Acoustic Radiation Force Impulse Imaging for Non-Invasive Assessment of Renal Histopathology in Chronic Kidney Disease

Objective

To investigate the stiffness values obtained by acoustic radiation force impulse (ARFI) quantification in assessing renal histological fibrosis of chronic kidney disease (CKD).

Methods

163 patients with CKD and 32 healthy volunteers were enrolled between June 2013 and April 2014. ARFI quantification, given as shear wave velocity (SWV), was performed to measure renal parenchyma stiffness. Diagnostic performance of ARFI imaging and conventional ultrasound (US) were compared with histologic scores at renal biopsy. Intra- and inter-observer reliability of SWV measurement was analyzed.

Results

In CKD patients, SWV measurements correlated significantly with pathological parameters (r = −0.422–−0.511, P<0.001), serum creatinine (r = −0.503, P<0.001), and glomerular filtration rate (r = 0.587, P<0.001). The mean SWV in kidneys with severely impaired (histologic score: ≥19 points) was significant lower than that mildly impaired (histologic score: ≤9 points), moderately impaired (histologic score: 10–18 points), and control groups (all P<0.001). Receiver operating characteristic (ROC) curves analyses indicated that the area under the ROC curve for the diagnosis of renal histological fibrosis using ARFI imaging was superior to these conventional US parameters. Using the optimal cut-off value of 2.65 m/s for the diagnosis of mildly impaired kidneys, 2.50 m/s for moderately impaired kidneys, and 2.33 m/s for severely impaired kidneys, the corresponding area under the ROC curves were 0.735, 0.744, and 0.895, respectively. Intra- and intre-observer agreement of SWV measurements were 0.709 (95% CI: 0.390–0.859, P<0.001) and 0.627 (95% CI: 0.233–0.818, P = 0.004), respectively.

Conclusions

ARFI may be an effective tool for evaluating renal histological fibrosis in CKD patients.     

Circulating Levels of Dimethylarginines,Chronic Kidney Disease and Long-Term Clinical Outcome in Non-ST-Elevation Myocardial Infarction

Background

Mechanisms linking chronic kidney disease (CKD) and adverse outcomes in acute coronary syndromes (ACS) are not fully understood. Among potential key players, reduced nitric oxide (NO) synthesis due to its endogenous inhibitors, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine could be involved. We measured plasma concentration of arginine, ADMA and SDMA and investigated their relationship with CKD and long-term outcome in non-ST-elevation myocardial infarction (NSTEMI).

Methodology/Principal Findings

We prospectively measured arginine, ADMA, and SDMA at hospital admission in 104 NSTEMI patients. CKD was defined as an estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m². We considered a primary end point of combined cardiac death and re-infarction at a median follow-up of 21 months. In CKD (n = 33) and no-CKD (n = 71) patients, arginine and ADMA were similar, whereas SDMA was significantly higher in CKD patients (0.65±0.23 vs. 0.42±0.12 µmol/L; P<0.0001). Twenty-four (23%) patients had an adverse cardiac event during follow-up: 12 (36%) were CKD and 12 (17%) no-CKD patients (P = 0.02). When study population was stratified according to arginine, ADMA and SDMA median values, only SDMA (median 0.46 µmol/L) was associated with the primary end-point (P = 0.0016). In models adjusted for age, hemoglobin and left ventricular ejection fraction, the hazard ratio (HR) for CKD and SDMA were high (HR 2.93, interquartile range [IQR] 1.15–7.53; P = 0.02 and HR 6.80, IQR 2.09–22.2; P = 0.001, respectively) but, after mutual adjustment, only SDMA remained significantly associated with the primary end point (HR 5.73, IQR 1.55–21.2; P = 0.009).

Conclusions/Significance

In NSTEMI patients, elevated SDMA plasma levels are associated with CKD and worse long-term prognosis.     

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.     

Virtual Touch Tissue Quantification of Acoustic Radiation Force Impulse: A New Ultrasound Elastic Imaging in the Diagnosis of Thyroid Nodules

Objective

Virtual touch tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) is a new quantitative technique to measure tissue stiffness. The study was aimed to assess the usefulness of VTQ in the diagnosis of thyroid nodules.

