bluuebunny/crossref_metadata_2025 huggingface dataset:
Low mercury concentrations cause oxidative stress and endothelial dysfunction in conductance and resistance arteries
Authors: Wiggers G. A. , Peçanha F. M. , Briones A. M. , Pérez-Girón J. V. , Miguel M. , Vassallo D. V. , Cachofeiro V. , Alonso M. J. , Salaices M.
Published: July 2008

Increased cardiovascular risk after mercury exposure has been described, but the underlying mechanisms are not well explored. We analyzed the effects of chronic exposure to low mercury concentrations on endothelium-dependent responses in aorta and mesenteric resistance arteries (MRA). Wistar rats were treated with mercury chloride (1st dose 4.6 μg/kg, subsequent dose 0.07 μg·kg−1·day−1im, 30 days) or vehicle. Blood levels at the end of treatment were 7.97 ± 0.59 ng/ml. Mercury treatment: 1) did not affect systolic blood pressure; 2) increased phenylephrine-induced vasoconstriction; 3) reduced acetylcholine-induced vasodilatation; and 4) reduced in aorta and abolished in MRA the increased phenylephrine responses induced by either endothelium removal or the nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine methyl ester (l-NAME, 100 μM). Superoxide dismutase (SOD, 150 U/ml) and the NADPH oxidase inhibitor apocynin (0.3 mM) decreased the phenylephrine-induced contraction in aorta more in mercury-treated rats than controls. In MRA, SOD did not affect phenylephrine responses; however, when coincubated with l-NAME, the l-NAME effect on phenylephrine response was restored in mercury-treated rats. Both apocynin and SOD restored the impaired acetylcholine-induced vasodilatation in vessels from treated rats. Endothelial NOS expression did not change in aorta but was increased in MRA from mercury-treated rats. Vascular O2−production, plasmatic malondialdehyde levels, and total antioxidant status increased with the mercury treatment. In conclusion, chronic exposure to low concentrations of mercury promotes endothelial dysfunction as a result of the decreased NO bioavailability induced by increases in oxidative stress. These findings offer further evidence that mercury, even at low concentrations, is an environmental risk factor for cardiovascular disease.
Endothelial and vascular dysfunctions and insulin resistance in rats fed a high-fat, high-sucrose diet
Authors: Bourgoin Frédéric , Bachelard Hélène , Badeau Mylène , Mélançon Sébastien , Pitre Maryse , Larivière Richard , Nadeau André
Published: July 2008

This study was designed to examine the effects of a high-fat, high-sucrose (HFHS) diet on vascular and metabolic actions of insulin. Male rats were randomized to receive an HFHS or regular chow diet for 4 wk. In a first series of experiments, the rats had pulsed Doppler flow probes and intravascular catheters implanted to measure blood pressure, heart rate, and regional blood flows. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine skeletal muscle glucose transport activity and to determine in vitro vascular reactivity, endothelial nitric oxide synthase (eNOS) protein expression in muscle and vascular tissues and endothelin content, nitrotyrosine formation, and NAD(P)H oxidase protein expression in vascular tissues. The HFHS-fed rats displayed insulin resistance, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, elevated blood pressure, and impaired insulin-mediated renal and skeletal muscle vasodilator responses. A reduction in endothelium-dependent vasorelaxation, accompanied by a decreased eNOS protein expression in muscles and blood vessel endothelium, and increased vascular endothelin-1 protein content were also noted in HFHS-fed rats compared with control rats. Furthermore, the HFHS diet induced a reduced insulin-stimulated glucose transport activity in muscles and increased levels of NAD(P)H oxidase protein and nitrotyrosine formation in vascular tissues. These findings support the importance of eNOS protein in linking metabolic and vascular disease and indicate the ability of a Westernized diet to induce endothelial dysfunction and to alter metabolic and vascular homeostasis.
Endothelial EphA receptor stimulation increases lung vascular permeability
Authors: Larson Jacqueline , Schomberg Stacey , Schroeder William , Carpenter Todd C.
Published: July 2008

Mediators of angiogenesis such as VEGFs and angiopoietins may regulate pulmonary vascular permeability under normal and pathological conditions. Ephrin family receptor tyrosine kinases are expressed in the vasculature and also regulate angiogenesis under some circumstances, but whether they also modulate lung vascular permeability is unknown. We hypothesized that stimulation of lung endothelial EphA receptors with ephrin-a1 ligand would alter pulmonary vascular permeability and tested this idea in vivo and in vitro. We found that ephrin-a1 ligand and EphA2 receptors are expressed in distal normal lung vasculature and that their expression is increased in injured lung, suggesting a link to mechanisms of increased permeability. Intravenous injection of ephrin-a1 caused a large increase in the leakage of labeled albumin into the lungs of rats within 30 min (293 ± 27 vs. 150 ± 6 ng/mg dry lung, P < 0.01), along with histological evidence of the formation of endothelial disruptions. In cultured lung vascular endothelial cells, stimulation with ephrin-a1 increased monolayer permeability by 44% ( P < 0.01), a permeability change similar to that seen with VEGF stimulation of the same cells. Ephrin-a1 stimulation in vivo and in vitro was associated with histological evidence for disruptions of tight and adherens junctions. These observations describe a novel role for ephrin-a1 and EphA receptors in the regulation of vascular permeability in the lung.
Bones benefits gained by jump training are preserved after detraining in young and adult rats
Authors: Honda Akiko , Sogo Naota , Nagasawa Seigo , Kato Takeru , Umemura Yoshihisa
Published: July 2008

