Pesticide risk assessments are usually based on short-term acute toxicity tests, while longer-term population dynamic related traits, critical to the success of biological control and Integrated Pest Management (IPM) programs, are often overlooked. This is increasingly important with respect to new biopesticides that frequently cause no short-term acute effects, but that can induce multiple physiological and behavioral sublethal effects, leading to a decrease in population growth and ecosystem services. In this study we assessed the lethal and sublethal effects of six biopesticides [abamectin, azadirachtin, Bacillus thuringiensis, borax plus citrus oil (Prev-Am®), emamectin benzoate, and spinosad], used in tomato crops to control the invasive pest Tuta absoluta (Lepidoptera: Gelechiidae), on adults and pupae of the parasitoid Bracon nigricans (Hymenoptera: Braconidae). Data on female survival and production of female offspring were used to calculate population growth indexes as a measure of population recovery after pesticide exposure. Spinosad caused 100% and 80% mortality in exposed adults (even 10 d after the treatment) and pupae, respectively. Although most of the biopesticides had low levels of acute toxicity, multiple sublethal effects were observed. The biocontrol activity of both females that survived 1-h and 10-d old residues, and females that emerged from topically treated pupae was significantly affected by the application of the neurotoxic insecticides emamectin benzoate and abamectin. Furthermore, very low B. nigricans demographic growth indices were estimated for these two insecticides, indicating potential local extinction of the wasp populations. Among the tested products, Bt proved to be the safest for B. nigricans adults and pupae. Our findings emphasize that acute toxicity assessment alone cannot fully predict the actual impact of pesticides on non-target parasitoids. Thus, sublethal effects related to the species specific life-history variables must be carefully considered in order to assess pesticide risks and to incorporate new pesticides, including biopesticides, into IPM programmes.
MicroRNAs circulating in the blood, stabilized by complexation with proteins and/or additionally by encapsulation in lipid vesicles, are currently being evaluated as biomarkers. The consequences of their differential association with lipids/vesicles for their stability and use as biomarkers are largely unexplored and are subject of the present study.
The levels of a set of selected microRNAs were determined by quantitative reverse-transcription PCR after extraction from sera or vesicle- and non-vesicle fractions prepared from sera. The stability of these microRNAs after incubation with RNase A or RNase inhibitor, an inhibitor of RNase A family enzymes was studied.
The levels of microRNA-1 and microRNA-122, but not those of microRNA-16, microRNA-21 and microRNA-142-3p, declined significantly during a 5-h incubation of the sera. RNase inhibitor prevented the loss of microRNAs in serum as well as the degradation of microRNA-122, a microRNA not expressed in blood cells, in whole blood. Stabilization of microRNA-122 was also achieved by hemolysis. Prolonged incubation of the sera led to enrichment of vesicle-associated relative to non-vesicle-associated microRNAs. Vesicle-associated microRNAs were more resistant to RNase A treatment than the respective microRNAs not associated with vesicles.
Serum microRNAs showed differential stability upon prolonged incubation. RNase inhibitor might be useful to robustly preserve the pattern of cell-free circulating microRNAs. In the case of microRNAs not expressed in blood cells this can also be achieved by hemolysis. Vesicle-associated microRNAs appeared to be more stable than those not associated with vesicles, which might be useful to disclose additional biomarker properties of miRNAs.
Cardiac pathologies are among the leading causes of mortality and morbidity in industrialized countries, with myocardial infarction (MI) representing one of the major conditions leading to heart failure (HF). Hitherto, the development of consistent, stable, and reproducible models of closed-chest MI in large animals, meeting the clinical realism of a patient with HF subsequent to chronic ischemic necrosis, has not been successful. We hereby report the design and ensuing application of a novel porcine experimental model of closed-chest chronic ischemia suitable for biomedical research, mimicking post-MI HF. We also emphasize the key procedural steps involved in replicating this unprecedented model, from femoral artery and vein catheterization to MI induction by permanent occlusion of the left anterior descending coronary artery through superselective deployment of platinum-nylon coils, as well as endomyocardial biopsy sampling for histologic analysis and cell harvesting. Our model could indeed represent a valuable contribution and tool for translational research, providing precious insights to understand and overcome the many hurdles concerning, and currently quenching, the preclinical steps mandatory for the clinical translation of new cardiovascular technologies for personalized HF treatments.
