RESUMEN
In Sjögren's disease (SjD), the salivary glandular epithelial cells can induce the chemotaxis of B cells by secreting B-cell chemokines such as C-X-C motif chemokine ligand 13 (CXCL13). Syndecan-1 (SDC-1) is a major transmembrane heparan sulfate proteoglycan (HSPG) predominantly expressed on epithelial cells that binds to and regulates heparan sulfate (HS)-binding molecules, including chemokines. We aimed to determine whether SDC-1 plays a role in the pathogenesis of SjD by acting on the binding of HS to B-cell chemokines. To assess changes in glandular inflammation and SDC-1 concentrations in the submandibular gland (SMG) and blood, female NOD/ShiLtJ and sex- and age-matched C57BL/10 mice were used. In the SMG of NOD/ShiLtJ mice, inflammatory responses were identified at 8 weeks of age, but increased SDC-1 concentrations in the SMG and blood were observed at 6 weeks of age, when inflammation had not yet started. As the inflammation of the SMG worsened, the SDC-1 concentrations in the SMG and blood increased. The expression of the CXCL13 and its receptor C-X-C chemokine receptor type 5 (CXCR5) began to increase in the SMG at 6 weeks of age and continued until 12 weeks of age. Immunofluorescence staining in SMG tissue and normal murine mammary gland cells confirmed the co-localization of SDC-1 and CXCL13, and SDC-1 formed a complex with CXCL13 in an immunoprecipitation assay. Furthermore, NOD/ShiLtJ mice were treated with 5 mg/kg HS intraperitoneally thrice per week for 6-10 weeks of age, and the therapeutic effects in the SMG were assessed at the end of 10 weeks of age. NOD/ShiLtJ mice treated with HS showed attenuated salivary gland inflammation with reduced B-cell infiltration, germinal center formation and CXCR5 expression. These findings suggest that SDC-1 plays a pivotal role in the pathogenesis of SjD by binding to CXCL13 through the HS chain.
Asunto(s)
Linfocitos B , Quimiocina CXCL13 , Heparitina Sulfato , Síndrome de Sjögren , Sindecano-1 , Sindecano-1/metabolismo , Animales , Quimiocina CXCL13/metabolismo , Ratones , Femenino , Linfocitos B/metabolismo , Linfocitos B/inmunología , Síndrome de Sjögren/metabolismo , Síndrome de Sjögren/patología , Heparitina Sulfato/metabolismo , Ratones Endogámicos C57BL , Quimiotaxis , Ratones Endogámicos NOD , Glándula Submandibular/metabolismo , Glándula Submandibular/patología , Humanos , Receptores CXCR5/metabolismo , Unión ProteicaRESUMEN
BACKGROUND: Infectious meningoencephalitis (ME) is a major global health concern. Viruses are the most frequently implicated etiologies, whereas bacterial causes, although life-threatening, constitute a lesser proportion of ME cases, together with other pathogens. The strict implementation of COVID-19 mitigation measures led to the decreased viral and non-viral infectious diseases. Therefore, this study aimed to investigate the effect of these mea-sures on ME-causing pathogens by age groups. METHODS: This retrospective study aimed to determine and compare the rates of pathogen-positive ME cases during the pre-pandemic (P-1) and pandemic (P-2) periods. Molecular diagnostic methods using the cerebrospinal fluid of patients from all age groups were included. The positivity rate difference of the ME-causing pathogens between the two study periods was compared and the distribution pattern of the pathogens among the age groups was determined. RESULTS: The overall positivity rate for at least one ME-causing pathogen during P-1 was 22.0% (503/2,284), which significantly declined to 7.3% (83/1,141) during P-2 (p < 0.001). Particularly, a statistically significant decline in the pathogen positivity was observed in the groups 4 - 6 (≥ 3 years) (p < 0.001, p < 0.001, and p = 0.041, respectively). Specifically, the enterovirus cases decreased significantly, whereas the varicella zoster virus and herpes simplex virus-2 cases increased. Among bacterial causes, the S. agalactiae, S. pneumoniae, and E. coli K1 ME cases significantly increased. Men and women had no significant differences in the positivity rate during either study period. CONCLUSIONS: COVID-19 mitigation measures significantly impacted the positivity rates and the distribution of ME-causing agents, especially in the age groups ≥ 3 years, although not uniformly.
