Diagnostic and Prognostic Impact of Circulating YKL-40, IL-6, and CA 19.9 in Patients with Pancreatic Cancer

Purpose

We tested the hypothesis that high plasma YKL-40 and IL-6 associate with pancreatic cancer and short overall survival.

Patients and Methods

In all, 559 patients with pancreatic cancer from prospective biomarker studies from Denmark (n = 448) and Germany (n = 111) were studied. Plasma YKL-40 and IL-6 were determined by ELISAs and serum CA 19.9 by chemiluminescent immunometric assay.

Results

Odds ratios (ORs) for prediction of pancreatic cancer were significant for all biomarkers, with CA 19.9 having the highest AUC (CA 19.9: OR = 2.28, 95% CI 1.97 to 2.68, p<0.0001, AUC = 0.94; YKL-40: OR = 4.50, 3.99 to 5.08, p<0.0001, AUC = 0.87; IL-6: OR = 3.68, 3.08 to 4.44, p<0.0001, AUC = 0.87). Multivariate Cox analysis (YKL-40, IL-6, CA 19.9, age, stage, gender) in patients operated on showed that high preoperative IL-6 and CA 19.9 (dichotomized according to normal values) were independently associated with short overall survival (CA 19.9: HR = 2.51, 1.22–5.15, p = 0.013; IL-6: HR = 2.03, 1.11 to 3.70, p = 0.021). Multivariate Cox analysis of non-operable patients (Stage IIB-IV) showed that high pre-treatment levels of each biomarker were independently associated with short overall survival (YKL-40: HR = 1.30, 1.03 to 1.64, p = 0.029; IL-6: HR = 1.71, 1.33 to 2.20, p<0.0001; CA 19.9: HR = 1.54, 1.06 to 2.24, p = 0.022). Patients with preoperative elevation of both IL-6 and CA 19.9 had shorter overall survival (p<0.005) compared to patients with normal levels of both biomarkers (45% vs. 92% alive after 12 months).

Conclusions

Plasma YKL-40 and IL-6 had less diagnostic impact than CA 19.9. Combination of pretreatment YKL-40, IL-6, and CA 19.9 may have clinical value to identify pancreatic cancer patients with the poorest prognosis.     

Cutaneous Chronic Graft-Versus-Host Disease Does Not Have the Abnormal Endothelial Phenotype or Vascular Rarefaction Characteristic of Systemic Sclerosis

Background

The clinical and histologic appearance of fibrosis in cutaneous lesions in chronic graft-versus -host disease (c-GVHD) resembles the appearance of fibrosis in scleroderma (SSc). Recent studies identified distinctive structural changes in the superficial dermal microvasculature and matrix of SSc skin. We compared the dermal microvasculature in human c-GVHD to SSc to determine if c-GVHD is a suitable model for SSc.

Methodology/Principal Findings

We analyzed skin biopsies of normal controls (n = 24), patients with SSc (n = 30) and c-GVHD with dermal fibrosis (n = 133)). Immunostaining was employed to identify vessels, vascular smooth muscle, dermal matrix, and cell proliferation. C-GVHD and SSc had similar dermal matrix composition and vascular smooth muscle pathology, including intimal hyperplasia. SSc, however, differed significantly from c-GVHD in three ways. First, there were significantly fewer (p = 0.00001) average vessels in SSc biopsies (9.8) when compared with c-GVHD (16.5). Second, in SSc, endothelial markers were decreased significantly (19/19 and 12/14 for VE cadherin and vWF (p = <0.0001 and <0.05), respectively). In contrast, 0/13 c-GVHD biopsies showed loss of staining with canonical endothelial markers. Third, c-GVHD contained areas of microvascular endothelial proliferation not present in the SSc biopsies.

Conclusions/Significance

The sclerosis associated with c-GVHD appears to resemble wound healing. Focal capillary proliferation occurs in early c-GVHD. In contrast, loss of canonical endothelial markers and dermal capillaries is seen in SSc, but not in c-GVHD. The loss of VE cadherin in SSc, in particular, may be related to microvascular rarefaction because VE cadherin is necessary for angiogenesis. C-GVHD is a suitable model for studying dermal fibrosis but may not be applicable for studying the microvascular alterations characteristic of SSc.     

