Impact of Rescue-Thrombolysis during Cardiopulmonary Resuscitation in Patients with Pulmonary Embolism

Background

Cardiac arrest in patients with pulmonary embolism (PE) is associated with high morbidity and mortality. Thrombolysis is expected to improve the outcome in these patients. However studies evaluating rescue-thrombolysis in patients with PE are missing, mainly due to the difficulties of clinical diagnosis of PE. We aimed to determine the success influencing factors of thrombolysis during resuscitation in patients with PE.

Methodology/Principal Findings

We analyzed retrospectively the outcome of 104 consecutive patients with confirmed (n = 63) or highly suspected (n = 41) PE and monitored cardiac arrest. In all patients rtPA was administrated for thrombolysis during cardiopulmonary resuscitation. In 40 of the 104 patients (38.5%) a return of spontaneous circulation (ROSC) could be achieved successfully. Patients with ROSC received thrombolysis significantly earlier after CPR onset compared to patients without ROSC (13.6±1.2 min versus 24.6±0.8 min; p<0.001). 19 patients (47.5%) out of the 40 patients with initially successful resuscitation survived to hospital discharge. In patients with hospital discharge thrombolysis therapy was begun with a significantly shorter delay after cardiac arrest compared to all other patients (11.0±1.3 vs. 22.5±0.9 min; p<0.001).

Conclusion

Rescue-thrombolysis should be considered and started in patients with PE and cardiac arrest, as soon as possible after cardiac arrest onset.     

Fluctuation of Serum Sodium and Its Impact on Short and Long-Term Mortality following Acute Pulmonary Embolism

Background

Baseline hyponatremia predicts acute mortality following pulmonary embolism (PE). The natural history of serum sodium levels after PE and the relevance to acute and long-term mortality after the PE is unknown.

Methods

Clinical details of all patients (n = 1023) admitted to a tertiary institution from 2000–2007 with acute PE were retrieved retrospectively. Serum sodium results from days 1, 3–4, 5–6, and 7 of admission were pre-specified and recorded. We excluded 250 patients without day-1 sodium or had <1 subsequent sodium assessment, leaving 773 patients as the studied cohort. There were 605 patients with normonatremia (sodium≥135 mmol/L throughout admission), 57 with corrected hyponatremia (day-1 sodium<135 mmol/L, then normalized), 54 with acquired hyponatremia and 57 with persistent hyponatremia. Patients’ outcomes were tracked from a state-wide death registry and analyses performed using multivariate-regression modelling.

Results

Mean (±standard deviation) day-1 sodium was 138.2±4.3 mmol/L. Total mortality (mean follow-up 3.6±2.5 years) was 38.8% (in-hospital mortality 3.2%). There was no survival difference between studied (n = 773) and excluded (n = 250) patients. Day-1 sodium (adjusted hazard ratio [aHR] 0.89, 95% confidence interval [CI] 0.83–0.95, p = 0.001) predicted in-hospital death. Relative to normonatremia, corrected hyponatremia increased the risk of in-hospital death 3.6-fold (95% CI 1.20–10.9, p = 0.02) and persistent hyponatremia increased the risk 5.6-fold (95% CI 2.08–15.0, p = 0.001). Patients with either persisting or acquired hyponatremia had worse long-term survival than those who had corrected hyponatremia or had been normonatremic throughout (aHR 1.47, 95% CI 1.06–2.03, p = 0.02).

Conclusion

Sodium fluctuations after acute PE predict acute and long-term outcome. Factors mediating the correction of hyponatremia following acute PE warrant further investigation.     

Gated F-18 FDG PET for Assessment of Left Ventricular Volumes and Ejection Fraction Using QGS and 4D-MSPECT in Patients with Heart Failure: A Comparison with Cardiac MRI

Purpose

Ventricular function is a powerful predictor of survival in patients with heart failure (HF). However, studies characterizing gated F-18 FDG PET for the assessment of the cardiac function are rare. The aim of this study was to prospectively compare gated F-18 FDG PET and cardiac MRI for the assessment of ventricular volume and ejection fraction (EF) in patients with HF.

Methods

Eighty-nine patients with diagnosed HF who underwent both gated F-18 FDG PET/CT and cardiac MRI within 3 days were included in the analysis. Left ventricular (LV) end-diastolic volume (EDV), end-systolic volume (ESV), and EF were obtained from gated F-18 FDG PET/CT using the Quantitative Gated SPECT (QGS) and 4D-MSPECT software.

