Prevalence of PTSD and Depression among Junior Middle School Students in a Rural Town Far from the Epicenter of the Wenchuan Earthquake in China

Context

On May12^th 2008, a devastating earthquake measuring 8.0 on the Richter scale, struck Wenchuan county and surrounding areas in China. The prevalence of mental illness among children and adolescents in a rural town far from the earthquake epicenter is unknown.

Objective

To assess the prevalence of posttraumatic stress disorder (PTSD) and depression among junior middle school students in a rural town Ningqiang county, 327 km from the earthquake epicenter.

Design, Setting, and Participants

A population-based mental health survey was conducted in March, 2009.

Main Outcome Measure

Survey Self-designed General Condition Survey Scale, Children''s Revised Impact of Event Scale (CRIES-13), and the Depression Self-rating Scale for Children (DSRSC) were used to sample 1,841 junior middle school students in Ningqiang county, ten months after the Wenchuan earthquake.

Results

The prevalence rate of a high-risk for PTSD was 28.4%, with 32.7% among females, 23.8% among males (female vs. male, p<0.001), 38.6% in the severe exposure group and 24.3% in the mild exposure group (severe vs. mild exposure, p<0.001). For depressive symptoms, the overall prevalence was 19.5%, with 24.0% among females, 14.7% among males, 24.5% in the severe exposure group and 17.5% in the mild exposure group (female vs. male, p<0.001; severe vs. mild exposure, p<0.001, respectively). In multivariate analysis, factors such as “having felt despair”, or “danger” and “having own house destroyed or damaged” were significantly associated with PTSD symptoms. Female gender and delayed evacuation in females, and earthquake related experiences in males were significantly associated with depression.

Conclusion

Traumatic events experienced during the earthquake were significantly associated with symptoms of PTSD and depression in children and adolescents, ten months after the Wenchuan earthquake. These data highlight a need for mental health services for children and adolescents in rural areas, far from earthquake epicenters.     

Short fetal leukocyte telomere length and preterm prelabor rupture of the membranes

Background

Rupture of the fetal membranes is a common harbinger of imminent labor and delivery. Telomere shortening is a surrogate for oxidative stress (OS) and senescence. Fetal leukocyte and placental membrane DNA telomere lengths were evaluated to determine their association with preterm prelabor rupture of the membranes (pPROM) or spontaneous preterm births with intact membranes (PTB), compared to term birth.

Methods

Telomere lengths were quantified in cord blood leukocytes (n = 133) from three major groups: 1) pPROM (n = 28), 2) PTB (n = 69) and 3) uncomplicated full term births (controls, n = 35), using real-time quantitative PCR. Placental membrane specimens (n = 18) were used to correlate fetal leukocyte and placental telomere lengths. Telomere length differences among the groups were analyzed by ANOVA. Pearson correlation coefficients determined relationships between leukocyte and placental membrane telomere lengths.

Results

In pregnancies with intact membranes, fetal leukocyte telomere length was inversely proportional to gestational age. The mean telomere length decreased as gestation progressed, with the shortest at term. pPROM had telomere lengths (9962±3124 bp) that were significantly shorter than gestational age-matched PTB (11546±4348 bp, p = 0.04), but comparable to term births (9011±2497 bp, p = 0.31). Secondary analyses revealed no effects of race (African American vs. Caucasian) or intraamniotic infection on telomere length. A strong Pearson''s correlation was noted between fetal leukocyte and placental membrane telomere lengths (ρ = 0.77; p<0.01).

Conclusions

Fetal leukocyte telomere length is reduced in pPROM compared to PTB but is similar to term births. pPROM represents a placental membrane disease likely mediated by OS-induced senescence.     

Physical fitness and telomere length in patients with coronary heart disease: findings from the Heart and Soul Study

Background

Short telomere length (TL) is an independent predictor of mortality in patients with coronary heart disease (CHD). However, the relationship between physical fitness and TL has not been explored in these patients.

