Effect of Dietary Spice Supplementations on Welfare Status of Sea Bass, <Emphasis Type="Italic">Dicentrarchus labrax</Emphasis> L.

The present study investigated the effects of dietary thyme, rosemary and fenugreek supplementation on welfare status of sea bass, Dicentrarchus labrax L. assessed by blood parameters. Three experimental diets were supplemented with 1 % of the different spices. After 45 days of the feeding trial, the spices did not significantly affect the erythrocyte count, hematocrit ratio, hemoglobin level and superoxide dismutase activity (P > 0.05). However, white blood cell count, neutrophils, monocytes, phagocytic activity, lysozyme activity and myeloperoxidase activity were enhanced in spice treated groups (P < 0.05). Fish fed with the rosemary diet showed a higher respiratory burst activity as opposed to the control group (P < 0.05). Spice-supplemented diets significantly decreased serum glucose, triglyceride, cholesterol, low density lipoprotein, very low density lipoprotein, alkaline phosphatase, glutamic oxaloacetic transaminase, glutamic pyruvic transaminase, creatine kinase and lactate dehydrogenase levels (P < 0.05). On the other hand, the total protein, globulin, lipase and high density lipoprotein levels increased (P < 0.05). However, serum bilirubin, phosphorus, magnesium, chloride, calcium and iron were similar to those of the treatment groups (P > 0.05). The results of the present study indicate that dietary supplementation of 1 % thyme, rosemary or fenugreek in commercial diets could improve some hematological, immunological and biochemical status in sea bass hence they can be utilized as immunostimulants and health promoter in fish culture.     

Histogram Analysis of T1-Weighted,T2-Weighted,and Postcontrast T1-Weighted Images in Primary CNS Lymphoma: Correlations with Histopathological Findings—a Preliminary Study

Purpose

Previously, some reports mentioned that magnetic resonance imaging (MRI) can predict histopathological features in primary CNS lymphoma (PCNSL). The reported data analyzed diffusion-weighted imaging findings. The aim of this study was to investigate possible associations between histopathological findings, such as tumor cellularity, nucleic areas and proliferation index Ki-67, and signal intensity on T1-weighted and T2-weighted images in PCNSL.

Procedures

For this study, 18 patients with PCNSL were retrospectively investigated by histogram analysis on precontrast and postcontrast T1-weighted and fluid-attenuated inversion recovery (FLAIR) images. For every patient, histopathology parameters, nucleic count, total nucleic area, and average nucleic area, as well as Ki-67 index, were estimated.

Results

Correlation analysis identified several statistically significant associations. Skewness derived from precontrast T1-weighted images correlated with Ki-67 index (p = ? 0.55, P = 0.028). Furthermore, entropy derived from precontrast T1-weighted images correlated with average nucleic area (p = 0.53, P = 0.04). Several parameters from postcontrast T1-weighted images correlated with nucleic count: maximum signal intensity (p = 0.59, P = 0.017), P75 (p = 0.56, P = 0.02), and P90 (p = 0.52, P = 0.04) as well as SD (p = 0.58, P = 0.02). Maximum signal intensity derived from FLAIR sequence correlated with nucleic count (p = 0.50, P = 0.03).

Conclusion

Histogram-derived parameters of conventional MRI sequences can reflect different histopathological features in PSNCL.

     

Pulmonary hypertension and right ventricular dysfunction in patients with left to right shunt coronary artery fistula: evaluation with cardiac CT

In this study, we aimed to evaluate whether patients with left to right shunt coronary artery fistula (LRSCAF) are predisposed to developing pulmonary hypertension and right ventricular dysfunction compared with healthy individuals. The value of cardiac CT findings in determining the necessity of intervention for these patients was investigated. We retrospectively studied 19 patients with LRSCAF and 19 healthy patients. Several parameters were observed on cardiac CT by two radiologists, including pulmonary trunk diameter (PA diameter), right ventricular diameter (RVD), left ventricular diameter (LVD), RVD/LVD ratio, septal bowing and CT score of right ventricular dysfunction (CSRVD). Data from both groups were compared. The inter- and intra-observer variabilities and correlations were examined. The disease group was further divided into intervention (n = 9) and non-intervention (n = 10) groups, and their data were compared. All cardiac CT findings showed significant intra- and inter-observer correlation without significant variability. Mann–Whitney U tests and χ² analysis showed that PA diameter, RVD/LVD ratio acquired from two observers, and CSRVD were higher in the disease group than in the control group (all P values < 0.05 for χ² and almost all P values < 0.05 for Mann–Whitney U). The RVD/LVD ratio and CSRVD were higher in the intervention group than in the non-intervention group (all P values < 0.05). Receiver operating curve analysis identified RVD/LVD = 1.036 and CSRVD = 3.5 as the best cut-off values to determine the necessity of further intervention. Patients with LRSCAF are more predisposed to pulmonary hypertension and right ventricular dysfunction compared with the normal population. RVD/LVD > 1.0 and CSRVD ≥ 4.0 may determine the necessity of intervention for patients with LRSCAF.     

