bluuebunny/crossref_metadata_2025 huggingface dataset:
A video analysis technique for organ dose assessment in pediatric fluoroscopy: Applications to voiding cystourethrograms (VCUG)
Authors: Bolch Wesley E. , Pomije Brian D. , Sessions Jennifer B. , Arreola Manuel M. , Williams Jonathan L. , Pazik Frank D.
Published: April 2003

The time‐sequence videotape‐analysis methodology, originally developed by Sulieman et al. [Radiol. 178, 653–658 (1991)] for use in tissue dose estimation in adult fluoroscopy exams, has been adapted to the study of the newborn voiding cystourethrogram (VCUG). Individual frames of fluoroscopic and radiographic video were analyzed with respect to unique combinations of field size, field center, projection, tube potential, and mA or mAs, respectively. A modified version of the stylized ORNL newborn model was coupled to the MCNP4C radiation transport code to report organ doses per unit entrance air kerma (free‐in‐air) for each identified x‐ray field. A series of urinary bladder models was additionally developed representing the organ at differing stages of contrast filling. The technique was subsequently applied to two patients, a 3‐month male and a 1‐month female, examined via a conventional fluoroscopy system used just prior to departmental conversion to digital systems. The effective dose to these patients was estimated as 0.47 mSv and 1.36 mSv, respectively (ratio of 2.9). Corresponding ratios of cumulative fluoroscopy time and entrance air kerma were 2.2 and 1.6, respectively. For the male patient, the mean percent dose contribution from fluoroscopy for all irradiated organs was while that value for the female patient was
MOSFET dosimetry for microbeam radiation therapy at the European Synchrotron Radiation Facility
Authors: Bräuer‐Krisch E. , Bravin A. , Lerch M. , Rosenfeld A. , Stepanek J. , Di Michiel M. , Laissue J. A.
Published: April 2003

Preclinical experiments are carried out with ∼20–30 μm wide, ∼10 mm high parallel microbeams of hard, broad‐“white”‐spectrum x rays (∼50–600 keV) to investigate microbeam radiation therapy (MRT) of brain tumors in infants for whom other kinds of radiotherapy are inadequate and/or unsafe. Novel physical microdosimetry (implemented with MOSFET chips in the “edge‐on” mode) and Monte Carlo computer‐simulated dosimetry are described here for selected points in the peak and valley regions of a microbeam‐irradiated tissue‐equivalent phantom. Such microbeam irradiation causes minimal damage to normal tissues, possible because of rapid repair of their microscopic lesions. Radiation damage from an array of parallel microbeams tends to correlate with the range of peak‐valley dose ratios (PVDR). This paper summarizes comparisons of our dosimetric MOSFET measurements with Monte Carlo calculations. Peak doses at depths <22 mm are 18% less than Monte Carlo values, whereas those depths >22 mm and valley doses at all depths investigated (2 mm–62 mm) are within 2–13 % of the Monte Carlo values. These results lend credence to the use of MOSFET detector systems in edge‐on mode for microplanar irradiation dosimetry.
Vessel size measurements in angiograms: Manual measurements
Authors: Hoffmann Kenneth R. , Dmochowski Jacek , Nazareth Daryl P. , Miskolczi László , Nemes Balazs , Gopal Anant , Wang Zhou , Rudin Stephen , Bednarek Daniel R.
Published: April 2003

Vessel size measurement is perhaps the most often performed quantitative analysis in diagnostic and interventional angiography. Although automated vessel sizing techniques are generally considered to have good accuracy and precision, we have observed that clinicians rarely use these techniques in standard clinical practice, choosing to indicate the edges of vessels and catheters to determine sizes and calibrate magnifications, i.e., manual measurements. Thus, we undertook an investigation of the accuracy and precision of vessel sizes calculated from manually indicated edges of vessels. Manual measurements were performed by three neuroradiologists and three physicists. Vessel sizes ranged from 0.1–3.0 mm in simulation studies and 0.3–6.4 mm in phantom studies. Simulation resolution functions had full‐widths‐at‐half‐maximum (FWHM) ranging from 0.0 to 0.5 mm. Phantom studies were performed with 4.5 in., 6 in., 9 in., and 12 in. image intensifier modes, magnification factor = 1, with and without zooming. The accuracy and reproducibility of the measurements ranged from 0.1 to 0.2 mm, depending on vessel size, resolution, and pixel size, and zoom. These results indicate that manual measurements may have accuracies comparable to automated techniques for vessels with sizes greater than 1 mm, but that automated techniques which take into account the resolution function should be used for vessels with sizes smaller than 1 mm.
A Grangeat‐type half‐scan algorithm for cone‐beam CT
Authors: Lee Seung Wook , Wang Ge
Published: April 2003