Methods

In a cross sectional study of 944 outpatients with stable CHD, we performed exercise treadmill testing, assessed self-reported physical activity, and measured leukocyte TL using a quantitative PCR assay. We used generalized linear models to calculate mean TL (T/S ratio), and logistic regression models to compare the proportion of patients with short TL (defined as the lowest quartile), among participants with low, medium and high physical fitness, based on metabolic equivalent tasks achieved (METs).

Results

229 participants had low physical fitness (<5 METS), 334 had moderate physical fitness (5–7 METS), and 381 had high physical fitness (>7 METS). Mean ± T/S ratio ranged from 0.86±0.21 (5349±3781 base pairs) in those with low physical fitness to 0.95±0.23 (5566±3829 base pairs) in those with high physical fitness (p<.001). This association remained strong after adjustment for numerous patient characteristics, including measures of cardiac disease severity and physical inactivity (p = 0.005). Compared with participants with high physical fitness, those with low physical fitness had 2-fold greater odds of having TL in the lowest quartile (OR 2.39, 95% CI 1.60–3.55; p<.001). This association was similar after multivariable adjustment (OR 1.94, 95%CI, 1.18–3.20; p = 0.009). Self-reported physical inactivity was associated with shorter TL in unadjusted analyses, but not after multivariable adjustment.

Conclusions

We found that worse objectively-assessed physical fitness is associated with shorter leukocyte telomere length in patients with CHD. The clinical implications of this association deserve further study.     

The relationship between telomere length and mortality in chronic obstructive pulmonary disease (COPD)

Some have suggested that chronic obstructive pulmonary disease (COPD) is a disease of accelerated aging. Aging is characterized by shortening of telomeres. The relationship of telomere length to important clinical outcomes such as mortality, disease progression and cancer in COPD is unknown. Using quantitative polymerase chain reaction (qPCR), we measured telomere length of peripheral leukocytes in 4,271 subjects with mild to moderate COPD who participated in the Lung Health Study (LHS). The subjects were followed for approximately 7.5 years during which time their vital status, FEV₁ and smoking status were ascertained. Using multiple regression methods, we determined the relationship of telomere length to cancer and total mortality in these subjects. We also measured telomere length in healthy “mid-life” volunteers and patients with more severe COPD. The LHS subjects had significantly shorter telomeres than those of healthy “mid-life” volunteers (p<.001). Compared to individuals in the 4^th quartile of relative telomere length (i.e. longest telomere group), the remaining participants had significantly higher risk of cancer mortality (Hazard ratio, HR, 1.48; p = 0.0324) and total mortality (HR, 1.29; p = 0.0425). Smoking status did not make a significant difference in peripheral blood cells telomere length. In conclusion, COPD patients have short leukocyte telomeres, which are in turn associated increased risk of total and cancer mortality. Accelerated aging is of particular relevance to cancer mortality in COPD.     

Work-related exhaustion and telomere length: a population-based study

Background

Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.

Methods

We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30–64. Work-related exhaustion was assessed using the Maslach Burnout Inventory - General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method.

Results

After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008).

Conclusions

These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.     

Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study

Background

Dementia takes decades to develop, and effective prevention will likely require early intervention. Thus, it is critical to identify biomarkers of preclinical disease, allowing targeting of high-risk subjects for preventive efforts. Since telomeres shorten with age and oxidative stress, both of which are important contributors to the onset of dementia, telomere length might be a valuable biomarker.

Methodology/Principal Findings

Among 62 participants of the Nurses'' Health Study, we conducted neurologic evaluations, including patient and caregiver interviews, physical exam, neurologic exam, and neuropsychologic testing. We also conducted magnetic resonance imaging (MRI) in a sample of 29 of these women. In these preliminary data, after adjustment for numerous health and lifestyle factors, we found that truncated telomeres in peripheral blood leukocytes segregate with preclinical dementia states, including mild cognitive impairment (MCI); the odds of MCI were 12-fold higher (odds ratio = 12.00, 95% confidence interval 1.24–116.5) for those with shorter telomere length compared to longer telomere length. In addition, decreasing telomere length was strongly related to decreasing hippocampal volume (p = 0.038).

