Role of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Modulating Vascular Smooth Muscle Cells by Activating Large-Conductance Potassium Ion Channels

International audienceIn this chapter we propose to discuss the role of K+ ion channels in stimulating vasodilatation by altering the membrane potential of vascular smooth muscle cells. We present evidence that the K+ channels are modulated by a direct action of non-steroidal antiinflammatory drugs (NSAIDs) to activate the K+ ion channels

Assessment and Treatment of Combat-Related Posttraumatic Stress Disorder: Results from STRONG STAR and the Consortium to Alleviate PTSD

Extensive research has been conducted since 11 September 2001 to develop and evaluate evidence-based treatments for combat-related posttraumatic stress disorder (PTSD) in active duty United States military personnel treated in the combat theater and in garrison. This chapter reviews the results of 20 PTSD clinical trials funded by the United States Department of Defense and Department of Veterans Affairs on the treatment of combat-related PTSD. All of the studies were conducted under the leadership and management of two research consortia: the South Texas Research Organizational Network Guiding Studies on Trauma and Resilience (STRONG STAR) Consortium and the Consortium to Alleviate PTSD

Observations of the Polar Ionosphere by the Vertical Incidence Pulsed Ionospheric Radar at Jang Bogo Station, Antarctica

Korea Polar Research Institute (KOPRI) installed an ionospheric sounding radar system called Vertical Incidence Pulsed Ionospheric Radar (VIPIR) at Jang Bogo Station (JBS) in 2015 in order to routinely monitor the state of the ionosphere in the auroral oval and polar cap regions. Since 2017, after two-year test operation, it has been continuously operated to produce various ionospheric parameters. In this article, we will introduce the characteristics of the JBS-VIPIR observations and possible applications of the data for the study on the polar ionosphere. The JBS-VIPIR utilizes a log periodic transmit antenna that transmits 0.5–25 MHz radio waves, and a receiving array of 8 dipole antennas. It is operated in the Dynasonde B-mode pulse scheme and utilizes the 3-D inversion program, called NeXtYZ, for the data acquisition and processing, instead of the conventional 1-D inversion procedure as used in the most of digisonde observations. The JBS-VIPIR outputs include the height profiles of the electron density, ionospheric tilts, and ion drifts with a 2-minute temporal resolution in the bottomside ionosphere. With these observations, possible research applications will be briefly described in combination with other observations for the aurora, the neutral atmosphere and the magnetosphere simultaneously conducted at JBS

Ground-based Observations of the Polar Region Space Environment

Jang Bogo Station (JBS), the second Korean Antarctic research station, was established in Terra Nova Bay, Antarctica (74.62°S 164.22°E) in February 2014 in order to expand the Korea Polar Research Institute (KOPRI) research capabilities. One of the main research areas at JBS is space environmental research. The goal of the research is to better understand the general characteristics of the polar region ionosphere and thermosphere and their responses to solar wind and the magnetosphere. Ground-based observations at JBS for upper atmospheric wind and temperature measurements using the Fabry-Perot Interferometer (FPI) began in March 2014. Ionospheric radar (VIPIR) measurements have been collected since 2015 to monitor the state of the polar ionosphere for electron density height profiles, horizontal density gradients, and ion drifts. To investigate the magnetosphere and geomagnetic field variations, a search-coil magnetometer and vector magnetometer were installed in 2017 and 2018, respectively. Since JBS is positioned in an ideal location for auroral observations, we installed an auroral all-sky imager with a color sensor in January 2018 to study substorms as well as auroras. In addition to these observations, we are also operating a proton auroral imager, airglow imager, global positioning system total electron content (GPS TEC)/scintillation monitor, and neutron monitor in collaboration with other institutes. In this article, we briefly introduce the observational activities performed at JBS and the preliminary results of these observations

Caveat medicus:Clinician experiences in publishing reports of serious oncology-associated adverse drug reactions

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician's wife called the post-reporting time the "Maalox month," while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions

Revising Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, criteria for the bipolar disorders: Phase I of the AREDOC project

Objective: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. Method: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. Results: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge ‘impairment’ (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. Conclusion: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically

Meta-Analysis of Genomewide Association Studies Reveals Genetic Variants for Hip Bone Geometry

