Πέμπτη 29 Νοεμβρίου 2018
Intracholecystic papillary-tubular neoplasm of the gallbladder originating in the cystic duct with extensive intraepithelial progress in the common bile duct
Abstract
A 59-year-old man with anorexia who had a history of cholecystectomy was referred to our hospital. Imaging examinations revealed a contrast-enhanced tumor in the residual cystic duct and a part of the common bile duct. Endoscopic retrograde cholangiopancreatography and peroral-cholangioscopy showed a papillary tumor with movement and a change in the shape. Under a diagnosis of primary cystic duct cancer, subtotal stomach-preserving pancreaticoduodenectomy was performed. The microscopic examination of a resected specimen revealed intracholecystic papillary-tubular neoplasm located in the residual cystic duct, forming a polypoid protrusion to the common bile duct and extensive intraepithelial progress in the common bile duct.
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Genetic diversity and population structure of Lychnis wilfordii (Caryophyllaceae) with newly developed 17 microsatellite markers
Abstract
Lychnis wilfordii (Regel) Maxim. is a perennial plant designated as an endangered species by the Korean government because of rapid reduction in its population size. Thus, a population genetic study of this species is needed to establish the strategy for management and conservation based on scientific evidences. The goals of this study were to develop useful microsatellite markers for L. wilfordii and to understand current genetic status of L. wilfordii in Korean peninsula. Seventeen microsatellite markers were identified using next-generation sequencing and bioinformatic analysis and then analyzed genetic diversity in one hundred forty-five individuals from Korea (KI1, KI2, and KP), China (CX, CF) and Russia (RP). Analysis of molecular variance (AMOVA), principal coordinates analysis (PCoA) and STRUCTURE results consistently showed discontinuity among L. wilfordii populations. AMOVA showed that the percentage of variation among populations was 53%, which was higher than the variation within populations (19%). PCoA showed that the populations were divided into three genetic clusters, (1) Chinese (CX, CF), (2) Russian (RP) populations and Korean populations (KI1, KI2) excluding KP, and (3) the KP population. In particular, KP, the most southern population on the Korean peninsula, showed significantly lower observed and expected heterozygosity, number of effective alleles, and Shannon index (I) than those of KI1 and KI2. L. wilfordii showed high differentiation between populations with low genetic diversity within populations. Among Korean populations, KP is likely to be affected by genetic drift due to small population size, low genetic diversity and limited gene flow.
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Association between CD53 genetic polymorphisms and tuberculosis cases
Abstract
Background
Tetraspanin proteins are expressed in various immune cells, and they play an important role in tuberculosis formation. CD53 is a protein in the tetraspanin family that is expressed in many white blood cells. In particular, it plays an important role in cytokine regulation and interaction between natural killer (NK) cells and antigen-presenting cells (APCs).
Objectives
The purpose of this study was to investigate whether the single nucleotide polymorphisms (SNPs) difference of CD53 gene could affect TB case.
Methods
In this study, we investigated the effects of genetic polymorphism of CD53 on the pathogenesis of tuberculosis based on Korean Association Resource (KARE) data. Logistic regression analysis was used to determine the effect of SNPs of the CD53 gene on tuberculosis in TB cases and control groups. We also examined the effect of SNPs on tuberculosis in gene expression.
Results
Eight SNPs of CD53 were found to be associated with TB case. The SNP showing the greatest significance in this association was rs4839583 (odds ratio = 0.83, 95% confidence interval 0.72–0.96, p = 0.010). These genetic variants might be involved in cytokine regulation through the Jun pathway, and are thought to affect the immune responses and pathogenesis of TB.
Discussion
CD53 is a type of tetraspanin that is expressed on various immune cells. In this study, we identified eight statistically significant SNPs in CD53 gene, confirming that it could be involved in the regulation of CD53 gene expression.
Conclusion
Associations between genetic variants and tuberculosis facilitated better understanding of the differences in the incidence of tuberculosis in various populations.
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SNZ3 Encodes a PLP Synthase Involved in Thiamine Synthesis in Saccharomyces cerevisiae
Pyridoxal 5'-phosphate (the active form of vitamin B6) is a cofactor that is important for a broad number of biochemical reactions and is essential for all forms of life. Organisms that can synthesize pyridoxal 5'-phosphate use either the deoxyxylulose phosphate-dependent or -independent pathway, the latter is encoded by a two-component pyridoxal 5'-phosphate synthase. Saccharomyces cerevisiae contains three paralogs of the two-component SNZ/SNO pyridoxal 5'-phosphate synthase. Past work identified the biochemical activity of Snz1p, Sno1p and provided in vivo data that SNZ1 was involved in pyridoxal 5'-phosphate biosynthesis. Snz2p and Snz3p were considered redundant isozymes and no growth condition requiring their activity was reported. Genetic data herein showed that either SNZ2 or SNZ3 are required for efficient thiamine biosynthesis in Saccharomyces cerevisiae. Further, SNZ2 or SNZ3 alone could satisfy the cellular requirement for pyridoxal 5'-phosphate (and thiamine), while SNZ1 was sufficient for pyridoxal 5'-phosphate synthesis only if thiamine was provided. qRT-PCR analysis determined that SNZ2,3 are repressed ten-fold by the presence thiamine. In total, the data were consistent with a requirement for PLP in thiamine synthesis, perhaps in the Thi5p enzyme, that could only be satisfied by SNZ2 or SNZ3. Additional data showed that Snz3p is a pyridoxal 5'-phosphate synthase in vitro and is sufficient to satisfy the pyridoxal 5'-phosphate requirement in Salmonella enterica when the medium has excess ammonia.