Modern CT and micro‐CT scanners are rapidly moving from fan‐beam toward cone‐beam geometry. Half‐scan CT algorithms are advantageous in terms of temporal resolution, and widely used in fan‐beam and cone‐beam geometry. While existing half‐scan algorithms for cone‐beam CT are in the Feldkamp framework, in this paper we compensate missing data explicitly in the Grangeat framework, and formulate a half‐scan algorithm in the circular scanning case. The half‐scan spans 180° plus two cone angles that guarantee sufficient data for reconstruction of the midplane defined by the source trajectory. The smooth half‐scan weighting functions are designed for the suppression of data inconsistency. Numerical simulation results are reported for verification of our formulas and programs. This Grangeat‐type half‐scan algorithm produces excellent image quality, without off‐mid‐plane artifacts associated with Feldkamp‐type half‐scan algorithms. The Grangeat‐type half‐scan algorithm seems promising for quantitative and dynamic biomedical applications of CT and micro‐CT.
Brachytherapy dosimetry of and sources using an updated cross section library for the MCNP Monte Carlo transport code
Authors: Bohm Tim D. , DeLuca Paul M. , DeWerd Larry A.
Published: April 2003

Permanent implantation of low energy (20–40 keV) photon emitting radioactive seeds to treat prostate cancer is an important treatment option for patients. In order to produce accurate implant brachytherapy treatment plans, the dosimetry of a single source must be well characterized. Monte Carlo based transport calculations can be used for source characterization, but must have up to date cross section libraries to produce accurate dosimetry results. This work benchmarks the MCNP code and its photon cross section library for low energy photon brachytherapy applications. In particular, we calculate the emitted photon spectrum, air kerma, depth dose in water, and radial dose function for bothandbased seeds and compare to other published results. Our results show that MCNP's cross section library differs from recent data primarily in the photoelectric cross section for low energies and low atomic number materials. In water, differences as large as 10% in the photoelectric cross section and 6% in the total cross section occur atandphoton energies. This leads to differences in the dose rate constant of 3% and 5%, and differences as large as 18% and 20% in the radial dose function for theandbased seeds, respectively. Using a partially updated photon library, calculations of the dose rate constant and radial dose function agree with other published results. Further, the use of the updated photon library allows us to verify air kerma and depth dose in water calculations performed using MCNP's perturbation feature to simulate updated cross sections. We conclude that in order to most effectively use MCNP for low energy photon brachytherapy applications, we must update its cross section library. Following this update, the MCNP code system will be a very effective tool for low energy photon brachytherapy dosimetry applications.
Monte Carlo dosimetry of HDR brachytherapy sources
Authors: Papagiannis P. , Angelopoulos A. , Pantelis E. , Sakelliou L. , Karaiskos P. , Shimizu Y.
Published: April 2003

Monte Carlo based dosimetry is presented for three HDR sources with a unique configuration of two active pellets in contact or spaced 9 and 11 mm apart. Results are presented in Cartesian “away and along” as well as polar coordinates following the AAPM TG‐43 dosimetric formalism. Iso‐dose rate contours around the sources in Cartesian coordinates reveal that significant differences between the three source designs exist only close to the source centers where dose rate distributions bear the effect of the unique source configurations. Dose rate constants of all three sources are accurately described by an equation of the form: cm, 90°) where is the dose rate constant of a bare point source and G(1 cm,90°) is the “exact” source geometry factor as defined by the TG‐43. Radial dose and anisotropy function data extracted using the point source approximated geometry factors are tabulated for all three source designs. Finally, the dependence and variation of the above TG‐43 parameters are discussed and it is demonstrated that the dosimetric properties of high‐energy photon emitters are largely dependent on radionuclide source distribution.
Monte Carlo calculated correction factors for primary standards of air kerma
Authors: Rogers D. W. O. , Kawrakow Iwan
Published: April 2003

Many laboratories with cavity chambers as primary standards for air kerma are considering using additional Monte Carlo calculated correction factors, in particular the correction for attenuation and scatter in the walls,and possibly the correction for point of measurement,Standards labs also use Monte Carlo calculated Spencer‐Attix stopping‐power ratios for graphite to air. The purpose of this article is to investigate the sensitivity of these calculations to their details and to assign uncertainties to the calculated values. We also investigate the correction needed for the Canadian primary standard to account for a polystyrene insulator,and find that it is quite largeThe article shows that the values of correction factors are very robust and insensitive to most details of the calculations except the values of the underlying electron stopping powers which have a significant effect on the stopping‐power ratio and onThe 1% uncertainties on the photon cross‐sections have a negligible effect on these correction factors except forAs a result of these investigations, with no change in the stopping power data used, the Canadian primary standard of air kerma in abeam needs to be increased by 0.54%.
Image guided position verification for intensity modulated radiotherapy of prostate cancer (in English)
Authors: Nederveen Aart J.
Published: April 2003

The aim of this thesis is to provide a practical framework for dose escalation in the prostate using intensity modulated radiotherapy (IMRT) and to find out if marker based on‐line position verification is clinically feasible and effective. We present a class solution for dose escalation in the prostate in which the issue of dose escalation is dealt with separately from the choice of margins and nominal rectum dose. We study verification and correction of the prostate position during treatment based on implanted gold markers. To perform such position verification in an automated way several requirements should be met. Thanks to the use of an a‐Si flat‐panel imager and a dedicated software algorithm, markers of 1 mm diameter and 5 mm length can be detected automatically (success rate >90%), fast (within 1 s) and accurate (better than 0.3 mm). Marker migration appears to be present, but remains very small (standard deviation 0.5 mm). The effect of prostate volume alteration during treatment appears to be smaller than the inaccuracy that is present due to volume delineation. For 10 patients that were treated in a feasibility study no major toxicity related to marker implantation was noticed. In a group of 23 patients off‐line marker based position verification was proved to reduce the standard deviations of the systematic error to below 1 mm. Intratreatment prostate motions could be visualized as well and appeared to be very small on average (standard deviation <1 mm). We conclude that marker based position verification provides a reliable method for decreasing the geometrical deviations during prostate irradiation .
What do patients value in their hospital care? An empirical perspective on autonomy centred bioethics
Authors: Joffe S , Manocchia M , Weeks J C , Cleary P D
Published: April 2003

