ResearchPad - plasma-volume https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Digestibility of black soldier fly larvae (<i>Hermetia illucens</i>) fed to leopard geckos (<i>Eublepharis macularius</i>)]]> https://www.researchpad.co/article/elastic_article_7714 Black soldier fly (BSF) larvae have been marketed as an excellent choice for providing calcium to reptiles without the need of dusting or gut loading. However, previous studies have indicated that they have limited calcium digestibility and are deficient in fat soluble vitamins (A, D3, and E). In this feeding and digestibility trial, 24 adult male leopard geckos were fed one of three diets for 4 months: 1) whole, vitamin A gut loaded larvae; 2) needle pierced, vitamin A gut loaded larvae; or 3) whole, non-gut loaded larvae. Fecal output from the geckos was collected daily and apparent digestibility was calculated for dry matter, protein, fat, and minerals. There were no differences in digestibility coefficients among groups. Most nutrients were well digested by the leopard geckos when compared to previous studies, with the exception of calcium (digestibility co-efficient 43%), as the calcium-rich exoskeleton usually remained intact after passage through the GI tract. Biochemistry profiles revealed possible deficits occurring over time for calcium, sodium, and total protein. In regards to vitamin A digestibility, plasma and liver vitamin A concentrations were significantly higher in the supplemented groups (plasma- gut loaded groups: 33.38 ± 7.11 ng/ml, control group: 25.8 ± 6.72 ng/ml, t = 1.906, p = 0.04; liver- gut loaded groups: 28.67 ± 18.90 μg/g, control group: 14.13 ± 7.41 μg/g, t = 1.951, p = 0.03). While leopard geckos are able to digest most of the nutrients provided by BSF larvae, including those that have been gut loaded, more research needs to be performed to assess whether or not they provide adequate calcium in their non-supplemented form.

]]>
<![CDATA[Association between Hypoalbuminaemia and Mortality in Patients with Community-Acquired Bacteraemia Is Primarily Related to Acute Disorders]]> https://www.researchpad.co/article/5989da6aab0ee8fa60b92c29

We sought to investigate whether hypoalbuminaemia was mainly caused by acute or chronic factors in patients with community-acquired bacteraemia. In this population-based study, we considered 1844 adult cases of community-acquired bacteraemia that occurred in Funen, Denmark between 2000 and 2008. We used a stepwise prognostic predisposition-insult-response-organ dysfunction (PIRO) logistic regression model by initially including age and comorbidity, then added bacterial species, and finally sepsis severity. The models were furthermore analysed using receiver operating characteristic (ROC) curves. Outcomes comprised mortality incidence on days 0–30 and 31–365 after the bacteraemia episode. Each step was performed with and without baseline albumin level measured on the date of bacteraemia. In 422 patients, their latest albumin measurement taken 8–30 days before the date of bacteraemia was also used in the analysis together with the baseline albumin level. For each decrease of 1g/L in plasma albumin level, the odds ratios (95% confidence intervals) of mortality in the period of 0–30 days after bacteraemia were 0.86 (0.84–0.88) in both predisposition (P) and predisposition-insult (PI) models and 0.87 (0.85–0.89) in the full PIRO-model. The AUC values were 0.78 and 0.66 for mortality in the period of 0–30 days in the model comprising only predisposition factors with and without albumin levels added as a factor, respectively. The AUC values in the full PIRO-model were 0.81 and 0.73 with and without consideration of albumin levels, respectively. A higher proportion of patients died within 30 days if there was a decrease in the albumin level between days 8 and 30 before bacteraemia and the actual bacteraemia date. A single plasma albumin measurement on the bacteraemia date was a better prognostic predictor of short-term mortality than the sepsis severity score.

]]>
<![CDATA[AltitudeOmics: Rapid Hemoglobin Mass Alterations with Early Acclimatization to and De-Acclimatization from 5260 m in Healthy Humans]]> https://www.researchpad.co/article/5989db07ab0ee8fa60bc8c4b

It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7±5.8% (mean ± SD; n = 20; p<0.01) at ALT7 and 7.6±6.6% (n = 21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (−6.0±3.7%; n = 20; p = 0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (−6.3±3.0%; n = 13) versus 21 days (−5.7±5.0; n = 7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r = −0.64; n = 13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia.

