Free Medicine Research Articles

P1-151 Free access to medicines for hypertension and diabetes in the population covered by the family health program

IntroductionAccess to medicines is an indicator of the quality and effectiveness of the health system and essential to hypertension and diabetes patients.ObjectiveEstimate the factors associated with lack of free access...

Ironing out neurodegeneration: Iron chelation for neuroprotection

Iron is one of the substances for which the adage “Too much of a good thing is not better” holds true. Iron's ability to readily shift its redox state facilitates cellular respiration but can also catalyze the production of harmful hydroxyl radical when iron's level or location is inappropriate. In this issue of Free Radical Biology & Medicine, the paper by Obolensky et al. highlights the neuroprotective potential of iron chelation, even when iron dysregulation is not the primary cause of the degeneration. Their carefully executed study shows that retinal degeneration in rd10 mice can be ameliorated by treatment with the iron chelator zinc–deferoxamine (Zn-DFO). Rd10 mice have a mutation in the rod photoreceptor phosphodiesterase, required for phototransduction, resulting in a nearly complete loss of both rod and cone photoreceptors by about 6 weeks of age. Mice given Zn-DFO by ip injection beginning at postnatal day 4 have relatively preserved retinal structure and function at several ages, as well as diminished oxidative stress. The number of rods and cones is higher in the treated mice. Electroretinography reveals improved rod and cone function with the Zn-DFO treatment. Both immunostaining and biochemical assays reveal diminished oxidative stress in the Zn-DFO-treated mice. This study builds upon several previous publications showing neuroprotection by iron chelation. DFO protects the rat retina from photo-oxidative stress [1] and from ischemia–reperfusion injury [2]. The oral iron chelator deferiprone protects iron-overloaded retinas of ceruloplasmin/hephaestin knockout mice against oxidative stress and retinal degeneration. It also ameliorates a movement disorder and early mortality associated with brain iron accumulation in these mice [3]. Intraperitoneal injection of the endogenous iron-chelating protein transferrin alsomarkedly protects the rd10 retina from degeneration [4]. Iron chelation can also protect the brain. The chelator salicylaldehyde isonicotinoyl hydrazine protects the rodent spinal cord against trauma [5]. Both elevated levels of the endogenous iron-storage protein ferritin and administration of the metal chelator clioquinol protect the mouse brain against the neurotoxin MPTP, which induces a Parkinson-like neurodegeneration [6]. The mechanism of neuroprotection by these iron chelators is probably prevention of iron-catalyzed oxidative stress, as several of the above studies correlate diminished oxidative stress with chelator administration. Iron excess, or mislocalization, has been associated with age-related neurodegeneration such as age-related macular degeneration [7], Alzheimer disease [8], and Parkinson disease [9], so it is primed to exacerbate ongoing degeneration in these conditions. It can also be released from red blood cells after hemorrhage, or from dying neighbors in ongoing neurodegeneration. Iron dysregulation caused by ongoing neurodegeneration could also accelerate disease. For example, retinas of rd10 mice have altered levels of iron, ferritin, and transferrin [10]. Iron may be mishandled during neurodegeneration because its regulation is also influenced by inflammation and hypoxia, potentially leading to toxic iron stores. Inappropriate iron handling can clearly lead to brain and retina degeneration, as in the hereditary diseases aceruloplasminemia [11], Friedreich ataxia [12], and pantothenate kinase-associated neurodegeneration [13]. Mice with iron-regulatory protein knockout or low ferritin levels also experience neurodegeneration [14]. The above studies support the use of iron chelators in clinical trials for neurodegeneration such as in Alzheimer disease [15] and Friedreich ataxia [16]. Route of administration and toxicity are important considerations. Some chelators can readily cross the blood–brain and blood–retinal barriers. Iron deficiency must be avoided, but it is likely that this could be achieved by careful monitoring and by choosing chelators that can bind or redistribute loosely bound, potentially toxic iron in the central nervous system without stripping iron from iron requiring proteins.

Comment on “Pharmacologic ascorbate synergizes with gemcitabine in preclinical models of pancreatic cancer,” i.e., all we are saying is, give C a chance

The paper in this issue of Free Radical Biology and Medicine titled “Pharmacologic ascorbate synergizes with gemcitabine in pre-clinical models of pancreatic cancer” by Michael G. Espey and colleagues presents a compelling case for the addition of pharmacological, i.e. high-dose, intravenous ascorbate (vitamin C, AscH−) to the standard of care for treatment of pancreatic cancer, which currently is gemcitabine at many institutions [1].

