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Regulation of cyclin-substrate docking by a G1 arrest signaling pathway and the Cdk inhibitor Far1

Tue, 08/19/2014 - 9:23am

Eukaryotic cell division is often regulated by extracellular signals. In budding yeast, signaling from mating pheromones arrests the cell cycle in G1 phase. This arrest requires the protein Far1, which is thought to antagonize the G1/S transition by acting as a Cdk inhibitor (CKI), although the mechanisms remain unresolved. Recent studies found that G1/S cyclins (Cln1 and Cln2) recognize Cdk substrates via specific docking motifs, which promote substrate phosphorylation in vivo. Here, we show that these docking interactions are inhibited by pheromone signaling and that this inhibition requires Far1. Moreover, Far1 mutants that cannot inhibit docking are defective at cell-cycle arrest. Consistent with this arrest function, Far1 outcompetes substrates for association with G1/S cyclins in vivo, and it is present in large excess over G1/S cyclins during the precommitment period where pheromone can impose G1 arrest. Finally, a comparison of substrates that do and do not require docking suggests that Far1 acts as a multimode inhibitor that antagonizes both kinase activity and substrate recognition by Cln1/2-Cdk complexes. Our findings uncover a novel mechanism of Cdk regulation by external signals and shed new light on Far1 function to provide a revised view of cell-cycle arrest in this model system.

Gestational Diabetes and Hypertensive Disorders of Pregnancy Among Women Veterans Deployed in Service of Operations in Afghanistan and Iraq

Mon, 08/18/2014 - 3:47pm

Objective: To determine the prevalence of gestational diabetes (GDM) and hypertensive disorders of pregnancy (HDP) among women Veterans using Department of Veterans Affairs (VA) maternity benefits previously deployed in service of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND), and whether pregnancy complications were associated with VA use following delivery.

Methods: We identified the study population through linkage with the Department of Defense roster and VA administrative and clinical data. GDM and HDP were identified by International Classification of Diseases, Ninth Revision codes in VA inpatient or outpatient files. Similarly, we constructed a nationally representative sample of deliveries from the Nationwide Inpatient Sample. We calculated standardized incidence ratios (SIR) adjusted for age and year of delivery to compare rates of GDM and HDP. Proportional hazards regression was used to determine whether pregnancy complications were associated with use of VA following delivery.

Results: Between 2001 and 2010, 2,288 women OEF/OIF/OND Veterans used VA maternity benefits; 5.2% had GDM and 9.6% had HDP. Compared with women delivering in the United States, women OEF/OIF/OND Veterans using VA maternity benefits had higher risk of developing GDM (SIR: 1.40; 95% confidence interval [CI] 1.16, 1.68) and HDP (SIR: 1.32; 95% CI 1.15, 1.51). Among women OEF/OIF/OND Veterans using VA maternity benefits, GDM (HR 1.01, 95% CI 0.83, 1.24) and HDP (HR 1.07, 95% CI 0.92, 1.25) were not associated with use of VA following delivery.

Conclusions: Non-VA providers should be aware of their patients' Veteran status and the associated elevated risk for pregnancy complications. Within VA, focused efforts to optimize Veterans' preconception and postpartum health are needed.

State of Reproductive Health In Women Veterans – VA Reproductive Health Diagnoses and Organization of Care

Mon, 08/18/2014 - 3:47pm

Reproductive health (RH) is a critical part of health. For women, RH encompasses gynecological health throughout life, preconception care, maternity care, cancer care, and the interaction of RH with other mental and medical conditions. Reproductive Health is defined as a state of complete physical, mental, and social well-be­ing and not merely the absence of reproductive disease or infirmity. This definition highlights the importance of taking a health systems approach that integrates RH care issues and services with other aspects of care needed across the life course. The RH needs of women are shaped by their stages of life and life experiences. For women Veterans, their military experiences may influence their RH in important ways. Given the increasing numbers of women in the military and women Veterans, it is critical to understand key aspects of RH in this unique population of women. This first report of the State of Reproductive Health in Women Veterans provides an overview of the RH diagnoses of women Veterans utilizing the Department of Veterans Affairs (VA) health care services, VA delivery of RH care, and a vision for RH in VA.