]]>
<![CDATA[Validation of Blood Volume Fraction Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging in Porcine Skeletal Muscle]]> https://www.researchpad.co/article/5989db53ab0ee8fa60bdcb25

The purpose of this study was to assess the accuracy of fractional blood volume (vb) estimates in low-perfused and low-vascularized tissue using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). The results of different MRI methods were compared with histology to evaluate the accuracy of these methods under clinical conditions. vb was estimated by DCE-MRI using a 3D gradient echo sequence with k-space undersampling in five muscle groups in the hind leg of 9 female pigs. Two gadolinium-based contrast agents (CA) were used: a rapidly extravasating, extracellular, gadolinium-based, low-molecular-weight contrast agent (LMCA, gadoterate meglumine) and an extracellular, gadolinium-based, albumin-binding, slowly extravasating blood pool contrast agent (BPCA, gadofosveset trisodium). LMCA data were evaluated using the extended Tofts model (ETM) and the two-compartment exchange model (2CXM). The images acquired with administration of the BPCA were used to evaluate the accuracy of vb estimation with a bolus deconvolution technique (BD) and a method we call equilibrium MRI (EqMRI). The latter calculates the ratio of the magnitude of the relaxation rate change in the tissue curve at an approximate equilibrium state to the height of the same area of the arterial input function (AIF). Immunohistochemical staining with isolectin was used to label endothelium. A light microscope was used to estimate the fractional vascular area by relating the vascular region to the total tissue region (immunohistochemical vessel staining, IHVS). In addition, the percentage fraction of vascular volume was determined by multiplying the microvascular density (MVD) with the average estimated capillary lumen, π(d2)2, where d = 8μm is the assumed capillary diameter (microvascular density estimation, MVDE). Except for ETM values, highly significant correlations were found between most of the MRI methods investigated. In the cranial thigh, for example, the vb medians (interquartile range, IQRs) of IHVS, MVDE, BD, EqMRI, 2CXM and ETM were vb = 0.7(0.3)%, 1.1(0.4)%, 1.1(0.4)%, 1.4(0.3)%, 1.2(1.8)% and 0.1(0.2)%, respectively. Variances, expressed by the difference between third and first quartiles (IQR) were highest for the 2CXM for all muscle groups. High correlations between the values in four muscle groups—medial, cranial, lateral thigh and lower leg - estimated with MRI and histology were found between BD and EqMRI, MVDE and 2CXM and IHVS and ETM. Except for the ETM, no significant differences between the vb medians of all MRI methods were revealed with the Wilcoxon rank sum test. The same holds for all muscle regions using the 2CXM and MVDE. Except for cranial thigh muscle, no significant difference was found between EqMRI and MVDE. And except for the cranial thigh and the lower leg muscle, there was also no significant difference between the vb medians of BD and MVDE. Overall, there was good vb agreement between histology and the BPCA MRI methods and the 2CXM LMCA approach with the exception of the ETM method. Although LMCA models have the advantage of providing excellent curve fits and can in principle determine more physiological parameters than BPCA methods, they yield more inaccurate results.

]]>
<![CDATA[The effects of residual platelets in plasma on plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdb988

Due to controversial evidence in the literature pertaining to the activity of plasminogen activator inhibitor-1 in platelets, we examined the effects of residual platelets present in plasma (a potential pre-analytical variable) on various plasminogen activator inhibitor-1 and plasminogen activator inhibitor-1-related assays. Blood samples were collected from 151 individuals and centrifuged at 352 and 1500 g to obtain plasma with varying numbers of platelet. In a follow-up study, blood samples were collected from an additional 23 individuals, from whom platelet-poor (2000 g), platelet-containing (352 g) and platelet-rich plasma (200 g) were prepared and analysed as fresh-frozen and after five defrost-refreeze cycles (to determine the contribution of in vitro platelet degradation). Plasminogen activator inhibitor-1 activity, plasminogen activator inhibitor-1 antigen, tissue plasminogen activator/plasminogen activator inhibitor-1 complex, plasma clot lysis time, β-thromboglobulin and plasma platelet count were analysed. Platelet α-granule release (plasma β-thromboglobulin) showed a significant association with plasminogen activator inhibitor-1 antigen levels but weak associations with plasminogen activator inhibitor-1 activity and a functional marker of fibrinolysis, clot lysis time. Upon dividing the study population into quartiles based on β-thromboglobulin levels, plasminogen activator inhibitor-1 antigen increased significantly across the quartiles while plasminogen activator inhibitor-1 activity and clot lysis time tended to increase in the 4th quartile only. In the follow-up study, plasma plasminogen activator inhibitor-1 antigen was also significantly influenced by platelet count in a concentration-dependent manner. Plasma plasminogen activator inhibitor-1 antigen levels increased further after complete platelet degradation. Residual platelets in plasma significantly influence plasma plasminogen activator inhibitor-1 antigen levels mainly through release of latent plasminogen activator inhibitor-1 with limited effects on plasminogen activator inhibitor-1 activity, tissue plasminogen activator/plasminogen activator inhibitor-1 complex or plasma clot lysis time. Platelets may however also have functional effects on plasma fibrinolytic potential in the presence of high platelet counts, such as in platelet-rich plasma.

