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1.
J AOAC Int ; 102(2): 363-368, 2019 Mar 01.
Article in English | MEDLINE | ID: mdl-30458900

ABSTRACT

One of the world's oldest spices, cinnamon is also one of the most popular. Species of the genus Cinnamomum offer a variety of extractable oils with aroma and flavor characteristics of importance to the flavor industry, so differentiating cinnamon samples for culinary-based applications is very important. Cinnamon also has reported health benefits associated with specific phytochemical constituents, but its composition can vary greatly depending on species and source region. A substantial amount of the research reported on cinnamon does not provide thorough documentation of the source and taxonomic identification of the study material, a very common issue with studies of food and medicinal plants. In the interest of providing some clarity to the discussion of the health benefits and culinary attributes of the different cinnamon types in the marketplace, we offer the results of a long-term chemotaxonomic study of cinnamon samples sourced from different regions of the world and link those chemical data to classical taxonomic identification of the source plants. We provide details of the effective use of an automated chemotaxonomic analytical method to differentiate cinnamons from various geographic regions. Also included are chromatographic data for the polyphenolic/procyanidin fractions of each species, as cinnamon type-A procyanidins are often the purported source of biological activity in cinnamon and cinnamon extracts.


Subject(s)
Automation , Cinnamomum zeylanicum/chemistry , Cinnamomum zeylanicum/classification , Biflavonoids/analysis , Catechin/analysis , Chromatography, Gas , Chromatography, High Pressure Liquid , Polyphenols/analysis , Proanthocyanidins/analysis , Software , Species Specificity
2.
Transl Androl Urol ; 7(6): 912-919, 2018 Dec.
Article in English | MEDLINE | ID: mdl-30505727

ABSTRACT

BACKGROUND: To evaluate safety, acceptability and pilot efficacy of transcutaneous low-frequency tibial nerve stimulation (TNS) using a novel device as home-based neuromodulation. METHODS: In this single-centre pilot study, 48 patients with overactive bladder (OAB) (24 with neurogenic and 24 with idiopathic OAB) were randomized to use a self-applicating ambulatory skin-adhering device stimulating transcutaneously the tibial nerve at 1 Hz for 30 minutes, either once daily or once weekly, for 12 weeks. Changes in OAB symptoms and QoL were measured at baseline, weeks 4, 8, and 12 using validated scoring instruments (ICIQ-OAB and ICIQ-LUTSqol), 3-day bladder diary and a Global Response Assessment (GRA) at week 12. RESULTS: Thirty-four patients completed the study (idiopathic n=15, neurogenic n=19). No significant adverse effects were noted. Patients found the device acceptable. Eighteen patients (53%) reported a moderate or marked improvement in symptoms from the GRA. Between baseline and week-12, ICIQ-OAB part A sub-scores improved from mean (SD) 9.3 (2.5) to 7.5 (3.1), and from 9.1 (1.9) to 5.9 (1.7) in the daily and the weekly arms, respectively. ICIQ-LUTSqol part A sub-scores improved from mean (SD) 51 (12.8) to 44.2 (13.1) and 44.9 (9.0) to 35.9 (8.8) in the daily and the weekly arms, respectively. Bladder diary mean 24-hour frequency episodes improved from 11.5 to 8.8 at week 12 for both arms. CONCLUSIONS: This novel ambulatory transcutaneous TNS (TTNS) device is safe and acceptable for use in patients reporting OAB symptoms as a form of home-based neuromodulation. A larger study however is required to confirm clinical efficacy.

3.
Wound Repair Regen ; 26(2): 228-237, 2018 03.
Article in English | MEDLINE | ID: mdl-29617058

ABSTRACT

The aim of this multicenter, prospective, observer-blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25-2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12-week follow-up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110-75; Control-73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention-to-treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice.