We investigated the osteogenic responses to jump training and subsequent detraining in young and adult male rats to test the following hypotheses: 1) jump training has skeletal benefits; 2) these skeletal benefits are preserved with subsequent detraining throughout bone morphometric changes; and 3) there are no differences between young and adult rats during detraining in terms of the maintenance of exercise-induced changes. Twelve-week-old (young) and 44-wk-old (adult) rats were divided into the following four groups: young-sedentary, young-exercised, adult-sedentary, and adult-exercised. The exercised groups performed jump training (height = 40 cm, 10 jumps/day, 5 days/wk) for 8 wk followed by 24 wk of being sedentary. Tibial bone mineral content and bone mineral density in vivo significantly increased with jump training, and the effects were maintained after detraining in both the young and adult exercised groups, although the benefits of training became somewhat diminished. After 24 wk of detraining, the beneficial effects of training on bone mass and strength were preserved and associated with morphometric changes, such as periosteal perimeter, cortical area, and moment of inertia. There were no significant age-exercise interactions in such parameters, except for the periosteal perimeter. These results suggest that there are few differences in bone accommodation and maintenance by training and detraining between young and adult rats.
MRI analysis of structural changes in skeletal muscles and surrounding tissues following long-term walking exercise with training equipment
Authors: Nakai Ryusuke , Azuma Takashi , Sudo Mai , Urayama Shin-ichi , Takizawa Osamu , Tsutsumi Sadami
Published: July 2008

Muscular recovery after exercise is an important topic in sports medicine, and accurate and quantitative measurements of changes in muscle are required to assess muscular recovery. In the present study, we report a new analytical method to measure muscular changes quantitatively. The technique consists of three independent methods: image processing of two-dimensional MR images, morphological analysis using three-dimensional MR images, and diffusion tensor MRI. Using this method, we investigated changes in the quadriceps and biceps femoris and gluteus maximus muscles and surrounding tissues before and after 1 mo of exercise wearing training equipment. The subjects were 21 healthy adult female volunteers, 14 of whom wore training equipment and 7 who wore normal equipment. The percentage of adipose tissue in muscle after exercise in subjects who wore training equipment was on average 4.4% ( P < 0.001) lower than that before exercise, and the peak point of the dorsal hip after exercise with use of the equipment was on average 10.8 mm higher than that before exercise. Further, the fractional anisotropy of water diffusion in muscles increased by an average of 0.039 ( P < 0.001) after exercise with use of training equipment. In contrast, there was no significant difference before and after exercise in subjects who wore normal equipment. These results show that walking exercise while wearing training equipment thickens and tightens the muscular fiber tissues. This noninvasive measurement approach may allow quantitation of the athletic ability of the muscles, which is not measured conventionally, and is an effective method for analyzing skeletal muscles.
Regulation of Mesangial Cell Alpha-Smooth Muscle Actin Expression in 3-Dimensional Matrix by High Glucose and Growth Factors
Authors: Whiteside Catharine , Munk Snezana , Ispanovic Eric , Wang Hong , Goldberg Howard , Kapus Andras , Xia Ling
Published: July 2008

Background/Aims: We postulated that α-smooth muscle actin expressed in primary cultured mesangial cells is down-regulated in 3-dimensional (D) culture and up-regulated by high glucose and growth factors. Methods: Primary rat mesangial cells were growth-arrested in 5.6 mM (NG) or 30 mM (HG) glucose for 14 days in 3-D Matrigel. Alpha-SM actin expression was analyzed by immunoblotting, real-time PCR and by α-SM actin promoter activity in response to 24 h stimulation with endothelin-1 (ET-1), angiotensin II (Ang II) or HG. Results: Alpha-SM actin mRNA, protein and promoter activity were reduced to significantly lower levels in 3-D cells compared to cells in 2-D. Up-regulation of α-SM expression was stimulated by ET-1, Ang II and HG. Specific inhibitors of protein kinase C (PKC)-α, -β or -ζ prevented α-SM upregulation in HG. In NG, PKC and ERK1/2 activation were required for α-SM actin accumulation in 3-D in response to ET-1 or Ang II. In HG, enhanced expression of α-SM actin in response to ET-1 or Ang II was unchanged during PKC or ERK1/2 inhibition. Conclusion: Mesangial cells in 3-D express low levels of α-SM actin representing a more differentiated state. Regulation of α-SM actin expression is dependent on specific PKC isozyme and ERK1/2 signaling.
A Distinct Population of Tubular Cells in the Distal S3 Segment Contributes to S3 Segment Regeneration in Rats following Acute Renal Failure Induced by Uranyl Acetate
Authors: Sakakima Masanori , Fujigaki Yoshihide , Yamamoto Tatsuo , Hishida Akira
Published: July 2008

Background: We previously reported that early regenerating cells found at the distal area of the S3 segment of the nephron (designated as target cells) were label-retaining cells in uranyl acetate (UA)-induced acute renal failure (ARF) in rats. In this study, we examined the contribution of these target cells to S3 segment repair after UA treatment. We also discriminated target cells from bromodeoxyuridine (BrdU)-label-retaining cells labeled under normal conditions and examined their capacity to proliferate following a second insult and their resistance to 5-fluorouracil (5-FU). Methods: Target cells were labeled and tracked using a 3H-thymidine pulse/chase approach after UA (4 mg/kg) injection to rats. Normal rats were labeled with BrdU, and cells positive for BrdU and Ki67 were analyzed after UA treatment. The kinetics of target cells was examined after a second dose of UA and treatment with 5-FU. Results: The target cells were strongly labeled by 3H-thymidine and were predominantly found in the distal quarter of the S3 segment until 40 weeks after generating ‘label-diluted’ cells throughout the S3 segment. Cells labeled with BrdU under normal conditions did not express Ki67 after UA treatment but target cells were Ki67-positive. The target cells underwent further proliferation following the second treatment with UA and were transiently arrested by 5-FU treatment at G0/G1 after UA. Conclusions: The target cells are slow-cycling cells, resistant to 5-FU treatment and have the capacity to undergo further proliferation following a second insult with UA. These data suggest the presence of a distinct population of cells that can regenerate the S3 segment in UA-induced ARF.
Association of Polymorphism (Val66Met) of Brain-Derived Neurotrophic Factor with Suicide Attempts in Depressed Patients
Authors: Sarchiapone Marco , Carli Vladimir , Roy Alec , Iacoviello Licia , Cuomo Chiara , Latella Maria Carmela , di Giannantonio Massimo , Janiri Luigi , de Gaetano Monica , Janal Malvin N.
Published: July 2008

