bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Risk Assessment in Asymptomatic Individuals With Exercise Testing and Framingham Risk Scores
Authors: Mora Samia , Redberg Rita F. , Sharrett A. Richey , Blumenthal Roger S.
Published: September 2005

Background—

National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines recommend the use of Framingham risk scores (FRS) for cardiovascular assessment of asymptomatic individuals. We hypothesized that risk prediction could be improved with 2 non-ECG exercise test measures, exercise capacity (metabolic equivalents, or METs) and heart rate recovery (HRR).

Methods and Results—

An asymptomatic cohort with baseline treadmill tests (n=6126; 46% women, FRS <20%) was followed up prospectively for 20 years. Individuals with low (median or less) HRR or METs experienced 91% of all cardiovascular disease (CVD) deaths (225/246). After FRS adjustment, low HRR and METs individually were highly significant predictors of CVD death, but low HRR and METs together were associated with substantially higher risk (adjusted hazard ratio compared with high HRR/high METs for women 8.51, 95% CI 3.65 to 19.84; for men, 3.53, 95% CI 2.03 to 6.15;
P
<0.001 for both). At 10-year follow-up, FRS-adjusted CVD death risk associated with low HRR/low METs was less than at 20 years but remained significant (women 3.83, 95% CI 1.09 to 13.47, and men 2.70, 95% CI 1.11 to 6.55). The application of HRR/METs information to FRS assessment identified those at high risk (>0.5% annual CVD mortality) in half of women with FRS 6% to 9% and 10% to 19% and just under half of men with FRS 10% to 19%. Low HRR/low METs was also associated with an increased relative risk of CVD death in individuals with low-risk FRS (FRS <6% in women and <10% in men), but absolute CVD mortality rates were low in this subgroup.

Conclusions—

Exercise testing may be a useful adjunct for clinical risk assessment in asymptomatic women with FRS 6% to 19% and men with FRS 10% to 19%.
Danon Disease as an Underrecognized Cause of Hypertrophic Cardiomyopathy in Children
Authors: Yang Zhao , McMahon Colin J. , Smith Liana R. , Bersola Jeathrina , Adesina Adekunle M. , Breinholt John P. , Kearney Debra L. , Dreyer William J. , Denfield Susan W. , Price Jack F. , Grenier Michelle , Kertesz Naomi J. , Clunie Sarah K. , Fernbach Susan D. , Southern James F. , Berger Stuart , Towbin Jeffrey A. , Bowles Karla R. , Bowles Neil E.
Published: September 2005

Background—

Some patients with hypertrophic cardiomyopathy (HCM) or left ventricular hypertrophy also present with skeletal myopathy and Wolff-Parkinson-White (WPW) syndrome; mutations in the gene encoding the lysosome-associated protein-2 (LAMP-2) have been identified in these patients, suggesting that some of these patients have Danon disease. In this study we investigated the frequency of
LAMP2
mutations in an unselected pediatric HCM population.

Methods and Results—

LAMP2
was amplified from genomic DNA isolated from peripheral lymphocytes of 50 patients diagnosed with HCM and analyzed by direct DNA sequencing. In 2 of the 50 probands (4%), nonsense mutations were identified. In 1 family the proband initially presented with HCM as a teenager, which progressed to dilated cardiomyopathy (DCM) and heart failure. Skeletal myopathy and WPW were also noted. The teenage sister of the proband is a carrier of the same
LAMP2
mutation and has HCM without skeletal myopathy or WPW. The other proband presented with HCM, WPW, and skeletal myopathy as a teenager, whereas his carrier mother developed DCM during her 40s. Skeletal and cardiac muscle sections revealed the absence of LAMP-2 on immunohistochemical staining.

Conclusions—

LAMP2
mutations may account for a significant proportion of cases of HCM in children, especially when skeletal myopathy and/or WPW is present, suggesting that Danon disease is an underrecognized entity in the pediatric cardiology community.
N-Terminal Pro–Brain Natriuretic Peptide or Troponin Testing Followed by Echocardiography for Risk Stratification of Acute Pulmonary Embolism
Authors: Binder Lutz , Pieske Burkert , Olschewski Manfred , Geibel Annette , Klostermann Beate , Reiner Christian , Konstantinides Stavros
Published: September 2005

Background—

Brain natriuretic peptide (BNP) and N-terminal (NT)-proBNP have recently emerged as promising parameters for risk assessment in acute pulmonary embolism (PE). However, their positive predictive value is low, and the prognostic implications of NT-proBNP or troponin elevation alone are questionable.

Methods and Results—

To determine whether the combination of NT-proBNP testing with echocardiography may identify both low-risk and high-risk patients with PE, we examined 124 consecutive patients with proved PE. All underwent echocardiography on admission to detect right ventricular dysfunction. NT-proBNP and troponin concentrations were measured in one core laboratory. The primary end point was death or major in-hospital complications. The cutoff level of 1000 pg/mL had a high negative predictive value (95% for a complicated course, 100% for death), but NT-proBNP ≥1000 pg/mL did not independently predict an adverse outcome. Combination of NT-proBNP testing with echocardiography identified 3 major risk groups. A positive echocardiogram was associated with a 12-fold elevation in complication risk compared with patients with low NT-proBNP (
P
=0.002), whereas NT-proBNP elevation without right ventricular dysfunction on echocardiography only slightly increased the risk of an adverse outcome (
P
=0.17). The combination of cardiac troponin testing with echocardiography yielded similar complication rates in the lowest-risk group and a similar magnitude of risk elevation for the highest-risk patients, but it also increased the number of intermediate-risk groups.