]]>
<![CDATA[Repeated quantitative measurements of De Novo synthesis of albumin and fibrinogen]]> https://www.researchpad.co/article/5989db50ab0ee8fa60bdc064

The possibility of using two different isotopomers, for the incorporation of isotopically labeled amino acids, was explored to enable longitudinal studies of de novo synthesis of two export liver proteins, albumin and fibrinogen. The agreement of the synthesis rates between the two different labels was evaluated along with the reproducibility of repeated experiments using different time intervals. Healthy volunteers were studied in a standardized fed state. Protocol A (n = 10) involved two measurements 48 hours apart. Protocol B (n = 6) involved three measurements at baseline and five hours and then seven days after the initial measurement. De novo synthesis of albumin and fibrinogen by the incorporation of D5-phenylalanine or D8-phenylalanine were measured using the flooding dose technique. Albumin and fibrinogen were isolated from plasma using standard techniques. Fractional and absolute synthesis rates were calculated. Repeated measurements employing the two isotoptomers showed good agreement for albumin fractional synthesis rate after 48 hours (p = 0.92) and after 7 days (p = 0.99), with a coefficient of variation of 5.9% when using the same isotopic label. For fibrinogen, the coefficient of variation for the fractional synthesis rate employing the same isotopic label was 16.6%. Repeated measurements after 48 hours and seven days showed less agreement although there was no statistical difference (P = 0.32 and P = 0.30 respectively). Repeated measurement after five hours showed a statistical significant difference for the fractional synthesis rate of fibrinogen (p = 0.008) but not for albumin (p = 0.12). Repeated measurements of albumin de novo synthesis more than 48 hours apart show acceptable agreement using either one or two different isotopic labels. For fibrinogen the larger intra-individual scatter necessitates larger study groups to detect changes in longitudinal studies. Repeated measurements within 48 hours need to be validated further.

]]>
<![CDATA[Enabling Metabolomics Based Biomarker Discovery Studies Using Molecular Phenotyping of Exosome-Like Vesicles]]> https://www.researchpad.co/article/5989da57ab0ee8fa60b8f34f

Identification of sensitive and specific biomarkers with clinical and translational utility will require smart experimental strategies that would augment expanding the breadth and depth of molecular measurements within the constraints of currently available technologies. Exosomes represent an information rich matrix to discern novel disease mechanisms that are thought to contribute to pathologies such as dementia and cancer. Although proteomics and transcriptomic studies have been reported using Exosomes-Like Vesicles (ELVs) from different sources, exosomal metabolome characterization and its modulation in health and disease remains to be elucidated. Here we describe methodologies for UPLC-ESI-MS based small molecule profiling of ELVs from human plasma and cell culture media. In this study, we present evidence that indeed ELVs carry a rich metabolome that could not only augment the discovery of low abundance biomarkers but may also help explain the molecular basis of disease progression. This approach could be easily translated to other studies seeking to develop predictive biomarkers that can subsequently be used with simplified targeted approaches.

]]>
<![CDATA[Circulating Microvesicles Are Elevated Acutely following Major Burns Injury and Associated with Clinical Severity]]> https://www.researchpad.co/article/5989da4dab0ee8fa60b8d3e1

Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology.

]]>
<![CDATA[Extracellular Fluid/Intracellular Fluid Volume Ratio as a Novel Risk Indicator for All-Cause Mortality and Cardiovascular Disease in Hemodialysis Patients]]> https://www.researchpad.co/article/5989da58ab0ee8fa60b8f497

Background

In hemodialysis patients, fluid overload and malnutrition are accompanied by extracellular fluid (ECF) expansion and intracellular fluid (ICF) depletion, respectively. We investigated the relationship between ECF/ICF ratio (as an integrated marker reflecting both fluid overload and malnutrition) and survival and cardiovascular disease (CVD) in the context of malnutrition-inflammation-arteriosclerosis (MIA) complex.

