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Objective: Distinguishing immunoglobulin G4 (IgG4)-related disease ocular involvement (IgG4-ROD) from other non-IgG4 pathologies in the orbit and eyeball is often complex. The objective was to compare clinical, analytical, imaging, and anatomopathological features of IgG4-ROD with other inflammatory and/or autoimmune ocular diseases (non-IgG4-ROD). Methods: An observational, descriptive, and retrospective study included 18 patients diagnosed with IgG4-ROD according to Umehara’s 2011 and/or 2020 comprehensive criteria, from 3 centers. Additionally, 12 patients with non-IgG4-ROD between 2014 and 2022 were selected, forming 2 groups. Data collection involved visualizing medical records. Demographic profile, clinical manifestations, analytical, histopathological, and radiological findings were analyzed using SPSS Statistics 19. Categorical variables were presented as frequencies and percentages, and continuous variables as means with standard deviation or median with interquartile range. Proportions were compared using the chi-square test, and means and medians were compared using T-tests and nonparametric tests. A confidence level of α=.05 was selected. Results: Thirty patients were analyzed: 18 with IgG4-ROD and 12 with non-IgG4-ROD. Among the latter, diagnoses included Histiocytosis (n=4), Amyloidosis (n=3), malignant secondary malignancy (n=2), and other conditions (n=3). Female sex predominated in IgG4-ROD (78% vs. 50%, P=.12). Mean age was 44 years, with no group difference (P=.26). Bilateral involvement was more common in non-IgG4 (92% vs. 72%, P=.21). Predominant symptoms in IgG4-ROD were proptosis, ocular pain, xerophthalmia, palpebral edema, and diplopia, while palpebral edema and ocular motility disturbance were more usual in other pathologies. Proptosis, xerophthalmia, and diplopia were significantly more frequent in IgG4-ROD (P=.042, P=.021, P=.021, respectively). Parotid involvement showed significant association in IgG4-ROD at 33% (P=.031). Statistically significant differences were observed in elevated serum IgG4 levels (67%, P=.002), IgG (P=.037), and IgG2 levels ≥ 5.3 g/L (56%, P=.023) in IgG4-ROD. There was also a significant difference between the association of eosinophilia and the non-IgG4 group (67% vs. 22%, P=.034), as did mean serum IgG value and the IgG4-ROD group (P=.037). Lacrimal gland involvement associated with IgG4-ROD (P=.032). Histopathologically, IgG4- ROD showed significant associations with lymphoplasmacytic infiltrate (100%, P=.004), storiform fibrosis (36%, P=.05), and presence of Eosinophils (64%, P=.003). Conclusion: Immunoglobulin G4-related ophthalmic disease showed significant associations with xerophthalmia, proptosis, diplopia, and parotid involvement. Elevated serum IgG4, IgG, and IgG2 levels were also linked to this condition. Imaging studies revealed lacrimal gland involvement. Furthermore, lymphoplasmacytic infiltrate, storiform fibrosis, and eosinophil presence were significant in histopathological findings. Conversely, serum eosinophilia, bilateral involvement, and palpebral edema in imaging studies were statistically related to the non-IgG4 group.

In Saccharomyces cerevisiae, the CBC-Tif4631p-dependent exosomal targeting (CTEXT) complex consisting of Cbc1/2p, Tif4631p and Upf3p promotes the exosomal degradation of aberrantly long 3'-extended, export-defective transcripts and a small group of normal (termed 'special') mRNAs. We carried out a systematic analysis of all previously characterized functional domains of the major CTEXT component Tif4631p by deleting each of them and interrogating their involvement in the nuclear surveillance of abnormally long 3'-extended and export-defective messages. Our analyses show that the N-terminal RNA recognition motif 1 (RRM1) and poly(A)-binding protein (PAB) domains of Tif4631p, spanning amino acid residues, 1-82 and 188-299 in its primary structure, respectively, play a crucial role in degrading these aberrant messages. Furthermore, the physical association of the nuclear exosome with the altered/variant CTEXT complex harboring any of the mutant Tif4631p proteins lacking either the RRM1 or PAB domain becomes abolished. This finding indicates that the association between CTEXT and the exosome is accomplished via interaction between these Tif4631p domains with the major exosome component, Rrp6p. Abolition of interaction between altered CTEXT (harboring any of the RRM1/PAB-deleted versions of Tif4631p) and the exosome further leads to the impaired recruitment of the RNA targets to the Rrp6p subunit of the exosome carried out by the RRM1/PAB domains of Tif4631p. When analyzing the Tif4631p-interacting proteins, we identified a DEAD-box RNA helicase (Dbp2p), as an interacting partner that turned out to be a previously unknown component of CTEXT. The present study provides a more complete description of the CTEXT complex and offers insight into the functional relationship of this complex with the nuclear exosome., (© 2023 Federation of European Biochemical Societies.)