Subject(s)
Diabetic Foot/therapy , Foot/blood supply , Free Radical Scavengers/metabolism , Free Radical Scavengers/therapeutic use , Nitric Oxide/metabolism , Nitric Oxide/therapeutic use , Wound Healing/physiology , Aged , Ankle Brachial Index , Diabetic Foot/pathology , Female , Humans , Male , Microcirculation , Middle Aged , Prospective Studies , Single-Blind Method , Treatment Outcome
4.
Platelets ; 29(2): 162-170, 2018 Mar.
Article in English | MEDLINE | ID: mdl-28503981

ABSTRACT

Despite the interwoven nature of platelet activation and the coagulation system in thrombosis, few studies relate both analysis of protein and cellular parts of coagulation in the same population. In the present study, we use matched ex vivo samples to determine the influences of standard antiplatelet therapies on platelet function and use advanced rheological analyses to assess clot formation. Healthy volunteers were recruited following fully informed consent then treated for 7 days with single antiplatelet therapy of aspirin (75 mg) or prasugrel (10 mg) or with dual antiplatelet therapy (DAPT) using aspirin (75 mg) plus prasugrel (10 mg) or aspirin (75 mg) plus ticagrelor (90 mg). Blood samples were taken at day 0 before treatment and at day 7 following treatment. We found that aspirin plus prasugrel or aspirin plus ticagrelor inhibited platelet responses to multiple agonists and reduced P-selectin expression. Significant platelet inhibition was coupled with a reduction in fractal dimension corresponding to reductions in mean relative mass both for aspirin plus prasugrel (-35 ± 16% change, p = 0.04) and for aspirin plus ticagrelor (-45 ± 14% change, p = 0.04). Aspirin alone had no effect upon measures of clot structure, whereas prasugrel reduced fractal dimension and mean relative mass. These data demonstrate that platelets are important determinants of clot structure as assessed by fractal dimension (df) and that effective platelet inhibition is associated with a weaker, more permeable fibrin network. This indicates a strong association between the therapeutic benefits of antiplatelet therapies and their abilities to reduce thrombus density that may be useful in individual patients to determine the functional relationship between platelet reactivity, eventual clot quality, and clinical outcome. df could represent a novel risk stratification biomarker useful in individualizing antiplatelet therapies.


Subject(s)
Blood Coagulation/drug effects , Blood Platelets/metabolism , Platelet Activation/drug effects , Thrombosis/metabolism , Female , Fractals , Humans , Male
5.
Arterioscler Thromb Vasc Biol ; 37(5): 949-956, 2017 05.
Article in English | MEDLINE | ID: mdl-28279968

ABSTRACT

OBJECTIVE: Aspirin together with thienopyridine P2Y12 inhibitors, commonly clopidogrel, is a cornerstone of antiplatelet therapy. However, many patients receiving this therapy display high on-treatment platelet reactivity, which is a major therapeutic hurdle to the prevention of recurrent thrombotic events. The emergence of uninhibited platelets after thrombopoiesis has been proposed as a contributing factor to high on-treatment platelet reactivity. Here, we investigate the influences of platelet turnover on platelet aggregation in the face of different dual-antiplatelet therapy strategies. APPROACH AND RESULTS: Traditional light transmission aggregometry, cytometry, advanced flow cytometric imaging, and confocal microscopy were used to follow the interactions of populations of platelets from healthy volunteers and patients with stable cardiovascular disease. Newly formed, reticulated platelets overproportionately contributed to, and clustered at, the core of forming aggregates. This phenomenon was particularly observed in samples from patients treated with aspirin plus a thienopyridine, but was absent in samples taken from patients treated with aspirin plus ticagrelor. CONCLUSIONS: Reticulated platelets are more reactive than older platelets and act as seeds for the formation of platelet aggregates even in the presence of antiplatelet therapy. This is coherent with the emergence of an uninhibited subpopulation of reticulated platelets during treatment with aspirin plus thienopyridine, explained by the short pharmacokinetic half-lives of these drugs. This phenomenon is absent during treatment with ticagrelor, because of its longer half-life and ability to act as a circulating inhibitor. These data highlight the important influences of pharmacokinetics on antiplatelet drug efficacies, especially in diseases associated with increased platelet turnover.