Results

LV EDV and LV ESV measured by QGS were significantly lower than those measured by cardiac MRI (both P<0.0001). In contrast, the corresponding values for LV EDV for 4D-MSPECT were comparable, and LV ESV was underestimated with borderline significance compared with cardiac MRI (P = 0.047). LV EF measured by QGS and cardiac MRI showed no significant differences, whereas the corresponding values for 4D-MSPECT were lower than for cardiac MRI (P<0.0001). The correlations of LV EDV, LV ESV, and LV EF between gated F-18 FDG PET/CT and cardiac MRI were excellent for both QGS (r = 0.92, 0.92, and 0.76, respectively) and 4D-MSPECT (r = 0.93, 0.94, and 0.75, respectively). However, Bland-Altman analysis revealed a significant systemic error, where LV EDV (−27.9±37.0 mL) and ESV (−18.6±33.8 mL) were underestimated by QGS.

Conclusion

Despite the observation that gated F-18 FDG PET/CT were well correlated with cardiac MRI for assessing LV function, variation was observed between the two imaging modalities, and so these imaging techniques should not be used interchangeably.     

Determinants of Consistent Condom Use among College Students in China: Application of the Information-Motivation-Behavior Skills (IMB) Model

Background

Due to the increase incidents of premarital sex and the lack of reproductive health services, college students are at high risk of HIV/AIDS infections in China. This study was designed to examine the predictors of consistency of condom use among college students based on the Information-Motivation-Behavioral Skills (IMB) model and to describe the relationships between the model constructs.

Methods

A cross-sectional study was conducted to assess HIV/AIDS related information, motivation, behavioral skills and preventive behavior among college students in five colleges and universities in Nanjing, China. An anonymous questionnaire survey was conducted for data collection, and the structural equation model (SEM) was used to assess the IMB model.

Results

A total of 3183 participants completed this study. The average age was 19.90 years (SD = 1.43, range 16 to 25). 342 (10.7%) participants of them reported having had premarital sex, among whom 30.7% reported having had a consistent condom use, 13.7% with the experience of abortion (including the participants whose sex partner has the same experience), 32.7% of participants had experience of multiple sex partners. The final IMB model provided acceptable fit to the data (CFI = 0.992, RMSEA = 0.028). Preventive behavior was significantly predicted by behavioral skills (β = 0.754, P<0.001). Information (β = 0.138, P<0.001) and motivation (β = 0.363, P<0.001) were indirectly affected preventive behavior, and was mediated through behavioral skills.

Conclusions

The results of the study demonstrate the utility of the IMB model for consistent condom use among college students in China. The main influencing factor of preventive behavior among college students is behavioral skills. Both information and motivation could affect preventive behavior through behavioral skills. Further research could develop preventive interventions based on the IMB model to promote consistent condom use among college students in China.     

Physician Presence in an Ambulance Car Is Associated with Increased Survival in Out-of-Hospital Cardiac Arrest: A Prospective Cohort Analysis

The presence of a physician seems to be beneficial for pre-hospital cardiopulmonary resuscitation (CPR) of patients with out-of-hospital cardiac arrest. However, the effectiveness of a physician''s presence during CPR before hospital arrival has not been established. We conducted a prospective, non-randomized, observational study using national data from out-of-hospital cardiac arrests between 2005 and 2010 in Japan. We performed a propensity analysis and examined the association between a physician''s presence during an ambulance car ride and short- and long-term survival from out-of-hospital cardiac arrest. Specifically, a full non-parsimonious logistic regression model was fitted with the physician presence in the ambulance as the dependent variable; the independent variables included all study variables except for endpoint variables plus dummy variables for the 47 prefectures in Japan (i.e., 46 variables). In total, 619,928 out-of-hospital cardiac arrest cases that met the inclusion criteria were analyzed. Among propensity-matched patients, a positive association was observed between a physician''s presence during an ambulance car ride and return of spontaneous circulation (ROSC) before hospital arrival, 1-month survival, and 1-month survival with minimal neurological or physical impairment (ROSC: OR = 1.84, 95% CI 1.63–2.07, p = 0.00 in adjusted for propensity and all covariates); 1-month survival: OR = 1.29, 95% CI 1.04–1.61, p = 0.02 in adjusted for propensity and all covariates); cerebral performance category (1 or 2): OR = 1.54, 95% CI 1.03–2.29, p = 0.04 in adjusted for propensity and all covariates); and overall performance category (1 or 2): OR = 1.50, 95% CI 1.01–2.24, p = 0.05 in adjusted for propensity and all covariates). A prospective observational study using national data from out-of-hospital cardiac arrests shows that a physician''s presence during an ambulance car ride was independently associated with increased short- and long-term survival.     

