Co-morditities of environmental diseases: A common cause

ABSTRACT The global pandemic of non-vector borne environmental diseases may, in large part, be attributed to chronic exposures to ever increasing levels of exogenous lipophilic chemicals. These chemicals include persistent organic pollutants, semi-volatile compounds and low molecular weight hydrocarbons. Such chemicals facilitate the sequential absorption of otherwise not absorbed more toxic hydrophilic species that attack numerous body organs and systems, leading to environmental disease. Co-morbidities of noncommunicable environmental diseases are alarmingly high, with as many as half of all individuals chronically ill with two or more diseases. Co-morbidity is to be anticipated, since all of the causative chemicals identified have independently been shown to trigger the individual diseases.

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Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides

Thrombosis and Haemostasis ◽

10.1160/th05-05-0318 ◽

2005 ◽

Vol 94 (12) ◽

pp. 1265-1269 ◽

Cited By ~ 34

Author(s):

Susanne Alban ◽

Roland Kaufmann ◽

Edelgard Lindhoff-Last ◽

Wolf-Henning Boehncke ◽

Ralf J. Ludwig ◽

...

Keyword(s):

Molecular Weight ◽

Heparin Therapy ◽

Delayed Type Hypersensitivity ◽

Published Data ◽

Low Molecular Weight ◽

Hypersensitivity Reactions ◽

Type Iv ◽

Total Data ◽

The Individual

SummaryEczematous lesions, resulting from type IV sensitizations are well-known and relatively frequent cutaneous adverse effects of s.c. heparin therapy. If anticoagulation is further required intravenous heparin, heparinoids or lepirudin may be used as a substitute. However, these alternatives are not optimal in terms of practicability and/or safety-profiles. As molecular weight of different heparin preparations has repetitively been implied to determine the frequency of sensitization, we hypothesized, that due to its low molecular weight the pentasaccharide fondaparinux may provide a practicable and safe anticoagulant therapy in patients with delayed type hypersensitivity reactions (DTH) to heparin and other oligosaccharides. To test this concept, patients referred for diagnosis of cutaneous reactions after s.c. anticoagulant treatment underwent a series of in vivo skin allergyand challenge-tests with unfractionated heparin, a series of low molecular weight heparins (nadroparin, dalteparin, tinzaparin, enoxaparin and certoparin), the heparinoid danaparoid and the synthetic pentasaccharide fondaparinux. In total, data from twelve patients was evaluated. In accordance with previously published data, we report a high crossreactivity among heparins and heparinoids. In contrast – and in support of our initial hypothesis – sensitization towards the synthetic pentasaccharide fondaparinux was rarely observed. Plotting the cumulative incidence against the determined molecular weight of the individual anticoagulant preparations, shows that molecular weight generally is a key determinant of sensitization towards heparins and other oligosaccharides (r2=0.842, p=0.009). Hence, fondaparinux may be used as a therapeutic alternative in patients with cutaneous DTH relations towards heparin and other polysaccharides.

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Clinical and Laboratory Validation of the 2nd International Standard of Low Molecular Weight Heparin (IS 2003-01/608) in the Anti-Xa, Anti-LIA Heptest and Prothrombinase Induced Clotting (PiCT) Tests.

Blood ◽

10.1182/blood.v106.11.4147.4147 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4147-4147

Author(s):

D. Hoppensteadt ◽

W. Jeske ◽

D. Fareed ◽

F. Baltasar ◽

J. M. Walenga ◽

...

Keyword(s):

