Clinical trial of a formal group fatigue program in multiple sclerosis.

Fatigue: Take Control is a novel program to teach fatigue management to people with multiple sclerosis (MS) following recommendations in the Fatigue and Multiple Sclerosis guideline. Fatigue: Take Control includes six 2-hour group sessions with DVD viewing, discussion and homework and accompanying participant and leader workbooks. While many people have participated in Fatigue: Take Control programs, its efficacy has not been determined. The objective of this study was to determine whether participation in Fatigue: Take Control reduces fatigue and increases self-efficacy in people with MS. Thirty participants were randomly assigned to a group who immediately participated in the program (FTC) or a wait-list group (WL). The primary outcome was the Modified Fatigue Impact Scale (MFIS) and secondary outcomes were the Multiple Sclerosis Self-Efficacy Scale (MSSE) and the Fatigue Severity Scale (FSS). The MFIS was administered on 10 occasions. Other measures were administered on four occasions. A mixed model tested the effects using all observations. Compared with the WL, the FTC group had significantly more improvement on the MFIS [F(1, 269) = 7.079, p = 0.008] and the MSSE [F(1, 111) = 5.636, p = 0.019]. No significant effect was found for the FSS. Across all visits, fatigue was significantly lower and self-efficacy was significantly higher for the FTC group compared with the WL group. This pilot study demonstrated significant effects in fatigue and self-efficacy among subjects taking the Fatigue: Take Control program, suggesting that this comprehensive program based on the Fatigue and Multiple Sclerosis guideline may be beneficial in MS.

Flexibility of TCR repertoire and permissiveness of HLA-DR3 molecules in experimental autoimmune thyroiditis in nonobese diabetic mice.

Experimental autoimmune thyroiditis (EAT) is inducible in genetically susceptible mice by immunization with mouse thyroglobulin (mTg). With susceptibility linked to MHC class II, EAT is useful in studying human leukocyte antigen (HLA) associations with Hashimoto's thyroiditis. In non-obese diabetic (NOD) mice, approximately 10% thyroiditis incidence occurs with aging. This potential was exploited to examine the T cell repertoire and HLA association in EAT. Similar to B10.K-Vbeta(c)mice with TCRBV genes reduced by approximately 70%, mTg-immunized NOD-Vbeta(c)mice developed thyroiditis comparable to controls, indicating plasticity of the TCR repertoire for pathogenic epitopes. HLA association was evaluated by introducing HLA-DRA/DRB1*0301 (DR3) transgene into class II-negative NOD mice (Ab(0)/NOD). Previously, this HLA-DR3 transgene rendered EAT-resistant B10.M and Ab(0)mice susceptible to both mTg- and hTg-induced EAT. These results are now confirmed. mTg-induced thyroiditis in DR3+ Ab(0)/NOD mice was comparable to that in NOD and DR3- NOD mice, and the proliferative response was stronger. By comparison, NOD mice were only moderately susceptible to hTg-induced EAT. However, thyroiditis was more severe in DR3+ Ab(0)/NOD than in DR3- NOD mice, with no difference in proliferative response to hTg harbouring heterologous epitopes. The confirmed permissiveness of HLA-DR3 molecules on an NOD background for EAT induction by both mTg and hTg supports the importance of this class II gene implicated in some patient studies.

Correlates of expressed and received violence across relationship types among men and women substance abusers.

This study examined expressed and received violence among men and women in substance abuse treatment. Rates of past-year partner violence (PV) did not differ by gender, although men reported markedly higher rates of nonpartner violence (NPV). Compared with PV, NPV was associated with more demographic and background factors (e.g., childhood aggression and conduct problems, family history of violence). The most consistent correlates of violence across relationship types were age, minority status, drug-related consequences, psychiatric distress, and frequency of childhood aggression. Only a few gender-specific correlates were identified; most notably, witnessing father-to-mother violence was related to received PV only for women. Identification of correlates of expressed and received violence in partner and nonpartner relationships is essential for the assessment and treatment of individuals in substance abuse treatment settings.

Predictors of expressed partner and non-partner violence among patients in substance abuse treatment.