Introduction: Recent post-mortem studies of suicide victims have implicated brain-derived neurotrophic factor (BDNF) in suicide. Therefore, it was decided to examine the possible role of a gene in the regulation of BDNF activity in relation to suicidal behaviour among depressed patients. Method: A series of 170 depressed patients were evaluated for their history of suicide attempts and genotyped for the BDNF Val66Met polymorphism (SNP ID: rs6265). Depressed patients who had (n = 97) or had not (n = 73) attempted suicide were compared. Results: Depressed patients who carried the BDNF Val66Met polymorphism variant (GA + AA) appeared to show a significantly increased risk of suicidal behaviour. The risk of a suicide attempt was also significantly higher among those reporting higher levels of childhood emotional, physical and sexual abuse. Secondary analyses suggested that depression severity was a significant risk factor only in the wild-type BDNF genotype, and that the risk of suicide attempts was more predictable within the wild-type group. Conclusion: These preliminary data suggest that BDNF may play a role in the suicidal behaviour of depressed patients.
How Depression May Increase Cardiac Risk: Effect of Hypercortisolism on Platelet Activation Markers
Authors: Baranyai Réka , Nonell Annemarie , Deuschle Michael , Lederbogen Florian
Published: July 2008

Introduction: Hypercortisolism, as seen in the majority of patients with major depression, may be associated with the generation of platelets that show signs of increased activation. Methods: Within a study using a placebo-controlled double-blind cross-over design, 9 healthy subjects ingested hydrocortisone (daily dose = 40 mg) or placebo on 7 consecutive days. At the end of each study segment, we analyzed platelets for the surface activation markers P-selectin, glycoprotein 53, and PAC-1 and measured platelet-leucocyte aggregates in serum. Results: Hydrocortisone ingestion was not associated with changes in the platelet activation markers P-selectin and PAC-1 or the number of circulating platelet-leucocyte aggregates but with a trend (p = 0.056) toward higher expression of glycoprotein 53 on the platelet surface. Conclusions: Induction of hypercortisolism in healthy volunteers was not associated with a major increase in platelet activation markers.
Frequent Attenders in Primary Care: Impact of Medical, Psychiatric and Psychosomatic Diagnoses
Authors: Ferrari S. , Galeazzi G.M. , Mackinnon A. , Rigatelli M.
Published: July 2008

Background: Anxiety, mild depression and somatization are common in primary care (PC). Several studies have suggested that they may play a role in causing an excessive use of health care services, especially when combined with medical morbidity. The present case-control study explored how psychiatric and psychosomatic diagnoses and perceived quality of life are associated with the phenomenon of frequent attendance. Method: Fifty most frequent attenders (FAs) in a 1-year period at a PC clinic in Italy were compared with 50 randomly selected average frequency attenders at the same clinic. Sociodemographic and medical data were collected from PC files. The SCID-brief version for research and the Structured Interview for Diagnostic Criteria for Use in Psychosomatic Research (DCPR) were administered to both patient groups. Quality of life was also assessed. Results: FA status was associated with being female, older, less well educated, and living with their spouses and/or children. Medical-psychiatric comorbidity was more frequent in the FA group than in the control group. The median number of psychosomatic-DCPR syndromes per patient was 4 among FAs compared to only 1 in controls. Functional somatic symptoms secondary to a psychiatric disorder, type A behavior, irritable mood, and demoralization were significantly associated with being an FA. Perceived quality of life was significantly lower among FAs, although this was no longer significant after adjusting for sociodemographic variables. Conclusions: The present study confirms the association between medical-psychiatric comorbidity and frequent utilization of PC resources. It suggests a role for DCPR criteria in revealing subthreshold psychiatric comorbidity predicting a pattern of frequent attendance.
Positive Psychological Impact of Treating Victims of Politically Motivated Violence among Hospital-Based Health Care Providers
Authors: Shiri Shimon , Wexler Isaiah D. , Alkalay Yasmin , Meiner Zeev , Kreitler Shulamith
Published: July 2008

Background: Health care personnel treating victims of politically motivated violence are at risk for traumatic stress symptoms. Few studies have assessed the positive psychological impact of politically motivated violence on health care workers. In this study, the level of positive psychological impact among health care workers with recurrent exposure to victims of politically motivated violence was examined. Methods: A validated questionnaire survey of health care personnel treating victims of politically motivated violence during 2000–2005 in two hospital settings was conducted. Positive psychological impact was assessed by the Posttraumatic Growth Inventory and traumatic stress symptoms were assessed using the Revised Posttraumatic Stress Disorder Inventory. Subjects included physicians (surgeons and anesthesiologists), nurses, and psychotherapists. Results: The rate of response to the mail-in questionnaires was 68.3% (n = 138). The sample consisted of 70 physicians, 37 nurses, and 31 hospital-based psychotherapists. Positive psychological impact was noted for the entire sample and among all professions. Traumatic stress symptoms predicted positive psychological impact for the entire sample and for each profession, and there was a curvilinear relationship between traumatic stress symptoms and positive psychological impact. Women experienced greater levels of positive psychological impact. Conclusions: Hospital-based health care providers treating victims of politically motivated violence experience both positive and negative psychological impact. Individuals who are more traumatized by their experience are more likely to also have a positive psychological impact.
The Role of the TGF/Smad Signaling Pathway in Peritoneal Fibrosis Induced by Peritoneal Dialysis Solutions
Authors: Yao Qiang , Pawlaczyk Krzysztof , Ayala Ernesto Rodríguez , Styszynski Arkadiusz , Breborowicz Andrzej , Heimburger Olof , Qian Jia Qi , Stenvinkel Peter , Lindholm Bengt , Axelsson Jonas
Published: July 2008

