tbuckley/cabot-search huggingface dataset:
Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy
Authors: Michael A. Wortley, John J. Adcock, Eric D. Dubuis, Sarah A. Maher, Sara J. Bonvini, Isabelle Delescluse, Ross Kinloch, Gordon McMurray, Christelle Perros-Huguet, Marianthi Papakosta, Mark A. Birrell, Maria G. Belvisi
Journal: European Respiratory Journal (2017)

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity <i>via</i> elevation of endocannabinoids. Primary vagal ganglia neurons, tissue bioassay, <i>in vivo</i> electrophysiology and a conscious guinea pig cough model were utilised to investigate a role for fatty acid amides in modulating sensory nerve activation in vagal afferents. FAAH inhibition produced antitussive activity in guinea pigs with concomitant plasma elevation of the fatty acid amides <i>N</i>-arachidonoylethanolamide (anandamide), palmitoylethanolamide, <i>N</i>-oleoylethanolamide and linoleoylethanolamide. Palmitoylethanolamide inhibited tussive stimulus-induced activation of guinea pig airway innervating vagal ganglia neurons, depolarisation of guinea pig and human vagus, and firing of C-fibre afferents. These effects were mediated <i>via</i> a cannabinoid CB<sub>2</sub>/G<sub>i/o</sub>-coupled pathway and activation of protein phosphatase 2A, resulting in increased calcium sensitivity of calcium-activated potassium channels. These findings identify FAAH inhibition as a target for the development of novel, antitussive agents without the undesirable side-effects of direct cannabinoid receptor agonists.
131I-Evans blue: evaluation of necrosis targeting property and preliminary assessment of the mechanism in animal models
Authors: Qiaomei Jin, Xin Shan, Qi Luo, Dongjian Zhang, Yuanyu Zhao, Nan Yao, Fei Peng, Dejian Huang, Zhiqi Yin, Wei Liu, Jian Zhang
Journal: Acta Pharmaceutica Sinica B (2017)

Necrosis is a form of cell death, which is related to various serious diseases such as cardiovascular disease, cancer, and neurodegeneration. Necrosis-avid agents (NAAs) selectively accumulated in the necrotic tissues can be used for imaging and/or therapy of related diseases. The aim of this study was to preliminarily investigate necrosis avidity of 131I-evans blue (131I-EB) and its mechanism. The biodistribution of 131I-EB at 24 h after intravenous administration showed that the radioactivity ratio of necrotic to viable tissue was 3.41 in the liver and 11.82 in the muscle as determined by γ counting in model rats. Autoradiography and histological staining displayed preferential uptake of 131I-EB in necrotic tissues. In vitro nuclear extracts from necrotic cells exhibited 82.3% of the uptake in nuclei at 15 min, as well as 79.2% of the uptake at 2 h after 131I-EB incubation. The DNA binding study demonstrated that evans blue (EB) has strong binding affinity with calf-thymus DNA (CT-DNA) (Ksv=5.08×105 L/(mol/L)). Furthermore, the accumulation of 131I-EB in necrotic muscle was efficiently blocked by an excess amount of unlabeled EB. In conclusion, 131I-EB can not only detect necrosis by binding the DNA released from necrotic cells, but also image necrotic tissues generated from the disease clinically.
AB0939 Change in the surgical treatment for cervical spine disorders related to rheumatoid arthritis during recent 15 decades
Authors: K Sakuraba, K Kai, H Miyahara
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Since the appearance of biological DMARDs in Japan, disease control of rheumatoid arthritis has been ameliorated. Inflamed synovitis and destructive arthritis declined dramatically, which resulted in a decrease in the number of synovectomy and joint prosthesis gradually. On the other hand, surgeries for hand or foot disorders have been increasing. However, it is unclear about the surgery for cervical spine disorder. <h3>Objectives</h3> We clarified the change in the surgical treatments for cervical spine disorder related to RA patients at our institution. <h3>Methods</h3> From 2001 to 2015, we identified 71 RA patients with a cervical spine surgery. The mean age was 65.4 years (range, 44–90 years). The patients consisted 11 males and 60 females. The mean disease duration was 20 years (range, 0–52 years). They were classified into three subgroups according to the affected level: the upper lesions (UL) such as atlantoaxial subluxation, the middle and lower lesions (MLL) including subaxial subluxation, and the expanded lesions (EL) which have both features. Individual groups were assessed the change of the number of surgical treatment. In addition, we divided the period into first seven years (from 2001 to 2007) and last eight years (from 2008 to 2015), and compared each other. <h3>Results</h3> There were 38 patients in UL, 25 patients in MLL and 8 patients in EL. Most patients in UL were underwent atlantoaxial fixation by Magerl and Brooks procedure, and the number of them was constant throughout the entire period. Occipito-cervical fusion has been decreasing. Although there were much surgeries of MLL disorder in last 8 years than that in first 7 years, most of them did not have RA change such as endplate erosion and subluxation. <h3>Conclusions</h3> There was no significant change in EL throughout all periods. In conclusion, surgeries for cervical spine disorder of RA patients remained in our institute. However, disorders related to RA within them, especially MLL, were decreasing. it indicates that expansion of RA remission has led to the reduction of cervical spine surgeries with RA change. <h3>Disclosure of Interest</h3> None declared
Clinical characteristics of ALK+ NSCLC patients (pts) treated with crizotinib beyond disease progression (PD): Potential implications for management.
