Nuclear Overhauser Enhancement Imaging of Glioblastoma at 7 Tesla: Region Specific Correlation with Apparent Diffusion Coefficient and Histology

Objective

To explore the correlation between Nuclear Overhauser Enhancement (NOE)-mediated signals and tumor cellularity in glioblastoma utilizing the apparent diffusion coefficient (ADC) and cell density from histologic specimens. NOE is one type of chemical exchange saturation transfer (CEST) that originates from mobile macromolecules such as proteins and might be associated with tumor cellularity via altered protein synthesis in proliferating cells.

Patients and Methods

For 15 patients with newly diagnosed glioblastoma, NOE-mediated CEST-contrast was acquired at 7 Tesla (asymmetric magnetization transfer ratio (MTR_asym) at 3.3ppm, B1 = 0.7 μT). Contrast enhanced T1 (CE-T1), T2 and diffusion-weighted MRI (DWI) were acquired at 3 Tesla and coregistered. The T2 edema and the CE-T1 tumor were segmented. ADC and MTR_asym values within both regions of interest were correlated voxelwise yielding the correlation coefficient r_Spearman (r_Sp). In three patients who underwent stereotactic biopsy, cell density of 12 specimens per patient was correlated with corresponding MTR_asym and ADC values of the biopsy site.

Results

Eight of 15 patients showed a weak or moderate positive correlation of MTR_asym and ADC within the T2 edema (0.16≤r_Sp≤0.53, p<0.05). Seven correlations were statistically insignificant (p>0.05, n = 4) or yielded r_Sp≈0 (p<0.05, n = 3). No trend towards a correlation between MTR_asym and ADC was found in CE-T1 tumor (-0.31<r_Sp<0.28, p<0.05, n = 9; p>0.05, n = 6). The biopsy-analysis within CE-T1 tumor revealed a strong positive correlation between tumor cellularity and MTR_asym values in two of the three patients (r_Sp ^patient3 = 0.69 and r_Sp ^patient15 = 0.87, p<0.05), while the correlation of ADC and cellularity was heterogeneous (r_Sp ^patient3 = 0.545 (p = 0.067), r_Sp ^patient4 = -0.021 (p = 0.948), r_Sp ^patient15 = -0.755 (p = 0.005)).

Discussion

NOE-imaging is a new contrast promising insight into pathophysiologic processes in glioblastoma regarding cell density and protein content, setting itself apart from DWI. Future studies might be based on the assumption that NOE-mediated CEST visualizes cellularity more accurately than ADC, especially in the CE-T1 tumor region.     

Associations of Sedentary Behaviour,Physical Activity,Blood Pressure and Anthropometric Measures with Cardiorespiratory Fitness in Children with Cerebral Palsy

Background

Children with cerebral palsy (CP) have poor cardiorespiratory fitness in comparison to their peers with typical development, which may be due to low levels of physical activity. Poor cardiorespiratory fitness may contribute to increased cardiometabolic risk.

Purpose

The aim of this study was to determine the association between sedentary behaviour, physical activity and cardiorespiratory fitness in children with CP. An objective was to determine the association between cardiorespiratory fitness, anthropometric measures and blood pressure in children with CP.

Methods

This study included 55 ambulatory children with CP [mean (SD) age 11.3 (0.2) yr, range 6-17 yr; Gross Motor Function Classification System (GMFCS) levels I and II]. Anthropometric measures (BMI, waist circumference and waist-height ratio) and blood pressure were taken. Cardiorespiratory fitness was measured using a 10 m shuttle run test. Children were classified as low, middle and high fitness according to level achieved on the test using reference curves. Physical activity was measured by accelerometry over 7 days. In addition to total activity, time in sedentary behaviour and light, moderate, vigorous, and sustained moderate-to-vigorous activity (≥10 min bouts) were calculated.

Results

Multiple regression analyses revealed that vigorous activity (β = 0.339, p<0.01), sustained moderate-to-vigorous activity (β = 0.250, p<0.05) and total activity (β = 0.238, p<0.05) were associated with level achieved on the shuttle run test after adjustment for age, sex and GMFCS level. Children with high fitness spent more time in vigorous activity than children with middle fitness (p<0.05). Shuttle run test level was negatively associated with BMI (r² = -0.451, p<0.01), waist circumference (r² = -0.560, p<0.001), waist-height ratio (r² = -0.560, p<0.001) and systolic blood pressure (r² = -0.306, p<0.05) after adjustment for age, sex and GMFCS level.

