Inside EMS Podcast: EMS cartoons provide therapeutic, humorous twist

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​​In this Inside EMS Podcast episode, co-hosts Chris Cebollero and Kelly Grayson are joined by Lenwood "Lenny" Brown III to discuss his new EMS cartoon Jakes Comics. Brown is a career firefighter/EMT and has been involved with emergency services for over 10 years. He pulls from his experience to highlight the lighter side of the job.

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Predicting stroke volume and arterial pressure fluid responsiveness in liver cirrhosis patients using dynamic preload variables: A prospective study of diagnostic accuracy.

BACKGROUND: Predicting whether a fluid challenge will elicit 'fluid responsiveness' in stroke volume (SV) and arterial pressure is crucial for managing hypovolaemia and hypotension. Pulse pressure variation (PPV), SV variation (SVV) and the plethysmographic variability index (PVI) have been shown to predict SV fluid responsiveness, and the PPV/SVV ratio has been shown to predict arterial pressure fluid responsiveness under various conditions. However, these variables have not been investigated in liver cirrhosis patients. OBJECTIVE: The objective was to evaluate SV and arterial pressure fluid responsiveness in liver cirrhosis patients by using dynamic preload and vascular tone variables. DESIGN: A prospective study of diagnostic accuracy. SETTINGS: A single-centre trial conducted from November 2013 to April 2015. PATIENTS: Thirty-one adult patients, recipients of a living donor liver transplantat. INTERVENTION: An intraoperative fluid challenge with 10 ml kg-1 of 0.9% normal saline. MAIN OUTCOME MEASURES: PPV, SVV, cardiac index and systemic vascular resistance index were measured using the Pulse index Continuous cardiac system. The PVI and perfusion index were measured using the Masimo Radical 7 co-oximeter. The PPV, SVV and PVI were measured to investigate SV fluid responsiveness, and the PPV/SVV ratio, perfusion index and systemic vascular resistance index were measured to investigate arterial pressure fluid responsiveness. RESULTS: The areas under the receiver operating characteristic curves for PPV, SVV and PVI were 0.794, 0.754 and 0.800, respectively (all P

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CRISPR/Cas9 Mediated Insertion of loxP Sites in the Mouse Dock7 Gene Provides an Effective Alternative to Use of Targeted Embryonic Stem Cells

Targeted gene mutation in the mouse is a primary strategy to understand gene function and relation to phenotype. The Knockout Mouse Project (KOMP) had an initial goal to develop a public resource of mouse embryonic stem (ES) cell clones that carry null mutations in all genes. Indeed, many useful novel mouse models have been generated from the publically accessible targeted mouse ES cell lines. However, there are limitations, including incorrect targeting or cassette structure, and difficulties with germline transmission of the allele from chimeric mice. In our experience, using a small sample of targeted ES cell clones, we were successful ~50% of the time in generating germline transmission of a correctly targeted allele. With the advent of CRISPR/Cas9 as a mouse genome modification tool, we assessed the efficiency of creating a conditional targeted allele in one gene, dedicator of cytokinesis 7 (Dock7), for which we were unsuccessful in generating a null allele using a KOMP targeted ES cell clone. The strategy was to insert loxP sites to flank either exons 3 and 4, or exons 3 through 7. By coinjecting Cas9 mRNA, validated sgRNAs, and oligonucleotide donors into fertilized eggs from C57BL/6J mice, we obtained a variety of alleles including mice homozygous for the null alleles mediated by non-homologous end joining, alleles with one of the two desired loxP sites, and correctly targeted alleles with both loxP sites. We also found frequent mutations in the inserted loxP sequence, which is partly attributable to the heterogeneity in the original oligonucleotide preparation.

