Description: Background and Purpose— We systematically compared and appraised contemporary guidelines on management of asymptomatic and symptomatic carotid artery stenosis. Methods— We systematically searched for guideline recommendations on carotid endarterectomy (CEA) or carotid angioplasty/stenting (CAS) published in any language between January 1, 2008, and January 28, 2015. Only the latest guideline per writing group was selected. Each guideline was analyzed independently by 2 to 6 authors to determine clinical scenarios covered, recommendations given, and scientific evidence used. Results— Thirty-four eligible guidelines were identified from 23 different regions/countries in 6 languages. Of 28 guidelines with asymptomatic carotid artery stenosis procedural recommendations, 24 (86%) endorsed CEA (recommended it should or may be provided) for 50% to 99% average-surgical-risk asymptomatic carotid artery stenosis, 17 (61%) endorsed CAS, 8 (29%) opposed CAS, and 1 (4%) endorsed medical treatment alone. For asymptomatic carotid artery stenosis patients considered high-CEA-risk because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 13 guidelines (46%). Thirty-one of 33 guidelines (94%) with symptomatic carotid artery stenosis procedural recommendations endorsed CEA for patients with 50% to 99% average-CEA-risk symptomatic carotid artery stenosis, 19 (58%) endorsed CAS and 9 (27%) opposed CAS. For high-CEA-risk symptomatic carotid artery stenosis because of comorbidities, vascular anatomy, or undefined reasons, CAS was endorsed in 27 guidelines (82%). Guideline procedural recommendations were based only on results of trials in which patients were randomized 12 to 34 years ago, rarely reflected medical treatment improvements and often understated potential CAS hazards. Qualifying terminology summarizing recommendations or evidence lacked standardization, impeding guideline interpretation, and comparison. Conclusions— This systematic review has identified many opportunities to modernize and otherwise improve carotid stenosis management guidelines.

Description: Immuno-PET provides valuable information about tumor location, phenotype, susceptibility to therapy, and treatment response, especially to targeted radioimmunotherapy. In this study, we prepared antiepidermal growth factor receptor (EGFR) antibody via identical chelator, 3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-trience-3,6,9,-triacetic acid (PCTA), labeled with 64 Cu or 177 Lu to evaluate the EGFR expression levels using immuno-PET and the feasibility of radioimmunotherapy in an esophageal squamous cell carcinoma (ESCC) model. Methods: Cetuximab was conjugated with p -SCN-Bn-PCTA and radiolabeled with 64 Cu or 177 Lu. In vitro EGFR expression levels were determined and compared using flow cytometry and cell binding assay. In vivo EGFR expression levels were evaluated via immuno-PET imaging of 64 Cu-cetuximab and biodistribution analysis. Micro-SPECT/CT imaging, biodistribution, and radioimmunotherapy studies of 177 Lu-cetuximab were performed in the ESCC model. Therapeutic responses were monitored using 18 F-FDG PET and immunohistochemical staining. Results: 64 Cu- or 177 Lu-labeled antibodies showed high radiolabeling yield (〉98%), stability (〉90%), and favorable immunoreactivity. In vitro EGFR status measured by cell binding assay was correlated with the flow cytometry data. Immuno-PET, micro-SPECT/CT, and biodistribution demonstrated specific uptake in ESCC tumors depending on the EGFR expression levels. Tumor accumulation of 64 Cu- and 177 Lu-cetuximab was peaked at 48 and 120 h, respectively. Radioimmunotherapy with 177 Lu-cetuximab showed significant inhibition of tumor growth ( P 〈 0.01) and marked reduction of 18 F-FDG SUV compared with that of control ( P 〈 0.05). Terminal deoxynucleotidyl transferase dUTP nick-end labeling positivity and Ki-67 staining indices increased and decreased, respectively, in the radioimmunotherapy group compared with other groups ( P 〈 0.01). Conclusion: 64 Cu-cetuximab immuno-PET represented EGFR expression levels in ESCC tumors, and 177 Lu-cetuximab radioimmunotherapy effectively inhibited the tumor growth. The diagnostic and therapeutic convergence radiopharmaceutical 64 Cu-/ 177 Lu-PCTA-cetuximab may be useful as a diagnostic tool in patient selection and a potent radioimmunotherapy agent in EGFR-positive ESCC tumors.

