Vascular and neoplastic risk in a large cohort of patients with polycythemia vera.

PURPOSE: The clinical course of polycythemia vera is often complicated by thrombosis as well as by the possible transition to myeloid metaplasia with myelofibrosis or acute myeloid leukemia. The aim of this study was to assess the rate of these complications in subjects receiving currently recommended treatments. PATIENTS AND METHODS: Overall, 1,638 patients from 12 countries were enrolled onto a large, prospective multicenter project aimed at describing the clinical history of polycythemia vera for the following outcomes: survival, the cumulative rate of cardiovascular death and thrombosis, the cumulative rate of leukemia, myelodysplasia, and myelofibrosis. The mean duration of the disease at entry and the duration of the follow-up were 4.9 and 2.7 years, respectively. RESULTS: The overall mortality rate of 3.7 deaths per 100 persons per year resulted from a moderate risk of cardiovascular death and a high risk of death from noncardiovascular causes (mainly hematologic transformations). Age older than 65 years and a positive history of thrombosis were the most important predictors of cardiovascular events. Antiplatelet therapy, but not cytoreductive treatment, was significantly associated with a lower risk of cardiovascular events. We found a consistent association between age and risk of leukemia, and between duration of the disease with risk of myelofibrosis. CONCLUSION: The European Collaboration on Low-Dose Aspirin in Polycythemia Vera study documents that large international collaborative studies are feasible in this field, in which few epidemiologic data are available. The persistently high mortality rate from hematologic malignancies characterizes the unmet therapeutic need of polycythemic patients and suggests a priority for future studies in this disease.     

Rapid and efficient identification of cysteine-rich peptides by random screening of a venom gland cDNA library from the hexathelid spider Macrothele gigas.

We identified novel 10 multi-cysteine peptides, namely Magi 7-16, from the spider Macrothele gigas by simple random cDNA screening of the venom gland. Mass analysis of the crude venom detected the mass numbers of the cross-linked forms of all peptides, confirming their presence in the venom. Magi 11, a C-terminus amidated peptide, was chemically synthesized and was indistinguishable from the native peptide proving the feasibility of the method for peptide identification. Moreover, toxicological assays showed diverse lethal or paralytic activities of these peptide toxins on mice and/or insects.     

Inhibition of Neu-Induced Mammary Carcinogenesis in Transgenic Mice Expressing ERΔ3, a Dominant Negative Estrogen Receptor α Variant

The estrogen receptor ?? (ER??) splicing variant with an in-frame deletion of exon 3 (ER??3) is frequently expressed in the normal breast, but its influence on tumorigenesis has not been explored. In vitro, ER??3 has dominant negative activity, suggesting it may suppress estrogen stimulation in the breast. ER??3 may inhibit classical signaling on estrogen response element (ERE)-regulated genes as well as activate non-classical pathways at Sp1 and AP-1 sites. Transgenic mice were developed that express mouse ER??3 in all tissues examined, including the mammary gland. To investigate if ER??3 expression affects tumorigenesis, ER??3 mice were crossbred with MMTV-Neu mice. Mammary tumor onset was significantly delayed in ER??3/Neu versus MMTV-Neu females and metastatic incidence and burden was significantly reduced. Consequently, ER??3 expression suppressed tumor development and metastasis in this aggressive model of HER2/Neu-positive breast cancer. To determine if ER ligands with anticancer activity may augment ER??3 protection, the bitransgenic mice were treated with tamoxifen and soy isoflavones starting at age 2?months. Soy protein with isoflavones (181?mg/1,800?kcal) did not affect tumor development in MMTV-Neu or ER??3/Neu mice; however, metastatic progression was not inhibited in soy-treated ER??3/Neu mice, as it was in untreated ER??3/Neu mice. In contrast, tamoxifen (20?mg/1,800?kcal) significantly enhanced tumor prevention in ER??3/Neu versus MMTV-Neu mice (98?% vs. 81?% tumor free). The results in ER??3/Neu mice demonstrate that ER??3 influences estrogen-dependent mammary carcinogenesis and, thus, may be protective in women expressing ER??3 in the breast. However, exposure to different estrogens may augment or block its beneficial effects.     

Heart-hand syndrome

Heart–hand syndromes show substantial clinical and genetic heterogeneity. The unusual case of a patient with a heart–hand syndrome consisting of preaxial polydactylia, postaxial syndactylia, parachute mitral valve, mild subaortic stenosis, and double outlet right ventricle is presented and discussed. The importance of distinguishing Holt–Oram syndrome from its phenocopies and other heart–hand syndromes is underlined.     