Authors: Gregory Alan Otterson, Gregory J. Riely, Alice Tsang Shaw, Lucio Crinò, Dong-Wan Kim, Renato Martins, Ravi Salgia, Caicun Zhou, Benjamin J. Solomon, Keith D. Wilner, Anna Polli, Yiyun Tang, Cynthia Huang Bartlett, Sai-Hong Ignatius Ou
Journal: Journal of Clinical Oncology (2012)

7600 Background: Crizotinib is a first-in-class oral ALK inhibitor for the treatment (tx) of advanced ALK-positive (ALK+) NSCLC. Dramatic and prolonged responses to crizotinib are common, but pts do experience PD. Methods: Clinical characteristics of ALK+ NSCLC pts enrolled onto two multicenter, single arm trials of crizotinib (A8081001, PROFILE 1005) with investigator-defined PD who were allowed to continue crizotinib if, in the investigator’s opinion, there was reasonable evidence of ongoing clinical benefit were assessed. A period of ≥2 wks was chosen as a reasonable minimum duration of post-PD crizotinib tx. Results: As of 1 June 2011, 146 pts (A8081001, n=61, PROFILE 1005, n=85) had PD. PD was observed in new lesions only (1 organ site, n=62; &gt;1 organ site, n=18), target ± new lesions (≥ 1 organ site, n=55), clinical PD (n=9), and no site assessment (n=2). Most common new lesions in single organ sites were brain (brain MRI not mandatory; n=25), liver (n=20), bone (n=4), and kidney (n=1). Of the 146 pts, 78 (53%) received crizotinib post-PD for at least 2 wks, 91% of whom had ECOG PS 0 or 1 at PD. In these 78 pts, PD was observed in new lesions only (1 organ site, n=39; &gt;1 organ site, n=4), target ± new lesions (≥ 1 organ site, n=29), and clinical PD (n=6); the most common sites for single organ PD were brain (n=20), liver (n=9), and other (n=10). Best response before PD (% CR/PR, SD, PD) was 62/27/12 in the 78 pts who received ≥2 weeks’ tx post-PD and 31/37/32 in the 68 pts who received &lt;2 weeks’ tx post-PD or discontinued. Median duration of crizotinib tx post-PD (n=78) was 10 weeks (range 2–84). 20 pts with PD in brain only (concurrent local tx or radiation permitted) continue to receive crizotinib (range 3–82 weeks post-PD). Conclusions: Following initial crizotinib tx, PD most commonly occurred at a single organ site in ALK+ NSCLC pts. The majority of pts receiving crizotinib post-PD had good PS, and tended to have single-site PD (most often the brain or liver), and a prior response on crizotinib. Given these observations, pts may be able to continue with crizotinib for a period of time following clinical or documented progression.