Diabetic neutrophil mitochondrial dysfunction: An inflammatory situation?

Diabetic neutrophil mitochondrial dysfunction: An inflammatory situation?

Increased Coronary Heart Disease Risk Determined by High High-Density Lipoprotein Cholesterol and C-Reactive Protein: Modulation by Variation in the CETP Gene

Epidemiological evidence strongly favors the notion that the risk of cardiovascular disease (CVD) is inversely related to the plasma high-density lipoprotein (HDL) cholesterol concentration.1 Low HDL cholesterol is still predictive of high CVD risk in subjects with low LDL cholesterol,2 as well as during statin treatment.3 These observational data and other studies, which show that HDL particles contain a large number of antioxidative, antiinflammatory, and antiproliferative proteins, underlie the generally held view that HDL particles have atheroprotective properties.1–5 However, evidence is accumulating supporting the concept that high HDL cholesterol levels do not always predict reduced CVD risk. The Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) trial and the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk case-control study revealed that (recurrent) CVD risk is not decreased in subjects with the highest HDL cholesterol and the greatest mean HDL particle size.6 More recently, a high HDL cholesterol, high C-reactive protein (CRP) subgroup of individuals at increased risk for a first cardiovascular event was identified in the community-dwelling Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort using the “outcome event mapping approach,” a graphical exploratory data analysis tool that has been originally developed by Corsetti et al.7 Applying this analytic method to the Thrombogenic Factors and Recurrent Coronary Events (THROMBO) postinfarction cohort, the presence of a subgroup …

Resurrecting Hope for Antioxidant Treatment of Cardiovascular Disease

Oxidative stress has been associated with cardiovascular disease and the development of hypertension in both humans and in animal models. Antioxidant therapy has been successful in ameliorating disease in animals, but the results from human studies have been largely disappointing. Despite these negative results, a wealth of evidence suggests that oxidative stress is involved in the development of cardiovascular disease both in humans and animal models. Because global attenuation of cellular reactive oxygen species (ROS) may not be advantageous, more recent therapeutic strategies target specific subcellular sources of oxidative stress. Most studies implicate plasmalemmal membrane-bound NADPH oxidase as a key mediator of ROS generation in cardiovascular disease. However, in the current issue of Circulation Research , Dikalova et al1 demonstrate that specific attenuation of mitochondrial derived oxidants prevents the development of angiotensin II–induced hypertension in the mouse. Perhaps more interesting is the mechanism: inhibition of a mitochondrial ROS-triggered activation of NADPH oxidase, interrupting a vicious cycle of ROS production. The novel approach of targeting the inciting source of ROS (mitochondria) to prevent accelerated oxidant production may hold more promise for humans by eliminating pathological but not homeostatic sources of ROS. Seminal observations by Harrison et al2 showed evidence of increased oxidative stress within the systemic vasculature in an Angiotensin II–induced rat model of hypertension, piquing interest in a possible etiologic role for ROS in this condition. In animal models, stimulating ROS production can induce hypertension,2,3 whereas treatment with a variety of antioxidants including vitamin C and E, or targeted inhibition of enzymatic oxidant production, can reduce blood pressure.3–6 Hypertensive patients demonstrate increased NAD(P)H oxidase activity7 with elevated levels of hydrogen peroxide in plasma.8 Antioxidant treatment leads to enhanced vasodilation in both forearm and coronary arteries of human hypertensive subjects,9,10 indicating a functional vasomotor …

Experimental Errors: Paul Bert and the Alabama Tenure Killings

Experimental Errors: Paul Bert and the Alabama Tenure Killings

Scientific Opinion on the substantiation of health claims related to alpha lipoic acid and protection of body lipids from oxidative damage (ID 1434, 3134), maintenance of normal blood cholesterol concentrations (ID 3134), increased beta‐oxidation of fatty acids (ID 3134), maintenance of normal blood glucose concentrations (ID 1435, 3162), and “regeneration of genes, regeneration of gene transcription and the influence to