Molecular Weight ◽

International Standards ◽

Clinical Monitoring ◽

Low Molecular Weight ◽

Therapeutic Trial ◽

Global Test ◽

International Standard ◽

Assay Methods ◽

The Individual ◽

Concentration Curves

Abstract Background: Because of the relative insensitivity of the global clot based assays such as the activated partial thromboplastin time (APTT), the low molecular weight heparins (LMWHs) are potency evaluated/optimized in the anti-Xa (AXa) and heptest. A new clot based assay namely, prothrombin induced clotting time (PiCT) is sensitive to the anticoagulant effects of LMWHs and related drugs. As the LMWHs are standardized using the anti-Xa methods, using the International Standards, this study was designed to cross validate the 2nd International Standard for LMWHs(NIBSC 01/608) in various assay methods. Methods: Commercially available LMWHs, Dalteparin (D), Enoxaparin (E), Tinzaparin (T) and the 1st International Standard (85/600) were crossed referenced against the 2nd International Standard (NIBSC 01/608) using an amidolytic AXa method. Each of these LMWHs were compared in the AXa, adjusted concentration range of 0–1.0 U/ml using the Heptest, AXa, AIIa and PiCT. In addition plasma samples from patients receiving a LMWH, E for therapeutic and interventional purposes were measured using various tests. Results: The AXa potency adjusted LMWHs (D, E, and T) and 1st International Standard provided superimposable concentration curves in the amidolytic AXa assays. However marked differences in the heptest and PiCT were noted. Major differences were noted in the AIIA levels, even between the two International standards. When patients samples (n=75) from a therapeutic trial (1.0 mg/kg BID/SC) were evaluated, assay based differences were further amplified. The amidolytic AXa assay consistently measured higher AXa levels. When the two standards were cross-referenced with one another in different assays, major differences were noted in the clot-based assays. Even in the AXa assay at equivalent AXa levels, differences were obvious. Conclusions: These results suggest that both of the International Standards of LMWH are valid for only the cross standardization of the AXa activities of LMWHs. If any of the other methods were used, significantly different results were obtained with each of the individual LMWHs. Thus, the 2nd International Standard should only be used for amidolytic AXa assay for potency referencing purposes. Moreover, the stated potency of the 2nd Internation Standard may need to be readjusted against the 1st Standard to obtain valid results. These standards are of limited value in the clinical monitoring of LMWHs. It is therefore proposed that each of the LMWHs should be cross referenced by its own standard and the clinical monitoring of these drugs should only be carried out utilizing the specific drug used in a given patient. The PiCT test offers a global test which is capable of monitoring the effects of all components of heparins regardless of their affinity to serpines. Moreover, the effect of TFPI released on clotting processes is also measured. Thus, the PiCT test provides a physiologically relevant anticoagulant index.

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Thrombin Generation Is a Sensitive Measure of Low Molecular Weight Heparin Anticoagulant Activity.

Blood ◽

10.1182/blood.v116.21.1099.1099 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1099-1099

Author(s):

Alexander Gatt ◽

Anne Riddell ◽

Lesley Lanning ◽

Saman Aghighi ◽

Pamala Kanagasapathy ◽

...

Keyword(s):

Molecular Weight ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Anticoagulant Activity ◽

Coagulation Cascade ◽

Low Molecular Weight ◽

Acute Thrombosis ◽

Coagulation Proteins ◽

Risk Patients ◽

The Individual

Abstract Abstract 1099 Current guidelines recommend monitoring of low molecular weight heparins (LMWHs) using the anti-Xa assay in high risk patients like those with renal impairment, pregnancy or overweight and in children. However, it is well accepted that this test does not accurately predict the anticoagulant effect of these drugs1. This is understandable since the various LMWHs available affect the coagulation cascade in different ways relative to their different molecular structure. Notoriously, the larger LMWHs like Tinzaparin have a higher anti-IIa to anti-Xa ratio that is not detected by the anti-Xa assay. We hypothesized that thrombin generation (TG) is a better, more sensitive way how to monitor LMWH anticoagulant activity since it is a measure of the interplay of all coagulation proteins. Blood samples from patients with acute thrombosis, pregnancy and other conditions and having LMWH monitoring were analysed using a chromogenic anti-Xa assay and a TG assay as per Hemker et al2 together with a chromogenic anti-IIa and FVIII clotting assay (FVIII:C). A tissue factor trigger of 10pM Innovin was used for the TG experiments. Patient samples were divided into 2 groups: those on Tinzaparin (n=45) or Enoxaparin (n=39). There was no difference between the FVIII:C levels of the Tinzaparin and Enoxaparin groups (mean 250 vs 327IU/ml P>0.05). A higher lower mean anti-Xa and a higher mean anti-IIa level was achieved with Tinzaparin (0.48 vs 0.63 U/ml P= >0.05 for anti-Xa and 0.3 vs 0.15U/ml P=0.005 for anti-IIa respectively). The endogenous thrombin potential (ETP) was significantly lower with Tinzaparin than Enoxaparin despite a higher anti-Xa (705 vs 1216nM.min P=0.006). Linear regression analysing TG with anti-Xa of the two LMWHs shows that 1.0U/ml antiXa activity for Enoxaparin is as potent as 0.7U/ml Tinzaparin in suppressing TG to similar levels. Significant inter-individual variation in TG suppression was noted with both LMWHs. This study demonstrates that anti-Xa results achieved for different LMWHs do not have the same anticoagulant significance. Using TG, we achieved similar therapeutic anti-Xa levels as achieved from the individual LMWH clinical trials3. It is clear that TG is a better test to predict LMWH anticoagulant activity. This needs to be proven in clinical studies. 1. Baglin T et al British Journal of Haematol. 2006; 133(1): 19–34. 2. Hemker HC et al Pathophysiol Haemost Thromb, 33, 4-15. Boneu B and de Moorloose P. Semin Thromb Hemost 2001; 27(5): 519–522. Disclosures: No relevant conflicts of interest to declare.