Because alcohol and drug use disorders (SUDs) can influence quality of care, we compared patients with and without SUDs on frequency of catheterization, revascularization, and in-hospital mortality after acute myocardial infarction (AMI).
This study employed hospital discharge data identifying all adult AMI admissions (ICD-9-CM code 410) between April 1996 and December 2001. Patients were classified as having an SUD if they had alcohol and/or drug (not nicotine) abuse or dependence using a validated ICD-9-CM coding definition. Catheterization and revascularization data were obtained by linkage with a clinically-detailed cardiac registry. Analyses (controlling for comorbidities and disease severity) compared patients with and without SUDs for post-MI catheterization, revascularization, and in-hospital mortality.
Of 7,876 AMI unique patient admissions, 2.6% had an SUD. In adjusted analyses mortality was significantly higher among those with an SUD (odds ratio (OR) 2.02; 95%CI: 1.10–3.69), while there was a trend toward lower catheterization rates among those with an SUD (OR 0.75; 95%CI: 0.55–1.01). Among the subset of AMI admissions who underwent catheterization, the adjusted hazard ratio for one-year revascularization was 0.85 (95%CI: 0.65–1.11) with an SUD compared to without.
Alcohol and drug use disorders are associated with significantly higher in-hospital mortality following AMI in adults of all ages, and may also be associated with decreased access to catheterization and revascularization. This higher mortality in the face of poorer access to procedures suggests that these individuals may be under-treated following AMI. Targeted efforts are required to explore the interplay of patient and provider factors that underlie this finding.
The ICH E7 guideline intends to improve the knowledge about medicines in geriatric patients. As a legislative document, it might not reflect the needs of healthcare professionals. This study investigated what information healthcare professionals, regulatory agencies and pharmaceutical industries consider necessary for rational drug prescribing to older individuals.
Methods and Findings
A 29-item-questionnaire was composed, considering the representation in trials, pharmacokinetics, efficacy, safety, and convenience of use in older individuals, with space for additions. Forty-three European professionals with an interest in medication for older individuals were included. In order to investigate their relevance, five items were included in a second questionnaire, with 11 control items. Median scores, differences between clinical and non-clinical respondents and response consistency were analysed. Consistency was present in 10 control items. Therefore, all items of the first questionnaire and the five additional items were analysed. Thirty-seven (86%) respondents returned the first questionnaire; 31/37 (84%) the second. Information about age-related differences in adverse events, locomotor effects, drug-disease interactions, dosing instructions, and information about the proportion of included 65+ patients was considered necessary by most respondents. Clinicians considered information significantly more important than the non-clinical respondents about the inclusion of 75+, time-until-benefit in older people, anticholinergic effects, drug-disease interactions, and convenience of use. Main study limitations are the focus on information for daily practice, while the ICH E7 guideline is a legislative document focused on market approval of a new medicine. Also, a questionnaire with a Likert scale has its limitations; this was addressed by providing space for comments.
This study reveals that items considered necessary are currently not included in the ICH E7 guideline. Also, clinicians’ and non-clinicians’ opinions differed significantly in 15% of the items. Therefore, all stakeholders should collaborate to improve the availability of information for the rational prescribing to older individuals.
Statistical interactions are a common component of data analysis across a broad range of scientific disciplines. However, the statistical power to detect interactions is often undesirably low. One solution is to elevate the Type 1 error rate so that important interactions are not missed in a low power situation. To date, no study has quantified the effects of this practice on power in a linear regression model.
A Monte Carlo simulation study was performed. A continuous dependent variable was specified, along with three types of interactions: continuous variable by continuous variable; continuous by dichotomous; and dichotomous by dichotomous. For each of the three scenarios, the interaction effect sizes, sample sizes, and Type 1 error rate were varied, resulting in a total of 240 unique simulations.