Methods

Seventy-seven patients from a single hemodialysis unit were prospectively enrolled. The ECF/ICF volume was measured by segmental multi-frequency bioimpedance analysis. MIA and volume status were measured by serum albumin, C-reactive protein (CRP), pulse wave velocity (PWV) and plasma B-type natriuretic peptide (BNP), respectively.

Results

The mean ECF/ICF ratio was 0.56±0.06 and the cut-off value for maximum discrimination of survival was 0.57. Compared with the low ECF/ICF group, the high ECF/ICF group (ratio≥0.57, 42%) had higher all-cause mortality, CVD, CRP, PWV, and BNP, but lower serum albumin. During the 5-year follow-up, 24 all-cause mortality and 38 CVD occurred (18 and 24, respectively, in the high ECF/ICF group versus 6 and 14 respectively in the low ECF/ICF group, P<0.001). In the adjusted Cox analysis, the ECF/ICF ratio nullifies the effects of the MIA and volume status on survival and CVD and was an independent predictor of all-cause mortality and CVD: hazard ratio (95% confidence interval); 1.12 (1.01–1.25) and 1.09 (1.01–1.18) for a 0.01 increase in the ECF/ICF ratio. The degree of malnutrition (albumin), inflammation (CRP), arteriosclerosis (PWV), and fluid overload (BNP) were correlated well with the ECF/ICF ratio.

Conclusions

Hemodialysis patients with high ECF/ICF ratio are not only fluid overloaded, but malnourished and have stiff artery with more inflammation. The ECF/ICF ratio is highly related to the MIA complex, and is a major risk indicator for all-cause mortality and CVD.

]]>
<![CDATA[Comparison of Cerebral Blood Volume and Plasma Volume in Untreated Intracranial Tumors]]> https://www.researchpad.co/article/5989d9d5ab0ee8fa60b65869

Purpose

Plasma volume and blood volume are imaging-derived parameters that are often used to evaluation intracranial tumors. Physiologically, these parameters are directly related, but their two different methods of measurements, T1-dynamic contrast enhanced (DCE)- and T2-dynamic susceptibility contrast (DSC)-MR utilize different model assumptions and approaches. This poses the question of whether the interchangeable use of T1-DCE-MRI derived fractionated plasma volume (vp) and relative cerebral blood volume (rCBV) assessed using DSC-MRI, particularly in glioblastoma, is reliable, and if this relationship can be generalized to other types of brain tumors. Our goal was to examine the hypothetical correlation between these parameters in three most common intracranial tumor types.

Methods

Twenty-four newly diagnosed, treatment naïve brain tumor patients, who had undergone DCE- and DSC-MRI, were classified in three histologically proven groups: glioblastoma (n = 7), meningioma (n = 9), and intraparenchymal metastases (n = 8). The rCBV was obtained from DSC after normalization with the normal-appearing anatomically symmetrical contralateral white matter. Correlations between these parameters were evaluated using Pearson (r), Spearman's (ρ) and Kendall’s tau-b (τB) rank correlation coefficient.

Results

The Pearson, Spearman and Kendall’s correlation between vp with rCBV were r = 0.193, ρ = 0.253 and τB = 0.33 (p-Pearson = 0.326, p-Spearman = 0.814 and p-Kendall = 0.823) in glioblastoma, r = -0.007, ρ = 0.051 and τB = 0.135 (p-Pearson = 0.970, p-Spearman = 0.765 and p-Kendall = 0.358) in meningiomas, and r = 0.289, ρ = 0.228 and τB = 0.239 (p-Pearson = 0.109, p-Spearman = 0.210 and p-Kendall = 0.095) in metastasis.

Conclusion

Results indicate that no correlation exists between vp with rCBV in glioblastomas, meningiomas and intraparenchymal metastatic lesions. Consequently, these parameters, as calculated in this study, should not be used interchangeably in either research or clinical practice.

]]>
<![CDATA[Optimised Pre-Analytical Methods Improve KRAS Mutation Detection in Circulating Tumour DNA (ctDNA) from Patients with Non-Small Cell Lung Cancer (NSCLC)]]> https://www.researchpad.co/article/5989daf2ab0ee8fa60bc1ae5

Introduction

Non-invasive mutation testing using circulating tumour DNA (ctDNA) is an attractive premise. This could enable patients without available tumour sample to access more treatment options.

Materials & Methods

Peripheral blood and matched tumours were analysed from 45 NSCLC patients. We investigated the impact of pre-analytical variables on DNA yield and/or KRAS mutation detection: sample collection tube type, incubation time, centrifugation steps, plasma input volume and DNA extraction kits.