EFSA JournalVolume 8, Issue 2 1474 OpinionOpen Access Scientific Opinion on the substantiation of health claims related to alpha lipoic acid and protection of body lipids from oxidative damage (ID 1434, 3134), maintenance of normal blood cholesterol concentrations (ID 3134), increased beta-oxidation of fatty acids (ID 3134), maintenance of normal blood glucose concentrations (ID 1435, 3162), and “regeneration of genes, regeneration of gene transcription and the influence to activity NF kappa B” (ID 3133) pursuant to Article 13(1) of Regulation (EC) No 1924/2006 EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this author EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA), EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)Search for more papers by this author First published: 25 February 2010 https://doi.org/10.2903/j.efsa.2010.1474Citations: 2 Panel members: Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Hannu Korhonen, Pagona Lagiou, Martinus Løvik, Rosangela Marchelli, Ambroise Martin, Bevan Moseley, Monika Neuhäuser-Berthold, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Stephan Strobel, Inge Tetens, Daniel Tomé, Hendrik van Loveren, and Hans Verhagen. Correspondence: nda@efsa.europa.eu Acknowledgement: The Panel wishes to thank for the preparation of this opinion: The members of the Working Group on Claims : Carlo Agostoni, Jean-Louis Bresson, Susan Fairweather-Tait, Albert Flynn, Ines Golly, Marina Heinonen, Hannu Korhonen, Martinus Løvik, Ambroise Martin, Hildegard Przyrembel, Seppo Salminen, Yolanda Sanz, Sean (J.J.) Strain, Inge Tetens, Hendrik van Loveren and Hans Verhagen. The membres of the Claims Sub-Working Group on Cardiovascular Health/Oxidative Stress: Antti Aro, Marianne Geleijnse, Marina Heinonen, Ambroise Martin, Wilhem Stahl and Henk van den Berg. Adoption date: 21 December 2009 Published date: 25 February 2010 Question number: EFSA-Q-2008-2171, EFSA-Q-2008-2172, EFSA-Q-2008-3865, EFSA-Q-2008-3866, EFSA-Q-2008-3894 On request from: European Commission AboutPDF ToolsExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References Marangon K, Devaraj S, Tirosh O, Packer L and Jialal I, 1999. Comparison of the effect of alpha-lipoic acid and alpha-tocopherol supplementation on measures of oxidative stress. Free Radical Biology and Medicine, 27, 1114– 1121. Citing Literature Volume8, Issue2February 20101474 ReferencesRelatedInformation

NO Way to Relax

The roles of nitric oxide (NO) in the heart have been studied intensely ever since the first report nearly 2 decades ago showing that endogenous NO modulates cardiac myocyte function.1 All 3 NO synthase (NOS) isoforms have been found in mammalian heart tissues (see reviews in Massion et al2 and Belge et al3). A complex array of myocyte and nonmyocyte cells in the heart express NOS isoforms, and the local generation of NO2,3 and reactive oxygen species (ROS)4 may exert both autocrine and paracrine effects on cellular function. Not only is the endothelial isoform of NOS (eNOS, or NOS3) robustly expressed in the endothelial cells of the cardiac vasculature, but eNOS is also present within cardiac myocytes, where the enzyme associates with the scaffolding/regulatory protein caveolin-3 in T tubules in plasmalemmal caveolae.5 The neuronal NOS (nNOS, or NOS1) is also expressed in cardiac myocytes, where the enzyme appears to be localized in the sarcoplasmic reticulum and modulates phospholamban phosphorylation.6 Although both eNOS and nNOS appear to be physiologically expressed in cardiac tissues, the inflammation-related NOS isoform (iNOS, or NOS2) only appears in the heart after immunoactivation; iNOS may modulate the decline in myocardial function seen in sepsis.7 There have been innumerable studies of the cardiac effects of various NOS inhibitors, NO-donating drugs, and NO itself.2 The cardiac phenotypes of NOS “knockout” mouse models have been characterized extensively, and mice lacking 1, 2, or all 3 NOS isoforms have been generated and characterized.8 In addition, the roles of NOS substrates, cofactors, and allosteric modulators have been explored exhaustively in diverse cardiac model systems. Emerging from this broad range of experimental evidence is an increasingly clear view that NO and NOS are key determinants of cardiac function. Yet the molecular mechanisms and …

TOX 21: New Dimensions of Toxicity Testing

On the ground floor of the National Institutes of Health Chemical Genomics Center (NCGC) in Rockville, Maryland, a $10-million automated laboratory spends all day and night screening chemicals at speeds no team of human researchers could ever match. In a week, depending on the nature of the assay, it can yield up to 2.2 million molecular data points derived from thousands of chemicals tested at 15 concentrations each.

