Extraintestinal Manifestations of Pediatric Inflammatory Bowel Disease: Prevalence, Presentation and anti-TNF Treatment.

Background: There is a paucity of data on extraintestinal manifestations (EIM) and their treatment in pediatric patients with inflammatory bowel disease (IBD). Methods: Since 2008, the Pediatric Swiss IBD Cohort Study has collected data on the pediatric IBD population in Switzerland. Data on 329 patients were analyzed retrospectively. Results: 55 patients (16.7%) suffered from 1-4 EIM (39 Crohn's disease, 12 ulcerative colitis and 4 IBD-Unclassified (IBD-U) patients). At IBD onset, presence of EIM was more frequent than in the adult population (8.5% vs. 5.0%, p = 0.014). EIM were more frequent in CD when compared to UC/IBD-U (22.5 vs. 10.3%, p = 0.003). The most prevalent EIM were peripheral arthritis (26/329, 7.9%) and aphthous stomatitis (24/329, 7.3%). 27.6% of all EIM appeared before IBD diagnosis. Median time between IBD diagnosis and occurrence of first EIM was 1 month (-37.5-149.0). 31 of the 55 patients (56.4%) were treated with one or more anti-TNF agents. IBD patients with EIM were more likely to be treated with anti-TNF compared to those without (56.4% vs. 35.0%, p = 0.003). Response rates to anti-TNF depended on underlying EIM and were best for peripheral arthritis (61.5%) and uveitis (66.7%). Conclusions: In a cohort of pediatric IBD patients, EIM were frequently encountered. In up to 30%, EIM appeared before IBD diagnosis. Knowledge of these findings might translate into an increased awareness of underlying IBD, thereby decreasing diagnostic delay. Anti- TNF for the treatment of certain EIM is effective although a substantial proportion of new EIM might present despite ongoing anti-TNF therapy. (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Survey on Clinical Practice of Primary Prophylaxis in Portal Hypertension in Children.

Primary prophylaxis in portal hypertension in children is controversial, as there are few studies documenting its efficacy on the risk of bleeding. 28 centres out of the 38 we contacted returned a completed questionnaire about their clinical practices. More than 75% of the centres use endoscopy to screen patients diagnosed with portal cavernoma, biliary atresia, cystic fibrosis and other fibrotic chronic liver diseases with suspected portal hypertension. In cases of grade 2 varices with red marks and grade 3 varices more than 90% of centres perform sclerotherapy or endoscopic variceal ligation (EVL). Non-cardio selective beta blockers where used by approximately 20% of centres. In conclusion, despite the absence of scientific recommendations there is a tacit consensus concerning the need to screen children with clinical signs of portal hypertension, and to provide primary prophylaxis in cases of endoscopic patterns of high risk varices. (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Effect of Differential Enteral Protein on Growth and Neurodevelopment in Infants

Objective: To determine if higher enteral protein intake leads to improved head growth at 40 weeks postmenstrual age (PMA) in preterm infants less than 32 weeks or 1500 g. Method: Randomized controlled trial in which 120 infants were assigned to either group A with higher enteral protein intake achieved by fortification with higher protein containing fortifier [1 g/100 ml expressed breast milk (EBM)] or to group B with lower enteral protein intake where fortification was done with standard available protein fortifier (0.4 g /100 ml EBM). Results: The mean (SD) protein intake was higher in group A as compared to group B; 4.2 (0.47) vs 3.6 (0.37) g/kg/day, P

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Correlation of Transient Elastography With Severity of Cystic Fibrosis Related Liver Disease.

Objective: To evaluate whether liver stiffness measurement (LSM), determined by transient elastography (TE), correlates with presence and severity of liver disease (LD) in children and young adults with cystic fibrosis (CF). Methods: Subjects underwent LSM at routine CF visits. Presence and severity of CFLD was determined by clinical parameters. Subjects were classified as no CFLD, CFLD without portal hypertension (PHTN), and CFLD with PHTN. LSM was compared to AST/platelet ratio index (APRI) as a correlate to severity of CFLD. Results: 249 subjects [53%male; mean age 14 +/- 7y; 7(3%)

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The destination defines the journey: an examination of the kinematics of hand-to-mouth movements

Long-train electrical stimulation of the motor and premotor cortices of nonhuman primates can produce either hand-to-mouth or grasp-to-inspect movements, depending on the precise location of stimulation. Furthermore, single-neuron recording studies identify discrete neuronal populations in the inferior parietal and ventral premotor cortices that respond uniquely to either grasp-to-eat or grasp-to-place movements, despite their identical mechanistic requirements. These studies demonstrate that the macaque motor cortex is organized around producing functional, goal-oriented movements, rather than simply fulfilling muscular prerequisites of action. In humans, right-handed hand-to-mouth movements have a unique kinematic signature; smaller maximum grip apertures are produced when grasping to eat than when grasping to place identical targets. This is evidence that the motor cortex in humans is also organized around producing functional movements. However, in both macaques and humans, grasp-to-eat/hand-to-mouth movements have always been elicited using edible targets and have (necessarily) been paired with mouth movement. It is therefore unknown whether the kinematic distinction is a natural result of grasping food and/or is simply attributable to concurrent opening of the mouth while grasping. In experiment 1, we used goal-differentiated grasping tasks, directed toward edible and inedible targets, to show that the unique kinematic signature is present even with inedible targets. In experiment 2, we used the same goal-differentiated grasping tasks, either coupled with or divorced from an open-mouth movement, to show that the signature is not attributable merely to a planned opening of the mouth during the grasp. These results are discussed in relation to the role of hand-to-mouth movements in human development, independently of grasp-to-eat behavior.

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White matter and cognition: making the connection

Whereas the cerebral cortex has long been regarded by neuroscientists as the major locus of cognitive function, the white matter of the brain is increasingly recognized as equally critical for cognition. White matter comprises half of the brain, has expanded more than gray matter in evolution, and forms an indispensable component of distributed neural networks that subserve neurobehavioral operations. White matter tracts mediate the essential connectivity by which human behavior is organized, working in concert with gray matter to enable the extraordinary repertoire of human cognitive capacities. In this review, we present evidence from behavioral neurology that white matter lesions regularly disturb cognition, consider the role of white matter in the physiology of distributed neural networks, develop the hypothesis that white matter dysfunction is relevant to neurodegenerative disorders, including Alzheimer's disease and the newly described entity chronic traumatic encephalopathy, and discuss emerging concepts regarding the prevention and treatment of cognitive dysfunction associated with white matter disorders. Investigation of the role of white matter in cognition has yielded many valuable insights and promises to expand understanding of normal brain structure and function, improve the treatment of many neurobehavioral disorders, and disclose new opportunities for research on many challenging problems facing medicine and society.

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Cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change in speech

Neuroimaging studies suggest that the cerebellum might play a role in both speech perception and speech perceptual learning. However, it remains unclear what this role is: does the cerebellum help shape the perceptual decision, or does it contribute to the timing of perceptual decisions? To test this, we used transcranial direct current stimulation (tDCS) in combination with a speech perception task. Participants experienced a series of speech perceptual tests designed to measure and then manipulate (via training) their perception of a phonetic contrast. One group received cerebellar tDCS during speech perceptual learning, and a different group received sham tDCS during the same task. Both groups showed similar learning-related changes in speech perception that transferred to a different phonetic contrast. For both trained and untrained speech perceptual decisions, cerebellar tDCS significantly increased the time it took participants to indicate their decisions with a keyboard press. By analyzing perceptual responses made by both hands, we present evidence that cerebellar tDCS disrupted the timing of perceptual decisions, while leaving the eventual decision unaltered. In support of this conclusion, we use the drift diffusion model to decompose the data into processes that determine the outcome of perceptual decision-making and those that do not. The modeling suggests that cerebellar tDCS disrupted processes unrelated to decision-making. Taken together, the empirical data and modeling demonstrate that right cerebellar tDCS dissociates the timing of perceptual decisions from perceptual change. The results provide initial evidence in healthy humans that the cerebellum critically contributes to speech timing in the perceptual domain.

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Responses of cerebellar Purkinje cells during fictive optomotor behavior in larval zebrafish

Although most studies of the cerebellum have been conducted in mammals, cerebellar circuitry is highly conserved across vertebrates, suggesting that studies of simpler systems may be useful for understanding cerebellar function. The larval zebrafish is particularly promising in this regard because of its accessibility to optical monitoring and manipulations of neural activity. Although several studies suggest that the cerebellum plays a role in behavior at larval stages, little is known about the signals conveyed by particular classes of cerebellar neurons. Here we use electrophysiological recordings to characterize subthreshold, simple spike, and climbing fiber responses in larval zebrafish Purkinje cells in the context of the fictive optomotor response (OMR)—a paradigm in which fish adjust motor output to stabilize their virtual position relative to a visual stimulus. Although visual responses were prominent in Purkinje cells, they lacked the direction or velocity sensitivity that would be expected for controlling the OMR. On the other hand, Purkinje cells exhibited strong responses during fictive swim bouts. Temporal characteristics of these responses are suggestive of a general role for the larval zebrafish cerebellum in controlling swimming. Climbing fibers encoded both visual and motor signals but did not appear to encode signals that could be used to adjust OMR gain, such as retinal slip. Finally, the observation of diverse relationships between simple spikes and climbing fiber responses in individual Purkinje cells highlights the importance of distinguishing between these two types of activity in calcium imaging experiments.

