Search

Aneurysmal extension of abdominal aortic aneurysms (AAAs) to the common iliac artery (CIA) presents a technical challenge to successful endovascular abdominal aortic aneurysm repair (EVAR). In the present study, we compared sac shrinkage and perioperative outcomes after the bell-bottom technique (BBT), internal iliac artery embolization and external iliac artery extension (EIE), and iliac branch endoprosthesis (IBE).Using the Vascular Quality Initiative database, a retrospective analysis was conducted for patients who had undergone EVAR from 2013 to 2019. The demographic, anatomic, and perioperative data were analyzed. All patients with a proximal aortic neck length 10 mm and aortic graft diameter32 mm were excluded from the analysis. The patients were subdivided into four groups according to the distal limb strategy: group 1, control group with a bilateral common iliac artery limb 20 mm; group 2, BBT with either a unilateral or bilateral limb20 mm; group 3, EIE technique; and group 4, IBE. The primary endpoint was the maximal change in the aortic diameter during follow-up. The secondary endpoints included postoperative complications and the rate of endoleak.The records for 14,455 patients who had undergone EVAR were queried and 5788 met the anatomic criteria. The average age was 73 years, and 86.3% were men. The maximal change in the aortic diameter in the control, BBT, IBE, and EIE groups was -7.2 mm, -6.1 mm, -4.6 mm, and -6.8 mm, respectively (P = .06). The differences were not statistically significant on univariate analysis at an average follow-up of 405 days. However, on multivariable analysis (P = .01), compared with the control group, the BBT and IBE groups were 18.4% (odds ratio [OR], 0.816; 95% confidence interval [CI], 0.68-0.98) and 48.0% (OR, 0.52; 95% CI, 0.33-0.82) less likely to experience aneurysmal shrinkage, respectively. In contrast, the EIE group showed no significant difference in shrinkage compared with that in the control group. Multivariable analysis of the groups also revealed that compared directly with the BBT group, the EIE group was 69.5% more likely to have experienced shrinkage in the aortic aneurysmal diameter (OR, 1.70; 95% CI, 1.05-2.75). The BBT and IBE groups had a significantly higher rate of type II endoleaks (17.63% and 16.95%, respectively; P = .03). The EIE group had a higher rate of type Ib endoleaks (1.9%) compared with the BBT (1.1%), IBE (1.7%), and control (0.3%) groups (P = .01). No differences were found between the groups in terms of postoperative myocardial infarction (P = .47) or respiratory (P = .61) or intestinal (P = .71) complications. However, the rates of limb complications and reoperation were higher in the EIE group.The present study revealed that the EIE technique was more likely to demonstrate shrinkage in the aortic aneurysmal diameter than were the BBT and IBE groups compared with the control group on multivariable analysis. The EIE technique was also more likely to result in aneurysmal sac shrinkage than was the BBT group, albeit with greater rates of limb-related complications.

Purpose: Percutaneous lower extremity revascularization is being performed via upper extremity, pedal, or popliteal access with increasing frequency. This study aimed to compare periprocedural outcomes of popliteal (POA) and upper extremity (UEA) access for the treatment of isolated superficial femoral artery (SFA) occlusive disease. Materials and Methods: A retrospective cohort study compared the outcomes of patients undergoing primary percutaneous intervention of SFA occlusive disease with POA or UEA using the Vascular Quality Initiative database from December 2010 to June 2019. Our primary endpoint was technical success. Secondary endpoints included factors associated with perioperative complications. Results: A total of 349 patients underwent isolated SFA intervention through the popliteal, radial, or brachial artery. UEA was performed in 188 (53.9%) patients and POA in 161 (46.1%). Technical success with TASC A lesions was 95.8% and with TASC D lesions, 65.0%. POA had a higher proportion of TASC D lesions (24.8% vs 10.6%, pConclusions: There is no difference in technical success between UEA and POA when treating isolated SFA occlusive disease, and UEA is associated with a higher complication rate. Technical success is dependent on calcification and TASC II classification. Based on similar technical success rates and low complication rates, POA should be considered as a viable alternative to UEA when planning endovascular interventions.

Background Endovascular management of isolated profunda femoris artery occlusive disease has not been well studied. Our aim is to analyze the outcomes of endovascular management of profunda artery occlusive disease. Methods This is a retrospective analysis using data from the Vascular Quality Initiative. All patients from 2013 to 2018 treated percutaneously for isolated profunda artery occlusive disease were included. Endovascular treatment included plain balloon alone, stent, stent graft, atherectomy, and drug-coated balloon without any concomitant endovascular or surgical treatment. Demographic, procedural, and follow-up data were obtained. Primary end points were primary patency, improvement of symptoms, and need for reintervention. Univariate and multivariable analysis was used to assess for significant variables. Results Of the 105,568 lower extremity endovascular interventions performed during this time period, there were 361 procedures (0.3%) performed on 341 patients for isolated profunda artery occlusive disease. The average age of these patients was 67.8 years (+/− 11.8), with 59.8% being men. The most common indication for treatment of the profunda artery was claudication (44.8%), followed by tissue loss (28.5%) and rest pain (26.0%). The most common treatment modality was plain balloon (58.5%), followed by stent (18.6%), drug-coated balloon (10.0%), atherectomy (9.4%), and stent graft (3.6%). At a mean follow-up of 13 months (+/−4.6), data were available for 238 patients (69.7%). Overall primary patency at 13 months was 92.9%. There was no significant difference in terms of patency for each treatment modality (Table I). Preoperative ambulatory status, aspirin, and statin were significantly associated with patency. At most recent follow-up, 67% of patients had improvement of their symptoms, whereas 29% were unchanged. Reintervention data were available for 247 patients, with a reintervention rate of 15.8% (n = 39) and a mean reintervention time of 226 days (+/− 173), with the majority of reinterventions (62%) occurring in the plain balloon group. Reinterventions were primarily endovascular (64%) with 9 patients (23%) undergoing surgical reintervention. Conclusions Endovascular management of profunda femoris artery occlusive disease has acceptable one-year patency rates with low reintervention rates. Endovascular treatment may be an acceptable alternative to selected patients who are high-risk for surgery.

Patients with critical limb ischemia (CLI) often require lower extremity bypass surgery for limb salvage. A myocardial infarction (MI) is a major postoperative risk. Our objective is to assess the utility of preoperative stress test in determining patient outcomes.This is a retrospective study utilizing the national Vascular Quality Initiative database. We collected data from 2013-2018 on all patients undergoing lower extremity bypass for CLI and assessed whether or not they had a preoperative stress test. Rates of an MI were then compared between groups of patients who either did not receive a stress test, had a normal stress test or a positive stress test. An MI was distinguished as troponin only and electrocardiogram (EKG)/clinical. Our secondary end point was in-hospital mortality. Univariate and multivariate analysis with the stress test as a covariate was used to determine significance.During this time period, 29,937 bypasses were performed on 27,219 patients. The average age was 67.5 years (±11.09), 66.3% were men, and 17.3% were African American. Risk factors included hypertension (89.5%), diabetes (55.9%), congestive heart failure (20%), coronary artery disease (32.5%), coronary artery bypass graft (22.2%), and percutaneous coronary intervention (21%). 19,108 patients (64.1%) did not undergo the stress test before bypass, 6,830 (22.9%) had a normal stress test, and 2,898 (9.7%) had a positive stress test. Overall rate of an MI was 4%, with 2% being troponin only and 2% EKG/clinical. The positive stress test had a higher rate of troponin only (2.85%) as well as EKG/clinical (3.37%) MI. For every 10 year increase in age, the odds of having a postoperative MI increased by 27% (P 0.0001). Overall in-hospital mortality was 1.4%. Patients with positive stress tests had a 2.6% mortality compared with normal/not performed at 1.3%. Of the patients who died, 21.5% had an EKG/clinical MI. Of those patients, 50% did not have a stress test, 12% had normal stress tests, and 23% had positive stress tests. When comparing rates of patients who died or had an MI, there was no difference between patients who had no or a normal stress test (7.29%) versus those who had a positive stress test (7.58%), (P = 0.11).A positive stress test before lower extremity bypass is a significant predictor of a postoperative MI. However, mortality increase was minimal in patients with a positive stress test. Therefore, the stress test result should not delay care for patients needing urgent revascularization.

