Adiponectin Provides Additional Information to Conventional Cardiovascular Risk Factors for Assessing the Risk of Atherosclerosis in Both Genders

Background

This study evaluated the relation between adiponectin and atherosclerosis in both genders, and investigated whether adiponectin provides useful additional information for assessing the risk of atherosclerosis.

Methods

We measured serum adiponectin levels and other cardiovascular risk factors in 1033 subjects (454 men, 579 women) from the Korean Genomic Rural Cohort study. Carotid intima–media-thickness (CIMT) was used as measure of atherosclerosis. Odds ratios (ORs) with 95% confidence intervals (95% CI) were calculated using multiple logistic regression, and receiver operating characteristic curves (ROC), the category-free net reclassification improvement (NRI) and integrated discrimination improvement (IDI) were calculated.

Results

After adjustment for conventional cardiovascular risk factors, such as age, waist circumference, smoking history, low-density and high-density lipoprotein cholesterol, triglycerides, systolic blood pressure and insulin resistance, the ORs (95%CI) of the third tertile adiponectin group were 0.42 (0.25–0.72) in men and 0.47 (0.29–0.75) in women. The area under the curve (AUC) on the ROC analysis increased significantly by 0.025 in men and 0.022 in women when adiponectin was added to the logistic model of conventional cardiovascular risk factors (AUC in men: 0.655 to 0.680, p = 0.038; AUC in women: 0.654 to 0.676, p = 0.041). The NRI was 0.32 (95%CI: 0.13–0.50, p<0.001), and the IDI was 0.03 (95%CI: 0.01–0.04, p<0.001) for men. For women, the category-free NRI was 0.18 (95%CI: 0.02–0.34, p = 0.031) and the IDI was 0.003 (95%CI: −0.002–0.008, p = 0.189).

Conclusion

Adiponectin and atherosclerosis were significantly related in both genders, and these relationships were independent of conventional cardiovascular risk factors. Furthermore, adiponectin provided additional information to conventional cardiovascular risk factors regarding the risk of atherosclerosis.     

Development and Validation of a Bedside Score to Predict Early Death in Cancer of Unknown Primary Patients

Background

We have investigated predictors of 90-day-mortality in a large cohort of non-specific cancer of unknown primary patients.

Methods

Predictors have been identified by univariate and then logistic regression analysis in a single-center cohort comprising 429 patients (development cohort). We identified four predictors that produced a predictive score that has been applied to an independent multi-institutional cohort of 409 patients (validation cohort). The score was the sum of predictors for each patient (0 to 4).

Results

The 90-day-mortality-rate was 33 and 26% in both cohorts. Multivariate analysis has identified 4 predictors for 90-day-mortality: performance status>1 (OR = 3.03, p = 0.001), at least one co-morbidity requiring treatment (OR = 2.68, p = 0.004), LDH>1.5×the upper limit of normal (OR = 2.88, p = 0.007) and low albumin or protein levels (OR = 3.05, p = 0.007). In the development cohort, 90-day-mortality-rates were 12.5%, 32% and 64% when the score was [0–1], 2 and [3]–[4], respectively. In the validation cohort, risks were 13%, 25% and 62% according to the same score values.

Conclusions

We have validated a score that is easily calculated at the beside that estimates the 90-days mortality rate in non-specific CUP patients. This could be helpful to identify patients who would be better served with palliative care rather than aggressive chemotherapy.     

Measurement of Visceral Fat: Should We Include Retroperitoneal Fat?

Objective

Whether retroperitoneal fat should be included in the measurement of visceral fat remains controversial. We compared the relationships of fat areas in peritoneal, retroperitoneal, and subcutaneous compartments to metabolic syndrome, adipokines, and incident hypertension and diabetes.

Methods

We enrolled 432 adult participants (153 men and 279 women) in a community-based cohort study. Computed tomography at the umbilicus level was used to measure the fat areas.

Results

Retroperitoneal fat correlated significantly with metabolic syndrome (adjusted odds ratio (OR), 5.651, p<0.05) and the number of metabolic abnormalities (p<0.05). Retroperitoneal fat area was significantly associated with blood pressure, plasma glycemic indices, lipid profile, C-reactive protein, adiponectin (r = −0.244, P<0.05), and leptin (r = 0.323, p<0.05), but not plasma renin or aldosterone concentrations. During the 2.94±0.84 years of follow-up, 32 participants developed incident hypertension. Retroperitoneal fat area (hazard ration (HR) 1.62, p = 0.003) and peritoneal fat area (HR 1.62, p = 0.009), but not subcutaneous fat area (p = 0.14) were associated with incident hypertension. Neither retroperitoneal fat area, peritoneal fat area, nor subcutaneous fat areas was associated with incident diabetes after adjustment.