Methods

173 pathologically proven thyroid nodules in 142 patients were included and all were examined by conventional ultrasound (US), conventional elasticity imaging (EI) and VTQ of ARFI. The tissue stiffness for VTQ was expressed as shear wave velocity (SWV) (m/s). Receiver-operating characteristic curve (ROC) analyses were performed to assess the diagnostic performance. Intra- and inter-observer reproducibility of VTQ measurement was assessed.

Results

The SWVs of benign and malignant thyroid nodules were 2.34±1.17 m/s (range: 0.61–9.00 m/s) and 4.82±2.53 m/s (range: 2.32–9.00 m/s) respectively (P<0.001). The mean SWV ratios between each nodule and the adjacent thyroid tissue were 1.19±0.67 (range: 0.31–6.87) for benign and 2.50±1.54 (range: 0.85–6.69) for malignant nodules (P<0.001). ROC analyses indicated that the area under the curve was 0.861 (95% CI : 0.804, 0.918) (P<0.001) for SWV and 0.831(95% CI : 0.761, 0.900)(P<0.001) for the SWV ratio. The cutoff points for the differential diagnosis were 2.87 m/s for SWV and 1.59 for SWV ratio. The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value for EI were 65.9%, 66.7%, 66.5%, 40.3%, and 85.1%, respectively, and were 63.6%–75%, 82.2%–88.4%, 80.3%–82.1%, 58.9%–65.1%, and 87.7%–90.5%, respectively, for VTQ. The diagnostic value of VTQ is the highest for nodules >20 mm and lowest for those ≤10 mm. The correlation coefficients were 0.904 for intraobserver measurement and 0.864 for interobserver measurement.

Conclusions

VTQ of ARFI provides quantitative and reproducible information about the tissue stiffness, which is useful for the differentiation between benign and malignant thyroid nodules. The diagnostic performance of VTQ is higher than that of conventional EI.     

Soluble Tumor Necrosis Factor Related Apoptosis Inducing Ligand Level as a Predictor of Severity of Sepsis and the Risk of Mortality in Septic Patients

Background

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) as a member of the TNF gene superfamily induces apoptosis primarily in tumor cells. TRAIL also plays an important role in the modulation of inflammatory responses, especially in the process of immune paralysis. The aim of the present study was to examine soluble TRAIL (sTRAIL) levels in septic patients in an attempt to explore the association between sTRAIL level and the risk of mortality.

Methods

Plasma sTRAIL levels were detected by ELISA in 50 septic patients and 20 healthy volunteers. HLA-DR expression in monocytes was detected by flow cytometry. Selective biochemical parameters were recorded, and patients were monitored in a 28-day period for mortality.

Results

The mean plasma sTRAIL level in septic patients was significantly lower than that in healthy controls (16.9±8.3 vs. 68.3±8.6 pg/ml, P<0.01), and was significantly higher in 28-day survivors than those in non-survivors (19.4±9.8 vs. 13.9±4.7 pg/ml, P<0.05). Univariate analysis indicated that plasma sTRAIL level was positively correlated with monocyte and lymphocyte counts and HLA-DR expression level (r = 0.5, P<0.01; r = 0.3, P<0.05; r = 0.43, P<0.01, respectively). STRAIL level was negatively correlated with APACHE II score, BUN and age (r = −0.48, P<0.01; r = −0.29, P<0.05; r = −0.45, P<0.01, respectively). Multiple linear regression analysis indicated that the predictor of plasma soluble TRAIL level was HLA-DR expression (P<0.01).

Conclusion

Low plasma sTRAIL levels were associated with immune paralysis and a high risk of mortality in patients with septic shock. sTRAIL may prove to be a potential biomarker of immune function and predict the survival of septic patients.     

De Novo Lipogenesis and Cholesterol Synthesis in Humans with Long-Standing Type 1 Diabetes Are Comparable to Non-Diabetic Individuals

Background

Synthesis of lipid species, including fatty acids (FA) and cholesterol, can contribute to pathological disease. The purpose of this study was to investigate FA and cholesterol synthesis in individuals with type 1 diabetes, a group at elevated risk for vascular disease, using stable isotope analysis.

