bluuebunny/crossref_metadata_2025 huggingface dataset:
MDM2 SNP309 Is Associated with Endometrial Cancer Risk
Authors: Terry Kathryn , McGrath Monica , Lee I-Min , Buring Julie , De Vivo Immaculata
Published: April 2008

Mouse double-minute 2 homologue (MDM2) is a key negative regulator of p53, a tumor suppressor gene that initiates cell cycle arrest and apoptosis in response to DNA damage and other cellular stresses. A T > G polymorphism found in the promoter region of MDM2 (SNP309) increases MDM2 expression and thereby attenuates p53 activity. We genotyped the MDM2 polymorphism SNP309 in endometrial cancer case-control studies nested within the Nurses' Health Study (454 cases and 1,132 controls) and the Women's Health Study (137 cases and 411 controls). Due to a significant difference in genotype distribution by ethnicity, we restricted our analyses to Caucasians. We calculated odds ratios and 95% confidence intervals using conditional and unconditional logistic regression adjusted for age at menarche, parity and age at first birth, postmenopausal hormone use at diagnosis, age at menopause and menopausal status at diagnosis, first-degree family history of colon cancer, body mass index at diagnosis, and cigarette smoking status at diagnosis. Women with a heterozygous genotype had no greater risk whereas those with a homozygous variant genotype had a greater risk than women with a wild-type genotype for the MDM2 SNP309 (covariate-adjusted odds ratio, 1.87; 95% confidence interval, 1.29-2.73) for endometrial cancer. We observed no association between age at diagnosis and genotype. Women carrying two copies of the MDM2 SNP309 variant may be at greater risk of endometrial cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(4):983–6)
Molecular Characterization of Putative Modulatory Factors in Two Spanish Families with A1555G Deafness
Authors: Otaegui D. , Irizar H. , Goicoechea M. , Pérez-Tur J. , Belar M. , López de Munain A.
Published: April 2008

The aim of this work is to characterize possible modifying factors in 2 large families carrying the A1555G mitochondrial mutation. The heteroplasmy of the mutation, the presence of aminoglycosides, the cosegregation with other mitochondrial mutations, the proposed linkage in chromosome 8 and the association with TRMU and MTO1 genes were studied. None of the mentioned modifying factors were related with the phenotype presentation of A1555G mutation. However, TRMU G28T single nucleotide polymorphism is present in 1 of the studied families.
Pica Behavior Induced by Body Rotation in Mice
Authors: Li Zhiyuan , Zhang Xiaodong , Zheng Jiemin , Huang Mao
Published: April 2008

Objectives: To study whether rotational stimulus induced pica and whether the vestibular apparatus was necessary for obtaining rotation-induced pica in mice. Methods: Pica behavior in mice was investigated following 60 min of rotation once daily at 70 rpm (15 s on with 5 s off) for 3 consecutive days. After evaluating vestibular function and histology of vestibular epithelia, we examined rotation-induced kaolin intake, so-called pica, in sham-lesioned and chemically labyrinthectomized mice. Results: The labyrinthectomized mice exhibited loss of the contact righting and swimming capability while the destruction of hair cells of vestibular epithelia was observed. Moreover, mice subjected to rotation, but not labyrinthectomized mice, showed a significant increase in kaolin intake at the last 2 rotation sessions and the first postrotation session. Conclusions: The findings indicated that a functioning vestibular system is necessary for rotation-evocating pica in mice and thus pica can be a behavioral index of motion sickness in mice.
Prevention of Heart Failure
Authors: Schocken Douglas D. , Benjamin Emelia J. , Fonarow Gregg C. , Krumholz Harlan M. , Levy Daniel , Mensah George A. , Narula Jagat , Shor Eileen Stuart , Young James B. , Hong Yuling
Published: April 2008

The increase in heart failure (HF) rates throughout the developed and developing regions of the world poses enormous challenges for caregivers, researchers, and policymakers. Therefore, prevention of this global scourge deserves high priority. Identifying and preventing the well-recognized illnesses that lead to HF, including hypertension and coronary heart disease, should be paramount among the approaches to prevent HF. Aggressive implementation of evidence-based management of risk factors for coronary heart disease should be at the core of HF prevention strategies. Questions currently in need of attention include how to identify and treat patients with asymptomatic left ventricular systolic dysfunction (Stage B HF) and how to prevent its development. The relationship of chronic kidney disease to HF and control of chronic kidney disease in prevention of HF need further investigation. Currently, we have limited understanding of the pathophysiological basis of HF in patients with preserved left ventricular systolic function and management techniques to prevent it. New developments in the field of biomarker identification have opened possibilities for the early detection of individuals at risk for developing HF (Stage A HF). Patient groups meriting special interest include the elderly, women, and ethnic/racial minorities.

