BACKGROUND:Combined burn and traumatic brain injury (TBI) treatment priorities may not align due to opposing fluid resuscitation paradigms used in treating burns and TBI. We developed a porcine model ...of combined thermal injury/TBI and compared an “aggressive” fluid resuscitation strategy using the Parkland formula and a “restrictive” resuscitation strategy using the modified Brooke formula.
METHODS:Twenty eight swine were deeply anesthetized and received a 40% total body surface area full thickness burn injury and TBI. Swine were then randomized to receive restrictive or aggressive resuscitation for eight hours after which time animals were euthanized and necropsy was performed. Volume of brain injury was assessed after analyzing segmental slices of brain tissue.
RESULTS:There were no differences between the restrictive and aggressive resuscitation groups in blood pressure, heart rate, central venous pressure, intra-cranial pressure (ICP), or serum lactate levels after 8 hours of resuscitation. Urine output was higher in the aggressive resuscitation group. The restrictive group had a significantly higher serum BUN compared to baseline and compared to the aggressive group. There was no significant difference in size of brain injury between groups.
CONCLUSIONS:Both restrictive and aggressive resuscitation demonstrated adequate resuscitation at eight hours post-injury. Increased serum BUN in the restrictive group may be an indicator of early acute kidney injury, despite adequate urine output. Resuscitation strategy did not appear to affect ICP or the size of brain injury.
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•Larval hemocoelic infections are transstadially transmitted to adult mosquitoes.•Prevalence and intensity of transstadially-passaged infections vary with stage and age.•Larval ...injury, immune stimulation or infection decrease pupation and eclosion.•Larval hemocoelic infections decrease adult female longevity.•Larval hemocoelic infections have complex effects on body size.
During all life stages, mosquitoes are exposed to pathogens, and employ an immune system to resist or limit infection. Although much attention has been paid to how adult mosquitoes fight infection, little is known about how an infection during the larval stage affects the biology of the resultant adult. In this study, we investigated whether a bacterial infection in the hemocoel of the African malaria mosquito, Anopheles gambiae, is transstadially transmitted from larvae to adults (both females and males), and whether immune stimulation in the hemocoel as a larva alters development or biological traits of the adult. Specifically, larvae were injected in the hemocoel with either fluorescent microspheres or Escherichia coli, and the following traits were examined: transstadial transmission, larval development to adulthood, adult survival, and adult body size. Our results show that transstadial transmission of hemocoel contents occurs from larvae to pupae and from pupae to adults, but that bacterial prevalence and intensity varies with age. Injury, immune stimulation or infection decreases the proportion of larvae that undergo pupation and eclosion, infection decreases the longevity of adult females, and treatment has complex effects on the body size of the resultant adults. The present study adds larval hemocoelic infection to the known non-genetic factors that reduce overall fitness by negatively affecting development and adult biological traits that influence mosquito vector competence.
Increasing resistance to every major class of antibiotics and a dearth of novel classes of antibacterial agents in development pipelines has created a dwindling reservoir of treatment options for ...serious bacterial infections. The bacterial type IIA topoisomerases, DNA gyrase and topoisomerase IV, are validated antibacterial drug targets with multiple prospective drug binding sites, including the catalytic site targeted by the fluoroquinolone antibiotics. However, growing resistance to fluoroquinolones, frequently mediated by mutations in the drug-binding site, is increasingly limiting the utility of this antibiotic class, prompting the search for other inhibitor classes that target different sites on the topoisomerase complexes. The highly conserved ATP-binding subunits of DNA gyrase (GyrB) and topoisomerase IV (ParE) have long been recognized as excellent candidates for the development of dual-targeting antibacterial agents with broad-spectrum potential. However, to date, no natural product or small molecule inhibitors targeting these sites have succeeded in the clinic, and no inhibitors of these enzymes have yet been reported with broad-spectrum antibacterial activity encompassing the majority of Gram-negative pathogens. Using structure-based drug design (SBDD), we have created a novel dual-targeting pyrimidoindole inhibitor series with exquisite potency against GyrB and ParE enzymes from a broad range of clinically important pathogens. Inhibitors from this series demonstrate potent, broad-spectrum antibacterial activity against Gram-positive and Gram-negative pathogens of clinical importance, including fluoroquinolone resistant and multidrug resistant strains. Lead compounds have been discovered with clinical potential; they are well tolerated in animals, and efficacious in Gram-negative infection models.
Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual ...disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
Peatlands are found around the world and cover ∼3.4% of the Earth’s surface. In the UK, peatlands cover 17.2% or ∼1.58 Mha of the land surface and occur mainly in upland areas covering the headwaters ...of most major British rivers. However, large areas are now subject to prescribed vegetation burning despite policy guidance that recommends a strong presumption against burning on deep blanket peat. Wildfires occur sporadically but are forecast to increase in frequency in the future. This paper provides a synthesis of current knowledge about how UK peatland-dominated river catchments respond to fires caused by prescribed vegetation burning and uncontrolled wildfire. We provide insight into the effects of fire on the hydrology, biogeochemistry, and biota of peatland river ecosystems, and the peatland-soil-driven controls on these effects at the catchment scale. Burning increases the depth to water table and water-table variability, although some small-scale studies indicate shallower water table in some places. More work is needed on fire effects on peatland river flow, but recent results suggest a complex response with smaller flow peaks for burned systems associated with most rainfall events, but enhanced peaks compared to unburned systems for the top quintile of rainfall events with the largest total rain. Evidence from biogeochemical studies suggests that fire leads to increased dissolved organic C concentrations in rivers. River biota responses primarily include significant reductions in the density of grazing mayflies but increases among detritivores including Chironomidae and Baetis mayflies. We provide a conceptual synthesis that links the main responses of terrestrial and aquatic systems to fire, and we summarize some major research gaps that should be prioritized to inform future policy around peatland management.
The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that ...two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine 'modulation bias' in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.
Abstract Objective Central melanocortin pathways are well-established regulators of energy balance. However, scant data exist about the role of systemic melanocortin peptides. We set out to determine ...if peripheral α-melanocyte stimulating hormone (α-MSH) plays a role in glucose homeostasis and tested the hypothesis that the pituitary is able to sense a physiological increase in circulating glucose and responds by secreting α-MSH. Methods We established glucose-stimulated α-MSH secretion using humans, non-human primates, and mouse models. Continuous α-MSH infusions were performed during glucose tolerance tests and hyperinsulinemic-euglycemic clamps to evaluate the systemic effect of α-MSH in glucose regulation. Complementary ex vivo and in vitro techniques were employed to delineate the direct action of α-MSH via the melanocortin 5 receptor (MC5R)–PKA axis in skeletal muscles. Combined treatment of non-selective/selective phosphodiesterase inhibitor and α-MSH was adopted to restore glucose tolerance in obese mice. Results Here we demonstrate that pituitary secretion of α-MSH is increased by glucose. Peripheral α-MSH increases temperature in skeletal muscles, acts directly on soleus and gastrocnemius muscles to significantly increase glucose uptake, and enhances whole-body glucose clearance via the activation of muscle MC5R and protein kinase A. These actions are absent in obese mice, accompanied by a blunting of α-MSH-induced cAMP levels in skeletal muscles of obese mice. Both selective and non-selective phosphodiesterase inhibition restores α-MSH induced skeletal muscle glucose uptake and improves glucose disposal in obese mice. Conclusion These data describe a novel endocrine circuit that modulates glucose homeostasis by pituitary α-MSH, which increases muscle glucose uptake and thermogenesis through the activation of a MC5R-PKA-pathway, which is disrupted in obesity.
This article provides an historical perspective on the Journal of Pediatric Psychology (JPP) on the occasion of its 50th anniversary.
Former and current editors of JPP participated in a symposium at ...the 2019 Society of Pediatric Psychology Annual Conference (SPPAC), each highlighting prominent types of articles published during their terms, the influence of these papers over time, and their reflections on the next 50 years of the journal. Their presentations were summarized and integrated for this article. Additional data on editorial teams, special issues, and publication metrics over time are included.
The data demonstrate changes over time in the growth, scope, and impact of JPP. The article also shows the consistency in areas of emphasis over time. Anticipated topics for the future were quite consistent across editors and included increased use of technology, broader attention to teams and approaches, and methodological advances as the field will continue to grow.
This article provides an unusual collaboration among editors of JPP, providing an historical perspective on the journal's growth over time and anticipation of continued impact into the future.
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