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Biomedical subjects

M Blank

Publications and source records attributed to M Blank.

At least 91 records · Page 5Linked to original sources
PubMed1999

Inhibition of diabetes in NOD mice by idiotypic induction of SLE.

The present study was undertaken to investigate whether active induction of systemic lupus erythematosus (SLE) in non-obese diabetic (NOD) mice could affect their development of insulin-dependent diabetes mellitus (IDDM). NOD mice were immunized with a human IgM mAb carrying the 16/6 idiotype (MIV-7) or with control human IgM. The mice were bled monthly and tested for SLE-associated autoantibodies in the serum and for the presence of leukopenia, thrombocytopenia, proteinuria and immunoglobulin deposits in the kidneys. The development of diabetes was determined by a blood glucose level exceeding 15 mM on two consecutive weekly determinations and by the presence of insulitis in the pancreas. The NOD mice immunized with MIV-7 developed high and persistent levels of autoantibodies, including anti-DNA, anti-histones and anti-cardiolipin, untreated mice and those immunized with normal human IgM did not produce these autoantibodies. The MIV-7-immunized mice also manifested an elevated erythrocyte sedimentation rate, leukopenia, thrombocytopenia and significant proteinuria, as well as deposits of Ig in their kidney glomeruli. Thus, NOD mice immunized with MIV-7 developed both autoantibodies and clinical features of SLE. The MIV-7-treated mice, however, showed a significantly lower incidence of IDDM (25%vs. 90%, P<0.003), accompanied by amelioration of the insulitis. The present study indicates that the induction of SLE by idiotypic immunization can protect NOD mice from developing IDDM, pointing to the importance of immune dysregulation in shift from one autoimmune disease to another.

Animals↗
PubMed1999

Care provision and community adjustment of rural consumers with serious mental illness.

The purpose of this study was to examine the predictors of successful community living in a sample of rural individuals with severe and persistent mental illness (N = 40). Multimeasure/multisource indicators of consumer status, care provider attitudes, and care provider support provision were employed to predict community adjustment as measured by satisfaction with quality of life. Separate semistructured interviews were conducted with consumers, their case manager, and a family member or adult home provider. Reliability of the measures was established within acceptable limits. The multiple regression analyses showed that life stress and informal care-provider attitudes satisfied the inclusion criteria. R2 was .61 (F[2, 37] = 29.10, p < .001). Quality-of-life satisfaction was predicted primarily by consumer status characteristics.

Adult↗
PubMed1999

Predicting whether patients receive continuity of care after discharge from state hospitals: policy implications.

This article reports the results of a comprehensive study of predictors of factors influencing continuity of care for individuals discharged from state hospitals to communities. Continuity of care is defined and the predisposing, enabling and need factors are examined using a statewide database. The conceptual model is based on community support system principles, and it drives the research. The findings will influence policy, which will then affect community support system principles. Logistic regression analysis is employed as statistical analysis that lends itself to graphical form. Implications for policy and future research are presented.

Aftercare↗
PubMed1999

Chromosomal promoter replacement in Saccharomyces cerevisiae: construction of conditional lethal strains for the cloning of glycosyltransferases from various organisms.

Heterologous complementation in yeast has been a successful tool for cloning and characterisation of genes from various organisms. Therefore we constructed conditionally lethal Saccharomyces cerevisiae strains by replacing the endogenous promoter from the genes of interest (glycosyltransferases) by the stringently regulated GAL1-promoter, by a technique called chromosomal promoter replacement. Such yeast strains were constructed for the genes Alg 1, Alg7, Sec59, Wbp1 involved in N-Glycosylation, the genes Gpi2, Gpi3/Spt14, Gaal, Pis1, involved in GPI-anchor biosynthesis and Dpm involved in both pathways. All strains show the expected conditionally lethal phenotype on glucose-containing medium when expression of the respective gene is turned off.

Chromosomes, Fungal↗
PubMed1999

Anti-idiotype immunomodulation of experimental anti-phospholipid syndrome via effect on Th1/Th2 expression.

