Effects of phlebotomy-induced reduction of body iron stores on metabolic syndrome: results from a randomized clinical trial.
BMC Med. 2012 ;10:54. Epub 2012 May 30. PMID: 22647517
Khosrow S Houschyar, Rainer Lüdtke, Gustav J Dobos, Ulrich Kalus, Martina Broecker-Preuss, Thomas Rampp, Benno Brinkhaus, Andreas Michalsen
Department of Internal Medicine, Kliniken Essen-Mitte, University Duisburg-Essen, Essen, Germany.
BACKGROUND: Metabolic syndrome (METS) is an increasingly prevalent but poorly understood clinical condition characterized by insulin resistance, glucose intolerance, dyslipidemia, hypertension, and obesity. Increased oxidative stress catalyzed by accumulation of iron in excess of physiologic requirements has been implicated in the pathogenesis of METS, but the relationships between cause and effect remain uncertain. We tested the hypothesis that phlebotomy-induced reduction of body iron stores would alter the clinical presentation of METS, using a randomized trial.
METHODS: In a randomized, controlled, single-blind clinical trial, 64 patients with METS were randomly assigned to iron reduction by phlebotomy (n = 33) or to a control group (n = 31), which was offered phlebotomy at the end of the study (waiting-list design). The iron-reduction patients had 300 ml of blood removed at entry and between 250 and 500 ml removed after 4 weeks, depending on ferritin levels at study entry. Primary outcomes were change in systolic blood pressure (SBP) and insulin sensitivity as measured by Homeostatic Model Assessment (HOMA) index after 6 weeks. Secondary outcomes included HbA1c, plasma glucose, blood lipids, and heart rate (HR).
RESULTS: SBP decreased from 148.5± 12.3 mmHg to 130.5 ± 11.8 mmHg in the phlebotomy group, and from 144.7 ± 14.4 mmHg to 143.8 ± 11.9 mmHg in the control group (difference -16.6 mmHg; 95% CI -20.7 to -12.5; P<0.001). No significant effect on HOMA index was seen. With regard to secondary outcomes, blood glucose, HbA1c, low-density lipoprotein/high-density lipoprotein ratio, and HR were significantly decreased by phlebotomy. Changes in BP and HOMA index correlated with ferritin reduction.
CONCLUSIONS: In patients with METS, phlebotomy, with consecutive reduction of body iron stores, lowered BP and resulted in improvements in markers of cardiovascular risk and glycemic control. Blood donation may have beneficial effects for blood donors with METS.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT01328210 Please see related article: http://www.biomedcentral.com/1741-7015/10/53.
Article Published Date : Dec 31, 2011
Microfluidic whole blood testing of platelet response to pharmacological agents.
Platelets. 2017 Jan 19;:1-6
Authors: Li R, Grosser T, Diamond SL
Platelets present a number of intracellular and transmembrane targets subject to pharmacological modulation, either for cardiovascular disease reduction or as an unintended drug response. Microfluidic devices allow human blood to clot on a defined surface under controlled hemodynamic and pharmacological conditions. The potencies of a number of antiplatelet and anticancer drugs have been tested with respect to platelet deposition on collagen under flow. Inhibitors of cyclooxygenase-1 (COX-1) reduce platelet deposition, either when added ex vivo to blood or ingested orally by patients prior to testing. Some individuals display a functional "aspirin-insensitivity" in microfluidic assay. When certain nonsteroidal anti-inflammatory drugs (NSAIDs) are taken orally, they block COX-1 acetylation by aspirin with concomitant reduction of aspirin efficacy against platelets in microfluidic assay. Both P2Y1 and P2Y12 inhibitors reduce platelet deposition under flow, as do NO donors and iloprost that target the guanylate cyclase and the prostacyclin receptor, respectively. In a microfluidic assay of 37 kinase inhibitors, dasatinib had potent antiplatelet activity, while bosutinib was less potent. Dasatinib and bosutinib have known profiles against numerous kinases, revealing overlapping and nonoverlapping activities relevant to their unique actions against platelets. Also, dasatinib caused a marked and specific inhibition of GPVI signaling induced by convulxin, consistent with a dasatinib-associated bleeding risk. Microfluidic devices facilitate drug library screening, dose-response testing, and drug-drug interaction studies. Kinase inhibitors developed as anticancer agents may present antiplatelet activities that are detectable by microfluidic assay and potentially linked to bleeding risks.
PMID: 28102731 [PubMed - as supplied by publisher]
CD14(++) CD16(-) monocytes are the main source of 11β-HSD type 1 after IL-4 stimulation.
Int Immunopharmacol. 2017 Feb;43:156-163
Authors: Kunnathully V, Gomez-Lira M, Bassi G, Poli F, Zoratti E, La Verde V, Idolazzi L, Gatti D, Viapiana O, Adami S, Rossini M
The anti-inflammatory actions of IL-4 are well established through earlier findings. However, the exact mechanism it uses to downregulate the pro-inflammatory cytokine production through monocytes and macrophages is poorly understood. In this study, we examined the effect of IL-4 in the induction of 11β-HSD1 in the two main classes of monocytes, CD14(++) CD16(-) (CD14) and CD14(+) CD16(+) (CD16). Peripheral Blood Mononuclear Cells (PBMCs) were isolated from 17 healthy donors and were sorted into CD14 and CD16 subpopulations using cell sorting. Effect of IL-4 on 11β-HSD1-enzyme activity was measured in sorted and unsorted monocytes using Homogeneous Time-Resolved Fluorescence (HTRF) and M1/M2 polarization analysis was performed by flow cytometry. Our results indicate that CD14 cells are the major source of 11β-HSD1 enzyme after IL-4 stimulation and that M2 phenotype is not a pre-requisite for its synthesis.
PMID: 27998829 [PubMed - indexed for MEDLINE]
S-Nitrosothiols as Platforms for Topical Nitric Oxide Delivery.
Basic Clin Pharmacol Toxicol. 2016 Oct;119 Suppl 3:49-56
Authors: Ganzarolli de Oliveira M
Nitric oxide (NO) is a small radical species involved in several fundamental physiological processes, including the control of vascular tone, the immune response and neuronal signalling. Endothelial dysfunction with the decreased NO bioavailability is the underlying cause of several diseases and has led to the development of a wide range of systemic NO donor compounds to lower the blood pressure and control hypertensive crises. However, several potential therapeutic actions of NO, not related to the cardiovascular system, demand exclusively local actions. Primary S-nitrosothiols (RSNOs) are endogenously found NO carriers and donors and have emerged as platforms for the localized delivery of NO in topical applications. Formulations for this purpose have evolved from low molecular weight RSNOs incorporated in polymeric films, hydrogels and viscous vehicles, to polymeric RSNOs where the SNO moiety is covalently bound to the polymer backbone. The biological actions displayed by these formulations include the increase in dermal vasodilation, the acceleration of wound healing, the killing of infectious microorganisms and an analgesic action against inflammatory pain. This MiniReview focuses on the state of the art of experimental topical formulations for NO delivery based on S-nitrosothiols and their potential therapeutic applications.
PMID: 27030007 [PubMed - indexed for MEDLINE]
Intravenous immune globulin suppresses angiogenesis in mice and humans.
Signal Transduct Target Ther. 2016;1:
Authors: Yasuma R, Cicatiello V, Mizutani T, Tudisco L, Kim Y, Tarallo V, Bogdanovich S, Hirano Y, Kerur N, Li S, Yasuma T, Fowler BJ, Wright CB, Apicella I, Greco A, Brunetti A, Ambati BK, Helmers SB, Lundberg IE, Viklicky O, Leusen JH, Verbeek JS, Gelfand BD, Bastos-Carvalho A, De Falco S, Ambati J
Human intravenous immune globulin (IVIg), a purified IgG fraction composed of ~ 60% IgG1 and obtained from the pooled plasma of thousands of donors, is clinically used for a wide range of diseases. The biological actions of IVIg are incompletely understood and have been attributed both to the polyclonal antibodies therein and also to their IgG (IgG) Fc regions. Recently, we demonstrated that multiple therapeutic human IgG1 antibodies suppress angiogenesis in a target-independent manner via FcγRI, a high-affinity receptor for IgG1. Here we show that IVIg possesses similar anti-angiogenic activity and inhibited blood vessel growth in five different mouse models of prevalent human diseases, namely, neovascular age-related macular degeneration, corneal neovascularization, colorectal cancer, fibrosarcoma and peripheral arterial ischemic disease. Angioinhibition was mediated by the Fc region of IVIg, required FcγRI and had similar potency in transgenic mice expressing human FcγRs. Finally, IVIg therapy administered to humans for the treatment of inflammatory or autoimmune diseases reduced kidney and muscle blood vessel densities. These data place IVIg, an agent approved by the US Food and Drug Administration, as a novel angioinhibitory drug in doses that are currently administered in the clinical setting. In addition, they raise the possibility of an unintended effect of IVIg on blood vessels.
PMID: 26925256 [PubMed - as supplied by publisher]
A novel dual NO-donating oxime and c-Jun N-terminal kinase inhibitor protects against cerebral ischemia-reperfusion injury in mice.
Neurosci Lett. 2016 Apr 08;618:45-9
Authors: Atochin DN, Schepetkin IA, Khlebnikov AI, Seledtsov VI, Swanson H, Quinn MT, Huang PL
The c-Jun N-terminal kinase (JNK) has been shown to be an important regulator of neuronal cell death. Previously, we synthesized the sodium salt of 11H-indeno[1,2-b]quinoxalin-11-one (IQ-1S) and demonstrated that it was a high-affinity inhibitor of the JNK family. In the present work, we found that IQ-1S could release nitric oxide (NO) during its enzymatic metabolism by liver microsomes. Moreover, serum nitrite/nitrate concentration in mice increased after intraperitoneal injection of IQ-1S. Because of these dual actions as JNK inhibitor and NO-donor, the therapeutic potential of IQ-1S was evaluated in an animal stroke model. We subjected wild-type C57BL6 mice to focal ischemia (30min) with subsequent reperfusion (48h). Mice were treated with IQ-1S (25mg/kg) suspended in 10% solutol or with vehicle alone 30min before and 24h after middle cerebral artery (MCA) occlusion (MCAO). Using laser-Doppler flowmetry, we monitored cerebral blood flow (CBF) above the MCA during 30min of MCAO provoked by a filament and during the first 30min of subsequent reperfusion. In mice treated with IQ-1S, ischemic and reperfusion values of CBF were not different from vehicle-treated mice. However, IQ-1S treated mice demonstrated markedly reduced neurological deficit and infarct volumes as compared with vehicle-treated mice after 48h of reperfusion. Our results indicate that the novel JNK inhibitor releases NO during its oxidoreductive bioconversion and improves stroke outcome in a mouse model of cerebral reperfusion. We conclude that IQ-1S is a promising dual functional agent for the treatment of cerebral ischemia and reperfusion injury.
PMID: 26923672 [PubMed - indexed for MEDLINE]
[An experience of hepatitis B control in a rural area in Far North Cameroon].
Med Sante Trop. 2015 Oct-Dec;25(4):422-7
Authors: Loriette M, Birguel J, Damza R, Ratoua M, Karsikam S, Sobnangou JJ, Aurenche C, Lunel-Fabiani F, Huraux JM
Experience of four years of control of the transmission of hepatitis B in a rural area in Far North Cameroon is presented: (i) prevention of mother to child transmission, (ii) HBsAg screening before blood transfusion, (iii) detection of HIV/HBV co-infections, (iv) protection of healthcare workers. The prevalence of HBsAg is very high in the four populations studied: 18.2% of pregnant women, 16.9% of candidate for blood donation, 14.4% of people living with HIV and 18 % of healthcare workers. Despite limited resources, effective actions are possible. Prevention of mother to child transmission of HBV with vaccination at birth has been set up, with bottlenecks - similar to those observed in HIV - but decreasing over the study. The screening of all potential blood donors has been reached over the years for HIV, HBsAg and HCV, which has led to the eviction of one out of five potential blood donors. Screening of healthcare workers reminded us that adult protection is based on a very early vaccination and not when hiring, even if it is possible to diagnose rare adults eligible for vaccination by research of anti-HBc antibody. A program of hepatitis B control, essential in Africa, appears feasible in rural areas in a framework of an overall improvement in care delivery.
PMID: 26643767 [PubMed - indexed for MEDLINE]
Novel vitamin D analogues; cytotoxic and anti-proliferative activity against a diffuse large B-cell lymphoma cell line and B-cells from healthy donors.
J Steroid Biochem Mol Biol. 2016 Nov;164:98-105
Authors: Kozielewicz P, Grafton G, Kutner A, Curnow SJ, Gordon J, Barnes NM
Calcitriol (1,25-dihydroxyvitamin D3, 1,25D3) and vitamin D side-chain modified analogs (VDAs) have gained considerable attention as potential drugs in the treatment of acute myeloid leukemia (AML), yet studies of the impact of 1,25D3 and VDAs upon other haematological malignancies are more limited. To address this gap in knowledge, we have examined the action of 1,25D3 and VDAs on a human cell line (DOHH2, K422) typifying diffuse large B-cell lymphoma (DLBCL) and also peripheral blood B-cells isolated from healthy donors. 1,25D3 and certain VDAs displayed moderate cytotoxic and pro-apoptotic actions upon DLBCL cells. 1,25D3 and VDAs (100nM) caused the death of approximately 40% DOHH2 cells after 24h stimulation, similar to their impact on HL-60 cells (acute myeloid leukaemia cell line). In addition, 1,25D3 and VDAs displayed concentration and time-dependent anti-proliferative actions upon stimulated B-cells from healthy donors. The VDAs inhibited proliferation by approximately 30%. Hence VDAs may offer therapeutic potential for the treatment of DLBCL or conditions benefitted by B-cell depletion.
PMID: 26485664 [PubMed - in process]
In Vivo Effects of Mesenchymal Stromal Cells in Two Patients With Severe Acute Respiratory Distress Syndrome.
Stem Cells Transl Med. 2015 Oct;4(10):1199-213
Authors: Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalén M, Jitschin R, Rodin S, Corbascio M, El Andaloussi S, Wiklander OP, Nordin JZ, Skog J, Romain C, Koestler T, Hellgren-Johansson L, Schiller P, Joachimsson PO, Hägglund H, Mattsson M, Lehtiö J, Faridani OR, Sandberg R, Korsgren O, Krampera M, Weiss DJ, Grinnemo KH, Le Blanc K
UNLABELLED: Mesenchymal stromal cells (MSCs) have been investigated as a treatment for various inflammatory diseases because of their immunomodulatory and reparative properties. However, many basic questions concerning their mechanisms of action after systemic infusion remain unanswered. We performed a detailed analysis of the immunomodulatory properties and proteomic profile of MSCs systemically administered to two patients with severe refractory acute respiratory distress syndrome (ARDS) on a compassionate use basis and attempted to correlate these with in vivo anti-inflammatory actions. Both patients received 2×10(6) cells per kilogram, and each subsequently improved with resolution of respiratory, hemodynamic, and multiorgan failure. In parallel, a decrease was seen in multiple pulmonary and systemic markers of inflammation, including epithelial apoptosis, alveolar-capillary fluid leakage, and proinflammatory cytokines, microRNAs, and chemokines. In vitro studies of the MSCs demonstrated a broad anti-inflammatory capacity, including suppression of T-cell responses and induction of regulatory phenotypes in T cells, monocytes, and neutrophils. Some of these in vitro potency assessments correlated with, and were relevant to, the observed in vivo actions. These experiences highlight both the mechanistic information that can be gained from clinical experience and the value of correlating in vitro potency assessments with clinical effects. The findings also suggest, but do not prove, a beneficial effect of lung protective strategies using adoptively transferred MSCs in ARDS. Appropriate randomized clinical trials are required to further assess any potential clinical efficacy and investigate the effects on in vivo inflammation.
SIGNIFICANCE: This article describes the cases of two patients with severe refractory adult respiratory syndrome (ARDS) who failed to improve after both standard life support measures, including mechanical ventilation, and additional measures, including extracorporeal ventilation (i.e., in a heart-lung machine). Unlike acute forms of ARDS (such in the current NIH-sponsored study of mesenchymal stromal cells in ARDS), recovery does not generally occur in such patients.
PMID: 26285659 [PubMed - indexed for MEDLINE]
The role of uncertainty regarding the results of screening immunoassays in blood establishments.
Transfus Apher Sci. 2015 Apr;52(2):252-5
Authors: Pereira P, Westgard JO, Encarnação P, Seghatchian J, de Sousa G
The risk of uncertain results in infectious agents' tests is recognized in blood establishments, being particularly evident during the blood donor selection. The current risk-based approaches require risk assessment and "risk-based thinking". Accordingly, the blood establishment should consider the effect of uncertainty in all the technical decisions taken in a screening laboratory. Since the post-transfusion safety is one of the blood establishments' goals, the risk of post-transfusion infection should be evaluated and actions taken to decrease the chance of blood donations validation use false negative results. This article reviews and discusses the sources of uncertainty of infectious agents' reported results in blood establishments. It describes a set of sources of uncertainty that should be considered in screening immunoassay's decisions. The infectious agents' uncertainty concern is critical for reporting reliable results.
PMID: 25754470 [PubMed - indexed for MEDLINE]
[Organization for the coverage of the transfusional needs of patients with hemoglobinopathy at the Établissement français du sang Bretagne].
Transfus Clin Biol. 2015 Mar;22(1):5-11
Authors: Thibert JB, Danic B, Delamaire M, Delugin L, Dugor C, Le Vacon F, Nimubona S, Treussard D, Vasse J, Semana G
UNLABELLED: Brittany is a low prevalence region for hemoglobinopathies. Despite of that, the number of patients is increasing each year. In 2013, 140 patients were known at the EFS Bretagne, and medical consultations are growing for 50% each year since 2011. The consequence is an increase of needs of 22% of compatible packed red blood cells. To anticipate the announced progress, various actions were implemented as study groups, creation of a new informatic prescription for red blood cells phenotyping, promotion of donation, transfusion organisation.
RESULTS: Fifthty-nine percent of the 400 ABO RH-KELL, FY, JK, MNS 3, 4, red blood cells were realised on the basis of this new informatic prescription, as the 99% of the packed red blood cells identified Fy (a- b-). So, 92% of the compatible transfused packed red blood cells were already in stock when the patients needed them.
CONCLUSIONS: In Brittany, that organisation leads to assume qualitative and quantitative transfusion for sickle cell disease in more than 90% of cases, with fast distribution. In the same time promotion of donation is done to increase the diversity of donors.
PMID: 25441455 [PubMed - indexed for MEDLINE]
Postdonation information and blood component retrievals: realigning blood center and hospital actions based on risk assessment.
Transfus Med Rev. 2014 Oct;28(4):226-34
Authors: Eder AF, Goldman M
Blood centers often receive information from individuals after blood donation that should have resulted in their deferral and may attempt to retrieve distributed blood components that did not meet all quality standards and regulations. Typically, the information is discovered or reported only after the components from the donation have been transfused. Blood centers may notify the transfusion service and provide a statement of the potential risk, if any, associated with the blood components, but the transfusion service must decide if further investigation, notification of the transfusing physician, or counseling of the patient is warranted. Currently, postdonation information (PDI) affects an estimated 1 in 600 donations in the United States. Despite the regularity with which PDI occurs, there has been little analysis of the main sources of PDI, associated transfusion risk, or the actual benefit of various actions taken as a result of PDI. However, blood centers attempt to retrieve thousands of components each year for PDI: actions that can cause confusion, concern, and complaints from hospitals and transfusion services. Postdonation information is largely a reflection of the inherent limitations of the current donor screening process, which is error-prone and uses broad, precautionary questions to guard against theoretical or extremely remote risks. This article reviews the most commonly reported PDI and available information on the possible risk associated with the transfused components from the involved donations, to formulate a framework for blood center retrieval actions and hospital notification that is consistent with current regulations and commensurate with the likelihood of adverse outcomes associated with the most commonly reported PDI.
PMID: 25311469 [PubMed - indexed for MEDLINE]
Recent developments in the effects of nitric oxide-donating statins on cardiovascular disease through regulation of tetrahydrobiopterin and nitric oxide.
Vascul Pharmacol. 2014 Nov;63(2):63-70
Authors: Ma S, Ma CC
Since the discovery of the importance of nitric oxide (NO) to the human body three decades ago, numerous laboratory and clinical studies have been done to explore its potential therapeutic actions on many organs. In the cardiovascular system, NO works as a volatile signaling molecule regulating the vascular permeability and vascular tone, preventing thrombosis and inflammation, as well as inhibiting the smooth muscle hyperplasia. Thus, NO is important in the prevention and treatment of cardiovascular disease. NO is synthesized by NO synthase (NOS) with tetrahydrobiopterin (BH4) as the crucial cofactor. Many studies have been done to form nitric oxide donors so as to deliver NO directly to the vessel walls. In addition, NO moieties have been incorporated into existing therapeutic agents to enhance the NO bioavailability, including statins. Statins are inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA), the rate-limiting enzyme of the mevalonate pathway. By inhibiting this pathway, statins lower blood cholesterol and exert their pleiotropic effects through activity in reaction cascades, such as Rho/ROCK and Rac 1/NADPH oxidase pathways. Statins have also been observed to implement their non-lipid effects by promoting BH4 synthesis with increase of NO bioavailability. Furthermore, NO-donating statins in laboratory studies have demonstrated to produce better therapeutic effects than their parent's drugs. They offer better anti-inflammatory, anti-proliferative and antithrombotic actions on cardiovascular system. They also cause better revascularization in peripheral ischemia and produce greater enhancement in limb reperfusion and salvage. In addition, it has been shown that NO-donating statin caused less myotoxicity, the most common side effect related to treatment with statins. The initial studies have demonstrated the superior therapeutic effects of NO-donating statins while producing fewer side effects.