FRI0526 Anti-osteoporotic therapy decrease cancer risk in patients with osteoporotic vertebral fractures
Authors: Y-C Chen, C-H Ko
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Some studies had looked at the long-term effect of anti-osteoporotic therapy on risks of different cancers in the general population. But epidemiological studies have consistently reported a reduced risk of breast cancer in bisphosphonate users. so there is little data to establish definitive conclusions. <h3>Objectives</h3> This study aimed to determine if anti-osteoporotic therapy can influence cancer risk in patients with osteoporotic vertebral fracture. <h3>Methods</h3> This retrospective study reviewed of cases of osteoporosis patients with acute vertebral fractures between 2001 and 2015. Anti-osteoporotic therapy were recorded (alendronate, ibandronate, zolendronic acid, raloxifen, teriparatide, denosumab). We followed these patients to develop cancer. All associated co-morbidities were recorded. Cox regression analysis were performed. <h3>Results</h3> There were 1128 patients with acute vertebral fractures were enrolled, among them 693 patients accepted anti-osteoporotic therapy, 432 were not. The mean age of anti-osteoporotic therapy was 73.86±7.52, while the age of nonanti-osteoporotic therapy was 72.82±10.92 (p=0.059). 15 (2.2%) patients of anti-osteoporotic therapy developed cancer, while 24 (5.6%) patients of non-antiosteoporotic therapy developed cancer (p=0.004). After adjusting for potential confounders, patients with antiosteoporotic therapy still had a lower cancer risk (<i>p</i>=0.038; HR: 0.428, 95% CI: 0.192∼0.955). The cancer risk also increased among smokers (<i>p</i>=0.002; HR: 10.505; 95% CI: 2.375∼46.462). <h3>Conclusions</h3> In this study, anti-osteoporotic therapy decrease cancer risk. So we could safely use these drugs in osteoporotic management. <h3>References</h3> British Journal of Cancer (2013) 109, 795–806. <h3>Acknowledgements</h3> We thanked Kaohsiung Chang Gang Memorial hospital for data support. <h3>Disclosure of Interest</h3> None declared
Abstract 15501: True Bipolar Left Ventricular Pacing is Associated With Better Survival in Cardiac Resynchronization Therapy Patients
Authors: Valentina Kutyifa, Arthur J Moss, Kenneth Stein, Paul J Wang, Dan Musat, Paul Jones, Scott Wehrenberg
Journal: Circulation (2015)

Introduction: Prior studies suggested better outcomes in cardiac resynchronization therapy (CRT) patients with true bipolar left ventricular (LV) pacing compared to unipolar or extended bipolar LV pacing. However, we lack confirmatory data from larger patient cohorts. Methods: We reviewed de-identified device data from 65,620 HF patients with an RF-enabled CRT-D device followed on the LATITUDE system (LATITUDE® system, Boston Scientific, St. Paul, MN). Long-term survival was assessed by LV lead pacing polarity. Patients with LV bipolar leads paced between the LV tip and ring were identified as LV true bipolar pacing, while those with LV bipolar leads paced between the LV tip or LV ring to the RV coil were identified as LV extended bipolar pacing. Unipolar LV pacing was assessed as a separate sub-group. Kaplan-Meier survival analysis and multivariable Cox hazards regressions models were utilized to assess all-cause mortality by LV lead pacing polarity. Results: There were 24,033 patients (37%) with LV true bipolar pacing, 38,327 patients (58%) with extended bipolar LV pacing, and 3260 patients (5%) with LV unipolar pacing. LV true bipolar pacing was associated with a significantly higher likelihood of survival during follow-up compared to patients with LV unipolar pacing (log-rank p&lt;0.001), that translated into a significant 28% reduction in all-cause mortality (HR 0.72, 95% CI: 0.65-0.80, p&lt;0.001) after adjustment for age and gender (Figure). The survival benefit between LV true bipolar pacing and LV extended bipolar pacing was smaller, but nevertheless statistically significant (HR=0.91, 95% CI: 0.65-0.80; p&lt;0.001). Conclusion: In this large patient cohort, true bipolar LV pacing was associated with better long-term survival in cardiac resynchronization therapy patients compared to LV unipolar or LV extended bipolar pacing. When feasible, programming true bipolar LV lead pacing polarity should be considered in cardiac resynchronization therapy patients.