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Sour taste increases swallowing and prolongs hemodynamic responses in the cortical swallowing network

Sour stimuli have been shown to upregulate swallowing in patients and in healthy volunteers. However, such changes may be dependent on taste-induced increases in salivary flow. Other mechanisms include genetic taster status (Bartoshuk LM, Duffy VB, Green BG, Hoffman HJ, Ko CW, Lucchina LA, Weiffenbach JM. Physiol Behav 82: 109–114, 2004) and differences between sour and other tastes. We investigated the effects of taste on swallowing frequency and cortical activation in the swallowing network and whether taster status affected responses. Three-milliliter boluses of sour, sour with slow infusion, sweet, water, and water with infusion were compared on swallowing frequency and hemodynamic responses. The sour conditions increased swallowing frequency, whereas sweet and water did not. Changes in cortical oxygenated hemoglobin (hemodynamic responses) measured by functional near-infrared spectroscopy were averaged over 30 trials for each condition per participant in the right and left motor cortex, S1 and supplementary motor area for 30 s following bolus onset. Motion artifact in the hemodynamic response occurred 0–2 s after bolus onset, when the majority of swallows occurred. The peak hemodynamic response 2–7 s after bolus onset did not differ by taste, hemisphere, or cortical location. The mean hemodynamic response 17–22 s after bolus onset was highest in the motor regions of both hemispheres, and greater in the sour and infusion condition than in the water condition. Genetic taster status did not alter changes in swallowing frequency or hemodynamic response. As sour taste significantly increased swallowing and cortical activation equally with and without slow infusion, increases in the cortical swallowing were due to sour taste.

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High-fidelity optical excitation of cortico-cortical projections at physiological frequencies

Optogenetic activation of axons is a powerful approach for determining the synaptic properties and impact of long-range projections both in vivo and in vitro. However, because of the difficulty of measuring activity in axons, our knowledge of the reliability of optogenetic axonal stimulation has relied on data from somatic recordings. Yet, there are many reasons why activation of axons may not be comparable to cell bodies. Thus we have developed an approach to more directly assess the fidelity of optogenetic activation of axonal projections. We expressed opsins (ChR2, Chronos, or oChIEF) in the mouse primary visual cortex (V1) and recorded extracellular, pharmacologically isolated presynaptic action potentials in response to axonal activation in the higher visual areas. Repetitive stimulation of axons with ChR2 resulted in a 70% reduction in the fiber volley amplitude and a 60% increase in the latency at all frequencies tested (10–40 Hz). Thus ChR2 cannot reliably recruit axons during repetitive stimulation, even at frequencies that are reliable for somatic stimulation, likely due to pronounced channel inactivation at the high light powers required to evoke action potentials. By comparison, oChIEF and Chronos evoked photocurrents that inactivated minimally and could produce reliable axon stimulation at frequencies up to 60 Hz. Our approach provides a more direct and accurate evaluation of the efficacy of new optogenetic tools and has identified Chronos and oChIEF as viable tools to interrogate the synaptic and circuit function of long-range projections.

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Postsynaptic nicotinic acetylcholine receptors facilitate excitation of developing CA1 pyramidal neurons

The hippocampus plays a key role in learning and memory. The normal development and mature function of hippocampal networks supporting these cognitive functions depends on afferent cholinergic neurotransmission mediated by nicotinic acetylcholine receptors. Whereas it is well-established that nicotinic receptors are present on GABAergic interneurons and on glutamatergic presynaptic terminals within the hippocampus, the ability of these receptors to mediate postsynaptic signaling in pyramidal neurons is not well understood. We use whole cell electrophysiology to show that heteromeric nicotinic receptors mediate direct inward currents, depolarization from rest and enhanced excitability in hippocampus CA1 pyramidal neurons of male mice. Measurements made throughout postnatal development provide a thorough developmental profile for these heteromeric nicotinic responses, which are greatest during the first 2 wk of postnatal life and decrease to low adult levels shortly thereafter. Pharmacological experiments show that responses are blocked by a competitive antagonist of α4β2* nicotinic receptors and augmented by a positive allosteric modulator of α5 subunit-containing receptors, which is consistent with expression studies suggesting the presence of α4β2 and α4β2α5 nicotinic receptors within the developing CA1 pyramidal cell layer. These findings demonstrate that functional heteromeric nicotinic receptors are present on CA1 pyramidal neurons during a period of major hippocampal development, placing these receptors in a prime position to play an important role in the establishment of hippocampal cognitive networks.

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Sciatic nerve stimulation activates the retrotrapezoid nucleus in anesthetized rats

Retrotrapezoid nucleus (RTN) neurons sustain breathing automaticity. These neurons have chemoreceptor properties, but their firing is also regulated by multiple synaptic inputs of uncertain function. Here we test whether RTN neurons, like neighboring presympathetic neurons, are excited by somatic afferent stimulation. Experiments were performed in Inactin-anesthetized, bilaterally vagotomized, paralyzed, mechanically ventilated Sprague-Dawley rats. End-expiratory CO₂ (eeCO₂) was varied between 4% and 10% to modify rate and amplitude of phrenic nerve discharge (PND). RTN and presympathetic neurons were recorded extracellularly below the facial motor nucleus with established criteria. Sciatic nerve stimulation (SNstim, 1 ms, 0.5 Hz) slightly increased blood pressure (6.6 ± 1.6 mmHg) and heart rate and, at low eeCO₂ (<5.5%), entrained PND. Ipsi- and contralateral SNstim produced the known biphasic activation of presympathetic neurons. SNstim evoked a similar but weaker biphasic response in up to 67% of RTN neurons and monophasic excitation in the rest. At low eeCO_2, RTN neurons were silent and responded more weakly to SNstim than at high eeCO₂. RTN neuron firing was respiratory modulated to various degrees. The phasic activation of RTN neurons elicited by SNstim was virtually unchanged at high eeCO₂ when PND entrainment to the stimulus was disrupted. Thus RTN neuron response to SNstim did not result from entrainment to the central pattern generator. Overall, SNstim shifted the relationship between RTN firing and eeCO₂ upward. In conclusion, somatic afferent stimulation increases RTN neuron firing probability without altering their response to CO_2. This pathway may contribute to the hyperpnea triggered by nociception, exercise (muscle metabotropic reflex), or hyperthermia.

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Nonreciprocal mechanisms in up- and downregulation of spinal motoneuron excitability by modulators of KCNQ/Kv7 channels

KCNQ/K_v7 channels form a slow noninactivating K⁺ current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/K_v7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K⁺ current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/K_v7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/K_v7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/K_v7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/K_v7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/K_v7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/K_v7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/K_v7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners.

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Comparison of the color selectivity of macaque V4 neurons in different color spaces

Chromatic selectivity has been studied extensively in various visual areas at different stages of visual processing in the macaque brain. In these studies, color stimuli defined in the Derrington-Krauskopf-Lennie (DKL) color space with a limited range of cone contrast were typically used in early stages, whereas those defined in the Commission Internationale de l'Eclairage (CIE) color space, based on human psychophysical measurements across the gamut of the display, were often used in higher visual areas. To understand how the color information is processed along the visual pathway, it is necessary to compare color selectivity obtained in different areas on a common color space. In the present study, we tested whether the neural color selectivity obtained in DKL space can be predicted from responses obtained in CIE space and whether stimuli with limited cone contrast are sufficient to characterize neural color selectivity. We found that for most V4 neurons, there was a strong correlation between responses measured using the two chromatic coordinate systems, and the color selectivities obtained with the two stimulus sets were comparable. However, for some neurons preferring high- or low-saturation colors, stimuli defined in DKL color space did not adequately capture the neural color selectivity. This is mainly due to the use of stimuli within a limited range of cone contrast. We conclude that regardless of the choice of color space, the sampling of colors across the entire gamut is important to characterize neural color selectivity fully or to compare color selectivities in different areas so as to understand color representation in the visual system.

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Is realistic neuronal modeling realistic?

Scientific models are abstractions that aim to explain natural phenomena. A successful model shows how a complex phenomenon arises from relatively simple principles while preserving major physical or biological rules and predicting novel experiments. A model should not be a facsimile of reality; it is an aid for understanding it. Contrary to this basic premise, with the 21st century has come a surge in computational efforts to model biological processes in great detail. Here we discuss the oxymoronic, realistic modeling of single neurons. This rapidly advancing field is driven by the discovery that some neurons don't merely sum their inputs and fire if the sum exceeds some threshold. Thus researchers have asked what are the computational abilities of single neurons and attempted to give answers using realistic models. We briefly review the state of the art of compartmental modeling highlighting recent progress and intrinsic flaws. We then attempt to address two fundamental questions. Practically, can we realistically model single neurons? Philosophically, should we realistically model single neurons? We use layer 5 neocortical pyramidal neurons as a test case to examine these issues. We subject three publically available models of layer 5 pyramidal neurons to three simple computational challenges. Based on their performance and a partial survey of published models, we conclude that current compartmental models are ad hoc, unrealistic models functioning poorly once they are stretched beyond the specific problems for which they were designed. We then attempt to plot possible paths for generating realistic single neuron models.

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Coordinating long-latency stretch responses across the shoulder, elbow, and wrist during goal-directed reaching

The long-latency stretch response (muscle activity 50–100 ms after a mechanical perturbation) can be coordinated across multiple joints to support goal-directed actions. Here we assessed the flexibility of such coordination and whether it serves to counteract intersegmental dynamics and exploit kinematic redundancy. In three experiments, participants made planar reaches to visual targets after elbow perturbations and we assessed the coordination of long-latency stretch responses across shoulder, elbow, and wrist muscles. Importantly, targets were placed such that elbow and wrist (but not shoulder) rotations could help transport the hand to the target—a simple form of kinematic redundancy. In experiment 1 we applied perturbations of different magnitudes to the elbow and found that long-latency stretch responses in shoulder, elbow, and wrist muscles scaled with perturbation magnitude. In experiment 2 we examined the trial-by-trial relationship between long-latency stretch responses at adjacent joints and found that the magnitudes of the responses in shoulder and elbow muscles, as well as elbow and wrist muscles, were positively correlated. In experiment 3 we explicitly instructed participants how to use their wrist to move their hand to the target after the perturbation. We found that long-latency stretch responses in wrist muscles were not sensitive to our instructions, despite the fact that participants incorporated these instructions into their voluntary behavior. Taken together, our results indicate that, during reaching, the coordination of long-latency stretch responses across multiple joints counteracts intersegmental dynamics but may not be able to exploit kinematic redundancy.

