Positive allosteric modulation of AMPA receptors from efficacy to toxicity: the interspecies exposure-response continuum of the novel potentiator PF-4778574.

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) positive allosteric modulation (i.e., "potentiation") has been proposed to overcome cognitive impairments in schizophrenia, but AMPAR overstimulation can be excitotoxic.

Neurophysiological signals as potential translatable biomarkers for modulation of metabotropic glutamate 5 receptors.

The Group I metabotropic glutamate receptor subtype 5 (mGluR5) is widely distributed in the brain with dense expression in the cerebral cortex, hippocampus, and basal ganglia. These receptors have been implicated in psychiatric and neurological disorders such as schizophrenia, Fragile X syndrome, addiction, anxiety/depression, Parkinson's disease and neuropathic pain. The present study evaluated the effects of the mGluR5 negative allosteric modulators (NAMs) 4-difluoromethoxy-3-(pyridine-2-ylethynyl)phenyl)5H-pyrrolo[3,4-b]pyridine-6(7H)-yl methanone (GRN-529) and methyl (3aR,4S,7aR)-4-hydroxy-4-[(3-methylphenyl)ethynyl]octahydro-1H-indole-1-carboxylate (AFQ056) on polysomnographic (PSG) and quantitative electroencephalographic (qEEG) measures in freely moving rats.

Modeling the public health impact of malaria vaccines for developers and policymakers.

Background: Efforts to develop malaria vaccines show promise. Mathematical model-based estimates of the potential demand, public health impact, and cost and financing requirements can be used to inform investment and adoption decisions by vaccine developers and policymakers on the use of malaria vaccines as complements to existing interventions. However, the complexity of such models may make their outputs inaccessible to non-modeling specialists.

Therapeutic doses of antidepressants are projected not to inhibit human α4β2 nicotinic acetylcholine receptors.

Inhibition of central α4β2 nAChRs by antidepressants, proposed to contribute to their clinical efficacy, was assessed for monoamine reuptake inhibitors (amitriptyline, nortriptyline, fluoxetine, sertraline, paroxetine, citalopram) by comparing projected human unbound brain drug concentrations (Cu,b) at therapeutic doses with concentrations that inhibit human α4β2 nAChRs in vitro. Inhibitory concentrations (IC50) were determined by patch clamp and ranged from 0.8-3.

Feeding Ecology of northern bearded sakis (Chiropotes sagulatus) in Guyana.

Bearded sakis (genus Chiropotes) are among the most highly specialized primate seed predators. However, long-term studies of the genus in continuous forests, with a full community of sympatric primates, are rare. Here I present data on monthly variation in the diet of Chiropotes sagulatus from a long-term study in a continuous forest in Guyana.

Assessment of adverse effects of neurotropic drugs in monkeys with the "drug effects on the nervous system" (DENS) scale.

Research into therapeutics for neuropsychiatric disorders is increasingly focusing on drugs with new mechanisms of action, and such agents are often assessed in preclinical studies using nonhuman primates. However, researchers lack a standardised method to compare different drugs for common adverse effects on the nervous system. We have developed a new scale for this purpose, named "Drug Effects on the Nervous System" (DENS), and tested its utility in an analysis of the second-generation antipsychotic risperidone in monkeys.

Rhythmic theta and delta activity of cortical and hippocampal neuronal networks in genetically or pharmacologically induced N-methyl-D-aspartate receptor hypofunction under urethane anesthesia.

N-Methyl-d-aspartate receptor (NMDAR) antagonists mimic several symptoms of schizophrenia in healthy subjects, and are used in preclinical disease models. In the present study, the impact of pharmacologically and genetically induced NMDAR hypofunction was assessed in rats and mice, including the NMDAR hypomorphic (Grin1) mice, with respect to neuronal network oscillations. Field potentials were recorded from the ventro-medial prefrontal cortex (mPFC) and hippocampus (CA1) in rats, as well as spontaneous and elicited hippocampal theta oscillations in response to brainstem stimulation in Grin1 and wild-type (WT) mice under anesthesia.

Calmodulin mutations associated with recurrent cardiac arrest in infants.

Background: Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.

Methods And Results: We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents.

Comparative genomic analysis of East Asian and non-Asian Helicobacter pylori strains identifies rapidly evolving genes.

Helicobacter pylori infection is a risk factor for the development of gastric adenocarcinoma, a disease that has a high incidence in East Asia. Genes that are highly divergent in East Asian H. pylori strains compared to non-Asian strains are predicted to encode proteins that differ in functional activity and could represent novel determinants of virulence.

The MANDATE model for evaluating interventions to reduce postpartum hemorrhage.

Objective: To create a comprehensive model of the comparative impact of various interventions on maternal, fetal, and neonatal (MFN) mortality.

Methods: The major conditions and sub-conditions contributing to MFN mortality in low-resource areas were identified, and the prevalence and case fatality rates documented. Available interventions were mapped to these conditions, and intervention coverage and efficacy were identified.

Downregulated Th17 responses are associated with reduced gastritis in Helicobacter pylori-infected children.

Helicobacter pylori induces less gastric inflammation in children than adults. Here we investigated whether this reduced inflammation involves dysregulated T helper type 17 (Th17) responses. H.

International survey on evaluation and management of eosinophilic esophagitis.