Circulating phthalates during critical illness in children are associated with long-term attention deficit: a study of a development and a validation cohort

Purpose

Environmental phthalate exposure has been associated with attention deficit disorders in children. We hypothesized that in children treated in the pediatric intensive care unit (PICU), circulating phthalates leaching from indwelling medical devices contribute to their long-term attention deficit.

Methods

Circulating plasma concentrations of di(2-ethylhexyl)phthalate (DEHP) metabolites were quantified in 100 healthy children and 449 children who had been treated in PICU and were neurocognitively tested 4 years later. In a development patient cohort (N = 228), a multivariable bootstrap study identified stable thresholds of exposure to circulating DEHP metabolites above which there was an independent association with worse neurocognitive outcome. Subsequently, in a second patient cohort (N = 221), the observed independent associations were validated.

Results

Plasma concentrations of DEHP metabolites, which were virtually undetectable [0.029 (0.027–0.031) µmol/l] in healthy children, were 4.41 (3.76–5.06) µmol/l in critically ill children upon PICU admission (P < 0.001). Plasma DEHP metabolite concentrations decreased rapidly but remained 18 times higher until PICU discharge (P < 0.001). After adjusting for baseline risk factors and duration of PICU stay, and further for PICU complications and treatments, exceeding the potentially harmful threshold for exposure to circulating DEHP metabolites was independently associated with the attention deficit (all P ≤ 0.008) and impaired motor coordination (all P ≤ 0.02). The association with the attention deficit was confirmed in the validation cohort (all P ≤ 0.01). This phthalate exposure effect explained half of the attention deficit in post-PICU patients.

Conclusions

Iatrogenic exposure to DEHP metabolites during intensive care was independently and robustly associated with the important attention deficit observed in children 4 years after critical illness. Clinicaltrials.gov identifier: NCT00214916.

     

Short-Term Effects of a Combined Nutraceutical on Lipid Level,Fatty Liver Biomarkers,Hemodynamic Parameters,and Estimated Cardiovascular Disease Risk: A Double-Blind,Placebo-Controlled Randomized Clinical Trial

Introduction

There is a growing interest in nutraceuticals improving cardiovascular risk factor levels and related organ damage.

Methods

This double-blind, placebo-controlled randomized clinical trial aims to compare the effect of a combined nutraceutical containing red yeast rice (10 mg), phytosterols (800 mg), and l-tyrosol (5 mg) on lipid profile, blood pressure, endothelial function, and arterial stiffness in a group of 60 patients with polygenic hypercholesterolemia resistant to Mediterranean diet.

Results

After 8 weeks of treatment, when compared to the placebo group, the active treated patients experienced a more favorable percentage change in total cholesterol (?16.3% vs 9.9%, P < 0.001 always), LDL-C (?23.4% vs ?13.2%, P < 0.001 always), and hepatic steatosis index (?2.8%, P < 0.01 vs ?1.8%, P < 0.05). Moreover, ALT (?27.7%, P < 0.001), AST (?13.8%, P = 0.004), and serum uric acid (?12.3%, P = 0.005) were reduced by the tested nutraceutical compound both compared to randomization and to placebo, which did not affect these parameters (P < 0.01 for all). Regarding the hemodynamic parameters, there was a decrease of systolic blood pressure (?5.6%) with the active treatment not observed with placebo (P < 0.05 vs baseline and placebo) and endothelial reactivity improved, too (?13.2%, P < 0.001 vs baseline). Consequently, the estimated 10-year cardiovascular risk score improved by 1.19% (SE 0.4%) (P = 0.01) in the nutraceutical-treated patients.

Conclusion

The tested nutraceutical association is able to improve the positive effects of a Mediterranean diet on a large number of CV risk factors and consequently of the estimated CV risk.

Trial registration

ClinicalTrials.gov identifier NCT02492464.

Funding

IBSA Farmaceutici.

     

Peritumoral Brain Edema in Meningiomas Depends on Aquaporin-4 Expression and Not on Tumor Grade,Tumor Volume,Cell Count,or Ki-67 Labeling Index

Purpose

The aim of this study was to investigate to which degree the peritumoral brain edema in patients with meningiomas depends on aquaporin-4 (AQP4) expression, tumor grade, tumor volume, Ki-67 expression, and cell count.