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PlayBionic: Game-Based Interventions to Encourage Patient Engagement and Performance in Prosthetic Motor Rehabilitation
Prosthetic motor rehabilitation usually relies on the highly repetitive training of movements. Patients might drop out of training because the rehabilitation process is long and often discouraging. Game-based interventions provide a potentially useful alternative to standard myoelectric (electromyographic [EMG]) training and can increase engagement with training.
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Control Mechanisms of Static and Dynamic Balance in Adults With and Without Vestibular Dysfunction in Oculus Virtual Environments
Deficits in sensory integration and fear of falling in complex environments contribute to decreased participation of adults with vestibular disorders. With recent advances in virtual reality technology, head-mounted displays are affordable and allow manipulation of the environment to test postural responses to visual changes.
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Academy News – November PM&R
As the primary medical society for the specialty of PM&R, your Academy is focused on moving the specialty and you forward. Our mission is to lead the advancement of physiatry's impact throughout health care. Your Academy will ensure that:
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Barriers, Facilitators and Interventions to Support Virtual Reality Implementation in Rehabilitation: A Scoping Review
Virtual reality and active video games (VR/AVGs) are promising rehabilitation tools because of their potential to facilitate abundant, motivating, and feedback-rich practice. However, clinical adoption remains low despite a growing evidence base and the recent development of clinically accessible and rehabilitation-specific VR/AVG systems. Given clinicians' eagerness for resources to support VR/AVG use, a critical need exists for knowledge translation (KT) interventions to facilitate VR/AVG integration into clinical practice.
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Virtual Reality and Noninvasive Brain Stimulation in Stroke: How Effective Is Their Combination for Upper Limb Motor Improvement?—A Meta-Analysis
Efforts to augment post-stroke upper limb (UL) motor improvement include the use of newer interventions such as noninvasive brain stimulation (NIBS) and task practice in virtual reality environments (VEs). Despite increasing interest in using a combination of these 2 interventions, the effectiveness of this combination to enhance UL motor improvement outcomes has not been examined.
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Virtual Reality in Rehabilitation—Using Technology to Enhance Function
Virtual reality (VR) in rehabilitation capitalizes on rapidly evolving technologies to maximize function and quality of life. Virtual Reality Environments (VEs) have been suggested to be the closest human equivalent of enriched environments [1,2], which are known to be invaluable in promoting recovery, an idea first suggested in 1996 [3]. The use of VR allows designing personalized training environments combining elements such as practice intensity, variability, and task-specificity, in addition to motivation and feedback.
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Three Epidural Steroid Techniques
A 32-year-old man presents to your clinic with 6-week onset of left-sided low back pain radiating down his left posterolateral leg to the top of his left foot. His symptoms include painful shooting electrical sensations, numbness and tingling, and mild weakness in raising his foot. His deep tendon reflexes are normal and he has a positive slump sit test result on the left lower extremity. His primary care physician prescribed gabapentin and a course of oral steroids (methylprednisolone), with minimal benefit.
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Simplified follow-up of patients with mild chronic hepatitis C in areas with limited access to antiviral therapy
In some areas of the world, antiviral therapy for chronic hepatitis C (CHC) is not available for all patients. The optimal interval for liver stiffness measures (LSM) and noninvasive scores to assess fibrosis progression has not been studied. We evaluated the usefulness of consecutive LSM, APRI, FIB-4 and Forns scores to predict disease progression.
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Engineered periosteum-bone biomimetic bone graft enhances posterolateral spine fusion in a rabbit model
Bone marrow derived mesenchymal stem cells (BMSCs) and periosteum-derived cells (PDCs) have shown great viability in terms of osteogenic potential and have been considered the major cellular source for skeletal tissue engineering. Using a PDCs-impregnated cell sheet to surround a BMSCs-impregnated tricalcium phosphate (TCP) scaffold might create a periosteum-bone biomimetic bone graft substitute to enhance spine fusion.
