Cytomegalovirus Viral Load Kinetics in Patients with HIV/AIDS Admitted to a Medical Intensive Care Unit: A Case for Pre-Emptive Therapy

Background

Cytomegalovirus (CMV) infection is associated with severe diseases in immunosuppressed patients; however, there is a lack of data for pre-emptive therapy in patients with HIV/AIDS.

Method

This was a retrospective study, which enrolled patients diagnosed with HIV/AIDS (CD4<200 cells/μl), who had detectable CMV viral load (VL) during their stay in an adult medical intensive care unit between 2009–2012.

Results

After screening 82 patients’ records, 41 patients met the enrolment criteria. Their median age was 37 (interquartile range [IQR]: 31–46), and median CD4 count was 29 cells/μl (IQR: 5–55). Sixteen patients (39%) had serial measurements of CMV VL before treatment with ganciclovir. Patients whose baseline CMV VL values were between 1,000–3,000 copies/ml had significantly higher values (median of 14,650 copies/ml) on follow-up testing done 4–12 days later. Those with undetectable VLs at baseline testing had detectable VLs (median of 1,590 copies/ml) mostly within 20 days of follow-up testing. Patients who had VLs >1,000 copies/ml at baseline testing had significantly higher mortality compared to those who had <1,000 copies/ml {hazard ratio of 3.46, p = 0.003 [95% confidence interval (CI): 1.55–7.71]}. Analysis of the highest CMV VL per patient showed that patients who had VLs of >5,100 copies/ml and did not receive ganciclovir had 100% mortality compared to 58% mortality in those who received ganciclovir at VLs of >5,100 copies/ml, 50% mortality in those who were not treated and had low VLs of <5,100 copies/ml, and 44% mortality in those who had ganciclovir treatment at VLs of <5,100 copies/ml (p = 0.084, 0.046, 0.037, respectively).

Conclusion

This study showed a significantly increased mortality in patients with HIV/AIDS who had high CMV VLs, and suggests that a threshold value of 1,000 copies/ml may be appropriate for pre-emptive treatment in this group.     

Atrophy Rates in Asymptomatic Amyloidosis: Implications for Alzheimer Prevention Trials

There is considerable interest in designing therapeutic studies of individuals at risk of Alzheimer disease (AD) to prevent the onset of symptoms. Cortical β-amyloid plaques, the first stage of AD pathology, can be detected in vivo using positron emission tomography (PET), and several studies have shown that ∼1/3 of healthy elderly have significant β-amyloid deposition. Here we assessed whether asymptomatic amyloid-PET-positive controls have increased rates of brain atrophy, which could be harnessed as an outcome measure for AD prevention trials. We assessed 66 control subjects (age = 73.5±7.3 yrs; MMSE = 29±1.3) from the Australian Imaging Biomarkers & Lifestyle study who had a baseline Pittsburgh Compound B (PiB) PET scan and two 3T MRI scans ∼18-months apart. We calculated PET standard uptake value ratios (SUVR), and classified individuals as amyloid-positive/negative. Baseline and 18-month MRI scans were registered, and brain, hippocampal, and ventricular volumes and annualized volume changes calculated. Increasing baseline PiB-PET measures of β-amyloid load correlated with hippocampal atrophy rate independent of age (p = 0.014). Twenty-two (1/3) were PiB-positive (SUVR>1.40), the remaining 44 PiB-negative (SUVR≤1.31). Compared to PiB-negatives, PiB-positive individuals were older (76.8±7.5 vs. 71.7±7.5, p<0.05) and more were APOE4 positive (63.6% vs. 19.2%, p<0.01) but there were no differences in baseline brain, ventricle or hippocampal volumes, either with or without correction for total intracranial volume, once age and gender were accounted for. The PiB-positive group had greater total hippocampal loss (0.06±0.08 vs. 0.02±0.05 ml/yr, p = 0.02), independent of age and gender, with non-significantly higher rates of whole brain (7.1±9.4 vs. 4.7±5.5 ml/yr) and ventricular (2.0±3.0 vs. 1.1±1.0 ml/yr) change. Based on the observed effect size, recruiting 384 (95%CI 195–1080) amyloid-positive subjects/arm will provide 80% power to detect 25% absolute slowing of hippocampal atrophy rate in an 18-month treatment trial. We conclude that hippocampal atrophy may be a feasible outcome measure for secondary prevention studies in asymptomatic amyloidosis.     

