Increased salivary syndecan-1 level is associated with salivary gland function and inflammation in patients with Sjögren's syndrome.

OBJECTIVE: Syndecan-1 (SDC-1), a transmembrane heparin sulphate proteoglycan predominantly expressed on epithelial cells, also exists in a soluble form through ectodomain shedding. SDC-1 expression and shedding may be modulated in the inflammatory milieu of primary Sjögren's syndrome (SS). We investigated SDC-1 expression in minor salivary glands (MSGs) and analysed the association between salivary or plasma levels of SDC-1 and clinical parameters in SS. METHOD: We measured salivary and plasma SDC-1 levels via an enzyme-linked immunosorbent assay and assessed the salivary flow rates (SFRs) in 70 patients with SS and 35 healthy subjects. Disease activity indices, serological markers, salivary gland scintigraphy, and MSG biopsy were evaluated in patients with SS. RESULTS: SDC-1 expression was upregulated on ductal epithelial cells in inflamed salivary glands. Salivary SDC-1 levels in patients significantly exceeded those in healthy subjects [median (interquartile range) 49.0 (20.7-79.1) vs 3.7 (1.7-6.3) ng/mL, p < 0.001] and inversely correlated with SFRs (r = -0.358, p = 0.032) and ejection fractions of the parotid (r = -0.363, p = 0.027) and submandibular (r = -0.485, p = 0.002) glands in salivary gland scintigraphy. Plasma SDC-1 levels were significantly correlated with the EULAR Sjögren's Syndrome Disease Activity Index (r = 0.507, p < 0.001) and EULAR Sjögren's Syndrome Patient Reported Index (r = 0.267, p = 0.033). Focus scores were correlated with salivary SDC-1 levels (r = 0.551, p = 0.004). CONCLUSIONS: Salivary and plasma SDC-1 levels may constitute potential biomarkers for salivary gland function and disease activity, respectively, in SS.

Incidence and Distribution of the Pathogens Causing Central Nervous System Infections at the University Hospital of Korea.

BACKGROUND: The pathogens involved in central nervous system (CNS) infections are various, such as viruses, bacteria, and fungi, so a syndromic approach can be required. In addition, since their rapid and accurate detection is very crucial, molecular diagnostics using cerebrospinal fluid is becoming the emerging standard method. METHODS: The study was conducted retrospectively to identify the incidence and distribution patterns of the pathogens according to gender, age, season, and month and to analyze their codetection from August 2017 to July 2020. It was also conducted to investigate turn-around times (TATs) according to the detection method. The detection methods were FilmArray® Meningitis/Encephalitis (M/E) method (FilmArray), Cepheid® Xpert EV assay (Xpert), and Multiplex PCR method for five species of bacteria. RESULTS: The overall incidence for at least one pathogen was 13.9% (346/2,496). The highest incidence was shown in age group 4 (3 - 6 years), with 27.4%. The detection rates by FilmArray, Xpert, and Multiplex PCR method were 39.8%, 41.7%, and 0.4%, respectively. Enterovirus (EV) showed the highest incidence rate, which accounted for 37.0%. The distribution of the pathogens according to the age groups were the highest in age group 4, with 47.5% (168/354), followed by 27.4% (97/354) in age group 5. Of the ten cases in which bacteria were detected, S. agalactiae accounted for 60.0% (6/10), most of which occurred in age group 1. E. coli K1, L. monocytogenes, and N. meningitidis were not detected. In the viral distribution, EV accounted for the highest proportion in all age groups. The overall proportion of EV accounted for 87.6% (310/354), followed by human parechovirus with 2.8% (10/354). The most commonly detected season was summer, comprising 75.1%. A total of eight cases of co-detection with two pathogens accounted for 1.6% (8/507) in FilmArray. In FilmArray, all TATs were found to be shorter than Xpert. CONCLUSIONS: The information on the incidence and distribution patterns of the pathogens causing CNS infections and their rapid detection are critically important to clinicians in the management of immunocompromised patients, elderly, and children. The expeditious molecular diagnostics for these pathogens would be valuable in medical decisions by clinicians.

CCR5 gene polymorphism is a genetic risk factor for radiographic severity of rheumatoid arthritis.

The chemokine receptor [C-C chemokine receptor 5 (CCR5)] is expressed on diverse immune effecter cells and has been implicated in the pathogenesis of rheumatoid arthritis (RA). This study sought to determine whether single-nucleotide polymorphisms (SNPs) in the CCR5 gene and their haplotypes were associated with susceptibility to and severity of RA. Three hundred fifty-seven patients with RA and 383 healthy unrelated controls were recruited. Using a pyrosequencing assay, we examined four polymorphisms -1118 CTAT(ins) (/del) (rs10577983), 303 A>G (rs1799987), 927 C>T (rs1800024), and 4838 G>T (rs1800874) of the CCR5 gene, which were distributed over the promoter region as well as the 5' and 3' untranslated regions. No significant difference in the genotype, allele, and haplotype frequencies of the four selected SNPs was observed between RA patients and controls. CCR5 polymorphisms of -1118 CTAT(del) (P = 0.012; corrected P = 0.048) and 303 A>G (P = 0.012; corrected P = 0.048) showed a significant association with radiographic severity in a recessive model, and, as a result of multivariate logistic regression analysis, were found to be an independent predictor of radiographic severity. When we separated the erosion score from the total Sharp score, the statistical significance of CCR5 polymorphisms showed an increase; -1118 CTAT(ins) (/del) (P = 0.007; corrected P = 0.028) and 303 A>G (P = 0.007; corrected P = 0.028). Neither SNPs nor haplotypes of the CCR5 gene showed a significant association with joint space narrowing score. These results indicate that genetic polymorphisms of CCR5 are an independent risk factor for radiographic severity denoted by modified Sharp score, particularly joint erosion in RA.