In general, power to detect the interaction effect was either so low or so high at α = 0.05 that raising the Type 1 error rate only served to increase the probability of including a spurious interaction in the model. A small number of scenarios were identified in which an elevated Type 1 error rate may be justified.
Routinely elevating Type 1 error rate when testing interaction effects is not an advisable practice. Researchers are best served by positing interaction effects a priori and accounting for them when conducting sample size calculations.
To date, insertable cardiac monitors (ICM) have been implanted in the hospital without critical evaluation of other potential settings. Providing alternatives to in-hospital insertion may increase access to ICM, decrease waiting times for patients awaiting diagnosis, and reduce hospital resources.
This was a prospective, non-randomized, clinical trial involving nine clinical sites throughout the United States designed to assess the feasibility of ICM implants in a non-hospital setting. Other than the Reveal® ICM, implant supplies and techniques were left to physician discretion in patients who met indications. Patients were followed up to 90 days post-implant. The primary objective was to characterize the number of procedure-related adverse events that required surgical intervention within 90 days.
Sixty-five patients were implanted at nine out-of-hospital sites. The insertion procedure was well tolerated by all patients. There were no deaths, systemic infections or endocarditis. There were two (3%) procedure-related adverse events requiring device explant and four (6%) adverse events not requiring explant. ICM use led to 16 diagnoses (24.6%) with 9 patients proceeding to alternate cardiac device implants during the course of the 90-day follow up.
Out-of-hospital ICM insertion can be accomplished with comparable procedural safety and represents a reasonable alternative to the in-hospital setting.
Clinicaltrials.gov registration number:
To investigate the extent to which clinicians avoid well-established drug-drug interactions that cause statin-induced myopathy. We hypothesised that clinicians would avoid combining erythromycin or verapamil/diltiazem respectively with atorvastatin or simvastatin. In patients with statin-fibrate combination therapy, we hypothesised that gemfibrozil was avoided to the preference of bezafibrate or fenofibrate. When combined with verapamil/diltiazem or fibrates, we hypothesized that the dispensed doses of atorvastatin/simvastatin would be decreased.
Cross-sectional analysis of nationwide dispensing data. Odds ratios of interacting erythromycin, verapamil/diltiazem versus respective prevalence of comparator drugs doxycycline, amlodipine/felodipine in patients co-dispensed interacting statins simvastatin/atorvastatin versus patients unexposed (pravastatin/fluvastatin/rosuvastatin) was calculated. For fibrates, OR of gemfibrozil versus fenofibrate/bezafibrate in patients co-dispensed any statin was assessed.
OR of interacting erythromycin versus comparator doxycycline did not differ between patients on interacting and comparator statins either in patients dispensed high or low statin doses (adjusted OR 0.87; 95% CI 0.60–1.25 and 0.92; 95% CI 0.69–1.23). Interacting statins were less common among patients dispensed verapamil/diltiazem as compared to patients on amlodipine/felodipine (OR high dose 0.62; CI 0.56–0.68 and low dose 0.63; CI 0.58–0.68). Patients on any statin were to a lesser extent dispensed gemfibrozil compared to patients not dispensed a statin (OR high dose 0.65; CI 0.55–0.76 and low dose 0.70; CI 0.63–0.78). Mean DDD (SD) for any statin was substantially higher in patients co-dispensed gemfibrozil 178 (149) compared to patients on statin monotherapy 127 (93), (p<0.001).
Prescribers may to some extent avoid co-prescription of statins with calcium blockers and fibrates with an increased risk of myopathy. We found no evidence for avoiding co-prescriptions of statins and antibiotics with an increased risk of statin-induced adverse drug reactions. Co-prescription of statins and gemfibrozil is paradoxically associated with a marked increased statin dose, further aggravating the risk for severe myopathy.