Procedures

Thirty-three patients (25 women, 8 men; mean age 56.6 ± 16.0 years) with an intracranial meningioma underwent a standardized magnetic resonance (MR) examination prior to surgical resection. Edema indices (EIs) and tumor volumes were measured on the MR images. Tumor grade was classified according to the World Health Organization, and the proliferation index was estimated on Ki-67 antigen-stained specimens. Tumor cell count was evaluated. Eighteen specimens were stained for AQP4 expressioon.

Results

Significant intergroup differences between AQP4 expression grades and EIs were observed (P = 0.03), and a positive correlation was detected between EIs and AQP4 expression grades (r = 0.54; P < 0.05). A ROC analysis with EI as a test variable revealed an AUC of 0.77 (95 % CI 0.55–0.99) for the prediction of a moderate-to-strong AQP4 expression. An EI ≥1.5 predicted a moderate-to-high AQP4 expression with a sensitivity of 77 % and a specificity of 60 %. EI values of 2.2 and 3.5 reached sensitivity/specificity values of 69/80 % and 54/100 %, respectively. The AQP4 expression did not show any significant correlations with tumor grading, tumor volume, Ki-67 expression, or cell count. Moreover, we observed no significant positive or negative correlations between the EI and tumor grading (P = 0.7), tumor volume (P = 0.19), Ki-67 index (P = 0.9), and cell count (P = 0.34).

Conclusion

Peritumoral brain edema in patients with meningiomas may depend on AQP4 expression grades and not on tumor grade, tumor volume, Ki-67 expression, and cell count. The amount of edema predicted AQP4 expressions with moderate-to-good sensitivity and specificity.

     

A Randomized Trial Investigating the Pharmacokinetics,Pharmacodynamics, and Safety of Subcutaneous Semaglutide Once-Weekly in Healthy Male Japanese and Caucasian Subjects

Introduction

Semaglutide is a glucagon-like peptide-1 analogue for once-weekly subcutaneous treatment of type 2 diabetes. This trial compared the pharmacokinetics, pharmacodynamics, and safety of semaglutide in Japanese and Caucasian subjects.

Methods

In this single-center, double-blind, parallel-group, 13-week trial, 44 healthy male subjects (22 Japanese, 22 Caucasian) were randomized within each race to semaglutide 0.5 mg (n = 8), 1.0 mg (n = 8), placebo 0.5 mg (n = 3) or 1.0 mg (n = 3). The primary endpoint was semaglutide exposure at steady state [area under the curve (AUC_0–168h)].

Results

Steady-state exposure of semaglutide was similar for both populations: AUC_0–168h estimated race ratio (ERR), Japanese/Caucasian: 0.5 mg, 1.06; 1.0 mg, 0.99; maximum concentration (C_max) ERR: 0.5 mg, 1.06; 1.0 mg, 1.02. Exposure after the first dose (0.25 mg) was slightly higher in Japanese versus Caucasian subjects (AUC_0–168h ERR 1.11; C_max ERR 1.14). Dose-dependent increases in AUC_0–168h and C_max occurred in both populations. Accumulation was as expected, based on the half-life (t_1/2, ~ 1 week) and dosing interval of semaglutide. Significant body weight reductions were observed with semaglutide 0.5 mg and 1.0 mg in Japanese (both p ≤ 0.05) and Caucasian (both p ≤ 0.05) subjects versus placebo. No new safety issues were identified.

Conclusions

The pharmacokinetic, pharmacodynamic, and safety profiles of semaglutide were similar in Japanese and Caucasian subjects, suggesting that no dose adjustment is required for the clinical use of semaglutide in Japanese subjects.

Funding

Novo Nordisk A/S, Denmark.

Trial registration

ClinicalTrials.gov identifier NCT02146079. Japanese trial registration number JapicCTI-142550.

     

Non-invasive assessment of liver fibrosis using acoustic structure quantification: comparison with transient elastography in chronic viral hepatitis

Purpose

The purpose of this study was to evaluate the diagnostic efficacy of acoustic structure quantification (ASQ) parameters [mode, average, and focal distribution (FD) ratio] in the staging of hepatic fibrosis in patients with chronic viral hepatitis and to compare it with transient elastography (TE) by using liver biopsy as reference standard.