Future research ought to focus on obtaining a much better knowledge of genetics and HF, especially both genetic risk factors for development of HF and genetic markers as tools to guide prevention. Lastly, a national awareness campaign should be created and implemented to increase public awareness of HF and the importance of its prevention. Heightened public awareness will provide a platform for advocacy to create national research programs and healthcare policies dedicated to the prevention of HF.
Enzymatic Activity of Lysosomal Carboxypeptidase (Cathepsin) A Is Required for Proper Elastic Fiber Formation and Inactivation of Endothelin-1
Authors: Seyrantepe Volkan , Hinek Aleksander , Peng Junzheng , Fedjaev Michael , Ernest Sheila , Kadota Yoshito , Canuel Maryssa , Itoh Kohji , Morales Carlos R. , Lavoie Julie , Tremblay Johanne , Pshezhetsky Alexey V.
Published: April 2008

Background—

Lysosomal carboxypeptidase, cathepsin A (protective protein, CathA), is a component of the lysosomal multienzyme complex along with β-galactosidase (GAL) and sialidase Neu1, where it activates Neu1 and protects GAL and Neu1 against the rapid proteolytic degradation. On the cell surface, CathA, Neu1, and the enzymatically inactive splice variant of GAL form the elastin-binding protein complex. In humans, genetic defects of CathA cause galactosialidosis, a metabolic disease characterized by combined deficiency of CathA, GAL, and Neu1 and a lysosomal storage of sialylated glycoconjugates. However, several phenotypic features of galactosialidosis patients, including hypertension and cardiomyopathies, cannot be explained by the lysosomal storage. These observations suggest that CathA may be involved in hemodynamic functions that go beyond its protective activity in the lysosome.

Methods and Results—

We generated a gene-targeted mouse in which the active CathA was replaced with a mutant enzyme carrying a Ser190Ala substitution in the active site. These animals expressed physiological amounts of catalytically inactive CathA protein, capable of forming lysosomal multienzyme complex, and did not develop secondary deficiency of Neu1 and GAL. Conversely, the mice showed a reduced degradation rate of the vasoconstrictor peptide, endothelin-1, and significantly increased arterial blood pressure. CathA-deficient mice also displayed scarcity of elastic fibers in lungs, aortic adventitia, and skin.

Conclusions—

Our results provide the first evidence that CathA acts in vivo as an endothelin-1–inactivating enzyme and strongly confirm a crucial role of this enzyme in effective elastic fiber formation.
Death Without Prior Appropriate Implantable Cardioverter-Defibrillator Therapy
Authors: Koller Michael T. , Schaer Beat , Wolbers Marcel , Sticherling Christian , Bucher Heiner C. , Osswald Stefan
Published: April 2008

Background—

Implantable cardioverter-defibrillators (ICDs) improve survival in selected patients with left ventricular systolic dysfunction in randomized trials. Competing death without prior appropriate ICD therapy might preclude benefit from ICD implantation in a less selected routine-care population.

Methods and Results—

We selected all patients with ischemic or dilated cardiomyopathy with an ICD implanted for primary or secondary prevention from a single-center prospective registry between 1994 and 2006. The end point was time to first appropriate ICD therapy/confirmed ventricular fibrillation or death without prior appropriate ICD therapy. We analyzed cumulative incidence functions and used competing risk regression to study predictors of appropriate ICD therapy or prior death. In 442 patients, 73 deaths occurred during a median follow-up of 3.6 years (maximum, 12.7 years). The cumulative incidence of first appropriate ICD therapy until year 7 was 52%, whereas 11% died without prior ICD therapy. The cumulative incidence of appropriate ICD therapy for ventricular fibrillation was 13%, whereas 23% died without prior therapy for ventricular fibrillation. Appropriate ICD therapy was twice as likely in secondary prevention compared with primary prevention, whereas death rates before ICD therapy were similar in both groups. Diuretic use for heart failure compared with nonuse predicted a 4-fold-increased risk of death prior to ICD therapy, although the incidence of appropriate ICD therapy was similar in both groups.

Conclusion—

In a contemporary ICD population, the risk of death without prior appropriate ICD therapy is substantial, especially in patients with advanced heart failure.
Comparison of “Risk-Adjusted” Hospital Outcomes
Authors: Shahian David M. , Normand Sharon-Lise T.
Published: April 2008

Background—

A frequent challenge in outcomes research is the comparison of rates from different populations. One common example with substantial health policy implications involves the determination and comparison of hospital outcomes. The concept of “risk-adjusted” outcomes is frequently misunderstood, particularly when it is used to justify the direct comparison of performance at 2 specific institutions.

Methods and Results—

Data from 14 Massachusetts hospitals were analyzed for 4393 adults undergoing isolated coronary artery bypass graft surgery in 2003. Mortality estimates were adjusted using clinical data prospectively collected by hospital personnel and submitted to a data coordinating center designated by the state. The primary outcome was hospital-specific, risk-standardized, 30-day all-cause mortality after surgery. Propensity scores were used to assess the comparability of case mix (covariate balance) for each Massachusetts hospital relative to the pool of patients undergoing coronary artery bypass grafting surgery at the remaining hospitals and for selected pairwise comparisons. Using hierarchical logistic regression, we indirectly standardized the mortality rate of each hospital using its expected rate. Predictive cross-validation was used to avoid underidentification of true outlying hospitals. Overall, there was sufficient overlap between the case mix of each hospital and that of all other Massachusetts hospitals to justify comparison of individual hospital performance with that of the remaining hospitals. As expected, some pairwise hospital comparisons indicated lack of comparability. This finding illustrates the fallacy of assuming that risk adjustment per se is sufficient to permit direct side-by-side comparison of healthcare providers. In some instances, such analyses may be facilitated by the use of propensity scores to improve covariate balance between institutions and to justify such comparisons.