Asunto(s)
COVID-19 , Meningoencefalitis , Humanos , COVID-19/epidemiología , COVID-19/diagnóstico , Estudios Retrospectivos , Meningoencefalitis/epidemiología , Meningoencefalitis/líquido cefalorraquídeo , Meningoencefalitis/virología , Meningoencefalitis/diagnóstico , Adulto , Niño , Preescolar , Persona de Mediana Edad , Adolescente , Adulto Joven , Lactante , Masculino , Femenino , Anciano , Pandemias , SARS-CoV-2/aislamiento & purificación , Anciano de 80 o más Años , Recién NacidoRESUMEN
Raynaud's phenomenon (RP) is a condition characterized by episodic, excessive vasoconstriction in the fingers and toes, triggered by cold or stress. This leads to a distinctive sequence of color changes in the digits. Pallor indicates reduced blood flow due to oxygen deprivation, while erythema appears as reperfusion. RP can be primary, with no identifiable underlying cause, or secondary, associated with other conditions. These conditions include autoimmune diseases, most commonly systemic sclerosis, vascular diseases; and neurological conditions. While the exact cause of RP remains unclear, genetic and hormonal (estrogen) factors are likely contributors. The pathogenesis of RP involves a complex interaction between the vascular wall, nerves, hormones, and humoral factors, disrupting the balance between vasoconstriction and vasodilation. In primary RP, the vascular abnormalities are primarily functional. However, in secondary RP, both functional and structural components occur in blood vessels. This explains why digital tissue damage frequently occurs in secondary RP but not primary RP. Diagnosis of RP is primarily clinical. Recent advancements in imaging techniques have aided in diagnosis and monitoring, but nail fold capillaroscopy remains the gold standard for distinguishing between primary and secondary RP. If there are signs of acute ischemic injury, vascular imaging, particularly preoperatively, is crucial to rule out other vaso-occlusive conditions. Management of RP focuses on alleviating symptoms and preventing tissue damage. Vasodilator medications are the first-line treatment when general measures like warmth and stress management are not sufficient. Dihydropyridine calcium channel blockers (CCBs), such as nifedipine, are commonly used for vasodilation. Phosphodiesterase-5 inhibitors and prostaglandin analogs are alternative options for patients who do not respond to CCBs or have ischemic tissue damage. Bosentan, an endothelin-1 receptor antagonist, has shown effectiveness in treating and preventing digital ulcers, especially in patients with multiple ulcers. For severe cases, botulinum toxin injections or sympathectomy surgery can be used to control RP symptoms. However, botulinum toxin injections require repeated administration, and sympathectomy's long-term effectiveness is uncertain. Fat grafting is a promising surgical therapy for promoting healing and preventing tissue injury.
RESUMEN
Anti-phospholipid syndrome (APS) nephropathy is an autoimmune disease that is sometimes accompanied by systemic lupus erythematosus (SLE). Here, we report the use of rituximab to treat a case of APS nephropathy in a SLE patient with recurrent vascular thrombosis. A 52-year-old woman, who had been diagnosed with SLE 11 years earlier, was referred to a nephrology clinic for evaluation of azotaemia and proteinuria. She had experienced spontaneous abortion at 35 years of age. The patient had been diagnosed with right popliteal thrombosis at 39 years of age, and with left pulmonary artery thrombosis and SLE at 41 years of age. Before admission, she was undergoing anticoagulant and immunosuppressive therapies, with follow-up in the rheumatology clinic. At her last outpatient clinic visit before admission, she exhibited mild bilateral lower-limb pitting oedema, impaired renal function and proteinuria. Renal biopsy revealed arteriolar wall thickening, with thrombi in the capillary lumina and marked inflammatory cell infiltration in the interstitium. The patient was treated with warfarin and high-dose corticosteroids. Intravenous rituximab (500 mg) was also administered twice at a 4-week interval. Her renal function did not worsen any further, and her proteinuria decreased. Here we report the successful use of rituximab to treat APS nephropathy in a patient with SLE, who had progressive renal insufficiency.
RESUMEN
BACKGROUND: Hereditary breast/ovarian cancer is associated with BRCA gene mutations. As large volumes of clinical data on BRCA variants are continuously updated, their clinical interpretation may change, leading to their reclassification. This study analyzed the class and proportion of the changed clinical interpretations of BRCA variants to validate the need for periodic reviews of these variants. METHODS: This retrospective study reinterpreted previously reported BRCA1 and BRCA2 exon variants according to the 2015 American College of Medical Genetics and Genomics guidelines and the clinical significance of the recent public genomic database. Reanalyzed results were obtained for patients tested for BRCA genetic mutation for 10 years and 4 months. RESULTS: We included data from 4,058 patients, with 595 having at least one pathogenic variant (P), likely pathogenic variant (LP), or variant of uncertain significance (VUS) at a detection rate of 14.66%. The numbers of exon and intron variants were 562 (87.81%) and 78 (12.19%), respectively. BRCA1 exhibited a significantly higher P/LP detection rate of 6.96% compared to that of BRCA2 at 6.89% (p < 0.001). Conversely, BRCA2 demonstrated a significantly higher VUS rate of 10.38% compared to that of BRCA1 at 5.08% (p < 0.001). Among BRCA1 mutations, substitutions were the most prevalent in P/LP and VUS. Among BRCA2 mutations, deletions were most prevalent in P/LP, and substitutions were most prevalent in VUS. Among the 131 patients with P/LP in BRCA1 exons, the clinical interpretation was reclassified in two cases (1.53%), one VUS and one benign/likely benign (B/LB), and 48 cases (48.00%) with VUS were reclassified; one to P/LP and 47 to B/LB. Among the 138 patients with P/LP in BRCA2 exons, the clinical interpretation was reclassified in six (4.35%), five to VUS, and one to B/LB, and all 74 with VUS were reclassified to B/LB. CONCLUSIONS: We determined the class and proportion of reclassified BRCA variants. In conclusion, reviews are required to provide clinical guidance, such as determining treatment direction and preventive measures in the future.