Conclusions—

Our results support a simple risk stratification algorithm for patients with PE, with the use of NT-proBNP or troponin testing as an initial step that should be followed by echocardiography if elevated levels of the biomarker are found.
A Strengths Perspective in Understanding and Working with Clients with Psychosis and Records of Violence
Authors: Yip Kam-Shing
Published: September 2005

Clients labeled psychotic and having records of violence have long been seen as dangerous and resistant. Within a medical disease orientation, institutionalization, social control, and medication are applied in treating and rehabilitating these clients. By means of a case illustration, this article shows that violence and psychosis are understandable and predictable. From a strengths perspective, clients with psychosis and records of violence are victims of an oppressive social environment. Empathic understanding and normal interactions within a supportive social environment can rehabilitate them and help them to recover in the community.
Long-Term Benefits from Psychotherapy: A 30-Year Retrospective by Client and Therapist
Authors: Walsh Roger , Bugental James
Published: September 2005

This article offers a uniquely long-term examination by a client and therapist, mental health professionals, of their therapeutic work together and of related principles of psychotherapy. The dialogue includes discussions of the experience of surprise as a hallmark of effective therapy, the extent to which the authors are usually alienated from their subjective experience, and ways in which introspective sensitivity can be fostered and alienation overcome. Other topics include the nature of therapeutic insights and their similarity to those valued by contemplatives, their state-dependency and multiple grades of significance, and the illusion of final insights and attainments. The dialogue goes on to discuss the emergence and implications of synesthesia and increased energy, comparisons of psychotherapy and meditation, the mind as potentially self-healing and self-actualizing, and therapeutic processes that foster self-trust.
Special Considerations for the Supervision of Home-Based Counselors
Authors: Lawson Gerard
Published: September 2005

Home-based counseling is often the most effective intervention for families that have a child at risk for removal from the home. Whereas the process of home-based counseling has received a fair amount of attention in the literature, there has been little attention paid to the supervision of the counselors who provide the services. This article presents some of the unique challenges inherent in providing home-based counseling and specific supervision considerations designed to support home-based counselors and the families they serve.
Engaging Men in Couples Counseling: Strategies for Overcoming Ambivalence and Inexpressiveness
Authors: Englar-Carlson Matt , Shepard David S.
Published: September 2005

Greater attention in scholarly literature has recently been drawn to the unique mental health and clinical needs of men. This article summarizes the existing literature on engaging men in couples counseling. Specifically, strategies are presented to assist counselors to (a) address the help-seeking process for men, (b) assess the role of masculine socialization on presenting concerns and for the process of counseling, and (c) help counselors work with male discomfort with emotions. Clinical examples and vignettes are offered to highlight how these strategies can be applied in couples counseling.
Teaching Theories of Couples Counseling: The Use of Popular Movies
Authors: Shepard David S. , Brew Leah
Published: September 2005

This article presents a model for using Hollywood films to teach theories of couples counseling. The authors first review the literature on using motion pictures as an instructional strategy in counselor education and psychology courses in general; advantages and disadvantages are highlighted. Next, they describe how they integrate movies into a typical one-semester course that emphasizes communications, systems, and psychodynamic models. The authors discuss the films they show, how each film illustrates constructs specific to the theory being taught, the exercises they use to enhance the learning experience, and student responses. They conclude by citing the advantages of using films to teach couples counseling if the instructor uses a variety of strategies to maximize student learning.
A Cross-Cultural Validation of the Attachment Style Questionnaire: A Malaysian Pilot Study
Authors: Ng Kok-Mun , Trusty Jerry , Crawford Ron
Published: September 2005

In response to the need for a culturally valid attachment measure for Malaysians, the present study examined the psychometric properties of the items and scales of the Attachment Style Questionnaire. The questionnaire is a broad-based self-report measure originally developed in Australia. Results of the study only partially supported the validity of the measure. Several items in the measure lack reliability and validity. One of its scales was found to have questionable content validity. This study illustrates several issues highlighted in the literature regarding the use of assessment measures in multicultural and cross-cultural settings.
Cultivating Resilience in Children From Divorced Families
Authors: Chen Jen-De , George Rebecca A.
Published: September 2005

The statistics for divorce in the United States are alarming. Among the shouting there are voices that are not being heard: the children’s. Empirical research has shown that the implementation of protective measures may increase the probability of a child becoming resilient in the face of divorce. This review of current literature is written to discuss what resiliency is and what protective factors will benefit the child. Counseling implications will be presented also.
Helping Families Search for Solutions: Working With Adolescents
Authors: Paylo Matthew J.
Published: September 2005