OP0133 Colour doppler ultrasonography of facial and occipital arteries in patients with giant cell arteritis: the frequency of involvement and the role of their assessment in daily practice: a prospective study
Authors: R Jese, Ž Rotar, M Tomšič, A Hočevar
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Giant cell arteritis (GCA) is the most common systemic large and medium size artery vasculitis in Western countries. Colour Doppler Sonography (CDS) allows us to study the involvement of the cranial arteries other than the temporal arteries in GCA which cannot be safely biopsied such as the facial (FaA), and occipital (OcA) arteries. <h3>Objectives</h3> We aimed to estimate the frequency of the FaA, and OcA involvement in GCA; and to explore the clinical characteristics of these subgroups of patients. <h3>Methods</h3> From 1 January 2014 to 31 December 2016, we prospectively performed a CDS of the FaA, and OcA in addition to the temporal (TA), and the extracranial supra-aortic arteries in all newly diagnosed patients suspected of having GCA. We used a Philips IU22 with a 5–17.5 MHz multi-frequency linear probe from January 2014 to August 2016 and a Philips Epiq 7 with a 5–18 MHz multi-frequency linear probe from September 2016 to December 2016. All the arteries were evaluated in two planes for the highly specific <i>halo</i>-sign. <h3>Results</h3> During the 36-month observation period we performed a CDS of the cranial and extra-cranial arteries in 93 GCA (66.7% female) patients. The patients9 median (IQR) age was 73.7 (66.1–79.1) years, and they had a median (IQR) symptom duration of 30 (21–90) days. We observed the <i>halo</i>-sign on the FaA, and OcA in 38 (40.9%), and 29 (31.2%) cases, respectively. The FaA, and OcA were simultaneously affected in 18/93 (19.4%) cases. The FaA, or OcA were affected in 4/22 (18.2%) patients with a negative TA CDS. Patients with an FaA involvement had the highest frequency of severe visual manifestations, with permanent visual loss representing 70% of all visual manifestations. Patients with an OcA involvement least commonly had extracranial large vessel disease. <h3>Conclusions</h3> A fifth of patients with a negative CDS of the TAs had signs of vasculitis only on the CDS of the FaA, or OcA. The CDS of the FaA, and OcA identified approximately 5% more patients with GCA than the CDS of the TA alone. <h3>Disclosure of Interest</h3> None declared
AB0722 The impact of a referral strategy for axial spondyloarthritis in young patients with chronic low back pain: short term outcomes of the impact study
Authors: L Van Hoeven, A Korver, C Appels, J Hazes, F van den Hoogen, M van Oosterhout, J Oostveen, J Spoorenberg, I Tchetverikov, T Kuijper, B Koes, A Weel
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> A substantial amount of young patients with chronic low back pain (CLBP) have axial spondyloarthritis (axSpA), but early recognition of these patients is difficult for general practitioners (GPs). Recently, the CaFaSpA referral rule has been published and externally validated. It is an easy to use referral strategy that has shown to be able to identify patients with CLBP at high risk for axSpA in a primary care setting. The CaFaSpA referral rule consists of 4 items: inflammatory back pain, family history of axSpA or related disease, good reaction to NSAIDs and duration of back pain ≥5 years. If at least 2 out of 4 items are present, the referral rule is positive and a referral to a rheumatologist is advised. <h3>Objectives</h3> To assess the effect of the CaFaSpA referral rule on disability in young CBPP patients by comparing it with usual care, using the format of an impact analysis. <h3>Methods</h3> A cluster randomized controlled trial with GP practices as clusters. GP practices were randomized to either the intervention (use of the referral strategy) or control (usual care) group. Within these GP practices, patients aged 18–45 years with current CLBP were recruited. The primary outcome was disability caused by low back pain, measured with the Roland Morris Disability Questionnaire (RMDQ) scale 0–24. RMDQ score was obtained at baseline and 4 months after a referral advice was made. A higher RMDQ score means more disability. For statistical analysis a linear mixed effects regression model was used. <h3>Results</h3> 92 primary care practices were randomized, 679 patients participated (64% women, mean age 36.2 years (SD7.5) and median CLBP duration 9 years (IQR 4–15 years). 333 patients were randomized to the intervention group, both groups had similar characteristics at baseline. Sixty percent of participants had a positive referral rule. RMDQ scores are shown in table 1. Sub scores are shown for patients with a positive outcome of the referral rule (PRR) and a negative outcome of the referral rule (NRR). The change in RMDQ score after 4 months in the intervention group was -0.74 (95% confidence interval (CI) -1.31 – -0.18) and in the control group -0.46 (95% CI -0.98 – 0.05). There was no significant difference between groups. <h3>Conclusions</h3> Compared with usual care, use of the CaFaSpA referral rule in CLBP patients in a primary care setting did not significantly impact disability in these patients, 4 months after a referral advice was made. Results after 12 and 24 months should be awaited before definitive conclusions about the impact of the CaFaSpA referral rule for axSpA in CLBP patients can be made. <h3>Disclosure of Interest</h3> None declared