Conclusions

Retroperitoneal fat is similar to peritoneal fat, but differs from subcutaneous fat, in terms of its relationship with metabolic syndrome and incident hypertension. Retroperitoneal fat area should be included in the measurement of visceral fat for cardio-metabolic studies in human.     

Biomarker Changes Associated with Tuberculin Skin Test (TST) Conversion: A Two-Year Longitudinal Follow-Up Study in Exposed Household Contacts

Background

A high prevalence (50–80%) of Tuberculin Skin Test Positivity (TST+ ≥10 mm indurations) has been reported in TB endemic countries. This pool forms a huge reservoir for new incident TB cases. However, immune biomarkers associated with TST conversion are largely unknown. The objective of this study was to identify immune biomarkers associated with TST conversion after acute Mycobacterium tuberculosis (MTB) exposure.

Methodology/Principal Findings

A 24 month longitudinal study was carried out in a recently MTB exposed cohort of household contacts (HC = 93; 75% TST+). Control group consisted of unexposed community controls (EC = 59; 46%TST+). Cytokine secretion was assessed in whole blood cultures in response to either mycobacterial culture filtrate (CF) antigens or mitogens (PHA or LPS) using Elisa methodology. Compared to the EC group, the HC group at recruitment (Kruskal-Wallis Test) showed significantly suppressed IFN γ (p = 0.0001), raised IL-10 (p = 0.0005) and raised TNF α (p = 0.001) in response to CF irrespective of their TST status. Seventeen TST-HC, showed TST conversion when retested at 6 months. Post TST conversion (paired t tests) significant increases were observed for CF induced IFN γ (p = 0.038), IL-10 (p = 0.001) and IL-6 (p = 0.006). Cytokine responses were also compared in the exposed HC group with either recent infection [(TST converters (N = 17)] or previous infection [TST+ HC (N = 54)] at 0, 6, 12 and 24 months using ANOVA on repeated measures. Significant differences between the exposed HC groups were noted only at 6 months. CF induced IFN γ was higher in previously infected HC group (p = 0.038) while IL-10 was higher in recently infected HC group (p = 0.041). Mitogen induced cytokine secretion showed similar differences for different group.

Conclusions/Significance

Our results suggest that TST conversion is associated with early increases in IFN γ and IL-10 responses and precedes latency by several months post exposure.     

Urinary Collagen Fragments Are Significantly Altered in Diabetes: A Link to Pathophysiology

Background

The pathogenesis of diabetes mellitus (DM) is variable, comprising different inflammatory and immune responses. Proteome analysis holds the promise of delivering insight into the pathophysiological changes associated with diabetes. Recently, we identified and validated urinary proteomics biomarkers for diabetes. Based on these initial findings, we aimed to further validate urinary proteomics biomarkers specific for diabetes in general, and particularity associated with either type 1 (T1D) or type 2 diabetes (T2D).

Methodology/Principal Findings

Therefore, the low-molecular-weight urinary proteome of 902 subjects from 10 different centers, 315 controls and 587 patients with T1D (n = 299) or T2D (n = 288), was analyzed using capillary-electrophoresis mass-spectrometry. The 261 urinary biomarkers (100 were sequenced) previously discovered in 205 subjects were validated in an additional 697 subjects to distinguish DM subjects (n = 382) from control subjects (n = 315) with 94% (95% CI: 92–95) accuracy in this study. To identify biomarkers that differentiate T1D from T2D, a subset of normoalbuminuric patients with T1D (n = 68) and T2D (n = 42) was employed, enabling identification of 131 biomarker candidates (40 were sequenced) differentially regulated between T1D and T2D. These biomarkers distinguished T1D from T2D in an independent validation set of normoalbuminuric patients (n = 108) with 88% (95% CI: 81–94%) accuracy, and in patients with impaired renal function (n = 369) with 85% (95% CI: 81–88%) accuracy. Specific collagen fragments were associated with diabetes and type of diabetes indicating changes in collagen turnover and extracellular matrix as one hallmark of the molecular pathophysiology of diabetes. Additional biomarkers including inflammatory processes and pro-thrombotic alterations were observed.

Conclusions/Significance

These findings, based on the largest proteomic study performed to date on subjects with DM, validate the previously described biomarkers for DM, and pinpoint differences in the urinary proteome of T1D and T2D, indicating significant differences in extracellular matrix remodeling.     

Depression,Anxiety and Glucose Metabolism in the General Dutch Population: The New Hoorn Study

Background

There is a well recognized association between depression and diabetes. However, there is little empirical data about the prevalence of depressive symptoms and anxiety among different groups of glucose metabolism in population based samples. The aim of this study was to determine whether the prevalence of increased levels of depression and anxiety is different between patients with type 2 diabetes and subjects with impaired glucose metabolism (IGM) and normal glucose metabolism (NGM).

