GABA is well-known to be a critical regulator of the body's physiological response to stress through tight regulation of hypothalamic-pituitary-adrenal (HPA) axis function.
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Cardiac sympathetic neurons (SNs) finely tune the rate and strength of heart contractions to match the blood demand, both at rest and during acute stresses, through the release of norepinephrine (NE). Junctional sites at the interface between the two cell types have been observed, but whether direct neuro-cardiac coupling has a role in heart physiology has not thus far been clearly demonstrated.
We investigated the dynamics of SN/cardiomyocyte intercellular signalling, both by FRET-based imaging of cAMP in co-cultures, as a readout of cardiac β-AR activation, and in vivo, using optogenetics in transgenic mice with SN-specific expression of Channelrhodopsin-2. We demonstrate that SNs and cardiomyocytes interact at specific sites both in the human and rodent heart, and in co-cultures. Accordingly, neuronal activation elicited intracellular cAMP increases only in directly contacted myocytes and cell-cell coupling utilized a junctional extracellular signalling domain with elevated NE concentration. In the living mouse, optogenetic activation of cardiac SNs innervating the sino-atrial node resulted in an instantaneous chronotropic effect, which shortened the heartbeat interval with single beat precision. Remarkably, inhibition of the optogenetically elicited chronotropic responses required a high dose of propranolol (20-50 mg/Kg), suggesting that sympathetic neurotransmission in the heart occurs at locally elevated NE concentration.
Our in vitro and in vivo data suggest that the control of cardiac function, by SNs, occurs via direct intercellular coupling due to the establishment of a specific junctional-site.
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Despite its evolutionary and clinical significance, appetitive conditioning has been rarely investigated in humans. It has been proposed that this discrepancy might stem from the difficulty in finding suitable appetitive stimuli that elicit strong physiological responses. However, this might also be due to a possible lack of sensitivity of the psychophysiological measures commonly used to index human appetitive conditioning. Here, we investigated whether the postauricular reflex—a vestigial muscle microreflex that is potentiated by pleasant stimuli relative to neutral and unpleasant stimuli—may provide a valid psychophysiological indicator of appetitive conditioning in humans. To this end, we used a delay differential appetitive conditioning procedure, in which a neutral stimulus was contingently paired with a pleasant odor (CS+), while another neutral stimulus was not associated with any odor (CS−). We measured the postauricular reflex, the startle eyeblink reflex, and skin conductance response (SCR) as learning indices. Taken together, our results indicate that the postauricular reflex was potentiated in response to the CS+ compared with the CS−, whereas this potentiation extinguished when the pleasant odor was no longer delivered. In contrast, we found no evidence for startle eyeblink reflex attenuation in response to the CS+ relative to the CS−, and no effect of appetitive conditioning was observed on SCR. These findings suggest that the postauricular reflex is a sensitive measure of human appetitive conditioning and constitutes a valuable tool for further shedding light on the basic mechanisms underlying emotional learning in humans.
Microbial Drug Resistance, Ahead of Print.
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Publication date: Available online 10 March 2018
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Jean-François Lam, Laurent Gosselin, Paula W. Rushton
ObjectiveTo provide a comprehensive description of the current state of knowledge regarding the use of virtual technology (VT) for wheelchair skills training.Data sourcesThe Cochrane Library, MEDLINE, CINAHL, EMBASE, ACM, IEEE Xplore, Inspec, and Web of Science databases were searched for relevant articles from 1990 to February 2016.Study selectionWe included peer-reviewed studies or long conference proceedings that examined the use of VT as a medium to provide a wheelchair skills training intervention for any population with any diagnosis using any research design. One investigator screened the titles and abstracts, then 2 investigators independently reviewed the full-text articles. Disagreements regarding inclusion were resolved by consensus or a third reviewer. Ten studies were included out of 4994 initially identified.Data extractionTwo investigators extracted data to systematically assess the studies' findings into 6 tables (study design and participant characteristics, equipment and technology used, intervention characteristics, outcome measures, and outcomes).Data synthesisMost studies demonstrated that VT wheelchair skills training showed improved outcomes such as simulation score, completion time, and number of collisions in the virtual environment and/or in real world. However, subject characteristics, equipment, virtual environment, intervention tasks, and outcome measures varied across the studies.ConclusionsThere exists a variety of studies using VT as an intervention for wheelchair skills training. Given the positive outcomes for most of the studies, it appears as though VT may indeed be a solution that can help to alleviate barriers to wheelchair skills training and subsequently improve wheelchair user skill.