The shy Angeli and his elusive creature: the HNO route to vasodilation

what we now call Angeli's salt (AS) was discovered more than a century ago by the Italian chemist Angelo Angeli (Fig. 1) . He found that “salts of nitroxylaminic acid are readily resolved into the corresponding nitrites and the unsaturated residue nitroxyl” (HNO), proposing their use as suppliers of HNO (3). However, by analogy with the genial but very reclusive personality of the discoverer (17), the physiological properties of HNO didn't draw too much attention until early 1990s. In their seminal work, Fukuto and colleagues (19) reported that HNO elicits vasorelaxation in both the rabbit aorta and bovine intrapulmonary artery by a soluble guanylate cyclase (sGC)- dependent pathway. Later, it was evident that the thiol-donating agent l-cysteine can discriminate the vasodilatative profile of HNO from that of nitric oxide (NO·) or nitrosothiols: AS/HNO action can be blocked by this agent, whereas the NO· effect is potentiated (36). In combination with the suggestion that NO· is the only species able to directly activate sGC (9), these data led to the conclusion that HNO-induced vasorelaxation is due to its intracellular conversion to NO· with subsequent activation of sGC. For several years, this idea has relegated HNO to a mere precursor of the presence and biological activity of NO·, de facto negating to HNO its own right to exist.

Leukocyte Telomere Length, Hypertension, and Atherosclerosis

In this issue of Hypertension , Yang et al1 report that leukocyte telomere length (LTL) is shorter in hypertensive patients than in their normotensive peers. What’s more, after 5 years of follow-up, the authors observed that hypertensive patients with short LTL were more likely to develop atherosclerotic coronary artery disease, whereas normotensive persons with short LTL were more likely to become hypertensive. Several features of this study merit attention. First, the study was conducted in a Chinese cohort, whereas the information we have about the relationships between LTL and cardiovascular risks is primarily derived from white populations. Second, the size of the cohort (388 hypertensive and 379 normotensive persons) and the meticulous attention devoted to characterizing hypertension lend credibility to the findings. Third, the 5-year follow-up period provided the opportunity to explore the potential cardiovascular ramifications of having a short LTL. Thus, the findings of this work indicate that the association between LTL and risks for coronary artery atherosclerosis apply not only to white but also to Chinese populations. What is the biological meaning of the associations between LTL and aging-related diseases, principally atherosclerosis and its risk factors? The short answer is: we do not know. What we do know is that LTL is highly variable at birth and throughout life.2 We also know that age-dependent LTL shortening is much faster in early life than during adulthood,3 probably because of the rapid proliferation of hematopoietic stem cells (HSCs) during growth and development. In fact, LTL shortening throughout life largely mirrors telomere shortening in HSCs. In these cells, like in other somatic cells with rudimentary activity of telomerase (the reverse transcriptase that adds telomere repeats onto …

PENGALAMAN PERAWATAN IBU YANG MEMILIKI BAYI GIZI BURUK DI KABUPATEN REJANG LEBONG, BENGKULU: STUDI FENOMENOLOGI

Caring Experiences of Mothers Who Have Malnourished Infants In Rejang Lebong District, Bengkulu Province: A Phenomenological Study). Background: Rejang Lebong District has the highest prevalence of malnourished under-fives among all districts of Bengkulu Province. Theoretically, to overcome malnutrition a good strategy of nutrition education to mothers and nurturing the children were really required. Therefore, the problem came out how mothers nurturing their malnourished children in Rejang Lebong District. Objectives: This research aims was to find out the experience of nursing malnourished children by mothers in Rejang Lebong Municipality. Methods: A qualitative approach was used to conduct this research by using Focus Group Discussion particularly phenomenology approach. In order to collect information 20 respondents were interviewed consisted of: 4 midwives, 3 community leaders, 6 village leaders, and 7 cadres. Results: The result showed that colostrums was not given to babies, because of dirty milk, children were not given breast milk cause of lack of breast milk mother. Moreover, children frequently was given snack which was not nutritious food. Other aspects were that people used drinking water from the river which was not good quality, moreover them others did not use soap to wash the dishes. Conclusions: Malnourished children frequently got sick accompanied by fever, diarrhea, cough, influenza, and to overcome these diseases the mothers brought their children to the health center and midwife, however, most of them cured by buying free medicine. The knowledge of mothers about the usage of colostrums, breast care, nutritious food, avoiding from infection diseases and nurturing their children still were not good enough. Keywords: malnourished infants, mothers' caring experiences, phenomenological study.

