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Biomedical subjects

M Blank

Publications and source records attributed to M Blank.

At least 127 records · Page 7Linked to original sources
PubMed1997

Do electromagnetic fields interact directly with DNA?

The mechanisms whereby electromagnetic (EM) fields stimulate changes in biosynthesis in cells are not known. It has has generally been assumed that EM fields first interact with cell membranes, but this pathway may not be only one. Interactions with membranes are well documented, but recent studies of EM signal transduction in the membrane Na,K-ATPase are best explained by direct interaction of electric and magnetic fields with mobile charges within the enzyme. Interaction with moving charges may be a mechanism that is operative in other biopolymers. Recent studies on DNA have shown that large electron flows are possible within the stacked base pairs of the double helix. Therefore, gene activation by magnetic fields could be due to direct interaction with moving electrons within DNA. Electric fields as well as magnetic fields stimulate transcription, and both fields could interact with DNA directly. The mechanism of EM field-stimulated transcription may be related to the process in striated muscles, where endogenous electrical activity induces the synthesis of new proteins.

Cell Membrane↗
PubMed1997

Animal models for antiphospholipid syndrome in pregnancy.

Experimental models for antipospholipid syndrome (APS) have been established recently in lupus-prone mice and induced in naive mice. The induction of APS is performed by passive infusion or active immunization of antiphospholipid antibodies (aPL) or the cofactor beta 2GP-1. High levels of diverse aPL develop in the animals in conjunction with clinical manifestations similar to the human disease, entailing low fecundity rate, fetal resorptions, thrombocytopenia, prolonged activated partial thromboplastin time, and neurological and behavioral impairments. The pathogenicity of aPL was confirmed in an in vivo thrombosis model. Immunomodulation of APS manifestations and treatment regimens in the experimental models are discussed.

Animals↗
PubMed1997

Pathogenicity of human anti-platelet factor 4 (PF4)/heparin in vivo: generation of mouse anti-PF4/heparin and induction of thrombocytopenia by heparin.

Heparin-induced thrombocytopenia/thrombosis (HIT) is a severe thrombotic disorder that occurs in approximately 1% of patients treated with heparin. Affected patients commonly develop antibodies that recognize PF4/heparin complexes that may form on the surface of activated platelets and on the endothelium. However, it has not been established that anti-PF4/heparin antibodies are responsible for the clinical manifestations of HIT. To address this issue, we employed a recently developed model of active immunity to study the effect of IgG anti-PF4/heparin antibody in vivo. In previous studies we have shown that it is possible to induce autoimmune diseases such as systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS) or vasculitis in naive mice by active immunization with anti-DNA, anti-cardiolipin and anti-neutrophil cytoplasmic antibodies, respectively. Immunized animals develop anti-idiotypic antibodies (Ab2) and, after 2-4 months, anti-anti-idiotypic antibodies (Ab3). Ab3s generated in this manner often simulate the binding activity of Ab1 and their expression correlates with the development of specific clinical manifestations typical of the respective human disease. Based on this experience, naive BALB/c mice were immunized with IgG anti-PF4/heparin antibodies isolated from two patients with HIT. The actively immunized mice developed mouse anti-PF4/heparin antibody (Ab3). Administration of unfractionated heparin, but not low molecular weight heparin (LMWH), to the actively immunized animals induced thrombocytopenia by day 4 of drug exposure. There was no evidence of thrombosis. The results of this study support the importance of anti-PF4/heparin antibodies in the pathogenesis of HIT. Further, this model may help to elucidate the factors responsible for thrombosis as well as providing means to assess new treatment options for patients with this disorder.

Animals↗
PubMed1997

Oxidized low-density lipoprotein (Ox-LDL) but not LDL aggravates the manifestations of experimental antiphospholipid syndrome (APS).