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The C-terminal domain (CTD) of the largest subunit of RNA polymerase II (RNAPII) is required to regulate transcription and to integrate it with other essential cellular processes. In the budding yeast Saccharomyces cerevisiae, the CTD of Rpb1p consists of 26 conserved heptad repeats that are post-translationally modified to orchestrate protein factor binding at different stages of the transcription cycle. A long-standing question in the study of the CTD is if there are any functional differences between the 26 repeats. In this study, we present evidence that repeats of identical sequence have different functions based on their position within the CTD. We assembled plasmids expressing Rpb1p with serine to alanine substitutions in three defined regions of the CTD and measured a range of phenotypes for yeast expressing these constructs. Mutations in the beginning and middle regions of the CTD had drastic, and region-specific effects, while mutating the distal region had no observable phenotype. Further mutational analysis determined that Ser5 within the first region of repeats was solely responsible for the observed growth differences and sequencing fast-growing suppressors allowed us to further define the functional regions of the CTD. This mutational analysis is consistent with current structural models for how the RNAPII holoenzyme and the CTD specifically would reside in complex with Mediator and establishes a foundation for studying regioselective binding along the repetitive RNAPII CTD.
Risk of melanoma is in part determined by genetic factors. Currently the only established high penetrance familial melanoma genes are CDKN2A and CDK4. Recent studies reported germline variants in POT1 in melanoma families. In the present study, we sequenced the entire POT1 gene in 694 patients from the M3-study. Patients with multiple primary melanomas (n=163) or with a positive family history (n=133) were classified as high-risk melanoma patients. Additionally, 200 single primary melanoma patients and 198 non-melanoma controls were sequenced. For prediction analysis 10 different tools were used. In total 53 different variants were found, of which 8 were detected in high-risk melanoma patients, only. Two out of these 8 variants were located in exons and were non-synonymous: g.124510982 G>A (p.R80C) and g.124491977 T>G (p.N300H). While g.124491977 T>G was predicted to be neutral, 80% of the prediction tools classified g.124510982 G>A as deleterious. The variant, g.124467236 T>C, which possibly causes a change in the splice site was identified in a case with a positive family history in the present study. Another variant in the 5-UTR, g.124537261 A>G, was found in 2 high-risk patients. So, in conclusion, melanoma associated POT1 germline variants seem to be rare. Further studies are required to evaluate the role of POT1 for genetic counselling.
Effective genome engineering should lead to a desired locus change with minimal adverse impact to the genome itself. However, flanking loci with site-directed recombinase recognition sites, such as those of the phage FC31 integrase, allows for creation of platforms for cassette exchange and manipulation of genomic regions in an iterative manner, once specific loci have been targeted. Here we show that a genomic locus engineered with inverted minimal phage FC31 attP/attB sites can undergo efficient recombinase-mediated cassette exchange (RMCE) in the fruit fly Drosophila melanogaster.