Background: Peritoneal dialysis (PD) solutions contribute to peritoneal membrane damage. We investigated how conventional and biocompatible PD solutions with different glucose concentrations affect morphological and functional signs of peritoneal fibrosis as well as the TGF-β1/Smad signaling pathway in a chronic PD rat model. Methods: Non-uremic male Wistar rats (n = 28) were dialyzed thrice daily for 28 days with 20 ml of a conventional solution (Dianeal® 1.36%, D1, or 3.86%, D3) or a biocompatible solution (Physioneal® 1.36%, P1, or 3.86%, P3). A peritoneal equilibration test was performed. Six rats without dialysis served as controls. Results: The use of conventional solutions, particularly D3, resulted in expansion of the submesothelial compact zone, loss of mesothelial cell layer integrity, hypercellularity, accumulation of collagen I, increased vessel numbers and increased TGF-β1/Smad expression, but this did not significantly change fluid and solute peritoneal transport characteristics. In comparison with D1 and D3, the use of P1 and P3 was associated with less TGF-β1/Smad expression and less expansion of the submesothelial cell layer. Conclusions: Our findings indicate that biocompatible solutions with less glucose may decrease the rate of peritoneal fibrosis. The TGF-β1/Smad pathway is stimulated by PD solutions, representing a plausible pathophysiological mechanism.
Circulating Endothelial Progenitor Cells in Patients with ANCA-Associated Vasculitis
Authors: Závada Jakub , Kideryová Linda , Pytlík Robert , Vaňková Zdenka , Tesař Vladimír
Published: July 2008

Background/Aims: Bone marrow-derived endothelial progenitor cells (EPCs) are believed to contribute to endothelial repair after vascular damage. To investigate the potential for microvascular repair in patients with ANCA-associated vasculitis (AAV), we conducted a cross-sectional study determining the number of circulating EPCs in patients with AAV, chronic uremia, atherosclerosis, and in healthy volunteers. Methods: The number of circulating EPCs was determined by colony-forming assay in 41 patients with AAV, 15 hemodialysis patients (without vasculitis), 13 patients with peripheral arterial occlusive disease (PAOD), and 25 healthy controls. Results: Patients with AAV had a significantly lower number of CFU-Hill than healthy subjects (median 0.3 vs. 19.5 CFU-Hill/ml blood, p < 0.0001), but not than patients on hemodialysis or with PAOD. Neither institution of treatment nor entering remission increased the number of EPCs in AAV patients. The number of EPCs did not correlate with markers of disease activity. AAV patients with glomerular filtration rate <15 ml/min had an even lower number of circulating EPCs than patients with better preserved renal function (median 0.05 vs. 1.2 CFU-Hill/ml, p = 0.015) and patients with anti-MPO positivity had a trend towards a higher number of EPCs than patients with anti-PR3 antibodies (median 3.1 vs. 0.18 CFU-Hill/ml, p = 0.06). Conclusion: Patients with AAV have a significant and persistent deficiency of circulating EPCs. A low number of EPCs could reflect an impaired mechanism of vascular repair and may contribute to repeated relapses in these patients.
Diabetes Mellitus: Is It Protective against Aortic Root Dilatation?
Authors: Chen Xiao-Feng , Wang Jian-An , Lin Xian-Fang , Tang Li-Jiang , Yu Wei-Fang , Chen Han , Xie Xiao-Jie , Jiang Jian-Jun , Peng Xiao-Hui
Published: July 2008

Objectives: There is evidence of a negative association between diabetes and both abdominal aortic aneurysm and aortic diameter. However, little information is available on the relation between diabetes and aortic root diameter. Methods: We studied 109 patients with type 2 diabetes. Two-dimensional echocardiography was used to measure the aortic root at the aortic annulus, the sinus of Valsalva, the sinotubular junction and the proximal part of the ascending aorta. Measured mean values were compared with 218 age- and sex-matched patients without diabetes. A comparison of the prevalence of aortic regurgitation between the 2 groups was also performed. Results: In patients with diabetes, the mean aortic root dimensions were significantly smaller than in nondiabetic patients (p < 0.05). The prevalence of aortic root dilatation was significantly higher in nondiabetic subjects than in patients with diabetes (9.63 vs. 2.75%; p = 0.025). In the multivariable regression model, diabetes was a significant negative determinant of aortic root size at all measured sites. The prevalence of aortic regurgitation tended to be higher in nondiabetic subjects than in diabetic participants (11 vs. 18.8%); however, the difference did not achieve statistical significance (p = 0.071). Conclusions: In patients with diabetes, the aortic root dimension is significantly smaller than in patients without diabetes.
Is Greater Social Support a Protective Factor against Elder Mistreatment?
Authors: Dong XinQi , Simon Melissa A.
Published: July 2008