Asunto(s)
Neoplasias de la Mama , Neoplasias Ováricas , Femenino , Humanos , Estudios Retrospectivos , Predisposición Genética a la Enfermedad , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Mutación , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Pruebas Genéticas/métodos , Proteína BRCA1/genética , Proteína BRCA2/genéticaRESUMEN
Ibuprofen, one of the most commonly prescribed nonsteroidal anti-inflammatory drugs, has not been fully assessed for embryonic toxicity in vertebrates. Here, we systematically assessed the embryotoxicity of ibuprofen in Xenopus laevis at various concentrations during embryogenesis. Embryos were treated with different concentrations of ibuprofen, ranging from 8 to 64 mg/L, at 23 °C for 96 h, and examined daily and evaluated at 72 hpf. Lethal or teratogenic effects were documented. For histological analysis, paraffin embedded embryos were transversely sectioned at a thickness of 10-µm and stained with hematoxylin and eosin. Total RNA was isolated from embryos at stages 6, 12, 22 and 36, and real-time quantitative PCR was performed. Ibuprofen-treated embryos showed delayed or failed dorsal lip formation and its closure at the beginning of gastrulation. This resulted in herniation of the endodermal mass after gastrulation under high concentrations of ibuprofen-treated embryos. Underdeveloped intestines with stage and/or intestinal malrotation, distorted microcephaly, and hypoplastic heart, lungs, and pronephric tubules were observed in ibuprofen-treated embryos. Cephalic, cardiac, and truncal edema were also observed in them. The severity of the deformities was observed in a concentration-dependent manner. The teratogenic index was 2.28. These gross and histological disruptions correlated well with the altered expression of each organ marker gene. In conclusion, ibuprofen induced delayed and disrupted gastrulation in the early developmental stage and multiorgan malformation later in the organogenesis stage of Xenopus laevis embryos.
Asunto(s)
Ibuprofeno , Teratógenos , Animales , Xenopus laevis , Ibuprofeno/toxicidad , Desarrollo Embrionario , Antiinflamatorios no Esteroideos/farmacología , Embrión no MamíferoRESUMEN
The EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), and other patient-reported outcomes (PROs), such as the visual analog scale (VAS) for symptoms and EULAR sicca score (ESS), are used to assess the disease activity of primary Sjögren's syndrome (pSS). Recently, Clinical ESSDAI (ClinESSDAI) and Clinical Trials ESSDAI (ClinTrialsESSDAI) were developed for objective clinical disease activity indexes. However, the relationship of ClinESSDAI and ClinTrialsESSDAI with PROs as well as that between ESSPRI and other PROs and the objective parameters of glandular function in pSS have not been established. Herein, we investigated the correlation of ESSPRI and other PROs with the objective parameters of glandular function and the relationship of PROs with ClinESSDAI and ClinTrialsESSDAI in 66 patients with pSS. Correlations were calculated with Spearman's correlation coefficient. ClinTrialsESSDAI was correlated with ESSPRI, dryness (ESSPRI-Dryness), fatigue, and pain domains of ESSPRI, VAS for oral dryness (oral-VAS), and patient's global assessment. Although ESSPRI did not correlate with the objective parameters of glandular function, ESSPRI-Dryness, ESS, and oral- and ocular-VAS did. These results suggest that ESSPRI-Dryness, ESS, and VAS for symptoms, but not ESSPRI, reflect the glandular dysfunction and that ClinTrialsESSDAI correlates with PROs for dryness in pSS.
