Isolation and partial characterization of neurofibrillary tangles and amyloid plaque core in Alzheimer's disease: immunohistological studies

Fractions enriched in neurofibrillary tangles (NFT) and amyloid fibrils were isolated from the cerebral cortex of three cases of senile dementia of the Alzheimer type. Distilled water suspensions of these fractions were excluded from all pore size gels and resisted digestion with various proteolytic enzymes. Formic acid/chloroform treatment of each fraction resulted in the appearance of 4,000-6,000, 15,000-17,000 and 24,000 molecular weight proteins, with concomitant diminution in the amount of excluded material at the top of each gel. The 4,000-6,000 dalton band was best seen in fractions containing randomly arranged amyloid fibrils, and its amino acid composition resembled that of the recently reported "beta" protein. A polyclonal antiserum to purified NFT reacted with tangles in neurons and in dystrophic neurites around plaques by immunoperoxidase staining. No reaction was obtained with cerebrovascular or plaque core amyloid immunohistologically, or with the 4-6 kD protein on immunoblots. Cross-reactivity with the neurofibrillary lesions occurring in Pick's disease, progressive supranuclear palsy, postencephalitic Parkinsonism and dementia pugilistica was also seen. Specific binding of this antiserum to the double filamentous structure was confirmed by immunoelectron microscopy. Although the presence of "beta" protein in both NFT and amyloid-containing fractions suggests that it may be an important constituent of both, cross-contamination cannot be excluded.     

Association study of IRAK-M and SIGIRR genes with SLE in a large European-descent population

Objective: The aim of this study was to evaluate the relevance of genetic variants of interleukin receptor-associated kinase-M (IRAK-M) (rs11465955, rs1624395, rs1152888 and rs1370128) and single immunoglobulin IL1-1R-related molecule (SIGIRR) (rs3210908) genes in systemic lupus erythematosus (SLE) in four independent European-descent populations. Methods: Our study population consisted of a total of 2033 SLE patients and 2357 healthy controls from Spain, Germany, Italy and Argentina. The genotyping was performed using a polymerase chain reaction (PCR) system with pre-developed TaqMan allelic discrimination assay. Genetic association between the genotyped markers was determined by PLINK v1.07. Results: After a meta-analysis including these four populations, a trend of association between rs11465955 (P(meta) (-analysis) =?0.06), rs1370128 (P(meta) (-analysis) =?0.07) and rs1624395 (P(meta) (-analysis) =?0.06) polymorphisms was found. However, these differences did not reach statistical significance. In addition, we did not find any association between SLE and the rs1152888 IRAK-M (P(meta) (-analysis) =?0.13) and the rs3210908 SIGIRR (P(meta) (-analysis) =?0.40) polymorphisms after the meta-analysis. No evidence of association with IRAK-M haplotypes was found. Conclusion: These results suggest that the tested variations of IRAK-M and SIGIRR genes do not confer a relevant role in the susceptibility to SLE in European-descent populations.     

Syndemic and syndemogenesis of low back pain in Latin-American population: a network and cluster analysis

Clinical Rheumatology - Although low back pain (LBP) is a high-impact health condition, its burden has not been examined from the syndemic perspective. To compare and assess clinical,...     

Sequence similarities among kappa IIIb chains of monoclonal human IgM kappa autoantibodies

Light chains of the serologically and chemically defined V region sub- subgroup kappa IIIb are preferentially associated with several types of human IgM kappa (monoclonal) autoantibodies and are remarkably homologous in primary structure, as evidenced by partial amino acid sequence data. To establish the extent of homology among such proteins, we have determined the complete variable region (V) sequence of the light chains of four monoclonal IgM kappa autoantibodies, of which two (GAR and GOT) are rheumatoid factors (RFs), the third (SON) has anti- apo beta lipoprotein specificity, and the fourth (PIE) binds specifically to intermediate filaments. The region encoded by the V kappa segment gene (positions 1-95) in all four light (L) chains is virtually identical in sequence, differing by only one residue in the FR3 of protein SON and in the first CDR of protein GOT. Further, the CDR3 of kappa chain SON contains an additional residue (prolyl) located at the carboxyl-terminus of the V segment. The region encoded by the J gene (positions 96-108) is identical after position 96 for the two RFs GAR and GOT (J kappa 2), but different in proteins SON (J kappa 4) and PIE (J kappa 1). The amino acid residue at position 96, located in CDR3 at the site of combinatoriaL joining of the V kappa and J kappa gene segments and involved as a contacting residue in the hapten binding site, is different in all four light chains. These results demonstrate the extensive homology in sequence among light chains of IgM kappa autoantibodies and indicate that a particular V kappa germ line gene, kappa IIIb, is expressed as a phylogenetic response to certain self antigens or as part of a selection process by which these autoimmune responses are regulated.     

Epidemiology of systemic lupus erythematosus

Introduction: Systemic lupus erythematosus (SLE) is a disease distributed worldwide, which occurs in both genders, and across racial/ethnic and age groups; however, higher rates are observed in adults, in women and in non-Caucasians. Genetic, environmental, sociodemographic and methodological issues are responsible not only for these differences but for the variable course and outcome of the disease. Non-Caucasians have a more severe disease with a higher risk for early mortality and damage accrual. Males also have a more severe disease; however, a negative impact of male gender on lupus outcomes has not been firmly established. Childhood-onset is associated with a more severe disease; moreover, it is also associated with higher damage and diminished survival; finally, late-onset lupus is mild but it is associated with higher damage accrual and a diminished survival.