Non-Selective Calcium Channel Blocker Bepridil Decreases Secondary Pathology in Mice after Photothrombotic Cortical Lesion

Experimental studies have identified a complex link between neurodegeneration, β-amyloid (Aβ) and calcium homeostasis. Here we asked whether early phase β-amyloid pathology in transgenic hAPP_SL mice exaggerates the ischemic lesion and remote secondary pathology in the thalamus, and whether a non-selective calcium channel blocker reduces these pathologies. Transgenic hAPP_SL (n = 33) and non-transgenic (n = 30) male mice (4–5 months) were subjected to unilateral cortical photothrombosis and treated with the non-selective calcium channel blocker bepridil (50 mg/kg, p.o., once a day) or vehicle for 28 days, starting administration 2 days after the operation. Animals were then perfused for histological analysis of infarct size, Aβ and calcium accumulation in the thalamus. Cortical photothrombosis resulted in a small infarct, which was associated with atypical Aβ and calcium accumulation in the ipsilateral thalamus. Transgenic mice had significantly smaller infarct volumes than non-transgenic littermates (P<0.05) and ischemia-induced rodent Aβ accumulation in the thalamus was lower in transgenic mice compared to non-transgenic mice (P<0.01). Bepridil decreased calcium load in the thalamus (P<0.01). The present data suggest less pronounced primary and secondary pathology in hAPP_SL transgenic mice after ischemic cortical injury. Bepridil particularly decreased calcium pathology in the thalamus following ischemia.     

Fluid Overload,Pulse Wave Velocity,and Ratio of Brachial Pre-Ejection Period to Ejection Time in Diabetic and Non-Diabetic Chronic Kidney Disease

Fluid overload is one of the characteristics in chronic kidney disease (CKD). Changes in extracellular fluid volume are associated with progression of diabetic nephropathy. Not only diabetes but also fluid overload is associated with cardiovascular risk factors The aim of the study was to assess the interaction between fluid overload, diabetes, and cardiovascular risk factors, including arterial stiffness and left ventricular function in 480 patients with stages 4–5 CKD. Fluid status was determined by bioimpedance spectroscopy method, Body Composition Monitor. Brachial-ankle pulse wave velocity (baPWV), as a good parameter of arterial stiffness, and brachial pre-ejection period (bPEP)/brachial ejection time (bET), correlated with impaired left ventricular function were measured by ankle-brachial index (ABI)-form device. Of all patients, 207 (43.9%) were diabetic and 240 (50%) had fluid overload. For non-diabetic CKD, fluid overload was associated with being female (β = –2.87, P = 0.003), heart disease (β = 2.69, P = 0.04), high baPWV (β = 0.27, P = 0.04), low hemoglobin (β = –1.10, P<0.001), and low serum albumin (β = –5.21, P<0.001) in multivariate analysis. For diabetic CKD, fluid overload was associated with diuretics use (β = 3.69, P = 0.003), high mean arterial pressure (β = 0.14, P = 0.01), low bPEP/ET (β = –0.19, P = 0.03), low hemoglobin (β = –1.55, P = 0.001), and low serum albumin (β = –9.46, P<0.001). In conclusion, baPWV is associated with fluid overload in non-diabetic CKD and bPEP/bET is associated with fluid overload in diabetic CKD. Early and accurate assessment of these associated cardiovascular risk factors may improve the effects of entire care in late CKD.     

Early Vascular Aging in Young and Middle-Aged Ischemic Stroke Patients: The Norwegian Stroke in the Young Study

Background

Ischemic stroke survivors have high risk of cardiovascular morbidity and mortality even at young age, suggesting that early arterial aging is common among such patients.

Methods

We measured aortic stiffness by carotid-femoral pulse wave velocity (PWV) in 205 patients (69% men) aged 15–60 years with acute ischemic stroke in the prospective Norwegian Stroke in the Young Study. High for age carotid-femoral PWV was identified in the reference normogram.