Ox-LDL is thought to play a major role in atherogenesis. The mechanisms mediating the deleterious influences of Ox-LDL include foam cell formation and cell cytotoxicity. The production of anti-Ox-LDL antibodies results in the formation of immune complexes which are taken up at enhanced rate by macrophages, leading to foam cell formation. APS is characterized by repeated venous and arterial thromboembolic phenomena, recurrent fetal loss and thrombocytopenia, associated with the presence of antibodies to negatively charged phospholipids (aPL) (i.e. cardiolipin, phosphatidylserine). Phospholipids bear structural resemblance to LDL, and several studies have indeed proved that aPL display cross-reactivity with anti-Ox-LDL antibodies. In this study we assessed the capacity of oxidized and native forms of LDL to aggravate the clinical picture of experimentally induced APS in naive mice. Mice were actively immunized intradermally with anticardiolipin antibodies and developed a clinical picture resembling APS in humans. Subsequently, the mice were infused with either Ox-LDL, native LDL or PBS, and similar regimens were applied to controls. APS mice infused with Ox-LDL were found to exhibit a significantly more severe form of the disease in comparison with native LDL- and PBS-infused mice, expressed by lower platelet counts (261,000/mm3, 535,000/mm3 and 455,000/mm3, respectively), longer activated partial thromboplastin time (aPTT) (99 +/- 12 s, 63 +/- 8 s and 74 +/- 8 s, respectively) and higher fetal resorption rates (72.7%, 34.4% and 32.6%, respectively). The results of this study show that Ox-LDL, compared with native LDL, aggravates the clinical manifestations of experimental APS and suggest that cross-reactivity of Ox-LDL with phospholipids may provide a pathogenic explanation for this effect.

Animals↗
PubMed1997

Immunologic characterization and functional properties of murine antibodies raised against deleted mutants of human beta 2-glycoprotein I.

beta 2-Glycoprotein I (beta 2GPI) is a 50 kDa molecule proposed as a principal target of 'autoimmune' antiphospholipid antibodies (aPL). We have used deleted mutants (DM) representing different domains of beta 2GPI (I-IV, IV-V and V) for immunization of naive mice and studied the characteristics of the respective murine IgG preparations in comparison with affinity-purified IgG from two patients with primary antiphospholipid syndrome. Immunization with beta 2GPI and with the DM produced anti-beta 2GPI antibodies, part of which reacted with negatively charged phospholipids (PL), whereas reactivity with cardiolipin was evident only in the IgG from mice immunized with beta 2GPI. These results are consistent with the presumption that aPL are induced following the in vivo association of beta 2GPI (used for immunization) with resident negatively charged PL. Accordingly, DM which either lack the PL binding site or aPL attachment locus did not elicit, upon immunization, antibodies reactive with PL. Further, murine anti-beta 2GPI IgG and human 'autoimmune' aPL were similar, albeit not identical, in terms of DM requirement for PL binding and charge dependency. Murine antibodies and human aPL, regardless of their binding characteristics, were found to bind significantly to platelets upon their activation with thrombin and to promote platelet activation. The results of the current study emphasize the dissimilarities between human 'autoimmune' aPL and murine anti-beta 2GPI. Thus, anti-beta 2GPI antibodies to different DM as well as human aPL are capable of binding and activating human platelets provided beta 2GPI is present.

Animals↗
PubMed1997

Rural mental health leaders' perceptions of stigma and community issues.

This paper provides a description of the attitudes of rural leaders toward mental health issues using data collected in two rural counties (one in Virginia and one in North Carolina). Study participants (N = 63) are individuals identified as leaders making a significant positive contribution to mental health issues in each county. While the counties were matched on a number of demographic characteristics, the counties had one difference believed important: one had a county mental health center located within the county boundary while the other had no in-county mental health center. The study found that rural leaders believed that other community members held attitudes toward mentally ill persons that were more discriminatory than their own. In addition, rural leaders expressed that mental health was a more important concern to them than it was to the community as a whole. Finally, the importance placed on issues of importance to the community and the resulting issue of priority of relevance varied in response to the occupation of respondents. The study presents an approach to understanding how occupational structures affect community issue priorities among rural leaders.

Attitude to Health↗
PubMed1997

New methods of treatment in an experimental murine model of systemic lupus erythematosus induced by idiotypic manipulation.