Interleukin-1β-31C/T and -511T/C Polymorphisms Were Associated with Preeclampsia in Chinese Han Population

Objective

The purpose of our study is to investigate the relationship between IL-1β -31C/T (rs1143627) and -511T/C (rs16944) polymorphisms and the preeclampsia (PE), and analyze the Linkage disequilibrium (LD) and haplotype frequency of the two polymorphism loci.

Methods

Polymorphisms at -31C/T and -511T/C of IL-1β were genotyped with the method of polymerase chain reaction-restriction fragment length polymorphism (PCR- RFLP) in 232 PE and 447 control subjects. Genotype and allele frequencies between case-control groups were compared by chi-square(X²) tests. Two-point LD and haplotype frequency analyses were done with the software Haploview4.2.

Results

Significant statistical differences were found between PE and control groups regarding genotype and allele frequencies of the two polymorphisms of IL-1β (For IL-1β -31C/T: X² = 11.478, P = 0.003; For IL-1β-511T/C: X² = 9.687, P = 0.008). LD analysis revealed that the IL-1β -31C/T SNP was in high LD with the IL-1β-511C/T SNP(D′ = 0.92, r² = 0.79). Both CT and TC haplotypes showed significant differences between case and control groups. Only the plasma level of Prothrombin Time had a significantly statistical difference among TT, CT and CC groups of the preeclamptic two polymorphisms of IL-1β-31C/T and -511T/C (for IL-1β-31C/T, F = 1.644, P = 0.01; F = 1.587, P = 0.016).

Conclusion

Our results revealed IL-1β was associated with the PE in Chinese Han population. The CT haplotype may increase the risk of PE, while haplotype TC could be considered as a protective haplotype of PE.     

Acute Cardiac Disorder or Pneumonia and Concomitant Presence of Pulmonary Embolism

Purpose

To determine the frequency of apparent acute pulmonary embolism (PE) and of concomitant disease in computed tomography pulmonary angiography (CTPA); to compare the frequency of PE in patients with pneumonia or acute cardiac disorder (acute coronary syndrome, tachyarrhythmia, acute left ventricular heart failure or cardiogenic shock), with the frequency of PE in patients with none of these alternative chest pathologies (comparison group).

Methods

Retrospective analysis of all patients who received a CTPA at the emergency department (ED) within a period of four years and 5 months.

Results

Of 1275 patients with CTPA, 28 (2.2%) had PE and concomitant radiologic evidence of another chest disease; 3 more (0.2%) had PE and an acute cardiac disorder without radiological evidence of heart failure. PE was found in 11 of 113 patients (10%) with pneumonia, in 5 of 154 patients (3.3%) with an acute cardiac disorder and in 186 of 1008 patients (18%) in the comparison group. After adjustment for risk factors for thromboembolism and for other relevant patient’s characteristics, the proportion of CTPAs with evidence of PE in patients with an acute cardiac disorder or pneumonia was significantly lower than in the comparison group (OR 0.13, 95% CI 0.05–0.33, p<0.001 for patients with an acute cardiac disorder, and OR 0.45, 95% CI 0.23–0.89, p = 0.021 for patients with pneumonia).

Conclusion

The frequency of PE and a concomitant disease that can mimic PE was low. The presence of an acute cardiac disorder or pneumonia was associated with decreased odds of PE.     

Association of Early Repolarization Pattern on ECG with Risk of Cardiac and All-Cause Mortality: A Population-Based Prospective Cohort Study (MONICA/KORA)

Background

Early repolarization pattern (ERP) on electrocardiogram was associated with idiopathic ventricular fibrillation and sudden cardiac arrest in a case-control study and with cardiovascular mortality in a Finnish community-based sample. We sought to determine ERP prevalence and its association with cardiac and all-cause mortality in a large, prospective, population-based case-cohort study (Monitoring of Cardiovascular Diseases and Conditions [MONICA]/KORA [Cooperative Health Research in the Region of Augsburg]) comprised of individuals of Central-European descent.