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Contextual processing in unpredictable auditory environments: the limited resource model of auditory refractoriness in the rhesus

Auditory refractoriness refers to the finding of smaller electroencephalographic (EEG) responses to tones preceded by shorter periods of silence. To date, its physiological mechanisms remain unclear, limiting the insights gained from findings of abnormal refractoriness in individuals with schizophrenia. To resolve this roadblock, we studied auditory refractoriness in the rhesus, one of the most important animal models of auditory function, using grids of up to 32 chronically implanted cranial EEG electrodes. Four macaques passively listened to sounds whose identity and timing was random, thus preventing animals from forming valid predictions about upcoming sounds. Stimulus onset asynchrony ranged between 0.2 and 12.8 s, thus encompassing the clinically relevant timescale of refractoriness. Our results show refractoriness in all 8 previously identified middle- and long-latency components that peaked between 14 and 170 ms after tone onset. Refractoriness may reflect the formation and gradual decay of a basic sensory memory trace that may be mirrored by the expenditure and gradual recovery of a limited physiological resource that determines generator excitability. For all 8 components, results were consistent with the assumption that processing of each tone expends ~65% of the available resource. Differences between components are caused by how quickly the resource recovers. Recovery time constants of different components ranged between 0.5 and 2 s. This work provides a solid conceptual, methodological, and computational foundation to dissect the physiological mechanisms of auditory refractoriness in the rhesus. Such knowledge may, in turn, help develop novel pharmacological, mechanism-targeted interventions.

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Rapid classification of hippocampal replay content for real-time applications

Sharp-wave ripple (SWR) events in the hippocampus replay millisecond-timescale patterns of place cell activity related to the past experience of an animal. Interrupting SWR events leads to learning and memory impairments, but how the specific patterns of place cell spiking seen during SWRs contribute to learning and memory remains unclear. A deeper understanding of this issue will require the ability to manipulate SWR events based on their content. Accurate real-time decoding of SWR replay events requires new algorithms that are able to estimate replay content and the associated uncertainty, along with software and hardware that can execute these algorithms for biological interventions on a millisecond timescale. Here we develop an efficient estimation algorithm to categorize the content of replay from multiunit spiking activity. Specifically, we apply real-time decoding methods to each SWR event and then compute the posterior probability of the replay feature. We illustrate this approach by classifying SWR events from data recorded in the hippocampus of a rat performing a spatial memory task into four categories: whether they represent outbound or inbound trajectories and whether the activity is replayed forward or backward in time. We show that our algorithm can classify the majority of SWR events in a recording epoch within 20 ms of the replay onset with high certainty, which makes the algorithm suitable for a real-time implementation with short latencies to incorporate into content-based feedback experiments.

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Developmental restoration of LTP deficits in heterozygous CaMKII{alpha} KO mice

The Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of long-term potentiation (LTP) and depression (LTD), two opposing forms of synaptic plasticity underlying learning, memory and cognition. The heterozygous CaMKIIα isoform KO (CaMKIIα^+/–) mice have a schizophrenia-related phenotype, including impaired working memory. Here, we examined synaptic strength and plasticity in two brain areas implicated in working memory, hippocampus CA1 and medial prefrontal cortex (mPFC). Young CaMKIIα^+/– mice (postnatal days 12–16; corresponding to a developmental stage well before schizophrenia manifestation in humans) showed impaired hippocampal CA1 LTP. However, this LTP impairment normalized over development and was no longer detected in older CaMKIIα^+/– mice (postnatal weeks 9–11; corresponding to young adults). By contrast, the CaMKIIα^+/– mice failed to show the developmental increase of basal synaptic transmission in the CA1 seen in wild-type (WT) mice, resulting in impaired basal synaptic transmission in the older CaMKIIα^+/– mice. Other electrophysiological parameters were normal, including mPFC basal transmission, LTP, and paired-pulse facilitation, as well as CA1 LTD, depotentiation, and paired-pulse facilitation at either age tested. Hippocampal CaMKIIα levels were ~60% of WT in both the older CaMKIIα^+/– mice and in the younger WT mice, resulting in ~30% of adult WT expression in the younger CaMKIIα^+/– mice; levels in frontal cortex were the same as in hippocampus. Thus, in young mice, ~30% of adult CaMKIIα expression is sufficient for normal LTD and depotentiation, while normal LTP requires higher levels, with ~60% of CaMKIIα expression sufficient for normal LTP in adult mice.

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Resveratrol defends blood-brain barrier integrity in experimental autoimmune encephalomyelitis mice

The mouse autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), is primarily characterized as dysfunction of the blood-brain barrier (BBB). Resveratrol exhibits anti-inflammatory, antioxidative, and neuroprotective activities. We investigated the beneficial effects of resveratrol in protecting the integrity of the BBB in EAE mice and observed improved clinical outcome in the EAE mice after resveratrol treatment. Evans blue (EB) extravasation was used to detect the disruption of BBB. Western blot were used to detected the tight junction proteins and adhesion molecules zonula occludens-1 (ZO-1), occludin, ICAM-1, and VCAM-1. Inflammatory factors inducible nitric oxide synthase (iNOS), IL-1β, and arginase 1 were evaluated by quantitative RT-PCR (qPCR) and IL-10 by ELISA. NADPH oxidase (NOX) levels were evaluated by qPCR, and its activity was analyzed by lucigenin-derived chemiluminescence. Resveratrol at doses of 25 and 50 mg/kg produced a dose-dependent decrease in EAE paralysis and EB leakage, ameliorated EAE-induced loss of tight junction proteins ZO-1, occludin, and claudin-5, as well as repressed the EAE-induced increase in adhesion proteins ICAM-1 and VCAM-1. In addition, resveratrol suppressed the EAE-induced overexpression of proinflammatory transcripts iNOS and IL-1β and upregulated the expression of anti-inflammatory transcripts arginase 1 and IL-10 cytokine in the brain. Furthermore, resveratrol downregulated the overexpressed NOX2 and NOX4 in the brain and suppressed NADPH activity. Resveratrol ameliorates the clinical severity of MS through maintaining the BBB integrity in EAE mice.

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A systematic analysis of neurons with large somatosensory receptive fields covering multiple body regions in the secondary somatosensory area of macaque monkeys

Previous neurophysiological studies performed in macaque monkeys have revealed complex somatosensory responses in the secondary somatosensory area (SII), such as large receptive fields (RFs), as well as bilateral ones. However, systematic analyses of neurons with large RFs have not been performed. In the present study, we recorded single-unit activities in SII of awake macaque monkeys to investigate systematically large RFs by dividing the whole body into four body regions (head, trunk, forelimb, and hindlimb). Recorded neurons were classified into two types, according to whether the RFs were confined to one body region: single (n = 817) and combined (n = 282) body-region types. These two types were distinct in terms of the percentage of bilateral RFs: 55% in the single-region type and 90% in the combined type, demonstrating that two types of RF enlargement occur simultaneously in the combined type, namely, RF convergence from different body regions and RF convergence from both hemibodies. Among the combined-type RFs, two tendencies of RF convergence were found: 1) the distal parts of the limbs (i.e., hand and foot) and the mouth are interconnected, and 2) the trunk RFs extend continuously toward the distal parts of the limb and head to cover the entire body surface. Our distribution analysis on unfolded maps clarified that neurons having RFs with these two tendencies were distributed within specific subregions in SII.

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Interactive effect of acute pain and motor learning acquisition on sensorimotor integration and motor learning outcomes

Previous work has demonstrated differential changes in early somatosensory evoked potentials (SEPs) when motor learning acquisition occurred in the presence of acute pain; however, the learning task was insufficiently complex to determine how these underlying neurophysiological differences impacted learning acquisition and retention. To address this limitation, we have utilized a complex motor task in conjunction with SEPs. Two groups of 12 participants (n = 24) were randomly assigned to either a capsaicin (capsaicin cream) or a control (inert lotion) group. SEP amplitudes were collected at baseline, after application, and after motor learning acquisition. Participants performed a motor acquisition task followed by a pain-free retention task within 24–48 h. After motor learning acquisition, the amplitude of the N20 SEP peak significantly increased (P < 0.05) and the N24 SEP peak significantly decreased (P < 0.001) for the control group while the N18 SEP peak significantly decreased (P < 0.01) for the capsaicin group. The N30 SEP peak was significantly increased (P < 0.001) after motor learning acquisition for both groups. The P25 SEP peak decreased significantly (P < 0.05) after the application of capsaicin cream. Both groups improved in accuracy after motor learning acquisition (P < 0.001). The capsaicin group outperformed the control group before motor learning acquisition (P < 0.05) and after motor learning acquisition (P < 0.05) and approached significance at retention (P = 0.06). Improved motor learning in the presence of capsaicin provides support for the enhancement of motor learning while in acute pain. In addition, the changes in SEP peak amplitudes suggest that early SEP changes reflect neurophysiological alterations accompanying both motor learning and mild acute pain.

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Synaptic and intrinsic homeostasis cooperate to optimize single neuron response properties and tune integrator circuits

Homeostatic processes that provide negative feedback to regulate neuronal firing rate are essential for normal brain function, and observations suggest that multiple such processes may operate simultaneously in the same network. We pose two questions: why might a diversity of homeostatic pathways be necessary, and how can they operate in concert without opposing and undermining each other? To address these questions, we perform a computational and analytical study of cell-intrinsic homeostasis and synaptic homeostasis in single-neuron and recurrent circuit models. We demonstrate analytically and in simulation that when two such mechanisms are controlled on a long time scale by firing rate via simple and general feedback rules, they can robustly operate in tandem to tune the mean and variance of single neuron's firing rate to desired goals. This property allows the system to recover desired behavior after chronic changes in input statistics. We illustrate the power of this homeostatic tuning scheme by using it to regain high mutual information between neuronal input and output after major changes in input statistics. We then show that such dual homeostasis can be applied to tune the behavior of a neural integrator, a system that is notoriously sensitive to variation in parameters. These results are robust to variation in goals and model parameters. We argue that a set of homeostatic processes that appear to redundantly regulate mean firing rate may work together to control firing rate mean and variance and thus maintain performance in a parameter-sensitive task such as integration.

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Contrasting roles of Ih and the persistent sodium current at subthreshold voltages during naturalistic stimuli

The subthreshold activity of hippocampal CA1 pyramidal neurons is regulated by the persistent sodium current (I_NaP) and the h-current (I_h), carried by tetrodotoxin-sensitive sodium channels and hyperpolarization-activated cyclic-nucleotide-gated channels, respectively. Recently, Yamada-Hanff and Bean (J Neurophysiol 114: 2376–2389, 2015) used pharmacological methods to discern the roles of I_h and I_NaP at subthreshold voltages during naturalistic stimuli. We discuss these findings in the context of dorsoventral heterogeneity in the hippocampus and suggest further applications of the method.