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EEG analysis in anti-NMDA receptor encephalitis: description of typical patterns
Anti-N-methyl D-aspartate receptor encephalitis (anti-NMDARE) is the most frequent human autoimmune encephalitis and is primarily directed against the NR1 subunit of the NMDAR (Dalmau et al., 2008). Clinical symptoms are initially marked by psychiatric manifestations, impaired cognition and seizures followed by movement disorders, loss of consciousness, and dysautonomia (Dalmau et al., 2011, 2008; Irani et al., 2010; Titulaer et al., 2013) The association of one of these symptoms and anti-NMDAR IgG antibodies detection made a definite diagnosis (Graus et al., 2016).
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The value of genetic testing for family health history of adopted persons
The value of genetic testing for family health history of adopted persons
The value of genetic testing for family health history of adopted persons, Published online: 29 November 2018; doi:10.1038/s41576-018-0080-4
The lack of family health history experienced by most adopted persons can represent a marked disadvantage for these individuals. Genetic testing has the potential to reliably and usefully fill informational gaps, but considerable challenges need to be addressed to assemble an economic case for affordability.
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Short rare minisatellite variant of BORIS -MS2 is related to bladder cancer susceptibility
Abstract
Background
BORIS/CTCFL, a paralog of CTCF and member of the cancer-testicular antigen family, is abnormally activated in multiple cancers.
Objective
We investigated the relationship between polymorphic variants of the BORIS minisatellite 2 (BORIS-MS2), located within the 5′ upstream promoter region of BORIS, and bladder cancer.
Methods
We used case-control study with 516 controls and 113 bladder cancer patients. To evaluate whether minisatellite variants play a role in BORIS expression, we examined the transcript levels of a reporter gene linked to these minisatellites in cell lines. We also examined BORIS expression in cancerous and non-cancerous bladder tissue.
Results
A statistically significant association was identified between the short rare allele (13-repeat) and bladder cancer incidence (odds ratio (OR) 2.97, 95% confidence interval (CI) [1.14, 7.74]; P = 0.020). In particular, short rare alleles in the younger group (aged < 65) were associated with statistically significant increase in bladder cancer risk (OR 5.38, CI [1.32, 21.87]; P = 0.01). The BORIS-MS2 region acted as a negative regulator, and the expression level of the luciferase reporter in bladder cancer cells was less effectively inhibited than in normal cells. Furthermore, the expression of BORIS mRNA significantly differed (P < 0.05) between normal and cancerous muscle-invasive bladder cancer tissues, and relationship to clinical parameters was observed.
Conclusions
The short rare allele of BORIS-MS2 could be used to identify bladder cancer risk. BORIS expression levels have been shown to increase with the progression of bladder cancer, could be used as a biomarker for its progression.
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Heterotopic chondroid tissue of the main bile duct mimicking Klatskin tumor: case report and review of the literature
Abstract
Heterotopic tissue in the bile duct is a very rare condition. There are a few case reports of heterotopic tissue including gastric and pancreatic cells. However, we could not find any data regarding heterotopic chondroid tissue obstructing the common bile duct in the literature. A 56-year-old woman was admitted to our hospital with complaints of progressive jaundice and pruritus. Laboratory test results were within the normal limits except bilirubin and alkaline phosphatase which were 10.8 mg/dL and 256 IU/L, respectively. Endoscopic retrograde cholangiography (ERCP) and computed tomography (CT) revealed a biliary stricture confined to the upper part of the common bile duct. The patient was operated as soon as the bilirubin level dropped below 5 mg/dL by percutaneous transhepatic cholangiography. Despite the lack of a precise confirmation, the patient was prepared for operation considering the possibility of a malignant biliary tumor since the radiographic mass findings together with hyperbilirubinemia were highly suggestive of malignancy. The patient underwent total extrahepatic bile duct resection and Roux-en-Y hepaticojejunostomy, and was discharged without any postoperative complications. Histologic examination of the bile duct and the nodule revealed the presence of a well-demarcated chondroid tissue within the subepithelial connective tissue. Herein, we presented the first case, to our knowledge, of heterotopic chondroid tissue of the common bile duct in the literature. It is a benign condition that should be considered in the differential diagnosis of stricture and mass-forming lesions of the bile duct.
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Calcineurin/AKAP interactions: therapeutic targeting of a pleiotropic enzyme with a little help from its friends
Abstract
The ubiquitous Ca2+/calmodulin‐dependent phosphatase calcineurin is a key regulator of pathological cardiac hypertrophy whose therapeutic targeting in heart disease has been elusive due to its role in other essential biologic processes. Calcineurin is targeted to diverse intracellular compartments by association with scaffold proteins, including by multivalent A‐kinase anchoring proteins (AKAPs) that bind PKA and other important signaling enzymes determining cardiac myocyte function and phenotype. Calcineurin anchoring by AKAPs confers specificity to calcineurin function in the cardiac myocyte. Targeting of calcineurin "signalosomes" may provide a rationale for inhibiting the phosphatase in disease.
