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Valerio Sansone,1,2 Emanuele Maiorano,1 Alessandro Galluzzo,1 Valerio Pascale1,2 1Department of Orthopaedics, University of Milan, 2Department of Orthopaedics, I.R.C.C.S. Istituto Ortopedico Galeazzi, Milan, Italy Abstract: Calcific tendinopathy (CT) of the shoulder is a common, painful condition characterized by the presence of calcium deposits in the rotator cuff tendons. Current theories indicate that CT may be the result of a cell-mediated process in which, after a stage of calcium deposition, calcifications are spontaneously resorbed. However, in a minority of cases, this self-healing process is somehow disrupted, resulting in symptoms. Recent literature shows an emerging role of biological and genetic factors underlying CT. This new evidence could supplement the classic mechanical theory of rotator cuff tendinopathy complicated by calcium precipitation, and it may also explain why the majority of the therapies currently in use are only able to provide partially satisfactory outcomes. This review aims to summarize the current knowledge about the pathological processes underlying CT of the shoulder and thereby justify the quest for advanced biological treatments of this condition when it becomes symptomatic. Keywords: rotator cuff tendons, calcific tendinopathy, calcific deposits, shoulder, tendinitis, review

Introduzione: la vaccinazione antinfluenzale (VA) rappresenta uno degli interventi raccomandati per proteggere non solo operatori sanitari e pazienti ad alto rischio, ma la popolazione tutta. Lo scopo dello studio è stato valutare l’adesione alla VA da parte del personale infermieristico dedicato all’assistenza dei pazienti immunocompromessi presso l’A.O.U. “Federico II” di Napoli negli ultimi cinque anni. Ulteriori obiettivi sono stati: rilevare il fabbisogno formativo e comprendere i motivi della mancata adesione alla VA. Metodo: lo studio osservazionale è stato condotto da giugno a settembre 2015; è stato somministrato un questionario rivolto agli infermieri utilizzando un modulo di analisi on-line creato con la piattaforma G-Drive di Google. Risultati: sono stati somministrati un totale di 227 questionari con un tasso di adesione del 67.8%. Il 61.3% del campione creda nelle vaccinazioni quali strumenti importanti per la riduzione/eliminazione delle malattie. Nell’anno 2014-15, l’89% del campione non ha praticato la vaccinazione antinfluenzale. Negli ultimi 5 anni il 20.8% dichiara di essersi vaccinato soltanto una volta, l’11% due o più volte, mentre il 68.2% non si è mai vaccinato. Un ulteriore bisogno di informazioni è emerso nell’80% del campione. Conclusioni: l’assenza di un protocollo aziendale e le misconception sulla VA sembrano essere i principali elementi che hanno determinato i risultati. Vi è la necessità di attuare interventi capaci di stimolare gli operatori a comprendere l’importanza della VA, sviluppando una maggiore l’adesione.

Efficacy and safety of Givinostat, an oral histone deacetylase inhibitor for the treatment of Duchenne muscular dystrophy (DMD) have been assessed in the Epidys phase 3 study in ambulant boys (NCT02851797). DSC/14/2357/51 (NCT03373968) is an ongoing open label, long-term study of givinostat in 194 DMD subjects enrolled in givinostat studies and treated until marketing approval. 142 subjects from DSC/14/2357/51 were matched to 142 subjects from ImagingDMD (NCT01484678) and CINRG (NCT00468832) natural history studies (control group) using propensity score matching based on baseline results of functional tests and type of steroid. The median age at disease progression milestones, i.e., persistent loss to perform 4 stair climb (Lo4SC), loss of rise from floor (LoR), and loss of ambulation (LoA) were analyzed. Kaplan-Meier hazard ratios (HR) for givinostat vs control group and 95% CI were calculated using Cox proportional hazard model. Twenty-one (14.8%) patients showed Lo4SC in the Givinostat group vs 52 (36.6%) in the control group (HR=0.39 [0.24, 0.65], p<0.001). Median age at Lo4SC was 17.9 years (95% CI 15.65-NE) in the Givinostat group vs 13.9 (95% CI 13.50 14.88) in the control group. Forty-five (31.7%) patients show LoR in the Givinostat vs 61 (43.0%) in the control group (HR=0.66 (0.45, 0.96), p=0.028) at a median age of 14.9 years (95% CI 13.60-15.97) in the Givinostat group vs 12.9 (95% CI 12.20 14.33) in the control group. Fourteen (9.9%) subjects show LoA in the Givinostat group vs 39 (27.5%) in the control group (HR=0.42 (0.23, 0.76), p=0.004) at a median age of 18.1 years (95%CI 18.09, NE) in the givinostat group vs 15.2 (95%CI 14.70 18.31) in the control group. These results show that patients treated with givinostat, when compared with matched, steroid-treated controls, delays the occurrence of disease milestones. These results confirm givinostat efficacy demonstrated in Epidys Study with longer-term treatment. [ABSTRACT FROM AUTHOR]