Paraoxonase and Coronary Heart Disease Risk

Organophosphates were first synthesized in the 1930s as insecticides1 and were subsequently shown to have direct neurotoxic effects in mammals, as well. The neurotoxicity is derived from their ability to inhibit acetylcholinesterase by covalently modifying the active-site serine group in the enzyme. Mazur2 first demonstrated the presence of an organophosphate-hydrolyzing enzyme in mammalian tissue, an observation that ultimately led to the identification of a human paraoxonase in serum in 1953.3 Paraoxonase—so named because of its ability to hydrolyze the toxic metabolite of parathion, paraoxon—was also shown early after its identification to manifest arylesterase activity, an effect that was underappreciated until the enzyme was found to play a role in modulating vascular oxidant stress many years later. Article see p 147 The paraoxonase story is a good example of the power of language to mislead. There is no teleological reason for mammals to have evolved an enzyme that can hydrolyze synthetic organophosphates; yet, paraoxonase was isolated in an effort to understand the endogenous metabolism of these exogenous neurotoxins. The enzymatic activity for which the enzyme is named is screened by using synthetic substrates without regard for the native substrate or its role in human (patho)biology. This focus on one aspect of the enzyme’s function, overemphasized by its denotation, delayed an appreciation of other potential—and perhaps more relevant—roles. In 1991, Mackness et al4 showed that paraoxonase …

RETRACTED: Expression of the longevity proteins by both red and white wines and their cardioprotective components, resveratrol, tyrosol, and hydroxytyrosol

Resveratrol increases longevity through SirT1, which is activated with NAD(+) supplied by an anti-aging enzyme PBEF. SirT1 interacts with an anti-aging transcription factor, FoxO1, which is negatively regulated by Akt. Since white wine could have similar health benefits as red wine, we determined if white wine and its cardioprotective components possess anti-aging properties by feeding rats with these compounds. The hearts expressed SirT, FoxO, and PBEF in the order of white wine>resveratrol>tyrosol>hydroxytyrosol>red wine, while cardioprotection shown by reduction of infarct size and cardiomyocyte apoptosis followed a different pattern: resveratrol>red wine>hydroxytyrosol>white wine>tyrosol, suggesting the existence of different signaling mechanisms for the induction of longevity and survival.

Highlight Commentary on “Influence of lung oxidant and antioxidant status on alveolarization: Role of light-exposed total parenteral nutrition”

Bronchopulmonary dysplasia (BPD) is a frequent complication of premature newborns, particularly very low birth-weight babies (< 1500 g). Undoubtedly multiple mechanisms contribute to the adverse outcomes associated with BPD but oxidative stress is one causative factor. In this issue of Free Radical Biology and Medicine, Lavoie et al. describe the increased peroxide generation when the multivitamin solution used for nutritional support, total parenteral nutrition (TPN), is exposed to ambient light. Because the premature newborn has limited antioxidant capacity, this increased oxidative burden from the TPN becomes increasingly significant. Infusion of this light-exposed solution in a newborn guinea pig decreased lung tissue vitamin C but not vitamin E. When the multivitamin and lipid solutions were mixed and then exposed to light, alveolarization of the developing lung was decreased. This study by Lavoie et al. highlights simple measures that can potentially decrease the oxidant burden delivered to this vulnerable population and improve alveolarization.