Low Frequency Magnetic Fields Enhance Antitumor Immune Response against Mouse H22 Hepatocellular Carcinoma

Objective

Many studies have shown that magnetic fields (MF) inhibit tumor growth and influence the function of immune system. However, the effect of MF on mechanism of immunological function in tumor-bearing mice is still unclear.

Methods

In this study, tumor-bearing mice were prepared by subcutaneously inoculating Balb/c mice with hepatocarcinoma cell line H22. The mice were then exposed to a low frequency MF (0.4 T, 7.5 Hz) for 30 days. Survival rate, tumor growth and the innate and adaptive immune parameters were measured.

Results

MF treatment could prolong survival time (n = 28, p<0.05) and inhibit tumor growth (n = 9, p<0.01) in tumor-bearing mice. Moreover, this MF suppressed tumor-induced production of cytokines including interleukin-6 (IL-6), granulocyte colony- stimulating factor (G-CSF) and keratinocyte-derived chemokine (KC) (n = 9–10, p<0.05 or 0.01). Furthermore, MF exposure was associated with activation of macrophages and dendritic cells, enhanced profiles of CD4⁺ T and CD8⁺ T lymphocytes, the balance of Th17/Treg and reduced inhibitory function of Treg cells (n = 9–10, p<0.05 or 0.01) in the mice model.

Conclusion

The inhibitory effect of MF on tumor growth was related to the improvement of immune function in the tumor-bearing mice.     

A Comparison of the Predictive Power of Anthropometric Indices for Hypertension and Hypotension Risk

Background and Aims

It is commonly accepted that body fat distribution is associated with hypertension, but the strongest anthropometric indicator of the risk of hypertension is still controversial. Furthermore, no studies on the association of hypotension with anthropometric indices have been reported. The objectives of the present study were to determine the best predictors of hypertension and hypotension among various anthropometric indices and to assess the use of combined indices as a method of improving the predictive power in adult Korean women and men.

Methods

For 12789 subjects 21–85 years of age, we assessed 41 anthropometric indices using statistical analyses and data mining techniques to determine their ability to discriminate between hypertension and normotension as well as between hypotension and normotension. We evaluated the predictive power of combined indices using two machine learning algorithms and two variable subset selection techniques.

Results

The best indicator for predicting hypertension was rib circumference in both women (p = <0.0001; OR = 1.813; AUC = 0.669) and men (p = <0.0001; OR = 1.601; AUC = 0.627); for hypotension, the strongest predictor was chest circumference in women (p = <0.0001; OR = 0.541; AUC = 0.657) and neck circumference in men (p = <0.0001; OR = 0.522; AUC = 0.672). In experiments using combined indices, the areas under the receiver operating characteristic curves (AUC) for the prediction of hypertension risk in women and men were 0.721 and 0.652, respectively, according to the logistic regression with wrapper-based variable selection; for hypotension, the corresponding values were 0.675 in women and 0.737 in men, according to the naïve Bayes with wrapper-based variable selection.

Conclusions

The best indicators of the risk of hypertension and the risk of hypotension may differ. The use of combined indices seems to slightly improve the predictive power for both hypertension and hypotension.     

Reduced Ventricular Arrhythmogeneity and Increased Electrical Complexity in Normal Exercised Rats

Background

The mechanisms whereby aerobic training reduces the occurrence of sudden cardiac death in humans are not clear. We test the hypothesis that exercise-induced increased resistance to ventricular tachycardia and fibrillation (VT/VF) involve an intrinsic remodeling in healthy hearts.