Methods and Findings

Electrocardiograms of 1,945 participants aged 35–74 y, representing a source population of 6,213 individuals, were analyzed applying a case-cohort design. Mean follow-up was 18.9 y. Cause of death was ascertained by the 9th revision of the International Classification of Disease (ICD-9) codes as documented in death certificates. ERP-attributable effects on mortality were determined by a weighted Cox proportional hazard model adjusted for covariables. Prevalence of ERP was 13.1% in our study. ERP was associated with cardiac and all-cause mortality, most pronounced in those of younger age and male sex; a clear ERP-age interaction was detected (p = 0.005). Age-stratified analyses showed hazard ratios (HRs) for cardiac mortality of 1.96 (95% confidence interval [CI] 1.05–3.68, p = 0.035) for both sexes and 2.65 (95% CI 1.21–5.83, p = 0.015) for men between 35–54 y. An inferior localization of ERP further increased ERP-attributable cardiac mortality to HRs of 3.15 (95% CI 1.58–6.28, p = 0.001) for both sexes and to 4.27 (95% CI 1.90–9.61, p<0.001) for men between 35–54 y. HRs for all-cause mortality were weaker but reached significance.

Conclusions

We found a high prevalence of ERP in our population-based cohort of middle-aged individuals. ERP was associated with about a 2- to 4-fold increased risk of cardiac mortality in individuals between 35 and 54 y. An inferior localization of ERP was associated with a particularly increased risk. Please see later in the article for the Editors'' Summary     

The N-Terminal Propeptide of Type III Procollagen in Patients with Acute Coronary Syndrome: A Link between Left Ventricular End-Diastolic Pressure and Cardiovascular Events

Background

Despite the usefulness of N-terminal propeptide of type III procollagen (PIIINP) in detecting enhanced collagen turnover in patients with congestive heart failure, the value added by PIIINP to the use of clinical variables and echocardiography in relation to directly measured left ventricular (LV) end-diastolic pressure (EDP) and the outcome of acute coronary syndrome (ACS) has not been clearly defined.

Methods and Results

This study involved 168 adult patients with ACS, who underwent echocardiography, measurement of serum PIIINP levels, and cardiac catheterization. Pulsed wave tissue Doppler imaging (PWTDI), which revealed mean peak systolic (s′), early (e′), and late diastolic (a′) velocities, was carried out and the eas index of LV function was evaluated: e′/(a′×s′). The patients were divided into three study groups based on the degree of LVEDP – normal (<16 mmHg), intermediate (16–30 mmHg), and high (>30 mmHg) LVEDP. All patients were followed-up to determine cardiac-related death and revascularization. Patients with high LVEDP had significantly more PIIINP than those with intermediate or normal LVEDP (all post hoc p<0.05). The presence of coronary artery disease, the left atrial volume index (LAVI), the ratio of transmitral early and late diastolic flow velocities, a′, and the eas index were significantly correlated with LVEDP. According to multiple stepwise analysis, PIIINP, LAVI and the eas index were the three independent predictors of the level of LVEDP (PIIINP, p <0.001; LAVI, p = 0.007; eas index, p = 0.021). During follow-up (median, 24 months), 32 participants suffered from cardiac events, PIIINP and LAVI were significant predictors of cardiac mortality and hospitalization (PIIINP, hazard ratio (HR) 2.589, p = 0.002; LAVI, HR 1.040, p = 0.027).

Conclusions

PIIINP is a highly effective means to evaluate LVEDP in patients with ACS. The PIIINP is also correlated with cardiac mortality and revascularization, providing an additional means of evaluating and managing patients with ACS.     

