bluuebunny/crossref_metadata_2025 huggingface dataset:
Are Shades of Gray Prognostically Useful in Reporting Myocardial Perfusion Single-Photon Emission Computed Tomography?
Authors: Abidov Aiden , Hachamovitch Rory , Hayes Sean W. , Friedman John D. , Cohen Ishac , Kang Xingping , De Yang Ling , Thomson Louise , Germano Guido , Slomka Piotr , Berman Daniel S.
Published: May 2009

Background—

We have advocated the use of a 5-category “normal,” “probably normal,” “equivocal,” “probably abnormal,” and “definitely abnormal” approach to final interpretation of myocardial perfusion single-photon emission computed tomography (SPECT). The prognostic value of expressing levels of certainty compared with a dichotomous normal/abnormal classification or categories for summed stress scores is unclear.

Methods and Results—

Myocardial perfusion SPECT (MPS) was visually assessed using a standard semiquantitative approach, yielding summed scores that were used for preliminary interpretation using 5 levels of certainty. The interpreter was permitted to then shift the level of certainty in the final interpretation by 1 degree, based on nonperfusion MPS variables and available clinical information. To examine the prognostic value of expressing levels of clinical certainty, we evaluated 20 740 unique consecutive patients who underwent rest Tl-201/stress Tc-99m sestamibi MPS (34.3% vasodilator stress), of whom 845 (4.4%) were lost to follow-up and 1695 were excluded from prognostic analysis due to an early revascularization (<60 days after MPS). The remaining 18 200 patients (59.1% men; age, 65�13 years) were followed up for cardiac death for a mean of 2.7�1.7 years. During the follow-up, a total of 591 cardiac death events occurred. By univariable analysis, there were substantial differences in the distribution of follow-up cardiac death by the category of clinical MPS certainty. The clinical certainty was found to be an independent multivariable predictor of cardiac death in the study population and better identified patients at increased risk of cardiac death than the approaches based solely on the standard categories of summed perfusion scores or based solely on categories of segmental perfusion scores.

Conclusions—

The use of multicategory reporting of MPS results incorporating nonperfusion MPS results and clinical information enhances risk stratification compared with both a dichotomous normal/abnormal approach or approaches based solely on segmental categories of perfusion scores. Whether this enhanced risk stratification based on the clinical certainty of the MPS interpretation leads to a more effective therapeutic regimen, tailored to the individual patient’s need, requires further prospective evaluation.
Age-Associated Increases in Pulmonary Artery Systolic Pressure in the General Population
Authors: Lam Carolyn S.P. , Borlaug Barry A. , Kane Garvan C. , Enders Felicity T. , Rodeheffer Richard J. , Redfield Margaret M.
Published: May 2009

Background—

In contrast to the wealth of data on isolated systolic hypertension involving the systemic circulation in the elderly, much less is known about age-related change in pulmonary artery systolic pressure (PASP) and its prognostic impact in the general population. We sought to define the relationship between PASP and age, to evaluate which factors influence PASP, and to determine whether PASP is independently predictive of mortality in the community.

Methods and Results—

A random sample of the Olmsted County, Minn, general population (n=2042) underwent echocardiography and spirometry and was followed up for a median of 9 years. PASP was measured from the tricuspid regurgitation velocity. Left ventricular diastolic pressure was estimated with Doppler echocardiography (E/e′ ratio), and arterial stiffening was assessed from the brachial artery pulse pressure. Among 1413 subjects (69%) with measurable PASP (age, 63±11 years; 43% male), median PASP was 26 mm Hg (25th to 75th percentile, 24 to 30 mm Hg) and increased with age (
r
=0.31,
P
<0.001). Independent predictors of PASP were age, pulse pressure, and mitral E/e′ (all
P
≤0.003). Increasing PASP was associated with higher mortality (hazard ratio, 2.73 per 10 mm Hg;
P
<0.001). In subjects without cardiopulmonary disease (any heart failure, coronary artery disease, hypertension, diabetes mellitus, or chronic obstructive lung disease), the age-adjusted hazard ratio was 2.74 per 10 mm Hg (
P
=0.016).

Conclusions—

We provide the first population-based evidence of age-related increase in pulmonary artery pressure, its association with increasing left heart diastolic pressures and systemic vascular stiffening, and its negative impact on survival. Pulmonary artery pressure may serve as a novel cardiovascular risk factor and potential therapeutic target.
Angiotensin II Type 2 Receptor Antagonizes Angiotensin II Type 1 Receptor–Mediated Cardiomyocyte Autophagy
Authors: Porrello Enzo R. , D'Amore Angelo , Curl Claire L. , Allen Andrew M. , Harrap Stephen B. , Thomas Walter G. , Delbridge Lea M.D.
Published: May 2009