Pancreatitis Quality of Life Instrument: Development of a New Instrument

Mon, 08/18/2014 - 10:26am

Objectives: The goal of this project was to develop the first disease-specific instrument for the evaluation of quality of life in chronic pancreatitis.

Methods: Focus groups and interview sessions were conducted, with chronic pancreatitis patients, to identify items felt to impact quality of life which were subsequently formatted into a paper-and-pencil instrument. This instrument was used to conduct an online survey by an expert panel of pancreatologists to evaluate its content validity. Finally, the modified instrument was presented to patients during precognitive testing interviews to evaluate its clarity and appropriateness.

Results: In total, 10 patients were enrolled in the focus groups and interview sessions where they identified 50 items. Once redundant items were removed, the 40 remaining items were made into a paper-and-pencil instrument referred to as the Pancreatitis Quality of Life Instrument. Through the processes of content validation and precognitive testing, the number of items in the instrument was reduced to 24.

Conclusions: This marks the development of the first disease-specific instrument to evaluate quality of life in chronic pancreatitis. It includes unique features not found in generic instruments (economic factors, stigma, and spiritual factors). Although this marks a giant step forward, psychometric evaluation is still needed prior to its clinical use.

A radiation oncologist's story: high tech meets high touch

Wed, 08/13/2014 - 2:20pm

Personal reflection on the interplay between radiation oncology, which has long been on the leading edge of technological advances in treatment planning and delivery systems, and the personal side of medicine, often known as high touch.

Targeted germ line disruptions reveal general and species-specific roles for paralog group 1 hox genes in zebrafish

Tue, 08/12/2014 - 2:54pm

BACKGROUND: The developing vertebrate hindbrain is transiently segmented into rhombomeres by a process requiring Hox activity. Hox genes control specification of rhombomere fates, as well as the stereotypic differentiation of rhombomere-specific neuronal populations. Accordingly, germ line disruption of the paralog group 1 (PG1) Hox genes Hoxa1 and Hoxb1 causes defects in hindbrain segmentation and neuron formation in mice. However, antisense-mediated interference with zebrafish hoxb1a and hoxb1b (analogous to murine Hoxb1 and Hoxa1, respectively) produces phenotypes that are qualitatively and quantitatively distinct from those observed in the mouse. This suggests that PG1 Hox genes may have species-specific functions, or that anti-sense mediated interference may not completely inactivate Hox function in zebrafish.

RESULTS: Using zinc finger and TALEN technologies, we disrupted hoxb1a and hoxb1b in the zebrafish germ line to establish mutant lines for each gene. We find that zebrafish hoxb1a germ line mutants have a more severe phenotype than reported for Hoxb1a antisense treatment. This phenotype is similar to that observed in Hoxb1 knock out mice, suggesting that Hoxb1/hoxb1a have the same function in both species. Zebrafish hoxb1b germ line mutants also have a more severe phenotype than reported for hoxb1b antisense treatment (e.g. in the effect on Mauthner neuron differentiation), but this phenotype differs from that observed in Hoxa1 knock out mice (e.g. in the specification of rhombomere 5 (r5) and r6), suggesting that Hoxa1/hoxb1b have species-specific activities. We also demonstrate that Hoxb1b regulates nucleosome organization at the hoxb1a promoter and that retinoic acid acts independently of hoxb1b to activate hoxb1a expression.

CONCLUSIONS: We generated several novel germ line mutants for zebrafish hoxb1a and hoxb1b. Our analyses indicate that Hoxb1 and hoxb1a have comparable functions in zebrafish and mouse, suggesting a conserved function for these genes. In contrast, while Hoxa1 and hoxb1b share functions in the formation of r3 and r4, they differ with regards to r5 and r6, where Hoxa1 appears to control formation of r5, but not r6, in the mouse, whereas hoxb1b regulates formation of r6, but not r5, in zebrafish. Lastly, our data reveal independent regulation of hoxb1a expression by retinoic acid and Hoxb1b in zebrafish.

