Nicotinamide Prevents Diabetic Brain Inflammation via NAD+-Dependent Deacetylation Mechanisms.

This study investigated the effect of nicotinamide (NAM) supplementation on the development of brain inflammation and microglial activation in a mouse model of type 1 diabetes mellitus. C57BL/6J male mice, which were made diabetic with five consecutive, low-dose (55 mg/kg i.p.) streptozotocin (STZ) injections. Diabetic mice were randomly distributed in different experimental groups and challenged to different doses of NAM (untreated, NAM low-dose, LD, 0.1%; NAM high-dose, HD, 0.25%) for 25 days. A control, non-diabetic group of mice was used as a reference. The NAD+ content was increased in the brains of NAM-treated mice compared with untreated diabetic mice (NAM LD: 3-fold; NAM HD: 3-fold, p-value < 0.05). Immunohistochemical staining revealed that markers of inflammation (TNFα: NAM LD: -35%; NAM HD: -46%; p-value < 0.05) and microglial activation (IBA-1: NAM LD: -29%; NAM HD: -50%; p-value < 0.05; BDKRB1: NAM LD: -36%; NAM HD: -37%; p-value < 0.05) in brains from NAM-treated diabetic mice were significantly decreased compared with non-treated T1D mice. This finding was accompanied by a concomitant alleviation of nuclear NFκB (p65) signaling in treated diabetic mice (NFκB (p65): NAM LD: -38%; NAM HD: -53%, p-value < 0.05). Notably, the acetylated form of the nuclear NFκB (p65) was significantly decreased in the brains of NAM-treated, diabetic mice (NAM LD: -48%; NAM HD: -63%, p-value < 0.05) and inversely correlated with NAD+ content (r = -0.50, p-value = 0.03), suggesting increased activity of NAD+-dependent deacetylases in the brains of treated mice. Thus, dietary NAM supplementation in diabetic T1D mice prevented brain inflammation via NAD+-dependent deacetylation mechanisms, suggesting an increased action of sirtuin signaling.

[Sacral neuromodulation. Long-term results]. / Neuromodulación. sacra. Resultados a largo plazo.

Sacral neuromodulation involves electrical stimulation of af­ferent nerve roots to restore the balance between inhibitory and excitatory reflexes who improve the functional activity of the pelvic floor. With benefits in patients with fecal inconti­nence, constipation and chronic anorectal pain. Objective. The aim of this study is present the results obtained with sacral neuromodulation for the treatment of patients with fecal incontinence, severe and intractable chronic constipa­tion and chronic anorectal pain. Patients and methods. 33 patients had indication for transitory electrical sacral stimu­lation, 25 patients performed transitory electrical stimula­tion for fecal incontinence, 5 with refractary constipation and 3 with chronic anorectal pain. In cases of fecal inconti­nence, the patients performed previous anorectal manometry and ultrasonography examination of anal sphincters. When the constipation is the indication, we performed stimulation in patients with severe and refractary constipation like step before total colectomy. In cases of chronic anorectal pain, the electrical transitory test was performed according to our treatment algorithm for management of functional anorectal pain. In all cases, if the patients had satisfactory results after 2 weeks period the definitive implant was placed. Results. Mean follow-up was 69 months (range 6-130). Definitve implant was placed for treatment of fecal incontinence in 23 patients with a decrease in fecal incontinence scores in 98%, with an average success rate of 66% (range: 45-92). In cases of constipation, 3 definitive implants were placed, the mean follow-up was 77 months (range: 51-96) with a success rate between 50%-80% as measured by bowel frequency. We performed definitive electrical stimulation in 3 patients wit chronic and intractable anorectal pain. Response rates as measured by visual analog scale were between 40%-70%. Conclusions. Sacral neuromodulation is an area in constant growth, with more indications. The success depends on the correct indication and the patients need to be treated with other therapeutic options before sacral neuromodulation.

Increased ER-mitochondrial coupling promotes mitochondrial respiration and bioenergetics during early phases of ER stress.

