 0.3 to 0.8 m in diameter). While strong evidence is still lacking, we suggest that groundwater discharge occasionally occurs through these unit pockmarks during periods of intense precipitation. Hence, this study reveals the existence of three pockmark systems of variable morphology and mechanisms of formation within the same lake, reflecting different hydrological and biogeochemical regimes. Moreover, it underscores the potential importance of pockmarks in influencing hydrological and CH4 budgets in lakes. Clearly more work on quantifying seasonal fluxes of groundwater and CH4 release via lacustrine pockmarks is required, and it needs to be seen whether the observations made in Lake Thun are universal and apply also to many other lacustrine environments worldwide.

The Eastern European Alps are characterized by slow active deformation with low- to moderate seismicity. Recurrence rates of severe earthquakes exceed the time span of historical documentation. Therefore, historical and instrumental earthquake records might be insufficient for seismic hazard assessment and high-quality paleoseismic data is required. However, primary geological observations of postglacial fault activity are scarcely found, because major faults are buried below thick sedimentary sequences in glacially overdeepened valleys. Moreover, high erosion rates, gravitational slope processes and penetrative anthropogenic landscape modification often obscure geomorphic features related to surface ruptures. Here we present one of the rare paleoseismic data sets showing both on-fault evidence as subaqueous surface ruptures and off-fault evidence as multiple coeval mass-transport deposits (MTDs) and megaturbidites within a single high-resolution seismic-stratigraphic framework of the inner-alpine lake Achensee. Co-occurrence of on-fault and off-fault paleoseismic evidence on three stratigraphic levels indicates seismic activity with inferred moment magnitudes MW ∼6–6.5 of the local, lake-crossing Sulzgraben-Eben thrust at ∼8.3 ka BP and twice in Late Glacial times. Additional eight stratigraphic levels with only off-fault paleoseismic evidence document severe seismic shaking related to the historical MW ∼5.7 earthquake in Hall (CE 1670) and seven Holocene earthquakes, which have exceeded a local seismic intensity of ∼VI (EMS-98) at Achensee. Furthermore, we discuss natural and methodological influencing factors and potential pitfalls for the elaboration of a subaqueous paleoseismic record based on surface ruptures and multiple, coeval MTDs.

IntroductionThe 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 methodsWe 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.ResultsThe 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).DiscussionMutations 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.ConclusionOur 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.

In this paper, we present a concise and technique-heavy route to the synthesis of dimedone for a second-year organic chemistry curriculum. Our preparation of dimedone guides students through a Michael addition followed by a Dieckmann cyclization, basic ester hydrolysis, and thermal decarboxylation, while allowing time for mechanistic discussion and analysis of the product. The wide variety of techniques covered led this to be a pedagogically diverse experiment. This task is thoroughly tested and suitable for a 6 hour laboratory class (with a 1 hour lunch break) or two 3 hour stand-alone sessions.

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Nav1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Nav1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Nav1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: −28.6 ± 1.5 mV and Gly241Val: −30.2 ± 1.3 mV vs. WT: −18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the SCN4A gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.

IntroductionThe aim of this international collaborative effort was to report 36-month longitudinal changes using the 6MWT in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53.Materials and methodsOf the 92 patients included in the study, 24 had deletions amenable to skip exon 44, 27 exon 45, 18 exon 51, and 28 exon 53. Five patients with a single deletion of exon 52 were counted in both subgroups skipping exon 51 and 53.ResultsThe difference between subgroups amenable to skip different exons was not significant at 12 months but became significant at both 24 (p≤0.05) and 36 months (p≤0.01).DiscussionMutations amenable to skip exon 53 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had better results both at baseline and at follow up. Deletions amenable to skip exon 45 were associated with a more variable pattern of progression. Single exon deletions were more often associated with less drastic changes but this was not always true in individual cases.ConclusionOur results confirm that the progression of disease can differ between patients with different deletions, although the changes only become significant from 24 months onwards. This information is relevant because there are current clinical trials specifically targeting patients with these subgroups of mutations.

[This corrects the article DOI: 10.1371/journal.pone.0218683.].

Abstract Since respiratory insufficiency is the main cause of death in patients affected by Duchenne Muscular Dystrophy (DMD), the present study aims at establishing a new non-invasive method to evaluate the clinical parameters of respiratory conditions of experimental models affected by DMD. With this purpose in mind, we evaluated the cardiorespiratory clinical conditions, the changes in the intercostal muscles, the diaphragmatic mobility, and the respiratory cycles in Golden Retriever Muscular Dystrophy (GRMD) employing ultrasonography (US). A control group consisting of dogs of the same race, but not affected by muscular dystrophy, were used in this study. The results showed that inspiration, expiration and plateau movements (diaphragm mobility) were lower in the affected group. Plateau phase in the affected group was practically non-existent and showed that the diaphragm remained in constant motion. Respiratory rate reached 15.5 per minute for affected group and 26.93 per minute for the control group. Expiration and inspiration movements of intercostal muscles reached 8.99mm and 8.79mm, respectively, for control group and 7.42mm and 7.40mm, respectively, for affected group. Methodology used in the present analysis proved to be viable for the follow-up and evaluation of the respiratory model in GRMD and may be adapted to other muscular dystrophy experimental models.