Conclusions

Participation in physical activity, particularly at a vigorous intensity, is associated with high cardiorespiratory fitness in children with CP. Low cardiorespiratory fitness is associated with increased cardiometabolic risk.     

Regional Distribution and Evolution of Gray Matter Damage in Different Populations of Multiple Sclerosis Patients

Background

Both gray-matter (GM) atrophy and lesions occur from the earliest stages of Multiple Sclerosis (MS) and are one of the major determinants of long-term clinical outcomes. Nevertheless, the relationship between focal and diffuse GM damage has not been clarified yet. Here we investigate the regional distribution and temporal evolution of cortical thinning and how it is influenced by the local appearance of new GM lesions at different stages of the disease in different populations of MS patients.

Methods

We studied twenty MS patients with clinically isolated syndrome (CIS), 27 with early relapsing-remitting MS (RRMS, disease duration <5 years), 29 with late RRMS (disease duration ≥ 5 years) and 20 with secondary-progressive MS (SPMS). The distribution and evolution of regional cortical thickness and GM lesions were assessed during 5-year follow-up.

Results

The results showed that new lesions appeared more frequently in hippocampus and parahippocampal gyri (9.1%), insula (8.9%), cingulate cortex (8.3%), superior frontal gyrus (8.1%), and cerebellum (6.5%). The aforementioned regions showed the greatest reduction in thickness/volume, although (several) differences were observed across subgroups. The correlation between the appearance of new cortical lesions and cortical thinning was stronger in CIS (r² = 50.0, p<0.001) and in early RRMS (r² = 52.3, p<0.001), compared to late RRMS (r² = 25.5, p<0.001) and SPMS (r² = 6.3, p = 0.133).

Conclusions

We conclude that GM atrophy and lesions appear to be different signatures of cortical disease in MS having in common overlapping spatio-temporal distribution patterns. However, the correlation between focal and diffuse damage is only moderate and more evident in the early phase of the disease.     

Effortless Attention as a Biomarker for Experienced Mindfulness Practitioners

Objective

The present study aimed at comparing frontal beta power between long-term (LTM) and first-time meditators (FTM), before, during and after a meditation session. We hypothesized that LTM would present lower beta power than FTM due to lower effort of attention and awareness.

Methods

Twenty one participants were recruited, eleven of whom were long-term meditators. The subjects were asked to rest for 4 minutes before and after open monitoring (OM) meditation (40 minutes).

Results

The two-way ANOVA revealed an interaction between the group and moment factors for the Fp1 (p<0.01), F7 (p = 0.01), F3 (p<0.01), Fz (p<0.01), F4 (p<0.01), F8 (p<0.01) electrodes.

Conclusion

We found low power frontal beta activity for LTM during the task and this may be associated with the fact that OM is related to bottom-up pathways that are not present in FTM.

Significance

We hypothesized that the frontal beta power pattern may be a biomarker for LTM. It may also be related to improving an attentive state and to the efficiency of cognitive functions, as well as to the long-term experience with meditation (i.e., life-time experience and frequency of practice).     

Tumor T1 Relaxation Time for Assessing Response to Bevacizumab Anti-Angiogenic Therapy in a Mouse Ovarian Cancer Model

Purpose

To assess whether T₁ relaxation time of tumors may be used to assess response to bevacizumab anti-angiogenic therapy. Procedures: 12 female nude mice bearing subcutaneous SKOV3ip1-LC ovarian tumors were administered bevacizumab (6.25ug/g, n=6) or PBS (control, n=6) therapy twice a week for two weeks. T₁ maps of tumors were generated before, two days, and 2 weeks after initiating therapy. Tumor weight was assessed by MR and at necropsy. Histology for microvessel density, proliferation, and apoptosis was performed.