Conclusions—

Risk-adjusted outcomes, commonly the focus of public report cards, have a specific interpretation. Using indirect standardization, these outcomes reflect a provider’s performance for its specific case mix relative to the expected performance of an average provider for that same case mix. Unless study design or post hoc adjustments have resulted in reasonable overlap of case-mix distributions, such risk-adjusted outcomes should not be used to directly compare one institution with another.
Involvement of Tumor Necrosis Factor-α in Angiotensin II–Mediated Effects on Salt Appetite, Hypertension, and Cardiac Hypertrophy
Authors: Sriramula Srinivas , Haque Masudul , Majid Dewan S.A. , Francis Joseph
Published: April 2008

Hypertension is considered a low-grade inflammatory condition induced by various proinflammatory cytokines, including tumor necrosis factor (TNF)-α. Recent studies have implicated an involvement of TNF-α in the development of salt-sensitive hypertension induced by angiotensin II (Ang II). To understand further the relationship between TNF-α and Ang II, we examined the responses to Ang II in TNF-α knockout (TNF-α−/−) mice in the present study. A continuous infusion of Ang II (1 μg/kg per minute) for 2 weeks was given to both TNF-α−/−and wild-type (WT) mice with implanted osmotic minipumps. Daily measurement of water intake, salt intake, and urine output were performed using metabolic cages. Blood pressure was monitored continuously with implanted radiotelemetry. Ang II administration for 2 weeks caused increases in salt (0.2±0.07 to 5.6±0.95 mL/d) and water (5.4±0.34 to 11.5±1.2 mL/d) intake and in mean arterial pressure (115±1 to 151±3 mm Hg) in wild-type mice, but these responses were absent in TNF-α−/−mice (0.2±0.04 to 0.3±0.09 mL/d, 5.5±0.2 to 6.1±0.07 mL/d, and 113±2 to 123±3 mm Hg, respectively). Cardiac hypertrophy induced by Ang II was significantly attenuated in TNF-α−/−mice compared with wild-type mice. In a group of TNF-α−/−mice, when replacement therapy was made with recombinant TNF-α, Ang II induced similar responses in salt appetite, mean arterial pressure, and cardiac hypertrophy, as observed in wild-type mice. These results suggest that TNF-α plays a mechanistic role in mediating chronic Ang II–induced effects on salt appetite and blood pressure, as well as on cardiac hypertrophy.
Acute Effects of Passive Smoking on Peripheral Vascular Function
Authors: Argacha Jean-François , Adamopoulos Dionysios , Gujic Marko , Fontaine David , Amyai Nadia , Berkenboom Guy , van de Borne Philippe
Published: April 2008

Environmental tobacco smoke (ETS) acutely affects peripheral and coronary vascular tone. Whether ETS exerts specific deleterious effects on aortic wave reflection through nicotine exposure, whether they persist after ETS cessation, and whether the smoke environment impairs microvascular function and increases asymmetrical dimethyl-arginine levels are not known. We tested these hypotheses in a randomized, crossover study design in 11 healthy male nonsmokers. The effects of 1 hour of exposure to ETS, as compared with a nontobacco smoke and normal air, on augmentation index corrected for heart rate and skin microvascular hyperemia to local heating were examined. Augmentation index increased both during (
P
=0.01) and after (
P
<0.01) the ETS session but remained unchanged in the nontobacco smoke session when compared with normal air. Nicotine levels after the exposure were related to the peak rise in augmentation index (
r
=0.84;
P
<0.01), denoting a predominant role of nicotine in ETS vascular effects. This was confirmed in a second set of experiments (n=14), where the sublingual administration of nicotine was associated with an acute impairment in wave reflection as compared with placebo (
P
=0.001). Both ETS and nontobacco smokes increased plasma asymmetrical dimethyl-arginine levels (
P
<0.001), but only ETS reduced the late rise in skin blood flow in response to heating (
P
=0.03). In conclusion, passive smoking specifically increases aortic wave reflection through a nicotine-dependent pathway and impairs microvascular function, even after the end of the exposure. However, both tobacco and nontobacco passive smoking inhalation increase plasma asymmetrical dimethyl-arginine levels.
Ecto-5′-Nucleotidase Deficiency Exacerbates Pressure-Overload–Induced Left Ventricular Hypertrophy and Dysfunction
Authors: Xu Xin , Fassett John , Hu Xinli , Zhu Guangshuo , Lu Zhongbing , Li Yunfang , Schnermann Jurgen , Bache Robert J. , Chen Yingjie
Published: April 2008