Background: Epirubicin (EPI) is an important anticancer drug that is well-known for its cardiotoxic side effect. Studying epigenetic modification such as DNA methylation can help to understand the EPI-related toxic mechanisms in cardiac tissue. In this study, we analyzed the DNA methylation profile in a relevant human cell model and inspected the expression of differentially methylated genes at the transcriptome level to understand how changes in DNA methylation could affect gene expression in relation to EPI-induced cardiotoxicity. Methods: Human cardiac microtissues were exposed to either therapeutic or toxic (IC20) EPI doses during 2 weeks. The DNA and RNA were collected from microtissues in triplicates at 2, 8, 24, 72, 168, 240, and 336 hours of exposure. Methylated DNA immunoprecipitation-sequencing (MeDIP-seq) analysis was used to detect DNA methylation levels in EPI-treated and control samples. The MeDIP-seq data were analyzed and processed using the QSEA package with a recently published workflow. RNA sequencing (RNA-seq) was used to measure global gene expression in the same samples. Results: After processing the MeDIP-seq data, we detected 35, 37, 15 candidate genes which show strong methylated alterations between all EPI-treated, EPI therapeutic and EPI toxic dose-treated samples compared to control, respectively. For several genes, gene expressions changed compatibly reflecting the DNA methylation regulation. Conclusions: The observed DNA methylation modifications provide further insights into the EPI-induced cardiotoxicity. Multiple differentially methylated genes under EPI treatment, such as SMARCA4, PKN1, RGS12, DPP9, NCOR2, SDHA, POLR2A, and AGPAT3, have been implicated in different cardiac dysfunction mechanisms. Together with other differentially methylated genes, these genes can be candidates for further investigations of EPI-related toxic mechanisms. Data Repository: The data has been generated by the HeCaToS project (http://www.ebi.ac.uk/biostudies) under accession numbers S-HECA433 and S-HECA434 for the MeDIP-seq data and S-HECA11 for the RNA-seq data. The R code is available on Github (https://github.com/NhanNguyen000/MeDIP).

Background Patients undergoing carotid endarterectomy (CEA) often experience postoperative hemodynamic changes that require intravenous medications for hypo- and hypertension. Prior studies have found these changes to be associated with increased risks of 30-day mortality, stroke, myocardial infarction (MI), and length of stay (LOS). Our aim is to investigate preoperative risk factors associated with the need for postoperative intravenous medications for blood pressure control. Methods A retrospective review of an internally maintained prospective database of patients undergoing carotid interventions between January 2014 and March 2019 was performed. Demographic data, clinical history, and perioperative data were recorded. Carotid artery stents and reinterventions were excluded. Our primary end points were the need to intervene with intravenous medication for either postoperative hypotension [systolic blood pressure (SBP) 160 mm Hg). Results A total of 221 patients were included in the study after excluding those with a prior ipsilateral CEA or carotid artery stent. The mean age was 72.3 (±8.9) years, 157 (71%) patients were male, and 78 (35.3%) were Caucasian. Following CEA, 151 (68.3%) patients were normotensive, while 33 (14.9%) and 37 (16.7%) required medication for hypotension and hypertension, respectively. A univariate logistic regression identified 5 variables as being associated with postoperative blood pressure including race, history of MI, prior percutaneous transluminal coronary angioplasty (PTCA), statin use, and angiotensin-converting enzyme-inhibitor/angiotensin-receptor blocker (ARB) use. A stepwise regression selection found race, prior MI, and statin use to be associated with our primary end points. The hypertensive group was more likely to have a history of MI compared to the hypotensive and normotensive groups (40.5% vs. 27.3% vs. 18.5%, P = 0.02), PTCA (43.2% vs. 39.4% vs. 23.8%, P = 0.03), and statin use (94.6% vs. 93.9% vs. 78.8%, P = 0.01). Mean LOS was also the highest for the hypertensive group, followed by hypotensive and normotensive patients [2.0 (±1.6) vs. 1.8 (±2.4) vs. 1.3 (±0.8), P = 0.002]. Multivariable logistic regression demonstrated that non-Caucasian patients [odds ratio (OR) 2.72, 95% confidence interval (CI) 1.26–5.86, P = 0.01] and those with a history of MI (OR 2.98, 95% CI 1.33–6.67) were more likely to have postoperative hypertension compared to patients who were Caucasian or had no history of MI. Conclusions Postoperative hypertension is associated with non-Caucasian race and a history of MI. Given the potential implications for adverse perioperative outcomes including MI, mortality, and LOS, it is important to continue to elucidate potential risk factors in order to further tailor the perioperative management of patients undergoing CEA.

In patients with abdominal aortic aneurysms, 10-20% has concomitant thoracic aortic pathologies. These are typically managed with staged endovascular aneurysm repair (EVAR) and thoracic endovascular aortic repair (TEVAR) due to a perceived higher risk of spinal cord ischemia from a simultaneous intervention. We aimed to determine the outcomes of patients undergoing simultaneous EVAR and TEVAR for concomitant aneurysms.A retrospective cohort study was performed using the Vascular Quality Initiative registry from December 2003 to January 2021. Patients undergoing same day EVAR and TEVAR were included and analyzed in accordance with the Society for Vascular Surgery reporting standards. Primary outcomes were technical success and spinal cord ischemia.Simultaneous EVAR and TEVAR were performed in 25 patients. Median age was 75.0 (interquartile range [IQR], 63.0-79.0) years and 20 (80.0%) patients were male. Two (4.0%) patients were symptomatic and 4 (16.0%) presented with rupture. Median maximum infrarenal and thoracic aortic diameter was 57.0 (IQR, 52.0-65.0). Infrarenal aortic neck length was 15.0 mm (IQR, 10.0-25.0), and diameter was 27.0 mm (IQR, 24.5-30.0). Median procedure time was 185.0 min (IQR, 117.8-251.3), fluoroscopy time 32.7 min (IQR, 21.8-63.1), and contrast volume 165 mL (IQR, 115.0-207.0). There were 3 (12.0%) Type Ia endoleaks and 3 (12.0%) Type II endoleaks in EVAR's, with 1 (4.0%) Type Ia and 1 (4.0%) Type II endoleak in TEVARs. In-hospital mortality occurred in 3 (12.0%) patients (1 elective, 2 ruptures). Spinal cord ischemia occurred in 1 (4.0%) patient. This patient had a symptomatic aneurysm. Thoracic coverage extended from Zone 4 to Zone 5 and an emergent spinal drain was placed postoperatively. Symptoms were present on discharge. There was 1 (4.0%) conversion to open repair which occurred in a ruptured aneurysm. Technical success was achieved in 19 (76.0%) patients, however when excluding ruptured aneurysms, was achieved in 17 (81.0%) patients. Follow-up data was available for 19 (76.0%) patients at a median of 426.0 (IQR, 329.0-592.5) days postoperatively. A total of 3 (12.0%) patients died during the late mortality period, at a mean of 509.0 (±503.7) days. Median change in abdominal and thoracic aortic sac diameter was -1.35 mm (IQR, -11.5 to 2.5) and 8.0 (IQR, -10.5 to 12.0), respectively.Simultaneous EVAR and TEVAR for concomitant abdominal and thoracic aortic aneurysms can be performed with low rates of spinal cord ischemia. Short- and mid-term outcomes are acceptable.

Transient receptor potential vanilloid 4 (TRPV4) is a non-selective mechanosensitive ion channel expressed by various macrophage populations. Recent reports have characterized the role of TRPV4 in shaping the activity and phenotype of macrophages to influence the innate immune response to pathogen exposure and inflammation. TRPV4 has been studied extensively in the context of inflammation and inflammatory pain. Although TRPV4 activity has been generally described as pro-inflammatory, emerging evidence suggests a more complex role where this channel may also contribute to anti-inflammatory activities. However, detailed understanding of how TRPV4 may influence the initiation, maintenance, and resolution of inflammatory disease remains limited. This review highlights recent insights into the cellular processes through which TRPV4 contributes to pathological conditions and immune processes, with a focus on macrophage biology. The potential use of high-throughput and omics methods as an unbiased approach for studying the functional outcomes of TRPV4 activation is also discussed.