Results

Patients were on average 49±10 years old, 34% had a history of hypertension and 37% had metabolic syndrome (MetS). In the total study population, higher PWV was associated with history of hypertension (β = 0.18), higher age (β = 0.34), systolic blood pressure (BP) (β = 0.28) and serum creatinine (β = 0.18) and lower high-density lipoprotein (HDL) cholesterol (β = –0.10, all p<0.01) in multivariate linear regression analysis (multiple R² = 0.42, p<0.001). High for age PWV was found in 18% of patients. In univariate analyses, known hypertension was associated with a 6-fold, MetS with a 4-fold and presence of carotid plaque with a 3.7-fold higher risk for high for age PWV (all p<0.01). In multiple logistic regression analysis higher systolic BP (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.02–1.06; p<0.01), history of hypertension (OR 3.59; 95% CI 1.52–8.51; p<0.01), low HDL cholesterol (OR 3.03; 95% CI 1.00–9.09; p = 0.05) and higher serum creatinine (OR 1.04; 95% CI 1.01–1.06; p<0.01) were associated with high for age PWV.

Conclusions

Higher PWV is common in younger and middle-aged ischemic stroke patients and associated with a clustering of classical cardiovascular risk factors.ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01597453","term_id":"NCT01597453"}}NCT01597453     

Association between Apolipoprotein E Gene Polymorphism and the Risk of Coronary Artery Disease in Chinese Population: Evidence from a Meta-Analysis of 40 Studies

Background

Epidemiological studies have evaluated the association between apolipoprotein E (ApoE) gene polymorphism and coronary artery disease (CAD) risk which developed inconsistent conclusions. To derive a more precise estimation of the relationship in Chinese population, we performed this meta-analysis.

Methods

Databases, including PubMed, EMbase, Web of Science, CBMdisc and CNKI, were searched to get the genetic association studies. Additionally, hand searching of the references of identified articles were performed. All the statistical tests were performed using Review Manager 5.1.2 and Stata 11.0.

Results

We identified a total of 40 studies, including 4,564 CAD cases and 3,985 controls. The results showed evidence for significant association between ApoE ε4 allele and CAD risk (for ε2/ε4 vs. ε3/ε3: OR = 1.86, 95% CI = 1.42–2.43, p<0.00001; for ε3/ε4 vs. ε3/ε3: OR = 2.34, 95% CI = 2.07–2.65, p<0.00001; for ε4/ε4 vs. ε3/ε3: OR = 2.89, 95% CI = 1.87–4.47, p<0.00001; for ε4 allele vs. ε3 allele: OR = 2.11, 95% CI = 1.91–2.35, p<0.00001).

Conclusions

The present meta-analysis suggests an association between ApoE ε4 allele and increased risk of CAD in Chinese population. However, due to the small sample size in most of the included studies and the selection bias existed in some studies, the results should be interpreted with caution.     

Plasma Levels of Soluble Urokinase-Type Plasminogen Activator Receptor Associate with the Clinical Severity of Acute Puumala Hantavirus Infection

Objectives

Urokinase-type plasminogen activator receptor is a multifunctional glycoprotein, the expression of which is increased during inflammation. It is known to bind to β₃-integrins, which are elementary for the cellular entry of hantaviruses. Plasma soluble form of the receptor (suPAR) levels were evaluated as a predictor of severe Puumala hantavirus (PUUV) infection and as a possible factor involved in the pathogenesis of the disease.

Design

A single-centre prospective cohort study.

Subjects and Methods

Plasma suPAR levels were measured twice during the acute phase and once during the convalescence in 97 patients with serologically confirmed acute PUUV infection using a commercial enzyme-linked immunosorbent assay (ELISA).

Results

The plasma suPAR levels were significantly higher during the acute phase compared to the control values after the hospitalization (median 8.7 ng/ml, range 4.0–18.2 ng/ml vs. median 4.7 ng/ml, range 2.4–12.2 ng/ml, P<0.001). The maximum suPAR levels correlated with several variables reflecting the severity of the disease. There was a positive correlation with maximum leukocyte count (r = 0.475, p<0.001), maximum plasma creatinine concentration (r = 0.378, p<0.001), change in weight during the hospitalization (r = 0.406, p<0.001) and the length of hospitalization (r = 0.325, p = 0.001), and an inverse correlation with minimum platelet count (r = −0.325, p = 0.001) and minimum hematocrit (r = −0.369, p<0.001).