Autophagy has emerged as an important process in the pathogenesis of cardiovascular diseases, but the proximal triggers for autophagy are unknown. Angiotensin II plays a central role in the pathogenesis of cardiac hypertrophy and heart failure. In this study, we used angiotensin II type 1 (AT
1
) and type 2 (AT
2
) receptor–expressing adenoviruses in cultured neonatal cardiomyocytes to provide the first demonstration that neonatal cardiomyocyte autophagic activity is differentially modulated by AT
1
and AT
2
receptor subtypes. Angiotensin II stimulation (48 hours) of neonatal cardiomyocytes expressing the AT
1
receptor alone (Ad-AT
1
; 10 multiplicities of infection) induced a significant increase in the number of HcRed-LC3 autophagosomes per cell (17.3±1.6 versus 33.3±4.1 autophagosomes per cell;
P
<0.05). Coexpression of a high ratio of AT
2
:AT
1
(Ad-AT
2
:Ad-AT
1
multiplicity of infection ratio: 20:5) receptors completely abrogated the AT
1
-mediated increase in autophagy (9.3±1.4 versus 33.3±4.1 autophagosomes per cell;
P
<0.05). Treatment with the AT
2
receptor antagonist PD123319 did not reverse the AT
2
-mediated antiautophagic effect. AT
1
- and AT
2
-mediated autophagic responses were also assessed in cardiomyocytes from a genetic model that exhibits neonatal myocardial growth suppression. In these neonate myocyte cultures, AT
1
receptor activation induced a marked increase in the number of myocytes containing cytoplasmic vacuoles compared with the control (22.7±4.1% versus 1.1±0.6%;
P
<0.001) and was characterized by a nonapoptotic autophagic phenotype. The incidence of cardiomyocyte autophagic vacuolization in this myocyte population decreased dramatically to only 0.4±0.2% in myocytes infected with a high ratio of Ad-AT
2
:Ad-AT
1
. This study provides the first description of reciprocal regulation of cardiomyocyte autophagic induction by the AT
1
and AT
2
receptor subtypes.
Effects of Renal Perfusion Pressure on Renal Medullary Hydrogen Peroxide and Nitric Oxide Production
Authors: Jin Chunhua , Hu Chunyan , Polichnowski Aaron , Mori Takefumi , Skelton Meredith , Ito Sadayoshi , Cowley Allen W.
Published: May 2009

Studies were designed to determine the effects of increases of renal perfusion pressure on the production of hydrogen peroxide (H
2
O
2
) and NO
2
−
+NO
3
−
within the renal outer medulla. Sprague-Dawley rats were studied with either the renal capsule intact or removed to ascertain the contribution of changes of medullary blood flow and renal interstitial hydrostatic pressure on H
2
O
2
and NO
2
−
+NO
3
−
production. Responses to three 30-minute step changes of renal perfusion pressure (from ≈85 to ≈115 to ≈145 mm Hg) were studied using adjustable aortic occluders proximal and distal to the left renal artery. Medullary interstitial H
2
O
2
determined by microdialysis increased at each level of renal perfusion pressure from 640 to 874 to 1593 nmol/L, as did H
2
O
2
urinary excretion rates, and these responses were significantly attenuated by decapsulation. Medullary interstitial NO
2
−
+NO
3
−
increased from 9.2 to 13.8 to 16.1 μmol/L, with parallel changes in urine NO
2
−
+NO
3
−
, but decapsulation did not significantly blunt these responses. Over the range of renal perfusion pressure, medullary blood flow (laser-Doppler flowmetry) rose ≈30% and renal interstitial hydrostatic pressure rose from 7.8 to 19.7 cm H
2
O. Renal interstitial hydrostatic pressure and the natriuretic and diuretic responses were significantly attenuated with decapsulation, but medullary blood flow was not affected. The data indicate that pressure-induced increases of H
2
O
2
emanated largely from increased tubular flow rates to the medullary thick-ascending limbs of Henle and NO largely from increased medullary blood flow to the vasa recta. The parallel pressure-induced increases of H
2
O
2
and NO indicate a participation in shaping the “normal” pressure-natriuresis relationship and explain why an imbalance in either would affect the blood pressure salt sensitivity.
Antihypertensive Medication Use During Pregnancy and the Risk of Cardiovascular Malformations
Authors: Caton Alissa R. , Bell Erin M. , Druschel Charlotte M. , Werler Martha M. , Lin Angela E. , Browne Marilyn L. , McNutt Louise-Anne , Romitti Paul A. , Mitchell Allen A. , Olney Richard S. , Correa Adolfo
Published: May 2009

We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n=5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n=4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings.
Chronotherapy With the Angiotensin-Converting Enzyme Inhibitor Ramipril in Essential Hypertension
Authors: Hermida Ramón C. , Ayala Diana E.
Published: May 2009

Clinical studies have demonstrated a different effect on blood pressure of some angiotensin-converting enzyme inhibitors when administered in the morning versus the evening. Their administration at bedtime resulted in a higher effect on nighttime blood pressure as compared with morning dosing. This study investigated the administration time-dependent effects of ramipril on ambulatory blood pressure. We studied 115 untreated hypertensive patients, 46.7±11.2 years of age, randomly assigned to receive ramipril (5 mg/d) as a monotherapy either on awakening or at bedtime. Blood pressure was measured for 48 hours before and after 6 weeks of treatment. The blood pressure reduction during diurnal activity was similar for both treatment times. Bedtime administration of ramipril, however, was significantly more efficient than morning administration in reducing asleep blood pressure. The awake:asleep blood pressure ratio was decreased after ramipril on awakening but significantly increased toward a more dipping pattern after bedtime dosing. The proportion of patients with controlled ambulatory blood pressure increased from 43% to 65% (
P
=0.019) with bedtime treatment. Nocturnal blood pressure regulation is significantly better achieved at bedtime as compared with morning administration of ramipril, without any loss in efficacy during diurnal active hours. This might be clinically important, because nighttime blood pressure has been shown to be a more relevant marker of cardiovascular risk than diurnal mean values. The change in the dose-response curve, increased proportion of controlled patients, and improved efficacy on nighttime blood pressure with administration of ramipril at bedtime should be taken into account when prescribing this angiotensin-converting enzyme inhibitor for treatment of essential hypertension.
Regulation of Renin Gene Expression by Oxidative Stress
Authors: Itani Hana , Liu Xuebo , Sarsour Ehab H. , Goswami Prabhat C. , Born Ella , Keen Henry L. , Sigmund Curt D.
Published: May 2009