Conclusions

These preliminary data suggest that telomere length may be a possible early marker of dementia risk, and merits further study in large, prospective investigations.     

Apathy, but not depression, reflects inefficient cognitive strategies in Parkinson's disease

Background

The relationship between apathy, depression and cognitive impairment in Parkinson''s disease (PD) is still controversial. The objective of this study is to investigate whether apathy and depression are associated with inefficient cognitive strategies in PD.

Methods

In this prospective clinical cohort study conducted in a university-based clinical and research movement disorders center we studied 48 PD patients. Based on clinical evaluation, they were classified in two groups: PD with apathy (PD-A group, n = 23) and PD without apathy (PD-NA group, n = 25). Patients received clinical and neuropsychological evaluations. The clinical evaluation included: Apathy Evaluation Scale-patient version, Hamilton Depression Rating Scale-17 items, the Unified Parkinson''s Disease Rating Scale and the Hoehn and Yahr staging system; the neuropsychological evaluation explored speed information processing, attention, working memory, executive function, learning abilities and memory, which included several measures of recall (immediate free, short delay free, long delay free and cued, and total recall).

Findings

PD-A and PD-NA groups did not differ in age, disease duration, treatment, and motor condition, but differed in recall (p<0.001) and executive tasks (p<0.001). Immediate free recall had the highest predictive value for apathy (F =  10.94; p = 0.002). Depression and apathy had a weak correlation (Pearson index  = 0.3; p<0.07), with three items of the depression scale correlating with apathy (Pearson index between .3 and.4; p<0.04). The depressed and non-depressed PD patients within the non-apathetic group did not differ.

Conclusion

Apathy, but not depression, is associated with deficit in implementing efficient cognitive strategies. As the implementation of efficient strategies relies on the fronto-striatal circuit, we conclude that apathy, unlike depression, is an early expression of executive impairment in PD.     

Genetic variation in telomere maintenance genes, telomere length and breast cancer risk

Background

Telomeres at the ends of eukaryotic chromosomes play a critical role in maintaining the integrity and stability of the genome and participate in the initiation of DNA damage/repair responses.

Methods

We performed a case-control study to evaluate the role of three SNPs (TERT-07, TERT-54 and POT1-03) in telomere maintenance genes previously found to be significantly associated with breast cancer risk. We used sister-sets obtained from the New York site of the Breast Cancer Family Registry (BCFR). Among the 313 sister-sets, there were 333 breast cancer cases and 409 unaffected sisters who were evaluated in the current study. We separately applied conditional logistic regression and generalized estimating equations (GEE) models to evaluate associations between the three SNPs and breast cancer risk within sister-sets. We examined the associations between genotype, covariates and telomere length among unaffected sisters using a GEE model.

Results

We found no significant associations between the three SNPs in telomere maintenance genes and breast cancer risk by both conditional logistic regression and GEE models, nor were these SNPs significantly related to telomere length. Among unaffected sisters, shortened telomeres were statistically significantly correlated with never hormone replacement therapy (HRT) use. Increased duration of HRT use was significantly associated with reduced telomere length. The means of telomere length were 0.77 (SD = 0.35) for never HRT use, 0.67 (SD = 0.29) for HRT use <5yrs and 0.59 (SD = 0.24) for HRT use ≥5yrs after adjusting for age of blood donation and race and ethnicity.

Conclusions

We found that exogenous hormonal exposure was inversely associated with telomere length. No significant associations between genetic variants and telomere length or breast cancer risk were observed. These findings provide initial evidence to understand hormonal exposure in the regulation of telomere length and breast cancer risk but need replication in prospective studies.     

Household tobacco smoke and admission weight predict severe bronchiolitis in infants independent of deprivation: prospective cohort study

Objectives

To examine demographic, environmental and clinical factors associated with severe bronchiolitis in infants admitted to hospital and quantify the independent effects of these factors.