Allenyl carbonate was used as a 1,3-butadiene surrogate to develop a photocatalytically sustainable protocol for cobalt-catalyzed crotylation of aldehydes. The developed method tolerated a wide range of aromatic and aliphatic aldehydes with retention of functional groups under mild conditions and produced good-to-excellent yields of crotylated secondary alcohols. Based on preliminary mechanistic studies and literature precedents, a plausible mechanism is proposed.

Rosai-Dorfman disease is characterized by dilated lymph node sinuses filled with lymphocytes, plasma cells, and histiocytes. Many of these histiocytes classically exhibit emperipolesis of lymphocytes and plasma cells. Abundant immunoglobulin G4+ plasma cells occur in some cases, and a potential relationship with immunoglobulin G4-related disease has been suggested. Here, we report 3 cases of immunoglobulin G4-associated Rosai-Dorfman disease. Immunoglobulin G4-related disease was suspected based on immunoglobulin G4+ plasma cell infiltration, but the final diagnosis was immunoglobulin G4-associated Rosai-Dorfman disease. At present, the evidence does not support a link between immunoglobulin G4-associated Rosai-Dorfman disease and immunoglobulin G4-related disease, and one condition should not be considered part of the spectrum of the other. We believe it is of paramount importance to increase the awareness of immunoglobulin G4-associated Rosai-Dorfman disease for pathologists who interpret the biopsies and clinicians who integrate the diagnosis and treat such patients to not overdiagnose immunoglobulin G4-related disease.

Induction of unfolded protein response involves activation of transcription factor Hac1p that is encoded by HAC1 pre-mRNA harboring an intron and a bipartite element (BE), which is subjected to nuclear mRNA decay by the nuclear exosome/Cbc1p-Tif4631p-dependent Exosome Targeting (CTEXT) complex. Using a combination of genetic and biochemical approaches, we demonstrate that a Rab-GTPase Ypt1p controls unfolded protein response signaling dynamics. This regulation relies on the nuclear localization of a small fraction of the cellular Ypt1p pool in the absence of endoplasmic reticulum (ER)-stress causing a strong association of the nuclear Ypt1p with pre- HAC1 mRNA that eventually promotes sequential recruitments of NNS, CTEXT, and the nuclear exosome onto this pre-mRNA. Recruitment of these decay factors onto pre- HAC1 mRNA is accompanied by its rapid nuclear decay that produces a precursor RNA pool lacking functional BE thereby causing its inefficient targeting to Ire1p foci leading to their diminished splicing and translation. ER stress triggers rapid relocalization of the nuclear pool of Ypt1p to the cytoplasm leading to its dissociation from pre- HAC1 mRNA thereby causing decreased recruitment of these decay factors to precursor HAC1 RNA leading to its diminished degradation. Reduced decay results in an increased abundance of pre- HAC1 mRNA with intact functional BE leading to its enhanced recruitment to Ire1p foci.