Methods

Individuals with type 1 diabetes (n = 9) and age-, sex-, and BMI-matched non-diabetic subjects (n = 9) were recruited. On testing day, meals were provided to standardize food intake and elicit typical feeding responses. Blood samples were analyzed at fasting (0 and 24 h) and postprandial (2, 4, 6, and 8 hours after breakfast) time points. FA was isolated from VLDL to estimate hepatic FA synthesis, whereas free cholesterol (FC) and cholesteryl ester (CE) was isolated from plasma and VLDL to estimate whole-body and hepatic cholesterol synthesis, respectively. Lipid synthesis was measured using deuterium incorporation and isotope ratio mass spectrometry.

Results

Fasting total hepatic lipogenesis (3.91±0.90% vs. 5.30±1.22%; P = 0.41) was not significantly different between diabetic and control groups, respectively, nor was synthesis of myristic (28.60±4.90% vs. 26.66±4.57%; P = 0.76), palmitic (12.52±2.75% vs. 13.71±2.64%; P = 0.65), palmitoleic (3.86±0.91% vs. 4.80±1.22%; P = 0.65), stearic (5.55±1.04% vs. 6.96±0.97%; P = 0.29), and oleic acid (1.45±0.28% vs. 2.10±0.51%; P = 0.21). Postprandial lipogenesis was also not different between groups (P = 0.38). Similarly, fasting synthesis of whole-body FC (8.2±1.3% vs. 7.3±0.8%/day; P = 0.88) and CE (1.9±0.4% vs. 2.0±0.3%/day; P = 0.96) and hepatic FC (8.2±2.0% vs. 8.1±0.8%/day; P = 0.72) was not significantly different between diabetic and control subjects.

Conclusions

Despite long-standing disease, lipogenesis and cholesterol synthesis was not different in individuals with type 1 diabetes compared to healthy non-diabetic humans.     

The Relationship of Omental and Subcutaneous Adipocyte Size to Metabolic Disease in Severe Obesity

Objective

Several studies have reported the existence of a subgroup of obese individuals with normal metabolic profiles. It remains unclear what factors are responsible for this phenomenon. We proposed that adipocyte size might be a key factor in the protection of metabolically healthy obese (MHO) individuals from the adverse effects of obesity.

Subjects

Thirty-five patients undergoing bariatric surgery were classified as MHO (n = 15) or metabolically unhealthy obese (MUO, n = 20) according to cut-off points adapted from the International Diabetes Federation definition of the metabolic syndrome. Median body mass index (BMI) was 48 (range 40–71).

Results

There was a moderate correlation between omental adipocyte size and subcutaneous adipocyte size (r = 0.59, p<0.05). The MHO group had significantly lower mean omental adipocyte size (80.9±10.9 µm) when compared with metabolically unhealthy patients (100.0±7.6 µm, p<0.0001). Mean subcutaneous adipocyte size was similar between the two groups (104.1±8.5 µm versus 107.9±7.1 µm). Omental, but not subcutaneous adipocyte size, correlated with the degree of insulin resistance as measured by HOMA-IR (r = 0.73, p<0.0005), as well as other metabolic parameters including triglyceride/HDL-cholesterol ratio and HbA1c. Twenty-eight patients consented to liver biopsy. Of these, 46% had steatohepatitis and fibrosis. Fifty percent (including all the MHO patients) had steatosis only. Both omental and subcutaneous adipocyte size were significantly associated with the degree of steatosis (r = 0.66, p<0.0001 and r = 0.63, p<0.005 respectively). However, only omental adipocyte size was an independent predictor of the presence or absence of fibrosis.

Conclusion

Metabolically healthy individuals are a distinct subgroup of the severely obese. Both subcutaneous and omental adipocyte size correlated positively with the degree of fatty liver, but only omental adipocyte size was related to metabolic health, and possibly progression from hepatic steatosis to fibrosis.     

Serum Retinol-Binding Protein 4 as a Marker for Cardiovascular Disease in Women

Background

Elevated serum level of retinol-binding protein 4 (RBP4) has been associated with obesity-related co-morbidities including insulin resistance, dyslipidemia and hypertension.