Increased arterial pressure, angiotensin II, and cytokines each result in feedback inhibition of renin gene expression. Because angiotensin II and cytokines can stimulate reactive oxygen species production, we tested the hypothesis that oxidative stress may be a mediator of this inhibition. Treatment of renin-expressing As4.1 cells with the potent cytokine tumor necrosis factor-α caused an increase in the steady-state levels of cellular reactive oxygen species, which was reversed by the antioxidant
N
-acetylcysteine. Exogenous H
2
O
2
caused a dose- and time-dependent decrease in the level of endogenous renin mRNA and decreased the transcriptional activity of a 4.1-kb renin promoter fused to luciferase, which was maximal when the renin enhancer was present. The effect of H
2
O
2
appeared to be specific to renin, because there was no change in the expression of β-actin or cyclophilin mRNA or transcriptional activity of the SV40 promoter. The tumor necrosis factor-α–induced decrease in renin mRNA was partially reversed by either
N
-acetylcysteine or panepoxydone, a nuclear factor κB (NFκB) inhibitor. Interestingly, H
2
O
2
did not induce NFκB in As4.1 cells, and panepoxydone had no effect on the downregulation of renin mRNA by H
2
O
2
. The transcriptional activity of a cAMP response element-luciferase construct was decreased by both tumor necrosis factor-α and H
2
O
2
. These data suggest that cellular reactive oxygen species can negatively regulate renin gene expression via an NFκB-independent mechanism involving the renin enhancer and inhibiting cAMP response element–mediated transcription. Our data further suggest that tumor necrosis factor-α decreases renin expression through both NFκB-dependent and NFκB-independent mechanisms, the latter involving the production of reactive oxygen species.
Misconduct Among Chinese American Adolescents
Authors: Juang Linda P. , Nguyen Huong H.
Published: May 2009

This study examined the relation between acculturation and misconduct among Chinese American adolescents. The sample included 309 adolescents (mean age = 14.7 years, SD = 0.71; 54% female), recruited from two high schools in an ethnically diverse, urban city on the West Coast. Findings showed that acculturation (i.e., generational status and U.S. and Chinese cultural involvements) did not predict misconduct. But specific cultural values (i.e., family obligation and autonomy expectations) did. Specifically, youth with stronger family obligation and later autonomy expectations engaged in less misconduct. Such findings suggest that examining specific and developmentally-salient cultural values may be especially helpful in explaining why some Chinese Americans engage in misconduct.
Ethnic Minority Youth in Youth Programs
Authors: Lee Sun-A , Borden Lynne M. , Serido Joyce , Perkins Daniel F.
Published: May 2009

The authors examine perceptions that young people hold regarding their participation in community-based youth programs. Specifically, this study assesses young people’s sense of psychological safety, their relationships with adult staff, their learning of social skills, and how different ethnic groups experience these factors. Data for the study come from a national evaluation study of youth programs. Participants in this study include 272 White, 100 Asian or Pacific Islander, 61 African American, and 57 Hispanic youth. The results indicate that African American youth are more likely to feel psychologically safe and to have positive relationships with adult staff compared to the other youth. In addition, with the exception of African American youth, the associations between feeling safe and having positive relationships with adult staff and perception of learning social skills were significantly related. The possible explanations of these findings and directions for future research are discussed.
Democracy’s Orphans: Rights, Responsibility, and the Role of the State in the Lives of Incarcerated Youth
Authors: Gardner Joby
Published: May 2009

Transition to adulthood is increasingly complex, extended, and challenging. Working-class Brown and Black young men face very difficult transitions, as they are overrepresented in the justice system, poverty, foster care, special education, and among victims of violence. What effects do these developments have on young people’s places in free democratic society and on the contours and possibilities of youth citizenship? Specifically, how do incarcerated young men view the breadth and limits of democratic citizenship? This article analyzes voices of 25 incarcerated youth and those working with them—recorded through interviews, autobiography, and taped youth club meetings. Findings reveal that incarcerated young men experience expanding responsibilities, notably, criminal penalties; contracting rights and protections; and institutions and systems oriented to their expected failure. Voices presented critique the role of the democratic state (via the justice, educational, and other youth-serving systems) in protecting democracy for marginalized youth and other incumbent citizens.
(Almost) A Closer Walk with Thee
Authors: Hirsch Arnold R.
Published: May 2009