Description: Background and Purpose— Since its introduction, controversy has existed about the administration of intravenous heparin for the treatment of acute ischemic stroke. We studied trends in the intravenous heparin use during a 6-year time period and the potential influence of clinical guidelines in national language on intravenous heparin administration in Korea. Methods— On the basis of a prospective nationwide multicenter stroke registry, we collected data on patients with acute ischemic stroke who arrived within 7 days of symptom onset during the time period 2008 to 2013. We studied patient demographics, prestroke medical history, stroke characteristics, and stroke treatment. Data from a total of 23 425 patients from 12 university hospitals or regional stroke centers were analyzed. Results— The administration of intravenous heparin steadily decreased throughout the study period: 9.7% in 2008, 10.9% in 2009, 9.4% in 2010, 6.0% in 2011, 4.7% in 2012, and 4.3% in 2013 ( P for trend 〈0.001). The reduced intravenous heparin use was associated with moderate stroke severity, atrial fibrillation, and stroke of cardioembolic, other-, and undetermined etiology. In a multivariable logistic model, increase of 1 calendar year (odds ratio, 0.89; 95% confidence interval, 0.84–0.95; P 〈0.001) and release of clinical practice guidelines in Korean (odd ratio, 0.74; 95% confidence interval, 0.59–0.91; P 〈0.01) were independent factors associated with reduction in the frequency of intravenous heparin use. Conclusions— Use of intravenous heparin for acute ischemic stroke treatment has decreased in Korea, and this change may be attributable to the spread and successful implementation of regional clinical practice guidelines.

Description: Background and Purpose— The association between family history of stroke and stroke recurrence remains unclear. Methods— Using a web-based multicenter stroke registry database, information on history of stroke in first-degree relatives was collected prospectively for acute ischemic stroke patients who were hospitalized within 7 days of onset. The collected information was categorized as follows: type of the affected relative(s) with stroke (paternal, maternal, sibling, or 2 or more) and age of the relative’s stroke onset (〈50, 50–59, 60–69, and ≥70 years). Stroke recurrence was captured prospectively using a predetermined protocol. Subgroup analyses were performed according to the patient’s age at the index stroke. Results— Among 7642 patients, 937 (12.3%) had a history of stroke in their first-degree relatives and 475 (6.2%: 201 within and 274 after 3 weeks from index stroke) experienced stroke recurrence (median follow-up, 365 days). In multivariable Cox proportional hazard models, overall family history was not associated with stroke recurrence (hazard ratio, 1.08; 95% confidence interval, 0.81–1.43). However, the details of their family histories, including relative’s age at stroke onset (〈50 years: hazard ratio, 2.14; 95% confidence interval, 1.004–4.54) and stroke history in a sibling (hazard ratio, 1.67; 95% confidence interval, 1.09–2.58), were independently associated with stroke recurrence after adjusting for potential confounders. The associations appeared to be stronger in young adults with stroke (age, 〈55 years) than in older stroke patients. Conclusions— This study suggests that elevated risks of recurrent stroke are associated with having relatives with early-onset stroke and siblings with stroke histories, implying that additional precautions may be needed in such populations.

Description: The large-conductance calcium-activated potassium channel (BK Ca channel) plays critical roles in smooth muscle relaxation. In urinary bladder smooth muscle, BK Ca channel activity underlies the maintenance of the resting membrane potential and repolarization of the spontaneous action potential triggering the phasic contraction. To identify novel BK Ca channel activators, we screened a library of natural compounds using a cell-based fluorescence assay and a hyperactive mutant BK Ca channel ( Lee et al., 2013 ). From 794 natural compounds, kurarinone, a flavanone from Sophora flavescens , strongly potentiated BK Ca channels. When treated from the extracellular side, this compound progressively shifted the conductance-voltage relationship of BK Ca channels to more negative voltages and increased the maximum conductance in a dose-dependent manner. Whereas kurarinone strongly potentiated the homomeric BK Ca channel composed of only the α subunit, its effects were much smaller on heteromeric channels coassembled with auxiliary β subunits. Although the activation kinetics was not altered significantly, the deactivation of BK Ca channels was dramatically slowed by kurarinone treatment. At the single-channel level, kurarinone increased the open probability of the BK Ca channel without affecting its single-channel conductance. Kurarinone potently relaxed acetylcholine-induced contraction of rat bladder smooth muscle and thus decreased the micturition frequency of rats with overactive bladder symptoms. These results indicate that kurarinone can directly potentiate BK Ca channels and demonstrate the therapeutic potentials of kurarinone and its derivatives for developing antioveractive bladder medications and supplements.

Description: Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling...