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Not an American cell phone... Full coverage !

Heroin works, annywhere, Mr. ..? A-ha: https://youtube/djV11Xbc914 http://ift.tt/2f8d2ev GSM, -Norwegian innvention. 4G+ is the "Hot stuff" here :-) ExEMTNor

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Not an American cell phone... Full coverage !

Heroin works, annywhere, Mr. ..? A-ha: https://youtube/djV11Xbc914 http://ift.tt/2f8d2ev GSM, -Norwegian innvention. 4G+ is the "Hot stuff" here :-) ExEMTNor

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Influence of exercise and aging on extracellular matrix composition in the skeletal muscle stem cell niche

Skeletal muscle is endowed with a remarkable capacity for regeneration, primarily due to the reserve pool of muscle resident satellite cells. The satellite cell is the physiologically quiescent muscle stem cell that resides beneath the basal lamina and adjacent to the sarcolemma. The anatomic location of satellite cells is in close proximity to vasculature where they interact with other muscle resident stem/stromal cells (e.g., mesenchymal stem cells and pericytes) through paracrine mechanisms. This mini-review describes the components of the muscle stem cell niche, as well as the influence of exercise and aging on the muscle stem cell niche. Although exercise promotes ECM reorganization and stem cell accumulation, aging is associated with dense ECM deposition and loss of stem cell function resulting in reduced regenerative capacity and strength. An improved understanding of the niche elements will be valuable to inform the development of therapeutic interventions aimed at improving skeletal muscle regeneration and adaptation over the life span.

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Deflation-activated receptors, not classical inflation-activated receptors, mediate the Hering-Breuer deflation reflex

Many airway sensory units respond to both lung inflation and deflation. Whether those responses to opposite stimuli come from one sensor (one-sensor theory) or more than one sensor (multiple-sensor theory) is debatable. One-sensor theory is commonly presumed in the literature. This article proposes a multiple-sensor theory in which a sensory unit contains different sensors for sensing different forces. Two major types of mechanical sensors operate in the lung: inflation- and deflation-activated receptors (DARs). Inflation-activated sensors can be further divided into slowly adapting receptors (SARs) and rapidly adapting receptors (RARs). Many SAR and RAR units also respond to lung deflation because they contain DARs. Pure DARs, which respond to lung deflation only, are rare in large animals but are easily identified in small animals. Lung deflation-induced reflex effects previously attributed to RARs should be assigned to DARs (including pure DARs and DARs associated with SARs and RARs) if the multiple-sensor theory is accepted. Thus, based on the information, it is proposed that activation of DARs can attenuate lung deflation, shorten expiratory time, increase respiratory rate, evoke inspiration, and cause airway secretion and dyspnea.

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Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality?

With advancing age, skeletal muscle function declines as a result of strength loss. These strength deficits are largely due to reductions in muscle size (i.e., quantity) and its intrinsic force-producing capacity (i.e., quality). Age-induced reductions in skeletal muscle quantity and quality can be the consequence of several factors, including accumulation of reactive oxygen and nitrogen species (ROS/RNS), also known as oxidative stress. Therefore, the purpose of this mini-review is to highlight the published literature that has demonstrated links between aging, oxidative stress, and skeletal muscle quantity or quality. In particular, we focused on how oxidative stress has the potential to reduce muscle quantity by shifting protein balance in a deficit, and muscle quality by impairing activation at the neuromuscular junction, excitation-contraction (EC) coupling at the ryanodine receptor (RyR), and cross-bridge cycling within the myofibrillar apparatus. Of these, muscle weakness due to EC coupling failure mediated by RyR dysfunction via oxidation and/or nitrosylation appears to be the strongest candidate based on the publications reviewed. However, it is clear that age-associated oxidative stress has the ability to alter strength through several mechanisms and at various locations of the muscle fiber.

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Effect of alterations in blood volume with bed rest on glucose tolerance

Bed rest leads to rapid impairments in glucose tolerance. Plasma volume and thus dilution space for glucose are also reduced with bed rest, but the potential influence on glucose tolerance has not been investigated. Accordingly, the aim was to investigate whether bed rest-induced impairments in glucose tolerance are related to a concomitant reduction in plasma volume. This hypothesis was tested mechanistically by restoring plasma volume with albumin infusion after bed rest and parallel determination of glucose tolerance. Fifteen healthy volunteers (age 24 ± 3 yr, body mass index 23 ± 2 kg/m², maximal oxygen uptake 44 ± 8 ml·min^–1·kg^–1; means ± SD) completed 4 days of strict bed rest. Glucose tolerance [oral glucose tolerance test (OGTT)] and plasma and blood volumes (carbon monoxide rebreathing) were assessed before and after 3 days of bed rest. On the fourth day of bed rest, plasma volume was restored by means of an albumin infusion prior to an OGTT. Plasma volume was reduced by 9.9 ± 3.0% on bed rest day 3 and area under the curve for OGTT was augmented by 55 ± 67%. However, no association (R² = 0.09, P = 0.33) between these simultaneously occurring responses was found. While normalization of plasma volume by matched albumin administration (408 ± 104 ml) transiently decreased (P < 0.05) resting plasma glucose concentration (5.0 ± 0.4 to 4.8 ± 0.3 mmol/l), this did not restore glucose tolerance. Bed rest-induced alterations in dilution space may influence resting glucose values but do not affect area under the curve for OGTT.

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Postinjury biomechanics of Achilles tendon vary by sex and hormone status

Achilles tendon ruptures are common injuries. Sex differences are present in mechanical properties of uninjured Achilles tendon, but it remains unknown if these differences extend to tendon healing. We hypothesized that ovariectomized females (OVX) and males would exhibit inferior postinjury tendon properties compared with females. Male, female, and OVX Sprague-Dawley rats (n = 32/group) underwent acclimation and treadmill training before blunt transection of the Achilles tendon midsubstance. Injured hindlimbs were immobilized for 1 wk, followed by gradual return to activity and assessment of active and passive hindlimb function. Animals were euthanized at 3 or 6 wk postinjury to assess tendon structure, mechanics, and composition. Passive ankle stiffness and range of motion were superior in females at 3 wk; however, by 6 wk, passive and active function were similar in males and females but remained inferior in OVX. At 6 wk, female tendons had greater normalized secant modulus, viscoelastic behavior, and laxity compared with males. Normalized secant modulus, cross-sectional area and tendon glycosaminoglycan composition were inferior in OVX compared with females at 6 wk. Total fatigue cycles until tendon failure were similar among groups. Postinjury muscle fiber size was better preserved in females compared with males, and females had greater collagen III at the tendon injury site compared with males at 6 wk. Despite male and female Achilles tendons withstanding similar durations of fatigue loading, early passive hindlimb function and tendon mechanical properties, including secant modulus, suggest superior healing in females. Ovarian hormone loss was associated with inferior Achilles tendon healing.

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Novel methodology to perform sulfur hexafluoride (SF6)-based multiple-breath wash-in and washout in infants using current commercially available equipment

Multiple-breath inert gas washout (MBW) is ideally suited for early detection and monitoring of serious lung disease, such as cystic fibrosis, in infants and young children. Validated commercial options for the MBW technique are limited, and suitability of nitrogen (N₂)-based MBW is of concern given the detrimental effect of exposure to pure O₂ on infant breathing pattern. We propose novel methodology using commercially available N₂ MBW equipment to facilitate 4% sulfur hexafluoride (SF₆) multiple-breath inert gas wash-in and washout suitable for the infant age range. CO₂, O₂, and sidestream molar mass sensor signals were used to accurately calculate SF₆ concentrations. An improved dynamic method for synchronization of gas and respiratory flow was developed to take into account variations in sidestream sample flow during MBW measurement. In vitro validation of triplicate functional residual capacity (FRC) assessments was undertaken under dry ambient conditions using lung models ranging from 90 to 267 ml, with tidal volumes of 28-79 ml, and respiratory rates 20–60 per minute. The relative mean (SD, 95% confidence interval) error of triplicate FRC determinations by washout was –0.26 (1.84, –3.86 to +3.35)% and by wash-in was 0.57 (2.66, –4.66 to +5.79)%. The standard deviations [mean (SD)] of percentage error among FRC triplicates were 1.40 (1.14) and 1.38 (1.32) for washout and wash-in, respectively. The novel methodology presented achieved FRC accuracy as outlined by current MBW consensus recommendations (95% of measurements within 5% accuracy). Further clinical evaluation is required, but this new technique, using existing commercially available equipment, has exciting potential for research and clinical use.

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Dissociation between short-term unloading and resistance training effects on skeletal muscle Na+,K+-ATPase, muscle function, and fatigue in humans

Physical training increases skeletal muscle Na⁺,K⁺-ATPase content (NKA) and improves exercise performance, but the effects of inactivity per se on NKA content and isoform abundance in human muscle are unknown. We investigated the effects of 23-day unilateral lower limb suspension (ULLS) and subsequent 4-wk resistance training (RT) on muscle function and NKA in 6 healthy adults, measuring quadriceps muscle peak torque; fatigue and venous [K⁺] during intense one-legged cycling exercise; and skeletal muscle NKA content ([³H]ouabain binding) and NKA isoform abundances (immunoblotting) in muscle homogenates (α_1-3, β_1–2) and in single fibers (α_1–3, β₁). In the unloaded leg after ULLS, quadriceps peak torque and cycling time to fatigue declined by 22 and 23%, respectively, which were restored with RT. Whole muscle NKA content and homogenate NKA α_1–3 and β_1–2 isoform abundances were unchanged with ULLS or RT. However, in single muscle fibers, NKA α₃ in type I (–66%, P = 0.006) and β₁ in type II fibers (–40%, P = 0.016) decreased after ULLS, with other NKA isoforms unchanged. After RT, NKA α₁ (79%, P = 0.004) and β₁ (35%, P = 0.01) increased in type II fibers, while α₂ (76%, P = 0.028) and α₃ (142%, P = 0.004) increased in type I fibers compared with post-ULLS. Despite considerably impaired muscle function and earlier fatigue onset, muscle NKA content and homogenate α₁ and α₂ abundances were unchanged, thus being resilient to inactivity induced by ULLS. Nonetheless, fiber type-specific downregulation with inactivity and upregulation with RT of several NKA isoforms indicate complex regulation of muscle NKA expression in humans.