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Improved Placement of Multi-Mapping Small RNAs

High-throughput sequencing of small RNAs (sRNA-seq) is a popular method used to discover and annotate microRNAs (miRNAs), endogenous short interfering RNAs (siRNAs) and Piwi-associated RNAs (piRNAs). One of the key steps in sRNA-seq data analysis is alignment to a reference genome. sRNA-seq libraries often have a high proportion of reads which align to multiple genomic locations, which makes determining their true origins difficult. Commonly used sRNA-seq alignment methods result in either very low precision (choosing an alignment at random) or sensitivity (ignoring multi-mapping reads). Here, we describe and test an sRNA-seq alignment strategy that uses local genomic context to guide decisions on proper placements of multi-mapped sRNA-seq reads. Tests using simulated sRNA-seq data demonstrated that this local-weighting method outperforms other alignment strategies using three different plant genomes. Experimental analyses with real sRNA-seq data also indicate superior performance of local-weighting methods for both plant miRNAs and heterochromatic siRNAs. The local-weighting methods we have developed are implemented as part of the sRNA-seq analysis program ShortStack, which is freely available under a general public license. Improved genome alignments of sRNA-seq data should increase the quality of downstream analyses and genome annotation efforts.

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Identification of Novel Regulators of the JAK/STAT Signaling Pathway that Control Border Cell Migration in the Drosophila Ovary

The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway is an essential regulator of cell migration both in mammals and fruit flies. Cell migration is required for normal embryonic development and immune response but can also lead to detrimental outcomes, such as tumor metastasis. A cluster of cells termed "border cells" in the Drosophila ovary provides an excellent example of a collective cell migration, in which two different cell types coordinate their movements. Border cells arise within the follicular epithelium and are required to invade the neighboring cells and migrate to the oocyte to contribute to a fertilizable egg. Multiple components of the STAT signaling pathway are required during border cell specification and migration; however, the functions and identities of other potential regulators of the pathway during these processes are not yet known. To find new components of the pathway that govern cell invasiveness, we knocked down 48 predicted STAT modulators using RNAi expression in follicle cells, and assayed defective cell movement. We have shown that seven of these regulators are involved in either border cell specification or migration. Examination of the epistatic relationship between candidate genes and Stat92E reveals that the products of two genes, protein tyrosine phosphatase 61f (ptp61f) and brahma (brm), interact with Stat92E during both border cell specification and migration.

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Morphine Suppresses Lung Cancer Cell Proliferation Through the Interaction with Opioid Growth Factor Receptor: An In Vitro and Human Lung Tissue Study.

BACKGROUND: There have been inconsistent reports on whether opioids promote or inhibit lung cancer growth. In this study, we suggest that opioid growth factor receptor (OGFR), a negative regulator of cell proliferation, is a binding site of morphine and is involved in subsequent morphine-induced lung cancer growth suppression. METHODS: The expression and distribution of OGFR in human lung cancer tissues and cell lines were assessed with immunohistochemistry and real-time reverse transcription polymerase chain reaction. The human lung cancer cell line, H1975 (adenocarcinoma), which overexpressed OGFR but not [mu]-opioid receptors, was selected for further analysis to verify the interaction between morphine and OGFR and the impact of morphine on cancer cell growth. RESULTS: OGFR was expressed in lung cancer tissues and all cancer cell lines tested. Adenocarcinoma showed a higher OGFR expression than squamous cell carcinoma (reverse transcription polymerase chain reaction relative quantitation value: median [interquartile range], 13.1 [9.3-20.0] vs 4.3 [2.2-6.6]; P = 0.003). OGFR expression showed an inverse correlation with cell proliferation (r = -0.92, P = 0.0001). Morphine treatment reduced the median H1975 cell number by approximately 23% (P = 0.03). Growth suppression by morphine was attenuated when OGFR was knocked down. A confocal experiment demonstrated binding of morphine to OGFR. Growth suppression by morphine occurred in the S phase of the cell cycle. CONCLUSIONS: Lung cancer tissues and cell lines express OGFR. Morphine interacts with OGFR and may suppress lung cancer progression. (C) 2016 International Anesthesia Research Society

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Mapping General Anesthetic Sites in Heteromeric [gamma]-Aminobutyric Acid Type A Receptors Reveals a Potential For Targeting Receptor Subtypes.

IV general anesthetics, including propofol, etomidate, alphaxalone, and barbiturates, produce important actions by enhancing [gamma]-aminobutyric acid type A (GABAA) receptor activation. In this article, we review scientific studies that have located and mapped IV anesthetic sites using photoaffinity labeling and substituted cysteine modification protection. These anesthetics bind in transmembrane pockets between subunits of typical synaptic GABAA receptors, and drugs that display stereoselectivity also show remarkably selective interactions with distinct interfacial sites. These results suggest strategies for developing new drugs that selectively modulate distinct GABAA receptor subtypes. (C) 2016 International Anesthesia Research Society

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The Perioperative Use of Dexmedetomidine in Pediatric Patients with Congenital Heart Disease: An Analysis from the Congenital Cardiac Anesthesia Society-Society of Thoracic Surgeons Congenital Heart Disease Database.