This article was never intended to be an analytical treatment of Hurricane Katrina's impact on the New Orleans metropolitan area. It was, from the start, an opportunistic effort to bring a historian's powers of observation to bear on a catastrophic event sure to have life-altering effects for generations. Finding myself an unwilling participant-observer, I attempted to record what I saw and thought as Katrina killed more than a thousand people, displaced many times that many, and flattened a land mass the size of Great Britain. I looked, at all times, for the nexus of structure and agency, for the conjunction of the natural and the confected, and for the point at which New Orleans' unique history intersected with this singular event.
Understanding Spatial Variation in Tax Sheltering: The Role of Demographics, Ideology, and Taxes
Authors: Gentry William M. , Kahn Matthew E.
Published: May 2009

Taxpayers shelter income from taxation both through illegal evasion and legal avoidance. This tax sheltering creates a difference between a household's actual income and what it reports to the tax authorities. While tax sheltering is a central concern for designing a tax system, the private nature of this behavior complicates evaluating the magnitude and determinants of such behavior. In this article, we combine zip-code level data on reported income from the Internal Revenue Service and the Census Bureau to examine three types of determinants of tax sheltering: (1) tax policy variables, including tax rates (2) political attitudes toward taxation; and (3) demographics. Our estimates suggest that higher tax rates increase the amount of tax sheltering. In terms of political support, our results suggest that places with voters who are either more conservative or less supportive of tax increases actually shelter less income.
A Cross-Cultural Investigation of Students’ Perceptions of the Effectiveness of Pedagogical Tools
Authors: Mahrous Abeer A. , Ahmed Anis Ahmed
Published: May 2009

Despite the growing number of international education programmes, students’ response to various pedagogical tools used in these programmes has rarely been examined. Accordingly, business academics teaching on such programmes may not be sure as to which pedagogical tools to use. This study empirically investigates how various teaching tools affect undergraduate students’ perception of the learning process. A self-administered survey was used to gather data from 461 undergraduate students in the Middle East, the United Kingdom and the United States. Findings demonstrate that the students from each region have a different opinion with regard to the impact of various teaching tools on their learning outcomes. The implications of this for business educators are discussed.
Genocide
Authors: Quigley John
Published: May 2009

This article explores the utility of genocide as a vehicle for the prosecution of individual persons and legal action against a state. It is suggested in the article that for prosecution of individual persons, other categories of offenses may be more effective, hence that genocide may be superfluous. It is suggested that, even though the Genocide Convention (1948) aimed primarily at defining an offense for which individuals would be prosecuted, genocide is an act for which states as well are legally responsible. Legal action against states in the International Court of Justice may be a more useful application of genocide, particularly because such action may aid in stopping atrocities as they are occurring whereas, criminal prosecutions typically are brought only after the fact. Several technical impediments, however, restrict the Court's capacity to deal with genocide, and they, it will be suggested, limit the Court's effectiveness in this regard.
International Criminal Investigations of Genocide and Crimes Against Humanity
Authors: Cencich John R.
Published: May 2009

This article deals with the unique problems that are associated with undertaking international criminal investigations, and it is written from the perspective of a war crimes investigator. Ten problems are identified in relation to investigating violations of international humanitarian law such as genocide, crimes against humanity, and violations of the laws and customs of war. The problems range from differences between legal systems and the unique elements of international crimes on one hand to personal security and counterintelligence operations on the other. The article provides an analysis of the problems international war crimes investigators face on a day-to-day basis and also the first inside look at the strategies that were used in the investigation that resulted in an indictment of the first sitting head-of-state in history, Slobodan Milošević. Recommendations are made with the view to minimizing those problems and maximizing the successful investigation and prosecution of high-level perpetrators at an international venue.
The Humanity of Global Environmental Ethics
Authors: Wapner Paul , Matthew Richard A.
Published: May 2009

Over the past decade, scholars have begun to develop the discipline of global environmental ethics. In doing so, they have encountered two obstacles. First, much environmentalism cloaks itself in the discourse of prudence and security, and thus, ethical concerns are difficult to identify. Second, when scholars do recognize ethical issues, they explain them in terms of how people treat the nonhuman world and advance a biocentric or ecocentric moral sensibility. This is a problem to the degree that it neglects countless instances of environmental injustice that involve the way humans treat each other, using nature as a medium. This article illuminates the nonprudential dimensions of global environmental affairs and explains how a focus on the way humans mistreat each other can serve as a central ethical focus for understanding and addressing environmental injustice. Overall, it aims to provide a vocabulary for advancing an anthropocentric sensibility toward global environmental ethical concern.
Partner Stalking
Authors: Logan TK , Walker Robert
Published: May 2009

Partner stalking may remain one of the least clearly understood forms of intimate violence. This review examines the literature guided by two main goals: (a) to examine how partner stalking is distinct from nonpartner forms of stalking and (b) to describe areas of research on partner stalking that need to be systematically addressed to deepen the understanding of partner stalking and to craft more effective mental health and criminal justice responses. These areas of research include three overarching questions: (a) Is partner stalking a unique form of psychological dominance or is it just “business as usual”? (b) What components characterize stalking differently from business as usual for women? and (c) How is psychological distress within the context of partner stalking best characterized?
Psychopathy in Adolescence Predicts Official Reports of Offending in Adulthood
Authors: Lynam Donald R. , Miller Drew J. , Vachon David , Loeber Rolf , Stouthamer-Loeber Magda
Published: May 2009