Objectives: Left subclavian artery (LSA) revascularization in thoracic endovascular aortic repair (TEVAR) remains controversial. Left subclavian artery coverage without revascularization can cause stroke and death. TEVAR has gained popularity for the treatment of chronic type B aortic dissection (cTBD). Using the Vascular Quality Initiative (VQI) database, we reviewed outcomes of LSA revascularization in TEVAR for cTBD. Methods: The VQI registry identified 5683 patients treated with TEVAR from July 2010 to July 2016, including 208 repairs for cTBD. We analyzed outcomes per the Society for Vascular Surgery reporting standards. Results: Of the 208 patients, 150 (72.1%) were male with a median age of 65.0 years (interquartile range [IQR], 55.0-72.0). Median aneurysm diameter was 5.7 cm (IQR, 5.0-6.5 cm). Data on the patency of the LSA was available in 131 (63.0%) patients. Twenty-five (19.1%) had occlusion of the LSA without revascularization, while 106 (80.9%) maintained patency or had revascularization. Successful device delivery occurred in all 131 (100%) patients. Maintaining LSA patency did not affect the rate of cerebrovascular accident ( P = .16), spinal cord ischemia ( P = 1.00), or death ( P = 1.00). This was also nonsignificant when analyzing the subgroup of 98 elective cases. There was no difference in the rates of endoleak. Any intervention for the LSA (revascularization or occlusion) led to a longer procedure time (203.6 minutes vs 163.7 minutes, P = .04). Conclusions: Maintaining LSA patency during TEVAR for cTBD offers no advantage in perioperative morbidity or endoleak. Occlusion of LSA may be performed safely in this cohort and revascularization reserved for those who have anatomy that compromises perfusion to critical organs.

Background Placement of inferior vena cava (IVC) filters can be complicated by venous injury, filter misplacement, angulation, insertion site injury, and procedure-related death. Currently, no studies exist evaluating the correlation between obesity and adverse outcomes of IVC filters. We aimed to assess the outcomes of IVC filter placement in the obese population using the Vascular Quality Initiative database. Methods The Vascular Quality Initiative registry identified 7258 patients who underwent IVC filter placement from January 2013 to June 2017. Patients were divided into three groups based on their body mass index (BMI): normal/overweight (BMI 40). Periprocedural outcomes were analyzed. Results The mean age was 63.6 ± 16.6 years and 3444 patients (47%) were female. BMI was less than 30 in 4115 (56.7%), 30 to 40 in 2148 (29.6%), and greater than 40 in 995 (13.7%) patients. A complication or IVC filter-related death occurred in 142 patients (2.6%). Adverse events included angulation (1.3%), IVC filter misplacement (0.5%), insertion site injury (0.3%), IVC filter-related death (0.1%), and venous injury (0.06%). In multivariable analysis, increased BMI was found to be associated with angulation (P = .03), but was not associated with IVC filter misplacement (P = .43), or any complication or IVC filter-related death (P = .22). A subgroup analysis of IVC filter placements using only fluoroscopy demonstrated that the risk of angulation was significantly higher in patients with a BMI of greater than 40 compared with a BMI of less than 30 (odds ratio, 2.12; 95% confidence interval, 1.07-4.21; P = .03). There was not enough evidence to conclude that BMI was associated with any other outcome. Conclusions IVC filter insertion has low complication rates. Increased BMI is associated with an increased risk of IVC filter angulation; there is no evidence of association between BMI and other periprocedural complications.

Medical students experience extensive pressure during their undergraduate courses. Given the complex associations between psychological factors in association with academic pressure. We investigated the study with objectives: To examine psychological factors related to academic pressure by analysing interactions between 'study motivation', 'study environment', 'study conditions', 'teacher quality', 'training programme', 'management system', 'evaluation', and 'extracurricular activities' using a network analysis approach. A total of 878 medical students majoring in general medicine from the first, third, and fifth years of a six-year course at the largest medical university in central and highland regions of Vietnam were involved in this cross-sectional study. The approach used was convenient cluster sampling with a self-administered questionnaire by the participants. Network analysis for pairwise correlations between psychological factors was estimated . Important factors in the network analysis were calculated using centrality indices including node strength (S), closeness (C), and betweenness (B). The higher score of S, C, and B indicate the more importance of the node. The results obtained from the network analysis of eight psychological factors showed that 'teaching quality' was mostly connected with other factors overall, while the 'training programme' was seen in both genders and freshman students. 'Study conditions' and 'training programme' were mostly connected with other factors in junior and senior students, respectively. The strong pairwise correlation was confirmed: management system and evaluation activity, followed by study environment and study conditions, and teaching quality and training programme. Additionally, nodes with high centrality were shown to be 'management system' (S = 0.97, C = 0.019, B = 1), and 'training programme' (S = 0.96, C = 0.021, B = 4). Our study findings indicate that satisfaction with the training programme amongst eight psychological factors is the most important factor affecting academic pressure among medical students. The training programme is linked with teaching quality, whereas the management system is correlated with evaluation activity.

The human P-glycoprotein (P-gp) and the NorA transporter are the major culprits of multidrug resistance observed in various bacterial strains and cancer cell lines, by extruding drug molecules out of the targeted cells, leading to treatment failures in clinical settings. Inhibiting the activity of these efflux pumps has been a well-known strategy of drug design studies in this regard. In this manuscript, our earlier published machine learning models and homology structures of P-gp and NorA were utilized to screen a chemolibrary of 95 in-house chalcone derivatives, identifying two hit compounds, namely, F88 and F90, as potential modulators of both transporters, whose activity on

Background Brainstem encephalitis is a serious complication of hand foot and mouth disease (HFMD) in children. Autonomic nervous system (ANS) dysregulation and hypertension may occur, sometimes progressing to cardiopulmonary failure and death. Vietnamese national guidelines recommend use of milrinone if ANS dysregulation with Stage 2 hypertension develops. We wished to investigate whether magnesium sulfate (MgSO4) improved outcomes in children with HFMD if used earlier in the evolution of the ANS dysregulation (Stage 1 hypertension). Methods During a regional epidemic we conducted a randomized, double-blind, placebo-controlled trial of MgSO4 in children with HFMD, ANS dysregulation and Stage 1 hypertension, at the Hospital for Tropical Diseases in Ho Chi Minh city. Study participants received an infusion of MgSO4 or matched placebo for 72 h. We also reviewed data from non-trial HFMD patients in whom milrinone failed to control hypertension, some of whom received MgSO4 as second line therapy. The primary outcome for both analyses was a composite of disease progression within 72 h - addition of milrinone (trial participants only), need for ventilation, shock, or death. Results Between June 2014 and September 2016, 14 and 12 participants received MgSO4 or placebo respectively, before the trial was stopped due to futility. Among 45 non-trial cases with poorly controlled hypertension despite high-dose milrinone, 33 received MgSO4 while 12 did not. There were no statistically significant differences in the composite outcome between the MgSO4 and the placebo/control groups in either study (adjusted relative risk (95%CI) of [6/14 (43%) vs. 6/12 (50%)], 0.84 (0.37, 1.92), p = 0.682 in the trial and [1/33 (3%) vs. 2/12 (17%)], 0.16 (0.01, 1.79), p = 0.132 in the observational cohort). The incidence of adverse events was similar between the groups. Potentially toxic magnesium levels occurred very rarely with the infusion regime used. Conclusion Although we could not demonstrate efficacy in these studies, there were no safety signals associated with use of 30-50 mg/kg/hr. MgSO4 in severe HFMD. Intermittent outbreaks of HFMD are likely to continue across the region, and an adequately powered trial is still needed to evaluate use of MgSO4 in controlling hypertension in severe HFMD, potentially involving a higher dose regimen. Trial registration ClinicalTrials.gov Identifier: NCT01940250 (Registered 22 AUG 2013). Trial sponsor: University of Oxford Electronic supplementary material The online version of this article (10.1186/s12879-019-4356-x) contains supplementary material, which is available to authorized users.

The humanized monoclonal antibody hR3, both alone and in combination with other chemotherapeutic agents and radiotherapy, can be used to treat head and neck cancers. Substantial progress has been made in the development of targeted radioimmunotherapy using iodine-131 (hR3 was labeled withThe purified radioimmunoconjugates with specific activities of 187-191 MBq/mg had radiochemical purity98% and80% immunoreactivity with HEp-2 cells. Mice with HEp-2 xenografts treated with

Evaluation of liver fibrosis is necessary to make the therapeutic decision and assess the prognosis of CHB patients. The current study aimed to describe the progression and identify some influencing factors in patients with chronic hepatitis B at a General Hospital in Northern Vietnam. The longitudinal study included 55 eligible subjects diagnosed Hepatitis-B-virus. Dependent variable was the aspartate aminotransferase/platelet ratio index and we collected some demographic variables and disease related and behaviour variables. Bayesian Model Averaging was used to select variables into model. Mixed-effect linear models were used to evaluate the change of the aspartate aminotransferase/platelet ratio index over time and identify related factors. the aspartate aminotransferase/platelet ratio index differences between examinations, age of participants, working status were statistically significant. This pattern indicated that the average the aspartate aminotransferase/platelet ratio index of the population decreased by 0.005 (95% CI=-0.009; -0.001) after each patient's visit, and increased by 0.013 if the patient's age increased by 1 year (95% CI=0.005; 0.0219). For non-working patients, the aspartate aminotransferase/platelet ratio index was lower, coefficient was -0.054 (95% CI=-0.108; 0.001). Other variables such as gender, education level, time for disease detection, drinking tea, alcohol consumption, forgetting to take medicine and the aspartate aminotransferase/platelet ratio index were not significantly different. The study showed that the majority of study subjects had average the aspartate aminotransferase/platelet ratio index, and were relatively well controlled and treated during the study. Age and working status are factors that influence the the aspartate aminotransferase/platelet ratio index.