BACKGROUND: Dexmedetomidine is a selective [alpha]-2 receptor agonist with a sedative and cardiopulmonary profile that makes it an attractive anesthetic for pediatric patients with congenital heart disease (CHD). Although several smaller, single-center studies suggest that dexmedetomidine use is gaining traction in the perioperative setting in children with CHD, there are limited multicenter data, with little understanding of the variation in use across age ranges, procedural complexity, and centers. The aim of this study was to use the Congenital Cardiac Anesthesia Society-Society of Thoracic Surgeons (CCAS-STS) registry to describe patient- and center-level variability in the use of dexmedetomidine in the perioperative setting in children with heart disease. METHODS: To describe the use of dexmedetomidine in patients for CHD surgery, we analyzed all index cardiopulmonary bypass operations entered in the CCAS-STS database from 2010 to 2013. Patient and operative characteristics were compared between those who received intraoperative dexmedetomidine and those who did not. Selective outcomes associated with dexmedetomidine use were also described. RESULTS: Of the 12,142 operations studied, 3600 (29.6%) received perioperative dexmedetomidine (DEX) and 8542 did not receive the drug (NoDEX). Patient characteristics were different between the 2 groups with the DEX group generally exhibiting both lower patient and procedural risk factors. Patients who received dexmedetomidine were more likely to have a lower level of Society of Thoracic Surgeons mortality complexity than patient who did not receive it. Consistent with their overall lower risk profile, children in the DEX group also demonstrated improved outcomes compared with patients who did not receive dexmedetomidine. CONCLUSIONS: We described the growing use of dexmedetomidine in children anesthetized for surgical repair of CHD. Dexmedetomidine appears to be preferentially given to older and larger children who are undergoing less complex CHD surgery. We believe that the data provided in this study are the largest investigating the use of an anesthetic drug in CHD patients. It is also the first analysis of the anesthesia data in the CCAS-STS Congenital Heart Disease database. (C) 2016 International Anesthesia Research Society

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The role of expected reward in frontal eye field during natural scene search

When a saccade is expected to result in a reward, both neural activity in oculomotor areas and the saccade itself (e.g. its vigor and latency) are altered (compared to when no reward is expected). As such, it is unclear whether the correlations of neural activity with reward indicate a representation of reward beyond a movement representation; the modulated neural activity may simply represent the differences in motor output due to expected reward. Here, to distinguish between these possibilities, we trained monkeys to perform a natural scene search task while we recorded from the frontal eye field (FEF). Indeed, when reward was expected (i.e., saccades to the target), FEF neurons showed enhanced responses. Moreover, when monkeys accidentally made eye movements to the target, firing rates were lower than when they purposively moved to the target. Thus, neurons were modulated by expected reward rather than simply the presence of the target. We then fit a model that simultaneously included components related to expected reward and saccade parameters. While expected reward led to shorter latency and higher velocity saccades, these behavioral changes could not fully explain the increased FEF firing rates. Thus, FEF neurons appear to encode motivational factors such as reward expectation, above and beyond the kinematic and behavioral consequences of imminent reward.

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Shared and Distinct Retinal Input to the Mouse Superior Colliculus and Dorsal Lateral Geniculate Nucleus

The mammalian retina conveys the vast majority of information about visual stimuli to two brain regions: the dorsal lateral geniculate nucleus (dLGN) and the superior colliculus (SC). The degree to which retinal ganglion cells (RGCs) send similar or distinct information to the two areas remains unclear despite the important constraints that different patterns of RGC input place on downstream visual processing. To resolve this ambiguity we injected a glycoprotein-deficient rabies virus coding for the expression of a fluorescent protein into the dLGN or SC; rabies virus labeled a smaller fraction of RGCs than lipophilic dyes like DiI but, crucially, did not label RGC axons of passage. ~80% of the RGCs infected by rabies virus injected into the dLGN were co-labeled with DiI injected into the SC, suggesting that many dLGN-projecting RGCs also project to the SC. However, functional characterization of RGCs revealed that the SC receives input from several classes of RGCs that largely avoid the dLGN - in particular, RGCs in which (1) sustained changes in light intensity elicit transient changes in firing rate and/or (2) a small range of stimulus sizes or temporal fluctuations in light intensity elicit robust activity. Taken together, our results illustrate several unexpected asymmetries in the information that the mouse retina conveys to two major downstream targets and suggest that differences in the output of dLGN and SC neurons reflect, at least in part, differences in the functional properties of RGCs that innervate the SC but not the dLGN.