Design

Prospective cohort study.

Setting

Alder Hey Children''s Hospital, Liverpool, United Kingdom.

Participants

378 infants admitted to hospital with a diagnosis of bronchiolitis, of whom 299 (79%) were antigen positive to respiratory syncytial virus (RSV).

Outcome

Severity of disease during admission, defined as “no need for supplemental oxygen” (reference group), “any need for supplemental oxygen” and “any need for mechanical ventilation”.

Results

Univariate analysis found male sex (p = 0.035) and tobacco smoking by a household member (p<0.001) were associated with need for both supplemental oxygen and mechanical ventilation. Premature birth, low gestation, low birth weight, low admission weight and low corrected age on admission were also associated with need for mechanical ventilation (all p≤0.002). Deprivation scores (IMD 2004) were significantly higher in households where a member smoked compared to non-smoking households (p<0.001). The odds of smoking predicted by deprivation were 7 times higher (95%CI (3.59, 14.03)), when comparing the least and most deprived quintiles of the study population. Family history of atopic disease and deprivation score were not associated with severe disease. Multivariate multinomial logistic regression which initially included all covariates, found household tobacco smoking (adjusted OR = 2.45, 95%CI (1.60, 3.74) predicted need for oxygen supplementation. Household tobacco smoking (adjusted OR = 5.49, (2.78, 10.83)) and weight (kg) on admission (adjusted OR = 0.51, (0.40, 0.65)) were both significant predictors in the final model for mechanical ventilation. The same associations and similar size of effects were found when only children with proven RSV infection were included in analysis.

Conclusions

Low admission weight and householder tobacco smoking increased the risk of severe bronchiolitis in infants admitted to hospital. These effects were independent of a standard deprivation measure. NIHR Study Ref. DHCS/G121/10.     

Comparative study of scientific publications in urology and nephrology journals originating from USA, china and Japan (2001-2010)

Background

In the past decade, scientific research has developed rapidly in China, but the growth seems to vary widely between different disciplines. In this study, we aimed to compare the quantity and quality of publications in urology and nephrology journals from USA, China and Japan.

Methods

Journals listed in the “Urology and Nephrology” category of Science Citation Index Expanded subject categories were included. Scientific papers in these journals written by researchers from USA, Japan and China were retrieved from the “PubMed” and “Web of Knowledge” online databases.

Results

The annual number of total scientific articles increased significantly from 2001 to 2010 in China, and has ranked second in the world since 2006. In the field of urology and nephrology, the annual number increased significantly from 2001 to 2010 in USA and China; but not in Japan. The share of articles increased significantly over time in China, decreased significantly in Japan, and remained unchanged in USA. In 2010, USA contributed 32.17% of the total world output in urology and nephrology field and ranked 1^st; Japan contributed 5.19% and ranked 5^th; China contributed 3.83% and ranked 9^th. Publications from USA had the highest accumulated IFs and the highest total citations of articles (USA>Japan>China, p<0.001). No significant difference was found in average IF among the three countries. USA published the most articles in the top 10 urology and nephrology journals (USA(35165)>Japan(6704)>China(2233), p<0.001). Researchers from USA published more clinical trials and randomized controlled trials than Japan and China (USA>Japan>China, p<0.001).

Conclusion

Although China has undergone significant increase in annual number and percentage of scientific publication in urology and nephrology journals in the past decade, it still lags far behind USA and Japan in the field of urology and nephrology in terms of quantity and quality.     

S100A9 is a biliary protein marker of disease activity in primary sclerosing cholangitis

Background and Aims

Bile analysis has the potential to serve as a surrogate marker for inflammatory and neoplastic disorders of the biliary epithelium and may provide insight into biliary pathophysiology and possible diagnostic markers. We aimed to identify biliary protein markers of patients with primary sclerosing cholangitis (PSC) by a proteomic approach.

