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Pulse pressure, wide [keywords]
- Human blood glycosaminoglycans: isolation and analysis. [Journal Article]
- Methods Mol Biol 2015.:95-103.
Glycosaminoglycans (GAGs) are linear polysaccharides having disaccharide building blocks consisting of an amino sugar (N-acetylglucosamine, or N-acetylgalactosamine) and a uronic acid (glucuronic acid or iduronic acid) or galactose. Glycosaminoglycans have sulfated residues at various positions except for hyaluronan, and those sulfated residues regulate the biological functions of a wide variety of proteins, primarily through high-affinity interactions mediated by specific patterns/densities of sulfation and sugar sequences. Alteration of GAG structure is associated with a number of disease conditions and therefore the analyses of GAG structures and their sulfation patterns are important for the development of disease biomarkers and for treatment options. Extensive structural and quantitative analyses of GAGs from human blood are largely unexplored which may be due to the exhaustive isolation process because of the presence of too much interfering proteins and lipids such as serum albumin. Therefore we established a new GAG isolation method using the least amount (~200 μl) of human blood, consisting of a combination of proteolytic digestion and selective ethanol precipitation of GAGs, digestion of GAGs recovered on the filter cup by direct addition of GAG lyase reaction solution, and subsequent high-pressure liquid chromatography of unsaturated disaccharide products that enable to analyze GAG structures and contents. This isolation method offers an 80 % recovery of GAGs and can be applied to analyze a minute GAG content (≥1 nmol) from the least amount of biological fluids. Hence the method could be useful for the development of disease biomarkers.
- Multiplexed fluidic plunger mechanism for the measurement of red blood cell deformability. [JOURNAL ARTICLE]
- Lab Chip 2014 Oct 17.
The extraordinary deformability of red blood cells gives them the ability to repeatedly transit through the microvasculature of the human body. The loss of this capability is part of the pathology of a wide range of diseases including malaria, hemoglobinopathies, and micronutrient deficiencies. We report on a technique for multiplexed measurements of the pressure required to deform individual red blood cell through micrometer-scale constrictions. This measurement is performed by first infusing single red blood cells into a parallel array of ~1.7 μm funnel-shaped constrictions. Next, a saw-tooth pressure waveform is applied across the constrictions to squeeze each cell through its constriction. The threshold deformation pressure is then determined by relating the pressure-time data with the video of the deformation process. Our key innovation is a self-compensating fluidic network that ensures identical pressures are applied to each cell regardless of its position, as well as the presence of cells in neighboring constrictions. These characteristics ensure the consistency of the measurement process and robustness against blockages of the constrictions by rigid cells and debris. We evaluate this technique using in vitro cultures of RBCs infected with P. falciparum, the parasite that causes malaria, to demonstrate the ability to profile the deformability signature of a heterogeneous sample.
- Comparison of Serum Adipocytokine Levels according to Metabolic Health and Obesity Status. [JOURNAL ARTICLE]
- Endocrinol Metab (Seoul) 2014 Sep 29.
Metabolic health is an emerging concept that is highly correlated with various metabolic complications, and adipocytokines have been causally linked to a wide range of metabolic diseases. Thus, this study compared serum adipocytokine levels according to metabolic health and obesity status.Four hundred and fifty-six nondiabetic subjects (mean age, 40.5 years) were categorized into four groups according to metabolic health and obesity status: metabolically healthy nonobese (MHNO), metabolically healthy obese (MHO), metabolically unhealthy nonobese (MUHNO), and metabolically unhealthy obese (MUHO). Being metabolically healthy was defined as the presence of fewer than two of the following five metabolic abnormalities: high blood pressure, high fasting blood glucose, high triglyceride, low high density lipoprotein cholesterol, and being in the highest decile of the homeostatic model assessment of insulin resistance index. Obesity status was assessed using body mass index (BMI), with obesity defined as a BMI higher than 25 kg/m². Levels of serum interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor α (TNF-α), and adipocyte fatty acid binding protein (A-FABP) were also evaluated.Of the 456 subjects, 247 (54.2%) were in the MHNO group, 66 (14.5%) were in the MHO group, 66 (14.5%) were in the MUHNO group, and 77 (16.9%) were in the MUHO group. There were no significant differences in IL-6 or MCP-1 levels among the groups, but levels of TNF-α and A-FABP were significantly higher in the MUHNO group compared to the MHNO group.High TNF-α and A-FABP levels are significantly associated with metabolically unhealthiness in nonobese Korean individuals.
- Numerical Simulation of Particle Transport and Deposition in the Pulmonary Vasculature. [JOURNAL ARTICLE]
- J Biomech Eng 2014 Oct 1.