Subject(s)
Adenosine/analogs & derivatives , Aspirin/pharmacokinetics , Blood Platelets/drug effects , Coronary Artery Disease/drug therapy , Platelet Aggregation Inhibitors/pharmacokinetics , Purinergic P2Y Receptor Antagonists/pharmacokinetics , Thienopyridines/pharmacokinetics , Thrombopoiesis , Adenosine/administration & dosage , Adenosine/pharmacokinetics , Adolescent , Adult , Aged , Aged, 80 and over , Aspirin/administration & dosage , Blood Platelets/metabolism , Case-Control Studies , Coronary Artery Disease/blood , Coronary Artery Disease/diagnosis , Drug Therapy, Combination , Half-Life , Humans , Male , Middle Aged , Platelet Aggregation/drug effects , Platelet Aggregation Inhibitors/administration & dosage , Platelet Function Tests , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/adverse effects , Thienopyridines/administration & dosage , Ticagrelor , Young Adult
6.
Hum Mol Genet ; 26(5): 989-1002, 2017 03 01.
Article in English | MEDLINE | ID: mdl-28087731

ABSTRACT

Genome-wide association studies have revealed an association between variation at the SLC4A7 locus and blood pressure. SLC4A7 encodes the electroneutral Na+/HCO3- co-transporter NBCn1 which regulates intracellular pH (pHi). We conducted a functional study of variants at this locus in primary cultures of vascular smooth muscle and endothelial cells. In both cell types, we found genotype-dependent differences for rs13082711 in DNA-nuclear protein interactions, where the risk allele is associated with increased SLC4A7 expression level, NBCn1 availability and function as reflected in elevated steady-state pHi and accelerated recovery from intracellular acidosis. However, in the presence of Na+/H+ exchange activity, the SLC4A7 genotypic effect on net base uptake and steady-state pHi persisted only in vascular smooth muscle cells but not endothelial cells. We found no discernable effect of the missense polymorphism resulting in the amino acid substitution Glu326Lys. The finding of a genotypic influence on SLC4A7 expression and pHi regulation in vascular smooth muscle cells provides an insight into the molecular mechanism underlying the association of variation at the SLC4A7 locus with blood pressure.


Subject(s)
Hypertension/metabolism , Muscle, Smooth, Vascular/metabolism , Sodium-Bicarbonate Symporters/genetics , Alleles , Amino Acid Substitution/genetics , Animals , Blood Pressure/genetics , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Endothelial Cells/metabolism , Gene Expression Regulation , Genome-Wide Association Study , Genotype , Humans , Hydrogen-Ion Concentration , Hypertension/genetics , Hypertension/pathology , Muscle, Smooth, Vascular/pathology , Mutation , Rats , Sodium/metabolism , Sodium-Bicarbonate Symporters/biosynthesis
7.
PLoS Genet ; 12(7): e1006127, 2016 07.
Article in English | MEDLINE | ID: mdl-27389912

ABSTRACT

Genome-wide association studies have revealed an association between coronary heart disease (CHD) and genetic variation on chromosome 13q34, with the lead single nucleotide polymorphism rs4773144 residing in the COL4A2 gene in this genomic region. We investigated the functional effects of this genetic variant. Analyses of primary cultures of vascular smooth muscle cells (SMCs) and endothelial cells (ECs) from different individuals showed a difference between rs4773144 genotypes in COL4A2 and COL4A1 expression levels, being lowest in the G/G genotype, intermediate in A/G and highest in A/A. Chromatin immunoprecipitation followed by allelic imbalance assays of primary cultures of SMCs and ECs that were of the A/G genotype revealed that the G allele had lower transcriptional activity than the A allele. Electrophoretic mobility shift assays and luciferase reporter gene assays showed that a short DNA sequence encompassing the rs4773144 site interacted with a nuclear protein, with lower efficiency for the G allele, and that the G allele sequence had lower activity in driving reporter gene expression. Analyses of cultured SMCs from different individuals demonstrated that cells of the G/G genotype had higher apoptosis rates. Immunohistochemical and histological examinations of ex vivo atherosclerotic coronary arteries from different individuals disclosed that atherosclerotic plaques with the G/G genotype had lower collagen IV abundance and thinner fibrous cap, a hallmark of unstable, rupture-prone plaques. A study of a cohort of patients with angiographically documented coronary artery disease showed that patients of the G/G genotype had higher rates of myocardial infarction, a phenotype often caused by plaque rupture. These results indicate that the CHD-related genetic variant at the COL4A2 locus affects COL4A2/COL4A1 expression, SMC survival, and atherosclerotic plaque stability, providing a mechanistic explanation for the association between the genetic variant and CHD risk.