The preliminary results of an international collaborative study examining premature menopause in fragile X carriers are presented. A total of 760 women from fragile X families was surveyed about their fragile X carrier status and their menstrual and reproductive histories. Among the subjects, 395 carried a premutation, 128 carried a full mutation, and 237 were noncarriers. Sixty-three (16%) of the premutation carriers had experienced menopause prior to the age of 40 compared with none of the full mutation carriers and one (0.4%) of the controls. Based on these preliminary data, there is a significant association between fragile X premutation carrier status and premature menopause.
fragile X syndrome; premature ovarian failure; premature menopause; fragile X premutation
In fledgling areas of research, evidence supporting causal assumptions is often scarce due to the small number of empirical studies conducted. In many studies it remains unclear what impact explicit and implicit causal assumptions have on the research findings; only the primary assumptions of the researchers are often presented. This is particularly true for research on the effect of faculty’s teaching performance on their role modeling. Therefore, there is a need for robust frameworks and methods for transparent formal presentation of the underlying causal assumptions used in assessing the causal effects of teaching performance on role modeling. This study explores the effects of different (plausible) causal assumptions on research outcomes.
This study revisits a previously published study about the influence of faculty’s teaching performance on their role modeling (as teacher-supervisor, physician and person). We drew eight directed acyclic graphs (DAGs) to visually represent different plausible causal relationships between the variables under study. These DAGs were subsequently translated into corresponding statistical models, and regression analyses were performed to estimate the associations between teaching performance and role modeling.
The different causal models were compatible with major differences in the magnitude of the relationship between faculty’s teaching performance and their role modeling. Odds ratios for the associations between teaching performance and the three role model types ranged from 31.1 to 73.6 for the teacher-supervisor role, from 3.7 to 15.5 for the physician role, and from 2.8 to 13.8 for the person role.
Different sets of assumptions about causal relationships in role modeling research can be visually depicted using DAGs, which are then used to guide both statistical analysis and interpretation of results. Since study conclusions can be sensitive to different causal assumptions, results should be interpreted in the light of causal assumptions made in each study.
Observational studies show moderate alcohol use negatively associated with ischemic heart disease (IHD) and cardiovascular disease (CVD). However, healthier attributes among moderate users compared to never users may confound the apparent association. A potentially less biased way to examine the association is Mendelian randomization, using alcohol metabolizing genes which influence alcohol use.
We used instrumental variable analysis with aldehyde dehydrogenase 2 (ALDH2) genotypes (AA/GA/GG) as instrumental variables for alcohol use to examine the association of alcohol use (10 g ethanol/day) with CVD risk factors (blood pressure, lipids and glucose) and morbidity (self-reported IHD and CVD) among men in the Guangzhou Biobank Cohort Study.
ALDH2 genotypes were a credible instrument for alcohol use (F-statistic 74.6). Alcohol was positively associated with HDL-cholesterol (0.05 mmol/L per alcohol unit, 95% confidence interval (CI) 0.02 to 0.08) and diastolic blood pressure (1.15 mmHg, 95% CI 0.23 to 2.07) but not with systolic blood pressure (1.00 mmHg, 95% CI -0.74 to 2.74), LDL-cholesterol (0.03 mmol/L, 95% CI -0.03 to 0.08), log transformed triglycerides (0.03 mmol/L, 95% CI -0.01 to 0.08) or log transformed fasting glucose (0.01 mmol/L, 95% CI -0.006 to 0.03), self-reported CVD (odds ratio (OR) 0.98, 95% CI 0.76 to 1.27) or self-reported IHD (OR 1.10, 95% CI 0.83 to 1.45).
Low to moderate alcohol use among men had the expected effects on most CVD risk factors but not fasting glucose. Larger studies are needed to confirm the null associations with IHD, CVD and fasting glucose.
The single-row and double-row fixation techniques have been widely used for rotator cuff tears. However, whether the double-row technique produces superior clinical or anatomic outcomes is still considered controversial. This study aims to use meta-analysis to compare the clinical and anatomical outcomes between the two techniques.
The Pubmed, Embase, and Cochrane library databases were searched for relevant studies published before November 1, 2012. Studies clearly reporting a comparison of the single-row and double-row techniques were selected. The Constant, ASES, and UCLA scale systems and the rotator cuff integrity rate were evaluated. The weighted mean differences and relative risks were calculated using a fixed-effects or random-effects model.
