bluuebunny/crossref_metadata_2025 huggingface dataset:
The Application of the Theory of Reasoned Action and Planned Behavior to Prevention Science in Counseling Psychology
Authors: Romano John L. , Netland Jason D.
Published: October 2007

The theory of reasoned action and planned behavior (TRA/PB) is a model of behavior change that has been extensively studied in the health sciences but has had limited exposure in the counseling psychology literature. The model offers counseling psychologists a framework to conceptualize prevention research and practice. The model is important to consider since the training of counseling psychologists is heavily dominated by theories of psychotherapy that emphasize remediation rather than prevention. This article discusses a brief history and explanation of TRA/PB along with relevant research, limitations, and multicultural considerations. Elicitation research, an important component of the model, receives emphasis because it solicits population-specific cognitions and social influences relevant to targeted behaviors, thus strengthening prevention interventions. An example demonstrates how TRA/PB can be used as a theoretical framework to support prevention research. Recommendations for prevention training of counseling psychologists are presented.
Transgender Identities and Public Policy in the United States
Authors: Taylor Jami Kathleen
Published: October 2007

This article examines an emerging issue within the field of governance, the intersection of public policy with transgender identity. It is important that administrators better understand this issue given the lack of consistency in the current policy framework. This article addresses transgender identity's intersection with employment law, marriage, hate crimes, and the current legal framework for sex reassignment in the United States. The article also addresses how transgender identity contrasts with gay and lesbian identities with regard to public policy. Given widespread bias against this population, administrators are called to ensure that these individuals receive equal and equitable policy treatment.
Philanthropy, Voluntary Association, and Governance Beyond the State
Authors: Eikenberry Angela M.
Published: October 2007

There has been little discussion about the democratic impacts of new roles and expectations put on private philanthropy and voluntarism in an era of governance beyond the state. This article explores tensions philanthropic voluntary associations face in balancing their internal democratic effects of enhancing civic education and participation of members on the one hand with meeting needs and solving problems in the community on the other. This is brought into focus through an analysis of giving circles, groups that entail individuals pooling resources and then deciding together how and where to give these away. Giving circles highlight the trade-off between the grassroots independence and noncoercive collaborative action that enables voluntary associations to contribute to democratic governance and the ability for these institutions to adequately and comprehensively address community problems; a trade-off that becomes important if one is concerned with serving the public good in an era of government cutbacks and privatization.
Enduring Values in the British Civil Service
Authors: Dillman David L.
Published: October 2007

Despite the Blair government's claim that it wants to preserve the “enduring values” of the civil service, recent reforms seem to undermine long-standing constitutional conventions and the public service values that underpin them. This article examines the current debate by comparing the government's vision of a responsible bureaucracy as seen in its reform initiatives to the responses of other participants, especially the Committee on Standards in Public Life. It evaluates the effect of recent reforms on public service values and asks whether the approach taken by the committee to guard these values is sufficient.
Somatic Symptoms and Anxiety Among African American Adolescents
Authors: Kingery Julie Newman , Ginsburg Golda S. , Alfano Candice A.
Published: October 2007

Somatic symptoms are an associated feature of anxiety disorders that have received little research attention among non-White samples. In addition, the majority of previous studies have examined the influence of somatic symptoms in a cross-sectional rather than a prospective manner. This study examines the prevalence of 12 somatic symptoms, the association of somatic and anxiety symptoms (both concurrently and prospectively) with psychosocial functioning, and gender differences in somatic symptoms among a community sample of 114 African American adolescents (57 girls). In all, 83% of the sample reported at least one somatic symptom (some or most of the time within the past 2 weeks), and on average, adolescents reported 2.5 somatic symptoms. Somatic symptoms correlated positively with severity of anxiety symptoms and negatively with aspects of perceived competence. After the initial level of anxiety symptoms was controlled for, somatic symptoms were a unique predictor of perceived competence (at initial assessment) and anxiety symptoms (at 6-month follow-up). Overall, girls endorsed significantly more somatic symptoms than did boys. Findings replicate those of studies with White samples and suggest that somatic symptoms may be a risk factor for anxiety disorders among African American youth.
Perceived Racism and Ambulatory Blood Pressure in African American College Students
Authors: Hill LaBarron K. , Kobayashi Ihori , Hughes Joel W.
Published: October 2007

Experiences with racial discrimination may contribute to stress-induced blood pressure (BP) elevations among African Americans. It was reported that perceived racism was associated with ambulatory BP (ABP) during waking hours. This study examined perceived racism and ABP among 40 African American college students, who completed an ABP assessment from which daytime and nighttime averages were computed. Perceived frequency of experiences with racism and racial discrimination was measured using the Perceived Racism Scale. Controlling for gender and body mass index, perceived racism in academic settings was associated with higher diastolic BP (DBP) during waking hours and nighttime sleep. Systolic BP (SBP) was unrelated to perceived racism, and perceived racism in the public realm and in statements from Whites was unrelated to ABP. Perceived racism in academic settings predicted ambulatory DBP among college students. Previous laboratory research has found stronger effects of perceived racism for DBP than SBP. The hemodynamic regulation of BP may explain this phenomenon. Future laboratory and ambulatory studies should assess the contributions of vascular resistance and cardiac output to BP elevations associated with perceived racism.
Racial Centrality and Health Care Use Among African American Adults With Sickle Cell Disease
Authors: Bediako Shawn M. , Lavender Annette R. , Yasin Zahida
Published: October 2007