Methods

We studied 62 patients with chronic viral hepatitis. Each patient underwent ASQ evaluation and liver biopsy; 54 of these patients received TE. Thirty-six participants without any liver disease were enrolled as normal group, who also underwent ASQ evaluation and TE. All three parameters of ASQ were compared with the histologic fibrosis grade according to the METAVIR scoring (F0–F4). Statistical analysis was performed to investigate the correlations and the diagnostic values of ASQ parameters and compare them to TE.

Results

All three ASQ parameters and TE were significantly correlated with liver fibrosis stage. Of the ASQ parameters, the mode parameter showed the best correlation (P < 0.001). On the area under the receiver operating characteristic curve (AUROC), the mode parameter of ASQ analysis showed both significant correlation and good accuracy for diagnosis of F ≥ 1, F ≥ 2, and F ≥ 3. These values were significantly better than those of the average and FD ratio parameters in F ≥ 1 and F ≥ 2 (P < 0.05). There was no statistically significant difference in AUROC between the mode parameter and TE in diagnosis of F ≥ 1, F ≥ 2, or F ≥ 3.

Conclusions

The mode parameter is the most reliable ASQ parameter, comparable to TE, as a non-invasive method for the detection and grading of liver fibrosis in patients with chronic viral hepatitis.

     

Assessment of right ventricular function with 320-slice volume cardiac CT: comparison with cardiac magnetic resonance imaging

To evaluate the accuracy and feasibility of right ventricular function parameters measurement using 320-slice volume cardiac CT. Retrospective analysis of 50 consecutive patients (23 men, 27 women) with suspected pulmonary diseases was performed in electrocardiogram (ECG)-gated cardiac CT and cardiac magnetic resonance (CMR). Parameters including right ventricular end-diastolic volume (RVEDV), right ventricular end- systolic volume (RVESV), right ventricular stroke volume (RVSV), right ventricular cardiac output (RVCO), and right ventricular ejection fraction (RVEF) were semi-automatically and separately calculated from both CT and CMR data. Significant difference between measurements was measured by paired t test and two-variable linear regression analysis with Pearson’s correlation coefficient. Bland–Altman analysis was performed in each pair of parameters. There was little variability between the measurements by the two observers (kappa = 0.895–0.980, P < 0.05). There was good correlation between all parameters obtained by CT and CMR (P < 0.001): RVEDV (108.5 ± 21.9 ml, 113.5 ± 24.8 ml, r = 0.944), RVESV (69.8 ± 33.4 ml, 73.2 ± 35.4 ml, r = 0.972), RVSV (39.0 ± 13.2 ml, 40.2 ± 13.3 ml, r = 0.977), RVCO (2.6 ± 0.7 l, 2.6 ± 0.7 l. r = 0.958), RVEF (38.8 ± 19.1 %, 39.1 ± 19.3 %, r = 0.990), and there was no significant difference between CT and CMR measurements in RVEF (n = 50, t = ?0.677, P > 0.05). 320-slice volume cardiac CT is an accurate non-invasive technique to evaluate RV function.     

Semiautomatic three-dimensional CT ventricular volumetry in patients with congenital heart disease: agreement between two methods with different user interaction

To assess agreement between two semi-automatic, three-dimensional (3D) computed tomography (CT) ventricular volumetry methods with different user interactions in patients with congenital heart disease. In 30 patients with congenital heart disease (median age 8 years, range 5 days–33 years; 20 men), dual-source, multi-section, electrocardiography-synchronized cardiac CT was obtained at the end-systolic (n = 22) and/or end-diastolic (n = 28) phase. Nineteen left ventricle end-systolic (LV ESV), 28 left ventricle end-diastolic (LV EDV), 22 right ventricle end-systolic (RV ESV), and 28 right ventricle end-diastolic volumes (RV EDV) were successfully calculated using two semi-automatic, 3D segmentation methods with different user interactions (high in method 1, low in method 2). The calculated ventricular volumes of the two methods were compared and correlated. A P value <0.05 was considered statistically significant. LV ESV (35.95 ± 23.49 ml), LV EDV (88.76 ± 61.83 ml), and RV ESV (46.87 ± 47.39 ml) measured by method 2 were slightly but significantly smaller than those measured by method 1 (41.25 ± 26.94 ml, 92.20 ± 62.69 ml, 53.61 ± 50.08 ml for LV ESV, LV EDV, and RV ESV, respectively; P ≤ 0.02). In contrast, no statistically significant difference in RV EDV (122.57 ± 88.57 ml in method 1, 123.83 ± 89.89 ml in method 2; P = 0.36) was found between the two methods. All ventricular volumes showed very high correlation (R = 0.978, 0.993, 0.985, 0.997 for LV ESV, LV EDV, RV ESV, and RV EDV, respectively; P < 0.001) between the two methods. In patients with congenital heart disease, 3D CT ventricular volumetry shows good agreement and high correlation between the two methods, but method 2 tends to slightly underestimate LV ESV, LV EDV, and RV ESV.     