To quantify the transport and adhesion of drug particles in a complex vascular environment, computational fluid particle dynamics (CFPD) simulations of blood flow and drug particulate were conducted in three different geometries representing the human lung vasculature: artificial, original and over-smoothed geometry. The flow boundary conditions used include both steady-state inlet flow and pulsatile inlet flow. A fully developed flow profile was assumed as the inlet velocity and a lumped mathematical model was used for the calculation of the outlet pressure boundary condition. Blood flow was modeled as laminar and Newtonian. Particle trajectories were calculated by solving the force balance on the particle at each time step. Moreover, a receptor-ligand model was also integrated to simulate the particle binding probability. The results indicate that realistic unsteady flow significantly accelerates the binding activity over a wide range of particle sizes and also improves the particle deposition fraction in bifurcation regions. Furthermore, surface imperfections and geometrical complexity coupled with the pulsatility effect can enhance fluid mixing and accordingly particle binding efficiency. The primary outcome of this work provides a better understanding of drug delivery mechanisms in the human lung vasculature tree.
- Epidemiological and genome-wide association study of gastritis or gastric ulcer in korean populations. [Journal Article]
- Genomics Inform 2014 Sep; 12(3):127-33.
Gastritis is a major disease that has the potential to grow as gastric cancer. Gastric cancer is a very common cancer, and it is related to a very high mortality rate in Korea. This disease is known to have various reasons, including infection with Helicobacter pylori, dietary habits, tobacco, and alcohol. The incidence rate of gastritis has reported to differ between age, population, and gender. However, unlike other factors, there has been no analysis based on gender. So, we examined the high risk factors of gastritis in each gender in the Korean population by focusing on sex. We performed an analysis of 120 clinical characteristics and genome-wide association studies (GWAS) using 349,184 single-nucleotide polymorphisms from the results of Anseong and Ansan cohort study in the Korea Association Resource (KARE) project. As the result, we could not prove a strong relation with these factors and gastritis or gastric ulcer in the GWAS. However, we confirmed several already-known risk factors and also found some differences of clinical characteristics in each gender using logistic regression. As a result of the logistic regression, a relation with hyperlipidemia, coronary artery disease, myocardial infarction, hyperlipidemia therapy, hypotensive or antihypotensive drug, diastolic blood pressure, and gastritis was seen in males; the results of this study suggest that vascular disease has a potential association with gastritis in males.
- Randomized Trial of Telephone Outreach to Improve Medication Adherence and Metabolic Control in Adults With Diabetes. [JOURNAL ARTICLE]
- Diabetes Care 2014 Oct 14.
Medication nonadherence is a major obstacle to better control of glucose, blood pressure (BP), and LDL cholesterol in adults with diabetes. Inexpensive effective strategies to increase medication adherence are needed.In a pragmatic randomized trial, we randomly assigned 2,378 adults with diabetes mellitus who had recently been prescribed a new class of medication for treating elevated levels of glycated hemoglobin (A1C) ≥8% (64 mmol/mol), BP ≥140/90 mmHg, or LDL cholesterol ≥100 mg/dL, to receive 1) one scripted telephone call from a diabetes educator or clinical pharmacist to identify and address nonadherence to the new medication or 2) usual care. Hierarchical linear and logistic regression models were used to assess the impact on 1) the first medication fill within 60 days of the prescription; 2) two or more medication fills within 180 days of the prescription; and 3) clinically significant improvement in levels of A1C, BP, or LDL cholesterol.Of the 2,378 subjects, 89.3% in the intervention group and 87.4% in the usual-care group had sufficient data to analyze study outcomes. In intent-to-treat analyses, intervention was not associated with significant improvement in primary adherence, medication persistence, or intermediate outcomes of care. Results were similar across subgroups of patients defined by age, sex, race/ethnicity, and study site, and when limiting the analysis to those who completed the intended intervention.This low-intensity intervention did not significantly improve medication adherence or control of glucose, BP, or LDL cholesterol. Wide use of this strategy does not appear to be warranted; alternative approaches to identify and improve medication adherence and persistence are needed.
- Blood Pressure Levels in Male Carriers of Arg82Cys in CD300LG. [JOURNAL ARTICLE]
- PLoS One 2014; 9(10):e109646.