The present study examined an exploratory model of the confluence of racial centrality, pain, psychological variables, and health care use in a sample of African American adults with sickle cell disease. Significant path coefficients were observed between pain severity, perceived stress, and psychological symptoms. The model yielded direct effects for paths to health care use from pain frequency and racial centrality—indicating that participants who reported more frequent pain episodes tended to use more health care services and those who endorsed a highly central African American identity utilized fewer health care services. Generally, these findings suggest a need for expanded thinking about determinants of health care use in this population beyond psychological and physiological variables. These findings support a rationale for further exploring the sociocultural context of sickle cell and highlight a specific need for better understanding the complex relationships among multidimensional aspects of racial identity and health care use.
Early Cultures of Gentrification in London, 1955–1980
Authors: Moran Joe
Published: October 2007

This article investigates the early period of “gentrification” of the inner residential districts of London, when the process was particularly rich in cultural meaning and symbolism. It focuses on the distinctive culture of the gentrifiers, including styles of house refurbishment, interior design, gastronomy, entertaining, networking, and amateur property speculation, and suggests that this culture allowed the middle-class incomers to make sense of their new life choices and social identities. The gentrifiers promoted an idea of the “urban village” that enabled them to be both part of the inner city and separate from it, close to its amenities but cut off from its social problems. As the process developed momentum from the late 1960s onward, they used their influence as cultural producers and opinion formers to comment on the process of gentrification in a way that combined self-promotion, satire, guilt, and exculpation.
“Keep The 'L' Out Of Los Angeles”
Authors: Axelrod Jeremiah B.C.
Published: October 2007

In the spring of 1926 the voters of Los Angeles were asked to decide whether to accept a modern rapid transit system for their metropolis. The referendum campaign, a watershed moment in American urban history, forced citizens to choose whether their rapidly growing city should develop into a centralized conurbation of skyscrapers linked by an extensive transit infrastructure, like New York and Chicago, or become a metropolis dominated by low-density development. Crucially, the campaign—charged with vivid rhetoric and metaphor, mobilized primarily by local newspapers—ultimately turned on Angelenos' conceptions of race and class and on their notions of what cosmopolitan urbanism entailed. By election day, urbanity no longer connoted for Angelenos towering skyscrapers and unlimited progress, but the specter of slums, ghettoes, and darkness, both metaphorical and literal, as Southern Californians chose to abandon Jazz Age modernity for a mythology of whiteness and suburban sunshine.
Organizing the Ghetto
Authors: Ferguson Karen
Published: October 2007

This article traces the relationship between the Ford Foundation and the black-power incarnation of the Congress of Racial Equality (CORE) from 1967-1969, through two grants to CORE for voter registration and leadership training in Cleveland's black community. It uses this case to analyze what has often been seen as a key turning point in the history of American racial liberalism in the mid-1960s, when American society wrestled with the meaning of black freedom within the paradox of African Americans' newly reaffirmed legal equality and the social reality of structural inequality that continued to plague black people nationwide. While the race-conscious liberalism that resulted might be seen as new, this article argues that the asymmetrical relationship of the Ford Foundation and CORE was based on shared convictions about organizing the ghetto that were both mainstream and often longstanding. It also demonstrates the ongoing force of white power in the black-power era.
Neuromuscular and Lower Limb Biomechanical Differences Exist between Male and Female Elite Adolescent Soccer Players during an Unanticipated Side-cut Maneuver
Authors: Landry Scott C. , McKean Kelly A. , Hubley-Kozey Cheryl L. , Stanish William D. , Deluzio Kevin J.
Published: October 2007

Background

Female athletes are 2 to 8 times more likely than male athletes to injure the anterior cruciate ligament during a noncontact athletic maneuver. Identifying anterior cruciate ligament injury risk factors in female athletes may help with the development of preventive training programs aimed at reducing injury rates.

Hypothesis

Differences between genders in lower limb kinematics, kinetics, and neuromuscular patterns will be identified in an adolescent soccer population during an unanticipated side-cut maneuver.

Study Design

Controlled laboratory study.

Methods

Forty-two elite adolescent soccer players (21 male and 21 female) performed an unanticipated side-cut maneuver, with the 3-dimensional kinematic, kinetic, and electromyographic lower limb data being analyzed using principal component analysis.