Results

2 hr incubation time and double plasma centrifugation (2000 x g) reduced overall DNA yield resulting in lowered levels of contaminating genomic DNA (gDNA). Reduced “contamination” and increased KRAS mutation detection was observed using cell-free DNA Blood Collection Tubes (cfDNA BCT) (Streck), after 72 hrs following blood draw compared to EDTA tubes. Plasma input volume and use of different DNA extraction kits impacted DNA yield.

Conclusion

This study demonstrated that successful ctDNA recovery for mutation detection in NSCLC is dependent on pre-analytical steps. Development of standardised methods for the detection of KRAS mutations from ctDNA specimens is recommended to minimise the impact of pre-analytical steps on mutation detection rates. Where rapid sample processing is not possible the use of cfDNA BCT tubes would be advantageous.

]]>
<![CDATA[Temperature sensitive liposomes combined with thermal ablation: Effects of duration and timing of heating in mathematical models and in vivo]]> https://www.researchpad.co/article/5989db5eab0ee8fa60be0abc

Background

Temperature sensitive liposomes (TSL) are nanoparticles that rapidly release the contained drug at hyperthermic temperatures, typically above ~40°C. TSL have been combined with various heating modalities, but there is no consensus on required hyperthermia duration or ideal timing of heating relative to TSL administration. The goal of this study was to determine changes in drug uptake when heating duration and timing are varied when combining TSL with radiofrequency ablation (RF) heating.

Methods

We used computer models to simulate both RF tissue heating and TSL drug delivery, to calculate spatial drug concentration maps. We simulated heating for 5, 12 and 30 min for a single RF electrode, as well as three sequential 12 min ablations for 3 electrodes placed in a triangular array. To support simulation results, we performed porcine in vivo studies in normal liver, where TSL filled with doxorubicin (TSL-Dox) at a dose of 30 mg was infused over 30 min. Following infusion, RF heating was performed in separate liver locations for either 5 min (n = 2) or 12 min (n = 2). After ablation, the animal was euthanized, and liver extracted and frozen. Liver samples were cut orthogonal to the electrode axis, and fluorescence imaging was used to visualize tissue doxorubicin distribution.

Results

Both in vivo studies and computer models demonstrate a ring-shaped drug deposition within ~1 cm of the visibly coagulated tissue. Drug uptake directly correlated with heating duration. In computer simulations, drug concentration increased by a factor of 2.2x and 4.3x when heating duration was extended from 5 to either 12, or 30 minutes, respectively. In vivo, drug concentration was by a factor of 2.4x higher at 12 vs 5 min heating duration (7.1 μg/g to 3.0 μg/g). The computer models suggest that heating should be timed to maximize area under the curve of systemic plasma concentration of encapsulated drug.

Conclusions

Both computer models and in vivo study demonstrate that tissue drug uptake directly correlates with heating duration for TSL based delivery. Computational models were able to predict the spatial drug delivery profile, and may serve as a valuable tool in understanding and optimizing drug delivery systems.

]]>
<![CDATA[Algorithm Optimization in Methylation Detection with Multiple RT-qPCR]]> https://www.researchpad.co/article/5989dad2ab0ee8fa60bb67e4

Epigenetic markers based on differential methylation of DNA sequences are used in cancer screening and diagnostics. Detection of abnormal methylation at specific loci by real-time quantitative polymerase chain reaction (RT-qPCR) has been developed to enable high-throughput cancer screening. For tests that combine the results of multiple PCR replicates into a single reportable result, both individual PCR cutoff and weighting of the individual PCR result are essential to test outcome. In this opportunistic screening study, we tested samples from 1133 patients using the triplicate Epi proColon assay with various algorithms and compared it with the newly developed single replicate SensiColon assay that measures methylation status of the same SEPT9 gene sequence. The Epi proColon test approved by the US FDA (1/3 algorithm) showed the highest sensitivity (82.4%) at a lower specificity (82.0%) compared with the Epi proColon 2.0 CE version with 2/3 algorithm (75.1% sensitivity, 97.1% specificity) or 1/1 algorithm (71.3% sensitivity, 92.7% specificity). No significant difference in performance was found between the Epi proColon 2.0 CE and the SensiColon assays. The choice of algorithm must depend on specific test usage, including screening and early detection. These considerations allow one to choose the optimal algorithm to maximize the test performance. We hope this study can help to optimize the methylation detection in cancer screening and early detection.