VHA Health Care in Response to a New Generation of Female Veterans

Mon, 08/11/2014 - 2:36pm

This book surveys critical aspects of modern military health care in the US and various other Western countries with troops in Iraq and Afghanistan. This book covers health care issues prior to deployment, such as screening for mental health, evaluating long-term consequences of exposure to military service, and provision of insurance; care during a conflict, primarily battlefield clinics, battlefield trauma care, and evacuation procedures; and post- combat care, including serious war injuries, psychiatric, and long-term care. Bringing together research from a wide range of contributors, the volume provides readers with an extensive, up-to-date source of information on military medicine.

Understanding Reproductive Healthcare and Outcomes Among Women Veterans: A Review of Recent Research and Future Opportunities

Mon, 08/11/2014 - 2:36pm

Presentation focused on reproductive health issues among women Veterans in VA care. In particular, examines patterns of healthcare utilization for gender-specific conditions among women Veterans, as well as beliefs and preferences for reproductive health care services within the VA healthcare system. Then explores innovative new research aimed at better understanding reproductive health services and outcomes among women Veterans.

Pregnancy and Mental Health Care Among Women Veterans Returning from Iraq and Afghanistan

Mon, 08/11/2014 - 2:36pm

Presentation looking at pregnancy and mental health care in the VA system. Documents a study examining the prevalence of pregnancy care and comparing the mental health diagnoses among pregnant and non-pregnant women in VA care. Then examining the degree to which pregnant veterans receive VA mental health care during their pregnancy. Concludes that pregnant women veterans using VA care have a substantial mental health burden.

Principles of Multidisciplinary Management

Mon, 08/11/2014 - 11:45am

This chapter in the Cancer Concepts textbook describes the principles of multi-disciplinary management, meaning multi-specialty physician management of malignancies. Tumor Boards are the model for multi-disciplinary management. They may be site specific or include the entire spectrum of malignancy. At Tumor Boards, staging workup and treatment recommendations are made collectively, and then the treatments are delivered by the respective modality specialists and their individual teams. Improved clinical decision making leading to superior survival for patients with some diseases and better quality of life has been documented with multi-disciplinary management. Just like curative patients, palliative patients require multi-disciplinary management.

Rapid prototyping amphiphilic polymer/hydroxyapatite composite scaffolds with hydration-induced self-fixation behavior

Mon, 08/11/2014 - 9:17am

Two major factors hampering the broad use of rapid prototyped biomaterials for tissue engineering applications are the requirement for custom-designed or expensive research-grade three-dimensional (3-D) printers and the limited selection of suitable thermoplastic biomaterials exhibiting physical characteristics desired for facile surgical handling and biological properties encouraging tissue integration. Properly designed thermoplastic biodegradable amphiphilic polymers can exhibit hydration-dependent hydrophilicity changes and stiffening behavior, which may be exploited to facilitate the surgical delivery/self-fixation of the scaffold within a physiological tissue environment. Compared to conventional hydrophobic polyesters, they also present significant advantages in blending with hydrophilic osteoconductive minerals with improved interfacial adhesion for bone tissue engineering applications. Here we demonstrated the excellent blending of biodegradable, amphiphilic PLA-PEG-PLA (PELA) triblock co-polymer with hydroxyapatite (HA) and the fabrication of high-quality rapid prototyped 3-D macroporous composite scaffolds using an unmodified consumer-grade 3-D printer. The rapid prototyped HA-PELA composite scaffolds and the PELA control (without HA) swelled (66% and 44% volume increases, respectively) and stiffened (1.38-fold and 4-fold increases in compressive modulus, respectively) in water. To test the hypothesis that the hydration-induced physical changes can translate into self-fixation properties of the scaffolds within a confined defect, a straightforward in vitro pull-out test was designed to quantify the peak force required to dislodge these scaffolds from a simulated cylindrical defect at dry vs. wet states. Consistent with our hypothesis, the peak fixation force measured for the PELA and HA-PELA scaffolds increased 6-fold and 15-fold upon hydration, respectively. Furthermore, we showed that the low-fouling 3-D PELA inhibited the attachment of NIH3T3 fibroblasts or MSCs while the HA-PELA readily supported cellular attachment and osteogenic differentiation. Finally, we demonstrated the feasibility of rapid prototyping biphasic PELA/HA-PELA scaffolds for potential guided bone regeneration where an osteoconductive scaffold interior encouraging osteointegration and a non-adhesive surface discouraging fibrous tissue encapsulation is desired. This work demonstrated that by combining facile and readily translatable rapid prototyping approaches with unique biomaterial designs, biodegradable composite scaffolds with well-controlled macroporosities, spatially defined biological microenvironment, and useful handling characteristics can be developed.