Results

The female athletes had higher gastrocnemius activity, normalized to maximal voluntary isometric contractions, and a mediolateral gastrocnemius activation imbalance that was not present in the male athletes during early stance to midstance of the side-cut. Female athletes demonstrated greater rectus femoris muscle activity throughout stance, and the only hamstring difference identified was a mediolateral activation imbalance in male athletes only. Female athletes performed the side-cut with less hip flexion and more hip external rotation and also generated a smaller hip flexion moment compared with the male athletes.

Conclusion

This is the first study to identify gender-related differences in gastrocnemius muscle activity during an unanticipated cutting maneuver.

Clinical Relevance

The increased and imbalanced gastrocnemius muscle activity, combined with increased rectus femoris muscle activity and reduced hip flexion angles and moments in female subjects, may all have important contributing roles in the higher noncontact ACL injury rates observed in female athletes.
Women of the Storm
Authors: Pyles Loretta , Lewis Judith S.
Published: October 2007

Drawing from interviews with advocates that addressed disaster recovery issues after Hurricane Katrina, the authors highlight three groups of women—domestic violence/sexual assault workers, advocates of federal postdisaster policy, and members of public housing resident councils. Women's efforts to mobilize networks and resist unfair policies, particularly in the context of a disaster, are discussed.
Phases of Growth for Abused New Zealand Women
Authors: Giles Janice , Curreen Helen
Published: October 2007

The goal of this grounded-theory qualitative study is to inform practice for working with New Zealand women who experience male partner abuse. The basic psychosocial process of growing through adversity emerged as salient for all 10 participants. This process is composed of three highly interactive core categories (finding a path beyond abuse, getting a life, and becoming myself) and five sequential phases (falling for love, taking control, securing a base, making sense of it, and being myself). This article focuses on the phases of the process and reports patterns that are consistent with other studies that have identified phases of the process.
Understanding Community-Specific Rape Myths
Authors: McMahon Sarah
Published: October 2007

Using multiple measurement methods offers an opportunity to gain culturally specific information about rape myths. This study focuses on the subculture of student athletes and uses a survey, focus groups, and individual interviews to explore the meaning and role of rape myths. Although the survey indicates a low acceptance of rape myths, this finding is contradicted by the results of the focus groups and individual interviews. Subtle, yet pervasive, rape myths are discovered, as are myths that are unique to the student athlete community. This method provides a framework for social workers to explore rape myths in other communities and to subsequently develop appropriate educational and intervention programs to address and ultimately prevent rape.
Without Wages of Benefits
Authors: Cleaveland Carol
Published: October 2007

The Personal Responsibility and Work Opportunity Reconciliation Act of 1996 allowed states to impose sanctions, that is, to revoke cash assistance for nonpregnant women on welfare as punishment for noncompliance with the new work requirements. In addition, the law called for women's benefits from Temporary Assistance for Needy Family benefits to be terminated after 5 years. This article, which reports on an ethnographic study of 29 women in two Philadelphia neighborhoods during an 18-month period, illuminates the women's struggles with the receipt of welfare and a new law that compelled them to find work, even when it meant earning wages that were below the poverty level. It examines how the women attempted to achieve agency after they were sanctioned or had their benefits terminated.
Partner Abuse and Women's Substance Problems
Authors: Call Christine R. , Nelsen Judith C.
Published: October 2007

In this exploratory study, a convenience sample of 125 mostly low-income women of color who were in treatment for problems associated with misusing substances responded to standardized measures and researcher-developed questions about their use of substances and experiences with partner abuse. Most of the women stated that their substance problems began after their first incident of partner abuse and that their misuse of substances occurred before and after specific incidents of partner abuse. The women also described various strengths they had used to cope. Screening for substance problems and partner abuse in all settings, as well as the use of women's strengths in treatment, is suggested.
Pharmacogenetic Considerations in the Management of HIV Infection
Authors: Estes Kristina E. , Busse Kristin H. , Penzak Scott R.
Published: October 2007

Potent combination antiretroviral drug therapy has now been available to HIV-infected patients for more than a decade, resulting in a significant decline in disease-related morbidity and mortality. Nonetheless, a number of HIV-infected individuals fail to experience the full benefit of their antiretroviral medications; some lack a robust virologic response, while others experience treatment-limiting toxicities. A number of factors may contribute to variable drug response in patients with HIV infection. Virologic, immunologic, pharmacologic, and pharmacokinetic differences between HIV-infected patients have all been noted to contribute to interpatient variability in drug response. Recent data suggest that pharmacogenetic differences among HIV-infected individuals may also be an important variable that contributes to antiretroviral drug response. Pharmacogenetic studies of antiretroviral drug therapy have explored the influence of single nucleotide polymorphisms in genes responsible for key proteins involved in antiretroviral drug metabolism (cytochrome P50 enzymes) and drug transport (P-glycoprotein). In addition, the human leukocyte antigen genotype (HLA-B*57) has been found to predict abacavir-associated hypersensitivity reactions. Antiretroviral pharmacogenetics offers the possibility of optimizing virologic response and minimizing drug toxicity by individualizing anti-HIV pharmacotherapy. The authors review those genetic polymorphisms that have been shown, or are strongly suspected, to influence antiretroviral drug metabolism, transport, and toxicity.
Incorporating Pharmacogenomics into Practice
Authors: Ellingrod Vicki L. , Moline Jessica
Published: October 2007