This study examined reports of expressed partner and non-partner violence among men (n = 126) and women (n = 126) in the 12 months prior to substance abuse treatment. Rates of violence were 57% for partner, 53% for non-partner, and 75% collapsing across partner and non-partner relationships. Factors associated with partner and non-partner violence severity differed substantially. Partner violence was predicted by age, marital status, and drug problem severity. Non-partner violence was predicted by gender, income, alcohol and drug problem severity. The results highlight that individuals in substance abuse treatment are at high risk for violence, and targeted screening and intervention approaches should be routine in addictions treatment.

Gender differences in the development of substance-related problems: the impact of family history of alcoholism, family history of violence and childhood conduct problems.

OBJECTIVE: This study examined gender differences regarding the relative influence of family history of alcoholism (FHA) and family history of violence (FHV) on reported childhood conduct problems (CCP) and adult problems with alcohol, drugs and violence. METHOD: The participants were 110 men and 103 women with alcohol-related problems recruited within 30 days of enrolling in treatment for substance abuse or dependence. Participants completed self-report measures of pretreatment violence, FHV, CCP, substance use and consequences, and demographics; a semi-structured interview was used to assess FHA. RESULTS: Structural equation modeling (SEM) analyses revealed gender differences with regard to the influence of FHA and FHV as important factors in the development of childhood and adult behavioral problems. For women, the influence of FHA on subsequent childhood conduct problems and adult problems with alcohol was accounted for by FHV. For men, FHA was not directly associated with CCP or adult problems with alcohol and violence, but was associated with adult drug problems. For both men and women, FHV was associated with CCP, and CCP were associated with adult problems with drugs and violence. CONCLUSIONS: Overall, the analyses illustrate the relative importance of FHV as a risk factor in the developmental course leading to problems with drugs and violence among individuals with alcohol-related problems enrolled in treatment for substance abuse or dependence. Further, there was evidence that women may be impacted more than men by family background variables (both FHA and FHV) in terms of the development of adult problems with alcohol, drugs and violence.

Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis: role of MHC class II.

A few synthetic peptides corresponding to amino acid sequences on human thyroglobulin (Tg) have been reported to induce moderate thyroiditis or activate mouse Tg (MTg)-primed T cells to transfer thyroiditis in mice susceptible to experimental autoimmune thyroiditis. Using three pairs of 12-mer peptides (1-12, 2549-2560, 2559-2570), with thyroxine (T4) or noniodinated thyronine (T0) at the conserved, hormonogenic site 5, 2553, or 2567 respectively, we reported that iodination was not required for a Tg hormonogenic site to be a thyroiditogenic autoepitope. To determine the relative importance of MHC class II and T cell receptor (TCR) repertoire, we compared two EAT-susceptible k and s (CBA and A.SW) haplotypes and their respective MHC-identical strain (C57BR and SJL) with approximately 50% genomic deletion of TCR Vbeta genes. Whereas k and s strains develop MTg-induced EAT, vigorous immunization with peptides containing T4 or T0 at either 5 or 2553, but not at 2567, led to mild (10-20%) thyroiditis only in some mice of either k strain. TCR Vbeta gene differences played a minor role. T cell responses to all peptide pairs were quite similar in CBA and C57BR mice, and both hT0(2553) and hT4(2553) reciprocally primed and stimulated their T cells. In adoptive transfer, SJL mice were somewhat more responsive to peptide activation than A.SW but much weaker than k strains. By comparing T4- and T0-containing peptides in different haplotypes, we show further that antigenicity of conserved hormonogenic sites is intrinsic, dependent more on amino acid sequence and binding to appropriate class II molecules and less on TCR repertoire or iodination of T0.

Role of mouse and human class II transgenes in susceptibility to and protection against mouse autoimmune thyroiditis.