Description: Objective Serrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1 me+ ). We investigate genetic alterations in the serrated polyposis pathway. Design We used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies. Results In one out of four serrated polyposis families, we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype, along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps (16), adenomas (5) and cancer (1) examined, as well as coincidental BRAF mutation in 62.5% of the serrated polyps. Concurrently, somatic RNF43 mutations were identified in 34% of sporadic sessile/traditional serrated adenomas, but 0% of hyperplastic polyps (p=0.013). Lastly, in MSI CRCs, we found significantly more frequent RNF43 mutations in the MLH1 me+ (85%) versus MLH1 me– (33.3%) group (p〈0.001). These findings were validated in the TCGA MSI CRCs (p=0.005), which further delineated a significant differential involvement of three Wnt pathway genes between these two groups (RNF43 in MLH1 me+ ; APC and CTNNB1 in MLH1 me– ); and identified significant co-occurrence of BRAF and RNF43 mutations in the MSI (p〈0.001), microsatellite stable (MSS) (p=0.002) and MLH1 me+ MSI CRCs (p=0.042). Functionally, organoid culture of serrated adenoma or mouse colon with CRISPR-induced RNF43 mutations had reduced dependency on R-spondin1. Conclusions These results illustrate the importance of RNF43, along with BRAF mutation in the serrated neoplasia pathway (both the sporadic and familial forms), inform genetic diagnosis protocol and raise therapeutic opportunities through Wnt inhibition in different stages of evolution of serrated polyps.

Description: Phosphodiesterase 4B (PDE4B) plays a key role in regulating inflammation. Roflumilast, a phosphodiesterase (PDE)4-selective inhibitor, has recently been approved for treating severe chronic obstructive pulmonary disease (COPD) patients with exacerbation. However, there is also clinical evidence suggesting the development of tachyphylaxis or tolerance on repeated dosing of roflumilast and the...

Description: Background One third of patients presenting with initially mild strokes have unfavorable outcomes, and the efficacy of intravenous thrombolysis (IVT) in this population has not been proven. This study aimed to evaluate the comparative effectiveness of standard care with IVT versus without IVT in mild stroke patients. Methods and Results Using a multicenter stroke registry database, we identified patients with acute ischemic stroke who presented within 4.5 hours of symptom onset and had initial National Institutes of Health Stroke Scale scores ≤5. Multivariable logistic analysis and propensity score matching were used to adjust for baseline imbalances between the patients who did and did not receive IVT. Adjusted odds ratios and 95% CIs of IVT were estimated for 3-month modified Rankin Scale scores of 0 to 1 and symptomatic. Of 13 117 patients with stroke who were hospitalized between April 2008 and May 2012, 1386 met the eligibility criteria, and 194 (14.0%) were treated with IVT. For a modified Rankin Scale of 0 to 1 at 3 months, the adjusted odds ratios were 1.96 (95% CI, 1.28 to 3.00; P =0.002) by multivariable logistic analysis and 1.68 (1.10 to 2.56; P =0.02) by propensity score matching analysis, respectively. There was a statistically nonsignificant excess of symptomatic hemorrhagic transformation (odds ratios=3.76 [0.95 to 16.42; P =0.06] and 4.81 [0.84 to 49.34; P =0.09]), respectively. Conclusions In this observational registry-based study, standard care with IVT is more effective than not receiving IVT in mild ischemic stroke patients, and there is a statistically nonsignificant risk of symptomatic hemorrhagic transformation.

Description: Mucin overproduction is a hallmark of otitis media (OM). Streptococcus pneumoniae is one of the most common bacterial pathogens causing OM. Mucin MUC5AC plays an important role in mucociliary clearance of bacterial pathogens. However, if uncontrolled, excessive mucus contributes significantly to conductive hearing loss. Currently, there is a lack of effective therapeutic agents that suppress mucus overproduction. In this study, we show that a currently existing antistroke drug, vinpocetine, a derivative of the alkaloid vincamine, inhibited S. pneumoniae– induced mucin MUC5AC upregulation in cultured middle ear epithelial cells and in the middle ear of mice. Moreover, vinpocetine inhibited MUC5AC upregulation by inhibiting the MAPK ERK pathway in an MKP-1–dependent manner. Importantly, ototopical administration of vinpocetine postinfection inhibited MUC5AC expression and middle ear inflammation induced by S. pneumoniae and reduced hearing loss and pneumococcal loads in a well-established mouse model of OM. Thus, these studies identified vinpocetine as a potential therapeutic agent for inhibiting mucus production in the pathogenesis of OM.