Conclusion

Plasma suPAR values are markedly increased during acute PUUV infection and associate with the severity of the disease. The overexpression of suPAR possibly activates β₃-integrin in PUUV infection, and thus might be involved in the pathogenesis of the disease.     

Hepatic Hemodynamics and Fetal Growth: A Relationship of Interest for Further Research

Background

It is well known that hepatic hemodynamics is an important physiologic mechanism in the regulation of cardiac output (CO). It has been reported that maternal cardiac output relates to neonatal weight at birth.

Aims

In this study, we assessed the correlation between maternal hepatic vein Doppler flow parameters, cardiac output and neonatal birth weight.

Methods

Healthy women with uncomplicated second or third trimester pregnancy attending the outpatient antenatal clinic of Ziekenhuis Oost-Limburg in Genk (Belgium), had a standardized combined electrocardiogram-Doppler ultrasound with Impedance Cardiography, for measurement of Hepatic Vein Impedance Index (HVI  =  [maximum velocity – minimum velocity]/maximum velocity), venous pulse transit time (VPTT  =  time interval between corresponding ECG and Doppler wave characteristics) and cardiac output (heart rate x stroke volume). After delivery, a population-specific birth weight chart, established from a cohort of 27000 neonates born in the index hospital, was used to define customized birth weight percentiles (BW%). Correlations between HVI, VPTT, CO and BW% were calculated using Spearman''s ρ, linear regression analysis and R² goodness of fit in SPSS 22.0.

Results

A total of 73 women were included. There was a negative correlation between HVI and VPTT (ρ = −0.719, p<0.001). Both HVI and VPTT correlated with CO (ρ = −0.403, p<0.001 and ρ = 0.332, p<0.004 resp.) and with BW% (ρ = −0.341, p<0.003 and ρ = 0.296, p<0.011 resp.)

Conclusion

Our data illustrate that the known contribution of hepatic hemodynamics in the regulation of cardiac output is also true for women with uncomplicated pregnancies. Our study is the first to illustrate a potential link between maternal hepatic hemodynamics and neonatal birth weight. Whether this link is purely associative or whether hepatic vascular physiology has a direct impact on fetal growth is to be evaluated in more extensive clinical and experimental research.     

The Association of Growth Differentiation Factor-15 with Left Ventricular Hypertrophy in Hypertensive Patients

Growth differentiation factor-15 (GDF-15) has been identified as an endogenous anti-hypertrophy effect. However, the association of plasma GDF-15 levels with left ventricular hypertrophy (LVH) in hypertension is poorly understood. We investigate the effect of plasma GDF-15 levels on left ventricular hypertrophy (LVH) in hypertension. We measured the plasma levels of GDF-15 in 299 untreated hypertensive patients which consisted of 99 with LVH and 200 without LVH using immunoradiometric assay. All subjects were examined by the ultrasonic cardiograph to determine Left ventricular (LV) internal diameters, septal thickness, and posterior wall thickness. The associations of GDF-15 with left ventricular mass index (LVMI), LV end-systolic and –diastolic diameters, LV wall thickness, and LV ejection fraction were evaluated. We found that plasma GDF-15 levels in hypertensive patients with LVH [median 1101, 25th–75th percentiles (879–1344) ng/L] were higher than that in hypertensive patients without LVH [median 516, 25th–75th percentiles (344–640) ng/L] (P<0.001). After adjustment for traditional covariates, plasma GDF-15 levels were independently related to LVMI (R² = 0.53; β = 0.624, P<0.001), LV interventricular septal thickness (R² = 0.23; β = 0.087, P<0.01) and LV posterior wall thickness (R² = 0.26; β = 0.103, P<0.05). Our cross-sectional data on a hospital-based sample indicate that plasma GDF-15 levels are associated with LVH in hypertensive patients.     

Factors Affecting De Novo Urinary Retention after Holmium Laser Enucleation of the Prostate

Objective

Patients can experience urinary retention (UR) after Holmium laser enucleation of the prostate (HoLEP) that requires bladder distension during the procedure. The aim of this retrospective study is to identify factors affecting the UR after HoLEP.