Effect of Extended Water Stress on Growth,Tiller Mortality and Nutrient Recovery Under System of Rice Intensification

System of rice intensification was initially introduced to increase rice productivity in India, but is recently popularized as promising water saving practice. Sustaining rice productivity with minimal use of water is the need of the day. In this background, an experiment was designed to assess the effect of variable degrees of water stress namely no-stress, mild-stress and prolonged-stress imposed throughout the crop growth by scheduling irrigation at 1, 3 and 5 days, respectively after disappearance of ponded water under system of rice intensification with two different planting geometry and two contrasting varieties. Results clearly demonstrated that mild and prolonged stress during late vegetative stage (45–75 days after transplanting) greatly (P ≤ 0.05) enhanced (30.3–41.5 %) crop growth rate while, any level of stress during reproductive phase reduced (8.8–10.8 %) the rate of crop growth. Despite of higher tiller production under stress condition, large number of tillers failed to convert in ear-bearing tillers indicating higher tiller mortality under stress environment. Meanwhile, tiller density was not confirmed as a yield determinant while, the rice yield had higher correlation with grain weight panicle^?1 (r = 0.743*), filled grain percentage (r = 0.806*), test weight (r = 0.683*) and nutrient uptake. With increase in stress intensity, apparent recovery of nutrients significantly (P ≤ 0.05) reduced, and the decline rate was in the order of potassium > phosphorus > nitrogen. Rice crop imposed mild-stress maintained at par yield (P > 0.05) with no stress, however prolonged-stress resulted in significant yield loss. Thus, mild-stress throughout the crop growth can reduce the water requirement and would be an effective water management strategy under water limited conditions.     

Monitoring of Cardiac Remodeling in a Mouse Model of Pressure-Overload Left Ventricular Hypertrophy with [<Superscript>18</Superscript>F]FDG MicroPET

Purpose

This study aims to analyze the left ventricular function parameters, scar load, and hypertrophy in a mouse model of pressure-overload left ventricular (LV) hypertrophy over the course of 8 weeks using 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) micro-positron emission tomography (microPET) imaging.

Procedures

LV hypertrophy was induced in C57BL/6 mice by transverse aortic constriction (TAC). Myocardial hypertrophy developed after 2–4 weeks. ECG-gated microPET scans with [¹⁸F]FDG were performed 4 and 8 weeks after surgery. The extent of fibrosis was measured by histopathologic analysis. LV function parameters and scar load were calculated using QGS®/QPS®. LV metabolic volume (LVMV) and percentage injected dose per gram were estimated by threshold-based analysis.

Results

The fibrotic tissue volume increased significantly from 4 to 8 weeks after TAC (?1.67 vs. 3.91  mm³; P = 0.044). There was a significant increase of the EDV (4 weeks: 54 ± 15 μl, 8 weeks: 79 ± 32 μl, P < 0.01) and LVMV (4 weeks: 222 ± 24 μl, 8 weeks: 276 ± 52 μl, P < 0.01) as well as a significant decrease of the LVEF (4 weeks: 56 ± 17 %, 8 weeks: 44 ± 20 %, P < 0.01). The increase of LVMV had a high predictive value regarding the amount of ex vivo measured fibrotic tissue (R = 0.905, P < 0.001). The myocardial metabolic defects increased within 4 weeks (P = 0.055) but only moderately correlated with the fibrosis volume (R = 0.502, P = 0.021). The increase in end-diastolic volume showed a positive correlation with the fibrosis at 8 weeks (R = 0.763, P = 0.017).

Conclusions

[¹⁸F]FDG-PET is applicable for serial in vivo monitoring of the TAC mouse model. Myocardial hypertrophy, the dilation of the left ventricle, and the decrease in LVEF could be reliably quantified over time, as well as the developing localized scar. The increase in volume over time is predictive of a high fibrosis load.

