Age is a determinant factor for measures of concentration and effect in children requiring unfractionated heparin

2010 ◽  
Vol 103 (05) ◽  
pp. 1085-1090 ◽  
Author(s):  
Vera Ignjatovic ◽  
Linda Johnston ◽  
Robyn Summerhayes ◽  
Geoff Lane ◽  
Noel Cranswick ◽  
...  
Keyword(s):  
Serum Concentration ◽  
Unfractionated Heparin ◽  
Anticoagulant Activity ◽  
Venous Blood ◽  
Fold Increase ◽  
Age Related ◽  
Age Dependent ◽  
Proportional Increase ◽  
One Year

SummaryPrevious studies investigating continuous unfractionated heparin (UFH) therapy report age-related differences in UFH response in children, as measured by APTT and anti-Xa assay. This study determined the age-related response following administration of a single UFH bolus of 75–100 IU/kg in children. Venous blood samples were collected from children (n=56) at 15, 30, 45 and 120 minutes post-UFH. Anti-Xa, anti-IIa, APTT, TCT and protamine titration were performed on all samples. Age-dependent differences in the effect and concentration of UFH were identified for the anti-Xa, anti-IIa and protamine titration as-says, respectively. In addition, a trend suggesting a proportional increase in anti-Xa and anti-IIa-mediated UFH effect with age was evident. Logistic regression demonstrated an increase in protamine titration of 0.6 IU/ml for every year of age in samples collected 15 minutes post-UFH. UFH-mediated anti-IIa activity was reduced compared to anti-Xa activity across childhood, with a two-fold increase in anti-Xa to anti-IIa ratio in infants less than one year of age compared to teenagers in the setting of high UFH concentrations. This study demonstrates that the previously reported age-dependent response to UFH occurs in the context of an age-dependent serum concentration of UFH. The trend toward increased UFH serum concentration and anticoagulant activity with age may be related to short-term differences in UFH binding to coagulant and competitive plasma proteins in vivo.

Abstract 1421: In Vivo Measurement of Flow-Mediated Vasodilation in Living Rats using High Resolution Ultrasound: Age-Dependent Endothelial Dysfunction

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Christian Heiss ◽  
Richard E Sievers ◽  
Nicolas Amabile ◽  
Tony Y Momma ◽  
Shobha Natarajan ◽  
...  
Keyword(s):  
High Resolution ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Femoral Artery ◽  
Reactive Hyperemia ◽  
Surrogate Marker ◽  
Flow Measurements ◽  
Age Related ◽  
Age Dependent

In humans, endothelial function serves as a surrogate marker for cardiovascular health and is measured as changes in arterial diameter after temporary ischemia (flow-mediated dilation; FMD). We developed an FMD-related approach to study conduit artery vasodilation in living rats, and demonstrate a reduction in FMD in older versus younger animals consistent with age-related endothelial dysfunction. Diameter and Doppler-flow measurements were obtained from the femoral artery using high-resolution ultrasound (35 MHz). We observed dose-dependent vasodilation using both endothelium-dependent and endothelium-independent pharmacologic vasodilators (acetylcholine and nitroglycerine). Flow-dependent vasodilation was observed in response to flow increase induced both by adenosine and local saline infusion. Transient hindlimb ischemia led to reactive hyperemia with sequential flow velocity increase and femoral artery dilation, the latter of which was completely abolished by NO-synthase (NOS) inhibition with L-NMMA. To demonstrate its applicability in a model of endothelial dysfunction, we show that FMD is significantly reduced in older versus younger animals. While FMD was completely NOS-dependent in younger animals, NOS-dependent mechanisms accounted for only half of the FMD in older animals, with the remainder being blocked by charybdotoxin (CTx) and apamin suggesting contribution of endothelium-derived-hyperpolarizing-factor. Using this new integrative physiologic model to reproducibly study FMD in living rats, we show that age-dependent endothelial dysfunction is accompanied by a shift in mechanisms underlying vasodilatory endothelial function.