Methodology/Principal Findings

Cross-sectional data from a population-based cohort study of 2667 residents, 1261 men and 1406 women aged 40–65 years from the Hoorn region, the Netherlands. Depressive symptoms and anxiety were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D, score ≥16) and the Hospital Anxiety and Depression Scale – Anxiety Subscale (HADS-A, score ≥8), respectively. Glucose metabolism status was determined by oral glucose tolerance test. In the total study population the prevalence of depressive symptoms and anxiety for the NGM, IGM and type 2 diabetes were 12.5, 12.2 and 21.0% (P = 0.004) and 15.0, 15.3 and 19.9% (p = 0.216), respectively. In men, the prevalence of depressive symptoms was 7.7, 9.5 and 19.6% (p<0.001), and in women 16.4, 15.8 and 22.6 (p = 0.318), for participants with NGM, IGM and type 2 diabetes, respectively. Anxiety was not associated with glucose metabolism when stratified for sex. Intergroup differences (NGM vs. IGM and IGM vs. type 2 diabetes) revealed that higher prevalences of depressive symptoms are mainly manifested in participants with type 2 diabetes, and not in participants with IGM.

Conclusions

Depressive symptoms, but not anxiety are associated with glucose metabolism. This association is mainly determined by a higher prevalence of depressive symptoms in participants with type 2 diabetes and not in participants with IGM.     

Cardiac Complications Associated with Short-Term Mortality in Schizophrenia Patients Hospitalized for Pneumonia: A Nationwide Case-Control Study

Background

Pneumonia is one of most prevalent infectious diseases worldwide and is associated with considerable mortality. In comparison to general population, schizophrenia patients hospitalized for pneumonia have poorer outcomes. We explored the risk factors of short-term mortality in this population because the information is lacking in the literature.

Methods

In a nationwide schizophrenia cohort, derived from the National Health Insurance Research Database in Taiwan, that was hospitalized for pneumonia between 2000 and 2008 (n = 1,741), we identified 141 subjects who died during their hospitalizations or shortly after their discharges. Based on risk-set sampling in a 1∶4 ratio, 468 matched controls were selected from the study cohort (i.e., schizophrenia cohort with pneumonia). Physical illnesses were categorized as pre-existing and incident illnesses that developed after pneumonia respectively. Exposures to medications were categorized by type, duration, and defined daily dose. We used stepwise conditional logistic regression to explore the risk factors for short-term mortality.

Results

Pre-existing arrhythmia was associated with short-term mortality (adjusted risk ratio [RR] = 4.99, p<0.01). Several variables during hospitalization were associated with increased mortality risk, including incident arrhythmia (RR = 7.44, p<0.01), incident heart failure (RR = 5.49, p = 0.0183) and the use of hypoglycemic drugs (RR = 2.32, p<0.01). Furthermore, individual antipsychotic drugs (such as clozapine) known to induce pneumonia were not significantly associated with the risk.

Conclusions

Incident cardiac complications following pneumonia are associated with increased short-term mortality. These findings have broad implications for clinical intervention and future studies are needed to clarify the mechanisms of the risk factors.     

Liver Function Tests and Risk Prediction of Incident Type 2 Diabetes: Evaluation in Two Independent Cohorts

Background

Liver function tests might predict the risk of type 2 diabetes. An independent study evaluating utility of these markers compared with an existing prediction model is yet lacking.

Methods and Findings

We performed a case-cohort study, including random subcohort (6.5%) from 38,379 participants with 924 incident diabetes cases (the Dutch contribution to the European Prospective Investigation Into Cancer and Nutrition, EPIC-NL, the Netherlands), and another population-based cohort study including 7,952 participants with 503 incident cases (the Prevention of Renal and Vascular End-stage Disease, PREVEND, Groningen, the Netherlands). We examined predictive value of combination of the Liver function tests (gamma-glutamyltransferase, alanine aminotransferase, aspartate aminotransferase and albumin) above validated models for 7.5-year risk of diabetes (the Cooperative Health Research in the Region of Augsburg, the KORA study). Basic model includes age, sex, BMI, smoking, hypertension and parental diabetes. Clinical models additionally include glucose and uric acid (model1) and HbA1c (model2). In both studies, addition of Liver function tests to the basic model improved the prediction (C-statistic by∼0.020; NRI by∼9.0%; P<0.001). In the EPIC-NL case-cohort study, addition to clinical model1 resulted in statistically significant improvement in the overall population (C-statistic = +0.009; P<0.001; NRI = 8.8%; P<0.001), while addition to clinical model 2 yielded marginal improvement limited to men (C-statistic = +0.007; P = 0.06; NRI = 3.3%; P = 0.04). In the PREVEND cohort study, addition to clinical model 1 resulted in significant improvement in the overall population (C-statistic change = 0.008; P = 0.003; NRI = 3.6%; P = 0.03), with largest improvement in men (C-statistic change = 0.013; P = 0.01; NRI = 5.4%; P = 0.04). In PREVEND, improvement compared to clinical model 2 could not be tested because of lack of HbA1c data.