Objectives

The present study examined the relationship between serum level of RBP4 and various risk factors related to cardiovascular disease (CVD) in men and women.

Methods

284 subjects (139 males, 145 females), grouped into healthy (n = 60), obese diabetes (n = 60), non-obese diabetes (n = 60), obese non-diabetes (n = 60) and patients with CVD (n = 44), were assessed for anthropometric and biochemical parameters related to obesity, diabetes and CVD. In addition, serum levels of several adipokines, including fatty acid binding protein 4 (FABP4) and lipocalin 2 (LCN2) and RBP4 were measured using specific immunoassays.

Results

Serum RBP4 level correlated significantly with principal component derived from known risk factors of CVD (β = 0.20±0.06, P = 0.002). Significance of this correlation was limited to women (β = 0.20±0.06, P = 0.002) and it persisted even after adjusting for BMI (β = 0.19±0.06, P = 0.002). Overall (n = 284) serum RBP4 values significantly correlated with FABP4 (R = 0.19, p = 0.001). Serum FABP4 level of CVD subjects was significantly higher than healthy control (P = 0.001) and non-obese diabetes (P = 0.04) groups, but this difference was attributable to differences in BMI. Serum LCN2 level correlated well with RBP4 (R = 0.15, P = 0.008) and FABP4 (R = 0.36, P<0.001), but did not differ significantly between CVD and other groups.

Conclusions

Results of this study indicate a significant correlation between serum RBP4 and various established risk factors for CVD and suggest RBP4 may serve as an independent predictor of CVD in women.     

Low-Intensity Pulsed Ultrasound Induces Angiogenesis and Ameliorates Left Ventricular Dysfunction in a Porcine Model of Chronic Myocardial Ischemia

Background

Although a significant progress has been made in the management of ischemic heart disease (IHD), the number of severe IHD patients is increasing. Thus, it is crucial to develop new, non-invasive therapeutic strategies. In the present study, we aimed to develop low-intensity pulsed ultrasound (LIPUS) therapy for the treatment of IHD.

Methods and Results

We first confirmed that in cultured human endothelial cells, LIPUS significantly up-regulated mRNA expression of vascular endothelial growth factor (VEGF) with a peak at 32-cycle (P<0.05). Then, we examined the in vivo effects of LIPUS in a porcine model of chronic myocardial ischemia with reduced left ventricular ejection fraction (LVEF) (n = 28). The heart was treated with either sham (n = 14) or LIPUS (32-cycle with 193 mW/cm² for 20 min, n = 14) at 3 different short axis levels. Four weeks after the treatment, LVEF was significantly improved in the LIPUS group (46±4 to 57±5%, P<0.05) without any adverse effects, whereas it remained unchanged in the sham group (46±5 to 47±6%, P = 0.33). Capillary density in the ischemic region was significantly increased in the LIPUS group compared with the control group (1084±175 vs. 858±151/mm², P<0.05). Regional myocardial blood flow was also significantly improved in the LIPUS group (0.78±0.2 to 1.39±0.4 ml/min/g, P<0.05), but not in the control group (0.84±0.3 to 0.97±0.4 ml/min/g). Western blot analysis showed that VEGF, eNOS and bFGF were all significantly up-regulated only in the LIPUS group.

Conclusions

These results suggest that the LIPUS therapy is promising as a new, non-invasive therapy for IHD.     

Correlation of Prostatic Urethral Angle with the Severity of Urinary Symptom and Peak Flow Rate in Men with Small Prostate Volume

Purpose

To evaluate the effects of prostatic anatomical factors on male lower urinary tract symptoms (LUTS) and the peak flow rate (Qmax) in patients with small prostate volume (PV).

Materials and Methods

Records were obtained from a prospectively maintained database of first-visit men with LUTS. Patients whose total PV (TPV) was greater than 30 mL were excluded; 444 patients were enrolled in the study. The TPV, transitional zone volume (TZV), transitional zone index (TZI), intravesical prostatic protrusion (IPP), and prostatic urethral angle (PUA) were measured by transrectal ultrasonography. LUTS were evaluated using the International Prostate Symptom Score (IPSS) and the Overactive Bladder Symptom Score (OABSS) questionnaires. Uroflowmetric measurements were also made.