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Exploring the Critical Factors Limiting Polyaniline Biocompatibility

Polymers ◽

10.3390/polym11020362 ◽

2019 ◽

Vol 11 (2) ◽

pp. 362 ◽

Cited By ~ 2

Author(s):

Věra Kašpárková ◽

Petr Humpolíček ◽

Jaroslav Stejskal ◽

Zdenka Capáková ◽

Patrycja Bober ◽

...

Keyword(s):

Molecular Weight ◽

Flow Cytometry ◽

Cell Death ◽

Ammonium Persulfate ◽

Low Molecular Weight ◽

Synergic Effect ◽

Critical Factors ◽

Aniline Hydrochloride ◽

Crucial Information ◽

The Individual

Today, the application of polyaniline in biomedicine is widely discussed. However, information about impurities released from polyaniline and about the cytotoxicity of its precursors aniline, aniline hydrochloride, and ammonium persulfate are scarce. Therefore, cytotoxicity thresholds for the individual precursors and their combinations were determined (MTT assay) and the type of cell death caused by exposition to the precursors was identified using flow-cytometry. Tests on fibroblasts revealed higher cytotoxicity of ammonium persulfate than aniline hydrochloride. Thanks to the synergic effect, both monomers in combination enhanced their cytotoxicities compared with individual substances. Thereafter, cytotoxicity of polyaniline doped with different acids (sulfuric, nitric, phosphoric, hydrochloric, and methanesulfonic) was determined and correlated with impurities present in respective sample (HPLC). The lowest cytotoxicity showed polyaniline doped with phosphoric acid (followed by sulfuric, methanesulfonic, and nitric acid). Cytotoxicity of polyaniline was mainly attributed to the presence of residual ammonium persulfate and low-molecular-weight polar substances. This is crucial information with respect to the purification of polyaniline and production of its cytocompatible form.

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Fixed Doses of Anticoagulants Cause Wide Variation of Thrombin Generation

Blood ◽

10.1182/blood.v128.22.5012.5012 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5012-5012

Author(s):

Coenraad Hemker ◽

Saartje Bloemen ◽

Romy Kremers ◽

Hilde Kelchtermans ◽

Bas De Laat

Keyword(s):