Results

Bevacizumab treatment resulted in tumor growth inhibition (p<0.04, n=6), confirming therapeutic efficacy. Tumor T₁ relaxation times increased in bevacizumab treated mice 2 days and 2 weeks after initiating therapy (p<.05, n=6). Microvessel density decreased 59% and cell proliferation (Ki67+) decreased 50% in the bevacizumab treatment group (p<.001, n=6), but not apoptosis.

Conclusions

Findings suggest that increased tumor T₁ relaxation time is associated with response to bevacizumab therapy in ovarian cancer model and might serve as an early indicator of response.     

T1- Thresholds in Black Holes Increase Clinical-Radiological Correlation in Multiple Sclerosis Patients

Background

Magnetic Resonance Imaging (MRI) is an established tool in diagnosing and evaluating disease activity in Multiple Sclerosis (MS). While clinical-radiological correlations are limited in general, hypointense T1 lesions (also known as Black Holes (BH)) have shown some promising results. The definition of BHs is very heterogeneous and depends on subjective visual evaluation.

Objective

We aimed to improve clinical-radiological correlations by defining BHs using T1 relaxation time (T1-RT) thresholds to achieve best possible correlation between BH lesion volume and clinical disability.

Method

40 patients with mainly relapsing-remitting MS underwent MRI including 3-dimensional fluid attenuated inversion recovery (FLAIR), magnetization-prepared rapid gradient echo (MPRAGE) before and after Gadolinium (GD) injection and double inversion-contrast magnetization-prepared rapid gradient echo (MP2RAGE) sequences. BHs (BH_vis) were marked by two raters on native T1-weighted (T1w)-MPRAGE, contrast-enhancing lesions (CE lesions) on T1w-MPRAGE after GD and FLAIR lesions (total-FLAIR lesions) were detected separately. BH_vis and total-FLAIR lesion maps were registered to MP2RAGE images, and the mean T1-RT were calculated for all lesion ROIs. Mean T1 values of the cortex (CTX) were calculated for each patient. Subsequently, Spearman rank correlations between clinical scores (Expanded Disability Status Scale and Multiple Sclerosis Functional Composite) and lesion volume were determined for different T1-RT thresholds.

Results

Significant differences in T1-RT were obtained between all different lesion types with highest T1 values in visually marked BHs (BH_vis: 1453.3±213.4 ms, total-FLAIR lesions: 1394.33±187.38 ms, CTX: 1305.6±35.8 ms; p<0.05). Significant correlations between BH_vis/total-FLAIR lesion volume and clinical disability were obtained for a wide range of T1-RT thresholds. The highest correlation for BH_vis and total-FLAIR lesion masks were found at T1-RT>1500 ms (Expanded Disability Status Scale vs. lesion volume: r_BHvis = 0.442 and r_total-FLAIR = 0.497, p<0.05; Multiple Sclerosis Functional Composite vs. lesion volume: r_BHvis = -0.53 and r_total-FLAIR = -0.627, p<0.05).

Conclusion

Clinical-radiological correlations in MS patients are increased by application of T1-RT thresholds. With the short acquisition time of the MP2RAGE sequences, quantitative T1 maps could be easily established in clinical studies.     

Quantification of Calcium Amount in a New Experimental Model: A Comparison between Ultrasound and Computed Tomography

Purpose

Calcification is an important prognostic factor in aortic valve stenosis. However, there is no ultrasound (US) method available to accurately quantify calcification in this setting to date. We aimed to validate a new US method for measuring the amount of calcium in an in vitro model, and compare it to computed tomography (CT), the current imaging gold standard.

Materials and Methods

An agar phantom (2% agar) was made, containing 9 different amounts of calcium-hydroxyapatite Ca₅(PO₄)₃OH (2 to 50mg). The phantoms were imaged with micro-CT and US (10 MHz probe). The calcium area (area_calcium) and its maximum pixel value (PV_max) were obtained. These values were summed to calculate CT and US calcium scores (∑(area_calcium × PV_max)) and volumes (∑area_calcium). Both US- and CT-calcium scores were compared with the calcium amounts, and with each other.

Results

Both calcium scores correlated significantly with the calcium amount (R² = 0.9788, p<0.0001 and R² = 0.8154, p<0.0001 for CT and US respectively). Furthermore, there was a significant correlation between US and CT for calcium volumes (R² = 0.7392, p<0.0001) and scores (R² = 0.7391, p<0.0001).