The genetics of hypertension has been scrutinized in large-scale genome-wide association studies (GWAS) with a large number of common genetic variants identified, each exerting subtle effects on disease susceptibility. An amino acid polymorphism, p.Arg82Cys, in CD300LG was recently found to be associated with fasting HDL-cholesterol and triglyceride levels. The polymorphism has not been detected in hypertension GWAS potentially due to its low frequency, but CD300LG has been linked to blood pressure as CD300LG knockout mice have changes in blood pressure. Twenty-four-hour ambulatory blood pressure was obtained in human CD300LG CT-carriers to follow up on these observations.Twenty healthy male CD300LG rs72836561 CT-carriers matched for age and BMI with 20 healthy male CC-carriers. Office blood pressure, 24-hour ambulatory blood pressure, carotid intima-media thickness (CIMT), and fasting blood samples were evaluated. The clinical study was combined with a genetic-epidemiological study to replicate the association between blood pressure and CD300LG Arg82Cys in 2,637 men and 3,249 women.CT-carriers had a higher 24-hour ambulatory systolic blood pressure (122 mmHg versus 115; p = 0.01) and diastolic blood pressure (77 mmHg versus 72; p<0.01) compared with CC-carriers. There were no differences in CIMT between the two groups. Metalloproteinase-9 level was higher in CT-carriers than in CC-carriers (P<0.01). However, no association between office blood pressure and CD300LG genotype was detected in the genetic-epidemiological study.Although 24-hour blood pressure, measured with a sensitive method, in a small sample of CD300LG rs72836561 CT-carriers was higher than in CC-carriers, this did not translate into significant differences in office blood pressure in a larger cohort. This discrepancy which may reflect differences in methodological approach, underlines the importance of performing replication studies in a larger clinical context, but a formal rejection of a relation between blood pressure and CD300LG requires measurement of 24-hour ambulatory blood pressure in a larger cohort.
- Genetic, psychosocial and clinical factors associated with hippocampal volume in the general population. [JOURNAL ARTICLE]
- Transl Psychiatry 2014.:e465.
The hippocampus-crucial for memory formation, recall and mood regulation-is involved in the pathophysiology of dementia and depressive disorders. Recent genome-wide association studies (GWAS) have identified five genetic loci associated with hippocampal volume (HV). Previous studies have described psychosocial and clinical factors (for example, smoking, type 2 diabetes and hypertension) to have an impact on HV. However, the interplay between genetic, psychosocial and clinical factors on the HV remains unclear. Still, it is likely that genetic variants and clinical or psychosocial factors jointly act in modifying HV; it might be possible they even interact. Knowledge of these factors might help to quantify ones individual risk of or rather resilience against HV loss. We investigated subjects (N=2463; 55.7% women; mean age 53 years) from the Study of Health in Pomerania (SHIP-2; SHIP-TREND-0) who underwent whole-body magnetic resonance imaging (MRI) and genotyping. HVs were estimated with FreeSurfer. For optimal nonlinear model fitting, we used regression analyses with restricted cubic splines. Genetic variants and associated psychosocial or clinical factors were jointly assessed for potential two-way interactions. We observed associations between HV and gender (P<0.0001), age (P<0.0001), body height (P<0.0001), education (P=0.0053), smoking (P=0.0058), diastolic blood pressure (P=0.0211), rs7294919 (P=0.0065), rs17178006 (P=0.0002), rs6581612 (P=0.0036), rs6741949 (P=0.0112) and rs7852872 (P=0.0451). In addition, we found three significant interactions: between rs7294919 and smoking (P=0.0473), rs7294919 and diastolic blood pressure (P=0.0447) and between rs7852872 and rs6581612 (P=0.0114). We suggest that these factors might have a role in the individual susceptibility to hippocampus-associated disorders.
- Predicting the Effects of Blood Pressure-Lowering Treatment on Major Cardiovascular Events for Individual Patients With Type 2 Diabetes Mellitus: Results From Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation. [JOURNAL ARTICLE]
- Hypertension 2014 Oct 13.
Blood pressure-lowering treatment reduces cardiovascular risk in patients with diabetes mellitus, but the effect varies between individuals. We sought to identify which patients benefit most from such treatment in a large clinical trial in type 2 diabetes mellitus. In Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) participants (n=11 140), we estimated the individual patient 5-year absolute risk of major adverse cardiovascular events with and without treatment by perindopril-indapamide (4/1.25 mg). The difference between treated and untreated risk is the estimated individual patient's absolute risk reduction (ARR). Predictions were based on a Cox proportional hazards model inclusive of demographic and clinical characteristics together with the observed relative treatment effect. The group-level effect of selectively treating patients with an estimated ARR above a range of decision thresholds was compared with treating everyone or those with a blood pressure >140/90 mm Hg using net benefit analysis. In ADVANCE, there was wide variation in treatment effects across individual patients. According to the algorithm, 43% of patients had a large predicted 5-year ARR of ≥1% (number-needed-to-treat [NNT5] ≤100) and 40% had an intermediate predicted ARR of 0.5% to 1% (NNT5=100-200). The proportion of patients with a small ARR of ≤0.5% (NNT5≥200) was 17%. Provided that one is prepared to treat at most 200 patients for 5 years to prevent 1 adverse outcome, prediction-based treatment yielded the highest net benefit. In conclusion, a multivariable treatment algorithm can identify those individuals who benefit most from blood pressure-lowering therapy in terms of ARR of major adverse cardiovascular events and may be used to guide treatment decisions in individual patients with diabetes.
