Energy metabolism and mitochondrial defects in X-linked Charcot-Marie-Tooth (CMTX6) iPSC-derived motor neurons with the p.R158H PDK3 mutation.

Charcot-Marie-Tooth (CMT) is a group of inherited diseases clinically and genetically heterogenous, characterised by length dependent degeneration of axons of the peripheral nervous system. A missense mutation (p.R158H) in the pyruvate dehydrogenase kinase 3 gene (PDK3) has been identified as the genetic cause for an X-linked form of CMT (CMTX6) in two unrelated families. PDK3 is one of four PDK isoenzymes that regulate the activity of the pyruvate dehydrogenase complex (PDC). The balance between kinases (PDKs) and phosphatases (PDPs) determines the extend of oxidative decarboxylation of pyruvate to generate acetyl CoA, critically linking glycolysis and the energy producing Krebs cycle. We had shown the p.R158H mutation causes hyperactivity of PDK3 and CMTX6 fibroblasts show hyperphosphorylation of PDC, leading to reduced PDC activity and ATP production. In this manuscript we have generated induced pluripotent stem cells (iPSCs) by re-programming CMTX6 fibroblasts (iPSCCMTX6). We also have engineered an isogenic control (iPSCisogenic) and demonstrated that genetic correction of the p.R158H mutation reverses the CMTX6 phenotype. Patient-derived motor neurons (MNCMTX6) show increased phosphorylation of the PDC, energy metabolism defects and mitochondrial abnormalities, including reduced velocity of trafficking mitochondria in the affected axons. Treatment of the MNCMTX6 with a PDK inhibitor reverses PDC hyperphosphorylation and the associated functional deficits founds in the patient motor neurons, demonstrating that the MNCMTX6 and MNisogenic motor neurons provide an excellent neuronal system for compound screening approaches to identify drugs for the treatment of CMTX6.

[Conservative treatment of pediatric spleen trauma. Twenty years of experience]. / Trattamento conservativo dei traumi splenici in età pediatrica. Venti anni di esperienza.

OBJECTIVE: The spleen is the most frequently involved organ in abdominal blunt traumas. In the last decade the treatment has changed from an exclusive surgical approach to a conservative approach. We report our experience in the last twenty years. METHODS: Between 1983-2003, 54 patients with blunt abdominal traumas and isolated injury have been treated. The age at the time of diagnosis was 3 to 16 years (mean, 6.5). The diagnosis was made clinically and with imaging techniques (radiographic assessment, scintigraphy, US, CT). In all cases, a conservative treatment was started with continuous vital parameters monitoring, blood red cells count, hemoglobin, hematocrit; volume infusion and when necessary hemo-transfusion. Clinical follow-up and US monitoring were performed for six months after the trauma. RESULTS: In the period 1983-1993 a conservative treatment was tried in 23 patients; in 15 cases it was successfully, in 8 cases a laparotomy with splenectomy was necessary due to hemodinamic instability. In the second decade we observed 31 patients, all had been treated conservatively. The mean hospital stay was of 12 days with no deaths. CONCLUSIONS: Conservative treatment for splenic injuries in patients with hemodinamic stability is nowadays the treatment choice. Constantly monitoring of clinical, laboratory parameters and use of modern imaging techniques allows to follow the evolution of the lesion and to avoid, in most cases, a surgical treatment.

[Acute abdomen caused by Salmonella typhi acute appendicitis]. / Addome acuto da appendicite acuta secondaria a Salmonella typhi.

Salmonella infections can manifest themselves as acute abdominal problems and lead to emergency surgery. Some examples are: salmonella-related intestinal perforations, gallbladder involments, salpingitis, and peritonitis. Mesenteric lymphadenitis associated with salmonella mimics acute appendicitis and it is often difficult to establish a timely and tempestive diagnosis in children with right lower abdominal pain. Because of the difficult diagnostic process, a significant number of patients with salmonella infections present acute abdomen and undergo needless operations. Instead, in our case of salmonella-related acute abdomen, laparotomy was the right therapeutic choice. The conclusion is drawn that, even if there is not a precise diagnosis, in salmonella-related acute abdomen the surgical approach is the right choice, considering the high morbidity and mortality associated with untreated appendicitis and intestinal perforations.