Keap1 degradation by autophagy for the maintenance of redox homeostasis

The Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) system is essential for cytoprotection against oxidative and electrophilic insults. Under unstressed conditions, Keap1 serves as an adaptor for ubiquitin E3 ligase and promotes proteasomal degradation of Nrf2, but Nrf2 is stabilized when Keap1 is inactivated under oxidative/electrophilic stress conditions. Autophagy-deficient mice show aberrant accumulation of p62, a multifunctional scaffold protein, and develop severe liver damage. The p62 accumulation disrupts the Keap1-Nrf2 association and provokes Nrf2 stabilization and accumulation. However, individual contributions of p62 and Nrf2 to the autophagy-deficiency-driven liver pathogenesis have not been clarified. To examine whether Nrf2 caused the liver injury independent of p62, we crossed liver-specific Atg7::Keap1-Alb double-mutant mice into p62- and Nrf2-null backgrounds. Although Atg7::Keap1-Alb::p62(-/-) triple-mutant mice displayed defective autophagy accompanied by the robust accumulation of Nrf2 and severe liver injury, Atg7::Keap1-Alb::Nrf2(-/-) triple-mutant mice did not show any signs of such hepatocellular damage. Importantly, in this study we noticed that Keap1 accumulated in the Atg7- or p62-deficient mouse livers and the Keap1 level did not change by a proteasome inhibitor, indicating that the Keap1 protein is constitutively degraded through the autophagy pathway. This finding is in clear contrast to the Nrf2 degradation through the proteasome pathway. We also found that treatment of cells with tert-butylhydroquinone accelerated the Keap1 degradation. These results thus indicate that Nrf2 accumulation is the dominant cause to provoke the liver damage in the autophagy-deficient mice. The autophagy pathway maintains the integrity of the Keap1-Nrf2 system for the normal liver function by governing the Keap1 turnover.     

Analyses of Muscular Activity,Energy Metabolism,and Muscle Fiber Type Composition in a Patient with Bilateral Masseteric Hypertrophy

Hyperwork of the masseter muscles due to habitual parafunction is thought to induce masseteric hypertrophy (so called work hypertrophy). However, the causes underlying this disease are not yet fully understood. Recently, we had a patient with bilateral masseteric hypertrophy, and we performed a partial excision of the masseter muscles. In this patient's case, we examined muscular activity, energy metabolism, and fiber type composition of the masseter muscles using electromyograms (EMG), ³¹P-magnetic resonance spectroscopy (MRS), and enzyme-histochemistry. The EMG showed no hyperactivity, and the ³¹P-MRS showed normal energy spectral patterns and PCr contents of the masseter muscles. The fiber type composition, however, in the muscles in this case was very different from that in muscles with “work hypertrophy” and also that in normal masseter muscles: 1. Loss of type MB fibers; 2. Increases in type IIA and in type IM & IIC fibers; and 3. Decrease in type I fibers. The findings suggest that this is not a case of work hypertrophy but a case of compensatory hypertrophy possibly due to a lack of high-tetanus-tension type IIB fibers.     

Transbrachial coil embolization of a giant coronary artery fistula

Coronary artery fistulae can present late in adult life. We describe the case of a 71-year-old woman who developed a right coronary fistula, which was managed by percutaneous transbrachial coil embolization. Complete closure of the fistula was confirmed by follow-up angiography at 10 months.     

Laparoscopic Hartmann’s procedure for fecal peritonitis resulting from perforation of the left-sided colon in elderly and severely ill patients

Background

Traditional treatment for fecal peritonitis resulting from perforation of the left-sided colon has been performed using Hartmann??s procedure to reduce the high mortality caused by anastomotic leakage. However, the morbidity rates associated with abdominal incision (due in great part to wound infection, and dehiscence of abdominal fascia) are high. Therefore, we propose using laparoscopic Hartmann??s procedure with abdominal incisions only for the port site to reduce the high morbidity associated with the laparoscopic procedure as compared to open surgery.

Methods

Between April 2008 and July 2011, we treated 16 consecutive patients (median age, 83?years) with fecal peritonitis resulting from perforations in the left-sided colon due to various causes. The American Society of Anesthesiologists score of each patient was either IV or V. Patients underwent a four-port laparoscopic Hartmann??s procedure. Specimens were extracted through the stoma site. Irrigation of the abdominal cavity with more than 10?L of saline was performed in every case, as was insertion of three 10-mm silicon drains via the port site into the left- and right subphrenic spaces or the pouch of Douglas.

Results

The median total surgical time was 166?min (range, 123?C250?min). There were no intraoperative complications, and there was no need to convert to open surgery. Fourteen patients survived. There was no wound infection or dehiscence of abdominal fascia. Successful laparoscopic reversals of the laparoscopic Hartmann??s procedure were performed in all 14 survivors.

Conclusions

This laparoscopic Hartmann??s procedure is a promising surgical strategy for treating fecal peritonitis arising from perforation of the left-sided colon.     

Current Hot Potatoes in Atrial Fibrillation Ablation

Atrial fibrillation (AF) ablation has evolved to the treatment of choice for patients with drug-resistant and symptomatic AF. Pulmonary vein isolation at the ostial or antral level usually is sufficient for treatment of true paroxysmal AF. For persistent AF ablation, drivers and perpetuators outside of the pulmonary veins are responsible for AF maintenance and have to be targeted to achieve satisfying arrhythmia-free success rate. Both complex fractionated atrial electrogram (CFAE) ablation and linear ablation are added to pulmonary vein isolation for persistent AF ablation. Nevertheless, ablation failure and necessity of repeat ablations are still frequent, especially after persistent AF ablation. Pulmonary vein reconduction is the main reason for arrhythmia recurrence after paroxysmal and to a lesser extent after persistent AF ablation. Failure of persistent AF ablation mostly is a consequence of inadequate trigger ablation, substrate modification or incompletely ablated or reconducting linear lesions. In this review we will discuss these points responsible for AF recurrence after ablation and review current possibilities on how to overcome these limitations.