Background and purpose: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary‐care centers or enrolled in any disease registry. Methods: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. Results: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). Conclusions: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes. [ABSTRACT FROM AUTHOR]

Background and purpose: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. Methods: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow‐up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. Results: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well‐known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. Conclusions: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management. [ABSTRACT FROM AUTHOR]

Background and purpose Studies investigating psychological interventions for the promotion of well-being in people with amyotrophic lateral sclerosis (ALS) are lacking. The purpose of the current study was to examine the use of an ALS-specific mindfulness-based intervention for improving quality of life in this population. Methods A randomized, open-label and controlled clinical trial was conducted on the efficacy of an ALS-specific meditation programme in promoting quality of life. Adults who received a diagnosis of ALS within 18 months were randomly assigned either to usual care or to an 8-week meditation training based on the original mindfulness-based stress reduction programme and tailored for people with ALS. Quality of life, assessed with the ALS-Specific Quality of Life Revised scale, represented the primary outcome, whilst secondary outcomes included anxiety and depression, assessed with the Hospital Anxiety and Depression Scale, and specific quality of life domains. Participants were assessed at recruitment and after 2, 6 and 12 months. The efficacy of the treatment was assessed on an intention-to-treat basis of a linear mixed model. Results A hundred participants were recruited between November 2012 and December 2014. Over time, there was a significant difference between the two groups in terms of quality of life ( β = 0.24, P = 0.015, d = 0.89). Significant differences between groups over time were also found for anxiety, depression, negative emotions, and interaction with people and the environment. Conclusions An ALS-specific meditation programme is beneficial for the quality of life and psychological well-being of people with ALS. [ABSTRACT FROM AUTHOR]

Andersen–Tawil syndrome (ATS) is a rare autosomal dominant channelopathy characterized by periodic paralysis, cardiac dysrhythmias, and distinct facial and skeletal characteristics, that may be variably present in the affected members. Mutations in the KCNJ2 and KCNJ5 gene have been associated with this disorder. We describe a family in which several members presented with different ATS phenotypes. The proband, a 4-year-old boy, presented with recurrent episodes of muscle weakness from an early age; two siblings suffered cardiac arrhythmia but had never experienced episodes of paralysis; their mother reported occasional muscle pain after exercise and unspecified cardiac arrhythmias. The analysis of KCNJ2 gene in the proband disclosed the presence of a pathogenic mutation (p.R218W), that was subsequently confirmed in the other affected subjects. Our results underline the possible intrafamilial phenotypic variability, ranging from full clinical triad to exclusive cardiac or muscular involvement, representing a diagnostic challenge that may also delay adequate management. There are still limited data on the treatment of ATS; in our patient there was clinical improvement with dichlorphenamide. [ABSTRACT FROM AUTHOR]