In this column, the author focuses on the ways that family counselors can use solution-based therapies (solution-oriented and solution-focused) to work with families with adolescents in individual and/or family therapy. The theoretical foundation for solution-based therapies suggests techniques that help families focus on solutions and not remain stuck in problem thinking. These solution-based strategies facilitate the process of empowering families to find solution in the future while drawing on their own expertise and strengths to promote their desired change.
Understanding and Fostering Family Resilience
Authors: Simon Joan B. , Murphy John J. , Smith Shelia M.
Published: September 2005

Family resilience can be defined as the ability of a family to respond positively to an adverse situation and emerge from the situation feeling strengthened, more resourceful, and more confident than its prior state. This article presents a succinct literature review on family resilience, including its dimensions, working models, and the individual and family characteristics that contribute to family resilience. Borrowing largely from solution-focused principles and techniques, numerous practical applications of a resilience orientation to family-related assessment and treatment are described. The article concludes with a call for additional research and training in the area of family resilience.
The Gendered Nature of Sexual Scripts
Authors: Wiederman Michael W.
Published: September 2005

Social scripting theory points to the fact that much of sexual behavior seems to follow a script. Similar to scripts that stage actors use to guide their behavior, social scripts instruct members of a society as to appropriate behavior and the meanings to attach to certain behaviors. In Western cultures, scripts for sexual activity are markedly different for males and females. In this article, the goals are to provide (a) an introduction to social scripting theory, (b) an exploration of the ways and potential reasons sexual scripts differ by gender, and (c) a discussion of ways that a social scripting perspective can be applied to work with individuals and couples experiencing sexual problems.
Huckleberry Finn Reconsidered: An Interview With David Nylund
Authors: Kindsvatter Aaron
Published: September 2005

This article describes the views of author and therapist David Nylund on working with children and adolescents diagnosed with attention deficit hyperactivity disorder (ADHD). In this interview, Nylund shares his views on how pathologizing language can interfere with the bringing forth of the inherent skills, knowledge, and talents that parents, teachers, and children might otherwise adopt in coping with the problems associated with ADHD. In addition, Nylund shares his ideas about how the stances and techniques of narrative counseling can engender possibilities for therapeutic change.
Blended Families: A Critical Review of the Current Research
Authors: Portrie Torey , Hill Nicole R.
Published: September 2005

Current research on blended families is summarized to address blended family development, communication strategies, and relationships between stepparents and stepchildren. Considerations for family counselors and blended families are addressed. Implications for future research opportunities include multicultural issues within blended families and stepmothers’ relationships with their stepchildren.
The Role of Health Education and Behavior in Public Health Genetics
Authors: Kardia Sharon L. R. , Wang Catharine
Published: September 2005

This article highlights the important role of health behavior and health education (HBHE) research in public health genetics. Broadly defined, public health genetics is the integration of genetic advancements and technologies in the study and practice of public health. The potential role of HBHE within this area is presented across two intersecting continua—namely, the continuum between research and practice and the continuum between individual/personalized medicine and population health. The authors begin this article with an overview of current issues arising from the use of genetic information to improve the public’s health and provide a framework for understanding the multidimensional role of HBHE research in translating genetic research into medical and public health practice. An introduction to the nine articles and two practice notes included in this special issue is also provided to draw attention to the crosscutting themes and issues presented.
Communicating Risk Information in Genetic Counseling: An Observational Study
Authors: Michie Susan , Lester Kathryn , Pinto Julia , Marteau Theresa M.
Published: September 2005

This study investigates risk communication within genetic counselling. Transcripts of 115 U.K. genetic consultations were reliably coded into form of risk expression used, whether the patient responded with understanding and agreement or showed signs of misunderstanding or disagreement, or did not respond at all, and whether clinicians assessed patient comprehension. Of the 492 risk expressions used, 53% were words and 47% were numbers (32% probabilities and 15% percentages). There was no association between form of risk expression and response. Clinicians assessed comprehension on only 25% of occasions, less often following the use of words than numbers, and on only 9% of occasions when there was no response to their risk communication. Because patients did not respond to 43% of risk communications, there is a concern that patients may make decisions without understanding the risks involved.
Impact of Interpreters’ Approach on Latinas’ Use of Amniocentesis
Authors: Preloran H. Mabel , Browner C. H. , Lieber Eli
Published: September 2005

Communication difficulties in multicultural clinical settings can be exacerbated by translators, but their actual impact on medical decisions has not been systematically evaluated. This study sought to determine the influence of translators participating in clinical encounters in which English-speaking clinicians offered amniocentesis to Spanish-speaking women by conducting systematic observations of 61 prenatal genetic consultations and recording translators’ training and background characteristics and patients’ amniocentesis decisions. Translators’ behavioral styles were classified according to 10 inductively determined criteria. Translators’ approaches were classified as Distant, Authoritative, or Missionary. Whereas the first category remained emotionally detached, the others sought to build rapport and trust with the patient. Quantitative analysis revealed statistically significant associations between translation styles that sought to engender trust and likelihood the pregnant woman agreed to amniocentesis. The authors conclude that translators’ affective approaches can influence whether patients accept or decline amniocentesis.
The Role of the Family in Genetic Testing: Theoretical Perspectives, Current Knowledge, and Future Directions
Authors: Peterson Susan K.
Published: September 2005

