Idiopathic retroperitoneal fibrosis associated with Hashimoto's thyroiditis in a patient with a single functioning kidney

AbstractRetroperitoneal fibrosis (RPF) is a rare disease characterized by the presence of fibroinflammatory tissue around the abdominal aorta and ureteral entrapment in most cases. Idiopathic RPF is frequently reported in association with autoimmune diseases; however, there have been few reports of idiopathic RPF associated with Hashimoto's thyroiditis. Here, we report a case of idiopathic RPF with Hashimoto's thyroiditis in a patient with a single functioning kidney, which was successfully treated by corticosteroid therapy and transient intraureteral stent insertion with a double-J catheter

Beclin 1 functions as a negative modulator of MLKL oligomerisation by integrating into the necrosome complex

Necroptosis is a form of regulated cell death caused by formation of the necrosome complex. However, the factors modulating this process and the systemic pathophysiological effects of necroptosis are yet to be understood. Here, we identified that Beclin 1 functions as an anti-necroptosis factor by being recruited into the necrosome complex upon treatment with TNF alpha, Smac mimetic, and pan-caspase inhibitor and by repressing MLKL oligomerisation, thus preventing the disruption of the plasma membrane. Cells ablated or knocked-out for Beclin 1 become sensitised to necroptosis in an autophagy-independent manner without affecting the necrosome formation itself. Interestingly, the recruitment of Beclin 1 into the necrosome complex is dependent on the activation and phosphorylation of MLKL. Biochemically, the coiled-coil domain (CCD) of Beclin 1 binds to the CCD of MLKL, which restrains the oligomerisation of phosphorylated MLKL. Finally, Beclin 1 depletion was found to promote necroptosis in leukaemia cells and enhance regression of xenografted-tumour upon treatment with Smac mimetics and caspase inhibitors. These results suggest that Beclin 1 functions as a negative regulator in the execution of necroptosis by suppressing MLKL oligomerisation

Clinical significance of fragmented QRS complexes or J waves in patients with idiopathic ventricular arrhythmias

<div><p>Background</p><p>Idiopathic ventricular fibrillation (IVF) can cause sudden cardiac death. Previous studies have reported that J waves and fragmented QRS complexes (f-QRS) are arrhythmogenic markers and predictors of cardiac events. We evaluated the prevalence and clinical significance of J waves and f-QRS in patients with IVF.</p><p>Methods</p><p>We studied 81 patients who received an implantable cardioverter defibrillator (ICD) due to IVF between October 1999 and June 2015. We assessed the prevalence of J waves and f-QRS using electrocardiograms (ECGs). Patients were classified into three groups: J wave group (n = 35), f-QRS group (n = 20), or normal ECG group (n = 26). The control group included 81 subjects without heart disease who were matched for age, sex, and race. We compared syncope, sudden cardiac arrest, and appropriate ICD shock between the three groups.</p><p>Results</p><p>The follow-up duration was 4.1 years. J waves and f-QRS were more frequent in patients with IVF than in control subjects (43.2%, 21% vs. 24.7%, 19.7%, <i>P</i> < 0.001). Out of the three groups, clinical cardiac events were most frequent in the f-QRS group (50% vs. 45.7% vs. 11.5%, <i>P</i> = 0.028). A comparison of the combined group of J wave and f-QRS versus the normal ECG group revealed that the combined group had a higher frequency of clinical cardiac events than the normal ECG group (47.3% vs. 11.5%, respectively, <i>P</i> = 0.009).</p><p>Conclusions</p><p>Patients with IVF had higher prevalence of f-QRS or J waves. And patients with f-QRS or J waves were at higher risk of recurrent ventricular fibrillation.</p></div

Incidences of f-QRS and J waves in patients with IVF and matched -control subjects.

<p>Incidences of f-QRS and J waves in patients with IVF and matched -control subjects.</p

Patient baseline characteristics and clinical cardiac events.

<p>Patient baseline characteristics and clinical cardiac events.</p

ECG of patient with both f-QRS (III, aVF leads) and J wave (I, aVL leads).

<p>ECG of patient with both f-QRS (III, aVF leads) and J wave (I, aVL leads).</p

Clinical significance of fragmented QRS complexes or J waves in patients with idiopathic ventricular arrhythmias - Fig 3

<p>(A) Kaplan-Meier curves of clinical cardiac events in the three groups. (B) Kaplan-Meier curves of clinical cardiac events in the J wave group combined with f-QRS group versus the normal ECG group.</p

Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation

AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger protein 1 (MKRN1). MKRN1 depletion promotes glucose consumption and suppresses lipid accumulation due to AMPK stabilisation and activation. Accordingly, MKRN1-null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. We demonstrate also its therapeutic effect by administering shRNA targeting MKRN1 into obese mice that reverses non-alcoholic fatty liver disease. We suggest that ubiquitin-dependent AMPK degradation represents a target therapeutic strategy for metabolic disorders.© The Author(s) 201