Crohn's disease (CD) is a chronic inflammatory bowel disease traditionally requiring treatments with important side effects, such as anti-TNF (tumor necrosis factor) therapy, which is efficient only for 30 to 40% patients who, moreover, can become non-responders later (up to 50% of them) (Olesen et al., 2016). This therapy can further generate adverse effects like infections and up to half of the CD patients will not continue therapy (non-compliance). Therefore, because vagus nerve stimulation (VNS) is thought to activate the cholinergic anti-inflammatory pathway, an anti-tumor necrosis factor (TNF) pathway partly through the action of acetylcholine on immune cells releasing TNF (Bonaz et al., 2013), VNS is being evaluated in CD patients as an alternative (or a complement) to pharmaceutical treatments (Bonaz et al., 2016;2017a).
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Deep brain stimulation (DBS) of nuclei within the basal ganglia, typically the subthalamic nucleus and globus pallidus, has been used as an effective treatment of Parkinson's disease (PD), commonly in combination with dopamine-replacement medications (reviewed in Kalia et al., 2013; DeLong and Wichmann, 2015). Many studies have reported significant positive effects of DBS on clinical indices such as Unified Parkinson's Disease Rating Scale (UPDRS) scores and general characteristics of movements such as maximal force, peak velocity, and movement time (Brown et al., 1999; Alberts et al., 2008; Daneault et al., 2016).
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Emotion identification is a key element of nonverbal communication, with emotions often expressed through changes in facial expression, eye contact, body posture and movement. Across the life span, accurate identification of emotional expressions is essential for successful interpersonal functioning (Carstensen et al., 1997). Inferring the emotions that others are experiencing is an important feature in avoiding conflict and providing social support. Furthermore, intact emotion identification skills are essential to regulate behavior.
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Publication date: Available online 9 March 2018
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Marta Fontcuberta-PiSunyer, Sara Cervantes, Eulàlia Miquel, Sergio Mora-Castilla, Louise C. Laurent, Angel Raya, Ramon Gomis, Rosa Gasa
Posttranscriptional modifications of histones constitute an epigenetic mechanism that is closely linked to both gene silencing and activation events. Trimethylation of Histone3 at lysine 27 (H3K27me3) is a repressive mark that associates with developmental gene regulation during differentiation programs. In the developing pancreas, expression of the transcription factor Neurogenin3 in multipotent progenitors initiates endocrine differentiation that culminates in the generation of all pancreatic islet cell lineages, including insulin-producing beta cells. Previously, we showed that Neurogenin3 promoted the removal of H3K27me3 marks at target gene promoters in vitro, suggesting a functional connection between this factor and regulators of this chromatin mark. In the present study, we aimed to specifically evaluate whether targeting the activity of these histone modifiers can be used to modulate pancreatic endocrine differentiation. Our data show that chemical inhibition of the H3K27me3 demethylases Jmjd3/Utx blunts Neurogenin3-dependent gene activation in vitro. Conversely, inhibition of the H3K27me3 methyltransferase Ezh2 enhances both the transactivation ability of Neurogenin3 in cultured cells and the formation of insulin-producing cells during directed differentiation from pluripotent cells. These results can help improve current protocols aimed at generating insulin-producing cells for beta cell replacement therapy in diabetes.
Over the last decade, single-incision laparoscopic cholecystectomy (SLC) has gained popularity, although it is not evident if benefits of this procedure overcome the potential increased risk. Aim of the study is to compare the outcome of SLC with conventional multi-incision laparoscopic cholecystectomy (MLC) in a meta-analysis of randomized controlled trials only.
A systematic Medline, Embase, and Cochrane Central Register of Controlled Trials literature search of articles on SLC and MLC for any indication was performed in June 2017. The main outcomes measured were overall adverse events, pain score (VAS), cosmetic results, quality of life, and incisional hernias. Linear regression was used to model the effect of each procedure on the different outcomes.