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Evidence for the infiltration of gas bubbles into the arterial circulation and neuronal injury following "yo-yo" dives in pigs

"Yo-yo" diving may place divers at a greater risk of neurologic decompression illness (DCI). Using a rat model, we previously demonstrated that "yo-yo" diving has a protective effect against DCI. In the current study, we evaluated the risk of neurologic DCI following "yo-yo" dives in a pig model. Pigs were divided into four groups. The Control group (group A) made a square dive, without excursions to the surface ("peeps"). Group B performed two "peeps," group C performed four "peeps," and group D did not dive at all. All dives were conducted on air to 5 atm absolute, for 30-min bottom time. Echocardiography was performed to detect cardiac gas bubbles before the dive, immediately after, and at 90-min postdive. Motor performance was observed during the 5-h postdive period. Symptoms increased dramatically following a dive with four "peeps." Gas bubbles were detected in the right ventricle of all animals except for the sham group and in the left ventricle only after the four-peep dive. Neuronal cell injury was found in the spinal cord in each of the three experimental groups, tending to decrease with an increase in the number of "peeps." A four-peep "yo-yo" dive significantly increased the risk of neurologic DCI in pigs. Following a four-peep dive, we detected a higher incidence of bubbles in the left ventricle, supporting the common concern regarding an increased risk of neurologic DCI, albeit there was no direct correlation with the frequency of "red neurons" in the spinal cord.

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Validity and reliability of measuring resting muscle sympathetic nerve activity using short sampling durations in healthy humans

Resting muscle sympathetic nerve activity (MSNA) demonstrates high intraindividual reproducibility when sampled over 5–30 min epochs, although shorter sampling durations are commonly used before and during a stress to quantify sympathetic responsiveness. The purpose of the present study was to examine the intratest validity and reliability of MSNA sampled over 2 and 1 min and 30 and 15 s epoch durations. We retrospectively analyzed 68 resting fibular nerve microneurographic recordings obtained from 53 young, healthy participants (37 men; 23 ± 6 yr of age). From a stable 7-min resting baseline, MSNA (burst frequency and incidence, normalized mean burst amplitude, total burst area) was compared among each epoch duration and a standard 5-min control. Bland-Altman plots were used to determine agreement and bias. Three sequential MSNA measurements were collected using each sampling duration to calculate absolute and relative reliability (coefficients of variation and intraclass correlation coefficients). MSNA values were similar among each sampling duration and the 5-min control (all P > 0.05), highly correlated (r = 0.69–0.93; all P < 0.001), and demonstrated no evidence of fixed bias (all P > 0.05). A consistent proportional bias (P < 0.05) was present for MSNA burst frequency (all sampling durations) and incidence (1 min and 30 and 15 s), such that participants with low and high average MSNA underestimated and overestimated the true value, respectively. Reliability decreased progressively using the 30- and 15-s sampling durations. In conclusion, short 2 and 1 min and 30 s sampling durations can provide valid and reliable measures of MSNA, although increased sample size may be required for epochs ≤30 s, due to poorer reliability.

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Hypercapnic ventilatory response is decreased in a mouse model of excessive erythrocytosis

The impact of cerebral erythropoietin (Epo) in the regulation of the hypercapnic ventilatory response (HcVR) is controversial. While we reported that cerebral Epo does not affect the central chemosensitivity in C57Bl6 mice receiving an intracisternal injection of sEpoR (the endogenous antagonist of Epo), a recent study in transgenic mice with constitutive high levels of human Epo in brain and circulation (Tg6) and in brain only (Tg21), showed that Epo blunts the HcVR, maybe by interacting with central and peripheral chemoreceptors. High Epo serum levels in Tg6 mice lead to excessive erythrocytosis (hematocrit ~80–90%), the main symptom of chronic mountain sickness (CMS). These latter results support the hypothesis that reduced central chemosensitivity accounts for the hypoventilation observed in CMS patients. To solve this intriguing divergence, we reevaluate HcVR in Tg6 and Tg21 mouse lines, by assessing the metabolic rate [O consumption (V) and CO production (V)], a key factor modulating ventilation, the effect of which was not considered in the previous study. Our results showed that the decreased HcVR observed in Tg6 mice (~70% reduction; < 0.01) was due to a significant decrease in the metabolism (~40%; < 0.0001) rather than Epo's effect on CO chemosensitivity. Additional analysis in Tg21 mice did not reveal differences of HcVR or metabolism. We concluded that cerebral Epo does not modulate the central chemosensitivity system, and that a metabolic effect upon CO inhalation is responsible for decreased HcVR observed in Tg6 animals. As CMS patients also show decreased HcVR, our findings might help to better understand respiratory disorders at high altitude.

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Dorsomedial hypothalamic NPY affects cholecystokinin-induced satiety via modulation of brain stem catecholamine neuronal signaling

Increased neuropeptide Y (NPY) gene expression in the dorsomedial hypothalamus (DMH) has been shown to cause hyperphagia, but the pathway underlying this effect remains less clear. Hypothalamic neural systems play a key role in the control of food intake, in part, by modulating the effects of meal-related signals, such as cholecystokinin (CCK). An increase in DMH NPY gene expression decreases CCK-induced satiety. Since activation of catecholaminergic neurons within the nucleus of solitary tract (NTS) contributes to the feeding effects of CCK, we hypothesized that DMH NPY modulates NTS neural catecholaminergic signaling to affect food intake. We used an adeno-associated virus system to manipulate DMH NPY gene expression in rats to examine this pathway. Viral-mediated hrGFP anterograde tracing revealed that DMH NPY neurons project to the NTS; the projections were in close proximity to catecholaminergic neurons, and some contained NPY. Viral-mediated DMH NPY overexpression resulted in an increase in NPY content in the NTS, a decrease in NTS tyrosine hydroxylase (TH) expression, and reduced exogenous CCK-induced satiety. Knockdown of DMH NPY produced the opposite effects. Direct NPY administration into the fourth ventricle of intact rats limited CCK-induced satiety and overall TH phosphorylation. Taken together, these results demonstrate that DMH NPY descending signals affect CCK-induced satiety, at least in part, via modulation of NTS catecholaminergic neuronal signaling.

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Reassessing wanting and liking in the study of mesolimbic influence on food intake

Humans and animals such as rats and mice tend to overconsume calorie-dense foods, a phenomenon that likely contributes to obesity. One often-advanced explanation for why we preferentially consume sweet and fatty foods is that they are more "rewarding" than low-calorie foods. "Reward" has been subdivided into three interdependent psychological processes: hedonia (liking a food), reinforcement (formation of associations among stimuli, actions, and/or the food), and motivation (wanting the food). Research into these processes has focused on the mesolimbic system, which comprises both dopamine neurons in the ventral tegmental area and neurons in their major projection target, the nucleus accumbens. The mesolimbic system and closely connected structures are commonly referred to as the brain's "reward circuit." Implicit in this title is the assumption that "rewarding" experiences are generally the result of activity in this circuit. In this review, I argue that food intake and the preference for calorie-dense foods can be explained without reference to subjective emotions. Furthermore, the contribution of mesolimbic dopamine to food intake and preference may not be a general one of promoting or coordinating behaviors that result in the most reward or caloric intake but may instead be limited to the facilitation of a specific form of neural computation that results in conditioned approach behavior. Studies on the neural mechanisms of caloric intake regulation must address how sensory information about calorie intake affects not just the mesolimbic system but also many other forms of computation that govern other types of food-seeking and food-oriented behaviors.

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Effects of estrogen replacement on stress-induced cardiovascular responses via renin-angiotensin system in ovariectomized rats

The purpose of this study was to determine whether chronic estrogen replacement in ovariectomized rats inhibits the pressor response to psychological stress by attenuating the activation of the renin-angiotensin system. Female Wistar rats aged 9 wk were ovariectomized. After 4 wk, the rats were randomly assigned to be implanted subcutaneously with pellets containing either 17β-estradiol (E2) or placebo (Pla). After 4 wk of treatment, the rats underwent cage-switch stress and, in a separate experiment, a subset received an infusion of angiotensin II. The cage-switch stress rapidly elevated blood pressure (BP) and heart rate (HR) as measured by radiotelemetry in both groups. However, the BP and HR responses to the stress were significantly attenuated in the E2 group compared with the Pla group. An angiotensin II type 1 receptor blocker, losartan, given in drinking water, abolished the difference in the pressor response to stress between the two groups. Moreover, the stress-induced elevation in plasma renin activity and angiotensin II concentration was significant in the Pla group, but not in the E2 group. In addition, the expression of renin mRNA in the kidney was lower in the E2 group relative to the Pla group. Finally, we found that intravenous angiotensin II infusion increased BP and decreased HR to a similar degree in both groups. These results suggest that the inhibitory effects of estrogen on psychological stress-induced activation of the renin-angiotensin system could be at least partially responsible for the suppression of the pressor responses to psychological stress seen in estrogen-replaced ovariectomized rats.