scholarly journals Age-Related Changes in Peripheral Nerves of the Dog. II. A Morphologic and Morphometric Study of Cross-Sectional Nerve

1982 ◽  
Vol 19 (4) ◽  
pp. 379-398 ◽  
Author(s):  
K. G. Braund ◽  
J. A. McGuire ◽  
C. E. Lincoln
Keyword(s):  
Fold Increase ◽  
Morphometric Study ◽  
First Year ◽  
Fiber Density ◽  
Cross Sectional ◽  
Quantitative Measurements ◽  
Age Related ◽  
Large Fiber ◽  
One Year ◽  
First Year Of Life

Qualitative histologic studies and quantitative measurements were made on cross-sectional preparations of common peroneal and ulnar nerves of 32 neuromuscular disease-free dogs from birth to 15 years of age, to provide normative data not available previously. Minimal lesions were seen in nerves of dogs from birth to seven years; however, in older dogs, the incidence of axonal degeneration and segmental demyelination and remyelination increased. Total fiber density of both nerves was over 40,000 fibers/mm2 at birth and declined rapidly during the first six to nine months to level off at about 10,000 fibers/mm2 by one year of age. Density of small (< 5 μm) and large (≥ 5 μm) diameter fibers attained adult values by one year of age. The frequency distribution of the myelinated fibers was unimodal at birth and became bimodal between three and six months of age. The peaks of the small and large fiber groups occurred at 3 μm and 6 μm, respectively. Larger diameter fibers (10 μm to 12 μm) reached adult values between nine months and one year of age. A 2.5 fold increase in mean fiber diameter occurred during the first year of life. There was no statistically significant change in any histometric parameter after maturity (approximately one year of age).

scholarly journals Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Yoanna Ariosa-Morejon ◽  
Alberto Santos ◽  
Roman Fischer ◽  
Simon Davis ◽  
Philip Charles ◽  
...  
Keyword(s):  
Skeletal Maturity ◽  
Tissue Level ◽  
Skeletal Maturation ◽  
Healthy Life ◽  
Adult Mice ◽  
Age Related ◽  
Age Dependent ◽  
Protein Incorporation ◽  
New Protein

Collagen-rich tissues have poor reparative capacity that predisposes to common age-related disorders such as osteoporosis and osteoarthritis. We used in vivo pulsed SILAC labelling to quantify new protein incorporation into cartilage, bone, and skin of mice across the healthy life course. We report dynamic turnover of the matrisome, the proteins of the extracellular matrix, in bone and cartilage during skeletal maturation, which was markedly reduced after skeletal maturity. Comparing young adult with older adult mice, new protein incorporation was reduced in all tissues. STRING clustering revealed changes in epigenetic modulators across all tissues, a decline in chondroprotective growth factors such as FGF2 and TGFβ in cartilage, and clusters indicating mitochondrial dysregulation and reduced collagen synthesis in bone. Several pathways were implicated in age-related disease. Fewer changes were observed for skin. This methodology provides dynamic protein data at a tissue level, uncovering age-related molecular changes that may predispose to disease.

scholarly journals CGRP outflow into jugular blood and cerebrospinal fluid and permeance for CGRP of rat dura mater

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Miriam Risch ◽  
Birgit Vogler ◽  
Mária Dux ◽  
Karl Messlinger
Keyword(s):  
Blood Flow ◽  
Cerebrospinal Fluid ◽  
Dura Mater ◽  
Ex Vivo ◽  
Venous Blood ◽  
Extracellular Fluid ◽  
Fold Increase ◽  
Primary Headaches ◽  
Subarachnoidal Space