Proposed targeting of Calcineurin/AKAP complexes. By using peptide displacement to compete for Calcineurin binding to AKAPs, we may be able to prevent its downstream functions including induction of cardiac disease.
This article is protected by copyright. All rights reserved
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Inhibition of non‐receptor tyrosine kinase Src induces phosphoserine 256‐independent aquaporin‐2 membrane accumulation
Key Points
Aquaporin‐2 (AQP2) is crucial for water homeostasis, and vasopressin (VP) induces AQP2 membrane trafficking by increasing intracellular cAMP, activating PKA, and causing phosphorylation of AQP2 at serine 256, 264 and 269 residues and dephosphorylation of serine 261 residue on the AQP2 c‐terminus. It is thought that serine 256 is the master regulator of AQP2 trafficking, and its phosphorylation has to precede the change of phosphorylation state of other serine residues. We found that Src inhibition causes serine 256 independent AQP2 membrane trafficking and induces phosphorylation of serine 269 independent of serine 256. This targeted phosphorylation of serine 269 is important for Src inhibition induce AQP2 membrane accumulation. Without serine 269, Src inhibition exerts no effect on AQP2 trafficking. This result helps us better understand the independent pathways that can target different AQP2 residues, and design new strategies to induce or sustain AQP2 membrane expression when VP signaling is defective.
Abstract
Aquaporin‐2 (AQP2) is essential for water homeostasis. Upon stimulation by vasopressin, AQP2 is phosphorylated at serine 256 (S256), S264 and S269, and dephosphorylated at S261. It is thought that S256 is the master regulator of AQP2 trafficking and membrane accumulation, and that its phosphorylation has to precede phosphorylation of other serine residues. In this study, we found that VP reduces Src kinase phosphorylation: by suppressing Src using the inhibitor dasatinib and siRNA, we could increase AQP2 membrane accumulation in cultured AQP2‐expressing cells and in kidney collecting duct principal cells. Src inhibition increased exocytosis and inhibited clathrin‐mediated endocytosis of AQP2, but exerted its effect in a cAMP, PKA and S256 phosphorylation (pS256) independent manner. Despite the lack of S256 phosphorylation, dasatinib increased phosphorylation of S269, even in S256A mutant cells in which S256 phosphorylation cannot occur. To confirm the importance of pS269 in AQP2 re‐distribution, we expressed an AQP2 S269A mutant in LLC‐PK1 cells, and found that dasatinib no longer induced AQP2 membrane accumulation. In conclusion, Src inhibition causes phosphorylation of S269 independently of pS256, and induces AQP2 membrane accumulation by inhibiting clathrin‐mediated endocytosis and increasing exocytosis. We conclude that S269 can be phosphorylated without pS256, and pS269 alone is important for AQP2 apical membrane accumulation under some conditions. These data increase our understanding of the independent pathways that can phosphorylate different residues in the AQP2 c‐terminus, and suggest new strategies to target distinct AQP2 serine residues to induce membrane expression of this water channel when VP signaling is defective.
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A randomized controlled trial comparing efficacy of early video capsule endoscopy with standard of care in the approach to non-hematemesis GI bleeding (with videos)
Gastrointestinal Endoscopy
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Demographic and comorbidity predictors of adherence to diagnostic colonoscopy in the Danish Colorectal Cancer Screening Program: A nationwide cross-sectional study
Clinical Epidemiology
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Proton pump inhibitors use and risk of chronic kidney disease in diabetic patients
Diabetes Research and Clinical Practice
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Association Between Breastfeeding and Childhood Cardiovascular Disease Risk Factors
Abstract
Introduction The immediate benefits of breastfeeding are well-established but the long-term health benefits are less well-known. West Virginia (WV) has a higher prevalence of cardiovascular disease (CVD) and lower breastfeeding rates compared to national averages. There is a paucity of research examining the relationship between breastfeeding and subsequent childhood CVD risk factors, an issue of particular relevance in WV. Methods This study used longitudinally linked data from three cross-sectional datasets in WV (N = 11,980). The information on breastfeeding was obtained retrospectively via parental recall when the child was in the fifth grade. The outcome variables included blood pressure measures [systolic blood pressure (SBP), diastolic blood pressure (DBP)] and lipid profile [total cholesterol (TC), low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL), non-HDL, and triglycerides (TG)]. Multiple regression analyses were performed, adjusting for childhood body mass index (BMI) and additional covariates. Results Only 43% of mothers self-reported ever breastfeeding. The unadjusted analysis showed that children who were ever vs. never breastfed had significantly lower SBP (b = − 1.39 mmHg; 95% CI − 1.97, − 0.81), DBP (b = − 0.79 mmHg; 95% CI − 1.26, − 0.33), log-TG (b = − 0.08; 95% CI − 0.1, − 0.05), and higher HDL (b = 0.95 mg/dL; 95% CI 0.33, 1.56). After adjustment for the child's BMI, socio-demographic and lifestyle factors, log-TG remained significantly associated with breastfeeding (b = − 0.04; 95% CI − 0.06, − 0.01; p = 0.01). Conclusion The observed protective effect of any breastfeeding on childhood TG level was small but significant. This finding provides some support for a protective effect of breastfeeding on later CVD risk.