Background: Elder mistreatment (EM) is a pervasive global health issue and a violation of basic human rights. Our prior study indicates that EM is alarmingly common in an urban Chinese population, yet little is known about risk and/or protective factors for EM. Objective: This study’s goal was to examine the association of social support with the risk of EM and underlying hypothesis is that greater social support is associated with a lower risk for EM. Methods: A cross-sectional descriptive study was performed in a major urban medical center in Nanjing, China. A total of 412 subjects aged 60 years or older who presented to the general medical clinic were surveyed. Social support was assessed using validated instruments Social Support Index (SSI); direct questions were asked about their mistreatment since age 60 using the modified Vulnerability to Abuse Screening Scale (VASS). Results: EM was found in 35% of the participants. After adjusting for potential confounding factors, several factors were associated with a lower risk of mistreatment: having someone to listen to and talk to (OR = 0.18, 95% CI, 0.08–0.39), having someone to get you good advice from (OR = 0.15 (0.07–0.34)), having someone to show love and affection to (OR = 0.30 (0.12–0.75)), having someone available who can help with daily chores (OR = 0.43 (0.22–0.85)), having contact with someone they can trust and confide in (OR = 0.08 (0.03–0.23)), and having someone they can count on for emotional support (OR = 0.11 (0.04–0.28)). Regarding total social support scores (range 1–32), every point higher in social support was associated with a 6% lower risk for EM (OR = 0.94 (0.91–0.97)). Greater social support was associated with a 59% lower risk for EM (OR = 0.41 (0.19–0.90)). Conclusion: Greater social support may be a protective factor against EM in this population. Prospective studies are needed to confirm this finding. Interventions that improve social support may prevent EM.
Neutrophil Gelatinase-Associated Lipocalin Reflects the Severity of Renal Impairment in Subjects Affected by Chronic Kidney Disease
Authors: Bolignano Davide , Lacquaniti Antonio , Coppolino Giuseppe , Campo Susanna , Arena Adriana , Buemi Michele
Published: July 2008

Neutrophil gelatinase-associated lipocalin (NGAL) is a small 25-kDa protein released from kidney tubular cells after harmful stimuli. It represents one of the most promising future biomarkers in the diagnostic field of acute kidney injury (AKI), as the increase in NGAL levels is a good predictor of a brief-term onset of AKI, notably anticipating the resulting increase in serum creatinine. However, recent studies also suggest a possible role for NGAL in chronic kidney disease (CKD). For this reason we evaluated serum (sNGAL) and urinary NGAL (uNGAL) in a cohort of CKD patients in order to verify the relationship with the severity of renal impairment. In CKD patients sNGAL, uNGAL and the fractional excretion of this protein were notably increased as compared to controls. Furthermore both sNGAL and uNGAL were correlated with serum creatinine and, inversely, with residual glomerular filtration rate (GFR): this last relationship was found to be even closer than that found between GFR and serum creatinine. Multivariate models validate these correlations as independent, confirming that in these patients NGAL is a better predictor of GFR than serum creatinine. The results confirm NGAL as an important biomarker in clinical nephrology, extending to CKD the pathophysiological role of this protein in tubular adaptations to renal damage.
Retardation of Retinal Vascular Development in Apelin-Deficient Mice
Authors: Kasai Atsushi , Shintani Norihito , Kato Hideaki , Matsuda Satoshi , Gomi Fumi , Haba Ryota , Hashimoto Hitoshi , Kakuda Michiya , Tano Yasuo , Baba Akemichi
Published: July 2008

Objective—

Apelin is an endogenous ligand for the G protein-coupled receptor, APJ, and participates in multiple physiological processes. To identify the roles of endogenous apelin, we investigated the phenotype of apelin-deficient (apelin-KO) mice.

Methods and Results—

Apelin-KO mice showed impaired retinal vascularization and ocular development, which were analyzed by histology, immunohistochemistry, real-time polymerase chain reaction, and the mouse corneal micropocket assay. Apelin-KO mice showed significantly impaired retinal vascularization in the early postnatal period. Retinal apelin/APJ mRNAs were transiently upregulated during the first 2 postnatal weeks but were undetectable in adults. There were no differences in VEGF or FGF2 mRNA expression, or in the morphology and localization of GFAP-positive astrocytes, in the apelin-KO retinas at P5. The corneal pocket assay showed that angiogenic responses to VEGF and FGF2 were remarkably decreased in apelin-KO mice. The reduced responses to VEGF and FGF2 in apelin-KO mice were partially restored by apelin, but apelin alone did not induce angiogenesis.

Conclusions—

Our results suggest that spatiotemporally regulated apelin/APJ signaling participates in retinal vascularization in a cooperative manner with VEGF or FGF2, and contributes to normal ocular development.
Air Pollution Exposure Potentiates Hypertension Through Reactive Oxygen Species-Mediated Activation of Rho/ROCK
Authors: Sun Qinghua , Yue Peibin , Ying Zhekang , Cardounel Arturo J. , Brook Robert D. , Devlin Robert , Hwang Jing-Shiang , Zweier Jay L. , Chen Lung Chi , Rajagopalan Sanjay
Published: July 2008

Objective—

Fine particulate matter <2.5 μm (PM
2.5
) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM
2.5
in the angiotensin II (AII) infusion model.

