A monoclonal antibody directed against a granule membrane glycoprotein (GMP-140/PADGEM, P-selectin, CD62P) inhibits ristocetin-induced platelet aggregation

P-selectin (also called CD62, GMP-140, PADGEM, CD62P) is a recently described member of a family of vascular adhesion receptors expressed by activated platelets and endothelial cells that are involved in leucocyte cell adhesion. The aim of this study was to characterize a new monoclonal antibody (LYP7) directed against activated human blood platelets that inhibits ristocetin-induced platelet aggregation. Immunoadsorbent affinity chromatography and immunoprecipitation studies showed that LYP7 (IgG₁) bound a surface-labelled glycoprotein (GP) which changed its apparent molecular mass (M_r) on reduction from 138 kD (situated below GPIIb) to 148 kD (above GPIIbα). LYP7 and S12, a monoclonal antibody directed against P-selectin immunoprecipitated the same band. Using ELISA assay, purified P-selectin was shown to bind LYP7 and S12 monoclonal antibodies. Binding sites of ¹²⁵I-labelled LYP7, which was greatly increased on thrombin-stimulated (2 U/ml) washed platelets (10825±2886, mean ±SD) (K_d=1.5±0.5 nm ) compared to resting platelets (2801±1278, mean ±SD) (K_d=1.5±0.6 nm ), was found to be normal on thrombin-stimulated platelets taken from a patient with grey platelet syndrome or a patient with Glanzmann thrombasthenia. LYP7 (IgG₁, F(ab′)₂ or Fab fragments) inhibited ristocetin-induced platelet aggregation of platelets in a dose-dependent fashion without affecting the binding of von Willebrand (vWf ) factor. However, agglutination of formaldehyde-fixed platelets induced by ristocetin was not affected by monoclonal antibody LYP7. In addition, the binding of thrombin-activated platelets to neutrophils was inhibited by monoclonal antibody LYP7. These results strongly suggest that P-selectin, by promoting cell–cell contact, may play an active role in platelet–platelet interactions.     

Brachial plexus injury during open heart surgery--controlled prospective study

BACKGROUND: Postoperative brachial plexus injury is often reported because the brachial plexus is stretched by sternotomy and the use of sternal retractors during open heart surgery. In many studies, brachial plexus injuries have been demonstrated by postoperative electrophysiological studies in susceptible patients. In this study, we estimated the incidence, severity, and type of brachial plexus injuries by routine preoperative and postoperative electrophysiological studies of patients undergoing open heart surgery. METHODS: Patients undergoing coronary artery bypass grafting (CABG) surgery (Group 1), heart valve surgery (Group 2), or peripheral vascular surgery (Group 3) were included in the investigation. Electrophysiological studies of both upper extremities were performed five days before and three weeks after the operation. RESULTS: Peripheral nerve problems were found preoperatively in 23 of the 112 patients (21 %). These problems persisted, but similar findings were obtained postoperatively from the left upper extremities of six of the 42 CABG (14 %) and two of the 24 heart valve (8 %) patients who had had normal preoperative evaluations. The patients with injured nerves were older and had undergone longer operation times. There were no differences between the patients with injured nerves and the others with respect to mammary artery harvesting or other operative variables. CONCLUSIONS: There are no reports in the literature of routine preoperative and postoperative electrophysiological studies in large patient groups to evaluate brachial plexus injury during open heart surgery. It is known that heart surgery sometimes causes partial brachial plexus injury, especially in the lower trunk. However, these peripheral nerve problems are usually not considered clinically important and are not investigated. Patients undergoing open heart surgery must be closely followed up for peripheral nerve injury during the postoperative period.     

Factor V Leiden mutation and other thrombophilia markers in childhood ischemic stroke.

The aim of this study was to evaluate the association between ischemic childhood stroke and thrombophilia. The prevalence of thrombophilia risk factors in 30 unrelated children with ischemic stroke were compared with 33 age-matched control subjects. Patients and control group were tested for the presence of activated protein C (APC) resistance, antiphospholipid antibodies (APLA), increased factor VIII levels, and for the deficiency of protein C (PC), protein S (PS), and antithrombin. When APCR was detected in patients or in controls, factor V Leiden (FVL) mutation was also tested. Seventeen of 30 patients (56.6%) had at least one thrombophilia marker compared with only 5 of 33 control subjects (15.1%). Three children with ischemic stroke (10%) were affected with a combination of two or more thrombophilia markers whereas none of the children in the control group had a combination of risk factors. Seven of 30 children with ischemic stroke (23.3%) and one of 33 control subjects (3.03%) had APC resistance and in all of them FVL mutation were found. The prevalence of FVL mutation was higher among pediatric stroke patients than among control subjects (p < 0.05). None of the patients but one child from the control group (3.03%) had PS deficiency. Antithrombin and PC deficiencies and the presence of APLA and increased factor VIII levels were more frequent in the pediatric stroke patients than in controls but the difference was not statistically significant (p > 0.05). These data confirm that stroke in children is commonly associated with a combination of multiple risk factors and especially the prevalence of FVL mutation is increased in children with ischemic stroke compared with control subjects.     