This study examined whether endogenous extracellular adenosine acts to facilitate the adaptive response of the heart to chronic systolic overload. To examine whether endogenous extracellular adenosine can protect the heart against pressure-overload–induced heart failure, transverse aortic constriction was performed on mice deficient in extracellular adenosine production as the result of genetic deletion of CD73. Although there was no difference in left ventricular size or function between CD73-deficient mice (knockout [KO] mice) and wild-type mice under unstressed conditions, aortic constriction for 2 or 4 weeks induced significantly more myocardial hypertrophy, left ventricular dilation, and left ventricular dysfunction in KO mice compared with wild-type mice. Thus, after 2 weeks of transverse aortic constriction, left ventricular fractional shortening decreased to 27.4±2.5% and 21.9±1.7% in wild-type and KO mice, respectively (
P
<0.05). Consistent with a role of adenosine in reducing tissue remodeling, KO mice displayed increased myocardial fibrosis and myocyte hypertrophy compared with wild-type mice. Furthermore, adenosine treatment reduced phenylephrine-induced cardiac myocyte hypertrophy and collagen production in cultured neonatal rat cardiac myocytes and cardiac fibroblasts, respectively. Consistent with a role for adenosine in modulating cardiomyocyte hypertrophy, KO mice demonstrated increased activation of mammalian target of rapamycin signaling, accompanied by higher expression of the hypertrophy marker atrial natriuretic peptide. Conversely, the adenosine analogue 2-chloro-adenosine significantly reduced cell size, mammalian target of rapamycin/p70 ribosomal S6 kinase activation, and atrial natriuretic peptide expression in cultured neonatal cardiomyocytes. These data demonstrate that CD73 helps to preserve cardiac function during chronic systolic overload by preventing maladaptive tissue remodeling.
Choices for Whom?
Authors: Tse Thomas Kwan-choi
Published: April 2008

School choice programs have proliferated around the world since the 1980s. Following this international trend, the Direct Subsidy Scheme (DSS) was launched in 1991 to revitalize Hong Kong's private school sector. DSS schools receive a similar subsidy per student to that received by aided schools, but they may charge fees and have greater control over curricula, entrance requirements, and management than their public school counterparts. Drawing on a number of documents and reports over the period 1987-2006, this article centers on the notion of choice and its related arguments. By revealing the discrepancies between rhetoric and reality, it shows how a policy purporting to appeal to choice, diversity, and competition undermines equality, community, and democracy. Under the provision of DSS, the benefits some parents and schools enjoy by being afforded more choices are often achieved at the expense of fewer choices for others.
Negational Categorization and Intergroup Behavior
Authors: Zhong Chen-Bo , Phillips Katherine W. , Leonardelli Geoffrey J. , Galinsky Adam D.
Published: April 2008

Individuals define themselves, at times, as who they are (e.g., a psychologist) and, at other times, as who they are not (e.g., not an economist). Drawing on social identity, optimal distinctiveness, and balance theories, four studies examined the nature of negational identity relative to affirmational identity. One study explored the conditions that increase negational identification and found that activating the need for distinctiveness increased the accessibility of negational identities. Three additional studies revealed that negational categorization increased outgroup derogation relative to affirmational categorization and the authors argue that this effect is at least partially due to a focus on contrasting the self from the outgroup under negational categorization. Consistent with this argument, outgroup derogation following negational categorization was mitigated when connections to similar others were highlighted. By distinguishing negational identity from affirmational identity, a more complete picture of collective identity and intergroup behavior can start to emerge.
Effects of Semantic Incompatibility on Rating Response
Authors: Lam Tony C. M. , Kolic Mary
Published: April 2008

Semantic incompatibility, an error in constructing measuring instruments for rating oneself, others, or objects, refers to the extent to which item wordings are incongruent with, and hence inappropriate for, scale labels and vice versa. This study examines the effects of semantic incompatibility on rating responses. Using a 2 × 2 factorial design with semantic compatibility and scale packedness as the between-subjects factors, 160 university students were randomly assigned to four treatment conditions. Analysis of their responses to a 10-item academic ability self-assessment rating scale shows a significant difference in means between positive-packed and equal-interval conditions when item wordings and scale labels are semantically compatible. The semantically compatible conditions also show smaller variability and a slightly higher internal consistency of responses than the semantically incompatible conditions. The authors conclude that when rating scales are semantically incompatible, respondents tend to ignore the scale labels, use a greater variety of strategies to generate responses, and produce less reliable responses.
Governance, Hubris, and Justice in Modern Tragedy
Authors: Lambropoulos Vassilis
Published: April 2008

Hubris is a notion that has recently acquired special urgency, as it seems to express in the post-communist era the demands of justice during the tragic clash between governance and violence. This ethico-political notion deserves to be studied not only in ancient writings but in modern drama and thought as well. Nikos Kazantzakis' unduly neglected Capodistria (1944) dramatizes the dilemmas of civic action during the democratic constitution of a polity. A reading of this tragedy from the perspective of political theory suggests ways in which the meaning of hubris in modernity may be better understood.
Effect of Molding Condition on Mechanical Properties of Injection Molded Nylon 6-Clay Nanocomposites
Authors: Shia Chung Chen  , Hui Li Chen  , Pe Ming Hsu
Published: April 2008