PMID: 25139660 [PubMed - indexed for MEDLINE]
[Improving blood safety: errors management in transfusion medicine].
Srp Arh Celok Lek. 2014 May-Jun;142(5-6):384-90
Authors: Bujandrić N, Grujić J, Krga-Milanović M
INTRODUCTION: The concept of blood safety includes the entire transfusion chain starting with the collection of blood from the blood donor, and ending with blood transfusion to the patient. The concept involves quality management system as the systematic monitoring of adverse reactions and incidents regarding the blood donor or patient. Monitoring of near-miss errors show the critical points in the working process and increase transfusion safety.
OBJECTIVE: The aim of the study was to present the analysis results of adverse and unexpected events in transfusion practice with a potential risk to the health of blood donors and patients.
METHODS: One-year retrospective study was based on the collection, analysis and interpretation of written reports on medical errors in the Blood Transfusion Institute of Vojvodina.
RESULTS: Errors were distributed according to the type, frequency and part of the working process where they occurred. Possible causes and corrective actions were described for each error. The study showed that there were not errors with potential health consequences for the blood donor/patient. Errors with potentially damaging consequences for patients were detected throughout the entire transfusion chain. Most of the errors were identified in the preanalytical phase. The human factor was responsible for the largest number of errors.
CONCLUSION: Error reporting system has an important role in the error management and the reduction of transfusion-related risk of adverse events and incidents. The ongoing analysis reveals the strengths and weaknesses of the entire process and indicates the necessary changes. Errors in transfusion medicine can be avoided in a large percentage and prevention is cost-effective, systematic and applicable.
PMID: 25033600 [PubMed - indexed for MEDLINE]
Pharmacological strategy designed to limit ischemia-reperfusion injury in brain dead donor kidneys.
Prog Urol. 2014 Jun;24 Suppl 1:S26-30
Authors: Branchereau J, Barrou B
Ischemia-reperfusion injury is a complex physiological process responsible for delayed renal function or primary graft non-function, explicitly when kidney allograft are issued from expanded criteria donor. The purpose of this review is to detail the detrimental phenomenons altering kidney allograft's integrity in brain dead donor, therefore suggesting pharmacological interventions aiming to reduce ischemia-reperfusion injuries and improving transplantation outcome. This ischemia-reperfusion phenomenon must therefore be anticipated through the whole procedure starting at the stage of conditioning of the potential donor. Hormonal and haemodynamic consequences of brain death modify perfusion and oxygenation conditions of the organs Thus, after describing the autonomic, metabolic, endocrine and chemokine storm occurring during brain death, the authors focus on strategies to prevent hemodynamic instability in the donor and to limit the consequences of hormonal and immunological changes on organs that will eventually be transplanted.
PMID: 24950929 [PubMed - indexed for MEDLINE]
Prevalence and trend of major transfusion-transmissible infections among blood donors in Western China, 2005 through 2010.
PLoS One. 2014;9(4):e94528
Authors: Song Y, Bian Y, Petzold M, Ung CO
BACKGROUND: The prevalence of transfusion-transmissible infections (TTIs) in blood donations is important for evaluating blood safety and potential risks to the population. This study investigated the prevalence of TTIs among blood donors in Western China and suggested measures for policy-makers.
METHODS: The screening results of 66,311 donations between 2005 and 2010 from a central blood center in Western China were analyzed. The prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), and syphilis infections were expressed in percentages for the entire study group as well as groups by demographic characteristics and donation frequency, with differences analyzed using Fisher's exact or Chi-square test. Logistic regression was performed to identify the influencing factors of the detected results.
RESULTS: 1,769 (2.67%, 95% CI 2.55-2.79%) of the donated blood had serological evidence of infection with at least one pathogen and 44 (0.07%, 95% CI 0.05-0.09%) showed evidence of multiple infections. The seroprevalence of HBV, HCV, HIV, and syphilis infections was 0.87% (95% CI 0.80-0.94%), 0.86% (95% CI 0.79-0.93%), 0.31% (95% CI 0.26-0.35%), and 0.70% (95% CI 0.64-0.76%) respectively. Trend analysis for the prevalence of TTIs showed a significant increase from 2.44% to 3.71% (χ2 = 100.72, p = 0.00) over this 6-year period. The positive rates for TTIs varied along demographic lines. The top three risk factors in test-positive donors were identified as age, education level and donation frequency. The older age group and lower educated group were linked to a higher prevalence of TTIs. A decreasing prevalence was associated with an increasing frequency of blood donations (χ2 = 562.78, p = 0.00).
CONCLUSIONS: Hepatitis B and C were found most, and often in conjunction with syphilis. These were the primary threats to blood safety. The high positivity rate and the increasing prevalence of TTIs among blood donors in Western China call for further actions.
PMID: 24714490 [PubMed - indexed for MEDLINE]
Gamma irradiation preserves immunosuppressive potential and inhibits clonogenic capacity of human bone marrow-derived mesenchymal stromal cells.
J Cell Mol Med. 2014 Jun;18(6):1184-93
Authors: de Andrade AV, Riewaldt J, Wehner R, Schmitz M, Odendahl M, Bornhäuser M, Tonn T
Mesenchymal stromal cells (MSCs) are promising candidates for the treatment of graft-versus-host and autoimmune diseases. Here, by virtue of their immunosuppressive effects, they are discussed to exhibit inhibitory actions on various immune effector cells, including T lymphocytes that promote the underlying pathology. While it becomes apparent that MSCs exhibit their therapeutic effect in a transient manner, they are usually transplanted from third party donors into heavily immunocompromised patients. However, little is known about potential late complications of persisting third party MSCs in these patients. We therefore analysed the effect of gamma irradiation on the potency and proliferation of MSCs to elucidate an irradiation dose, which would allow inhibition of MSC proliferation while at the same time preserving their immunosuppressive function. Bone marrow-derived MSCs (BM-MSCs) were gamma-irradiated at increasing doses of 5, 10 and 30 Gy and subsequently assessed by colony formation unit (CFU)-assay, Annexin V-staining and in a mixed lymphocyte reaction, to assess colony growth, apoptosis and the immunosuppressive capacity, respectively. Complete loss of proliferative capacity measured by colony formation was observed after irradiation with a dose equal to or greater than 10 Gy. No significant decrease of viable cells was detected, as compared to non-irradiated BM-MSCs. Notably, irradiated BM-MSCs remained highly immunosuppressive in vitro for at least 5 days after irradiation. Gamma irradiation does not impair the immunosuppressive capacity of BM-MSCs in vitro and thus might increase the safety of MSC-based cell products in clinical applications.
PMID: 24655362 [PubMed - indexed for MEDLINE]
Contributions of endothelial nitric oxide synthase, noradrenaline, and neuropeptide Y to local warming-induced cutaneous vasodilatation in men.
Microvasc Res. 2013 Nov;90:128-34
Authors: Hodges GJ, Sparks PA
We performed a two-part study to determine the roles of endothelial nitric oxide synthase (eNOS) and the vasoconstrictor nerves neurotransmitters noradrenaline (NA) and neuropeptide Y (NPY) in the cutaneous vasodilator response to local skin warming. Forearm skin sites were instrumented with intradermal microdialysis fibres, local heaters, and laser-Doppler flow (LDF) probes. Sites were locally heated from 34 to 42°C. LDF was expressed as cutaneous vascular conductance (CVC; LDF/mean arterial pressure). In Part I, we tested whether sympathetic noradrenergic nerves acted via eNOS. In 8 male participants, treatments were as follows: 1) untreated; 2) bretylium tosylate (BT), preventing sympathetic neurotransmitter release; 3) l-NAA to inhibit eNOS; and 4) combined BT+l-NAA. At treated sites, the initial peak response was markedly reduced, and the plateau phase response to 35min of local warming was also reduced (P<0.05), which was not different among those sites (P>0.05). In Part II, we tested whether NA and NPY were involved in the vasodilator response to local warming. In Part IIa, treatments were: 1) untreated; 2) propranolol and yohimbine to antagonize α- and β-receptors; 3) l-NAA; and 4) combined propranolol, yohimbine, and l-NAA. In Part IIb, conditions were: 1) untreated; 2) BIBP to antagonize Y1-receptors; 3) l-NAA; and 4) combined BIBP and l-NAA. All treatments caused a reduction in the initial peak and plateau responses to local skin warming (P<0.05). The results of Part II indicate that both NA and NPY play roles in the cutaneous vasodilator response and their actions are achieved via eNOS. These data indicate that NA and NPY are involved in the initial, rapid rise in skin blood flow at the onset of local skin warming. However, their vasodilator actions in response to local skin warming appears to be manifested through eNOS.
PMID: 24012636 [PubMed - indexed for MEDLINE]
[Personalized medicine in transplantation therapy].
Rinsho Byori. 2013 May;61(5):428-33
Authors: Nakatani K
Personalized medicine based on pharmacogenomics is being developed at the clinical stage. Various evidence is accumulating in transplantation therapy. Tacrolimus, a calcineurin inhibitor, is usually used for immunosuppressive therapy after transplantation. Tacrolimus is mainly metabolized by cytochrome P450 isozymes, CYP3A4 and CYP3A5, expressed in the intestine as well as in the liver. Recent studies of pharmacogenomics have reported that several single nucleotide polymorphisms (SNPs) of CYP3A5 are correlated with gene expression and enzyme activity. Phenotypes of CYP3A5 are typed as expressors (*1/*1 and *1/*3) or non-expressors (*3/*3) . In living-donor liver transplantation, CYP3A5 phenotypes could predict the blood concentration of tacrolimus. In particular, preoperative assessment of CYP3A5 genotypes in both recipients (intestine) and donors (graft liver) is required for predicting tacrolimus pharmacokinetics. In kidney transplantation, blood tacrolimus concentrations were significantly different between expressors and non-expressors. Genotyping and phenotyping of recipients were useful to predict blood tacrolimus levels in early phase of post-transplantation. Furthermore, phenotypes of CYP3A5 could predict the initial dose of tacrolimus. Combination therapy was performed after bone marrow transplantation to prevent complications. Genotyping and phenotyping of metabolic enzymes for combination dugs would be useful for predicting drug actions. In conclusion, phenotyping based on pharmacogenomics supports personalized medicine in transplantation therapy. In future, multiplex testing should be developed to support personalized medicine in various fields.
PMID: 23947183 [PubMed - indexed for MEDLINE]
Nitroxyl donors retain their depressor effects in hypertension.
Am J Physiol Heart Circ Physiol. 2013 Sep 15;305(6):H939-45
Authors: Irvine JC, Ravi RM, Kemp-Harper BK, Widdop RE
Nitroxyl (HNO), the redox congener of nitric oxide, has numerous vasoprotective actions including an ability to induce vasodilation and inhibit platelet aggregation. Given HNO is resistant to scavenging by superoxide and does not develop tolerance, we hypothesised that HNO would retain its in vivo vasodilatory action in the setting of hypertension. The in vitro and in vivo vasodilator properties of the HNO donors Angeli's salt (AS) and isopropylamine/NONOate (IPA/NO) were compared with the NO donor diethylamine/NONOate (DEA/NO) in spontaneously hypertensive rats (SHR) and normotensive [Wistar-Kyoto (WKY) rats]. AS (10, 50, and 200 μg/kg), IPA/NO (10, 50, and 200 μg/kg), and DEA/NO (1, 5, and 20 μg/kg) caused dose-dependent depressor responses in conscious WKY rats of similar magnitude. Depressor responses to AS and IPA/NO were significantly attenuated (P < 0.01) after infusion of the HNO scavenger N-acetyl-l-cysteine (NAC), confirming that AS and IPA/NO function as HNO donors in vivo. In contrast, responses to DEA/NO were unchanged following NAC infusion. Depressor responses to AS and IPA/NO in conscious SHR retained their sensitivity to the inhibitory effects of NAC (P < 0.01), yet those to DEA/NO in SHR were significantly (P < 0.05) enhanced following NAC infusion. Importantly, depressor responses to AS, IPA/NO, and DEA/NO were preserved in hypertension and vasorelaxation to AS and DEA/NO, in isolated aorta, unchanged in SHR as compared with WKY rats. This study has shown for the first time that HNO donors exert antihypertensive effects in vivo and may, therefore, offer a therapeutic alternative to traditional nitrovasodilators in the treatment of cardiovascular disorders such as hypertension.
PMID: 23851276 [PubMed - indexed for MEDLINE]
Scotblood 2012: transfusion/transplant medicine in the 2nd decade of the 21st century.
Transfus Apher Sci. 2013 Jun;48(3):415-20
Authors: Colligan D, McGowan N, Seghatchian J
Transfusion medicine is a technology-based discipline, undergoing continual changes for improvement. It requires staff at all levels to be continually educated and trained in appropriate multidisciplinary skills, in line with the rapid developments in all areas of transfusion practice: from blood/organ collection, through processing and storage to the more advanced cellular and hospital-based transfusion/transplantation therapies. Whilst the majority of the challenges to improve hospital and general transfusion practice can be overcome through team work, education, timely objectives and perseverance, it is important to envisage opportunities for implementing digital technologies to reduce all of the applicable hazards associated with transfusion. These can vary widely from new and emerging pathogens to limitations of supply due to growing demographic changes in populations. In the first decade of 21st century we have already witnessed unprecedented advances in haematopoietic stem cell transplantation to minimise the toxicities of graft versus host disease (GvHD), and in cell therapy to explore immunotherapy against cancer and other malignant disorders. Today there are 1000 genome project hapmaps that only the extreme cost of their implementation to routine practices may limit. Transfusion medicine, like all disciplines of medicine, nevertheless, will face difficult choices between increasing healthcare technology and increasing worldwide health. Drs. Colligan and McGowan, the new lead organisers of this wonderful yearly educational programme have agreed to follow the previous organisers' strategy to make a summary report of their meeting to become available, through TRASCI to broader interested groups, with the sprit that "sharing is caring". The main highlights of the 2012 conference were: targeting transfusion practices in hospital, a continuing journey; emerging infections and the potential causes and possible remedial actions; building for the future; the challenging issues of donor recruitment/retention; and finally; the application of Information Technology as a decision making tool, utilising clinical audit monitoring to evaluate good practice. This year's conference also coincided with the retirement of Martin Bruce OBE, after his 41years distinguished career, who gave the most delightful and humorous talk of a" life time of learning" which delighted all the participants. Finally, 2012 also marked the retirements of the previous lead Scotblood organisers Prof. Robin Fraser and Dr. Hagop Bessos after over thirty years service to SNBTS, and to whom we would like to dedicate this meeting report and wish them a happy and healthy retirement. This commentary comprises summaries of the presentations, based in part on the abstracts provided by the speakers.
PMID: 23643474 [PubMed - indexed for MEDLINE]
Certification of donor apheresis nurses: keys to develop an effective training program.
Transfus Apher Sci. 2013 Jun;48(3):307-9
Authors: Vrielink H, van den Burg PJ, van Antwerpen C, van Dongen R, Durant M, de Fijter A, van de Griendt A, Kivit R, Lubberdink A, de Kort WL
Within Sanquin Blood Supply, a training program to train apheresis nurses was developed. The parts of the work for which qualification should be necessary was analysed. Based on this analysis, a modular program with theoretical and practical information and knowledge was developed. The modular program consists of two sections: a theoretical and technical / practical. The theoretical section consists of by the project group identified themes including basic hematology (e.g. the characteristics, kinetics, physiology and function of blood cells), basic apheresis physiology, indications for apheresis procedures, criteria for donors apheresis, difficulties and risks of procedures as well as the actions to be taken in case of side effects, and introduction to the apheresis machine available, including the mechanism of the machine. The program for the technical / practical section consists of machine and procedure knowledge (in theory and practise) and troubleshooting. To conclude each individual module, tests in theory and capability to perform procedures are taken. Each trainee needs to demonstrate to have sufficient insight and skill to master all the relevant critical features of the work. Also a text-book for the trainee was written. This educational program provides an approach to educate and test apheresis donor nurses. The combination of theoretical and practical components and monitoring of the progression are an important basis.
PMID: 23619330 [PubMed - indexed for MEDLINE]
[The blood donors' haemovigilance in France].
Transfus Clin Biol. 2013 May;20(2):182-92
Authors: Ounnoughene N, Sandid I, Carlier M, Joussemet M, Ferry N
This work aim to present the descriptive analysis of serious adverse reactions in donors (dSAR's), which were notified in 2010 and 2011 in the French national haemovigilance database "e-FIT" (Internet secured haemovigilance reporting system). Some data, which are necessary for this analysis, also come from the regional haemovigilance coordinators' reports (RHC). The other parts of haemovigilance in the context of donation, without donors adverse reactions, such as post-donation information (PDI), adverse events occurred in the blood collection steps of the transfusion chain and epidemiology are not subject to this work analysis. This work shows that the quality of the data gradually improved since the setting up of the notification system of dSAR's. These data are particularly rich in learning lessons, but are still improving. It allows us to confirm that donor's safety, blood components quality, while preserving the blood components self-sufficiency in France, remains a priority. For these reasons, it is important to continue this haemovigilance awareness and to implement necessary actions that would be required for the protection of the donor's health and comfort during donation.
PMID: 23587615 [PubMed - indexed for MEDLINE]
[Transfusion safety. Introduction and identifying the problem].
Gac Med Mex. 2013 Jan-Feb;149(1):73-80
Authors: Ambriz Fernández R
The problems that exist in our country in the security of the transfusion chain affect every step in the recruitment, donor selection, and aseptic collection, screening tests, production of blood components, storage, transportation and transfusion to recipient. Some of which can lead to fatal cases or moving slowly because of the fragmentation of our health system.With the principles of ethics, we must move towards a unified national blood system overcoming the conflicts of interest that affect the impact on administrative certifications; decrease the irrational use of resources, optimize costs and achieve a transfusion medicine security system and haemovigilance of the at the hospital. There has to be some regional blood banks well-coordinated in health institutions, with central management systems of quality and more specialized procedures,the latter can be achieved with more than 150 public blood banks, transforming them into positions of blood collection of voluntary donation of repetition. The resources would be released equip regional banks. Also required to provide education and legislation ad hoc for goals in voluntary blood donation and focused mainly the university population and centralize information for haemovigilance based computer systems specific hospitals, that reduce errors and restrict risk blood components involved in fatal cases, and reduce the possibility of punitive actions. It has international advice of the whole transfusion chain.
PMID: 23435078 [PubMed - indexed for MEDLINE]
Guidelines for maintenance of adult patients with brain death and potential for multiple organ donations: the Task Force of the Brazilian Association of Intensive Medicine the Brazilian Association of Organs Transplantation, and the Transplantation Center of Santa Catarina.
Transplant Proc. 2012 Oct;44(8):2260-7
Authors: Westphal GA, Caldeira Filho M, Fiorelli A, Vieira KD, Zaclikevis V, Bartz M, Wanzuita R, Teixeira C, Franke C, Machado FO, Friedman G, Andrade J, Matos JD, Lamgaro DM, Silva E, Costa G, Coelho ME, Oliveira MC, Youssef NC, Akamine N, Duarte P, Lisboa R, Mazzali M, Ferraz Neto BH, Task Force of the Brazilian Association of Intensive Medicine, Brazilian Association of Organs Transplantation, Transplantation Center of Santa Catarina
INTRODUCTION: The organ shortage for transplantation, the principal factor that increases waiting lists, has become a serious public health problem. In this scenario, the intensivist occupies a prominent position as one of the professionals that first has a chance to identify brain death and to be responsible for the maintenance of the potential deceased donor.
OBJECTIVE: This report attempts to establish guidelines for care and maintenance of adult deceased donor organs guiding and standardizing care provided to patients with brain death.
METHOD: These guidelines were composed by intensivists, transplant coordinators, professionals from various transplant teams, and used transplant center. The formulated questions were forwarded to all members and recommendations were constructed after an extensive literature review selecting articles with the highest degree of evidence.
RESULTS: Guidelines were developed in the form of questions reflecting frequent experiences in clinical intensive care practices. The main questions were: Is there an optimal interval for keeping organs of deceased donors viable? What actions are considered essential for maintaining deceased donors in this period? What are the limits of body temperature? How should the patient be warmed? Which laboratory tests should be performed? What is the collection interval? What are the limits in the laboratory and the capture scenario? What are the limits of blood pressure? When and how should one use catecholamines?
CONCLUSIONS: This pioneer project involved a multidisciplinary team working in organ transplantation seeking to provide treatment guidance to increase the number of viable organs from deceased adult donors.
PMID: 23026569 [PubMed - indexed for MEDLINE]
Regulation of inflammatory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors.