A Randomized Pilot Trial of a Moderate Carbohydrate Diet Compared to a Very Low Carbohydrate Diet in Overweight or Obese Individuals with Type 2 Diabetes Mellitus or Prediabetes

We compared the effects of two diets on glycated hemoglobin (HbA1c) and other health-related outcomes in overweight or obese adults with type 2 diabetes or prediabetes (HbA1c>6%). We randomized participants to either a medium carbohydrate, low fat, calorie-restricted, carbohydrate counting diet (MCCR) consistent with guidelines from the American Diabetes Association (n = 18) or a very low carbohydrate, high fat, non calorie-restricted diet whose goal was to induce nutritional ketosis (LCK, n = 16). We excluded participants receiving insulin; 74% were taking oral diabetes medications. Groups met for 13 sessions over 3 months and were taught diet information and psychological skills to promote behavior change and maintenance. At 3 months, mean HbA1c level was unchanged from baseline in the MCCR diet group, while it decreased 0.6% in the LCK group; there was a significant between group difference in HbA1c change favoring the LCK group (−0.6%, 95% CI, −1.1% to −0.03%, p = 0.04). Forty-four percent of the LCK group discontinued one or more diabetes medications, compared to 11% of the MCCR group (p = 0.03); 31% discontinued sulfonylureas in the LCK group, compared to 5% in the MCCR group (p = 0.05). The LCK group lost 5.5 kg vs. 2.6 kg lost in MCCR group (p = 0.09). Our results suggest that a very low carbohydrate diet coupled with skills to promote behavior change may improve glycemic control in type 2 diabetes while allowing decreases in diabetes medications.This clinical trial was registered with ClinicalTrials.gov, number {"type":"clinical-trial","attrs":{"text":"NCT01713764","term_id":"NCT01713764"}}NCT01713764.     

Role of Peptidergic Nerve Terminals in the Skin: Reversal of Thermal Sensation by Calcitonin Gene-Related Peptide in TRPV1-Depleted Neuropathy

To investigate the contribution of peptidergic intraepidermal nerve fibers (IENFs) to nociceptive responses after depletion of the thermal-sensitive receptor, transient receptor potential vanilloid subtype 1 (TRPV1), we took advantage of a resiniferatoxin (RTX)-induced neuropathy which specifically affected small-diameter dorsal root ganglion (DRG) neurons and their corresponding nerve terminals in the skin. Thermal hypoalgesia (p<0.001) developed from RTX-treatment day 7 (RTXd7) and became normalized from RTXd56 to RTXd84. Substance P (SP)(+) and TRPV1(+) neurons were completely depleted (p = 0.0001 and p<0.0001, respectively), but RTX had a relatively minor effect on calcitonin gene-related peptide (CGRP)(+) neurons (p = 0.029). Accordingly, SP(+) (p<0.0001) and TRPV1(+) (p = 0.0008) IENFs were permanently depleted, but CGRP(+) IENFs (p = 0.012) were only transiently reduced and had recovered by RTXd84 (p = 0.83). The different effects of RTX on peptidergic neurons were attributed to the higher co-localization ratio of TRPV1/SP than of TRPV1/CGRP (p = 0.029). Thermal hypoalgesia (p = 0.0018) reappeared with an intraplantar injection of botulinum toxin type A (botox), and the temporal course of withdrawal latencies in the hot-plate test paralleled the innervation of CGRP(+) IENFs (p = 0.0003) and CGRP contents in skin (p = 0.01). In summary, this study demonstrated the preferential effects of RTX on depletion of SP(+) IENFs which caused thermal hypoalgesia. In contrast, the skin was reinnervated by CGRP(+) IENFs, which resulted in a normalization of nociceptive functions.     

Association of Genetic Variants in Wnt Signaling Pathway with Tuberculosis in Chinese Han Population

Compelling studies have implicated that the Wnt signaling pathway plays an important role in the development and progression of tuberculosis, however, there is little literature addressing the role of polymorphisms in Wnt pathway on tuberculosis. We took a pathway based candidate gene approach to investigate the possible correlation between genetic variants in Wnt pathway and tuberculosis. Three single nucleotide polymorphisms (SNPs) in Wnt pathway (rs4135385 in CTNNB1 gene, rs7832767 in SFRP1 gene, and rs11079571 in AXIN2 gene) were genotyped in 422 Chinese Han tuberculosis patients and 402 frequency matched (age, gender, and ethnicity) controls using high-resolution melting analysis. The genotype and allelic frequencies of rs4135385 and rs7832767 were significantly different among patients and controls. The dominant model of rs4135385 was significantly associated with an increased risk of tuberculosis (AG/GG versus AA: OR = 1.49, 95% CI = 1.06–2.09, p = 0.019). The recessive model of rs7832767 posed a significant higher risk for tuberculosis (TT versus TC/CC, OR = 2.70, 95% CI = 1.41–5.18, p = 0.002). These SNPs were further evaluated whether they were correlated with the site of tuberculosis and the level of inflammatory markers. Rs7832767 was significantly associated with the level of CRP (p = 0.014), and the patients carrying T allele might present with elevated CRP values (OR = 1.90, 95% CI = 1.21–2.96, p = 0.005). Our study provided the first evidence that rs4135385 and rs7832767 were associated with tuberculosis risk, and genetic variants in Wnt signaling pathway might participate in genetic susceptibility to tuberculosis in Chinese Han population. Further epidemiological and functional studies in larger populations are warranted to verify our results.     