Risk Factors for Severe Hypoglycemia in Black and White Adults With Diabetes: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Alexandra K. Lee, Clare J. Lee, Elbert S. Huang, A. Richey Sharrett, Josef Coresh, Elizabeth Selvin
Journal: Diabetes Care (2017)

OBJECTIVE Severe hypoglycemia is a rare but important complication of type 2 diabetes. Few studies have examined the epidemiology of hypoglycemia in a community-based population. RESEARCH DESIGN AND METHODS We included 1,206 Atherosclerosis Risk in Communities (ARIC) Study participants with diagnosed diabetes (baseline: 1996–1998). Severe hypoglycemic events were identified through 2013 by ICD-9 codes from claims for hospitalizations, emergency department visits, and ambulance use. We used Cox regression to evaluate risk factors for severe hypoglycemia. RESULTS The mean age of participants was 64 years, 32% were black, and 54% were female. During a median follow-up period of 15.2 years, there were 185 severe hypoglycemic events. Important risk factors after multivariable adjustment were as follows: age (per 5 years: hazard ratio [HR] 1.24; 95% CI 1.07–1.43), black race (HR 1.39; 95% CI 1.02–1.88), diabetes medications (any insulin use vs. no medications: HR 3.00; 95% CI 1.71–5.28; oral medications only vs. no medications: HR 2.20; 95% CI 1.28–3.76), glycemic control (moderate vs. good: HR 1.78; 95% CI 1.11–2.83; poor vs. good: HR 2.62; 95% CI 1.67–4.10), macroalbuminuria (HR 1.95; 95% CI 1.23–3.07), and poor cognitive function (Digit Symbol Substitution Test z score: HR 1.57; 95% CI 1.33–1.84). In an analysis of nontraditional risk factors, low 1,5-anhydroglucitol, difficulty with activities of daily living, Medicaid insurance, and antidepressant use were positively associated with severe hypoglycemia after multivariate adjustment. CONCLUSIONS Poor glycemic control, glycemic variability as captured by 1,5-anhydroglucitol, kidney damage, and measures of cognitive and functional impairments were strongly associated with increased risk of severe hypoglycemia. These factors should be considered in hypoglycemia risk assessments when individualizing diabetes care for older adults.
Identification of an HLA Class I Allele Closely Involved in the Pathogenesis of Acquired Aplastic Anemia
Authors: Yoshitaka Zaimoku, Hiroyuki Takamatsu, Kazuyoshi Hosomichi, Tatsuhiko Ozawa, Noriharu Nakagawa, Tatsuya Imi, Hiroyuki Kishi, Koichi Kashiwase, Shinji Nakao
Journal: Blood (2016)
SAT0578 Leflunomide inhibits the apoptosis of human embryonic lung fibroblasts infected by human cytomegalovirus
Authors: Q Ren, H Zeng
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> The immunomodulatory drug leflunomide (LEF) is frequently used for treating human cytomegalovirus (HCMV), but its antiviral mechanism is still unclear. <h3>Objectives</h3> In this study,we therefore investigated the effects of the active LEF metabolite A771726 on the HCMV lifecycle in human embryonic lung fibroblasts. We clarified the mechanism of LEF antiviral infection, and provide a new way to treat immune dysfunction patients with HCMV infection. <h3>Methods</h3> The experiment was divided into four groups:the control group, the HCMV group, the ganciclovir + HCMV group as well as the LEF + HCMV group. MTT was usedfor assessmentof the cell inhibitory rate. Apoptosis was measured by staining with fluoresceinisothiocyanate Annexin V and propidium iodide. Statistical significance was determined by paired <i>t-</i>test using SPSS software. <h3>Results</h3> The results of the study showed that cell proliferation was significantly inhibited by HCMV at 24 hours and 48 hours. With increasing HCMV concentration, the value-added inhibition of the cells was significantly decreased compared with the control group, and was statistically significant (<i>P</i>&lt;0.01). Ganciclovir can increase proliferation of cellsinfected with HCMV;compared with the control group it was statistically significant (<i>P</i>&lt;0.05). Meanwhile,with LEF treatment cell proliferation was significantly improved at 24 hours and 48 hours, with statistical significance (<i>P</i>&lt;0.05). The apoptosis rate of human embryonic lung fibroblasts infected with HCMV increased significantly at 24 hours, 48 hours and 72 hours,and as time goes on the apoptosis rate increases statistically significantly (<i>P</i>&lt;0.01) compared with the control group The apoptosis rate of theHCMV infection group decreased by adding LEF,and was statistically significant (<i>P</i>&lt;0.05). <h3>Conclusions</h3> In this studywe show that LEF is an exciting new drug for cytomegalovirus infection. LEF significantly inhibited HCMV infection-induced apoptosis and proliferation, playing an important role in the treatment of patients infected by HCMV. In this study we explored the potential usefulness of LEF for cytomegalovirus infection and found it to be a cost-effective new treatment for cytomegalovirus infection that deserves further study. <h3>Disclosure of Interest</h3> None declared