In this study, the effects of varying molding conditions, including melt temperature, mold temperature, and injection speed, on the mechanical properties of injection molded nylon-6/fluoromica nanocomposite (Unitika) were investigated. A DSC test and SEM were used to examine the microstructure of material and verify the experimental results. Results showed that the addition of 5 wt% nano-fluoromica particles to pure nylon-6 increases the tensile strength over 20% and the flexural strength more than 38%, but decreases impact strength by less than 2%. Results also indicate that the tensile strength and flexural strength of the nylon-6/fluoromica nanocomposite increase with increased melt temperature, mold temperature, and injection speed. However, the impact strength of nylon-6/fluoromica nanocomposite increased with increased melt temperature, but decreased with increasing mold temperature and injection speed. The DSC measurement revealed that the crystallinity of nylon-6/fluoromica nanocomposite increases with all molding parameters. The SEM results also indicate that the nylon-6/fluoromica nanocomposite is more brittle than the pure nylon-6.
Women Arrested for Partner Violence and Substance Use
Authors: Simmons Catherine A. , Lehmann Peter , Cobb Norman
Published: April 2008

Discrepancies exist in research examining substance problems within groups of women arrested for intimate partner violence (IPV). In some studies women IPV arrestees have been found to be at high risk for substance-related problems, whereas in others they are found to be at low risk for substance-related problems. The current study explores these discrepancies then compares a sample of women court ordered to a domestic violence diversion program ( n = 78) to a matched sample of men ( n = 78) in the same program using police report information, self-report measures, the Substance Abuse Subtle Screening Inventory—3, and the Millon Clinical Multiaxial Inventory—III alcohol and drug subscales. Women IPV arrestees had a low occurrence of substance use during the arresting incident, a low incidence of substance-related diagnoses, and fewer substance-related problems than did men IPV arrestees. However, women demonstrated personality structures susceptible to nondiagnosable, hazardous drinking patterns.
Comparison of 3-D Body Scan Data to Quantify Upper-Body Postural Variation in Older and Younger Women
Authors: Ashdown Susan P. , Na Hyunshin
Published: April 2008

As women age, changes occur in their posture and bilateral symmetry that affect the fit of clothing. These changes have been documented in many studies. Anthropometric measures made in previous studies, however, were limited to linear measurements (circumferences or lengths) and included only one angle, the shoulder slope. In this study, the authors took detailed measurements using a 3-D body scanner to validate previous studies and more precisely quantify body changes in older women. They compared upper-body measurements of 40 women aged 19-35 to those of 40 women aged 55+. Using these measurements, we quantified the differences in posture and the differences in the amount of bilateral variation between the older and younger women. Nineteen upper-body angles, 16 linear measurements, and one proportional measurement were included in the study. Of the 36 body measurements taken, 21 measurements were significantly different between the two groups of women.
Biotechnology and the Popular Press in Northern Belgium
Authors: Maeseele Pieter A. , Schuurman Dimitri
Published: April 2008

The media representation of biotechnology has received widespread attention during the last decade. Two gaps, however, are present in this literature, both of which are addressed in this study. We present data from a content analysis of coverage appearing in three popular newspapers in Northern Belgium between January 2000 and October 2004 ( N = 506). The main findings reveal that the trends identified in the European elite press from 1992 to 1999 are confirmed and strengthened after 2000 in popular press coverage, resulting in a greater diversity of sources and perspectives than before. Our findings also reveal that different media sources achieve standing to strategically frame the biotech issue in advantageous terms, resulting in different representations for each application. Hegemonic discourse in terms of a source-generated pro-biotechnology bias is found to be solid for biomedical biotechnology, heavily under siege by challengers in the case of agricultural biotechnology, and characterized by dissension in the case of reproductive cloning.
Patriarchy Reasserted
Authors: Dragiewicz Molly
Published: April 2008

The backlash against gender-sensitive responses to women's victimization, offending, and imprisonment is inseparable from contemporary reaction against feminism and other progressive movements. The backlash against the American Violence Against Women Act (VAWA) provides a prime example of this resistance. Despite widespread support for VAWA and other policies designed to address violence against women, some constituencies object to their existence. The author investigates fathers' rights rhetoric on VAWA as an example of antifeminist backlash.
War, memory, and the public mediation of affect: The National World War II Memorial and American imperialism
Authors: Doss Erika
Published: April 2008

Contemporary America is deeply engaged in `memorial mania', a national obsession with issues of memory and history and an urgent, excessive desire to secure those issues with various forms of public commemoration. War memorials are especially flourishing, seen locally in small towns and larger cities, and nationally in the dedication of the National World War II Memorial in Washington, DC in 2004; indeed, memorials to World War II's `greatest generation' are especially popular. This article considers how and why contemporary American publics are emotionally persuaded by these new fronts of war memory, and by dominant tropes of militarism, imperialism and masculine authority. Central to this discussion are the ways in which public feelings of gratitude mobilize contemporary American war memory. What does it mean to say `thank you' to the greatest generation today? Why is such gratitude being so urgently expressed today, some 60 years after World War II ended?
Genotype-phenotype correlation in combined deficiency of factor V and factor VIII
Authors: Zhang Bin , Spreafico Marta , Zheng Chunlei , Yang Angela , Platzer Petra , Callaghan Michael U. , Avci Zekai , Ozbek Namik , Mahlangu Johnny , Haw Tabitha , Kaufman Randal J. , Marchant Kandice , Tuddenham Edward G. D. , Seligsohn Uri , Peyvandi Flora , Ginsburg David
Published: April 2008