This article addresses conceptual challenges and theoretical approaches for examining the role of the family in responding and adapting to genetic testing for inherited conditions. Using a family systems perspective, family-based constructs that are relevant to genetic testing may be organized into three domains: family communication, organization and structure of family relationships, and health-related cognitions and beliefs shared within families. Empirical findings are presented from key content areas in family-based genetics research, including family communication, how genetic testing affects family relationships, psychological responses to genetic testing in the family context, and family-based influences on health decisions. Future research should explore decision making about genetic testing or behavior change specifically within the context of the family system and should identify family-based determinants of genetic testing outcomes.
Enhanced Counseling for Women Undergoing BRCA1/2 Testing: Impact on Subsequent Decision Making About Risk Reduction Behaviors
Authors: Miller Suzanne M. , Roussi Pagona , Daly Mary B. , Buzaglo Joanne S. , Sherman Kerry , Godwin Andrew K. , Balshem Andrew , Atchison Margaret E.
Published: September 2005

The authors evaluated the impact of an enhanced counseling intervention, designed to promote well-informed decision making for follow-up risk reduction options for ovarian cancer, among high-risk women undergoing BRCA1/2 testing ( N = 77). Following standard genetic counseling, participants received either an enhanced counseling session—designed to help participants anticipate their reactions to possible test outcomes and plan for postresult consequences—or a general health information control session. One week after disclosure of test results, women in the enhanced counseling group experienced a greater reduction in avoidant ideation, suggesting more complete processing of risk feedback. At the 6-monthfollow-up, intervention respondents reported seeking out more information about prophylactic oophorectomy and were more likely to have actually undergone preventive surgery. The results indicate that the use of enhanced counseling can play an important role in decision making about risk reduction behaviors following BRCA1/2 testing.
Contributions of Public Health to Genetics Education for Health Care Professionals
Authors: Burke Wylie
Published: September 2005

With growing knowledge about the role of genetics in health, genetics education for health care professionals has taken on increasing importance. Many efforts are under way to develop new genetics curricula. Although such efforts are primarily the responsibility of health professional schools and professional societies, the public health system is an important stakeholder, and different sectors of public health have opportunities to enhance educational efforts. These include the development of authoritative information sources about the clinical utility of genetic susceptibility and pharmacogenetic tests, creation of networks that link professionals in underserved regions to educational materials and consultative backup, and sponsorship of forums for multidisciplinary discussion of controversial issues. Public health input can help to ensure an appropriate emphasis on health outcomes as new genomic tests and technologies come into use, thus helping to protect society from the social and medical costs of genetic tests with limited clinical value.
CD8+T cells specific for cancer germline gene antigens are found in many patients with multiple myeloma, and their frequency correlates with disease burden
Authors: Goodyear Oliver , Piper Karen , Khan Naeem , Starczynski Jane , Mahendra Prem , Pratt Guy , Moss Paul
Published: September 2005

The expression of cancer germline antigens (CGAgs) is normally restricted to the testis but is also present in many types of malignant cells including plasma cells from patients with myeloma. Because T-cell immune responses to CGAg have been identified in patients with solid tumors, this may offer a novel target for immunotherapy in patients with myeloma. We have used 12 peptide epitopes from a range of CGAgs to screen for CGAg-specific T cells in blood from patients with multiple myeloma at various stages of their disease. T cells from 15 of 37 patients responded to one or more CGAg peptides and the magnitude of the CGAg-specific CD8+ T-cell response ranged between 0.0004% and 0.1% of the total CD8+ T-cell pool. Serial analyses showed that these immune responses were detectable in individual patients at multiple time points during the course of their disease. In patients undergoing treatment or in disease relapse, the magnitude of the CGAg-specific T-cell response was positively correlated with the level of paraprotein. Functional T cells specific for CGAgs are therefore present in a proportion of patients with multiple myeloma and offer the possibility of a novel approach for immunotherapy in this disease.
Endothelial targeting of a recombinant construct fusing a PECAM-1 single-chain variable antibody fragment (scFv) with prourokinase facilitates prophylactic thrombolysis in the pulmonary vasculature
Authors: Ding Bi-Sen , Gottstein Claudia , Grunow Andrea , Kuo Alice , Ganguly Kumkum , Albelda Steven M. , Cines Douglas B. , Muzykantov Vladimir R.
Published: September 2005