Elevation of Peripheral BDNF Promoter Methylation Links to the Risk of Alzheimer's Disease

Brain derived neurotrophic factor (BDNF) has been known to play an important role in various mental disorders or diseases such as Alzheimer''s disease (AD). The aim of our study was to assess whether BDNF promoter methylation in peripheral blood was able to predict the risk of AD. A total of 44 AD patients and 62 age- and gender-matched controls were recruited in the current case-control study. Using the bisulphite pyrosequencing technology, we evaluated four CpG sites in the promoter of the BDNF. Our results showed that BDNF methylation was significantly higher in AD cases than in the controls (CpG1: p = 10.021; CpG2: p = 0.002; CpG3: p = 0.007; CpG4: p = 0.005; average methylation: p = 0.004). In addition, BDNF promoter methylation was shown to be significantly correlated with the levels of alkaline phosphatase (ALP), glucose, Lp(a), ApoE and ApoA in males (ALP: r = −0.308, p = 0.042; glucose: r = −0.383, p = 0.010; Lp(a): r = 0.333, p = 0.027; ApoE: r = −0.345, p = 0.032;), ApoA levels in females (r = 0.362, p = 0.033), and C Reactive Protein (CRP) levels in both genders (males: r = −0.373, p = 0.016; females: r = −0.399, p = 0.021). Our work suggested that peripheral BDNF promoter methylation might be a diagnostic marker of AD risk, although its underlying function remains to be elaborated in the future.     

Depression and Health Related Quality of Life in Adolescent Survivors of a Traumatic Brain Injury: A Pilot Study

Traumatic brain injury is (TBI) a leading cause of morbidity and mortality in youth. Adult survivors of a severe pediatric TBI are vulnerable to global impairments, including greater employment difficulties, poor quality of life (HRQoL) and increased risk of mental health problems. When estimating the health related quality of life in adolescents, the presence of anxiety and depression and the quality of social relationships are important considerations, because adolescents are entrenched in social development during this phase of maturation. The influence of anxiety, depression and loneliness on health related quality of life in adolescent survivors of TBI has not been documented. This pilot study aimed to identify and measure the relationship between anxiety, depression and loneliness and perceived health related quality of life in adolescent survivors of a TBI. Method: mixed method/cohort pilot study (11 adolescents, mild to severe TBI; 9 parents), using self-report and proxy-report measures of anxiety, depression, health related quality of life, loneliness and clinical psychiatric interviews (adolescent only). Results: Self-reported depression was significantly correlated with self-reported HRQoL (rs [11] = −0.88, p<0.001). Age at injury was significantly correlated with self-reported HRQoL (rs [11] = −0.68, p = 0.02). Self-reported depression predicted self-reported HRQoL (R² = 0.79, F [1, 10] = 33.48, p<0.001), but age at injury did not (R² = 0.19, F [1, 10] = 2.09, p = 0.18). Conclusions: Our results suggest that depression is a predictor of health related quality of life in youth post-TBI. The possibility of using targeted assessment and therapy for depression post-TBI to improve health related quality of life should be explored.     

Heart Mitochondrial Proteome Study Elucidates Changes in Cardiac Energy Metabolism and Antioxidant PRDX3 in Human Dilated Cardiomyopathy

Background

Dilated cardiomyopathy (DCM) is a public health problem with no available curative treatment, and mitochondrial dysfunction plays a critical role in its development. The present study is the first to analyze the mitochondrial proteome in cardiac tissue of patients with DCM to identify potential molecular targets for its therapeutic intervention.