Abstract Background Calcitonin gene-related peptide (CGRP) is released from activated meningeal afferent fibres in the cranial dura mater, which likely accompanies severe headache attacks. Increased CGRP levels have been observed in different extracellular fluid compartments during primary headaches such as migraine but it is not entirely clear how CGRP is drained from the meninges. Methods We have used an in vivo preparation of the rat to examine after which time and at which concentration CGRP applied onto the exposed parietal dura mater appears in the jugular venous blood and the cerebrospinal fluid (CSF) collected from the cisterna magna. Recordings of meningeal (dural) and cortical (pial) blood flow were used to monitor the vasodilatory effect of CGRP. In a new ex vivo preparation we examined how much of a defined CGRP concentration applied to the arachnoidal side penetrates the dura. CGRP concentrations were determined with an approved enzyme immunoassay. Results CGRP levels in the jugular plasma in vivo were slightly elevated compared to baseline values 5-20 min after dural application of CGRP (10 μM), in the CSF a significant three-fold increase was seen after 35 min. Meningeal but not cortical blood flow showed significant increases. The spontaneous CGRP release from the dura mater ex vivo was above the applied low concentration of 1 pM. CGRP at 1 nM did only partly penetrate the dura. Conclusions We conclude that only a small fraction of CGRP applied onto the dura mater reaches the jugular blood and, in a delayed manner, also the CSF. The dura mater may constitute a barrier for CGRP and limits diffusion into the CSF of the subarachnoidal space, where the CGRP concentration is too low to cause vasodilatation.

scholarly journals Impaired dynamics of brain precapillary sphincters and first order capillaries explains reduced neurovascular functions in aging

2021 ◽  
Author(s):  
Changsi Cai ◽  
Stefan Andreas Zambach ◽  
Soeren Grubb ◽  
Kirsten Joan Thomsen ◽  
Barbara Lykke Lind ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Reactivity ◽  
Brain Aging ◽  
Capillary Density ◽  
Nitric Oxide Synthase Inhibitor ◽  
First Order ◽  
Age Related ◽  
Age Dependent ◽  
Synthase Inhibitor

The microvascular inflow tract (MIT), i.e. penetrating arterioles, precapillary sphincters and first order capillaries, is the bottleneck for brain blood flow and energy supply. However, the exact structural and functional alterations during aging remain elusive. Using in vivo 4-dimensional (xyzt) two-photon imaging, we showed an age-dependent decrease in vaso-responsivity, which was accompanied by reduced sensitivity of MIT to pinacidil and papaverine, and to vasoconstrictors endothelin-1 and to L-NAME, a nitric oxide synthase inhibitor. Reduced responsivity was accompanied by an age-dependent decrease in capillary density close to the arterioles and by loss of pericyte processes, whereas the number of pericyte somas and the pericyte αSMA density were preserved. The age-related reduction in vascular reactivity was most pronounced at precapillary sphincters, highlighting its crucial role for capillary blood flow regulation. Mathematical modeling further revealed dysregulated but protected pressure and flow in aged mice towards vasoconstriction. Prevention of reduced responsivity of the MIT may ameliorate the blood flow decrease associated with brain aging and age-related brain frailty.

scholarly journals Depletion of the Third Complement Component Ameliorates Age-Dependent Oxidative Stress and Positively Modulates Autophagic Activity in Aged Retinas in a Mouse Model

2017 ◽  
Vol 2017 ◽  
pp. 1-17 ◽  
Author(s):  
Dorota Rogińska ◽  
Miłosz P. Kawa ◽  
Ewa Pius-Sadowska ◽  
Renata Lejkowska ◽  
Karolina Łuczkowska ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Global Gene Expression ◽  
Complement Component ◽  
Oxidative Stress Marker ◽  
Age Related ◽  
Age Dependent ◽  
Autophagic Activity

The aim of the study was to investigate the influence of complement component C3 global depletion on the biological structure and function of the aged retina. In vivo morphology (OCT), electrophysiological function (ERG), and the expression of selected oxidative stress-, apoptosis-, and autophagy-related proteins were assessed in retinas of 12-month-old C3-deficient and WT mice. Moreover, global gene expression in retinas was analyzed by RNA arrays. We found that the absence of active C3 was associated with (1) alleviation of the age-dependent decrease in retinal thickness and gradual deterioration of retinal bioelectrical function, (2) significantly higher levels of antioxidant enzymes (catalase and glutathione reductase) and the antiapoptotic survivin and Mcl-1/Bak dimer, (3) lower expression of the cellular oxidative stress marker—4HNE—and decreased activity of proapoptotic caspase-3, (4) ameliorated retinal autophagic activity with localization of ubiquitinated protein conjugates commonly along the retinal pigment epithelium (RPE) layer, and (5) significantly increased expression of several gene sets associated with maintenance of the physiological functions of the neural retina. Our findings shed light on mechanisms of age-related retinal alterations by identifying C3 as a potential therapeutic target for retinal aging.

