Τετάρτη, 18 Οκτωβρίου 2017

Reduction of Recurrence Risk of Pancreatitis in Cystic Fibrosis with Ivacaftor: Case Series.

The effect of ivacaftor in cystic fibrosis (CF) patients with recurrent pancreatitis is unknown. We conducted a multicenter retrospective study of CF patients taking ivacaftor who had a history of recurrent pancreatitis. During the first three months of therapy, only one of the six patients had an episode of pancreatitis, which was managed on an outpatient basis. Between three and twelve months on ivacaftor therapy, none of the patients had recurrence of pancreatitis or required hospitalization. The use of ivacaftor was associated with a reduced frequency and recurrence rate of pancreatitis in CF patients. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Choice of Endoscopic Procedure in Children With Clinically Suspected Gastrointestinal Graft-Versus-Host Disease.

Objectives: Gastrointestinal graft-versus-host disease (GI-GVHD) is a potentially life-threatening complication after hematopoietic stem cell transplantation. Symptoms indicating GI-GVHD motivates endoscopy with biopsy sampling and histopathological confirmation. However, optimal extent of endoscopy in children is presently unknown. Therefore, we aimed to evaluate if biopsies from the rectosigmoid area versus the rest of the colon/ileocolon with or without biopsies from simultaneous upper endoscopy, were equally reliable for detection of GI-GVHD and relevant differential diagnoses. Methods: Retrospective multicentre study based on histopathological re-evaluation of biopsies and hospital record data, collected from children with suspected GI-GVHD. Results: Forty-four children with 51 endoscopic occasions (81 procedures) were included. Thirty-nine of 51 (76.5%) were diagnosed as GI-GVHD, 14 (27.4%) received a differential diagnosis and 7 (13.7%) had normal histology findings. Co-morbidity, i.e. simultaneous detection of a differential diagnosis and GI-GVHD, was observed in 9 (23.1%) cases. CMV infection was the most frequent differential diagnosis, 6/7 were detected in biopsies from rectosigmoid- and esophagogastroduodenal areas. Sensitivity for detection of GI-GVHD in biopsies collected from rectosigmoid-ileocolonic-, rectosigmoid-, or esophagogastroduodenal areas were 97.4%, 84.6%, 83.3%, respectively, and 97.4% when the latter two were merged. The difference, non-detected GI-GVHD in the rectosigmoid area versus detected elsewhere in the GI tract, was statistically significant (p = 0.03). Conclusions: Biopsies collected from the rectosigmoid area solely, were not optimal for detection of paediatric GI-GVHD. However, when biopsy sampling from rectosigmoid- and upper GI tract areas were combined, the sensitivity for GI-GVHD was equally high as for ileocolonoscopy or full upper and lower endoscopy. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Male-specific Association Between Fat Free Mass Index and Faecal Microbiota in 2 to 3 Year Old Australian Children.

Objectives: Maturation of the gut microbiota has been shown to influence childhood growth while alterations in microbiota composition are proposed to be causally related to the development of overweight and obesity. The objective of this study is to explore the association between microbiota profile, body size and body composition in young children. Methods: Faecal microbiota was examined by 16S rRNA gene sequencing while body composition was assessed using the deuterium oxide dilution technique in a cohort of 37 well-nourished 2 to 3 year old Australian children. Results: Microbiota composition (weighted UniFrac distance) was shown to be significantly associated with FFMI (Fat Free Mass Index) Z score (p = 0.027, adonis) in boys but not girls. In boys, FFMI Z score was significantly correlated with the relative abundance of an OTU belonging to the Ruminococcaceae family (Rho = 0.822, p

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Donor Human Milk and Fortifier use in United States level 2, 3, and 4 Neonatal Care Hospitals.

Objective: In 2011 the United States Surgeon General issued a call to action to "identify and address obstacles to greater availability of safe banked donor milk for fragile infants." The purpose of this study is to analyze patterns in donor human milk (DHM) and fortifier use in level 2, 3, and 4 neonatal facilities in 2015 and to identify factors associated with non-use. Methods: Data from the 2015 Maternity Practices in Infant Nutrition and Care survey, conducted by the Center for Disease Control and Prevention, was analyzed for questions about feeding practices within neonatal hospitals. Results: The percentage of neonatal facilities that reported using DHM in 2015 was 38.3%, up 74% from 2011. The majority of level 3 and level 4 facilities reported using DHM (65.7% and 73.3% respectively) and fortifiers (96.1% and 91.9% respectively). Within DHM-using facilities, a wide range of DHM feeding patterns were reported. The prevalence of DHM use was higher in facilities that had the highest rates of mother's own milk feedings (P

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Awareness and Implementation of the 2014 ESPGHAN/NASPGHAN Guideline for Childhood Functional Constipation.

Objective: To assess if physicians approach children with functional constipation according to the 2014 ESPGHAN/NASPGHAN guideline. Methods: We invited pediatricians and pediatric gastroenterologists in the Netherlands and the U.S. to participate in this anonymous survey using a self-developed questionnaire containing 19 multiple-choice questions concerning evaluation and treatment of children with constipation. Results: We included 328 physicians (67% from the U.S., 34% from the Netherlands). The majority of U.S. responders (53%) worked in primary care whereas all Dutch responders worked in a hospital. In total, 31% of responders were not familiar with the guideline, (38% U.S. responders vs. 16% Dutch responders, p =1 year). Conclusions: Many responders were not familiar with the ESPGHAN/NASPGHAN guideline for functional constipation. Nonetheless, therapeutic decisions correlated fairly well with recommendations from the guideline, especially for children >=1 year. Guideline awareness and adherence remain to be improved. Future studies should focus on exploring strategies to improve guideline implementation through the development of digital learning tools. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Impact of Race and Ethnicity on Outcomes for Children Waitlisted for Pediatric Liver Transplantation.

Objective: African Americans and other minorities are known to face barriers to health care influencing their access to organ transplantation but it is not known whether these barriers exist among pediatric liver transplant waitlist candidates. We sought to determine whether outcomes on the waitlist (i.e., mortality, deceased donor liver transplantation (DDLT), and living-donor liver transplantation (LDLT)) varied by race/ethnicity. Methods: National registry data were studied to estimate the race/ethnicity-specific risk of waitlist mortality, DDLT and LDLT in children (

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Impaired IL-10 Receptor Mediated Suppression in Monocyte from Patients with Crohn's Disease.

Objectives: Interleukin-10 (IL-10) is an immunoregulatory cytokine that has a central role in suppressing pro-inflammatory responses. Patients with deleterious mutations in IL-10 or IL-10 receptor (IL-10R) genes develop severe colitis and perianal disease in the first months of life. Whether IL-10R expression and signaling in pediatric- or adult-onset Crohn's disease (CD) are altered is unknown. The objective of this study was to characterize IL-10R expression and IL-10R-mediated suppression in patients with CD. Methods: Monocytes were sorted from peripheral blood mononuclear cells of patients with CD and control subjects. IL-10R expression was determined by flow cytometry. Monocytes were stimulated with lipopolysaccharide (LPS) for 3 hours in the presence of different concentrations of IL-10 in order to determine IL-10-mediated suppression of TNF[alpha] production. Signaling through the IL-10R was evaluated by quantifying STAT3 phosphorylation in response to IL-10 stimulation. Results: Forty-two subjects were enrolled in this study: 19 with CD and 23 controls. Stimulation of monocytes with LPS markedly increased IL-10R expression in both groups but to a much lower extent in patients with CD. In addition, IL-10-mediated suppression of TNF[alpha] production upon LPS stimulation, and IL-10-induced STAT3 phosphorylation were attenuated in patients with CD vs. controls. Finally, LPS-stimulated monocytes from patients with CD secreted significantly lower quantities of IL-10, compared with control monocytes. Conclusions: IL-10R expression and signaling are decreased in monocytes from patients with CD. Additional studies are required to assess whether similar patterns occur in other innate immune cells, especially in the gut, and whether disease activity, medical therapy and genetic factors modulate these findings. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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The Case for Thoughtful prescribing of PPIs in Infants.

No abstract available

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Trends of Cholecystectomies for Presumed Biliary Dyskinesia in Children in the United States.