Methods and Results

16 left ventricular (LV) samples obtained from explanted human hearts with DCM (n = 8) and control donors (n = 8) were extracted to perform a proteomic approach to investigate the variations in mitochondrial protein expression. The proteome of the samples was analyzed by quantitative differential electrophoresis and Mass Spectrometry. These changes were validated by classical techniques and by novel and precise selected reaction monitoring analysis and RNA sequencing approach increasing the total heart samples up to 25. We found significant alterations in energy metabolism, especially in molecules involved in substrate utilization (ODPA, ETFD, DLDH), energy production (ATPA), other metabolic pathways (AL4A1) and protein synthesis (EFTU), obtaining considerable and specific relationships between the alterations detected in these processes. Importantly, we observed that the antioxidant PRDX3 overexpression is associated with impaired ventricular function. PRDX3 is significantly related to LV end systolic and diastolic diameter (r = 0.73, p value<0.01; r = 0.71, p value<0.01), fractional shortening, and ejection fraction (r = −0.61, p value<0.05; and r = −0.62, p value<0.05, respectively).

Conclusion

This work could be a pivotal study to gain more knowledge on the cellular mechanisms related to the pathophysiology of this disease and may lead to the development of etiology-specific heart failure therapies. We suggest new molecular targets for therapeutic interventions, something that up to now has been lacking.     

Intermittent Preventive Treatment for Malaria in Papua New Guinean Infants Exposed to Plasmodium falciparum and P. vivax: A Randomized Controlled Trial

Background

Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv).

Methods and Findings

In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10–43, p≤0.001) in children receiving SP-AQ and 12% (95% CI, −11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9–54, p = 0.012) and Pv incidence was 23% (95% CI, 0–41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4–51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, −24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p>0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%–2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention.

Conclusions

IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00285662","term_id":"NCT00285662"}}NCT00285662 Please see later in the article for the Editors'' Summary     

Obesity Has an Interactive Effect with Genetic Variation in the Activating Transcription Factor 6 Gene on the Risk of Pre-Diabetes in Individuals of Chinese Han Descent

Endoplasmic reticulum (ER) stress is one of the contributing factors to the development of β-cell failure in type 2 diabetes. ER stress response through ATF6 has been shown to play an important role in insulin resistance and pancreatic β-cell function. We investigated whether genetic polymorphisms in ATF6 were associated with the risk of pre-diabetes in a Chinese Han population, and whether they had a synergistic effect with obesity. Our samples included 828 individuals who were diagnosed as pre-diabetic, and 620 controls. The minor allele A at rs2340721 was associated with increased risk for pre-diabetes(p = 0.013), and this association was still significant after adjusting for gender, age, body mass index (BMI), and waist-hip ratio(p′ = 0.011). BMI, treated as a continuous variable, and rs2340721 had an interactive effect on pre-diabetic risk(p for interaction = 0.003, β = 0.106). Carriers of GG at rs7522210 were also at a higher risk compared to non-carriers (OR = 1.390, 95%CI:1.206–1.818, p = 0.013, adjusted OR′ = 1.516, 95%CI:1.101–2.006, p′ = 0.006). GG homozygotes had increased fasting blood glucose (FBG) levels(GG vs CX: 5.6±0.52 vs 5.5±0.57 mmol/L, p = 0.016), lower insulin levels (0,30,120 minutes after glucose load) (p<0.05), and reduced areas under the insulin curve than non-carriers(GG vs CX:67.3(44.2–102.3) vs 73.1(49.4–111.4), p = 0.014). rs10918270 was associated with FBG, and rs4657103 with 2 hour glucose levels after a 75 g glucose load. We also identified a haplotype of TTAG composed of rs4657103, rs2134697, rs2340721, and rs12079579, which was associated with pre-diabetes. The genetic variation in ATF6 is associated with pre-diabetes and has interactive effects with BMI on pre-diabetes in the Chinese Han population.     

