The key role of nitric oxide in hypoxia: hypoxic vasodilation and energy supply-demand matching

Significance: a mismatch between energy supply and demand induces tissue hypoxia with the potential to cause cell death and organ failure. Whenever arterial oxygen concentration is reduced, increases in blood flow - 'hypoxic vasodilation' - occur in an attempt to restore oxygen supply. Nitric oxide is a major signalling and effector molecule mediating the body's response to hypoxia, given its unique characteristics of vasodilation (improving blood flow and oxygen supply) and modulation of energetic metabolism (reducing oxygen consumption and promoting utilization of alternative pathways). Recent advances: this review covers the role of oxygen in metabolism and responses to hypoxia, the hemodynamic and metabolic effects of nitric oxide, and mechanisms underlying the involvement of nitric oxide in hypoxic vasodilation. Recent insights into nitric oxide metabolism will be discussed, including the role for dietary intake of nitrate, endogenous nitrite reductases, and release of nitric oxide from storage pools. The processes through which nitric oxide levels are elevated during hypoxia are presented, namely (i) increased synthesis from nitric oxide synthases, increased reduction of nitrite to nitric oxide by heme- or pterin-based enzymes and increased release from nitric oxide stores, and (ii) reduced deactivation by mitochondrial cytochrome c oxidase. Critical issues: several reviews covered modulation of energetic metabolism by nitric oxide, while here we highlight the crucial role NO plays in achieving cardiocirculatory homeostasis during acute hypoxia through both vasodilation and metabolic suppression Future directions: we identify a key position for nitric oxide in the body's adaptation to an acute energy supply-demand mismatc

Echocardiographic Guidance During Neonatal and Pediatric Jugular Cannulation for ECMO

Background Internal jugular vein extracorporeal membrane oxygenation (ECMO) cannula position is traditionally confirmed via plain film. Misplaced cannulae can result in need for repositioning and increased morbidity. Echocardiography (ECHO) may be used during cannulation as a more accurate means of guiding cannula position. This study reviews the effect of a protocol encouraging the use of ECHO at cannulation. Methods and materials Single institution retrospective review of patients who received ECMO support using jugular venous cannulation. We compared those who underwent ECHO (ECHO+) at the time of cannulation with those who did not (ECHO−). Results Eighty-nine patients were included: 26 ECHO+, 63 ECHO−. Most ECHO+ patients underwent dual-lumen veno-venous (VV) cannulation (65%); 32% of ECHO− patients had VV support (P = 0.003). There was no difference in the rate of cannula repositioning between the two groups: 8% ECHO+ and 10% ECHO−, P = 0.78. In the VV ECMO subgroup, ECHO+ patients required no repositioning (0/17), while 20% (4/20) of ECHO− VV patients did (P = 0.10). After cannulation, there were 0.58 ECHO studies per patient to verify cannula position in the ECHO+ group compared with 0.22 in the ECHO− group (P = 0.02). Each group had a major mechanical complication: atrial perforation from a guidewire during cannulation in ECHO+ and late atrial perforation from a loose cannula in ECHO−, and there was no difference in minor complications. Conclusions ECHO guidance during neonatal and pediatric jugular cannulation for ECMO did not decrease morbidity or reduce the need for cannula repositioning. ECHO may still be a useful adjunct for precise placement of a dual-lumen VV cannula and during difficult cannulations

Effect of ranitidine on acetaminophen-induced hepatotoxicity in dogs

The effect of ranitidine administration upon the hepatotoxic effect produced by a multidose acetaminophen administration regimen was examined. Seventy-two dogs received three subcutaneous injections of acetaminophen (750, 200, 200 mg/kg body wt) in DMSO (600 mg/ml) at time zero, 9 hr later, and 24 hr after the first dose. Ten control animals (group I) were not given ranitidine, the remaining 62 dogs received an intramus-cular injection of ranitidine 30 min before each acetaminophen dose. Three different doses of ranitidine were used (mg/kg body wt): 50 mg, group II (33 dogs); 75 mg, group III (14 dogs); 120 mg, group IV (15 dogs). Ranitidine reduced the expected acetaminophen-induced hepatoxicity in a dose-response manner. Moreover, a significant correlation was found between the ranitidine dose and the survival rate, as evidenced by transaminase levels in the serum and histology of the liver. This model of fulminant hepatic failure induced by acetaminophen and its modulation with ranitidine provides clinical investigators with a research tool that will be useful in the future investigation of putative medical and surgical therapies being investigated for use in the clinical management of fulminant hepatic failure. Because of the size of the animal used in this model, frequent and serial analyses of blood and liver were available for study to determine the effect of therapy within a given animal as opposed to within groups of animals. © 1990 Plenum Publishing Corporation