Background: Biliary dyskinesia is a controversial clinical entity. Standardized diagnostic test and management guidelines are lacking in children. Published data suggest that long-term outcomes of surgical and medical management are similar. We sought to determine national population-based trends of cholecystectomies performed in children for biliary dyskinesia and associated healthcare expenditure in the US over a 10-year period. Methods: Using Nationwide Inpatient Sample and the International Classification of Diseases, the 9th revision clinical modification codes, we identified children who had a cholecystectomy for biliary dyskinesia from 2002-2011 in the United States. Results: A total of 66,380 cholecystectomies were identified as primary procedural diagnosis using weighted analysis from 2002 to 2011 in children. Biliary dyskinesia was the primary indication for cholecystectomy in 6,674 (10.8%) of the patients. Over the study period, the number of cholecystectomies performed for biliary dyskinesia in children increased from 6.6% in 2002 to 10.6% in 2011, a majority were adolescent white Caucasian females. The annual health care expenditure for surgical management of biliary dyskinesia for children in the U.S. was estimated to almost $16 million/year. Conclusion: Despite lack of standardized diagnostic criteria and variable outcomes of surgical intervention reported in pediatric literature, cholecystectomies are commonly performed for children with biliary dyskinesia in the United States. Consensus guidelines for the diagnosis and management of this controversial disorder in children are needed. (C) 2017 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Different Contributions of Primary Motor Cortex, Reticular Formation and Spinal Cord to Fractionated Muscle Activation

Coordinated movement requires patterned activation of muscles. In this study we examined differences in selective activation of primate upper limb muscles by cortical and sub-cortical regions. Five macaque monkeys were trained to perform a reach and grasp task, and electromyogram (EMG) was recorded from 10-24 muscles while weak single-pulse stimuli were delivered through microelectrodes inserted in the motor cortex (M1), reticular formation (RF) or cervical spinal cord (SC). Stimulus intensity was adjusted to a level just above threshold. Stimulus-evoked effects were assessed from averages of rectified EMG. M1, RF and SC activated 1.5±0.9, 1.9±0.8 and 2.5±1.6 muscles per site (mean±SD); only M1 and SC differed significantly. In between recording sessions, natural muscle activity in the home cage was recorded using a miniature data logger. A novel analysis assessed how well natural activity could be reconstructed by stimulus-evoked responses. This provided two measures: normalized vector length L, reflecting how closely aligned were natural and stimulus-evoked activity, and normalized residual R, measuring the fraction of natural activity not reachable using stimulus-evoked patterns. Average values for M1, RF and SC were L=119.1±9.6, 105.9±6.2 and 109.3±8.4 and R=50.3±4.9, 56.4±3.5 and 51.5±4.8 respectively. RF was significantly different from M1 and SC on both measures. RF is thus able to generate an approximation to the motor output with less activation than required by M1 and SC, but M1 and SC are more precise in reaching the exact activation pattern required. Cortical, brainstem and spinal centers likely play distinct roles as they cooperate to generate voluntary movements.



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Paired corticospinal-motoneuronal stimulation increases maximal voluntary activation of human adductor pollicis

Paired corticospinal-motoneuronal stimulation (PCMS), which delivers repeated pairs of transcranial magnetic stimuli (TMS) and maximal motor nerve stimuli, can alter corticospinal transmission to low threshold motoneurones in the human spinal cord. To determine whether similar changes occur for high threshold motoneurones, we tested whether maximal voluntary activation and force can be affected by PCMS in healthy individuals. On two separate days, healthy participants (n=14) performed brief thumb adduction MVCs before and after a control protocol (TMS only) or PCMS designed to facilitate corticospinal transmission to adductor pollicis. Peripheral nerve stimulation alone was not performed. During each MVC, a superimposed twitch was elicited by a supramaximal stimulus delivered to the ulnar nerve. With muscles relaxed following the maximal contraction, a similar stimulus elicited a resting twitch. Voluntary activation was calculated as (1- superimposed twitch/resting twitch)*100%. While voluntary activation decreased over time in both conditions, the decrease was less after PCMS (-0.4 ± 4.1%) than after the control protocol (-4.9 ± 4.9%, p = 0.007). This was supported by a greater increase in EMG after PCMS than control (7 ± 13% vs. -3 ± 10%; p = 0.043). However, maximal force was not affected. The findings indicate a modest effect of PCMS on maximal neural drive to adductor pollicis, suggesting that PCMS can affect corticospinal transmission to high threshold motoneurones.



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Carotid chemoreceptors tune breathing via multipath routing: Reticular chain and loop operations supported by parallel spike train correlations

We tested the hypothesis that carotid chemoreceptors tune breathing through parallel circuit paths that target distinct elements of an inspiratory neuron chain in the ventral respiratory column (VRC). Microelectrode arrays were used to monitor neuronal spike trains simultaneously in the VRC, peri-nucleus tractus solitarius-medial medulla (p-NTS-MM), the dorsal parafacial region of the lateral tegmental field (FTL-pF), and medullary raphé nuclei together with phrenic nerve activity during selective stimulation of carotid chemoreceptors or transient hypoxia in 19 decerebrate, neuromuscularly-blocked, and artificially ventilated cats. Of 994 neurons tested, 56% had a significant change in firing rate. A total of 33,422 cell pairs were evaluated for signs of functional interaction; 63% of chemoresponsive neurons were elements of at least one pair with correlational signatures indicative of paucisynaptic relationships. We detected evidence for post-inspiratory neuron inhibition of rostral VRC I-Driver (preBötzinger) neurons, an interaction predicted to modulate breathing frequency, and for reciprocal excitation between chemoresponsive p-NTS neurons and more downstream VRC inspiratory neurons for control of breathing depth. Chemoresponsive peri-columnar tonic expiratory neurons, proposed to amplify inspiratory drive by disinhibition, were correlationally linked to afferent and efferent "chains" of chemoresponsive neurons extending to all monitored regions. The chains included coordinated clusters of chemoresponsive FTL pF neurons with functional links to wide-spread medullary sites involved in the control of breathing. The results support long-standing concepts on brain stem network architecture and a circuit model for peripheral chemoreceptor modulation of breathing with multiple circuit loops and chains tuned by tegmental field neurons with quasi-periodic discharge patterns.



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Spatio-temporal characteristics of retinal response to network-mediated photovoltaic stimulation

Subretinal prostheses aim at restoring sight to patients blinded by photoreceptor degeneration using electrical activation of the surviving inner retinal neurons. Today, such implants deliver visual information with low-frequency stimulation, resulting in discontinuous visual percepts. We measured retinal responses to complex visual stimuli delivered at video rate via a photovoltaic subretinal implant and by visible light. Using a multielectrode array to record from retinal ganglion cells (RGCs) in the healthy and degenerated rat retina ex-vivo, we estimated their spatio-temporal properties from the spike-triggered average (STA) responses to photovoltaic binary white noise stimulus with 70μm pixel size at 20Hz frame rate. The average photovoltaic receptive field size was 194±3μm (S.E.M.), similar to that of visual responses (221±4μm), but response latency was significantly shorter with photovoltaic stimulation. Both visual and photovoltaic receptive fields had an opposing center-surround structure. In the healthy retina, ON RGCs had photovoltaic OFF responses, and vice versa. This reversal is consistent with depolarization of photoreceptors by electrical pulses, as opposed to their hyperpolarization under increasing light, although alternative mechanisms cannot be excluded. In degenerate retina, both ON and OFF photovoltaic responses were observed, but in the absence of visual responses, it is not clear what functional RGC types they correspond to. Degenerate retina maintained the antagonistic center-surround organization of receptive fields. These fast and spatially localized network-mediated ON and OFF responses to subretinal stimulation via photovoltaic pixels with local return electrodes raise confidence in the possibility of providing more functional prosthetic vision.



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Phosphorylation of Connexin 43 Induced by Traumatic Brain Injury Promotes Exosome Release

Traumatic brain injury (TBI) caused by the external force leads to the neuronal dysfunction and even death. TBI has been reported to significantly increase the phosphorylation of glial gap junction protein connexin 43 (Cx43), which in turn propagates damages into surrounding brain tissues. However, the neuroprotective and anti-apoptosis effects of glia-derived exosomes have also been implicated in recent studies. Therefore, we detected whether TBI-induced phosphorylation of Cx43 would promote exosome release in rat brain. To generate TBI model, adult male Sprague-Dawley rats were subjected to lateral fluid percussion injury. Phosphorylated Cx43 protein levels and exosome activities were quantified using western blot analysis following TBI. Long-term potentiation (LTP) was also tested in rat hippocampal slices. TBI significantly increased the phosphorylated Cx43 and exosome markers expression in rat ipsilateral hippocampus, but not cortex. Blocking the activity of Cx43 or ERK, but not JNK, significantly suppressed TBI-induced exosome release in hippocampus. Furthermore, TBI significantly inhibited the induction of LTP in hippocampal slices, which could be partially but significantly restored by pretreatment with exosomes. The results implicated that TBI-activated Cx43 could mediate a nociceptive effect by propagating the brain damages, as well as a neuroprotective effect by promoting exosome release.