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The influence of humic substances on uranium biomineralization induced by Bacillus sp. dwc-2
Publication date: February 2019
Source: Journal of Environmental Radioactivity, Volume 197
Author(s): Hong Tu, Tu Lan, Guoyuan Yuan, Changsong Zhao, Jun Liu, Feize Li, Jijun Yang, Jiali Liao, Yuanyou Yang, Dongqi Wang, Ning Liu
Abstract
In this paper, the influence of humic acid (HA) and fulvic acid (FA) on biomineralization behaviour was evaluated. The results showed HA and FA did not obviously inhabit or promote the precipitation of U-phosphate minerals. The data from molecular dynamic simulation indicated that the free energy for the dissociation of uranyl the PO43− -uranyl was 202.49 kJ/mol, which was much larger than that form HA-uranyl (88.3 kJ/mol). These simulated results revealed the less competitiveness of HA and FA with PO43− for uranyl and explained why HA and FA had less impacted on the formation of U-phosphate minerals. However, the influence of HA/FA on the morphology was obvious, the microstructure of the bio-minerals changed from small particles to lamellar stacking structure with the addition of HA or FA. The findings of this study are helpful for us to gain a better understanding natural U-phosphate biomineralization behaviour.
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Exposure to ionizing radiation affects the growth of ectomycorrhizal fungi and induces increased melanin production and increased capacities of reactive oxygen species scavenging enzymes
Publication date: February 2019
Source: Journal of Environmental Radioactivity, Volume 197
Author(s): David Kothamasi, Jean Wannijn, May Van Hees, Robin Nauts, Axel Van Gompel, Nathalie Vanhoudt, Hildegarde Vandenhove
Abstract
Ectomycorrhizal (EM) fungi form symbioses with dominant tree families in boreal, temperate and tropical ecosystems and are important drivers of ecosystem function. EM fungal hyphae extend over a large area making them susceptible to enhanced radiation levels from naturally occurring or anthropogenically originating radioisotopes in the rhizosphere. In this study, the in-vitro effects of ionizing radiation on the growth and biomass of EM fungi Suillus luteus, S. bovinus and Rhizopogon luteolus were investigated. EM fungal cultures were exposed to gamma radiation from a 137Cs source for 137 h in darkness at 21 °C at dose rates of 404, 108.5 and 54.9 mGy h−1 resulting in total absorbed doses of 55.21, 14.82 and 7.50 Gy respectively. Cultures grown in the dark at 21 °C but not exposed to the 137Cs source served as the control. Our results show that EM fungi vary in their sensitivity to ionizing radiation. EM fungi used in this study produced melanin and reactive oxygen species scavenging enzymes such as catalase and superoxide dismutase as a response to ionizing radiation.
Graphical abstract
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Editorial Board
Publication date: December 2018
Source: Gene Expression Patterns, Volume 30
Author(s):
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Characterization of PI3KCA and BRAF mutations in gastric adenocarcinoma: An approach to a personalized targeted therapy for Moroccan HER2 overexpressed patients
Publication date: Available online 28 November 2018
Source: Arab Journal of Gastroenterology
Author(s): Hanaa Amrani Hassani Joutei, Nabila Marchoudi, Wafaa Mahfoud, Ilham Sadaoui, Taoufiq Fechtali, Hakima Benomar
Abstract
Background and study aims
Targeted therapies have an increasing importance in digestive oncology. To our knowledge, we are the first to report the distribution of PI3KCA and BRAF mutations in Moroccan HER2 overexpressed patients, in order to introduce targeted therapy in the arsenal of therapeutic modalities for management in Morocco.
Patients and methods
98 gastric adenocarcinoma tissue samples were collected. Further histological and immunohistochemical examinations were carried out at the Laboratory of Anatomy Pathology in Pasteur Institute-Morocco, in order to select HER2 positive cases. Out of 98 cases, 16 were found to be HER2-positive. The molecular study was performed for 55 good quality tissue samples including the HER2-positive ones, and activating mutations in H1047R PI3KCA and V600E BRAF were analyzed by Cast-PCR and Real-time PCR, respectively, at the Department of Molecular Biology, ANOUAL Specialized Center-Casablanca, Morocco. Statistical analyses were performed using the Epi-info software (version 6.09).
Results
Pi3KCA mutation was present in 8 cases (14,54%). BRAF mutation was present in 4 cases (7,27%) and 3 cases showed concomitant mutations. In total, 9 cases (16,36%) had PI3KCA and/or BRAF mutations.