We describe a technique for treating Eaton stage IV osteoarthritis of the first ray, which is a development of our previously published technique for treating trapeziometacarpal arthritis. This simple technique is based on a limited resection arthroplasty of the first trapeziometacarpal and the scaphotrapezial joints, with the aim of inducing the formation of a narrow pseudoarthrosis at both sites. A total of 26 consecutive patients were treated for Eaton stage IV arthritis at a mean follow-up of 4.7 years (range 3.2–6.6). There were statistically significant improvements in all clinical parameters: mean appositional and oppositional pinch strength, mean DASH score (65 points pre-operatively to 8.7 points at final follow-up), and in mean visual analogue scale score (8.6 to 0.2 points). Although a larger cohort and a longer follow-up will be necessary to evaluate this new technique fully, these results encourage us to believe that the limited excision arthroplasty of the trapeziometacarpal and scaphotrapezial joints is a viable alternative to the existing surgical treatments for stage IV thumb arthritis.Level of evidence: 4 [ABSTRACT FROM AUTHOR]

Purpose: Chronic tendinopathy is a degenerative process causing pain and disability. Current treatments include biophysical therapies, such as pulsed electromagnetic fields (PEMF). The aim of this study was to compare, for the first time, the functional in vitro response of human tendon cells to different dosages of PEMF, varying in field intensity and duration and number of exposures.Methods: Tendon cells, isolated from human semitendinosus and gracilis tendons (hTCs; n = 6), were exposed to different PEMF treatments (1.5 or 3 mT for 8 or 12 h, single or repeated treatments). Scleraxis (SCX), COL1A1, COL3A1 and vascular endothelial growth factor-A (VEGF-A) expression and cytokine production were assessed.Results: None of the different dosages provoked apoptotic events. Proliferation of hTCs was enhanced by all treatments, whereas only 3 mT-PEMF treatment increased cell viability. However, the single 1.5 mT-PEMF treatment elicited the highest up-regulation of SCX, VEGF-A and COL1A1 expression, and it significantly reduced COL3A1 expression with respect to untreated cells. The treated hTCs showed a significantly higher release of IL-1β, IL-6, IL-10 and TGF-β. Interestingly, the repeated 1.5 mT-PEMF significantly further increased IL-10 production.Conclusions: 1.5 mT-PEMF treatment was able to give the best results in in vitro healthy human tendon cell culture. Although the clinical relevance is not direct, this investigation should be considered an attempt to clarify the effect of different PEMF protocols on tendon cells, in particular focusing on the potential applicability of this cell source for regenerative medicine purpose, both in surgical and in conservative treatment for tendon disorders. [ABSTRACT FROM AUTHOR]

We describe a technique that arose from the observation of the clinical outcome of failed arthrodeses of the thumb carpometacarpal joint. In these cases a pseudoarthrosis developed which, surprisingly, rarely lead to a poor clinical outcome. Thus we developed a simple technique which deliberately caused the formation of a narrow pseudoarthrosis in the carpometacarpal joint. We present a retrospective review of 248 consecutive patients treated for Eaton stages II and III osteoarthritis. We observed a statistically significant improvement in mean appositional and oppositional pinch strength, mean DASH score (63.8 pre-operatively to 10.5 at final follow-up), and the mean pain score (8.3 to 0.2). We conclude that trapeziometacarpal limited excision arthroplasty is a simple and reliable alternative to existing surgical techniques for treating Stage II or III thumb carpometacarpal joint arthritis. [ABSTRACT FROM PUBLISHER]

Low frequency pulsed electromagnetic field (PEMF) has proven to be effective in the modulation of bone and cartilage tissue functional responsiveness, but its effect on tendon tissue and tendon cells (TCs) is still underinvestigated. PEMF treatment (1.5 mT, 75 Hz) was assessed on primary TCs, harvested from semitendinosus and gracilis tendons of eight patients, under different experimental conditions (4, 8, 12 h). Quantitative PCR analyses were conducted to identify the possible effect of PEMF on tendon-specific gene transcription (scleraxis, SCX and type I collagen, COL1A1); the release of pro- and anti-inflammatory cytokines and of vascular endothelial growth factor (VEGF) was also assessed. Our findings show that PEMF exposure is not cytotoxic and is able to stimulate TCs' proliferation. The increase of SCX and COL1A1 in PEMF-treated cells was positively correlated to the treatment length. The release of anti-inflammatory cytokines in TCs treated with PEMF for 8 and 12 h was significantly higher in comparison with untreated cells, while the production of pro-inflammatory cytokines was not affected. A dramatically higher increase of VEGF-A mRNA transcription and of its related protein was observed after PEMF exposure. Our data demonstrated that PEMF positively influence, in a dose-dependent manner, the proliferation, tendon-specific marker expression, and release of anti-inflammatory cytokines and angiogenic factor in a healthy human TCs culture model. [ABSTRACT FROM AUTHOR]