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Passive sensorimotor stimulation triggers long lasting alpha-band fluctuations in visual perception

Movement planning and execution rely on the anticipation and online control of the incoming sensory input. Evidence suggests that sensorimotor processes may synchronize visual rhythmic activity in preparation of action performance. Indeed, we recently reported periodic fluctuations of visual contrast sensitivity which are time-locked to the onset of an intended movement of the arm. However, the origin of the observed visual modulations has so far remained unclear due to the endogenous (and thus temporally undetermined) activation of the sensorimotor system that is associated with voluntary movement initiation. Here, we activated the sensorimotor circuitry involved in the hand control in an exogenous and controlled way by means of peripheral stimulation of the median nerve and characterized the spectrotemporal dynamics of the ensuing visual perception. The stimulation of the median nerve triggers robust and long-lasting (1 s) alpha-band oscillations in visual perception, whose strength is temporally modulated in a way that is consistent with the changes in alpha power described at the neurophysiological level after sensorimotor stimulation. These findings provide evidence in support of a causal role of the sensorimotor system in modulating oscillatory activity in visual areas with consequences for visual perception.



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The intrinsic physiology of inhibitory neurons changes over auditory development

During auditory development, changes in membrane properties promote the ability of excitatory neurons in the brainstem to code aspects of sound, including the level and timing of a stimulus. Some of these changes coincide with hearing onset, suggesting that sound-driven neural activity produces developmental plasticity of ion channel expression. While it is known that the coding properties of excitatory neurons are modulated by inhibition in the mature system, it is unknown whether there are also developmental changes in the membrane properties of brainstem inhibitory neurons. We investigated the primary source of inhibition in the avian auditory brainstem, the superior olivary nucleus (SON). The present studies test the hypothesis that, as in excitatory neurons, the membrane properties of these inhibitory neurons change following hearing onset. We examined SON neurons at different stages of auditory development: embryonic days 14-16 (E14-16), a time at which cochlear ganglion neurons are just beginning to respond to sound, later embryonic stages (E18-19), and after hatching (P0-P2). We used in vitro whole-cell patch electrophysiology to explore physiological changes in SON. Age-related changes were observed at the level of a single spike and in multi-spiking behavior. In particular, tonic behavior, measured as a neuron's ability to sustain tonic firing over a range of current steps, became more common later in development. Voltage-clamp recordings and biophysical models were employed to examine how age-related increases in ion currents enhance excitability in SON. Our findings suggest that concurrent increases in sodium and potassium currents underlie the emergence of tonic behavior.



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The fate of non-selected activity in saccadic decisions: distinct goal-related and history-related modulation.

The Global Effect (GE) traditionally refers to the tendency of effectors (e.g. hand, eyes) to first land in between two nearby stimuli - forming a unimodal distribution. By measuring a shift of this distribution, recent studies used the GE to assess the presence of decision-related inputs on the motor map for eye movements. However, this method cannot distinguish whether one stimulus is inhibited or the other is facilitated and could not detect situations where both stimuli are inhibited or facilitated. Here, we detect deviations in the bimodal distribution of landing positions for remote stimuli, and find that this bimodal GE reveals the presence, location and polarity (facilitation or inhibition) of history-related and goal-related modulation of the non-selected activity (e.g. the distractor activity in correct trials, and the target activity in error trials). We tested, for different inter-stimulus distances, the effect of the rarity of double-stimulus trials, and the difference between performing a discrimination task compared to free choice. Our work shows that the effect of rarity is symmetric and decreases with inter-stimulus distances, while the effect of goal-directed discrimination is asymmetric - occurring only when the distractor is selected for the saccade - and maintained across inter-stimulus distances. These results suggest that the former effect changes the response property of the motor map, while the latter specifically facilitates the target location.



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Path Perturbation Detection Tasks Reduce MSTd Neuronal Self-Movement Heading Responses

We presented optic flow and real movement heading stimuli while recording MSTd neuronal activity. Monkeys were alternately engaged in three tasks: visual detection of optic flow heading perturbations, vestibular detection of real movement heading perturbations, and auditory detection of brief tones. Push-button RTs were fastest for tones, and slower for visual and vestibular heading perturbations, suggesting that the tone detection task was easier. Neuronal heading selectivity was strongest during the tone detection task, and weaker during the visual and vestibular heading perturbation detection tasks. Heading selectivity was weaker during visual and vestibular path perturbation detection, despite our presented heading cues only in the visual and vestibular modalities. We conclude that focusing on the self-movement transients of path perturbation distracted the monkeys from their heading and reduced neuronal responsiveness to heading direction.



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Caenorhabditis elegans BUB-3 and SAN-1/MAD3 Spindle Assembly Checkpoint Components Are Required for Genome Stability in Response to Treatment with Ionizing Radiation

Relatively little is known about the crosstalk between the spindle assembly checkpoint and the DNA damage response, especially in multicellular organisms. We performed a Caenorhabditis elegans forward genetic screen to uncover new genes involved in the repair of DNA damage induced by ionizing radiation. We isolated a mutation, gt2000 which confers hypersensitivity to ionizing radiation and showed that gt2000 introduces a premature stop in bub-3. BUB-3 is a key component of the spindle assembly checkpoint. We provide evidence that BUB-3 acts during development and in the germline; irradiated bub-3(gt2000) larvae are developmentally retarded and form abnormal vulvae. Moreover, bub-3(gt2000) embryos sired from irradiated worms show increased levels of lethality. Both bub-3 and san-1 (the Caenorhabditis elegans homologue of MAD3) deletion alleles confer hypersensitivity to ionizing radiation, consistent with the notion that the spindle assembly checkpoint pathway is required for DNA damage response. bub-3(gt2000) is moderately sensitive to the crosslinking drug cisplatin but not to UV light or methyl methanesulfonate. This is consistent with role in dealing with DNA double-strand breaks and not with base damage. Double mutant analysis revealed that bub-3 does not act within any of the three major pathways involved in the repair of double-strand breaks. Finally, the cdc-20 gain-of-function mutant cdc-20/fzy-1(av15), which is refractory to the cell cycle delay conferred by the spindle checkpoint showed phenotypes similar to bub-3 and san-1 mutants. We speculate that BUB-3 is involved in DNA damage response through regulation of cell cycle timing.



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Modulation of Global Transcriptional Regulatory Networks as a Strategy for Increasing Kanamycin Resistance of the Translational Elongation Factor-G Mutants in Escherichia coli

Evolve and resequence experiments have provided us a tool to understand bacterial adaptation to antibiotics. In our previous work, we had used short term evolution to isolate mutants resistant to the ribosome targeting antibiotic kanamycin, and reported that Escherichia coli develops low cost resistance to kanamycin via  different point mutations in the translation Elongation Factor-G (EF-G). Furthermore, we had shown that the resistance of EF-G mutants could be increased by second site mutations in the genes rpoD / cpxA / topA / cyaA. Mutations in three of these genes had been discovered in earlier screens for aminoglycoside resistance. In this work we expand our understanding of these second site mutations, the goal being to understand how these mutations affect the activities of the mutated gene products to confer resistance.  We show that the mutation in cpxA most likely results in an active Cpx stress response. Further evolution of an EF-G mutant in a higher concentration of kanamycin than what was used in our previous experiments identified the cpxA locus as a primary target for a significant increase in resistance. The mutation in cyaA results in a loss of catalytic activity and probably results in resistance via altered CRP function. Despite a reduction in cAMP levels, the CyaAN600Y mutant has a transcriptome indicative of increased CRP activity, pointing to an unknown non-catalytic role for CyaA in gene expression. From the transcriptomes of double and single mutants we describe the epistasis between the mutation in EF-G and these second site mutations. We show that the large scale transcriptomic changes in the topoisomerase I (FusAA608E-TopAS180L) mutant likely result from increased negative supercoiling in the cell. Finally, genes with known roles in aminoglycoside resistance were present among the mis-regulated genes in the mutants.



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Macroglossia During Awake Craniotomy: A Near Miss.

No abstract available

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Comparison of posterior retroperitoneal and transabdominal lateral approaches in robotic adrenalectomy: an analysis of 200 cases

Abstract

Background

Although numerous studies have been published on robotic adrenalectomy (RA) in the literature, none has done a comparison of posterior retroperitoneal (PR) and transabdominal lateral (TL) approaches. The aim of this study was to compare the outcomes of robotic PR and TL adrenalectomy.

Methods

This is a retrospective analysis of a prospectively maintained database. Between September 2008 and January 2017, perioperative outcomes of patients undergoing RA through PR and TL approaches were recorded into an IRB-approved database. Clinical and perioperative parameters were compared using Student's t test, Wilcoxon rank-sum test, and χ 2 test. Multivariate regression analysis was performed to determine factors associated with total operative time.

Results

188 patients underwent 200 RAs. 110 patients were operated through TL and 78 patients through PR approach. Overall, conversion rate to open was 2.5% and 90-day morbidity 4.8%. The perioperative outcomes of TL and PR approaches were similar regarding estimated blood loss, rate of conversion to open, length of hospital stay, and 90-day morbidity. PR approach resulted in a shorter mean ± SD total operative time (136.3 ± 38.7 vs. 154.6 ± 48.4 min; p = 0.005) and lower visual analog scale pain score on postoperative day #1 (4.3 ± 2.5 vs. 5.4 ± 2.4; p = 0.001). After excluding tumors larger than 6 cm operated through TL approach, the difference in operative times persisted (136.3 ± 38.7 vs. 153.7 ± 45.7 min; p = 0.009). On multivariate regression analysis, increasing BMI and TL approaches were associated with longer total operative time.

