Anti-factor VIII antibodies of hemophiliac patients are frequently directed towards nonfunctional determinants and do not exhibit isotypic restriction

A significant proportion of hemophilia A patients receiving transfusions of factor VIII (FVIII) develop a specific antibody response towards FVIII. These antibodies are usually detected by assays in which they inhibit the function of the molecule, such as the Bethesda clotting test. We have prepared anti-FVIII antibodies by specific immunoadsorption from the plasma of four hemophiliacs with stable inhibitor levels. The isotypic distribution of such antibodies was determined and their capacity to bind to insolubilized FVIII was compared with their inhibitory activity in two functional assays, namely, the Bethesda assay and a chromogenic assay. In addition, the FVIII epitope specificity was determined by competition with monoclonal antibodies for the binding to insolubilized FVIII. We show here that (1) anti-FVIII antibodies are not isotypically restricted; thus, a significant proportion of specific IgG2 was found; (2) antibodies are frequently directed towards epitopes of FVIII that are not directly involved in the function of the molecule and therefore escape detection in the Bethesda method or chromogenic assay; and (3) each patient shows a unique pattern of FVIII epitope recognition. We conclude that evaluation of anti-FVIII antibodies by a functional method does not provide an accurate evaluation of the specific antibody response. These findings have important implications for the comparison of the immunogenicity of FVIII molecules produced by different technologies and for the development of methods to control anti-FVIII antibody production.     

In vivo expression of the B7 costimulatory molecule by subsets of antigen-presenting cells and the malignant cells of Hodgkin's disease

The B-lymphocyte/accessory-cell activation antigen B7 (BB1) has been shown in vitro to stimulate T-lymphocyte proliferation and cytokine production via CD28 present on the latter cells. In this study, benign lymphoid tissues, lymphomas, and extralymphoid inflammatory sites were examined immunohistochemically using anti-B7 and other relevant monoclonal antibodies. B7 was expressed by benign transformed germinal center B cells, as it was by B cells of follicular lymphomas. B7 was also expressed by a subpopulation (a mean of 31% to 65%) of macrophages and dendritic cells in a variety of lymphoid tissues. It was present in abundance on all macrophages constituting sarcoid granulomas in lymph nodes. In extralymphoid inflammation, 17% to 35% of macrophages expressed B7 only weakly. Cases of Hodgkin's disease showed expression of B7 by the majority of Reed-Sternberg cells or malignant mononuclear variants, a phenomenon that potentially contributes to the lymphocytic accumulation that is a feature of this condition. CD28+ T cells were seen in all areas where T cells were present. B7+ and CD28+ cells colocalized in, for example, lymphoid follicles, lymph node paracortex, sarcoid granulomas, and Hodgkin's disease tissue, indicating a potential for cellular interaction via these molecules at these sites.     

Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia is characterized by moderate thrombocytopenia and thrombotic complications, whereas quinine/quinidine-induced thrombocytopenia usually presents with severe thrombocytopenia and bleeding. Using flow cytometry and assays of procoagulant activity, we investigated whether sera from patients with these immune drug reactions could stimulate normal platelets to generate platelet-derived microparticles with procoagulant activity. Sera or purified IgG from patients with heparin-induced thrombocytopenia stimulated the formation of platelet-derived microparticles in a heparin-dependent fashion. Further studies showed that heparin-induced thrombocytopenia sera also produced a marked increase in procoagulant activity. In contrast, sera from patients with quinine- or quinidine-induced thrombocytopenia did not generate platelet-derived microparticles nor generate increased procoagulant activity. However, quinine/quinidine-induced thrombocytopenia sera produced a significant increase in the binding of IgG to platelets in a drug-dependent fashion, whereas sera from patients with heparin-induced thrombocytopenia demonstrated no drug-dependent binding of IgG to platelets. We also observed increased levels of circulating microparticles in patients with acute heparin-induced thrombocytopenia compared with control patients. Our observations indicate that the generation of procoagulant platelet-derived microparticles in vivo is a plausible explanation for the thrombotic complications observed in some patients with heparin-induced thrombocytopenia.     

A Short Review of the Treatment of Headaches Using Osteopathic Manipulative Treatment

Purpose of Review

This review highlights the importance of osteopathic manipulative treatment (OMT) in headache sufferers. OMT is a viable option for patients who either do not wish to use pharmaceuticals or who have contraindications to pharmaceuticals. Patients with headaches that are refractory to other treatment options may also be candidates for OMT. Multiple headache etiologies are amenable to this non-invasive treatment option and they will be reviewed here. Although there are advantages to using this treatment method, there are also shortcomings in the literature, which will be discussed.

Recent Findings

Roughly 45 million Americans suffer from headaches every year. Many headache sufferers are unable to find relief through conventional treatment options. OMT is a useful non-invasive treatment option with little to no side effects. There are multiple headache types. Migraine, tension-type headache, combat-related events, post-traumatic headache, sinusitis, tooth extraction, concussions, and others have all shown benefit from OMT.

Summary

OMT is a non-invasive treatment option for individuals suffering from various types of headaches. This treatment option is tailored to the individual needs of the patient and is delivered by licensed and experienced osteopathic physicians. This review of literature also highlights where there is need for further research in the field.

     

The excitation and inhibition of sexual receptivity in female hamsters by progesterone: time and dose relationships, neural localization and mechanisms of action.

Ovariectomized hamsters were administered estradiol benzoate (EB) and 44 h later, progesterone (P.) Lordosis behavior was induced. When an additional dose of P was given up to 24 h prior to or 24 h after the EB, EB-P facilitation of lordosis was inhibited. Additional hamsters were given varying doses of P (25-200 mu) following EB using both excitatory and inhibitory paradigms. Inhibition of EB-induced lordosis was effected with a lower dose of P than was the facilitation of EB induced lordosis by P. Hamsters were also given intracerebral implants of P using excitatory and inhibitory paradigms. No excitatory loci were found. Inhibition of EB-induced lordosis was effected by implants in the posterior hypothalamus and anterior mesencephalon, but not by diencephalic implants. Other hamsters were administered tritiated estradiol (E2) plus P prior to, concurrent with, or shortly after the E2. P had no effect upon the accumulation of E2 by any brain sites, although E2 was found to concentrate to a greater degree in the diencephalon than in the mesencephalon or cortex. The estrogen-induced depletion and replenishment of hypothalamic cytosol estrogen receptors was also studied. Concurrent P treatment had no effect upon the receptor depletion-replenishment process. It was concluded that P can both facilitate and inhibit estrogen-induced lordosis and that the inhibitory effects of P are not upon estrogen-sensitive cells in the brain.