HLA-DR B1 and DQ B1 polymorphisms in patients with coronary artery ectasia

OBJECTIVES: The purpose of our study was to evaluate the significance of polymorphisms in HLA class II genes in coronary artery ectasia (CAE) patients. METHODS AND RESULTS: Twenty-six patients with CAE without associated cardiac defects were enrolled in the study. CAE was defined as luminal dilation of 1.5- to 2.0-fold of normal limits. Ninety-five healthy subjects who were donors for different organ transplantations, were chosen as control group. Physical examination, electrocardiography and chest X-ray were completely normal in these cases. Both the patients and the control group were screened and compared for their HLA class II genotypes. HLA-DR B1*13, DR16, DQ2 and DQ5 genotypes were significantly more frequent in the patient group.When the known risk factors of coronary heart disease were compared in the patients carrying these genotypes with the non-carrying group, no significant differences were encountered. CONCLUSIONS: HLA-DR B1*13, DR16, DQ2 and DQ5 may be associated with the pathogenesis and increase the risk of CAE.     

Clinical experience with the Carpentier-Edwards porcine bioprosthesis: short-term results (from 2 to 4.5 years)

All patients undergoing a heart valve replacement with a glutaraldehyde Carpentier-Edwards xenograft from April 1978 through December 1980 were reviewed. This analysis included 189 patients: 117 having a mitral valve replacement (MVR), 45 having an aortic valve replacement (AVR), and 27 having mitral and aortic valve replacements (MAVR). Out of 174 patients discharged from the hospital, one was lost to follow-up and is excluded from the analysis. There were 11 late deaths, which represent an incidence of 1.89% per patient-year for the MVR (6/106), 0.83% per patient-year for the AVR (1/41), and 5.83% per patient-year for the MAVR (4/26). There were 6 instances of infective endocarditis (4 MVR, 2 MAVR), which represent a linearized incidence o 1.26% and 2.91% per patient-year for the MVR and MAVR respectively. All were successfully treated with medication. There were 10 thromboembolic events in 7 patients (6 MVR had 9 events and 1 AVR had 1 event). This represents a linearized incidence of 2.84% and 0.83% per patient-year for MVR and AVR, respectively. Primary tissue failure was observed in 3 patients (2 MVR, 1 MAVR), who required reoperation for explantation of the mitral valves. This represents an overall linearized incidence of mitral failures of 0.78% per patient-year. The probability of being free from primary tissue failure is 95.9 +/- 4.9% for all mitral prostheses at 4.5 years of follow-up. These current results indicate that the Carpentier-Edwards porcine xenograft valve can be considered as a valid alternative for heart valve replacement.     

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.     

Pulmonary artery diastolic pressure: a simultaneous Doppler echocardiography and catheterization study

Pulmonary hypertension is an important determinant of the clinical presentation of and surgical approach to patients with heart disease. To confirm the utility of continuous wave Doppler echocardiography in assessing the pulmonary artery diastolic pressure in patients with pulmonary regurgitation, 51 patients representing the wide hemodynamic spectrum of pulmonary artery pressure underwent simultaneous determination of pulmonary artery diastolic pressure by continuous wave Doppler echocardiography and cardiac catheterization. Pulmonary artery diastolic pressure was estimated from the Doppler recordings by the end-diastolic pressure gradient obtained by the modified Bernoulli equation plus the estimated right atrial pressure. A correlation was observed (r = 0.935, SEE = 7.4 mmHg) between Doppler and catheterization pulmonary artery diastolic pressure. In addition, comparison between the mean diastolic pressure gradient across the pulmonary valve by Doppler and pulmonary artery diastolic pressure at catheterization yielded a high correlation (r = 0.947, SEE = 5.1 mmHg). These data demonstrate that continuous wave Doppler echocardiography is a useful noninvasive technique for evaluating the pulmonary artery diastolic pressure in patients with pulmonary regurgitation.     

Right-sided endomyocardial fibrosis with recurrent pulmonary emboli leading to irreversible pulmonary hypertension.

A 26 year old Saudi man with features of both Loeffer's endocarditis and endomyocardial fibrosis presented with mild symptoms and pulmonary emboli. Echocardiographic examination showed obliteration of the right ventricular apex by an attached mass. The results of haemodynamic studies were somewhat abnormal and medical treatment was started. Despite anticoagulation with warfarin the patient's condition deteriorated rapidly over a four month period after a further episode of pulmonary embolism and the development of pulmonary hypertension. Two haemodynamic studies performed four months apart were typical of pulmonary hypertension and later right ventricular failure; they showed none of the characteristics of restriction. Pulmonary embolectomy was attempted but there was no cleavage plane between the organised thrombi and the endothelium of the pulmonary artery. The patient died of severe pulmonary hypertension and right ventricular failure several days after operation. Surgical intervention in the early stages of right-sided endomyocardial fibrosis might have prevented the development of pulmonary embolism and pulmonary hypertension.