Methods and Results

Thirty rats were divided into a sedentary (CTRL, n = 16) and two exercise groups: short- (4 weeks, ST, n = 7) and long-term (8 weeks, LT, n = 7) trained groups. Following the exercise program hearts were isolated and studied in a Langendorff perfusion system. An S₁–S₂ pacing protocol was applied at the right ventricle to determine inducibility of VT/VF. Fast Fourier transforms were applied on ECG time-series. In-vivo measurements showed training-induced increase in aerobic capacity, heart-to-body weight ratio and a 50% low-to-high frequency ratio reduction in the heart rate variability (p<0.05). In isolated hearts the probability for VF decreased from 26.1±14.4 in CTRL to 13.9±14.1 and 6.7±8.5% in the ST and LT, respectively (p<0.05). Duration of VF also decreased from 19.0±5.7 in CTRL to 8.8±7.1 and 6.0±5.8 sec in ST and LT respectively (p<0.05). Moreover, the pacing current required for VF induction increased following exercise (2.9±1.7 vs. 5.4±2.1 and 8.5±0.9 mA, respectively; p<0.05). Frequency analysis of ECG revealed an exercise-induced VF transition from a narrow single peak spectrum at 17 Hz in CTRL to a broader range of peaks ranging between 8.8 and 22.5 Hz in the LT group (p<0.05).

Conclusion

Exercise in rats leads to reduced VF propensity associated with an intrinsic cardiac remodeling related to a broader spectral range and faster frequency components in the ECG.     

The E-Wave Deceleration Rate E/DT Outperforms the Tissue Doppler-Derived Index E/e' in Characterizing Lung Remodeling in Heart Failure with Preserved Ejection Fraction

Background

Diastolic dysfunction in heart failure with preserved ejection fraction (HFpEF) may result in pulmonary congestion and lung remodeling. We evaluated the usefulness of major diastolic echocardiographic parameters and of the deceleration rate of early transmitral diastolic velocity (E/DT) in predicting lung remodeling in a rat model of HFpEF.

Methods and Results

Rats underwent aortic banding (AoB) to induce pressure overload (PO). Left ventricular hypertrophy fully developed 2 weeks after AoB. At 4 and 6 weeks, the lung weight-to-body weight ratio (LW/BW), a sensitive marker for pulmonary congestion and remodeling, dramatically increased despite preserved fractional shortening, indicating the presence of HFpEF. The time course of LW/BW was well reflected by E/DT, by the ratio of early to late transmitral diastolic velocity (E/A) and the deceleration time of E (DT), but not by the ratio of transmitral to mitral annular early diastolic velocity (E/e''). In agreement, the best correlation with LW/BW was found for E/DT (r = 0.76; p<0.0001), followed by E/A (r = 0.69; p<0.0001), DT (r = −0.62; p<0.0001) and finally E/e'' (r = 0.51; p<0.001). Furthermore, analysis of receiver-operating characteristic curves for the prediction of increased LW/BW revealed excellent area under the curve values for E/DT (AUC = 0.98) and DT (AUC = 0.95), which are significantly higher than that of E/e'' (AUC = 0.82). In a second approach, we also found that the new parameter E/DT correlated well with right ventricular weight index and echocardiographic measures of right ventricular systolic function.

Conclusions

The novel parameter E/DT outperforms the tissue Doppler index E/e'' in detecting and monitoring lung remodeling induced by pressure overload. The results may provide a handy tool to point towards secondary lung disease in HFpEF and warrant further clinical investigations.     

Cerebrospinal Fluid Immunoglobulin Kappa Light Chain in Clinically Isolated Syndrome and Multiple Sclerosis

Background

Oligoclonal bands (OCB) are the most widely used CSF test to support the diagnosis of MS and to predict conversion of clinically isolated syndrome (CIS) to multiple sclerosis (MS). Since OCB tests are based on non-quantitative and difficult to standardise techniques, measurement of immunoglobulin kappa free light chains (KFLC) may represent an easier to use quantitative test.

Methods

KFLC were measured in CSF and serum of 211 patients using ELISA. These include patients without any inflammatory central nervous system reaction (NIND, n = 77), MS (n = 20), viral CNS infections (V-CNS-I, n = 10), neuroborreliosis (NB, n = 17) and other bacterial CNS infections (B-CNS-I, n = 10). Furthermore a cohort of 77 patients with CIS, including 39 patients that remained CIS over follow-up of two years (CIS-CIS) and 38 patients that developed MS over the same follow-up time (CIS-MS).