We describe a 47-year-old man who referred to the Emergency Department for sudden global amnesia and left mild motor impairment in the setting of increased arterial blood pressure. The acute episode resolved within 24 hours. Despite general recovery and the apparent transitory nature of the event, a persistent selective impairment in recollecting events from some specific topics of his personal life became apparent. Complete neuropsychological tests one week after the acute onset and 2 months later demonstrated a clear retrograde memory deficit contrasting with the preservation of anterograde memory and learning abilities. One year later, the autobiographic memory deficit was unmodified, except for what had been re-learnt. Brain MRI was normal while H20 brain PET scans demonstrated hypometabolism in the right globus pallidus and putamen after 2 weeks from onset, which was no longer present one year later. The absence of a clear pathomechanism underlying focal amnesia lead us to consider this case as an example of functional retrograde amnesia. [ABSTRACT FROM AUTHOR]

A previous study in proximal myotonic myopathy (PROMM/DM-2) and myotonic dystrophy type 1 (DM-1) using brain positron emission tomography demonstrated a reduced cerebral blood flow in the frontal and temporal regions associated with cognitive impairment. The objective was to investigate further cognitive and behavioural aspects in a new series of patients with DM-1 and PROMM/DM-2. Nineteen patients with genetically determined PROMM/DM-2 and 21 patients with moderately severe DM-1 underwent neuropsychological testing and neuropsychiatric interviews. DM-1 and PROMM/DM-2 patients had significantly lower scores on tests of frontal lobe function compared to controls. Neuropsychiatric interviews demonstrated an avoidant trait personality disorder in both patient groups. Brain single photon emission computed tomography showed frontal and parieto-occipital hypoperfusion. The results suggest that there is a specific cognitive and behavioural profile in PROMM/DM-2 and in DM-1, and that this profile is associated with hypoperfusion in frontal and parieto-occipital regions of the brain. [Copyright &y& Elsevier]

Cardiac involvement in myotonic dystrophy type 1 (DM1) is well known. In contrast, the severity and frequency of cardiac abnormalities in proximal myotonic myopathy (PROMM) are still unclear. To identify similarities and differences in the rate of progression of muscle weakness and cardiac disturbances in these two disorders, 16 patients with PROMM (3q-unlinked PROMM: n=10; uniformative for linkage: n=6) were compared to 33 patients with moderately severe myotonic dystrophy type 1 (DM1). There was no significant difference in disease duration between PROMM and DM1. Patients underwent serial manual muscle strength testing, EKG, 24-h Holter monitoring, 2D-echocardiography. Muscle weakness progressed slowly in both groups. Most DM1 patients developed conduction defects. No significant atrioventricular disturbances on initial and follow-up examinations were found in PROMM patients. One patient developed right bundle branch block. Many families with PROMM appear to have more benign cardiac manifestations and less severe prognosis compared to DM1. Further studies of subgroups of PROMM (linked to the 3q21 locus and without linkage) are necessary to determine whether the cardiac conduction disturbances are more common in a specific genotype of PROMM. [Copyright &y& Elsevier]