The goal for this issue of the Journal of Pharmacy Practice is to provide an overview of pharmacogenomics and highlight research done in select therapeutic areas such as oncology, psychiatry, cardiology, and HIV, although pharmacogenomics is taking center stage in other therapeutic areas as well. At the root of all pharmacogenomic investigations is pharmacy, which is why it is so important for pharmacists to gain an understanding of this field and clinical applications of this science, particularly as it relates to their practice and their patients. Pharmacists are experts in pharmacokinetics and pharmacodynamics, and they therefore represent ideal health care professionals for incorporating pharmacogenomics into therapeutic drug monitoring. We are currently in a critical period of time in which pharmacists need to become engaged in the decision-making process regarding how best to implement pharmacogenomics into clinical practice. As part of this chapter, we will outline the role of the Human Genome Project and the Food and Drug Administration, both of which are instrumental to the advancement of pharmacogenomics. Lastly, we will be summarizing some of the barriers we still face regarding clinical applicability of this science and the potential role of genetic counselors in the incorporation of this science into clinical practice.
Pharmacogenetics of the Cytochrome P450 Enzyme System: Review of Current Knowledge and Clinical Significance
Authors: Amal Al Omari  , Murry Daryl J.
Published: October 2007

Genetic variation in drug metabolizing enzymes is an important contributor to interindividual variation in drug disposition and response and is associated with significant clinical consequences. Many commonly used drugs are dependent on the cytochrome P450 monooxygenase enzymes (CYP450) for their metabolism and elimination. At present, more than 57 active human CYP450 genes are known, and the majority of these genes are polymorphic. Despite the large number of CYP450 genes, only the CYP1, CYP2, and CYP3 families of enzymes have a major role in drug metabolism. Approximately 10 CYP450s are responsible for the metabolism of a large number of pharmacologic agents in human beings. The polymorphic forms of the CYP450s are responsible for the development of a significant number of adverse drug reactions and may also contribute to drug response. Genetic polymorphisms have now been identified in the genes encoding all the main CYP450s that contribute to drug and other xenobiotic metabolism, and there are marked interethnic differences in the distribution and frequency of variant alleles. A review of the progress in the pharmacogenetics of P450s that are important for drug metabolism is presented with particular emphasis on the clinical relevance of this research.
Pharmacogenomics of Anticancer Agents: Implications for Clinical Pharmacy Practice
Authors: Grabinski Jodi L.
Published: October 2007

Hematology and oncology have been two of the leading areas in pharmacogenomics. The use of genetic information to guide therapy has been practiced for a number of years. The identification of polymorphisms within drug-metabolizing enzymes of anticancer agents such as 6-mercaptopurine and irinotecan has led to subsequent changes in package-insert labeling and tests approved by the US Food and Drug Administration to identify polymorphisms. Many studies within oncology are now conducting pharmacogenomic analyses in drug development to identify predictors of response and/or toxicity. For clinical pharmacists, knowledge in the area of pharmacogenomics and drug metabolism is important to understand and integrate pharmacogenomics into clinical practice. This article will review a number of different agents used in the realm of oncology and will identify how pharmacogenomics has or will potentially affect treatment decisions in the future with the goal of improving patient care and outcomes.
Clinical Pharmacogenetics of the Major Adenosine Triphosphate−Binding Cassette and Solute Carrier Drug Transporters
Authors: Streetman Daniel S.
Published: October 2007

Interindividual variability in drug response is a significant problem in clinical practice, and it is likely that genetic variation among the drug transport genes are major contributors to such variability. Numerous genetic alterations affecting the members of the adenosine triphosphate-binding cassette (ABC) and solute carrier (SLC) families of transporters have been identified. Considerable data exist regarding how mutations in the ABCB1 gene that encodes p-glycoprotein impact drug disposition and response in vivo, but many study reports are conflicting on both the direction of any effect as well as the significance of any alteration. Many possible reasons for such discrepant study results have been identified, and efforts to improve the quality of such pharmacogenetic clinical association studies are ongoing. For most other clinically important transporters relatively, little clinical data exist regarding the significance of known genetic variants despite in vitro evidence of altered function for many of these transporters. What clinical data do exist suggest that certain mutations in ABCG2 and SLCO1B1 may be of importance clinically. Until the current uncertainties regarding the importance of genetic variants in drug transporter genes are clarified, the clinical application of existing pharmacogenetic data should be done with caution.
Pharmacogenomics in Psychiatry
Authors: Leckband Susan G. , Bishop Jeffrey R. , Ellingrod Vicki L.
Published: October 2007