Abstract Intra‐arterial transplantation of mesoangioblasts proved safe and partially efficacious in preclinical models of muscular dystrophy. We now report the first‐in‐human, exploratory, non‐randomized open‐label phase I–IIa clinical trial of intra‐arterial HLA‐matched donor cell transplantation in 5 Duchenne patients. We administered escalating doses of donor‐derived mesoangioblasts in limb arteries under immunosuppressive therapy (tacrolimus). Four consecutive infusions were performed at 2‐month intervals, preceded and followed by clinical, laboratory, and muscular MRI analyses. Two months after the last infusion, a muscle biopsy was performed. Safety was the primary endpoint. The study was relatively safe: One patient developed a thalamic stroke with no clinical consequences and whose correlation with mesoangioblast infusion remained unclear. MRI documented the progression of the disease in 4/5 patients. Functional measures were transiently stabilized in 2/3 ambulant patients, but no functional improvements were observed. Low level of donor DNA was detected in muscle biopsies of 4/5 patients and donor‐derived dystrophin in 1. Intra‐arterial transplantation of donor mesoangioblasts in human proved to be feasible and relatively safe. Future implementation of the protocol, together with a younger age of patients, will be needed to approach efficacy.

Despite global recognition of the social, economic and ecological impacts of deforestation, the world is losing forests at an alarming rate. Global and regional efforts by policymakers and donors to reduce deforestation need science-driven information on where forest loss is happening, and where it may happen in the future. We used spatially-explicit globally-consistent variables and global historical tree cover and loss to analyze how global- and regional-scale variables contributed to historical tree cover loss and to model future risks of tree cover loss, based on a business-as-usual scenario. Our results show that (1) some biomes have higher risk of tree cover loss than others; (2) variables related to tree cover loss at the global scale differ from those at the regional scale; and (3) variables related to tree cover loss vary by continent. By mapping both tree cover loss risk and potential future tree cover loss, we aim to provide decision makers and donors with multiple outputs to improve targeting of forest conservation investments. By making the outputs readily accessible, we anticipate they will be used in other modeling analyses, conservation planning exercises, and prioritization activities aimed at conserving forests to meet national and global climate mitigation targets and biodiversity goals.

Microtubule-based kinesin motors have many cellular functions, including the transport of a variety of cargos. However, unconventional roles have recently emerged, and kinesins have also been reported to act as scaffolding proteins and signaling molecules. In this work, we further extend the notion of unconventional functions for kinesin motor proteins, and we propose that Kif13b kinesin acts as a signaling molecule regulating peripheral nervous system (PNS) and central nervous system (CNS) myelination. In this process, positive and negative signals must be tightly coordinated in time and space to orchestrate myelin biogenesis. Here, we report that in Schwann cells Kif13b positively regulates myelination by promoting p38γ mitogen-activated protein kinase (MAPK)-mediated phosphorylation and ubiquitination of Discs large 1 (Dlg1), a known brake on myelination, which downregulates the phosphatidylinositol 3-kinase (PI3K)/v-AKT murine thymoma viral oncogene homolog (AKT) pathway. Interestingly, Kif13b also negatively regulates Dlg1 stability in oligodendrocytes, in which Dlg1, in contrast to Schwann cells, enhances AKT activation and promotes myelination. Thus, our data indicate that Kif13b is a negative regulator of CNS myelination. In summary, we propose a novel function for the Kif13b kinesin in glial cells as a key component of the PI3K/AKT signaling pathway, which controls myelination in both PNS and CNS.

The role of timed items, and more specifically, of the time to rise from the floor, has been reported as an early prognostic factor for disease progression and loss of ambulation. The aim of our study was to investigate the possible effect of the time to rise from the floor test on the changes observed on the 6MWT over 12 months in a cohort of ambulant Duchenne boys.A total of 487 12-month data points were collected from 215 ambulant Duchenne boys. The age ranged between 5.0 and 20.0 years (mean 8.48 ±2.48 DS).The results of the time to rise from the floor at baseline ranged from 1.2 to 29.4 seconds in the boys who could perform the test. 49 patients were unable to perform the test at baseline and 87 at 12 month The 6MWT values ranged from 82 to 567 meters at baseline. 3 patients lost the ability to perform the 6mwt at 12 months. The correlation between time to rise from the floor and 6MWT at baseline was high (r = 0.6, p