Persististrombus deperditus (Sowerby) from the Lower Miocene of Kutch, Gujarat, western India is represented by two size classes in our collection. Statistical analyses discriminate the size morphs. Large size variations generally result from either (1) sexual differences or (2) ecophenotypic causes. All the living species of the family Strombidae, wherever examined, are characterized by sexual size dimorphism (SSD). Persististrombus deperditus shares all the characters of SSD in these recent species. Size variations due to difference in ecological factors generally occur in allopatric populations. Similar variations are known to characterize sympatric sub-populations of molluscs living only in the intertidal zone, where upper and lower shorefaces differ significantly in physico-chemical and biological properties. Persististrombus deperditus comes from a stable shelf setting that received less siliciclastic input in response to transgression. Hence, its size dimorphism is considered to have sexual origin. This is the first report of SSD in a fossil strombid gastropod. It is argued that fecundity selection was the primary driving force behind the evolution of SSD in this gonochoristic gastropod species. Hence, the larger morph is the female., Competing Interests: We have no competing interests.

Unfolded protein response (UPR) is triggered by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), which is accomplished by a dramatic induction of genes encoding ER chaperones. Activation of these genes involves their rapid transcription by Hac1p, encoded by the HAC1 precursor transcript harboring an intron and a bipartite element (3'-BE) in the 3'-UTR. ER stress facilitates intracellular targeting and recruitment of HAC1 pre-mRNA to Ire1p foci (requiring 3'-BE), leading to its non-spliceosomal splicing mediated by Ire1p/Rlg1p. A critical concentration of the pre-HAC1 harboring a functional 3'-BE element is governed by its 3'→5' decay by the nuclear exosome/DRN. In the absence of stress, pre-HAC1 mRNA undergoes a rapid and kinetic 3'→5' decay leading to a precursor pool, the majority of which lack the BE element. Stress, in contrast, causes a diminished decay, thus resulting in the production of a population with an increased abundance of pre-HAC1 mRNA carrying an intact BE, which facilitates its more efficient recruitment to Ire1p foci. This mechanism plays a crucial role in the timely activation of UPR and its prompt attenuation following the accomplishment of homeostasis. Thus, a kinetic mRNA decay provides a novel paradigm for mRNA targeting and regulation of gene expression.

Calciphylaxis has been defined as tissue sensitivity to calcification, described mainly in patients with chronic renal insufficiency, renal transplant, or parathyroid dysfunction. There are few cases described in patients with rheumatoid arthritis that do not suffer from renal failure or hyperparathyroidism. Another case is presented of calciphylaxis in a woman with inactive rheumatoid arthritis., (Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

We describe the case of a 51-year-old woman with a seropositive, erosive, and non-nodular rheumatoid arthritis of 15 year of evolution. The patient had poor compliance with medical visits and treatment. She came to the clinic with persistent pancytopenia and spleen and liver enlargement. Liver and bone marrow biopsies were carried out and amyloidosis, neoplasias and infections were ruled out. We discuss the differential diagnosis of pancytopenia and spleen and liver enlargement in a long-standing rheumatoid arthritis patient., (Copyright © 2014 Elsevier España, S.L.U. All rights reserved.)

Objective: To identify susceptibility loci for rheumatoid arthritis (RA) in Latin American individuals with admixed European and Amerindian genetic ancestry., Methods: Genotyping was performed in 1,475 patients with RA and 1,213 control subjects, using a customized BeadArray containing 196,524 markers covering loci previously associated with various autoimmune diseases. Principal components analysis (EigenSoft package) and Structure software were used to identify outliers and define the population substructure. REAP software was used to define cryptic relatedness and duplicates, and genetic association analyses were conducted using Plink statistical software., Results: A strong genetic association between RA and the major histocompatibility complex region was observed, localized within BTNL2/DRA-DQB1- DQA2 (P = 7.6 × 10(-10) ), with 3 independent effects. We identified an association in the PLCH2-HES5-TNFRSF14-MMEL1 region of chromosome 1 (P = 9.77 × 10(-6) ), which was previously reported in Europeans, Asians, and Native Canadians. We identified one novel putative association in ENOX1 on chromosome 13 (P = 3.24 × 10(-7) ). Previously reported associations were observed in the current study, including PTPN22, SPRED2, STAT4, IRF5, CCL21, and IL2RA, although the significance was relatively moderate. Adjustment for Amerindian ancestry improved the association of a novel locus in chromosome 12 at C12orf30 (NAA25) (P = 3.9 × 10(-6) ). Associations with the HLA region, SPRED2, and PTPN22 improved in individuals positive for anti-cyclic citrullinated peptide antibodies., Conclusion: Our data define, for the first time, the contribution of Amerindian ancestry to the genetic architecture of RA in an admixed Latin American population by confirming the role of the HLA region and supporting the association with a locus in chromosome 1. In addition, we provide data for novel putative loci in chromosomes 12 and 13., (Copyright © 2013 by the American College of Rheumatology.)