Objective:Contemporary ethical accounts of the patient-provider relationship emphasise respect for patient autonomy and shared decision making. We sought to examine the relative influence of involvement in decisions, confidence and trust in providers, and treatment with respect and dignity on patients’ evaluations of their hospital care.

Design:Cross-sectional survey.

Setting:Fifty one hospitals in Massachusetts.

Participants:Stratified random sample of adults (N=27 414) discharged from a medical, surgical, or maternity hospitalisation between January and March, 1998. Twelve thousand six hundred and eighty survey recipients responded.

Main outcome measure:Respondent would definitely be willing to recommend the hospital to family and friends.

Results:In a logistic regression analysis, treatment with respect and dignity (odds ratio (OR) 3.4, 99% confidence interval (CI) 2.8 to 4.2) and confidence and trust in providers (OR 2.5, CI 2.1 to 3.0) were more strongly associated with willingness to recommend than having enough involvement in decisions (OR 1.4, CI 1.1 to 1.6). Courtesy and availability of staff (OR 2.5, CI 2.1 to 3.1), continuity and transition (OR 1.9, CI 1.5 to 2.2), attention to physical comfort (OR 1.8, CI 1.5 to 2.2), and coordination of care (OR 1.5, CI 1.3 to 1.8) were also significantly associated with willingness to recommend.

Conclusions:Confidence and trust in providers and treatment with respect and dignity are more closely associated with patients’ overall evaluations of their hospitals than adequate involvement in decisions. These findings challenge a narrow emphasis on patient autonomy and shared decision making, while arguing for increased attention to trust and respect in ethical models of health care.
Consensus and contention regarding redundant publications in clinical research: cross-sectional survey of editors and authors
Authors: Yank V , Barnes D
Published: April 2003

Objectives:To examine the perspectives of journal editors and authors on overlapping and redundant publications in clinical research.

Design:Pretested cross-sectional survey, containing both forced choice and open ended questions, administered by mail to the senior editors (N=99) and one randomly selected author (N=99) from all journals in theAbridged Index Medicus(1996) that published clinical research.

Main measurements:The views of editors and authors about the extent of redundant publications, why they occur, how to prevent and respond to cases, and when the publication of overlapping manuscripts is justified.

Results:Seventy two per cent (N=71) of editors and 65% (N=64) of authors completed the survey. There was consensus between both groups that redundant publications occur because authors feel the pressure to publish and journals do not do enough to publicise, criticise, and punish cases, and that the publication of most types of overlapping articles is unacceptable. Sixty seven per cent of authors but only 31% of editors felt, however, that it was justified to publish an overlapping article in a non-peer reviewed symposium supplement, and 68% of editors but 39% of authors supported imposing restrictions on guilty authors’ future submissions. In written comments, 15% to 30% of both groups emphasised that it was justified to publish overlapping articles when there were different or non-English-speaking audiences, new data, strengthened methods, or disputed findings.

Conclusions:Editors, authors, and other academic leaders should together develop explicit guidelines that clarify points of contention and ambiguity regarding overlapping manuscripts.
Concern for families and individuals in clinical genetics
Authors: Parker M , Lucassen A
Published: April 2003

Clinical geneticists are increasingly confronted with ethical tensions between their responsibilities to individual patients and to other family members. This paper considers the ethical implications of a “familial” conception of the clinical genetics role. It argues that dogmatic adherence to either the familial or to the individualistic conception of clinical genetics has the potential to lead to significant harms and to fail to take important obligations seriously.

Geneticists are likely to continue to be required to make moral judgments in the resolution of such tensions and may find it useful to have access to ethics training and support.
Balancing autonomy and responsibility: the ethics of generating and disclosing genetic information
Authors: Hallowell N , Foster C , Eeles R , Ardern-Jones A , Murday V , Watson M
Published: April 2003

Using data obtained during a retrospective interview study of 30 women who had undergone genetic testing—BRCA1/2mutation searching—this paper describes how women, previously diagnosed with breast/ovarian cancer, perceive their role in generating genetic information about themselves and their families. It observes that when describing their motivations for undergoing DNA testing and their experiences of disclosing genetic information within the family these women provide care based ethical justifications for their actions. Finally, it argues that generating genetic information and disclosing this information to kin raise different types of ethical issues. The implications of these findings for ethical debates about informed choice in the context of genetic testing are discussed.
What exactly is an exact copy? And why it matters when trying to ban human reproductive cloning in Australia
Authors: Gogarty B
Published: April 2003

This paper examines the current Australian regulatory response to human reproductive cloning. The central consideration is the capacity of the current regulatory regime to effectively deter human cloning efforts. A legislative prohibition on human cloning must be both effective and clear enough to allow researchers to know what practices are acceptable.

