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

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

Is abdominal wall contraction important for normal voiding in the female rat?

BACKGROUND: Normal voiding behavior in urethane-anesthetized rats includes contraction of the abdominal wall striated muscle, similar to the visceromotor response (VMR) to noxious bladder distension. Normal rat voiding requires pulsatile release of urine from a pressurized bladder. The abdominal wall contraction accompanying urine flow may provide a necessary pressure increment for normal efficient pulsatile voiding. This study aimed to evaluate the occurrence and necessity of the voiding-associated abdominal wall activity in urethane-anesthetized female rats METHODS: A free-voiding model was designed to allow assessment of abdominal wall activity during voiding resulting from physiologic bladder filling, in the absence of bladder or urethral instrumentation. Physiologic diuresis was promoted by rapid intravascular hydration. Intercontraction interval (ICI), voided volumes and EMG activity of the rectus abdominis were quantified. The contribution of abdominal wall contraction to voiding was eliminated in a second group of rats by injecting botulinum-A (BTX, 5 U) into each rectus abdominis to induce local paralysis. Uroflow parameters were compared between intact free-voiding and BTX-prepared animals. RESULTS: Abdominal wall response is present in free voiding. BTX preparation eliminated the voiding-associated EMG activity. Average per-void volume decreased from 1.8 ml to 1.1 ml (p < 0.05), and reduced average flow from 0.17 ml/sec to 0.11 ml/sec (p < 0.05). Intercontraction interval (ICI) was not changed by BTX pretreatment. CONCLUSION: The voiding-associated abdominal wall response is a necessary component of normal voiding in urethane anesthetized female rats. As the proximal urethra may be the origin of the afferent signaling which results in the abdominal wall response, the importance of the bladder pressure increment due to this response may be in maintaining a normal duration intermittent pulsatile high frequency oscillatory (IPHFO)/flow phase and thus efficient voiding. We propose the term Voiding-associated Abdominal Response (VAR) for the physiologic voiding-associated EMG/abdominal wall response, to distinguish it from the visceromotor response (VMR) to noxious bladder distension

Abiotic conditions in cephalopod (Sepia officinalis) eggs: embryonic development at low pH and high pCO2

Low pO(2) values have been measured in the perivitelline fluids (PVF) of marine animal eggs on several occasions, especially towards the end of development, when embryonic oxygen consumption is at its peak and the egg case acts as a massive barrier to diffusion. Several authors have therefore suggested that oxygen availability is the key factor leading to hatching. However, there have been no measurements of PVF pCO(2) so far. This is surprising, as elevated pCO(2) could also constitute a major abiotic stressor for the developing embryo. As a first attempt to fill this gap in knowledge, we measured pO(2), pCO(2) and pH in the PVF of late cephalopod (Sepia officinalis) eggs. We found linear relationships between embryo wet mass and pO(2), pCO(2) and pH. pO(2) declined from > 12 kPa to less than 5 kPa, while pCO(2) increased from 0.13 to 0.41 kPa. In the absence of active accumulation of bicarbonate in the PVF, pH decreased from 7.7 to 7.2. Our study supports the idea that oxygen becomes limiting in cephalopod eggs towards the end of development; however, pCO(2) and pH shift to levels that have caused significant physiological disturbances in other marine ectothermic animals. Future research needs to address the physiological adaptations that enable the embryo to cope with the adverse abiotic conditions in their egg environment

Forecasting the term structure of government bond yields in unstable environments

In this paper we model and predict the term structure of US interest rates in a data-rich and unstable environment. The dynamic Nelson-Siegel factor model is extended to allow the model dimension and the parameters to change over time, in order to account for both model uncertainty and sudden structural changes, in one setting. The proposed specification performs better than several alternatives, since it incorporates additional macro-finance information during hard times, while it allows for more parsimonious models to be relevant during normal periods. A dynamic variance decomposition measure constructed from our model shows that parameter uncertainty and model uncertainty regarding different choices of predictors explain a large proportion of the predictive variance of bond yields