Pharmacogenomics may provide us with the means to expedite treatment for patients with various psychiatric disorders. Treatment is presently hampered by individual variation in medication response that often results in an extended trial-and-error process of treatment until the optimal medication is found. This can extend the time until treatment optimization to months or years. Much of this variation may be genetically based. This review discusses current pharmacogenomics research in mood disorders and in schizophrenia. Although the field is in an early stage, results already suggest that DNA tests will one day be of clinical value in the optimal selection of medications for mood and thought disorders.
Cardiovascular Pharmacogenomics
Authors: Momary Kathryn M.
Published: October 2007

There is substantial interpatient variability in response to many medications used to treat cardiovascular disease. This variability has led many to believe that genetic variation may be affecting response to cardiovascular drugs. The effect of genetics on response to β -blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), diuretics, statins, ezetimibe, warfarin, aspirin, and clopidogrel has been well studied. This article will review, by drug class, some of the more promising lines of research in cardiovascular pharmacogenomics, some of which have already left the bench and moved to the bedside. Perhaps the best example of pharmacogenomics transitioning from the bench to the bedside is CYP2C9 and VKORC1 genotyping with warfarin. The focus in cardiovascular pharmacogenomics is switching from smaller gene association studies to genetic analyses from large, controlled clinical trials. However, before clinical pharmacogenomic testing can be used in cardiovascular medicine, prospective pharmacogenomic data will be necessary.
Probable Labetalol-Induced Hepatotoxicity
Authors: Ginzburg Regina , Singleton Resa , Barr Wendy B.
Published: October 2007

This article reports a case of probable hepatotoxicity induced by therapeutic doses of labetalol. A 34-year-old postpartum woman was started on labetalol during a preeclamptic episode in the hospital. During the patient's 4-week postpartum office visit, she reported having dark urine for the previous 2 weeks. A liver function test showed substantial enzyme elevation, which improved after discontinuation of labetalol therapy. Labetalol-induced hepatotoxicity, although uncommon, can occur. Published data report this occurrence only in middle-aged or older patients. This appears to be the first case report of postpartum labetalol-induced hepatotoxicity. Hepatotoxicity may occur as a result of labetalol therapy. More judicious monitoring in patients on labetalol therapy may be warranted to prevent serious outcomes.
The Effects of Redistricting on Voting Behavior in Incumbent U.S. House Elections, 1992—1994
Authors: McKee Seth C.
Published: October 2007

Although numerous studies have assessed the influence of the 1990s redistricting on U.S. House elections, without exception, these published studies rely on aggregate data (e.g., district-level data). Likewise, the author uses aggregate data, but he also departs from previous studies by using survey data to assess the influence of redistricting on vote choice in the 1992 and 1994 U.S. House elections. Unlike past studies, with the use of survey data, the author makes more definitive statements regarding the effects of redistricting on vote choice. The 1990s redistricting was an important factor contributing to the Republicans' House majority because voters drawn into districts with a different incumbent standing for reelection were much more likely to vote Republican.
Fanning the Flames
Authors: Newman Brian , Caleb Smith Mark
Published: October 2007

Both religion and mass media are politically important in the United States. However, little is known about the political role of religious media. Religious media might be politically influential because they help translate religion into political thinking and because their consumers are likely to internalize the political cues these media provide. We find that almost a quarter of the public claims to have relied on religious media when making voting decisions in 2000. Religious media users felt significantly closer to George W. Bush and Pat Buchanan and farther away from Al Gore and were more likely to vote for Bush and Republican House candidates than nonusers, even after controlling for a host of religious and political variables. These findings reflect more than self-selection effects and suggest that religious media have a polarizing effect on the candidate evaluations and voting behavior of their core audience of political conservatives.
The Legislative Politics of Congressional Redistricting Commission Proposals
Authors: Karch Andrew , McConnaughy Corrine M. , Theriault Sean M.
Published: October 2007

Many politicians and reformers have suggested that allowing non- or bipartisan redistricting commissions to draw congressional districts will make elections more competitive and reduce partisan polarization. Although such commissions reduce the power of political parties and elected officials, they have been considered in 24 states from 1999 to 2006. We combine an analysis of national patterns of bill consideration with an intensive examination of legislative activity in three states. Our study suggests that internal pressures, such as redistricting controversies, and external pressures, such as the initiative process, contribute to the consideration of redistricting commission legislation. Furthermore, the precise combination of internal and external pressures in a state leads proposals to take one of two paths in the legislative process: a “partisan path” dominated by legislative insiders and interparty wrangling and a “good government path” where outside interest groups exercise more influence and the debate surrounds specific features of the proposal.
IL-21–mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes
Authors: Li Yongqing , Yee Cassian
Published: October 2007