Conclusion

We developed a new US method that accurately quantifies the amount of calcium in an in vitro model. Moreover it is strongly correlated with CT.     

Neural Network Prediction of ICU Length of Stay Following Cardiac Surgery Based on Pre-Incision Variables

Background

Advanced predictive analytical techniques are being increasingly applied to clinical risk assessment. This study compared a neural network model to several other models in predicting the length of stay (LOS) in the cardiac surgical intensive care unit (ICU) based on pre-incision patient characteristics.

Methods

Thirty six variables collected from 185 cardiac surgical patients were analyzed for contribution to ICU LOS. The Automatic Linear Modeling (ALM) module of IBM-SPSS software identified 8 factors with statistically significant associations with ICU LOS; these factors were also analyzed with the Artificial Neural Network (ANN) module of the same software. The weighted contributions of each factor (“trained” data) were then applied to data for a “new” patient to predict ICU LOS for that individual.

Results

Factors identified in the ALM model were: use of an intra-aortic balloon pump; O₂ delivery index; age; use of positive cardiac inotropic agents; hematocrit; serum creatinine ≥ 1.3 mg/deciliter; gender; arterial pCO₂. The r² value for ALM prediction of ICU LOS in the initial (training) model was 0.356, p <0.0001. Cross validation in prediction of a “new” patient yielded r² = 0.200, p <0.0001. The same 8 factors analyzed with ANN yielded a training prediction r² of 0.535 (p <0.0001) and a cross validation prediction r² of 0.410, p <0.0001. Two additional predictive algorithms were studied, but they had lower prediction accuracies. Our validated neural network model identified the upper quartile of ICU LOS with an odds ratio of 9.8(p <0.0001).

Conclusions

ANN demonstrated a 2-fold greater accuracy than ALM in prediction of observed ICU LOS. This greater accuracy would be presumed to result from the capacity of ANN to capture nonlinear effects and higher order interactions. Predictive modeling may be of value in early anticipation of risks of post-operative morbidity and utilization of ICU facilities.     

The Association of Human Apolipoprotein C-III Sialylation Proteoforms with Plasma Triglycerides

Introduction

Apolipoprotein C-III (apoC-III) regulates triglyceride (TG) metabolism. In plasma, apoC-III exists in non-sialylated (apoC-III_0a without glycosylation and apoC-III_0b with glycosylation), monosialylated (apoC-III₁) or disialylated (apoC-III₂) proteoforms. Our aim was to clarify the relationship between apoC-III sialylation proteoforms with fasting plasma TG concentrations.

Methods

In 204 non-diabetic adolescent participants, the relative abundance of apoC-III plasma proteoforms was measured using mass spectrometric immunoassay.

Results

Compared with the healthy weight subgroup (n = 16), the ratios of apoC-III_0a, apoC-III_0b, and apoC-III₁ to apoC-III₂ were significantly greater in overweight (n = 33) and obese participants (n = 155). These ratios were positively correlated with BMI z-scores and negatively correlated with measures of insulin sensitivity (S_i). The relationship of apoC-III₁ / apoC-III₂ with S_i persisted after adjusting for BMI (p = 0.02). Fasting TG was correlated with the ratio of apoC-III_0a / apoC-III₂ (r = 0.47, p<0.001), apoC-III_0b / apoC-III₂ (r = 0.41, p<0.001), apoC-III₁ / apoC-III₂ (r = 0.43, p<0.001). By examining apoC-III concentrations, the association of apoC-III proteoforms with TG was driven by apoC-III_0a (r = 0.57, p<0.001), apoC-III_0b (r = 0.56. p<0.001) and apoC-III₁ (r = 0.67, p<0.001), but not apoC-III₂ (r = 0.006, p = 0.9) concentrations, indicating that apoC-III relationship with plasma TG differed in apoC-III₂ compared with the other proteoforms.

Conclusion

We conclude that apoC-III_0a, apoC-III_0b, and apoC-III₁, but not apoC- III₂ appear to be under metabolic control and associate with fasting plasma TG. Measurement of apoC-III proteoforms can offer insights into the biology of TG metabolism in obesity.     