Results

PUA (r = 0.269, P<0.001), TZV (r = 0.160, P<0.001), and TZI (r = 0.109, P = 0.022) significantly correlated with the IPSS. Qmax (r = −0.334, P<0.001) and OABSS (r = 0.211, P<0.001) correlated only with PUA. In a multivariate regression analysis, PUA and age were independently associated with IPSS, OABSS, and Qmax. For IPSS of 20 or greater, the area under the ROC curve (AUC) of PUA was 0.667 and the cut-off value was 43.7°. When Qmax was 10 mL/s or less, the AUC of PUA was 0.664 and the cut-off value was 43.5°.

Conclusions

PUA has a significant association with symptom severity and Qmax among prostatic anatomical factors analyzed in men with LUTS and small PV. PUA should be considered as an important clinical factor in male LUTS management. Furthermore, the impact of PUA on response to medical treatment and disease progression needs to be investigated.     

Fatty Acid- and Cholesterol Transporter Protein Expression along the Human Intestinal Tract

Background

Protein distribution profiles along the human intestinal tract of transporters involved in the absorption of cholesterol and long-chain fatty acids (LCFA) have been scarcely evaluated.

Methodology/Principal Findings

In post-mortem samples from 11 subjects, intestinal transporter distribution profiles were determined via Western Blot. Differences in transporter protein levels were statistically tested using ANOVA and Tukey''s Post Hoc comparisons. Levels in all segments were expressed relative to those in duodenum. Except for ABCG5 and FATP4, levels (mean±SEM) were the highest in the ileum. For ABCA1, ileal levels (1.80±0.26) differed significantly from those in duodenum (P = 0.049) and proximal colon (0.92±0.14; P = 0.029). ABCG8 levels in ileum (1.91±0.30) differed from those in duodenum (P = 0.041) and distal colon (0.84±0.22; P = 0.010) and jejunum (1.64±0.26) tended to be higher than distal colon (0.84±0.22; P = 0.087). Ileal NPC1L1 levels (2.56±0.51) differed from duodenum levels (P = 0.019) and from distal colon (1.09±0.22; P = 0.030). There was also a trend (P = 0.098) for higher jejunal (2.23±0.37) than duodenal NPC1L1 levels. The levels of ABCG5 did not correlate with those of ABCG8. FAT/CD36 levels in ileum (2.03±0.42) differed from those in duodenum (P = 0.017), and proximal and distal colon (0.89±0.13 and 0.97±0.15 respectively; P = 0.011 and P = 0.014). FABPpm levels in ileum (1.04±0.13) differed from proximal (0.64±0.07; P = 0.026) and distal colon (0.66±0.09; P = 0.037).

Conclusions/Significance

The distribution profiles showed a bell-shape pattern along the GI-tract with the highest levels in ileum for ABCA1, ABCG8, NPC1L1, FATCD36 and FABPm, suggesting a prominent role for ileum in transporter-mediated uptake of cholesterol and LCFAs.     

Determinants of Posterior Corneal Biometric Measurements in a Multi-Ethnic Asian Population

Purpose

To describe the corneal and anterior segment determinants of posterior corneal arc length (PCAL) and posterior corneal curvature (PCC).

Methods

Cross-sectional, population-based study of 1069 subjects (1069 eyes) aged 40–80 years, from three major Asian ethnic groups. All underwent anterior segment optical coherence tomography imaging and analysis with Zhongshan Angle Assessment Program. Our main outcome measures were determinants of PCAL and PCC using adjusted, multivariate linear regression analysis, adjusted for confounders to obtain the estimated marginal means (EMM) with standard error (SE).