Objective Symptomatic and ruptured abdominal aortic aneurysms (AAAs) are increasingly being managed with endovascular aneurysm repair (EVAR). We aimed to identify the outcomes of symptomatic and ruptured AAAs that had undergone EVAR with a chimney or snorkel technique (ChEVAR). Methods A retrospective cohort study was performed using the Vascular Quality Initiative registry from March 2013 to July 2019. All patients with symptomatic and ruptured AAAs with a proximal aortic zone of disease from 6 to 9 who had undergone ChEVAR were included. The outcomes were analyzed in accordance with the Society for Vascular Surgery reporting standards for EVAR. Results ChEVAR was performed in 77 patients (ruptured, 35 [45.5%]; symptomatic, 42 [54.5%]). The median age was 73.0 years (interquartile range [IQR], 67.0-81.0 years), and 54 patients (70.1%) were men. The median maximum aneurysm diameter was 67.5 mm (IQR, 54.5-83.3 mm). All patients had American Society of Anesthesiologists class ≥III. For the patients with ruptured AAAs, the mean lowest preoperative systolic blood pressure was 95.3 ± 29.3 mm Hg. The fluoroscopy time was 57.4 minutes (IQR, 41.2-79.0 minutes). The proximal aortic zone of disease was zone 6 in 9 (11.7%), zone 7 in 21 (27.3%), zone 8 in 36 (46.8%), and zone 9 in 11 (14.3%) patients. ChEVAR involved more than one vessel in 55 patients (71.4%). No significant difference was found in 30-day mortality between the patients with ruptured vs symptomatic AAAs (11.4% vs 7.1%; P = .695). Reintervention was required for 10 patients (13.0%) at a median of 9 postoperative days, 2 (20.0%) of whom died. Postoperatively, 31 patients (40.3%) had experienced a major complication. A type I endoleak had occurred in nine patients (11.7%), two (22.2%) of whom died. Long-term follow-up data were available for 38 patients (49.4%) at a median of 406.5 days (IQR, 326.8-602.0 days) postoperatively. Of the 18 patients with long-term radiographic data, sac growth was detected in 4 (22.2%). A total of 14 patients had died at a median of 26.5 days (IQR, 3.0-468.5 days). Conclusions ChEVAR for symptomatic and ruptured AAAs can be performed with acceptable rates of morbidity and mortality. Long-term data are needed to determine the durability.

In this study, we employed wearable sensor technology to identify the kinematic features that are associated with the gait abnormalities seen in cerebellar ataxia. Measurements were made at self-selected slow, preferred and fast walking speeds with three sensors attached to the participant’s body. Velocity irregularity and resonant frequency characteristics were identified as key features of interest concerning truncal and lower limb movements. Using the principal component analysis, differentiating features of both trunk and lower limb movements were combined to produce an enhanced distinction between the patients and the normal subjects, in addition to obtaining a better correlation with the expert clinician’s assessments. The different speed of walking contributed to separation and correlation with medical severity rating scales such as SARA to varying degrees The results of truncal movement in the medio-lateral plane (at the slow gait speed) and antero-posterior movement (at all 3 gait speeds) provided the effective metrics in the diagnosis and severity rating of ataxic gait of CA patients. Furthermore, from the selected dominant features of the trunk and lower limb, principal component description suggested that overall clinical assessments are predominantly influenced by the lower body peripheral movements particularly at higher walking speeds.

Medical students' mask-making can provide valuable insights into personal and professional identity formation and wellness. A subset of first- and second-year medical students attending a medical school wellness retreat participated in a mask-making workshop. Faculty-student teams examined student masks and explanatory narratives using visual and textual analysis techniques. A quantitative survey assessed student perceptions of the experience. We identified an overarching theme: "Reconciliation/reclamation of authentic identity." The combination of nonverbal mask-making and narrative offers rich insights into medical students' experience and thinking. This activity promoted reflection and self-care, while providing insight regarding personal and professional development.

ABCG2 is an ABC membrane protein reverse transport pump, which removes toxic substances such as medicines out of cells. As a result, drug bioavailability is an unexpected change and negatively influences the ADMET (absorption, distribution, metabolism, excretion, and toxicity), leading to multi-drug resistance (MDR). Currently, in spite of promising studies, screening for ABCG2 inhibitors showed modest results. The aim of this study was to search for small molecules that could inhibit the ABCG2 pump. We first used the WISS MODEL automatic server to build up ABCG2 homology protein from 655 amino acids. Pharmacophore models, which were con-structed based on strong ABCG2 inhibitors (IC50 &lt, 1 μM), consist of two hydrophobic (Hyd) groups, two hydrogen bonding acceptors (Acc2), and an aromatic or conjugated ring (Aro|PiR). Using molecular docking method, 714 substances from the DrugBank and 837 substances from the TCM with potential to inhibit the ABCG2 were obtained. These chemicals maybe favor synthesized or extracted and bioactivity testing.

// Manh-Cuong Vo 1, * , Thanh-Nhan Nguyen-Pham 1, 2, * , Hyun-Ju Lee 1 , Sung-Hoon Jung 1, 2 , Nu-Ri Choi 1 , My-Dung Hoang 1 , Hyeoung-Joon Kim 2 and Je-Jung Lee 1, 2 1 Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea 2 Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Jeollanamdo, Republic of Korea * These authors have contributed equally to this work Correspondence to: Je-Jung Lee, email: drjejung@chonnam.ac.kr Keywords: chaetocin, dendritic cells, multiple myeloma Received: April 25, 2016 Accepted: March 24, 2017 Published: April 29, 2017 ABSTRACT Dendritic cells (DC)-based vaccines are considered useful in cancer immuno-therapy, and the interactions of DC and dying tumor cells are important and promising for cancer immunotherapy. We investigated whether chaetocin could be used to induce death of myeloma cells, for loading onto DCs can affect DCs function. In this study, we show that the dying myeloma cells treated with chaetocin resulted in the induction of heat shock protein (HSP) 90, which was inhibited by antioxidant N-acetyl cysteine, and showed an increase in the expression of MAGE-A3 and MAGE-C1/CT7. DCs loaded with chaetocin-treated dying myeloma cells produced low levels of IL-10 and enhanced the cross presentation of DCs. Additionally, these DCs most potently inhibited regulatory T cells, induced Th1 polarization and activated myeloma-specific cytotoxic T lymphocytes compared with DCs loaded with UVB-irradiated dying myeloma cells. These results suggest that the pretreatment of myeloma cells with chaetocin can enhance DC function through the up-regulation of HSP90 and cancer testis antigens in dying myeloma cells and can potently induce the Th1 polarization of DCs and myeloma-specific cytotoxic T lymphocytes.

Lenalidomide (LEN) has been used as an immunomodulatory drug with direct and indirect anti-tumor effects. In this study, we evaluated the effect of LEN on the differentiation, maturation, and function of dendritic cells (DCs) in patients with multiple myeloma in vitro. Various doses of LEN were added after the monocytes had differentiated into immature DCs and were activated into mature DCs. LEN (5 μg/mL) was the optimal concentration to promote differentiation and maturation of DCs. Immature DCs treated with LEN exhibited enhanced endocytic capacity. Mature DCs treated with LEN produced higher levels of interleukin-12p70, possessed stronger allogeneic T-cell stimulation capacity, reduced the number of suppressor cells, and generated antigen-specific cytotoxic T lymphocytes more potently compared with control DCs. These results suggest that LEN enhanced the function of DCs generated from patients with multiple myeloma by stimulating the capacity of allogeneic T cells, inhibiting the generation of immunosuppressive cells, inducing naïve T cells toward Th1 polarization, and generating potent myeloma-specific cytotoxic T lymphocytes.