This paper asks whether the current Australian regime evinces these qualities and suggests that Australia should follow the example set in the UK by the enactment of theHuman Reproductive Cloning Act 2001.
Is there an ethical difference between preimplantation genetic diagnosis and abortion?
Authors: Cameron C , Williamson R
Published: April 2003

When a person at risk of having a child with a genetic illness or disease wishes to have an unaffected child, this can involve difficult choices. If the pregnancy is established by sexual intercourse, the fetus can be tested early in pregnancy, and if affected a decision can be made to abort in the hope that a future pregnancy with an unaffected fetus ensures. Alternatively, preimplantation genetic diagnosis (PGD) can be used after in vitro fertilisation (IVF) to select and implant an unaffected embryo that hopefully will proceed to term and produce a healthy baby. We are aware that many individuals at risk regard the latter as ethically more acceptable than the former, and examine whether there is an ethical difference between these options. We conclude that PGD and implantation of an unaffected embryo is a more acceptable choice ethically than prenatal diagnosis (PND) followed by abortion for the following reasons:

Choice after PGD is seen as ethically neutral because a positive result (“a healthy pregnancy”) balances a negative result (“the destruction of the affected embryo”) simultaneously (assuming the pregnancy proceeds to full term and a healthy baby is born). While there is usually the intention to establish a healthy pregnancy after an abortion, this is not simultaneous;

A woman sees abortion as a personal physical violation of her integrity, and as the pregnancy proceeds she increasingly identifies with and gives ethical status to the embryo/fetus as it develops in utero and not in the laboratory;

Many people see aborting a fetus as “killing”, whereas in the case of PGD the spare embryos are “allowed to die”. We argue that this difference of opinion gives further weight to our conclusion, but note that this has been addressed and debated at length by others.
Issues of consent and feedback in a genetic epidemiological study of women with breast cancer: Table 1
Authors: Richards M P M , Ponder M , Pharoah P , Everest S , Mackay J
Published: April 2003

Women (N=21) who had had breast cancer and had been enrolled in a large genetic breast cancer epidemiological study were interviewed about their experience of participation in the study, their attitudes to the confidentiality of data, and the feedback of personal and general research results. Collection of family history information seemed more salient in indicating the genetic nature of the study than the enrolment information sheet. There were no concerns about confidentiality.

While participants would have welcomed general feedback about the results of the study and were critical that this had not been provided, the feedback of personal information proved complicated and, sometimes, difficult. It is suggested that individual feedback of genetic test information in epidemiological studies should be undertaken only when there are specific reasons.
Differences in medical students’ attitudes to academic misconduct and reported behaviour across the years—a questionnaire study
Authors: Rennie S C , Rudland J R
Published: April 2003

Objectives:This study aimed to determine attitudinal and self reported behavioural variations between medical students in different years to scenarios involving academic misconduct.

Design:A cross-sectional study where students were given an anonymous questionnaire that asked about their attitudes to 14 scenarios describing a fictitious student engaging in acts of academic misconduct and asked them to report their own potential behaviour.

Setting:Dundee Medical School.

Participants:Undergraduate medical students from all five years of the course.

Method:Questionnaire survey.

Main measurements:Differences in medical students’ attitudes to the 14 scenarios and their reported potential behaviour with regards to the scenarios in each of the years.

Results:For most of the scenarios there was no significant difference in the response between the years. Significant differences in the responses were found for some of the scenarios across the years, where a larger proportion of year one students regarded the scenario as wrong and would not engage in the behaviour, compared to other years. These scenarios included forging signatures, resubmitting work already completed for another part of the course, and falsifying patient information.

Conclusion:Observed differences between the years for some scenarios may reflect a change in students’ attitudes and behaviour as they progress though the course. The results may be influenced by the educational experience of the students, both in terms of the learning environment and assessment methods used. These differences may draw attention to the potential but unintentional pressures placed on medical students to engage in academic misconduct. The importance of developing strategies to engender appropriate attitudes and behaviours at the undergraduate level must be recognised.
COMBINED INVARIANTS TO LINEAR FILTERING AND ROTATION
Authors: FLUSSER JAN , ZITOVÁ BARBARA
Published: April 2003

A new class of moment-based features invariant to image rotation, translation, scaling, contrast changes and also to convolution with an unknown PSF are introduced in this paper. These features can be used for the recognition of objects captured by a nonideal imaging system of unknown position and blurring parameters.
TOPOLOGICAL PEELING AND APPLICATIONS
Authors: CHEN DANNY Z. , LUAN SHUANG , XU JINHUI
Published: April 2003

We present a new approach, called topological peeling, for traversing a portion AR of the arrangement formed by n lines within a convex region R on the plane. Topological peeling visits the cells of AR in a fashion of propagating a "wave" of a special shape (called a double-wriggle curve) starting at a single source point. This special traversal fashion enables us to solve several problems (e.g., computing shortest paths) on planar arrangements to which previously best known arrangement traversal techniques such as topological sweep and topological walk may not be directly applicable. Our topological peeling algorithm takes O(K + n log (n + r)) time and O(n + r) space, where K is the number of cells in AR and r is the number of boundary vertices of R. Comparing with topological walk, topological peeling uses a simpler and more efficient way to sweep different types of lines, and relies heavily on exploring small local structures, rather than a much larger global structure. Experiments show that, on average, topological peeling outperforms topological walk by 10–25% in execution time.
CONWAY POLYNOMIAL OF A FIBERED SOLVABLE LINK
Authors: NEUMANN WALTER D.
Published: April 2003