Means to prevent thrombus extension and local recurrence remain suboptimal, in part because of the limited effectiveness of existing thrombolytics. In theory, plasminogen activators could be used for this purpose if they could be anchored to the vascular lumen by targeting stably expressed, noninternalized determinants such as platelet-endothelial-cell adhesion molecule 1 (PECAM-1). We designed a recombinant molecule fusing low-molecular-weight single-chain prourokinase plasminogen activator (lmw-scuPA) with a single-chain variable fragment (scFv) of a PECAM-1 antibody to generate the prodrug scFv/lmw-scuPA. Cleavage by plasmin generated fibrinolytically active 2-chain lmw-uPA. This fusion protein (1) bound specifically to PECAM-1-expressing cells; (2) was rapidly cleared from blood after intravenous injection; (3) accumulated in the lungs of wild-type C57BL6/J, but not PECAM-1 null mice; and (4) lysed pulmonary emboli formed subsequently more effectively than lmw-scuPA, thereby providing support for the concept of thromboprophylaxis using recombinant scFv-fibrinolytic fusion proteins that target endothelium.
Molecular profiling of CD34+ cells identifies low expression of CD7, along with high expression of proteinase 3 or elastase, as predictors of longer survival in patients with CML
Authors: Yong Agnes S. M. , Szydlo Richard M. , Goldman John M. , Apperley Jane F. , Melo Junia V.
Published: September 2005

Although most patients with chronic myeloid leukemia (CML) have the same initial molecular abnormality, the BCR-ABL fusion gene, the duration of chronic phase (CP) varies widely. To identify the possible molecular basis of this heterogeneity, we studied CD34+ cells collected at diagnosis from 68 patients with CML-CP. By using oligonucleotide microarray screening, we performed gene-expression profiling on 2 subsets of patients, one comprising patients with an “aggressive disease” who developed blastic transformation (BT) within 3 years of diagnosis (n = 10) and, at the other extreme, patients with an “indolent disease” whose BT occurred 7 or more years from diagnosis (n = 9). This screening revealed 20 genes differentially expressed in patients with aggressive and indolent disease, which were validated by quantitative reverse transcriptase/polymerase chain reaction (Q-RT/PCR). A multivariate Cox regression model identified the combination of low CD7 expression with high expression of proteinase 3 or elastase as associated with longer survival in the complete cohort of 68 patients. This differential pattern of gene expression probably reflects the intrinsic heterogeneity of the disease; if so, assessing expression levels of selected genes at diagnosis may be valuable in predicting duration of survival in patients treated with imatinib and the newer tyrosine kinase inhibitors.
Genetic variation in the fibrinogen gamma gene increases the risk for deep venous thrombosis by reducing plasma fibrinogen γ′ levels
Authors: Uitte de Willige Shirley , de Visser Marieke C. H. , Houwing-Duistermaat Jeanine J. , Rosendaal Frits R. , Vos Hans L. , Bertina Rogier M.
Published: September 2005

We investigated the association between haplotypes of fibrinogen alpha (FGA), beta (FGB), and gamma (FGG), total fibrinogen levels, fibrinogen γ′ (γA/γ′ plus γ′/γ′) levels, and risk for deep venous thrombosis. In a population-based case-control study, the Leiden Thrombophilia Study, we typed 15 haplotype-tagging single nucleotide polymorphisms (htSNPs) in this gene cluster. None of these haplotypes was associated with total fibrinogen levels. In each gene, one haplotype increased the thrombosis risk approximately 2-fold. After adjustment for linkage disequilibrium between the genes, only FGG-H2 homozygosity remained associated with risk (odds ratio [OR], 2.4; 95% confidence interval [95% CI], 1.5-3.9). FGG-H2 was also associated with reduced fibrinogen γ′ levels and reduced ratios of fibrinogen γ′ to total fibrinogen. Multivariate analysis showed that reduced fibrinogen γ′ levels and elevated total fibrinogen levels were both associated with an increased risk for thrombosis, even after adjustment for FGG-H2. A reduced fibrinogen γ′ to total fibrinogen ratio (less than 0.69) also increased the risk (OR, 2.4; 95% CI, 1.7-3.5). We propose that FGG-H2 influences thrombosis risk through htSNP 10034C/T [rs2066865] by strengthening the consensus of a CstF site and thus favoring the formation of γA chain above that of γ′ chain. Fibrinogen γ′ contains a unique high-affinity, nonsubstrate binding site for thrombin, which seems critical for the expression of the antithrombin activity that develops during fibrin formation (antithrombin 1).
Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation
Authors: Giaccone Luisa , McCune Jeannine S. , Maris Michael B. , Gooley Theodore A. , Sandmaier Brenda M. , Slattery John T. , Cole Scott , Nash Richard A. , Storb Rainer F. , Georges George E.
Published: September 2005