Eight studies were included in this meta-analysis. The weighted mean differences of the ASES (−0.84; P = 0.04; I2 = 0%) and UCLA (−0.75; P = 0.007; I2 = 0%) scales were significantly low in the single-row group for full-thickness rotator cuff tears. For tear sizes smaller than 3 cm, no significant difference was found between the groups no matter in Constant (P = 0.95; I2 = 0%), ASES (P = 0.77; I2 = 0%), or UCLA (P = 0.24; I2 = 13%) scales. For tear sizes larger than 3 cm, the ASES (−1.95; P = 0.001; I2 = 49%) and UCLA (−1.17; P = 0.006; I2 = 0%) scales were markedly lower in the single-row group. The integrity of the rotator cuff (0.81; P = 0.0004; I2 = 10%) was greater and the partial thickness retear rate (1.93; P = 0.007; I2 = 10%) was less in the double-row group. Full-thickness retears showed no difference between the groups (P = 0.15; I2 = 0%).
The meta-analysis suggests that the double-row fixation technique increases post-operative rotator cuff integrity and improves the clinical outcomes, especially for full-thickness rotator cuff tears larger than 3 cm. For tear sizes smaller than 3 cm, there was no difference in the clinical outcomes between the two techniques.
Level of Evidence
To evaluate whether external suction is more advantageous than water seal in patients undergoing selective pulmonary resection (SPR) for lung neoplasm.
Summary of Background Data
Whether external suction should be routinely applied in postoperative chest drainage is still unclear, particularly for lung neoplasm patients. To most surgeons, the decision is based on their clinical experience.
Randomized control trials were selected. The participants were patients undergoing SPR with lung neoplasm. Lung volume reduction surgery and pneumothorax were excluded. Suction versus non-suction for the intervention. The primary outcome was the incidence of persistent air leak (PAL). The definition of PAL was air leak for more than 3–7 days. The secondary outcomes included air leak duration, time of drainage, postoperative hospital stay and the incidence of postoperative pneumothorax. Studies were identified from literature collections through screening. Bias was analyzed and meta-analysis was used.
From the 1824 potentially relevant trials, 6 randomized control trials involving 676 patients were included. There was no difference between external suction and water seal in decreasing the incidence of PAL [95% confidence interval (CI) 0.81−2.16; z = 1.10; P = 0.27]. Regarding secondary outcomes, there were no differences in time of drainage (95% CI−0.36−1.56, P = 0.22), postoperative hospital stay (95% CI -.31−.54, P = 0.87) or incidence of postoperative pneumothorax (95% CI 0.18−.02, P = 0.05) between external suction and water seal.
For participants, no differences are identified in terms of PAL incidence, drainage time, length of postoperative hospital stay or incidence of postoperative pneumothorax between external suction and water seal. The bias analysis should be emphasized. To the limitations of the bias and methodological differences among the included studies, we have no recommendation on whether external suction should be routinely applied after lung neoplasm SPR. More high-quality randomized controlled trials are needed.
Systematic Review Registration
We report on a case of delayed hemolytic transfusion reaction (DHTR) occurred 7 days after an erythrocytapheresis or eritroexchange procedure (EEX) treated with rituximab and glucocorticoids in a 15-years old patient with sickle cell disease. EEX was performed despite a previous diagnosis of alloimmunization, in order to reduce hemoglobin S rate before a major surgery for avascular necrosis of the femoral head. A first dose of rituximab was administered before EEX. However, rituximab couldn’t prevent DHTR that occurred with acute hemolysis, hemoglobinuria and hyperbilirubinemia. A further dose of rituximab and three boli of methylprednisolone were given after the onset of the reaction. It is likely that the combined use of rituximab and steroids managed to gradually improve both patient’s general conditions and hemoglobin levels. Nor early or late side effects were registered in a 33-months follow-up period. This report suggests the potential effectiveness and safety of rituximab in combination with steroids in managing and mitigating the symptoms of delayed post-transfusional hemolytic reactions in alloimmunized patients affected by sickle cell disease with absolute need for erythrocytapheresis.