Arthritis Rheum. 2012 Dec;64(12):3856-66
Authors: Yarilina A, Xu K, Chan C, Ivashkiv LB
OBJECTIVE: JAK inhibitors have been developed as antiinflammatory and immunosuppressive agents and are currently undergoing testing in clinical trials. The JAK inhibitors CP-690,550 (tofacitinib) and INCB018424 (ruxolitinib) have demonstrated clinical efficacy in rheumatoid arthritis (RA). However, the mechanisms that mediate the beneficial actions of these compounds are not known. The purpose of this study was to examine the effects of both JAK inhibitors on inflammatory and tumor necrosis factor (TNF) responses in human macrophages.
METHODS: In vitro studies were performed using peripheral blood macrophages derived from healthy donors and treated with TNF and using synovial fluid macrophages derived from patients with RA. Levels of activated STAT proteins and other transcription factors were detected by Western blotting, and gene expression was measured by real-time polymerase chain reaction analysis. The in vivo effects of JAK inhibitors were evaluated in the K/BxN serum-transfer model of arthritis.
RESULTS: JAK inhibitors suppressed the activation and expression of STAT-1 and downstream inflammatory target genes in TNF-stimulated and RA synovial macrophages. In addition, JAK inhibitors decreased nuclear localization of NF-κB subunits in TNF-stimulated and RA synovial macrophages. CP-690,550 significantly decreased the expression of interleukin-6 in synovial macrophages. JAK inhibitors augmented nuclear levels of NF-ATc1 and cJun, followed by increased formation of osteoclast-like cells. CP-690,550 strongly suppressed K/BxN serum-transfer arthritis, which is dependent on macrophages, but not lymphocytes.
CONCLUSION: Our findings demonstrate that JAK inhibitors suppress macrophage activation and attenuate TNF responses and further suggest that suppression of cytokine/chemokine production and innate immunity contribute to the therapeutic efficacy of JAK inhibitors.
PMID: 22941906 [PubMed - indexed for MEDLINE]
Calcium channel blockers prevent endothelial cell activation in response to necrotic trophoblast debris: possible relevance to pre-eclampsia.
Cardiovasc Res. 2012 Dec 01;96(3):484-93
Authors: Chen Q, Guo F, Liu S, Xiao J, Wang C, Snowise S, Stone PR, Chamley LW
AIMS: Pre-eclampsia is characterized by endothelial activation, which is triggered by placental factor(s). One such factor may be trophoblastic debris that is shed into the maternal blood to become trapped against the maternal pulmonary endothelium. Phagocytosis of necrotic trophoblastic debris (NTD) induces endothelial cell activation with increased secretion of interleukin-6 (IL-6) and transforming growth factor β1 (TGFβ1), which may induce systemic endothelial cell activation. In addition to its effects on vascular smooth muscle, evidence suggests that nifedipine may also affect the endothelium, contributing to the therapeutic benefits of the drug. We investigated whether nifedipine could reverse the endothelial cell activation induced by NTD.
METHODS AND RESULTS: Trophoblastic debris was collected from placental explants and exposed to endothelial cells with or without nifedipine, verapamil, or a nitric oxide (NO) donor for 24 h. Endothelial cell activation was measured by cell-surface intracellular adhesion molecule-1 and E-selectin, as well as monocyte adhesion. The activation of endothelial cells exposed to NTD or sera from pre-eclamptic women was significantly reduced by nifedipine or verapamil. In addition, the increases in the levels of IL-6 or TGFβ1 in conditioned media from endothelial cells following phagocytosis of NTD were significantly reduced by nifedipine. These actions of nifedipine were reversed by the NO synthetase inhibitor l-NAME and mimicked by a NO donor.
CONCLUSION: Our results suggest that calcium channel blockers may have a direct effect upon endothelial cells, reducing the endothelial cell activation that is a key pathogenic feature of pre-eclampsia. This action may be mediated, in part, by NO.
PMID: 22933321 [PubMed - indexed for MEDLINE]
Recommendations in the event of a suspected transfusion-related acute lung injury (TRALI).
Acta Clin Belg. 2012 May-Jun;67(3):201-8
Authors: Van der Linden P, Lambermont M, Dierick A, Hübner R, Benoit Y, De Backer D, De Paep R, Ferrant A, Latinne D, Muylle L, Selleslag D, Szabo B, Thomas I, Vandekerckhove B, Deneys V, Working Group of the Superior Health Council
The following recommendations, which aim at improving the clinical diagnosis ofTRALI and the laboratory investigations that can support it, were drawn up by a working group of the Superior Health Council. TRALI is a complication of blood transfusion that is both serious and underreported. Systematic reporting may help to develop preventive actions. Therefore, the Superior Health Council recommends that there should be a more stringent surveillance of patients who receive a blood component transfusion. The clinician should pay very close attention to any change in the patient's respiratory status (cf. dyspnoea and arterial desaturation), which should be notified systematically to the haemovigilance contact person in the hospital.
PMID: 22897069 [PubMed - indexed for MEDLINE]
Amelioration of melatonin on oxidative stress and genotoxic effects induced by cisplatin in vitro.
Toxicol Mech Methods. 2012 Oct;22(8):631-7
Authors: Surendran D, Geetha CS, Mohanan PV
In this study, we made an effort to evaluate the possible protective actions of melatonin on cisplatin-induced oxidative damage in mice brain homogenate and genotoxic effects in human lymphocytes under in vitro conditions. The tissue homogenate was divided into three parts. The first portion was kept as control treated with dimethyl sulphoxide (DMSO) (group 1) while the second and third portion were treated with 24 µg/g tissue cisplatin alone (group 2) and 24 µg/g tissue cisplatin in combination with 3 mM melatonin (group 3), respectively. We measured the oxidative stress biomarkers such as lipid peroxidation, 8-hydroxy 2' deoxyguanosine (8-OHdG) and antioxidant parameters such as reduced glutathione, superoxide dismutase, glutathione peroxidase, and glutathione reductase in brain homogenate. Likewise peripheral venous blood was collected from healthy donors and human lymphocyte culture was done using karyotyping medium. Cultures were divided into three groups. Group 1 was the control i.e. lymphocytes treated with DMSO 5 µg/mL. In group 2, lymphocytes were treated with 2 µg/mL cisplatin and group 3 with a combination of 2 µg/mL cisplatin and 0.3 mM melatonin. Incubation of tissue homogenates with cisplatin elevated the malondialdehyde and 8-OHdG levels which were then reversed by melatonin. Reduction in antioxidant parameters with respect to corresponding controls were also restored by melatonin treatment. Furthermore, supplementation of melatonin was found to modulate the chromosome damage elicited by cisplatin which was determined using Giemsa (GTG) banding and karyotyping. These findings suggest that melatonin improves the cellular function and helps them to survive in the belligerent environment created by free radicals.
PMID: 22889322 [PubMed - indexed for MEDLINE]
Some new approaches to the management of hepatocellular carcinoma.
Semin Oncol. 2012 Aug;39(4):369-73
Authors: Carr BI
A concordance of multiple advances is changing the management of hepatocellular carcinoma (HCC). These include: (1) identification of preventable and treatable causal factors, including hepatitis B and obesity (non-alcoholic steatotic hepatitis [NASH]); (2) description of molecular and proteomic profiles for HCC prognosis, disease subtyping, and drug selection; (3) identification of circulating tumor cells for non-invasive molecular typing; (4) identification of tumor stem cells, for HCC subtyping and as treatment targets; (5) large numbers of multi-kinase inhibitors that are currently undergoing clinical trial assessment and comparison; (6) an array of newer therapies of different drug classes, aimed at a wide range of targets in cell growth, apoptosis, autophagy, and tumor invasion pathways; (7) newer regional chemotherapy and radiotherapy regimens and delivery systems; (8) the extension of liver transplantation to larger HCCs and its wider availability through use of living-related organ donors; (9) new radiological techniques to assess the changes in HCC vascularity associated with angiogenic drug actions; (10) re-evaluation of the importance of tumor biopsy to obtain molecular signatures; (11) recognition of the importance of non-tumor liver parenchyma for tumor growth control and as a source of prognostic profiling in HCC patients; (12) the evaluation of kinase- and other inhibitors in neo-adjuvant and adjuvant therapy associated with resection and liver transplant and minimization of transplant waiting list drop-out; (13) re-evaluation of the role or limitation of tumor responses, since kinase inhibitors can enhance survival without HCC size responses; and (14) the development of combination therapies to enhance tumor control rates, either using drugs targeting differing pathways, or kinase-inhibitors combined with either chemotherapy drugs or yttrium 90.
PMID: 22846855 [PubMed - indexed for MEDLINE]
FoxP3 T cells and the pathophysiologic effects of brain death and warm ischemia in donor kidneys.
Clin J Am Soc Nephrol. 2012 Sep;7(9):1481-9
Authors: Baan CC, Peeters AM, Demmers MW, Mol WM, Boer K, Samsom JN, Rowshani AT, Ijzermans JN, Weimar W
BACKGROUND AND OBJECTIVES: Forkhead box P3 regulatory T cells control inflammatory responses, but it remains unclear whether they inhibit brain death-initiated inflammation and tissue injury in deceased kidney donors. DESIGN, SETTING, PARTICIPANTS, MEASUREMENT: To study the actions of regulatory T cells at various stages of the donation and transplantation procedure, forkhead box P3, regulatory and inflammatory cytokine expression, and tissue injury markers were determined in time 0 kidney biopsies from deceased and living donors. Additionally, the interaction between forkhead box P3+ T cells and kidney injury molecule-1 by activated primary tubular epithelial cells was studied.
RESULTS: After cold storage, the deceased donor kidneys expressed the higher mRNA levels of kidney injury molecule-1 and CD3ε. In these samples, the inflammatory cytokines IL-8 and IFN-γ and markers associated with regulation (forkhead box P3, TGF-β, and IL-10) were highly expressed compared with living donor kidneys. Correlations were found between mRNA expression levels of forkhead box P3 and kidney injury molecule-1 and forkhead box P3 and IFN-γ. Immunohistochemical analysis confirmed the presence of forkhead box P3+ T cells in donor kidneys. Renal function (analyzed by serum creatinine levels) at the first week posttransplantation correlated with kidney injury molecule-1 and forkhead box P3 mRNA levels. In vitro studies showed that kidney injury molecule-1 expression by primary tubular epithelial cells was 63% (mean) lower when cocultured with regulatory T cells compared with control T cells.
CONCLUSIONS: These results show that donor forkhead box P3+ T cells infiltrate the deceased donor kidney, where they may control inflammatory and injury responses.
PMID: 22745276 [PubMed - indexed for MEDLINE]
Future preventive and therapeutic targets for transfusion-related acute lung injury.
Curr Pharm Des. 2012;18(22):3285-92
Authors: Curtis BR
Transfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-associated death for nearly a decade. Recent TRALI mitigation strategies focused on reduction of leukocyte antibodies in high volume plasma products appear to be successful in reducing TRALI events and deaths, but additional preventive measures are needed. Future possibilities include, screening of donors for neutrophil antibodies, processing of blood products to reduce or remove biologic response modifiers, and the more judicious use of blood. There are currently no specific TRALI therapies. The pathogenesis of TRALI and acute lung injury-acute respiratory distress syndrome (ALI-ARDS) is quite similar; both involving interactions of activated platelets, neutrophils, and pulmonary endothelium resulting in lung damage, capillary leak, and pulmonary edema. Greater understanding of these interactions and the key molecules involved will lead to development of potential new targets for therapy. In this review, future possible preventive measures to further reduce the occurrence of TRALI will be discussed, including TRALI caused by biologic response modifiers (BRMs), like bioactive lipids and sCD40L, which are not addressed by current preventive actions that only target leukocyte antibodies in high-volume plasma products. Insights already gained from studies of ALI-ARDS treatments will be summarized and discussed as possible therapeutic targets for treatment of patients experiencing TRALI.
PMID: 22621267 [PubMed - indexed for MEDLINE]
Cord blood banking: regulations, ethics and practice in a disputed Italian case.
Clin Ter. 2012;163(1):e27-8
Authors: Petrini C
Current Italian regulations allow the free storage in public biobanks within the Italian National Health Service (SSN) of voluntarily donated cord blood, which can then be made available for transplantation in Italian and foreign patients. The same regulations allow the free storage of cord blood for directed use (in other words, for all cases in which it can be used for a family member suffering from a disease that can be cured through the use of hematopoietic stem cells) and in cases where a family runs a high risk of genetic disorders. This article briefly describes and discusses an episode involving an Italian hospital: an appeal by a woman led to a court provision imposing the collection and storage of a cord blood unit outside the conditions established by law. The provision aroused controversy and led to a series of inappropriate actions.
PMID: 22362241 [PubMed - indexed for MEDLINE]
Bacterial skin flora and contamination of blood components: do we defer blood donors wisely?
Vox Sang. 2012 Aug;103(2):93-8
Authors: Pastila S, Lönnroth M, Heikkilä R, Heikkilä H, Carlson P
BACKGROUND AND OBJECTIVES: Bacterial infection through contaminated blood is currently the greatest infection risk in relation to a transfusion. Deferral of prospective blood donors with a skin disorder is a common practise, because bacteria usually originate from the donor's skin. The effectiveness of current deferral guidelines to prevent the bacterial contamination of blood has not been assessed.
MATERIALS AND METHODS: We recruited 55 blood donors with a skin disorder that prevented donation, and matched three controls for each case. The donors filled out a questionnaire and one bacterial culture sample was taken from venepuncture forearm skin.
RESULTS: The median total number of colony forming skin bacteria was significantly higher in the cases (224 CFUs per sample) than controls (105 CFU per sample). Staphylococcus aureus was significantly more often present on the skin in cases (49%) as compared to controls (7%). Regarding other bacterial genera, no difference between cases and controls was found.
CONCLUSIONS: This study shows that our current guidelines for deferral of blood donors with skin disorders effectively identifies individuals with a high number of bacteria on their skin, as well as S. aureus carriers. However, deferral due to skin disorders had only a minor impact on blood product contamination when compared to other actions.
PMID: 22348231 [PubMed - indexed for MEDLINE]
Hydrogen sulfide: a gasotransmitter of clinical relevance.
J Mol Med (Berl). 2012 Mar;90(3):255-63
Authors: Vandiver M, Snyder SH
Though the existence of hydrogen sulfide (H2S) in biological tissues has been known for over 300 years, it is the most recently appreciated of the gasotransmitters as a physiologic messenger molecule. The enzymes cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS) had long been speculated to generate H2S, and inhibitors of these enzymes had been employed to characterize influences of H2S in various organs. Definitive evidence that H2S is a physiologic regulator came with the development of mice with targeted deletion of CSE and CBS. Best characterized is the role of H2S, formed by CSE, as an endothelial derived relaxing factor that normally regulates blood pressure by acting through ATP-sensitive potassium channels. H2S participates in various phases of the inflammatory process, predominantly exerting anti-inflammatory actions. Currently, the most advanced efforts to develop therapeutic agents involve the combination of H2S donors with non-steroidal anti-inflammatory drugs (NSAIDs). The H2S releasing moiety provides cytoprotection to gastric mucosa normally adversely affected by NSAIDs while the combination of H2S and inhibition of prostaglandin synthesis may afford synergistic anti-inflammatory influences.
PMID: 22314625 [PubMed - indexed for MEDLINE]
Towards a framework for organ donation in the UK.
Br J Anaesth. 2012 Jan;108 Suppl 1:i56-67
Authors: Murphy PG, Smith M
Implementation of the recommendations from the Organ Donation Taskforce has introduced for the first time into the UK a nationwide framework for deceased donation. This framework is based, in principle, upon a conviction that donation should be viewed as part of end-of-life care and that the actions often necessary to facilitate it become justified when donation is recognized to be consistent with the wishes and interests of a dying patient. The implementation of the Taskforce recommendations across the complex landscape of acute hospital care in the UK represents a challenging programme of change management that has three more or less distinct phases. This programme has involved first creating and communicating the Taskforce's vision for donation in the UK, secondly introducing the structural elements of this new framework into hospital practice, and finally creating the environment in which these new elements can deliver the overall programme goals. Implementation has focused heavily upon areas of practice where significant opportunities to increase donor numbers exist. It is recognized that the greatest challenge is to overcome the societal and clinical behaviours and beliefs that currently create barriers to donation. Although national audit data may point to some of these areas of practice, international comparisons suggest that differences in approach to the care of patients with catastrophic brain injury may have a profound influence on the size of the potential donor pool.
PMID: 22194432 [PubMed - indexed for MEDLINE]
Xenotropic murine leukemia virus-related virus does not pose a risk to blood recipient safety.
Transfusion. 2012 Feb;52(2):298-306
Authors: Dodd RY, Hackett J, Linnen JM, Dorsey K, Wu Y, Zou S, Qiu X, Swanson P, Schochetman G, Gao K, Carrick JM, Krysztof DE, Stramer SL
BACKGROUND: When xenotropic murine leukemia virus-related virus (XMRV) was first reported in association with chronic fatigue syndrome, it was suggested that it might offer a risk to blood safety. Thus, the prevalence of the virus among blood donors and, if present, its transmissibility by transfusion need to be defined.
STUDY DESIGN AND METHODS: Two populations of routine blood donor samples (1435 and 13,399) were obtained for prevalence evaluations; samples from a linked donor-recipient repository were also evaluated. Samples were tested for the presence of antibodies to XMRV-related recombinant antigens and/or for XMRV RNA, using validated, high-throughput systems.
RESULTS: The presence of antibodies to XMRV could not be confirmed among a total of 17,249 blood donors or recipients (0%; 95% confidence interval [CI], 0%-0.017%); 1763 tested samples were nonreactive for XMRV RNA (0%; 95% CI, 0%-0.17%). Evidence of infection was absent from 109 recipients and 830 evaluable blood samples tested after transfusion of a total of 3741 blood components.
CONCLUSIONS: XMRV and related murine leukemia virus (MLV) markers are not present among a large population of blood donors and evidence of transfusion transmission could not be detected. Thus, these viruses do not currently pose a threat to blood recipient safety and further actions relating to XMRV and MLV are not justified.
PMID: 22098340 [PubMed - indexed for MEDLINE]
Advanced assessment of platelet function during adult donor care.
Prog Transplant. 2011 Sep;21(3):228-35
Authors: Powner DJ, Allison TA, Zakaria A
Abnormal platelet function may complicate the assessment and treatment of continuing blood loss, hypotension, and coagulation disorders during adult donor care. Antiplatelet drugs, such as aspirin, nonsteroidal anti-inflammatory drugs, clopidogrel (Plavix), ticlopidine (Ticlid), prasugrel (Effient), abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat) are commonly prescribed for older patients. These medications may be part of home therapy or may be given during acute cardiac or cerebrovascular crises that may lead to brain death and organ donation. This discussion reviews normal platelet formation and function, drug actions, methods to evaluate medication effects, pharmacological characteristics, treatment recommendations for platelet transfusion, and risks attendant with those infusions.
PMID: 21977884 [PubMed - indexed for MEDLINE]
In vitro recovery of Th1/Th2 balance in PBMCs from patients with immune thrombocytopenia through the actions of IL-18BPa/Fc.
Thromb Res. 2011 Dec;128(6):e119-24
Authors: Shan NN, Ji XB, Wang X, Li Y, Liu X, Zhu XJ, Hou M
To determine the effects of IL-18BPa/Fc on the cytokine production and survival of peripheral blood mononuclear cells (PBMCs) of immune thrombocytopenia (ITP), PBMCs isolated from patients with ITP and healthy donors were treated with or without of IL-18BPa/Fc. The production of IFN-γ, IL-2, tumor necrosis factor (TNF)-α, IL-4, IL-5 and IL-10 was measured by ELISA, and mRNA expression of IFN-γ and IL-18R was evaluated by RT-PCR. Besides, flow cytometric analysis of cell apoptosis was performed by staining with annexin V-FITC/ Propidium Iodide (PI). The proliferation rate of PBMCs was examined by CCK-8 assay. IL-18BPa/Fc at 10 ng/ml significantly stimulated IL-10 secretion from PBMCs in patients with ITP and healthy donors, while it decreased IFN-γ release. Further, IL-18BPa/Fc enhanced dexamethason(DEX) reduction of PHA-induced IFN-γ production by an additional 38.9%(DEX 20 nmol/l) and 49.9%(DEX 50 nmol/l) in ITP patients. Interestingly, the treatment of PBMCs with IL-18BPa/Fc increased the percentage of early apoptotic cells in patients with ITP. In conclusion, IL-18BPa/Fc, via neutralizing the biologic activity of mature IL-18, accelerates lymphocyte apoptosis and downregulates IFN-γ, while permitting the production of Th2 cytokine IL-10. These observations suggest a role of IL-18BPa/Fc in the recovery of Th1/Th2 balance, as well as its therapeutic potential in the treatment of ITP.