Conclusions

Liver function tests modestly improve prediction for medium-term risk of incident diabetes above basic and extended clinical prediction models, only if no HbA1c is incorporated. If data on HbA1c are available, Liver function tests have little incremental predictive value, although a small benefit may be present in men.     

Does Simplicity Compromise Accuracy in ACS Risk Prediction? A Retrospective Analysis of the TIMI and GRACE Risk Scores

Background

The Thrombolysis in Myocardial Infarction (TIMI) risk scores for Unstable Angina/Non-ST–elevation myocardial infarction (UA/NSTEMI) and ST-elevation myocardial infarction (STEMI) and the Global Registry of Acute Coronary Events (GRACE) risk scores for in-hospital and 6-month mortality are established tools for assessing risk in Acute Coronary Syndrome (ACS) patients. The objective of our study was to compare the discriminative abilities of the TIMI and GRACE risk scores in a broad-spectrum, unselected ACS population and to assess the relative contributions of model simplicity and model composition to any observed differences between the two scoring systems.

Methodology/Principal Findings

ACS patients admitted to the University of Michigan between 1999 and 2005 were divided into UA/NSTEMI (n = 2753) and STEMI (n = 698) subpopulations. The predictive abilities of the TIMI and GRACE scores for in-hospital and 6-month mortality were assessed by calibration and discrimination. There were 137 in-hospital deaths (4%), and among the survivors, 234 (7.4%) died by 6 months post-discharge. In the UA/NSTEMI population, the GRACE risk scores demonstrated better discrimination than the TIMI UA/NSTEMI score for in-hospital (C = 0.85, 95% CI: 0.81–0.89, versus 0.54, 95% CI: 0.48–0.60; p<0.01) and 6-month (C = 0.79, 95% CI: 0.76–0.83, versus 0.56, 95% CI: 0.52–0.60; p<0.01) mortality. Among STEMI patients, the GRACE and TIMI STEMI scores demonstrated comparably excellent discrimination for in-hospital (C = 0.84, 95% CI: 0.78–0.90 versus 0.83, 95% CI: 0.78–0.89; p = 0.83) and 6-month (C = 0.72, 95% CI: 0.63–0.81, versus 0.71, 95% CI: 0.64–0.79; p = 0.79) mortality. An analysis of refitted multivariate models demonstrated a marked improvement in the discriminative power of the TIMI UA/NSTEMI model with the incorporation of heart failure and hemodynamic variables. Study limitations included unaccounted for confounders inherent to observational, single institution studies with moderate sample sizes.

Conclusions/Significance

The GRACE scores provided superior discrimination as compared with the TIMI UA/NSTEMI score in predicting in-hospital and 6-month mortality in UA/NSTEMI patients, although the GRACE and TIMI STEMI scores performed equally well in STEMI patients. The observed discriminative deficit of the TIMI UA/NSTEMI score likely results from the omission of key risk factors rather than from the relative simplicity of the scoring system.     

Endothelial Progenitor Cells and Cardiovascular Events in Patients with Chronic Kidney Disease – a Prospective Follow-Up Study

Background

Endothelial progenitor cells (EPCs) mediate vascular repair and regeneration. Their number in peripheral blood is related to cardiovascular events in individuals with normal renal function.

Methods

We evaluated the association between functionally active EPCs (cell culture) and traditional cardiovascular risk factors in 265 patients with chronic kidney disease stage V receiving hemodialysis therapy. Thereafter, we prospectively assessed cardiovascular events, e.g. myocardial infarction, percutaneous transluminal coronary angioplasty (including stenting), aorto-coronary bypass, stroke and angiographically verified stenosis of peripheral arteries, and cardiovascular death in this cohort.

Results

In our patients EPCs were related only to age (r = 0.154; p = 0.01). During a median follow-up period of 36 months 109 (41%) patients experienced a cardiovascular event. In a multiple Cox regression analysis, we identified EPCs (p = 0.03) and patient age (p = 0.01) as the only independent variables associated with incident cardiovascular events. Moreover, a total of 70 patients died during follow-up, 45 of those due to cardiovascular causes. Log rank test confirmed statistical significance for EPCs concerning incident cardiovascular events (p = 0.02).

Conclusions

We found a significant association between the number of functionally active EPCs and cardiovascular events in patients with chronic kidney disease. Thus, defective vascular repair and regeneration may be responsible, at least in part, for the enormous cardiovascular morbidity in this population.     

