Pharmacological Inhibition of PKCθ Counteracts Muscle Disease in a Mouse Model of Duchenne Muscular Dystrophy.

Inflammation plays a considerable role in the progression of Duchenne Muscular Dystrophy (DMD), a severe muscle disease caused by a mutation in the dystrophin gene. We previously showed that genetic ablation of Protein Kinase C θ (PKCθ) in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease. RESEARCH IN CONTEXT: Duchenne muscular dystrophy (DMD) is a severe muscle disease affecting 1:3500 male births. DMD is caused by a mutation in dystrophin gene, coding for a protein required for skeletal and cardiac muscle integrity. Lack of a functional dystrophin is primarily responsible for the muscle eccentric contraction-induced muscle damage, observed in dystrophic muscle. However, inflammation plays a considerable role in the progression of DMD. Glucocorticoids, which have anti-inflammatory properties, are being used to treat DMD with some success; however, long term treatment with these drugs induces muscle atrophy and wasting, outweighing their benefit. The identification of specific targets for anti-inflammatory therapies is one of the ongoing therapeutic options. Although blunting inflammation would not be a "cure" for the disease, the emerging clue is that multiple strategies, addressing different aspects of the pathology, which may eventually converge, may be successful. In this context, we previously showed that genetic ablation of Protein Kinase C θ (PKCθ), an enzyme known to be involved in immune response, in mdx, the mouse model of DMD, improves muscle healing and regeneration, preventing massive inflammation. To establish whether pharmacological targeting of PKCθ in DMD can be proposed as a therapeutic option, in this study we treated young mdx mice with the PKCθ inhibitor Compound 20 (C20). We show that C20 treatment led to a significant reduction in muscle damage associated with reduced immune cells infiltration, reduced inflammatory pathways activation, and maintained muscle regeneration. Importantly, C20 treatment is efficient in recovering muscle performance in mdx mice, by preserving muscle integrity. Together, these results provide proof of principle that pharmacological inhibition of PKCθ in DMD can be considered an attractive strategy to modulate immune response and prevent the progression of the disease.

Isolated jejunal perforation after blunt trauma. Report of three cases.

Small bowel perforation occurs in 3% to 5% of cases of blunt abdominal trauma. The initial clinical exam can be unremarkable because signs of hollow viscus injury (HVI) may take time to develop. Conventional radiograms are often unable to diagnosis of this subset of trauma. Three cases of jejunal perforation after a blunt abdominal trauma are described. One of these showed at laparotomy small sero muscular diastasis of the jejunum and multiple ecchymosis of the small bowel without peritonitis. The detection of this subset of trauma patients has improved markedly with CT, which has led to a decrease in the number of negative laparotomies performed. In our report CT imaging showed a increased thickness of bowel loop wall in left ipocondrium in the first and second case. In our small experience this sign suggest us a jejunal contusion in which an isolated perforating is always possible.

[Duplex US evaluation of mesenteric vessels in acute abdomen. Prospective study on 325 patients]. / La valutazione ecocolor-Doppler degli assi vascolari mesenterici nell'addome acuto. Studio prospettico su 325 pazienti.

BACKGROUND: Acute Mesenteric Insufficiency (AMI) is a surgical emergency with a difficult methodological approach. Its high mortality is mainly due to delay in the correct diagnosis. In turn this is due to the lack of specificity of the clinical presentation and of the laboratory data and abdominal radiographic findings, especially in the early-middle phase. PURPOSE: To evaluate the positive predictive value (PPV) and negative predictive value (NPV) of Duplex Ultrasound (DU) of mesenteric vessels in the diagnosis of acute mesenteric ischaemia. PATIENTS AND METHODS: 325 patients were prospective analyzed with Duplex US (Aloka ssd 1700); 120 with acute abdomen (group A); 120 healthy subjects without abdomen preparation (group B); 85 healthy subjects with abdomen preparation (group C). We considered the B mode visualization, the vessel extension and diameter, the colour signal capture (enhancement), the velocitograms with systolic peak velocity and medium diastolic velocity. RESULTS: In 32 patients with high suspect of AMI we founded 21 really negative results, 3 wrong positive results, 5 really positive results, 3 false negative results. The PPV and NPV were respectively 0.62 and 0.87. CONCLUSIONS: The Duplex Us is more useful rather exclude than confirm AMI.

Decision-making in adult thalassemia patients undergoing unrelated bone marrow transplantation: quality of life, communication and ethical issues.

Bone marrow transplantation (BMT) represents a potentially curative treatment of thalassemia. For patients without an HLA-identical sibling donor, recourse to an unrelated donor is a practicable option but the candidates and their families are faced with a difficult decision. They can either choose to continue the supportive therapy, with no chance of definitive cure, or they accept the mortality risk of BMT in the hope of obtaining a definitive resolution of the disease. We investigated the communication strategies and the post transplantation quality of life (QoL) in 19 adult thalassemia patients surviving after an unrelated donor BMT. The patients were given two questionnaires: a questionnaire to evaluate pre-transplantation communication factors and the EORTC QLQ-C30 questionnaire to assess global QoL. All patients were satisfied with the communication modalities employed by the physicians. The global post transplantation QoL in our patient cohort was found to be good. The approach used in this study may offer a contribution to understanding the decision-making process leading to the choice of a treatment with a high mortality risk for a chronic, non-malignant disease. Finally, some ethical issues of this therapeutic approach are briefly addressed.