Methods and Results—

Sprague-Dawley rats were exposed to PM
2.5
or filtered air (FA) for 10 weeks. At week 9, minipumps containing AII were implanted and the responses studied over a week. Mean concentration of PM
2.5
inside the chamber was 79.1±7.4 μg/m
3
. After AII infusion, mean arterial pressure was significantly higher in PM
2.5
-AII versus FA-AII group. Aortic vasoconstriction to phenylephrine was potentiated with exaggerated relaxation to the Rho-kinase (ROCK) inhibitor Y-27632 and increase in ROCK-1 mRNA levels in the PM
2.5
-AII group. Superoxide (O
2
·
−
) production in aorta was increased in the PM
2.5
-AII compared to the FA group, inhibitable by apocynin and L-NAME with coordinate upregulation of NAD(P)H oxidase subunits p22
phox
and p47
phox
and depletion of tetrahydrobiopterin. In vitro exposure to ultrafine particles (UFP) and PM
2.5
was associated with an increase in ROCK activity, phosphorylation of myosin light chain, and myosin phosphatase target subunit (MYPT1). Pretreatment with the nonspecific antioxidant N-Acetylcysteine and the Rho kinase inhibitors (Fasudil and Y-27632) prevented MLC and MYPT-1 phosphorylation by UFP suggesting a O
2
·−
-mediated mechanism for PM
2.5
and UFP effects.

Conclusions—

Short-term air pollution exaggerates hypertension through O
2
·−
-mediated upregulation of the Rho/ROCK pathway.
Overexpression of Human ABCG1 Does Not Affect Atherosclerosis in Fat-Fed ApoE-Deficient Mice
Authors: Burgess Braydon , Naus Kathryn , Chan Jeniffer , Hirsch-Reinshagen Veronica , Tansley Gavin , Matzke Lisa , Chan Benny , Wilkinson Anna , Fan Jianjia , Donkin James , Balik Danielle , Tanaka Tracie , Ou George , Dyer Roger , Innis Sheila , McManus Bruce , Lütjohann Dieter , Wellington Cheryl
Published: July 2008

Objective—

The purpose of this study was to evaluate the effects of whole body overexpression of human ABCG1 on atherosclerosis in apoE
−/−
mice.

Methods and Results—

We generated BAC transgenic mice in which human ABCG1 is expressed from endogenous regulatory signals, leading to a 3- to 7-fold increase in ABCG1 protein across various tissues. Although the ABCG1 BAC transgene rescued lung lipid accumulation in ABCG1
−/−
mice, it did not affect plasma lipid levels, macrophage cholesterol efflux to HDL, atherosclerotic lesion area in apoE
−/−
mice, or levels of tissue cholesterol, cholesterol ester, phospholipids, or triglycerides. Subtle changes in sterol biosynthetic intermediate levels were observed in liver, with chow-fed ABCG1 BAC Tg mice showing a nonsignificant trend toward decreased levels of lathosterol, lanosterol, and desmosterol, and fat-fed mice exhibiting significantly elevated levels of each intermediate. These changes were insufficient to alter ABCA1 expression in liver.

Conclusions—

Transgenic human ABCG1 does not influence atherosclerosis in apoE
−/−
mice but may participate in the regulation of tissue cholesterol biosynthesis.
Lipoprotein(a) Is Associated Differentially With Carotid Stenosis, Occlusion, and Total Plaque Area
Authors: Klein Jonathan H. , Hegele Robert A. , Hackam Daniel G. , Koschinsky Marlys L. , Huff Murray W. , Spence J. David
Published: July 2008

Background—

Lipoprotein(a) [Lp(a)] is a putative risk factor for myocardial infarction and stroke and is related to thrombosis and impaired fibrinolysis. We studied relationships of Lp(a) with carotid stenosis, occlusion, and total plaque area, distinct phenotypes of atherosclerosis that may be differentially affected by cardiovascular risk factors.

Methods and Results—

Multivariable linear regression analysis was used to study relationships of Lp(a) to phenotypes of carotid atherosclerosis among 876 consecutive patients from an atherosclerosis prevention clinic with complete data for all variables used in the model. Occlusion of an internal carotid artery was present in 22 (2.5%) patients (one with bilateral occlusions). Risk factors predicted carotid plaque area, stenosis, and occlusion differently. Lp(a) was a significant independent predictor of baseline stenosis (
P
<0.0001) but not of plaque area (
P
=0.13); in logistic regression, Lp(a) significantly predicted occlusion (
P
=0.001). Patients with occlusion had significantly higher levels of Lp(a): 0.27±0.25 g/L versus 0.17±0.18 g/L without occlusion;
P
=0.007.

Conclusion—

Lp(a) was a significant independent predictor of carotid stenosis and occlusion, but not of carotid plaque area, supporting the hypothesis that the effect of Lp(a) on atherogenesis and cardiovascular risk is largely related to thrombosis and impaired fibrinolysis. Stenosis and occlusion may not be attributable to plaque progression, but to plaque rupture and thrombosis; this relationship may also apply to other arterial beds.
Lipoprotein Particle Concentrations May Explain the Absence of Coronary Protection in the Women’s Health Initiative Hormone Trials
Authors: Hsia Judith , Otvos James D. , Rossouw Jacques E. , Wu LieLing , Wassertheil-Smoller Sylvia , Hendrix Susan L. , Robinson Jennifer G. , Lund Bernedine , Kuller Lewis H.
Published: July 2008

Objective—

The Women’s Health Initiative randomized hormone trials unexpectedly demonstrated an increase in early coronary events. In an effort to explain this finding, we examined lipoprotein particle concentrations and their interactions with hormone therapy in a case–control substudy.

Methods and Results—

We randomized 16 608 postmenopausal women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10 739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo, and measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy at baseline and year 1 in 354 women with early coronary events and matched controls. Postmenopausal hormone therapy raised high-density lipoprotein cholesterol and particle concentration and reduced low-density lipoprotein cholesterol (LDL-C; all
P
<0.001 versus placebo). In contrast, neither unopposed estrogen nor estrogen with progestin lowered low-density lipoprotein particle concentration (LDL-P).

