Characterization of a monoclonal antibody having selective reactivity with normal and neoplastic plasma cells

A myeloma cell-reactive monoclonal antibody (MoAb), MM4, was generated from BALB/c mice immunized with alternate injections of cells from two human multiple myeloma (MM) cell lines. Screening by the enzyme-linked immunosorbent assay (ELISA) technique showed that MM4 reacted with human MM cell lines (7 of 7 positive), as well as bone marrow aspirates from MM patients (4 of 4 cases positive). MM4 did not react with marrow aspirates from control patients (3 cases), or with peripheral blood mononuclear (PBM) cells from normal subjects, lymphocytic (12 cases) and myelogenous (8 cases) leukemia patients. In addition, MM4 was negative with polymorphonuclear leukocytes and RBCs from normal donors. By means of the immunoperoxidase technique, the MM4-reactive antigen was detected in paraffin-embedded, Zenker formalin-fixed bone marrow biopsies of MM (12 of 12 cases positive), Waldenstrom's macroglobulinemia (2 of 2 cases positive), asymptomatic plasma cell dyscrasia (4 of 4 cases positive), and certain lymphomas (2 of 5 cases positive). Marrow biopsies from lymphocytic (5 cases) and myelogenous (5 cases) leukemias were uniformly negative. The MM4-reactive antigen also was expressed on plasma cells generated from pokeweed mitogen (PWM)-stimulated normal PBM cultures. The pattern of reactivity of MM4 with lymphocytes of B origin was similar to that of the plasma cell MoAb PCA-1. Competitive binding studies showed, however, that these two MoAbs recognized distinct antigenic determinants. These observations suggest that MM4 may be useful for the study of human plasma cell dyscrasias.     

ET-1 actions in the kidney: evidence for sex differences

Hypertension and chronic kidney disease are more common in men than in premenopausal women at the same age. In animal models, females are relatively protected against genetic or pharmacological procedures that produce high blood pressure and renal injury. Overactivation or dysfunction of the endothelin (ET) system modulates the progression of hypertension or kidney diseases with the ET_A receptor primarily mediating vasoconstriction, injury and anti-natriuresis, and ET_B receptors having opposite effects. The purpose of this review is to examine the role of the ET system in the kidney with a focus on the inequality between the sexes associated with the susceptibility to and progression of hypertension and kidney diseases. In most animal models, males have higher renal ET-1 mRNA expression, greater ET_A-mediated responses, including renal medullary vasoconstriction, and increased renal injury. These differences are reduced following gonadectomy suggesting a role for sex hormones, mainly testosterone. In contrast, females are relatively protected from high blood pressure and kidney damage via increased ET_B versus ET_A receptor function. Furthermore, ET_A receptors may have a favourable effect on sodium excretion and reducing renal damage in females. In human studies, the genetic polymorphisms of the ET system are more associated with hypertension and renal injury in women. However, the knowledge of sex differences in the efficacy or adverse events of ET_A antagonists in the treatment of hypertension and kidney disease is poorly described. Increased understanding how the ET system acts differently in the kidneys between sexes, especially with regard to receptor subtype function, could lead to better treatments for hypertension and renal disease.

LINKED ARTICLES

This article is part of a themed section on Endothelin. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.168.issue-1     

Evaluation of the BBMEC model for screening the CNS permeability of drugs

Combinatorial synthesis and high-throughput pharmacology screening have greatly increased compound throughput in modern drug-discovery programs. For CNS drugs, it is also important to determine permeability to the blood--brain barrier. Yet, given the increased pace of discovery, it difficult to conduct this screen in a timely fashion. In this presentation, we describe several improvements to an existing CNS permeability screen, the bovine brain microvessel endothelial cell (BBMEC) model. By implementation of these incremental process improvements, we have achieved a robust, facile screen for determination of CNS permeability of multiple compounds.     

Comparative effectiveness research in the “real” world: lessons learned in a study of treatment-resistant hypertension

Comparative effectiveness research (CER) is vital to translate new efficacious diagnostic and therapeutic approaches into effectiveness in usual clinical practice settings. Studying the practice environment in which effectiveness protocols are implemented is necessary to identify the complex challenges that can limit translation of evidence. These issues were addressed in our National Heart, Lung, and Blood Institute-funded R34, “Controlling Blood Pressure in Treatment-Resistant Hypertension (TRH): A Pilot Study.” Qualitative methods were used in this cluster (clinic)-randomized, four-arm pilot study of TRH in eight diverse, community-based practices including: (i) focus group discussions with practice staff and physicians; (ii) conference calls with physicians; and (iii) discussions with research coordinators. Sources were summarized and analyzed by content analysis. Results include data segregated into categories representing facilitators of and barriers to research. Key facilitators included: (i) early success in controlling challenging TRH patients (ii) improved management of TRH, and (iii) reimbursement for study time and expenses. Barriers included: (i) time-consuming regulatory requirements; (ii) limited training and research experience of some study coordinators; and (iii) reluctance of some physicians to refer to Hypertension Specialists. Qualitative assessment is valuable for identifying facilitators and barriers to CER. This information is important in designing and implementing CER to accelerate translation of clinical efficacy into effectiveness.     

Placental malaria is associated with attenuated CD4 T-cell responses to tuberculin PPD 12 months after BCG vaccination

Background  

Placental malaria (PM) is associated with prenatal malaise, but many PM+ infants are born without symptoms. As malaria has powerful immunomodulatory effects, we tested the hypothesis that PM predicts reduced T-cell responses to vaccine challenge.     

Flammability and combustion hazard of preserved human tissues

Preservation techniques have evolved over the years to respond to the need of longer dissection periods, with formaldehyde being widely used for this purpose. In recent years, efforts have been focusing on reducing the health hazards of this fixative and the rigidity of the tissues embalmed with it. With every embalming technique that they are either developing or resurrecting from various protocols, institutions need to assess the fire and health hazards of all the chemicals being used. Compliance with the storage and handling safeguards listed in the Material Safety Data Sheet of each chemical, needs to be accompanied by infrastructure changes. To reduce the health hazards of formaldehyde, institutions are taking appropriate countermeasures directed at the source itself, by using substitutes or injecting formaldehyde chelating agents, and are adopting high performance air extraction systems to protect the users. However, little is known about the flammability risk of embalmed human bodies. During a recent visit to McGill University morgue by architects and safety inspectors to expand it, we were asked about the flammability risk of the embalmed specimens, so we carried out a flashpoint test to evaluate the flammability potential of specimens embalmed with each of our three embalming techniques: formaldehyde-based, Thiel, and phenol-based. With the phenol-based embalming showing the most risks, attention should be drawn to all institutions who are experimenting with various embalming techniques to evaluate the flammability potential of their embalmed specimens.