Forty-six trials were included and data from 5141 participants were analysed; 2444 underwent SLC and 2697 MLC, respectively. Mortality reported was nil in both treatment groups. Overall adverse events were higher in the SLC group (RR 1.41; p < 0.001) compared to MLC group, as well severe adverse events (RR 2.06; p < 0.001) and even mild adverse events (RR 1.23; p = 0.041). This was confirmed also when only trials including 4-port techniques (RR 1.37, p = 0.004) or 3-port techniques were considered (RR 1.89, p = 0.020). The pain score showed a standardized mean difference (SMD) of − 0.36 (p < 0.001) in favour of SLC. Cosmetic outcome by time point scored a SMD of 1.49 (p < 0.001) in favour of SLC. Incisional hernias occurred more frequently (RR 2.97, p = 0.005) in the SLC group.
Despite SLC offers a better cosmetic outcome and reduction of pain, the consistent higher rate of adverse events, both severe and mild, together with the higher rate of incisional hernias, should suggest to reconsider the application of single incision techniques when performing cholecystectomy with the existing technology.
Publication date: Available online 8 March 2018
Source:International Journal of Psychophysiology
Author(s): J.K. Dierijck, A.D. Wright, J.D. Smirl, K. Bryk, P. van Donkelaar
Although balance control has been studied extensively following acute concussion, little is known regarding repetitive sub-concussive head impacts or chronic exposure to multiple concussive events. Quiet stance postural control was characterized in contact sport athletes at pre-season (n = 135) and post-season (n = 48) to evaluate the effects of subconcussive trauma to the head. To determine the impact of acute concussion on postural control, athletes diagnosed with a concussion during the season (n = 12) were tested at 72-h, 2-weeks, and 1-month post-injury. Because only 4 of the concussed athletes completed baseline testing, control athletes (n = 12) matched for sport, age, body mass index (BMI), and previous concussion history served as a comparison group. Finally, the effects of previous concussion history on quiet stance postural control were determined by comparing pre-season data in contact sport athletes with either zero (Hx0, n = 50) or three or more (Hx3+, n = 25) previous concussions. A force plate was used to compare changes in centre-of-pressure root-mean-square displacement (RMSdisp) and mean-velocity (COPvel) in the anterior/posterior (AP) and medial/lateral (ML) directions. One-minute trials were performed with feet hip-width apart, hands-on-hips, and A) eyes-open and B) eyes-closed. Biomechanical head-impact exposure (impacts over 10 g) was indexed over the season using mastoid-fixed impact sensors. In acutely injured athletes, repeated-measures ANOVA revealed a significant effect of time for RMSdisp AP with increased displacement at 2 weeks compared to 72 h (p = 0.008, 95% CI: −0.180, −0.310 cm). No other COP variables were affected by acute concussion. Moreover, there was no effect of concussion history or repeated sub-concussive impacts on any quiet stance metric. Additionally, head-impact exposure metrics were not correlated with COP metrics. Taken together, the data suggests alterations in COP sway during quiet stance persist in the acute 2-week period after injury. These findings were not present with either a history of multiple concussions or exposure to sub-concussive head impacts indicating acute concussion does not have appear to have long term effects for these measures.
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New-onset atrial fibrillation (NOAF) is the most common perioperative complication of heart surgery, typically occurring in the perioperative period. NOAF commonly occurs in patients who are elderly, or have left atrial enlargement, or left ventricular hypertrophy. Various factors have been identified as being involved in the development of NOAF, and numerous approaches have been proposed for its prevention and treatment. Risk factors include diabetes, obesity, and metabolic syndrome. For prevention of NOAF, β-blockers and amiodarone are particularly effective and are recommended by guidelines. NOAF can be treated by rhythm/rate control, and antithrombotic therapy. Treatment is required in patients with decreased cardiac function, a heart rate exceeding 130 beats/min, or persistent NOAF lasting for ≥ 48 h. It is anticipated that anticoagulant therapies, as well as hemodynamic management, will also play a major role in the management of NOAF. When using warfarin as an anticoagulant, its dose should be adjusted based on PT-INR. PT-INR should be controlled between 2.0 and 3.0 in patients aged < 70 years and between 1.6 and 2.6 in those aged ≥ 70 years. Rate control combined with antithrombotic therapies for NOAF is expected to contribute to further advances in treatment and improvement of survival.