PMID: 21911248 [PubMed - indexed for MEDLINE]
Vasorelaxant and antiaggregatory actions of the nitroxyl donor isopropylamine NONOate are maintained in hypercholesterolemia.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1405-14
Authors: Bullen ML, Miller AA, Dharmarajah J, Drummond GR, Sobey CG, Kemp-Harper BK
Nitroxyl (HNO) displays pharmacological and therapeutic actions distinct from those of its redox sibling nitric oxide (NO(•)). It remains unclear, however, whether the vasoprotective actions of HNO are preserved in disease. The ability of the HNO donor isopropylamine NONOate (IPA/NO) to induce vasorelaxation, its susceptibility to tolerance development, and antiaggregatory actions were compared with those of a clinically used NO(•) donor, glyceryl trinitrate (GTN), in hypercholesterolemic mice. The vasorelaxant and antiaggregatory properties of IPA/NO and GTN were examined in isolated carotid arteries and washed platelets, respectively, from male C57BL/6J mice [wild-type (WT)] maintained on either a normal diet (WT-ND) or high fat diet (WT-HFD; 7 wk) as well as apolipoprotein E-deficient mice maintained on a HFD (ApoE(-/-)-HFD; 7 wk). In WT-ND mice, IPA/NO (0.1-30 μmol/l) induced concentration-dependent vasorelaxation and inhibition of collagen (30 μg/ml)-stimulated platelet aggregation, which was predominantly soluble guanylyl cyclase/cGMP dependent. Compared with WT-HFD mice, ApoE(-/-)-HFD mice displayed an increase in total plasma cholesterol levels (P < 0.001), vascular (P < 0.05) and platelet (P < 0.05) superoxide (O(2)(·-)) production, and reduced endogenous NO(•) bioavailability (P < 0.001). Vasorelaxant responses to both IPA/NO and GTN were preserved in hypercholesterolemia, whereas vascular tolerance developed to GTN (P < 0.001) but not to IPA/NO. The ability of IPA/NO (3 μmol/l) to inhibit platelet aggregation was preserved in hypercholesterolemia, whereas the actions of GTN (100 μmol/l) were abolished. In conclusion, the vasoprotective effects of IPA/NO were maintained in hypercholesterolemia and, thus, HNO donors may represent future novel treatments for vascular diseases.
PMID: 21803947 [PubMed - indexed for MEDLINE]
Anti-angiotensin type 1 receptor antibodies associated with antibody mediated rejection in donor HLA antibody negative patients.
Transplantation. 2010 Dec 27;90(12):1473-7
Authors: Reinsmoen NL, Lai CH, Heidecke H, Haas M, Cao K, Ong G, Naim M, Wang Q, Mirocha J, Kahwaji J, Vo AA, Jordan SC, Dragun D
BACKGROUND: Angiotensin type 1 receptor (AT1R) mediates most physiologic and pathophysiologic actions of its endogenous ligand, angiotensin II, with overactivity leading to vascular remodeling and hypertension. Antibodies to AT1R are implicated in several vascular pathologies. The aim of our study was to determine the impact of antibody to AT1R on clinical outcomes including antibody mediated rejection (AMR), with or without C4d deposition, in patients whose sera contained no donor human leukocyte antigen (HLA)-specific antibody (HLA-DSA).
METHODS: Pretransplant sera from 97 recipients and sera obtained at the time of acute rejection (AR) were tested by Luminex-based single-antigen bead assays to determine HLA-DSA and antibodies to major histocompatibility class I chain-related gene A (MICA). The presence of antibody to AT1R was determined by a cell-based ELISA method using a cutoff of 17 units to distinguish high from low binding.
RESULTS: Sera from 63 recipients were determined to have no HLA-DSA and no donor-specific MICA antibodies pretransplant and at the time of AR, and 16 of these recipients were diagnosed with AR including 7 with AMR and 9 with cellular AR (cell-mediated rejection). High-binding AT1R antibodies were identified for six of seven in the AMR+ group and zero of nine in the cell-mediated rejection+ group (P=0.0009).
CONCLUSIONS: A strong association was observed between the presence of high binding to AT1R and AMR in recipients whose sera contained no antibody to donor HLA or MICA. Assessing the AT1R antibody status along with the HLA-DSA provides additional information to determine the immunologic risk for recipients.
PMID: 21030904 [PubMed - indexed for MEDLINE]
Vane's blood-bathed organ technique adapted to examine the endothelial effects of cardiovascular drugs in vivo.
Pharmacol Rep. 2010 May-Jun;62(3):462-7
Authors: Gryglewski RJ, Mackiewicz Z
This study describes a modification of Vane's blood-bathed organ technique (BBOT). This new technique consisted of replacing the cascade of contractile smooth muscle organs within the traditional BBOT by a single collagen strip cut from a rabbit's hind leg tendon. Utilizing the extracorporeal circulation of an anesthetized heparinized mongrel cat or Wistar rat, arterial blood was dripped (1-3 ml min(-1)) over a collagen strip. This resulted in a gain in weight of the strip, which was due to the deposition of platelet aggregates and a few blood cells trapped over the strip. Arterial blood that had been used for the superfusion was pumped back into the animal's venous system. However, when this technique is adapted to human volunteers, the superfusing blood should be discarded. In animal experiments, intravenous injections of a variety of classic fibrinolytic agents (e.g., streptokinase) promoted the formation of platelet thrombi. Nitric oxide donors (e.g., SIN-1) at non-hypotensive doses hardly affected the mass of platelet thrombi deposited over the collagen strip, whereas endogenous prostacyclin (e.g., released from vascular endothelium by bradykinin) or exogenous prostacyclin and its stable analogues (e.g., iloprost) dissipated platelet thrombi as measured by a loss in the weight of the blood superfused collagen strip. This model allowed us to assay numerous drugs for their releasing properties of endogenous prostacyclin from vascular endothelium. These drugs included lipophilic angiotensin converting enzyme inhibitors (ACE-Is), which act in vivo as bradykinin potentiating factors (BPF). Other PGI(2)-releasers included statins (e.g., atorvastatin and simvastatin), thienopyridines (e.g., ticlopidine and clopidogrel), a number of thromboxane synthase inhibitors, flavonoids, bradykinin itself, cholinergic M receptor agonists and nicotinic acid derivatives. The thrombolytic actions of lipophilic ACE-Is (e.g., quinapril and perindopril) were prevented by pretreatment with either bradykinin B(2) receptor antagonists (e.g., icatibant) or with endothelial COX-2 inhibitors (e.g., rofecoxib, celecoxib and high dose aspirin). The inhibition of endothelial nitric oxide synthetase (eNOS) by L-NAME hardly blunted the thrombolytic response to ACE-Is. Hence, it can be concluded that many recognized cardiovascular drugs apart from their known basic mechanisms of action, may also behave as releasers of endogenous endothelial prostacyclin. Furthermore, in many instances, this effect may be the primary mechanism of their therapeutic efficacy.
PMID: 20631409 [PubMed - indexed for MEDLINE]
Activation of AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside in the muscle microcirculation increases nitric oxide synthesis and microvascular perfusion.
Arterioscler Thromb Vasc Biol. 2010 Jun;30(6):1137-42
Authors: Bradley EA, Eringa EC, Stehouwer CD, Korstjens I, van Nieuw Amerongen GP, Musters R, Sipkema P, Clark MG, Rattigan S
OBJECTIVE: To investigate the effects of activation of the AMP-activated protein kinase (AMPK) on muscle perfusion and to elucidate the mechanisms involved.
METHODS AND RESULTS: In a combined approach, we studied the vasoactive actions of AMPK activator by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) on rat cremaster muscle resistance arteries ( approximately 100 mum) ex vivo and on microvascular perfusion in the rat hindlimb in vivo. In isolated resistance arteries, AICAR increased Thr172 phosphorylation of AMPK in arteriolar endothelium, which was predominantly located in microvascular endothelium. AICAR induced vasodilation (19+/-4% at 2 mmol/L, P<0.01), which was abolished by endothelium removal, inhibition of NO synthase (with N-nitro-L-arginine), or AMPK (with compound C). Smooth muscle sensitivity to NO, determined by studying the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP), was not affected by AICAR except at the highest dose. AICAR increased endothelial nitric oxide synthase activity, as indicated by Ser1177 phosphorylation. In vivo, infusion of AICAR markedly increased muscle microvascular blood volume (approximately 60%, P<0.05), as was evidenced by contrast-enhanced ultrasound, without effects on blood pressure, femoral blood flow, or hind leg glucose uptake.
CONCLUSIONS: Activation of AMPK by AICAR activates endothelial nitric oxide synthase in arteriolar endothelium by increasing its Ser1177 phosphorylation, which leads to vasodilation of resistance arteries and recruitment of microvascular perfusion in muscle.
PMID: 20224051 [PubMed - indexed for MEDLINE]
Hepatoprotective effects of the nitric oxide donor isosorbide-5-mononitrate alone and in combination with the natural hepatoprotectant, silymarin, on carbon tetrachloride-induced hepatic injury in rats.
Inflammopharmacology. 2010 Apr;18(2):87-94
Authors: Abdel Salam OM, Sleem AA, Shafee N
The aim of this study was to investigate the effect of the nitric oxide donor isosorbide-5-mononitrate (5-ISMN) alone or in combination with the natural hepatoprotectant with anti-oxidant activity silymarin on the carbon tetrachloride (CCl(4))-induced hepatic injury in rats. 5-ISMN (1.8, 3.6 or 7.2 mg/kg), silymarin (25 mg/kg) or 5-ISMN (1.8, 3.6 or 7.2 mg/kg) combined with silymarin was given once daily orally simultaneously with CCl(4) and for 15 days thereafter. Liver damage was assessed by determining serum enzyme activities and hepatic histopathology. 5-ISMN given at the above doses conferred significant protection against the hepatotoxic actions of CCl(4) in rats, reducing serum alanine aminotransferase (ALT) levels by 31.2, 39.3 and 61.6%, respectively, when compared with controls. Serum aspartate aminotransferase (AST) levels decreased by 19.8, 22.7 and 59.4%, respectively, while alkaline phosphatase (ALP) decreased by 26.1 and 32.6% by the drug at 3.6 and 7.2 mg/kg, respectively. When silymarin was added to 5-ISMN (1.8, 3.6 or 7.2 mg/kg), ALT decreased by 32.8, 59.6, 70.2% and AST by 28.7, 50.3, 60%, when compared with CCl(4) control group levels. Silymarin in combination with 3.6 or 7.2 mg/kg 5-ISMN resulted in 37.5 and 39.2% reductions in ALP when compared with CCl(4) control group. Meanwhile, silymarin alone reduced ALT, AST and ALP levels by 65.9, 52 and 62.3%, respectively. Blood levels of reduced glutathione were markedly decreased in CCl(4)-treated rats. Reduced glutathione levels were increased by the administration of 5-ISMN and restored to near normal values by silymarin treatment. Histopathological alterations by CCl(4) were markedly reduced after treatment with 5-ISMN alone or in combination with silymarin. Histopathologic examination of the livers of CCl(4)-treated rats administered 5-ISMN at 7.2 mg/kg showed marked restoration of the normal architecture of the liver tissue and minimal fibrosis. Silymarin co-administered with 5-ISMN resulted in further improvement of the histologic picture. These results indicates that treatment with 5-ISMN protects against hepatocellular necrosis induced by CCl(4). The study suggests a potential therapeutic use for 5-ISMN in combination with silymarin in liver injury.
PMID: 20069380 [PubMed - indexed for MEDLINE]
Enhancement of the anti-inflammatory and anti-arthritic effects of theophylline by a low dose of a nitric oxide donor or non-specific nitric oxide synthase inhibitor.
Br J Pharmacol. 2009 Dec;158(7):1835-47
Authors: Gomaa A, Elshenawy M, Afifi N, Mohammed E, Thabit R
BACKGROUND AND PURPOSE: Although there are many new specific phosphodiesterase inhibitors with anti-inflammatory activity, none have yet reached the market because of their low therapeutic efficacy. Our study was aimed to evaluate the anti-inflammatory and anti-arthritic effect of an established phosphodiesterase inhibitor, theophylline, and to investigate the effect of the nitric oxide (NO) donor, sodium nitroprusside (SNP) or NO synthase inhibitor, L-N(G)-monomethyl arginine (L-NMMA) on its actions.
EXPERIMENTAL APPROACH: The effects of theophylline alone and combined with SNP or L-NMMA on the pathogenesis of adjuvant-induced arthritis in rats were evaluated.
KEY RESULTS: Prophylactic or therapeutic doses of theophylline significantly ameliorated the pathogenesis of adjuvant arthritis in rats as evidenced by a significant decrease in the arthritis index, hind paws volume, ankle joint diameter, fever, body weight loss and hyperalgesia in a dose-dependent manner. Inflammatory cellular infiltrate in synovium of ankle joint and pannus formation were also markedly inhibited. Interleukin-10 (IL-10) levels were significantly increased in arthritic rats given theophylline alone or in combination with either SNP or L-NMMA. Co-administration of a low dose of SNP or L-NMMA enhanced significantly the anti-inflammatory and anti-arthritic effect of theophylline. In contrast, a high dose of SNP counteracted the anti-inflammatory and anti-arthritic effects of theophylline.
CONCLUSIONS AND IMPLICATION: These findings confirm the anti-inflammatory and anti-arthritic activities of theophylline and suggest a new approach to enhance the anti-inflammatory and anti-arthritic effects of theophylline would be to administer it in combination with a low dose of a NO donor or a non-specific NO synthase inhibitor.
PMID: 19888960 [PubMed - indexed for MEDLINE]
Exploiting cGMP-based therapies for the prevention of left ventricular hypertrophy: NO* and beyond.
Pharmacol Ther. 2009 Dec;124(3):279-300
Authors: Ritchie RH, Irvine JC, Rosenkranz AC, Patel R, Wendt IR, Horowitz JD, Kemp-Harper BK
Left ventricular hypertrophy (LVH), an increased left ventricular (LV) mass, is common to many cardiovascular disorders, initially developing as an adaptive response to maintain myocardial function. In the longer term, this LV remodelling becomes maladaptive, with progressive decline in LV contractility and diastolic function. Indeed LVH is recognised as an important blood-pressure independent predictor of cardiovascular morbidity and mortality. The clinical efficacy of current treatments for LVH is reduced, however, by their tendency to slow disease progression rather than induce its reversal, and thus the development of new therapies for LVH is paramount. The signalling molecule cyclic guanosine-3',5'-monophosphate (cGMP), well-recognised for its role in regulating vascular tone, is now being increasingly identified as an important anti-hypertrophic mediator. This review is focused on the various means by which cGMP can be stimulated in the heart, such as via the natriuretic peptides, to exert anti-hypertrophic actions. In particular we address the limitations of traditional nitric oxide (NO*) donors in the face of the potential therapeutic advantages offered by novel alternatives; NO* siblings, ligands of the cGMP-generating enzymes, soluble (sGC) and particulate guanylyl cyclases (pGC), and phosphodiesterase inhibitors. Further impact of cGMP within the cardiovascular system is also discussed with a view to representing cGMP-based therapies as innovative pharmacotherapy, alone or concurrent with standard care, for the management of LVH.
PMID: 19723539 [PubMed - indexed for MEDLINE]
[Internal quality control of the blood products in the Lomé National Blood Transfusion Centre].
Tunis Med. 2008 Jul;86(7):698-703
Authors: Fétéké L, Mawussi K, Lakté P, Kuéviakoe IM, Haudrechy D, Ségbéna AY
AIM: Evaluate the conformity of blood red cells units prepared in the Lomé CNTS with European norms concerning volume, haemoglobin content and haematocrite. Measure the conservation of the haemostatic properties and the rate of haemostasis factors V and VIII in the fresh frozen plasma. Measure the rate of residual cells in the plasma.
METHODS: In the year 2006, from March 1st to April 15th, we analysed the quality of 135 units of whole blood, red blood cells (RBC) and plasma from blood donors in the Lomé National Blood Transfusion Centre. The quality control had concerned: the volume of whole blood units; the volume, the haemoglobin content and the haematocrite of red blood cells units; the volume, the prothrombin rate, the cephalin with activator time (TCA), the rate of haemostasis factors V and VIII and the number of residual cells (red cells, leucocytes and platelets) in the plasma.
RESULTS: Among the 135 units of whole blood which were controlled, 50.57% were in conformity with the norms concerning the volume. The red blood cells units were in conformity with norms concerning their volume, their haemoglobin content and their haematocrite respectively in 21.48%, 80.75% and 20% of the cases. The volume of 75.56% of the plasma units controlled were conform with the norm. All of the plasma units were conform with the norm concerning the number of residual platelets while the number of residual red blood cells and leucocytes were conform respectively in 80.74% and 60%. The percentage of conformity concerning the prothrombin rate, the TCA, the coagulation factor V and the factor VIII were respectively 66.67; 97.78; 48.89 and 47.4 before freezing, and 54.81; 88.14; 64.44; 84.44 a month after freezing.
CONCLUSION: To improve the quality of the new blood products of the Lomé CNTS, some correctives actions must be applied concerning the adequate volume of blood which must be collected from the donors, the position of the blood bags in during the centrifugation and the volume of plasma which must be take out of the bag of red cells.
PMID: 19472735 [PubMed - indexed for MEDLINE]
[What plans need to be carried out to increase the plasma collection by the EFS?].
Transfus Clin Biol. 2009 May;16(2):233-6
Authors: Schneider T
The need of plasma derivatives increases in France. The Etablissement français du sang (EFS) carries out plans for supplying plasma to the Laboratoire français du fractionnement et des biotechnologies (LFB). Different kinds of actions are taken or will be taken according to the way of plasma processing. For plasma issued from whole blood, the increase is correlated with the increase of whole blood collection for the patients' need of red cells concentrates and the optimized plasma volume of plasma concentrate. For plasma issued from combined aphaeresis and the production of pooled platelets concentrates, synthetic media is favoured. Plasma aphaeresis is a specific way to satisfy requirements of the LFB. Communication choice of the blood collection's place, effects of the new law on blood donors selection, the process of aphaeresis collection, blood tests qualification are subjects of study and actions.
PMID: 19442553 [PubMed - indexed for MEDLINE]
Naproxcinod, a new cyclooxygenase-inhibiting nitric oxide donator (CINOD).
Expert Opin Biol Ther. 2009 May;9(5):649-57
Authors: Geusens P
BACKGROUND: COX-inhibiting nitric oxide donators (CINODs) are a new class of drugs that combine the actions of the parent COX inhibitor with nitric oxide (NO), with the aim of reducing potential toxicity of the parent drug, while maintaining its analgesic and anti-inflammatory effects. AZD3582 (Naproxcinod) is the first in the class of CINODs.
OBJECTIVE/METHODS: To review the effects of NO donation, CINODS in general and naproxen in osteoarthritis (OA), based on literature in PubMed.
RESULTS: In preclinical and human studies, this drug produced similar analgesic and anti-inflammatory effects to its parent naproxen, with improved gastrointestinal safety in OA patients. The results of recent clinical trials, which were designed to study effects on blood pressure, are expected shortly, after peer-review.
CONCLUSIONS: As naproxen is considered the safest COX inhibitor choice from a cardiovascular perspective, AZD3582 has the potential to become a new drug treatment in patients with OA, in whom pain and function are not controlled by the use of analgesics.
PMID: 19392579 [PubMed - indexed for MEDLINE]
[Estimating the microcosts of blood transfusion for hemato-oncological patients].
Acta Med Port. 2008 Nov-Dec;21(6):575-80
Authors: Brilhante D, Macedo A, Santos A
INTRODUCTION: There are several ways of treating and preventing chemotherapy-associated anaemia, namely with erythropoiesis stimulating agents and blood transfusion, that remains an option. Since erythropoiesis stimulating agents have a high unitary cost, it is crucial to evaluate their cost-effectiveness, namely versus transfusion. The objective of this study is to calculate the cost of a blood transfusion, carried out at the Immunohemotherapy Outward of Instituto Português de Oncologia, Francisco Gentil, in Lisbon as treatment for neoplasia-associated anaemia.
METHODOLOGY: Cross sectional, observational study from the perspective of the Hospital and the National Health Service, which evaluates the resources and direct costs, associated with a blood transfusion of two erythrocyte concentrate (EC) units in hemato-oncology patients. Data regarding consumables, human resources, laboratory analysis and occupation of facilities was collected for a period of seven consecutive days, regarding both blood donation and transfusion procedures in the Immunohemotherapy Outward of Instituto Português de Oncologia, Francisco Gentil, in Lisbon.
RESULTS: The total cost of a two EC unit transfusion was estimated at euro 676.2, with the greatest part of this cost being attributed to blood preparation, analysis and storage.
CONCLUSION: Determining reliable costs in relation to medical actions and procedures is essential in analysing the cost-effectiveness of new drugs. This study evaluated the cost for the transfusion of two EC units and the results presented are similar to those obtained in other European countries by several authors.
PMID: 19331791 [PubMed - indexed for MEDLINE]
Impact of anti-inflammatory agents on the gene expression profile of stimulated human neutrophils: unraveling endogenous resolution pathways.