Lack of Association between the Tagging SNP A+930→G of SOCS3 and Type 2 Diabetes Mellitus: Meta-Analysis of Four Independent Study Populations

Background

The suppressor of cytokine signalling 3 (SOCS3) provides a link between cytokine action and their negative consequences on insulin signalling. Thus SOCS3 is a potential candidate gene for type 2 diabetes (T2DM).

Methodology/Principal Findings

Based on HapMap we identified the polymorphism A+930→G (rs4969168) as a haplotype tagging SNP (htSNP) sufficiently covering the genetic variation of the whole gene. We therefore examined the association between rs4969168 within SOCS3 and T2DM in three independent study populations; one prospective case-cohort study and two cross-sectional study populations. Due to the low frequency of individuals being homozygous for the polymorphism a dominant model of inheritance was assumed. The case-cohort study with 2,957 individuals (764 of them with incident T2DM) showed no effect of the polymorphism on diabetes risk (hazard ratio (95%CI): 0.86 (0.66–1.13); p = 0.3). Within the MeSyBePo-study population 325 subjects had T2DM from a total of 1,897 individuals, while the second cross-sectional cohort included 851 cases of T2DM within a total of 1653 subjects. According to the results in the prospective study, no association with T2DM was found (odds ratio (95%CI): 0.78 (0.54–1.12) for MesyBepo and 1.13 (0.90–1.42) for the Leipzig study population). There was also no association with metabolic subtraits such as insulin sensitivity (p = 0.7), insulin secretion (p = 0.8) or the hyperbolic relation of both, the disposition index (p = 0.7). In addition, no evidence for interaction with BMI or sex was found. We subsequently performed a meta-analysis, additionally including the publicly available data from the T2DM-subcohort of the WTCCC (n = 4,855). The overall odds ratio within that meta-analysis was 0.96 (0.88–1.06).

Conclusions/Significance

There is no strong effect of the common genetic variation within the SOCS3 gene on the development of T2DM.     

In Very Young Infants Severity of Acute Bronchiolitis Depends On Carried Viruses

Background

RT amplification reaction has revealed that various single viruses or viral co-infections caused acute bronchiolitis in infants, and RV appeared to have a growing involvement in early respiratory diseases. Because remaining controversial, the objective was to determine prospectively the respective role of RSV, RV, hMPV and co-infections on the severity of acute bronchiolitis in very young infants.

Methods and Principal Findings

209 infants (median age: 2.4 months) were enrolled in a prospective study of infants <1 year old, hospitalized for a first episode of bronchiolitis during the winter epidemic season and with no high risk for severe disease. The severity was assessed by recording SaO₂% at admission, a daily clinical score (scale 0–18), the duration of oxygen supplementation and the length of hospitalization. Viruses were identified in 94.7% by RT amplification reaction: RSV only (45.8%), RV only (7.2%), hMPV only (3.8%), dual RSV/RV (14.3%), and other virus only (2%) or coinfections (9%). RV compared respectively with RSV and dual RSV/RV infection caused a significant less severe disease with a lower clinical score (5[3.2–6] vs. 6[4–8], p = 0.01 and 5.5[5–7], p = 0.04), a shorter time in oxygen supplementation (0[0–1] days vs. 2[0–3] days, p = 0.02 and 2[0–3] days, p = 0.03) and a shorter hospital stay (3[3–4.7] days vs.6 [5–8] days, p = 0.001 and 5[4–6] days, p = 0.04). Conversely, RSV infants had also longer duration of hospitalization in comparison with RSV/RV (p = 0.01) and hMPV (p = 0.04). The multivariate analyses showed that the type of virus carried was independently associated with the duration of hospitalization.

Conclusion

This study underlined the role of RV in early respiratory diseases, as frequently carried by young infants with a first acute bronchiolitis. RSV caused the more severe disease and conversely RV the lesser severity. No additional effect of dual RSV/RV infection was observed on the severity.     

The Prevalence of Depression in White-European and South-Asian People with Impaired Glucose Regulation and Screen-Detected Type 2 Diabetes Mellitus

Background

There is a clear relationship between depression and diabetes. However, the directionality of the relationship remains unclear and very little research has considered a multi-ethnic population. The aim of this study was to determine the prevalence of depression in a White-European (WE) and South-Asian (SA) population attending a community diabetes screening programme, and to explore the association of depression with screen-detected Type 2 diabetes mellitus (T2DM) and impaired glucose regulation (IGR).

