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1.  The Effect of Fibromyalgia and Widespread Pain on the Clinically Significant Temporomandibular Muscle and Joint Pain Disorders - A Prospective 18-Month Cohort Study 
Although most cases of Temporomandibular Muscle and Joint Disorders (TMJD) are mild and self-limiting, about 10% of TMJD patients develop severe disorders associated with chronic pain and disability. It has been suggested that fibromyalgia and widespread pain play a significant role in the Temporomandibular Muscle and Joint Disorders (TMJD) chronicity. This paper assessed the effects of fibromyalgia and widespread pain on clinically significant TMJD pain (GCPS II-IV). Four hundred eighty-five participants recruited from the Minneapolis/St. Paul area through media advertisements and local dentists received examinations and completed the Graded Chronic Pain Scale (GCPS) at baseline and at 18th months. Baseline widespread pain (OR: 2.53, P=0.04) and depression (OR: 5.30, P=0.005) were associated with onset of clinically significant pain (GCPS II-IV) within 18 months after baseline. The risk associated with baseline fibromyalgia was moderate, but not significant (OR: 2.74, P=0.09). Persistence of clinically significant pain was related to fibromyalgia (OR: 2.48, P=0.02) and with depression (OR: 2.48, P=0.02). These results indicate that these centrally generated pain conditions play a role in the onset and persistence of clinically significant TMJD.
PMCID: PMC2943982  PMID: 20466595
Temporomandibular disorders; widespread pain; fibromyalgia; risk factors; chronic pain
2.  Interactions between Multiple Genetic Determinants in the 5′ UTR and VP1 Capsid Control Pathogenesis of Chronic Post-Viral Myopathy caused by Coxsackievirus B1 
Virology  2007;372(1):35-47.
Mice infected with coxsackievirus B1 Tucson (CVB1T) develop chronic, post-viral myopathy (PVM) with clinical manifestations of hind limb muscle weakness and myositis. The objective of the current study was to establish the genetic basis of myopathogenicity in CVB1T. Using a reverse genetics approach, full attenuation of PVM could only be achieved by simultaneously mutating four sites located at C706U in the 5′ untranslated region (5′ UTR) and at Y87F, V136A, and T276A in the VP1 capsid. Engineering these four myopathic determinants into an amyopathic CVB1T variant restored the ability to cause PVM. Moreover, these same four determinants controlled PVM expression in a second strain of mice, indicating that the underlying mechanism is operational in mice of different genetic backgrounds. Modeling studies predict that C706U alters both local and long-range pairing in the 5′ UTR, and that VP1 determinants are located on the capsid surface. However, these differences did not affect viral titers, temperature stability, pH stability, or the antibody response to virus. These studies demonstrate that PVM develops from a complex interplay between viral determinants in the 5′ UTR and VP1 capsid and have uncovered intriguing similarities between genetic determinants that cause PVM and those involved in pathogenesis of other enteroviruses.
PMCID: PMC2352162  PMID: 18029287
coxsackievirus; enterovirus; post-viral myopathy; myositis; muscle; weakness; inflammation; pathogenesis; viral genetics; VP1 capsid
3.  Multiple Viral Determinants Mediate Myopathogenicity in Coxsackievirus B1-Induced Chronic Inflammatory Myopathy 
Journal of Virology  2003;77(21):11849-11854.
Mice infected with myopathic coxsackievirus B1 Tucson (CVB1T) develop chronic inflammatory myopathy (CIM) consisting of hind limb weakness and inflammation. Amyopathic virus variants are infectious but attenuated for CIM. In this report, viral clones, chimeras, and sequencing were used to identify viral determinants of CIM. Chimeras identified several regions involved in CIM and localized a weakness determinant to nucleotides 2493 to 3200 of VP1. Sequencing of multiple clones and viruses identified five candidate determinants that were strictly conserved in myopathic viruses with one located in the 5′ untranslated region (UTR), three in the VP1 capsid, and one in the 3C protease. Taken together, these studies implicate Tyr-87 and/or Val-136 as candidate determinants of weakness. They also indicate that there are at least two determinants of inflammation and one additional determinant of weakness encoded by myopathic CVB1T.
PMCID: PMC229355  PMID: 14557670
4.  Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus 
Arthritis Research  2001;3(5):299-305.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies to a wide range of self-antigens. Recent genome screens have implicated numerous chromosomal regions as potential SLE susceptibility loci. Among these, the 1q41 locus is of particular interest, because evidence for linkage has been found in several independent SLE family collections. Additionally, the 1q41 locus appears to be syntenic with a susceptibility interval identified in the NZM2410 mouse model for SLE. Here, we report the results of genotyping of 11 microsatellite markers within the 1q41 region in 210 SLE sibpair and 122 SLE trio families. These data confirm the modest evidence for linkage at 1q41 in our family collection (LOD = 1.21 at marker D1S2616). Evidence for significant linkage disequilibrium in this interval was also found. Multiple markers in the region exhibit transmission disequilibrium, with the peak single marker multiallelic linkage disequilibrium noted at D1S490 (pedigree disequilibrium test [PDT] global P value = 0.0091). Two- and three-marker haplotypes from the 1q41 region similarly showed strong transmission distortion in the collection of 332 SLE families. The finding of linkage together with significant transmission disequilibrium provides strong evidence for a susceptibility locus at 1q41 in human SLE.