Mice with experimental anti-phospholipid syndrome (APS), induced by active immunization with a human anti-cardiolipin MoAb (H-3), were treated with mouse anti-idiotypic MoAb (anti-H3, named S2.9) and with an irrelevant anti-idiotype. The immunized mice produced high titres of mouse anti-cardiolipin antibodies along with clinical manifestations of experimental APS: prolonged activated partial thromboplastin time (aPTT), thrombocytopenia and high rate of fetal loss. Treatment with the specific anti-Id (S2.9) as a whole molecule or F(ab)2 fraction, resulted in a decrease in serum levels of the anti-cardiolipin antibodies, rise in platelet count, shortened aPTT and reduced rate of fetal loss. The anti-Id effect was associated with a rise in the number of IL-2 and interferon-gamma (IFN-gamma)-secreting cells (Th1) and reduction in IL-4- and IL-6-secreting cells (Th2). The beneficial effect of the anti-Id treatment in mice with experimental APS induced by active immunization with an idiotype further supports the idiotypic aetiology of experimental APS and points to the role of Th1 cytokines in suppression of its manifestations.

Abortion, Habitual↗
PubMed1999

Dystrophin and beta-dystroglycan in photoreceptor terminals from normal and mdx3Cv mouse retinae.

Mutations in the dystrophin gene cause muscular dystrophy as well as cognitive impairments, including an abnormal dark-adapted electroretinogram. To investigate the basis for the ocular phenotype, we analysed dystrophin and the dystrophin-associated protein beta-dystroglycan in retinae from mdx3Cv mice. This strain has a mutation in the dystrophin gene and abnormalities in the electroretinogram which are similar to those of muscular dystrophy patients. Despite an overall reduction of all dystrophin isoforms and of beta-dystroglycan in retinal tissue from mutant mice, we observed no apparent change in the histotypic layering of the retina, or in the ultrastructure of several specific cell types, including rods and cones. In retinae from wild type and mdx3Cv mice, dystrophin and beta-dystroglycan were concentrated in small extensions of rod and cone photoreceptor terminals protruding into the outer plexiform layer. Beta-dystroglycan but not dystrophin was also clustered around the inner limiting membrane and the capillary basal laminae. While the labelling pattern around the basal laminae was not altered in the mutant mice, we found that the area as well as the intensity of the dystrophin and beta-dystroglycan immunoreactivity associated with the terminals of rod photoreceptors were severely reduced. The same parameters were much less affected in cone terminals. These results show, that dystrophin and beta-dystroglycan are differentially distributed in the retina, and that a severe reduction of dystrophin has no gross effect on retinal structure, but could influence intraretinal signalling at the level of the photoreceptor terminals. Moreover, the mutation in mdx3Cv mice has a selective effect on rods, providing an explanation for the altered electroretinogram.

Animals↗
PubMed1999

Characteristics and pathogenic role of anti-beta2-glycoprotein I single-chain Fv domains: induction of experimental antiphospholipid syndrome.

Antiphospholipid syndrome is characterized by the presence of high titers of anti-beta(2)-glycoprotein I (beta(2)GPI) antibodies, lupus anticoagulant associated with thromboembolic phenomena, thrombocytopenia and recurrent fetal loss. Single-chain Fv (scFv) were prepared from four anti-beta(2)GPI mAb, CAM, CAL, CAR and 2C4C2, and one anti-ssDNA. All five scFv showed the same antigen binding properties as the original mAb. Replacement of the pathogenic CAM V(H) domain with the non-pathogenic CAL V(H) or anti-ssDNA V(H) decreased the binding affinity of the scFv to beta(2)GPI and completely abrogated the anticoagulant activity. Exchanging the CAM V(H) with anti-DNA V(H) resulted in a shift from anti-beta(2)GPI to anti-ssDNA binding of the scFv. Replacement of the CAM V(L) with CAL V(L) did not affect the binding and activity. BALB/c mice were immunized with the anti-beta(2)GPI scFv, and the scFv resulting from the substitution of the heavy (H) and light (L) chains. The mice which were immunized with CAM, 2C4C2 and CAR scFv developed clinical manifestations of experimental anti-phospholipid syndrome. Elevated titers of mouse anti-cardiolipin (aCL), anti-beta(2)GPI, associated with lupus anticoagulant activity, thrombocytopenia, prolonged activated partial thromboplastin time and a high percentage of fetal resorptions were detected, in the CAM scFv group and in the scFv composed of CAM V(H) groups. High titers of aCL, anti-beta(2)GPI, anti-ss/dsDNA and anti-histone associated with lupus findings were observed in the sera of the 2C4C2 scFv-immunized mice. Immunization with CAL scFv did not lead to any clinical findings. The current study shows that scFv of pathogenic antibodies are capable of inducing the same clinical manifestations as the whole antibody molecule upon active immunization. Replacement of H/L chains point to the importance of the V(H) domains in the pathogenic potential of anti-beta(2)GPI.