Enhancing Stewardship of Community-Engaged Research Through Governance

Objectives. We explored the relationship of community-engaged research final approval type (tribal government, health board, or public health office (TG/HB); agency staff or advisory board; or individual or no community approval) with governance processes, productivity, and perceived outcomes.Methods. We identified 294 federally funded community-engaged research projects in 2009 from the National Institutes of Health’s Research Portfolio Online Reporting Tools, Centers for Disease Control and Prevention’s Prevention Research Centers, and Native American Research Centers for Health databases. Two hundred (68.0%) investigators completed a survey about governance processes and productivity measures; 312 partners (77.2% of 404 invited) and 138 investigators (69.0% of 200 invited) completed a survey about perceived outcomes.Results. Projects with TG/HB approval had increased likelihood of community control of resources (odds ratios [ORs] ≥ 4.80). Projects with other approvals had decreased likelihood of development or revision of institutional review board policies (ORs ≤ 0.37), having written agreements (ORs ≤ 0.17), and agreements about publishing (ORs ≤ 0.28), data use (ORs ≤ 0.17), and publishing approval (ORs ≤ 0.14).Conclusions. Community-engaged research projects with TG/HB approval had strong stewardship of project resources and agreements. Governance as stewardship protects community interests; thus, is an ethical imperative for communities, especially native communities, to adopt.Researchers working with native communities (American Indian, Alaska Native, and Native Hawaiian peoples), other racial/ethnic minority communities, or other communities facing disparities that experience similar mistrust for past research issues, health inequities (e.g., gays and lesbians or people with disabilities), or both, have advocated the use of participatory research to enhance community health.1–6 Such approaches include tribal participatory research, community-based participatory research, and participatory action research and are generally grouped as community-engaged research (CEnR). There is a continuum of engagement,7 but CEnR that involves collaborative partnership and shared leadership between community members and (academic) researchers in all phases of the research can build capacity of all partners, create research that benefits the community, and enhance translation of research findings to the community.8–13 These approaches have attraction because they can advance cocreation of the research, contribute culturally centered methods, and foster research capacity.1,2,14,15Although CEnR approaches have appeal, they still require governance to provide protection, oversight, guidance, legitimacy, and community benefit. Governance over CEnR is complex and involves numerous practices and policies.16,17 Historically, oversight responsibilities have been held by institutional review boards (IRBs) that uphold federal standards established by the Office for Human Research Protections.18,19 Use of IRBs (e.g., university IRBs or Indian Health Service IRBs) for research oversight characterizes governance as regulation as the focus is on balancing the needs of protection of individuals from harm while trying to foster scientific innovation. However, when research partners consider other functions of governance alongside legal regulation (e.g., use of tribal governments or community-based review boards), the quality of research can be strengthened and more attention paid to the benefits and harm of the research for the community.20–22In recent years, policymakers, CEnR researchers, and community organizations have advocated a broader perspective of governance, one that can be characterized as stewardship of research. Governance as stewardship enhances protection of the community, helps to foster research partnerships and appropriate access to and approval of research by community bodies, ensures benefit for the community, provides legitimacy of the research, shares responsibility for the research, provides community control, and builds research capacity in communities.20–23 For example, when native communities steward research, new patterns emerge between academic and community partners that might involve (1) community and academic partners requiring and committing to oversight by a tribal council or community board, (2) review boards or tribal governments insisting the that project demonstrate benefits to the community (not just individuals), (3) all partners committing to tribal ownership of the data, and (4) all partners working to use data and disseminate findings following tribal review.2,24–27Although nontribal communities do not have a tribal council for formal governance, they establish various governance mechanisms such as oversight by faith-based networks or leaders, health boards or public health offices, project advisory boards, or community partner boards.21,28–30 Stewardship by these governing entities may involve (1) academic partners that engage in collaboration with the community to produce the research, (2) projects that use culturally relevant research designs and instruments to enhance the quality of the research, (3) projects that hire community members on research projects to build research capacity, and (4) academic partners that encourage community engagement and participation.2–4,21,28 In both native and nonnative communities, stewardship practices lead to enhanced trust of the research process by community partners, relationships that balance community and academic institutional power, IRB processes that reflect community interests and not just biomedical interests, inclusion of cultural frameworks that fit the community, and academic members committed to community engagement.21,28,31Enhancing stewardship of research through governance has focused on several activities. First, increasingly, native and nonnative communities are asserting their roles in overseeing research by developing community IRBs and other forms of research oversight.23,32,33 Second, research review can protect community knowledge by establishing protocols for oversight and can affirm tribal or community authority to approve and guide research that will benefit the community.21,22,28–30,33,34 Third, the National Congress of American Indians35–37 asserts that tribes, as sovereign nations, have regulatory authority over research that takes place on tribal lands and with tribal citizens. Several tribes have exercised governance by establishing research codes, research review boards, and formal agreements with research institutions, and some intertribal entities have established research oversight in urban and cross-tribal regions.33,38Despite the expanded view of ethical issues within CEnR projects and an upsurge in community governance expectations from communities and some funders, there has been little research that has examined the role of governance in research specifically, as well as concerns that these processes might inhibit research. Some researchers and policy analysts suggest that tribal research review is perceived as slowing or blocking research development and dissemination.25,35 A tension related to data ownership to ensure risks and benefits are considered for communities, individual research participants, and research funders also exists.What has been lacking in these discussions to date has been research about the associations of governance with agreements, control of resources, productivity, and perceived outcomes of CEnR. Agreements are the accepted standards or protocols for the research partnership such as mission and objectives, group dynamics, and dissemination.12,39 Control of resources is whether the community, academic institution, or both hire personnel and manage project resources.12,40 Research productivity measures include garnering funding, disseminating scholarship, developing new measures centered in cultural or community perspectives, and establishing new research regulation.3,23,28,30 These measures are important as the need to generate, disseminate, and regulate new knowledge and practices are core goals of funding agencies and, to a lesser extent, communities.Perceived outcomes of CEnR focus on the contributions to health, and encompass changes in power relations, sustainability, community transformation, improved health of the community, and capacity building for individuals and agencies.12 These outcomes are important as they are health outcomes or factors that enhance public health. Ultimately, the success of a CEnR project is determined by research productivity and improvement of health outcomes.The notion of governance also has often been a source of mystery and conflict in research partnerships. We sought to foster understanding and provide context around governance as “stewardship” in research partnerships in both native and nonnative communities by focusing on the type of final approval of CEnR—the body or individual who endorsed and approved the project on behalf of the community and allowed it to continue. This approval is a key factor for legitimacy, community involvement, oversight, and guidance of the project.26,35 Furthermore, the type of approval has not been studied, whereas the general oversight of research ethics through community or tribal IRBs has garnered recent research focus.21,33,38 Examining the type of approval allows an exploration of how governance as stewardship balances needs for authority and accountability, control and capacity building, and protection and benefits.     