Insular cortex is a trait marker for pain processing in fibromyalgia syndrome--blood oxygenation level-dependent functional magnetic resonance imaging study in Korea.

OBJECTIVES: To investigate the variability in cerebral activation according to pain intensity and the association between variability in cerebral activation and clinical features in patients with fibromyalgia syndrome (FMS) using functional magnetic resonance imaging (fMRI). METHODS: Nineteen FMS female patients and 22 age-matched healthy female controls were enrolled in this study. Changes in cerebral activation area were measured using blood oxygenation level-dependent (BOLD) contrast fMRI after application of both medium and high pressure stimuli to the left thumbnail bed. RESULTS: We identified the insular cortex (IC) and superior temporal gyrus (STG) as regions of interest (ROIs) in this analysis. Cerebral activation at the bilateral IC in response to high pressure stimuli was significantly greater in FMS patients than it was in the controls, whereas there were no differences in BOLD signal changes in the STG regions between FMS patients and controls, irrespective of pain level. Prominent signal changes at both ROIs in FMS patients were noted between high and medium pressure (p<0.001 contralateral IC, p=0.001 for ipsilateral IC, p=0.008 for contralateral STG, and p=0.049 for ipsilateral STG). BOLD signal changes on the contralateral STG after medium stimuli were correlated with tender point count (r=0.586, p=0.013). CONCLUSIONS: This study revealed more distinct signal variability in the ICs in FMS patients than in those of controls in response to high pressure stimuli. The IC can therefore be considered to be a region susceptible to pain perception in FMS patients.

Functional variability of the adenosine A3 receptor (ADORA3) gene polymorphism in aspirin-induced urticaria.

BACKGROUND: To improve understanding of aspirin hypersensitivity, this study focused on adenosine as a noncyclooxygenase target molecule of aspirin. Adenosine may affect the release of histamine from cutaneous mast cells through a mechanism mediated by the adenosine A3 receptor. OBJECTIVES: To investigate the genetic contribution of adenosine A3 receptor gene (ADORA3) polymorphisms in the pathogenesis of aspirin-induced urticaria (AIU) in a case-control association study in a Korean population. METHODS: A case-control association study was performed in 385 patients with AIU and 213 normal controls from a Korean population. The functional variability of genetic polymorphisms in the ADORA3 gene was analysed in in vitro studies that included a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA), and ex vivo studies that included real-time polymerase chain reaction for mRNA expression in peripheral blood mononuclear cells and a histamine release assay. RESULTS: A significant association of ADORA3 promoter polymorphism at -1050G/T was found with the phenotype of AIU. Patients with AIU showed higher frequency of the haplotype, ht1 (T(-1050) C(-564) ), compared with normal healthy controls. Moreover, ht1 (TC) was found to be a high-transcript haplotype by the luciferase activity assay, and a -564C allele-specific DNA binding protein was found by EMSA. Increased basophil histamine release was noted in subjects who had the high-transcript haplotype, ht1 (TC). CONCLUSION: These results suggest that the high-transcript haplotype, ht1 (TC), of the ADORA3 gene may contribute to the development of cutaneous hyper-reactivity to aspirin, leading to the clinical presentation of AIU.

Combination treatment with leflunomide and methotrexate for patients with active rheumatoid arthritis.

OBJECTIVE: To determine the efficacy and safety of the combination of leflunomide and methotrexate for the treatment of patients with active rheumatoid arthritis (RA) in an open, non-comparative, multicentre trial. METHODS: Seventy-four patients with active RA were enrolled to receive concomitantly leflunomide (no loading dose, 10 mg/day) and methotrexate (starting at 7.5 mg/week and titrating up to 15 mg/week) for 20 weeks. The primary end-point was a 20% improvement in the American College of Rheumatology (ACR) criteria at 20 weeks. Safety measures included evaluation of adverse events at each visit and laboratory data, including haematology and liver function tests. Intention-to-treat analyses were conducted. RESULTS: Sixty-five patients completed 20 weeks of treatment, and 71.6% were responders based on the ACR20 criteria. After 20 weeks, the mean changes were -16.3 for tender joint count, -12.0 for swollen joint count, -44.0 for physician global assessment, -34.3 for patient global assessment, -22.7 for erythrocyte sedimentation rate, and -0.65 for the Health Assessment Questionnaire score. Adverse events occurred in 40.5% of the patients, and were considered serious in four patients who discontinued therapy. Abnormal liver function was noted for 16 patients (21.6%). Two of these patients were withdrawn from the study; after discontinuing the medication, their liver function recovered fully. CONCLUSION: THE combination of leflunomide and methotrexate was effective and well tolerated in the treatment of active RA patients. This combination may be a useful option as an initial treatment for active RA before starting biological agents.

