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Biomedical subjects

R R Singh

Publications and source records attributed to R R Singh.

At least 19 recordsLinked to original sources
PubMed2001

Statistical mechanics of prion diseases.

We present a two-dimensional, lattice based, protein-level statistical mechanical model for prion diseases (e.g., mad cow disease) with concomitant prion protein misfolding and aggregation. Our studies lead us to the hypothesis that the observed broad incubation time distribution in epidemiological data reflect fluctuation dominated growth seeded by a few nanometer scale aggregates, while much narrower incubation time distributions for innoculated lab animals arise from statistical self-averaging. We model "species barriers" to prion infection and assess a related treatment protocol.

Animals↗
PubMed2001

High-energy magnon dispersion and multimagnon continuum in the two-dimensional Heisenberg antiferromagnet.

We use quantum Monte Carlo simulations and numerical analytic continuation to study high-energy spin excitations in the two-dimensional S = 1/2 Heisenberg antiferromagnet at low temperature. We present results for both the transverse (x) and longitudinal (z) dynamic spin structure factors Sx,z(q,omega) at q = (pi,0) and (pi/2, pi/2). Linear spin-wave theory predicts no dispersion on the line connecting these momenta. Our calculations show that in fact the magnon energy at (pi,0) is 10% lower than at (pi/2, pi/2). We also discuss the transverse and longitudinal multimagnon continua and their relevance to neutron scattering experiments.

Journal Article↗
PubMed2001

Treatment with a consensus peptide based on amino acid sequences in autoantibodies prevents T cell activation by autoantigens and delays disease onset in murine lupus.

OBJECTIVE: To test the hypothesis that an artificial peptide, based on an algorithm describing T cell stimulatory sequences from the VH regions of murine IgG antibodies to DNA, is an effective tolerogen in vivo in the (NZB/NZW)F1 (BWF1) mouse model of systemic lupus erythematosus. METHODS: Using proliferative T cell responses to 439 Ig peptides, an algorithm was constructed that describes the amino acid sequences likely to stimulate BWF1 T cells. Stimulatory (pConsensus [pCONS]) or nonstimulatory (pNegative [pNEG]) peptides were synthesized. Groups of 10-week-old (healthy) or 20-week-old (diseased) BWF1 mice received monthly intravenous injections of 1,000 microg of peptide or saline. Ex vivo splenic T cell responses and in vivo clinical effects were measured. RESULTS: Tolerance was induced by pCONS, but not by pNEG, with respect to ex vivo T cell proliferation and T cell help for antibodies to DNA. T cell help for IgG anti-DNA was impaired not only after T cell stimulation by pCONS but also after stimulation by some peptides from nucleosomal and Ro antigens. Treatment with pCONS significantly delayed the onset of nephritis and inhibited increases in the plasma levels of total IgG, IgG antibodies to DNA, nucleosome, cardiolipin, interferon-gamma, and interleukin-4. In contrast, antibody responses to an exogenous antigen were not impaired. Survival was significantly prolonged in both healthy and diseased mice treated with pCONS. CONCLUSION: Induction of immune tolerance in response to treatment with pCONS in autoreactive T cell helper populations is highly effective in delaying the appearance of multiple autoantibodies, cytokine increases, and nephritis in BWF1 mice, and dramatically prolongs survival. A striking effect is the ability of the peptide to tolerize T cell help for anti-DNA that is induced by multiple, structurally unrelated self antigens.

Algorithms↗
PubMed2001

Comparative study between IMRT with NOMOS BEAK and linac-based radiosurgery in the treatment of intracranial lesions.

A comparative study was undertaken to examine intracranial irradiation using intensity-modulation radiation therapy (IMRT) and linear accelerator-based radiosurgery. The IMRT was examined using the Peacock system with a BEAK attachment. A clinical case involving a metastatic brain lesion, treated with 3 radiosurgery isocenters, was planned for IMRT. The radiosurgery was planned using the Leibinger planning system. The IMRT was planned using the CORVUS planning system. The CORVUS planning system uses an inverse planning algorithm, a recent development in radiotherapy. Isodose distributions and dose volume histograms were generated and compared. Analysis of the dosimetry shows that the dose conformity and homogeneity within the target using the RTOG guidelines are superior for IMRT. The advantages of IMRT using inverse planning system include the ease of planning and execution of treatment, especially for cases that involve concave targets that require multiple isocenters using radiosurgery.

Algorithms↗
PubMed2000

Dosimetric study of the narrow beams of 60Co teletherapy unit for stereotactic radiosurgery.