Conclusion

This study shows that robotic PR and TL approaches are equally safe and efficacious. With experience, shorter operative time and less postoperative pain can be achieved with PR technique. This supports the preferential utilization of PR approach in high-volume centers with enough experience.



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Modified peroral endoscopic myotomy: a “Push and Pull” technique

Abstract

Background

Peroral endoscopic myotomy (POEM) is a minimally invasive yet challenging procedure for achalasia. Additional technological innovations and improvements are important for simplifying the procedure.

Methods

We report the successful use of a modified POEM procedure, which utilized a "Push and Pull" technique, on a patient with achalasia.

Results

Our modifications resulted in a short operation time of only 35 min. No complications arose during or after the procedure, up to a follow-up period of 6 months, and symptoms were significantly and quickly improved.

Conclusions

This modified procedure shortens operation time and lowers the difficulty of the operation, while leaving the safety and efficacy uncompromised.



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Minimally invasive liver resection for primary and metastatic liver tumors: influence of age on perioperative complications and mortality

Abstract

Background

As minimally invasive technique becomes more popular, an increasing number of elderly patients were considered for minimally invasive liver resection (MILR). Limited physiologic reserve remains a major concern, which frequently leads surgeons to recommend nonresectional alternatives. We sought to evaluate complications and outcomes of elderly patients undergoing MILR.

Methods

Eight hundred and thirty-one patients who underwent MILR were classified into groups A, B, and C based on age [(< 70, n = 629), (70–79, n = 148), (≥ 80, n = 54) years old, respectively].

Results

Gender distribution, BMI, and cirrhotic status were comparable among all groups. Groups B and C had higher MELD (p = 0.047) and ASA (p = 0.001) scores. Operative time (170, 157, 152 min; p = 0.64) and estimated blood loss (145, 130, 145 ml; p = 0.95) were statistically equal. Overall postoperative complications were greater in groups B and C (12.9 and 9.3 vs. 6.5%, respectively). Complications in group C were all minor. Clavien–Dindo grade III–IV complications were higher in group B when compared to group A (6.8 vs. 2.7%, p = 0.43). There was no significant difference in cardiopulmonary complications, thromboembolic events, ICU admissions, and transfusion rates seen in groups B and C when compared to group A. Duration of hospital stay was statistically longer in groups B and C (3.6, 3.5 vs. 2.5 days, p = 0.0012). 30- and 90-day mortality rates were comparable among the groups, irrespective of age.

Conclusions

In spite of greater preoperative comorbidities and ASA score, there was no significant increase in postoperative morbidity after minimally invasive liver resection in patients ≥ 70 years of age.



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Endoscopic submucosal dissection for undifferentiated-type early gastric cancer: short- and long-term outcomes

Abstract

Background and aims

Application of endoscopic submucosal dissection (ESD) for undifferentiated-type early gastric cancers (EGCs) remains controversial owing to limited data regarding long-term outcomes. We aimed to evaluate the feasibility of ESD for undifferentiated-type EGCs that meet the expanded criteria (EC).

Methods

We performed a retrospective analysis of 66 patients who underwent ESD for undifferentiated-type EGC between January 2005 and December 2014. We evaluated the rates of en bloc, complete, and curative resections along with overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS).

Results

Of the 66 patients, the EC group included 38 patients and the beyond-EC group included 28 patients. The overall rates of en bloc, complete, and curative resection of the 66 lesions were 92.4% (61/66), 65.2% (43/66), and 48.5% (32/66), respectively. Of the 34 patients with non-curative resection, 18 underwent additional surgery. Local remnant cancer was detected in 1 patient (1/18, 5.6%), and none of the 18 patients had lymph node metastasis. On multivariate analysis, tumors > 2 cm [odd ratio (OR) 6.183, 95% confidence interval (CI) 1.279–29.880, p = 0.023) and submucosal invasion depth (OR 6.226, 95% CI 1.881–20.606, p = 0.003) were independent predictors of incomplete resection. All 26 patients with more than 1 year of follow-up after curative resection survived without any evidence of local or distant recurrences over a median follow-up period of 36 months. The OS, DSS, and RFS rates of patients with curative ESD were 93.8, 100, and 100%, respectively.

Conclusions

ESD may have favorable long-term outcomes in patients with undifferentiated-type EGC after curative resection.



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Radiologically defining horizontal gaze using EOS® imaging – a prospective study of healthy subjects and a retrospective audit

Background ContextAs sagittal alignment of the cervical spine is important for maintaining horizontal gaze, it is important to determine the former for surgical correction. However, horizontal gaze remains poorly-defined from a radiological point-of-view.PurposeTo establish radiographic criteria to define horizontal gaze.Study design/SettingThis study was conducted at a tertiary healthcare institution over a 1-month period.Patient SampleA prospective cohort of healthy patients was used to determine the best radiological criteria for defining horizontal gaze.

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Clinical evaluation of an innovative operative procedure in treatment of the tethered cord syndrome.

The Tethered cord syndrome (TCS) characterized by urination dysfunction has long been a worldwide clinical problem, of which clinical effects remains controversial.

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Mesenchymal progenitor cells primed with pentosan polysulfate promote lumbar intervertebral disc regeneration in an ovine model of microdiscectomy

Neural compression associated with lumbar disc herniation is usually managed surgically by microdiscectomy. However, 10 – 20% patients re-present with debilitating back pain and approximately 15% require further surgery.

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Percutaneous balloon kyphoplasty for treatment of very severe osteoporotic vertebral compression fractures: a case-controlled study

There exists controversy regarding percutaneous balloon kyphoplasty (PBK) in patients with very severe osteoporotic vertebral compression fracture (vsOVCF).

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The utility of preoperative labs in predicting postoperative complications following posterolateral lumbar fusion

Several studies have suggested that lab results have minimal impact on clinical decision-making in surgery. Despite the widespread use of preoperative testing in spine surgery and the large volume of posterolateral lumbar fusions (PLFs) being performed each year, no study has assessed the ability of preoperative labs to predict adverse events following PLF.

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Decompression vs Fusion for Grade I Degenerative Spondylolisthesis: A Meta-Analysis

BACKGROUND CONTEXT: Degenerative spondylolisthesis (DS) remains one of the most common indications for spine surgery. Although large multi-institutional trials supported surgical treatment for this pathology, and recent meta-analysis has compared different fusion techniques, the best surgical management option for patients with only grade 1 disease has not been determined.

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Effect of Direct-Acting Antivirals on future occurrence of hepatocellular carcinoma in compensated cirrhotic patients

The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events.

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Post-polypectomy bleeding after colonoscopy on uninterrupted aspirin/non steroideal antiflammatory drugs: systematic review and meta-analysis

The aim of this systematic review and meta-analysis was to assess the risk of post-polypectomy bleeding (PPB) in patients that underwent colorectal polypectomy and exposed to ASA/NSAIDs.

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Quadruple, sequential, and concomitant first-line therapies for H. pylori eradication: a prospective, randomized study.

Current Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country.

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Effect of Direct-Acting Antivirals on future occurrence of hepatocellular carcinoma in compensated cirrhotic patients

The achievement of high rates of sustained virological response (SVR) with direct-acting antivirals (DAAs) in hepatitis C virus (HCV) infected patients will reduce decompensating terminal events.

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Post-polypectomy bleeding after colonoscopy on uninterrupted aspirin/non steroideal antiflammatory drugs: systematic review and meta-analysis

The aim of this systematic review and meta-analysis was to assess the risk of post-polypectomy bleeding (PPB) in patients that underwent colorectal polypectomy and exposed to ASA/NSAIDs.

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Quadruple, sequential, and concomitant first-line therapies for H. pylori eradication: a prospective, randomized study.

Current Italian guidelines recommend 10-day bismuth-based or bismuth-free (sequential and concomitant) regimens for first-line H. pylori eradication. However, comparison among these regimens is lacking in our country.

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Heller myotomy versus Heller myotomy with Dor fundoplication for achalasia: long-term symptomatic follow-up of a prospective randomized controlled trial

Abstract

Background

Our prior randomized controlled trial of Heller myotomy alone versus Heller plus Dor fundoplication for achalasia from 2000 to 2004 demonstrated comparable postoperative resolution of dysphagia but less gastroesophageal reflux after Heller plus Dor. Patient-reported outcomes are needed to determine whether the findings are sustained long-term.

Methods

We actively engaged participants from the prior randomized cohort, making up to six contact attempts per person using telephone, mail, and electronic messaging. We collected patient-reported measures of dysphagia and gastroesophageal reflux using the Dysphagia Score and the Gastroesophageal Reflux Disease-Health-Related Quality of Life (GERD-HRQL) instrument. Patient-reported re-interventions for dysphagia were verified by obtaining longitudinal medical records.