Increasing evidence indicates that endoplasmic reticulum (ER) stress activates the adaptive unfolded protein response (UPR), but that beyond a certain degree of ER damage, this response triggers apoptotic pathways. The general mechanisms of the UPR and its apoptotic pathways are well characterized. However, the metabolic events that occur during the adaptive phase of ER stress, before the cell death response, remain unknown. Here, we show that, during the onset of ER stress, the reticular and mitochondrial networks are redistributed towards the perinuclear area and their points of connection are increased in a microtubule-dependent fashion. A localized increase in mitochondrial transmembrane potential is observed only in redistributed mitochondria, whereas mitochondria that remain in other subcellular zones display no significant changes. Spatial re-organization of these organelles correlates with an increase in ATP levels, oxygen consumption, reductive power and increased mitochondrial Ca²âº uptake. Accordingly, uncoupling of the organelles or blocking Ca²âº transfer impaired the metabolic response, rendering cells more vulnerable to ER stress. Overall, these data indicate that ER stress induces an early increase in mitochondrial metabolism that depends crucially upon organelle coupling and Ca²âº transfer, which, by enhancing cellular bioenergetics, establishes the metabolic basis for the adaptation to this response.

Tapón anal bioprotésico. Eficacia en el tratamiento de las fístulas anales complejas / Bioprosthetic anal plug. Eficacy in the treatment of the complex anal fistulas

Introducción: Las fistulas anales complejas son de difícil manejo y en general afectan la calidad de vida de los pacientes que las padecen. Cuando el trayecto compromete gran cantidad del músculo esfinteriano existe el riesgo de una incontinencia postoperatoria. Para prevenir el daño, en los últimos años surgieron tratamientos alternativos, entre ellos el tapón bioprotésico anal. Objetivo: Demostrar la eficacia del tapón bioprotésico anal en el tratamiento de las fistulas anales complejas. Diseño: Estudio observacional retrospectivo. Pacientes y métodos: Se colocaron 15 tapones en 12 pacientes (6 varones) con una edad promedio de 47 años (rango, 26-71). El 62 por ciento de los pacientes presentaban antecedentes de dos o más cirugias previas por fístulas anales complejas (9 transesfinterianas altas, l extraesfinteriana, l recto-vaginal, l pouch-vaginal). Se utilizó la ecografía endoanal de 3600 como estudio complementario del diagnóstico en todos los casos. El procedimiento fue realizado bajo anestesia general, en posición de litotomía y se utilizó profilaxis antibiótica. Una vez localizado el trayecto fistuloso se irrigó con solución de iodopovidona para ubicar el orificio primario. Se colocó el tapón anal a través del trayecto fistuloso fijándolo al orifico interno y recortando el excedente al nivel del orificio externo. El tiempo de seguimiento fue de 2 a 13 meses. Resultados: El tratamiento fue exitoso en 8 pacientes con una única colocación del tapón. De los casos recidivados, se les colocó un nuevo tapón a tres pacientes; evolucionando con éxito dos de ellos. El porcentaje global de respuesta favorable fue del 82 por ciento. No se registró morbi-mortalidad referida al método. Conclusión: El tratamiento de las fistulas anales con el tapón bioprotésico es una alternativa segura y efectiva, con posibilidades de volver a realizarse sin afectar la continencia.

Introduction: The complex anal fistulas have a difficult treatment and generally affect the patients’ lifestyle. When the tracts run through the upper anal sphincters the risk of postoperative incontinence is higher. The anal bioprosthetic plug is an alternative treatment for preventing the damage. Aim: To demonstrate the efficacy of the anal plug in the treatment of the complex anal fistulas. Design: Observational retrospective study. Patients and Methods: Fifteen plugs were applied to 12 patients (6 males), mean age 47 (range, 26-71) years. The 62 per cent of patients had multiple previous surgeries for complex fistulas (9 high transsphincteric, 1 extrasphincteric, 1 recto-vaginal, 1 pouch-vaginal fistulas). The 360º anal ultrasound was applied in all cases. The surgical technique was performed under general anesthesia, in lithotomy position, with antibiotics prophylaxis. During surgery iodopovidone was used to confirm the localization of the internal opening. The plug was inserted via the fistula tract and attached to the internal opening. Any portion of the plug implanted remaining out of the tract was removed. The length of follow-up was 2 to 13 months. Results: The treatment was successful in 8 patients with one plug implantation. In 3 cases of recurrence, another plug was inserted and two fistulas healed. The overall success rate was 82 pre cent. There was no morbidity or mortality with the method. Conclusion: The anal bioprosthetic plug is a safe and effective treatment for anal fistulas, with the possibility of re-implantation without affecting anal continence.