Myocardial fibrosis is a key histopathological component that drives the progression of heart disease leading to heart failure and constitutes a therapeutic target. Recent preclinical and clinical studies have implicated galectin-3 (Gal-3) as a pro-fibrotic molecule and a biomarker of heart disease and fibrosis. However, our knowledge is poor on the mechanism(s) that determine the blood level or regulate cardiac expression of Gal-3. Recent studies have demonstrated that enhanced β-adrenoceptor activity is a determinant of both circulating concentration and cardiac expression of Gal-3. Pharmacological or transgenic activation of β-adrenoceptors leads to increased blood levels of Gal-3 and up-regulated cardiac Gal-3 expression, effect that can be reversed with the use of β-adrenoceptor antagonists. Conversely, Gal-3 gene deletion confers protection against isoprenaline-induced cardiotoxicity and fibrogenesis. At the transcription level, β-adrenoceptor stimulation activates cardiac mammalian sterile-20-like kinase 1, a pivotal kinase of the Hippo signalling pathway, which is associated with Gal-3 up-regulation. Recent studies have suggested a role for the β-adrenoceptor-Hippo signalling pathway in the regulation of cardiac Gal-3 expression thereby contributing to the onset and progression of heart disease. This implies a therapeutic potential of the suppression of Gal-3 expression. In this review, we discuss the effects of β-adrenoceptor activity on Gal-3 as a biomarker and causative mediator in the setting of heart disease and point out pivotal knowledge gaps. LINKED ARTICLES: This article is part of a themed section on Adrenoceptors-New Roles for Old Players. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.14/issuetoc.

(1) Background: Measuring joint range of motion has traditionally occurred with a universal goniometer or expensive laboratory based kinematic analysis systems. Technological advances in wearable inertial measurement units (IMU) enables limb motion to be measured with a small portable electronic device. This paper aims to validate an IMU, the &lsquo, Biokin&rsquo, for measuring shoulder range of motion in healthy adults, (2) Methods: Thirty participants completed four shoulder movements (forward flexion, abduction, and internal and external rotation) on each shoulder. Each movement was assessed with a goniometer and the IMU by two testers independently. The extent of agreement between each tester&rsquo, s goniometer and IMU measurements was assessed with intra-class correlation coefficients (ICC) and Bland-Altman 95% limits of agreement (LOA). Secondary analysis compared agreement between tester&rsquo, s goniometer or IMU measurements (inter-rater reliability) using ICC&rsquo, s and LOA, (3) Results: Goniometer and IMU measurements for all movements showed high levels of agreement when taken by the same tester, ICCs &gt, 0.90 and LOAs &lt, &plusmn, 5 degrees. Inter-rater reliability was lower, ICCs ranged between 0.71 to 0.89 and LOAs were outside a prior defined acceptable LOAs (i.e., &gt, 5 degrees), (4) Conclusions: The current study provides preliminary evidence of the concurrent validity of the Biokin IMU for assessing shoulder movements, but only when a single tester took measurements. Further testing of the Biokin&rsquo, s psychometric properties is required before it can be confidently used in routine clinical practice and research settings.

Introduction: This research aimed to determine the association of the combination of H. pylori infection and TP53 codon 72 polymorphism with non-cardia gastric cancer (GC) in Vietnam. Methodology: A total of 164 patients with non-cardia GC and 164 patients with peptic ulcer disease or functional dyspepsia in controls matched by sex and age were enrolled. H. pylori infection was diagnosed by rapid urease test and polymerase chain reaction (PCR). The cagA gene-positivity and vacA sm subtypes were determined by multiplex PCR. Genotypes of TP53 codon 72 polymorphism were determined by PCR-restriction fragment length polymorphism. Results: The prevalence of H. pylori infection in GC and control group were 61.6% and 55.4%, respectively. The rates of cagA-positive strains in the two H. pylori-positive groups were 80.2% and 71.4%, respectively. There was no statistically significant difference in TP53 codon 72 genotype distribution between GC group (frequencies of Arg/Arg, Arg/Pro and Pro/Pro genotypes were 31.1%, 43.3% and 25.6%, respectively) and controls (29.3%, 52.4% and 18.3%, respectively), p = 0.172. The significant difference in genotype distribution was observed in recessive model (Pro/Pro vs Arg/Arg + Arg/Pro) when stratifying by H. pylori infection (OR = 2.02, 95% CI 1.03–3.96, p = 0.041) and by cagA-positivity (OR = 2.33, 95% CI 1.07–5.07, p = 0.032). Conclusions: This study suggests a synergistic interaction between H. pylori infection, especially cagA-positive H. pylori, and Pro/Pro genotype of TP53 codon 72 polymorphism might play a significant role in the pathogenesis of GC in the Vietnamese population.

Breast-fed infants have Bifidobacterium-rich gut microbiota compared to infants fed formula. Fucosylated oligosaccharides are the major components of human milk oligosaccharide (HMO) which confer various beneficial effects including prebiotic effect and protection from pathogenic infection on the host. A novel prebiotics was developed using bifidobacterial β-galactosidase and fucose and lactose as substrates. Structure analysis revealed it as β-D-galactopyranosyl-(1 → 3)-O-L-fucopyranose named as β-galactosyl fucose (gal-fuc), which is different from common fucosylated HMOs with α1-2, α1-3, and α1-4 linkages. Among the four Lactobacillus strains examined, all but L. delbrueckii subsp. bilgaricus KCTC 3635 grew better on gal-fuc than on β-GOS. Among the 11 bifidobacterial species examined, all except for B. bifium used gal-fuc as much as GOS. Moreover, the gal-fuc was noticeably better used by Bifidobacterium infantis, the major intestinal bacteria of breast fed infant. Among 15 non-probiotic bacteria, only 4 strains used gal-fuc better than β-GOS. In conclusion, a novel gal-fuc is expected to contribute to beneficial changes of gut microbiota. Graphical abstract A novel form of β-galactosyl fucose with an improved prebiotic effect.

Prostate cancer patients with liver metastases have a poor prognosis. To date, no study exists investigating the relationship between liver tumor burden and clinical laboratory markers.Metastatic castrate-resistant prostate cancer (mCRPC) patients with radiographic evidence of liver metastases were selected for this study. Volumetric measurements of liver metastases were ascertained for all available patients. Prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin (ALB), total bilirubin and hemoglobin (HGB) levels were then assessed to coincide with the scan dates. Univariate and multivariate mixed-model regression analysis were performed to evaluate the relationship between laboratory markers and liver lesion volume. Data sets with non-normal distribution were logarithmically transformed. Akaike information criteria (AIC) was used to identify the most reliable multivariate model.In our heavily pretreated liver-metastatic patient population, univariate analysis demonstrated a statistically significant positive correlation between PSA (p = 0.0002), ALP (p = 0.0305), AST (p 0.0001), ALT (p = 0.0049), and LDH (p = 0.0019) and liver lesion volume. Additionally, ALB (p = 0.0006) and HGB (p = 0.0103) had statistically significant negative correlation. Multivariate analysis identified AST and hemoglobin assessments as the best predictors of increasing liver lesion burden. Preliminary data on circulating tumor DNA (ctDNA) mutational and amplification findings are also reported.Analysis identified AST and hemoglobin as optimal predictors of liver lesion volume. These patients have a heavy burden of ctDNA abnormalities. Further studies with a larger patient population are needed to verify these results. Micro Abstract: This study investigates the association between liver lesion burden and clinical laboratory markers in castrate-resistant prostate cancer patients with hepatic metastases. Our univariate analysis identified multiple laboratory markers as significant indicators of worsening hepatic disease. Multivariate analysis demonstrated that AST and hemoglobin were the most effective predictors of change in liver lesion volume.

Background The annual incidence of snakebites in Vietnam is not known and only few publications about snakebite envenoming and medically relevant snakes can be found in English language literature. The present community-based surveys provide data on incidence of snakebites in three different geographic regions of Thua Thien Hue (TT Hue) province, central Vietnam and snake species responsible for bites in this region. Methodology/results The cross-sectional community based surveys were conducted from March to July 2017. Multistage cluster sampling was applied and snakebite incidence was calculated at 58 snakebites per 100,000 person-years for the entire province, and 172, 69 and 10 snakebites per 100,000 person-years in the mountainous, coastal and urban region of TT Hue province, respectively. Thirty-one snakebite victims interviewed during the surveys reported 18 (58%) green pit viper bites (Trimeresurus species), 5 (16%) cobra bites (Naja kaouthia, Naja siamensis), 2 (7%) krait bites (Bungarus candidus, Bungarus fasciatus), 2 (7%) red-necked keelback bites (Rhabdophis subminiatus) and 4 bites from unidentified snakes (13%). The outcome was favourable for 28 snakebite victims (90%), two (6%) had minor sequelae and one (3%) victim died after a Malayan krait bite. Two hundred and twenty-one snakebite patients were treated in 9 district hospitals and one central hospital in TT Hue between 2014 and 2016. Eighty green pit vipers (84%), 12 cobras (13%) and 3 kraits (3%) were responsible for bites in 95 patients where snake identification was documented. Conclusions Incidence of snakebites is surprisingly low in TT Hue province in central Vietnam in comparison to other regions in Asia, particularly to neighbouring Lao PDR. However, snakebites are still a significant health problem in the mountainous region and green pit vipers and cobras cause the vast majority of bites.