Effects of a 12-Week Hatha Yoga Intervention on Metabolic Risk and Quality of Life in Hong Kong Chinese Adults with and without Metabolic Syndrome

Objective

To determine the efficacy of a 12-week Hatha yoga intervention to improve metabolic risk profiles and health-related quality of life (HRQoL) in Chinese adults with and without metabolic syndrome (MetS).

Methods

We conducted a controlled trial within an university-affiliated hospital. 173 Chinese men and women aged 18 or above were assigned to either the yoga intervention group (n = 87) or the control group (n = 86). Primary outcomes included 12-week change in metabolic risk factors and MetS z score. Secondary outcome was HRQoL (Medical Outcomes Short Form Survey at 12 weeks).

Results

The mean age of participants was 52.0 (SD 7.4, range 31-71) years. Analysis involving the entire study population revealed that the yoga group achieved greater decline in waist circumference (p<0.001), fasting glucose (p<0.01), triglycerides (p<0.05), and MetS z score (p<0.01). Yoga training also improved general health perceptions (p<0.01), physical component score (p<0.01), and social functioning (p<0.01) domains score of HRQoL. However, no significant differences between groups were observed in the mean change of systolic/diastolic blood pressures or high-density lipid protein cholesterol (all p>0.05). There were no significant differences in the intervention effects on waist circumference and MetS z score between the MetS subgroups (both p>0.05).

Conclusion

A 12-week Hatha yoga intervention improves metabolic risk profiles and HRQoL in Chinese adults with and without MetS.

Trial Registration

Australian New Zealand Clinical Trials Registry ACTRN12613000816752     

Systemic Inflammation Predicts All-Cause Mortality: A Glasgow Inflammation Outcome Study

Introduction

Markers of the systemic inflammatory response, including C-reactive protein and albumin (combined to form the modified Glasgow Prognostic Score), as well as neutrophil, lymphocyte and platelet counts have been shown to be prognostic of survival in patients with cancer. The aim of the present study was to examine the prognostic relationship between these markers of the systemic inflammatory response and all-cause, cancer, cardiovascular and cerebrovascular mortality in a large incidentally sampled cohort.

Methods

Patients (n = 160 481) who had an incidental blood sample taken between 2000 and 2008 were studied for the prognostic value of C-reactive protein (>10mg/l, albumin (>35mg/l), neutrophil (>7.5×10⁹/l) lymphocyte and platelet counts. Also, patients (n = 52 091) sampled following the introduction of high sensitivity C-reactive protein (>3mg/l) measurements were studied. A combination of these markers, to make cumulative inflammation-based scores, were investigated.

Results

In all patients (n = 160 481) C-reactive protein (>10mg/l) (HR 2.71, p<0.001), albumin (>35mg/l) (HR 3.68, p<0.001) and neutrophil counts (HR 2.18, p<0.001) were independently predictive of all-cause mortality. These associations were also observed in cancer, cardiovascular and cerebrovascular mortality before and after the introduction of high sensitivity C-reactive protein measurements (>3mg/l) (n = 52 091). A combination of high sensitivity C-reactive protein (>3mg/l), albumin and neutrophil count predicted all-cause (HR 7.37, p<0.001, AUC 0.723), cancer (HR 9.32, p<0.001, AUC 0.731), cardiovascular (HR 4.03, p<0.001, AUC 0.650) and cerebrovascular (HR 3.10, p<0.001, AUC 0.623) mortality.

Conclusion

The results of the present study showed that an inflammation-based prognostic score, combining high sensitivity C-reactive protein, albumin and neutrophil count is prognostic of all-cause mortality.     

A Comparison of Radiologic Tumor Volume and Pathologic Tumor Volume in Renal Cell Carcinoma (RCC)

Objective

To investigate the difference between preoperative radiologic tumor volume (RTV) and postoperative pathologic tumor volume (PTV) in patients who received nephrectomy for renal cell carcinoma (RCC).

Materials and Methods

We reviewed 482 patients who underwent preoperative computed tomography (CT) within 4 weeks before radical or partial nephrectomy for renal cell carcinoma. RTV measured by a three dimensional rendering program was compared with PTV (π/6ⅹheightⅹlengthⅹwidth) measured in surgical specimen according to pathologic tumor size and histologic subtype. Correlation of the inter-quartile range (IQR) of the RTV and Fuhrman nuclear grade was also investigated.