Efforts to reproducibly isolate tumor antigen–specific T cells from patients would be facilitated by removing immunoregulatory barriers. Using a human model for eliciting T-cell responses to tumor-associated antigens, we develop a novel strategy that eliminates nearly all Foxp3-expressing cells through the combination of CD25 depletion and IL-21 treatment resulting in a more than 150-fold decrease in Foxp3+ cells to virtually undetectable levels and a more than 200-fold increase in antigen-specific cytotoxic T lymphocytes (CTLs). The extent of Foxp3 elimination and degree of expansion of antigen-specific CTLs shown in this study have not previously been achievable and are unique to IL-21. We demonstrate for the first time a possible mechanism for IL-21–mediated expansion of antigen-specific CTLs that involves suppression of Foxp3-expressing cells and reversal of inhibition to tumor-associated antigen–specific CTL generation in vitro. Taken together, the combination of CD25 depletion and IL-21 exposure, by releasing regulatory constraints, leads to markedly enhanced CTL induction and represents a robust strategy for the ex vivo generation of antigen-specific T cells for adoptive cellular therapy.
Locus control region elements HS1 and HS4 enhance the therapeutic efficacy of globin gene transfer in β-thalassemic mice
Authors: Lisowski Leszek , Sadelain Michel
Published: October 2007

Globin gene transfer in autologous hematopoietic stem cells is a promising therapeutic option for subjects with β-thalassemia major. In this approach, high level, erythroid-specific globin transgene expression should correct ineffective erythropoiesis and hemolytic anemia following the delivery of only 1 to 2 vector copies per cell. The generation of vectors that provide high-level globin expression and require low vector copy (VC) integration is therefore essential for both safety and efficacy. We show here the major roles played by 2 lesser-known locus control region elements, termed HS1 and HS4. Partial deletions within HS4 markedly reduce in vivo globin expression requiring multiple VC per cell to correct the anemia. Most strikingly, addition of HS1 to HS2-3-4 increases globin expression by 52%, yielding 9 g Hb/VC in β-thalassemic mice. Thus, while vectors encoding HS2-3-4 provide curative levels of hemoglobin at 1 to 2 copies per cell, adding HS1 is a promising alternative strategy if upcoming clinical trials prove higher levels of expression to be necessary.
Human ribosomal protein L13a is dispensable for canonical ribosome function but indispensable for efficient rRNA methylation
Authors: Chaudhuri Sujan , Vyas Keyur , Kapasi Purvi , Komar Anton A. , Dinman Jonathan D. , Barik Sailen , Mazumder Barsanjit
Published: October 2007

Previously, we demonstrated that treatment of monocytic cells with IFN-γ causes release of ribosomal protein L13a from the 60S ribosome and subsequent translational silencing of Ceruloplasmin (Cp) mRNA. Here, evidence using cultured cells demonstrates that Cp mRNA silencing is dependent on L13a and that L13a-deficient ribosomes are competent for global translational activity. Human monocytic U937 cells were stably transfected with two different shRNA sequences for L13a and clonally selected for more than 98% abrogation of total L13a expression. Metabolic labeling of these cells showed rescue of Cp translation from the IFN-γ mediated translational silencing activity. Depletion of L13a caused significant reduction of methylation of ribosomal RNA and of cap-independent translation mediated by Internal Ribosome Entry Site (IRES) elements derived from p27, p53, and SNAT2 mRNAs. However, no significant differences in the ribosomal RNA processing, polysome formation, global translational activity, translational fidelity, and cell proliferation were observed between L13a-deficient and wild-type control cells. These results support the notion that ribosome can serve as a depot for releasable translation-regulatory factors unrelated to its basal polypeptide synthetic function. Unlike mammalian cells, the L13a homolog in yeast is indispensable for growth. Thus, L13a may have evolved from an essential ribosomal protein in lower eukaryotes to having a role as a dispensable extra-ribosomal function in higher eukaryotes.
Bone Fragility Contributes to the Risk of Fracture in Children, Even After Moderate and Severe Trauma
Authors: Clark Emma M , Ness Andy R , Tobias Jon H
Published: October 2007

We prospectively examined whether the relationship between skeletal fragility and fracture risk in children 9.9 ± 0.3 (SD) yr is affected by trauma level. Bone size relative to body size and humeral vBMD showed similar inverse relationships with fracture risk, irrespective of whether fractures followed slight or moderate/severe trauma.

Introduction: Fracture risk in childhood is related to underlying skeletal fragility. However, whether this relationship is confined to low-trauma fractures or whether skeletal fragility also contributes to the risk of fracture caused by higher levels of trauma is currently unknown.

Materials and Methods: Total body DXA scan results obtained at 9.9 yr of age were linked to reported fractures over the following 2 yr in children from the Avon Longitudinal Study of Parents and Children. DXA scan results that were subsequently derived included total body less head (TBLH) bone size relative to body size (calculated from TBLH area adjusted for height and weight) and humeral volumetric BMD (vBMD; derived from subregional analysis at this site). Trauma level was assigned using the Landin classification based on a questionnaire asking about precipitating causes.