Animals↗
PubMed1999

Mental disorders and help seeking in a rural impoverished population.

OBJECTIVE: This study examined the impact of an in-home screening and educational intervention on help seeking among rural impoverished individuals with untreated mental disorders. The effect of including a significant other in the intervention and reasons for not seeking help were explored. METHOD: The sample was randomly selected from households in nine rural counties in Virginia. The short form of the CIDI was used to screen 646 adult residents. Respondents who screened positive were randomly assigned to one of three groups: 1) no intervention, 2) an educational intervention, or 3) the educational intervention with a significant other. A list of local sources of health and mental health care was distributed. At one-month post interview, respondents were telephoned to inquire about help seeking. RESULTS: Almost one-third (32.4%) of these respondents screened positive for at least one disorder. Five hundred and sixty-six (87.6%) were successfully followed up, and thirty-three of the 566 (5.8%) reported that they had sought professional help since the interview. Eighty-four subjects who screened positive and received the educational intervention reported in follow up that they had discussed the interview with a friend or family member, but only eleven (13.1%) received encouragement to seek treatment. The predominant reason endorsed for not seeking help was "felt there was no need," even among respondents who were informed that they had a disorder. CONCLUSIONS: A significant proportion of this rural impoverished sample screened positive for a mental disorder. Few individuals sought professional help and significant others did not encourage them to seek treatment. The implication of these results for investigators and service providers is that motivating individuals to seek mental health services is a complex process; more attention must be devoted to the development of culturally relevant methods for facilitating help seeking.

Adult↗
PubMed1999

Antibodies to the cytoplasm, cell membrane and nuclear membrane of malignant neoplasms in pooled normal human polyspecific immunoglobulin G.

IVIg is a preparation of normal polyspecific IgG obtained from pooled plasma of a large number of healthy donors. IVIg treatment of patients with chronic lymphocytic leukemia induced a reduction in the total number of lymphocytes in the peripheral blood. Regression of Kaposi's sarcoma was also noted in an HIV patient treated with IVIg. The aim of this study was to determine whether F(ab')2 prepared from IVIg binds to cellular structures of different tumor tissues. Biotinylated F(ab')2 was prepared from 3 different preparations of IVIg and from affinity purified IgG from a patient with multiple myeloma. Direct immunohistochemistry using a streptavidin peroxidase staining method was performed on biopsy samples of 18 different tumor tissues. Positive staining of the cytoplasm, cell membrane and nuclear membrane of several types of malignant tumors by F(ab')2 from IVIg was immunohistochemically demonstrated. Nuclear staining of tumor cells by IVIg was rare. IVIg bound to different tumors of epithelial origin, especially colon carcinoma, breast carcinoma and squamous cell carcinoma of the lung. Malignant tumors of mesenchymal origin such as leiomyosarcoma have also demonstrated positive staining by IVIg. IVIg contains antibodies to the cytoplasm, nuclear membrane and cell membrane of different malignant tumors especially of epithelial origin. This binding might provide a basis for the assumption that IVIg treatment of cancer patients may induce antibody dependent cell mediated cytotoxicity response against tumors, and implies that it can be potentially beneficial as adjuvant treatment of malignant diseases.

Antibody Affinity↗
PubMed1999

Functional MR imaging of the motor cortex in healthy volunteers and patients with brain tumours: qualitative and quantitative results.