Results

There was a significant positive linear correlation between RTV and PTV (p<0.001, r = 0.911), and the mean RTV and mean PTV were not significantly different (79.0 vs 76.9cm³, p = 0.393). For pathologic tumor size (PTS) <4cm, the mean RTV was larger than the mean PTV (10.9 vs 7.1cm³, p<0.001). For a PTS of 4-7cm, the mean RTV was larger than the mean PTV (56.0 vs 44.7cm³, p<0.001). However, for a PTS ≥7cm, there was no statistical difference between RTV and PTV (p>0.05). Among patients with clear cell RCC, the mean RTV was significantly larger than the mean PTV (p = 0.042), not for non-clear cell group (p = 0.055). As the quartile of the RTV increased, the Fuhrman grade also increased (p<0.001).

Conclusions

RTV was correlated with PTV and pathologic grade. RTV was larger than the PTV for a tumor size 7 cm or less or in clear cell RCC. RTV may be useful to measure tumor burden preoperatively.     

Insulin Resistance Change and Antiretroviral Therapy Exposure in HIV-Infected and Uninfected Rwandan Women: A Longitudinal Analysis

Background

We longitudinally assessed predictors of insulin resistance (IR) change among HIV-uninfected and HIV-infected (ART-initiators and ART-non-initiators) Rwandan women.

Methodology

HIV-infected (HIV+) and uninfected (HIV-) women provided demographic and clinical measures: age, body mass index (BMI) in Kg/(height in meters)², Fat-Mass (FMI) and Fat-Free-Mass (FFMI) index, fasting serum glucose and insulin. Homeostasis Model Assessment (HOMA) was calculated to estimate IR change over time in log₁₀ transformed HOMA measured at study enrollment or prior to ART initiation in 3 groups: HIV- (n = 194), HIV+ ART-non-initiators (n=95) and HIV+ ART-initiators (n=371). ANCOVA linear regression models of change in log₁₀-HOMA were fit with all models included the first log₁₀ HOMA as a predictor.

Results

Mean±SD log₁₀-HOMA was -0.18±0.39 at the 1^st and -0.21±0.41 at the 2^nd measure, with mean change of 0.03±0.44. In the final model (all women) BMI at 1^st HOMA measure (0.014; 95% CI=0.006-0.021 per kg/m²; p<0.001) and change in BMI from 1^st to 2^nd measure (0.024; 95% CI=0.013-0.035 per kg/m²; p<0.001) predicted HOMA change. When restricted to subjects with FMI measures, FMI at 1^st HOMA measure (0.020; 95% CI=0.010-0.030 per kg/m²; p<0.001) and change in FMI from 1^st to 2^nd measure (0.032; 95% CI=0.020-0.043 per kg/m²; p<0.0001) predicted change in HOMA. While ART use did not predict change in log₁₀-HOMA, untreated HIV+ women had a significant decline in IR over time. Use or duration of AZT, d4T and EFV was not associated with HOMA change in HIV+ women.

Conclusions

Baseline BMI and change in BMI, and in particular fat mass and change in fat mass predicted insulin resistance change over ~3 years in HIV-infected and uninfected Rwandan women. Exposure to specific ART (d4T, AZT, EFV) did not predict insulin resistance change in ART-treated HIV-infected Rwandan women.     

Effect of Acute Intermittent CPAP Depressurization during Sleep in Obese Patients

Background

Obstructive Sleep Apnea (OSA) describes intermittent collapse of the airway during sleep, for which continuous positive airway pressure (CPAP) is often prescribed for treatment. Prior studies suggest that discontinuation of CPAP leads to a gradual, rather than immediate return of baseline severity of OSA. The objective of this study was to determine the extent of OSA recurrence during short intervals of CPAP depressurization during sleep.

Methods

Nine obese (BMI = 40.4 ± 3.5) subjects with severe OSA (AHI = 88.9 ± 6.8) adherent to CPAP were studied during one night in the sleep laboratory. Nasal CPAP was delivered at therapeutic (11.1 ± 0.6 cm H₂0) or atmospheric pressure, in alternating fashion for 1-hour periods during the night. We compared sleep architecture and metrics of OSA during CPAP-on and CPAP-off periods.

