Shock Index Values and Trends in Pediatric Sepsis: Predictors or Therapeutic Targets? A retrospective observational study

BACKGROUND: Shock index (SI) (heart rate/systolic blood pressure) has been used to predict outcome in both adult and pediatric sepsis within the intensive care unit (ICU). We aimed to evaluate the utility of SI prior to pediatric ICU (PICU) admission. METHODS: We conducted a retrospective observational study of children referred to a pediatric intensive care transport service (PICTS) between 2005 and 2011. The predictive value of SI, heart rate and blood pressure at three pre-specified time points (at referral to PICTS, at PICTS arrival at the referring hospital, and at PICU admission), and changes in SI between the time points, were evaluated. Death within the first 48 hours of ICU admission (early death) was the primary outcome variable. RESULTS: Over the seven-year period, 572 children with sepsis were referred to the PICTS. Thirty-nine children died prior to transport to a PICU, while 474 were transported alive. Adjusting for age, time-points and time duration in a multi-level regression analysis, SI was significantly higher in those who died early. There was a significant improvement in SI with the transport team in survivors but not in non-survivors. However, the predictive value of a change in SI for mortality was no better than either a change in heart rate or blood pressure. CONCLUSIONS: The absolute or change in SI does not predict early death any more than heart rate and systolic blood pressure individually in children with sepsis

A two-neuron system for adaptive goal-directed decision-making in Lymnaea

During goal-directed decision-making, animals must integrate information from the external environment and their internal state to maximize resource localization while minimizing energy expenditure. How this complex problem is solved by the nervous system remains poorly understood. Here, using a combined behavioural and neurophysiological approach, we demonstrate that the mollusc Lymnaea performs a sophisticated form of decision-making during food-searching behaviour, using a core system consisting of just two neuron types. The first reports the presence of food and the second encodes motivational state acting as a gain controller for adaptive behaviour in the absence of food. Using an in vitro analogue of the decision-making process, we show that the system employs an energy management strategy, switching between a low- and high-use mode depending on the outcome of the decision. Our study reveals a parsimonious mechanism that drives a complex decision-making process via regulation of levels of tonic inhibition and phasic excitation

Distributed network organization underlying feeding behavior in the mollusk Lymnaea

The aim of the work reviewed here is to relate the properties of individual neurons to network organization and behavior using the feeding system of the gastropod mollusk, Lymnaea. Food ingestion in this animal involves sequences of rhythmic biting movements that are initiated by the application of a chemical food stimulus to the lips and esophagus. We investigated how individual neurons contribute to various network functions that are required for the generation of feeding behavior such as rhythm generation, initiation ('decision making'), modulation and hunger and satiety. The data support the view that feeding behavior is generated by a distributed type of network organization with individual neurons often contributing to more than one network function, sharing roles with other neurons. Multitasking in a distributed type of network would be 'economically' sensible in the Lymnaea feeding system where only about 100 neurons are available to carry out a variety of complex tasks performed by millions of neurons in the vertebrate nervous system. Having complementary and potentially alternative mechanisms for network functions would also add robustness to what is a 'noisy' network where variable firing rates and synaptic strengths are commonly encountered in electrophysiological recording experiments

Why the South Pacific Convergence Zone is diagonal

During austral summer, the majority of precipitation over the Pacific Ocean is concentrated in the South Pacific Convergence Zone (SPCZ). The surface boundary conditions required to support the diagonally (northwest-southeast) oriented SPCZ are determined through a series of experiments with an atmospheric general circulation model. Continental configuration and orography do not have a significant influence on SPCZ orientation and strength. The key necessary boundary condition is the zonally asymmetric component of the sea surface temperature (SST) distribution. This leads to a strong subtropical anticyclone over the southeast Pacific that, on its western flank, transports warm moist air from the equator into the SPCZ region. This moisture then intensifies (diagonal) bands of convection that are initiated by regions of ascent and reduced static stability ahead of the cyclonic vorticity in Rossby waves that are refracted toward the westerly duct over the equatorial Pacific. The climatological SPCZ is comprised of the superposition of these diagonal bands of convection. When the zonally asymmetric SST component is reduced or removed, the subtropical anticyclone and its associated moisture source is weakened. Despite the presence of Rossby waves, significant moist convection is no longer triggered; the SPCZ disappears. The diagonal SPCZ is robust to large changes (up to +/-6 degC) in absolute SST (i.e. where the SST asymmetry is preserved). Extreme cooling (change less than -6 degC) results in a weaker and more zonal SPCZ, due to decreasing atmospheric temperature, moisture content and convective available potential energy