Molecular Weight ◽

Low Molecular Weight Heparin ◽

Standard Dose ◽

Vitamin K Antagonists ◽

Factor Xa ◽

Target Range ◽

Low Molecular Weight ◽

Standard Dosage ◽

Variance Table ◽

The Individual

Abstract Current practice in the prevention of venous thromboembolism (VTE) is either controlled dosage of vitamin K antagonists (VKA) or standard dosage of a low molecular weight heparin (LMWH) or an orally administrated direct inhibitor of thrombin or factor Xa (DOACs). This is justified by clinical trials showing the non-inferiority of standard dosage to VKA treatment - disregarding that the latter could be improved upon. Whether standard dosage is optimal for the individual patient depends upon how well (s)he is represented by the "average" patient that meets the inclusion criteria of the trial. Here we show that in a set of normal plasmas the individual thrombin generating power (the endogenous thrombin potential: ETP), after spiking with a fixed concentration (~ IC50) of different anticoagulants show such a wide variation that, even when plasma levels would be identical, a considerable percentage of patients could be over- or under-anticoagulated. Consequently adapted doses must be considered if better results than those with VKA are our aim. We recall that the ETP is close to constant in the individual person but varies in the population with a broad log-normal distribution (CV 16%). The ETP is highly correlated to the risk of thrombosis: The relative risk of VTE in the upper quartile being 5 - 7 times higher than that in the lower one (Winckers K., et al., poster PO617, ISTH 2015, Toronto). Reducing the ETP is the common feature of all antithrombotic therapy. The desired range of reduction is not exactly known. In congenital bleeding disorders bleeding risks increase sharply at ETP below 33%. In monitoring VKA treatment an INR below 2, which corresponds to an ETP > 66% of normal, is generally considered inadequate. We therefore arbitrarily choose the range 33 - 66% of normal, as a target range (TR). Experimental: Individual plasmas from 60 normal healthy volunteers were spiked with a fixed amount of either unfractionated heparin (UFH), low molecular weight heparin (LMWH), antithrombin binding pentasaccharide (penta), DOAC acting on thrombin or DOAC acting on factor Xa. We found the residual ETP to be highly variable (table column 3), obviously because the variation in susceptibility to the inhibitor superimposes upon the natural variation. Using these CVs we calculated what % falls either above or below the target range. The total variance of the ETP under treatment is the combined effect of natural variance, the pharmacokinetic- and the pharmacodynamic -variance. Here we determined pharmacodynamic effects only and calculated the % of ETP values that would fall outside the target range A: if there would be no pharmacokinetic variance (table column 4 & 5) and B: If the pharmacokinetic variance would equal the pharmacodynamic variance (table column 6 & 7). It is seen that in any case over 15% of the population will be outside the target range and that in the more likely case that pharmacokinetic variation counts as much as pharmacodynamic variation does around half of all patients will be outside the safe range. This could be avoided by measuring the effect of a standard dose of anticoagulant on the ETP once and increasing the dose in those with an ETP > 66% and decreasing it in those with ETP < 33%. The present work is meant to provide the rationale for starting clinical studies on the actual variation of the ETP attained under standard dosage of different anticoagulants and the effects thereon of personalised dose adjustment. Table Table. Disclosures Hemker: Diagnostica Stago: Consultancy.

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Aggregation, Sedimentation, and Dissolution of Copper Oxide Nanoparticles: Influence of Low-Molecular-Weight Organic Acids from Root Exudates

Nanomaterials ◽

10.3390/nano9060841 ◽

2019 ◽

Vol 9 (6) ◽

pp. 841 ◽

Cited By ~ 3

Author(s):

Cheng Peng ◽

Hong Tong ◽

Peng Yuan ◽

Lijuan Sun ◽

Lei Jiang ◽

...

Keyword(s):

Molecular Weight ◽

Organic Acids ◽

Root Exudates ◽

Copper Oxide Nanoparticles ◽

Rice Root ◽

Low Molecular Weight ◽

Plant Interactions ◽

Cuo Nps ◽

The Individual ◽

Almost All

The rhizosphere is an essential pathway for the uptake of metal-based nanoparticles (MNPs) by plant roots. However, the interaction between root exudates and MNPs is still unclear. In this study, we initially identified the major low-molecular-weight organic acids (LMWOAs) in the rice root exudates using hydroponics. Then, the individual LMWOAs were added to CuO nanoparticle suspensions to investigate their effects on the environmental behavior of the MNPs. The results showed that both the variety and the concentration of LMWOAs impacted the aggregation, sedimentation, and dissolution of CuO nanoparticles (NPs). Almost all LMWOAs except succinic acid inhibited the aggregation of CuO NPs by enhancing the electrostatic repulsive force between NPs. The presence of citric and oxalic acids rather than lactic acid greatly improved the stability of CuO NP suspensions, but other acids showed a low promoting and high inhibiting effect on NP sedimentation. Moreover, all the LMWOAs from root exudates facilitated the dissolution of CuO NPs with a positive dose-dependent correlation, especially formic acid. Notably, citric acid, as the most abundant LMWOAs in rice root exudates, largely determined the aggregation, sedimentation, and dissolution of CuO NPs. This study provides a better understanding on NP–plant interactions in the rhizosphere.