Results

The overall mean (± SD) of PCC was: 6.51±0.39 mm; and PCAL was: 12.52±0.59 mm. Malays had a relatively longer PCAL (EMM = 12.74 mm, SE = 0.04 mm) than Chinese (EMM = 12.48 mm, SE = 0.03 mm, P<0.001), and Indians (EMM = 12.42 mm, SE = 0.03 mm, P<0.001). Anterior segment parameters had weak-moderate correlations with PCAL, which included: anterior chamber depth (ACD) (r = 0.55, P<0.001), PCC (r = 0.27, P<0.001), anterior corneal curvature (ACC) (r = 0.14, P<0.001) and central corneal thickness (CCT) (r = −0.07, P = 0.023). In multivariate analysis, anterior segment parameters explained only 37.6% of the variance of PCAL, with ACD being the most important determinant (partial R²  = 0.300; P<0.001). The determinants of PCC included ACC, PCAL and CCT (explaining 72.1% variation of PCC), with ACC being the most important determinant (partial R²  = 0.683; P<0.001).

Conclusion

There was moderate correlation of PCAL with ACD, but anterior segment parameters accounted for only a small proportion of the variation in PCAL. The significant differences in PCAL and PCC amongst different Asian ethnic groups suggests that there is a need to consider this factor when planning for anterior segment surgeries such as endothelial keratoplasty.     

Coagulation and Fibrinolysis Index Profile in Patients with ANCA-Associated Vasculitis

Background

Previous studies observed the high prevalence of venous thromboembolism in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study analyzed the coagulation and fibrinolysis index profile in AAV patients.

Methods

The current study recruited 321 AAV patients in active stage and 78 AAV patients in quiescent stage. Coagulation and fibrinolysis index profiles in these AAV patients were analysed, and their associations with various clinical and pathological parameters were further investigated.

Results

The circulating levels of D-dimer, fibrin degradation products and platelet count were significantly higher in AAV patients in active stage compared with those in remission [0.8 (0.4, 1.5) mg/L vs. 0.28 (0.2, 0.55) mg/L, P<0.05; 5.6 (5.0, 10.0) mg/L vs. 1.9 (1.2, 2.8) mg/L, P<0.05; 269±127×10⁹/L vs. 227±80×10⁹/L, P<0.05, respectively]. Among the 321 AAV patients in active stage, compared with patients with normal levels of D-dimer, patients with elevated D-dimer levels had significantly higher levels of initial serum creatinine, erythrocyte sedimentation rate, C reactive protein and the Birmingham Vasculitis Activity Scores (P = 0.014, P<0.001, P<0.001, P = 0.002, respectively). Moreover, correlation analysis showed that the levels of D-dimer correlated with erythrocyte sedimentation rate and C reactive protein levels (r = 0.384, P<0.001; r = 0.380, P<0.001, respectively).

Conclusion

Patients with active AAV are in hypercoagulable states, and circulating levels of D-dimer are associated with disease activity of AAV.     

Antenatal Dexamethasone after Asphyxia Increases Neural Injury in Preterm Fetal Sheep

Background and Purpose

Maternal glucocorticoid treatment for threatened premature delivery dramatically improves neonatal survival and short-term morbidity; however, its effects on neurodevelopmental outcome are variable. We investigated the effect of maternal glucocorticoid exposure after acute asphyxia on injury in the preterm brain.

Methods

Chronically instrumented singleton fetal sheep at 0.7 of gestation received asphyxia induced by complete umbilical cord occlusion for 25 minutes. 15 minutes after release of occlusion, ewes received a 3 ml i.m. injection of either dexamethasone (12 mg, n = 10) or saline (n = 10). Sheep were killed after 7 days recovery; survival of neurons in the hippocampus and basal ganglia, and oligodendrocytes in periventricular white matter were assessed using an unbiased stereological approach.

Results

Maternal dexamethasone after asphyxia was associated with more severe loss of neurons in the hippocampus (CA3 regions, 290±76 vs 484±98 neurons/mm², mean±SEM, P<0.05) and basal ganglia (putamen, 538±112 vs 814±34 neurons/mm², P<0.05) compared to asphyxia-saline, and with greater loss of both total (913±77 vs 1201±75/mm², P<0.05) and immature/mature myelinating oligodendrocytes in periventricular white matter (66±8 vs 114±12/mm², P<0.05, vs sham controls 165±10/mm², P<0.001). This was associated with transient hyperglycemia (peak 3.5±0.2 vs. 1.4±0.2 mmol/L at 6 h, P<0.05) and reduced suppression of EEG power in the first 24 h after occlusion (maximum −1.5±1.2 dB vs. −5.0±1.4 dB in saline controls, P<0.01), but later onset and fewer overt seizures.