Subject(s)
Collagen Type IV/genetics , Coronary Disease/genetics , Genome-Wide Association Study , Myocardial Infarction/genetics , Alleles , Coronary Disease/pathology , Female , Genotype , Humans , Male , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/pathology , Mutation , Myocardial Infarction/pathology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/pathology , Polymorphism, Single Nucleotide
8.
Hum Mol Genet ; 25(18): 4117-4126, 2016 09 15.
Article in English | MEDLINE | ID: mdl-27466201

ABSTRACT

Genome-wide association studies have revealed a relationship between inter-individual variation in blood pressure and the single nucleotide polymorphism rs13107325 in the SLC39A8 gene. This gene encodes the ZIP8 protein which co-transports divalent metal cations, including heavy metal cadmium, the accumulation of which has been associated with increased blood pressure. The polymorphism results in two variants of ZIP8 with either an alanine (Ala) or a threonine (Thr) at residue 391. We investigated the functional impact of this variant on protein conformation, cadmium transport, activation of signalling pathways and cell viability in relation to blood pressure regulation. Following incubation with cadmium, higher intracellular cadmium was detected in cultured human embryonic kidney cells (HEK293) expressing heterologous ZIP8-Ala391, compared with HEK293 cells expressing heterologous ZIP8-Thr391. This Ala391-associated cadmium accumulation also increased the phosphorylation of the signal transduction molecule ERK2, activation of the transcription factor NFκB, and reduced cell viability. Similarly, vascular endothelial cells with the Ala/Ala genotype had higher intracellular cadmium concentration and lower cell viability than their Ala/Thr counterpart following cadmium exposure. These results indicate that the ZIP8 Ala391-to-Thr391 substitution has an effect on intracellular cadmium accumulation and cell toxicity, providing a potential mechanistic explanation for the association of this genetic variant with blood pressure.


Subject(s)
Blood Pressure/genetics , Cadmium/toxicity , Cation Transport Proteins/genetics , Genome-Wide Association Study , Blood Pressure/drug effects , Cell Survival/drug effects , Endothelial Cells/drug effects , HEK293 Cells , Humans , Kidney/drug effects , Male , Testis/drug effects
9.
Br J Radiol ; 89(1062): 20160108, 2016 Jun.
Article in English | MEDLINE | ID: mdl-27033180

ABSTRACT

OBJECTIVE: The purpose of this work was to assess heating and radiofrequency (RF) deposition and image quality effects of a prototype three-section carbon fibre flatbed insert for use in MRI. METHODS: RF deposition was assessed using two different thermometry techniques, infrared thermometry and Bragg-grating thermometry. Image quality effects were assessed with and without the flatbed insert in place by using mineral oil phantoms and a human subject. RESULTS: Neither technique detected heating of the insert in typical MRI examinations. We found that the insert was less suitable for MRI applications owing to severe RF shielding artefact. For spin-echo (SE), turbo spin-echo (TSE) and gradient-echo sequences, the reduction in signal-to-noise ratio (SNR) was as much as 89% when the insert was in place compared with the standard couch, making it less suitable as a patient-support material. Turning on the MultiTransmit switch together with using the scanner's quadrature body coil improved the reduction in SNR from 89% to 39% for the SE sequence and from 82% to 12% for the TSE sequence. CONCLUSION: No evidence was found to support reports in the literature that carbon fibre is an unsuitable material for use in MRI because of heating. ADVANCES IN KNOWLEDGE: This study suggests that carbon fibre is less suitable for large-scale MRI applications owing to it causing severe RF shading. Further research is needed to establish the suitability of the flatbed for treatment planning using alternative sequences or whether an alternative carbon fibre composite for large-scale MRI applications or a design that can minimize shielding can be found.


Subject(s)
Beds , Carbon , Hot Temperature , Magnetic Resonance Imaging/instrumentation , Patient Positioning/instrumentation , Radiotherapy Planning, Computer-Assisted/instrumentation , Carbon Fiber , Equipment Design , Equipment Failure Analysis , Materials Testing , Radiotherapy, Image-Guided/instrumentation
10.
Br J Clin Pharmacol ; 81(4): 621-33, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26561399