RESUMEN
BACKGROUND: Although the detection of respiratory viruses other than severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was significantly reduced because of quarantine due to the coronavirus disease (COVID-19) pandemic, an epidemic of several viruses was reported unexpectedly. We also detected a change in the pattern of human metapneumovirus (HMPV) outbreak compared to that before the COVID-19 pandemic. Therefore, the authors intended to identify the incidence and altered distribution pattern of the HMPV outbreak and provide useful information for clinical practice. METHODS: This retrospective study investigated the incidence and distribution of HMPV from March 2020 to December 2022 during the COVID-19 pandemic. Detection of respiratory microorganisms was performed by multiplex polymerase chain reaction using a commercial kit and FilmArray assay. RESULTS: The overall incidence of at least one respiratory microorganism was 50.3% (1,152/2,290). HMPV was not detected between March 2020 and June 2022. However, it was suddenly detected in July 2022 and continued for approximately five months until November 2022. In particular, the detection rate of HMPV was high in September and October 2022, accounting for approximately 76.1% (51/67) of the total HMPV-positive cases. Seasonally, 92.5% (62/67) of HMPV cases were detected in autumn, while the rest of the cases were detected in summer. The HMPV detection rate, according to the age group, was highest in group 4 (3 - 6 years) at 7.4% (27/367), followed by group 3 (4 months to 2 years) at 3.6% (31/861). In HMPV-positive cases, the rate of more than two respiratory pathogens was 46.3% (31/67). An analysis of co-infecting pathogens showed that HMPV with rhinovirus A/B/C/ enteroviruses accounted for the highest percentage (51.6%), followed by HMPV with respiratory syncytial virus (48.4%). CONCLUSIONS: The COVID-19 pandemic has caused several changes in our lives. This study confirmed that the seasonal distribution of HMPV was different from that before the COVID-19 pandemic. Therefore, it can be assumed that the distribution of other respiratory microorganisms could have changed and it appears that changes could occur in previously known viral epidemiology. Clinicians should therefore be alert to this possibility.
Asunto(s)
COVID-19 , Metapneumovirus , Infecciones por Paramyxoviridae , Virus Sincitial Respiratorio Humano , Infecciones del Sistema Respiratorio , Virus , Humanos , Lactante , Preescolar , Niño , Metapneumovirus/genética , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/epidemiología , Pandemias , Estudios Retrospectivos , COVID-19/epidemiología , SARS-CoV-2 , Brotes de Enfermedades , Hospitales Universitarios , República de Corea/epidemiología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiologíaRESUMEN
Central nervous system (CNS) manifestations of systemic lupus erythematosus (SLE) are diverse and often difficult to distinguish from SLE-unrelated events. CNS vasculitis is a rare manifestation, which is seen in less than 10% of post-mortem studies, and lesions with multifocal cerebral cortical microinfarcts associated with small-vessel vasculitis are the predominant feature. However, CNS vasculitis presenting as a tumor-like mass lesion in SLE has rarely been reported. Herein, we report a case of cerebral vasculitis mimicking a brain tumor in a 39-year-old female with SLE. A biopsy of the brain mass revealed fibrinoid necrosis and leukocytoclastic vasculitis. The neurological deficits and systemic symptoms improved after treatment with corticosteroids and immunosuppressive agents. To the best of our knowledge, there are no reports of biopsy-proven cerebral vasculitis presenting as a brain mass in patients with SLE in Korea.
RESUMEN
The Pfizer-BioNTech mRNA vaccine is a US Food and Drug Administration-approved coronavirus disease 2019 (COVID-19) vaccine. Although it is reported to be safe and effective, immune dysregulation leading to autoimmunity has become an area of concern. Retroperitoneal fibrosis (RPF) is an immune-mediated fibroinflammatory disease characterized by the deposition of fibrous tissues, primarily around the abdominal aorta and iliac arteries. Herein, we report a case of RPF following Pfizer BioNTech COVID-19 mRNA vaccination. To the best of our knowledge, there have been no published reports on RPF after COVID-19 mRNA vaccination. A 58-year-old woman with no history of autoimmune diseases presented with acute onset of epigastric pain 5 weeks after the second dose of the Pfizer-BioNTech vaccine. She had been diagnosed with stage I breast cancer 9 years ago and was in complete remission on admission. Abdominal computed tomography showed preaortic soft-tissue infiltration around the origin of the superior mesenteric artery but no evidence of breast cancer recurrence. Considering the temporal relationship between current symptoms and vaccination and the absence of other possible causes, she was diagnosed with RPF secondary to Pfizer-BioNTech vaccine-induced autoimmunity. This case may raise awareness of the possibility of RPF development following COVID-19 mRNA vaccination.