Methodology/Principal Findings

Participants were recruited from general practices in Leicestershire (United Kingdom) between August 2004 and December 2007. 4682 WE (40–75 years) and 1327 SA participants (25–75 years) underwent an Oral Glucose Tolerance Test, detailed history, anthropometric measurements and completed the World Health Organisation-Five (WHO-5) Wellbeing Index. Depression was defined by a WHO-5 wellbeing score ≤13. Unadjusted prevalence of depression for people in the total sample with T2DM and IGR was 21.3% (21.6% in WE, 20.6% in SA, p = 0.75) and 26.0% (25.3% in WE, 28.9% in SA, p = 0.65) respectively. For people with normal glucose tolerance, the prevalence was 25.1% (24.9% in WE, 26.4% in SA, p = 0.86). Age-adjusted prevalences were higher for females than males. Odds ratios adjusted for age, gender, and ethnicity, showed no significant increase in prevalent depression for people with T2DM (OR = 0.95, 95%CI 0.62 to 1.45) or IGR (OR = 1.17, 95%CI 0.96 to1.42).

Conclusions

Prior to the knowledge of diagnosis, depression was not significantly more prevalent in people with screen detected T2DM or IGR. Differences in prevalent depression between WE and SA people were also not identified. In this multi-ethnic population, female gender was significantly associated with depression.     

Natural Killer Cells in Obesity: Impaired Function and Increased Susceptibility to the Effects of Cigarette Smoke

Background

Obese individuals who smoke have a 14 year reduction in life expectancy. Both obesity and smoking are independantly associated with increased risk of malignancy. Natural killer cells (NK) are critical mediators of anti-tumour immunity and are compromised in obese patients and smokers. We examined whether NK cell function was differentially affected by cigarette smoke in obese and lean subjects.

Methodology and Principal Findings

Clinical data and blood were collected from 40 severely obese subjects (BMI>40 kg/m²) and 20 lean healthy subjects. NK cell levels and function were assessed using flow cytometry and cytotoxicity assays. The effect of cigarette smoke on NK cell ability to kill K562 tumour cells was assessed in the presence or absence of the adipokines leptin and adiponectin. NK cell levels were significantly decreased in obese subjects compared to lean controls (7.6 vs 16.6%, p = 0.0008). NK function was also significantly compromised in obese patients (30% +/− 13% vs 42% +/−12%, p = 0.04). Cigarette smoke inhibited NK cell ability to kill tumour cell lines (p<0.0001). NK cells from obese subjects were even more susceptible to the inhibitory effects of smoke compared to lean subjects (33% vs 28%, p = 0.01). Cigarette smoke prevented NK cell activation, as well as perforin and interferon-gamma secretion upon tumour challenge. Adiponectin but not leptin partially reversed the effects of smoke on NK cell function in both obese (p = 0.002) and lean controls (p = 0.01).

Conclusions/Significance

Obese subjects have impaired NK cell activity that is more susceptible to the detrimental effects of cigarette smoke compared to lean subjects. This may play a role in the increase of cancer and infection seen in this population. Adiponectin is capable of restoring NK cell activity and may have therapeutic potential for immunity in obese subjects and smokers.     

Ten-Year Mortality and Cardiovascular Morbidity in the Finnish Diabetes Prevention Study—Secondary Analysis of the Randomized Trial

Background

The Finnish Diabetes Prevention Study (DPS) was a randomized controlled trial, which showed that it is possible to prevent type 2 diabetes by lifestyle changes. The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally randomized either into an intervention or control group. Furthermore, we compared these results with a population-based cohort comprising individuals of varying glucose tolerance states.

Methods and Findings

Middle-aged, overweight people with IGT (n = 522) were randomized into intensive intervention (including physical activity, weight reduction and dietary counseling), or control “mini-intervention” group. Median length of the intervention period was 4 years and the mean follow-up was 10.6 years. The population-based reference study cohort included 1881 individuals (1570 with normal glucose tolerance, 183 with IGT, 59 with screen-detected type 2 diabetes, 69 with previously known type 2 diabetes) with the mean follow-up of 13.8 years. Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register. Among the DPS participants who consented for register linkage (n = 505), total mortality (2.2 vs. 3.8 per 1000 person years, hazard ratio HR = 0.57, 95% CI 0.21–1.58) and cardiovascular morbidity (22.9 vs. 22.0 per 1000 person years, HR = 1.04, 95% CI 0.72–1.51) did not differ significantly between the intervention and control groups. Compared with the population-based cohort with impaired glucose tolerance, adjusted HRs were 0.21 (95% CI 0.09–0.52) and 0.39 (95% CI 0.20–0.79) for total mortality, and 0.89 (95% CI 0.62–1.27) and 0.87 (0.60–1.27) for cardiovascular morbidity in the intervention and control groups of the DPS, respectively. The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort (adjusted HR 0.30, 95% CI 0.17–0.54), but there was no significant difference in the risk of CVD (adjusted HR 0.88, 95% CI 0.64–1.21).