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Temporal dynamics of visual category representation in the macaque inferior temporal cortex

Object categories are recognized at multiple levels of hierarchical abstractions. Psychophysical studies have shown a more rapid perceptual access to the mid level category information (e.g. human faces) than the higher (superordinate; e.g. animal) or the lower (subordinate; e.g. face identity) levels. Mid level category members share many features while few features are shared between members of different mid level categories. To better understand the neural basis of expedited access to mid level category information we examined neural responses of the inferior temporal (IT) cortex of macaque monkeys viewing a large number of object images. We found an earlier representation of mid level categories in the IT population and single unit responses compared to superordinate and subordinate level categories. The short latency representation of mid level category information shows that visual cortex first divides the category shape space at its sharpest boundaries defined by high/low within/between group similarity. This short latency mid level category boundary map may be prerequisite for representation of other categories at more global and finer scales.

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Recording extracellular neural activity in the behaving monkey using a semi-chronic and high-density electrode system

We describe a technique to semi-chronically record the cortical extracellular neural activity in the behaving monkey employing commercial high-density electrodes. After the design and construction of low cost microdrives that allows varying the depth of the recording locations after the implantation surgery, we recorded the extracellular unit activity from pools of neurons at different depths in the presupplementary motor cortex (pre-SMA) of a Rhesus monkey trained in a synchronization-tapping task. The collected data was processed to classify cells as putative pyramidal cells or interneurons and to identify monosynaptic connections between cell pairs. Analysis of the population activity revealed a highly repetitive ensemble dynamics over distinct trials of the synchronization task. These results show that the semi-chronic technique is a viable option for the large-scale parallel recording of local circuit activity at different depths in the cortex of the macaque monkey and other large species.

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Motor learning and cross-limb transfer rely upon distinct neural adaptation processes

Performance benefits conferred in the untrained limb after unilateral motor practice are termed cross-limb transfer. Although the effect is robust, the neural mechanisms remain incompletely understood. Here we use non-invasive brain stimulation to reveal that the neural adaptations that mediate motor learning in the trained limb are distinct from those that underlie cross-limb transfer to the opposite limb. Thirty-six participants practiced a ballistic motor task with their right index finger (150 trials), followed by intermittent-theta burst stimulation (iTBS) applied to the trained (contralateral) primary motor cortex (cM1 group), the untrained (ipsilateral) M1 (iM1 group), or the vertex (sham group). Following stimulation, another 150 training trials were undertaken. Motor performance and corticospinal excitability were assessed before motor training, pre- and post-iTBS, and following the second training bout. For all groups, training significantly increased performance and excitability of the trained hand, and performance, but not excitability, of the untrained hand, indicating transfer at the level of task performance. The typical faciltatory effect of iTBS on MEPs was reversed for cM1, suggesting homeostatic metaplasticity, and prior performance gains in the trained hand were degraded, suggesting that iTBS interfered with learning. In stark contrast, iM1 iTBS facilitated both performance and excitability for the untrained hand. Importantly, the effects of cM1 and iM1 iTBS on behaviour were exclusive to the hand contralateral to stimulation, suggesting that adaptations within the untrained M1 contribute to cross-limb transfer. However, the neural processes that mediate learning in the trained hemisphere versus transfer in the untrained hemisphere appear distinct.

