Ventilation, Gas Exchange, and Aerobic Scope in a Small Monitor Lizard, Varanus gilleni

Standard rates of 02 consumption (Vo2) in the dark of Varanus gi/leni (mean mass = 30 g) were measured at 25, 31, 34, and 37 C. At 37 C, the mean value (195 ml 02 STPD kg-1 h-1) was 22% lower than that predicted by a regression equation for lizards as a group (Bennett and Dawson 1976). Despite appearing to be asleep, three- to fourfold elevations in standard Vo2 were seen in lizards with lightweight, transparent respiratory masks. Vo2 was also measured during treadmill exercise at speeds from 5 to 15 m min-1 and during bouts of maximal exercise. Varanus gilleni has the highest factorial aerobic scope (27.5) of any lizard examined to date. The cost of transport in V.gi/leni is relatively high and may relate to short limb length. Pulmonary ventilation and gas exchange (VE, Vo2, Vco2) were simultaneously measured at 25 C, during warming from 25 to 35 C, and again after several hours at 35 C. Air-convection requirements for C02 and 02 were independent of temperature. The patterns of lung ventilation suggest that arterial Pco2 and pH are constant with rising temperature, behavior that is common to that in large varanids and in contrast to that in other reptiles

Delayed oral LY333013 rescues mice from highly neurotoxic, lethal doses of Papuan Taipan (Oxyuranus scutellatus) venom

There is an unmet need for economical snakebite therapies with long shelf lives that are effective even with delays in treatment. The orally bioavailable, heat-stable, secretory phospholipase A2 (sPLA2) inhibitor, LY333013, demonstrates antidotal characteristics for severe snakebite envenoming in both field and hospital use. A murine model of lethal envenoming by a Papuan taipan (Oxyuranus scutellatus) demonstrates that LY333013, even with delayed oral administration, improves the chances of survival. Furthermore, LY333013 improves the performance of antivenom even after it no longer reverses neurotoxic signs. Our study is the first demonstration that neurotoxicity from presynaptic venom sPLA2S can be treated successfully, even after the window of therapeutic antivenom has closed. These results suggest that sPLA2 inhibitors have the potential to reduce death and disability and should be considered for the initial and adjunct treatment of snakebite envenoming. The scope and capacity of the sPLA2 inhibitors ability to achieve these endpoints requires further investigation and development effortsUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto Clodomiro Picado (ICP)UCR::Vicerrectoría de Docencia::Salud::Facultad de Microbiologí

Development of a Unifying Target and Consensus Indicators for Global Surgical Systems Strengthening: Proposed by the Global Alliance for Surgery, Obstetric, Trauma, and Anaesthesia Care (The G4 Alliance)

After decades on the margins of primary health care, surgical and anaesthesia care is gaining increasing priority within the global development arena. The 2015 publications of the Disease Control Priorities third edition on Essential Surgery and the Lancet Commission on Global Surgery created a compelling evidenced-based argument for the fundamental role of surgery and anaesthesia within cost-effective health systems strengthening global strategy. The launch of the Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care in 2015 has further coordinated efforts to build priority for surgical care and anaesthesia. These combined efforts culminated in the approval of a World Health Assembly resolution recognizing the role of surgical care and anaesthesia as part of universal health coverage. Momentum gained from these milestones highlights the need to identify consensus goals, targets and indicators to guide policy implementation and track progress at the national level. Through an open consultative process that incorporated input from stakeholders from around the globe, a global target calling for safe surgical and anaesthesia care for 80% of the world by 2030 was proposed. In order to achieve this target, we also propose 15 consensus indicators that build on existing surgical systems metrics and expand the ability to prioritize surgical systems strengthening around the world

Ventilation, Gas Exchange, and Aerobic Scope in a Small Monitor Lizard, Varanus gilleni

Standard rates of 02 consumption (Vo2) in the dark of Varanus gi/leni (mean mass = 30 g) were measured at 25, 31, 34, and 37 C. At 37 C, the mean value (195 ml 02 STPD kg-1 h-1) was 22% lower than that predicted by a regression equation for lizards as a group (Bennett and Dawson 1976). Despite appearing to be asleep, three- to fourfold elevations in standard Vo2 were seen in lizards with lightweight, transparent respiratory masks. Vo2 was also measured during treadmill exercise at speeds from 5 to 15 m min-1 and during bouts of maximal exercise. Varanus gilleni has the highest factorial aerobic scope (27.5) of any lizard examined to date. The cost of transport in V.gi/leni is relatively high and may relate to short limb length. Pulmonary ventilation and gas exchange (VE, Vo2, Vco2) were simultaneously measured at 25 C, during warming from 25 to 35 C, and again after several hours at 35 C. Air-convection requirements for C02 and 02 were independent of temperature. The patterns of lung ventilation suggest that arterial Pco2 and pH are constant with rising temperature, behavior that is common to that in large varanids and in contrast to that in other reptiles

Neuromuscular Weakness and Paralysis Produced by Snakebite Envenoming: Mechanisms and Proposed Standards for Clinical Assessment

