Liver mitochondrial DNA damage and genetic variability of Cytochrome b - a key component of the respirasome - drive the severity of fatty liver disease.

BACKGROUND AND AIMS: The progression of nonalcoholic fatty liver disease (NAFLD) into severe histological forms (steatohepatitis - NASH) is paralleled by the occurrence of complex molecular processes. Mitochondrial dysfunction is a hallmark feature of advanced disease. Mitochondrially encoded cytochrome B (cytochrome b, MT-CYB), a member of the oxidative phosphorylation system, is a key component of the respirasome supercomplex. Here, we hypothesized that NAFLD severity is associated with liver tissue cytochrome b mutations and damaged mitochondrial DNA (mtDNA). METHODS: We included 252 liver specimens of NAFLD patients - in whom histological disease ranged from mild to severe - which were linked to clinical and biochemical information. Tissue molecular explorations included MT-CYB sequencing and analysis of differential mtDNA damage. Profiling of circulating Krebs cycle metabolites and global liver transcriptome was performed in a subsample of patients. Tissue levels of 4-hydroxynonenal - a product of lipid peroxidation and 8-hydroxy-2'-deoxyguanosine, a marker of oxidative damage - were measured. RESULTS: Compared to simple steatosis, NASH is associated with a higher level of MT-CYB variance, 12.1 vs. 15.6 substitutions per 103  bp (P = 5.5e-10). The burden of variants was associated with increased levels of 2-hydroxyglutarate, branched-chain amino acids, and glutamate, and changes in the global liver transcriptome. Liver mtDNA damage was associated with advanced disease and inflammation. NAFLD severity was associated with increased tissue levels of DNA oxidative adducts and lipid peroxyl radicals. CONCLUSION: NASH is associated with genetic alterations of the liver cellular respirasome, including high cytochrome b variation and mtDNA damage, which may result in broad cellular effects.

Nefrectomía laparascopica retroperitoneal / Retroperitoneal laparoscopic nephrectomy

Dede julio de 1997 hasta la fecha se efctuaron distintos tipos de cirugías laparoscópicas urológicas en el Hospital "Evita Pueblo" de Berazategui provincia de Buenos Aires. Entre ellas se realizaron dos nefrectomías laparoscópicas retroperitoneales. Se detallan indicaciones y técnica utilizada en 2 pacientes con riñones hipotróficas derechos, sin complicaciones. En la primera cirigía las piezas quirúrgicas fueron extraídas por una minilumbotomía, y en la segunda en bolsa de nylosn, fragmentada con pinza de restos. Dado que las indicaciones para nefrectpmías laparoscópicas retroperitoneales son escasas, en riñones pequeños, se abre un campo importante que posibilitaría ampliar dicha norma(AU)

Nefrectomía laparascopica retroperitoneal / Retroperitoneal laparoscopic nephrectomy

Dede julio de 1997 hasta la fecha se efctuaron distintos tipos de cirugías laparoscópicas urológicas en el Hospital "Evita Pueblo" de Berazategui provincia de Buenos Aires. Entre ellas se realizaron dos nefrectomías laparoscópicas retroperitoneales. Se detallan indicaciones y técnica utilizada en 2 pacientes con riñones hipotróficas derechos, sin complicaciones. En la primera cirigía las piezas quirúrgicas fueron extraídas por una minilumbotomía, y en la segunda en bolsa de nylosn, fragmentada con pinza de restos. Dado que las indicaciones para nefrectpmías laparoscópicas retroperitoneales son escasas, en riñones pequeños, se abre un campo importante que posibilitaría ampliar dicha norma

Pancreatic duct occlusion in the management of acute necrotizing pancreatitis in a canine model.

Based on results reported by others in using prolamine (Ethibloc; Ethicon Gmb H) to treat patients with chronic pancreatitis, without any observed pancreatic complications, we decided to use pancreatic duct occlusion experimentally in dogs in which we induced acute pancreatitis by the injection of calcium chloride into the pancreatic duct. This injection proved to be 100% lethal in the 5 animals constituting the control group, none of which were treated after the injection. Acute pancreatitis was then induced in 57 animals, also by injection of calcium chloride. These dogs were then treated with one of three substances that share the same physical properties: prolamine; Tissucol (Immuno AG, Vienna), a biologic tissue adhesive; silicone (Xantopren, Bayer Dental D-5090 Leverkusen). Thirty-seven dogs were treated with prolamine, 10 dogs with Tissucol, and 10 with silicone. The mortality rate in the 57 treated animals was 12.2%, compared to the 100% rate in the untreated control group. The mechanical action achieved by blocking the pancreatic duct shows how the evolution of acute pancreatitis at different stages could be modified. This specific treatment limits the pathophysiologic process of acute pancreatitis in dogs. These findings provide us with a promising outlook for the treatment of this severe illness.

[Experimental acute necrotico-hemorrhagic pancreatitis in dogs. Treatment by intraductal block]. / Pancréatite aiguë nécrotico-hémorragique expérimentale chez le chien. Traitement par blocage intra-canalaire.

The aim of this experimental study was to demonstrate that the mortality of calcium chlorine induced acute pancreatitis in the dog was decreased by the intraductal injection of solid substances. Seventy-two dogs were used. In the control group (n = 5) the mortality was 100%. Three different drugs were used for the intraductal injection: Ethibloc (n = 37), Tissucol (n = 10) and silicones (n = 10). The mortality rate has been respectively of 13.5, 10 and 10%. In order to define at which level of the pancreatic duct the obstruction had a maximum efficiency, 10 dogs underwent a distal ligation of the pancreatic duct after induction of the pancreatitis. The mortality rate in this group was 100%. It can be therefore concluded that only the complete obstruction of the pancreatic duct decreases the mortality rate in this experimental model.

Primeras observaciones sobre la aplicacion de la prolamina en la pancreatitis aguda necrohemorragica en el hombre. / First observations about the use of prolamine in acute necrohemorrhagic pancreatitis in the man

Continuando una serie de estudios experimentales se presentan las 2 primeras observaciones en el ser humano, de pancreatitis aguda grave tratadas mediante bloqueo intraductal pancreatico con prolamina; existian lesiones hemorragicas severas. Se efectuo ademas colecistectomia, drenaje del coledoco, duodenotomia y papiloesfinterectomia. Ambas enfermas evolucionaron bien, aunque una de ellas con una fistula pancreatica y un absceso subhepatico que curaron espontaneamente. Se evalua la posibilidad de emplear esta droga indicando la intervencion precoz. Se sugiere la posibilidad de combinar el tratamiento quirurgico con el endoscopico para la aplicacion de la droga sin necesidad de hacerlo por via transduodenopapilar

Primeras observaciones sobre la aplicacion de la prolamina en la pancreatitis aguda necrohemorragica en el hombre. / First observations about the use of prolamine in acute necrohemorrhagic pancreatitis in the man

Continuando una serie de estudios experimentales se presentan las 2 primeras observaciones en el ser humano, de pancreatitis aguda grave tratadas mediante bloqueo intraductal pancreatico con prolamina; existian lesiones hemorragicas severas. Se efectuo ademas colecistectomia, drenaje del coledoco, duodenotomia y papiloesfinterectomia. Ambas enfermas evolucionaron bien, aunque una de ellas con una fistula pancreatica y un absceso subhepatico que curaron espontaneamente. Se evalua la posibilidad de emplear esta droga indicando la intervencion precoz. Se sugiere la posibilidad de combinar el tratamiento quirurgico con el endoscopico para la aplicacion de la droga sin necesidad de hacerlo por via transduodenopapilar