In addition to improving insulin sensitivity in type 2 diabetes, the thiazolidinedione family of compounds and the pharmacologic activation of their best-characterized target PPARγ have been proposed as a therapeutic option for cancer treatment. In this study, we reveal a new mode of action for the thiazolidinedione rosiglitazone that can contribute to tumorigenesis. Rosiglitazone activated a tumorigenic paracrine communication program in a subset of human melanoma cells that involves the secretion of cytokines, chemokines, and angiogenic factors. This complex blend of paracrine signals activated nonmalignant fibroblasts, endothelial cells, and macrophages in a tumor-friendly way. In agreement with these data, rosiglitazone promoted human melanoma development in xenografts, and tumors exposed to rosiglitazone exhibited enhanced angiogenesis and inflammation. Together, these findings establish an important tumorigenic action of rosiglitazone in a subset of melanoma cells. Although studies conducted on cohorts of diabetic patients report overall benefits of thiazolidinediones in cancer prevention, our data suggest that exposure of established tumors to rosiglitazone may be deleterious. Significance: These findings uncover a novel mechanism by which the thiazolidinedione compound rosiglitazone contributes to tumorigenesis, thus highlighting a potential risk associated with its use in patients with established tumors. Cancer Res; 78(22); 6447–61. ©2018 AACR.

Cerebellar Ataxia (CA) leads to deficiencies in muscle movement and lack of coordination that is often manifested as gait and balance disabilities. Conventional CA clinical assessments are subjective, cumbersome and provide less insight into the functional capabilities of patients. This cross-sectional study investigates the use of wearable inertial sensors strategically positioned on the front-chest and upper-back locations during the Romberg and Trunk tests for objective assessment of human postural balance due to CA. The primary aim of this paper is to quantify the performance of postural stability of 34 patients diagnosed with CA and 22 healthy subjects as controls. Several forms of entropy descriptions were considered to uncover characteristics of movements intrinsic to CA. Indeed, correlation with clinical observation is vital in ascertaining the validity of the inertial measurements in addition to capturing unique features of movements not typically observed by the practicing clinician. Both of these aspects form an integral part of the underlying objective assessment scheme. Uncertainty in the velocity contained a significant level of information with respect to truncal instability and, based on an extensive clustering and discrimination analysis, fuzzy entropy was identified as an effective measure in characterising the underlying disability. Front-chest measurements demonstrated a strong correlation with clinical assessments while the upper-back measurements performed better in classifying the two cohorts, inferring that the standard clinical assessments are relatively influenced by the frontal observations. The Romberg test was confirmed to be an effective test of neurological diagnosis as well as a potential candidate for objective assessment resulting in a significant correlation with the clinical assessments. In contrast, the Trunk test is observed to be relatively less informative.

Recently, numerous comprehensive studies have been concentrating on the intricate kinematics of the wrist joint functionality captured with dart thrower's movement. It is envisaged that the wrist capability in performing daily activities can be more accurately characterized or encapsulated in the dart thrower's movement. This study examines the characteristic function of wrist movements during dart-throwing motion using only gyroscopic data measured from inertial sensors. A multi-dimensional form of dart throwing trajectory is described using quaternion representation associated with distance metric to quantitatively validate the functional wrist performance between two cohorts; healthy controls and patients. Eight normal subjects and eight patients engaged in a series of clinical trials conducted after undergoing post-surgical reconstructive procedures of the wrist joint. The discriminative results in terms of silhouette clustering evaluation show that the use of distance metric values based quaternion trajectory is well-matched consistently with subjective expert assessments. Our proposed approach captures the relative motions underpinning the wrist joint instead of relying on the traditional measure based on the range of motion measure. Therefore, this paper proposes a reliable approach to dynamically capture the wrist functionality during dart thrower's movement; a movement envisaged to describe the ability to engage in daily life activities. These quantitative outcomes in terms of measurement consistency will provide insightful information in understanding the significant changes in wrist joint signatures associated with various scenarios.

Preclinical studies have demonstrated that anti-galectin-3 (Gal-3) interventions are effective in attenuating cardiac remodeling, fibrosis, and dysfunction. We determined, in a transgenic (TG) mouse model of fibrotic cardiomyopathy, whether Gal-3 expression was elevated and whether Gal-3 played a critical role in disease development. We studied mice with fibrotic cardiomyopathy attributable to cardiac overexpression of human β

During the Vietnam War, the United States military sprayed over 74 million litres of Agent Orange (AO) to destroy forest cover as a counterinsurgency tactic in Vietnam, Laos and Cambodia. The main ingredient was contaminated by 2,3,7,8-tetrachlorodibenzo-paradioxin (TCDD). DNA methylation (DNAm) differences are potential biomarker of environmental toxicants exposure. The aim of this study was to perform a preliminary investigation of the DNAm levels from peripheral blood of the present-day Vietnamese population, including individuals whose parents, according to historical data, were exposed to AO/TCDD during the war. 94 individuals from heavily sprayed areas (cases) and 94 individuals from non-sprayed areas (controls) were studied, and historical data on alleged exposure of parents collected. 94 cases were analysed considering those whose father/parents participated in the war (N = 29) and considering the place of residence of both parents (64 living in sprayed areas versus 30 in non-contaminated areas). DNAm levels in CYP1A1 and IGF2 genes were measured (MALDI-TOF technology). The analyses showed that: 1) one CpG site in the CYP1A1 and one in the IGF2 gene showed significant differences in DNAm levels between cases and controls; 2) the CYP1A1 region resulted to be hypomethylated (in 9 out of 16 sites/units; p-val

Nanoparticles in the field of dendritic cell (DC) research are emerging as a promising method of enhancing the efficacy of cancer immunotherapy. We investigated the effect of branched polyethylenimine-superparamagnetic iron oxide nanoparticles (bPEI-SPIONs) on tumor cells loaded onto DCs. The tumor antigens were prepared as follows: (1) apoptotic U266 cells with ultraviolet B (UVB) irradiation followed by a 2 h incubation in the absence (2 h postirradiated cells) or (2) presence of bPEI-SPIONs (bPEI-SPION 2 h postirradiated cells) and (3) apoptotic U266 cells with UVB irradiation followed by an overnight 16 h incubation (16 h postirradiated cells). bPEI-SPIONs render U266 cells sensitive to UVB irradiation through reactive oxygen species production to accelerate apoptotic death. The 2 h postirradiated cells and bPEI-SPION 2 h postirradiated cells released immunogenic proteins, including Hsp70, Hsp90, and HMGB1. The DCs loaded with bPEI-SPION 2 h postirradiated cells showed the highest IL-12p70 production and Th1 polarization compared with other DCs. These results suggest that bPEI-SPIONs are a promising method of enhancing the immunogenicity of tumor cells and promoting Th1 polarization of DCs loaded with these tumor cells.

A 36-year-old woman presents to the emergency department with a 4-day history of progressive lower abdominal pain accompanied by nausea.

BACKGROUND. Alopecia areata (AA) is a common autoimmune disease with a lifetime risk of 1.7%; there are no FDA-approved treatments for AA. We previously identified a dominant IFN-γ transcriptional signature in cytotoxic T lymphocytes (CTLs) in human and mouse AA skin and showed that treatment with JAK inhibitors induced durable hair regrowth in mice by targeting this pathway. Here, we investigated the use of the oral JAK1/2 inhibitor ruxolitinib in the treatment of patients with moderate-to-severe AA. METHODS. We initiated an open-label clinical trial of 12 patients with moderate-to-severe AA, using oral ruxolitinib, 20 mg twice per day, for 3–6 months of treatment followed by 3 months follow-up off drug. The primary endpoint was the proportion of subjects with 50% or greater hair regrowth from baseline to end of treatment. RESULTS. Nine of twelve patients (75%) demonstrated a remarkable response to treatment, with average hair regrowth of 92% at the end of treatment. Safety parameters remained largely within normal limits, and no serious adverse effects were reported. Gene expression profiling revealed treatment-related downregulation of inflammatory markers, including signatures for CTLs and IFN response genes and upregulation of hair-specific markers. CONCLUSION. In this pilot study, 9 of 12 patients (75%) treated with ruxolitinib showed significant scalp hair regrowth and improvement of AA. Larger randomized controlled trials are needed to further assess the safety and efficacy of ruxolitinib in the treatment of AA. TRIAL REGISTRATION. Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01950780","term_id":"NCT01950780"}}NCT01950780. FUNDING. Locks of Love Foundation, the Alopecia Areata Initiative, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), and the Irving Institute for Clinical and Translational Research/Columbia University Medical Center Clinical and Translational Science Award (CUMC CTSA).