Conclusion
The association between HER2 expression and PI3KCA alteration in gastric adenocarcinoma is most probably necessary to identify trastuzumab responders. Consequently, the 83,64% rate of HER2-positive patients harboring wild-type mutations possibly represents the portion of patients responding to trastuzumab while the 16,36% rate of patients carrying at least one of the studied mutations represents the portion of potentially non responsive patients to the targeted therapy, and thus may be considered as good candidates for multi-drug targeted therapy.
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Analysis of 17 948 pediatric patients undergoing procedural sedation with a combination of intranasal dexmedetomidine and ketamine
Summary
Background
Intranasal procedural sedation using dexmedetomidine is well described in the literature. The combination of intranasal dexmedetomidine and ketamine is a novel approach for which there are little data on the rate of successful sedation or adverse events.
Objectives
The aim of this study is to evaluate the rate of successful sedation and adverse events of intranasal procedural sedation using a combination of dexmedetomidine and ketamine for diagnostic examination in children.
Methods
This was a retrospective study and data were collected after ethics approval. A total of 17 948 pediatric patients (7718 females, 10 230 males) in a tertiary hospital in China were evaluated. Patients received a combination of 2 μg kg−1 of dexmedetomidine and 1 mg kg−1 of ketamine intranasally for procedural sedation. The level of sedation and recovery was assessed by the Modified Observer Assessment of Alertness/Sedation scale and the Modified Aldrete Score.
Results
The rate of intranasal sedation success was 93% (16691/17948), intranasal sedation rescue was 1.8% (322/17948), and intranasal sedation failure was 5.2% (935/17948). Sedation success was defined as successful completed the diagnostic examination and obtained adequate diagnostic‐quality images and reports. Intranasal sedation success, rescue and failure were respectively defined as sedation success with intranasal a single dose, additional bolus dose and the need for intravenous (IV) medications/inhalation agents. Median sedation time was 62 min (interquartile range: 55‐70 min), median time for onset of sedation was 15 min (interquartile range: 15‐20 min), and median sedation recovery time was 45 min (interquartile range: 38‐53 min). Incidence of adverse events was low (0.58%; 105/17948), with major and minor adverse event being reported in 0.02% (4/17948) and 0.56% (101/17948) patients, respectively. Postoperative nausea and vomiting was the most common (0.3%; 53/17948) minor adverse event.
Conclusion
Procedural sedation using a combination of intranasal dexmedetomidine and ketamine is associated with acceptable effectiveness and low rates of adverse events.
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Three-Dimensional Take-off Step Kinetics of Long Jumpers with and without a Transtibial Amputation
Purpose The loads applied on the musculo-skeletal system during the long jump take-off step are not well established for non-amputee athletes or athletes with a lower extremity amputation. Information on joint loading and potential injury mechanisms is important for improving training or rehabilitation protocols, prosthetic design and the general understanding of the long jump. Methods Three-dimensional take-off step kinematics and kinetics were used for inverse dynamic model calculations on three male athletes with and seven male athletes without a below the knee amputation (BKA). Athletes with BKA used their affected leg as their take-off leg. Results Despite equivalent long jump performance, ground reaction force application characteristics were widely different and calculated joint loads were significantly lower in athletes with BKA compared to non-amputee athletes during the take-off step. The take-off step of the long jump for athletes with BKA seems to be dominated by sagittal plane movements, while for non-amputee athletes it involves sagittal plane movement and compensatory joint work in the frontal plane. Conclusions Coaches and athletes should adapt training protocols to the unique musculo-skeletal loading patterns of long jumpers with or without a BKA. Specifically, non-amputee athletes should strengthen the muscles responsible for hip and knee extension, as well as for frontal plane stabilization, early in the season to avoid injuries. The presented data enables clinicians to identify potential causes of pain or injury more differentially in both groups of athletes and might stimulate future research in the field of robotics and prosthetic components. Furthermore, the altered joint mechanics of athletes with BKA versus non-amputees serves as an explanation for their previously described more effective take-off step. Corresponding author: Johannes Funken, MSc, German Sport University Cologne, Institute of Biomechanics and Orthopaedics, Am Sportpark Müngersdorf 6, 50933 Cologne, Germany. Email: j.funken@dshs-koeln.de. Phone: +49(0)22149827662 Funding was provided by the Japan Broadcasting Cooperation (NHK). JF was funded by a graduate fellowship of the German Sport University Cologne. HH was funded by JSPS KAKENHI Grant Number 26702027. AMG's contribution to this project was also partially supported by the BADER Consortium, a US Department of Defense Congressionally Directed Medical Research Programs cooperative agreement (W81XWH-11-2-0222). None of the authors had any conflict of interest associated with the study. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine. Accepted for publication November 2018. © 2018 American College of Sports Medicine
