Next-Generation SINE Compound KPT-8602 Ameliorates Dystrophic Pathology in Zebrafish and Mouse Models of DMD.

Duchenne muscular dystrophy (DMD) is a progressive, X-linked childhood neuromuscular disorder that results from loss-of-function mutations in the DYSTROPHIN gene. DMD patients exhibit muscle necrosis, cardiomyopathy, respiratory failure, and loss of ambulation. One of the major driving forces of DMD disease pathology is chronic inflammation. The current DMD standard of care is corticosteroids; however, there are serious side effects with long-term use, thus identifying novel anti-inflammatory and anti-fibrotic treatments for DMD is of high priority. We investigated the next-generation SINE compound, KPT-8602 (eltanexor) as an oral therapeutic to alleviate dystrophic symptoms. We performed pre-clinical evaluation of the effects of KPT-8602 in DMD zebrafish (sapje) and mouse (D2-mdx) models. KPT-8602 improved dystrophic skeletal muscle pathologies, muscle architecture and integrity, and overall outcomes in both animal models. KPT-8602 treatment ameliorated DMD pathology in D2-mdx mice, with increased locomotor behavior and improved muscle histology. KPT-8602 altered the immunological profile of the dystrophic mice, and reduced circulating osteopontin serum levels. These findings demonstrate KPT-8602 as an effective therapeutic in DMD through by promotion of an anti-inflammatory environment and overall improvement of DMD pathological outcomes.

The physical and chemical nature of technegas.

UNLABELLED: Technegas, the discrete radio-aerosol particle, containing 99mTc has been investigated, and the chemical evolution and physical properties of the particle demonstrated. METHODS: A commercial technegas generator was used to produce aerosols according to standard clinical procedures. The aerosols were collected by electrostatic precipitation and examined with transition electron microscopy (TEM), scanning electron microscopy (SEM) and force microscopy. The chemical evolution was examined by x-ray techniques and thermogravimetric analysis. RESULTS: The active particle was identified as hexagonal platelets of metallic technetium contained within a thin layer of graphitic carbon. This composite structure is discussed in light of the metal particle behaving as a template for the carbon capsule. The average size of the observed hexagonal platelets, 30-60 nm, was only weakly dependent on the concentration of technetium in the crucible. CONCLUSION: The mechanism for the formation of the technegas pancreas has been developed and the particles involved characterized. It appears that the use of other metals also leads to the formation of similar materials.

Penetrating torso trauma: triple-contrast helical CT in peritoneal violation and organ injury--a prospective study in 200 patients.

PURPOSE: To assess the accuracy of computed tomography (CT) in demonstrating the presence or absence of peritoneal violation and type of intraperitoneal organ injury, if any, in hemodynamically stable patients with penetrating torso trauma but without definite peritoneal signs or radiographic evidence of free intraperitoneal air. MATERIALS AND METHODS: During a 29-month period, helical CT with oral, rectal, and intravenous contrast material (triple-contrast) was performed in 200 hemodynamically stable patients, including 169 men (age range, 15-85 years; mean age, 31 years) and 31 women (age range, 17-45 years; mean age, 28 years) with penetrating torso trauma. The study group included 86 patients with gunshot wounds, 111 with stab wounds, and three impaled by sharp objects. CT scans were evaluated prospectively by three trauma radiologists for evidence of peritoneal violation to determine injury to intra- or retroperitoneal solid organs, bowel, mesentery, vascular structures, diaphragm, and urinary tract. Sensitivity, specificity, and accuracy of CT in the diagnosis of peritoneal violation were determined. RESULTS: CT findings aided diagnosis of peritoneal violation in 34% of patients (68 of 200) and were negative for peritoneal violation in 66% of patients (132 of 200). Two patients with negative CT findings failed to improve with observation and underwent therapeutic laparotomy. CT had 97% sensitivity (66 of 68 findings), 98% specificity (130 of 132 findings), and 98% accuracy (196 of 200 findings) for peritoneal violation. CT aided diagnosis of 28 hepatic, 34 bowel or mesenteric, seven splenic, and six renal injuries. Laparotomy based on CT findings in 38 patients was considered therapeutic in 87% (33 of 38) and nontherapeutic in 8% (three of 38) and had negative results in 5% (two of 38). CONCLUSION: Triple-contrast helical CT accurately demonstrates peritoneal violation and visceral injury in patients with penetrating torso wounds.