Results

Among living participants, 27/41 (66%) were contacted and all completed the follow-up study at a mean of 11.8 years postoperatively. Median Dysphagia Scores and GERD-HRQL scores were slightly worse for Heller than Heller plus Dor but were not statistically different (6 vs 3, p = 0.08 for dysphagia, 15 vs 13, p = 0.25 for reflux). Five patients in the Heller group and 6 in Heller plus Dor underwent re-intervention for dysphagia with most occurring more than five years postoperatively. One patient in each group underwent redo Heller myotomy and subsequent esophagectomy. Nearly all patients (96%) would undergo operation again.

Conclusions

Long-term patient-reported outcomes after Heller alone and Heller plus Dor for achalasia are comparable, providing support for either procedure.



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Laparoscopic choledochoduodenostomy as a reliable rescue procedure for complicated bile duct stones

Abstract

Background

Endoscopic retrograde cholangiopancreatography (ERCP) with stone extraction is generally accepted as first line management for common bile duct (CBD) stones. CBD exploration, either by open or laparoscopic approach nowadays, is usually reserved for ERCP failures, complicated stone locations, along with altered anatomical situations. The aim of this study was to highlight the increasing role of laparoscopic choledochoduodenostomy which is not only a reliable but also as a rescue procedure for those failed ERCP cases due to complicated bile duct stones.

Materials and methods

It is a retrospective review of the database, from a tertiary care teaching institution from India, from Jan 2012 up to December 2016.

Results

Out of total 30 patients who underwent laparoscopic choledochoduodenostomy, 28 had failed ERC stone clearance while two patients were directly offered drainage in view of unfavorable anatomy. The major reasons for failed ERC stone clearance were as follows—multiple large calculi (42.8%), recurrent stones (21.4%), and associated stricture (21.4%). Mean operating time was 130 (± 27) minutes with mean blood loss of 60 (± 19) ml. Stone extraction was successful, primarily by milking in 13 (43.33%) patients, rest required augmentation by Dormia basket/balloon. Two patients (6.66%) developed controlled bile leak which resolved with conservative treatment. The median length of hospital stay was 5 days (IQR 3–9). Mean duration of follow-up was 17 (± 3.2) months.

Conclusion

Laparoscopic common bile duct exploration with choledochoduodenostomy has been shown to be a safe, reliable, and efficient method for treating complex CBDS, especially after failed ERCP procedures.



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Paramedic and EMT Positions Available - DMCare

Paramedic and EMT Positions available at all locations located in Michigan, Ohio and Illinois. Apply at http://ift.tt/2i0VH8n Employer provides: Experience based pay 4 Blue Cross Blue Shield plan options starting as low as $15.00 per month Free Education Bonus Incentive Opportunities Basic EMT Responsibilities: Performs pre-hospital duties in compliance with all state EMS rules and regulations ...

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Paramedic and EMT Positions Available - Beaumont Mobile Medical Transportation

Paramedic and EMT Positions available at all locations located in Michigan, Ohio and Illinois. Apply at http://ift.tt/2i0VH8n Employer provides: Experience based pay 4 Blue Cross Blue Shield plan options starting as low as $15.00 per month Free Education Bonus Incentive Opportunities Basic EMT Responsibilities: Performs pre-hospital duties in compliance with all state EMS rules and regulations ...

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Paramedic and EMT Positions Available - Community EMS

COMMUNITY EMS Paramedic and EMT Positions available at all locations located in Michigan, Ohio and Illinois. Apply at http://ift.tt/2i0VH8n Employer provides: Experience based pay 4 Blue Cross Blue Shield plan options starting as low as $15.00 per month Free Education Bonus Incentive Opportunities Basic EMT Responsibilities: Performs pre-hospital duties in compliance with all state EMS rules and ...

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FirstNet applications for EMS connectivity, situational awareness

FirstNet, the nationwide wireless broadband network dedicated to public safety, is ahead of schedule, under budget and poised to change the practice of EMS

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Whelen Engineering introduces SurfaceMax™ series Super-LED® lightheads

CHESTER, Conn. Whelen's SurfaceMax Series features the versatility and performance of the Hundred Series, with a full-fill optic and all-new patented mounting technology, providing easy installation and a clean look. The SurfaceMax Series mounts to a variety of applications and is available in Warning, Brake/Tail/Turn, and Turn Arrow models. Features SurfaceMax lightheads are Rated IP67 for ...

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What are the benefits, risks of binding a pelvic fracture?

World Trauma Symposium speaker describes pelvic fracture anatomy, pathophysiology and evidence for reducing bleeding and improving patient survival with a pelvic splint

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Whelen Engineering introduces SurfaceMax lightheads

The SurfaceMax Series lightheads are compatible with the Scan-Lock app for Apple and Android devices

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Verathon launches portable handheld video laryngoscope system

GlideScope Go is designed to provide clear airway views in a wide variety of settings

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H&H Medical introduces the H*VENT vented chest dressing

The six-port design allows for multidirectional drainage toward gravity, allowing patients to be transported on their side

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H&H Medical announces acquisition of rights to SWAT-T tourniquet

The SWAT-T includes an elastic design to give the product the ability to treat a variety of injuries

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Mild Zellweger syndrome due to a novel PEX6 mutation: correlation between clinical phenotype and in silico prediction of variant pathogenicity

Abstract

Zellweger syndrome (ZS) is a consequence of a peroxisome biogenesis disorder (PBD) caused by the presence of a pathogenic mutation in one of the 13 genes from the PEX family. ZS is a severe multisystem condition characterized by neonatal appearance of symptoms and a shorter life. Here, we report a case of ZS with a mild phenotype, due to a novel PEX6 gene mutation. The patient presented subtle craniofacial dysmorphic features and slightly slower psychomotor development. At the age of 2 years, he was diagnosed with adrenal insufficiency, hypoacusis, and general deterioration. Magnetic resonance imaging showed a symmetrical hyperintense signal in the frontal and parietal white matter. Biochemical tests showed elevated liver transaminases, elevated serum very long chain fatty acids, and phytanic acid. After the death of the child at the age of 6 years, molecular diagnostics were continued in order to provide genetic counseling for his parents. Next generation sequencing (NGS) analysis with the TruSight One™ Sequencing Panel revealed a novel homozygous PEX6 p.Ala94Pro mutation. In silico prediction of variant severity suggested its possible benign effect. To conclude, in the milder phenotypes, adrenal insufficiency, hypoacusis, and leukodystrophy together seem to be pathognomonic for ZS.



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Editorial Board

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Publication date: December 2017
Source:Journal of Human Evolution, Volume 113





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The revised stratigraphy of the hominin-bearing site of Kromdraai (Gauteng, South Africa) and associated perspectives

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Publication date: January 2018
Source:Journal of Human Evolution, Volume 114
Author(s): Laurent Bruxelles, Richard Maire, Amélie Beaudet, Raymond Couzens, Francis Duranthon, Jean-Baptiste Fourvel, Dominic Stratford, Francis Thackeray, José Braga
The Plio-Pleistocene site of Kromdraai B (South Africa), located in the 'Cradle of Humankind' area recognized in 1998 by UNESCO, corresponds to a Plio-Pleistocene paleokarst that yielded the holotype of Paranthropus robustus in 1938. Since that discovery, thousands of faunal remains (including additional hominin fossils) and stone tools have been discovered there. Here we report a new study of the karstic fillings of the hominin-bearing site of Kromdraai, which enables a reappraisal of its stratigraphy. The deposits correspond to a talus cone fed by one entrance that progressively filled the cave, which is larger than previously thought. Based on the stratigraphy, geometry, and composition of the breccias, we propose a new and more complex evolution of the cave. Four main periods of cave filling can be distinguished, corresponding to four kinds of deposits directly related to the evolution of the cave, and which show the progressive dismantling of the cavity and increasing influence from the landscape surface. This filling regime, however, is not continuous, and major unconformities identified may cover long periods of time. Despite this, an overall coherence emerges from the history of the cave and its deposits, the paleontological and paleoanthropological data, and the archaeological studies. It is now possible to reinterpret the discoveries from earlier investigations and place them in their general stratigraphic context. Our study shows that Kromdraai spans a much longer time span of hominin evolution than previously proposed. In addition, the breccias from the central part of the Kromdraai B site provide some of the first data on at least part of a hitherto unrecorded period at Sterkfontein: a phase marked by a major erosional unconformity between Members 4 and 5, before 2.20 Ma.



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Editorial Board

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Publication date: November 2017
Source:Journal of Human Evolution, Volume 112





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Liver Masses: What Physicians Need to Know About Ordering and Interpreting Liver Imaging

Abstract

Purpose of Review

This paper reviews diagnostic imaging techniques used to characterize liver masses and the imaging characteristics of the most common liver masses.