Conclusions—

Postmenopausal hormone therapy–induced reductions in LDL-C were not paralleled by favorable effects on LDL-P. This finding may account for the absence of coronary protection conferred by estrogen in the randomized hormone trials.
AMP-Activated Protein Kinase Promotes the Differentiation of Endothelial Progenitor Cells
Authors: Li Xiaoxia , Han Yingying , Pang Wei , Li Chenghong , Xie Xuefen , Shyy John Y.-J. , Zhu Yi
Published: July 2008

Objective—

Endothelial progenitor cells (EPCs) can differentiate into endothelial cells (ECs) and participate in postnatal vasculogenesis, but the mechanism of EPC differentiation remains largely unknown. We investigated the role of AMP-activated protein kinase (AMPK) in EPC differentiation and functions.

Methods and Results—

Vascular endothelial growth factor caused the phosphorylation of AMPK, acetyl-coenzymeA (CoA) carboxylase (ACC), and eNOS in human cord blood-derived EPCs. The expression of EC markers, including VE-cadherin and intercellular adhesion molecule1 (ICAM-1), was also increased but blocked by Compound C, an AMPK inhibitor. AICAR, an AMPK agonist, increased the phosphorylation of ACC and eNOS and the expression of EC markers in a time- and dose-dependent manner, which reinforces the positive effect of AMPK on EPC differentiation. The effects of AICAR could be blocked by treatment with L-NAME, an eNOS inhibitor. Functionally, AICAR increased but Compound C decreased the angiogenesis of EPCs in vitro and in vivo. Furthermore, lovastatin promoted the activation of AMPK and eNOS, the expression of EC markers, tube formation, adhesion, and in vivo vasculogenesis of EPCs, which could be blocked by treatment with Compound C.

Conclusion—

The activation of eNOS by AMPK during EPC differentiation provides a novel mechanism for the pleiotropic effects of statins in benefiting the cardiovascular system.
Reactive Oxygen Species-Induced Activation of p90 Ribosomal S6 Kinase Prolongs Cardiac Repolarization Through Inhibiting Outward K
+
Channel Activity
Authors: Lu Zhibo , Abe Jun-ichi , Taunton Jack , Lu Yan , Shishido Tetsuro , McClain Carolyn , Yan Chen , Xu Sheng Ping , Spangenberg Thomas M. , Xu Haodong
Published: July 2008

p90 ribosomal S6 kinase (p90RSK) is activated in cardiomyopathies caused by conditions such as ischemia/reperfusion injury and diabetes mellitus in which prolongation of cardiac repolarization and frequent arrhythmias are common. Molecular mechanisms underlying the electric remodeling in cardiac diseases are largely unknown. In the present study, we determined the role of p90RSK activation in the modulation of voltage-gated K
+
channel activity determining cardiac repolarization. Mice with increased cardiac p90RSK activity due to transgenic expression of p90RSK (p90RSK-Tg) had prolongation of QT intervals and of ventricular myocyte action potential durations. Fast transient outward K
+
current (
I
to,f
), slow delayed outward K
+
current (
I
K,slow
), and steady-state K
+
current (
I
SS
) were significantly decreased in p90RSK-Tg mouse ventricular myocytes. mRNA levels of Kv4.3, Kv4.2, Kv1.5, Kv2.1, and KChIP2 from ventricles between p90RSK-Tg and nontransgenic littermate control mice were similar, as assessed by quantitative reverse transcriptase–polymerase chain reaction, indicating that p90RSK regulates voltage-gated K
+
channels through posttranslational modification. Kv4.3- and Kv1.5- rather than Kv4.2- and Kv2.1-encoded channels in HEK 293 cells were inhibited by p90RSK. In vitro phosphorylation analysis showed that Kv4.3 was phosphorylated by p90RSK at 2 conserved sites,
Ser516
and
Ser550
. p90RSK expression significantly inhibited Kv4.3- and Kv4.3 and KChIP2-encoded channel activities in HEK 293 cells, whereas p90RSK’s effects were blocked by amino acid mutation(s) at phosphorylation site(s) in Kv4.3. Hydrogen peroxide, a mediator of induced cardiac p90RSK activation in ischemia/reperfusion injury and diabetes mellitus, had effects similar to those of p90RSK on Kv4.3- or Kv4.3- and KChIP2-encoded channels. Fluoromethylketone, a specific p90RSK inhibitor, abolished hydrogen peroxide effects. These findings indicate that p90RSK activation is critical for reactive oxygen species-mediated inhibition of voltage-gated K
+
channel activity and leads to prolongation of cardiac repolarization.
Connexin40 Imparts Conduction Heterogeneity to Atrial Tissue
Authors: Leaf David E. , Feig Jonathan E. , Vasquez Carolina , Riva Pamela L. , Yu Cindy , Lader Joshua M. , Kontogeorgis Andrianos , Baron Elvera L. , Peters Nicholas S. , Fisher Edward A. , Gutstein David E. , Morley Gregory E.
Published: July 2008