We compute Kauffman's potential function (equivalent to the Conway polynomial) for any solvable fibered link. Solvable links are links that can be built from the unknot by iterated cabling and summing. Links that arise in complex algebraic geometry are generally of this type.
Pressure-Induced Activation of Extracellular Signal-Regulated Kinase 1/2 in Small Arteries
Authors: Eskildsen-Helmond Yvonne E.G. , Mulvany Michael J.
Published: April 2003

Extracellular signal-regulated kinase 1/2 (ERK1/2) may play a central signaling role in vascular remodeling. We investigated a possible combined role for the renin-angiotensin system and platelet-derived growth factor β-receptor (PDGF-β-R) in pressure-induced ERK1/2 activation in intact rat mesenteric small arteries. In an organ culture model, vessels were pressurized (70 mm Hg) for 1 hour plus a 5-minute intervention period. The intervention was either a rise in intraluminal pressure (up to 140 mm Hg) or challenge with angiotensin II (Ang II, 0.1 μmol/L) or PDGF-BB (30 μg/L). ERK1/2 activation was determined by Western blotting as formation of phosphorylated ERK1/2. All interventions caused ERK1/2 activation that was inhibited by the MEK inhibitor PD98059. The response to pressure was inhibited by an ACE inhibitor (perindoprilat), an Ang II receptor type 1 (R-AT
1
) antagonist (candesartan), and tyrosine kinase inhibitors (genistein, herbimycin A). An R-AT
2
antagonist (PD123319) had no significant effect. Both a PDGF-receptor tyrosine kinase inhibitor (RPR101511A) and a neutralizing PDGF-β-R antibody (AF385) inhibited the activation of ERK1/2 caused by PDGF-BB, Ang II, and pressure. That the latter interventions could indeed inhibit the PDGF-β-R was supported by experiments with unmounted vessels in which PDGF-β-R activation was measured by Western blot; both PDGF-BB and Ang II–mediated PDGF-β-R activation were inhibited by RPR101511A and AF385. Immunohistochemistry showed that ERK1/2 and PDGF-β-R was located in the adventitia, tunica media, and intima. The results suggest that pressure in rat mesenteric small arteries causes acute activation of ERK1/2 through pathways involving Ang II and PDGF-β-R.
Akt Is a Major Downstream Target of PI3-Kinase Involved in Angiotensin II–Induced Proliferation
Authors: Dugourd Céline , Gervais Marianne , Corvol Pierre , Monnot Catherine
Published: April 2003

Different signal transduction cascades have been implicated in angiotensin II (Ang II)–mediated cell growth, such as the extracellular signal-regulated kinase 1/2 (ERK1/2) and the phosphatidylinositol 3-kinase (PI3K) pathways. To identify the downstream targets of PI3K involved in Ang II–induced proliferation, we used both rat aortic smooth muscle (RASM) cells and a CHO cell line stably expressing the rat AT
1A
receptor. The ERK1/2 and PI3K pathways are independently activated and implicated in Ang II–mediated DNA synthesis and cell number increase in these 2 cell lines. In addition, a specific inhibitor of Akt inhibited Ang II–induced Akt phosphorylation, DNA synthesis and proliferation in CHO-AT
1A
or RASM cells. A dominant-negative mutant of Akt was also found to selectively block Ang II–induced proliferation of CHO-AT
1A
cells. To further elucidate the signaling events leading to Akt activation, we used an AT
1
receptor mutant (AT
1A
D74E), deficient for Gq protein coupling, and the intracellular calcium chelator BAPTA-AM. Although altered Akt and ERK1/2 activation was observed in the CHO-AT
1A
D74E cell line, blockade of intracellular calcium elevation did not affect phosphorylation of these kinases. These results provide the first evidence of a specific and necessary role of Akt in Ang II–induced proliferation through a Gq protein–dependent calcium-independent pathway.
Plasma Brain Natriuretic Peptide Levels and Blood Pressure Tracking in the Framingham Heart Study
Authors: Freitag Michael H. , Larson Martin G. , Levy Daniel , Benjamin Emelia J. , Wang Thomas J. , Leip Eric P. , Wilson Peter W.F. , Vasan Ramachandran S.
Published: April 2003