Combined deficiency of factor V and factor VIII (F5F8D) is caused by mutations in one of 2 genes, either LMAN1 or MCFD2. Here we report the identification of mutations for 11 additional F5F8D families, including 4 novel mutations, 2 in MCFD2 and 2 in LMAN1. We show that a novel MCFD2 missense mutation identified here (D81Y) and 2 previously reported mutations (D89A and D122V) abolish MCFD2 binding to LMAN1. Measurement of platelet factor V (FV) levels in 7 F5F8D patients (4 with LMAN1 and 3 with MCFD2 mutations) demonstrated similar reductions to those observed for plasma FV. Combining the current data together with all previous published reports, we performed a genotype-phenotype analysis comparing patients with MCFD2 mutations with those with LMAN1 mutations. A previously unappreciated difference is observed between these 2 classes of patients in the distribution of plasma levels for FV and factor VIII (FVIII). Although there is considerable overlap, the mean levels of plasma FV and FVIII in patients with MCFD2 mutations are significantly lower than the corresponding levels in patients with LMAN1 mutations. No differences in distribution of factor levels are observed by sex. These data suggest that MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2.
Translocations targeting CCND2, CCND3, and MYCN do occur in t(11;14)-negative mantle cell lymphomas
Authors: Wlodarska Iwona , Dierickx Daan , Vanhentenrijk Vera , Van Roosbroeck Katrien , Pospís̆ilová Helena , Minnei Francesca , Verhoef Gregor , Thomas José , Vandenberghe Peter , De Wolf-Peeters Chris
Published: April 2008

The genetics of t(11;14)(q13;q32)/cyclin D1–negative mantle cell lymphoma (MCL) is poorly understood. We report here 8 MCL cases lacking t(11;14) or variant CCND1 rearrangement that showed expression of cyclin D1 (2 cases), D2 (2 cases), and D3 (3 cases). One case was cyclin D negative. Cytogenetics and fluorescence in situ hybridization detected t(2;12)(p11;p13)/IGK-CCND2 in one of the cyclin D2-positive cases and t(6;14)(p21;q32)/IGH-CCND3 in one of the cyclin D3-positive cases. Moreover, we identified a novel cryptic t(2;14)(p24;q32) targeting MYCN in 2 blastoid MCLs: one negative for cyclin D and one expressing cyclin D3. Interestingly, both cases showed expression of cyclin E. Notably, all 3 blastoid MCLs showed a monoallelic deletion of RB1 associated with a lack of expression of RB1 protein and monoallelic loss of p16. In sum-mary, this study confirms frequent aberrant expression of cyclin D2 and D3 in t(11;14)-negative MCLs and shows a t(11;14)-independent expression of cy-clin D1 in 25% of present cases. Novel findings include cyclin E expression in 2 t(11;14)-negative MCLs characterized by a cryptic t(2;14)(p24;q32) and identification of MYCN as a new lymphoma oncogene associated with a blastoid MCL. Clinically important is a predisposition of t(11;14)-negative MCLs to the central nervous system involvement.
Interventions designed to improve the quality and efficiency of medication use in managed care: A critical review of the literature – 2001–2007
Authors: Lu Christine Y , Ross-Degnan Dennis , Soumerai Stephen B , Pearson Sallie-Anne
Published: April 2008

Background

Managed care organizations use a variety of strategies to reduce the cost and improve the quality of medication use. The effectiveness of such policies is not well understood. The objective of this research was to update a previous systematic review of interventions, published between 1966 and 2001, to improve the quality and efficiency of medication use in the US managed care setting.

Methods

We searched MEDLINE and EMBASE for publications from July 2001 to January 2007 describing interventions targeting drug use conducted in the US managed care setting. We categorized studies by intervention type and adequacy of research design using commonly accepted criteria. We summarized the outcomes of well-controlled strategies and documented the significance and magnitude of effects for key study outcomes.

Results

We identified 164 papers published during the six-year period. Predominant strategies were: educational interventions (n = 20, including dissemination of educational materials, and group or one-to-one educational outreach); monitoring and feedback (n = 22, including audit/feedback and computerized monitoring); formulary interventions (n = 66, including tiered formulary and patient copayment); collaborative care involving pharmacists (n = 15); and disease management with pharmacotherapy as a primary focus (n = 41, including care for depression, asthma, and peptic ulcer disease). Overall, 51 studies met minimum criteria for methodological adequacy. Effective interventions included one-to-one academic detailing, computerized alerts and reminders, pharmacist-led collaborative care, and multifaceted disease management. Further, changes in formulary tier-design and related increases in copayments were associated with reductions in medication use and increased out-of-pocket spending by patients. The dissemination of educational materials alone had little or no impact, while the impact of group education was inconclusive.