Results

CSF-serum ratio of KFLC (Q KFLC) was elevated in all patients with MS, 86.8% of patients with CIS-MS and 61.5% of patients with CIS-CIS. It was significantly elevated in CIS with presence of OCB (p<0.001). Q KFLC significantly correlated with other CSF variables such as CSF leukocyte count (p<0.001, R = 0.46), CSF CXCL13 levels (p<0.001, R = 0.64) and also intrathecal IgG synthesis (p<0.001, R = 0.74) as determined by nephelometry and quotient diagram. OCB were detected in 66.7% of CIS-CIS and in 92.1% of CIS-MS.

Conclusions

Although the measurement of CSF KFLC is a rapid and quantitative easy to standardize tool, it is almost equal but not superior to OCB with regard to diagnostic sensitivity and specificity in patients with early MS.     

Mechanical Ventilation Drives Inflammation in Severe Viral Bronchiolitis

Introduction

Respiratory insufficiency due to severe respiratory syncytial virus (RSV) infection is the most frequent cause of paediatric intensive care unit admission in infants during the winter season. Previous studies have shown increased levels of inflammatory mediators in airways of mechanically ventilated children compared to spontaneous breathing children with viral bronchiolitis. In this prospective observational multi-center study we aimed to investigate whether this increase was related to disease severity or caused by mechanical ventilation.

Materials and Methods

Nasopharyngeal aspirates were collected <1 hour before intubation and 24 hours later in RSV bronchiolitis patients with respiratory failure (n = 18) and non-ventilated RSV bronchiolitis controls (n = 18). Concentrations of the following cytokines were measured: interleukin (IL)-1α, IL-1β, IL-6, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1α.

Results

Baseline cytokine levels were comparable between ventilated and non-ventilated infants. After 24 hours of mechanical ventilation mean cytokine levels, except for MIP-1α, were elevated compared to non-ventilated infected controls: IL-1α (159 versus 4 pg/ml, p<0.01), IL-1β (1068 versus 99 pg/ml, p<0.01), IL-6 (2343 versus 958 pg/ml, p<0.05) and MCP-1 (174 versus 26 pg/ml, p<0.05).

Conclusions

Using pre- and post-intubation observations, this study suggests that endotracheal intubation and subsequent mechanical ventilation cause a robust pulmonary inflammation in infants with RSV bronchiolitis.     

Heart Failure Induces Significant Changes in Nuclear Pore Complex of Human Cardiomyocytes

Aims

The objectives of this study were to analyse the effect of heart failure (HF) on several proteins of nuclear pore complex (NPC) and their relationship with the human ventricular function.

Methods and Results

A total of 88 human heart samples from ischemic (ICM, n = 52) and dilated (DCM, n = 36) patients undergoing heart transplant and control donors (CNT, n = 9) were analyzed by Western blot. Subcellular distribution of nucleoporins was analysed by fluorescence and immunocytochemistry. When we compared protein levels according to etiology, ICM showed significant higher levels of NDC1 (65%, p<0.0001), Nup160 (88%, p<0.0001) and Nup153 (137%, p = 0.004) than those of the CNT levels. Furthermore, DCM group showed significant differences for NDC1 (41%, p<0.0001), Nup160 (65%, p<0.0001), Nup153 (155%, p = 0.006) and Nup93 (88%, p<0.0001) compared with CNT. However, Nup155 and translocated promoter region (TPR) did not show significant differences in their levels in any etiology. Regarding the distribution of these proteins in cell nucleus, only NDC1 showed differences in HF. In addition, in the pathological group we obtained good relationship between the ventricular function parameters (LVEDD and LVESD) and Nup160 (r = −0382, p = 0.004; r = −0.290, p = 0.033; respectively).

Conclusions

This study shows alterations in specific proteins (NDC1, Nup160, Nup153 and Nup93) that compose NPC in ischaemic and dilated human heart. These changes, related to ventricular function, could be accompanied by alterations in the nucleocytoplasmic transport. Therefore, our findings may be the basis for a new approach to HF management.     

Sperm Recovery and IVF after Testicular Sperm Extraction (TESE): Effect of Male Diagnosis and Use of Off-Site Surgical Centers on Sperm Recovery and IVF

Objective

Determine whether testicular sperm extractions and pregnancy outcomes are influenced by male and female infertility diagnoses, location of surgical center and time to cryopreservation.