Results: Of the 6204 children with available data, 549 (8.9%) reported at least one fracture over the follow-up period, and trauma level was assigned in 280 as follows: slight trauma, 56.1%; moderate trauma, 41.0%; severe trauma, 2.9%. Compared with children without fractures, after adjustment for age, sex, socioeconomic status, and ethnicity, children with fractures from both slight and moderate/severe trauma had a reduced bone size relative to body size (1133 cm2 in nonfractured children versus 1112 cm2 for slight trauma fractures, p < 0.001; 1112 cm2 for moderate/severe trauma fractures, p = 0.001) and reduced humeral vBMD (0.494 g/cm3 in nonfractured children versus 0.484 g/cm3 for slight trauma fractures, p = 0.036; and 0.482g/cm3 for moderate/severe trauma fractures, p = 0.016).

Conclusions: Skeletal fragility contributes to fracture risk in children, not only in fractures caused by slight trauma but also in those that result from moderate or severe trauma.
Osteogenic Differentiation of Human Adipose Tissue-Derived Stem Cells Is Modulated by the miR-26a Targeting of the SMAD1 Transcription Factor
Authors: Luzi Ettore , Marini Francesca , Sala Silvia Carbonell , Tognarini Isabella , Galli Gianna , Brandi Maria Luisa
Published: October 2007

The molecular mechanisms that regulate hADSC differentiation toward osteogenic precursors and subsequent bone-forming osteoblasts is unknown. Using osteoblast precursors obtained from subcutaneous human adipose tissue, we observed that microRNA-26a modulated late osteoblasts differentiation by targeting the SMAD1 transcription factor.

Introduction: Elucidation of the molecular mechanisms guiding human adipose tissue-derived stem cells (hADSCs) differentiation is of extreme importance for improving the treatment of bone-related diseases such as osteoporosis. The aim of this study was to identify microRNA as a regulator of the osteogenic differentiation of hADSCs.

Materials and Methods: Osteoblast differentiation of hADSCs was induced by treatment with dexamethasone, ascorbic acid, and β-glycerol phosphate. The expression of osteoblastic phenotype was evaluated after the induction by simultaneous monitoring of alkaline phosphatase activity, the expression of genes involved in osteoblastic differentiation by real-time RT-PCR, and mineralization at the same time. MicroRNA expression was determined by Northern blot, and transfection of both antisense miR-RNA and sensor plasmids was done to validate the inhibitory role of microRNA during hADSC osteogenesis. Western blot was used to determine the expression levels of the SMAD1 protein. qRT-PCR analysis was used to compare the expression patterns of osteoblastic markers in transfected cells.

Results and Conclusions: We analyzed the role of microRNA 26a (miR-26a) during differentiation of hADSCs. Northern blot analysis of miR-26a during hADSC differentiation showed increased expression, whereas expression of the SMAD1 protein was complementary to that of miR-26a. Because the highest expression of miR-26a and the lowest expression of SMAD1 protein were reached at hADSC terminal differentiation, we carried out our study during the late stages of hADSC differentiation. The inhibition of miR-26a, by 2′-O-methyl-antisense RNA, increased protein levels of its predicted target, SMAD1 transcription factor, in treated osteoblasts, upregulating bone marker genes and thus enhancing osteoblast differentiation. Our data suggest a role for miR-26a in the differentiation induced by treatment with dexamethasone, ascorbic acid, and β-glycerol phosphate of hADSCs toward the osteogenic lineage by targeting its predicted target, the SMAD1 protein. This study contributes to a better knowledge of molecular mechanisms governing hADSC differentiation by proposing a microRNA-based control of late differentiation.
Identifying the Relative Contributions of Rac1 and Rac2 to Osteoclastogenesis
Authors: Wang Yongqiang , Lebowitz Dina , Sun Chunxiang , Thang Herman , Grynpas Marc D , Glogauer Michael
Published: October 2007

Rac small GTPases may play an important regulatory role in osteoclastogenesis. Our in vitro and in vivo results show that both Rac1 and Rac2 are required for optimal osteoclast differentiation, but Rac1 is more critical. Rac1 is the key Rac isoform responsible for regulating ROS generation and the actin cytoskeleton during the multiple stages of osteoclast differentiation.

Introduction: Recent evidence suggests that the Rac small GTPases may play an important regulatory role in osteoclastogenesis. This finding is important because bisphosphonates may regulate their antiresorptive/antiosteoclast effects through the modification of Rho family of small GTPases.

Materials and Methods: To elucidate the specific roles of the Rac1 and Rac2 isoforms during osteoclastogenesis, we used mice deficient in Rac1, Rac2, or both Rac1 and Rac2 in monocyte/osteoclast precursors. Macrophage-colony stimulating factor (M-CSF)– and RANKL-mediated osteoclastogenesis in vitro was studied by using bone marrow-derived mononucleated preosteoclast precursors (MOPs). The expression of osteoclast-specific markers was examined using quantitative real-time PCR and Western blot analysis. Free actin barbed ends in bone marrow MOPs after M-CSF stimulation was determined. The ability of MOPs to migrate toward M-CSF was assayed using Boyden chambers. Margin spreading on heparin sulfate-coated glass and RANKL-induced reactive oxygen species generation were also performed. Functional assays of in vitro-generated osteoclasts were ascertained using dentine sections from narwal tusks. Osteoclast levels in vivo were counted in TRACP and immunohistochemically stained distal tibial sections. In vivo microarchitexture of lumbar vertebrate was examined using μCT 3D imaging and analysis.