Conclusion

There is good evidence for the effectiveness of several strategies in changing drug use in the managed care environment. However, little is known about the cost-effectiveness of these interventions. Computerized alerts showed promise in improving short-term outcomes but little is known about longer-term outcomes. Few well-designed, published studies have assessed the potential negative clinical effects of formulary-related interventions despite their widespread use. However, some evidence suggests increases in cost sharing reduce access to essential medicines for chronic illness.
Effect of Molecular Therapeutics on Liver Regeneration in a Murine Model
Authors: Van Buren George , Yang Anthony D. , Dallas Nikolaos A. , Gray Michael J. , Lim Sherry J. , Xia Ling , Fan Fan , Somcio Ray , Wu Yan , Hicklin Daniel J. , Ellis Lee M.
Published: April 2008

Purpose

Unresectable metastatic colorectal cancer (CRC) can be rendered resectable with systemic chemotherapy in approximately 20% of cases. Most patients with metastatic CRC receive chemotherapy with the addition of targeted therapy with anti–vascular endothelial growth factor (VEGF) or anti–epidermal growth factor receptor (EGFR) antibodies. We sought to determine whether anti-VEGF receptor (VEGFR) or anti-EGFR therapy would impair liver regeneration after partial hepatectomy (PH) in mice.

Materials and Methods

Mice underwent either 66% PH or sham laparotomy. In the first experiment, mice in the PH group were randomly assigned to receive daily intraperitoneal injections of monoclonal antibodies (MoABs) to murine VEGFR-2 or nonspecific MoABs (control). In the second experiment, mice in the PH group were randomly assigned to receive intraperitoneal injections of antimurine EGFR or nonspecific (control) MoABs. In both experiments, therapy was initiated the day before surgery and continued until the mice were killed on day 5. Livers were collected and processed.

Results

Anti–VEGFR-2 therapy slightly impaired liver regeneration and hepatic cell proliferation compared with control. Hematoxylin and eosin staining showed no differences in liver morphology. CD105 staining showed decreased levels of activated endothelium in livers in the VEGFR-2 MoAB group. VEGFR-2 MoAB therapy decreased the levels of the cell cycle regulators cyclin D1 and cyclin D3 and the regenerative cytokine interleukin-6. Anti-EGFR therapy had no effect on liver regeneration or cellular proliferation.

Conclusion

Anti–VEGFR-2 therapy slightly impaired liver regeneration in this murine model, whereas anti-EGFR therapy had no effect on liver regeneration.
Randomized Phase III Trial Comparing Bexarotene (L1069-49)/Cisplatin/Vinorelbine With Cisplatin/Vinorelbine in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT I
Authors: Ramlau Rodryg , Zatloukal Petr , Jassem Jacek , Schwarzenberger Paul , Orlov Sergei V. , Gottfried Maya , Pereira Jose Rodrigues , Temperley Guillermo , Negro-Vilar Rosa , Rahal Samia , Zhang Joseph K. , Negro-Vilar Andres , Dziewanowska Zofia E.
Published: April 2008

Purpose

This study evaluated whether the combination of the synthetic rexinoid bexarotene with first-line cisplatin/vinorelbine therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with stage IIIB with pleural effusion or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to open-label bexarotene 400 mg/m2/d with cisplatin/vinorelbine or to cisplatin/vinorelbine alone. Antilipid agents were initiated on or before day 1 in the bexarotene arm. Primary efficacy end point was overall survival. Primary, secondary and supportive efficacy analyses were conducted.

Results

A total of 623 patients (312 control, 311 bexarotene) were enrolled. Overall, no significant difference in survival occurred between the two treatment groups. However, an unplanned retrospective analysis showed that a subpopulation of bexarotene patients (n = 98 of 306) who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had longer median survival compared with control patients (12.3 v 9.9 months; log-rank P = .08). Within that subgroup, those who benefited the most included males, smokers, those with stage IV disease, and those with a 6-month prior weight loss of 5% or more. Incidence, type and severity of grade 3/4 adverse events were comparable between arms, except for leukopenia (higher in chemotherapy arm) and hyperlipemia, hypothyroidism, dyspnea, and headache (higher in chemotherapy/bexarotene arm).

Conclusion

The addition of bexarotene to first-line chemotherapy did not increase survival in patients with advanced NSCLC. However, a subgroup (32%) of bexarotene-treated patients developing high-grade hypertriglyceridemia appeared to have better survival (12.3 months) than controls; thus triglyceride response may be a biomarker of survival benefit with bexarotene.
Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT II
Authors: Blumenschein George R. , Khuri Fadlo R. , von Pawel Joachim , Gatzemeier Ulrich , Miller Wilson H. , Jotte Robert M. , Le Treut Jacques , Sun Show-Li , Zhang Jinkun K. , Dziewanowska Zofia E. , Negro-Vilar Andres
Published: April 2008

Purpose

The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m2/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted.

Results

A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss ≥ 5%, and had stage IV disease. The incidence and severity of most adverse events were similar between arms, although hyperlipidemia, neutropenia, fatigue, leukopenia, arthralgia, and diarrhea were more frequent in the bexarotene arm.