erythrocytapheresis; rituximab; alloimunization; avascular necrosis of femoral head; sickle cell disesase
Countless studies have demonstrated that many emergency-room visits and hospital admissions are drug-related and that a significant proportion of these drug-related visits (DRVs) are preventable. It has not been previously studied which DRVs could be prevented through enhanced monitoring of therapy. The objective of the study was to determine the incidence of DRVs attributed to laboratory or physiologic abnormalities. Three authors independently performed comprehensive searches in relevant health care databases using pre-determined search terms. Articles discussing DRV associated with poisoning, substance abuse, or studied among existing in-patient populations were excluded. Study country, year, sample, design, duration, DRV identification method, proportion of DRVs associated with laboratory or physiologic abnormalities and associated medications were extracted. The three authors independently assessed selected relevant articles according to the Strengthening the reporting of observational studies in epidemiology (STROBE) as applicable according to the studies' methodology. The initial literature search yielded a total of 1,524 articles of which 30 articles meeting inclusion criteria and reporting sufficient laboratory or physiologic data were included in the overall analysis. Half employed prospective methodologies, which included both chart review and patient interview; however, the overwhelming majority of identified studies assessed only adverse drug reactions (ADRs) as a drug-related cause for DRV. The mean (range) prevalence of DRVs found in all studies was 15.4% (0.44%–66.7%) of which an association with laboratory or physiologic abnormalities could be attributed to a mean (range) of 29.4% (4.3%–78.1%) of cases. Most laboratory-associated DRVs could be linked to immunosuppressant, antineoplastic, anticoagulant and diabetes therapy, while physiologic-associated DRVs were attributed to cardiovascular therapies and NSAIDs. Significant proportions of laboratory and physiologic abnormalities contribute to DRVs and are consistently linked to specific drugs. These therapies are potential targets for enhanced medication monitoring initiatives to proactively avert potential DRVs.
Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects.
We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group.
Circulating MMP-9 and WBC count are significantly correlated in men (R2 = 0.13, p<0.001) and women (R2 = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R2 = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R2 = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers.
WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans.
It is unknown whether the observed increase in computed tomography pulmonary angiography (CTPA) utilization has resulted in increased detection of pulmonary emboli (PEs) with a less severe disease spectrum.
Trends in utilization, diagnostic yield, and disease severity were evaluated for 4,048 consecutive initial CTPAs performed in adult patients in the emergency department of a large urban academic medical center between 1/1/2004 and 10/31/2009. Transthoracic echocardiography (TTE) findings and peak serum troponin levels were evaluated to assess for the presence of PE-associated right ventricular (RV) abnormalities (dysfunction or dilatation) and myocardial injury, respectively. Statistical analyses were performed using multivariate logistic regression.
268 CTPAs (6.6%) were positive for acute PE, and 3,780 (93.4%) demonstrated either no PE or chronic PE. There was a significant increase in the likelihood of undergoing CTPA per year during the study period (odds ratio [OR] 1.05, 95% confidence interval [CI] 1.04–1.07, P<0.01). There was no significant change in the likelihood of having a CTPA diagnostic of an acute PE per year (OR 1.03, 95% CI 0.95–1.11, P = 0.49). The likelihood of diagnosing a less severe PE on CTPA with no associated RV abnormalities or myocardial injury increased per year during the study period (OR 1.39, 95% CI 1.10–1.75, P = 0.01).
CTPA utilization has risen with no corresponding change in diagnostic yield, resulting in an increase in PE detection. There is a concurrent rise in the likelihood of diagnosing a less clinically severe spectrum of PEs.
Better understanding of acute stress responses is important for revision of DSM-5. However, the latent structure and relationship between different aspects of acute stress responses haven’t been clarified comprehensively. Bifactor item response model may help resolve this problem.