Understanding Health-Care Needs of Sexual and Gender Minority Veterans: How Targeted Research and Policy Can Improve Health

Fri, 08/08/2014 - 10:58am

Given the size of the patient population of the Veterans Health Administration (VHA), it is likely the largest single provider of health care for sexual and gender minority (SGM) individuals in the United States, including lesbian, gay, bisexual, and transgender persons. However, current VHA demographic data-collection strategies limit the understanding of how many SGM veterans there are, thereby making a population-based understanding of the health needs of SGM veterans receiving care in VHA difficult. In this article, we summarize the emergent research findings about SGM veterans and the first initiatives that have been implemented by VHA to promote quality care. Though the research on SGM veterans is in its infancy, it suggests that SGM veterans share some of the health risks noted in veterans generally and also risks associated with SGM status. Some promising resiliency factors have also been identified. These findings have implications for both VHA and non-VHA systems in the treatment of SGM veterans. However, more research on the unique needs of SGM veterans is needed to fully understand their health risks and resiliencies in addition to health-care utilization patterns.

Sourcebook: Women Veterans in the Veterans Health Administration. Volume 2: Sociodemographics and Use of VHA and Non-VA Care (Fee)

Fri, 08/08/2014 - 10:58am

Describes sociodemographic characteristics and health care utilization patterns of women Veteran patients in the VHA. Its primary purpose is to present data to inform policy and program planning as VHA implements and evaluates new ways of providing care to women Veterans. Provides data about women residing in rural versus urban areas and by examining use of health care through VHA’s “Non-VA Care (Fee)” system, which is comprised of services provided to Veterans by non-VHA providers but reimbursed through VHA.

Produced by the Women’s Health Evaluation Initiative, Women’s Health Services, Veterans Health Administration, Department of Veterans Affairs, Washington DC.

Cynicism: Incident diabetes and worsening of metabolic syndrome in postmenopausal women

Thu, 08/07/2014 - 4:15pm

Objective: To determine if self-reported cynical hostility predicted incident diabetes or increase in number of symptoms associated with metabolic syndrome in postmenopausal women.

Design: Prospective study of a subsample of women (n = 3,658) participating in the Women's Health Initiative Clinical Trial.

Methods: Subjects: Postmenopausal women aged 50 to 79 years at baseline who were enrolled in the Women's Health Initiative Dietary Modification Trial, Hormone Trial or both. Measures: The Cynicism subscale of the Cook-Medley Hostility Questionnaire was used to assess cynical hostility at baseline. Incident diabetes was ascertained by self-report of treatment with insulin or oral hypoglycemic medication at one year. Metabolic syndrome was defined based on number of Adult Treatment Panel (ATP) III criteria met at one year.Statistical Analysis: The relationship between baseline cynical hostility and incident diabetes and worsening of metabolic syndrome was assessed from baseline to one year using multivariable Cox proportional hazards models and multivariable logistic regression models, respectively.

Results: Incident diabetes was 36% higher among women in the upper tertile for baseline cynical hostility compared to the lowest tertile (p-trend = 0.05). The odds of a worsening of metabolic syndrome was 27% greater in the highest cynical hostility tertile compared to the lowest tertile (p-trend = 0.04).