PLoS One. 2009;4(3):e4902
Authors: St-Onge M, Dumas A, Michaud A, Laflamme C, Dussault AA, Pouliot M
Adenosine, prostaglandin E(2), or increased intracellular cyclic AMP concentration each elicit potent anti-inflammatory events in human neutrophils by inhibiting functions such as phagocytosis, superoxide production, adhesion and cytokine release. However, the endogenous molecular pathways mediating these actions are poorly understood. In the present study, we examined their impact on the gene expression profile of stimulated neutrophils. Purified blood neutrophils from healthy donors were stimulated with a cocktail of inflammatory agonists in the presence of at least one of the following anti-inflammatory agents: adenosine A(2A) receptor agonist CGS 21680, prostaglandin E(2), cyclic-AMP-elevating compounds forskolin and RO 20-1724. Total RNA was analyzed using gene chips and real-time PCR. Genes encoding transcription factors, enzymes and regulatory proteins, as well as secreted cytokines/chemokines showed differential expression. We identified 15 genes for which the anti-inflammatory agents altered mRNA levels. The agents affected the expression profile in remarkably similar fashion, suggesting a central mechanism limiting cell activation. We have identified a set of genes that may be part of important resolution pathways that interfere with cell activation. Identification of these pathways will improve understanding of the capacity of tissues to terminate inflammatory responses and contribute to the development of therapeutic strategies based on endogenous resolution.
PMID: 19295914 [PubMed - indexed for MEDLINE]
Correlation of in vitro and in vivo kinetics of nitric oxide donors in ocular tissues.
J Ocul Pharmacol Ther. 2009 Apr;25(2):105-12
Authors: Carreiro S, Anderson S, Gukasyan HJ, Krauss A, Prasanna G
In the eye, nitric oxide (NO) is involved in the regulation of intraocular pressure (IOP) and ocular blood flow. The main purpose of this study was to measure the kinetics of NO release from NO donors in ocular cells and tissues using in vivo and in vitro models and demonstrate the link between the kinetics of NO release with the functional effect, IOP. Nitric oxide release was measured in human ocular cells using a fluorescent dye, diaminofluorescein (DAF), following treatment with short-acting sodium nitroprusside (SNP) and longer-acting S-nitroso-N-acetylpenicillamine (SNAP) NO donors. Both SNP and SNAP were also administered topically to rabbits; IOP was measured and levels of NO and cGMP were assessed as biomarkers over a time course in the aqueous humor (AH) and iris/ciliary body (ICB). Time- and concentration-dependent increases in NO level were produced by SNP and SNAP in human ocular cells. Both NO and cGMP levels appeared to be elevated following treatment with the aforementioned NO donors in rabbit ocular tissues. Transient IOP lowering was accompanied with these biochemical estimations in rabbits, with time of maximal effect being shifted to the right for longer-acting SNAP as compared with short-acting SNP. In vitro and in vivo NO/cGMP assay results displayed a correlation between short- and longer-acting NO donors, discriminating their respective temporal actions in the eye. Due to their translatability, the in vitro DAF assay and in vivo NO fluorometric assay can therefore be potentially useful in screening novel NO donors with different temporal/kinetic profiles.
PMID: 19284325 [PubMed - indexed for MEDLINE]
Nitric oxide-releasing agent, LA419, reduces atherogenesis in apolipoprotein E-deficient mice.
Naunyn Schmiedebergs Arch Pharmacol. 2009 May;379(5):489-500
Authors: Carnicer R, Guillén N, Arbonés-Mainar JM, Navarro MA, Guzmán MA, Barranquero C, Arnal C, Gascón S, Acín S, Mourelle M, Osada J
LA419 is a novel nitric oxide-donor with antioxidant properties. The effect of this compound on the development of atherosclerosis was investigated in apolipoprotein E-deficient mice. Male mice were randomized to receive vehicle or 5 mg/kg/day LA419 for 12 weeks. At the end of this period, plasma lipid and lipoprotein parameters, oxidative stress markers and hepatic fat, and mRNA levels were measured as well as en face and cross-sectional lesion areas of the aorta. Data showed that LA419 administration reduced atherosclerotic foci and cross-sectional lesion areas by decreasing the intimae presence of macrophage-derived foam cells despite an increase in plasma cholesterol. This agent induced a significant reduction in body weight gain and mass of adipose tissue. Furthermore, compared with placebo, LA419 administration significantly reduced plasma triglycerides and apolipoprotein C-III levels as well as systemic oxidative stress, estimated by plasma 8-isoprostane. Conversely, nonesterified fatty acid and HDL cholesterol levels remained unchanged, as well as apolipoproteins A-I, A-IV, and B and paraoxonase activity. Plasma triglycerides were significantly associated with plasma levels of apolipoprotein C-III and hepatic Fsp27 mRNA expression. These results indicate that administration of LA419 modulates lesion development. These actions are partly independent of total cholesterol as well as HDL particles and related to triglyceridemia and oxidative stress. Hypotriglyceridemia is associated with an equal number of apoB-containing particles. Hence, LA419 administration could be used as a safe alternative to control the metabolic syndrome and atherosclerosis.
PMID: 19050853 [PubMed - indexed for MEDLINE]
Nitric oxide and cardiovascular effects: new insights in the role of nitric oxide for the management of osteoarthritis.
Arthritis Res Ther. 2008;10 Suppl 2:S3
Authors: Mackenzie IS, Rutherford D, MacDonald TM
Nitric oxide (NO) is an important mediator in both health and disease. In addition to its effects on vascular tone and platelet function, it plays roles in inflammation and pain perception that may be of relevance in osteoarthritis. Many patients with osteoarthritis take nonsteroidal anti-inflammatory drugs (NSAIDs) long term for pain control. Over recent years concern has been raised about the possible cardiovascular side effects of NSAIDs. The reasons for this possible increased cardiovascular risk with NSAIDs are not yet entirely clear, although changes in blood pressure, renal salt handling and platelet function may contribute. Recently, drugs that chemically link a NSAID with a NO donating moiety (cyclo-oxygenase-inhibiting NO-donating drugs [CINODs]) were developed. NO is an important mediator of endothelial function, acting as a vasodilator and an inhibitor of platelet aggregation, and having anti-inflammatory properties. The potential benefits of CINODs include the combination of effective analgesic and anti-inflammatory actions with NO release, which might counterbalance any adverse cardiovascular effects of NSAIDs. Effects of CINODs in animal studies include inhibition of vasopressor responses, blood pressure reduction in hypertensive rats and inhibition of platelet aggregation. CINODs may also reduce ischemic damage to compromised myocardial tissue. In addition, endothelial dysfunction is a recognized feature of inflammatory arthritides, and therefore a drug that might provide slow release of NO to the vasculature while treating pain is an attractive prospect in these conditions. Further studies of the effects of CINODs in humans are required, but these agents represent a potential exciting advance in the management of osteoarthritis.
PMID: 19007428 [PubMed - indexed for MEDLINE]
Response of adiponectin and its receptors to changes in metabolic state after gastric bypass surgery: dissociation between adipose tissue expression and circulating levels.
Surg Obes Relat Dis. 2009 Mar-Apr;5(2):172-80
Authors: Savu MK, Phillips SA, Oh DK, Park K, Gerlan C, Ciaraldi TP, Henry RR
BACKGROUND: Adiponectin is an adipokine with anti-atherogenic and insulin-sensitizing properties. Specific adiponectin receptors, adiponectin receptors 1 (AdipoR1) and 2 (AdipoR2), are present in adipose tissue, indicating adiponectin might have autocrine/paracrine effects on its production or action. In addition, endoplasmic reticulum oxidoreductase 1-Lalpha might mediate regulation of its secretion. The study aim was to determine the subcutaneous adipose tissue (SAT) adiponectin gene and protein expression and their correlation to metabolic parameters during metabolically distinct times after gastric bypass surgery.
METHODS: A total of 12 morbidly obese male patients underwent SAT biopsy during gastric bypass surgery, active weight loss (negative energy state), and at weight stabilization (steady state energy). The SAT mRNA and protein content of adiponectin, AdipoR1 and AdipoR2, and endoplasmic reticulum oxidoreductase 1-Lalpha protein levels and the serum levels of adiponectin were assessed.
RESULTS: SAT adiponectin, AdipoR1, and AdipoR2 gene expression increased significantly at the negative energy state, with no further change at steady state energy (P<.05, P<.05, and P=.04, respectively), without significant increases in protein at any stage. Changes in SAT adiponectin protein correlated with changes in AdipoR1 and AdipoR2 during steady state energy (P=.003 and P=.002, respectively). Changes in SAT adiponectin expression did not correlate with those in circulating levels. Changes in endoplasmic reticulum oxidoreductase 1-Lalpha did not correlate with either SAT or circulating levels of adiponectin.
CONCLUSION: Our data indicate distinct functions of adiponectin receptors, AdipoR1 and AdipoR2, mediate the autocrine/paracrine actions of adiponectin. The lack of correlation between changes in SAT adiponectin gene and protein expression and its circulating levels suggests that adipose tissue synthesis and release of adiponectin are highly regulated pathways.
PMID: 18996753 [PubMed - indexed for MEDLINE]
Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis.
Neurology. 2008 Oct 21;71(17):1350-4
Authors: Krumbholz M, Meinl I, Kümpfel T, Hohlfeld R, Meinl E
BACKGROUND: Natalizumab, a humanized anti-alpha4 integrin monoclonal antibody, reduces relapses and disease progression in patients with multiple sclerosis (MS). Whereas its presumed mode of action is inhibition of T cell/monocyte entry into the brain, little is known about its specific effect on B cells, which are increasingly recognized to participate in MS pathogenesis.
METHODS: We obtained serial blood samples from 17 patients before and during natalizumab therapy for relapsing-remitting MS for up to 16 months, and blood samples from 10 untreated patients with MS and 13 healthy donors. We determined numbers of mature and immature lymphocyte subsets by flow cytometry for CD3, CD4, CD8, CD19, CD138, and CD10 in 111 samples. We analyzed marker transcripts for immature hematopoietic cells by quantitative PCR for CD34, Vprebeta1 (pre-B lymphocyte gene 1), and DNTT (terminal deoxynucleotidyltransferase) in 65 samples.
RESULTS: Natalizumab therapy increased CD19(+) mature B cells more than other lymphocytes/monocytes in blood (2.8-fold versus 1.3-1.8-fold increase in cells/microL; p < 0.01). Even greater was the increase of immature CD19(+)CD10(+) pre-B cells (7.4-fold; p < 0.01). This pattern remained stable during treatment for up to 16 months. Transcripts of lymphocyte precursors (Vprebeta1 and DNTT) were elevated more than transcripts for CD34.
CONCLUSIONS: Circulating B cells and especially pre-B cells are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.
PMID: 18936427 [PubMed - indexed for MEDLINE]
Compartmentation and compartment-specific regulation of PDE5 by protein kinase G allows selective cGMP-mediated regulation of platelet functions.
Proc Natl Acad Sci U S A. 2008 Sep 09;105(36):13650-5
Authors: Wilson LS, Elbatarny HS, Crawley SW, Bennett BM, Maurice DH
It is generally accepted that nitric oxide (NO) donors, such as sodium nitroprusside (SNP), or phosphodiesterase 5 (PDE5) inhibitors, including sildenafil, each impact human platelet function. Although a strong correlation exists between the actions of NO donors in platelets and their impact on cGMP, agents such as sildenafil act without increasing global intra-platelet cGMP levels. This study was undertaken to identify how PDE5 inhibitors might act without increasing cGMP. Our data identify PDE5 as an integral component of a protein kinase G1beta (PKG1beta)-containing signaling complex, reported previously to coordinate cGMP-mediated inhibition of inositol-1, 4, 5-trisphosphate receptor type 1 (IP(3)R1)-mediated Ca(2+)-release. PKG1beta and PDE5 did not interact in subcellular fractions devoid of IP(3)R1 and were not recruited to IP(3)R1-enriched membranes in response to cGMP-elevating agents. Activation of platelet PKG promoted phosphorylation and activation of the PDE5 fraction tethered to the IP(3)R1-PKG complex, an effect not observed for the nontethered PDE5. Based on these findings, we elaborate a model in which PKG selectively activates PDE5 within a defined microdomain in platelets and propose that this mechanism allows spatial and temporal regulation of cGMP signaling in these cells. Recent reports indicate that sildenafil might prove useful in limiting in-stent thrombosis and the thrombotic events associated with the acute coronary syndromes (ACS), situations poorly regulated with currently available therapeutics. We submit that our findings may define a molecular mechanism by which PDE5 inhibition can differentially impact selected cellular functions of platelets, and perhaps of other cell types.
PMID: 18757735 [PubMed - indexed for MEDLINE]
[Changes in amino acid patterns of blood plasma in tumor patients treated with anticancer drug NSC-631570: possible approaches to cancer diagnostics].
Biomed Khim. 2008 May-Jun;54(3):289-300
Authors: Glazev AA, Nefedov LI
In our early experimental (with W-256, SM-1 and PC-1 tumors) and clinical (breast, bladder and prostate cancers) studies the use of the anticancer drug NSC-631570 was proven to be safe and highly effective, inhibiting protein synthesis in cancer cells, selectively accumulating in cancer tissue after a single intravenous administration and controlling cancer-induced metabolic imbalance. This drug inhibits metabolic processes in the tumor and causes metabolic disorders in cancer cells. Moreover, NSC-631570 induced the changes in certain amino acids concentrations in biological fluids and tumor tissue in animal models and cancer patients. These changes cannot be explained by metabolic amino acid disorders in cancer known so far. In this study the effects of NSC-631570 on blood plasma amino acids has been investigated. Blood was sampled from 10 healthy donors and 29 patients with different types of cancer (stomach, rectal, lung, breast, bladder, prostate, and leukemia). Comparison of NSC-531570 effects in plasma of healthy donors and cancer patients has shown, that this compoumd: 1) affects amino acids with positively charged (His, Arg) or not charged (Tyr, Thr, Gln) R-groups; 2) decreases concentration of His and increase the concentrations of beta-Ala and Tau. These changes depend on the concentration of NSC-631570 and the type of cancer. On the basis of the literature data and the results of our studies we suggest that Ukrain's biological actions in cancer are realized at least partly through selective interaction with amino acids, their derivatives, and plasma proteins. These data provide the background for the using Ukrain in the cancer detection and investigating the mechanisms of carcinogenesis.
PMID: 18712085 [PubMed - indexed for MEDLINE]
Oxidative process in erythrocytes of individuals with hemoglobin S.
Hematology. 2008 Jun;13(3):187-92
Authors: Chaves MA, Leonart MS, do Nascimento AJ
The understanding of the oxidative stress mechanisms helps to explain many of the processes of cellular lesion and death, especially those related to the hemolytic diseases. Sickle cell anemia, thalassemias and G6-PD deficiency are among the more frequent genetic anomalies accompanied by oxidative stress. In the sickle cells, one of the factors that predisposes to the hemolytic process is the oxidative degradation of the hemoglobin S due to its deoxigenation leading to hemichrome formation and precipitation as Heinz bodies. The oxidative stress contributes to the sickle process and shortening of the erythrocyte survival. Here we analyzed the oxidative process in erythrocytes of patients with two different genotypes for HbS (AS and SS). Units of blood from donors of the Center of Hematology and Hemotherapy of Paraná (HEMEPAR), from normal individuals (AA) and from heterozygote individuals (AS), and venous blood collected from patients with sickle cell anemia (SS) were analyzed. In order to evaluate the protective action of the vitamins C and E in oxidative stress, erythrocytes were treated with antioxidant substances, vitamin C and vitamin E, and then treated with the oxidant tert-butilhydroperoxide (TBHP). The oxidative action induced by TBHP was observed in erythrocytes AA<AS<SS, by the increase in the content of Heinz bodies, methemoglobin, hemolysis, GSH depletion and lowering activities of the enzymes G6-PD and GR. The protective actions of the vitamins C and E for the oxidative stress induced by TBHP were observed for the erythrocytes in the lowering Heinz bodies, methemoglobin, hemolysis, and partial recovery of GSH more efficiently in AS and SS erythrocytes. Recovery was not observed in the levels of the activities of the enzymes G6-PD and GR, under the vitamins actions. The results obtained confirmed the higher susceptibility of the sickle erythrocyte to oxidation which necessitates precaution in the transfusion adequacy of AS erythrocytes. On the other hand, the protective effect of the vitamins C and E over the oxidative stress observed in erythrocytes AS and SS open perspectives for their use for treatment of patients with sickle cell anemias, as well as in the preservation of transfusional erythrocyte bag units.
PMID: 18702879 [PubMed - indexed for MEDLINE]
Effects of taurine on aortic rings isolated from fructose-fed insulin resistance Sprague-Dawley rat are changed.
Cardiovasc Drugs Ther. 2008 Dec;22(6):461-8
Authors: Xue W, Zhang M, Li J, Wu D, Niu L, Liang Y
PURPOSE: To observe and compare the effect of taurine on contractions of aortic rings isolated from normal (NC) and insulin resistance (IR) Sprague-Dawley rats, and to explore its underlying mechanism(s).
METHODS: The IR animal model was made by feeding rats with high fructose diet for 8 weeks. Aortic rings were isolated and suspended in a tissue bath, and tensions were recorded isometrically. The effects of taurine on provoked contractions of the rings were assessed in absence or presence of different potassium channel or NO-synthase inhibitors.
RESULTS: Taurine (20-80 mM) concentration-dependently relaxed precontractions induced by KCl (30 mM) and phenylephrine (1 microM) in NC rings, but enhanced the precontractions in IR rings. Denudation of the endothelium and pretreatment with N(G)-nitro-L-arginine methylester ester (0.1 mM) reversed the contraction enhancement of taurine to relaxation in IR rings. Tetraethylammonium (10 mM) nearly abolished taurine-induced relaxation of NC rings, and augmented taurine-induced contraction enhancement in IR rings. Iberiotoxin (100 nM) only augmented the contraction enhancement in IR rings. 4-Aminopyridine (1 mM), glibenclamide (10 microM) and indomethacin (10 muM) had no influence on the effect of taurine in both NC and IR rings.
CONCLUSION: Taurine enhances contractions in IR aortic rings but relaxes the contractions in normal rat aortic ring; the enhancement is endothelium-dependent and the relaxation is endothelium-independent. TEA-sensitive K(+) channel may be involved in these actions; BK(Ca) channel dysfunction and endothelium-derived substances may be related to the contraction enhancement induced by taurine in IR aorta.
PMID: 18612804 [PubMed - indexed for MEDLINE]
Anti-inflammatory actions of intravenous immunoglobulin.
Annu Rev Immunol. 2008;26:513-33
Authors: Nimmerjahn F, Ravetch JV
The remarkable success story of the therapeutic application of pooled immunoglobulin G (IgG) preparations from thousands of donors, the so-called intravenous IgG (IVIG) therapy, to patients with a variety of hematological and immunological disorders began more than half a century ago. Since then, the use of this primary blood product has increased constantly, resulting in the serious danger of shortages in supply. Despite its widespread use and therapeutic success, the mechanisms of action, especially of the anti-inflammatory activity, are only beginning to be understood. In this review, we summarize the clinical use of IVIG for different diseases and discuss recent data on the molecular mechanisms that might explain how this potent drug mediates its activity in vivo.
PMID: 18370923 [PubMed - indexed for MEDLINE]
Southern Cone Initiative for the elimination of domestic populations of Triatoma infestans and the interruption of transfusional Chagas disease. Historical aspects, present situation, and perspectives.
Mem Inst Oswaldo Cruz. 2007 Oct 30;102 Suppl 1:11-8
Authors: Dias JC
Created in 1991 by the governments of Argentina, Bolivia, Brazil, Chile, Paraguay, and Uruguay, the Southern Cone Initiative (SCI) has been extremely important for Chagas disease control in this region. Its basic objective was to reach the interruption of this disease, chiefly by means of the elimination of the principal vector Triatoma infestans and by the selection of safe donors in the regional blood banks. After a summarized historic of SCI, the text shows the advance of technical and operative activities, emphasizing some factors for the initiative success, as well as some difficulties and constraints. The future of SCI will depend of the continuity of the actions and of political priority. Scientific community has been highly responsible for this initiative and its maintenance. At the side of this, national and international efforts must be involved and reinforced to assure the accomplishment of the final targets of SCI. Very specially, the Pan American Health Organization has cooperated with the Initiative in all its moments and activities,being the most important catalytic and technical factor for SCI success.
PMID: 17891281 [PubMed - indexed for MEDLINE]
Reciprocal actions of platelet-secreted TGF-beta1 on the production of VEGF and HGF by human tendon cells.
Plast Reconstr Surg. 2007 Mar;119(3):950-9
Authors: Anitua E, Sanchez M, Nurden AT, Zalduendo M, de la Fuente M, Azofra J, Andia I
BACKGROUND: Autologous platelet-rich matrices can be an aid in surgery by promoting and accelerating tissue healing because of the release of growth factors including transforming growth factor (TGF)-beta1 and platelet-derived growth factor (PDGF) from platelet alpha-granules.
METHODS: PDGF and TGF-beta1 were quantified in supernatants collected from platelet-rich matrices prepared in vitro (n = 45 donors) and they correlated with the number of platelets and showed a constant ratio (p < 0.05). Tendon cells in culture were exposed to the supernatants (n = 4 donors) from either platelet-rich or platelet-poor matrices, differing in their content of platelet-secreted molecules. These treatments were modified by either neutralizing or adding PDGF or TGF-beta1. Effects were compared in terms of proliferation, procollagen I, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) production.
RESULTS: PDGF was a partial contributor to cell proliferation, whereas exogenous TGF-beta1 acted as a negative modulator (p < 0.05). The production of type I collagen was similar regardless of differences in the concentration of TGF-beta1. Moreover, addition of exogenous TGF-beta1 promoted a significant increase in collagen synthesis only in the absence of other platelet-released substances (p < 0.05). Exogenous TGF-beta1 increased the synthesis of VEGF and simultaneously abolished the production of HGF. Furthermore, antibody-mediated neutralization of TGF-beta1 induced a decrease in VEGF synthesis and concomitantly a substantial production of HGF (p < 0.05).