In this article we have presented our experiences and those of others with various experimental and novel treatments in an experimental model of murine SLE, induced by immunisation with pathogenic anti-DNA antibody (fig 4). Many of the treatments (summarised in the table) were highly effective in ameliorating clinical, serological, and histological manifestations of the disease. According to our results, it seems that hormonal treatments--such as testosterone metabolites, anti-oestrogens, or bromocriptine--as well as immunomodulation with IVIG or anti-CD4 antibodies, hold the most promising potential for application in lupus patients. We believe, therefore, that these types of treatment should receive high priority in human trials. It should be emphasised, however, that the timing of treatment may be critical, since several treatments were effective when used before or during the induction of the disease. This limitation may pose difficulty for human application, since the aetiology of SLE is still obscure and is probably multifactorial38; therefore it is not yet possible to identify patients at risk of developing SLE. Nevertheless, those treatments which proved to be effective might be used early in the course of the disease in lupus patients and hence influence the outcome of the disease, or may even induce partial or complete remission.

Animals↗
PubMed1997

Atherosclerosis in LDL-receptor knockout mice is accelerated by immunization with anticardiolipin antibodies.

Atherosclerosis is a process initiated by accumulation of macrophages in distinct areas of endothelial cell damage and uptake of large amounts of lipids. Recently, it has been shown that the immune system plays an active part in the progression of the atherosclerotic plaque although its precise role has not yet been elucidated. Anticardiolipin antibodies (aCL) are generally found in the sera of patients with the antiphospholipid syndrome (APS) and are associated with a prothrombotic state. Several authors have demonstrated that aCL can activate platelets and endothelial cells as well as increase oxidized low density lipoprotein (LDL) uptake by macrophages. In the present study we sought to assess the effect of immunization with aCL (Ab1, leading to the production of mouse aCL-Ab3) on the progression of atherosclerosis. Two groups of 8-weeks old female LDL-receptor knockout mice (n = 13 per group) were immunized with IgG purified from the serum of an APS patient or with normal human IgG, respectively. The aCL immunized mice developed high titres of 'self' aCL (detected using the standard aCL ELISA) as compared with the normal human IgG immunized mice, whereas no differences were noted between both study groups with respect to the serum lipid levels. The extent of fatty streak formation was significantly higher in the aCL immunized mice in comparison with the human IgG injected mice (mean aortic lesion size of 5308 +/- 471 microns2 vs 1027 +/- 184 microns2, respectively, P < 0.01). The immunohistochemical analysis of the atherosclerotic plaques from both mouse groups did not display differences in cellular composition. The results of the study show that mouse aCL induced by immunization with human aCL from an APS patient enhance atherogenesis in LDL-RKO mice and imply that these antibodies may play a role in atherosclerosis development in patients with the APS.

Animals↗
PubMed1996

Cloning and functional expression of glycosyltransferases from parasitic protozoans by heterologous complementation in yeast: the dolichol phosphate mannose synthase from Trypanosoma brucei brucei.

The gene for the enzyme dolichol phosphate mannose (Dol-P-Man) synthase from the parasitic protozoan Trypanosoma brucei brucei (T. brucei) was cloned by screening a T. brucei cDNA library and then sequenced. The library was constructed in a yeast expression vector and the positive clone was identified by complementation of a temperature-sensitive defect in the yeast strain DPM 1-6 [Orlean, Albright and Robbins (1988) J. Biol. Chem. 263, 17499-17507]. The insert of this clone displayed an open reading frame of 801 nucleotides coding for a putative protein of 267 amino acids. The deduced protein sequence showed an identity of 49% and a similarity of 69% with the published yeast sequence. Additional features of the T. brucei sequence are the presence of a putative signal sequence, a C-terminal transmembrane domain, a consensus sequence for phosphorylation by cAMP-dependent protein kinase and a stretch of five nucleotides immediately upstream from the putative initiation codon that could function as a prokaryotic ribosome binding site. A consensus sequence for dolichol binding (FI/VXF/YXXIPFXF/Y) found in the yeast protein could not be detected in the putative transmembrane domain of the T. brucei sequence. Biochemical characterization of the recombinant protein showed that it is functionally expressed in the yeast strain DPM 1-6 and Escherichia coli. In both constructs Dol-P-Man synthesis was shown in a cell-free system. Synthesis was stimulated by exogenous dolichol phosphate and inhibited by amphomycin. These results confirm that we have cloned the T. brucei Dol-P-Man synthase by heterologous complementation in yeast, an approach that might be applicable for other glycosyltransferases from various sources.

Amino Acid Sequence↗
PubMed1996

HLA DRB1*DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis.