The purpose of this study was to compare functional magnetic resonance (MR) imaging of the motor cortex in healthy volunteers and patients with brain tumours. Functional MR imaging was performed in 14 healthy volunteers and 14 patients with tumours in or near the primary motor cortex with groups being matched for age, sex, and handedness. Functional images were acquired during motion of the right and left hand. Time courses of signal intensity within the contralateral, ipsilateral, and supplementary motor cortex as well as z-maps were calculated, their quality being assessed visually. Mean signal increase between activation and rest were evaluated within the contralateral, ipsilateral, and supplementary motor cortex, the activated area in those regions of interest was measured using z-maps. The quality of functional MR experiments was generally lower in patients than in volunteers. The quantitative results showed a trend towards increased ipsilateral activation in volunteers during left hand compared to right hand motion and in patients during motion of the affected compared to the non-affected hand. Considering quantitative and qualitative results, significantly increased ipsilateral activation was found in patients compared to healthy volunteers. In conclusion, functional MR imaging quality was significantly reduced in patient studies compared to healthy volunteers, even if influences of age, sex, and handedness were excluded. Increased ipsilateral activation was found in patients with brain tumours which can be interpreted by an improved connectivity between both hemispheres.

Adult↗
PubMed1999

A comparison of autoantibody production in asymptomatic and symptomatic women with silicone breast implants.

OBJECTIVE: We previously reported an increased preponderance of a broad range of autoantibodies in symptomatic women with silicone breast implants. The objective of this study was to investigate the frequency of autoantibody production in asymptomatic compared to symptomatic women with silicone implants. One hundred twenty-two asymptomatic women were recruited to our center for autoantibody detection through an advocate dealing with breast implant liabilities. METHODS: Autoantibody detection in 86 asymptomatic women was done blindly on a panel of 15 different antibodies (dsDNA, ssDNA, histones, SSA/Ro, SSB/La, RNP, cardiolipin, phosphatidylserine, pyruvate dehydrogenase, Scl-70, NC-1, silicone, collagen I, II, and IV). Clinical variables, specific questioning about related silicone implant symptoms, and a rheumatological examination were performed blindly by a certified rheumatologist. The findings were recorded and at a later stage compared with positive autoantibody detection. The normal control group consisted of age and sex matched Israeli women without known autoimmune disease. In the positive control group were symptomatic women previously tested for antibody production. The autoantibodies were assessed by ELISA. Values from individual patients were considered positive only when greater than 3 standard deviations above the control mean. RESULTS: The mean ages of 86 asymptomatic and 116 symptomatic women were 46.2+/-11.2 and 45.7+/-8.3 years, respectively. Breast implants were in place for a mean period of 8.2+/-5.0 years in the asymptomatic group and 15.0+/-5.6 years in the symptomatic group. The incidence of increased titers of autoantibodies ranged from 2 to 13% for 13 different autoantibodies among asymptomatic women. Among symptomatic women, 20% harbored 4 autoantibodies and 8% had 6 autoantibodies. The most common antibodies in the asymptomatic group were: dsDNA 8%; ssDNA 9%; SSB/La 13%; silicone 9%; collagen II 9%. No autoantibodies were found for NC-1, Scl-70, or RNP. Among the symptomatic group, the most common autoantibodies were histone ribosomal phosphate, SSA, SSB, Scl-70, cardiolipin, phosphatidylserine, GM2-ganglioside, and NC-1. Comparison of autoantibody incidence in asymptomatic and symptomatic women with silicone breast implants revealed an increased incidence of anti-SSB/La and anticollagen II in both groups. Polyclonality was more prominent in the group of symptomatic women with silicone breast implants, but also evident in 3 asymptomatic women. CONCLUSION: The mean duration of implant in the asymptomatic group was significantly less compared with the symptomatic group (p<0.01). The development of autoantibodies may be related to implant duration.

