Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and IL-6, suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human

Oxidative stress in Duchenne muscular dystrophy: focus on the NRF2 redox pathway

Oxidative stress is involved in the pathogenesis of Duchenne muscular dystrophy (DMD), an X-linked genetic disorder caused by mutations in the dystrophin gene and characterized by progressive, lethal muscle degeneration and chronic inflammation. In this study, we explored the expression and signaling pathway of a master player of the anti-oxidant and anti-inflammatory response, namely NRF2, in muscle biopsies of DMD patients. We classified DMD patients in two age groups (Class I, 0-2 years and Class II, 2-9 years), in order to evaluate the antioxidant pathway expression during the disease progression. We observed that altered enzymatic antioxidant responses, increased levels of oxidized glutathione and oxidative damage are differently modulated in the two age classes of patients and well correlate with the severity of pathology. Interestingly, we also observed a modulation of relevant markers of the inflammatory response, such as heme oxygenase 1 and IL-6, suggesting a link between oxidative stress and chronic inflammatory response. Of note, using a transgenic mouse model, we demonstrated that IL-6 overexpression parallels the antioxidant expression profile and the severity of dystrophic muscle observed in DMD patients. This study advances our understanding of the pathogenic mechanisms underlying DMD and defines the critical role of oxidative stress on muscle wasting with clear implications for disease pathogenesis and therapy in human

Aortic Valve Neocuspidalization May Be a Viable Alternative to Ross Operation in Pediatric Patients

The aim of the study was to evaluate the medium-term results of aortic valve neocuspidalization according to Ozaki compared to Ross procedure for treatment of isolated aortic valve disease in pediatric age. Thirty-eight consecutive patients with congenital or acquired aortic valve disease underwent either Ozaki (n = 22) or Ross (n = 16) operation between 01/2015 and 05/2020. The primary outcome was progression of aortic valve disease and aortic ring and root dimension, whereas secondary outcome was freedom from reintervention or death by type of operation. Median age was 12.4 (8.8-15.8) years and the prevailing lesion was stenosis in 20 cases (52%) and incompetence in 18 (48%). One death occurred in the Ross group in the early postoperative period, while there were no deaths in the Ozaki group. Effective treatment of aortic valve stenosis or regurgitation occurred in both groups and remained stable over a median follow-up of 18.2 (5-32) months. In Ozaki group, 3 patients required aortic valve replacement at 4.9, 3.5, and 33 months, respectively. In Ross group, 1 patient required Melody pulmonary valve replacement, whereas none required aortic valve surgery. Finally, significantly higher aortic transvalvular gradient at follow-up was recorded in Ozaki group compared to Ross group. Overall, there was no significant difference in freedom from reoperation or death between the two groups. The medium-term outcome of Ozaki and Ross in pediatric patients is similar, despite an increased tendency of the former to develop aortic transvalvular gradient in the follow-up. Future larger multicenter studies with longer follow-up are warranted to confirm these results

Human Herpesvirus 6 Infection Following Haploidentical Transplantation: Immune Recovery and Outcome