Recent Findings

The role of recently adopted ultrasound and magnetic resonance imaging contrast agents will be emphasized.

Summary

Contrast-enhanced ultrasound is an inexpensive exam which can confirm benignity of certain liver masses without ionizing radiation. Magnetic resonance imaging using hepatocyte-specific gadolinium-based contrast agents can help confirm or narrow the differential diagnosis of liver masses.



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Fundamental Epidemiology Terminology and Measures: It Really Is All in the Name

Epidemiology is the study of how disease is distributed in populations and the factors that influence or determine this distribution. Clinical epidemiology denotes the application of epidemiologic methods to questions relevant to patient care and provides a highly useful set of principles and methods for the design and conduct of quantitative clinical research. Validly analyzing, correctly reporting, and successfully interpreting the findings of a clinical research study often require an understanding of the epidemiologic terms and measures that describe the patterns of association between the exposure of interest (treatment or intervention) and a health outcome (disease). This statistical tutorial thus discusses selected fundamental epidemiologic concepts and terminology that are applicable to clinical research. Incidence is the occurrence of a health outcome during a specific time period. Prevalence is the existence of a health outcome during a specific time period. The relative risk can be defined as the probability of the outcome of interest (eg, developing the disease) among exposed individuals compared to the probability of the same event in nonexposed individuals. The odds ratio is a measure of risk that compares the frequency of exposure to a putative causal factor in the individuals with the health outcome (cases) versus those individuals without the health outcome (controls). Factors that are associated with both the exposure and the outcome of interest need to be considered to avoid bias in your estimate of risk. Because it takes into consideration the contribution of extraneous variables (confounders), the adjusted odds ratio provides a more valid estimation of the association between the exposure and the health outcome and thus is the preferably reported measure. The odds ratio closely approximates the risk ratio in a cohort study or a randomized controlled trial when the outcome of interest does not occur frequently (

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Intraoperative Esmolol as an Adjunct for Perioperative Opioid and Postoperative Pain Reduction: A Systematic Review, Meta-analysis, and Meta-regression

BACKGROUND: BACKGROUND:Esmolol is an ultrashort β-1 receptor antagonist. Recent studies suggest a role for esmolol in pain response modulation. The authors performed a meta-analysis to determine if the intraoperative use of esmolol reduces opioid consumption or pain scores. METHODS: METHODS:PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, pubget, and Google Scholar were searched. Studies were included if they were randomized, placebo- or opioid-controlled trials written in English, and performed on patients 18 years of age or older. For comparison of opioid use, included studies tracked opioid consumption intraoperatively and/or in the postanesthesia care unit. Pain score comparisons were performed during the first hour after surgery. RESULTS: RESULTS:Seventy-three studies were identified, 23 were included in the systematic review, and 19 were eligible for 1 or more comparisons. In 433 patients from 7 trials, intraoperative esmolol decreased intraoperative opioid consumption (Standard Mean Difference [SMD], −1.60; 95% confidence interval [CI], −2.25 to −0.96; P ≤ .001). In 659 patients from 12 trials, intraoperative esmolol decreased postanesthesia care unit opioid consumption (SMD, −1.21; 95% CI, −1.66 to −0.77; P ≤ .001). In 688 patients from 11 trials, there was insufficient evidence of change in postoperative 1 hour pain scores (SMD, −0.60; 95% CI, −1.44 to 0.24; P = .163). CONCLUSIONS: CONCLUSIONS:This meta-analysis demonstrates that intraoperative esmolol use reduces both intraoperative and postoperative opioid consumption, with no change in postoperative pain scores. Accepted for publication August 3, 2017. Funding: Support was provided solely from institutional and/or departmental sources of the Massachusetts General Hospital Department of Anesthesia, Critical Care and Pain Medicine, Boston, MA. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to T. Anthony Anderson, MD, PhD, Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Dr, H3590A MC5640, Stanford, CA 94305. Address e-mail to tanders0@stanford.edu. © 2017 International Anesthesia Research Society

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Standardized Care Versus Precision Medicine: Do We Really Need to Wait for Point-of-Care Testing?

No abstract available

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In Response: Subcellular Energetics and Metabolism A Cross-Species Framework

No abstract available

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In Response: Standardized Care Versus Precision Medicine; Do We Really Need to Wait for Point-of-Care Testing?

No abstract available

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Subcellular Energetics and Metabolism: A Cross-Species Framework

No abstract available

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Patient Harm in Cataract Surgery: A Series of Adverse Events in Massachusetts

Massachusetts state agencies received reports of 37 adverse events (AEs) involving cataract surgery from 2011 to 2015. Fifteen were anesthesia related, including 5 wrong eye blocks, 3 cases of hemodynamic instability, 2 retrobulbar hematoma/hemorrhages, and 5 globe perforations resulting in permanent loss of vision. While Massachusetts' reported AEs likely underrepresent the true number of AEs that occur during cataract surgery, they do offer useful signal data to indicate the types of patient harm occurring during these procedures. Accepted for publication August 16, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Karen C. Nanji, MD, MPH, Department of Anaesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114. Address e-mail to knanji@partners.org. © 2017 International Anesthesia Research Society

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Patient Blood Management in Pediatric Cardiac Surgery: A Review

Efforts to reduce blood product transfusions and adopt blood conservation strategies for infants and children undergoing cardiac surgical procedures are ongoing. Children typically receive red blood cell and coagulant blood products perioperatively for many reasons, including developmental alterations of their hemostatic system, and hemodilution and hypothermia with cardiopulmonary bypass that incites inflammation and coagulopathy and requires systemic anticoagulation. The complexity of their surgical procedures, complex cardiopulmonary interactions, and risk for inadequate oxygen delivery and postoperative bleeding further contribute to blood product utilization in this vulnerable population. Despite these challenges, safe conservative blood management practices spanning the pre-, intra-, and postoperative periods are being developed and are associated with reduced blood product transfusions. This review summarizes the available evidence regarding anemia management and blood transfusion practices in the perioperative care of these critically ill children. The evidence suggests that adoption of a comprehensive blood management approach decreases blood transfusions, but the impact on clinical outcomes is less well studied and represents an area that deserves further investigation. Accepted for publication August 24, 2017. Funding: None. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Jill M. Cholette, MD, 601 Elmwood Ave, Box 667, Rochester, NY 14642. Address e-mail to Jill_Cholette@urmc.rochester.edu. © 2017 International Anesthesia Research Society

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Photoplethysmography and Heart Rate Variability for the Diagnosis of Preeclampsia

BACKGROUND: BACKGROUND:The goal of this study was to determine a set of timing, shape, and statistical features available through noninvasive monitoring of maternal electrocardiogram and photoplethysmography that identifies preeclamptic patients. METHODS: METHODS:Pregnant women admitted to Labor and Delivery were monitored with pulse oximetry and electrocardiogram for 30 minutes. Photoplethysmogram features and heart rate variability were extracted from each data set and applied to a sequential feature selection algorithm to discriminate women with preeclampsia with severe features, from normotensive and hypertensive controls. The classification boundary was chosen to minimize the expected misclassification cost. The prior probabilities of the misclassification costs were assumed to be equal. RESULTS: RESULTS:Thirty-seven patients with clinically diagnosed preeclampsia with severe features were compared with 43 normotensive controls; all were in early labor or beginning induction. Six variables were used in the final model. The area under the receiver operating characteristic curve was 0.907 (standard error [SE] = 0.004) (sensitivity 78.2% [SE = 0.3%], specificity 89.9% [SE = 0.1%]) with a positive predictive value of 0.883 (SE = 0.001). Twenty-eight subjects with chronic or gestational hypertension were compared with the same preeclampsia group, generating a model with 5 features with an area under the curve of 0.795 (SE = 0.007; sensitivity 79.0% [SE = 0.2%], specificity 68.7% [SE = 0.4%]), and a positive predictive value of 0.799 (SE = 0.002). CONCLUSIONS: CONCLUSIONS:Vascular parameters, as assessed noninvasively by photoplethysmography and heart rate variability, may have a role in screening women suspected of having preeclampsia, particularly in areas with limited resources. Accepted for publication August 24, 2017. Funding: This material is based on study supported by the National Institutes of Health (Grant No. 1R41HD075550-1). Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Clinical trial identification number: UF IRB: 189–2011; URL of the registration site: http://irb.ufl.edu. Address correspondence to Tammy Y. Euliano, MD, Department of Anesthesiology, University of Florida College of Medicine, 1600 SW Archer Rd, P.O. Box 100254, Gainesville, FL 32610. Address e-mail to teuliano@anest.ufl.edu. © 2017 International Anesthesia Research Society

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An Intraplantar Hypertonic Saline Assay in Mice for Rapid Screening of Analgesics