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The Application of Ultrasound and Enzymes Could Be Promising Tools for Recovering Polyphenols during the Aging on Lees Process in Red Winemaking

Foods ◽

10.3390/foods11010019 ◽

2021 ◽

Vol 11 (1) ◽

pp. 19

Author(s):

Andrea Osete-Alcaraz ◽

Ana Belén Bautista-Ortín ◽

Paula Pérez-Porras ◽

Encarna Gómez-Plaza

Keyword(s):

Molecular Weight ◽

Phenolic Compounds ◽

Cell Walls ◽

Final Concentration ◽

Low Molecular Weight ◽

Acylated Anthocyanins ◽

The Individual ◽

Positive Effect ◽

Tannin Extraction ◽

Pectolytic Enzyme

The final concentration of phenolic compounds in wines is usually lower than what might be expected, given their concentration in grapes. This is in part due to the interactions between cell walls from grapes and yeast with phenolics during red winemaking. Most of these aggregates are insoluble and end up precipitating, forming part of the lees. The objective of this study is to determine the capacity of ultrasounds and/or enzymes treatments (β-glucanase and a pectolytic enzyme) to release the anthocyanins and tannins adsorbed in the lees. The ultrasound (US) applied for 120 min slightly favored the extraction of anthocyanins and doubled tannin extraction. Shorter sonication times did not show any positive effect. The combination of β-glucanase and pectolytic enzyme was always more effective in the liberation of anthocyanins (both no-acylated and acylated anthocyanins) and tannins than the enzymes acting separately. The combination of US (120 min), β-glucanase and pectolytic enzyme showed an additive effect, increasing the extraction of phenolic compounds with respect to the individual treatments and also releasing a large quantity of low molecular weight polysaccharides, compounds of enological importance. These results of this study could be of enological interest, facilitating and accelerating the aging on lees process, through the liberation of polysaccharides and the recovery of the phenolic compounds lost during vinification.

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Structural investigations on the lignin–carbohydrate complexes of Lolium perenne

Biochemical Journal ◽

10.1042/bj1390197 ◽

1974 ◽

Vol 139 (1) ◽

pp. 197-204 ◽

Cited By ~ 93

Author(s):

Ian M. Morrison

Keyword(s):

Molecular Weight ◽

Leaf Blade ◽

Alkaline Treatment ◽

Leaf Sheath ◽

Cross Linking ◽

Low Molecular Weight ◽

Coumaric Acid ◽

Borohydride Reduction ◽

Structural Investigations ◽

The Individual

1. Lignin–carbohydrate complexes isolated from leaf blade, leaf sheath and stem tissue of ryegrass by extraction with dimethyl sulphoxide were examined by fractionation procedures. Although the complexes are heterogeneous, heterogeneity is shown only in the ratio of the individual monosaccharide residues and not in the ratio of lignin to carbohydrate. 2. The molecular weight of the complexes is high (≥150000), but chemical modification by alkaline hydrolysis, borohydride reduction or lead tetra-acetate oxidation does not drastically decrease it. Low-molecular-weight fragments released by alkaline treatment were shown to contain acetic acid, ferulic acid and p-coumaric acid. 3. On the basis of the chemical stability of the complexes, it is postulated that at least three types of bonding may be present between lignin and carbohydrate, namely one cleaved on borohydride reduction, another cleaved by alkali and a linkage resistant to alkali. 4. The carbohydrate portion of the complexes is composed of β-(1→4)-linked d-glucose residues (cellulose) and β-(1→4)-linked chains of xylose residues. Side chains involving arabinose and galactose residues are linked to C-3 of some of the xylose residues. 5. How the components of the complexes are held together is not certain, but it is suggested that the phenolic acids may act as cross-linking agents.

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A high-performance oil-free backing pump for electron microscopes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100107691 ◽

1978 ◽

Vol 36 (1) ◽

pp. 110-111

Author(s):

G.K.W. Balkau ◽

E. Bez ◽

J.L. Farrant

Keyword(s):

Molecular Weight ◽

Electron Microscope ◽

Hot Spots ◽

High Performance ◽

Carbonaceous Material ◽

Contamination Rate ◽

Low Molecular Weight ◽

Principal Source ◽

Rotary Pumps ◽

Electron Microscopes

The earliest account of the contamination of electron microscope specimens by the deposition of carbonaceous material during electron irradiation was published in 1947 by Watson who was then working in Canada. It was soon established that this carbonaceous material is formed from organic vapours, and it is now recognized that the principal source is the oil-sealed rotary pumps which provide the backing vacuum. It has been shown that the organic vapours consist of low molecular weight fragments of oil molecules which have been degraded at hot spots produced by friction between the vanes and the surfaces on which they slide. As satisfactory oil-free pumps are unavailable, it is standard electron microscope practice to reduce the partial pressure of organic vapours in the microscope in the vicinity of the specimen by using liquid-nitrogen cooled anti-contamination devices. Traps of this type are sufficient to reduce the contamination rate to about 0.1 Å per min, which is tolerable for many investigations.

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