Materials and Methods

336 patients, which underwent HoLEP for a symptomatic benign prostatic hyperplasia between July 2008 and March 2012, were included in this study. Urethral catheters were routinely removed one or two days after surgery. UR was defined as the need for an indwelling catheter placement following a failure to void after catheter removal. Demographic and clinical parameters were compared between the UR (n = 37) and the non-urinary retention (non-UR; n = 299) groups.

Results

The mean age of patients was 68.3 (±6.5) years and the mean operative time was 75.3 (±37.4) min. Thirty seven patients (11.0%) experienced a postoperative UR. UR patients voided catheter free an average of 1.9 (±1.7) days after UR. With regard to the causes of UR, 24 (7.1%) and 13 (3.9%) patients experienced a blood clot-related UR and a non-clot related UR respectively. Using multivariate analysis (p<0.05), we found significant differences between the UR and the non-UR groups with regard to a morcellation efficiency (OR 0.701, 95% CI 0.498–0.988) and a bleeding-related complication, such as, a reoperation for bleeding (OR 0.039, 95% CI 0.004–0.383) or a transfusion (OR 0.144, 95% CI 0.027–0.877). Age, history of diabetes, prostate volume, pre-operative post-void residual, bladder contractility index, learning curve, and operative time were not significantly associated with the UR (p>0.05).

Conclusions

De novo UR after HoLEP was found to be self-limited and it was not related to learning curve, patient age, diabetes, or operative time. Efficient morcellation and careful control of bleeding, which reduces clot formation, decrease the risk of UR after HoLEP.     

Quantification of Mineralized Bone Response to Prostate Cancer by Noninvasive In Vivo μCT and Non-Destructive Ex Vivo μCT and DXA in a Mouse Model

Background

To compare nondestructive in vivo and ex vivo micro-computed tomography (μCT) and ex vivo dual-energy-X-ray-absorptiometry (DXA) in characterizing mineralized cortical and trabecular bone response to prostate cancer involving the skeleton in a mouse model.

Methodology/Principal Findings

In vivo μCT was performed before and 10 weeks after implantation of human prostate cancer cells (MDA-PCa-2b) or vehicle into SCID mouse femora. After resection, femora were imaged by nondestructive ex vivo specimen μCT at three voxel sizes (31 µ, 16 µ, 8 µ) and DXA, and then sectioned for histomorphometric analysis of mineralized bone. Bone mineral density (BMD), trabecular parameters (number, TbN; separation, TbSp; thickness, TbTh) and mineralized bone volume/total bone volume (BV/TV) were compared and correlated among imaging methods and histomorphometry. Statistical tests were considered significant if P<0.05. Ten weeks post inoculation, diaphyseal BMD increased in the femur with tumor compared to the opposite femur by all modalities (p<0.005, n = 11). Diaphyseal BMD by in vivo μCT correlated with ex vivo 31 and 16 µm μCT and histomorphometry BV/TV (r = 0.91–0.94, P<0.001, n = 11). DXA BMD correlated less with bone histomorphometry (r = 0.73, P<0.001, n = 11) and DXA did not distinguish trabeculae from cortex. By in vivo and ex vivo μCT, trabecular BMD decreased (P<0.05, n = 11) as opposed to the cortex. Unlike BMD, trabecular morphologic parameters were threshold-dependent and when using “fixed-optimal-thresholds,” all except TbTh demonstrated trabecular loss with tumor and correlated with histomorphometry (r = 0.73–0.90, P<0.05, n = 11).

Conclusions/Significance

Prostate cancer involving the skeleton can elicit a host bone response that differentially affects the cortex compared to trabeculae and that can be quantified noninvasively in vivo and nondestructively ex vivo.     

Serum γ-glutamyl Transferase Levels,Insulin Resistance and Liver Fibrosis in Patients with Chronic Liver Diseases

Background and Aims

Serum levels of γ-glutamyl-transpeptidase(γ-GT) were associated with liver disease severity and metabolic alterations, which in turn are able to affect hepatic damage. In patients with nonalcoholic fatty liver disease (NAFLD), genotype 1 chronic hepatitis C (G1CHC) and chronic hepatitis B (CHB), we assessed the link between liver fibrosis and γ-GT serum levels, and we evaluated if normal or high γ-GT serum levels affect the association between insulin resistance (IR) and severity of liver fibrosis.