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Advances in Technology: Blood-sampling at depth. Focus on "Development of an animal-borne blood sample collection device and its deployment for the determination of cardiovascular and stress hormones in submerged phocid seals"

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Endothelial and inflammatory responses to acute exercise in perimenopausal and late postmenopausal women

Endothelial dysfunction and inflammation are characteristics of subclinical atherosclerosis and may increase through progressive menopausal stages. Evaluating endothelial responses to acute exercise can reveal underlying dysfunction not apparent in resting conditions. The purpose of this study was to investigate markers of endothelial function and inflammation before and after acute exercise in healthy low-active perimenopausal (PERI) and late postmenopausal (POST) women. Flow-mediated dilation (FMD), CD31⁺/CD42b^– and CD62E⁺ endothelial microparticles (EMPs), and the circulating inflammatory factors monocyte chemoattractant protein 1 (MCP-1), interleukin 8 (IL-8), and tumor necrosis factor-α (TNF-α) were measured before and 30 min after acute exercise. Before exercise, FMD was not different between groups (PERI: 6.4 ± 0.9% vs. POST: 6.5 ± 0.8%, P = 0.97); however, after acute exercise PERI tended to improve FMD (8.5 ± 0.9%, P = 0.09), whereas POST did not (6.2 ± 0.8%, P = 0.77). Independent of exercise, we observed transient endothelial dysfunction in POST with repeated FMD measures. There was a group x exercise interaction for CD31⁺/CD42b^– EMPs (P = 0.04), where CD31⁺/CD42b^– EMPs were similar before exercise (PERI: 57.0 ± 6.7 EMPs/μl vs. POST: 58.5 ± 5.3 EMPs/μl, P = 0.86) but were higher in POST following exercise (PERI: 48.2 ± 6.7 EMPs/μl vs. POST: 69.4 ± 5.3 EMPs/μl, P = 0.023). CD62E⁺ EMPs were lower in PERI compared with POST before exercise (P < 0.001) and increased in PERI (P = 0.04) but did not change in POST (P = 0.68) in response to acute exercise. After acute exercise, MCP-1 (P = 0.055), TNF-α (P = 0.02), and IL-8 (P < 0.001) were lower in PERI but only IL-8 decreased in POST (P < 0.001). Overall, these data suggest that perimenopausal and late postmenopausal women display different endothelial and inflammatory responses to acute exercise.

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Nitric oxide synthase-mediated blood pressure regulation in obese melanocortin-4 receptor-deficient pregnant rats

Although obesity increases the risk for hypertension in pregnancy, the mechanisms responsible are unknown. Increased nitric oxide (NO) production results in vasodilation and reduced blood pressure during normal pregnancy in lean rats; however, the role of NO is less clear during obese pregnancies. We examined the impact of obesity on NO synthase (NOS)-mediated regulation of blood pressure during pregnancy by testing the hypothesis that NOS activity, expression, and regulation of vascular tone and blood pressure are reduced in obese pregnant rats. At gestational day 19, melanocortin-4 receptor (MC4R)-deficient obese rats (MC4R) had greater body weight and fat mass with elevated blood pressure and circulating sFlt-1 levels compared with MC4R pregnant rats. MC4R pregnant rats also had less circulating cGMP levels and reduced total NOS enzymatic activity and expression in mesenteric arteries. Despite decreased biochemical measures of NO/NOS in MC4R rats, NOS inhibition enhanced vasoconstriction only in mesenteric arteries from MC4R rats, suggesting greater NOS-mediated tone. To examine the role of NOS on blood pressure regulation in obese pregnant rats, MC4R and MC4R pregnant rats were administered the nonselective NOS inhibitor N^G-nitro-l-arginine methyl ester (l-NAME, 100 mg/l) from gestational day 14 to 19 in drinking water. The degree by which l-NAME raised blood pressure was similar between obese and lean pregnant rats. Although MC4R obese pregnant rats had elevated blood pressure associated with reduced total NOS activity and expression, they had enhanced NOS-mediated attenuation of vasoconstriction, with no evidence of alterations in NOS-mediated regulation of blood pressure.

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Chronic binge alcohol administration impairs glucose-insulin dynamics and decreases adiponectin in asymptomatic simian immunodeficiency virus-infected macaques

Alcohol use disorders (AUDs) frequently exist among persons living with HIV/AIDS. Chronic alcohol consumption, HIV infection, and antiretroviral therapy (ART) are independently associated with impairments in glucose-insulin dynamics. Previous studies from our laboratory have shown that chronic binge alcohol (CBA) administration decreases body mass index, attenuates weight gain, and accentuates skeletal muscle wasting at end-stage disease in non-ART-treated simian immunodeficiency virus (SIV)-infected male rhesus macaques. The aim of this study was to investigate whether CBA and ART alone or in combination alter body composition or glucose-insulin dynamics in SIV-infected male rhesus macaques during the asymptomatic phase of SIV infection. Daily CBA or sucrose (SUC) administration was initiated 3 mo before intrarectal SIV inoculation and continued until the study end point at 11 mo post-SIV infection. ART or placebo was initiated 2.5 mo after SIV infection and continued until study end point. Four treatment groups (SUC/SIV ± ART and CBA/SIV ± ART) were studied. CBA/SIV macaques had significantly decreased circulating adiponectin and resistin levels relative to SUC/SIV macaques and reduced disposition index and acute insulin response to glucose, insulin, and C-peptide release during frequently sampled intravenous glucose tolerance test, irrespective of ART status. No statistically significant differences were observed in homeostatic model assessment-insulin resistance values, body weight, total body fat, abdominal fat, or total lean mass or bone health among the four groups. These findings demonstrate CBA-mediated impairments in glucose-insulin dynamics and adipokine profile in asymptomatic SIV-infected macaques, irrespective of ART.

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Hypoxia-induced contraction of chicken embryo mesenteric arteries: mechanisms and developmental changes

The fetal cardiovascular responses to acute hypoxia include a redistribution of the cardiac output toward the heart and the brain at the expense of other organs, such as the intestine. We hypothesized that hypoxia exerts a direct effect on the mesenteric artery (MA) that may contribute to this response. Using wire myography, we investigated the response to hypoxia (Po₂ ~2.5 kPa for 20 min) of isolated MAs from 15- to 21-day chicken embryos (E15, E19, E21), and 1- to 45-day-old chickens (P1, P3, P14, P45). Agonist-induced pretone or an intact endothelium were not required to obtain a consistent and reproducible response to hypoxia, which showed a pattern of initial rapid phasic contraction followed by a sustained tonic contraction. Phasic contraction was reduced by elimination of extracellular Ca²⁺ or by presence of the neurotoxin tetrodotoxin, the α₁-adrenoceptor antagonist prazosin, or inhibitors of L-type voltage-gated Ca²⁺ channels (nifedipine), mitochondrial electron transport chain (rotenone and antimycin A), and NADPH oxidase (VAS2870). The Rho-kinase inhibitor Y27632 impaired both phasic and tonic contraction and, when combined with elimination of extracellular Ca²⁺, hypoxia-induced contraction was virtually abolished. Hypoxic MA contraction was absent at E15 but present from E19 and increased toward the first days posthatching. It then decreased during the first weeks of life and P45 MAs were unable to sustain hypoxia-induced contraction over time. In conclusion, the results of the present study demonstrate that hypoxic vasoconstriction is an intrinsic feature of chicken MA vascular smooth muscle cells during late embryogenesis and the perinatal period.

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Metabolic pathways of lung inflammation revealed by high-resolution metabolomics (HRM) of H1N1 influenza virus infection in mice

Influenza is a significant health concern worldwide. Viral infection induces local and systemic activation of the immune system causing attendant changes in metabolism. High-resolution metabolomics (HRM) uses advanced mass spectrometry and computational methods to measure thousands of metabolites inclusive of most metabolic pathways. We used HRM to identify metabolic pathways and clusters of association related to inflammatory cytokines in lungs of mice with H1N1 influenza virus infection. Infected mice showed progressive weight loss, decreased lung function, and severe lung inflammation with elevated cytokines [interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-] and increased oxidative stress via cysteine oxidation. HRM showed prominent effects of influenza virus infection on tryptophan and other amino acids, and widespread effects on pathways including purines, pyrimidines, fatty acids, and glycerophospholipids. A metabolome-wide association study (MWAS) of the aforementioned inflammatory cytokines was used to determine the relationship of metabolic responses to inflammation during infection. This cytokine-MWAS (cMWAS) showed that metabolic associations consisted of distinct and shared clusters of 396 metabolites highly correlated with inflammatory cytokines. Strong negative associations of selected glycosphingolipid, linoleate, and tryptophan metabolites with IFN- contrasted strong positive associations of glycosphingolipid and bile acid metabolites with IL-1β, TNF-α, and IL-10. Anti-inflammatory cytokine IL-10 had strong positive associations with vitamin D, purine, and vitamin E metabolism. The detailed metabolic interactions with cytokines indicate that targeted metabolic interventions may be useful during life-threatening crises related to severe acute infection and inflammation.

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Predominant cause of prolonged low-frequency force depression changes during recovery after in situ fatiguing stimulation of rat fast-twitch muscle

To investigate time-dependent changes in sarcoplasmic reticulum (SR) Ca²⁺ release and myofibrillar (my-) Ca²⁺ sensitivity during recovery from prolonged low-frequency force depression (PLFFD), rat gastrocnemius muscles were electrically stimulated in situ. After 0 h (R0), 0.5 h (R0.5), 2 h (R2), 6 h (R6), or 12 h of recovery, the superficial gastrocnemius muscles were excised and used for biochemical and skinned fiber analyses. At R0, R0.5, R2, and R6, the ratio of force at 1 Hz to that at 50 Hz was decreased in the skinned fibers. The ratio of depolarization-induced force to the maximum Ca²⁺-activated force (depol/Ca²⁺ force ratio) was utilized as an indicator of SR Ca²⁺ release. At R0, both the depol/Ca²⁺ force ratio and my-Ca²⁺ sensitivity were decreased. At R0.5 and R2, my-Ca²⁺ sensitivity was recovered, while the depol/Ca²⁺ force ratio remained depressed. At R6, my-Ca²⁺ sensitivity was decreased again, whereas the depol/Ca²⁺ force ratio was nearly restored. Western blot analyses demonstrated that decreased my-Ca²⁺ sensitivity at R6 and reduced depol/Ca²⁺ force ratio at R0, R0.5, and R2 were accompanied by depressions in S-glutathionylated troponin I and increases in dephosphorylated ryanodine receptor 1, respectively. These results indicate that, in the early stage of recovery, reduced SR Ca²⁺ release plays a primary role in the etiology of PLFFD, whereas decreased my-Ca²⁺ sensitivity is involved in the late stage, and suggest that S-glutathionylation of troponin I and dephosphorylation of ryanodine receptor 1 contribute, at least partly, to fatiguing contraction-induced alterations in my-Ca²⁺ sensitivity and SR Ca²⁺ release, respectively.