To delineate the longitudinal progression of the functional impairment and its impact on the quality of life among individuals with myotonic dystrophy type 1 (DM1). DM1 is an autosomal dominant disorder that causes progressive impairment of physical function. The disorder causes progressive distal weakness along with myotonia, a hallmark of the disease. To prepare for therapeutic trials, the DMCRN sought to understand the rate of progression on motor function measures as well as the impact these impairments have on the quality of life. The DMCRN is conducting a prospective 24-month observational study, "Establishing Biomarkers and Clinical Endpoints in Myotonic Dystrophy Type-1 (END DM)," with 700 clinically and genetically confirmed DM1 participants across 22 international academic centers. Functional tests such as the quantitative hand grip strength, 10-meter walk/run, 6-minute walk test, 4 stair climb, and timed up and go were performed by standard protocols. VHOT measures the time to open the fist after maximal handgrip, marking the time for the long finger to fully extend. We determine the relationship between functional tests, VHOT, and other patient reported measures of disease severity (Myotonic Dystrophy Health Index [MDHI] and DM ACTIV. Relationships between measures are analyzed using Spearman correlations or regression models to determine the patterns of association. 119 DM1 patients (mean age: 43.06 years ± 14.00, 44.5% male) were tracked longitudinally over 12 months, starting from baseline. They experienced their first symptom onset at an average age of 26.09 years ± 13.92. At the initial assessment, the mean VHOT was 5.93seconds (SD=5.25), and the 10-meter walk time was 5.71 seconds(SD=3.88); A significant correlation was found between the overall 10-meter walk time and the DM1 ACTIV total score (r=-0.77; p<0.05), whereas the correlation between VHOT and the DM1 ACTIV total score was weak (r=-0.08; p>0.05). In multivariate analyses, both the qHG and VHOT accounted for 14.0% of the variance in the MDHI hand function and 22.4% of the variance in the MDHI activity limitations. Adding the 10-meter walk to the model increased its predictive ability for MDHI subsections on hand function and activity limitations to 50.3% and 31.5%, respectively. The annual change in the 10-meter walk time was 9.32%, and the annual change in VHOT was 7.24%. DM1 is a progressive disorder of functional impairment. These data show that the functional impairment impacts the quality of life of those affected. The physical function tests, especially the 10-meter walk, correlate with disease severity. Annual changes in these tests underscore DM1′s slow progression, highlighting the importance of such assessments in managing and understanding the disease. [ABSTRACT FROM AUTHOR]

Spinal muscular atrophy (SMA) Type III is characterized by the loss of the SMN1 gene, resulting in progressive neuron degeneration. While initially ambulatory, patients may later face gait impairments, fatigue, and the risk of ambulation loss (LOA). This study investigates the variability of LOA and its correlation with treatments in a nationwide cohort of SMA Type III cases. Retrospective data from 28 Italian centers, representing the national segment of the ISMAC registry, were utilized. The analysis involved 429 individuals with Type III SMA. Initially, individual variables such as sex, SMN2 copy number, and SMA III subtype (IIIA and IIIB) were analyzed independently of treatment effects. Subsequently, treatment effects were incorporated, and interactions between variables were explored. Initial analysis revealed that individuals with higher SMN2 copy numbers had a lower risk of LOA, with a 57% lower risk for those with 4+ copies compared to 2 copies. Similarly, SMA IIIB individuals had a 78% lower risk of LOA compared to SMA IIIA. The second phase of analysis revealed that treatment status significantly influenced LOA risk, with treated individuals experiencing a 96% lower risk of LOA compared to untreated individuals. Subgroup analyses by SMA subtype and SMN2 copy number further revealed substantial associations. Treated SMA IIIA individuals had a 91% lower risk of LOA compared to untreated counterparts, while treated SMA IIIB individuals had an 88% lower risk. Moreover, higher SMN2 copy numbers were associated with a reduced risk of LOA among treated individuals. Those with 3SMN2 copies had an 85% lower risk, and those with 4+SMN2 copies had a 93% lower risk compared to untreated counterparts. These findings underscore the potential benefits of treatment in delaying ambulation loss in SMA Type III patients and highlight the importance of incorporating treatment effects into prognostic models for improved patient management. [ABSTRACT FROM AUTHOR]