Conclusion

Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.
Comparison of the Results of the Treatment of Adolescents and Young Adults With Standard-Risk Acute Lymphoblastic Leukemia With the Programa Español de Tratamiento en Hematología Pediatric-Based Protocol ALL-96
Authors: Ribera Josep-María , Oriol Albert , Sanz Miguel-Angel , Tormo Mar , Fernández-Abellán Pascual , del Potro Eloy , Abella Eugenia , Bueno Javier , Parody Ricardo , Bastida Pilar , Grande Carlos , Heras Inmaculada , Bethencourt Concepción , Feliu Evarist , Ortega Juan-José
Published: April 2008

Purpose

Retrospective studies have shown that adolescents and young adults with acute lymphoblastic leukemia (ALL) treated with pediatric protocols have better outcomes than similarly aged patients treated with adult protocols, but prospective studies comparing adolescents and young adults using pediatric schedules are scarce. The ALL-96 protocol was addressed to compare the toxicity and results of a pediatric-based protocol in adolescents (age 15-18 years) and young adults (age 19-30 years) with standard-risk (SR) ALL.

Patients and Methods

Adolescents (n = 35) and young adults (n = 46) received a standard five-drug/5-week induction course followed by two cycles of early consolidation, maintenance with monthly reinforcement cycles up to 1 year in continuous complete remission (CR) and 1 year with standard maintenance chemotherapy up to 2 years in CR.

Results

Adolescents and young adults were comparable in the main pretreatment ALL characteristics. The CR rate was 98% and. after a median follow-up of 4.2 years, 6-year event-free survival (EFS) and overall survival (OS) were 61% (95% CI, 51% to 72%) and 69% (95% CI, 59% to 79%), respectively, with no differences between adolescents and young adults. The hematologic toxicity in consolidation and reinforcement cycles was higher in young adults than in adolescents. Slow response to induction therapy was the only parameter associated with poor EFS (34% v 67%) and OS (40% v 76%).

Conclusion

The response to the pediatric ALL-96 protocol was identical in adolescents and young adults despite a slight increase in hematologic toxicity observed in adults. This justifies the age-unrestricted use of pediatric regimens to treat patients with SR ALL.
Variation in Bleomycin Hydrolase Gene Is Associated With Reduced Survival After Chemotherapy for Testicular Germ Cell Cancer
Authors: de Haas Esther C. , Zwart Nynke , Meijer Coby , Nuver Janine , Boezen H. Marike , Suurmeijer Albert J.H. , Hoekstra Harald J. , van der Steege Gerrit , Sleijfer Dirk Th. , Gietema Jourik A.
Published: April 2008

Purpose

Response to chemotherapy may be determined by gene polymorphisms involved in metabolism of cytotoxic drugs. A plausible candidate is the gene for bleomycin hydrolase (BLMH), an enzyme that inactivates bleomycin, an essential component of chemotherapy regimens for disseminated testicular germ-cell cancer (TC). We investigated whether the single nucleotide polymorphism (SNP) A1450G of the BLMH gene (rs1050565) is associated with survival.

Patients and Methods

Data were collected on survival and BLMH genotype of 304 patients with TC treated with bleomycin-containing chemotherapy at the University Medical Center Groningen, the Netherlands, between 1977 and 2003. Survival according to genotype was analyzed using Kaplan-Meier curves with log-rank testing and Cox regression analysis with adjustment for confounders.

Results

BLMH gene SNP A1450G has a significant effect on TC-related survival (log-rank P = .001). The homozygous variant (G/G) genotype (n = 31) is associated with decreased TC related survival compared with the heterozygous variant (A/G; n = 133) and the wild-type (A/A; n = 140). With Cox regression the G/G genotype proves to be an unfavorable prognostic factor, in addition to the commonly used International Germ Cell Consensus Classification prognosis group, with a hazard ratio of 4.97 (95% CI, 2.17 to 11.39) for TC-related death. Furthermore, the G/G genotype shows a higher prevalence of early relapses.

Conclusion

The homozygous variant G/G of BLMH gene SNP A1450G is associated with reduced survival and higher prevalence of early relapses in TC patients treated with bleomycin-containing chemotherapy. This association is hypothesis generating and may eventually be of value for risk classification and selection for alternative treatment strategies in patients with disseminated TC.
Lack of Community Insurance and Mammography Screening Rates Among Insured and Uninsured Women
Authors: Pagán José A. , Asch David A. , Brown Cynthia J. , Guerra Carmen E. , Armstrong Katrina
Published: April 2008

Purpose

To evaluate whether the proportion of the local population without health insurance coverage is related to whether women undergo mammography screening.

Methods

Survey data on 12,595 women 40 to 69 years of age from the 2000 to 2001 Community Tracking Study Household Survey were used to analyze the relation between community lack of insurance and whether the respondent had a mammogram within the past year.

Results

Women age 40 to 69 were less likely to report that they had a mammogram within the last year if they resided in communities with a relatively high uninsurance rate, even after adjusting for other factors. After adjusting for individual insurance and other factors, a 10-percentage-point decrease in the proportion of the local insured population is associated with a 17% (95% CI, 13% to 21%) decrease in the odds that a woman age 40 to 69 years will undergo mammography screening within a year.

Conclusion

Women living in communities with high uninsurance are substantially less likely to undergo mammography screening. These results are consistent with the view that the negative impact of uninsurance extends to everyone in the community regardless of individual health insurance status.