Methods

843 consecutive patients with chronic liver disease (CLD)(193 NAFLD, 481 G1CHC, 169 CHB) were evaluated by liver biopsy (Kleiner and Scheuer scores) and clinical and metabolic measurements. IR was diagnosed if HOMA>3. A serum γ-GT concentration of >36 IU/L in females and >61 IU/L in males was considered the threshold value for identifying high levels of γ-GT.

Results

By multivariate logistic regression analysis, abnormal γ-GT serum levels were independently linked to severe liver fibrosis in patients with NAFLD (OR2.711,CI1.120–6.564,p = 0.02), G1CHC (OR3.461,CI2.138–5.603,p<0.001) and CHB (OR2.778,CI1.042–7.414,p = 0.04), together with IR and liver necroinflammation, and with a negative predictive value>80%. Interestingly, among patients with high or normal γ-GT values, even if IR prevalence was significantly higher in patients with severe fibrosis compared to those without, IR remained significantly associated with severe fibrosis in patients with abnormal γ-GT values only (OR4.150,CI1.079–15.970,p = 0.03 for NAFLD; OR2.250,CI1.211–4.181,p = 0.01 for G1CHC; OR3.096,CI2.050–34.220,p = 0.01 for CHB).

Conclusions

In patients with CLD, IR is independently linked to liver fibrosis only in patients with abnormal γ-GT values, without differences according to liver disease etiology, and suggesting a role of γ-GT as a marker of metabolic-induced liver damage. These data could be useful for the clinical and pharmacologic management of patients with CLD.     

Comparing the Cervista HPV HR Test and Hybrid Capture 2 Assay in a Dutch Screening Population: Improved Specificity of the Cervista HPV HR Test by Changing the Cut-Off

The diagnostic performance of the widely-used Cervista HPV HR test was compared to the Hybrid Capture 2 (HC2) test in a Dutch population-based cervical cancer screening program. In 900 scrapings of women with normal cytomorphology, specificity was 90% (95%CI: 87.84–91.87) for the Cervista HPV HR test and 96% (95%CI: 94.76–97.37) for the HC2 test with 93% agreement between both tests (κ = 0.5, p<0.001). The sensitivity for CIN2+ using 65 scrapings of women with histological-confirmed CIN2+ was 91% (95%CI: 80.97–96.51) for the Cervista HPV HR test and 92% (95%CI: 82.94–97.43) for the HC2 test with 95% agreement between both tests (κ = 0.7, p<0.001). Fifty-seven of 60 HC2 negative/Cervista positive cases tested HPV-negative with PCR-based HPV assays; of these cases 56% were defined as Cervista triple-positive with FOZ values in all 3 mixes higher than the second cut-off of 1.93 (as set by manufacturer). By setting this cut-off at 5.0, specificity improved significantly without affecting sensitivity. External validation of this new cut-off at 5.0 in triple-positive scrapings of women selected from the SHENCCASTII database revealed that 22/24 histological normal cases now tested HPV-negative in the Cervista HPV HR test, while CIN2+ lesions remained HPV-positive. The intra-laboratory reproducibility of the Cervista HPV HR test (n = 510) showed a concordance of 92% and 93% for cut-off 1.93 and 5.0 (κ = 0.83 and κ = 0.84, p<0.001) and inter-laboratory agreement of the Cervista HPV HR test was 90% and 93% for cut-off 1.93 and 5.0 (κ = 0.80 and κ = 0.85, p<0.001). In conclusion, the specificity of the Cervista HPV HR test could be improved significantly by increasing the second cut-off from 1.93 to 5.0, without affecting the sensitivity of the test in a population-based screening setting.     

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.     