CONCLUSION: The balance between TGF-beta1 and the pools of platelet-secreted molecules may have important therapeutic implications in the control of angiogenesis and fibrosis.
PMID: 17312501 [PubMed - indexed for MEDLINE]
[Autologous blood pre-donation and perioperative use of erythropoietin].
Rev Med Suisse. 2006 Nov 22;2(88):2662-4, 2666-7
Authors: Michaeli B, Ravussin P, Chassot PG
The general concept of blood saving covers a number of technical and pharmacological actions which all aim to maintain the erythrocyte mass of the patient, and of which blood transfusion is only one. Severe anemia (Hb <60-80 g/l) increases postoperative mortality and morbidity. However, its correction by blood transfusion tends to worsen the prognosis. It is therefore imperative to conserve the patient's blood by any means possible. Detecting anemia is of primary importance. Whenever possible, its cause should be identified and treated. Depending on the detected anemia, as well as the blood loss expected during surgery, the patient should receive EPO (anemia with foreseeable moderate blood loss), or autologous pre-donation associated with EPO (anemia with foreseeable large blood loss).
PMID: 17265804 [PubMed - indexed for MEDLINE]
Aspects of nitric oxide in health and disease: a focus on hypertension and cardiovascular disease.
J Clin Hypertens (Greenwich). 2006 Dec;8(12 Suppl 4):2-16
Authors: Giles TD
Nitric oxide (nitrogen monoxide) (NO) plays an important role in a wide range of physiologic processes. A major mediator of endothelial function, NO regulates vasodilatory and antithrombotic actions in the vasculature and plays a role in reproductive functions, bronchodilation, bone formation, memory, insulin sensitivity, and gastrointestinal relaxation. NO is formed from NO synthase. Impaired NO bioactivity is strongly associated with endothelial dysfunction and cardiovascular disease, but is also implicated in a broad range of other disorders, including pulmonary hypertension, insulin resistance, erectile dysfunction, and preeclampsia. Numerous therapies designed to target NO are being investigated and developed, including NO donors and stimulants. The recent African-American Heart Failure Trial (A-HeFT) showed that the NO donor isosorbide dinitrate, combined with the vasodilator hydralazine, significantly reduced morbidity and mortality in black patients with moderate-to-severe heart failure. Antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation beta-blockers, are NO stimulants that have demonstrated significant improvement of endothelial function and NO bioactivity. Other cardiovascular therapies that may improve NO bioactivity include statins, l-arginine, and nonpharmacologic approaches such as exercise and dietary changes.
PMID: 17170602 [PubMed - indexed for MEDLINE]
The many antithrombotic actions of nitric oxide.
Curr Drug Targets. 2006 Oct;7(10):1243-51
Authors: Tziros C, Freedman JE
Vessel occlusion within a coronary artery is the precipitating event in unstable coronary syndromes and is primarily due to rupture of atheromatous plaque and subsequent thrombus formation. In the nondiseased vessel, the intact endothelium releases the vasodilator and antithrombotic agent nitric oxide (NO) preventing platelet adherence and activation. In the diseased vessel and during unstable coronary syndromes, release of both endothelial and platelet NO is impaired contributing to thrombus formation. Nitric oxide availability in the vascular system has been associated with various disease states, genetic variants, and medication use. Recently, through the development of new NO donors and by targeting specific signaling pathways, there has been an attempt to enhance the antithrombotic actions of NO as a means to manipulate arterial thrombosis.
PMID: 17073585 [PubMed - indexed for MEDLINE]
[The experience of a blood-bank doctor in Chile].
Transfus Clin Biol. 2006 Sep;13(3):203-5
Authors: Martinez C
Director of a blood transfusion service in Concepción, Chili, Dr. Christina Martinez reports on her experience in this centre and the actions undertaken in order to find resources and supports, to guarantee the operation of the centre and to enhance voluntary blood donation.
PMID: 17010653 [PubMed - indexed for MEDLINE]
Estimation of the residual risk for the transmission of HIV in blood donors from the mountain region of Santa Catarina.
Braz J Infect Dis. 2005 Dec;9(6):489-93
Authors: Spada C, Souza MA, Treitinger A
The HIV, in hemotheraphy, may be transmitted by erythrocyte, platelets, crioprecipitated, frozen fresh plasma and possibly, by other blood components. Appropriate legislations for this new reality were elaborated normatizing the hemotheraphy practices in Brazil, creating a set of procedures and actions aiming at guaranteeing the quality of the blood, during the whole process. However, the residual risk remains, and it can be calculated as a product of the incidence and period of the immunological window. The objective [corrected] of the present study was to determine the rate of residual risk of the HIV blood transmission, in the blood donors from the Mountain Region of Santa Catarina. In order to calculate the residual risk of the HIV markers, 4,857 donors of repetition from the 24,969 individuals who donated blood from 2000 to 2003 were evaluated, and the results showed a serumconversion, in one case. The method used to calculate the residual risk followed the model of the immunological incidence window used by Schreiber (1996), in the USA. A estimate risk of 1:50,000 was verified. The case was considered as confirmed when one of the HIV, in the Hemocenter, is considered one of the HIV markers, in 1:50.000, which confirms the hypothesis that the new legislation related to the Blood National Politics, with the introduction of more sensible tests is decreasing the immunological window, diminishing the residual and, consequently, intensifying the transfusion security.
PMID: 16410943 [PubMed - indexed for MEDLINE]
Developing an administrative plan for transfusion medicine--a global perspective.
Transfusion. 2005 Oct;45(4 Suppl):224S-40S
Authors: Sullivan P
Throughout the world blood services aim to provide a life-saving service by ensuring an adequate supply of safe blood. However, across the world blood services are at very different levels of development. Consequently, the actions taken in one country or region would not be appropriate in another. This paper aims to identify how suitable solutions can be developed to match the different prevailing circumstances of an individual country or region. In trying to do this it is important to look at the whole of the supply chain within a blood service and identify the part where a change could make the biggest impact. Four key areas are identified that are integral to this. These are the donor, testing of blood, hemovigilance, and overall management arrangements. Whilst the first two have largely been addressed in highly developed countries, there is still much work that could be done in these areas in developing countries. In particular, a move to voluntary nonremunerated donors worldwide would significantly improve overall safety. Hemovigilance systems are identified as a powerful tool to influence policy development, yet these are largely under developed throughout the world. In order to make high impact and sustainable changes it is important that those in the blood industry across the world work together to improve education and training, to share experience of best practice, and to move to develop agreed standards in transfusion medicine. It is imperative that developed countries recognize the importance of working with developing countries if the safety of the global blood supply is to be maintained and improved.
PMID: 16181405 [PubMed - indexed for MEDLINE]
Aseptic peritonitis due to peptidoglycan contamination of pharmacopoeia standard dialysis solution.
Lancet. 2005 Feb 12-18;365(9459):588-94
Authors: Martis L, Patel M, Giertych J, Mongoven J, Taminne M, Perrier MA, Mendoza O, Goud N, Costigan A, Denjoy N, Verger C, Owen WF
BACKGROUND: Manufacturers of parenteral solutions adhere to European and US Pharmacopoeia standards to define safety and sterility. In response to excess cases of aseptic peritonitis in peritoneal dialysis patients using icodextrin-containing dialysate that met all pharmacopoeia standards, a global recall was issued in May, 2002. We aimed to establish the cause of aseptic peritonitis.
METHODS: We analysed 186 reports of aseptic peritonitis between September, 2001, and January, 2003. Extensive physical, chemical, and microbiological investigations of recalled dialysate were done. We calculated dose-response curves for peptidoglycan-induced interleukin 6 elaboration in peripheral blood mononuclear cells (PBMCs) from healthy donors and for sterile peritonitis in rats.
FINDINGS: Although its chemical constituents and concentrations of endotoxin were within pharmacopoeia specifications, the dialysis solution elicited an interlukin 6 response in vivo and in vitro. We identified peptidoglycan from thermophilic acidophilic bacteria (Alicyclobacillus acidocaldarius) as the contaminating proinflammatory substance. In the PBMC assay, strong dose-response relations were noted between peptidoglycan concentrations and interleukin 6. In rats injected with peptidoglycan, dose-dependent increases of intraperitoneal neutrophils and pyrogenic cytokines were recorded. We measured a positive relation between peptidoglycan concentrations in recalled dialysate and reports of aseptic peritonitis. After implementation of corrective actions, the rate of peritonitis returned to baseline.
INTERPRETATION: Excess cases of aseptic peritonitis in peritoneal dialysis patients were due to peptidoglycan contamination of dialysate by Alicyclobacillus. This outbreak serves as an example of how contemporary parenteral products with microbial contaminants can be considered safe under current pharmacopoeia tests, but provoke adverse clinical effects.
PMID: 15708102 [PubMed - indexed for MEDLINE]
Angiotensin II impairs neurovascular coupling in neocortex through NADPH oxidase-derived radicals.
Circ Res. 2004 Nov 12;95(10):1019-26
Authors: Kazama K, Anrather J, Zhou P, Girouard H, Frys K, Milner TA, Iadecola C
Angiotensin II (Ang II) exerts detrimental effects on cerebral circulation, the mechanisms of which have not been elucidated. In particular, Ang II impairs the increase in cerebral blood flow (CBF) produced by neural activity, a critical mechanism that matches substrate delivery with energy demands in brain. We investigated whether Ang II exerts its deleterious actions by activating Ang II type 1 (AT1) receptors on cerebral blood vessels and producing reactive oxygen species (ROS) through NADPH oxidase. Somatosensory cortex CBF was monitored in anesthetized mice by laser-Doppler flowmetry. Ang II (0.25 microg/kg per minute IV) attenuated the CBF increase produced by mechanical stimulation of the vibrissae. The effect was blocked by the AT1 antagonist losartan and by ROS scavenger superoxide dismutase or tiron and was not observed in mice lacking the gp91phox subunit of NADPH oxidase or in wild-type mice treated with the NADPH oxidase peptide inhibitor gp91ds-tat. Ang II increased ROS production in cerebral microvessels, an effect blocked by the ROS scavenger Mn(III)tetrakis (4-benzoic acid) porphyrin and by the NADPH oxidase assembly inhibitor apocynin. Ang II did not increase ROS production in gp91-null mice. Double-label immunoelectron microscopy demonstrated that AT1 and gp91phox immunoreactivities were present in endothelium and adventitia of neocortical arterioles. Collectively, these findings suggest that Ang II impairs functional hyperemia by activating AT1 receptors and inducing ROS production via a gp91phox containing NADPH oxidase. The data provide the mechanistic basis for the cerebrovascular dysregulation induced by Ang II and suggest novel therapeutic strategies to counteract the effects of hypertension on the brain.
PMID: 15499027 [PubMed - indexed for MEDLINE]
Pressure-independent cardiac effects of angiotensin II in pigs.
Acta Physiol Scand. 2004 Oct;182(2):111-9
Authors: Broomé M, Haney M, Häggmark S, Johansson G, Aneman A, Biber B
BACKGROUND: Angiotensin II (Ang II) is a potent vasoconstrictor with an important role in the development of cardiovascular disease. Earlier results have shown a positive acute inotropic effect of Ang II in anaesthetized pigs together with significant vasoconstriction. This investigation was designed to study cardiac effects of Ang II, when blood pressure was maintained constant by experimental means.
METHODS: Ang II (200 microg h(-1)) was infused in anaesthetized pigs (n = 10) at two different arterial blood pressures, the first determined by the effects of Ang II alone, and the second maintained at baseline blood pressure with nitroprusside. Cardiac systolic and diastolic function was evaluated by analysis of left ventricular pressure-volume relationships.
RESULTS: Heart rate, end-systolic elastance (Ees) and pre-load adjusted maximal power (PWRmax EDV(-2)) increased at both blood pressure levels, although less when blood pressure was kept constant with nitroprusside. The time constant for isovolumetric relaxation (tau(1/2)) was prolonged with Ang II alone and shortened with Ang II infused together with nitroprusside.
CONCLUSION: Ang II infusion in the pig has inotropic and chronotropic properties independent of arterial blood pressure levels, although the effects seem to be blunted by pharmacological actions of the nitric oxide donor nitroprusside.
PMID: 15450107 [PubMed - indexed for MEDLINE]
Different effects of simvastatin and interferon beta on the proteolytic activity of matrix metalloproteinases.
Arch Neurol. 2004 Jun;61(6):929-32
Authors: Kieseier BC, Archelos JJ, Hartung HP
BACKGROUND: Interferon beta and statins are known to exert immunomodulatory actions by inhibiting gene transcription and translation of various proinflammatory molecules. Although interferon beta represents a mainstay in therapy for multiple sclerosis (MS), statins are considered a potential new approach in treating MS.
OBJECTIVE: To investigate the effect of interferon beta and statins on the posttranslational activity of matrix metalloproteinases (MMPs) released from mononuclear cells in vitro that were obtained from patients with MS and healthy donors.
DESIGN: Blood samples from 10 patients with a relapsing-remitting course of MS and 5 matched healthy individuals were studied. Peripheral blood mononuclear cells were isolated and stimulated with an antibody to CD3, phytohemagglutinin, or medium alone as a negative control. Proteolytic activity was investigated in the supernatants by means of sodium dodecyl sulfate-polyacrylamide gel electrophoresis zymography in which gels were incubated with interferon beta or simvastatin during development. Zones of gelatin digestion were visualized and quantified.
RESULTS: Incubation with interferon beta resulted in an inhibition of the gelatinolytic activity of MMP-9 and MMP-2. In contrast, simvastatin enhanced the proteolytic capacity of MMP-2 and MMP-9, with a statistically significant increase of MMP-2 activity when compared with findings in controls. There were no differences in the enzymatic response between patients with MS and healthy individuals.
CONCLUSIONS: Interferon beta exhibits inhibitory effects at the posttranslational level of MMP activity, whereas simvastatin augments the proteolytic activity of MMP-2 and MMP-9, suggesting that statins exert anti-inflammatory and proinflammatory effects. This dual mechanism of action should be considered, given the recent interest in developing these drugs for treatment of MS.
PMID: 15210533 [PubMed - indexed for MEDLINE]
Systolic hypertension in the elderly: pushing the frontiers of therapy--a suggested new approach.
J Clin Hypertens (Greenwich). 2004 Apr;6(4):192-7
Authors: Stokes GS
In elderly patients with systolic hypertension resistant to treatment with conventional therapy, increased aortic pulse wave reflection and a high augmentation index are often present. These findings are indicative of endothelial dysfunction and deficient generation of nitric oxide, a potent vasodilator in the arterial tree. In such patients, treatment with the nitric oxide donor extended-release isosorbide mononitrate characteristically produces prompt and sustained falls in both pulse wave reflection and systolic blood pressure. The adjunct use of this nitrate produces useful additional decreases in systolic blood pressure ranging from 10 to 45 mm Hg, often achieving target blood pressure goals in isolated systolic hypertension. By combining this endothelium-independent nitric oxide donor with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the potential exists to address both the nitric oxide deficiency and endothelial dysfunction of the vascular endothelium in these patients. Other possibilities for synergism with this combination include complementary hemodynamic, circadian, and metabolic actions together with prevention of nitrate tolerance. Isosorbide mononitrate may also be used successfully with calcium channel blockers, beta blockers, and diuretics.
PMID: 15073473 [PubMed - indexed for MEDLINE]
[Characteristics of the provision of hemotransfusion materials to the wounded and patients during antiterrorist operation].
Voen Med Zh. 2004 Jan;325(1):42-5, 96
Authors: Chechetkin AV, Popova NN, Kuz'min NS, Fedotov IuP
The authors analyze the experience of organization of the wounded and patient provision with hemotransfusion materials to render assistance during antiterrorist operation in Republic of Dagestan and Republic of Chechnya in 1999-2001. It is shown that supply of military treatment-and-prophylactic institutions deployed in the zone of military conflict, of specialized hospitals with hemotransfusion materials was the following: with blood preparations (at the expense of centralized deliveries), with blood components (91.8%, at the expense of centralized deliveries form the district blood transfusion station). The volume of stored blood taken from emergency reserve donors in the military treatment-and-prophylactic institutions located near the zone of military actions constituted 8.2% of the total volume of blood components received.
PMID: 15038266 [PubMed - indexed for MEDLINE]
[Therapy with NO donors-antiatherogenic and antioxidant actions].
Herz. 2004 Feb;29(1):116-22
Authors: Grosser N, Schröder H
Nitric acid esters such as glyceryl trinitrate were introduced into therapy more than a century ago and are still widely used for the treatment of myocardial ischemia and its main symptom angina pectoris. The basic mechanisms responsible for the vasodilatory and anti-ischemic action of organic nitrates involve bioactivation of, and nitric oxide (NO) release from, these compounds which have therefore been termed NO donors. The organic nitrate pentaerythritol tetranitrate (PETN) is known to possess antioxidant properties that are thought to be the underlying cause for its specific pharmacological profile. In contrast to other long-acting nitrates, PETN induces tolerance- free vasodilation in humans and was reported to prevent endothelial dysfunction as well as atherogenesis in cholesterol- fed rabbits. However, the exact nature of the vasoprotective signaling pathways triggered by PETN has remained obscure. The present study demonstrates that the active PETN metabolite PETriN stimulates protein expression of the antioxidant defense protein heme oxygenase-1 (HO-1; Figures 1 and 2). Additionally, PETriN enhanced the enzymatic activity of HO-1 measured as formation of the HO-1 metabolites bilirubin (Figure 3) and carbon monoxide (Figure 4) in lysates from endothelial cells. HO-1 induction subsequently led to a marked increase in protein expression of a second antioxidant protein, ferritin, via the HO-1-dependent release of free iron from endogenous heme sources (Figures 1 and 5). Pretreatment of endothelial cells with PETriN was followed by increased cellular resistance to oxidant injury mediated by hydrogen peroxide (Figure 6). Endothelial protection by PETriN was mimicked by exogenous bilirubin which led to an almost complete reversal of hydrogen peroxide-induced toxicity (Figure 8). Increased HO-1 and ferritin expression as well as endothelial protection occurred at micromolar concentrations of PETriN which are well within the range of plasma or tissue levels that can be expected during oral therapy. The capacity to protect the endothelium in vitro may translate into and explain the previously observed antiatherogenic actions of PETN in vivo. In this study, another long-acting nitrate, isosorbide dinitrate (ISDN), did not protect endothelial cells from oxidant damage (Figure 6). The absence of significant cytoprotection in the presence of ISDN was paralleled by a lack of HO-1 and ferritin stimulatory capacity (Figures 2 and 5). ISDN had no significant effect on carbon monoxide release or bilirubin formation (Figures 3 and 4). These observations are in agreement with results demonstrating small or nondetectable amounts of NO released from ISDN and its active metabolite isosorbide mononitrate (ISMN) measured as cyclic GMP formation in RFL-6 reporter cells (Figure 7). Interestingly and in contrast to PETN, isosorbide nitrates are known to induce tolerance to their cardiovascular effects, presumably via oxidant stress. Moreover, in earlier investigations aimed at assessing the antiatherogenic potential of nitrates, PETN but not isosorbide nitrates prevented plaque formation and endothelial dysfunction in animal models of atherosclerosis. Thus, the ability to activate HO-1 induction and associated antioxidant pathways apparently distinguishes PETN from other long-acting nitrates and may explain their different patterns of action in vivo (Figure 9).
PMID: 14968347 [PubMed - indexed for MEDLINE]
A nitric oxide-releasing derivative of enalapril, NCX 899, prevents progressive cardiac dysfunction and remodeling in hamsters with heart failure.
FASEB J. 2004 Mar;18(3):587-8
Authors: Iwanaga Y, Gu Y, Dieterle T, Presotto C, Del Soldato P, Peterson KL, Ongini E, Condorelli G, Ross J
Nitric oxide (NO) production is known to be impaired in heart failure. A new compound (NCX 899), a NO-releasing derivative of enalapril was characterized, and its actions were evaluated in Bio 14.6 cardiomyopathic (CM) hamsters with heart failure. The hamsters were randomized to oral treatment for 4 weeks with vehicle (n=11), NCX 899 (NCX, 25 mg/kg, n=10), or enalapril (25 mg/kg, n=10). In the vehicle group, fractional shortening by echocardiography decreased (-23.6+/-2.0%) and LV end-diastolic dimension) increased (+10.9+/-1.0%), whereas fractional shortening increased (+17.5+/-4.4%) in NCX and was unchanged in the enalapril group (both P<0.01 vs. vehicle). End-diastolic dimension decreased only in NCX. LV contractility (LVdP/dt max and Emax) was significantly greater in NCX than in enalapril or vehicle, while relaxation (Tau) was shortened in both NCX and enalapril vs. vehicle. ACE activity was inhibited equally by NCX and enalapril in the CM hamster, and plasma nitrate levels were increased only in NCX (P<0.05 vs. enalapril and vehicle). In aortic strips endothelium-independent relaxation occurred only with NCX. The superior effects of NO-releasing enalapril (NCX) vs. enalapril alone to enhance vascular effects, increase LV contractility and prevent unfavorable remodeling and are consistent with vascular delivery of exogenous NO. NCX 899 may hold promise for the future treatment of heart failure.