Hip geometry is an important predictor of fracture. We performed a meta-analysis of GWAS studies in adults to identify genetic variants that are associated with proximal femur geometry phenotypes. We analyzed four phenotypes: (i) femoral neck length; (ii) neck-shaft angle; (iii) femoral neck width, and (iv) femoral neck section modulus, estimated from DXA scans using algorithms of hip structure analysis. In the Discovery stage, 10 cohort studies were included in the fixed-effect meta-analysis, with up to 18,719 men and women ages 16 to 93 years. Association analyses were performed with ∼2.5 million polymorphisms under an additive model adjusted for age, body mass index, and height. Replication analyses of meta-GWAS significant loci (at adjusted genomewide significance [GWS], threshold p ≤ 2.6 × 10 –8 ) were performed in seven additional cohorts in silico. We looked up SNPs associated in our analysis, for association with height, bone mineral density (BMD), and fracture. In meta-analysis (combined Discovery and Replication stages), GWS associations were found at 5p15 (IRX1 and ADAMTS16); 5q35 near FGFR4; at 12p11 (in CCDC91); 11q13 (near LRP5 and PPP6R3 (rs7102273)). Several hip geometry signals overlapped with BMD, including LRP5 (chr. 11). Chr. 11 SNP rs7102273 was associated with any-type fracture (p = 7.5 × 10 –5 ). We used bone transcriptome data and discovered several significant eQTLs, including rs7102273 and PPP6R3 expression (p = 0.0007), and rs6556301 (intergenic, chr.5 near FGFR4) and PDLIM7 expression (p = 0.005). In conclusion, we found associations between several genes and hip geometry measures that explained 12% to 22% of heritability at different sites. The results provide a defined set of genes related to biological pathways relevant to BMD and etiology of bone fragility

Renal biopsy findings among Indigenous Australians: a nationwide review

Australia's Indigenous people have high rates of chronic kidney disease and kidney failure. To define renal disease among these people, we reviewed 643 renal biopsies on Indigenous people across Australia, and compared them with 249 biopsies of non-Indigenous patients. The intent was to reach a consensus on pathological findings and terminology, quantify glomerular size, and establish and compare regional biopsy profiles. The relative population-adjusted biopsy frequencies were 16.9, 6.6, and 1, respectively, for Aboriginal people living remotely/very remotely, for Torres Strait Islander people, and for non-remote-living Aboriginal people. Indigenous people more often had heavy proteinuria and renal failure at biopsy. No single condition defined the Indigenous biopsies and, where biopsy rates were high, all common conditions were in absolute excess. Indigenous people were more often diabetic than non-Indigenous people, but diabetic changes were still present in fewer than half their biopsies. Their biopsies also had higher rates of segmental sclerosis, post-infectious glomerulonephritis, and mixed morphologies. Among the great excess of biopsies in remote/very remote Aborigines, females predominated, with younger age at biopsy and larger mean glomerular volumes. Glomerulomegaly characterized biopsies with mesangiopathic changes only, with IgA deposition, or with diabetic change, and with focal segmental glomerulosclerosis (FSGS). This review reveals great variations in biopsy rates and findings among Indigenous Australians, and findings refute the prevailing dogma that most indigenous renal disease is due to diabetes. Glomerulomegaly in remote/very remote Aboriginal people is probably due to nephron deficiency, in part related to low birth weight, and probably contributes to the increased susceptibility to kidney disease and the predisposition to FSGS

LAP2 Is Widely Overexpressed in Diverse Digestive Tract Cancers and Regulates Motility of Cancer Cells

BACKGROUND: Lamina-associated polypeptides 2 (LAP2) is a nuclear protein that connects the nuclear lamina with chromatin. Although its critical roles in genetic disorders and hematopoietic malignancies have been described, its expression and roles in digestive tract cancers have been poorly characterized. METHODS: To examine the expression of LAP2 in patient tissues, we performed immunohistochemistry and real-time PCR. To examine motility of cancer cells, we employed Boyden chamber, wound healing and Matrigel invasion assays. To reveal its roles in metastasis in vivo, we used a liver metastasis xenograft model. To investigate the underlying mechanism, a cDNA microarray was conducted. RESULTS: Immunohistochemistry in patient tissues showed widespread expression of LAP2 in diverse digestive tract cancers including stomach, pancreas, liver, and bile duct cancers. Real-time PCR confirmed that LAP2β is over-expressed in gastric cancer tissues. Knockdown of LAP2β did not affect proliferation of most digestive tract cancer cells except pancreatic cancer cells. However, knockdown of LAP2β decreased motility of all tested cancer cells. Moreover, overexpression of LAP2β increased motility of gastric and pancreatic cancer cells. In the liver metastasis xenograft model, LAP2β increased metastatic efficacy of gastric cancer cells and mortality in tested mice. cDNA microarrays showed the possibility that myristoylated alanine-rich C kinase substrate (MARCKS) and interleukin6 (IL6) may mediate LAP2β-regulated motility of cancer cells. CONCLUSIONS: From the above results, we conclude that LAP2 is widely overexpressed in diverse digestive tract cancers and LAP2β regulates motility of cancer cells and suggest that LAP2β may have utility for diagnostics and therapeutics in digestive tract cancers