Adult↗
PubMed1999

A mouse model for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) occurs in 1% to 3% of patients receiving heparin and results from the development of antibodies that recognize heparin-platelet factor 4 (H-PF4) complexes that form on the surface of activated platelets and on the vascular endothelium. With the aim of studying the pathogenic importance of these anti-H-PF4 antibodies in vivo, we attempted to create an animal model of HIT. Such a model was produced by immunization of naive mice with affinity-purified IgG anti-H-PF4 antibodies from two patients with HIT. The immunized mice developed specific antibodies (anti-idiotypic) against the human anti-H-PF4 antibodies and 2 months later, anti-anti-idiotypic antibodies appeared, which functionally resembled the human HIT antibody. Indeed, when the animals bearing anti-anti-idiotypic antibodies were injected with heparin for 4 days, a significant decrease in their platelet counts was observed; however, heparin treatment was not associated with thrombosis in any of the immunized mice. Similar to the observation in HIT patients, injections of equivalent doses of low-molecular-weight (LMW) heparin to the immunized animals did not induce thrombocytopenia. The results of this study support the importance of anti-H-PF4 antibodies in the pathogenesis of HIT. The mouse HIT model may provide a convenient system for studies on the immunoregulation of anti-H-PF4 expression and for evaluation of potential therapeutic modalities.

Animals↗
PubMed1998

Application of magnetic field-induced heat shock protein 70 for presurgical cytoprotection.

To develop an alternative to hyperthermia for the induction of hsp70 for presurgical cytoprotection, we investigated the optimal exposure conditions for magnetic field induction of hsp70. Normal human breast cells (HTB124) were exposed to 60-Hz magnetic fields and hsp70 levels were measured following three different exposure conditions: continuous exposure up to 3 h, a single 20-min exposure, and a single 20-min exposure followed by repeated 20-min exposures at different field strengths. In cells exposed continuously for 3 h, hsp70 levels peaked (46%) within 20 min and returned to control levels by 2 h. Following a single 20-min exposure, the return of hsp70 levels to control values extended to more than 3 h. When cells underwent a 20-min exposure followed by repeated 20-min exposures (restimulation) with different field strengths, additional increases in hsp70 levels were induced: 31% at 1 h, 41% at 2 h, and 30% at 3 h.

Breast↗
PubMed1998

Oral tolerance to low dose beta 2-glycoprotein I: immunomodulation of experimental antiphospholipid syndrome.

Oral tolerance was induced in BALB/c mice by feeding low dose beta2-glycoprotein I (beta2GPI). The beta2GPI-fed mice did not develop serologic and clinical markers of experimental antiphospholipid syndrome (APS) upon immunization with the autoantigen. The treated group was characterized by low titers of serum anti-beta2GPI and anticardiolipin Abs in the serum, lack of fetal resorptions, low incidence of thrombocytopenia, and normal aPTT (activated partial thromboplastin time) values. Beta2GPI given orally before priming with beta2GPI resulted in complete prevention of experimental APS development; beta2GPI given at an early stage of the disease reduced clinical manifestations. However, administration of beta2GPI 70 days postimmunization had a less significant effect on disease expression. Tolerized mice exhibited a diminished T lymphocyte proliferation response to beta2GPI in comparison with beta2GPI-immunized mice fed with OVA. When nontolerant beta2GPI-primed T lymphocytes were mixed with T lymphocytes derived from tolerized mice, a significant inhibition of proliferation upon exposure to beta2GPI was observed. The induction of suppression was beta2GPI specific and driven, as well as TGF-beta mediated. The beta2GPI-specific response of T lymphocytes from the beta2GPI-fed mice was reversed by anti-TGF-beta Abs. The tolerance was adoptively transferred by CD8+ T cells from the tolerized mice into naive mice. Those CD8+ cells were MHC class I restricted, found to secrete TGF-beta, and had no cytolytic activity. Oral administration of beta2GPI suppressed priming of CTLs in the recipient mice. In sum, beta2GPI-induced oral tolerance has an immunomodulatory effect in experimental APS, demonstrating the importance of beta2GPI in the pathogenesis of the disease.

Administration, Oral↗
PubMed1998

Induction of early atherosclerosis in LDL-receptor-deficient mice immunized with beta2-glycoprotein I.