Conclusions

In preterm fetal sheep, exposure to maternal dexamethasone during recovery from asphyxia exacerbated brain damage.     

The Relationship between the Blood Pressure Responses to Exercise following Training and Detraining Periods

Background

Exercise training lowers blood pressure (BP), while BP increases and returns to pre-training values with detraining. Yet, there is considerable variability in these BP responses. We examined the relationship between the BP responses after 6 months of training followed by 2 weeks of detraining among the same people.

Methodology/Principal Findings

Subjects (n = 75) (X+SD, 50.2±10.6 yr) were sedentary, obese, and had prehypertension. They completed an aerobic (n = 34); resistance (n = 28); or aerobic + resistance or concurrent (n = 13) exercise training program. We calculated a metabolic syndrome z score (MetSz). Subjects were classified as BP responders (BP decreased) or non-responders (BP increased) to training and detraining. Linear and multivariable regression tested the BP response. Chi Square tested the frequency of responders and non-responders. The systolic BP (SBP, r = −0.474) and diastolic (DBP, r = −0.540) response to training negatively correlated with detraining (p<0.01), independent of modality (p>0.05). Exercise responders reduced SBP 11.5±7.8 (n = 29) and DBP 9.8±6.2 mmHg (n = 31); non-responders increased SBP 7.9.±10.9 (n = 46) and DBP 4.9±7.1 mmHg (n = 44) (p<0.001). We found 65.5% of SBP training responders were SBP detraining non-responders; while 60.9% of SBP training non-responders were SBP detraining responders (p = 0.034). Similarly, 80.6% of DBP training responders were DBP detraining non-responders; while 59.1% of DBP training non-responders were DBP detraining responders (p<0.001). The SBP detraining response (r = −0.521), resting SBP (r = −0.444), and MetSz (r = 0.288) explained 44.8% of the SBP training response (p<0.001). The DBP detraining response (r = −0.553), resting DBP (r = −0.450), and MetSz (r = 0.463) explained 60.1% of the DBP training response (p<0.001).

Conclusions/Significance

As expected most subjects that decreased BP after exercise training, increased BP after detraining. An unanticipated finding was most subjects that increased BP after exercise training, decreased BP after detraining. Reasons why the negative effects of exercise training on BP maybe reversed with detraining among some people should be explored further.

Trial Registration Information

ClinicalTrials.gov 1R01HL57354; 2003–2008; {"type":"clinical-trial","attrs":{"text":"NCT00275145","term_id":"NCT00275145"}}NCT00275145     

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.     

Association between Body Water Status and Acute Mountain Sickness

Purpose

The present study determined the association between body fluid variation and the development of acute mountain sickness (AMS) in adults.

Methods

Forty-three healthy participants (26 males and 17 females, age: 26±6 yr, height: 174±9 cm, weight: 68±12 kg) were passively exposed at a FiO₂ of 12.6% (simulated altitude hypoxia of 4500 m, PiO₂ = 83.9 mmHg) for 12-h. AMS severity was assessed using the Lake Louise Score (LLS). Food and drink intakes were consumed ad libitum and measured; all urine was collected. Before and after the 12-h exposure, body weight and plasma osmolality were measured and whole-body bioimpedance analysis was performed.

Results

The overall AMS incidence was 43% (38% males, 50% females). Participants who developed AMS showed lower fluid losses (3.0±0.9 vs. 4.5±2.0 ml/kg/h, p = 0.002), a higher fluid retention (1.9±1.5 vs. 0.6±0.8 ml/kg/h, p = 0.022), greater plasma osmolality decreases (−7±7 vs. −2±5 mOsm/kg, p = 0.028) and a larger plasma volume expansion (11±10 vs. 1±15%, p = 0.041) compared to participants not developing AMS. Net water balance (fluid intake – fluid loss) and the amount of fluid loss were strong predictors whether getting sick or not (Nagelkerkes r² = 0.532). The LLS score was related to net water balance (r = 0.358, p = 0.018), changes in plasma osmolality (r = −0.325, p = 0.033) and sodium concentration (r = −0.305, p = 0.047). Changes in the impedance vector length were related to weight changes (r = −0.550, p<0.001), fluid intake (r = −0.533, p<0.001) and net water balance (r = −0.590, p<0.001).