BACKGROUND: BACKGROUND:Development of new analgesics is limited by shortcomings of existing preclinical screening assays such as wide variations in response, suitability for a narrow range of analgesics, and propensity to induce tissue damage. Our aim was to determine the feasibility of a new in vivo animal assay as an analgesic screen based on nociceptive responses (licking and biting) after intraplantar (i.pl.) injection of hypertonic saline (HS) in mice. METHODS: METHODS:With approval from the Institutional Animal Care Committee, we conducted a randomized, investigator-blinded in vivo study in adult CD-1 mice. We first studied the concentration–response relationship, time course, and sex difference of animals' nociceptive responses to HS. Subsequently, we assessed the screening ability of the HS assay to detect a range of established analgesics belonging to different classes. Finally, we performed histopathologic studies to assess potential tissue damage. RESULTS: RESULTS:The response produced by i.pl. HS was greater and longer in female than in male mice. The responses to HS were concentration dependent with minimal variance. Ten percent HS evoked a maximal response within the first 5 minutes. Morphine dose-dependently attenuated animals' nociceptive responses (1–10 mg/kg intraperitoneally [i.p.]). The peripherally restricted µ-opioid receptor agonist, loperamide, reduced nociceptive responses when injected locally (30–100 µg/paw, i.pl.) but not systemically (1–10 mg/kg, i.p.). Acetylsalicylic acid (300 mg/kg, i.p.), naproxen (150 mg/kg, i.p), and acetaminophen (300 mg/kg, i.p.) all decreased nociceptive responses, as did i.pl. coinjections of lidocaine (0.003%–1%) with 10% HS. Histopathologic assessment revealed no tissue damage due to HS. CONCLUSIONS: CONCLUSIONS:The i.pl. HS assay is easily performed, rapidly detects standard analgesics, and produces minimal animal suffering without tissue damage. We propose this assay as a useful addition to the armamentarium of existing preclinical analgesic screens. Accepted for publication August 24, 2017. Funding: This work was funded in part by the Dr Jean Templeton Hugill Endowment for Anesthesia Memorial Fund and The University of British Columbia Faculty of Medicine. S.K.W.S. holds the Dr Jean Templeton Hugill Chair in Anesthesia. Conflicts of Interest: See Disclosures at the end of the article. Reprints will not be available from the authors. Address correspondence to Bernard A. MacLeod, MD, FRCPC, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. Address e-mail to bernard.macleod@gmail.com. © 2017 International Anesthesia Research Society

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The Influence of Age on Sensitivity to Dexmedetomidine Sedation During Spinal Anesthesia in Lower Limb Orthopedic Surgery

To investigate the influence of age on sensitivity to dexmedetomidine sedation in adult patients, we selected 79 patients scheduled for lower limb orthopedic surgery under spinal anesthesia to identify the dexmedetomidine ED50 for adequate sedation among different age groups. After a spinal anesthetic was placed, a dose of dexmedetomidine determined by the Dixon up–and–down method was administered over 15 minutes. The ED50 in the elderly group was lower than in the other 2 groups (elderly: 0.88 ± 0.07; middle aged: 1.16 ± 0.08; young: 1.21 ± 0.06 µg/kg; both P

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Pearls of Wisdom for High-Risk Laser Lead Extractions: A Focused Review

Due to new indications and improved technology, the incidence of laser lead extraction (LLE) has significantly increased over the past years. While LLE has been well studied and proven to be safe and effective, only few studies are geared toward the anesthesiologist's role during high-risk LLEs. This article utilized both a focused review and authors' experience to investigate anesthetic protocols during LLEs. Through this review, we recommend best practices for the anesthesiologist including appropriate procedure location, onsite availability of a cardiac surgeon, availability of a cardiopulmonary bypass machine, and intraoperative use of echocardiography to detect and address potential complications during high-risk LLEs. Accepted for publication August 31, 2017. Funding: None. Conflicts of Interest: See Disclosures at the end of the article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Portions of this submitted manuscript were presented at the Society of Cardiovascular Anesthesiologists Annual Meeting PBLD section in San Diego, CA, April 2016. Reprints will not be available from the authors. Address correspondence to Lilibeth Fermin, MD, MBA, 2950 Cleveland Clinic Blvd, Weston, FL 33331. Address e-mail to ferminl@ccf.org. © 2017 International Anesthesia Research Society

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A Survey Evaluating Burnout, Health Status, Depression, Reported Alcohol and Substance Use, and Social Support of Anesthesiologists

BACKGROUND: BACKGROUND:Burnout affects all medical specialists, and concern about it has become common in today's health care environment. The gold standard of burnout measurement in health care professionals is the Maslach Burnout Inventory-Human Services Survey (MBI-HSS), which measures emotional exhaustion, depersonalization (DP), and personal accomplishment. Besides affecting work quality, burnout is thought to affect health problems, mental health issues, and substance use negatively, although confirmatory data are lacking. This study evaluates some of these effects. METHODS: METHODS:In 2011, the American Society of Anesthesiologists and the journal Anesthesiology cosponsored a webinar on burnout. As part of the webinar experience, we included access to a survey using MBI-HSS, 12-item Short Form Health Survey (SF-12), Social Support and Personal Coping (SSPC-14) survey, and substance use questions. Results were summarized using sample statistics, including mean, standard deviation, count, proportion, and 95% confidence intervals. Adjusted linear regression methods examined associations between burnout and substance use, SF-12, SSPC-14, and respondent demographics. RESULTS: RESULTS:Two hundred twenty-one respondents began the survey, and 170 (76.9%) completed all questions. There were 266 registrants total (31 registrants for the live webinar and 235 for the archive event), yielding an 83% response rate. Among respondents providing job titles, 206 (98.6%) were physicians and 2 (0.96%) were registered nurses. The frequency of high-risk responses ranged from 26% to 59% across the 3 MBI-HSS categories, but only about 15% had unfavorable scores in all 3. Mean mental composite score of the SF-12 was 1 standard deviation below normative values and was significantly associated with all MBI-HSS components. With SSPC-14, respondents scored better in work satisfaction and professional support than in personal support and workload. Males scored worse on DP and personal accomplishment and, relative to attending physicians, residents scored worse on DP. There was no significant association between MBI-HSS and substance use. CONCLUSIONS CONCLUSIONSMany anesthesiologists exhibit some high-risk burnout characteristics, and these are associated with lower mental health scores. Personal and professional support were associated with less emotional exhaustion, but overall burnout scores were associated with work satisfaction and professional support. Respondents were generally economically satisfied but also felt less in control at work and that their job kept them from friends and family. The association between burnout and substance use may not be as strong as previously believed. Additional work, perhaps with other survey instruments, is needed to confirm our results. Accepted for publication May 9, 2017. Funding: Vanderbilt Institute for Clinical and Translational Research (VICTR, #VR8248). The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Reprints will not be available from the authors. Address correspondence to Steve Alan Hyman, MD, Department of Anesthesiology, Vanderbilt University Medical Center, 1301 Medical Center Dr, Nashville, TN 37205. Address e-mail to steve.hyman@vanderbilt.edu. © 2017 International Anesthesia Research Society

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Preventing Adverse Events in Cataract Surgery: Recommendations From a Massachusetts Expert Panel

Massachusetts health care facilities reported a series of cataract surgery–related adverse events (AEs) to the state in recent years, including 5 globe perforations during eye blocks performed by 1 anesthesiologist in a single day. The Betsy Lehman Center for Patient Safety, a nonregulatory Massachusetts state agency, responded by convening an expert panel of frontline providers, patient safety experts, and patients to recommend strategies for mitigating patient harm during cataract surgery. The purpose of this article is to identify contributing factors to the cataract surgery AEs reported in Massachusetts and present the panel's recommended strategies to prevent them. Data from state-mandated serious reportable event reports were supplemented by online surveys of Massachusetts cataract surgery providers and semistructured interviews with key stakeholders and frontline staff. The panel identified 2 principal categories of contributing factors to the state's cataract surgery–related AEs: systems failures and choice of anesthesia technique. Systems failures included inadequate safety protocols (48.7% of contributing factors), communication challenges (18.4%), insufficient provider training (17.1%), and lack of standardization (15.8%). Choice of anesthesia technique involved the increased relative risk of needle-based eye blocks. The panel's surveys of Massachusetts cataract surgery providers show wide variation in anesthesia practices. While 45.5% of surgeons and 69.6% of facilities reported increased use of topical anesthesia compared to 10 years earlier, needle-based blocks were still used in 47.0% of cataract surgeries performed by surgeon respondents and 40.9% of those performed at respondent facilities. Using a modified Delphi approach, the panel recommended several strategies to prevent AEs during cataract surgery, including performing a distinct time-out with at least 2 care-team members before block administration; implementing standardized, facility-wide safety protocols, including a uniform site-marking policy; strengthening the credentialing and orientation of new, contracted and locum tenens anesthesia staff; ensuring adequate and documented training in block administration for any provider who is new to a facility, including at least 10 supervised blocks before practicing independently; using the least invasive form of anesthesia appropriate to the patient; and finally, adjusting anesthesia practices, including preferred techniques, as evidence-based best practices evolve. Future research should focus on evaluating the impact of these recommendations on patient outcomes. Accepted for publication August 21, 2017. Funding: This work was supported, in part, by the Agency for Health care Research and Quality Grant #1K08HS024764-01. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Karen C. Nanji, MD, MPH, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, 55 Fruit St, Boston MA 02114. Address e-mail to knanji@partners.org. © 2017 International Anesthesia Research Society