- Is there a need for more diving science for divers? [Editorial]
- Diving Hyperb Med 2014 Sep; 44(3):122-3.
Decompression illness (DCI)/dysbaric disorders represent a complex spectrum of pathophysiological conditions with a wide variety of signs and symptoms related to dissolved gas and its subsequent phase change. Any significant organic or functional decrement in individuals who have recently been exposed to a reduction in environmental pressure (i.e., decompression) must be considered as evidence of DCI until proven otherwise. However, apart from the more obvious acute manifestations, individuals who have experienced repetitive exposures (e.g., commercial or professional divers and active recreational divers) may also develop sub-acute or chronic manifestations sub-clinically - insidious, even if subtle, and almost symptomless. It is, in fact, generally accepted that sub-clinical forms of DCI exist, with little or no reported symptoms, and that these may cause changes in the bones, the central nervous system and the lungs. All this has led us to analysing 'decompression stress', the actual way of understanding decompression. Current research into decompression sickness (DCS) is focused on biological markers that can be detected in the blood. Investigators are exploring the potential association between decompression stress and the presence of membrane microparticles (membrane-bound vesicles shed from a variety of cell types) in the blood. Microparticle levels increase in association with many physiological disease states as well as with the shearing stress caused by bubbles in the blood. The working hypothesis is that certain microparticles (possibly induced by inert gas bubbles) may initiate, be a marker of or contribute to the inflammatory response that leads to DCS. This investigation goes beyond the pure bubble model. While bubbles in the blood certainly play a key role in the development of DCS, their presence or absence does not reliably predict DCS symptom onset. Investigating this process at the molecular level may teach us a great deal more about DCS, providing insights that we hope will improve the effectiveness of both prevention and treatment. Approaches to evaluating decompression stress have considered a wide range of 'markers': different physiological changes after the dive (flow mediated dilatation reduction, blood pressure); personal susceptibility (VO2max, age); environmental factors (altitude, temperature); various physiological states (dehydration, increased vascular resistance as well as bubble counts, predictive decompression models, etc., etc. All this shows how far today's approach to decompression is removed from 'traditional' understanding. It reflects both the need to consider the phenomenon of decompression in a different way than previously and the advances in knowledge over the past 20 years of diving science research. The 14 researchers who have been working for three years under the PHYPODE European Project reached a point where they felt the need to publish a new book in English to allow divers to learn more about the modern approaches to understanding decompression and its problems. Almost every young scientist participating in the PHYPODE project had the responsibility of writing a chapter. This was by no means a simple job considering the different linguistic origins of this group of young researchers, many of whom had their own doctoral theses or research programmes to complete in parallel. Authors also include renowned and established scientists and diving medicine specialists. The intended readership is divers, as well as medically or scientifically educated individuals, interested in increasing their knowledge of the science behind diving and decompression. One may question this project considering the huge amount of information available on the internet on such a topic. Let us illustrate our motivation by means of a story from Japan where one of the major cosmetic companies received a customer complaint because he received an empty soap box. They launched a huge investigation and discovered that the defect arose in the packaging department. The plan was to develop a robust and reliable system ensuring zero defects in the process of product packaging and the company invested heavily in the design and implementation of a solution. A few weeks later, a similar problem occurred in a small soap-manufacturing company in India. This time the approach was very different. The manufacturer bought a big industrial fan and placed it facing the soap box chain. Boxes that were empty simply blew off the chain and the rest moved ahead to the storage house! Our aim was to keep the concepts as clear as possible but maintain the scientific integrity of the subject. References are limited and proposed as further reading. As many of those conceiving some of the new approaches are authors, this is our opportunity to be the "fan that blows empty boxes". As the PHYPODE Project has no means to receive profits from book sales or rights, the book will be published under the name of EUBS/PHYPODE, with EUBS being the beneficiary. The tentative title could be "Diving science for divers - What your diving instructor never told you". The final editor has to be decided during the Excom meeting in Wiesbaden and the book will then be published shortly after.