Conclusions

Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up. However, the statistical power may not be sufficient to detect small differences between the intervention and control groups. Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00518167","term_id":"NCT00518167"}}NCT00518167     

Low Acceptability of A/H1N1 Pandemic Vaccination in French Adult Population: Did Public Health Policy Fuel Public Dissonance?

Background

In July 2009, French public health authorities embarked in a mass vaccination campaign against A/H1N1 2009 pandemic-influenza. We explored the attitudes and behaviors of the general population toward pandemic vaccination.

Methodology/Principal Findings

We conducted a cross-sectional online survey among 2,253 French representative adults aged 18 to 64 from November 17 to 25, 2009 (completion rate: 93.8%). The main outcome was the acceptability of A/H1N1 vaccination as defined by previous receipt or intention to get vaccinated (“Yes, certainly”, “Yes, probably”). Overall 17.0% (CI 95%, 15.5% to 18.7%) of respondents accepted A/H1N1 vaccination. Independent factors associated with acceptability included: male sex (p = .0001); older age (p = .002); highest or lowest level of education (p = .016); non-clerical occupation (p = .011); having only one child (p = .008); and having received seasonal flu vaccination in prior 3 years (p<.0001). Acceptability was also significantly higher among pregnant women (37.9%) and other at risk groups with chronic diseases (34.8%) (p = .002). Only 35.5% of respondents perceived A/H1N1 influenza illness as a severe disease and 12.7% had experienced A/H1N1 cases in their close relationships with higher acceptability (p<.0001 and p = .006, respectively). In comparison to 26.0% respondents who did not consult their primary care physician, acceptability was significantly higher among 8.0% respondents who were formally advised to get vaccinated, and lower among 63.7% respondents who were not advised to get vaccinated (respectively: 15.8%, 59.5% and 11.7%- p<.0001). Among respondents who refused vaccination, 71.2% expressed concerns about vaccine safety.

Conclusions/Significance

Our survey occurred one week before the peak of the pandemic in France. We found that alarming public health messages aiming at increasing the perception of risk severity were counteracted by daily personal experience which did not confirm the threat, while vaccine safety was a major issue. This dissonance may have been amplified by having not involved primary care physicians in the mass vaccination campaign.     

Comparison of Estimated Glomerular Filtration Rate by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Equations with and without Cystatin C for Predicting Clinical Outcomes in Elderly Women

Background

Reduced estimated glomerular filtration rate (eGFR) using the cystatin-C derived equations might be a better predictor of cardiovascular disease (CVD) mortality compared with the creatinine-derived equations, but this association remains unclear in elderly individuals.

Aim

The aims of this study were to compare the predictive values of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C eGFR equations for all-cause mortality and CVD events (hospitalizations±mortality).

Methods

Prospective cohort study of 1165 elderly women aged>70 years. Associations between eGFR and outcomes were examined using Cox regression analysis. Test accuracy of eGFR equations for predicting outcomes was examined using Receiver Operating Characteristic (ROC) analysis and net reclassification improvement (NRI).

Results

Risk of all-cause mortality for every incremental reduction in eGFR determined using CKD-EPI-creatinine, CKD-EPI-cystatin C and the CKD-EPI-creatinine-cystatic C equations was similar. Areas under the ROC curves of CKD-EPI-creatinine, CKD-EPI-cystatin C and CKD-EPI-creatinine-cystatin C equations for all-cause mortality were 0.604 (95%CI 0.561–0.647), 0.606 (95%CI 0.563–0.649; p = 0.963) and 0.606 (95%CI 0.563–0.649; p = 0.894) respectively. For all-cause mortality, there was no improvement in the reclassification of eGFR categories using the CKD-EPI-cystatin C (NRI -4.1%; p = 0.401) and CKD-EPI-creatinine-cystatin C (NRI -1.2%; p = 0.748) compared with CKD-EPI-creatinine equation. Similar findings were observed for CVD events.

Conclusion

eGFR derived from CKD-EPI cystatin C and CKD-EPI creatinine-cystatin C equations did not improve the accuracy or predictive ability for clinical events compared to CKD-EPI-creatinine equation in this cohort of elderly women.     

IFNγ Response to Mycobacterium tuberculosis,Risk of Infection and Disease in Household Contacts of Tuberculosis Patients in Colombia

Objectives

Household contacts (HHCs) of pulmonary tuberculosis patients are at high risk of Mycobacterium tuberculosis infection and early disease development. Identification of individuals at risk of tuberculosis disease is a desirable goal for tuberculosis control. Interferon-gamma release assays (IGRAs) using specific M. tuberculosis antigens provide an alternative to tuberculin skin testing (TST) for infection detection. Additionally, the levels of IFNγ produced in response to these antigens may have prognostic value. We estimated the prevalence of M. tuberculosis infection by IGRA and TST in HHCs and their source population (SP), and assessed whether IFNγ levels in HHCs correlate with tuberculosis development.