Patients

One hundred and thirty men undergoing testicular sperm extraction and 76 couples undergoing 123 in vitro fertilization cycles with testicular sperm.

Outcome Measures

Successful sperm recovery defined as 1–2 sperm/0.5 mL by diagnosis including obstructive azoospermia (n = 60), non-obstructive azoospermia (n = 39), cancer (n = 14), paralysis (n = 7) and other (n = 10). Obstructive azoospermia was analyzed as congenital absence of the vas deferens (n = 22), vasectomy or failed vasectomy reversal (n = 37) and “other”(n = 1). Sperm recovery was also evaluated by surgical site including infertility clinic (n = 54), hospital operating room (n = 67) and physician’s office (n = 11). Treatment cycles were evaluated for number of oocytes, fertilization, embryo quality, implantation rate and clinical/ongoing pregnancies as related to male diagnosis, female diagnosis, and use of fresh or cryopreserved testicular sperm.

Results

Testicular sperm recovery from azoospermic males with all diagnoses was high (70 to 100%) except non-obstructive azoospermia (31%) and was not influenced by distance from surgical center to laboratory. Following in vitro fertilization, rate of fertilization was significantly lower with non-obstructive azoospermia (43%, p = <0.0001) compared to other male diagnoses (66%, p = <0.0001, 59% p = 0.015). No differences were noted in clinical pregnancy rate by male diagnosis; however, the delivery rate per cycle was significantly higher with obstructive azoospermia (38% p = 0.0371) compared to diagnoses of cancer, paralysis or other (16.7%). Women diagnosed with diminished ovarian reserve had a reduced clinical pregnancy rate (7.4% p = 0.007) compared to those with other diagnoses (44%).

Conclusion

Testicular sperm extraction is a safe and effective option regardless of the etiology of the azoospermia. The type of surgical center and/or its distance from the laboratory was not related to success. Men with non-obstructive azoospermia have a lower chance of successful sperm retrieval and fertilization.     

Multidisciplinary Team-Based Approach for Comprehensive Preoperative Pulmonary Rehabilitation Including Intensive Nutritional Support for Lung Cancer Patients

Background

To decrease the risk of postoperative complication, improving general and pulmonary conditioning preoperatively should be considered essential for patients scheduled to undergo lung surgery.

Objective

The aim of this study is to develop a short-term beneficial program of preoperative pulmonary rehabilitation for lung cancer patients.

Methods

From June 2009, comprehensive preoperative pulmonary rehabilitation (CHPR) including intensive nutritional support was performed prospectively using a multidisciplinary team-based approach. Postoperative complication rate and the transitions of pulmonary function in CHPR were compared with historical data of conventional preoperative pulmonary rehabilitation (CVPR) conducted since June 2006. The study population was limited to patients who underwent standard lobectomy.

Results

Postoperative complication rate in the CVPR (n = 29) and CHPR (n = 21) were 48.3% and 28.6% (p = 0.2428), respectively. Those in patients with Charlson Comorbidity Index scores ≥2 were 68.8% (n = 16) and 27.3% (n = 11), respectively (p = 0.0341) and those in patients with preoperative risk score in Estimation of Physiologic Ability and Surgical Stress scores >0.3 were 57.9% (n = 19) and 21.4% (n = 14), respectively (p = 0.0362). Vital capacities of pre- and post intervention before surgery in the CHPR group were 2.63±0.65 L and 2.75±0.63 L (p = 0.0043), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6815). Forced expiratory volumes in one second of pre- and post intervention before surgery in the CHPR group were 1.73±0.46 L and 1.87±0.46 L (p = 0.0012), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6424).

Conclusions

CHPR appeared to be a beneficial and effective short-term preoperative rehabilitation protocol, especially in patients with poor preoperative conditions.     

Angiotensin-Induced Abdominal Aortic Aneurysms in Hypercholesterolemic Mice: Role of Serum Cholesterol and Temporal Effects of Exposure

Objective

Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E^−/− mice.

Approach

A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time.