A possible causal association between infective dermatitis and HTLV-I infection was reported in 1990 and confirmed in 1992. We now report familial infective dermatitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in the Dermatology Unit at the University Hospital of the West Indies (U.H.W.I.) in Jamaica. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major histocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB1*DQB1* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune response to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I-seropositive younger son requires close clinical follow-up.

Adult↗
PubMed1996

The pathogenic role of anti-phosphatidylserine antibodies: active immunization with the antibodies leads to the induction of antiphospholipid syndrome.

Primary antiphospholipid syndrome (pAPS) can be experimentally induced in mice by immunization with anti-cardiolipin (aCL) antibodies (Abs). Recently, we have pointed to the pathogenic role of antiphosphatidylserine (aPS) Abs by inducing an experimental model of pAPS in naive mice following passive transfer of human aPS to the tail vein of ICR mice. The aim of the present study was to induce experimental pAPS in mice following active immunization with aPS. Mice were immunized with IgG and IgM aPS, purified from two patients with pAPS. The sera of the mice were examined for the presence of different antiphospholipid Abs, and the beta 2 GPI dependency of aPS, using an enzyme-linked immunosorbent assay (ELISA). Inhibition ELISA studies, with silica beads coated with phospholipids, were used to detect cross-reactivity of aPS or aCL to other phospholipids. The mice were also tested for the presence of thrombocytopenia, prolonged activated partial thromboplastin time (APTT), and the percentage of fetal resorptions. The purified IgG aPS but not IgM aPS had a strong lupus anticoagulant activity. Both IgG and IgM aPS were beta 2 GPI dependent and did not bind PS in the absence of the glycoprotein. The mice immunized with IgG aPS, but not IgM aPS, developed high titers of mouse aPS. The mice generated polyspecific Abs, cross-reacting with aCL and aPS, as well as individual aPS or aCL Abs. Only the mice immunized with IgG aPS developed clinical parameters of pAPS: prolonged APTT, thrombocytopenia, and an increased fetal resorption rate. In conclusion, active immunization with IgG, but not IgM, aPS induces experimental pAPS in naive mice, thus pointing to the participation of aPS in the idiotypic network.

Adult↗
PubMed1996

The diverse pathogenic potential of anti-DNA antibodies from various sources to induce experimental systemic lupus erythematosus.

It has previously been shown that immunization with pathogenic anti-DNA idiotypes (Ids; e.g. 16/6 Id) leads to the induction of experimental system lupus erythematosus (SLF) in naive mice. The disease is characterized by serological (e.g. anti-double-strand DNA), clinical (elevation of erythrocyte sedimentation rate, leukopenia and proteinuria) and histological (immune complex deposition in kidneys) parameters. To determine whether the 16/6 Id carrying anti-DNA antibodies has unique pathogenic ability, in the current study we have employed diverse sources of anti-DNA antibodies to induce experimental SLE. An IgM anti-DNA antibody lacking the 16/6 Id was able to induce the production of the serological markers of experimental SLE, but not the clinico-histological findings. Furthermore, an IgA anti-DNA (16/6 Id derived from the serum of a patient with celiac disease was very effective in inducing the whole presentation of experimental SLE. Other anti-DNA antibodies failed to induce the autoimmune condition. Combined with our previous experience, the current study points to the diverse potential of various anti-DNA antibodies to induce SLE. The 16/6 Id is only one of a list of the potent pathogenic anti-DNA Ids. These facts may explain in part the diversity of clinical presentations of SLE, including asymptomatic subjects who carry high serum titers of anti-DNA antibodies.

Animals↗
PubMed1996

Treatment of systemic lupus erythematosus and antiphospholipid syndrome: from experimental models to patients' bedside.

Animal models are of great value in the evaluation of novel and experimental treatments that cannot be tested directly on patients. In this article, we summarize the spectrum of murine models for systemic lupus erythematosus and antiphospholipid syndrome, focusing on animal models based on idiotypic immunization. Several therapeutic modalities that have been tested in those models had promising potential for application in human patients.

Animals↗
PubMed1996

Rural and urban differences in continuity of care after state hospital discharge.