Asunto(s)
Enfermedades Autoinmunes , Neoplasias de la Mama , Vacunas contra la COVID-19 , COVID-19 , Fibrosis Retroperitoneal , Femenino , Humanos , Persona de Mediana Edad , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Recurrencia Local de Neoplasia , Fibrosis Retroperitoneal/diagnóstico , Fibrosis Retroperitoneal/etiología , Estados Unidos , Vacunación/efectos adversos , VacunasRESUMEN
BACKGROUND: The incidence of respiratory viral diseases including parainfluenza virus (PIV) infection has decreased noticeably due to strict quarantine measures during the COVID-19 pandemic. However, the recent outbreak of PIV in children occurred unexpectedly and the distribution pattern showed prominent differences from before the COVID-19 pandemic. PIV is one of the major viral pathogens related to acute lower respiratory infection in young children and the elderly. Accordingly, the authors intended to identify the incidence and distribution pattern of PIV outbreaks and to contribute to public health by providing information on it. METHODS: This study was conducted retrospectively to investigate the incidence and distribution of PIV according to age group, gender, month, and season, and to analyze the co-infections from March 2020 to February 2022. The detection for respiratory microorganisms was performed through FilmArray assay. RESULTS: The overall incidence for at least one respiratory pathogen was 45.9% (665/1,450). PIV was not detected at all from March 2020 to August 2021. However, it was first detected in September 2021 and the rate in the month that followed, October, accounted for 60% (114/190) of the total PIV infections during the entire study period. It also accounted for 44.9% (190/423) of patients with respiratory pathogens from September 2021 to February 2022. It reached the highest proportion at 90.5% (114/126) in October 2021. As for the distribution according to the age groups, group 3 (58.4%) accounted for the highest percentage, followed by group 4 (21.1%). In the PIV positive cases, the overall rate of more than two respiratory pathogens was 32.6% (62/190). The most common pattern of co-infection was PIV3 with rhinovirus/enterovirus (67.7%), followed by PIV3 with adenovirus (8.1%) and PIV3 with rhinovirus/enterovirus and adenovirus (8.1%). CONCLUSIONS: The COVID-19 pandemic has brought about many changes in our daily lives. It has been confirmed that the seasonal distribution of PIV was distinctly different from before the COVID-19 pandemic. It is anticipated that this phenomenon will affect the incidence or distribution of other respiratory pathogens and viral epidemiology. Therefore, clinicians should pay attention to these changes in terms of public health.
Asunto(s)
COVID-19 , Infecciones por Paramyxoviridae , Infecciones del Sistema Respiratorio , Virus , Niño , Humanos , Lactante , Preescolar , Anciano , Estudios Retrospectivos , Pandemias , COVID-19/epidemiología , Infecciones del Sistema Respiratorio/diagnóstico , Infecciones del Sistema Respiratorio/epidemiología , Infecciones por Paramyxoviridae/diagnóstico , Infecciones por Paramyxoviridae/epidemiología , Hospitales , República de Corea/epidemiologíaRESUMEN
Objective: To investigate the histopathological characteristics of patients with lupus nephritis in the 2018 revised International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification and assess the prognostic factors. Methods: This study enrolled 92 patients with lupus nephritis, who had conventional treatment and renal biopsy. Each renal tissue was evaluated according to 2018 ISN/RPS classification, and quantified apoptotic regulator protein, the B-cell lymphoma-2 protein (Bcl-2), expressions in selected lymphocyte subsets were measured using novel computational approaches using multicolor confocal images. Histopathological characteristics and prognostic factors of end-stage renal disease (ESRD) and chronic kidney disease (CKD) were compared. Follow-up data were obtained, and survival analysis was conducted. Results: During follow-up period (average 74.3 months), 16 and 18 patients progressed ESRD and CKD, respectively. Multivariable analysis of age, sex, disease activity and pathological features in ISN/RPS demonstrated the extent of interstitial inflammation (grade 0~3) was significantly associated with both ESRD and CKD. When interstitial inflammation was divided into mild (grade 0, 1) and severe (grade 2, 3), Cox regression analysis showed that patients with severe interstitial inflammation were significantly increased risk of both ESRD and CKD (hazard ratio 4.67 and 3.8, respectively). Bcl-2 expression in CD4+ and CD20 cells was significantly higher in the severe interstitial inflammation group compared to in mild interstitial inflammation patients (p=0.006 and 0.010, respectively). Conclusion: The extent of interstitial inflammation can predict clinical renal outcomes. Significantly elevated Bcl-2 expression in both CD4+ and CD20 cells was found in severe interstitial inflammation compared with mild interstitial inflammation.