Results

The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (−0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86).

Conclusions

These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.     

Hemostatic Dysfunction Is Increased in Patients with Hepatosplenic Schistosomiasis Mansoni and Advanced Periportal Fibrosis

Background

Schistosomiasis mansoni is an endemic parasitic disease and a public health problem in Northeast Brazil. In some patients, hepatic abnormalities lead to periportal fibrosis and result in the most severe clinical form, hepatosplenic schistosomiasis. This study aimed to evaluate whether abnormal blood coagulation and liver function tests in patients with hepatosplenic schistosomiasis (n = 55) correlate with the severity of their periportal fibrosis.

Methodology/Principal Findings

Blood samples were used for liver function tests, hemogram and prothrombin time (International Normalized Ratio, INR). The blood coagulation factors (II, VII, VIII, IX and X), protein C and antithrombin IIa (ATIIa), plasminogen activator inhibitor 1 (PAI-1) and D-dimer were measured by photometry or enzyme linked immunosorbent assay. Hyperfibrinolysis was defined on the basis of PAI-1 levels and a D-dimer concentration greater than a standard cut-off of 483 ng/mL. Standard liver function tests were all abnormal in the patient group compared to healthy controls (n = 29), including raised serum transaminases (p<0.001) and lower levels of albumin (p = 0.0156). Platelet counts were 50% lower in patients, while for coagulation factors there was a 40% increase in the INR (p<0.001) and reduced levels of Factor VII and protein C in patients compared to the controls (both p<0.001). Additionally, patients with more advanced fibrosis (n = 38) had lower levels of protein C compared to those with only central fibrosis (p = 0.0124). The concentration of plasma PAI-1 in patients was one-third that of the control group (p<0.001), and D-dimer levels 2.2 times higher (p<0.001) with 13 of the 55 patients having levels above the cut-off.

Conclusion/Significance

This study confirms that hemostatic abnormalities are associated with reduced liver function and increased liver fibrosis. Of note was the finding that a quarter of patients with hepatosplenic schistosomiasis and advanced periportal fibrosis have hyperfibrinolysis, as judged by excessive levels of D-dimer, which may predispose them to gastrointestinal bleeding.     

Study on Risk Factors for Severe Hand,Foot and Mouth Disease in China

Background

Epidemics of HFMD are elevated every year globally, especially in mainland China. The disease now presents as an increasing threat to public health worldwide.

Methods

Five hundred and seventy-one EV71-infected HFMD patients in Beijing You''an Hospital were grouped by disease severity: Mild (no severe complication) (n = 221), and Severe group (complicated with brainstem encephalitis (BE), and/or pulmonary edema (PE) (n = 350)). Clinical and laboratory findings and levels of 7 serum cytokines were analyzed.

Results

Univariate analysis showed that (RR)>26/min (p<0.001), age<4 yo (p = 0.001), GLU>8.3 mmol/L (p = 0.008), CL<98 mmol/L (p = 0.026), and WBC>1.2×10⁹/L (p = 0.040) were associated with severe cases. Results of multivariate analysis indicated five independent risk factors (RR>26/min (p<0.001), Age<4 yo (p<0.001), GLU>8.3 mmol/L (p = 0.011), LYM>40% (p = 0.010), and ALT>40 U/L (p = 0.045)). In addition to single-factor analysis, we further analyzed the use of different combinations of risk factors. “GLU>8.3 and CL<98 and RR>26” (confidence ration (CR) = 100%) is the top indicator, followed by “ALT>40 and LYM>40% and RR>26 and Age<4 yo” (CR = 92.9%).Serum levels of IL-2, IL-4, IL-10, IFNγ, GM-CSF, and TNFα were higher in severe cases than in mild cases. A new evaluation scoring system by scoring each risk factor 1 and independent risk factor 2 was developed for early identification of severe HFMD cases.

Conclusions

Five independent risk factors, along with indicative combinations of risk factors, for severe cases were identified, and a scoring system was created to facilitate the use of indicators for early medical intervention.     

Correlation of Circulating MMP-9 with White Blood Cell Count in Humans: Effect of Smoking

Background

Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects.

Methods

We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group.