Naturally Occurring Alpha-Synuclein Autoantibodies in Parkinson’s Disease: Sources of (Error) Variance in Biomarker Assays

Alpha-synuclein (α-Syn) plays a pivotal role in the pathophysiology of Parkinson’s disease (PD), which can partly be modulated by innate and adaptive immune functions, and vice versa. Here, naturally occurring α-Syn autoantibodies (α-Syn-nAbs) may be effective against α-Syn pathoetiology and may serve as a PD biomarker. However, serum and cerebrospinal fluid α-Syn-nAbs levels still lack consistent evidence as required for a reliable PD biomarker. Serum and cerebrospinal fluid α-Syn-nAbs levels of 66 PD patients and 69 healthy controls were assessed using a validated ELISA assay. Moreover, potential sources of error variance including unspecific ELISA background signals, free serum hemoglobin concentrations, α-Syn plate coating procedures, and differences in α-Syn-nAbs standards, were investigated. PD patients and controls did not differ in serum (p = .49) nor cerebrospinal fluid (p = .29) α-Syn-nAbs levels. Interestingly, free serum hemoglobin concentrations were negatively correlated with α-Syn-nAbs levels in controls (Spearman  = −.41, p<.001), but not in PD patients ( = .16, p = .21). ELISA α-Syn plate coating procedures impacted inter-assay variability (same day coating: 8–16%; coating on different days: 16–58%). α-Syn-nAbs standards from different purification batches differed regarding optical density measured in ELISAs suggesting differences in α-Syn affinity. While α-Syn-nAbs levels may represent a potential PD biomarker, several methodological issues have to be considered to increase reproducibility of α-Syn-nAbs findings. Further studies using standardized protocols minimizing sources of error variance may be necessary to establish a reliable PD α-Syn-nAbs biomarker.     

Sleepiness,Long Distance Commuting and Night Work as Predictors of Driving Performance

Few studies have examined the effect of working night shift and long distance commuting. We examined the association between several sleep related and demographic variables, commuting distance, night work and use of mobile phones on driving performance. We used a prospective design to recruit participants and conducted a telephone survey (n = 649). The survey collected demographic and journey details, work and sleep history and driving performance concerning the day the participant was recruited. Participants also completed the Karolinska Sleepiness Scale and the Epworth Sleepiness Scale. Night workers reported significantly more sleepiness, shorter sleep duration and commuting longer distances. Seven variables were significant predictors of lane crossing. The strongest predictor was acute sleepiness (OR = 5.25, CI, 1.42–19.49, p<0.01) followed by driving ≥150 kms (OR = 3.61, CI, 1.66–7.81, p<0.001), obtaining less than 10 hours sleep in the previous 48 hours (OR = 2.58, CI, 1.03–6.46, p<0.05), driving after night shift (OR = 2.19, CI, 1.24–3.88, p<0.001), being <43 years old (OR = 1.95, CI, 1.11–3.41, p<0.05) and using mobile phones during the journey (OR = 1.90, CI, 1.10–3.27, p<0.05). Sleep related variables, long-distance commuting and night work have a major impact on lane crossing. Several interventions should be considered to reduce the level of sleepiness in night workers.     

Role of Circulating Angiotensin Converting Enzyme 2 in Left Ventricular Remodeling following Myocardial Infarction: A Prospective Controlled Study

Angiotensin-converting enzyme 2 (ACE2) cleaves Angiotensin-II to Angiotensin-(1–7), a cardioprotective peptide. Serum soluble ACE2 (sACE2) activity is raised in chronic heart failure, suggesting a compensatory role in left ventricular dysfunction. Our aim was to study the relationship between sACE2 activity, infarct size, left ventricular systolic function and remodeling following ST-elevation myocardial infarction (STEMI). A contrast-enhanced cardiac magnetic resonance study was performed acutely in 95 patients with first STEMI and repeated at 6 months to measure LV end-diastolic volume index, ejection fraction and infarct size. Baseline sACE2 activities, measured by fluorescent enzymatic assay 24 to 48 hours and at 7 days from admission, were compared to that obtained in 22 matched controls. Patients showed higher sACE2 at baseline than controls (104.4 [87.4–134.8] vs 74.9 [62.8–87.5] RFU/µl/hr, p<0.001). At seven days, sACE2 activity significantly increased from baseline (115.5 [92.9–168.6] RFU/µl/hr, p<0.01). An inverse correlation between sACE2 activity with acute and follow-up ejection fraction was observed (r = −0.519, p<0.001; r = −0.453, p = 0.001, respectively). Additionally, sACE2 directly correlated with infarct size (r = 0.373, p<0.001). Both, infarct size (β = −0.470 [95%CI:−0.691:−0.248], p<0.001) and sACE2 at 7 days (β = −0.025 [95%CI:−0.048:−0.002], p = 0.030) were independent predictors of follow-up ejection fraction. Patients with sACE2 in the upper tertile had a 4.4 fold increase in the incidence of adverse left ventricular remodeling (95% confidence interval: 1.3 to 15.2, p = 0.027). In conclusion, serum sACE2 activity rises in relation to infarct size, left ventricular systolic dysfunction and is associated with the occurrence of left ventricular remodeling.     