RESUMEN
BACKGROUND: Saliva contains various cells, proteins, and molecules, and it is emerging as a material for diagnosing various diseases. Syndecan-1 (SDC-1) is a member of cell surface heparan sulfate proteoglycans and is mainly expressed in epithelial cells and plasma cells. SDC-1 is known to be associated with various cancers and inflammatory response, but there are few studies related to the change of SDC-1 levels in the saliva and plasma of healthy individuals due to aging process. METHODS: The study was conducted on 61 females who were healthy without any metabolic diseases, systemic infection, and oral cavity lesions. The subjects were divided into two groups based on age. Those below 40 years were placed in Group I and those who were 40 years and above were placed in Group II. Saliva was collected according to the guideline and the salivary flow rate (SFR) was determined. SDC-1 levels in the plasma and saliva were measured using a commercially available sandwich ELISA method. RESULTS: Age was significantly different between Group I and II (28.0 ± 2.5 vs. 47.4 ± 5.5, p < 0.001). SFR also showed a significant difference between Group I and II [0.32 (0.13 - 0.39) vs. 0.25 (0.16 - 0.35) ng/mL, p = 0.003]. Salivary SDC-1 level in Group I was significantly higher than that in Group II (p < 0.001). In addition, plasma SDC-1 level in Group I was also higher than that in Group II (p < 0.001). SFR was not significantly correlated as age increased, but it showed a significant negative correlation with salivary SDC-1 (r = -0.607, p < 0.001) and plasma SDC-1 levels (r = -0.373, p = 0.003). Salivary SDC-1 level was significantly correlated with plasma SDC-1 level (r = 0.331, p = 0.012). CONCLUSIONS: In the younger group, the SFR, salivary, and plasma SDC-1 levels were significantly higher than in the older group. Salivary and plasma SDC-1 showed significant negative correlation as age increased. Although this study was not conducted on a large scale, it might be thought to provide information on the age-related variation for salivary and plasma SDC-1 levels in the aging process.
Asunto(s)
Saliva , Sindecano-1 , Ensayo de Inmunoadsorción Enzimática , Femenino , Estado de Salud , Humanos , PlasmaRESUMEN
This study evaluated the possibility of clinical remission suggested by the treat-to-target strategy and identified predictors of clinical remission in 139 patients with ankylosing spondylitis (AS) receiving tumor necrosis factor-α inhibitors (TNFi). Clinical remission criteria selected were AS Disease Activity Score Inactive Disease (ASDAS-ID) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) < 2 with normal C-reactive protein (CRP) levels (BASDAI-CRP). The longitudinal relationship between clinical parameters and clinical remission was assessed using generalized estimating equations (GEEs). Responders to ASDAS-ID and BASDAI-CRP increased from 32.4% to 68.9% and from 39.9% to 75.2% at months 3 and 33, respectively. Responders to ASDAS-ID and BASDAI-CRP almost overlapped. In the univariable GEE model, age and 3-month improvement in BASDAI, ASDAS-CRP, physician and patient global assessments, and spinal pain predicted clinical remission achievement, while the presence of syndesmophytes predicted ASDAS-CRP achievement, and normalized CRP at 3 months was associated with BASDAI-CRP achievement. Multivariable GEE analysis revealed age (odds ratio (OR): 0.67; 95% confidence interval (CI), 0.49-0.93) and 3-month BASDAI improvement (OR: 1.70; CI, 1.19-2.41) as independent predictors of ASDAS-ID achievement and age (OR: 0.69; CI, 0.54-0.89), 3-month BASDAI improvement (OR: 2.00; CI, 1.45-2.76), and normalized CRP at 3 months (OR: 3.72; CI, 1.39-9.95) as independent predictors of BASDAI-CRP achievement.
RESUMEN
The KOrean College of Rheumatology BIOlogics and targeted therapy (KOBIO) registry is a nationwide observational cohort that captures detailed data on exposure of patients to biologic and targeted synthetic disease-modifying anti-rheumatic drugs (DMARDs). This registry was launched in December 2012 with an aim to prospectively investigate clinical manifestations and outcomes of patients with rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis who initiated a biologic or targeted synthetic DMARD or switched to another. Demographic data, disease activity, current treatment, adverse events, terms based on Medical Dictionary for Regulatory Activities, and so on are registered for patients who are then followed up annually in a web-based unified platform. The KOBIO registry also recruits and collects data of patients with RA on conventional DMARDs for comparison. As of today, more than 5,500 patients were enrolled from 47 academic and community Rheumatology centers across Korea. The KOBIO registry has evolved to become a powerful database for clinical research to improve clinical outcomes and quality of treatment.