     

Sex Specific Seasonal Variation in Hematological and Serum Biochemical Indices of <Emphasis Type="Italic">Barilius bendelisis</Emphasis> from Central Himalaya,India

The study aimed to assess the effects of sex and season on hematological and serum biochemical indices of Barilius bendelisis. Hematological and biochemical results showed significant differences (p < 0.05) among seasons as well as between sexes. In summer, hemoglobin, hematocrit, erythrocyte and WBC number were highest and significantly (p < 0.05) different between sexes. Differential WBC count also showed marked seasonal variation but do not show any significant difference (p < 0.05) between male and female. Mean corpuscular volume and mean corpuscular hemoglobin was high in winter and low in summer. For males and females, mean corpuscular hemoglobin concentration was high in summer, rainy, and low in winter season. Cholesterol level and low-density lipids were high in autumn and low in spring. High-density lipids (HDL) and very low-density lipids (VLDL) also fluctuated in different seasons with maximum HDL in both sexes in autumn. Maximum VLDL for male was observed in summer and in spring for female. Triglycerides were high in autumn and summer and low in spring. Throughout winter the total protein, albumin and globulin levels were highest. Glucose level was higher in summer and autumn whereas, lower in winter in both male and female respectively. This study revealed that the variation in seasonal environmental parameters have direct effect on the health status of B. bendelisis. The baseline data generated in this study will serve as a tool for fish physiologists and pathologists in monitoring the stress, health and nutritional status of B. bendelisis under aquaculture production.     

Effect of Different Levels of Dietary Vitamin C on Growth Performance,Muscle Composition,Antioxidant and Enzyme Activity of <Emphasis Type="Italic">Macrobrachium rosenbergii</Emphasis>

A 12- week feeding trial was conducted to determine the effects of dietary vitamin C levels on the growth performance, antioxidant ability, muscle composition and enzyme activity in freshwater prawn, Macrobrachium rosenbergii. The experimental basal diets were supplemented with M. rosenbergii at the rates of 0 (control), 25, 50, 75, 150 and 300 mg/kg dry feed weight and the assays were in triplicate. Growth performance, body composition, antioxidant activity and serum biochemistry parameters were determined. However, the present investigation revealed that prawns fed with diet supplemented with 25–150 mg/kg of vitamins C shows enhanced (P < 0.05) growth performance, including final weight and weight gain. Additionally, prawns fed with 25–150 mg/kg of vitamins C supplemented diets achieved significant (P < 0.05) improvement in growth performance, digestive enzyme activities, and muscle biochemical composition, while, the prawns fed with 150 mg/kg of vitamin C showed enhanced performance respectively. However, the prawns fed with above 150–300 mg/kg showed poor performance. The antioxidant enzymatic activity (SOD, CAT) metabolic enzyme status in muscle showed no significant (P > 0.05) alterations in prawns fed with 25–150 mg/kg of vitamin C supplemented diets. Therefore, the present findings suggested that 150 mg/kg of vitamin C could be supplemented for flexible enhanced survival, growth, antioxidant defense system and production of M. rosenbergii.     

Evaluation of [<Superscript>99m</Superscript>Tc]Radiolabeled Macrophage Mannose Receptor-Specific Nanobodies for Targeting of Atherosclerotic Lesions in Mice

Purpose

Macrophage accumulation characterizes the development of atherosclerotic plaques, and the presence of certain macrophage subsets might be an indicator of plaque phenotype and (in)stability. The macrophage mannose receptor (MMR) is expressed on alternatively activated macrophages and found at sites of intraplaque hemorrhage and neovascularization. It has been proposed as target to identify vulnerable plaques. Therefore, we aimed to assess the feasibility of using anti-MMR nanobodies (Nbs) as molecular tracers for nuclear imaging in an animal model of atherosclerosis.

Procedure

Anti-MMR and control Nb, radiolabeled with Tc-99m, were injected in ApoE^?/? and/or C57Bl/6 mice (n = 6). In vivo competition studies involving pre-injection of excess of unlabeled anti-MMR Nb (n = 3) and injection of anti-MMR Nb in MMR^?/? mice (n = 3) were performed to demonstrate specificity. At 3 h p.i. radioactive uptake in organs, tissues and aorta segments were evaluated. Autoradiography and immunofluorescence were performed on aortic sections.

Results

Significantly higher uptake was observed in all aortic segments of ApoE^?/? mice injected with anti-MMR Nb compared to control Nb (1.36 ± 0.67 vs 0.38 ± 0.13 percent of injected dose per gram (%ID/g), p ≤ 0.001). Surprisingly, high aortic uptake was also observed in C57Bl/6 mice (1.50 ± 0.43%ID/g, p ≥ 0.05 compared to ApoE^?/?), while aortic uptake was reduced to background levels in the case of competition and in MMR^?/? mice (0.46 ± 0.10 and 0.22 ± 0.06%ID/g, respectively; p ≤ 0.001). Therefore, expression of MMR along healthy aortas was suggested. Autoradiography showed no specific radioactive signal within atherosclerotic plaques, but rather localization of the signal along the aorta, correlating with MMR expression in perivascular tissue as demonstrated by immunofluorescence.