Increased brain natriuretic peptide (BNP) expression in the ventricles antedates elevated blood pressure (BP) in experimental studies. We hypothesized that higher plasma BNP levels in nonhypertensive individuals may be associated with a greater likelihood of future BP increase and/or hypertension. We evaluated the relations of plasma BNP to longitudinal BP tracking and incidence of hypertension in 1801 nonhypertensive Framingham Heart Study participants (mean age, 56 years; 57% women) by using gender-specific multivariable logistic regression. Progression of BP stage was defined as an increment of one or more BP categories, as classified by the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Hypertension was defined as a systolic BP ≥140 or diastolic BP ≥90 mm Hg or use of antihypertensive medications. On follow-up 4 years from baseline, progression of BP category was observed in 36.2% of men and 33.1% of women; hypertension developed in 16.4% of men and 15.5% of women. In multivariable models adjusting for known risk factors, elevated plasma BNP level was associated with increased risk of BP progression in men (odds ratio of 1.15 for trend across categories,
P
=0.046) but not in women (
P
=0.82). There were no significant trends of increasing incidence of hypertension across BNP categories in men or women. In our community-based sample, higher plasma BNP levels were associated with increased risk of BP progression in men but not women. Additional investigations are warranted to confirm these findings and elucidate the basis for these gender-related differences.
History of Hypertension and Enhanced Thrombogenic Activity in Postinfarction Patients
Authors: Fadl Yazid Y. , Zareba Wojciech , Moss Arthur J. , Marder Victor J. , Sparks Charles S. , Miller Watelet Luc F. , Carroll Elizabeth R.
Published: April 2003

Hypertension is a risk factor for coronary thrombosis and death in cardiac patients mediated in part by endothelial damage or dysfunction and increased thrombogenicity. However, there are no data regarding the association between hypertension and thrombogenic activity in stable patients after myocardial infarction and limited data about the prognostic significance of thrombogenic factors in hypertensive patients after infarction. Therefore, levels of thrombogenic, lipid, and inflammatory factors were measured 2 months after an acute myocardial infarction in 461 hypertensive and 582 nonhypertensive patients. Thrombogenic factors included
d
-dimer, fibrinogen, plasminogen activator inhibitor-1, von Willebrand factor, factor VII, and factor VIIa. Lipid variables included cholesterol (total, HDL, LDL), triglyceride, lipoprotein (a), apolipoprotein-A1, and apolipoprotein-B. The prognostic significance of these factors for predicting cardiac events during a 2-year follow-up was evaluated in hypertensive and nonhypertensive patients. In comparison with nonhypertensive patients, those with hypertension had higher levels of
d
-dimer (607 versus 453 mg/L,
P
<0.001), fibrinogen (3.64 versus 3.43 g/L,
P
<0.001), plasminogen activator inhibitor-1 (29.7 versus 27.3 ng/mL,
P
=0.01), von Willebrand factor (159 versus 141 IU/dL;
P
<0.001), and higher levels of inflammatory markers (hsCRP and SAA). In multivariate analysis after adjustment for clinical covariates, elevated
d
-dimer was the only factor independently associated with a history of hypertension (OR, 1.38,
P
=0.05).
d
-Dimer was associated with an increased risk of recurrent cardiac events in both hypertensive (hazard ratio=3.02,
P
=0.005) and nonhypertensive (hazard ratio=2.42,
P
=0.02) patients. Thus, patients after infarction with a history of hypertension have enhanced thrombogenic activity, which predisposes them to recurrent cardiac events.
PI3-Kinase–Induced Hyperreactivity in DOCA-Salt Hypertension Is Independent of GSK-3 Activity
Authors: Loberg Robert D. , Northcott Carrie A. , Watts Stephanie W. , Brosius Frank C.
Published: April 2003

Phosphatidylinositol 3-kinase (PI3K) activity is increased in aortae from deoxycorticosterone (DOCA)-salt rats and enhanced PI3K activity contributes to the arterial hyperreactivity in these animals. Because PI3K activity is increased in DOCA-salt hypertension, we postulated that phosphorylation of Akt and glycogen synthase kinase 3 (GSK-3), serine threonine kinases that are downstream of PI3K, would be increased in DOCA-salt hypertension. In this study, we focused on GSK-3. Because GSK-3 activity is reduced by phosphorylation, we expected that its activity would be reduced in DOCA-salt hypertensive arteries and that reduced GSK-3 activity could contribute to enhanced adrenergic signaling and vascular smooth muscle hypertrophy that augment the heightened contractile response in DOCA-salt hypertension. Surprisingly, we observed a decrease in phosphorylation of GSK-3, indicating an increase in GSK-3 activity. To determine whether increased GSK-3 activity contributes to altered arterial reactivity in DOCA-salt animals, we measured isometric contraction to norepinephrine (NE) in the presence and absence of PI3K or GSK-3 inhibition. Addition of LY294002 (20 μmol/L), a PI3K inhibitor, resulted in a rightward shift in response to NE and normalized the NE-induced contractions in the DOCA hypertensive vessels. SB415286, a GSK-3 inhibitor, resulted in a slight rightward shift in response to NE in the DOCA-salt vessels. Thus, enhanced GSK-3 activity modestly augments the effects of PI3K but does not appear to contribute greatly to the altered arterial reactivity in DOCA-salt hypertension.
NADPH Oxidase Activity in Preeclampsia With Immortalized Lymphoblasts Used as Models
Authors: Lee Virginia M. , Quinn Paulene A. , Jennings Sonja C. , Ng Leong L.
Published: April 2003