Cardiac RAGE in Sepsis

See related article, pages 1239–1246 Sepsis is a systemic inflammatory response syndrome triggered by infection. The hallmarks of clinical sepsis are a broad range of systemic and organ function aberrations, including core temperature (hypothermia or hyperthermia), cardiac (rate and contractility), and respiratory and hematologic perturbations. When sepsis results in at least 1 organ failure or dysfunction, it is classified as severe sepsis. Severe sepsis with hypotension unresponsive to fluid resuscitation defines septic shock. Sepsis syndrome afflicts almost 750 000 patients in the United States each year, at a cost of almost $17 billion, and causes more than 200 000 deaths annually. The incidence of sepsis syndrome continues to rise along with the increase in life span and several other important risk factors. Sepsis without organ dysfunction is a relatively benign condition, and spontaneous recovery with conservative measures results in low in-hospital mortality (5% to 10%). Severe sepsis and septic shock carry high mortality, 30% to 50%, in spite of all that modern treatment offers.1–3 Genetic predisposing factors have been proposed including mutations in cytokine genes such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6. Most of these polymorphisms, implicated in increasing severity of sepsis, are associated with increases in these proinflammatory cytokines. Abnormalities in Toll-like receptor-4 and its signaling kinase, IRAK-4, have been associated with worse outcomes. The alarming increase in pathogens resistant to antibiotics that, in the past, were very effective in prevention and treatment of sepsis no doubt contributes to increases in severe sepsis prevalence in the elderly. The key mechanisms believed to initiate and propagate …

Early-Life Arsenic Exposure: Methylation Capacity and Beyond

Inorganic arsenic (iAs), a toxic metalloid, affects millions of people worldwide, mainly from drinking contaminated water. Arsenic is a human carcinogen that targets skin, lung, bladder, and possibly other sites. iAs and its methylated metabolites readily cross the placenta and reach the fetus [National Research Council (NRC) 1999], producing effects ranging from developmental toxicity to cancer (NRC 1999; Waalkes et al. 2007). Thus, early-life As exposures are drawing escalating health concerns. In this issue of Environmental Health Perspectives, Li et al. (2008) report on iAs metabolism in pregnant Bangladeshi women exposed to iAs through contaminated water. iAs is metabolized to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) for urinary excretion; urinary As speciation is widely used to assess As methylation capacity. Arsenic methylation capacity can be influenced by dietary intake of cysteine, methionine, folic acid, niacin, vitamin B12, and choline (Steinmaus et al. 2005), and dietary folic acid supplementation to malnourished arsenicosis patients can decrease As burden by decreasing blood MMA and increasing urinary DMA (Gamble et al. 2007). However, despite poor micronutrient status and high As exposure, the pregnant Bangladeshi women showed remarkably efficient As methylation. The median percentage of urinary DMA (74%) is in the upper range, and MMA (11%) in the lower range of what is commonly seen in urine of individuals from developed counties with much better nutrition (Vahter 2007). Women during childbearing years are more efficient at As methylation than men (Lindberg et al. 2007), particularly during pregnancy. This is likely due to the de novo synthesis of choline by the phosphatidylethanolamine methyltransferase (PEMT) pathway (Vahter 2007), which can be up-regulated by estrogen. Thus, the PEMT pathway may function in malnourished pregnant women to increase choline production needed for fetal development, and, perhaps fortuitously for As methylation (Vahter 2007). The remarkable efficiency of As methylation in malnourished pregnant women could also be an adaptive response to As exposure. Such adaptation might increase As methylation, and thereby excretion, during pregnancy, but perhaps at the expense of later toxicity. Methyl groups from S-adenosylmethionine are essential to both As and DNA methylation. DNA methylation status is a well-recognized controlling factor in gene expression. Furthermore, alterations in DNA methylation status are a recognized epigenetic mechanism in As carcinogenesis and are linked with As exposure in various systems (Pilsner et al. 2007; Waalkes et al. 2004). Gestation is a critical period of cell differentiation and genetic programming during development, and a highly sensitive time for initiation of chemical carcinogenesis (Waalkes et al. 2007). Thus, adaptation to As methylation in malnourished pregnant women could impact fetal development via altered gene expression. Activation of the PEMT pathway through estrogen signaling is clearly beneficial for As methylation (Vahter 2007). In contrast, aberrant estrogen signaling is linked with transplacental As carcinogenesis in mice (Waalkes et al. 2004, 2007). Arsenic also has potential synergistic effects with estrogenic carcinogens (Waalkes et al. 2007). Indeed, when in utero As exposure is followed by diethylstilbestrol treatment in newborn mice, tumors at multiple sites show synergistic increases in adulthood, including various estrogen sensitive targets (Waalkes et al. 2007). Recent data show that early-life As exposure has significant impact on human health (Fry et al. 2007; Smith et al. 2006). In newborns from mothers exposed to iAs through contaminated water in Thailand, altered transcript profiles in cord blood include stress-related genes and breast cancer/estrogen-signature genes (Fry et al. 2007), suggesting an adaptive response to As and pointing toward future health issues. Smith et al. (2006) observed a remarkable increase in lung cancer incidence in young adults in Chile who had been exposed to iAs in utero; this suggests a human transplacental carcinogenic potential for As. Thus, regardless of the immediate temporal tolerance to As during pregnancy, preventing early-life As exposure of the fetus and improving nutritional status of pregnant women may be critical for the health of future generations.