]]>
<![CDATA[Effects of vasoactive drugs on crystalloid fluid kinetics in septic sheep]]> https://www.researchpad.co/article/5989db4fab0ee8fa60bdbb1f

Purpose

Crystalloid fluid and vasoactive drugs are used in the early treatment of sepsis. The purpose of the present study was to examine how these drugs alter plasma volume expansion, peripheral edema, and urinary excretion.

Methods

Twenty-five anesthetized sheep were made septic by cecal puncture and a short infusion of lipopolysaccharide. After 50 min, a slow infusion of isotonic saline was initiated: the saline either contained no drug, norepinephrine (1 μg/kg/min), phenylephrine (3 μg/kg/min), dopamine (50 μg/kg/min), or esmolol (50 μg/kg/min). Ten min later, 20 mL/kg Ringer´s lactate solution was given over 30 min. Central hemodynamics, acid-base balance, and the urinary excretion were monitored. Frequent measurements of the blood hemoglobin concentration were used as input in a kinetic analysis, using a mixed effects modeling software.

Results

The fluid kinetic analysis showed slow distribution and elimination of Ringer´s lactate, although phenylephrine and dopamine accelerated the distribution. Once distributed, the fluid remained in the peripheral tissues and did not equilibrate adequately with the plasma. Overall, stimulation of adrenergic alpha1-receptors accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. A pharmacodynamic Emax model showed that Ringer´s lactate increased stroke volume by 13 ml/beat. Alpha1-receptors, but not beta1-receptors, further increased stroke volume, while both raised the mean arterial pressure. Modulation of the beta1-receptors limited the acidosis.

Conclusions

Stimulation of adrenergic alpha1-receptors with vasoactive drugs accelerated, while beta1-receptors retarded, the distribution and elimination of fluid. The tendency for peripheral accumulation of fluid was pronounced, in particular when phenylephrine was given.

]]>
<![CDATA[Kininogen Cleavage Assay: Diagnostic Assistance for Kinin-Mediated Angioedema Conditions]]> https://www.researchpad.co/article/5989d9daab0ee8fa60b673b1

Background

Angioedema without wheals (AE) is a symptom characterised by localised episodes of oedema presumably caused by kinin release from kininogen cleavage. It can result from a hereditary deficiency in C1 Inhibitor (C1Inh), but it can present with normal level of C1Inh. These forms are typically difficult to diagnose although enhanced kinin production is suspected or demonstrated in some cases.

Objectives

We wanted to investigate bradykinin overproduction in all AE condition with normal C1Inh, excluding cases with enhanced kinin catabolism, and to propose this parameter as a disease biomarker.

Methods

We retrospectively investigated high molecular weight kininogen (HK) cleavage pattern, using gel electrophoresis and immunorevelation. Plasma samples were drawn using the same standardised procedure from blood donors or AE patients with normal C1Inh conditions, normal kinin catabolism, and without prophylaxis.

Results

Circulating native HK plasma concentrations were similar in the healthy men (interquartile range: 98–175μg/mL, n = 51) and in healthy women (90–176μg/mL, n = 74), while HK cleavage was lower (p<0.001) in men (0–5%) than women (3–9%). Patients exhibited lower native HK concentration (p<10−4; 21–117μg/mL, n = 31 for men; 0–84μg/mL, n = 41 for women) and higher HK cleavage (p<10−4; 10–30% and 14–89%, respectively) than healthy donors. Pathological thresholds were set at: <72μg/mL native HK, >14.4% HK cleavage for men; <38μg/mL; native HK, >33.0% HK cleavage for women, with >98% specificity achieved for all parameters. In plasma from patients undergoing recovery two months after oestrogen/progestin combination withdrawal (n = 13) or two weeks after AE attack (n = 2), HK cleavage was not fully restored, suggesting its use as a post-attack assay.

Conclusion

As a diagnostic tool, HK cleavage can offer physicians supportive arguments for kinin production in suspected AE cases and improve patient follow-up in clinical trials or prophylactic management.

]]>
<![CDATA[Impact of experimental hypercalcemia on routine haemostasis testing]]> https://www.researchpad.co/article/5989db51ab0ee8fa60bdc206

Background

The blood to anticoagulant ratio is standardized according to the physiological calcium concentration in blood samples conventionally used for hemostasis testing. Specifically, one fixed volume of 0.109 mmol/L sodium citrate is added to 9 volumes of blood. Since little is known about the impact of hypercalcemia on the calcium-binding capacity of citrate, this study was planned to investigate the effect of experimental hypercalcemia on routine hemostasis testing.