Methods

Bile duct-derived bile samples were collected from PSC patients (n = 45) or patients with choledocholithiasis (n = 24, the control group). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to analyse the proteins, 2-D-gel patterns were compared by densitometry, and brush cytology specimens were analysed by RT-PCR.

Results

A reference bile-duct bile proteome was established in the control group without signs of inflammation or maligancy comprising a total of 379 non-redundant biliary proteins; 21% were of unknown function and 24% had been previously described in serum. In PSC patients, the biliary S100A9 expression was elevated 95-fold (p<0.005), serum protein expression was decreased, and pancreatic enzyme expression was unchanged compared to controls. The S100A9 expression was 2-fold higher in PSC patients with high disease activity than in those with low activity (p<0.05). The brush cytology specimens from the PSC patients with high disease activity showed marked inflammatory activity and leukocyte infiltration compared to the patients with low activity, which correlated with S100A9 mRNA expression (p<0.05).

Conclusions

The bile-duct bile proteome is complex and its analysis might enhance the understanding of cholestatic liver disease. Biliary S100A9 levels may be a useful marker for PSC activity, and its implication in inflammation and carcinogenesis warrants further investigation.     

High phobic anxiety is related to lower leukocyte telomere length in women

Background

Chronic psychological distress has been linked to shorter telomeres, an indication of accelerated aging. Yet, little is known about relations of anxiety to telomeres. We examined whether a typically chronic form of anxiety – phobic anxiety – is related to telomere length.

Methodology/Principal Findings

Relative telomere lengths (RTLs) in peripheral blood leukocytes were measured by quantitative real-time polymerase chain reaction among 5,243 women (aged 42–69 years) who: were participants in the Nurses'' Health Study; were controls in prior case-control studies of telomeres and disease, or randomly selected healthy participants in a cognitive function sub-study; had completed the Crown-Crisp phobic index proximal to blood collection. Adjusted least-squares mean RTLs (z-scores) were calculated across phobic categories. Higher phobic anxiety was generally associated with lower RTLs (age-adjusted p-trend = 0.09); this association was similar after adjustment for confounders – paternal age-at-birth, smoking, body mass index (BMI) and physical activity (p-trend = 0.15). Notably, a threshold was identified. Among women with Crown-Crisp<6 points, the multivariable-adjusted least-squares mean RTL z-score = 0.02 standard units; however, among the most phobic women (Crown-Crisp≥6), the multivariable-adjusted least-squares mean RTL z-score = −0.09 standard units (mean difference = −0.10 standard units; p = 0.02). The magnitude of this difference was comparable to that for women 6 years apart in age. Finally, effect modification by BMI, smoking and paternal age was observed: associations were stronger among highly phobic women with BMI≥25 kg/m², without smoking history, or born to fathers aged ≥40 years.

Conclusions/Significance

In this large, cross-sectional study high phobic anxiety was associated with shorter telomeres. These results point toward prospective investigations relating anxiety to telomere length change.     

Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study

Background

Leukocyte telomere length, an emerging marker of biological age, has been shown to predict cardiovascular morbidity and mortality. However, the natural history of telomere length in patients with coronary artery disease has not been studied. We sought to investigate the longitudinal trajectory of telomere length, and to identify the independent predictors of telomere shortening, in persons with coronary artery disease.

Methodology/Principal Findings

In a prospective cohort study of 608 individuals with stable coronary artery disease, we measured leukocyte telomere length at baseline, and again after five years of follow-up. We used multivariable linear and logistic regression models to identify the independent predictors of leukocyte telomere trajectory. Baseline and follow-up telomere lengths were normally distributed. Mean telomere length decreased by 42 base pairs per year (p<0.001). Three distinct telomere trajectories were observed: shortening in 45%, maintenance in 32%, and lengthening in 23% of participants. The most powerful predictor of telomere shortening was baseline telomere length (OR per SD increase = 7.6; 95% CI 5.5, 10.6). Other independent predictors of telomere shortening were age (OR per 10 years = 1.6; 95% CI 1.3, 2.1), male sex (OR = 2.4; 95% CI 1.3, 4.7), and waist-to-hip ratio (OR per 0.1 increase = 1.4; 95% CI 1.0, 2.0).