Cdk5 Is Required for Memory Function and Hippocampal Plasticity via the cAMP Signaling Pathway

Memory formation is modulated by pre- and post-synaptic signaling events in neurons. The neuronal protein kinase Cyclin-Dependent Kinase 5 (Cdk5) phosphorylates a variety of synaptic substrates and is implicated in memory formation. It has also been shown to play a role in homeostatic regulation of synaptic plasticity in cultured neurons. Surprisingly, we found that Cdk5 loss of function in hippocampal circuits results in severe impairments in memory formation and retrieval. Moreover, Cdk5 loss of function in the hippocampus disrupts cAMP signaling due to an aberrant increase in phosphodiesterase (PDE) proteins. Dysregulation of cAMP is associated with defective CREB phosphorylation and disrupted composition of synaptic proteins in Cdk5-deficient mice. Rolipram, a PDE4 inhibitor that prevents cAMP depletion, restores synaptic plasticity and memory formation in Cdk5-deficient mice. Collectively, our results demonstrate a critical role for Cdk5 in the regulation of cAMP-mediated hippocampal functions essential for synaptic plasticity and memory formation.Norman B. Leventhal FellowshipUnited States. National Institutes of Health (NIH T32 MH074249)United States. National Institutes of Health (NIH RO1 NS051874

Unilateral versus bilateral thyroarytenoid Botulinum toxin injections in adductor spasmodic dysphonia: a prospective study

OBJECTIVES: In this preliminary prospective study, we compared unilateral and bilateral thyroarytenoid muscle injections of Botulinum toxin (Dysport) in 31 patients with adductor spasmodic dysphonia, who had undergone more than 5 consecutive Dysport injections (either unilateral or bilateral) and had completed 5 concomitant self-rated efficacy and complication scores questionnaires related to the previous injections. We also developed a Neurophysiological Scoring (NPS) system which has utility in the treatment administration. METHOD AND MATERIALS: Data were gathered prospectively on voice improvement (self-rated 6 point scale), length of response and duration of complications (breathiness, cough, dysphagia and total voice loss). Injections were performed under electromyography (EMG) guidance. NPS scale was used to describe the EMG response. Dose and unilateral/bilateral injections were determined by clinical judgment based on previous response. Time intervals between injections were patient driven. RESULTS: Low dose unilateral Dysport injection was associated with no significant difference in the patient's outcome in terms of duration of action, voice score (VS) and complication rate when compared to bilateral injections. Unilateral injections were not associated with any post treatment total voice loss unlike the bilateral injections. CONCLUSION: Unilateral low dose Dysport injections are recommended in the treatment of adductor spasmodic dysphonia

Low-Rank Subspace Override for Unsupervised Domain Adaptation

Current supervised learning models cannot generalize well across domain boundaries, which is a known problem in many applications, such as robotics or visual classification. Domain adaptation methods are used to improve these generalization properties. However, these techniques suffer either from being restricted to a particular task, such as visual adaptation, require a lot of computational time and data, which is not always guaranteed, have complex parameterization, or expensive optimization procedures. In this work, we present an approach that requires only a well-chosen snapshot of data to find a single domain invariant subspace. The subspace is calculated in closed form and overrides domain structures, which makes it fast and stable in parameterization. By employing low-rank techniques, we emphasize on descriptive characteristics of data. The presented idea is evaluated on various domain adaptation tasks such as text and image classification against state of the art domain adaptation approaches and achieves remarkable performance across all tasks

A primer for the student joining the general thoracic surgery service tomorrow: Primer 2 of 7.

This medical student primer discusses general thoracic surgery, which involves treating pathologies involving all structures in the thorax except the heart, thoracic aorta, great vessels, and spine