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Aerobic Exercise Improves Microvascular Function in Older Adults
Microvascular function is reduced with age, disease, and inactivity. Exercise is well known to improve vascular health and has the potential to improve microvascular function in aging and disease. Purpose The study aimed to assess changes in peripheral microvascular function in sedentary older adults following aerobic exercise training. Methods Twenty-three, sedentary older adults (67±5 yrs, BMI=29±5, mean±SD) successfully completed a randomized 12-week graded treadmill walking intervention. The exercise group (EX) performed 40 minutes of uphill walking 4 days a week at 70% heart rate reserve. The control group (CON) maintained a sedentary lifestyle for 12 weeks. MRI measured blood-oxygen-level dependent (BOLD) responses of the soleus were used to evaluate microvascular function; brief (1s) maximal plantar flexion contractions were performed. Separately, blood flow in the popliteal artery was measured by ultrasound following brief contraction. Phosphorus magnetic resonance spectroscopy of the calf was used to examine muscle oxidative capacity and whole body peak oxygen consumption (V[Combining Dot Above]O2peak) was used to confirm training induced cardiorespiratory adaptations. Results Peak post-contraction BOLD response increased by 33% in EX (PRE:3.3±1.0%, POST:4.4±1.4%) compared to CON (PRE:3.0±1.3%, POST:3.2±1.5%), p
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Morning vs Evening Aerobic Training Effects on Blood Pressure in Treated Hypertension
Introduction The acute blood pressure (BP) decrease is greater after evening than morning exercise, suggesting that evening training may have a greater hypotensive effect. Objective To compare the hypotensive effect of aerobic training performed in the morning versus evening in treated hypertensives. Methods Fifty treated hypertensive men were randomly allocated to 3 groups: morning training (MT); evening training (ET); and control (C). Training groups cycled for 45min at moderate-intensity (progressing from the heart rate of the anaerobic threshold to 10% below the heart rate of the respiratory compensation point), while C stretched for 30 min. Interventions were conducted 3 times/week for 10 weeks. Clinic and ambulatory BP, hemodynamic, and autonomic mechanisms were evaluated before and after the interventions. Clinic assessments were performed in the morning (7-9a.m.) and evening (6-8p.m.). Between-within ANOVAs were used (P≤0.05). Results Only ET decreased clinic systolic BP differently from C and MT (morning assessment -5±6 mmHg and evening assessment -8±7 mmHg, P
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Analytical validity of a genotyping assay for use with personalized antihypertensive and chronic kidney disease therapy
Hypertension and chronic kidney disease are inextricably linked. Hypertension is a well-recognized contributor to chronic kidney disease progression and, in turn, renal disease potentiates hypertension. A generalized approach to drug selection and dosage has not proven effective in managing these conditions, in part, because patients with heterogeneous kidney disease and hypertension etiologies are frequently grouped according to functional or severity classifications. Genetic testing may serve as an important tool in the armamentarium of clinicians who embrace precision medicine. Increasing scientific evidence has supported the utilization of genomic information to select efficacious antihypertensive therapy and understand hereditary contributors to chronic kidney disease progression. Given the wide array of antihypertensive agents available and diversity of genetic renal disease predictors, a panel-based approach to genotyping may be an efficient and economic means of establishing an individualized blood pressure response profile for patients with various forms of chronic kidney disease and hypertension. In this manuscript, we discuss the validation process of a Clinical Laboratory Improvement Amendments-approved genetic test to relay information on 72 genetic variants associated with kidney disease progression and hypertension therapy. These genomic-based interventions, in addition to routine clinical data, may help inform physicians to provide personalized therapy. ✠Deceased. Correspondence to Michael T. Eadon, MD, 950 W Walnut St. E202, Indianapolis, IN 46202, USA Tel: +1 317 274 2502; fax: +1 317 274 8575; e-mail: meadon@iupui.edu Received May 29, 2018 Accepted October 11, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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CYP2D6 haplotypes with enhancer single-nucleotide polymorphism rs5758550 and rs16947 (*2 allele): implications for CYP2D6 genotyping panels