Conclusions/Significance

Leukocyte telomere length may increase as well as decrease in persons with coronary artery disease. Telomere length trajectory is powerfully influenced by baseline telomere length, possibly suggesting negative feedback regulation. Age, male sex, and abdominal obesity independently predict telomere shortening. The mechanisms and reversibility of telomeric aging in cardiovascular disease deserve further study.     

Gender differences in the risk of HIV infection among persons reporting abstinence, monogamy, and multiple sexual partners in northern Tanzania

Background

Monogamy, together with abstinence, partner reduction, and condom use, is widely advocated as a key behavioral strategy to prevent HIV infection in sub-Saharan Africa. We examined the association between the number of sexual partners and the risk of HIV seropositivity among men and women presenting for HIV voluntary counseling and testing (VCT) in northern Tanzania.

Methodology/ Principal Findings

Clients presenting for HIV VCT at a community-based AIDS service organization in Moshi, Tanzania were surveyed between November 2003 and December 2007. Data on sociodemographic characteristics, reasons for testing, sexual behaviors, and symptoms were collected. Men and women were categorized by number of lifetime sexual partners, and rates of seropositivity were reported by category. Factors associated with HIV seropositivity among monogamous males and females were identified by a multivariate logistic regression model. Of 6,549 clients, 3,607 (55%) were female, and the median age was 30 years (IQR 24–40). 939 (25%) females and 293 (10%) males (p<0.0001) were HIV seropositive. Among 1,244 (34%) monogamous females and 423 (14%) monogamous males, the risk of HIV infection was 19% and 4%, respectively (p<0.0001). The risk increased monotonically with additional partners up to 45% (p<0.001) and 15% (p<0.001) for women and men, respectively with 5 or more partners. In multivariate analysis, HIV seropositivity among monogamous women was most strongly associated with age (p<0.0001), lower education (p<0.004), and reporting a partner with other partners (p = 0.015). Only age was a significant risk factor for monogamous men (p = 0.0004).

Interpretation

Among women presenting for VCT, the number of partners is strongly associated with rates of seropositivity; however, even women reporting lifetime monogamy have a high risk for HIV infection. Partner reduction should be coupled with efforts to place tools in the hands of sexually active women to reduce their risk of contracting HIV.     

Reduced metabolism in brain "control networks" following cocaine-cues exposure in female cocaine abusers

Objective

Gender differences in vulnerability for cocaine addiction have been reported. Though the mechanisms are not understood, here we hypothesize that gender differences in reactivity to conditioned-cues, which contributes to relapse, are involved.

Method

To test this we compared brain metabolism (using PET and ¹⁸FDG) between female (n = 10) and male (n = 16) active cocaine abusers when they watched a neutral video (nature scenes) versus a cocaine-cues video.

Results

Self-reports of craving increased with the cocaine-cue video but responses did not differ between genders. In contrast, changes in whole brain metabolism with cocaine-cues differed by gender (p<0.05); females significantly decreased metabolism (−8.6%±10) whereas males tended to increase it (+5.5%±18). SPM analysis (Cocaine-cues vs Neutral) in females revealed decreases in frontal, cingulate and parietal cortices, thalamus and midbrain (p<0.001) whereas males showed increases in right inferior frontal gyrus (BA 44/45) (only at p<0.005). The gender-cue interaction showed greater decrements with Cocaine-cues in females than males (p<0.001) in frontal (BA 8, 9, 10), anterior cingulate (BA 24, 32), posterior cingulate (BA 23, 31), inferior parietal (BA 40) and thalamus (dorsomedial nucleus).

