Activation of apoptotic pathways in experimental acute afterload-induced right ventricular failure

Objective: The pathobiology of persistent right ventricular failure observed after an acute increase in right ventricular afterload remains incompletely understood. We hypothesized that persistent right ventricular dysfunction might be related to activation of apoptotic pathways. Design: Prospective, randomized, controlled animal study. Setting: University research laboratory. Subjects: Mongrel dogs. Interventions: Fourteen anesthetized dogs were randomized to a transient 90-min pulmonary artery constriction operation to induce persistent right ventricular failure or to a sham operation followed 30 mins later by hemodynamic measurements and sampling of cardiac tissue. Measurements and main results: We evaluated effective arterial elastance to estimate right ventricular afterload and end-systolic elastance to estimate right ventricular contractility. Transient increase in pulmonary artery pressure persistently increased effective arterial elastance from 0.75 ± 0.08 to 1.37 ± 0.18 mm Hg/mL and decreased end-systolic elastance from 1.06 ± 0.09 to 0.49 ± 0.09 mm Hg/mL, end-systolic elastance/effective arterial elastance from 1.44 ± 0.06 to 0.34 ± 0.03, and cardiac output from 3.78 ± 0.16 to 1.46 ± 0.10 L/min, indicating right ventricular failure. At the pathobiologic level, we assessed apoptosis by real-time quantitative polymerase chain reaction, Western blotting, enzyme-linked immunosorbent assay, and immunohistochemistry. As compared with the sham-operated group, and with the left ventricle in animals with persistent right ventricular failure, there were decreased right ventricular and septal expressions of Bcl-2 with no changes in expressions of Bax, resulting in an increased Bax/Bcl-2 ratio. Right ventricular and septal Bcl-XL, and right ventricular Bcl-w gene expressions were decreased as compared with the sham-operated group, whereas Bak gene expression did not change. There were activations of right ventricular caspases-8 and-9 and of right ventricular and septal caspase-3. Diffuse right ventricular and septal apoptosis was confirmed by terminal deoxynucleotidyl transferase dUTP nick-end labeling staining. There were also increased right ventricular and septal protein expressions of tumor necrosis factor-alpha. Conclusions: Acute afterload-induced persistent right ventricular failure appears to be related to an early activation of apoptotic pathways and to a local overexpression of tumor necrosis factor-alpha, a proinflammatory cytokine. Copyright © 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Hallmarks of neurodegenerative diseases

Decades of research have identified genetic factors and biochemical pathways involved in neurodegenerative diseases (NDDs). We present evidence for the following eight hallmarks of NDD: pathological protein aggregation, synaptic and neuronal network dysfunction, aberrant proteostasis, cytoskeletal abnormalities, altered energy homeostasis, DNA and RNA defects, inflammation, and neuronal cell death. We describe the hallmarks, their biomarkers, and their interactions as a framework to study NDDs using a holistic approach. The framework can serve as a basis for defining pathogenic mechanisms, categorizing different NDDs based on their primary hallmarks, stratifying patients within a specific NDD, and designing multi-targeted, personalized therapies to effectively halt NDDs

Bilateral exostoses of the internal auditory canal

A 54-year-old female patient presented to her physician with a 3-year-old history of bilateral tinnitus and hearing loss. She also complained of paresthesia in the periauricular area. There were no episodes of imbalance or vertigo

Synaptogyrin-3 mediates presynaptic dysfunction induced by Tau

Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer's disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer's disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau

A case of serious laryngeal edema unpredictably detected during laryngoscopy for orotracheal intubation following induction of anesthesia

We report a case of unpredictable and serious laryngeal edema probably caused by preoperative esophagogastroduodenoscopy (EGD). A 54-year-old man with type 2 diabetes mellitus was scheduled to undergo coronary artery bypass grafting (CABG). Two days before surgery, EGD was performed to explore the cause of occult bleeding, resulting in a slightly sore throat and an increased white blood cell count (18,300/μl). Without premedication, general anesthesia was uneventfully induced with intravenous midazolam (10 mg) and fentanyl (50 μg), followed by inhalation of sevoflurane (3%) and intravenous rocuronium (50 mg). Thereafter, manual ventilation was easily performed with a bag and mask. However, on laryngoscopy for orotracheal intubation, serious swelling with rubor and light pus in the epiglottis extending to the arytenoid cartilage was detected, leading to the cancellation of surgery. Immediately following intravenous drip of hydrocortisone (300 mg) and bolus of sugammadex (200 mg), the patient recovered smoothly from anesthesia without complications such as dyspnea, but his sore throat persisted. He was diagnosed with acute epiglottitis. Treatment consisted of intravenous cefazolin (2 g/day) and hydrocortisone (300 mg/day tapered to 100 mg/day) for 9 consecutive days. Consequently, the patient recovered gradually from the inflammation and underwent CABG as scheduled 28 days later. Anesthesiologists should be aware that EGD performed just before anesthesia could unpredictably cause acute epiglottitis, especially in immunocompromised patients, such as those with diabetes