PMID: 14734637 [PubMed - indexed for MEDLINE]
Membrane glucocorticoid receptors (mGCR) are expressed in normal human peripheral blood mononuclear cells and up-regulated after in vitro stimulation and in patients with rheumatoid arthritis.
FASEB J. 2004 Jan;18(1):70-80
Authors: Bartholome B, Spies CM, Gaber T, Schuchmann S, Berki T, Kunkel D, Bienert M, Radbruch A, Burmester GR, Lauster R, Scheffold A, Buttgereit F
Glucocorticoids mediate their therapeutic actions mostly by genomic effects via cytosolic receptors, but some effects are too rapid to be mediated by changes at the genomic level. The detailed mechanisms of these nongenomic actions are still unclear. Membrane-bound glucocorticoid receptors (mGCR) have been suggested to be involved, although their physiological existence in humans so far is hypothetical. For the first time we demonstrate the existence of mGCR on monocytes and B cells obtained from healthy blood donors using high-sensitivity immunofluorescent staining. Immunostimulation with lipopolysaccharide increases the percentage of mGCR-positive monocytes, which can be prevented by inhibiting the secretory pathway. Overexpression of the human glucocorticoid receptor alpha alone is not sufficient to enhance mGCR expression. These in vitro findings are consistent with our clinical observation that in patients with rheumatoid arthritis the frequency of mGCR positive monocytes is increased and positively correlated with disease activity. We conclude that mGCR are 1) indeed physiologically present in healthy blood donors, but remained unidentified by conventional techniques due to their small number per cell and 2) actively up-regulated and transported through the cell after immunostimulation. These receptors may reflect a feedback mechanism of the organism upon immunostimulation and/or play a role in pathogenesis.
PMID: 14718388 [PubMed - indexed for MEDLINE]
Anti-inflammatory and antiproliferative actions of PPAR-gamma agonists on T lymphocytes derived from MS patients.
J Leukoc Biol. 2004 Mar;75(3):478-85
Authors: Schmidt S, Moric E, Schmidt M, Sastre M, Feinstein DL, Heneka MT
Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-gamma isoform is expressed in human T lymphocytes, and oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-gamma agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-gamma agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-gamma agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50% and secretion of interferon-gamma and tumor necrosis factor alpha, by 30-50%. Inhibition of proliferation was increased to approximately 80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR-gamma agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-gamma agonists. Inhibition of proliferation was also observed in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot analysis revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-gamma agonists as immunomodulatory, therapeutic agents for autoimmune diseases.
PMID: 14657213 [PubMed - indexed for MEDLINE]
Geldanamycin and herbimycin A induce apoptotic killing of B chronic lymphocytic leukemia cells and augment the cells' sensitivity to cytotoxic drugs.
Blood. 2004 Mar 01;103(5):1855-61
Authors: Jones DT, Addison E, North JM, Lowdell MW, Hoffbrand AV, Mehta AB, Ganeshaguru K, Folarin NI, Wickremasinghe RG
We studied the actions of geldanamycin (GA) and herbimycin A (HMA), inhibitors of the chaperone proteins Hsp90 and GRP94, on B chronic lymphocytic leukemia (CLL) cells in vitro. Both drugs induced apoptosis of the majority of CLL isolates studied. Whereas exposure to 4-hour pulses of 30 to 100 nM GA killed normal B lymphocytes and CLL cells with similar dose responses, T lymphocytes from healthy donors as well as those present in the CLL isolates were relatively resistant. GA, but not HMA, showed a modest cytoprotective effect toward CD34+ hematopoietic progenitors from normal bone marrow. The ability of bone marrow progenitors to form hematopoietic colonies was unaffected by pulse exposures to GA. Both GA and HMA synergized with chlorambucil and fludarabine in killing a subset of CLL isolates. GA- and HMA-induced apoptosis was preceded by the up-regulation of the stress-responsive chaperones Hsp70 and BiP. Both ansamycins also resulted in down-regulation of Akt protein kinase, a modulator of cell survival. The relative resistance of T lymphocytes and of CD34+ bone marrow progenitors to GA coupled with its ability to induce apoptosis following brief exposures and to synergize with cytotoxic drugs warrant further investigation of ansamycins as potential therapeutic agents in CLL.
PMID: 14576064 [PubMed - indexed for MEDLINE]
IL-18BPa:Fc cooperates with immunosuppressive drugs in human whole blood.
Biochem Pharmacol. 2003 Aug 01;66(3):505-10
Authors: Nold M, Hauser IA, Höfler S, Goede A, Eberhardt W, Ditting T, Geiger H, Pfeilschifter J, Mühl H
The proinflammatory cytokine interleukin (IL)-18 appears to be involved in the pathogenesis of diseases associated with immunoactivation and inflammation. Consequently, blockage of IL-18 bioactivity by use of IL-18 binding protein (IL-18 BP) is likely a promising therapeutic concept. In the present study, we investigated immunomodulatory activities of IL-18 BPa:Fc in human whole blood cultures. We report that IL-18 BPa:Fc (200 ng/mL) significantly inhibited lipopolysaccharide (LPS, 10 ng/mL)/IL-12 (5 ng/mL)-induced release of interferon-gamma (IFNgamma) and matrix metalloproteinase-9 (MMP-9) from whole blood cultures of healthy donors. Notably, IL-18 BPa:Fc (200 ng/mL) further reinforced dexamethasone (5 nM)- or mycophenolic acid (2 microM)-mediated reduction of LPS/IL-12-induced IFNgamma production by an additional 50.5 or 49.9%, respectively. To investigate effects of IL-18 BP:Fc in the context of autoimmune diseases, experiments were performed with whole blood obtained from patients with systemic lupus erythematosus or Wegener's granulomatosis undergoing immunosuppressive therapy. After ex vivo stimulation with LPS (10 ng/mL), production of IFNgamma and MMP-9 was determined. Both mediators likely contribute to renal inflammation frequently seen in these diseases. In accord with the aforementioned data, LPS (10 ng/mL)-induced IFNgamma was significantly reduced by coincubation with IL-18 BPa:Fc at 200 ng/mL. IL-18 BPa:Fc also inhibited production of MMP-9. The present data demonstrate that IL-18 BPa:Fc has the potential to amplify anti-inflammatory actions of immunosuppressive drugs, and thus may prove to be a valuable novel pharmacological component in the treatment of human autoimmune diseases.
PMID: 12907250 [PubMed - indexed for MEDLINE]
The effect of clomethiazole on plasma concentrations of interleukin-6, -8, -1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation.
Anesth Analg. 2003 Jul;97(1):13-8, table of contents
Authors: Harmon D, Coleman E, Marshall C, Lan W, Shorten G
UNLABELLED: Clomethiazole (CMZ), a neuroprotective drug, has antiinflammatory actions. We investigated the effects of CMZ administration on plasma concentrations of interleukin (IL)-6, IL-8, IL-1beta, tumor necrosis factor-alpha, and neutrophil adhesion molecule expression during experimental extracorporeal circulation. Five healthy volunteers each donated 500 mL of blood, which was subsequently divided into equal portions. Identical extracorporeal circuits were simultaneously primed with donated blood (250 mL) and circulated for 2 h at 37 degrees C. CMZ was added to 1 of the circuits of each pair to achieve a total plasma concentration of 40 micro mol/L. Blood samples were withdrawn at (i) donation, (ii) immediately after addition of CMZ, and at (iii) 30, 60, 90, and 120 min after commencing circulation. Plasma concentrations of IL-6, IL-8, and tumor necrosis factor-alpha were less in the CMZ group compared with control after 60 min of circulation (2.2 [0.3] versus 3.2 [0.4], 14.9 [4.8] versus 21.9 [18.4], 63.3 [43.5] versus 132.2 [118.9] pg/mL, respectively, P < 0.05). After 120 min of circulation, neutrophils from CMZ-treated circuits showed significantly less CD18 expression compared with control (237.5 [97.4] versus 280.5 [111.5], P = 0.03). The addition of CMZ to experimental extracorporeal circuits decreases the inflammatory response. This effect may be of clinical benefit by decreasing inflammatory-mediated neurological injury during cardiopulmonary bypass.
IMPLICATIONS: Enhancement of gamma-aminobutyric acid(A)-mediated effects by clomethiazole (CMZ) and associated neuroprotection has been established in animal models of cerebral ischemia. In an ex vivo study, we demonstrated antiinflammatory activity of CMZ in experimental extracorporeal circulation. This represents a potential neuroprotective mechanism of CMZ in patients undergoing coronary artery bypass surgery.
PMID: 12818935 [PubMed - indexed for MEDLINE]
Potent antifibrillatory effects of intrapericardial nitroglycerin in the ischemic porcine heart.
J Am Coll Cardiol. 2003 May 21;41(10):1831-7
Authors: Kumar K, Nguyen K, Waxman S, Nearing BD, Wellenius GA, Zhao SX, Verrier RL
OBJECTIVES: We investigated the antiarrhythmic effects of intrapericardial nitroglycerin (NTG) during acute myocardial ischemia in the porcine heart.
BACKGROUND: Nitroglycerin is a nitric oxide donor that exerts potent effects on the cardiovascular system. Intrapericardial administration allows investigation of pharmacologic actions on cardiac tissue in an in vivo system while minimizing the confounding influences of systemic effects.
METHODS: In 29 closed-chest pigs, myocardial ischemia was induced by intraluminal balloon occlusion of the left anterior descending coronary artery. Arrhythmia incidence was monitored during 5-min balloon inflations performed without drug and at 15, 45, 75, and 105 min after NTG (4,000 microg bolus) administered by percutaneous transatrial access into the pericardial space. Electrocardiograms were monitored for ischemia-induced T-wave alternans (TWA), a marker of electrical instability. The antiadrenergic potential of NTG was investigated by examining the drug's suppression of dobutamine-induced increase in myocardial contractility.
RESULTS: Control coronary artery occlusion provoked ventricular fibrillation (VF) in all animals. Intrapericardial NTG suppressed VF at 45 min in all six pigs (p < 0.05) and reduced TWA across a parallel time course (from 459.1 +/- 144.4 microV before drug to 42.22 +/- 13.96 microV at 45 min, p = 0.047). The antifibrillatory effect occurred as early as 15 min and persisted for up to 75 min. Augmentation of maximum of the first time derivative of left ventricular pressure by dobutamine was blunted by intrapericardial NTG (from 3,999 +/- 196 mm Hg/s before NTG to 3,543 +/- 220 mm Hg/s at 15 min, p = 0.012).
CONCLUSIONS: Intrapericardial NTG exerts a robust antifibrillatory action. Potential mechanisms include reduction in electrical instability and blunting of adrenergic effects.
PMID: 12767672 [PubMed - indexed for MEDLINE]
Nitric oxide and S-nitrosothiols in human blood.
Clin Chim Acta. 2003 Apr;330(1-2):85-98
Authors: Giustarini D, Milzani A, Colombo R, Dalle-Donne I, Rossi R
The hypothesis that endothelial-derived relaxing factor (EDRF) is nitric oxide has stimulated a wealth of research into the significance of this novel intriguing molecule. Given its short life, many storage forms of NO as well as targets have been postulated. Among these, a pool of derivatives of NO (S-nitrosothiols, RSNOs) covalently bound to SH groups of proteins and low molecular weight thiols (e.g., glutathione) have been identified in various biological systems. The importance of RSNOs results from the very similar biological actions exhibited by both NO and RSNOs in vivo as well as in vitro. In particular, it has been observed that in the bloodstream, these molecules are able to provoke vasodilatation with a consequent fall in blood pressure and an antithrombotic effect by inhibition of platelet aggregation. Many hypotheses have been postulated about the biochemical species and the mechanisms involved in these processes, but many aspects have not yet been clarified. In addition, some RSNOs have been recently proposed to be clinical parameters, whose levels may vary under some pathological conditions. The therapeutic utility of RSNOs as an alternative to classic NO donors has also been suggested.Here, we provide a critical analysis of the main reports about the biochemical, physiological, pathological and therapeutic properties of RSNOs in the cardiovascular system. Particular attention is addressed to conflicting results and to discrepancies in the methodologies and models utilized. The numerous unanswered questions concerning the role of RSNOs in the control of vascular tone are discussed.
PMID: 12636927 [PubMed - indexed for MEDLINE]
Calcium antagonist clevidipine reduces myocardial reperfusion injury by a mechanism related to bradykinin and nitric oxide.
J Cardiovasc Pharmacol. 2002 Oct;40(4):564-70
Authors: Gourine AV, Pernow J, Poputnikov DM, Sjöquist PO
Certain calcium antagonists, in addition to their classic actions, can increase blood flow during ischemia via bradykinin- and nitric oxide (NO)-dependent mechanisms and protect the ischemic myocardium against reperfusion injury by enhancing NO bioavailability. The current study aimed to investigate the possible involvement of bradykinin and NO in the cardioprotective action of the short-acting calcium antagonist clevidipine during late ischemia and reperfusion. Anesthetized pigs were subjected to 45-min ligation of the left anterior descending coronary artery (LAD) followed by 4 h of reperfusion. Four groups were given vehicle, clevidipine, clevidipine in combination with the bradykinin B2 receptor antagonist HOE 140 or clevidipine in combination with HOE 140 and the NO donor S-nitroso-N-acetyl-D,L-penicillamine (SNAP) into the LAD during the last 10 min of ischemia and the first 5 min of reperfusion. There were no significant differences in hemodynamics among the groups before ischemia or during ischemia-reperfusion. The infarct size (IS) was 87% +/- 2% of the area at risk in the vehicle group. Clevidipine reduced the IS to 60% +/- 3% (p < 0.001 vs vehicle). When clevidipine was administered together with HOE 140, the protective effect of clevidipine was abolished (IS, 80% +/- 3%; p < 0.001 vs clevidipine), whereas addition of SNAP restored cardioprotection (IS, 62% +/- 5%; p < 0.001 vs vehicle). The increase in LAD blood flow by endothelium-dependent dilator substance P was significantly larger in the clevidipine group than in the other groups. The results suggest that the cardioprotective effect of clevidipine during late ischemia and early reperfusion is mediated via bradykinin- and NO-related mechanisms.
PMID: 12352318 [PubMed - indexed for MEDLINE]
Public policy and the sale of human organs.
Kennedy Inst Ethics J. 2002 Mar;12(1):47-64
Authors: Cohen CB
Gill and Sade, in the preceding article in this issue of the Kennedy Institute of Ethics Journal, argue that living individuals should be free from legal constraints against selling their organs. The present commentary responds to several of their claims. It explains why an analogy between kidneys and blood fails; why, as a matter of public policy, we prohibit the sale of human solid organs, yet allow the sale of blood; and why their attack on Kant's putative argument against the sale of human body parts is misplaced. Finally, it rejects the claim that the state is entitled to interfere with the actions of individuals only if such actions would harm others. We draw certain lines grounded in what Rawls has termed "public reason" beyond which we do not give effect to the autonomous self-regarding decisions of individuals. Public resistance to the sale of human body parts, no matter how voluntary or well informed, is grounded in the conviction that such a practice would diminish human dignity and our sense of solidarity. A system of organ donation, in contrast, conveys our respect for persons and honors our common humanity.
PMID: 12211266 [PubMed - indexed for MEDLINE]
Characterization of the hypotensive effect of S-nitroso-N-acetylcysteine in normotensive and hypertensive conscious rats.
Nitric Oxide. 2002 Aug;7(1):57-66
Authors: Ricardo KF, Shishido SM, de Oliveira MG, Krieger MH
S-Nitrosothiols (RSNOs) are potent vasodilators found naturally in vivo. A variety of synthetic RSNOs have been considered as potential nitric oxide (NO) donors for biomedical applications. We have characterized the hypotensive effect of the RSNO S-nitroso-N-acetylcysteine (SNAC) in normotensive and hypertensive conscious rats. SNAC reduced the medium arterial pressure in a dose-response manner in both normotensive and hypertensive animals. At the same doses (EC(50) of SNAC), SNAC showed a vasodilator effect in normotensive rats more potent and more prolonged than that of sodium nitroprusside (SNP). The hypotensive effect of SNAC was also more potent in methylene blue-treated rats, where the cGMP-dependent pathway had been blockaded. These data indicate that SNAC acts by both cGMP-dependent and cGMP-independent pathways. It was also shown that the thiol N-acetylcysteine (NAC) potentiates the action of SNP in hypertensive rats, pointing to the mediation of thiols in the vasodilator action of SNP in this condition. Such mediation may involve the formation of a more potent thiol complex with the nitroprusside anion or the transfer of NO to NAC, generating SNAC as a primary vasoactive species. The kinetic monitoring of the decomposition reactions of SNAC and SNP showed that both compounds are quite stable under the infusion conditions used. Therefore, their vasodilator action cannot be assigned to their breakdown with release of free NO in solution. As the two compounds are unlikely to cross the plasmalemma of smooth muscle cells, their actions are probably associated with the mediation of endogenous thiols in transnitrosation reactions.
PMID: 12175821 [PubMed - indexed for MEDLINE]
L-arginine deficiency and supplementation in experimental acute renal failure and in human kidney transplantation.
Kidney Int. 2002 Apr;61(4):1423-32
Authors: Schramm L, La M, Heidbreder E, Hecker M, Beckman JS, Lopau K, Zimmermann J, Rendl J, Reiners C, Winderl S, Wanner C, Schmidt HH
BACKGROUND: The "L-arginine paradox" refers to situations where L-arginine (L-Arg) supplementation stimulates nitric oxide (NO) synthesis, despite saturating intracellular concentrations. This paradox is frequently observed in acute renal failure (ARF). First, the effects of L-Arg on renal function of rats with ARF were studied. Based on the promising results from these initial studies, the second part of our study searched for a form of ARF in humans that could be studied easily under conditions with little variance and yet was linked with endothelial dysfunction. Thus, we investigated the effects of L-Arg supplementation immediately after kidney transplantation in 54 patients.
METHODS: In uranyl nitrate-induced ARF in rats the effects of L-Arg and L-NNA (inhibitor of nitric oxide synthase; NOS) on glomerular filtration rate (GFR), renal plasma flow (RPF), blood pressure (BP) and NOx (NO2- +NO3-) excretion were examined. Tissue L-Arg levels, NOS activities, immunodetection of NOS and superoxide dismutase (SOD), activities of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and xanthine oxidase, and nitrotyrosine immunoreactive protein (NT-IR) were determined and compared to sham operated animals. Secondly, in a randomized, double-blind study, the effects of L-Arg on GFR and RPF were investigated in 54 kidney transplant recipients, receiving IV L-Arg for three days. GFR and RPF were measured on days 1, 3, 5 and 10 by scintigraphy.
RESULTS: In experimental ARF, decreased RPF and GFR were associated with reduced tissue L-Arg levels, endothelial NOS-III expression, NO formation and NOx excretion. Reduction in GFR, RPF and NOx excretion were reversed upon administration of exogenous L-Arg. There also was a loss of Cu,Zn-SOD, a key enzyme against oxidative stress, and an elevation of NT-IR, an indicator of nitrosative stress and suggested marker for pathological actions of NO. However, NT-IR was not dependent on de novo NO synthesis and not related to the functional effects of l-Arg administration. In kidney transplant recipients receiving organs with a short cold ischemia time (CIT) and from young donors, that is, those with a higher likelihood of a functional endothelium, early administration of L-Arg improved renal function.
CONCLUSION: Both experimental and clinical data show that \L-Arg deficiency and endothelial dysfunction are pathomechanistically relevant in ARF. The data suggest a therapeutic potential for the administration of L-Arg in ARF and kidney transplantation, at least in patients receiving kidneys with shorter CIT and from younger donors.
PMID: 11918749 [PubMed - indexed for MEDLINE]
Novel nitric oxide donor (FK409) ameliorates liver damage during extended liver resection with warm ischemia in dogs.
J Am Coll Surg. 2001 Sep;193(3):264-71
Authors: Aiba M, Takeyoshi I, Ohwada S, Kawashima Y, Iwanami K, Sunose Y, Yamada T, Tsutsumi H, Matsumoto K, Morishita Y
BACKGROUND: Nitric oxide attenuates ischemia-reperfusion injury by maintaining organ circulation through its actions as a vasoregulator, an inhibitor of platelet aggregation, and an attenuator of leukocyte adhesion. Otherwise, the harmful effects of enhanced nitric oxide production induced by inducible nitric oxide synthase mediate ischemia-reperfusion injury. FK409 has been characterized as a spontaneous nitric oxide donor. The aim of this study was to evaluate the effects of FK409 on extended liver resection with ischemia using a canine model.
STUDY DESIGN: Adult mongrel dogs were subjected to 60 minutes of warm ischemia by partial inflow occlusion. After reperfusion the nonischemic lobes were resected and the remnant liver function was evaluated. The dogs were divided into two groups: the control group (n = 7) and the FK409 group (n = 6), which was given FK409 through the portal vein.
RESULTS: The hepatic tissue blood flow, serum liver enzymes levels, and serum endothelin-1 level after reperfusion were significantly better in the FK409 group than in the control group. Electron microscopy demonstrated that endothelial cells and Ito cells were well-preserved in the FK409 group. The 3-day survival rate was statistically better in the FK409 group (67%) than in the control group (14%).