Alteration of cell-cycle regulation in epithelial ovarian cancer.

In spite of the clinical importance of epithelial ovarian cancer (EOC), little is known about the pathobiology of its precursor lesions and progression. Regulatory mechanisms of the cell cycle are mainly composed of cyclins, cyclin-dependent kinases (CDK), and CDK inhibitors. Alteration of these mechanisms results in uncontrolled cell proliferation, which is a distinctive feature of human cancers. This review describes the current state of knowledge about the alterations of cell-cycle regulations in the context of p16-cyclin D1-CDK4/6-pRb pathway, p21-p27-cyclin E-CDK2 pathway, p14-MDM2-p53 pathway, and ATM-Chk2-CDC25 pathway, respectively. Recent evidence suggests that ovarian cancer is a heterogenous group of neoplasms with several different histologic types, each with its own underlying molecular genetic mechanism. Therefore, expression of cell cycle regulatory proteins should be tested separately according to each histologic type. In serous ovarian carcinoma, high expression of p16, p53, and p27 and low expression of p21 and cyclin E were shown. In addition, this review focuses on the prognostic significance of cell cycle-regulating proteins in EOC. However, it is difficult to compare the results from different groups due to diverse methodologies and interpretations. Accordingly, researchers should establish standardized criteria for the interpretation of immunohistochemical results.

Influence of VEGF gene polymorphisms on the severity of ankylosing spondylitis.

OBJECTIVES: To investigate the role of polymorphisms of the vascular endothelial growth factor (VEGF) gene in susceptibility to ankylosing spondylitis (AS), and their relationship to clinical features and radiographic severity. METHODS: This study included 157 patients with AS and 140 healthy unrelated controls. Polymorphisms of the VEGF gene were analysed by the polymerase chain reaction (PCR)-restriction fragment length polymorphism assay and amplification refractory mutation system-PCR. Haplotypes were reconstructed using the Bayesian algorithm. Radiographic severity was assessed by the Bath Ankylosing Spondylitis Radiological Index (BASRI). RESULTS: The genotype frequencies of the polymorphisms were in Hardy-Weinberg equilibrium. The distributions of genotypes and alleles did not differ between AS patients and controls. Among the six haplotypes reconstructed based on the tight linkage disequilibrium at positions -2578, -1154 and -634 (pairwise linkage disequilibrium coefficient, r = 0.361-0.706), no haplotype was associated with susceptibility to AS. Clinical features were analysed for the four haplotypes (CGC, CGG, AAG, AGG) which were prevalent. In carriers of the AGG haplotype, the frequency of cervical spine involvement was significantly higher (P = 0.002, P(corr) = 0.036) and that of patients showing a BASRI score >6 was also higher (P = 0.025, P(corr) = 0.45). CONCLUSIONS: This study demonstrates that polymorphisms of the VEGF gene may contribute to disease severity in AS.

Systemic lupus erythematosus complicated with cerebral venous sinus thrombosis : a report of two cases.

A rare manifestation of systemic lupus erythematosus (SLE) is cerebral venous sinus thrombosis (CVST), in which early diagnosis and aggressive therapy are of prime importance for favorable outcome. The pathogenesis of CVST is largely unknown, but it is thought to be caused by cerebral vasculitis, antiphospholipid antibodies or other conditions associated with enhanced coagulability. We describe two cases of SLE with CVST which were not associated with antiphospholipid antibodies. Both cases were treated with immunosuppressants (intravenous methylprednisolone and cyclophosphamide pulse therapy) and anticoagulant drugs (heparin and subsequent maintenance therapy with warfarin). There was a marked improvement of neurologic symptoms with the disappearance of thrombus in a follow-up MRI. The possibility of CVST should be considered in any patients with SLE who show neuropsychiatric manifestations.

Rheumatoid arthritis associated with myelodysplastic syndrome: a case report.

Myelodysplastic syndromes (MDS) are a group of refractory anemias resulting from a clonal stem cell disorder often associated with cytogenetic abnormalities. There is increasing recognition of immunological abnormalities in patients with MDS, including defective B- and T-cell function, hyper- or hypogammaglobulinemia and monoclonal gammopathy. MDS have been associated with Sjögren's syndrome, polymyalgia rheumatica, relapsing polychondritis and systemic lupus erythematosus. Although there may be various rheumatologic features, including acute arthritis in MDS, chronic inflammatory arthritis is uncommonly combined. There have been a few reports that described cases of rheumatoid arthritis (RA) concurrent with MDS, but advanced rheumatoid arthritis with typical joint deformities has rarely been reported. We report a case of rheumatoid arthritis with atlantoaxial subluxation combined with refractory anemia in a 31-year-old woman.