We describe a 42-year old woman with inactive systemic lupus erythematosus (SLE) at the time of her visit. She presented with an atypical movement disorder and partial continuous epilepsy. A brain biopsy excluded cerebral vasculitis and tumoral processes. We discuss the differential diagnosis of status epilepticus in a patient with systemic lupus erythematosus., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Objective: To examine the main clinical and laboratory data of patients initially diagnosed with polymyalgia rheumatica (PMR), which then developed another conditions., Material and Methods: We reviewed the clinical records of patients diagnosed with PMR in three hospitals in Argentina. Patients had a diagnosis of PMR if they met the following criteria: age ≥ 50 years, erythrocyte sedimentation rate (ESR) at the time of diagnosis > 40 mm, persistent pain and stiffness of at least one month of evolution in two of the following areas: neck, shoulders or proximal arms, hips or proximal lower limbs. Special attention was paid to symptoms or signs of "alarm" (beginning or during disease progression) for suspecting the presence of other non PMR disease within a period of ≤ 12 months., Results: Sixteen of the 200 patients (8%) had other diseases during follow up. Malignancies (n=4) and rheumatic diseases (n=4) were the most common entities, in addition to infective endocarditis (n=1), narrow cervical canal (n=1), Parkinson's disease (n=1), statin-related myalgia (n=1), hypothyroidism (n=1), vitamin D deficiency (n=1) and Calcium Pyrophosphate Deposition Disease (CPDD) (n=2). The average length change of diagnosis was 4.5±3 months. Ten patients had no response to steroids and two had persistently elevated ESR., Conclusion: In this study we highlight the importance of recognizing signs and symptoms along with laboratory data and lack of response to treatment as suspects for the diagnosis of other disease manifestations in patients with PMR symptoms., (Copyright © 2010 Elsevier España, S.L. All rights reserved.)

Objective: The aim of the present study is to describe the general characteristics of a cohort of patients with early arthritis in Argentina., Methods: CONAART (Consorcio Argentino de Artritis Temprana--Argentine Consortium for Early Arthritis) is an initiative of seven rheumatology centres across Argentina. Patients were included if they had at least one or more swollen joints and <2 years of disease duration. Social, demographic, familiar, hereditary, clinical and laboratory data were recollected. At first visit and every year, X-rays of hands and feet were performed and working characteristics and pharmaco-economic data were re-collected., Results: A total of 413 patients were included. Of them, 327 (79.2%) were women with a median age of 49 years and a median disease duration of 6 months. Of the total, 183 (44.3%) had RA (ACR 1987) and 167 (40.4%) undifferentiated arthritis (UA). Other diagnoses included: 12 crystalics, 11 PsA, 6 uSpA, 6 other CTD, 1 AS and 27 other diagnosis. As 85% of our population had RA and UA, we only compared these two groups of patients. Patients with RA had significantly worse activity parameters of the disease (DAS of 28 joints), functional capacity (HAQ) and quality of life (Rheumatoid Arthritis Quality of Life) than patients with UA. The frequency of RF and anti-CCP, and symmetrical distribution were also significantly higher in patients with RA compared with UA patients. All patients with RA initiated early specific treatment, in a period no longer than 6 months from the beginning of the disease., Conclusion: Early arthritis clinics are a useful tool to identify and treat patients with different forms of joint involvement.