An increasing number of reports indicate the efficacy of simulation training in anesthesiology resident education. Simulation education helps learners to acquire clinical skills in a safe learning environment without putting real patients at risk. This useful tool allows anesthesiology residents to obtain medical knowledge and both technical and non-technical skills. For faculty members, simulation-based settings provide the valuable opportunity to evaluate residents' performance in scenarios including airway management and regional, cardiac, and obstetric anesthesiology. However, it is still unclear what types of simulators should be used or how to incorporate simulation education effectively into education curriculums. Whether simulation training improves patient outcomes has not been fully determined. The goal of this review is to provide an overview of the status of simulation in anesthesiology resident education, encourage more anesthesiologists to get involved in simulation education to propagate its influence, and stimulate future research directed toward improving resident education and patient outcomes.
Transposable elements (TEs) are mobile genetic sequences that comprise a large portion of vertebrate genomes. The olive flounder (Paralichthys olivaceus) is a valuable marine resource in East Asia. The scope of most genomic studies on the olive flounder is limited to its immunology as their focus is the prevention of mass mortality of this species. Thus, for a broader understanding of the species, its genomic information is consistently in demand. Transcripts sequences were acquired from transcriptome analysis using gill tissues of 12 olive flounders. Distribution of TEs inserted in exonic region of the olive flounder genome was analyzed using RepeatMasker (http://www.repeatmasker.org/). We found 1140 TEs in the exonic region of the genome and long interspersed nuclear elements (LINEs) and long terminal repeats (LTRs) insertions occurred with forward orientation preferences. Transposons belonging to the hAt, Gypsy, and LINE 1 (L1) subfamilies were the most abundant DNA transposons, LTRs, and long interspersed elements (LINEs), respectively. Finally, we carried out a gene ontology analysis to determine the function of TE-fused genes. These results provide some genomic information about TEs that is useful for future research on changes in properties and functions of genes by TEs in the olive flounder genome.
Mathematical models and numerical simulation have tremendously enhanced our understanding of the mechanisms that underlie cardiac electrical and contractile function and their derangements, as well as the consequences of pharmacologic intervention.
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The cover image, by G. Şimşek Kaya et al., is based on the Original Article Expression of chemerin in the synovial fluid of patients with temporomandibular joint disorders, DOI: 10.1111/joor.12608.
Horses lose potential opportunities because of health problems. Available breeding strategies are not effective enough, probably also because of the different definition used and its genetic usefulness. The aim of the study was to compare the genetic background estimated by the genome-wide association study (GWAS) for osteochondrosis using two different scaling osteochondrosis (OC)/healthy and osteochondrosis dissecans (OCD)/healthy systems for evaluating the disease status of investigated fetlock joints. Two hundred one Warmblood horses trained for performance tests (87 stallions and 114 mares) were phenotyped and genotyped. Four fetlock x-ray images per horse were collected using the RTG Girth HF 80 and Vet Scan ray 3600. The DNA of each horse was genotyped using the BeadChip 70K. To identify SNPs that significantly affect the probability of osteochondrosis, two different methods were applied: the Cochran-Armitage test based on an additive mode of inheritance and logistic regression. The genetic background for osteochondrosis, expressed in the number of SNPs found with significant associations with osteochondrosis, was higher by evaluation in the scale of OCD/healthy horses (16 SNPs on several chromosomes mainly on the ECA1 and ECA10) than OC/healthy (2 SNPs on the ECA15 and one SNP on the ECA10). Detailed definition of osteochondrosis is needed in breeding and in veterinary practice. The genetic background for osteochondrosis and osteochondrosis dissecans seems not the same. Suggestive SNPs could be the candidate markers for osteochondrosis but should be checked on a larger population before usage.
We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in 2013. A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods.