Methods

Fifteen pooled citrated plasmas with matching lithium-heparin pooled plasma from patients with different values of prothrombin time (PT) were divided in three aliquots of 0.6mL each. The first paired aliquots of both citrate and lithium-heparin plasma were supplemented with 60μL of saline, the second paired aliquots with 30μL of saline and 30μL of calcium chloride and the third paired aliquots with 60μL of calcium chloride. Total and ionized calcium was measured in all aliquots of citrate and lithium-heparin plasma, whereas PT, activated partial thromboplastin time (APTT) and fibrinogen were measured in citrate plasma aliquots.

Results

Total calcium concentration gradually increased in both lithium-heparin and citrate plasma aliquots 2 and 3 compared to baseline aliquot 1. The concentration of ionized calcium also gradually increased in lithium-heparin plasma aliquots 2 and 3, whereas it remained immeasurable (i.e., <0.10 mmol/L) in all citrate plasma aliquots. No significant differences were observed for values of PT, APTT and fibrinogen in citrate plasma aliquots 2 and 3 compared to the baseline aliquot 1, with a mean bias was always comprised within the desirable quality specifications derived from biological variability data.

Conclusion

Hypercalcemia, up to severe hypercalcemia does not generate significant bias in results of first-line coagulations tests, so that hypothetical consideration of adjusting citrate-blood ratio is unjustified in hypercalcemic patients.

]]>
<![CDATA[Morbidity and Mortality in 7,684 Women According to Personal Hair Dye Use: The Copenhagen City Heart Study followed for 37 Years]]> https://www.researchpad.co/article/5989da77ab0ee8fa60b97290

Background

Permanent hair dye contains aromatic amines which are carcinogenic, and can cause allergic skin reactions. In the long term personal use of hair dye might therefore influence both morbidity and mortality.

Objectives

We tested the hypothesis that personal use of hair dye in women is associated with increased morbidity and mortality in the general population.

Methods

We included 7,684 women from the Copenhagen City Heart Study with information on the use of personal hair dye. We assessed the risk of cancer, skin diseases, other morbidities, and mortality during a median follow-up of 27 years (range 0–37).

Results

The multivariable adjusted hazard ratio for malignant melanoma in women with versus without personal use of hair dye was 2.07 (95% confidence interval 1.25–3.42). There was no increased risk of other cancer types. For other skin diseases and other major causes of morbidity we found no differences between the two groups, except for a minor excess of digestive diseases and increased risk of Parkinson’s disease among women using hair dye. Finally, we found no difference in all-cause mortality comparing women using personal hair dye or not. After correction for multiple comparisons, none of the results remained significant. However, in sensitivity analysis the excess risk of malignant melanoma remained increased with a hazard ratio of 2.58 (95%CI 1.33–5.03) among users of personal hair dye.

Conclusions

Personal use of hair dye does not have major influences on morbidity and mortality. Our finding of a 2-fold risk of malignant melanoma in women using hair dye is hypothesis generating.

]]>
<![CDATA[High-Intensity Jump Training Is Tolerated during 60 Days of Bed Rest and Is Very Effective in Preserving Leg Power and Lean Body Mass: An Overview of the Cologne RSL Study]]> https://www.researchpad.co/article/5989daacab0ee8fa60ba9be4

Purpose

Space agencies are looking for effective and efficient countermeasures for the degrading effects of weightlessness on the human body. The aim of this study was to assess the effects of a novel jump exercise countermeasure during bed rest on vitals, body mass, body composition, and jump performance.

Methods

23 male participants (29±6 years, 181±6 cm, 77±7 kg) were confined to a bed rest facility for 90 days: a 15-day ambulatory measurement phase, a 60-day six-degree head-down-tilt bed rest phase (HDT), and a 15-day ambulatory recovery phase. Participants were randomly allocated to the jump training group (JUMP, n = 12) or the control group (CTRL, n = 11). A typical training session consisted of 4x10 countermovement jumps and 2x10 hops in a sledge jump system. The training group had to complete 5–6 sessions per week.

Results

Peak force for the reactive hops (3.6±0.4 kN) as well as jump height (35±4 cm) and peak power (3.1±0.2 kW) for the countermovement jumps could be maintained over the 60 days of HDT. Lean body mass decreased in CTRL but not in JUMP (-1.6±1.9 kg and 0±1.0 kg, respectively, interaction effect p = 0.03). Resting heart rate during recovery was significantly increased for CTRL but not for JUMP (interaction effect p<0.001).