Pilot Study of the Association of the DDAH2 −449G Polymorphism with Asymmetric Dimethylarginine and Hemodynamic Shock in Pediatric Sepsis

Genetic variability in the regulation of the nitric oxide (NO) pathway may influence hemodynamic changes in pediatric sepsis. We sought to determine whether functional polymorphisms in DDAH2, which metabolizes the NO synthase inhibitor asymmetric dimethylarginine (ADMA), are associated with susceptibility to sepsis, plasma ADMA, distinct hemodynamic states, and vasopressor requirements in pediatric septic shock.In a prospective study, blood and buccal swabs were obtained from 82 patients ≤ 18 years (29 with severe sepsis/septic shock plus 27 febrile and 26 healthy controls). Plasma ADMA was measured using tandem mass spectrometry. DDAH2 gene was partially sequenced to determine the -871 6g/7 g insertion/deletion and -449G/C single nucleotide polymorphisms. Shock type ("warm" versus "cold") was characterized by clinical assessment. The -871 7g allele was more common in septic (17%) then febrile (4%) and healthy (8%) patients, though this was not significant after controlling for sex and race (p = 0.96). ADMA did not differ between -871 6g/7 g genotypes. While genotype frequencies also did not vary between groups for the -449G/C SNP (p = 0.75), septic patients with at least one -449G allele had lower ADMA (median, IQR 0.36, 0.30-0.41 µmol/L) than patients with the -449CC genotype (0.55, 0.49-0.64 µmol/L, p = 0.008) and exhibited a higher incidence of "cold" shock (45% versus 0%, p = 0.01). However, after controlling for race, the association with shock type became non-significant (p = 0.32). Neither polymorphism was associated with inotrope score or vasoactive infusion duration.The -449G polymorphism in the DDAH2 gene was associated with both low plasma ADMA and an increased likelihood of presenting with "cold" shock in pediatric sepsis, but not with vasopressor requirement. Race, however, was an important confounder. These results support and justify the need for larger studies in racially homogenous populations to further examine whether genotypic differences in NO metabolism contribute to phenotypic variability in sepsis pathophysiology

Super-Aggregations of Krill and Humpback Whales in Wilhelmina Bay, Antarctic Peninsula

Ecological relationships of krill and whales have not been explored in the Western Antarctic Peninsula (WAP), and have only rarely been studied elsewhere in the Southern Ocean. In the austral autumn we observed an extremely high density (5.1 whales per km2) of humpback whales (Megaptera novaeangliae) feeding on a super-aggregation of Antarctic krill (Euphausia superba) in Wilhelmina Bay. The krill biomass was approximately 2 million tons, distributed over an area of 100 km2 at densities of up to 2000 individuals m−3; reports of such ‘super-aggregations’ of krill have been absent in the scientific literature for >20 years. Retentive circulation patterns in the Bay entrained phytoplankton and meso-zooplankton that were grazed by the krill. Tagged whales rested during daylight hours and fed intensively throughout the night as krill migrated toward the surface. We infer that the previously unstudied WAP embayments are important foraging areas for whales during autumn and, furthermore, that meso-scale variation in the distribution of whales and their prey are important features of this system. Recent decreases in the abundance of Antarctic krill around the WAP have been linked to reductions in sea ice, mediated by rapid climate change in this area. At the same time, baleen whale populations in the Southern Ocean, which feed primarily on krill, are recovering from past exploitation. Consideration of these features and the effects of climate change on krill dynamics are critical to managing both krill harvests and the recovery of baleen whales in the Southern Ocean