Results: We show here that, although both Rac isoforms are required for normal osteoclast differentiation, Rac1 deletion results in a more profound reduction in osteoclast formation in vitro because of its regulatory role in pre-osteoclast M-CSF-mediated chemotaxis and actin assembly and RANKL-mediated reactive oxygen species generation. This Rac1 cellular defect also manifests at the tissue level with increased trabecular bone volume and trabeculae number compared with wildtype and Rac2-null mice. This unique mouse model has shown for the first time that Rac1 and Rac2 play different and nonoverlapping roles during osteoclastogenesis and will be useful for identifying the key roles played by these two proteins during the multiple stages of osteoclast differentiation.

Conclusions: Rac1 and Rac2 play different and nonoverlapping roles during osteoclastogenesis. This model showed that Rac1 is the key Rac isoform responsible for regulating ROS generation and the actin cytoskeleton during the multiple stages of osteoclast differentiation.
Lean Mass and Not Fat Mass Is Associated With Male Proximal Femur Strength
Authors: Travison Thomas G , Araujo Andre B , Esche Gretchen R , Beck Thomas J , McKinlay John B
Published: October 2007

Obesity is suspected to confer protection against fracture, but evidence is mixed. We examined proximal femur geometry and body composition measures in a diverse group of 1171 men (30–79 yr of age). Analyses showed that nonbone lean mass, but not fat mass, is independently associated with measures of proximal femur density, axial and bending strength, and resistance to buckling.

Introduction: Obesity is often said to confer protection against fracture, but the mechanisms driving such an association remain poorly understood. We hypothesized that the effect of increased body mass on bone structure would be accounted for by total and/or appendicular nonbone lean mass, and that once these trends were removed, fat mass would show no protective influence. To test this hypothesis, we examined body composition and geometric indices of proximal femur strength in an ethnically diverse (black, Hispanic, and white) sample of randomly selected men, 30–79 yr of age.

Materials and Methods: Data were obtained from N = 1171 community-dwelling subjects enrolled in the cross-sectional Boston Area Community Health/Bone study. Body composition was obtained by DXA. Hip geometry parameters at the narrow neck, intertrochanter, and shaft were obtained using Hip Structural Analysis of DXA images. These measures included BMD, bone material in cross-sections (cross-sectional area), bending strength (section modulus), and propensity to buckle under compression (average buckling ratio). Analyses controlled for age, race/ethnicity, height, and physical activity.

Results: In exploratory analyses, lean mass, fat mass, and BMI were each positively associated with hip strength. However, controlling for lean mass was sufficient to remove the positive, and induce a negative, association for fat mass or BMI. Associations between lean mass and hip strength were strongest and resistant to control for other measures. Lean mass alone was sufficient to account for a substantial proportion of racial/ethnic difference in hip strength measures, whereas fat mass exhibited no comparable explanatory power.

Conclusions: The positive association between relative weight and proximal femur strength is accounted for by lean mass, suggesting that, in men, the protective effect of BMI in preventing fracture is mediated not by adipose tissue but by the influence of increased muscle mass accompanying elevated BMI.
Modified Form of the Fibrinogen Bβ Chain (des-Gln Bβ), a Potential Long-Lived Marker of Pancreatitis
Authors: Schmidt David , Brennan Stephen O
Published: October 2007

Background: During an investigation of genetic variants of fibrinogen, we observed a novel form of the Bβ chain, with a mass decrease of approximately 128 Da, in one of the controls. The plasma sample originated from an individual who had experienced acute pancreatitis a week earlier but whose serum amylase activity had returned to normal. We investigated the structure of the modified fibrinogen and explored its relationship to pancreatic disease.

Method: Fibrinogen was isolated from the plasma of 9 individuals with increased pancreatic amylase activity (114–1826 U/L) and presumed pancreatitis and from 6 control individuals with amylase activities <56 U/L. Fibrinogen (or fibrin) Bβ chains were isolated by reversed-phase HPLC and analyzed directly by electrospray ionization mass spectrometry. Tryptic and CNBr peptide mapping and thrombin treatment pinpointed the location of the 128-Da loss in mass.

Results: The acquired fibrinogen Bβ chain modification was attributable to the loss of its C-terminal glutamine residue. Incubating purified fibrinogen with pancreatic carboxypeptidase A (CpA) produced an identical modification. The des-Gln Bβ fibrinogen accounted for >80% of the Bβ chains in 3 of the individuals with increased amylase but only approximately 5% of the Bβ chains in control samples.

Conclusion: Pancreatic CpA activity is used as an index of acute pancreatic disease, but given that the circulatory half-lives of fibrinogen and CpA are approximately 4 days and only 2.5 h, respectively, measuring des-Gln Bβ fibrinogen, the in vivo product of CpA activity, could provide clinicians with retrospective evidence of disease.