PMCID: PMC64842  PMID: 11549371
1q41; autoimmunity; linkage; systemic lupus erythematosus; transmission disequilibrium
5.  Molecular Mechanisms of Coxsackievirus Persistence in Chronic Inflammatory Myopathy: Viral RNA Persists through Formation of a Double-Stranded Complex without Associated Genomic Mutations or Evolution 
Journal of Virology  1999;73(12):10113-10121.
Enterovirus infection and persistence have been implicated in the pathogenesis of certain chronic muscle diseases. In vitro studies suggest that persistent enteroviruses mutate, evolving into forms that are less lytic and display altered tropism, but it is less clear whether these mechanisms operate in vivo. In this study, persistent coxsackievirus RNA from the muscle of mice afflicted with chronic inflammatory myopathy (CIM) was characterized and compared with RNA from a virus that had established a persistent infection of G8 mouse myoblasts for 30 passages in vitro. Competitive strand-specific reverse transcription-PCR and susceptibility to RNase I treatment revealed that plus- and minus-strand viral RNAs were present at nearly equivalent levels in muscle and that they persisted in a double-stranded conformation. All regions of the viral genome persisted and were amplified as a series of seven overlapping fragments. Restriction endonuclease fingerprinting coupled with sequencing indicated that there was no evolution of the viral genome associated with its persistence in muscle. This contrasted with the productive persistent infection that was established in myoblast cultures, where plus-strand RNA predominated and persistent virus developed distinct mutations. In vitro persistence proceeded by a carrier culture mechanism and was completely dependent on production of infectious virus, since persistent viral RNA was not detected in cultures subjected to antibody-mediated curing. These experiments demonstrate that persistence of coxsackievirus RNA in muscle is not facilitated by distinct genetic changes in the virus that give rise to replication-defective forms but occurs primarily through production of stable double-stranded RNA that is produced as the acute viral infection resolves. The data suggest a mechanism for coxsackievirus persistence in myofibers and perhaps other nondividing cells whereby cells that survive infection could harbor persistent viral RNA for extended times without producing detectable levels of infectious virus.
PMCID: PMC113063  PMID: 10559326
6.  Prostaglandin Suppression of Mitogen-Stimulated Lymphocytes In Vitro 
Journal of Clinical Investigation  1978;62(4):753-760.
In this study we further characterize the properties of the prostaglandin-producing suppressor cell. Overnight preincubation of peripheral blood mononuclear cells results in an increased response of the cells to phytohemagglutinin or Concanavalin A compared to the response of fresh cells. This increase in mitogen response with preincubation was similar in magnitude to the increase in mitogen response of fresh cells after the addition of indomethacin. The two manipulations were not additive; that is, after preincubation, indomethacin caused much less enhancement of mitogen stimulation of peripheral blood mononuclear cells (100 ± 12% increase before preincubation vs. 12 ± 6% after preincubation; mean±SEM, P < 0.001). Preincubated cells also lose sensitivity to inhibition by exogenous prostaglandin E2. It requires the addition of 100- to > 1,000-fold more exogenous PGE2 to produce comparable inhibition of phytohemagglutinin-stimulated preincubated cells than is required for inhibition of phytohemagglutinin-stimulated fresh cells.
The enhancing effect of indomethacin increases with decreasing doses of phytohemagglutinin. Indomethacin causes a 1,059±134% increase in [3H]thymidine incorporation at the lowest dose of phytohemagglutinin (0.2 μg/ml), and a 4±3% increase at the highest dose (20 μg/ml). This increase in response to indomethacin with a lower dose of phytohemagglutinin is due to increased sensitivity to inhibition by PGE2 at lower mitogen doses.
The prostaglandin-producing suppressor cell assay and the short-lived suppressor cell assay measure over-lapping phenomena. The increased suppressive effect of the prostaglandin-producing suppressor at suboptimal mitogen dose must be taken into account in the interpretation of any study where the response to a range of mitogen doses is studied.
PMCID: PMC371826  PMID: 701474
7.  Peripheral Blood Lymphocyte Cell Surface Markers during the Course of Systemic Lupus Erythematosus 
Journal of Clinical Investigation  1973;52(12):3046-3056.