ObjectiveIn the last few years some of the therapeutical approaches for Duchenne muscular dystrophy (DMD) are specifically targeting distinct groups of mutations, such as deletions eligible for skipping of individual exons. The aim of this observational study was to establish whether patients with distinct groups of mutations have different profiles of changes on the 6 minute walk test (6MWT) over a 12 month period.MethodsThe 6MWT was performed in 191 ambulant DMD boys at baseline and 12 months later. The results were analysed using a test for heterogeneity in order to establish possible differences among different types of mutations (deletions, duplications, point mutations) and among subgroups of deletions eligible to skip individual exons.ResultsAt baseline the 6MWD ranged between 180 and 560,80 metres (mean 378,06, SD 74,13). The 12 month changes ranged between -325 and 175 (mean -10.8 meters, SD 69.2). Although boys with duplications had better results than those with the other types of mutations, the difference was not significant. Similarly, boys eligible for skipping of the exon 44 had better baseline results and less drastic changes than those eligible for skipping exon 45 or 53, but the difference was not significant.Conclusionseven if there are some differences among subgroups, the mean 12 month changes in each subgroup were all within a narrow Range: from the mean of the whole DMD cohort. This information will be of help at the time of designing clinical trials with small numbers of eligible patients.

Malaria-associated acute lung injury/acute respiratory distress syndrome (ALI/ARDS) often results in morbidity and mortality. Murine models to study malaria-associated ALI/ARDS have been described; we still lack a method of distinguishing which mice will develop ALI/ARDS before death. This work aimed to characterize malaria-associated ALI/ARDS in a murine model and to demonstrate the first method to predict whether mice are suffering from ALI/ARDS before death. DBA/2 mice infected with Plasmodium berghei ANKA developing ALI/ARDS or hyperparasitemia (HP) were compared using histopathology, PaO2 measurement, pulmonary X-ray, breathing capacity, lung permeability, and serum vascular endothelial growth factor (VEGF) levels according to either the day of death or the suggested predictive criteria. We proposed a model to predict malaria-associated ALI/ARDS using breathing patterns (enhanced pause and frequency respiration) and parasitemia as predictive criteria from mice whose cause of death was known to retrospectively diagnose the sacrificed mice as likely to die of ALI/ARDS as early as 7 days after infection. Using this method, we showed increased VEGF levels and increased lung permeability in mice predicted to die of ALI/ARDS. This proposed method for accurately identifying mice suffering from ALI/ARDS before death will enable the use of this model to study the pathogenesis of this disease.

Chronic airway infection is a key aspect of the pathogenesis of bronchiectasis. A growing interest has been raised on non-tuberculous mycobacteria (NTM) infection. We aimed at describing the clinical characteristics, diagnostic process, therapeutic options and outcomes of bronchiectasis patients with pulmonary NTM (pNTM) disease. This was a prospective, observational study enrolling 261 adult bronchiectasis patients during the stable state at the San Gerardo Hospital, Monza, Italy, from 2012 to 2015. Three groups were identified: pNTM disease; chronic P. aeruginosa infection; chronic infection due to bacteria other than P. aeruginosa. NTM were isolated in 32 (12%) patients, and among them, a diagnosis of pNTM disease was reached in 23 cases. When compared to chronic P. aeruginosa infection, patients with pNTM were more likely to have cylindrical bronchiectasis and a “tree-in-bud” pattern, a history of weight loss, a lower disease severity and a lower number of pulmonary exacerbations. Among pNTM patients who started treatment, 68% showed a radiological improvement, and 37% achieved culture conversion without recurrence, while 21% showed NTM isolation recurrence. NTM isolation seems to be a frequent event in bronchiectasis patients, and few parameters might help to suspect NTM infection. Treatment indications and monitoring still remain an important area for future research.

Remodeling of extracellular matrix (ECM) is a critical step in peripheral nerve regeneration. In fact, in human neuropathies, endoneurial ECM enriched in fibrin and vitronectin associates with poor regeneration and worse clinical prognosis. Accordingly in animal models, modification of the fibrinolytic complex activity has profound effects on nerve regeneration: high fibrinolytic activity and low levels of fibrin correlate with better nerve regeneration. The urokinase plasminogen receptor (uPAR) is a major component of the fibrinolytic complex, and binding to urokinase plasminogen activator (uPA) promotes fibrinolysis and cell movement. uPAR is expressed in peripheral nerves, however, little is known on its potential function on nerve development and regeneration. Thus, we investigated uPAR null mice and observed that uPAR is dispensable for nerve development, whereas, loss of uPAR affects nerve regeneration. uPAR null mice showed reduced nerve repair after sciatic nerve crush. This was a consequence of reduced fibrinolytic activity and increased deposition of endoneurial fibrin and vitronectin. Exogenous fibrinolysis in uPAR null mice rescued nerve repair after sciatic nerve crush. Finally, we measured the fibrinolytic activity in sural nerve biopsies from patients with peripheral neuropathies. We showed that neuropathies with defective regeneration had reduced fibrinolytic activity. On the contrary, neuropathies with signs of active regeneration displayed higher fibrinolytic activity. Overall, our results suggest that enforced fibrinolysis may facilitate regeneration and outcome of peripheral neuropathies.