RESUMEN
The aim of this study was to investigate the relationship between long-term spinal mobility improvements and early disease activity changes or achievement of clinical response criteria in patients with ankylosing spondylitis (AS) treated with tumor necrosis factor (TNF-α) blockers.This retrospective study included 112 patients with AS treated with TNF-α blockers for up to 33 months. The paired t-test was used to compare outcome measures between visits. The correlation between disease activity changes and metrological improvements was analyzed using cumulative probability plots, Spearman correlation coefficient, and canonical correlation. The difference in metrological outcomes between responders and non-responders to clinical response criteria was also examined.Metrological and disease activity outcomes improved most markedly in month 3. All disease activity outcomes and ESR from baseline to month 3 (3-month) were significantly correlated with the Bath Ankylosing Spondylitis Metrology Index (BASMI10) improvements from baseline to month 33 (33-month). The 3-month changes in ankylosing spondylitis disease activity score (ASDAS-CRP) and patient's global assessment showed a significant correlation with the 33-month changes in chest expansion. Only responders according to ASDAS major improvement at month 3 demonstrated significant 33-month improvements in both BASMI10 and chest expansion, compared to non-responders. Responders according to Assessment of Spondylo Arthritis international Society 40 at month 3 showed significant 33-month improvements in BASMI10, but not chest expansion, compared to non-responders.The degree of early changes in disease activity outcomes influenced the extent of long-term metrological improvements in AS treated with TNF-α blockers. Additionally, the achievement of ASDAS- major improvement at month 3 predicted significant metrological improvements throughout long-term TNF-α-blocker therapy.
Asunto(s)
Espondilitis Anquilosante/tratamiento farmacológico , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Columna Vertebral/efectos de los fármacos , Inhibidores del Factor de Necrosis Tumoral/farmacologíaRESUMEN
OBJECTIVE: Clinical joint count assessment is important for detecting synovitis but its reliability is a subject of controversy. This study was undertaken to assess the correlation of positron emission tomography (PET)-derived parameters in 68 joints with disease activity and to compare the reliability of joint counts between PET with computed tomography (CT) and clinical assessment in patients with rheumatoid arthritis (RA). METHODS: We enrolled 91 patients with active RA (69 in a development group and 22 in a validation group) who underwent concurrent 18 F-fluorodeoxyglucose (18 F-FDG)-PET-CT and clinical disease activity evaluation. PET-derived parameters were compared with disease activity assessed using clinical joint count parameters. A Disease Activity Score (DAS) using counts of PET-positive joints was developed, and then validation studies were performed in an independent group. RESULTS: The number of PET-positive joints (of 28 and 68 joints) was significantly correlated with the swollen joint count (SJC) and tender joint count (TJC) and the DAS in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR). Intraobserver and interobserver reliability of PET for the affected joint counts were excellent. Interobserver reliability between nuclear medicine physicians and rheumatologists was good for the SJC and TJC in both 28 joints and 68 joints. After multivariate analyses, including ESR and patient's global assessment of disease activity (PtGA) in addition to PET-derived parameters, the PET/DAS was derived as (0.063 × number of PET-positive joints in 28 joints) + (0.011 × ESR) + (0.030 × PtGA). A significant correlation between the PET/DAS and the DAS28-ESR was confirmed in the validation group (P < 0.001). CONCLUSION: PET-CT could serve as a sensitive and reliable method in the evaluation of disease activity in RA patients, and may be applicable as a research tool, particularly in clinical trials.
Asunto(s)
Artritis Reumatoide/diagnóstico por imagen , Fluorodesoxiglucosa F18 , Tomografía Computarizada por Tomografía de Emisión de Positrones/estadística & datos numéricos , Radiofármacos , Índice de Severidad de la Enfermedad , Anciano , Femenino , Humanos , Articulaciones/diagnóstico por imagen , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Reproducibilidad de los ResultadosRESUMEN
Accidental or intentional misuse of acetaminophen (APAP) is the leading cause of acute liver failure in the Western world. Although mechanisms that trigger APAP-induced liver injury (AILI) are well known, those that halt the progression of APAP liver disease and facilitate liver recovery are less understood. Heparan sulfate proteoglycans (HSPGs) bind to and regulate various tissue injury factors through their heparan sulfate (HS) chains, but the importance of HSPGs in liver injury in vivo remains unknown. Here, we examined the role of syndecan-1, the major cell-surface HSPG of hepatocytes, in AILI. Ablation of syndecan-1 in mice led to unopposed progression of liver injury upon APAP overdose. However, direct APAP hepatoxicity and liver injury at early times post-APAP overdose were unaffected by syndecan-1, suggesting that syndecan-1 influences later mechanisms that lead to liver repair. The exuberant liver injury phenotypes in syndecan-1 null (Sdc1-/- ) mice were traced to a deficiency in protein kinase B (Akt) activation in hepatocytes, which led to a delayed increase in glycogen synthase kinase-3ß (GSK-3ß)-mediated hepatocyte apoptosis. Inhibition of Akt worsened, whereas inhibition of GSK-3ß and caspases protected mice from AILI. Moreover, administration of purified syndecan-1, HS, or engineered heparan compounds containing 2-O-sulfate groups rescued Sdc1-/- mice from AILI by potentiating Akt signaling and inhibiting GSK-3ß-mediated apoptosis in hepatocytes. In addition, HS showed a significantly prolonged therapeutic efficacy as compared to N-acetylcysteine. CONCLUSION: These results demonstrate that 2-O-sulfated domains in syndecan-1 HS halt disease progression and promote liver repair by enhancing hepatocyte survival in AILI. We propose that syndecan-1 is a critical endogenous factor that controls the balance between prosurvival signaling and apoptosis in hepatocytes in APAP liver disease. (Hepatology 2017;66:1601-1615).