In a study to determine differences in continuity of care for state hospital patients discharged to rural and urban areas, all community mental health centers in Virginia were asked to complete a brief questionnaire about each patient discharged to the centers in fiscal year 1992. Discharges to rural centers had significantly higher levels of continuity of care on four of five dimensions of continuity. The authors conjecture that rural centers' lower staff ratios and decreased role boundaries may make them better able than urban centers to carry out the diverse tasks needed to help discharged patients resume community living.

Adult↗
PubMed1996

Libman-Sacks endocarditis in the antiphospholipid syndrome: immunopathologic findings in deformed heart valves.

OBJECTIVE: To examine the potential immunologic mechanism and involvement of antiphospholipid antibodies in the pathogenesis of heart valve lesions in patients with the antiphospholipid syndrome (APS). METHODS: Immunoperoxidase and immunofluorescence staining methods were used to evaluate 13 heart valve specimens derived from eight patients with the APS, either primary or secondary to systemic lupus erythematosus. Primary antibodies to human immunoglobulins, complement components, serum albumin and a monoclonal anti-idiotypic antibody to human anticardiolipin antibodies (aCL) were employed. Various tissue specimens from a patient with the APS as well as deformed and normal valves from subjects without the APS were used as controls. RESULTS: Linear subendothelial deposition consisting of immunoglobulins with complement components but not of a non-specific serum protein was found in deformed valves from patients with the APS. None of the control valves or tissues disclosed similar deposition. The same pattern and location of staining was obtained by the anti-idiotypic antibody to aCL. A significant amount of IgG immunoglobulins that bound to cardiolipin was eluted from a valve of a patient with secondary APS. CONCLUSION: Deposits of immunoglobulins including aCL, and of complement components, are common in affected valves of patients with primary and secondary APS. Such deposits may be involved in the pathogenesis of valvular lesions.

Adult↗
PubMed1996

Modulation of experimental systemic lupus erythematosus with linomide.

OBJECTIVE: The objective of this study was to assess the beneficial effects of an early administration of low dose linomide, a new immunomodulator, in an animal model of experimental systemic lupus erythematosus (SLE). METHODS: Experimental SLE was induced in naive BALB/c mice, by immunization with anti-DNA mAb (MIV-7). Control Mice immunized with irrelevant human IgM served as controls. The immunized mice were treated with linomide (0.1 mg/ml in the drinking water), four weeks prior to the first immunization, at an early stage of the disease induction (one month after boost injection), or at a later stage (3 months following boost immunization). The treatment duration was 3 months in all schedules. The follow-up studies continued for 8 weeks after discontinuation of the treatment. The presence in the serum of autoantibodies against ssDNA, dsDNA histones, phospholipids and an irrelevant autoantigen-pyruvate dehydrogenase, was determined by enzyme-linked immunosorbent assay (ELISA). The clinical parameters assessed included erythrocyte sedimentation rate, peripheral blood cell counts and proteinuria. RESULTS: There was a 50-64% decrease in autoantibody levels in the sera of mice immunized with anti-DNA (MIV-7) mAb at the early stage of experimental SLE in mice which received linomide for a period of 3 months. No effect of linomide was noted in mice which received the drug during the later stages of experimental SLE when the disease was fully developed. Linomide had a preventive effect on the induction of experimental SLE in naive mice, when the treatment was initiated before the induction of the disease. This effect was abolished following cessation of the treatment. CONCLUSIONS: Linomide proved to be effective at the early stages of induction of the experimental SLE. However, the autoantibody levels rose following discontinuation of the therapy.

Adjuvants, Immunologic↗
PubMed1996

Immunomodulation of experimental APS: lessons from murine models.

During the last few years several murine models for APS have been described. These include spontaneous occurring disease, or APS induced by immunization with pathogenic autoantibodies. Employing those models, several treatment modalities, in different stages of the disease, were studied. Treatments which showed promising potential for application in patients with APS include immunomodulation with specific anti-idiotypic or anti-CD4 antibodies, treatment with IL-3, high-dose intravenous immunoglobulins, ciprofloxacin or bromocriptine, as well as antithrombotic and anticoagulant treatments using aspirin and/or low-molecular-weight heparin. Bone-marrow transplantation was also found to improve clinical and serological manifestations of the disease. These studies might promote the handling of controlled clinical trials assessing their efficacy in APS patients.

Animals↗