Extrinsic primary afferent signalling in the gut

Visceral sensory neurons activate reflex pathways that control gut function and also give rise to important sensations, such as fullness, bloating, nausea, discomfort, urgency and pain. Sensory neurons are organised into three distinct anatomical pathways to the central nervous system (vagal, thoracolumbar and lumbosacral). Although remarkable progress has been made in characterizing the roles of many ion channels, receptors and second messengers in visceral sensory neurons, the basic aim of understanding how many classes there are, and how they differ, has proven difficult to achieve. We suggest that just five structurally distinct types of sensory endings are present in the gut wall that account for essentially all of the primary afferent neurons in the three pathways. Each of these five major structural types of endings seems to show distinctive combinations of physiological responses. These types are: 'intraganglionic laminar' endings in myenteric ganglia; 'mucosal' endings located in the subepithelial layer; 'muscular–mucosal' afferents, with mechanosensitive endings close to the muscularis mucosae; 'intramuscular' endings, with endings within the smooth muscle layers; and 'vascular' afferents, with sensitive endings primarily on blood vessels. 'Silent' afferents might be a subset of inexcitable 'vascular' afferents, which can be switched on by inflammatory mediators. Extrinsic sensory neurons comprise an attractive focus for targeted therapeutic intervention in a range of gastrointestinal disorders.Australian National Health and Medical Research Counci

Increasing gene dosage greatly enhances recombinant expression of aquaporins in Pichia pastoris

<p>Abstract</p> <p>Background</p> <p>When performing functional and structural studies, large quantities of pure protein are desired. Most membrane proteins are however not abundantly expressed in their native tissues, which in general rules out purification from natural sources. Heterologous expression, especially of eukaryotic membrane proteins, has also proven to be challenging. The development of expression systems in insect cells and yeasts has resulted in an increase in successful overexpression of eukaryotic proteins. High yields of membrane protein from such hosts are however not guaranteed and several, to a large extent unexplored, factors may influence recombinant expression levels. In this report we have used four isoforms of aquaporins to systematically investigate parameters that may affect protein yield when overexpressing membrane proteins in the yeast <it>Pichia pastoris</it>.</p> <p>Results</p> <p>By comparing clones carrying a single gene copy, we show a remarkable variation in recombinant protein expression between isoforms and that the poor expression observed for one of the isoforms could only in part be explained by reduced transcript levels. Furthermore, we show that heterologous expression levels of all four aquaporin isoforms strongly respond to an increase in recombinant gene dosage, independent of the amount of protein expressed from a single gene copy. We also demonstrate that the increased expression does not appear to compromise the protein folding and the membrane localisation.</p> <p>Conclusions</p> <p>We report a convenient and robust method based on qPCR to determine recombinant gene dosage. The method is generic for all constructs based on the pPICZ vectors and offers an inexpensive, quick and reliable means of characterising recombinant <it>P. pastoris </it>clones. By using this method we show that: (1) heterologous expression of all aquaporins investigated respond strongly to an increase in recombinant gene dosage (2) expression from a single recombinant gene copy varies in an isoform dependent manner (3) the poor expression observed for AtSIP1;1 is mainly caused by posttranscriptional limitations. The protein folding and membrane localisation seems to be unaffected by increased expression levels. Thus a screen for elevated gene dosage can routinely be performed for identification of <it>P. pastoris </it>clones with high expression levels of aquaporins and other classes of membrane proteins.</p

The Impact of Thyroid Cancer and Post-Surgical Radioactive Iodine Treatment on the Lives of Thyroid Cancer Survivors: A Qualitative Study

BACKGROUND: Adjuvant treatment with radioactive iodine (RAI) is often considered in the treatment of well-differentiated thyroid carcinoma (WDTC). We explored the recollections of thyroid cancer survivors on the diagnosis of WDTC, adjuvant radioactive iodine (RAI) treatment, and decision-making related to RAI treatment. Participants provided recommendations for healthcare providers on counseling future patients on adjuvant RAI treatment. METHODS: We conducted three focus group sessions, including WDTC survivors recruited from two Canadian academic hospitals. Participants had a prior history of WDTC that was completely resected at primary surgery and had been offered adjuvant RAI treatment. Open-ended questions were used to generate discussion in the groups. Saturation of major themes was achieved among the groups. FINDINGS: There were 16 participants in the study, twelve of whom were women (75%). All but one participant had received RAI treatment (94%). Participants reported that a thyroid cancer diagnosis was life-changing, resulting in feelings of fear and uncertainty. Some participants felt dismissed as not having a serious disease. Some participants reported receiving conflicting messages from healthcare providers on the appropriateness of adjuvant RAI treatment or insufficient information. If RAI-related side effects occurred, their presence was not legitimized by some healthcare providers. CONCLUSIONS: The diagnosis and treatment of thyroid cancer significantly impacts the lives of survivors. Fear and uncertainty related to a cancer diagnosis, feelings of the diagnosis being dismissed as not serious, conflicting messages about adjuvant RAI treatment, and treatment-related side effects, have been raised as important concerns by thyroid cancer survivors