The study focused on the incremental predictive utility of psychopathy assessed at age 13 with the Childhood Psychopathy Scale (CPS) in predicting arrests and convictions between the ages of 18 and 26. Data from 338 men from the middle sample of the Pittsburgh Youth Study were used. A variety of control variables were included: demographics (race, family structure, socioeconomic status (SES), and neighborhood SES), parenting (physical punishment, inconsistent discipline, lax supervision, and low positive parenting), peer delinquency, and individual difference variables (impulsivity, verbal IQ, attention-deficit hyperactivity disorder, and conduct disorder). CPS scores at age 13 predicted the variety of arrests and convictions 5 to 13 years later, even after controlling for other well-established and well-measured risk factors. The study concluded that juvenile psychopathy is an important and useful risk factor for future antisocial behavior and also considered the implications of the findings and reasons for resistance to the juvenile psychopathy construct.
Blood Lead Levels in Early Childhood Predict Adulthood Psychopathy
Authors: Wright John Paul , Boisvert Danielle , Vaske Jamie
Published: May 2009

Using data from the Cincinnati Lead Study, this study examines the effects of postnatal blood lead concentrations in early childhood (78 months) on adult psychopathy and six subscales of the Psychopathic Personality Inventory. Results reveal that higher blood lead concentrations in early childhood are associated with higher levels of psychopathic symptoms in adulthood, controlling for the effects of gender, race, mother's IQ, child's intellectual achievement, and the quality of the home environment. Childhood lead levels predicted variation in Machiavellian Egocentricity, Social Potency, Impulsive Nonconformity, and Blame Externalization. Overall, these results implicate lead exposure in the etiology of psychopathy.
The Biosocial Underpinnings to Adolescent Victimization
Authors: Beaver Kevin M. , Boutwell Brian B. , Barnes J.C. , Cooper Jonathon A.
Published: May 2009

Behavioral genetic research has consistently revealed that antisocial behaviors are due partially to genetic factors and partially to environmental factors. Even in light of these findings, researchers have failed to examine the genetic and environmental contributors to adolescent victimization. The current study addressed this gap in the literature by analyzing a sample of twin pairs drawn from the National Longitudinal Study of Adolescent Health (Add Health). The results of the statistical models revealed that genetic factors explained about 40% to 45% of the variance in adolescent victimization, with the remaining variance attributable to the nonshared environment. Moreover, additional analyses revealed that 64% of the variance in repeat victimization was due to genetic factors. The implications that these findings have for victimization researchers are discussed.
Legionnaire's Disease — Part 2
Authors: Newsom SWB
Published: May 2009

The last 30 years has seen the development of knowledge about legionella; how the disease is spread, and its therapy. Unlike other water-borne spread, and its therapy. Unlike other water-borne microbes legionella appear naturally in water, and are spread to humans via aerosols. Most infections are sporadic, but outbreaks such as those in the UK at Kingston and Stafford Hospitals hit the headlines. The dangers of recycling hot water and wet cooling systems have become apparent, and the need for a high index of suspicion and quick response to finding unexpected cases — as in transplant patients in hospital or linked cases such as two BBC workers on one day — is essential.
Treatment of invasive streptococcal infection with a peptide derived from human high-molecular weight kininogen
Authors: Oehmcke Sonja , Shannon Oonagh , von Köckritz-Blickwede Maren , Mörgelin Matthias , Linder Adam , Olin Anders I. , Björck Lars , Herwald Heiko
Published: May 2009

Sepsis and septic shock remain an important medical problem, emphasizing the need to identify novel therapeutic opportunities. Hypovolemic hypotension, coagulation dysfunction, disturbed microcirculation, and multiorgan failure resulting from vascular leakage are often observed in these severe conditions. In the present study, we find that HKH20, a peptide derived from human high molecular weight kininogen (HK), down-regulates inflammatory reactions caused by Streptococcus pyogenes in a mouse model of sepsis. HK is a component of the pro-inflammatory and pro-coagulant contact system. Activation of the contact system in the bloodstream by S pyogenes leads to massive tissue damage in the lungs of the infected mice, which eventually results in the death of the animals. HKH20 inhibits activation of the contact system and protects mice with invasive S pyogenes infection from lung damage. In combination with clindamycin treatment, the peptide also significantly prolongs the survival of infected mice.
Thymic output, T-cell diversity, and T-cell function in long-term human SCID chimeras
Authors: Sarzotti-Kelsoe Marcella , Win Chan M. , Parrott Roberta E. , Cooney Myriah , Moser Barry K. , Roberts Joseph L. , Sempowski Gregory D. , Buckley Rebecca H.
Published: May 2009