Conclusions

Females showed greater brain reactivity to cocaine-cues than males but no differences in craving, suggesting that there may be gender differences in response to cues that are not linked with craving but could affect subsequent drug use. Specifically deactivation of brain regions from “control networks” (prefrontal, cingulate, inferior parietal, thalamus) in females could increase their vulnerability to relapse since it would interfere with executive function (cognitive inhibition). This highlights the importance of gender tailored interventions for cocaine addiction.     

CD62L (L-Selectin) Shedding for Assessment of Perioperative Immune Sensitivity in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Objective

To investigate the suitability of blood granulocyte and monocyte sensitivity, as measured by the quantity of different agonists required to induce CD62L shedding, for assessment of perioperative immune changes in patients undergoing cardiac surgery with cardiopulmonary bypass.

Methods

Patients scheduled for aortocoronary bypass grafting or for valve surgery were included in this prospective observational study. Blood samples were drawn before anesthesia induction, directly after surgery and 48 hours after anesthesia induction. We determined the concentration of two different inflammatory stimuli – lipoteichoic acid (LTA) and tumor necrosis factor alpha (TNF) - required to induce shedding of 50% of surface CD62L from blood granulocytes and monocytes. In parallel monocyte surface human leukocyte antigen (HLA)-DR, and plasma interleukin (IL)-8, soluble (s)CD62L, soluble (s)Toll-like receptor (TLR)-2 and ADAM17 quantification were used to illustrate perioperative immunomodulation.

Results

25 patients were enrolled. Blood granulocytes and monocytes showed decreased sensitivity to the TLR 2/6 agonist Staphylococcus aureus LTA immediately after surgery (p = 0.001 and p = 0.004 respectively). In contrast, granulocytes (p = 0.01), but not monocytes (p = 0.057) displayed a decreased postoperative sensitivity to TNF. We confirmed the presence of a systemic inflammatory response and a decreased immune sensitivity in the post-surgical period by measuring significant increases in the perioperative plasma concentration of IL-8 (p≤0.001) and sTLR (p = 0.004), and decreases in monocyte HLA-DR (p<0.001), plasma sCD62L (p≤0.001). In contrast, ADAM17 plasma levels did not show significant differences over the observation period (p = 0.401).

Conclusions

Monitoring granulocyte and monocyte sensitivity using the “CD62L shedding assay” in the perioperative period in cardiac surgical patients treated with the use of cardiopulmonary bypass reveals common changes in sensitivity to TLR2/6 ligands and to TNF stimulus. Further long-term follow-up studies will address the predictive value of these observations for clinical purposes.     

Heterogeneity of respiratory dendritic cell subsets and lymphocyte populations in inbred mouse strains

Background

Inbred mouse strains are used in different models of respiratory diseases but the variation of critical respiratory leukocyte subpopulations across different strains is unknown.

Methods

By using multiparameter flow cytometry we have quantitated respiratory leukocyte subsets including dendritic cells subpopulations, macrophages, classical T and B cells, natural killer cells, γδTCR+ T cells and lineage-negative leukocytes in the five most common inbred mouse strains BALB/c, C57BL/6, DBA/2, 129SV and C3H. To minimize confounding environmental factors, age-matched animals were received from the same provider and were housed under identical specific-pathogen-free conditions.

Results

Results revealed significant strain differences with respect to respiratory neutrophils (p=0.005; up to 1.4 fold differences versus C57BL/6 mice), eosinophils (p=0.029; up to 2.7 fold), certain dendritic cell subsets (p≤0.0003; up to 3.4 fold), T (p<0.001; up to 1.6 fold) and B lymphocyte subsets (p=0.005; up to 0.4 fold), γδ T lymphocytes (p=0.003; up to 1.6 fold), natural killer cells (p<0.0001; up to 0.6 fold) and lineage-negative innate leukocytes (p≤0.007; up to 3.6 fold). In contrast, total respiratory leukocytes, macrophages, total dendritic cells and bronchoalveolar lavage leukocytes did not differ significantly. Stimulation of respiratory leukocytes via Toll-like receptor 4 and 9 as well as CD3/CD28 revealed significant strain differences of TNF-α and IL-10 production.