Mouse experimental autoimmune thyroiditis (EAT), a model for Hashimoto's thyroiditis, is induced by immunizing with mouse thyroglobulin (MTg). To study the extent of H2A involvement in EAT, we introduced AaAb genes from susceptible k mice into resistant or intermediately susceptible strains which do not express H2E molecules. Thyroiditis was severe in resistant B10.M (H2(f)) mice carrying the double transgene AakAbk. Likewise, thyroid infiltration was significantly extended in intermediate B10.Q (H2(q)) mice with the same transgene. To examine the effect of H2E molecules in the presence of H2A-mediated susceptibility, we introduced an Eak transgene into E- B10.S mice to express the Ebetas molecule and observed significant reduction in EAT severity in B10.S(E+) mice. On the other hand, the presence of an Ebd transgene in B10.RQB3 (H2Aq) mice resulting in the expression of H2Ebetad molecules did not alter EAT susceptibility, suggesting a role for Eb gene polymorphism in protection against EAT. We have shown recently that the HLA-DRB1(*)0301 (DR3) transgene conferred EAT susceptibility to B10. M as well as class II-negative B10.Ab0 mice. However, we report here that the HLA-DQB1(*)0601 (DQ6b) transgene in B10.M or HLA-DQA1(*)0301/DQB1(*)0302 (DQ8) transgene in class II-negative Ab0 mice did not. These studies show the differential effects of class II molecules on EAT induction. Susceptibility can be determined when class II molecules from a single locus, H2A or HLA-DQ, are examined in transgenic mice, but the overall effect may depend upon the presence of both class II molecules H2A and H2E in mice and HLA-DQ and HLA-DR in humans.

Primary hormonogenic sites as conserved autoepitopes on thyroglobulin in murine autoimmune thyroiditis. Secondary role of iodination.

We hypothesized earlier that conserved T cell epitopes and those unique to mouse thyroglobulin (MTg) contributed to its total thyroiditogenicity in murine autoimmune thyroiditis. Recent studies of synthetic peptides from human Tg (HTg) revealed no immunodominant epitopes. The role of iodine residues, considered by some to render Tg immunogenic, became unclear, since only one 12-mer peptide contained thyroxine (T4) positioned at hormonogenic site 2553. It primed T cells for thyroiditis transfer, but noniodinated peptide containing thyronine (T0) was not compared. To determine 1) whether other primary hormonogenic sites were likewise immunogenic and 2) whether iodination was requisite for this and other sites to be an autoepitope, we derivatized three pairs of 12-mer peptides, 1-12, 2549-2560, 2559-2570, containing T0 or T4 at positions 5, 2553, or 2567, respectively. The six peptides were used to stimulate MTg-primed cells in vitro and to immunize mice. None directly induced thyroiditis; peptide Abs were the lowest in mice given hT0(2567) or hT4(2567). Of the three T4-containing peptides, hT4(5) and hT4(2553), but not hT4(2567), stimulated MTg-primed or HTg-primed T cells in vitro, with hT4(2553) being the stronger. Comparing hT0(2553) with hT4(2553), both activated MTg-primed, or peptide-primed, T cells to transfer thyroiditis. The marked immunogenicity of noniodinated hT0(2553) and the poor antigenicity of hT4(5) and hT4(2567) demonstrate that immunogenicity of a conserved hormonogenic site is dependent more on its amino acid sequence than on T4 substitution. Iodination may enhance antigenicity and/or binding affinity, but it is not required for a Tg hormonogenic site to be an autoepitope.

Noninvolvement of V beta 8+ T cells in murine thyroglobulin-induced experimental autoimmune thyroiditis.

In experimental autoimmune thyroiditis (EAT) induced with mouse thyroglobulin (MTg), T cell receptor (TCR) V beta gene usage in the pathogenesis of disease is unknown. We report here studies evaluating V beta 8 gene usage in EAT, as V beta 8+ T cells are reportedly involved in some experimental autoimmune diseases. Spleen cells (SC) from MTg-immunized CBA/J (H-2k) mice were activated in vitro for adoptive transfer into syngeneic recipients. Elimination of V beta 8+ T cells by treating recipients with V beta 8 monoclonal antibody (mAb) following transfer of MTg-activated SC did not reduce disease severity. Conversely. MTg-primed SC were stimulated in vitro with V beta 8 mAb or staphylococcal enterotoxin B, which activates V beta 8+ T cells in CBA/J mice. Neither activated population transferred disease, in contrast to cells activated with MTg. Thus, in MTg-induced EAT, V beta 8+ T cells do not play a major role in pathogenesis.

Depletion of CD4+ and CD8+ cells eliminates immunologic memory of thyroiditogenicity in murine experimental autoimmune thyroiditis.