Impulse propagation in cardiac tissue is a complex process in which intercellular coupling through gap junction channels is a critical component. Connexin40 (Cx40) is an abundant gap junction protein that is expressed in atrial myocytes. Alterations in the expression of Cx40 have been implicated in atrial arrhythmogenesis. The purpose of the current study was to assess the role of Cx40 in atrial impulse propagation. High-resolution optical mapping was used to study conduction in the right and left atrial appendages of isolated Langendorff-perfused murine hearts. Wild-type (Cx40
+/+
), heterozygous (Cx40
+/−
), and knockout (Cx40
−/−
) mice, both adult and embryonic, were studied to assess the effects of reduced Cx40 expression on sinus node function and conduction velocity at different pacing cycle lengths (100 and 60 ms). In both adult and late-stage embryonic Cx40
+/+
mice, heterogeneity in CV was found between the right and left atrial appendages. Either partial (Cx40
+/−
) or complete (Cx40
−/−
) deletion of Cx40 was associated with the loss of conduction heterogeneity in both adult and embryonic mice. Additionally, sinus node impulse initiation was found to be ectopic in Cx40
−/−
mice at 15.5 days postcoitus, whereas Cx40
+/+
mice showed normal activation occurring near the crista terminalis. Our findings suggest that Cx40 plays an essential role in establishing interatrial conduction velocity heterogeneity in the murine model. Additionally, we describe for the first time a developmental requirement for Cx40 in normal sinus node impulse initiation at 15.5 days postcoitus.
Lidocaine-Induced Brugada Syndrome Phenotype Linked to a Novel Double Mutation in the Cardiac Sodium Channel
Authors: Barajas-Martínez Hector M. , Hu Dan , Cordeiro Jonathan M. , Wu Yuesheng , Kovacs Richard J. , Meltser Henry , Kui Hong , Elena Burashnikov , Brugada Ramon , Antzelevitch Charles , Dumaine Robert
Published: July 2008

Brugada syndrome has been linked to mutations in SCN5A. Agents that dissociate slowly from the sodium channel such as flecainide and ajmaline unmask the Brugada syndrome electrocardiogram and precipitate ventricular tachycardia/fibrillation. Lidocaine, an agent with rapid dissociation kinetics, has previously been shown to exert no effect in patients with Brugada syndrome. We characterized a novel double mutation of SCN5A (V232I in DI-S4+L1308F in DIII-S4) identified in a rare case of lidocaine (1 mg/kg)-induced Brugada syndrome. We studied lidocaine blockade of I
Na
generated by wild-type and V232I+L1308F mutant cardiac sodium channels expressed in mammalian TSA201 cells using patch clamp techniques. Despite no significant difference in steady-state gating parameters between V232I+L1308F and wild-type sodium currents at baseline, use-dependent inhibition of I
Na
by lidocaine was more pronounced in V232I+L1308F versus wild-type (73.0±0.1% versus 18.23±0.04% at 10 μmol/L measured at 10 Hz, respectively). A dose of 10 μmol/L lidocaine also caused a more negative shift of steady-state inactivation in V232I+L1308F versus wild-type (−14.1±0.3 mV and −4.8±0.3 mV, respectively). The individual mutations produced a much less accentuated effect. We report the first case of lidocaine-induced Brugada electrocardiogram phenotype. The double mutation in SCN5A, V232I, and L1308F alters the affinity of the cardiac sodium channel for lidocaine such that the drug assumes Class IC characteristics with potent use-dependent block of the sodium channel. Our results demonstrate an additive effect of the 2 missense mutations to sensitize the sodium channel to lidocaine. These findings suggest caution when treating patients carrying such genetic variations with Class I antiarrhythmic drugs.
Involvement of Heat Shock Factor 1 in Statin-Induced Transcriptional Upregulation of Endothelial Thrombomodulin
Authors: Fu Qiang , Wang Junru , Boerma Marjan , Berbée Maaike , Qiu Xiaohua , Fink Louis M. , Hauer-Jensen Martin
Published: July 2008

Statins upregulate endothelial thrombomodulin (TM) by mechanisms that involve members of the Kruppel-like factor family. Although Kruppel-like factors are unequivocally implicated in this process, experimental evidence points to additional mechanisms. Deletion/mutation analysis of reporter constructs was used to demonstrate that mutation of the SP1/Kruppel-like factor element in the TM promoter only partially abolishes statin-induced TM upregulation, whereas simultaneous mutation of relevant heat shock elements and SP1/Kruppel-like factor element completely prevents statin-induced TM upregulation, thus demonstrating a role for heat shock factors (HSFs). We further identified the pathway by which statins increase binding of HSF1 to heat shock elements in the TM promoter. Specifically, statins caused NO-dependent dissociation of HSF1 from heat shock protein 90, nuclear translocation of HSF1, and binding to heat shock elements in the TM promoter. Statins also decreased nuclear content of the HSF1 chaperone 14-3-3β. In addition to reducing TM upregulation, inhibition of HSF1 reduced statin-induced upregulation of tissue plasminogen activator, whereas downregulation of thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor was unaffected. Knockdown of 14-3-3β or inhibition of HSF1 phosphorylation enhanced the effect of statins on TM and tissue plasminogen activator, but did not influence thrombomospondin, plasminogen activator inhibitor 1, or connective tissue growth factor. These data demonstrate that HSF1 is involved in statin-induced regulation of TM. They also suggest that analogous mechanisms may apply to genes that are upregulated by statins, but not to downregulated genes. These results may have broad implications and suggest the use of heat shock protein modulators to selectively regulate pleiotropic statin effects.
Imperial Discourse, Regional Elite, and Local Landscape on the South China Frontier, 1577-1722
Authors: Miles Steven
Published: July 2008

This article describes the consolidation of imperial control and the increase of regional migration on China's southern frontier from 1577 to 1722. After a large-scale military campaign, the Ming state created two neighboring counties in a mountainous area of Guangdong province that had previously been dominated by an unregistered, unsettled, and unruly segment of the population. The Chinese literati elite residing in the more settled and commercially prosperous delta downstream from the two new counties wrote numerous essays celebrating the spread of imperial rule across this landscape. These essays also reveal some ways in which the socioeconomic interests of the delta elite were served by the state's consolidation of the frontier. The two new counties offered opportunities for various kinds of delta residents: merchants organizing the extraction of natural resources, settlers claiming newly emptied lands, and aspiring literati taking advantage of new quotas and less competition in the civil service examinations.