The immunosuppressive drug mycophenolate mofetil (MMF) is used after nonmyeloablative hematopoietic cell transplantation (HCT); however, limited pharmacodynamic data are available. We evaluated plasma concentrations of mycophenolic acid (MPA), the active metabolite of MMF, and outcomes in 85 patients with hematologic malignancies conditioned with fludarabine and 2 Gy total body irradiation followed by HLA-matched unrelated-donor HCT and postgrafting cyclosporine and MMF. The first 38 patients received MMF 15 mg/kg twice daily; the next 47 patients received MMF 3 times daily. MPA pharmacokinetics were determined on days 7 and 21. Comparing the twice-daily and 3-times-daily MMF groups, the mean total MPA concentration steady state (Css) was 1.9 and 3.1 μg/mL; the unbound Css was 18 and 36 ng/mL, respectively (P < .001). Sixteen patients with a total MPA Css less than 3 μg/mL had low (< 50%) donor T-cell chimerism (P = .03), and 6 patients with MPA Css less than 2.5 μg/mL had graft rejection. An elevated unbound Css was associated with cytomegalovirus reactivation (P = .03). There were no significant associations between MPA pharmacokinetics and acute graft-versus-host disease (GVHD) or relapse. We conclude that increased MPA Css's predicted higher degrees of donor T-cell chimerism after unrelated donor nonmyeloablative HCT and suggest that targeting MPA Css's greater than 2.5 μg/mL could prevent graft rejection.
Impediment in upper airway stabilizing forces assessed by phrenic nerve stimulation in sleep apnea patients
Authors: Sériès F , Vérin E , Similowski T
Published: September 2005

Background

The forces developed during inspiration play a key role in determining upper airway stability and the occurrence of nocturnal breathing disorders. Phrenic nerve stimulation applied during wakefulness is a unique tool to assess Upper airway dynamic properties and to measure the overall mechanical effects of the inspiratory process on UA stability.

Objectives

To compare the flow/pressure responses to inspiratory and expiratory twitches between sleep apnea subjects and normal subjects.

Methods

Inspiratory and expiratory twitches using magnetic nerve stimulation completed in eleven untreated sleep apnea subjects and ten normal subjects.

Results

In both groups, higher flow and pressure were reached during inspiratory twitches. The two groups showed no differences in expiratory twitch parameters. During inspiration, the pressure at which flow-limitation occurred was more negative in normals than in apneic subjects, but not reaching significance (p = 0.07). The relationship between pharyngeal pressure and flow adequately fitted with a polynomial regression model providing a measurement of upper airway critical pressure during twitch. This pressure significantly decreased in normals from expiratory to inspiratory twitches (-11.1 ± 1.6 and -15.7 ± 1.0 cm H2O respectively, 95% CI 1.6–7.6, p < 0.01), with no significant difference between the two measurements in apneic subjects. The inspiratory/expiratory difference in critical pressure was significantly correlated with the frequency of nocturnal breathing disorders.

Conclusion

Inspiratory-related upper airway dilating forces are impeded in sleep apnea patients.
Predictors of post-operative mortality following treatment for non-ruptured abdominal aortic aneurysm
Authors: Urbonavicius Sigitas , Vorum Henrik , Urbonaviciene Grazina , Trumpickas Mindaugas , Pavalkis Dainius , Honoré Bent
Published: September 2005

The aim of this prospective study of patients undergoing repair of non-ruptured abdominal aortic aneurysm between 1999 and 2003 was to evaluate and compare risk factors for mortality after surgery, to determine a complex of informative factors for lethal outcome, and to define patient risk groups. Logistic regression analysis revealed a complex of informative factors, including female gender, previous myocardial infarction, age greater than 75 years, and clinical course of abdominal aortic aneurysm as important indicators for lethal outcome. A risk score model identified low-, moderate- and high-risk groups with mortality rates of 2.9%, 8.0% and 44.4%, respectively.
Novel type I interferon IL-28A suppresses hepatitis C viral RNA replication
Authors: Zhu Haizhen , Butera Mike , Nelson David R , Liu Chen
Published: September 2005

Interferon alpha (IFN-α)-based therapy is the currently approved treatment for chronic hepatitis C viral infection. The sustained antiviral response rate is approximately 50% for genotype-1 infection. The major challenge to the HCV community is to improve antiviral efficacy and to reduce the side effects typically seen in IFNα-based therapy. One of the strategies is to identify new interferons, which may have better efficacy and less undesirable side effects. In this report, we examined the role of IL-28A (IFN λ2), a novel type I IFN, in suppression of human hepatitis C viral RNA replication. We have cloned both the human genomic DNA and cDNA of IL-28A, and evaluated their biological activity using HCV RNA replicon cell culture system. The results show that IL-28A effectively inhibits HCV subgenomic RNA replication in a dose-dependent manner. Treatment of human hepatoma cells with IL-28A activates the JAK-STAT signaling pathway and induces the expression of some interferon-stimulated genes (ISGs), such as 6–16 and 1–8U. We also demonstrate that IL-28A induces expression of HLA class I antigens in human hepatoma cells. Moreover, IL-28A appears to specifically suppress HCV IRES-mediated translation. Although IL-28A receptor shares one subunit with the IL-10 receptor, IL-10 treatment has no detectable effect on IL-28A-induced antiviral activity. Interestingly, IL-28A can synergistically enhance IFNα antiviral efficacy. Our results suggest that IL-28A antiviral activity is associated with the activation of the JAK-STAT signaling pathway and expression of ISGs. The effectiveness of IL-28A antiviral activity and its synergistic effect on IFN-α indicate that IL-28A may be potentially used to treat HCV chronic infection.
Fludarabine in Combination With Alemtuzumab Is Effective and Feasible in Patients With Relapsed or Refractory B-Cell Chronic Lymphocytic Leukemia: Results of a Phase II Trial
Authors: Elter Thomas , Borchmann Peter , Schulz Holger , Reiser Marcel , Trelle Sven , Schnell Roland , Jensen Markus , Staib Peter , Schinköthe Timo , Stützer Hartmut , Rech Jürgen , Gramatzki Martin , Aulitzky Walter , Hasan Ibrahim , Josting Andreas , Hallek Michael , Engert Andreas
Published: September 2005

Purpose

To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL).