Conclusion

Participants tolerated the near-daily high-intensity jump training and maintained high peak forces and high power output during 60 days of bed rest. The countermeasure was effective in preserving lean body mass and partly preventing cardiac deconditioning with only several minutes of training per day.

]]>
<![CDATA[The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis]]> https://www.researchpad.co/article/5989daf5ab0ee8fa60bc29c6

Background

Although studies have demonstrated that physical exercise alters homocysteine levels in the blood, meta-analyses of the effects of acute exercise and exercise training on homocysteine blood concentration have not been performed, especially regarding the duration and intensity of exercise, which could affect homocysteine levels differently.

Objective

The aim of this meta-analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood.

Method

A review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using the online databases PubMed, SPORTDiscus, and SciELO to identify relevant studies published through June 2015. Review Manager was used to calculate the effect size of acute exercise and exercise training using the change in Hcy plasmaserum concentration from baseline to post-acute exercise and trained vs. sedentary control groups, respectively. Weighted mean differences were calculated using random effect models.

Results

Given the abundance of studies, acute exercise trials were divided into two subgroups according to exercise volume and intensity, whereas the effects of exercise training were analyzed together. Overall, 22 studies with a total of 520 participants indicated increased plasma homocysteine concentration after acute exercise (1.18 μmol/L, 95% CI: 0.71 to 1.65, p < .01). Results of a subgroup analysis indicated that either long-term exercise of low-to-moderate intensity (1.39 μmol/L, 95% CI: 0.9 to 1.89, p < .01) or short-term exercise of high intensity (0.83 μmol/L, 95% CI: 0.19 to 1.40, p < .01) elevated homocysteine levels in the blood. Increased homocysteine induced by exercise was significantly associated with volume of exercise, but not intensity. By contrast, resistance training reduced plasma homocysteine concentration (-1.53 μmol/L, 95% CI: -2.77 to -0.28, p = .02), though aerobic training did not. The cumulative results of the seven studies with a total of 230 participants in exercise training analysis did not demonstrate a significant impact on homocysteine levels in the blood (-0.56 μmol/L, 95% CI: -1.61 to 0.50, p = .23).

Conclusions

Current evidence demonstrates that acute exercise increases homocysteine levels in the blood independent of exercise duration and intensity. Resistance, but not aerobic training decreases plasma homocysteine levels.

]]>
<![CDATA[Quantitative Perfusion Analysis of First-Pass Contrast Enhancement Kinetics: Application to MRI of Myocardial Perfusion in Coronary Artery Disease]]> https://www.researchpad.co/article/5989db46ab0ee8fa60bd8ac7

Purpose

Perfusion analysis from first-pass contrast enhancement kinetics requires modeling tissue contrast exchange. This study presents a new approach for numerical implementation of the tissue homogeneity model, incorporating flexible distance steps along the capillary (NTHf).

Methods

The proposed NTHf model considers contrast exchange in fluid packets flowing along the capillary, incorporating flexible distance steps, thus allowing more efficient and stable calculations of the transit of tracer through the tissue. We prospectively studied 8 patients (62 ± 13 years old) with suspected CAD, who underwent first-pass perfusion CMR imaging at rest and stress prior to angiography. Myocardial blood flow (MBF) and myocardial perfusion reserve index (MPRI) were estimated using both the NTHf and the conventional adiabatic approximation of the TH models. Coronary artery lesions detected at angiography were clinically assigned to one of three categories of stenosis severity (‘insignificant’, ‘mild to moderate’ and ‘severe’) and related to corresponding myocardial territories.

Results

The mean MBF (ml/g/min) at rest/stress and MPRI were 0.80 ± 0.33/1.25 ± 0.45 and 1.68 ± 0.54 in the insignificant regions, 0.74 ± 0.21/1.09 ± 0.28 and 1.54 ± 0.46 in the mild to moderate regions, and 0.79 ± 0.28/0.63 ± 0.34 and 0.85 ± 0.48 in the severe regions, respectively. The correlation coefficients of MBFs at rest/stress and MPRI between the NTHf and AATH models were r = 0.97/0.93 and r = 0.91, respectively.

Conclusions

The proposed NTHf model allows efficient quantitative analysis of the transit of tracer through tissue, particularly at higher flow. Results of initial application to MRI of myocardial perfusion in CAD are encouraging.

]]>