ABSTRACT

AIMS: In vivo platelet function is a product of intrinsic platelet reactivity, modifiable by dual antiplatelet therapy (DAPT), and the extrinsic inhibitory endothelial mediators, nitric oxide (NO) and prostacyclin (PGI2 ), that are powerfully potentiated by P2Y12 receptor blockade. This implies that for individual patients endothelial mediator production is an important determinant of DAPT effectiveness. Here, we have investigated this idea using platelets taken from healthy volunteers treated with anti-platelet drugs. METHODS: Three groups of male volunteers (n = 8) received either prasugrel (10 mg), aspirin (75 mg) or DAPT (prasugrel + aspirin) once daily for 7 days. Platelet reactivity in the presence of diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA/NONOate) and PGI2 was studied before and following treatment. RESULTS: Ex vivo, PGI2 and/or DEA/NONOate had little inhibitory effect on TRAP-6-induced platelet reactivity in control conditions. However, in the presence of DAPT, combination of DEA/NONOate + PGI2 reduced platelet aggregation (74 ± 3% to 19 ± 6%, P < 0.05). In vitro studies showed even partial (25%) P2Y12 receptor blockade produced a significant (67 ± 2% to 39 ± 10%, P < 0.05) inhibition when DEA/NONOate + PGI2 was present. CONCLUSIONS: We have demonstrated that PGI2 and NO synergize with P2Y12 receptor antagonists to produce powerful platelet inhibition. Furthermore, even with submaximal P2Y12 blockade the presence of PGI2 and NO greatly enhances platelet inhibition. Our findings highlight the importance of endothelial mediator in vivo modulation of P2Y12 inhibition and introduces the concept of refining ex vivo platelet function testing by incorporating an assessment of endothelial function to predict thrombotic outcomes better and adjust therapy to prevent adverse outcomes in individual patients.


Subject(s)
Aspirin/pharmacology , Epoprostenol/pharmacology , Nitric Oxide/pharmacology , Platelet Activation/drug effects , Prasugrel Hydrochloride/pharmacology , Purinergic P2Y Receptor Antagonists/pharmacology , Adolescent , Adult , Aspirin/administration & dosage , Blood Platelets/drug effects , Drug Synergism , Epoprostenol/administration & dosage , Epoprostenol/metabolism , Healthy Volunteers , Humans , In Vitro Techniques , Male , Nitric Oxide/administration & dosage , Nitric Oxide/metabolism , Nitric Oxide Donors/pharmacology , Platelet Aggregation/drug effects , Prasugrel Hydrochloride/administration & dosage , Purinergic P2Y Receptor Antagonists/administration & dosage , Young Adult
12.
Circulation ; 131(7): 633-42, 2015 Feb 17.
Article in English | MEDLINE | ID: mdl-25492024

ABSTRACT

BACKGROUND: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified. METHODS AND RESULTS: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage. CONCLUSIONS: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.


Subject(s)
Anti-Inflammatory Agents/adverse effects , Arginine/analogs & derivatives , Cardiovascular Diseases/blood , Cyclooxygenase 2 Inhibitors/adverse effects , Cyclooxygenase 2/deficiency , Adult , Animals , Arginine/blood , Biomarkers/blood , Cardiovascular Diseases/drug therapy , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Organ Culture Techniques , Young Adult
13.
PLoS One ; 9(7): e99461, 2014.
Article in English | MEDLINE | ID: mdl-25006678

ABSTRACT

BACKGROUND AND OBJECTIVES: Vitamin D deficiency and endothelial dysfunction are non-traditional risk factors for cardiovascular events in chronic kidney disease. Previous studies in chronic kidney disease have failed to demonstrate a beneficial effect of vitamin D on arterial stiffness, left ventricular mass and inflammation but none have assessed the effect of vitamin D on microcirculatory endothelial function. STUDY DESIGN: We conducted a randomised controlled trial of 38 patients with non diabetic chronic kidney disease stage 3-4 and concomitant vitamin D deficiency (<16 ng/dl) who received oral ergocalciferol (50,000 IU weekly for one month followed by 50,000 IU monthly) or placebo over 6 months. The primary outcome was change in microcirculatory function measured by laser Doppler flowmetry after iontophoresis of acetylcholine. Secondary endpoints were tissue advanced glycation end products, sublingual functional capillary density and flow index as well as macrovascular parameters. Parallel in vitro experiments were conducted to determine the effect of ergocalciferol on cultured human endothelial cells. RESULTS: Twenty patients received ergocalciferol and 18 patients received placebo. After 6 months, there was a significant improvement in the ergocalciferol group in both endothelium dependent microcirculatory vasodilatation after iontophoresis of acetylcholine (p = 0.03) and a reduction in tissue advanced glycation end products (p = 0.03). There were no changes in sublingual microcirculatory parameters. Pulse pressure (p = 0.01) but not aortic pulse wave velocity was reduced. There were no significant changes in bone mineral parameters, blood pressure or left ventricular mass index suggesting that ergocalciferol improved endothelial function independently of these parameters. In parallel experiments, expression of endothelial nitric oxide synthase and activity were increased in human endothelial cells in a dose dependent manner. CONCLUSIONS: Ergocalciferol improved microcirculatory endothelial function in patients with chronic kidney disease and concomitant vitamin D deficiency. This process may be mediated through enhanced expression and activity of endothelial nitric oxide synthase. TRIAL REGISTRATION: Clinical trials.gov NCT00882401.