Severe combined immunodeficiency (SCID) is a syndrome of diverse genetic cause characterized by profound deficiencies of T, B, and sometimes NK-cell function. Nonablative human leukocyte antigen–identical or rigorously T cell–depleted haploidentical parental bone marrow transplantation (BMT) results in thymus-dependent genetically donor T-cell development in the recipients, leading to long-term survival. We reported previously that normal T-cell numbers, function, and repertoire developed by 3 to 4 months after transplantation in SCID patients, and the repertoire remained highly diverse for the first 10 years after BMT. The T-cell receptor diversity positively correlated with T-cell receptor excision circle levels, a reflection of thymic output. However, the fate of thymic function in SCID patients beyond 10 to 12 years after BMT remained to be determined. In this greater than 25-year follow-up study of 128 patients with 11 different molecular types of SCID after nonconditioned BMT, we provide evidence that T-cell function, thymic output, and T-cell clonal diversity are maintained long-term.
Zebrafish kidney stromal cell lines support multilineage hematopoiesis
Authors: Stachura David L. , Reyes Jason R. , Bartunek Petr , Paw Barry H. , Zon Leonard I. , Traver David
Published: May 2009

Studies of zebrafish hematopoiesis have been largely performed using mutagenesis approaches and retrospective analyses based upon gene expression patterns in whole embryos. We previously developed transplantation assays to test the repopulation potentials of candidate hematopoietic progenitor cells. We have been impaired, however, in determining cellular differentiation potentials by a lack of short-term functional assays. To enable more precise analyses of hematopoietic progenitor cells, we have created zebrafish kidney stromal (ZKS) cell lines. Culture of adult whole kidney marrow with ZKS cells results in the maintenance and expansion of hematopoietic precursor cells. Hematopoietic growth is dependent upon ZKS cells, and we show that ZKS cells express many growth factors and ligands previously demonstrated to be important in maintaining mammalian hematopoietic cells. In the absence of exogenous growth factors, ZKS cells maintain early hematopoietic precursors and support differentiation of lymphoid and myeloid cells. With the addition of zebrafish erythropoietin, ZKS cells also support the differentiation of erythroid precursors. These conditions have enabled the ability to ascertain more precisely the points at which hematopoietic mutants are defective. The development of robust in vitro assays now provide the means to track defined, functional outcomes for prospectively isolated blood cell subsets in the zebrafish.
NKT cells mediate pulmonary inflammation and dysfunction in murine sickle cell disease through production of IFN-γ and CXCR3 chemokines
Authors: Wallace Kori L. , Marshall Melissa A. , Ramos Susan I. , Lannigan Joanne A. , Field Joshua J. , Strieter Robert M. , Linden Joel
Published: May 2009

Ischemia-reperfusion injury (IRI) triggers an inflammatory cascade that is initiated by the activation of CD1d-restricted iNKT cells. In sickle cell disease (SCD), misshapen erythrocytes evoke repeated transient bouts of microvascular IRI. Compared with C57BL/6 controls, NY1DD mice have more numerous and activated (CD69+, interferon-γ+ [IFN-γ+]) lung, liver, and spleen iNKT cells that are hyperresponsive to hypoxia/reoxygenation. NY1DD mice have increased pulmonary levels of IFN-γ, IFN-γ–inducible chemokines (CXCL9, CXCL10), and elevated numbers of lymphocytes expressing the chemokine receptor CXCR3. Treating NY1DD mice with anti-CD1d antibody to inhibit iNKT cell activation reverses baseline pulmonary dysfunction manifested as elevated vascular permeability, decreased arterial oxygen saturation, and increased numbers of activated leukocytes. Anti-CD1d antibodies decrease pulmonary levels of IFN-γ and CXCR3 chemokines. Neutralization of CXCR3 receptors ameliorates pulmonary dysfunction. Crossing NY1DD to lymphocyte-deficient Rag1−/− mice decreases pulmonary dysfunction. This is counteracted by the adoptive transfer of 1 million NKT cells. Like mice, people with SCD have increased numbers of activated circulating iNKT cells expressing CXCR3. Together, these data indicate that iNKT cells play a pivotal role in sustaining inflammation in SCD mice by a pathway involving IFN-γ and production of chemotactic CXCR3 chemokines and that this mechanism may translate to human disease.
Valves of the deep venous system: an overlooked risk factor
Authors: Brooks Erin G. , Trotman Winifred , Wadsworth Marilyn P. , Taatjes Douglas J. , Evans Mark F. , Ittleman Frank P. , Callas Peter W. , Esmon Charles T. , Bovill Edwin G.
Published: May 2009

Deep venous valves are frequent sites of deep venous thrombosis initiation. However, the possible contribution of the valvular sinus endothelium has received little attention in studies of thrombosis risk. We hypothesized that the endothelium of valve sinus differs from that of vein lumen with up-regulation of anticoagulant and down-regulation of procoagulant activities in response to the local environment. In pursuit of this hypothesis, we quantified endothelial protein C receptor (EPCR), thrombomodulin (TM), and von Willebrand factor (VWF) by immunofluorescence in great saphenous veins harvested at cardiac bypass surgery. We found significantly increased expression of EPCR and TM in the valvular sinus endothelium as opposed to the vein lumenal endothelium, and the opposite pattern with VWF (paired t test for TM and EPCR, each P < .001; for VWF, P = .01). These data support our hypothesis and suggest that variation in valvular sinus thromboresistance may be an important factor in venous thrombogenesis.
β-catenin and transforming growth factor β have distinct roles regulating fibroblast cell motility and the induction of collagen lattice contraction
Authors: Poon Raymond , Nik Saeid Amini , Ahn Jessica , Slade Laura , Alman Benjamin A
Published: May 2009

Background

β-catenin and transforming growth factor β signaling are activated in fibroblasts during wound healing. Both signaling pathways positively regulate fibroblast proliferation during this reparative process, and the effect of transforming growth factor β is partially mediated by β-catenin. Other cellular processes, such as cell motility and the induction of extracellular matrix contraction, also play important roles during wound repair. We examined the function of β-catenin and its interaction with transforming growth factor β in cell motility and the induction of collagen lattice contraction.