Serum YKL-40 Level Is Associated with the Chemotherapy Response and Prognosis of Patients with Small Cell Lung Cancer

This study was to explore the association between the serum YKL-40 level and the clinical characteristics, the response to chemotherapy and prognosis in small cell lung cancer (SCLC). Serum YKL-40 levels were detected and compared in 120 patients with SCLC pre- and post-chemotherapy, and in 40 healthy controls. Receiver operating characteristics (ROC) curves were adopted for diagnosis and calculation of area under ROC curve in SCLC. The Kaplan–Meier method, univariate and multivariate Cox regression analysis were used to analyze the correlation between pre-chemotherapy serum YKL-40 levels and progression-free survival (PFS) and overall survival (OS). The pre-chemotherapy serum YKL-40 levels were significantly higher than those of the controls (p<0.001). The post-chemotherapy serum YKL-40 levels in the SCLC cases were lower than pre-chemotherapy serum YKL-40 levels in these cases (p = 0.026). The patients with high serum YKL-40 showed a poorer response to chemotherapy than those patients with low serumYKL-40 (p = 0.031). Univariate analysis revealed that SCLC patients with high serum YKL-40 had a shorter PFS and OS than those with low serum YKL-40 (HR of 1.74, p = 0.033; HR of 1.33, p = 0.001). Cox multivariate analysis indicated that YKL-40 was an independent prognostic indicator of PFS and OS (HR of 1.12, p = 0.029; HR of 1.84, p = 0.025). Kaplan–Meier survival curves further confirmed that patients with low serum YKL-40 have longer PFS and OS (p = 0.016 and p = 0.041, respectively). These results suggest that YKL-40 is a potential prognostic marker of chemotherapy response in SCLC.     

A Functional Polymorphism in a Serotonin Transporter Gene (5-HTTLPR) Interacts with 9/11 to Predict Gun-Carrying Behavior

On September 11, 2001, one of the deadliest terrorist attacks in US history took place on American soil and people around the world were impacted in myriad ways. Building on prior literature which suggests individuals are more likely to purchase a gun for self-protection if they are fearful of being victimized, the authors hypothesized that the terrorist attacks of 9/11 would lead to an increase in gun carrying among US residents. At the same time, a line of research has shown that a polymorphism in the 5-HTT gene (i.e., 5-HTTLPR) interacts with environmental stressors to predict a range of psychopathologies and behaviors. Thus, it was hypothesized that 9/11 and 5-HTTLPR would interact to predict gun carrying. The results supported both hypotheses by revealing a positive association between 9/11 and gun carrying (b = .426, odds ratio = 1.531, standard error for b = .194, z = 2.196, p = .028) in the full sample of respondents (n = 15,052) and a statistically significant interaction between 9/11 and 5-HTTLPR in the prediction of gun carrying (b = −1.519, odds ratio = .219, standard error for b = .703, z = −2.161, p = .031) in the genetic subsample of respondents (n = 2,350). This is one of the first studies to find an association between 9/11 and gun carrying and, more importantly, is the first study to report a gene-environment interaction (GxE) between a measured gene and a terrorist attack.     

Laparoscopic versus Open Radical Cystectomy in Bladder Cancer: A Systematic Review and Meta-Analysis of Comparative Studies

Background and Objective

More recently laparoscopic radical cystectomy (LRC) has increasingly been an attractive alternative to open radical cystectomy (ORC) and many centers have reported their early experiences in the treatment of bladder cancer. Evaluate the safety and efficacy of LRC compared with ORC in the treatment of bladder cancer.

Methods

A systematic search of Medline, Scopus, and the Cochrane Library was performed up to Mar 1, 2013. Outcomes of interest assessing the two techniques included demographic and clinical baseline characteristics, perioperative, pathologic and oncological variables, and post-op neobladder function and complications.

Results

Sixteen eligible trials evaluating LRC vs ORC were identified including seven prospective and nine retrospective studies. Although LRC was associated with longer operative time (p<0.001), patients might benefit from significantly fewer overall complications (p<0.001), less blood loss (p<0.001), shorter length of hospital stay (p<0.001), less need of blood transfusion (p<0.001), less narcotic analgesic requirement (p<0.001), shorter time to ambulation (p = 0.03), shorter time to regular diet (p<0.001), fewer positive surgical margins (p = 0.006), fewer positive lymph node (p = 0.05), lower distant metastasis rate (p = 0.05) and fewer death (p = 0.004). There was no significant difference in other demographic parameters except for a lower ASA score (p = 0.01) in LRC while post-op neobladder function were similar between the two groups.

Conclusions

Our data suggest that LRC appears to be a safe, feasible and minimally invasive alternative to ORC with reliable perioperative safety, pathologic & oncologic efficacy, comparable post-op neobladder function and fewer complications. Because of the inherent limitations of the included studies, further large sample prospective, multi-centric, long-term follow-up studies and randomized control trials should be undertaken to confirm our findings.