This study explores the possibility of using a telecobalt unit for radiosurgery. A dosimetric study was performed for the narrow beam of Cobalt 60 (60Co) unit with circular radiation fields in diameters of 11, 17, 20, 27, 32, 35, 40, and 44 mm. Percentage depth dose and off-axis ratio were measured with ion chamber and radiographic film. The tissue air ratio values derived from measurements agreed well with the calculated values for all cone sizes and depths, ranging from the depth of maximum ionization of 24 cm in water. A quantitative evaluation of treatment plans with 60Co and 6-MV photon beams was carried out. The penumbra of the narrow beam of 60Co was larger than that of the 6-MV beam by 1.3 mm on average. This difference in penumbra can be attributed to the large source size of 60Co units. The feasibility of using narrow-beam 60Co for stereotactic radiosurgery/radiotherapy is discussed.

Cobalt Radioisotopes↗
PubMed2000

The potential use of peptides and vaccination to treat systemic lupus erythematosus.

Studies in humans and mice with systemic lupus erythematosus (SLE) suggest that the development of autoantibodies and disease is dependent on T helper (Th) cells. This review highlights recent efforts to identify the antigens that activate such autoreactive Th cells. Various laboratories are using different approaches to identify the autoantigenic epitopes, which appear to be derived from diverse sources such as nucleosome core histones, ribonucleoproteins, and immunoglobulin variable regions. Identification of the putative autoantigenic epitopes has raised the possibility of peptide-specific vaccination as therapy for SLE. Indeed, vaccination of prenephritic lupus-susceptible mice with such peptides delays the development of autoantibodies and nephritis, and prolongs survival. Recent data suggest that peptide treatment can also influence established disease in older lupus mice. These studies offer new hope for a similar treatment approach in patients with SLE. Studies have begun to identify T cell epitopes in human disease.

Amino Acid Sequence↗
PubMed1998

Evidence for multiple mechanisms of polyclonal T cell activation in murine lupus.

Individuals with systemic autoantibody-mediated diseases such as lupus have polyclonal T and B cell activation. Yet, autoantibody production is restricted to certain autoantigens. The mechanisms underlying this phenomenon remain unclear. We propose three potential mechanisms by which autoreactive helper T cell responses diversify to become polyclonal, yet are restricted to certain antigens. First, using a model where self-Ig peptides spontaneously activate T cells and modulate disease in lupus mice, we demonstrate that the numbers of autoantibody-augmenting T helper peptides increased across the Ig molecule as mice aged ("intramolecular determinant spreading"). Secondly, a single T cell hybridoma established from a (NZB x NZW)F1 mouse immunized with one self-Ig peptide recognized several Ig-derived determinants, which had little sequence homology with the immunizing peptide. Such determinant degeneracy can lead to polyclonality. To explore a mechanism for restriction to certain autoantigens, a protein database search was done for homologies with sequences of selected stimulatory Ig peptides. Identical sequences of such determinants were not found in murine proteins other than Ig. These occurred infrequently in nonautoantibody Ig, but quite commonly in lupus-related autoantibodies such as antibodies to DNA, cardiolipin, and erythrocytes. Thus, determinant spreading and degenerate recognition in T cells coupled with recurring use of T cell determinant sequences among autoantibodies result in polyclonality that is restricted to certain autoantigens.

Aging↗
PubMed1998

Reciprocal T-B determinant spreading develops spontaneously in murine lupus: implications for pathogenesis.

Recent work from several laboratories has shown that, in contrast to the widely held notion that one autoimmune disease is caused by one or a few related autoantigenic determinants, autoimmunity is fundamentally a continuously evolving process. The autoimmune responses shift, drift and diversify with time not only to other determinants in the original antigen but also to other antigens. We have described a form of determinant spreading--reciprocal T-B determinant spreading--where the induction of first T cells by peptides from an autoantibody molecule could lead to help provided to a variety of B cells displaying a cross-reactive version of the original determinant. The response spreads in this way by reciprocal T-B stimulation until large cohorts of T and B cells have expanded. Such spontaneous expansion must be important in clinical disease, since tolerance induction to a limited set of T-cell determinant peptides derived from an anti-DNA antibody VH region delayed the appearance of IgG anti-dsDNA antibodies and onset of lupus nephritis in the NZB/NZW F1 mouse model of systemic lupus erythematosus. Understanding the diversification patterns in autoimmune responses has enormous implications in developing peptide-targeted therapies.

Animals↗
PubMed1998

Self Ig peptides that help anti-DNA antibody production: importance of charged residues.

