Disease progression in sporadic inclusion body myositis: observations in 78 patients.

Functional decline for each decade at symptom onset and need for cane, walker, or wheelchair were assessed in 78 biopsy-proved patients with sporadic inclusion body myositis. Patients with disease onset between 40 and 59 years used a walker after 10.2 +/- 5.8 years, whereas those with disease onset between 60 and 79 years used a walker after 5.7 +/- 5.0 years (p = 0.05). Because patients progress faster to disability when symptoms begin after the age of 60, age at disease onset may define patient subsets for stratification in clinical trials.

HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies.

We studied the HLA class II associations in patients with sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) and attempted to distinguish these myopathies on the basis of HLA allele assignments. Forty-five patients, 30 with s-IBM and 15 with h-IBM, underwent HLA class II allele-specific typing using polymerase chain reaction sequence-specific primers for 71 alleles contained in the DRbeta1, DRbeta3-5, and DQbeta1 loci. In s-IBM, we found a high (up to 77%) frequency of DRbeta1*0301, DRbeta3*0101 (or DRbeta3*0202) and DQbeta1*0201 alleles. No significant association with alleles in the DR and DQ haplotypes was found among the 15 h-IBM patients. The strong association of prominent alleles with s-IBM, but not h-IBM, suggests that s-IBM is a distinct disorder with an immunogenetic background that differs from h-IBM.

Immune-mediated conditions and antibodies associated with sporadic inclusion body myositis.

We reviewed 99 patients with sporadic inclusion body myositis (IBM), searching for a coexisting autoimmune disease, other conditions with altered immune function, or the presence of autoantibodies. Thirteen patients had one or more of 11 diseases with altered immune function. Forty-three patients had elevated titers of one or more of nine different, albeit nondisease-specific, autoantibodies. Twenty-five patients had dysproteinemia or dysproteinuria. We conclude that IBM is frequently associated with systemic immune disorders or nonspecific autoantibodies. Although aging may explain some of these phenomena, an altered immune function need to be considered in the pathogenesis of IBM.

Safety and efficacy of strength training in patients with sporadic inclusion body myositis.

We studied the effects of a 12-week progressive resistance strength training program in weakened muscles of 5 patients with sporadic inclusion body myositis (IBM). Strength was evaluated with Medical Research Council (MRC) scale ratings and quantitative isometric and dynamic tests. Changes in serum creatine kinase (CK), lymphocyte subpopulations, muscle size (determined by magnetic resonance imaging), and histology in repeated muscle biopsies were examined before and after training. After 12 weeks, the values of repetition maximum improved in the least weakened muscles, 25-120% from baseline. This dynamic effect was not captured by MRC or isometric muscle strength measurements. Serum CK, B cells, T-cell subsets, and NK cells remained unchanged. Repeat muscle biopsies did not reveal changes in the number and degree of degenerating fibers or inflammation. The size of the trained muscles did not change. We conclude that a supervised progressive resistance training program in IBM patients can lead to gains in dynamic strength of the least weak muscles without causing muscle fatigue and muscle injury or serological, histological, and immunological abnormalities. Even though the functional significance of these gains is unclear, this treatment modality is a safe and perhaps overlooked means of rehabilitation of IBM patients.

Effect of high-dose intravenous immunoglobulin on serum chemistry, hematology, and lymphocyte subpopulations: assessments based on controlled treatment trials in patients with neurological diseases.

The effect of intravenous immunoglobulin (IVIG) on various laboratory values was measured immediately before and after completion of serial monthly infusions of IVIG (2 g/kg) or an equal volume of placebo over 3-12 months, in 46 patients with neuromuscular diseases participating in controlled trials. Hematological, lymphocyte subpopulation, and chemistry values were analyzed and compared. After IVIG, but not placebo, a 34% reduction in lymphocytes was noted in 44/46 patients with a selective reduction of the T cells, but not the B or IL2R-positive cells. Counts returned to baseline within 30 days. Creatine kinase levels decreased by 23% and sedimentation rate increased by 275% after IVIG infusion. A nondilutional, artifactual, hyponatremia and hypomagnesemia was noted with IVIG but not placebo. We conclude that IVIG affects a variety of serum chemistry and hematological values either directly or artifactually by interfering with the laboratory method used for the assays. Transient lymphopenia is consistently seen, and may play a role in the immunomodulating effect of IVIG.

Identification of gonadal steroid receptors in meningiomas from dogs and cats.

Cytosolic assay was used to detect gonadal steroid receptors in brain tumor tissue from 6 dogs and 2 cats. For 4 samples, the maximal number of binding sites and the equilibrium dissociation constant were calculated, using Scatchard analysis. The concentration of receptor protein that was discovered was similar to that detected in hormone-sensitive tumors.

pH dependence of the kinetic parameters for 3-oxo-delta 5-steroid isomerase. Substrate catalysis and inhibition by (3S)-spiro[5 alpha-androstane-3,2'-oxiran]-17-one.

The pH-rate profiles for kcatobsd and (kcat/KM)obsd at 25.0 degrees C have been measured for 3-oxo-delta 5-steroid isomerase by using 5-androstene-3,17-dione (2), 5-pregnene-3,20-dione (3), and 5(10)-estrene-3,17-dione (4) as substrates. Results from the nonsticky substrate 4 suggest values for the pK of a catalytically important group on the free enzyme (pKE) of 4.57 and the pK of the same group in the enzyme-substrate complex of 4.74. For the sticky substrates 2 and 3, pKES is ca. 4.75 and 5.5, respectively. Analysis of the (kcat/KM)obsd vs. pH profile for 2 reveals that the intermediate E X S complex decomposes to products at a rate similar to its reversion to E + S. The pH-rate profile for inhibition of the isomerase by (3S)-spiro-[5 alpha-androstane-3,2'-oxiran]-17-one (7 beta) shows values for pKE of 4.75 and pKEI of 4.90. The similarity of the pH-rate profiles for isomerization of 4 and inhibition by 7 beta suggests that both reactions may be governed by the ionization state of the same carboxyl group of the enzyme.

4-Dimethylaminoazobenzenes: carcinogenicities and reductive cleavage by microsomal azo reductase.

Twenty-four 4-dimethylaminoazobenzenes (DABs) in which systematic structural modifications have been made in the prime ring have been studied for substrate specificity for microsomal azo reductase. The DABs were also evaluated for carcinogenicity and it was found that there was no correlation between carcinogenicity and extent of azo bond cleavage by azo reductase. While any substituent in the prime ring reduces the rate of cleavage of the azo bond relative to the unsubstituted dye, there is a correlation between substituent size and susceptibility to the enzyme. Substituent size was also found to be a significant factor in the induction of hepatomas by the dyes. Preliminary studies have shown that there appears to be a positive correlation between microsomal riboflavin content and the activity of the azo reductase.