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Incidence and Operative Factors Associated With Discretional Postoperative Mechanical Ventilation After General Surgery

BACKGROUND: BACKGROUND:Mechanical ventilation after general surgery is associated with worse outcomes, prolonged hospital stay, and increased health care cost. Postoperatively, patients admitted to the intensive care unit (ICU) may be categorized into 1 of 3 groups: extubated patients (EXT), patients with objective medical indications to remain ventilated (MED), and patients not meeting these criteria, called "discretional postoperative mechanical ventilation" (DPMV). The objectives of this study were to determine the incidence of DPMV in general surgery patients and identify the associated operative factors. METHODS: METHODS:At a large, tertiary medical center, we reviewed all surgical cases performed under general anesthesia from April 1, 2008 to February 28, 2015 and admitted to the ICU postoperatively. Patients were categorized into 1 of 3 cohorts: EXT, MED, or DPMV. Operative factors related to the American Society of Anesthesiologists Physical Status (ASA PS), duration of surgery, surgery end time, difficult airway management, intraoperative blood and fluid administration, vasopressor infusions, intraoperative arterial blood gasses, and ventilation data were collected. Additionally, anesthesia records were reviewed for notes indicating a reason or rationale for postoperative ventilation. Categorical variables were compared by χ2 test, and continuous variables by analysis of variance or Kruskal-Wallis H test. Categorical variables are presented as n (%), and continuous variables as mean ± standard deviation or median (interquartile range) as appropriate. Significance level was set at P≤ .05. RESULTS: RESULTS:Sixteen percent of the 3555 patients were categorized as DPMV and 12.2% as MED. Compared to EXT patients, those classified as DPMV had received significantly less fluid (2757 ± 2728 mL vs 3868 ± 1885 mL; P

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Thermal A-δ Nociceptors, Identified by Transcriptomics, Express Higher Levels of Anesthesia-Sensitive Receptors Than Thermal C-Fibers and Are More Suppressible by Low-Dose Isoflurane

We investigated the effect of isoflurane on 2 main types of thermal nociceptors: A-δ and C-fibers. Surprisingly, 1% inhaled isoflurane led to a hyperalgesic response to C-fiber thermal stimulation, whereas responses to A-δ thermal stimulation were blunted. We explored the hypothesis that differences in withdrawal behavior are mediated by differential expression of isoflurane-sensitive proteins between these types of thermal nociceptors. Multiple transcriptomic databases of peripheral neurons were integrated to reveal that isoflurane-susceptible proteins Htr3a, Kcna2, and Scn8a were enriched in thermosensitive A-δ neurons. This exploratory analysis highlights the differing role that volatile anesthetics might have on nociceptors in the peripheral nervous system. Accepted for publication August 24, 2017. Funding: This study was supported by the intramural research program of the National Institutes of Health (NIH), Clinical Center. S.J.R. was supported by the NIH Medical Research Scholars Program, a public–private partnership supported jointly by the NIH and generous contributions to the Foundation for the NIH from the Doris Duke Charitable Foundation, The American Association for Dental Research, the Colgate-Palmolive Company, Genentech, alumni of student research programs, and other individual supporters. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Michael J. Iadarola, PhD, Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bldg 10, Room 2C401, 10 Center Dr, MSC 1510, Bethesda, MD 20892. Address e-mail to miadarol@cc.nih.gov. © 2017 International Anesthesia Research Society

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Truncated μ-Opioid Receptors With 6 Transmembrane Domains Are Essential for Opioid Analgesia

BACKGROUND: BACKGROUND:Most clinical opioids act through μ-opioid receptors. They effectively relieve pain but are limited by side effects, such as constipation, respiratory depression, dependence, and addiction. Many efforts have been made toward developing potent analgesics that lack side effects. Three-iodobenzoyl-6β-naltrexamide (IBNtxA) is a novel class of opioid active against thermal, inflammatory, and neuropathic pain, without respiratory depression, physical dependence, and reward behavior. The μ-opioid receptor (OPRM1) gene undergoes extensive alternative precursor messenger ribonucleic acid splicing, generating multiple splice variants that are conserved from rodents to humans. One type of variant is the exon 11 (E11)–associated truncated variant containing 6 transmembrane domains (6TM variant). There are 5 6TM variants in the mouse OPRM1 gene, including mMOR-1G, mMOR-1M, mMOR-1N, mMOR-1K, and mMOR-1L. Gene-targeting mouse models selectively removing 6TM variants in E11 knockout (KO) mice eliminated IBNtxA analgesia without affecting morphine analgesia. Conversely, morphine analgesia is lost in an exon 1 (E1) KO mouse that lacks all 7 transmembrane (7TM) variants but retains 6TM variant expression, while IBNtxA analgesia remains intact. Elimination of both E1 and E11 in an E1/E11 double KO mice abolishes both morphine and IBNtxA analgesia. Reconstituting expression of the 6TM variant mMOR-1G in E1/E11 KO mice through lentiviral expression rescued IBNtxA but not morphine analgesia. The aim of this study was to investigate the effect of lentiviral expression of the other 6TM variants in E1/E11 KO mice on IBNtxA analgesia. METHODS: METHODS:Lentiviruses expressing 6TM variants were packaged in HEK293T cells, concentrated by ultracentrifugation, and intrathecally administered 3 times. Opioid analgesia was determined using a radiant-heat tail-flick assay. Expression of lentiviral 6TM variant messenger ribonucleic acids was examined by polymerase chain reaction (PCR) or quantitative PCR. RESULTS: RESULTS:All the 6TM variants restored IBNtxA analgesia in the E1/E11 KO mouse, while morphine remained inactive. Expression of lentiviral 6TM variants was confirmed by PCR or quantitative PCR. IBNtxA median effective dose values determined from cumulative dose–response studies in the rescued mice were indistinguishable from wild-type animals. IBNtxA analgesia was maintained for up to 33 weeks in the rescue mice and was readily antagonized by the opioid antagonist levallorphan. CONCLUSIONS: CONCLUSIONS:Our study demonstrated the pharmacological relevance of mouse 6TM variants in IBNtxA analgesia and established that a common functional core of the receptors corresponding to the transmembrane domains encoded by exons 2 and 3 is sufficient for activity. Thus, 6TM variants offer potential therapeutic targets for a distinct class of analgesics that are effective against broad-spectrum pain models without many side effects associated with traditional opioids. Funding: This work was supported, in part, by grants from a National Natural Science Foundation of China grant (81673412) to Z.L., the Peter F. McManus Charitable Trust, Mr William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, and the National Institute on Drug Abuse of the National Institutes of Health (DA06241 and DA07242 to G.W.P., and DA029244, DA013997, and DA04585 to Y.-X.P.), a core grant from the National Cancer Institute of the National Institutes of Health (CA08748) to the Memorial Sloan-Kettering Cancer Center. Accepted for publication August 24, 2017. The authors declare no conflicts of interest. Reprints will not be available from the authors. Address correspondence to Ying-Xian Pan, MD, PhD, Department of Neurology and the Molecular Pharmacology Program, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065. Address e-mail to pany@mskcc.org. © 2017 International Anesthesia Research Society

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Higher Operating Table for Optimal Needle-Entry Angle and Less Discomfort During Spinal Anesthesia

The aim of this study was to find the optimal table height to facilitate insertion of the spinal needle at a 90° angle and to reduce the anesthesiologist's discomfort. Sixty patients were randomly allocated according to landmarks on the anesthesiologist's body: umbilicus (group U), lowest rib margin (R), xiphoid process (X), and nipple (N). The coronal insertion angle between the patient's skin and the spinal needle was obtuse in groups U and R, and 90° in group X. We demonstrated that high operating tables at the xiphoid and nipple level facilitate more optimal needle entry angles while reducing the discomfort and joint flexion of anesthesiologists during spinal anesthesia. Funding: None. Accepted for publication August 4, 2017. The authors declare no conflicts of interest. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's website (http://ift.tt/KegmMq). Clinical trial number: This trial was registered at the Clinical Research Information Service http://ift.tt/1JTfppE. Identifier: KCT0001437. Reprints will not be available from the authors. Address correspondence to Jinhee Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea. Address e-mail to Anesing1@snu.ac.kr. © 2017 International Anesthesia Research Society

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“Difficult Airway” Bibliometrics: Importance of Capturing the Correct Literature

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Comparative Effectiveness Research in Health Services

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