Evaluation of polymerase chain reaction, adenosine deaminase, and interferon-gamma in pleural fluid for the differential diagnosis of pleural tuberculosis

STUDY OBJECTIVES: Pleural tuberculosis (TB) is a diagnostic challenge because of its nonspecific clinical presentation and paucibacillary nature. The inefficiency of conventional laboratory methods and the reliance on pleural biopsy have motivated the evaluation of alternative diagnostic strategies. We have evaluated polymerase chain reaction (PCR) directed to the IS6110 sequence of Mycobacterium tuberculosis, the determination of adenosine deaminase (ADA) activity, and measurement of interferon (IFN)-gamma levels in pleural fluid in the diagnosis of pleural TB. PATIENTS: ADA activity, IFN-gamma levels, and PCR were evaluated in 140 cases of pleural effusion, 42 with confirmed pleural TB, 19 with probable pleural TB, 70 with a nontuberculous etiology, and 9 having an undetermined etiology. RESULTS: ADA activity, IFN-gamma levels, and PCR were 88%, 85.7%, and 73.8% sensitive, respectively, and 85.7%, 97.1%, and 90% specific, respectively, for pleural TB that had been confirmed by either culture or pleural biopsy specimens. The combination of PCR, IFN-gamma measurement, and ADA activity determination allowed the selective increase of sensitivity and specificity for probable and confirmed cases compared to individual methods. Positive and negative predictive values for these individual or combined methods were maintained over a wide range of prevalence of pleural TB in the patient population presenting with pleural effusions. Fever and younger age were associated with tuberculous pleural effusion (p < 0. 0001), while blood in sputum and older age were associated with malignant etiology (p < 0.008). CONCLUSIONS: These clinical variables together with the use of ADA activity determination, PCR, and measurement of IFN-gamma levels provide the basis for the rapid and efficient diagnosis of pleural TB in different clinical settings.