Results

Floating three dimensional collagen lattices seeded with cells expressing conditional null and stabilized β-catenin alleles, showed a modest negative relationship between β-catenin level and the degree of lattice contraction. Transforming growth factor β had a more dramatic effect, positively regulating lattice contraction. In contrast to the situation in the regulation of cell proliferation, this effect of transforming growth factor β was not mediated by β-catenin. Treating wild-type cells or primary human fibroblasts with dickkopf-1, which inhibits β-catenin, or lithium, which stimulates β-catenin produced similar results. Scratch wound assays and Boyden chamber motility studies using these same cells found that β-catenin positively regulated cell motility, while transforming growth factor β had little effect.

Conclusion

This data demonstrates the complexity of the interaction of various signaling pathways in the regulation of cell behavior during wound repair. Cell motility and the induction of collagen lattice contraction are not always coupled, and are likely regulated by different intracellular mechanisms. There is unlikely to be a single signaling pathway that acts as master regulator of fibroblast behavior in wound repair. β-catenin plays dominant role regulating cell motility, while transforming growth factor β plays a dominant role regulating the induction of collagen lattice contraction.
Emodin targets the β-hydroxyacyl-acyl carrier protein dehydratase from Helicobacter pylori: enzymatic inhibition assay with crystal structural and thermodynamic characterization
Authors: Chen Jing , Zhang Liang , Zhang Yu , Zhang Haitao , Du Jiamu , Ding Jianping , Guo Yuewei , Jiang Hualiang , Shen Xu
Published: May 2009

Background

The natural product Emodin demonstrates a wide range of pharmacological properties including anticancer, anti-inflammatory, antiproliferation, vasorelaxant and anti-H. pylori activities. Although its H. pylori inhibition was discovered, no acting target information against Emodin has been revealed to date.

Results

Here we reported that Emodin functioned as a competitive inhibitor against the recombinant β-hydroxyacyl-ACP dehydratase from Helicobacter pylori (HpFabZ), and strongly inhibited the growth of H. pylori strains SS1 and ATCC 43504. Surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) based assays have suggested the kinetic and thermodynamic features of Emodin/HpFabZ interaction. Additionally, to inspect the binding characters of Emodin against HpFabZ at atomic level, the crystal structure of HpFabZ-Emodin complex was also examined. The results showed that Emodin inhibition against HpFabZ could be implemented either through its occupying the entrance of the tunnel or embedding into the tunnel to prevent the substrate from accessing the active site.

Conclusion

Our work is expected to provide useful information for illumination of Emodin inhibition mechanism against HpFabZ, while Emodin itself could be used as a potential lead compound for further anti-bacterial drug discovery.
Characterization of Vitis vinifera NPR1 homologs involved in the regulation of Pathogenesis-Related gene expression
Authors: Le Henanff Gaëlle , Heitz Thierry , Mestre Pere , Mutterer Jerôme , Walter Bernard , Chong Julie
Published: May 2009

Background

Grapevine protection against diseases needs alternative strategies to the use of phytochemicals, implying a thorough knowledge of innate defense mechanisms. However, signalling pathways and regulatory elements leading to induction of defense responses have yet to be characterized in this species. In order to study defense response signalling to pathogens inVitis vinifera, we took advantage of its recently completed genome sequence to characterize two putative orthologs ofNPR1, a key player in salicylic acid (SA)-mediated resistance to biotrophic pathogens inArabidopsis thaliana.

Results

Two cDNAs namedVvNPR1.1andVvNPR1.2were isolated fromVitis viniferacv Chardonnay, encoding proteins showing 55% and 40% identity to Arabidopsis NPR1 respectively. Constitutive expression ofVvNPR1.1andVvNPR1.2monitored in leaves ofV. viniferacv Chardonnay was found to be enhanced by treatment with benzothiadiazole, a SA analog. In contrast,VvNPR1.1andVvNPR1.2transcript levels were not affected during infection of resistantVitis ripariaor susceptibleV. viniferawithPlasmopara viticola, the causal agent of downy mildew, suggesting regulation of VvNPR1 activity at the protein level. VvNPR1.1-GFP and VvNPR1.2-GFP fusion proteins were transiently expressed by agroinfiltration inNicotiana benthamianaleaves, where they localized predominantly to the nucleus. In this system,VvNPR1.1andVvNPR1.2expression was sufficient to trigger the accumulation of acidic SA-dependent Pathogenesis-Related proteins PR1 and PR2, but not of basic chitinases (PR3) in the absence of pathogen infection. Interestingly, whenVvNPR1.1orAtNPR1were transiently overexpressed inVitis viniferaleaves, the induction of grapevinePR1was significantly enhanced in response toP. viticola.