Conclusions

No significant uptake of MMR-specific Nb could be observed in atherosclerotic lesions of ApoE^?/? mice in this study. A specific perivascular signal causing a non-negligible background level was demonstrated. This observation should be considered when using MMR as a target in molecular imaging of atherosclerosis, as well as use of translational animal models with vulnerable plaques.

     

Burden of Atopic Dermatitis in the United States: Analysis of Healthcare Claims Data in the Commercial,Medicare, and Medi-Cal Databases

Introduction

Comparative data on the burden of atopic dermatitis (AD) in adults relative to the general population are limited. We performed a large-scale evaluation of the burden of disease among US adults with AD relative to matched non-AD controls, encompassing comorbidities, healthcare resource utilization (HCRU), and costs, using healthcare claims data. The impact of AD disease severity on these outcomes was also evaluated.

Methods

Adult AD patients in the Commercial (n = 83,106), Medicare (n = 31,060), and Medi-Cal (n = 5550) databases were matched (1:1) to non-AD controls by demographic characteristics. AD patients were stratified by disease severity (higher, lower) using treatment as a surrogate measure of severity. The comorbidity burden, HCRU, and costs were evaluated during a 12-month follow-up period.

Results

In the Commercial, Medicare, and Medi-Cal populations, patients with AD had a significantly higher overall comorbidity burden (P < 0.0001), an increased risk of asthma and allergic rhinitis (both P < 0.0001), higher HCRU (P < 0.05), and higher mean total per patient costs (Commercial: US$10,461 versus US$7187; Medicare: US$16,914 versus US$13,714; Medi-Cal; US$19,462 versus US$10,408; all P < 0.0001), compared with matched non-AD controls. Higher disease severity was associated with an increased comorbidity burden (P < 0.0001), HCRU (P < 0.05), and total costs (Commercial: US$14,580 versus US$7192; Medicare: US$21,779 versus US$12,490; Medi-Cal; US$22,123 versus US$16,639; all P < 0.0001) relative to lower severity disease.

Conclusion

In this large-scale, healthcare claims database analysis, AD patients had a significantly higher comorbidity burden, HCRU, and costs compared with matched non-AD controls. Higher disease severity was associated with an even greater comorbidity and economic burden.

Funding

Sanofi and Regeneron Pharmaceuticals, Inc.

     

Segmental assessments of coronary plaque morphology and composition by virtual histology intravascular ultrasound and fractional flow reserve

Fractional flow reserve (FFR) is an index for identifying functionally significant stenotic lesions. A FFR value of ≤0.75 is considered clinically significant and indicative of physiological ischemia. Focal lesions with 30–80 % stenosis by angiography with lesion lengths of less than 20 mm were selected from left anterior descending arteries of 74 patients. The analysis for the total lesion was processed first, and then each lesion was divided into three segments to assess the each segment. Data on plaque geometry and composition of two FFR groups, FFR ≤ 0.75 and FFR > 0.75, were compared by total and segmental analysis. Lesions with FFR ≤ 0.75 had more fibrofatty tissue (13.5 ± 7.4 vs. 10.2 ± 6.5 %, p = 0.05) and less dense calcium (7.2 ± 5.3 vs. 11.9 ± 7.5 %, p = 0.01) compared to lesions with FFR > 0.75. The content of necrotic core in mid segments was higher compared to proximal and distal segments (22.9 ± 10.6, 20.2 ± 10.9, 17.1 ± 11.2 %, respectively, p = 0.032) in lesions with FFR > 0.75 but the difference was less obvious in lesions with FFR ≤ 0.75 (17.9 ± 9.9, 18.7 ± 9.9, 15.8 ± 9.0 %, respectively, p = 0.533). Coronary lesions with FFR > 0.75 have larger content of dense calcium and slightly less fibrofatty tissue compared to lesions with FFR ≤ 0.75. While segmental plaque compositions for each segment show noticeable variations in lesions with FFR > 0.75 such as high concentrations of necrotic core in mid segment, these differences in each segment become obscure in FFR ≤ 0.75 and are evenly distributed across the lesion.     

Can diffusion-weighted magnetic resonance imaging predict tumor recurrence of uterine cervical cancer after concurrent chemoradiotherapy?

Purpose

To retrospectively investigate the utility of diffusion-weighted imaging (DWI) for predicting clinical outcome after concurrent chemoradiotherapy (CCRT) in uterine cervical cancer.