Effects of a Low Molecular Weight Heparin (Fragmin®) and of Unfractionated Heparin on Coagulation Activation at the Site of Plug Formation In Vivo

1994 ◽  
Vol 72 (06) ◽  
pp. 831-835 ◽  
Author(s):  
Sabine Elchinger ◽  
Michael Wolzt ◽  
Malgorzata Nieszpaur-Los ◽  
Barbara Schneider ◽  
Klaus Lechner ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Unfractionated Heparin ◽  
Low Molecular Weight Heparin ◽  
Bleeding Time ◽  
Venous Blood ◽  
Coagulation System ◽  
Low Molecular Weight ◽  
Coagulation Activation

SummaryThe clinical benefits of unfractionated heparin (UFH) and low molecular weight heparin (LMWH) have been shown in many trials. However, the mode of action of heparin has not been fully elucidated. Thus, we wanted to study the effects of UFH and LMWH in vivo by measuring coagulation activation markers in blood obtained directly from a vascular injury site. In a double-blind, randomized, 3-way, cross-over study 18 healthy volunteers were given UFH (150 U/kg s.c.) and 2 doses of LMWH [35 U/kg s.c. (low dose, Id), 75 U/kg s.c. (high dose, hd)]. Prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and fibrinopeptide A (FPA) were measured in bleeding time blood and in venous blood before and after drug application. In addition, the effects of UFH and LMWH on in vitro coagulation tests were studied. Compared to base line, UFH and both IdLMWH and hdLMWH caused significant reductions of F1+2, TAT and FPA in bleeding time blood at 2 h. A marked effect of UFH and of hdLMWH was also seen at 5 h. The inhibition of FPA generation was more pronounced after hdLMWH compared to IdLMWH. In venous blood, UFH and LMWH caused reductions of F1+2, but not of TAT and FPA. In vitro, UFH predominantly affected the anti-IIa assays (activated partial thromboplastin time, thrombin time) and LMWH mainly the anti-Xa test system. Using a technique that investigates the activated coagulation system in vivo, a time- and dose dependent inhibitory effect of heparin on coagulation activation was detectable. Therefore, in our experimental setting a preferential inhibition of a particular portion of the coagulation system by one of the two heparin preparations was not detectable.

Development of a recombinant antithrombin variant as a potent antidote to fondaparinux and other heparin derivatives

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 2054-2060 ◽  
Author(s):  
Elsa P. Bianchini ◽  
Judicael Fazavana ◽  
Veronique Picard ◽  
Delphine Borgel
Keyword(s):  
Anticoagulant Activity ◽  
Fold Increase ◽  
Glycosylation Site ◽  
Dependent Manner ◽  
Heparin Derivatives ◽  
Dose Dependent ◽  
Heparin Derivative ◽  
In Vivo Administration

Abstract Heparin derivative-based therapy has evolved from unfractionated heparin (UFH) to low-molecular-weight heparins (LMWHs) and now fondaparinux, a synthetic pentasaccharide. Contrary to UFH or LMWHs, fondaparinux is not neutralized by protamine sulfate, and no antidote is available to counteract bleeding disorders associated with overdosing. To make the use of fondaparinux safer, we developed an antithrombin (AT) variant as a potent antidote to heparin derivatives. This variant (AT-N135Q-Pro394) combines 2 mutations: substitution of Asn135 by a Gln to remove a glycosylation site and increase affinity for heparins, and the insertion of a Pro between Arg393 and Ser394 to abolish its anticoagulant activity. As expected, AT-N135Q-Pro394 anticoagulant activity was almost abolished, and it exhibited a 3-fold increase in fondaparinux affinity. AT-N135Q-Pro394 was shown to reverse fondaparinux overdosing in vitro in a dose-dependent manner through a competitive process with plasma AT for fondaparinux binding. This antidote effect was also observed in vivo: administration of AT-N135Q-Pro394 in 2.5-fold molar excess versus plasma AT neutralized 86% of the anti-Xa activity within 5 minutes in mice treated with fondaparinux. These results clearly demonstrate that AT-N135Q-Pro394 can reverse the anticoagulant activity of fondaparinux and thus could be used as an antidote for this drug.