Background: : Recommendations regarding evaluation and management of eosinophilic esophagitis (EoE) remain incompletely defined. This survey assesses: how providers across the world diagnose, evaluate, and treat EoE and how educational activities affect management.

Methods: : A web-based survey was sent to the members of World Allergy Organization, American College of Allergy, Asthma, and Immunology, and American Academy of Allergy, Asthma, and Immunology.

Gis analysis of patch use and group cohesiveness of bearded sakis (chiropotes sagulatus) in the upper essequibo conservation concession, Guyana.

This study examines how northern bearded sakis (Chiropotes sagulatus) in Guyana adjust group cohesiveness according to the distribution and quality of food patches. I introduce a GIS based method for quantifying food patch quality and how it relates to bearded saki group spread and group size. While the concept of food patch is central to most models of primate socioecology, defining what constitutes a patch has been notoriously problematic in primate studies.

Total face, double jaw, and tongue transplantation: an evolutionary concept.

Background: The central face high-energy avulsive injury has been frequently encountered and predictably managed at the R Adams Cowley Shock Trauma Center. However, despite significant surgical advances and multiple surgical procedures, the ultimate outcome continues to reveal an inanimate, insensate, and suboptimal aesthetic result.

Methods: To effectively address this challenging deformity, a comprehensive multidisciplinary approach was devised.

Bronchoscopy and airway management in patients with mucopolysaccharidoses (MPS).

Introduction: Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders characterized by tissue deposition of glycosaminoglycans (GAG). Their musculoskeletal abnormalities and the GAG storage in the airway result in increased risk for patients undergoing anesthesia. This study evaluates a multi-disciplinary airway management approach and reports upper and lower airway findings of flexible bronchoscopy performed during these procedures.

Terrestrial activity in pitheciins (Cacajao, Chiropotes, and Pithecia).

Neotropical monkeys of the genera Cacajao, Chiropotes, and Pithecia (Pitheciidae) are considered to be highly arboreal, spending most of their time feeding and traveling in the upper canopy. Until now, the use of terrestrial substrates has not been analyzed in detail in this group. Here, we review the frequency of terrestrial use among pitheciin taxa to determine the ecological and social conditions that might lead to such behavior.

An evaluation of using rat-derived single-dose neuropharmacokinetic parameters to project accurately large animal unbound brain drug concentrations.

Previous publications suggest that interstitial fluid compound concentrations (C(ISF)) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal C(ISF) remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain compound concentration-to-unbound plasma compound concentration ratios (C(b,u)/C(p,u)) to project accurately dog and nonhuman primate (nhp) C(b,u), a C(ISF) surrogate, from measured C(p,u) for the highly permeable non-P-glycoprotein substrates N-{(3R,4S)-3-[4-(5-cyano-2-thienyl)phenyl]tetrahydro-2H-pyran-4-yl}propane-2-sulfonamide (PF-4778574) and [4-chloro-5-fluoro-2-(3-methoxy-2-methyl-phenoxy)-benzyl]-methylamine (CE-157119) and the P-glycoprotein substrates risperidone and 9-hydroxyrisperidone. First, in rats, it was determined for eight of nine commercial compounds that their single-dose-derived C(b,u)/C(p,u) were ≤2.

Reactions of doubly ionized benzene with nitrogen and water: a nitrogen-mediated entry into superacid chemistry.

Even in the highly diluted gas phase, rather than electron transfer the benzene dication C(6)H(6)(2+) undergoes association with dinitrogen to form a transient C(6)H(6)N(2)(2+) dication which is best described as a ring-protonated phenyl diazonium ion. Isotopic labeling studies, photoionization experiments using synchrotron radiation, and quantum chemical computations fully support the formation of protonated diazonium, which is in turn a prototype species of superacidic chemistry in solution. Additionally, reactions of C(6)H(6)(2+) with background water involve the transient formation of diprotonated phenol and, among other things, afford a long-lived C(6)H(6)OH(2)(2+) dication, which is attributed to the hydration product of Hogeveen's elusive pyramidal structure of C(6)H(6)(2+), as the global minimum of doubly ionized benzene.

Total face, double jaw, and tongue transplant research procurement: an educational model.

Background: Transplantation of a facial vascularized composite allograft is a highly complex procedure that requires meticulous planning and affords little room for error. Although cadaveric dissections are an essential preparatory exercise, they cannot simulate the true clinical experience of facial vascularized composite allograft recovery.

Methods: After obtaining institutional review board approval to perform a facial vascularized composite allograft research procurement, a 66-year-old, brain-dead donor was identified.

Total face, double jaw, and tongue transplant simulation: a cadaveric study using computer-assisted techniques.

Background: With the transplantation of more extensive facial vascularized composite allografts, fundamental craniofacial and aesthetic principles become increasingly important. In addition, computer-assisted planning and intraoperative navigation may improve precision and efficiency in these complex procedures.

Methods: Ten mock face transplants were performed in 20 cadavers.

Genome-wide recruitment to Polycomb-modified chromatin and activity regulation of the synovial sarcoma oncogene SYT-SSX2.

Background: SYT-SSX is the oncogene associated with synovial sarcoma (SS), a stem cell disease. SYT-SSX is thought to be responsible for sarcoma initiation and development. It interacts with components of Polycomb and SWI/SNF complexes, the two epigenetic controllers that maintain the heritable status of differentiation-specific genes in the stem/progenitor cell.