The purpose of this study is to develop a statistical model of acute stress responses, based on data from earthquake rescuers using Acute Stress Response Scale (ASRS). Through this model, we could better understand acute stress responses comprehensively, and provide preliminary information for computerized adaptive testing of stress responses.
Acute stress responses of earthquake rescuers were evaluated using ASRS, and state/trait anxiety were assessed using State-trait Anxiety Inventory (STAI). A hierarchical item response model (bifactor model) was used to analyze the data. Additionally, we tested this hierarchical model with model fit comparisons with one-dimensional and five-dimensional models. The correlations among acute stress responses and state/trait anxiety were compared, based on both the five-dimensional and bifactor models.
Model fit comparisons showed bifactor model fit the data best. Item loadings on general and specific factors varied greatly between different aspects of stress responses. Many symptoms (40%) of physiological responses had positive loadings on general factor, and negative loadings on specific factor of physiological responses, while other stress responses had positive loadings on both general and specific factors. After extracting general factor of stress responses using bifactor analysis, significant positive correlations between physiological responses and state/trait anxiety (r = 0.185/0.112, p<0.01) changed into negative ones (r = −0.177/−0.38, p<0.01).
Our results demonstrated bifactor structure of acute stress responses, and positive and negative correlations between physiological responses and stress responses suggested physiological responses could have negative feedback on severity of stress responses. This finding has not been convincingly demonstrated in previous research.
Second generation drug-eluting stents were developed to improve the safety and efficacy of first generation stents. So far, limited long term randomized data exist comparing the second generation everolimus-eluting stents (EES) with first generation sirolimus-eluting stents (SES).
A prospective, open-label, randomized, single center trial comparing EES and SES in all-comer patients. The primary endpoint was a composite of cardiac mortality, myocardial infarction and target vessel revascularization. Secondary endpoints included individual components of the composite, along with target lesion revascularization and stent thrombosis.
In total, 977 patients were randomized, of which 498 patients to EES and 479 to SES. Average age was 65.2±11.2 years and 71.6% of the population was male. Fifty percent of patients were treated for acute coronary syndrome, more often for ST-elevation myocardial infarctions in EES patients (13.7% vs. 9.2% in SES). In contrast, SES patients more often had prior interventions and showed more calcified lesions. Two-year follow-up was available in 98% of patients. The primary endpoint occurred in 10.7% of EES patients compared to 10.6% of SES patients (HR 1.00, 95% CI 0.68–1.48). Additionally, secondary endpoints were similar between groups. The rate of stent thrombosis was low for both stent types.
In this all-comer population, there were no differences in endpoints between EES and SES during two-year follow-up. Stent thrombosis rates were low, supporting the safety of drug-eluting stent appliance in clinical practice.
Remote ischemic preconditioning (RIPC) has been shown to enhance the tolerance of remote organs to cope with a subsequent ischemic event. We hypothesized that RIPC reduces postoperative neurocognitive dysfunction (POCD) in patients undergoing complex cardiac surgery.
We conducted a prospective, randomized, double-blind, controlled trial including 180 adult patients undergoing elective cardiac surgery with cardiopulmonary bypass. Patients were randomized either to RIPC or to control group. Primary endpoint was postoperative neurocognitive dysfunction 5–7 days after surgery assessed by a comprehensive test battery. Cognitive change was assumed if the preoperative to postoperative difference in 2 or more tasks assessing different cognitive domains exceeded more than one SD (1 SD criterion) or if the combined Z score was 1.96 or greater (Z score criterion).
According to 1 SD criterion, 52% of control and 46% of RIPC patients had cognitive deterioration 5–7 days after surgery (p = 0.753). The summarized Z score showed a trend to more cognitive decline in the control group (2.16±5.30) compared to the RIPC group (1.14±4.02; p = 0.228). Three months after surgery, incidence and severity of neurocognitive dysfunction did not differ between control and RIPC. RIPC tended to decrease postoperative troponin T release at both 12 hours [0.60 (0.19–1.94) µg/L vs. 0.48 (0.07–1.84) µg/L] and 24 hours after surgery [0.36 (0.14–1.89) µg/L vs. 0.26 (0.07–0.90) µg/L].