scholarly journals Integrated in vivo quantitative proteomics and nutrient tracing reveals age-related metabolic rewiring of pancreatic β-cell function

2018 ◽  
Author(s):  
Matthew Wortham ◽  
Jacqueline R. Benthuysen ◽  
Martina Wallace ◽  
Jeffrey N. Savas ◽  
Francesca Mulas ◽  
...  
Keyword(s):  
Cell Function ◽  
Coupling Factor ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Age Related ◽  
Β Cell Function ◽  
One Year ◽  
Old Mice ◽  
Age Related Changes

SummaryPancreatic β-cell physiology changes substantially throughout life; yet, the mechanisms that drive these changes are poorly understood. Here, we performed comprehensive in vivo quantitative proteomic profiling of pancreatic islets from adolescent and one-year-old mice. The analysis revealed striking differences in abundance of enzymes controlling glucose metabolism. We show that these changes in protein abundance are associated with higher activities of glucose metabolic enzymes involved in coupling factor generation as well as increased activity of the coupling factor-dependent amplifying pathway of insulin secretion. Nutrient tracing and targeted metabolomics demonstrated accelerated accumulation of glucose-derived metabolites and coupling factors in islets from one-year-old mice, indicating that age-related changes in glucose metabolism contribute to improved glucose-stimulated insulin secretion with age. Together, our study provides the first in-depth characterization of age-related changes in the islet proteome and establishes metabolic rewiring as an important mechanism for age-associated changes in β-cell function.

scholarly journals Through a Glass, Darkly:1 Reflections of Mutation From lacI Transgenic Mice

Genetics ◽  
2000 ◽  
Vol 155 (3) ◽  
pp. 1359-1367
Author(s):  
Gregory R Stuart ◽  
Barry W Glickman
Keyword(s):  
Dna Repair ◽  
Transgenic Mice ◽  
Base Pair ◽  
Fold Increase ◽  
Dna Damage And Repair ◽  
Age Related ◽  
Repair Efficiency ◽  
Cpg Dinucleotide ◽  
Repair Defect

Abstract The study of mutational frequency (Mf) and specificity in aging Big Blue lacI transgenic mice provides a unique opportunity to determine mutation rates (MR) in vivo in different tissues. We found that MR are not static, but rather, vary with the age or developmental stage of the tissue. Although Mf increase more rapidly early in life, MR are actually lower in younger animals than in older animals. For example, we estimate that the changes in Mf are 4.9 × 10−8 and 1.1 × 10−8 mutations/base pair/month in the livers of younger mice (&lt;1.5 months old) and older mice (≥1.5 months old), respectively (a 4-fold decrease), and that the MR are 3.9 × 10−9 and 1.3 × 10−7 mutations/base pair/cell division, respectively (~30-fold increase). These data also permit an estimate of the MR of GC → AT transitions occurring at 5′-CpG-3′ (CpG) dinucleotide sequences. Subsequently, the contribution of these transitions to age-related demethylation of genomic DNA can be evaluated. Finally, to better understand the origin of observed Mf, we consider the contribution of various factors, including DNA damage and repair, by constructing a descriptive mutational model. We then apply this model to estimate the efficiency of repair of deaminated 5-methylcytosine nucleosides occurring at CpG dinucleotide sequences, as well as the influence of the Msh2−/− DNA repair defect on overall DNA repair efficiency in Big Blue mice. We conclude that even slight changes in DNA repair efficiency could lead to significant increases in mutation frequencies, potentially contributing significantly to human pathogenesis, including cancer.

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