Respiratory and airway-protective muscle weakness caused by the blockade of neuromuscular transmission is a major cause of early mortality from snakebite envenoming (SBE). Once weakness is manifest, antivenom appears to be of limited effectiveness in improving neuromuscular function. Herein, we review the topic of venom-induced neuromuscular blockade and consider the utility of adopting clinical management methods originally developed for the safe use of neuromuscular blocking agents by anesthesiologists in operating rooms and critical care units. Failure to quantify neuromuscular weakness in SBE is predicted to cause the same significant morbidity that is associated with failure to do so in the context of using a clinical neuromuscular block in surgery and critical care. The quantitative monitoring of a neuromuscular block, and an understanding of its neurophysiological characteristics, enables an objective measurement of weakness that may otherwise be overlooked by traditional clinical examination at the bedside. This is important for the initial assessment and the monitoring of recovery from neurotoxic envenoming. Adopting these methods will also be critical to the conduct of future clinical trials of toxin-inhibiting drugs and antivenoms being tested for the reversal of venom-induced neuromuscular block

Functional Deactivation of the Major Neuronal Nicotinic Receptor Caused by Nicotine and a Protein Kinase C- Dependent Mechanism

SUMMARY The effect of nicotine on the major human neuronal nicotinic receptor (␣4␤2 subtype) was studied in permanently transfected HEK 293 cells. Prolonged exposure to low concentrations of nicotine (1 M) increased epibatidine binding but functionally deactivated the nicotinic receptor, abolishing Ca 2ϩ influx in response to an acute nicotine challenge. Deactivation could also be caused by down-regulating protein kinase C (PKC) activity with 0.5 M phorbol-12,13-dibutyrate or briefly incubating cells with the PKC inhibitor NPC-15437. Recovery from receptor deactivation caused by either nicotine treatment or PKC inhibition occurred slowly (4 -6 hr). Reversal of nicotineinduced deactivation was accelerated by the addition of inhibitors of protein phosphatases 2A and 2B. These data suggest a hypothetical mechanism of nicotine-induced deactivation that involves dephosphorylation of nicotinic receptors at PKC phosphorylation sites. The action of nicotine in the brain is mediated by a family of oligomeric ion channels whose opening is regulated by the binding of the neurotransmitter acetylcholine and drugs such as nicotine. Eleven different mammalian nAChR subunits (␣2-9 and ␤2-4) have been cloned (for reviews, see Refs. 1 and 2), and all the neuronal nicotinic receptors display a pronounced selectivity for Ca 2ϩ relative to Na ϩ (3-5). The most abundant receptor is composed of the ␣4 and ␤2 subunits with a stoichiometry of 2␣:3␤ (6) and is responsible for ϳ85% of the high affinity nicotine binding in the brain (6 -8). When nicotine is administered chronically to rats, a ϳ2-fold up-regulation of high affinity brain nicotinic receptors has been observed (9). This seems to be due to a dramatic decrease in the rate of degradation of the receptor in the cell membrane after nicotine treatment (10). The basis for this change in turnover is obscure. It has also been shown that chronic nicotine exposure leads to what has been termed "functional deactivation" of receptors to distinguish it from short term desensitization (11). Deactivation of neuronal nAChRs was first described and distinguished from receptor desensitization by Simasko et al. (12). The fact that chronic nicotine administration results in an increase in receptor number, coupled with a functional deactivation, suggests a mechanism for the addictive effects of nicotine (13). In this model, withdrawal of nicotine from an individual chronically exposed to the drug would result in reactivation of excess receptors, leading to craving, and prompting a further deactivating dose of the drug (13). Therefore, the relationship between nicotinic receptor number and intrinsic activity is a critical issue. In this report, we show that HEK 293 cells stably expressing the human ␣4␤2 nicotinic receptor subtype, after prolonged exposure to nicotine, display both a dramatic up-regulation of the receptor, together with a functional deactivation that is easily distinguished from simple short term desensitization. This functional deactivation can also be achieved by inhibition of PKC activity in the cells. Furthermore, phosphatase inhibitors increase the rate of recovery from nicotine-induced deactivation of the ␣4␤2 nicotinic receptor. Our data also indicate that the open state conformation per se, rather than calcium ion influx, directs formation of a deactivated receptor structure. Experimental Procedures Cloning human nicotinic receptor subunits. A human ␣4 subunit cDNA probe was generated by RT-PCR of total human brain RNA, with primers based on the rat ␣4 sequence. The resulting PCR fragment, which contained part of the human ␣4 sequence spanning nucleotides 755-985 (all numbering is from the ATG initiatio

Developing Small Molecule Therapeutics for the Initial and Adjunctive Treatment of Snakebite

The World Health Organization (WHO) recently added snakebite envenoming to the priority list of Neglected Tropical Diseases (NTD). It is thought that ~75% of mortality following snakebite occurs outside the hospital setting, making the temporal gap between a bite and antivenom administration a major therapeutic challenge. Small molecule therapeutics (SMTs) have been proposed as potential prereferral treatments for snakebite to help address this gap. Herein, we discuss the characteristics, potential uses, and development of SMTs as potential treatments for snakebite envenomation. We focus on SMTs that are secretory phospholipase A2 (sPLA2) inhibitors with brief exploration of other potential drug targets on venom molecules