Comparison of Texture Features Derived from Static and Respiratory-Gated PET Images in Non-Small Cell Lung Cancer

Background

PET-based texture features have been used to quantify tumor heterogeneity due to their predictive power in treatment outcome. We investigated the sensitivity of texture features to tumor motion by comparing static (3D) and respiratory-gated (4D) PET imaging.

Methods

Twenty-six patients (34 lesions) received 3D and 4D [¹⁸F]FDG-PET scans before the chemo-radiotherapy. The acquired 4D data were retrospectively binned into five breathing phases to create the 4D image sequence. Texture features, including Maximal correlation coefficient (MCC), Long run low gray (LRLG), Coarseness, Contrast, and Busyness, were computed within the physician-defined tumor volume. The relative difference (δ_3D-4D) in each texture between the 3D- and 4D-PET imaging was calculated. Coefficient of variation (CV) was used to determine the variability in the textures between all 4D-PET phases. Correlations between tumor volume, motion amplitude, and δ_3D-4D were also assessed.

Results

4D-PET increased LRLG ( = 1%–2%, p<0.02), Busyness ( = 7%–19%, p<0.01), and decreased MCC ( = 1%–2%, p<7.5×10⁻³), Coarseness ( = 5%–10%, p<0.05) and Contrast ( = 4%–6%, p>0.08) compared to 3D-PET. Nearly negligible variability was found between the 4D phase bins with CV<5% for MCC, LRLG, and Coarseness. For Contrast and Busyness, moderate variability was found with CV = 9% and 10%, respectively. No strong correlation was found between the tumor volume and δ_3D-4D for the texture features. Motion amplitude had moderate impact on δ for MCC and Busyness and no impact for LRLG, Coarseness, and Contrast.

Conclusions

Significant differences were found in MCC, LRLG, Coarseness, and Busyness between 3D and 4D PET imaging. The variability between phase bins for MCC, LRLG, and Coarseness was negligible, suggesting that similar quantification can be obtained from all phases. Texture features, blurred out by respiratory motion during 3D-PET acquisition, can be better resolved by 4D-PET imaging. 4D-PET textures may have better prognostic value as they are less susceptible to tumor motion.     

Dissecting the Gene Dose-Effects of the APOE ε4 and ε2 Alleles on Hippocampal Volumes in Aging and Alzheimer’s Disease

Objective

To investigate whether there is a specific dose-dependent effect of the Apolipoprotein E (APOE) ε4 and ε2 alleles on hippocampal volume, across the cognitive spectrum, from normal aging to Alzheimer’s Disease (AD).

Materials and Methods

We analyzed MR and genetic data on 662 patients from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database–198 cognitively normal controls (CN), 321 mild-cognitive impairment (MCI) subjects, and 143 AD subjects–looking for dose-dependent effects of the ε4 and ε2 alleles on hippocampal volumes. Volumes were measured using a fully-automated algorithm applied to high resolution T1-weighted MR images. Statistical analysis consisted of a multivariate regression with repeated-measures model.

Results

There was a dose-dependent effect of the ε4 allele on hippocampal volume in AD (p = 0.04) and MCI (p = 0.02)–in both cases, each allele accounted for loss of >150 mm³ (approximately 4%) of hippocampal volume below the mean volume for AD and MCI subjects with no such alleles (Cohen’s d = −0.16 and −0.19 for AD and MCI, respectively). There was also a dose-dependent, main effect of the ε2 allele (p<0.0001), suggestive of a moderate protective effect on hippocampal volume–an approximately 20% per allele volume increase as compared to CN with no ε2 alleles (Cohen’s d = 0.23).

Conclusion

Though no effect of ε4 was seen in CN subjects, our findings confirm and extend prior data on the opposing effects of the APOE ε4 and ε2 alleles on hippocampal morphology across the spectrum of cognitive aging.