Subject(s)
Ergocalciferols/administration & dosage , Kidney/blood supply , Microcirculation/drug effects , Renal Insufficiency, Chronic/drug therapy , Vitamin D Deficiency/drug therapy , Vitamins/administration & dosage , Administration, Oral , Adult , Comorbidity , Drug Administration Schedule , Ergocalciferols/therapeutic use , Female , Glycation End Products, Advanced/drug effects , Humans , Kidney/drug effects , Kidney/pathology , Male , Middle Aged , Renal Insufficiency, Chronic/physiopathology , Treatment Outcome , Vitamin D Deficiency/physiopathology , Vitamins/therapeutic use
14.
J Vasc Surg Venous Lymphat Disord ; 2(2): 160-5, 2014 Apr.
Article in English | MEDLINE | ID: mdl-26993181

ABSTRACT

OBJECTIVE: This study compares the effectiveness of a neuromuscular electrostimulation device (geko T-1; Firstkind Ltd, High Wycombe, UK) in enhancing lower limb blood perfusion with two leading intermittent pneumatic compression (IPC) devices, the Huntleigh Flowtron Universal (Huntleigh Healthcare Ltd, Cardiff, UK) and the Kendall SCD Express (Covidien plc, Dublin, Ireland). The subjects' tolerance of the devices was also compared. METHODS: Ten healthy subjects were recruited. The devices were fitted bilaterally, in a sequential manner, for 30 minutes. Ultrasound and laser Doppler fluxmetry assessments were performed. RESULTS: The geko T-1 device was superior to both IPC devices in increasing both venous and arterial blood volume flow by ∼30% (95% confidence interval [CI], 23.7%-82.4%; P ≤ .001). The geko T-1 increased arterial blood velocity by 24% (95% CI, 9.7%-24.5%; P ≤ .001). A substantial increase in the total microcirculatory blood velocity by ∼370% (95% CI, 13.5%-39.7%) was reported after the use of the geko T-1 (P ≤ .001). With use of the visual analog scale, no significant differences in discomfort were found between the geko T-1 device and the IPC devices (P >.05). CONCLUSIONS: The geko T-1 device is more effective than the IPC devices in increasing venous, arterial, and microcirculatory blood velocity. The devices studied were safe and well tolerated by healthy subjects.

15.
Am J Hum Genet ; 92(3): 366-74, 2013 Mar 07.
Article in English | MEDLINE | ID: mdl-23415669

ABSTRACT

Recent genome-wide association studies have revealed an association between variation at the ADAMTS7 locus and susceptibility to coronary artery disease (CAD). Furthermore, in a population-based study cohort, we observed an inverse association between atherosclerosis prevalence and rs3825807, a nonsynonymous SNP (A to G) leading to a Ser-to-Pro substitution in the prodomain of the protease ADAMTS7. In light of these data, we sought a mechanistic explanation for this association. We found that ADAMTS7 accumulated in smooth muscle cells in coronary and carotid atherosclerotic plaques. Vascular smooth muscle cells (VSMCs) of the G/G genotype for rs3825807 had reduced migratory ability, and conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of thrombospondin-5, an ADAMTS7 substrate that had been shown to be produced by VSMCs and inhibit VSMC migration. Furthermore, we found that there was a reduction in the amount of cleaved ADAMTS7 prodomain in media conditioned by VSMCs of the G/G genotype and that the Ser-to-Pro substitution affected ADAMTS7 prodomain cleavage. The results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD rendering a reduction in ADAMTS7 function.