A Critique of SAINT II

Marc Fisher MD Kennedy Lees MD Section Editors: The neutral results of the SAINT II study1 dashed the hopes for a second ischemic stroke drug in the near future. Although this is certainly disappointing for stroke neurologists, a careful analysis of the NXY-059 development program reveals several deficiencies, which if properly addressed, might revitalize and strengthen the field of neuroprotection for acute ischemic stroke. This critique points out several potential reasons for the failure of SAINT II to replicate the positive findings of SAINT 1,2 discusses the preclinical problems with NXY-059, and provides a perspective on the development of future neuroprotective agents for acute ischemic stroke. The SAINT II trial1 investigated the efficacy of the free-radical–trapping agent, NXY-059, for the treatment of acute ischemic stroke and failed to confirm the positive results of SAINT I.2 In the latter study with 1699 patients, NXY-059 showed for the first time in a large phase III trial that a drug other than tissue plasminogen activator (t-PA) might lead to significant improvement on the modified Rankin Scale (mRS) using a novel and controversial outcome analysis (Rankin shift analysis). The larger SAINT II trial with 3306 patients not only failed to replicate improvement on the same primary end point but all secondary end points (neurological deficits on the National Institutes of Health Stroke Scale (NIHSS) at 90 days and activities of daily living on the Barthel Index at 90 days) were identical between treatment groups. Besides the obvious possibility that the drug itself was inactive, which may be considered due to the known instability of free-radical–trapping agents, several additional problems were evident. Both trials were designed, in part, as combination studies, testing the addition of NXY-059 to standard therapy compared with t-PA alone in the 3-hour time window. SAINT II gave …

Evidence Mounts That Nitrite Contributes to Hypoxic Vasodilation in the Human Circulation

Hypoxic vasodilation is a conserved physiological response to hypoxia that matches blood flow and oxygen delivery to tissue metabolic demand. This fundamental physiological process has been characterized for >100 years since the initial description by Roy and Brown1 in 1880. Hypoxic vasodilation requires a sensor mechanism that can detect a divergence in the normal relationship between delivered blood oxygen and tissue oxygen consumption.2 This hypoxic sensor mechanism must be coupled to the feedback generation of vasodilatory effectors that increase blood flow to maintain adequate tissue oxygenation. In short, hypoxic vasodilation requires hypoxia and/or pH sensing coupled to the release of a vasodilating signal. In mammalian species, the set point for hypoxic vasodilation occurs as the hemoglobin desaturates from 60% to 40%, around a partial pressure of oxygen ranging from 40 to 20 mm Hg.3 Despite the fact that the hypoxic vasodilation response was discovered almost 150 years ago, the identities of the oxygen sensor mechanism and the specific feedback vasodilator effectors remain uncertain. Although a number of mediators have been considered, including adenosine, nitric oxide (NO), ATP-sensitive potassium (KATP) channels, endothelium-derived hyperpolarizing factor (candidates include CO, H2O2, or ONOO−), and prostacyclin,2,4 the specific blockade of many of these pathways fails to completely inhibit hypoxic vasodilation.2 Article p 670 The present study published by Maher and colleagues5 in this issue of Circulation provides compelling evidence in normal human volunteers that the circulating anion salt nitrite (NO2−) may be an effector of hypoxic vasodilation. They report that nitrite potently vasodilates the venous forearm circulation under resting conditions and potently vasodilates the arteriolar circulation during experimental hypoxia, achieved by systemic breathing of 11% oxygen. Their studies indicate that the vasodilatory effect of nitrite is maximal in the deoxygenated venous …