Conclusion

In conclusion, our data identified grapevine homologs of NPR1, and their functional analysis showed that VvNPR1.1 and VvNPR1.2 likely control the expression of SA-dependent defense genes. Overexpression ofVvNPR1has thus the potential to enhance grapevine defensive capabilities upon fungal infection. As a consequence, manipulatingVvNPR1and other signalling elements could open ways to strengthen disease resistance mechanisms in this crop species.
Therapeutic implications of selecting the SCORE (European) versus the D'AGOSTINO (American) risk charts for cardiovascular risk assessment in hypertensive patients
Authors: Gómez-Marcos Manuel A , Martínez-Salgado Carlos , Martin-Cantera Carlos , Recio-Rodríguez José I , Castaño-Sánchez Yolanda , Giné-Garriga Maria , Rodriguez-Sanchez Emiliano , García-Ortiz Luis
Published: May 2009

Background

No comparisons have been made of scales estimating cardiovascular mortality and overall cardiovascular morbidity and mortality. The study objectives were to assess the agreement between the Framingham-D'Agostino cardiovascular risk (CVR) scale and the chart currently recommended in Europe (SCORE) with regard to identification of patients with high CVR, and to describe the discrepancies between them and the attendant implications for the treatment of hypertension and hyperlipidaemia.

Methods

A total of 474 hypertensive patients aged 40–65 years monitored in primary care were enrolled into the study. CVR was assessed using the Framingham-D'Agostino scale, which estimates the overall cardiovascular morbidity and mortality risk, and the SCORE chart, which estimates the cardiovascular mortality risk. Cardiovascular risk was considered to be high for values ≥ 20% and ≥ 5% according to the Framingham-D'Agostino and SCORE charts respectively. Kappa statistics was estimated for agreement in classification of patients with high CVR. The therapeutic recommendations in the 2007 European Guidelines on Cardiovascular Disease Prevention were followed.

Results

Mean patient age was 54.1 (SD 7.3), and 58.4% were males. A high CVR was found in 17.5% using the SCORE chart (25.3% males, 6.6% females) and in 32.7% using the D'Agostino method (56.9% males, 12,7% females). Kappa coefficient was 0.52, and increased to 0.68 when the high CVR threshold was established at 29% according to D'Agostino. Hypertensive patients with high SCORE and non-high D'Agostino (1.7%) were characterized by an older age, diabetes, and a lower atherogenic index, while the opposite situation (16.9%) was associated to males, hyperlipidaemia, and a higher atherogenic index. Variables with a greater weight in discrepancies were sex and smoking. A 32.0% according to SCORE and 33.5% according to D'Agostino would be candidates to receive antihypertensive treatment, and 15.8% and 27.3% respectively to receive lipid-lowering treatment.

Conclusion

A moderate to high agreement was found. SCORE may underestimate risk in males with an unfavourable lipid profile, and D'Agostino in diabetics with a lower atherogenic risk. Use of the D'Agostino scale implies treating more patients with lipid-lowering and antihypertensive drugs as compared to SCORE.
Does the availability of positron emission tomography modify diagnostic strategies for solitary pulmonary nodules? An observational study in France
Authors: Lemonnier Irawati , Baumann Cédric , Jay Nicolas , Alzahouri Kazem , Arveux Patrick , Jolly Damien , Lejeune Catherine , Velten Michel , Vitry Fabien , Woronoff-Lemsi Marie-Christine , Guillemin Francis
Published: May 2009

Background

Previous studies showed that at the individual level, positron emission tomography (PET) has some benefits for patients and physicians in terms of cancer management and staging. We aimed to describe the benefits of (PET) in the management of solitary pulmonary nodules (SPNs) in a population level, in terms of the number of diagnostic and invasive tests performed, time to diagnosis and factors determining PET utilization.

Methods

In an observational study, we examined reports of computed tomography (CT) performed and mentioning "spherical lesion", "nodule" or synonymous terms. We found 11,515 reports in a before-PET period, 2002–2003, and 20,075 in an after-PET period, 2004–2005. Patients were followed through their physician, who was responsible for diagnostic management.

Results

We had complete data for 112 patients (73.7%) with new cases of SPN in the before-PET period and 250 (81.4%) in the after-PET period. Patients did not differ in mean age (64.9 vs. 64.8 years). The before-PET patients underwent a mean of 4 tests as compared with 3 tests for the after-PET patients (p = 0.08). Patients in the before-PET period had to wait 41.4 days, on average, before receiving a diagnosis as compared with 24.0 days, on average, for patients in the after-PET period who did not undergo PET (p < 0.001). In the after-PET period, 11% of patients underwent PET during the diagnostic process. A spiculated nodule was more likely to determine prescription for PET (p < 0.001). Multivariate analysis revealed that patients in both periods underwent fewer tests when PET was prescribed by general practitioners (p < 0.001) and if the nodule was not spiculated (p < 0.001). The proportion of unnecessary invasive approaches prescribed (47% vs. 49%) did not differ between the groups.

Conclusion

In our study, 1 year after the availability of PET, the technology was not the first choice for diagnostic management of SPN. Even though we observed a tendency for reduced number of tests and mean time to diagnosis with PET, these phenomena did not fully relate to PET availability in health communities. In addition, the availability of PET in the management of SPN diagnosis did not reduce the overall rate of unnecessary invasive approaches.