Young NZB/NZW F1 (BWF1) mice develop T cell repertoires that are spontaneously stimulated by peptides derived from the VH regions of BWF1 J558-encoded autoantibodies (autoAb) to DNA, but not to VH region peptides of a J558-encoded antibody to an exogenous antigen. Immunization of young BWF1 mice with selected Ig-derived peptides accelerates anti-DNA production and nephritis, and immune tolerance induction to a combination of these determinants delays anti-DNA production and disease onset. To further characterize this immunoregulatory circuitry, we asked whether this phenomenon of spontaneous T cell activation by VH region peptides is restricted to anti-DNA Ab of the VH J558 family, and what are the charge and structural attributes of these T cell determinants? We studied spontaneous T cell proliferative responses to peptides derived from an autoAb to DNA constructed from VH 7183 and found that it contains several T cell determinants. Both charge and size of certain amino acids (AA) within each peptide seemed to be important. Peptides containing arginine (R) or glutamic acid (E) were more likely to be T cell determinants than peptides without those AA; replacement of charged AA with uncharged AA abolished T cell recognition of a peptide. We previously reported that some Abs to DNA are enriched in R in their VH; pathogenic BWF1 IgG anti-DNA are enriched in positively and negatively charged AA in VH regions. Therefore, we speculate that peptides from natural IgM autoAb may initially activate BWF1 T cells, and as somatic mutations of Ig occur, charged AA introduced into V regions increase the number of T cell determinants, thus favoring upregulation of pathogenic Ab subsets. Therefore, in predisposed individuals, the ability of T cells to recognize more charged T cell determinants in autoAb may be one mechanism promoting development of disease.

Amino Acids↗
PubMed1997

Solitary fibrous tumor of urinary bladder: report of two cases.

The clinical and pathologic features of two cases of solitary fibrous tumor arising from urinary bladder wall are described. To our knowledge, solitary fibrous tumors have not been previously reported at this site. Both tumors showed typical histologic features of solitary fibrous tumor, were CD34 immunostain positive and pursued a benign clinical course on short term follow-up.

Diagnosis, Differential↗
PubMed1996

Neonatal peptide exposure can prime T cells and, upon subsequent immunization, induce their immune deviation: implications for antibody vs. T cell-mediated autoimmunity.

Neonatal exposure to antigen is believed to result in T cell clonal inactivation or deletion. Here we report that, contrary to this notion, neonatal injection of BALB/c mice with a hen egg lysozyme peptide 106-116 in putative "tolergenic" doses induced a T cell proliferative and an immunoglobulin G (IgG) antibody (Ab) response of both T helper cell 1 (Th1)- (IgG2a, IgG2b, and IgG 3) and Th2-dependent (IgG1) isotopes. Upon subsequent challenge with the peptide in complete Freund's adjuvant in adult life, although this neonatal regimen suppressed proliferation and the production of Th1 cytokines (interleukin[IL]-2 and interferon gamma), Th2 cytokine (IL-5, IL-4, and IL-10) secretion was increased, and the serum levels of Th1- and Th2-dependent isotypes of peptide-specific Ab remained elevated. The in vitro proliferative unresponsiveness in Th1 cells could be reversed by Abs to Th2 cytokines (IL-4 and IL-10). Thus, neonatal treatment with a peptide antigen induces T cell priming including production of IgG Abs of both Th1- and Th2-dependent isotypes. Upon subsequent peptide exposure, the peptide-specific T cell responses undergo an effective class switch in the direction of Th2, resulting in T cell proliferative unresponsiveness. Accordingly, this shift towards increased Ab production to autoantigen could be deleterious in individuals prone to antibody-mediated diseases. Indeed, neonatal treatment with a self-autoantigenic peptide from an anti-DNA monoclonal Ab (A6H 58-69) significantly increased the IgG anti-double-stranded DNA Ab levels in lupus-prone NZB/NZW F1 mice, despite suppressing peptide-specific T cell proliferation. This adverse clinical response is in sharp contrast to the beneficial outcome of neonatal treatment with autoantigens in Th1-mediated autoimmune diseases, such as autoimmune encephalomyelitis, as reported by others. A Th1 to Th2 immune deviation can explain the discordant biological responses after the presumed induction of neonatal tolerance in autoantibody- vs. Th-1 mediated autoimmune diseases.

Amino Acid Sequence↗
PubMed1995

T cell determinants from autoantibodies to DNA can upregulate autoimmunity in murine systemic lupus erythematosus.