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Carotid baroreflex function at the onset of cycling in men

Arterial baroreflex function is important for blood pressure control during exercise, but its contribution to cardiovascular adjustments at the onset of cycling exercise remains unclear. Fifteen healthy male subjects (24 ± 1 yr) performed 45-s trials of low- and moderate-intensity cycling, with carotid baroreceptor stimulation by neck suction at –60 Torr applied 0–5, 10–15, and 30–35 s after the onset of exercise. Cardiovascular responses to neck suction during cycling were compared with those obtained at rest. An attenuated reflex decrease in heart rate following neck suction was detected during moderate-intensity exercise, compared with the response at rest (P < 0.05). Furthermore, compared with the reflex decrease in blood pressure elicited at rest, neck suction elicited an augmented decrease in blood pressure at 0–5 and 10–15 s during low-intensity exercise and in all periods during moderate-intensity exercise (P < 0.05). The reflex depressor response at the onset of cycling was primarily mediated by an increase in the total vascular conductance. These findings evidence altered carotid baroreflex function during the first 35 s of cycling compared with rest, with attenuated bradycardic response, and augmented depressor response to carotid baroreceptor stimulation.

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Multiple Patient Reported Allergies are Associated with Worse Outcomes following Lumbar Spine Surgery

BACKGROUND CONTEXT: Recent studies have shown that multiple self-reported allergies independently predict worse outcomes following total joint arthroplasty. This is consistent with prior studies in spinal surgery suggesting that mental health measures such as SF-36 Mental Composite Score or the Distress and Risk Assessment Method (DRAM) correlate with clinical outcome. As opposed to those measures (Unlike those measures …?, allergies are a potentially useful predictor variable as they are routinely collected in every patient.

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A highly efficient method for enriching TALEN or CRISPR/Cas9-edited mutant cells

Publication date: Available online 1 November 2016
Source:Journal of Genetics and Genomics
Author(s): Hideyo Yasuda, Eunsu Kim, Abu Musa Md Talimur Reza, Jin-Hoi Kim




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miR-503-3p promotes epithelial–mesenchymal transition in breast cancer by directly targeting SMAD2 and E-cadherin

Publication date: Available online 1 November 2016
Source:Journal of Genetics and Genomics
Author(s): Zitong Zhao, Xinyi Fan, Lanfang Jiang, Zhongqiu Xu, Liyan Xue, Qimin Zhan, Yongmei Song
Although progress in clinical and basic research has significantly increased our understanding of breast cancer, little is known about the molecular mechanism underlying breast cancer metastasis. Identification of effective therapeutic targets to prevent breast cancer metastasis is urgently needed. The function of miR-503-3p has been investigated in other cancers, but its role in breast cancer remains undefined. Here, we found that miR-503-3p was overexpressed in breast cancer tissue and plasma compared with adjacent normal breast tissue and with plasma from healthy individuals. Moreover, we identified miR-503-3p to be an oncogene of breast cancer cell proliferation, migration and invasion. Upregulation of miR-503-3p in breast cancer cells inhibited expression of epithelial–mesenchymal transition (EMT)-related protein SMAD2 and the epithelial marker protein E-cadherin by directly binding to their mRNA 3′untranslated region, whereas increased expression of mesenchymal marker proteins, including vimentin and N-cadherin. Taken together, our findings support a critical role for miR-503-3p in induction of breast cancer EMT and suggest that plasma miR-503-3p may be a useful diagnostic biomarker for breast cancer.



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Synthetic Cannabinoid Receptor Agonists (SCRAs) Induced Seizure: A Case Report

2016-11-01T15-47-18Z
Source: Bağımlılık Dergisi - Journal of Dependence
Merih Altıntaş, Murat Kuru.
With an ever-increasing prevalence, exposing new challenges to healthcare personnel, the use of synthetic cannabinoid receptor agonists (SCRAs) affects many systems. Clinical manifestations that may be caused by it become more predictable day by day thanks to increasing number of case reports on this issue. The use of these substances gives rise to serious side effects, which in turn affect psychiatric, neurological, cardiovascular, renal and pulmonary systems. Recently, we also witness a growing number of reports indicating that SCRAs would lead to seizures. It is considered that notably the patients referred to emergency rooms due to SCRA induced toxicity may be experiencing a series of life-threatening clinical presentations, one of which would probably be seizure, and which may sometimes require intensive care follow-up. This shows that all clinicians and the society should be highly aware of and get prepared for potential hazards to be triggered by use of SCRAs. This report makes mention of a case where a patient without any record of seizure in his medical history, who experienced his first epileptic seizure following SCRAs induced intoxication, and where the seizure was hardly terminated.


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The Royal Road to the Obesity: A Case Report of Food Addiction

2016-11-01T15-47-18Z
Source: Bağımlılık Dergisi - Journal of Dependence
Ali Kandeğer, Hasan Bozkurt.
Increasing prevalence of obesity in the world and increasing role of processed foods in daily life has led to become the focal point of food addiction. In recent years, the animal studies and human brain imaging studies demonstrated the neurobiological and behavioral similarities between drug addiction and food addiction. Here, we aim to present a 13 year-old, female, adolescent who applied with complaints of anger and irritability and shows serious addictive behaviors of chocolate. Our patient with increasing chocolate consumption in the last two years was using atomoxetine 60 mg/day with ADHD. She gradually needs to more chocolate to be satisfied. She has complained of nervousness, irritability and serious chocolate-seeking behavior during chocolate deprivation. She gained weight in proportion to the increase in chocolate consumption. Her daily diet was increasingly deteriorated. We used behavioral approach and sertraline in her treatment and were observed that partially benefit from treatment. Combined data from retrospective accounts of adults and prospective observations of youth indicates that juveniles with ADHD are at increased risk for cigarette smoking and substance abuse and behavioral addiction such as internet addiction, gambling and sex addiction during adolescence. Recognition of the food addiction is important to fight against obesity, strengthening the treatment of choice in the food addiction and take political measures against food addiction is becoming inevitable.


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The Relationship between Perceived Parental Acceptance-Rejection and Self Destructive Behavior, Suicidal Ideation and Childhood Traumas in Cannabis Users

2016-11-01T15-47-18Z
Source: Bağımlılık Dergisi - Journal of Dependence
Sevim Berrin İnci, Melis İpçi, Ayşe Ender Altıntoprak, Ülkü Akyol Ardıç, Eyüp Sabri Ercan.
Objective: The purpose of the study was to explore the relationship between perceived parental acceptance-rejection in childhood and self destructive behavior, suicidal ideation and childhood traumas. Method: The sample consisted of 75 cannabis users men and control group that includes 75 men aged between 18-45 years of age.Cannabis users were enrolled in probationers from substance dependence unit in department of Psychiatry of the Ege University during the first consultation. The study consisted of 75 cannabis users men and control group that includes 75 men. Data were collected via the Demographic Information Form, Parental Acceptance-Rejection Questionnaire and Suicidal Behavior scale. MANOVA, Regression, t-test and Pearson Correlation Coefficient were performed. Results: The results showed that cannabis users perceived more reject from their parents. The findings revealed that there is a relationship between perceived parental acceptance-rejection and physical, verbal and emotional abuse in childhood. Cannabis users were more exposed to trauma in childhood than control group. In addition, suicial ideation was significantly associated with perceived acceptance from mother, also self-destructive behavior was associated with perceived acceptance from father. Conclusion: This study revealed that parental acceptance-rejection in cannabis users should be considered as a significant variable for self-destructive behavior, suicidal ideation and chidhood traumas.


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Validity and Reliability of DSM-5 Level 2 Substance Use Disorder Scale- Turkish Version

2016-11-01T15-47-18Z
Source: Bağımlılık Dergisi - Journal of Dependence
Şermin Yalın Sapmaz, Enis Sargın, Canem Ergin, Handan Özek Erkuran, Masum Öztürk, Ömer Aydemir.
Introduction: This study aimed to assess the validity and reliability of Turkish version of DSM-5 Level 2 Substance Use Disorder Scale. Methods: Study groups consisted of a clinical sample diagnosed with substance use disorder being treated in a child psychiatry unit and a community sample. A total number of 92 parents and 128 adolescents were included in the study. Clinical sample consisted of 34 adolescents between 11-17 years old that were diagnosed with substance use disorder according to DSM-5 diagnostic criteria and being followed up in Celal Bayar University Medical School Child Psychiatry Unit and Alcohol and Substance Treatment Unit for Children and Adolescents of Tepecik Research and Training Hospital and 33 parents. Addiction Profile Index for Adolescents (BAPI) form was used along with DSM-5 Level 2 Substance Use Disorder Scale for assessment. For reliability analyses, internal consistency coefficient and item-total score correlation analysis were carried out while concurrent validity was measured for validity analyses as well as developing ROC curve to identify discriminative quality of the scale regarding clinical and community samples. Results: Cronbach alpha internal consistency coefficient was found as 0.847 and 0.760 for child and parent forms, respectively as the result of reliability analyses. Regarding concurrent validity, correlation of the scales child form with BAPI- Adolescent form was 0.742. Area under the ROC curve as a result of ROC analysis yielded a measure of 0.964 for child form and 0.990 for parent form. Conclusion: Results indicate that DSM-5 Level 2 Substance Use Disorder Scale- Turkish Version could be utilized as a valid and reliable instrument for both clinical and research purposes.


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Description and Features of Risky Alcohol Drinking Behaviour

2016-11-01T15-47-18Z
Source: Bağımlılık Dergisi - Journal of Dependence
Erdal Vardar.
Today, alcohol one of the most popular substance in the world. There are various characteristics of alcohol consumption behaviour person to person. Also, there are social inequalities in drinking behaviors between the countries. The consume of four to five drink in a single occasion is a Risky single-occasion drinking (RSOD) behaviour sample. Risky single-occasion drinking (RSOD) is more common in late adolescence and early adulthood than in older age. Recently, RSOD has remarkable possible and negative health effects was depicted. Espacially adolescent and young people consume alcohol as risky drinking behaviour for joyfull activities. This is also the age when young people in most countries are legally allowed to buy and drink alcohol, but they usually do not yet have adult responsibilities. For these reason, Adolescent and young persons are the most risky group for the RSOD behaviour. Finally, this trouble has more attracht attention because of the adolescent have a lot of hospital admission due to alcohol intoxication, about negatif health effects and legal issuese. This paper reviews of literature about RSOD and provides prevention of the RSOD.