Objective: To investigate 1 functional (rs17266594) and 2 potentially functional (rs10516487 and rs3733197) BANK1 variants, which were previously identified as systemic lupus erythematosus (SLE) susceptibility markers, to test whether they are associated with rheumatoid arthritis (RA)., Methods: Four different cohorts were included in the study: 1,080 RA patients and 1,368 healthy controls from Spain, 278 RA patients and 568 healthy controls from Sweden, 288 RA patients and 287 healthy controls from Argentina, and 288 RA patients and 288 healthy controls from Mexico. Samples were genotyped for BANK1 single-nucleotide polymorphisms (SNPs) using a TaqMan 5'-allele discrimination assay. Statistical analysis comparing allele and genotype distributions was performed with the chi-square test., Results: We did not find a significant association between RA and the rs10516487 and rs17266594 BANK1 polymorphisms. However, there was an increase in the major alleles among RA patients. Similarly, for rs3733197, there was an increase in the major allele among patients in every cohort. Nevertheless, this skewing reached statistical significance in the Spanish (P = 0.01, odds ratio [OR] 1.17 [95% confidence interval (95% CI) 1.03-1.32]) and Argentinean (P = 0.04, OR 1.31 [95% CI 1.00-1.72]) populations. We found a significant association of rs10516487 (P = 0.005, OR 1.15 [95% CI 1.04-1.28]) and rs3733197 (P = 0.0009, OR 1.17 [95% CI 1.07-1.29]) with RA in the pooled analysis. In a 3-SNP haplotype analysis, we found that the major TGG haplotype was significantly associated with RA (P = 0.005, OR 1.14 [95% CI 1.04-1.25]). In addition, we found a common CAA haplotype that was protective against RA (P = 0.0004, OR 0.82 [95% CI 0.74-0.92])., Conclusion: These results suggest that BANK1 SNPs and haplotypes may contribute to RA susceptibility with a low risk.

Objective: Recent findings suggest that interferon regulatory factor 5 (IRF-5) may play a crucial role in several cellular processes, including the transcription of genes for inflammatory cytokines. Two genetic variants of the IRF5 gene (rs2004640 in exon 1 and rs2280714 in the 3'-untranslated region) have been shown to exert functional modifications affecting IRF5 messenger RNA splicing and expression, and have been associated with genetic predisposition to systemic lupus erythematosus (SLE). The aim of this study was to analyze the possible contribution of the IRF5 gene to the predisposition to rheumatoid arthritis (RA)., Methods: Three case-control cohorts from Spain (724 RA patients and 542 healthy controls), Sweden (281 RA patients 474 healthy controls), and Argentina (284 RA patients and 286 healthy controls) were independently analyzed. Genotyping for IRF5 rs2004640 and rs2280714 was performed using a TaqMan 5' allele-discrimination assay., Results: In the 3 cohorts studied, no statistically significant differences in allele or genotype frequencies of the rs2004640 and rs2280714 IRF5 polymorphisms were observed between RA patients and controls. Accordingly, haplotype analysis revealed that none of the IRF5 haplotypes was associated with genetic predisposition to RA., Conclusion: Our results suggest that the IRF5 functional polymorphisms analyzed do not seem to be implicated in genetic susceptibility to RA.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of autoantibodies against intracellular components, the formation of immune complexes, and inflammation in various organs, typically the skin and kidney glomeruli. The etiology of the disease is not well understood but is most likely the result of the interaction between genetic and environmental factors. In order to identify susceptibility loci for SLE, we have performed genome scans with microsatellite markers covering the whole genome in families from Argentina, Italy, and Europe. The results reveal a heterogeneous disease with different susceptibility loci in different family sets. We have found significant linkage to chromosome 17p12-q11 in the Argentine set of families. The maximum LOD score was given by marker D17S1294 in combination with D17S1293, when assuming a dominant inheritance model (Z = 3.88). We also analyzed a repeat in the promoter region of the NOS2A gene, a strong candidate gene in the region, but no association was found. The locus on chromosome 17 has previously been identified in genetic studies of multiple sclerosis families. Several other interesting regions were found at 1p35, 1q31, 3q26, 5p15, 11q23 and 19q13, confirming previously identified loci for SLE or other autoimmune diseases., (Copyright 2004 Springer-Verlag)