(NZB x NZW) F1 (BWF1) mice develop spontaneous T cell autoimmunity to VH region determinants of syngeneic anti-DNA before the onset of clinical disease. In this study, we characterized the immunogenicity, MHC binding, and lymphokine secretion patterns induced by T cell determinants from the VH region of one such anti-DNA mAb (A6.1) and examined their role in the regulation of autoimmunity. Determinants were identified by proliferation of syngeneic splenic T cells from young, unprimed BWF1 mice in response to overlapping 12-mer peptides representing the entire VH region sequence. Immunization of young BWF1 mice with any of three determinants (A6H 34-45 [p34], A6H 58-69 [p58], and A6H 84-95 [p84]) elicited proliferative responses upon in vitro recall. Upon immunization with the whole A6.1 molecule, however, proliferative responses could be recalled only to the p58 peptide, defining this as immunodominant. The other two peptides (p34 and p84) elicited minimal or no proliferation and could be termed cryptic. Proliferative responses elicited by the cryptic determinants were restricted by a single class II (I-Ed for p34 and I-Au for p84), whereas the immunodominant p58 determinant was restricted by both I-Ed and I-Eu. The cryptic p34 and p84 bound strongly to I-Ed and I-Au, respectively, whereas the immunodominant p58 peptide bound poorly to I-Ed. A6H p84 elicited T cells that secreted lymphokines in a pattern consistent with a Th1-like phenotype, whereas p58 induced a Th2-like cytokine pattern. Immunization with p34 or p84, or adoptive transfer of a p84-reactive T cell line to young BWF1 mice significantly increased IgG anti-DNA levels, accelerated nephritis, and decreased survival. In conclusion, in BWF1 mice, autoreactive T cells recognizing both cryptic and dominant self-determinants on anti-DNA autoantibodies escape deletion or anergy induction. Furthermore, since these cells are spontaneously activated before the onset of clinical disease, they may be involved in the development of the autoimmune process.

Animals↗
PubMed1995

Genital tract abnormalities and female sexual function impairment in systemic sclerosis.

OBJECTIVE: Our purpose was to determine the involvement of the female genital tract and its functional consequences on menstrual and sexual aspects in systemic sclerosis. STUDY DESIGN: Sixty women with systemic sclerosis and 23 age- and disease duration-matched women with either rheumatoid arthritis or systemic lupus erythematosus were surveyed with a comprehensive questionnaire addressing problems before and after disease onset. Fourteen systemic sclerosis patients also had gynecologic evaluations. RESULTS: Vaginal dryness (71%), ulcerations (23%), and dyspareunia (56%) were significantly more frequent in patients with systemic sclerosis after disease onset than before and also in comparison with control subjects. Vaginal tightness and constricted introitus were present in 5 of 60 systemic sclerosis patients. More than half of systemic sclerosis patients reported a decrease in the number (p = 0.04) and intensity (p = 0.02) of orgasms, compared to < 20% of control subjects. The desire and frequency of coitus and the sexual satisfaction index were impaired equally in each group. Skin tightness, reflux-heartburn, and muscle weakness adversely affected sexual relations more in systemic sclerosis than in control subjects. On gynecologic examination 5 of 11 systemic sclerosis patients had small-sized uteri, and 3 of them had early menopause at 29, 38, and 43 years. Seven of 16 (44%) women with systemic sclerosis, compared with 6% of normal women in the United States, attained natural menopause before age 45. CONCLUSIONS: Although impairment in various indexes of sexual function occurs in a number of autoimmune diseases, decreased orgasmic function appears to be limited to systemic sclerosis. Vaginal involvement and other systemic sclerosis-related systemic symptoms adversely influence sexual relations. Menstrual abnormalities, including early menopause, affect many patients. Genital tract involvement occurs in a substantial proportion. Prospective longitudinal studies are warranted.

Adult↗
PubMed1995

Immune tolerance to autoantibody-derived peptides delays development of autoimmunity in murine lupus.

Mechanisms that initiate and maintain autoantibody (autoAb) production in individuals with autoimmune diseases like SLE are poorly understood. Inadequate suppression of autoreactive T cells and/or unusual activation of T and B cells may underlie the persistence of pathogenic autoAbs in lupus. Here, we examine the possibility that in mice with lupus, autoAb molecules may be upregulating their own production by activating self-reactive T cells via their own processed peptides; downregulation of this circuit may decrease autoAb production and delay the development of lupus. We found that before the onset of clinical disease, lupus-prone (NZB/NZW) F1 [BWF1] (but not MHC-matched nonautoimmune mice) developed spontaneous T cell autoimmunity to peptides from variable regions of heavy chains (VH) of syngeneic anti-DNA mAbs but not to peptides from the VH region of an mAb to an exogenous antigen. Tolerizing young BWF1 mice with intravenous injections of autoAb-derived determinants substantially delayed development of anti-DNA antibodies and nephritis and prolonged survival. Thus, in such an autoAb-mediated disease, the presence of autoreactive T cells against VH region determinants of autoAbs may represent an important mechanism involved in the regulation of autoimmunity. Our findings show that tolerizing such autoreactive T cells can postpone the development of an autoimmune disease like SLE.

Amino Acid Sequence↗