Introduction CYP2D6 metabolizes ∼25% of all clinically used drugs, with numerous genetic polymorphisms affecting enzyme activity and drug response. Clinical utility of current CYP2D6 genotyping is partially compromised the unresolved complex haplotype structure of the CYP2D6 locus. We have identified a distal enhancer single-nucleotide polymorphism rs5758550 that robustly increases CYP2D6 expression, whereas rs16947 (CYP2D6*2), previously considered inert, reduces correct mRNA splicing and expression, thereby affecting presumed activity of other alleles on the *2 haplotype. Objective This study aims to determine the structure and frequency of haplotypes containing either rs5758550 or rs16947, or both, together with other relevant CYP2D6 alleles, assigning predictive enzyme activity scores to each, and addressing ambiguities in estimating diplotypes in different populations. Methods The structure and frequency of haplotypes containing rs5758550 and/or rs16947 in different populations were determined by using phased genotype data from 'The 1000 Genomes Project'. The assigned haplotype–phenotype relationship was tested by associating assigned CYP2D6 activity score with CYP2D6 enzyme activity in a cohort of 122 human liver microsomes. Results Addition of enhancer single-nucleotide polymorphism rs5758550 and *2 to a CYP2D6 panel improves prediction of CYP2D6 activity. Moreover, the haplotype containing rs5758550 and rs16947 predict extensive CYP2D6 activity more accurately than CYP2D6*2A, a surrogate marker for extensive activity. Conclusion With further studies, the results support possible incorporation of rs5758550 and rs16947 into CYP2D6 biomarker panels for more accurate prediction of CYP2D6 metabolizer status. Correspondence to Danxin Wang, MD, PhD, Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, 1345 Center Drive MSB PG-05B, Gainesville, FL 32610, USA Tel: +1 352 273 7673; fax: +1 352 273 6121; e-mail: danxin.wang@cop.ufl.edu Received June 13, 2018 Accepted November 10, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Effect of tacrolimus dispositional genetics on acute rejection in the first 2 weeks and estimated glomerular filtration rate in the first 3 months following kidney transplantation
Background CYP3A4/5 and P-glycoprotein (P-gp, ABCB1) affect tacrolimus (TAC) exposure in T cells and kidney cells. Genetic variability of these genes has been widely studied for effects on acute rejection and kidney function after transplantation, but findings remain contradictory. In addition, cytochrome P450 reductase (POR) is important for CYP3A4/5 activity, and the pregnane X receptor (NR1I2) regulates CYP3A4/5 and P-gp expression. However, the relationship between POR and NR1I2 genetics and acute rejection and kidney function has not been extensively investigated. Objective The aim of this study was to investigate the effect of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T, 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T) and POR*28 genotypes/haplotypes on acute rejection and kidney function in the first 3 months after transplant. Participants and methods The study included 165 kidney transplant recipients, who received TAC, mycophenolate and prednisolone, and 129 donors. TAC dose was adjusted to target trough blood concentrations of 8–15 ng/ml by therapeutic drug monitoring. Recipient and donor genotype/haplotype differences in acute rejection incidence within the first 2 weeks after transplant were assessed by logistic regression, adjusting for induction therapy, human leucocyte antigen mismatches, kidney transplant number, peak panel-reactive antibodies and donor type. Recipient and donor genotype/haplotype differences in estimated glomerular filtration rate in the first 3 months after transplant were assessed by linear mixed effects analysis, adjusting for acute rejection, delayed graft function and donor type. Results No genetic factors significantly affected acute rejection or estimated glomerular filtration rate after correction for multiple comparisons (P>0.004). Conclusion Recipient and donor dispositional genetics had no significant effect on short-term clinical outcomes in kidney transplant patients receiving TAC therapeutic drug monitoring. Correspondence to Rong Hu, MSc, Discipline of Pharmacology, Level 3, Helen Mayo South Building, The University of Adelaide, SA 5005, Australia Tel: +61 883 136 035; e-mail: rong.hu@adelaide.edu.au Received August 29, 2018 Accepted November 4, 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
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Transcriptomic analysis of cells in response to EV71 infection and 2A pro as a trigger for apoptosis via TXNIP gene
Abstract
Background
Enterovirus 71 (EV71) is the main pathogen of hand-foot-mouth disease (HFMD) and sometimes causes several neurological complications. However, the underlying mechanism of the host response to the virus infection remains unclear.
Objective
To reveal the cell-specific transcriptional response of cultured RD cells following infection with EV71, and better understand the molecular mechanisms of virus-host interactions.
Methods
The RD cells were infected with or without EV71 for 24 h, and then transcriptome sequencing and qRT-PCR were performed to analyze the transcriptome difference of functional genes.
Results
More than 15000 genes were identified in transcriptome sequencing. In comparison with uninfected RD cells, 329 DEGs were identified in cells infected with EV71. GO and KEGG pathway enrichment analysis showed that most of the DEGs were related to DNA binding, transcriptional regulation, immune response and inflammatory response, apoptosis inducing factors and enriched in JAK-STAT and MAPK signaling pathways. TXNIP (thioredoxin-interacting protein) gene was further demonstrated to play an important role participating in cellular apoptosis induced by EV71, and the apoptosis and death mediated by TXNIP during EV71 infection was triggered by viral 2A protease (2Apro), not 3C protease (3Cpro).
Conclusion
Our study demonstrated that RD cells have a significant response to EV71 infection, including immune response and apoptosis. 2Apro might be a key inducer relative to the cellular apoptosis and death mediated by TXNIP during EV71 infection. These data would contribute to preferably understand the process at the molecular level and provide theoretical foundation for diagnosis and treatment of EV71-related diseases.
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