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Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE)

Polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE) is an ultra rare neurodevelopmental disorder characterized by severe, infantile-onset intractable epilepsy, neurocognitive delay, macrocephaly, and craniofacial dysmorphism. The molecular diagnosis of this condition has thus far only been made in 16 Old Order Mennonite patients carrying a homozygous 7 kb founder deletion of exons 9–13 of STRADA. We performed clinical whole exome sequencing (WES) on a 4-year-old Indian male with global developmental delay, history of failure to thrive, infantile spasms, repetitive behaviors, hypotonia, low muscle mass, marked joint laxity, and dysmorphic facial features including tall forehead, long face, arched eyebrows, small chin, wide mouth, and tented upper lip. A homozygous single nucleotide duplication, c.842dupA (p.D281fs), in exon 10 of STRADA was identified. Sanger sequencing confirmed the mutation in the individual and identified both parents as carriers. In light of the molecular discoveries, the patient's clinical phenotype was considered to be a good fit for PMSE. We identified for the first time a homozygous point mutation in STRADA causing PMSE. Additional bi-allelic mutations related to PMSE thus far have not been observed in Baylor ∼6,000 consecutive clinical WES cases, supporting the rarity of this disorder. Our findings may have treatment implications for the patient since previous studies have shown rapamycin as a potential therapeutic agent for the seizures and cognitive problems in PMSE patients. © 2016 Wiley Periodicals, Inc.

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Hartsfield syndrome associated with a novel heterozygous missense mutation in FGFR1 and incorporating tumoral calcinosis

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Helicobacter pylori-Clarithromycin Resistance in Symptomatic Pediatric Patients in a High Prevalence Country.

Introduction: Failure to eradicate Helicobacter pylori despite antibiotic treatment is generally attributed to increasing clarithromycin resistance conferred by point mutations in the 23S-rRNA gene or metronidazole resistance attributed to rdxA gene deletion in patients. Scarce data for pediatric population are available from developing countries. Objectives: To determine the presence of A2142G/C and A2143G mutations in the 23S-rRNA gene and/or rdxA gene deletion in a group of symptomatic H. pylori-infected children recruited from an area with high infection rate and risk of gastric cancer. Patients and Methods: We recruited 118 patients referred for upper endoscopy for gastrointestinal symptoms. The presence of H. pylori was determined by urease test and histological staining. The rdxA gene deletion and 2142G/C and A2143G mutations were determined by PCR-RFLP. A subgroup of infected patients received a 14-day regimen of omeprazole, amoxicillin, and clarithromycin. The effectiveness of this regime was determined by stool antigen determination 8 weeks after treatment. Results: About 21% of the analyzed infected patients showed mutation in the 23S-rRNA gene, with the A2143G transition as the more frequent mutation, and 2% of the patients showed rdxA gene deletion. After treatment, 25% of the patients continued to harbor the bacteria; of these, 67% carried the A2143G mutation. Conclusions: H. pylori-infected pediatric patients from Chile show high prevalence of the mutation responsible for clarithromycin resistance. The failure to eradicate H. pylori can be attributed to the presence of A2143G mutation. (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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Fermented Milk Consumption and Common Infections in Children Attending Day-care Centers. A Randomized Trial.

Objectives: This multicenter, double-blind, randomized, placebo-controlled clinical trial investigated the effect of a fermented milk product containing the Lactobacillus casei CNCM I-1518 strain, on respiratory and gastro-intestinal common infectious diseases (CIDs) in children attending day-care centers in Russia. Methods: Children aged 3-6 years received 100 g of a fermented milk product (n = 300) or a control product (n = 299) twice-daily for 3 months, followed by a 1-month observation period. The primary outcome was the incidence of CIDs during the product consumption period. Results: There was no significant difference in the incidence of CIDs between the groups (N = 98 with fermented milk product vs. N = 93 with control product). The overall number of CIDs (and no severe cases at all) in both study groups and in all twelve centers, however, was unexpectedly low resulting in underpowering of the study. No differences were found between the groups in the duration or severity of disease, duration of sick leave from day-care centers, parental missed working days, or in quality of life dimensions on the PedsQL questionnaire (p > 0.05). However, there was a significantly lower incidence of the most frequently observed CID, rhinopharyngitis, in children consuming the fermented milk product compared to those consuming the control product (N = 81 vs. N = 100; relative risk RR [95% CI] = 0.82 [0.69; 0.96]; p = 0.017) when considering the entire study period. Conclusion: Although no other significant differences were shown between the fermented milk and control product groups in this study, lower incidence of rhinopharyngitis may indicate a beneficial effect of this fermented milk product. This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://ift.tt/OBJ4xP (C) 2016 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,

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