Conclusions

Participants developing AMS within 12 hours showed a positive net water balance due to low fluid loss. Thus measures to avoid excess fluid retention are likely to reduce AMS symptoms.     

The Vitamin D Status in Inflammatory Bowel Disease

Context

There is no consensus on the vitamin D status of children and adolescents with inflammatory bowel disease (IBD).

Aim

To determine the vitamin D status of patients with IBD by comparing their serum 25(OH)D concentration to that of healthy controls.

Hypothesis

Serum 25(OH)D concentration will be lower in patients with IBD compared to controls.

Subjects and Methods

A case-controlled retrospective study of subjects with IBD (n = 58) of 2–20 years (male n = 31, age 16.38±2.21 years; female n = 27, age16.56±2.08 years) and healthy controls (n = 116; male n = 49, age 13.90±4.59 years; female n = 67, age 15.04±4.12years). Study subject inclusion criteria: diagnosis of Crohn’s disease (CD) or ulcerative colitis (UC). Vitamin D deficiency was defined as 25(OH)D of (<20 ng/mL) (<50 nmol/L), overweight as BMI of ≥85^th but <95^th percentile, and obesity as BMI ≥95^th percentile. Data were expressed as mean ± SD.

Results

Patients with CD, UC, and their controls had mean serum 25(OH)D concentrations of 61.69±24.43 nmol/L, 53.26±25.51, and 65.32±27.97 respectively (ANOVA, p = 0.196). The overweight/obese controls had significantly lower 25(OH)D concentration compared to the normal-weight controls (p = 0.031); whereas 25(OH)D concentration was similar between the normal-weight and overweight/obese IBD patients (p = 0.883). There was no difference in 25(OH)D between patients with UC and CD, or between subjects with active IBD and controls. However, IBD subjects with elevated ESR had significantly lower 25(OH)D than IBD subjects with normal ESR (p = 0.025), as well as controls (65.3±28.0 nmol/L vs. 49.5±25.23, p = 0.045).

Conclusion

There is no difference in mean serum 25(OH)D concentration between children and adolescents with IBD and controls. However, IBD subjects with elevated ESR have significantly lower 25(OH)D than controls. Therefore, IBD subjects with elevated ESR should be monitored for vitamin D deficiency.     

Endothelial Function and Serum Concentration of Toxic Metals in Frequent Consumers of Fish

Background

Endothelial dysfunction is involved in the pathogenesis of atherosclerosis. Consumption of fish is associated with reduced cardiovascular risk, but there is paucity of data concerning its effect on endothelial function. Furthermore, investigation of the effects of fish consumption on health must take into account the ingestion of contaminants, including transition metals and some metalloids, which may have unfavorable effects on health, including those on the cardiovascular system. We investigated the association between fish consumption, endothelial function (flow mediated dilation of the brachial artery), and serum concentration of some toxic metals in apparently healthy people.

Methods

Twenty-nine high fish consumers (at least 3 portions a week) were compared with 25 low fish consumers (less than 1 portion a week). All participants were free of diabetes, cardiovascular or other systemic diseases. Serum metal (antimonium, arsenic, mercury, lead, cobalt, copper, zinc, selenium, strontium) concentrations were measured in subgroups of 24 high fish consumers and 19 low fish consumers.

Results

Both groups exhibited similar habitual dietary patterns, age and anthropometric characteristics. The high fish consumers had higher flow mediated dilation (9.7±1.8 vs. 7.3±1.9%; P<0.001), but also higher serum concentrations of mercury (5.87±2.69 vs. 1.65±1.10 mcg/L; P<0.001) and arsenic (6.04±3.25 vs. 2.30±1.58 mcg/L; P<0.001). The fasting plasma glucose concentrations were significantly correlated with both mercury (r = 0.39; P = 0.01) and arsenic concentrations (r = 0.55; P<0.001).

Conclusions

Habitual consumption of high amounts of fish is associated with better endothelial function despite higher serum concentrations of mercury and arsenic.