Asunto(s)
Acetaminofén/efectos adversos , Analgésicos no Narcóticos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Sindecano-1/metabolismo , Animales , Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Femenino , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Hepatocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-akt/metabolismoRESUMEN
Identification of the structure-function relationship of heparin, particularly between 2-O-, 6-O-, and N-sulfation and its anticoagulant or anti-inflammatory activities, is critical in order to evaluate the biological effects of heparin, especially in conjunction with modifications for oral formulation. In this study, we demonstrated that removal of 2-O, 6-O, or N-desulfation and their hydrophobic modifications have differential effects on the blocking of interactions between sLeX and P-and L-selectins, with highest inhibition by 6-O desulfation, which was consistent with their in vivo therapeutic efficacies on CIA mice. The 6-O desulfation of lower molecular weight heparin (LMWH) retained the ability of LMWH to interfere with T cell adhesion via selectin-sLeX interactions. Furthermore, 6DSHbD coated on the apical surface of inflamed endothelium directly blocked the adhesive interactions of circulating T cells, which was confirmed in vivo by suppressing T cell adhesion at post-capillary venular endothelium. Thus, in series with our previous study demonstrating inhibition of transendothelial migration, oral delivery of low anticoagulant LMWH to venular endothelium of inflamed joint tissues ameliorated arthritis by the stepwise inhibition of T cell recruitment and provides a rationale for the development of modified oral heparins as innovative agents for the treatment of chronic inflammatory arthritis.
Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Anticoagulantes/química , Anticoagulantes/uso terapéutico , Artritis/tratamiento farmacológico , Heparina/química , Heparina/uso terapéutico , Linfocitos T/efectos de los fármacos , Animales , Antiinflamatorios/farmacología , Anticoagulantes/farmacología , Artritis/inmunología , Artritis/patología , Adhesión Celular/efectos de los fármacos , Heparina/farmacología , Heparina de Bajo-Peso-Molecular/química , Heparina de Bajo-Peso-Molecular/farmacología , Heparina de Bajo-Peso-Molecular/uso terapéutico , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Sulfatos/química , Linfocitos T/inmunología , Linfocitos T/patología , Migración Transendotelial y Transepitelial/efectos de los fármacos , Vénulas/efectos de los fármacos , Vénulas/inmunología , Vénulas/patologíaRESUMEN
Methotrexate (MTX), an anchor drug for rheumatoid arthritis (RA), has been suffered from refractoriness and high toxicity limiting effective dosage. To mitigate these challenges, the ability to selectively deliver MTX to arthritis tissue is a much sought-after modality for the treatment of RA. In this study, we prepared mineralized nanoparticles (MP-HANPs), composed of PEGylated hyaluronic acid (P-HA) as the hydrophilic shell, 5ß-cholanic acid as the hydrophobic core, and calcium phosphate (CaP) as the pH-responsive mineral. Owing to the presence of CaP as the diffusion barrier, mineralized HANPs revealed the pH-responsiveness of release kinetics of MTX across neutral to acidic conditions. HANPs were internalized via receptor-mediated endocytosis in macrophages which involved molecular redundancy among major hyaladherins, including CD44, stabilin-2, and RHAMM. Following endocytosis, MP-HANPs loaded with doxorubicin revealed pH-dependent demineralization followed by dramatic acceleration of drug release into the cytosol compared to other HANPs. Furthermore, an in vivo study showed a significantly high paw-to-liver ratio of fluorescent intensity after systemic administration of MP-HANP-Cy5.5, indicating improved biodistribution of nanoparticles into arthritic paws in collagen-induced arthritis mice. Treatment with MTX-loaded MP-HANPs ameliorated inflammatory arthritis with remarkable safety at high dose of MTX. We highlight the distinct advantages of combining key benefits of biomineralization and PEGylation with HA-based nanoparticles for arthritis-selective targeting, thus suggesting MP-HANPs as a promising carrier of MTX for treatment of RA.