Patients and Methods

A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment.

Results

The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred.

Conclusion

The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.
Gene Expression Profiles in Paraffin-Embedded Core Biopsy Tissue Predict Response to Chemotherapy in Women With Locally Advanced Breast Cancer
Authors: Gianni Luca , Zambetti Milvia , Clark Kim , Baker Joffre , Cronin Maureen , Wu Jenny , Mariani Gabriella , Rodriguez Jaime , Carcangiu Marialuisa , Watson Drew , Valagussa Pinuccia , Rouzier Roman , Symmans W. Fraser , Ross Jeffrey S. , Hortobagyi Gabriel N. , Pusztai Lajos , Shak Steven
Published: September 2005

Purpose

We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk.

Methods

Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays.

Results

Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) –related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit.

Conclusion

Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.
Pharmacogenomic Discovery Approaches: Will the Real Genes Please Stand Up?
Authors: Walgren Richard A. , Meucci Melissa A. , McLeod Howard L.
Published: September 2005

Genetic inheritance plays a significant role in the interindividual variability of drug response. The field of pharmacogenomics seeks to identify genetic factors that influence drug response, including both those that are inherited and those that arise within tumors, and use this information to improve drug therapy. Candidate gene approaches have led to clinical tests for toxicity avoidance (eg, TPMT, UGT1A1) and efficacy prediction (eg, epidermal growth factor receptor–activating mutations). However, the “right” genes are not known for most anticancer drugs. Strategies for uncovering pharmacogenomic associations vary widely from monogenic candidate gene approaches to polygenic genome-wide approaches. This review will place in context clinically relevant pharmacogenomic discovery approaches, including the relative strengths and weaknesses and the challenges inherent with achieving the goal of individualized therapy.
Inferring a Tumor Progression Model for Neuroblastoma From Genomic Data
Authors: Bilke Sven , Chen Qing-Rong , Westerman Frank , Schwab Manfred , Catchpoole Daniel , Khan Javed
Published: September 2005

Purpose

The knowledge of the key genomic events that are causal to cancer development and progression not only is invaluable for our understanding of cancer biology but also may have a direct clinical impact. The task of deciphering a model of tumor progression by requiring that it explains (or at least does not contradict) known clinical and molecular evidence can be very demanding, particularly for cancers with complex patterns of clinical and molecular evidence.

Materials and Methods

We formalize the process of model inference and show how a progression model for neuroblastoma (NB) can be inferred from genomic data. The core idea of our method is to translate the model of clonal cancer evolution to mathematical testable rules of inheritance. Seventy-eight NB samples in stages 1, 4S, and 4 were analyzed with array-based comparative genomic hybridization.

Results

The pattern of recurrent genomic alterations in NB is strongly stage dependent and it is possible to identify traces of tumor progression in this type of data.

Conclusion

A tumor progression model for neuroblastoma is inferred, which is in agreement with clinical evidence, explains part of the heterogeneity of the clinical behavior observed for NB, and is compatible with existing empirical models of NB progression.
Connective Tissue Growth Factor Expression in the Human Corpus Luteum: Paracrine Regulation by Human Chorionic Gonadotropin
Authors: Duncan W. Colin , Hillier Stephen G. , Gay Eva , Bell Julie , Fraser Hamish M.
Published: September 2005

Context: The molecular mechanisms of luteolysis and its inhibition during maternal recognition of pregnancy remain unclear.

Objective: The objective of this study was to investigate the differential regulation of connective tissue growth factor (CTGF) expression in human corpora lutea using in vivo and in vitro models.

Design: Corpora lutea from different stages of the luteal phase and after luteal rescue with human chorionic gonadotropin (hCG) were studied. Primary cultures and cocultures of luteinized granulosa cells and luteal fibroblast-like cells were performed.

Setting: This study was performed at the research center of a university teaching hospital.

Patients: Women with regular cycles having hysterectomy for nonmalignant conditions and women undergoing oocyte collection for assisted conception were studied.

Interventions: CTGF localization was determined by in situ hybridization, and expression by quantitative RT-PCR.

Outcomes: The outcome measures were the effect of hCG on the expression and localization of CTGF mRNA in human corpora lutea and the effect of hCG on CTGF expression in primary cultures of luteinized granulosa cells and luteal fibroblast-like cells.