Results

Circulating MMP-9 and WBC count are significantly correlated in men (R² = 0.13, p<0.001) and women (R² = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R² = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R² = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers.

Conclusions

WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans.     

Faster Cognitive and Functional Decline in Dysexecutive versus Amnestic Alzheimer's Subgroups: A Longitudinal Analysis of the National Alzheimer's Coordinating Center (NACC) Database

Objective

To compare the rate of cognitive and functional decline in dysexecutive, typical and amnestic subgroups of Alzheimer’s disease.

Methods

943 participants from the National Alzheimer’s Coordinating Center (NACC) database who had a diagnosis of probable AD were followed for a mean of 2.3 years. A dysexecutive subgroup (n = 165) was defined as having executive performance >1.5 SD worse than memory performance, an amnestic subgroup (n = 157) was defined as having memory performance >1.5 SD worse than executive performance and a typical subgroup (n = 621) was defined as having a difference in executive and memory performance of <1.5 SD. Generalized estimating equations (GEE) were used to model decline on the Folstein Mini Mental Status Exam (MMSE), rise on the Clinical Dementia Rating (CDR) sum of boxes and rise on the total Functional Assessment Questionnaire (FAQ).

Results

Compared with the amnestic subgroup, the dysexecutive subgroup declined 2.2X faster on the Folstein MMSE (p<.001), rose 42% faster on the CDR sum of boxes (p = .03) and rose 33% faster on the total FAQ (p = .01). Rate of change for the typical subgroup fell between that of the amnestic and dysexecutive subgroups for the MMSE, CDR sum of boxes and total FAQ. Among a subset of participants (n = 129) who underwent autopsy, the dysexecutive, amnestic and typical subgroups did not differ in odds of having an AD pathologic diagnosis, suggesting that variation in non-AD pathologies across subtypes did not lead to the observed differences.

Conclusions

A dysexecutive subgroup of AD has a unique disease course in addition to cognitive phenotype.     

High Levels of Both n-3 and n-6 Long-Chain Polyunsaturated Fatty Acids in Cord Serum Phospholipids Predict Allergy Development

Background

Long-chain polyunsaturated fatty acids (LCPUFAs) reduce T-cell activation and dampen inflammation. They might thereby counteract the neonatal immune activation and hamper normal tolerance development to harmless environmental antigens. We investigated whether fatty acid composition of cord serum phospholipids affects allergy development up to age 13 years.

Methods

From a population-based birth-cohort born in 1996/7 and followed until 13 years of age (n = 794), we selected cases with atopic eczema (n = 37) or respiratory allergy (n = 44), as well as non-allergic non-sensitized controls (n = 48) based on diagnosis at 13 years of age. Cord and maternal sera obtained at delivery from cases and controls were analysed for proportions of saturated, monounsaturated and polyunsaturated fatty acids among serum phospholipids.

Results

The cord serum phospholipids from subject who later developed either respiratory allergy or atopic eczema had significantly higher proportions of 5/8 LCPUFA species, as well as total n-3 LCPUFA, total n-6 LCPUFA and total LCPUFA compared to cord serum phospholipids from controls who did not develop allergy (P<0.001 for all comparisons). Conversely, individuals later developing allergy had lower proportion of the monounsaturated fatty acid 18∶1n-9 as well as total MUFA (p<0.001) among cord serum phospholipids. The risk of respiratory allergy at age 13 increased linearly with the proportion of n-3 LCPUFA (P_trend<0.001), n-6 LCPUFA (P_trend = 0.001), and total LCPUFA (P_trend<0.001) and decreased linearly with the proportions of total MUFA (P_trend = 0.025) in cord serum phospholipids. Furthermore, Kaplan-Meier estimates of allergy development demonstrated that total LCPUFA proportion in cord serum phospholipids was significantly associated with respiratory allergy (P = 0.008) and sensitization (P = 0.002), after control for sex and parental allergy.

Conclusion

A high proportion of long-chain PUFAs among cord serum phospholipids may predispose to allergy development. The mechanism is unknown, but may involve dampening of the physiologic immune activation in infancy needed for proper maturation of the infant''s immune system.