Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune disease driven by lymphocyte activation against myelin autoantigens in the central nervous system leading to demyelination and neurodegeneration. The deoxyribonucleoside salvage pathway with the rate-limiting enzyme deoxycytidine kinase (dCK) captures extracellular deoxyribonucleosides for use in intracellular deoxyribonucleotide metabolism. Previous studies have shown that deoxyribonucleoside salvage activity is enriched in lymphocytes and required for early lymphocyte development. However, specific roles for the deoxyribonucleoside salvage pathway and dCK in autoimmune diseases such as MS are unknown. Here we demonstrate that dCK activity is necessary for the development of clinical symptoms in the MOG35-55 and MOG1-125 experimental autoimmune encephalomyelitis (EAE) mouse models of MS. During EAE disease, deoxyribonucleoside salvage activity is elevated in the spleen and lymph nodes. Targeting dCK with the small molecule dCK inhibitor TRE-515 limits disease severity when treatments are started at disease induction or when symptoms first appear. EAE mice treated with TRE-515 have significantly fewer infiltrating leukocytes in the spinal cord, and TRE-515 blocks activation-induced B and T cell proliferation and MOG35-55 -specific T cell expansion without affecting innate immune cells or naïve T and B cell populations. Our results demonstrate that targeting dCK limits symptoms in EAE mice and suggest that dCK activity is required for MOG35-55 -specific lymphocyte activation-induced proliferation.

Endoscopic transaxillary first rib resection for thoracic outlet syndrome: a safe surgical option.

BACKGROUND: Endoscopic-assisted transaxillary first rib resection is a novel approach in the management of thoracic outlet syndrome (TOS) and allows us to safely identify the neurovascular package and different structures. Our main objective is to assess the results of morbidity and mortality of the surgical treatment in TOS with this technique. METHODS: We carried out a prospective, longitudinal study with 22 surgical interventions of transaxillary first rib resection with endoscopic support in patients with TOS from January 2000 to January 2009 in a private hospital located in Puebla, Mexico. There were 16 females and six males with a mean age of 35 years. We found 16/22 (72.7%) patients with neurological symptoms and 6/22 (27.3%) with venous symptoms; 2/22 (9.09%) patients had effort thrombosis of the axillary-subclavian vein. RESULTS: Of the 22 interventions, we found fibrous bands in 8/22 patients (36.3%); 1/22 (4.5%) with type 1 cervical band and cervical rib grade II, 1/22 (4.5%) with type 2 cervical band and cervical rib grade I, 2/22 (9.09%) with band type 3, 1/22 (4.5%) with band type IV, 1/22 (4.5%) with band type V and 2/22 (9.09%) with band type VII and axillary-subclavian thrombosis. After the procedure, 20/22 (90.9%) patients showed total symptom improvement and 2/22 (9.1%) patients had mild paresthesias. There were no complications from nerve, vascular or pleural damage. CONCLUSIONS: This technique provides an ample margin of safety and improves visibility, reducing surgical complications.

Resección transaxilar de la primera costilla con apoyo endoscópico en el síndrome de salida de tórax: una opción quirúrgica segura / Endoscopic transaxillary first rib resection for thoracic outlet syndrome: a safe surgical option

Introducción: La resección transaxilar con apoyo endoscópico es una técnica quirúrgica novedosa en el manejo del síndrome de salida de tórax que permite identificar con seguridad el paquete vasculonervioso y las diferentes estructuras. Nuestro objetivo fue valorar los resultados de morbilidad y mortalidad del tratamiento quirúrgico en el síndrome de salida de tórax con esta técnica. Material y métodos: Estudio longitudinal prospectivo de 22 intervenciones quirúrgicas de resección transaxilar de la primera costilla, con apoyo endoscópico a pacientes con síndrome de salida de tórax, entre enero de 2000 y enero de 2009, en un hospital privado de la cuidad de Puebla, México. De ellos, 16 mujeres y seis hombres, con edad promedio de 35 años. Encontramos 16/22 (72.7 %) pacientes con síntomas neurológicos y 6/22 (27.3 %) con síntomas venosos; entre ellos, 2/22 (9.09 %) presentaban trombosis venosa de esfuerzo axilosubclavia. Resultados: Entre las 22 intervenciones encontramos bandas fibrosas en 8/22 pacientes (36.3 %): 1/22 (4.5 %) con una banda cervical tipo 1 y costilla cervical grado II, 1/22 (4.5 %) con banda cervical tipo 2 y costilla cervical grado I, 2/22 (9.09 %) con banda tipo 3, 1/22 (4.5 %) con banda tipo IV, 1/22 (4.5 %) con banda tipo V y 2/22 (9.09 %) con banda tipo VII y trombosis axilosubclavia. Después del procedimiento, 20/22 (90.9 %) pacientes manifestaron mejoría total y 2/22 (9.1 %), parestesias leves. No hubo complicaciones por lesiones nerviosas, vasculares o pleurales. Conclusiones: La técnica escrita provee un margen de seguridad amplio y mejora la visibilidad, disminuyendo las complicaciones quirúrgicas.

BACKGROUND: Endoscopic-assisted transaxillary first rib resection is a novel approach in the management of thoracic outlet syndrome (TOS) and allows us to safely identify the neurovascular package and different structures. Our main objective is to assess the results of morbidity and mortality of the surgical treatment in TOS with this technique. METHODS: We carried out a prospective, longitudinal study with 22 surgical interventions of transaxillary first rib resection with endoscopic support in patients with TOS from January 2000 to January 2009 in a private hospital located in Puebla, Mexico. There were 16 females and six males with a mean age of 35 years. We found 16/22 (72.7%) patients with neurological symptoms and 6/22 (27.3%) with venous symptoms; 2/22 (9.09%) patients had effort thrombosis of the axillary-subclavian vein. RESULTS: Of the 22 interventions, we found fibrous bands in 8/22 patients (36.3%); 1/22 (4.5%) with type 1 cervical band and cervical rib grade II, 1/22 (4.5%) with type 2 cervical band and cervical rib grade I, 2/22 (9.09%) with band type 3, 1/22 (4.5%) with band type IV, 1/22 (4.5%) with band type V and 2/22 (9.09%) with band type VII and axillary-subclavian thrombosis. After the procedure, 20/22 (90.9%) patients showed total symptom improvement and 2/22 (9.1%) patients had mild paresthesias. There were no complications from nerve, vascular or pleural damage. CONCLUSIONS: This technique provides an ample margin of safety and improves visibility, reducing surgical complications.