Experimental autoimmune thyroiditis (EAT) develops in genetically susceptible mice after immunization with mouse thyroglobulin (MTg), and is mediated by T cells, both CD4+ and CD8+, infiltrating the thyroid. Previous work showed that depletion of CD4+, but not CD8+, cells with rat monoclonal antibodies (mAbs) interfered with EAT induction. To test if concomitant CD4+ cell depletion and immunization led to EAT resistance, mice were reimmunized at an interval of 15 or 43 days after injection of CD4 mAbs. No resistance had been established; disease severity and anti-MTg titers were comparable to mice with primary immunization. Previous work also showed that treatment during advancing EAT with only CD4 mAbs on days 21, 25 led to long-lasting, reduced severity in EAT, whereas administration of CD8 mAbs alone reduced the smaller CD8+ subset only. However, therapy with both mAbs was most efficacious; > 50% of thyroids were purged of all cellular infiltrate after only two doses. Moreover, T cells emerging subsequent to depletion were not retained in the thyroid, despite ongoing antibody production. To test if nondepleting CD4 and CD8 mAbs were similarly effective for therapy, mAbs of the IgG2a isotype were administered during advancing EAT. No effect on thyroidal infiltration was observed, indicating that modulation of the CD4 and CD8 antigen without depletion was insufficient for efficacious therapy. To determine if combined therapy with depleting mAbs reestablished self tolerance, treated mice were reimmunized on days 70, 77, when T cell recovery was nearly complete. Thyroiditis was comparable to controls given primary immunization, despite high antibody levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Characterization of resistance to murine experimental autoimmune thyroiditis: duration and afferent action of thyroglobulin- and TSH-induced suppression.

Genetically susceptible mice develop experimental autoimmune thyroiditis (EAT) after immunization with mouse thyroglobulin (MTg). Earlier studies have shown that resistance to EAT induction can be activated by two regimens, pretreatment with deaggregated MTg (dMTg) or with thyroid-stimulating hormone (TSH). With both protocols, suppression is linked to a > or = 2-3 day increase in circulatory MTg level and is mediated by CD4+ suppressor T cells (Ts). To assess the duration of suppression, CBA (H-2k) mice were injected with dMTg or infused with TSH via an osmotic pump for 3-4 days and then challenged with MTg + adjuvant at intervals up to 73 days for dMTg-pretreated mice or up to 94 days for TSH-pretreated mice. Suppression was measurable for at least 73 days after injected dMTg. TSH-induced suppression was also long-lasting; resistance was strong 38 days after TSH infusion and was still measurable on Day 66. The Thy-1+, CD4+ Ts which transfer MTg-induced suppression were further characterized by treatment with I-J antibodies plus complement prior to transfer. This treatment abolished the transfer of suppression which acts in the afferent phase to interfere with EAT induction. The capacity of Ts to suppress the efferent phase of EAT was assessed in vitro and in vivo. Cells from dMTg-pretreated mice did not block the in vitro proliferative response of MTg-primed cells to MTg, nor did these cells, when left intact in situ, reduce the severity of disease produced by the adoptive transfer of thyroiditogenic cells. Similarly, TSH-induced suppression was ineffective in preventing adoptively transferred EAT. Since suppression, which correlates with a temporary increase of circulatory MTg, occurs only at the afferent phase of active immunization, these findings lend support to our earlier hypotheses that circulatory MTg serves a physiologic role in maintaining normal self-tolerance by sustaining low levels of Ts activation and that additional rise above baseline increases and prolongs resistance to EAT induction.

Resistance to experimental autoimmune thyroiditis is correlated with the duration of raised thyroglobulin levels.