Materials and methods

Seventy-four consecutive patients with biopsy-proven cervical cancer who received CCRT underwent DWI at 3T. All patients had MR examinations before therapy (preTx) and at 4 weeks of initiating therapy (midTx). At each point, ADC (apparent diffusion coefficient) was measured in the tumors and ADC change between preTx and midTx were also calculated. For predicting tumor recurrence, MR variables and clinical variables were evaluated and the results were compared.

Results

During a mean follow-up of 32.1 months, tumor recurrence developed in 15 (20%) patients: local recurrence (n = 7), distant metastasis (n = 5), and both (n = 3). MidTx tumor ADCs and tumor ADC changes between preTx and midTx were significantly different between the recurrence and non-recurrence groups (P < 0.05), while preTx tumor ADCs were not significantly different between the groups (P = 0.892). Univariate analysis revealed that histologic type, stage, preTx tumor size and volume, and tumor ADC change were significantly related to tumor recurrence (all P < 0.05). However, on multivariate analysis, tumor ADC changes [hazard ratio (HR) 0.886; 95% confidence interval (CI) 0.836–0.940; P = 0.001] and histological type (HR 6.063; 95% CI 1.404–26.187; P = 0.016) were the significant independent predictors of tumor recurrence.

Conclusion

Tumor ADC changes between preTx and midTx might be a useful biomarker for the prediction of cervical cancer recurrence after CCRT.

     

Midregional pro-atrial natriuretic peptide: a novel marker of myocardial fibrosis in patients with hypertrophic cardiomyopathy

We aimed to determine the diagnostic performance of biomarkers in predicting myocardial fibrosis assessed by late gadolinium enhancement (LGE) cardiovascular magnetic resonance imaging (CMR) in patients with hypertrophic cardiomyopathy (HCM). LGE CMR was performed in 40 consecutive patients with HCM. Left and right ventricular parameters, as well as the extent of LGE were determined and correlated to the plasma levels of midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), carboxy-terminal pro-vasopressin (CT-proAVP), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1) and interleukin-8 (IL-8). Myocardial fibrosis was assumed positive, if CMR indicated LGE. LGE was present in 26 of 40 patients with HCM (65%) with variable extent (mean: 14%, range: 1.3–42%). The extent of LGE was positively associated with MR-proANP (r = 0.4; P = 0.01). No correlations were found between LGE and MR-proADM (r = 0.1; P = 0.5), CT-proET-1 (r = 0.07; P = 0.66), CT-proAVP (r = 0.16; P = 0.3), MMP-9 (r = 0.01; P = 0.9), TIMP-1 (r = 0.02; P = 0.85), and IL-8 (r = 0.02; P = 0.89). After adjustment for confounding factors, MR-proANP was the only independent predictor associated with the presence of LGE (P = 0.007) in multivariate analysis. The area under the ROC curve (AUC) indicated good predictive performance (AUC = 0.882) of MR-proANP with respect to LGE. The odds ratio was 1.268 (95% confidence interval 1.066–1.508). The sensitivity of MR-proANP at a cut-off value of 207 pmol/L was 69%, the specificity 94%, the positive predictive value 90% and the negative predictive value 80%. The results imply that MR-proANP serves as a novel marker of myocardial fibrosis assessed by LGE CMR in patients with HCM.     

Haemato-biochemical Responses in Cyprinus carpio (Linnaeus, 1758) Fry Exposed to Sub-lethal Concentration of a Phenylpyrazole Insecticide, Fipronil

The present study evaluates the haemato-biochemical responses associated with fipronil exposure [(±)-5-amino-1-(2,6-dichloro-α,α,α-trifluoro-p-tolyl)-4-trifluoromethylsulfinyl-pyrazole-3-carbonitrile] in Cyprinus carpio fry. Fish were exposed to sublethal concentration (1/3rd of LC₅₀) (0.142 mg L^?1) for 15 days and corresponding changes in different haemato-biochemical parameters were recorded at the end of experimental period. Significant (P < 0.05) increase in white blood cell counts, blood glucose, serum complement reactive protein and serum cortisol level were noticed, whereas haemoglobin and serum total protein contents were significantly (P < 0.05) decreased. Aspartate amino transferase, catalase and super oxide dismutase activities were significantly (P < 0.05) increased while alkaline phosphatase and malate dehydrogenase activities were significantly (P < 0.05) decreased. Similarly, 47 % inhibition in acetylcholine esterase activity was noticed due to fipronil stress. Results indicated that sublethal exposure of fipronil can induce haemato-biochemical alterations causing stress to C. carpio fry. Thus, haemato-biochemical parameters can be used as biomarkers for the sublethal toxicity of fipronil in the water bodies.