BACKGROUND: Immunization with beta2-glycoprotein I (beta2GPI), the probable target of autoimmune anticardiolipin antibodies, results in experimental antiphospholipid syndrome in different mouse strains. The present study was undertaken to evaluate the effect of beta2GPI immunization on the progression of atherosclerosis. METHODS AND RESULTS: In the first experiment, 3 groups of LDL receptor-deficient (LDL-RD) mice (n=15 per group) were immunized with either beta2GPI or ovalbumin or were not immunized and were fed a chow diet for 12 weeks. In a second experiment, 3 groups of LDL-RD mice (n=10 per group) were immunized similarly and fed an atherogenic diet for 6 weeks. All beta2GPI-immunized mice developed high titers of anti-beta2GPI antibodies as well as a specific lymph node proliferation to beta2GPI. The average cholesterol levels did not differ between the mice fed similar diets, regardless of the immunization protocol. Atherosclerosis was enhanced in the beta2GPI-immunized mice (mean aortic lesion, 26 000+/-5700 microm2) in comparison with their ovalbumin-immunized (mean, 3000+/-1099 microm2; P<0.01) and nonimmunized (mean, 2250+/-700 microm2; P<0.01) littermates. The average lesion size in the beta2GPI-immunized mice fed an atherogenic diet (mean, 98 000+/-8305 microm2) was larger than the ovalbumin-immunized mice (mean, 81 250+/-12 933 microm2; P=NS) or the nonimmunized controls (mean, 75 625+/-7281 microm2; P=NS). The atherosclerotic plaques in the beta2GPI-immunized mice appeared to be more mature, and denser infiltration of CD4 lymphocytes was present in the subendothelium of the aortic sinuses from this group of mice. CONCLUSIONS: The results of the present study provide the first direct evidence for the proatherogenic effect of ss2GPI immunization and establish a new model for immune-mediated atherosclerosis.

Animals↗
PubMed1998

Magnetic field activation of protein-DNA binding.

The mechanisms involved in sensing, signaling, and coordinating changes resulting from magnetic field-induced stress show substantial similarities to those of heat shock, e.g., magnetic field-induced heat shock 70 gene (HSP70) expression involves heat shock factor (HSF) activation and heat shock element binding. However, an additional requirement for transactivation of HSP70 expression by magnetic fields is the binding of Myc protein, indicating that additional elements and/or pathways are involved in the induction of HSP70 expression by magnetic fields. To investigate the possible participation of additional genetic elements in magnetic field-induced HSP70 expression, we examined both magnetic field exposure and heat shock on protein-DNA binding of the transcription factors HSF, AP-1, AP-2, and SP-1 in four human cell lines. The binding sites for these transcription factors are present in the HSP70 promoter. AP-1 binding activity, normally not increased by heat shock, was increased by magnetic fields; heat shock induced an increase only in HSF binding. Although intersecting and converging signaling pathways could account for the multiplicity of elements involved in magnetic field-induced HSP70 transcription, direct interaction of magnetic fields with DNA is also a possible mechanism. Because magnetic fields penetrate the cell, they could well react with conducting electrons present in the stacked bases of the DNA.

Binding, Competitive↗
PubMed1998

Myc-mediated transactivation of HSP70 expression following exposure to magnetic fields.

We investigated c-myc protein-binding sites on the HSP70 promoter as modulators of the induction of HSP70 gene expression in response to magnetic field stimulation (8microT at 60Hz) and whether the presence of c-myc protein potentiates transactivation of HSP70 expression. A 320 base pair region in the HSP70 promoter (+1 to -320) was analyzed. This region contains two c-myc-protein binding sites with consensus sequences located at -230 and -160 nucleotide positions (relative to the transcription initiation site) and overlapping with the region reported for the regulation of HSP70 gene expression by c-myc protein. This promoter region is upstream of other regulatory sequences, including the heat shock element (HSE), AP-2, and serum response element (SRE). Transfectants containing both c-myc protein-binding sites, HSP-MYC A and HSP-MYC B, and exposed to magnetic fields showed a 3.0-fold increase in expression of CAT activity as compared with sham-exposed control transfectants. Transfectants containing one c-myc binding site, HSP-MYC A, and exposed to magnetic fields showed a 2.3-fold increase in CAT expression. Transfectants in which both HSP-MYC A and HSP-MYC B binding sites were deleted showed no magnetic field sensitivity; values were virtually identical with sham-exposed controls. If the c-myc expression vector was not co-transfected with the constructs containing myc-binding sites, there was no difference in the expression of CAT activity between magnetically stimulated and sham-exposed controls, although both responded to heat shock. These data suggest that endogenous elevated levels of myc protein contribute to the induction of HSP70 in response to magnetic field stimulation.

Electromagnetic Fields↗