Methods

A cohort of 2060 HHCs was followed for 2–3 years after exposure to a tuberculosis case. Besides TST, IFNγ responses to mycobacterial antigens: CFP, CFP-10, HspX and Ag85A were assessed in 7-days whole blood cultures and compared to 766 individuals from the SP in Medellín, Colombia. Isoniazid prophylaxis was not offered to child contacts because Colombian tuberculosis regulations consider it only in children under 5 years, TST positive without BCG vaccination.

Results

Using TST 65.9% of HHCs and 42.7% subjects from the SP were positive (OR 2.60, p<0.0001). IFNγ response to CFP-10, a biomarker of M. tuberculosis infection, tested positive in 66.3% HHCs and 24.3% from the SP (OR = 6.07, p<0.0001). Tuberculosis incidence rate was 7.0/1000 person years. Children <5 years accounted for 21.6% of incident cases. No significant difference was found between positive and negative IFNγ responders to CFP-10 (HR 1.82 95% CI 0.79–4.20 p = 0.16). However, a significant trend for tuberculosis development amongst high HHC IFNγ producers was observed (trend Log rank p = 0.007).

Discussion

CFP-10-induced IFNγ production is useful to establish tuberculosis infection prevalence amongst HHC and identify those at highest risk of disease. The high tuberculosis incidence amongst children supports administration of chemoprohylaxis to child contacts regardless of BCG vaccination.     

Adipocytokines,Hepatic and Inflammatory Biomarkers and Incidence of Type 2 Diabetes. The CoLaus Study

Context

There is contradictory information regarding the prognostic importance of adipocytokines, hepatic and inflammatory biomarkers on the incidence of type 2 diabetes. The objective was to assess the prognostic relevance of adipocytokine and inflammatory markers (C-reactive protein – CRP; interleukin-1beta – IL-1β; interleukin-6– IL-6; tumour necrosis factor-α – TNF-α; leptin and adiponectin) and gamma-glutamyl transpeptidase (γGT) on the incidence of type 2 diabetes.

Methods

Prospective, population-based study including 3,842 non-diabetic participants (43.3% men, age range 35 to 75 years), followed for an average of 5.5 years (2003–2008). The endpoint was the occurrence of type 2 diabetes.

Results

208 participants (5.4%, 66 women) developed type 2 diabetes during follow-up. On univariate analysis, participants who developed type 2 diabetes had significantly higher baseline levels of IL-6, CRP, leptin and γGT, and lower levels of adiponectin than participants who remained free of type 2 diabetes. After adjusting for a validated type 2 diabetes risk score, only the associations with adiponectin: Odds Ratio and (95% confidence interval): 0.97 (0.64–1.47), 0.84 (0.55–1.30) and 0.64 (0.40–1.03) for the second, third and forth gender-specific quartiles respectively, remained significant (P-value for trend = 0.05). Adding each marker to a validated type 2 diabetes risk score (including age, family history of type 2 diabetes, height, waist circumference, resting heart rate, presence of hypertension, HDL cholesterol, triglycerides, fasting glucose and serum uric acid) did not improve the area under the ROC or the net reclassification index; similar findings were obtained when the markers were combined, when the markers were used as continuous (log-transformed) variables or when gender-specific quartiles were used.

Conclusion

Decreased adiponectin levels are associated with an increased risk for incident type 2 diabetes, but they seem to add little information regarding the risk of developing type 2 diabetes to a validated risk score.     

Association between Adiponectin Concentrations and Cardiovascular Disease in Diabetic Patients: A Systematic Review and Meta-Analysis

Background

This systematic review and meta-analysis of prospective studies evaluates the association between adiponectin concentrations and risk of cardiovascular disease (CVD) in individuals with diabetes mellitus (DM).

Methods

PubMed and Embase were searched for prospective studies on the association of adiponectin concentrations and risk of CVD up to June 2013. Random-effect model was selected to pool the relative risk (RR) and 95% CI.

Results

Five prospective cohort studies and one nested case-control studies met the included criterion. The estimated summary RR and 95% CI of five prospective cohort studies for type 2 diabetes comparing top vs low tertile of adiponectin concentrations was 0.99 (95% CI: 0.67–1.45), with significant heterogeneity between studies (p = 0.037, I ² = 60.9%). This heterogeneity was explained by one study conducted in Korean.

Conclusions

This study represents the first meta-analysis between adiponectin levels and CVD in diabetic patients and indicated no association was found. This result should be verified further by large sample size, long duration of follow-up, and well-designed prospective clinical trials.