Abstract Human herpesvirus 6 (HHV-6) is increasingly recognized as a potentially life-threatening pathogen in allogeneic hematopoietic stem cell transplantation (alloSCT). We retrospectively evaluated 54 adult patients who developed positivity to HHV-6 after alloSCT. The median time from alloSCT to HHV-6 reactivation was 34 days. HHV-6 was present in plasma samples from 31 patients, in bone marrow (BM) of 9 patients, in bronchoalveolar lavage fluid and liver or gut biopsy specimens from 33 patients, and in cerebrospinal fluid of 7 patients. Twenty-nine patients developed acute graft-versus-host disease (GVHD), mainly grade III-IV, and 15 had concomitant cytomegalovirus reactivation. The median absolute CD3 +  lymphocyte count was 207 cells/µL. We reported the following clinical manifestations: fever in 43 patients, skin rash in 22, hepatitis in 19, diarrhea in 24, encephalitis in 10, BM suppression in 18, and delayed engraftment in 11. Antiviral pharmacologic treatment was administered to 37 patients; nonetheless, the mortality rate was relatively high in this population (overall survival [OS] at 1 year, 38% ± 7%). A better OS was significantly associated with a CD3 +  cell count ≥200/µL at the time of HHV-6 reactivation ( P  = .0002). OS was also positively affected by the absence of acute GVHD grade III-IV ( P  = .03) and by complete disease remission ( P  = .03), but was not significantly influenced by steroid administration, time after alloSCT, type of antiviral prophylaxis, plasma viral load, or organ involvement. Although HHV-6 detection typically occurred early after alloSCT, better T cell immune reconstitution seems to have the potential to improve clinical outcomes. Our findings provide new insight into the interplay between HHV-6 and the transplanted immune system

Oral and Swallowing Abilities Tool (OrSAT) in nusinersen treated patients

Introduction The aim of the study was to longitudinally assess swallowing abilities in nusinersen-treated patients with type 1 spinal muscular atrophy. Methods Twenty infants with type 1 SMA (11 female and 9 male) treated with nusinersen between 3 weeks and 15 months of age, were assessed using the Oral and Swallowing Abilities Tool (OrSAT). The duration of the follow-up after treatment ranged between 12 months and 62 months. Results Twelve of the 20 infants had normal swallowing and there was no need for tube feeding at the time treatment started. Ten of the 12 had consistently normal swallowing with no need for tube feeding on follow-up. The other two required tube feeding but they regained the ability to eat some food by mouth. The remaining 8 infants already had tube feeding inserted at the time treatment started: 4 of them also had tracheostomy and they showed no changes on the OrSAT Scale. The other 4 who had tube feeding but no tracheostomy had partial functional improvement. Conclusion Our results suggest that the degree of functional impairment at the time treatment is started can help to predict the progression of swallowing abilities. The use of a structured assessment also helped to detect partial improvements.New interventions have radically altered the natural history of Spinal Muscular Atrophy. In this report, oral and swallowing outcomes are report following interventions, widening our understanding of the potential benefits of early treatment

Individual details of imaging and PUL findings at shoulder, arm and forearm level.

<p>The shading reflects the severity of involvement with the score of 0 shown as a white cell, score of 1 as pale green, score of 2 as yellow, score of 3 as orange and score of 4 as red. The grade 2.5 was used to identify patients with 2b involvement. Del = deltoid; suprasp = supraspinatus; infrasp = infraspinatus; subscap = subscapularis; pec = pectoralis; corac = coraco-brachialis; serr = serratus anterior; lat = latissimus dorsi; bic = biceps brachii; brac = brachialis;tri = triceps brachii; sup = supinator;pron = pronator teres;F cp = flexor carpi radialis; palm = palmar; F ds = flexor digitorum superficialis; F cu = flexor carpi ulnaris; Fdp = flexor digitorum profundus; Anc = anconeus; E cu = extensor carpi ulnaris; Edm = extensor digiti minimi; E d = extensor digitorum; E cr = extensor carpi radialis; Br R = brachioradialis; F pl = flexor pollicis longus; E pl = extensor pollicis longus. Ambulant (E) = ambulant early; Ambulant (L): ambulant late; Non ambulant (E) = non ambulant early; Non ambulant (L): non ambulant late.</p

T1-weighted axial MRI of the forearm.

<p>T1-weighted axial MRI of the forearm at the level of the radial tuberosity showing increased signal suggestive of fatty replacement in the forearm muscles, especially in the supinator (arrow) and pronator teres (arrowhead). The involvement is milder in the youngest ambulant patients aged 8 and 14 (a and b respectively) and more marked in the older non-ambulant ones, both aged 17 (c and d), with severe involvement shown in image d. R (radius); U (ulna).</p