We failed to demonstrate efficacy of a RIPC protocol with respect to incidence and severity of POCD and secondary outcome variables in patients undergoing a wide range of cardiac surgery. Therefore, definitive large-scale multicenter trials are needed.
Several regulators are involved in the control of cell cycle progression in the bacterial model system Caulobacter crescentus, which divides asymmetrically into a vegetative G1-phase (swarmer) cell and a replicative S-phase (stalked) cell. Here we report a novel functional interaction between the enigmatic cell cycle regulator GcrA and the N6-adenosine methyltransferase CcrM, both highly conserved proteins among Alphaproteobacteria, that are activated early and at the end of S-phase, respectively. As no direct biochemical and regulatory relationship between GcrA and CcrM were known, we used a combination of ChIP (chromatin-immunoprecipitation), biochemical and biophysical experimentation, and genetics to show that GcrA is a dimeric DNA–binding protein that preferentially targets promoters harbouring CcrM methylation sites. After tracing CcrM-dependent N6-methyl-adenosine promoter marks at a genome-wide scale, we show that these marks recruit GcrA in vitro and in vivo. Moreover, we found that, in the presence of a methylated target, GcrA recruits the RNA polymerase to the promoter, consistent with its role in transcriptional activation. Since methylation-dependent DNA binding is also observed with GcrA orthologs from other Alphaproteobacteria, we conclude that GcrA is the founding member of a new and conserved class of transcriptional regulators that function as molecular effectors of a methylation-dependent (non-heritable) epigenetic switch that regulates gene expression during the cell cycle.
Methylation of genomic DNA at a specific regulatory site can impact a myriad of processes in eukaryotic cells. In bacteria, methylation at the N6 position of adenosine (m6A) is known to mediate a non-adaptive immunity response to protect cells from foreign DNA. While m6A marks are not known to govern expression of cell cycle genes in Gammaproteobacteria, cell cycle transcription in the model alphaproteobacterium Caulobacter crescentus requires the m6A methyltransferase CcrM that introduces m6A marks at GAnTC sequences and the enigmatic factor GcrA. Investigating if a functional and biochemical relationship exists between CcrM and GcrA, we found that CcrM-dependent m6A marks recruit GcrA to the promoters of cell cycle genes in vitro and in vivo and is required for efficient transcription. GcrA interacts with RNA polymerase, explaining how cell cycle transcription is affected. Importantly, m6A-dependent binding is also seen in GcrA orthologs, indicating that this transcriptional regulatory mechanism by CcrM and GcrA is conserved in Alphaproteobacteria.
We investigated the effect of high-frequency electromagnetic fields (HF-EMFs) and 17-β-estradiol on connexins (Cxs), integrins (Ints), and estrogen receptor (ER) expression, as well as on ultrastructure of trophoblast-derived HTR-8/SVneo cells. HF-EMF, 17-β-estradiol, and their combination induced an increase of Cx40 and Cx43 mRNA expression. HF-EMF decreased Int alpha1 and β1 mRNA levels but enhanced Int alpha5 mRNA expression. All the Ints mRNA expressions were increased by 17-β-estradiol and exposure to both stimuli. ER-β mRNA was reduced by HF-EMF but augmented by 17-β-estradiol alone or with HF-EMF. ER-β immunofluorescence showed a cytoplasmic localization in sham and HF-EMF exposed cells which became nuclear after treatment with hormone or both stimuli. Electron microscopy evidenced a loss of cellular contact in exposed cells which appeared counteracted by 17-β-estradiol. We demonstrate that 17-β-estradiol modulates Cxs and Ints as well as ER-β expression induced by HF-EMF, suggesting an influence of both stimuli on trophoblast differentiation and migration.
Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m2 median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a –3.2 ml/m2 median decrease (interquartile range –4.5, –1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m2. On echocardiography, the median difference in the LVESVi change was 13.4 ml/m2 (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m2, p = 0.033) and echocardiography (9.4 ml/m2, p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R =+0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.