The crystal structure of metagenome-derived LC9-RNase H1 was determined. The structure-based mutational analyses indicated that the active site motif of LC9-RNase H1 is altered from DEDD to DEDN. In this motif, the location of the second glutamate residue is moved from αA-helix to β1-strand immediately next to the first aspartate residue, as in the active site of RNase H2. However, the structure and enzymatic properties of LC9-RNase H1 highly resemble those of RNase H1, instead of RNase H2. We propose that LC9-RNase H1 represents bacterial RNases H1 with an atypical DEDN active site motif, which are evolutionarily distinct from those with a typical DEDD active site motif.

SUV39H1 is a histone 3 lysine 9 (H3K9)-specific methyltransferase that is important for heterochromatin formation and the regulation of gene expression. Chaetocin specifically inhibits SUV39H1, resulted in H3K9 methylation reduction as well as reactivation of silenced genes in cancer cells. Histone deacetylase (HDAC) inhibitors inhibit deacetylases and accumulate high levels of acetylation lead to cell cycle arrest and apoptosis. In this study, we demonstrated that treatment with chaetocin enhanced apoptosis in human leukemia HL60, KG1, Kasumi, K562, and THP1 cells. In addition, chaetocin induced the expression of cyclin-dependent kinase inhibitor 2B (p15), E-cadherin (CDH1) and frizzled family receptor 9 (FZD9) through depletion of SUV39H1 and reduced H3K9 methylation in their promoters. Co-treatment with chaetocin and HDAC inhibitor trichostatin A (TSA) dramatically increased apoptosis and produced greater activation of genes. Furthermore, this combined treatment significantly increased loss of SUV39H1 and reduced histone H3K9 trimethylation responses accompanied by increased acetylation. Importantly, co-treatment with chaetocin and TSA produced potent antileukemic effects in leukemia cells derived from patients. These in vitro findings suggest that combination therapy with SUV39H1 and HDAC inhibitors may be of potential value in the treatment of leukemia.

Sphingosine 1-phosphate receptor 1 (S1P(1)) is a G protein-coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P(1) are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P(1) expressed on lymphocytes and S1P(1) expressed within the central nervous system. Agonists to S1P(1) and deficiency in S1P(1) both cause lymphocyte sequestration in the lymph nodes. In the present study, we show that S1P(1) antagonism induces lymphocyte sequestration in the lymph nodes similar to that observed with S1P(1) agonists while upregulating S1P(1) on lymphocytes and endothelial cells. Additionally, we show that S1P(1) antagonism reverses experimental autoimmune encephalomyelitis in mice without acting on S1P(1) expressed within the central nervous system, demonstrating that lymphocyte sequestration via S1P(1) antagonism is sufficient to alleviate autoimmune pathology.

Tracking soft-tissue targets has recently been cleared as a new application of Calypso, an electromagnetic wireless transponder tracking system, allowing for gated treatment of the liver based on the motion of the target volume itself. The purpose of this study is to describe the details of validating the Calypso system for wireless transponder tracking of the liver and to present the clinical workflow for using it to deliver gated stereotactic ablative radiotherapy (SABR).A commercial 3D diode array motion system was used to evaluate the dynamic tracking accuracy of Calypso when tracking continuous large amplitude motion. It was then used to perform end-to-end tests to evaluate the dosimetric accuracy of gated beam delivery for liver SABR. In addition, gating limits were investigated to determine how large the gating window can be while still maintaining dosimetric accuracy. The gating latency of the Calypso system was also measured using a customized motion phantom.The average absolute difference between the measured and expected positional offset was 0.3 mm. The 2%/2 mm gamma pass rates for the gated treatment delivery were greater than 97%. When increasing the gating limits beyond the known extent of planned motion, the gamma pass rates decreased as expected. The 2%/2 mm gamma pass rate for a 1, 2, and 3 mm increase in gating limits was measured to be 97.8%, 82.9%, and 61.4%, respectively. The average gating latency was measured to be 63.8 ms for beam-hold and 195.8 ms for beam-on. Four liver patients with 17 total fractions have been successfully treated at our institution.Wireless transponder tracking was validated as a dosimetrically accurate way to provide gated SABR of the liver. The dynamic tracking accuracy of the Calypso system met manufacturer's specification, even for continuous large amplitude motion that can be encountered when tracking liver tumors close to the diaphragm. The measured beam-hold gating latency was appropriate for targets that will traverse the gating limit each respiratory cycle causing the beam to be interrupted constantly throughout treatment delivery.

Anterior gradient-2 (AGR2) promotes tumor growth, cell migration and cellular transformation and its enhanced expression is almost completely restricted to malignant tissues, thus making AGR2 an interesting target for the development of immunotherapeutic strategies. We investigated whether the AGR2 molecule comprises human leukocyte antigen (HLA)-A*0201-binding epitopes recognized by human cytotoxic T lymphocytes (CTLs), which could be targeted in dendritic cell (DC)-based cancer immunotherapy against colorectal cancer (CRC). We reviewed the sequence of AGR2 for peptides that could potentially bind to HLA-A*0201 with the aid of a computer-based program. Five candidate peptides with different binding scores were synthesized and tested. These peptides were then assessed for their immunogenicity to elicit specific immune responses mediated by CTLs in vitro by means of enzyme-linked immunospot assays and CTL assays. AGR2 was highly expressed in several CRC cell lines, including DK01, DLD1, KM12C, HCT-8 and HT-29. DCs pulsed with AGR2-P2 (aa 11-19; LLVALSYTL) or AGR2-P4 (aa 127-135; RIMFVDPSL) generated potent CTLs that could lyse T2 cells pulsed with AGR2-P2 or AGR2-P4 and HLA-A0201(+) AGR2-positive CRC cell lines in a strong dose-dependent and HLA-A*0201-restricted manner. In conclusion, these novel epitopes derived from AGR2 protein may be attractive candidates for DC-based immunotherapy for CRC.

Background Hand, foot and mouth disease (HFMD) has become a major public health problem across the Asia-Pacific region, and is commonly caused by enterovirus A71 (EV-A71) and coxsackievirus A6 (CV-A6), CV-A10 and CV-A16. Generating pathogen whole-genome sequences is essential for understanding their evolutionary biology. The frequent replacements among EV serotypes and a limited numbers of available whole-genome sequences hinder the development of overlapping PCRs for whole-genome sequencing. We developed and evaluated a non-ribosomal random PCR (rPCR) and next-generation sequencing based assay for sequence-independent whole-genome amplification and sequencing of HFMD pathogens. A total of 16 EV-A71/CV-A6/CV-A10/CV-A16 PCR positive rectal/throat swabs (Cp values: 20.9–33.3) were used for assay evaluation. Results Our assay evidently outperformed the conventional rPCR in terms of the total number of EV-A71 reads and the percentage of EV-A71 reads: 2.6 % (1275/50,000 reads) vs. 0.1 % (31/50,000) and 6 % (3008/50,000) vs. 0.9 % (433/50,000) for two samples with Cp values of 30 and 26, respectively. Additionally the assay could generate genome sequences with the percentages of coverage of 94–100 % of 4 different enterovirus serotypes in 73 % of the tested samples, representing the first whole-genome sequences of CV-A6/10/16 from Vietnam, and could assign correctly serotyping results in 100 % of 24 tested specimens. In all but three the obtained consensuses of two replicates from the same sample were 100 % identical, suggesting that our assay is highly reproducible. Conclusions In conclusion, we have successfully developed a non-ribosomal rPCR and next-generation sequencing based assay for sensitive detection and direct whole-genome sequencing of HFMD pathogens from clinical samples. Electronic supplementary material The online version of this article (doi:10.1186/s12985-016-0580-9) contains supplementary material, which is available to authorized users.

The interaction between dendritic cells (DCs) and natural killer (NK) cells plays a key role in inducing DC maturation for subsequent T-cell priming. We investigated to generate potent DCs by stimulated with NK cells to induce myeloma-specific cytotoxic T lymphocytes (CTLs). NK cells-stimulated-DCs exhibited high expression of costimulatory molecules and high production of IL-12p70. These DCs induce high potency of Th1 polarization and exhibit a high ability to generate myeloma-specific CTLs responses. These results suggest that functionally potent DCs can be generated by stimulation with NK cells and may provide an effective source of DC-based immunotherapy in multiple myeloma.