We have used the mouse model of experimental autoimmune thyroiditis (EAT) to examine the hypothesis that the strengthening of self-tolerance to thyroglobulin by exogenous mouse thyroglobulin (MTg) or stimulation of endogenous MTg secretion by thyroid-stimulating hormone (TSH) is correlated with the length of time MTg rises above the normal range. Bacterial lipopolysaccharide (LPS) treatment increases the initial half-life of MTg from about 3 hr to about 5 hr, probably interfering with its clearance by the mononuclear phagocytic (reticuloendothelial) system. By pretreating mice with LPS, a subtolerogenic MTg dose is rendered tolerogenic. Similarly the effect of TSH infusion by osmotic minipumps, which stimulates MTg secretion and also strengthens tolerance to MTg, can be enhanced by injecting LPS shortly after pump implantation. The resulting increase in MTg level (due to delayed clearance of MTg) is greater than that from TSH alone and suppresses further the animals' susceptibility to disease induction by MTg and adjuvant. Moreover, resistance following pretreatment with LPS and subtolerogenic MTg is mediated by CD4+ suppressor T cells, as shown recently for the suppression in mice given high doses of tolerogenic MTg. These experiments are in full agreement with the hypothesis and confirm that small increases in circulating MTg concentrations, which could occur physiologically, can be effective in protecting against EAT induction.

Pathogenic mechanisms in murine autoimmune thyroiditis: short- and long-term effects of in vivo depletion of CD4+ and CD8+ cells.

Both murine CD4+ and CD8+ cells are found in the thyroid infiltrate in experimental autoimmune thyroiditis (EAT) induced with mouse thyroglobulin (MTg). MTg activation of immune cells in vitro enables CD4+ cells to transfer thyroiditis adoptively and to aid the cytotoxic capacity of CD8+ cells for thyroid monolayers. To dissect their relative contribution to pathogenesis in vivo, depleting doses of paired rat monoclonal antibodies (MoAb) recognizing two distinct CD4 or CD8 epitopes were injected alone or in combination. Early treatment with CD4 MoAb interfered with the induction and development of EAT, whereas similar treatment with CD8 MoAb reduced infiltration moderately and did not enhance antibody response. To examine the long-term effect of therapy on advancing EAT, administration of MoAb was delayed to days 21 and 25, and thyroids were analysed immunohistochemically on days 28 and 70. Whereas control mice showed about 30% CD4+ and CD8+ cells at a 2:1 ratio (the remainder being mostly macrophages) on both days 28 and 70, the CD4 therapy regime led to reduced severity and the lesions on day 70 contained very low percentage of CD4+ cells, but elevated percentage of CD8+ cells (ratio 1:3.5). The CD8 therapy regime led to reduced CD8+ cells without changing the range of CD4+ cells (ratio 4:1). Thus, subset involvement may be influenced by the MoAb used. When CD4 and CD8 MoAb were combined, greater than 50% of the thyroids were cleared of all inflammatory cells; lesions when found were very small and contained less than 10% T cells (ratio 1:1). Since emerging T cells were not retained in the thyroid despite ongoing antigenic stimulus leading to increased antibody titres, the therapeutic effect of MoAb, even at an advanced stage of disease, was long lasting.

Resistance to experimental autoimmune thyroiditis: L3T4+ cells as mediators of both thyroglobulin-activated and TSH-induced suppression.

Mechanisms suppressive to induction of murine experimental autoimmune thyroiditis (EAT) can be activated by pretreatment with tolerogenic doses of mouse thyroglobulin (MTg) or prior TSH infusion to raise circulatory MTg levels. MTg-activated suppressor T cells (Ts), shown earlier to be Thy-1+ and probably I-J+, were further characterized by in vivo administration of paired rat monoclonal antibodies to distinct epitopes on the L3T4 or Lyt-2 molecule, either on the day of, or subsequent to, initiation of the tolerogenic regimes. The cells required at the time of MTg pretreatment were L3T4+, Lyt-2- and low anti-L3T4 doses had no effect on their activation. The cells that mediated the strong MTg-induced resistance following pretreatment were also L3T4+; their suppressor function could only be abrogated by depletion of L3T4+, but not Lyt-2+, cells. Injection of cyclophosphamide (20-100 mg/kg) either prior to EAT induction or after Ts activation did not affect the severity of disease. Similarly, the suppressor state evoked by TSH infusion could only be abrogated by anti-L3T4 treatment. These findings indicate that both MTg-activated and TSH-induced suppression are mediated by L3T4+ cells. We hypothesize that MTg-specific Ts are present in normal, EAT-susceptible mice in low numbers to contribute to the maintenance of self-tolerance and that they are stimulated by increased levels of circulatory MTg to expand/differentiate and mediate the marked resistance to EAT induction.