Subject(s)
ADAM Proteins/genetics , Cell Movement/genetics , Coronary Artery Disease/genetics , Muscle, Smooth, Vascular/metabolism , Myocytes, Smooth Muscle/metabolism , ADAM Proteins/metabolism , ADAMTS7 Protein , Atherosclerosis/genetics , Atherosclerosis/metabolism , Cartilage Oligomeric Matrix Protein , Cohort Studies , Coronary Artery Disease/metabolism , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Genetic Predisposition to Disease , Genotype , Glycoproteins/genetics , Glycoproteins/metabolism , Humans , Matrilin Proteins , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/metabolism , Polymorphism, Single Nucleotide
16.
Hum Mol Genet ; 21(18): 4021-9, 2012 Sep 15.
Article in English | MEDLINE | ID: mdl-22706276

ABSTRACT

Variation on chromosome 9p21 is associated with risk of coronary artery disease (CAD). This genomic region contains the CDKN2A and CDKN2B genes which encode the cell cycle regulators p16(INK4a), p14(ARF) and p15(INK4b) and the ANRIL gene which encodes a non-coding RNA. Vascular smooth muscle cell (VSMC) proliferation plays an important role in the pathogenesis of atherosclerosis which causes CAD. We ascertained whether 9p21 genotype had an influence on CDKN2A/CDKN2B/ANRIL expression levels in VSMCs, VSMC proliferation and VSMC content in atherosclerotic plaques. Immunohistochemical examination showed that VSMCs in atherosclerotic lesions expressed p16(INK4a), p14(ARF) and p15(INK4b). Analyses of primary cultures of VSMCs showed that the 9p21 risk genotype was associated with reduced expression of p16(INK4a), p15(INK4b) and ANRIL (P = 1.2 × 10(-5), 1.4 × 10(-2) and 3.1 × 10(-9)) and with increased VSMC proliferation (P = 1.6 × 10(-2)). Immunohistochemical analyses of atherosclerotic plaques revealed an association of the risk genotype with reduced p15(INK4b) levels in VSMCs (P = 3.7 × 10(-2)) and higher VSMC content (P = 5.6 × 10(-4)) in plaques. The results of this study indicate that the 9p21 variation has an impact on CDKN2A and CDKN2B expression in VSMCs and influences VMSC proliferation, which likely represents an important mechanism for the association between this genetic locus and susceptibility to CAD.


Subject(s)
Atherosclerosis/genetics , Chromosomes, Human, Pair 9/genetics , Coronary Artery Disease/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Myocytes, Smooth Muscle/metabolism , RNA, Long Noncoding/genetics , Atherosclerosis/metabolism , Atherosclerosis/pathology , Cell Proliferation , Cells, Cultured , Coronary Artery Disease/metabolism , Coronary Artery Disease/pathology , Cyclin-Dependent Kinase Inhibitor p15/metabolism , Cyclin-Dependent Kinase Inhibitor p16/metabolism , Gene Expression , Genetic Association Studies , Genotype , Humans , Muscle, Smooth, Vascular/pathology , Myocytes, Smooth Muscle/physiology , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/metabolism , Polymorphism, Single Nucleotide , Primary Cell Culture , RNA, Long Noncoding/metabolism
17.
Results Pharma Sci ; 2: 1-8, 2012.
Article in English | MEDLINE | ID: mdl-25755988

ABSTRACT

INTRODUCTION: Dissolution is the amount of substance that goes into solution per unit time under standardised conditions of liquid/solid interface, solvent composition and temperature. Dissolution is one of the most important tools to predict the in-vivo bioavailability and in some cases to determine bioequivalence and assure interchangeability. AIM: To compare the differences in dissolution behaviour of solid dosage forms between innovators (reference products) and their generic counterparts (tested products). METHODS: Four replicates for each batch of 37 tested medicines was carried out using A PT-DT70 dissolution tester from Pharma Test. A total of 13 branded medicines and 24 generic counterparts were obtained locally and internationally to detect any differences in their dissolution behaviour. They were tested according to the British Pharmacopeia, European Pharmacopeia and the US Pharmacopeia with the rate of dissolution determined by ultra-violet Spectrophotometery. RESULTS: Most tested medicines complied with the pharmacopoeial specifications and achieved 85% dissolution in 60 min. However, some generic medicines showed significant differences in dissolution rate at 60 and 120 min. Many generic medicines showed a slower dissolution rate than their branded counterparts such as the generic forms of omeprazole 20 mg. Some showed an incomplete dissolution such as the generic form of nifedipine 10 mg. Other generics showed faster dissolution rate than their branded counterpart such as the generic forms of meloxicam 15 mg. Moreover, some generics from different batches of the same manufacturer showed significant differences in their dissolution rate such as the generic forms of meloxicam 7.5 mg. Nevertheless, some generic medicines violated the EMA and the FDA guidelines for industry when they failed to achieve 85% dissolution at 60 min, such as the generic form of diclofenac sodium 50 mg. CONCLUSION: Most medicines in this study complied with the pharmacopeial limits. However, some generics dissolved differently than their branded counterparts. This can clearly question the interchangeability between the branded and its generic counterpart or even among generics.