Upon activation, neutrophils release reactive oxygen species that are believed to contribute to the widespread manifestation of preeclampsia. Neutrophils have an NADPH oxidase enzyme that catalyzes the production of reactive oxygen species. Little is known about the manifestations of the activated response and the upstream signaling pathways that regulate this process in preeclampsia. It is hypothesized that genetic factors may contribute to the release of reactive oxygen species and consequently the pathophysiology of the disease. We used Epstein-Barr virus–immortalized lymphoblasts from third-trimester, preeclamptic, postpartum preeclamptic women and their respective control subjects to assess NADPH oxidase–mediated reactive oxygen species production by using luminol-derived chemiluminescence and dihydrorhodamine-123 fluorescence. There was no effect of pregnancy status on the lymphoblast phorbol ester–stimulated luminol chemiluminescence area under the curve. However, lymphoblasts from preeclamptic patients had significant elevation of the lymphoblast phorbol ester–stimulated luminol area under the curve (
F
statistic 10.922,
P
<0.002). Similar findings were evident with dihydrorhodamine-123. No differences were revealed between preeclamptic and control cells when measuring the abundance of the phox proteins using Western blotting. Studies with genistein and tyrphostin implicated tyrosine kinase–dependent mechanisms in the control of NADPH oxidase–associated increased reactive oxygen species production in preeclampsia. These data show that preeclampsia is associated with a predisposition to increased agonist-stimulated NADPH oxidase–mediated reactive oxygen species production. The enhancement of reactive oxygen species generation may be important in mediating the endothelial dysfunction seen in preeclampsia.
Alterations in G Protein and MAP Kinase Signaling Pathways During Cardiac Remodeling in Hypertension and Heart Failure
Authors: Kacimi Rachid , Gerdes Anthony Martin
Published: April 2003

The present study was undertaken to elucidate the G-protein and mitogen-activated kinase (MAP kinase) coupled signaling profile in a genetic model of hypertension and congestive heart failure (CHF) that mimics similar disease in humans. At the receptor level, Ang II type 1 receptor (AT
1R
) increased in left ventricular hypertrophy (LVH) and reverted to normal in CHF, whereas there was a downregulation of the Ang II type 2 receptor (AT
2R
) in CHF. At the transducer level, Gα
q
and Gα
12
protein levels were unchanged during LVH but decreased significantly in CHF. In contrast, Gβ and Gα
13
protein content were markedly upregulated in CHF. Furthermore, using phospho-specific antibodies in Western blots and in vitro kinase assays, we found at the effector level an upregulation of the small G-protein Rac1 activity during LVH but a decrease during CHF. In parallel, small G-protein Rho activity was significantly increased during LVH but was unchanged in failure. We found at the downstream level that MAP kinase isoforms extracellular signal regulated-kinase (ERK1/2), big mitogen-activated kinase (BMK1/ERK5), C-
jun
N-terminal–activated kinase (JNKs/SAPKs), and stress-activated kinase (p38) bioactivities were increased during LVH. During CHF, ERK1/2 and JNK1/2 kinase activities were decreased, whereas BMK1/ERK5 kinase activity reverted to normal values. In conclusion, this study demonstrates, for the first time, multistep alterations of G-protein and MAP kinase signaling pathways in LVH and progression to failure in a genetic model of hypertension and failure.
Differential Expression of AT
1
Receptors in the Pituitary and Adrenal Gland of SHR and WKY
Authors: Jöhren Olaf , Golsch Claudia , Dendorfer Andreas , Qadri Fatimunnisa , Häuser Walter , Dominiak Peter
Published: April 2003

The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT
1A
, AT
1B
, and AT
2
receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT
1A
receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT
1B
receptor mRNA was detected in the pituitary and adrenal gland. AT
2
receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT
1A
receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT
1B
receptor mRNA levels. In the adrenal gland of SHR, AT
1B
receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT
1B
receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT
1A
and AT
1B
receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT
1
receptors in an exaggerated endocrine stress response of SHR to ANG.
Long-Acting Ca
2+
Blockers Prevent Myocardial Remodeling Induced by Chronic NO Inhibition in Rats
Authors: Sanada Shoji , Node Koichi , Minamino Tetsuo , Takashima Seiji , Ogai Akiko , Asanuma Hiroshi , Ogita Hisakazu , Liao Yulin , Asakura Masanori , Kim Jiyoong , Hori Masatsugu , Kitakaze Masafumi
Published: April 2003