Areas covered: In this review, we discuss the incidence and prevalence of SLE, the impact of age, gender and race/ethnicity in SLE and in the survival of those affected.

Expert commentary: Age, gender and race/ethnicity impact disease expression in SLE patients; despite improvements in survival, mortality in SLE remains almost three times higher than in the general population.     

Clinical predictors of remission and low disease activity in Latin American early rheumatoid arthritis: data from the GLADAR cohort

Objectives

To identify baseline predictors of remission and low disease activity (LDA) in early rheumatoid arthritis (RA) from the GLADAR (Grupo Latino Americano De estudio de la Artritis Reumatoide) cohort.

Methods

Patients with 1- and 2-year follow-up visits were included. Remission and LDA were defined by DAS28-ESR (< 2.6 and ≤ 3.2, respectively). Baseline predictors examined were gender, ethnicity, age at diagnosis, socioeconomic status, symptoms’ duration, DMARDs, RF, thrombocytosis, anemia, morning stiffness, DAS28-ESR (and its components), HAQ-DI, DMARDs and corticosteroid use, and Sharp-VDH score. Multivariable binary logistic regression models (excluding DAS28-ESR components to avoid over adjustment) were derived using a backward selection method (α-level set at 0.05).

Results

Four hundred ninety-eight patients were included. Remission and LDA/remission were met by 19.3% and 32.5% at the 1-year visit, respectively. For the 280 patients followed for 2 years, these outcomes were met by 24.3% and 38.9%, respectively. Predictors of remission at 1 year were a lower DAS28-ESR (OR 1.17; CI 1.07–1.27; p = 0.001) and HAQ-DI (OR 1.48; CI 1.04–2.10; p = 0.028). At 2 years, only DAS28-ESR (OR 1.40; CI 1.17–1.6; p < 0.001) was a predictor. Predictors of LDA/remission at 1 year were DAS28-ESR (OR 1.42; CI 1.26–1.61; p < 0.001), non-use of corticosteroid (OR 1.74; CI 1.11–2.44; p = 0.008), and male gender (OR 1.77; CI 1.2–2.63; p = 0.036). A lower baseline DAS28-ESR (OR 1.45; CI 1.23–1.70; p < 0.001) was the only predictor of LDA/remission at 2 years.

Conclusions

A lower disease activity consistently predicted remission and LDA/remission at 1 and 2 years of follow-up in early RA patients from the GLADAR cohort.

The GLADEL multinational Latin American prospective inception cohort of 1,214 patients with systemic lupus erythematosus: ethnic and disease heterogeneity among "Hispanics"

Clinical and laboratory manifestations and outcome of systemic lupus erythematosus (SLE) may vary in different populations. A prospective multinational inception cohort should prove useful in identifying the influence of ethnicity on the clinical characteristics of SLE. We therefore analyzed clinical, laboratory, and prognostic variables in Latin American SLE patients with disease of recent onset who were entered into a prospective cohort, and compared these variables in the cohort's 3 major ethnic groups. Thirty-four centers from 9 Latin American countries participated by randomly incorporating SLE patients within 2 years of diagnosis into a standardized database. Participating centers were selected for their expertise in diagnosing and managing SLE. We were then able to evaluate prospectively socioeconomic variables, ethnicity, type of medical care, clinical and laboratory features, disease activity, damage, and mortality at each site. A coordinating center controlled the quality of the information submitted.Of the 1,214 SLE patients included in the cohort, 537 were mestizos, 507 were white, and 152 were African-Latin American (ALA). (There were also small numbers of pure Amerindian and oriental individuals.) Significant differences were found between them in socioeconomic characteristics, type of care, and level of education favoring whites. Mestizos and ALA were younger at onset. Delay to diagnosis and disease duration was shorter in ALA. Fever was more frequent in whites; discoid lesions in ALA; renal disease and lymphopenia in mestizos and ALA. Although we found differences in background variables between ethnic groups from different countries, mestizos from 2 distant countries (Argentina and Mexico) were clinically akin and showed similar differences to whites. Mortality was associated with lower education, poor medical coverage, and shorter follow-up. In an exploratory model nonwhite ethnicity was associated with renal disease and lymphopenia, damage, and cumulative American College of Rheumatology criteria. These differences in clinical, prognostic, socioeconomic, educational, and access to medical care features in Latin American lupus patients of 3 major ethnic groups from 9 different countries may have an impact on the patients' disease. "Hispanics," as they have come to be generically termed on the basis of language, actually constitute a markedly heterogeneous group of subjects.     

Recambio plasmático en las enfermedades autoinmunes sistémicas

Therapeutic apheresis encompasses a large number of techniques whose main purpose is to process patients’ blood through an extracorporeal device. The aim is to remove antibodies and preformed immune complex to avoid tissue damage, eliminate inflammatory mediators – such as complement and cytokines, which could contribute to further damage – restore deficiencies, and stimulate lymphocyte clones to improve the response to immunosuppressive therapy.Among the different types of apheresis, the most commonly used for the treatment of autoimmune diseases are plasma exchange and immunoadsorption.To aid the correct use of these procedures, the American Society for Apheresis has established more than 65 indications classified into different categories according to the level of evidence. In this review, we analyze the distinct therapeutic indications for the treatment of different autoimmune diseases.This review indicates that plasma exchange is a safe and effective therapeutic option for treating the serious manifestations of systemic autoimmune diseases and is a valid option for those patients with diseases refractory to conventional treatments.