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Convergence of CSA and CSB [Genetics]

Cockayne syndrome is a neurodegenerative accelerated aging disorder caused by mutations in the CSA or CSB genes. Although the pathogenesis of Cockayne syndrome has remained elusive, recent work implicates mitochondrial dysfunction in the disease progression. Here, we present evidence that loss of CSA or CSB in a neuroblastoma cell line...

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Ataluren promotes nonsense suppression [Genetics]

A premature termination codon (PTC) in the ORF of an mRNA generally leads to production of a truncated polypeptide, accelerated degradation of the mRNA, and depression of overall mRNA expression. Accordingly, nonsense mutations cause some of the most severe forms of inherited disorders. The small-molecule drug ataluren promotes therapeutic nonsense...

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Inheritance of extracellular RNAs [Genetics]

Experiences during the lifetime of an animal have been proposed to have consequences for subsequent generations. Although it is unclear how such intergenerational transfer of information occurs, RNAs found extracellularly in animals are candidate molecules that can transfer gene-specific regulatory information from one generation to the next because they can...

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Proposing a mechanism of action for ataluren [Genetics]

Protein synthesis follows the advice given in Alice in Wonderland: "'Begin at the beginning,' the King said gravely, 'and go on till you come to the end: then stop.'" (1). For most protein synthesis, "the beginning" is the first methionine codon (AUG) encountered by the ribosome downstream of the cap,...

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Genomic village [Genetics]

Genome sequencing has progressed incredibly in the past 15 y since the original human genome sequence reports were published (1). Medical genome sequencing has certainly advanced, from the early sequencing of healthy individuals (2), and families with genetic disease (3), to individual rare children with previously undescribed syndromes (4, 5)....

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Acute Rheumatic Fever: Global Persistence of a Preventable Disease

The persistence of acute rheumatic fever continues to be seen globally. Once thought to be eradicated in various parts of the world, the disease came back with a vengeance secondary to a lack of diligence on the part of providers. Today, the global burden of group A streptococcal infection, the culprit of the numerous sequelae manifested in acute rheumatic fever, is considerable. Although a completely preventable disease, rheumatic fever continues to exist. It is a devastating disease that involves long-term, multisystem treatment and monitoring for patients who were unsuccessful at eradicating the precipitating group A streptococcal infection.

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G-Shock introduces olive green color for GravityMaster

New Flight Jacket-Inspired Design for the Aviation Timepiece

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Clonal Spread of Colistin-Resistant Klebsiella pneumoniae Coproducing KPC and VIM Carbapenemases in Neonates at a Tunisian University Hospital

Microbial Drug Resistance , Vol. 0, No. 0.


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Chest pain, dysphagia and hematemesis in a new mother

A 37-year-old pregnant woman underwent urgent cesarean section at 32 weeks for eclampsia. The day of birth she presented with a hypertensive crisis that was resolved with medical therapy. Two days later she reported acute chest pain and dysphagia followed by hematemesis. An urgent upper endoscopy was performed. Immediately below the superior esophageal sphincter, a large, purple, non-pulsatile mass tearing the mucosa and protruding into the lumen was documented (Fig. 1A and B). Because the lesion occluded the esophageal lumen, the procedure was aborted.

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Chest pain, dysphagia and hematemesis in a new mother

A 37-year-old pregnant woman underwent urgent cesarean section at 32 weeks for eclampsia. The day of birth she presented with a hypertensive crisis that was resolved with medical therapy. Two days later she reported acute chest pain and dysphagia followed by hematemesis. An urgent upper endoscopy was performed. Immediately below the superior esophageal sphincter, a large, purple, non-pulsatile mass tearing the mucosa and protruding into the lumen was documented (Fig. 1A and B). Because the lesion occluded the esophageal lumen, the procedure was aborted.

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Sustaining and Expanding Evidence-Based Supported Employment: The Role of State Leaders Participating in a Learning Community

Abstract

State leaders often promote implementation of evidence-based practices but have difficulty sustaining and expanding them over time. This paper examines the activities of leaders in 13 states that have successfully implemented, sustained, and expanded evidence-based supported employment, known as Individual Placement and Support (IPS), for 4 to 12 years. We interviewed state leaders from 13 states participating in a learning community regarding the composition of their leadership team, participation in the learning community, interagency collaboration, state policy alignment, financing, training, and monitoring of fidelity and outcome. To assess state-level performance in implementing, sustaining, and expanding IPS services, we obtained measures of sustainment, expansion, program fidelity, and employment in the subsequent year and compared them to a priori benchmarks. The majority of states (between 69 % and 77 %) met benchmarks for sustainment, expansion, fidelity, and employment. States varied widely in specific actions to advance IPS, but all had established leadership teams, participated in the national learning community, and built an infrastructure supporting IPS. Leaders in 13 states participating in a learning community have adopted and maintained multiple strategies to sustain and expand evidence-based supported employment at a high level of fidelity with good employment outcomes.

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A comparison of single-handed chin lift and two-handed jaw thrust for tracheal intubation using a lightwand

Abstract

Purpose

In the present study, we evaluated the effects of single-handed chin lift and two-handed jaw thrust on lightwand-guided intubation and postoperative sore throat.

Methods

Sixty adult patients were included in the study. After induction of anesthesia, intubation was performed using a lightwand under single-handed chin lift or two-handed jaw thrust. In the single-handed chin lift group, the lightwand was inserted with the right hand after the mandible was lifted by placing the thumb of the left hand into the mouth. In the two-handed jaw thrust group, the lightwand was inserted while jaw thrust was achieved by an assistant using two hands. Lightwand search time, number of intubation attempts, and time to achieve intubation were assessed. Heart rate and mean arterial pressure were measured before and after intubation. Postoperative sore throat was evaluated at 1 and 24 h after surgery.

Results

Lightwand search time was significantly shorter in the two-handed jaw thrust group compared to the single-handed chin lift group (7.2 ± 4.6 vs. 12.1 ± 9.1 s, respectively; p = 0.016). The two-handed jaw thrust group had shorter intubation time than the single-handed chin lift group (21.0 ± 6.6 vs. 27.9 ± 9.9 s, respectively; p = 0.004). The number of intubation attempts and hemodynamic changes during intubation were similar between the two groups. The incidence and severity of postoperative sore throat were lower at 24 h after surgery in the two-handed jaw thrust group compared with the single-handed chin lift group (p = 0.011).

Conclusions

The two-handed jaw thrust facilitated lightwand-guided intubation, and reduced the incidence and severity of postoperative sore throat compared to the single-handed chin lift.

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Magnesium in obstetric anesthesia and intensive care

Abstract

Magnesium, one of the essential elements in the human body, has numerous favorable effects that offer a variety of possibilities for its use in obstetric anesthesia and intensive care. Administered as a single intravenous bolus dose or a bolus followed by continuous infusion during surgery, magnesium attenuates stress response to endotracheal intubation, and reduces intraoperative anesthetic and postoperative analgesic requirements, while at the same time preserving favorable hemodynamics. Applied as part of an intrathecal or epidural anesthetic mixture, magnesium prolongs the duration of anesthesia and diminishes total postoperative analgesic consumption with no adverse maternal or neonatal effects. In obstetric intensive care, magnesium represents a first-choice medication in the treatment and prevention of eclamptic seizures. If used in recommended doses with close monitoring, magnesium is a safe and effective medication.

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Outcomes of physician patients after non-cardiac surgery: a registry analysis

Abstract

Objectives

When physicians become patients, they may expect special privileges, extra attention from caregivers, and non-routine treatments. Consequently, physician patients may not be treated per routine—which possibly worsens care rather than improving it. We thus tested the primary hypothesis that in-hospital mortality and major complications after non-cardiac surgery are more common in physician patients than in non-physician patients.

Patients and methods

Perioperative data were extracted for patients who had non-cardiac surgery at the Cleveland Clinic between 2005 and 2013. We used propensity score matching to identify comparable groups of physician and non-physician patients. Matched physician and non-physician patients were compared on a composite of in-hospital mortality and major postoperative complications using a generalized equation average relative effects model. Secondly, the matched patients were also compared on reoperation using logistic regression and on duration of hospitalization using Kaplan–Meier analysis with the log-rank test and Cox proportional hazards regression.

Results

Among 21,173 qualifying patients, we matched 522 physician patients to 2448 non-physician controls. There were no significant differences between physician and non-physician patients in the composite of in-hospital mortality and major complications, with an estimated odds ratio across the outcome components (average relative effect) of 1.20 (95% confidence interval 0.77–1.87) for physicians vs. non-physicians, P = 0.41. There was also no difference in the risk of re-operation or duration of hospitalization.

Conclusions

A variety of important outcomes were similar in physician patients and matched non-physician patients after non-cardiac surgery.

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Non-coding variation in Disorders of Sex Development

ABSTRACT

Genetic studies in Disorders of Sex Development (DSD), representing a wide spectrum of developmental or functional conditions of the gonad, have mainly been oriented towards the coding genome. Application of genomic technologies, such as whole exome sequencing, result in a molecular genetic diagnosis in ~50% of cases with DSD. Many of the genes mutated in DSD encode transcription factors such as SRY, SOX9, NR5A1, and FOXL2, characterized by a strictly regulated spatiotemporal expression. Hence, it can be hypothesized that at least part of the missing genetic variation in DSD can be explained by non-coding mutations in regulatory elements that alter gene expression, either by reduced, mis- or overexpression of their target genes. In addition, structural variations such as translocations, deletions, duplications or inversions can affect the normal chromatin conformation by different mechanisms.

Here, we review non-coding defects in human DSD phenotypes and in animal models. The wide variety of non-coding defects found in DSD emphasizes that the regulatory landscape of known and to be discovered DSD genes has to be taken into consideration when investigating the molecular pathogenesis of DSD.

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