Peripheral blood lymphocytes from 23 patients with active systemic lupus erythematosus (SLE) were serially studied. Changes in bone marrow-derived lymphocytes (B cells), as measured by surface Ig receptors and C3 receptors, and in thymus-derived cells (T cells) measured by rabbit T-cell-specific antiserum and E-binding techniques, were correlated with fluctuations in clinical disease activity and treatment. In normal controls B- and T-cell percentages remained relatively stable, although the situation in SLE was much more labile. A relative and absolute decrease in T lymphocytes and cells bearing a receptor for C3 was found in active lupus. Absolute numbers of cells bearing surface Ig were decreased to a lesser extent, whereas the proportion of these cells was increased. It is postulated that the increase in autoantibody formation and diminished delayed hypersensitivity seen in systemic lupus may be due to a loss of T-lymphocyte function.
PMCID: PMC302579  PMID: 4584345
8.  Studies of T- and B-Lymphocytes in Patients with Connective Tissue Diseases 
Journal of Clinical Investigation  1973;52(2):283-295.
Peripheral blood lymphocytes from normal subjects as well as patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and active tuberculosis were studied for the relative distribution of bone marrow-derived lymphocytes (B-cells) and thymic-derived T-cells. B-cells were identified by direct immunofluorescence of surface Ig markers; T-cells were studied using rabbit antisera to pooled human fetal thymocytes absorbed with chronic lymphatic leukemia lymphocytes as a source of B-cells. In normal subjects, the sum of percentages of peripheral blood lymphocytes staining for surface Ig (B-cells) plus the percentage of cells staining with the absorbed antithymocyte antiserum closely approximated 100%. The mean value for percent B-cells among 51 normals tested was 22.9%±7.1; mean T-cells value was 75.3±13.95%. T-cell-specific antiserum stained 18% of normal human bone marrow lymphocytes, 42.5% of lymphocytes from normal spleens, and 98% of cells obtained from thoracic duct drainage of patients with RA. Specificity of antihuman thymocyte antiserum appeared to depend on the use of living cells.
When patients with RA were examined, a wide range (14-98%) of peripheral blood T-cell values was found. Values for low percentages of peripheral blood T-cells appeared to correlate to some extent with severe clinical disease. In 11 of 36 RA patients, the sum of identifiable B- plus T-cells accounted for only 34-55% of peripheral blood lymphocytes. The identity of the remaining “null” cells could not be identified.
3 of 24 SLE patients studied showed low percentages of peripheral blood T-cells, but no correlation could be drawn between T- to B-cell ratios and clinical disease activity. Among 21 patients with active tuberculosis, one had a low value for identifiable T-cells. No significant differences from normals in range or proportion of B-cells was identified in patients with active tuberculous infection.
PMCID: PMC302257  PMID: 4567306
The opsonic properties of immune γG-globulins isolated from patients with chronic septicemic conditions, principally subacute bacterial endocarditis were studied. Opsonic capacity as well as complement-fixing properties of γ-globulins appeared to be closely associated with integrity of Fc structures. Progressive pepsin digestion of immune γG-globulins, as monitored by successive loss of Gm(a) and Gm(b) antigens, abolished opsonic activity. Colostral γA, containing agglutinating antibacterial antibodies but no demonstrable complement-fixing activity, was devoid of opsonic capacity. Reduction of γ-globulin opsonins with 0.01 or 0.1 M mercaptoethanol progressively abolished opsonic activity in parallel with loss of ability of treated γ-globulins to fix complement with bacteria. Treatment of γ-globulin opsonins with 0.01 M sodium metaperiodate also produced complete loss of opsonic capacity in parallel with loss of Gm(b) Fc antigens. These findings, together with antiopsonic effects demonstrable with anti-γ-globulin factors showing primary reactivity with Fc structures, indicate that the opsonic property of immune γ-globulins requires the participation of structures integral to the Fc region of γ-globulin.
PMCID: PMC2138542  PMID: 4175321
10.  Serum opsonin, bacteria, and polymorphonuclear leukocyte interactions in subacute bacterial endocarditis 
Journal of Clinical Investigation  1968;47(5):1109-1120.
The effect of anti-γ-globulin factors on 7S γ-globulin opsonins from patients with subacute bacterial endocarditis has been examined with a quantitative in vitro phagocytosis system. Human anti-γ-globulin factors from patients with subacute bacterial endocarditis and rheumatoid arthritis inhibited the opsonic action of 7S γ-globulin specifically bound to bacteria. A similar antiopsonic effect was obtained with rabbit antiserum to human γG globulin. The antiopsonic effect of anti-γ-globulin factors did not correlate with their ability to potentiate agglutination of bacteria by 7S antibody. Competition was demonstrated between the antiopsonic effect of anti-γ-globulin factors and the phagocytosis-promoting action of heat-labile serum factors containing hemolytically active complement.
PMCID: PMC297263  PMID: 5645856

Results 1-10 (10)