Conclusion

Our study demonstrates significant strain heterogeneity of respiratory leukocyte subsets that may impact respiratory immunity in different disease models. Additionally, the results may help identification of optimal strains for purification of rare respiratory leukocyte subsets for ex vivo analyses.     

Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography

Background

In standard reference sources, the incidence of coronary artery disease (CAD) in patients with atrial fibrillation (AF) ranged between 24 and 46.5%. Since then, the incidence of cardiovascular risk factors (CRF) has increased and modern treatment strategies (“pill in the pocket”) are only applicable to patients without structural heart disease. The aim of this study was to investigate the incidence and severity of CAD in patients with AF.

Methods

From January 2005 until December 2009, we included 261 consecutive patients admitted to hospital with paroxysmal, persistent or permanent AF in this prospective study. All patients underwent coronary angiography and the Framingham risk score (FRS) was calculated. Patients with previously diagnosed or previously excluded CAD were excluded.

Results

The overall incidence of CAD in patients presenting with AF was 34%; in patients >70 years, the incidence of CAD was 41%. The incidence of patients undergoing a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) was 21%. Patients with CAD were older (73±8 years vs 68±10 years, p = 0.001), had significantly more frequent hypercholesterolemia (60% vs 30%, p<0.001), were more frequent smokers (26% vs 13%, p = 0.017) and suffered from angina more often (37% vs 2%, p<0.001). There was a significant linear trend among the FRS categories in percentage and the prevalence of CAD and PCI/CABG (p<0.0001).

Conclusions

The overall incidence of CAD in patients presenting with AF was relatively high at 34%; the incidence of PCI/CABG was 21%. Based upon increasing CRF in the western world, we recommend a careful investigation respecting the FRS to either definitely exclude or establish an early diagnosis of CAD – which could contribute to an early and safe therapeutic strategy considering type Ic antiarrhythmics and oral anticoagulation.     

Diminished Telomeric 3′ Overhangs Are Associated with Telomere Dysfunction in Hoyeraal-Hreidarsson Syndrome

Background

Eukaryotic chromosomes end with telomeres, which in most organisms are composed of tandem DNA repeats associated with telomeric proteins. These DNA repeats are synthesized by the enzyme telomerase, whose activity in most human tissues is tightly regulated, leading to gradual telomere shortening with cell divisions. Shortening beyond a critical length causes telomere uncapping, manifested by the activation of a DNA damage response (DDR) and consequently cell cycle arrest. Thus, telomere length limits the number of cell divisions and provides a tumor-suppressing mechanism. However, not only telomere shortening, but also damaged telomere structure, can cause telomere uncapping. Dyskeratosis Congenita (DC) and its severe form Hoyeraal-Hreidarsson Syndrome (HHS) are genetic disorders mainly characterized by telomerase deficiency, accelerated telomere shortening, impaired cell proliferation, bone marrow failure, and immunodeficiency.

Methodology/Principal Findings

We studied the telomere phenotypes in a family affected with HHS, in which the genes implicated in other cases of DC and HHS have been excluded, and telomerase expression and activity appears to be normal. Telomeres in blood leukocytes derived from the patients were severely short, but in primary fibroblasts they were normal in length. Nevertheless, a significant fraction of telomeres in these fibroblasts activated DDR, an indication of their uncapped state. In addition, the telomeric 3′ overhangs are diminished in blood cells and fibroblasts derived from the patients, consistent with a defect in telomere structure common to both cell types.

Conclusions/Significance

Altogether, these results suggest that the primary defect in these patients lies in the telomere structure, rather than length. We postulate that this defect hinders the access of telomerase to telomeres, thus causing accelerated telomere shortening in blood cells that rely on telomerase to replenish their telomeres. In addition, it activates the DDR and impairs cell proliferation, even in cells with normal telomere length such as fibroblasts. This work demonstrates a telomere length-independent pathway that contributes to a telomere dysfunction disease.