18.
Cardiovasc Res ; 93(4): 674-81, 2012 Mar 15.
Article in English | MEDLINE | ID: mdl-22166712

ABSTRACT

AIMS: Circulating endogenous, dietary, and foreign chemicals can contribute to vascular dysfunction. The mechanism by which the vasculature protects itself from these chemicals is unknown. This study investigates whether the pregnane X receptor (PXR), the major transcriptional regulator of hepatic drug metabolism and transport that responds to such xenobiotics, mediates vascular protection by co-ordinating a defence gene programme in the vasculature. METHODS AND RESULTS: PXR was detected in primary human and rat aortic endothelial and smooth muscle cells (SMC) and blood vessels including the human and rat aorta. Metabolic PXR target genes cytochrome P450 3A, 2B, 2C, and glutathione S-transferase mRNA and activity were induced by PXR ligands in rodent and human vascular cells and absent in the aortas from PXR-null mice stimulated in vivo or in rat aortic SMC expressing dominant-negative PXR. Activation of aortic PXR by classical agonists had several protective effects: increased xenobiotic metabolism demonstrated by bioactivation of the pro-drug clopidogrel, which reduced adenosine diphosphate-induced platelet aggregation; increased expression of multidrug resistance protein 1, mediating chemical efflux from the vasculature; and protection from reactive oxygen species-mediated cell death. CONCLUSION: PXR co-ordinately up-regulates drug metabolism, transport, and antioxidant genes to protect the vasculature from endogenous and exogenous insults, thus representing a novel gatekeeper for vascular defence.


Subject(s)
Cytochrome P-450 Enzyme System/metabolism , Endothelium, Vascular/metabolism , Glutathione Transferase/metabolism , Muscle, Smooth, Vascular/metabolism , Oxidative Stress/physiology , Receptors, Steroid/physiology , Xenobiotics/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , Animals , Aorta/cytology , Biological Transport/physiology , Cells, Cultured , Clopidogrel , Endothelium, Vascular/cytology , Humans , In Vitro Techniques , Mice , Mice, Knockout , Models, Animal , Muscle, Smooth, Vascular/cytology , Pregnane X Receptor , Rats , Rats, Wistar , Reactive Oxygen Species/metabolism , Receptors, Steroid/deficiency , Receptors, Steroid/genetics , Ticlopidine/analogs & derivatives , Ticlopidine/metabolism
19.
Transpl Int ; 24(8): 770-9, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21575080

ABSTRACT

Rising healthcare costs promote the generic substitution among patients because it is identifiable costs. A key concern is that patients should be involved in the decision of switching. The aim of this study was to examine renal transplant patients' views on generic substitution in the UK. A total of 163 renal patients were surveyed using 36 multiple-choice questions at Barts and The London Renal Transplant Clinic, in the UK. Transplant recipients over 18 years, able to read and write English and willing to fill in the questionnaire were targeted; 84% of patients were conscious of the availability of generic medicines, 70% understood the terms "generic" and "branded" in relation to medicines and 54% were aware of generic substitution practice. However, 75% did not know if they were taking generics and 84% felt that generics are not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. Moreover, many patients admitted that they would not accept the generic substitution of ciclosporin when become available in the UK. A number of factors such as patients' education, knowledge, severity of the disease, efficacy of generic medicines and patients' involvement in decisions regarding their health appear to drive patients' attitudes towards generic substitution.


Subject(s)
Drugs, Generic/economics , Kidney Transplantation/methods , Adult , Aged , Attitude to Health , Cyclosporine/economics , Drug Substitution , Female , Humans , Kidney Transplantation/economics , Male , Middle Aged , Surveys and Questionnaires , United Kingdom
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