Chronic inhibition of nitric oxide (NO) synthesis induces cardiac remodeling independent of systemic hemodynamic changes in rats. We examined whether long-acting dihydropyridine calcium channel blockers block myocardial remodeling and whether the activation of 70-kDa S6 kinase (p70S6K) and extracellular signal-regulated kinase (ERK) are involved. Ten groups of Wistar-Kyoto rats underwent 8 weeks of drug treatment consisting of a combination of NO synthase inhibitor
N
G
-nitro-
l
-arginine methyl ester (L-NAME), an inactive isomer (D-NAME), amlodipine (1 or 3 mg/kg per day), or benidipine (3 or 10 mg/kg per day). In other groups, L-NAME was also used in combination with a p70S6K inhibitor (rapamycin), a MEK inhibitor (PD98059), and hydralazine. Systolic blood pressure (SBP), heart rate, and left ventricular weight (LVW) were measured, together with histological examinations and kinase assay. L-NAME increased SBP and LVW (1048±22 versus 780±18 mg,
P
<0.01) compared with the control, showing a significant increase in cross-sectional area of cardiomyocytes after 8 weeks. Amlodipine, benidipine, or hydralazine equally attenuated the increase in SBP induced by L-NAME. However, both amlodipine and benidipine but not hydralazine attenuated the increase in LVW by L-NAME (789±27, 825±20 mg,
P
<0.01, and 1118±29 mg, NS, respectively), also confirmed by histological analysis. L-NAME caused a 2.2-fold/1.8-fold increase in p70S6K/ERK activity in myocardium compared with the control, both of which were attenuated by both amlodipine and benidipine but not hydralazine. Both rapamycin and PD98059 attenuated cardiac hypertrophy in this model. Thus, long-acting dihydropyridine calcium channel blockers inhibited cardiac hypertrophy induced by chronic inhibition of NO synthesis by inhibiting both p70S6K and ERK in vivo.
Mechanical Stretch-Induced Apoptosis in Smooth Muscle Cells Is Mediated by β
1
-Integrin Signaling Pathways
Authors: Wernig Florian , Mayr Manuel , Xu Qingbo
Published: April 2003

Recently we demonstrated that mechanical stress induces apoptosis of vascular smooth muscle cells in vitro and in vein grafts (Mayr et al.
FASEB J.
2000;15:261–270). The current study was designed to investigate molecular mechanisms of mechanical stretch–induced apoptosis. Smooth muscle cells cultivated on silicone elastomer plates precoated with collagen I, elastin, laminin, or Pronectin were subjected to cyclic mechanical stretch. Interestingly, in response to mechanical stress, the number of apoptotic cells increased significantly in cells growing on collagen I–coated plates but not on other matrixes. We therefore thought that receptors mediating binding to collagen I, such as integrin β
1
containing receptors, might be involved in signaling pathways leading to stretch-induced apoptosis. On collagen plates, mechanical stress rapidly activated p38 MAPK that phosphorylated p53 in smooth muscle cells. Lack of functional
Rac
completely abrogated p38 MAPK-p53 activation as well as apoptosis. Furthermore, mechanical stress resulted in increases of both integrin β
1
protein expression and activity as identified by Western blotting and
Shc
immunoprecipitation assays. Treatment with a β
1
-integrin–blocking antibody or integrin signaling inhibitor cytochalasin B but not growth factor receptor inhibitor suramin abrogated both stretch-induced phosphorylation of p38 MAPK and p53 expression. Akin to the inhibition of p38 MAPK-p53 signaling, pretreatment with a β
1
-integrin–blocking antibody or cytochalasin B but not suramin inhibited stretch-induced apoptosis on collagen plates. These results suggest that mechanical stress–induced apoptosis in vascular smooth muscle cells is mediated by β
1
-integrin–
rac
–p38-p53 signaling pathways.
Parallel Renal and Extremity Blood Supply Abnormalities in Nonmodulation
Authors: Sánchez Ramiro A. , Ramos Felipe , Giannone Carlos , Fischer Patricia , Masnatta Lucas , Baglivo Hugo P. , Ramírez Agustín J. , Hollenberg Norman K.
Published: April 2003

The aim of this work was to ascertain, in nonmodulating essential hypertension, whether the abnormality in the renal blood supply is extended to the extremities and showed a similar response to ACE inhibition and whether these abnormalities could be identified in normotensive offspring of hypertensives, as non-modulation is a familial process with genetic underpinnings. We measured forearm vascular blood flow (FBF) and forearm vascular resistance (FVR) by plethysmography and urinary albumin excretion in 20 normotensive without family story of hypertension (NT: 25±9 years), 10 modulating offspring of hypertensive parents (MHO: 25±6 years), 10 nonmodulating offspring of hypertensive parents (NMHO: 26±5 years), 12 modulating essential hypertensives (MHT: 34±5 years), and 11 nonmodulating essential hypertensives (NMHT: 32±4 years). Measurements were repeated in hypertensives after 3-month treatment with ramipril (5 mg daily). Nonmodulating individuals showed lower maximum FBF (NMHT: 41.96±3.3 mL/100 g per minute and NMHO: 35.6±9.0 mL/100 g per minute) than modulating subjects (MHT: 57.5±10.0 mL/100 g per minute and MHO: 51.8±7.0 mL/100 g per minute;
P
<0.003). Likewise, all nonmodulating subjects showed higher minimum FVR (NMHT: 2.5±0.2 AU; NMO: 2.8±0.5 AU) than modulating individuals (MHT: 1.9±0.5 AU; MHO, 1.8±0.3AU;
P
<0.025). Urinary albumin excretion was higher in NMHT and NMHO than MHT, MHO, and NT (
P
<0.05). Ramipril increased maximum FBF to 53.8±8.0 mL/100 g per minute and reduced minimum FVR to 1.9±0.5 AU in NMHT (
P
<0.01). Likewise, ramipril increased effective renal plasma flow and reduced renal vascular resistance and urinary albumin excretion only in NMHT (
P
<0.05). These results have shown an early involvement of the peripheral circulation in association with increased urinary albumin excretion not only in essential hypertensives but also in NMHO. The effectiveness of ramipril in reducing minimum FVR and urinary albumin excretion in NMHT also suggests a common mechanism.