CONCLUSIONS: FK409 appears to have protective effects during extended liver resection with ischemia.
PMID: 11548796 [PubMed - indexed for MEDLINE]
Lack of gastric toxicity of nitric oxide-releasing indomethacin, NCX-530, in experimental animals.
Dig Dis Sci. 2001 Aug;46(8):1805-18
Authors: Takeuchi K, Mizoguchi H, Araki H, Komoike Y, Suzuki K
The effects of a nitric oxide (NO) releasing derivative of indomethacin (NCX-530) on gastric ulcerogenic and healing responses were evaluated in rats and mice, in comparison with the parent compound indomethacin. Indomethacin (per os) produced damage in the rat stomach in a dose-dependent manner. NCX-530 (per os) itself, however, was not ulcerogenic and even showed a dose-dependent protection against HCl/ethanol-induced lesions in the rat stomach. Likewise, indomethacin given repeatedly delayed healing of gastric ulcers induced in mice by thermal cauterization, while NCX-530 did not affect the healing response and significantly promoted the healing as compared to indomethacin. These actions of NCX-530 were mimicked by the combined administration of a NO donor NOR-3 with indomethacin. The amount of NO metabolites was increased in both the gastric contents and serum when NCX-530, but not indomethacin, was given in pylorus-ligated stomachs. Neither indomethacin nor NCX-530 influenced gastric acid secretion and transmucosal potential difference, yet NCX-530 caused a marked increase of gastric mucosal blood flow, which was preventable by carboxy-PTIO, a scavenger of NO. Gastric motility was increased by indomethacin but not by NCX-530. In addition, NCX-530 inhibited PGE2 generation in both the intact and ulcerated gastric mucosa and showed antiinflammatory action on carrageenan-induced rat paw edema, as effectively as indomethacin. These results suggest that unlike indomethacin, NCX-530 caused neither an irritating action on the stomach nor healing impairment effect on the preexisting gastric ulcers, but conferred gastric protection against HCl/ethanol, despite causing cyclooxygenase inhibition and antiinflammatory action, as effectively as indomethacin. This NO-releasing indomethacin, probably by releasing NO, exerts protective influences, such as an increase of gastric mucosal blood flow, that counteract the potential damaging effects of cyclooxygenase inhibition by indomethacin.
PMID: 11508687 [PubMed - indexed for MEDLINE]
Role of guanylyl cyclase and cytochrome P-450 on renal response to nitric oxide.
Am J Physiol Renal Physiol. 2001 Sep;281(3):F420-7
Authors: López B, Moreno C, Salom MG, Roman RJ, Fenoy FJ
The present study evaluated whether inhibition of guanylyl cyclase (GC) with 1H-(1,2,4)oxadiazolo[4,3-a]quinoxaline-1-one (ODQ) and methylene blue (MB) or inhibition of the renal metabolism of arachidonic acid by cytochrome P-450 (CYP450) enzymes with 1-aminobenzotriazole (ABT) and N-hydroxy-N'-(4 butyl-2-methyl phenyl)formamidine (HET0016) alters the renal tubular and vascular effects of a nitric oxide (NO) donor in vivo. Intrarenal infusion of ODQ or MB at a dose of 170 nmol. kg(-1). min(-1) lowered renal blood flow (RBF) by 30 and 15%, respectively; glomerular filtration rate (GFR) by 26 and 18%, respectively; and sodium and water excretion by approximately 35%. In rats pretreated with nitro-L-arginine methyl ester (37 nmol. kg(-1). min(-1)) to block the endogenous production of NO, intrarenal infusion of the NO donor S-nitroso-N-acetylcysteine (S-NO-NAC; 50 nmol. kg(-1). min(-1)) increased RBF (18%), sodium (73%), and water excretion (61%). ODQ or MB administration blocked the effect of S-NO-NAC on RBF but not the diuretic and natriuretic response. Pretreatment of rats with ABT or HET0016 also abolished the renal vasodilatory response to the NO donor and reduced its diuretic and natriuretic effect. These results indicate that both activation of GC and inhibition of CYP450 enzymes contribute to the renal vascular actions of NO, whereas the natriuretic and diuretic actions of NO appear to be largely CYP450 dependent.
PMID: 11502591 [PubMed - indexed for MEDLINE]
Nitroglycerin induces late preconditioning against myocardial infarction in conscious rabbits despite development of nitrate tolerance.
Circulation. 2001 Aug 07;104(6):694-9
Authors: Hill M, Takano H, Tang XL, Kodani E, Shirk G, Bolli R
BACKGROUND: Recent studies suggest that the late phase of ischemic preconditioning (PC) can be mimicked by pretreatment with NO donors. The ability of clinically relevant NO donors to induce PC against infarction, however, has not been evaluated. Furthermore, it is unknown whether tolerance to the hemodynamic actions of nitrates also extends to their PC effects.
METHODS AND RESULTS: Conscious rabbits underwent a 30-minute coronary occlusion and 3 days of reperfusion. A 60-minute intravenous (IV) infusion of nitroglycerin (NTG) ending 1 hour before occlusion reduced infarct size, indicating an early PC effect. When the time interval between NTG infusion and occlusion was extended to 24 or 72 hours, the infarct-sparing action of NTG became even more pronounced, indicating a robust late PC effect. Transdermal NTG patches elicited a late PC effect that was (1) equivalent to that induced by IV NTG, demonstrating the efficacy of transdermal NTG as an alternative form of NTG delivery for inducing late PC, and (2) similar in nitrate-tolerant and -nontolerant rabbits, demonstrating that tolerance does not extend to the PC effects of NTG.
CONCLUSIONS: In conscious rabbits, administration of NTG via either the IV or the transdermal route elicits a robust protective effect against infarction that lasts for 72 hours. The magnitude of NTG-induced cardioprotection is equivalent to that observed during the late phase of ischemic PC and is not affected by the development of tolerance. These findings reveal a new action of nitrates and support novel applications of these drugs for protecting the ischemic myocardium in patients.
PMID: 11489777 [PubMed - indexed for MEDLINE]
Nitric oxide insufficiency, platelet activation, and arterial thrombosis.
Circ Res. 2001 Apr 27;88(8):756-62
Authors: Loscalzo J
Nitric oxide (NO) was originally discovered as a vasodilator product of the endothelium. Over the last 15 years, this vascular mediator has been shown to have important antiplatelet actions as well. By activating guanylyl cyclase, inhibiting phosphoinositide 3-kinase, impairing capacitative calcium influx, and inhibiting cyclooxygenase-1, endothelial NO limits platelet activation, adhesion, and aggregation. Platelets are also an important source of NO, and this platelet-derived NO pool limits recruitment of platelets to the platelet-rich thrombus. A deficiency of bioactive NO is associated with arterial thrombosis in animal models, individuals with endothelial dysfunction, and patients with a deficiency of the extracellular antioxidant enzyme glutathione peroxidase-3. This enzyme catalyzes the reduction of hydrogen and lipid peroxides, which limits the availability of these reactive oxygen species to react with and inactivate NO. The complex biochemical reactions that underlie the function and inactivation of NO in the vasculature represent an important set of targets for therapeutic intervention for the prevention and treatment of arterial thrombotic disorders.
PMID: 11325866 [PubMed - indexed for MEDLINE]
Review: effects of nitric oxide on eye diseases and their treatment.
J Ocul Pharmacol Ther. 2001 Apr;17(2):189-98
Authors: Chiou GC
Both underproduction and overproduction of nitric oxide (NO) could lead to various eye diseases. It is known that endothelial NO synthase (eNOS) and neuronal NOS (nNOS) are activated in normal tissues to produce NO for physiological functions. Thus, underproduction of NO results in various eye diseases which could be corrected by providing NOS substrates or NO donors to lower the intraocular pressure, increase ocular blood flow, relax ciliary muscle, etc. On the other hand, immunological NOS (iNOS) is inducible only in pathological conditions by endotoxins, inflammation, and certain cytokines, such as interleukin-1 (IL-1), IL-6, TNF (tumor necrosis factor) and the like. Once induced, iNOS will produce large amounts of NO for long periods of time, so that NO is converted into NO2, nitrite, peroxynitrite and free radicals to induce pathophysiological actions, such as optic nerve degeneration and posterior retinal degeneration lesion, which lead to glaucoma, retinopathy, age-related macular degeneration (AMD), myopia, cataracts and uveitis. To treat/prevent these eye diseases, inhibitors of iNOS activity and/or iNOS induction could be tried.
PMID: 11324986 [PubMed - indexed for MEDLINE]
Divergent effects of ischemia/reperfusion and nitric oxide donor on TNFalpha mRNA accumulation in rat organs.
Shock. 2001 Apr;15(4):312-7
Authors: Rahat MA, Lahat N, Smollar J, Brod V, Kinarty A, Bitterman H
We previously showed that serum TNFalpha bioactivity in rats is proportional to the extent of graded tissue injury caused by laparotomy, intestinal ischemia, and reperfusion and that the spleen is an important source of TNFalpha secretion in this condition. TNFalpha production varies, depending on the type and duration of tissue injury. It is also affected by other mediators, such as nitric oxide (NO). TNFalpha is known to increase NO production, but the effect of NO on the production of TNFalpha has not yet been fully elucidated. In this study we determined the levels of TNFalpha mRNA in rat organs after graded injury caused by anesthesia, laparotomy, intestinal ischemia, and reperfusion and evaluated the effects of the NO donor S-nitroso-N-acetylpenicillamine (SNAP) on it. Samples from different organs were removed, and TNFalpha gene expression was evaluated by semiquantitative RT-PCR. TNFalpha mRNA was not detected in the intestine (the ischemic organ) and in the kidney, brain, heart, or liver after all 4 experimental protocols. In the mesenteric lymph node (draining the ischemic organ) a basal level of expression of TNFalpha mRNA was detected in the control (anesthesia alone) group, which was increased significantly after ischemia. In the spleen (a remote immune organ not directly involved in the ischemia), a significant gradual increase in TNFalpha mRNA, which correlated to the severity of the experimental protocol, was observed. In the lung (a central participant in post-injury multiple organ failure), all interventions increased TNFalpha mRNA. Infusion of SNAP exerted a differential effect on TNFalpha mRNA: diminished its accumulation in the lymph node, enhanced it in the lung, and had no effect in the spleen. The divergent organ pattern of TNFalpha transcription emphasizes the importance of its localized expression, which is critical to the understanding of its autocrine and paracrine actions in ischemia and reperfusion.
PMID: 11303732 [PubMed - indexed for MEDLINE]
[The Hemovigilance Commission of the University Hospital Center].
Rev Med Liege. 2000 Sep;55(9):878-80
Authors: Baudoux E, Blaffart F, Bouffioux C, Caprasse M, Courtois F, Cremasco MR, De Pasqual E, Fassotte MF, Gillet P, Lamy M, Larbuisson R, Lemaire R, Merciny M, Moutschen M, Radermecker M, Remy B, Sondag D
As suggested by the National Blood Council, a Hemovigilance Committee was set up in the University Hospital of Liège in 1995. A multidisciplinary discussion takes place on any action aiming at the improvement of transfusion safety, and the follow-up of its implementation. The first issue to be discussed was the set up of a detailed documentation of all blood transfusions. The data are now recorded on a single document allowing proper identification of people and products involved, and of the eventual incidents. This document has lead to a better transfusion safety and to an improved administrative management of blood transfusion. The Commission has been coordinating two multi-centric studies analyzing the consumption of fresh blood products and the incidence of transfusion reactions. Among blood-saving policies, autologous transfusion and volume reduction of samples drawn for laboratory purposes have been discussed. Other measures were taken to improve the labeling of samples for cross-mach and to actively follow-up transfusion reactions. By its actions and advises, the Commission aims to direct strategies towards a safe and rational use of blood products.
PMID: 11105604 [PubMed - indexed for MEDLINE]
Antihypertensive properties of a nitric oxide-releasing naproxen derivative in two-kidney, one-clip rats.
Am J Physiol Heart Circ Physiol. 2000 Aug;279(2):H528-35
Authors: Muscará MN, McKnight W, Lovren F, Triggle CR, Cirino G, Wallace JL
Nonsteroidal anti-inflammatory drugs have been reported to exacerbate hypertension. In this study, we tested the hypothesis that a nitric oxide-releasing derivative of naproxen would ameliorate hypertension in the rat. Hypertension was induced by partially occluding one renal artery (the "2K,1C" model), and 2 wk later the rats started receiving naproxen, the nitric oxide-releasing derivative HCT-3012, or vehicle each day for 2 wk. Naproxen significantly exacerbated the hypertension. HCT-3012 significantly reduced blood pressure relative to both the naproxen- and vehicle-treated groups. Both naproxen and HCT-3012 markedly suppressed whole blood thromboxane B(2) synthesis. In studies of anesthetized rats, naproxen significantly enhanced the late hypertensive response to endothelin-1 and significantly blunted the early hypotensive response. In contrast, HCT-3102 did not affect either response to endothelin-1. In vitro, HCT-3012 significantly reduced the responsiveness of aortic rings to the contractile effects of phenylephrine. These studies suggest that HCT-3012 reduces blood pressure in hypertensive rats, not simply through the vasodilatory actions of the nitric oxide it releases, but through alterations in the responsiveness of the vasculature to endogenous pressor agents.
PMID: 10924050 [PubMed - indexed for MEDLINE]
Impaired monocyte CD11b expression in interstitial inflammation in hemodialysis patients.
Kidney Int. 2000 May;57(5):2099-106
Authors: Thylén P, Lundahl J, Fernvik E, Grönneberg R, Halldén G, Jacobson SH
BACKGROUND: It is not known to what extent intravascular phenotypic alterations in adhesion molecule expression induced by hemodialysis influence the recruitment of monocytes and their ability to up-regulate CD11b at the local site of inflammation in the interstitium. Using a skin suction chamber technique, we addressed these issues in eight hemodialysis patients and in eight healthy subjects.
METHODS: Two skin blisters were raised on the forearm of each individual and blister exudate collected. The blisters were then stimulated with autologous serum (active blister, intense inflammation) or buffer (control blister, intermediate inflammation), respectively. Thereafter the patients were treated with Cuprophan hemodialysis for four hours. After 10 hours, the exudate was aspirated from each chamber in all subjects. Monocyte count and expression of CD11b were analyzed in serum and blister fluid by flow cytometry. Then, monocytes from healthy blood donors were incubated in blister fluid from patients and healthy subjects in order to determine the local chemotactic activity in terms of CD11b up-regulation. Monocyte chemotactic protein-1 (MCP-1), a marker of systemic monocyte chemotactic activity, was also analyzed in serum at 0 and 10 hours in all individuals.
RESULTS: The number of monocytes at the site of inflammation in the interstitium in hemodialysis patients correlated with the expression of CD11b on transmigrated cells (r = 0.78, P < 0.001). Monocytes collected in the active blister fluid of dialysis patients expressed equal levels of CD11b as cells collected from healthy subjects. By contrast, monocytes collected from the control blisters of patients expressed lower levels of CD11b than cells from healthy subjects (P < 0.01), despite equal interstitial biological activity of CD11b-mobilizing factors in blister fluid from patients and healthy subjects and the fact that patients had higher systemic chemotactic activity in terms of MCP-1 concentration in serum (P < 0.001).
CONCLUSION: Monocytes from hemodialysis patients have the capacity to mobilize CD11b to the same extent as cells from healthy individuals at the inflammatory spot, but more intense stimuli are required for such actions, probably because of a transient refractoriness.
PMID: 10792630 [PubMed - indexed for MEDLINE]
[The drama of blood contamination in France. An approach to public health].
Presse Med. 2000 Mar 18;29(10):547-52
Authors: Manuel C, Auquier P, San Marco JL
The tragic HIV contamination of hemophilics and transfusion recipients between 1980 and 1985 in France led to low court proceeding the same events. In addition, last June a state minister was arraigned for not recalling transfused patients before 1985. This involves later events and announces other court actions. France is the only country where these dramatic events have take on the dimension of a major political scandal. Based on the scientific elements (reactions and articles in the international medical literature) and an analysis of the decisions made by France, a chronological examination of the disease and the risks for hemophiliacs and transfusion recipients offers helpful insight into possible options for reducing these risks. The interval between these the court proceeding allows time for further thought focusing on a serious deviation of public health in France.
PMID: 10761524 [PubMed - indexed for MEDLINE]
Lack of effect of sodium nitroprusside on insulin-mediated blood flow and glucose disposal in the elderly.
Metabolism. 2000 Mar;49(3):373-8
Authors: Meneilly GS, Battistini B, Floras JS
Insulin increases skeletal muscle blood flow in healthy young subjects by a nitric oxide (NO)-dependent mechanism. Impairment of this mechanism may contribute to the insulin resistance of normal aging, a state characterized by reduced endothelial production of NO, an attenuated effect of insulin on skeletal muscle blood flow, and resistance to insulin-mediated glucose uptake (IMGU). We tested the hypothesis that the NO donor sodium nitroprusside (SNP) would augment insulin-mediated vasodilation and thus increase IMGU in healthy elderly subjects. Experiments were performed with young (n = 9; age, 25 +/- 1 years; body mass index [BMI], 24 +/- 1 kg/m2) and old (n = 10; age, 78 +/- 2 years; BMI, 25 +/- 1 kg/m2) healthy subjects. Each group underwent two studies in random order. In one study (control), insulin was infused using the euglycemic clamp protocol for 240 minutes at a rate of 40 mU/m2/min (young) and 34 mU/m2/min (old). In the other study (SNP), SNP was coinfused with insulin from 120 to 240 minutes. At regular intervals in each study, blood samples were obtained and calf blood flow was measured using venous occlusion plethysmography. Glucose and insulin values were similar in control and SNP studies in both age groups. In the young, SNP had no effect on blood flow to the calf, but its action in calf resistance vessels augmented insulin-mediated vasodilation, since incremental calf vascular conductance was greater during SNP infusion (control v SNP, 0.027 +/- 0.002 v 0.040 +/- 0.008 mL/100 mL/min/mm Hg, P< .0001). However, SNP had no effect on insulin-mediated glucose disposal. In the elderly, SNP reduced the blood flow to the calf, but this was countered by its effect on calf resistance vessels such that vascular conductance was unaffected (control v SNP, 0.012 +/- 0.003 v 0.011 +/- 0.003 mL/100 mL/min/mm Hg, P = nonsignificant [NS]). Steady-state (180 to 240 minutes) glucose disposal (control v SNP, 7.47 +/- 0.47 v 6.54 +/- 0.56 mg/kg/min, P < .01) rates were significantly lower during SNP infusion. In summary, systemic infusion of SNP did not increase insulin-mediated glucose disposal in either young or old subjects. Thus, the present findings do not support the concept that increasing NO availability will enhance glucose disposal in either age group. However, because the incremental increases in IMGU during SNP infusion paralleled the changes in blood supply to the calf rather than calf vascular conductance, any potential benefits on NO delivery in elderly subjects may have been offset by the direct or reflex effects of systemic hypotension. Other stimuli to NO production that do not cause hypotension must be tested before this therapeutic strategy can be considered as a potential means for enhancing the metabolic actions of insulin in the elderly.
PMID: 10726917 [PubMed - indexed for MEDLINE]
Chronic oxidative stress in the RVLM modulates sympathetic control of circulation in pigs.
Pflugers Arch. 2000 Feb;439(4):489-94
Authors: Zanzinger J, Czachurski J
Oxidative stress is a key event in the pathogenesis of several cardiovascular diseases and may be similarly induced by long-term treatment with organic nitrates. We examined the effects of inhibiting extracellular oxidative stress in the rostral ventrolateral medulla (RVLM), the brain stem area which primarily controls sympathetic tone. Superoxide dismutase (SOD, 10 U/microl) was microinjected into the RVLM of anesthetized pigs that were either untreated (control, n=10), treated for 4 weeks with the organic nitrate isosorbidedinitrate (ISDN, 4 mg kg(-1) day(-1), n=6) or ISDN-treated followed by a 2-week recovery period (recovery, n=4). In control animals SOD produced moderate inhibitory effects on baseline sympathetic activity, indicated by decreases in renal sympathetic nerve activity (RSNA), mean arterial blood pressure (MAP), and heart rate (HR) without causing changes in femoral vascular conductance (FC). These effects of SOD were greatly enhanced in ISDN-treated pigs. Following the recovery period, SOD again produced smaller effects in the RVLM but they were, however, still significantly greater than in untreated animals. In contrast, the transmission of sympathoexcitatory reflexes by the RVLM, as evoked by sciatic nerve stimulation, was not affected by SOD injections in either experimental group. Furthermore, the number of NO-synthase-positive neurons in the RVLM region was significantly reduced both in ISDN-treated and the recovery pigs, suggesting that oxidative stress caused sustained changes in NOS activity within the brain stem. These data suggest that excitatory actions of oxidative stress contribute significantly to the generation of baseline sympathetic tone in the RVLM during long-term treatment with organic nitrates. Similar mechanisms could promote sympathetic tone in cardiovascular diseases that are associated with endogenous oxidative stress for longer periods.
PMID: 10678747 [PubMed - indexed for MEDLINE]