Conclusions: Cynical hostility may increase the risk for developing diabetes and worsening of the metabolic syndrome in postmenopausal women.

Prevention and Management of Chronic Disease through Worksite Health Promotion

Thu, 08/07/2014 - 4:15pm

Summarizes the rationale and scientific evidence for providing health promotion programs at worksites.

Collaborative Connection to the Past and Future: Introducing an Archival Program and Creating a History and Image Web Exhibit

Thu, 08/07/2014 - 8:33am

Objectives: Establishing an archival program and creating a digital exhibit highlighting the history of an institution provides invaluable outreach and support. There are opportunities for significant collaboration between affiliated organizations by building relationships and sharing expertise. This paper provides a project description and product evaluation of the collaboration between a large academic medical library and archives and an affiliated vaccine manufacturer. The planning, implementation, and outcomes are discussed, with generally applicable components of this project detailed. Finally, recommendations for similar project implementations are given.

Methods and Results: In collaboration with a medical library and archives, an affiliated, historic vaccine manufacturer developed a project to preserve and publicize its long, rich history. While initially there were many goals for the project, an archivist was hired for only 900 hours. Priorities, a timeline, and deliverables had to be negotiated. The result was the development of an institutional archival program and an online history and image exhibit, both serving as powerful outreach and marketing tools. The project had 2 notable components: the establishment of traditional archival procedures and activities, including supporting documentation for future work; and the research, selection, and implementation of an appropriate web platform supporting an image exhibit, comprehensive timeline, and narrative history. By developing a web exhibit, the vaccine manufacturer now has a visible product used for outreach and promotion. The creative manipulation of an open source, simple web service served the needs of the archivist, the institution, and the budget. Collaboration between the manufacturer and the medical school has increased general communication and connection between the two. Finally, by providing very clear guidelines, education, and documentation for the project and all aspects of archival work, invested parties could make more appropriate planning decisions and be better prepared to continue the project in the future. Collaboration, communication, and creativity by all parties grounded and guided this project and are crucial to any success in projects of this type.

Conclusions: The creative use of resources and the creation of clear foundational policies and procedures--while also providing education about the nature, importance, and work expectations of archives--led to valued deliverables and a successful project. While not all initial goals were able to be addressed, by creating realistic expectations and timelines, and producing an appreciated, visible product, the project was ultimately extended with additional funding and labor.

The Society of Behavioral Medicine position statement on the CMS decision memo on intensive behavior therapy for obesity

Wed, 08/06/2014 - 4:45pm

In 2011, the Centers for Medicare and Medicaid Services (CMS) issued a decision to cover intensive behavior therapy for obesity in the primary care setting. The Society of Behavioral Medicine (SBM) Public Policy Leadership Group reviewed the CMS decision and has issued a position statement. SBM is in support of the CMS decision to cover intensive behavior therapy for obesity but expresses significant concern that aspects of the decision will severely limit the impact of the decision. Concerns focus on the degree to which this care can be feasibly implemented in its current form given the limitations in providers who are covered and the short length of counseling visits relative to evidence-based protocols. SBM is in strong support of modifications that would include providers who have expertise in weight control (e.g., psychologists and dietitians) and to expand the treatment time to better match protocols with confirmed efficacy.

Trait anxiety, but not trait anger, predisposes obese individuals to emotional eating

Wed, 08/06/2014 - 4:45pm

The present study examined whether trait anxiety and trait anger are associated with vulnerability to emotional eating, particularly among obese individuals. Lean (n = 37) and obese (n = 24) participants engaged in a laboratory study where they completed measures of trait anxiety and trait anger at screening and then completed 3 counterbalanced experimental sessions involving different mood inductions (neutral, anxiety, anger). Following each mood induction, participants were provided with snack foods in a sham taste test. Models predicting snack intake revealed a significant trait anxietyxbody mass index group interaction, such that high trait anxiety was positively associated with food intake for obese individuals, but not their lean counterparts. Contrary to the hypothesis, trait anger was not associated with food intake for obese or lean participants. Results suggest that trait anxiety may be a risk factor for emotional eating among obese individuals.