Results

8/9 subjects tolerated CPAP withdrawal. The average AHI during CPAP-on and CPAP-off periods was 3.6 ± 0.6 and 15.8 ± 3.6 respectively (p<0.05). The average 3% ODI during CPAP-on and CPAP-off was 4.7 ± 2 and 20.4 ± 4.7 respectively (p<0.05). CPAP depressurization also induced more awake (p<0.05) and stage N1 (p<0.01) sleep, and less stage REM (p<0.05) with a trend towards decreased stage N3 (p = 0.064).

Conclusion

Acute intermittent depressurization of CPAP during sleep led to deterioration of sleep architecture but only partial re-emergence of OSA. These observations suggest carryover effects of CPAP.     

Serum Trimethylamine-N-Oxide Is Strongly Related to Renal Function and Predicts Outcome in Chronic Kidney Disease

Background

The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population.

Objective

To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality.

Methods

Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3–5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed.

Results

GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3–5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32–14.2; p = 0.016).

Conclusion

Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3–5 patients.     

Airway Response to Methacholine following Eucapnic Voluntary Hyperpnea in Athletes

Aim

To evaluate the changes in airway responsiveness to methacholine inhalation test (MIT) when performed after an eucapnic voluntary hyperpnea challenge (EVH) in athletes.

Methods

Two MIT preceded (visit 1) or not (visit 2) by an EVH, were performed in 28 athletes and 24 non-athletes. Twelve athletes and 13 non-athletes had airway hyperresponsiveness (AHR) to methacholine, and 11 athletes and 11 non-athletes had AHR to EVH (EVH+).

Results

The MIT PC₂₀ post-EVH was significantly lower compared to baseline MIT PC₂₀ by 1.3±0.7 doubling-concentrations in EVH+ athletes only (p<0.0001). No significant change was observed in EVH- athletes and EVH+/EVH- non-athletes. A significant correlation between the change in MIT PC₂₀ post-EVH and EVH+/EVH- status and athlete/nonathlete status was found (Adjusted R²=0.26 and p<0.001). Three (11%) athletes and one (4%) non-athlete had a change in the diagnosis of AHR when MIT was performed consecutively to EVH.

Conclusion

The responsiveness to methacholine was increased by a previous indirect challenge in EVH+ athletes only. The mechanisms for such increase remain to be determined. MIT and EVH should ideally be performed on separate occasions as there is a small but possible risk to obtain a false-positive response to methacholine when performed immediately after the EVH.

Trial Registration

ClinicalTrials.gov NCT00686491     

Subclinical Myocardial Dysfunction and Cardiac Autonomic Dysregulation Are Closely Associated in Obese Children and Adolescents: The Potential Role of Insulin Resistance

Background

The prevalence of obesity is increasing among children/adolescents. Subtle cardiovascular abnormalities, responsible for a higher mortality later in life, have been reported in obese children/adolescents. The aims of the study were to evaluate cardiovascular autonomic regulation, by means of spectrum analysis of R-R interval variability, and myocardial function, by means of standard and tissue Doppler echocardiography, in a group of non-hypertensive asymptomatic obese children and adolescents; furthermore, the influence of insulin resistance was tested.

Subjects and Methods

R-R interval variability was analyzed during both the 70° head-up tilt and 24-hour electrocardiographic holter monitoring. Spectrum analysis of R-R interval variability provided the indices of sympathetic (low frequency [LF_RR]) and vagal (high frequency [HF_RR]) modulation of the sinoatrial node. Homeostasis model assessment of insulin resistance (HOMA-IR) was used to classify obese children/adolescents (n=72) as insulin resistant (n=37) and non-insulin resistant (n=35).