For wide application of a dendritic cell (DC) vaccination in myeloma patients, easily available tumor antigens should be developed. We investigated the feasibility of cellular immunotherapy using autologous alpha-type 1-polarized dendritic cells (αDC1s) loaded with apoptotic allogeneic myeloma cells, which could generate myeloma-specific cytotoxic T lymphocytes (CTLs) against autologous myeloma cells in myeloma patients. Monocyte-derived DCs were matured by adding the αDC1-polarizing cocktail (TNFα/IL-1β/IFN-α/IFN-γ/poly-I:C) and loaded with apoptotic allogeneic CD138(+) myeloma cells from other patients with matched monoclonal immunoglobulins as a tumor antigen. There were no differences in the phenotypic expression between αDC1s loaded with apoptotic autologous and allogeneic myeloma cells. Autologous αDC1s effectively took up apoptotic allogeneic myeloma cells from other patients with matched subtype. Myeloma-specific CTLs against autologous target cells were successfully induced by αDC1s loaded with allogeneic tumor antigen. The cross-presentation of apoptotic allogeneic myeloma cells to αDC1s could generate CTL responses between myeloma patients with individual matched monoclonal immunoglobulins. There was no difference in CTL responses between αDC1s loaded with autologous tumor antigen and allogeneic tumor antigen against targeting patient's myeloma cells. Our data indicate that autologous DCs loaded with allogeneic myeloma cells with matched immunoglobulin can generate potent myeloma-specific CTL responses against autologous myeloma cells and can be a highly feasible and effective method for cellular immunotherapy in myeloma patients.

Ursolic acid is triterpene isolated from Uncaria rhynchophylla and is a pharmacologically active substance. The induction of dendritic cell maturation is critical for the induction of Ag-specific T-lymphocyte response and may be essential for the development of human vaccine relying on T cell immunity. In this study, we investigated that the effect of Ursolic acid on the phenotypic and functional maturation of human monocyte-derived dendritic cells in vitro. Dendritic cells harvested on day 8 were examined using functional assay. The expression levels of CD1a, CD80, CD83, CD86, HLA-DR and CCR7 on Ursolic acid-primed dendritic cells was slightly enhanced. Ursolic acid dose-dependently enhanced the T cell stimulatory capacity in an allogeneic mixed lymphocyte reaction, as measured by T cell proliferation. The production of IL-12p70 induced by Ursolic acid-primed dendritic cells was inhibited by the anti-Toll-like receptor-2 (TLR2) mAb and anti-TLR4 mAb. Moreover, Ursolic acid-primed dendritic cells expressed levels of mRNA coding for both TLR2 and TLR4. The majority of cells produced considerable interferon-gamma (IFN-gamma), but also small amounts of interleukin (IL-4)-4. Ursolic acid-primed dendritic cells have an intermediate migratory capacity towards CCL19 and CCL21. These results suggest that Ursolic acid modulates human dendritic cells function in a fashion that favors Th1 polarization via the activation of IL-12p70 dependent on TLR2 and/or TLR4, and may be used on dendritic cells-based vaccines for cancer immunotherapy.

A nonpharmacological method can be an alternative or complement to analgesics.The aim of this study was to evaluate if music medicine influences pain and anxiety in children undergoing lumbar punctures. A randomized clinical trial was used in 40 children (aged 7-12 years) with leukemia, followed by interviews in 20 of these participants. The participants were randomly assigned to a music group (n = 20) or control group (n = 20). The primary outcome was pain scores and the secondary was heart rate, blood pressure, respiratory rate, and oxygen saturation measured before, during, and after the procedure. Anxiety scores were measured before and after the procedure. Interviews with open-ended questions were conducted in conjunction with the completed procedures. The results showed lower pain scores and heart and respiratory rates in the music group during and after the lumbar puncture. The anxiety scores were lower in the music group both before and after the procedure. The findings from the interviews confirmed the quantity results through descriptions of a positive experience by the children, including less pain and fear.

To induce a potent cytotoxic T lymphocyte (CTL) response, various tumor antigens should be loaded onto dendritic cells (DCs). In multiple myeloma (MM), it is difficult to obtain a sufficient number of autologous tumor cells as a source of tumor antigens in the clinical setting. We investigated the feasibility of immunotherapy in patients with MM, using myeloma-specific CTLs generated in vitro by alpha-type 1-polarized DCs (alphaDC1s) loaded with the ultraviolet B-irradiated allogeneic myeloma cell line, ARH77. alphaDC1s significantly increased the expression of several costimulatory molecules without differences in loading with tumor antigens. alphaDC1s showed a high production of interleukin-12 during maturation and after subsequent stimulation with CD40L but were not significantly affected by loading tumor antigens. Myeloma-specific CTLs against autologous myeloma cells from MM patients were induced by alphaDC1s pulsed with apoptotic ARH77 cells. Our data indicate that autologous DCs loaded with an allogeneic myeloma cell line can generate potent myeloma-specific CTL responses against autologous myeloma cells and might provide a practical method for cellular immunotherapy in patients with MM.

The objective of our study was to evaluate the effects of paroxetine on emotional functioning in three arms: double-blind paroxetine (DBPX), single-blind paroxetine (SBPX), and double-blind placebo (DBPO). Healthy psychologists and psychiatrists were elected for their ability to analyze with correct sensibility changes in their emotions. Thirty nonanxious, nondepressed participants working as psychiatrists (N = 18) or psychologists (N = 12) were randomly assigned to receive an ambulatory treatment with paroxetine (DBPX N = 10, SBPX N = 10) or placebo (DBPO N = 10). Paroxetine was administered for 4 weeks at 20 mg/day. Emotional functioning was evaluated with the Emotional State Questionnaire (ESQ), a self-questionnaire designed to assess four emotional dimensions: “recognition,” “expression,” “internal emotional experience,” and “social context.” Changes in emotional measures from baseline to D0, D7, D14, D28, and D42 were compared between treatment groups. Analyses of ESQ showed in DBPX a significant decrease from baseline to D28 in internal emotional experience as compared to SBPX and DBPO groups. A different influence of gender between treatment groups on emotional recognition was observed. This is the first study assessing the impact of a 4-week paroxetine treatment on emotional functioning in healthy psychiatrists and psychologists. The DBPX group was distinguishable from both SBPX and DBPO groups by a decrease in internal emotional experience, suggesting that two factors could be involved in the clinical response to paroxetine: a decrease in emotional feeling and treatment awareness.

Objectives: We conducted a randomized trial to determine the efficacy of two topical hemostasis pads in promoting vascular hemostasis following PCI, and to assess the appropriate level of anticoagulation for sheath removal. Background: Pads coated with procoagulant materials are widely marketed and used to augment vascular hemostasis following PCI, yet clinical effectiveness and safety data are lacking. Methods: 184 patients who underwent PCI using the femoral approach were randomized to one of four methods of sheath removal: (1) at ACT < 250 using the Chito-Seal™ pad; (2) at ACT < 250 using the Clo-Sur PAD™; (3) at ACT < 250 using manual compression alone; (4) at ACT < 170 using manual compression alone. Results: Time to hemostasis was significantly shorter in the hemostasis pad groups compared to the conventional compression groups (16.2 ± 4.9, 16.0 ± 5.3, 19.3 ± 7.8, and 18.3 ± 5.7 min, respectively, P = 0.027), however overall bed rest times following intervention were not reduced by use of either hemostasis pad. The incidence of major or minor bleeding complications did not differ among groups. Irrespective of hemostasis pad use, removal of sheaths at higher ACT levels allowed shorter time to ambulation following PCI without an increase in bleeding events. Conclusions: The hemostasis pads tested shortened time to hemostasis compared to standard manual compression, although the absolute reduction in time to hemostasis was relatively small and did not translate into a reduction in overall bed rest time. Independent of hemostasis pad use, removal of arterial sheaths at higher than conventional activated clotting times was safe and resulted in significant reductions in time to ambulation. © 2006 Wiley-Liss, Inc.

In this Technical Note, we describe an in‐house video goggles feedback system assembled using several commercially available products. This goggle video feedback system is currently being used at University of Louisville and Mayo Clinic for both CT simulation and linac treatment delivery. The setup details, including specific recommendations, are provided, along with an alternative option for using the video goggles system. PACS number: 07.07Hj