Results: Luteal rescue reduced CTGF expression compared with that in the late luteal phase (P < 0.05). CTGF expression was localized to fibroblast-like cells and endothelial cells of larger blood vessels, not to steroidogenic cells. The expression of CTGF by fibroblast-like cells in vitro was not regulated by hCG. When cocultured with luteinized granulosa cells, fibroblast-like cell CTGF expression was inhibited by hCG (P < 0.001). This effect was independent of stimulated progesterone concentrations and was not blocked by follistatin or indomethacin. Both IL-1α (P < 0.05) and cAMP (P < 0.001) inhibited CTGF expression in fibroblast-like cells.

Conclusions: These results provide evidence for negative regulation of CTGF by hCG during luteal rescue mediated by paracrine signals.
Depression in Anorexia Nervosa: A Risk Factor for Osteoporosis
Authors: Konstantynowicz Jerzy , Kadziela-Olech Halina , Kaczmarski Maciej , Zebaze Roger M. D. , Iuliano-Burns Sandra , Piotrowska-Jastrzebska Janina , Seeman Ego
Published: September 2005

Context: Both anorexia nervosa (AN) and depression are associated with osteoporosis. We hypothesized that adolescent girls with AN and depression will have lower bone mineral density (BMD) than anorexic girls without depression.

Objective: The objective of this study was to investigate whether depression is an independent risk factor for osteoporosis in anorexic adolescent girls.

Design: This study was cross-sectional.

Setting: This study was conducted at the University Children’s Hospital (Bialystok, Poland) from October 2002 through September 2003.

Participants: Forty-five Caucasian anorexic girls aged 13–23 yr, matched by age, Tanner stage, weight, height, calcium intake, and duration of AN, were studied, including 14 with comorbid depression (based on Hamilton Depression Rating Scale and Montgomery-Asberg Depression Rating Scale) and 31 anorexic girls without depression.

Main Outcome Measures: Total body and lumbar spine (LS) BMD, fat mass, and lean mass assessed using dual-energy x-ray absorptiometry were compared between AN girls with and without depression.

Results: BMD was reduced in both groups, relative to reference data, but girls with AN and depression had lower BMD than those with AN alone (LS Z-scores, −2.6 ± 0.3 vs. −1.7 ± 0.3; P = 0.02) (mean ± sem). Quantitative assessment of depression correlated independently with total body BMD (r = −0.4; P < 0.05) and LS BMD (r = −0.6; P < 0.001).

Conclusion: Anorexic girls with depression are at higher risk of osteoporosis than those without depression. The mechanisms responsible for decreased BMD in depression are not known. Independent treatment of the depressive disorder in AN may partly alleviate the bone fragility.
Association of Mitochondrial Deoxyribonucleic Acid 16189 Variant (T→C Transition) with Metabolic Syndrome in Chinese Adults
Authors: Weng Shao-Wen , Liou Chia-Wei , Lin Tsu-Kung , Wei Yau-Huei , Lee Cheng-Feng , Eng Hock-Liew , Chen Shang-Der , Liu Rue-Tsuan , Chen Jung-Fu , Chen I-Ya , Chen Ming-Hong , Wang Pei-Wen
Published: September 2005

Objective: A common variant in mitochondrial DNA (mtDNA) at bp 16189 (T→C transition) has been associated with small birth size, adulthood hyperglycemia, and insulin resistance in Caucasians. In this study, we investigated whether mtDNA 16189 variant is associated with metabolic syndrome in Chinese subjects.

Methods: Six hundred fifteen Chinese adults, aged 40 yr or older, were recruited in this study. The 16189 variant of mtDNA was detected using PCR and restriction enzyme digestion. Metabolic syndrome was diagnosed on modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using body mass index (BMI) instead of waist circumference. An association study was performed with χ2 test and logistic regression analysis.

Results: The prevalence of the 16189 variant was higher in patients with metabolic syndrome than in those without: 44% (125 of 284) vs. 33.2% (110 of 331) (P = 0.006). The association between this 16189 variant of mtDNA and metabolic syndrome (P = 0.021) remained significant even after correcting for age and BMI. As to the individual traits, the prevalence of fasting plasma glucose of at least 110 mg/dl (≥6.1 mmol/liter) [(51.5% (121 of 235) vs. 42.1% (160 of 380); P = 0.023], type 2 diabetes mellitus [48.1% (113 of 235) vs. 39.2% (149 of 380); P = 0.031], and hypertriglyceridemia [44.3% (104 of 235) vs. 35.8% (136 of 380); P = 0.037] were significantly higher in subjects harboring the 16189 variant of mtDNA than those with the wild type. However, the prevalence of hypertension [53.2% (125 of 235) vs. 47.6% (181 of 380); P = 0.180], BMI greater than 25 kg/m2 [48.5% (114 of 235) vs. 43.9% (167 of 380); P = 0.270], and low high-density lipoprotein cholesterol [61.3% (144 of 235) vs. 54.7% (208 of 380); P = 0.111] did not reach a significant difference between the two groups. Furthermore, there was a trend of increasing frequency of occurrence of the 16189 variant in individuals having an increasing number of components of metabolic syndrome (Ptrend < 0.005).

Conclusion: Our data strongly suggest that mtDNA 16189 variant underlies susceptibility to metabolic syndrome in the Chinese population.