Results

In obese subjects: a) left ventricular mass was significantly (p<0.05) increased, whereas both the e/a ratio and the e''/a'' ratio were decreased; b) at rest, HF_RR was lower, and the LF_RR/HF_RR ratio was higher; c) during tilting, magnitude of tilt-induced inhibition of HF_RR was lower; d) during 24-hour electrocardiographic holter monitoring, LF_RR and the LF_RR/HF_RR ratio were higher, whereas HF_RR was lower; e) HOMA-IR inversely correlated with both the e''/a'' ratio (r=-0.655; p<0.001) and the tilt-induced LF_RR/HF_RR ratio (r=-0.933; p<0.001); and, f) the e''/a'' ratio correlated with the tilt-induced LF_RR/HF_RR ratio (r=0.501; p<0.001). Moreover, HF_RR at rest, magnitude of tilt-induced HF_RR reduction, and the e''/a'' ratio in insulin resistant obese children/adolescents were markedly lower when compared with the remaining subjects.

Conclusions

Subclinical abnormalities of myocardial function and of cardiac autonomic regulation were closely associated in obese children/adolescents and both correlated with the degree of insulin resistance.     

Cognitive and Typing Outcomes Measured Simultaneously with Slow Treadmill Walking or Sitting: Implications for Treadmill Desks

Purpose

This study compared cognitive (attention, learning, and memory) and typing outcomes during slow treadmill walking or sitting. Seventy-five healthy individuals were randomly assigned to a treadmill walking group (n=37; 23 female) or sitting group (n=38; 17 female).

Methods

The treadmill walking group completed a series of tests while walking at 1.5 mph. The sitting group performed the same tests while sitting at a standard desk. Tests performed by both groups included: the Rey Auditory Verbal Learning Test and a modified version of the Paced Auditory Serial Attention Test. In addition, typing performance was evaluated.

Results

Participants in the treadmill walking group performed worse on the Rey Auditory Verbal Learning Test for total learning than the sitting group; the main effect was significant (F(1,73)=4.75, p=0.03, η _p ²=0.06); however, short- and long-delay recall performance did not differ between groups (p>0.05). For the Paced Auditory Serial Attention Test, total number of correct responses was lower in the treadmill walking group relative to the sitting group; the main effect was significant (F(1,73)=4.97, p=0.03, η _p ²=0.06). The performance of both groups followed the same learning slope (Group x Trial interactions were not significant) for the Rey Auditory Verbal Learning Test and Paced Auditory Serial Attention Test. Individuals in the treadmill walking group performed significantly worse for all measures of typing (p<0.05).

Conclusion

Walking on a treadmill desk may result in a modest difference in total learning and typing outcomes relative to sitting, but those declines may not outweigh the benefit of the physical activity gains from walking on a treadmill.     

Accuracy of [18F]FDG PET/MRI for the Detection of Liver Metastases

Background

The aim of this study was to compare the diagnostic accuracy of [¹⁸F]FDG-PET/MRI with PET/CT for the detection of liver metastases.

Methods

32 patients with solid malignancies underwent [¹⁸F]FDG-PET/CT and subsequent PET/MRI of the liver. Two readers assessed both datasets regarding lesion characterization (benign, indeterminate, malignant), conspicuity and diagnostic confidence. An imaging follow-up (mean interval: 185±92 days) and/-or histopathological specimen served as standards of reference. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for both modalities. Accuracy was determined by calculating the area under the receiver operating characteristic (ROC) curve. Values of conspicuity and diagnostic confidence were compared using Wilcoxon-signed-rank test.

Results

The standard of reference revealed 113 liver lesions in 26 patients (malignant: n = 45; benign: n = 68). For PET/MRI a higher accuracy (PET/CT: 82.4%; PET/MRI: 96.1%; p<0.001) as well as sensitivity (67.8% vs. 92.2%, p<0.01) and NPV (82.0% vs. 95.1%, p<0.05) were observed. PET/MRI offered higher lesion conspicuity (PET/CT: 2.0±1.1 [median: 2; range 0–3]; PET/MRI: 2.8±0.5 [median: 3; range 0–3]; p<0.001) and diagnostic confidence (PET/CT: 2.0±0.8 [median: 2; range: 1–3]; PET/MRI 2.6±0.6 [median: 3; range: 1–3]; p<0.001). Furthermore, PET/MRI enabled the detection of additional PET-negative metastases (reader 1: 10; reader 2: 12).

Conclusions

PET/MRI offers higher diagnostic accuracy compared to PET/CT for the detection of liver metastases.