Prevalence, incidence, and risk factors of malignancy in patients with rheumatoid arthritis: a nationwide cohort study from Korea.

BACKGROUND/AIMS: This study aims to evaluate the incidence of malignancy in patients with rheumatoid arthritis (RA) and to investigate risk factors for such in a nationwide, population-based cohort. METHODS: In a large, prospective, observational cohort study, 5,077 patients with RA were enrolled from July 2009 to December 2011 and followed until February 2017. Standardized incidence ratios (SIRs) for malignancy were calculated using age- and sex-specific cancer rates in the Korean general population. Poisson regression was used to identify the risk of incident malignancy. RESULTS: The cohort included 5,023 participants with RA contributing 16,689 person-years of follow-up. A total of 148 malignancies were recorded. The risks of stomach cancer (SIR, 0.41; 95% confidence interval [CI], 0.21 to 0.74), colon cancer (SIR, 0.13; 95% CI, 0.03 to 0.37), and lung cancer (SIR, 0.35; 95% CI, 0.14 to 0.72) were lower in RA patients than in the general population. Poisson regression modeling demonstrated that the malignancy risk was more than two-fold greater in patients with thyroid disease than in those without thyroid disease. Hydroxychloroquine therapy was associated with a reduced risk (relative risk, 0.39; 95% CI, 0.189 to 0.801) of malignancy development. CONCLUSION: The overall risk of malignancy in patients with RA is decreased relative to in the general population. In particular, stomach, colon, and lung cancers in Korean RA patients are less common, while brain and central nervous system cancers in male RA patients are more frequent. The patients with thyroid disease and longer RA disease duration were at increased risk for developing malignancy, while hydroxychloroquine users were at lower risk.

Characteristic alterations of gut microbiota in uncontrolled gout.

Microbiome research has been on the rise recently for a more in-depth understanding of gout. Meanwhile, there is a need to understand the gut microbiome related to uric acid-lowering drug resistance. In this study, 16S rRNA gene-based microbiota analysis was performed for a total of 65 stool samples from 17 healthy controls and 48 febuxostat-treated gout patients (including 28 controlled subjects with decreased uric acid levels and 20 uncontrolled subjects with non-reduced uric acid levels). Alpha diversity of bacterial community decreased in the healthy control, controlled, and uncontrolled groups. In the case of beta diversity, the bacterial community was significantly different among groups (healthy control, controlled, and uncontrolled groups). Taxonomic biomarker analysis revealed the increased population of g-Bifidobacterium in healthy controls and g-Prevotella in uncontrolled patients. PCR further confirmed this result at the species level. Additionally, functional metagenomics predictions led to the exploration of various functional biomarkers, including purine metabolism. The results of this study can serve as a basis for developing potential new strategies for diagnosing and treating gout from microbiome prospects.

Real-world experiences of the diagnosis process in Korean patients with ankylosing spondylitis based on a self-report questionnaire.

OBJECTIVES: The diagnosis of ankylosing spondylitis (AS) is often delayed, which affects various clinical outcomes. This study examined the real-world situation of patients with AS during diagnosis and treatment. METHODS: Data were obtained from 26 tertiary care hospitals in Korea using a self-report questionnaire. The questionnaire assessed symptoms, pain, extra-articular manifestations, the initial pattern of pain before diagnosis, factors leading to delayed referral to rheumatology, time until receiving an AS diagnosis, comorbid diseases, treatment status, and disease education needs. RESULTS: Between September and October 2019, 1012 patients with AS completed the survey. Of these, 75.8% were men and 51.8% were in their 30s or 40s. Median disease duration was 76 months. The median time to diagnosis with AS was 12 months. When pain occurred, the medical departments most frequently visited first were orthopedic (61.5%) and rheumatology (18.7%) departments. The likelihood of the first visit being to the orthopedic department and the frequency of biologics use increased with the disease duration. The rates of uveitis, depressed mood, and comorbid diseases were higher in the group with delayed diagnosis. CONCLUSIONS: Physicians should be aware of subtypes of AS that take longer to diagnose and comorbid diseases in the real-world clinical setting.

Contribution of Personality Traits, Psychological Factors, and Health-Related Quality of Life to Medication Adherence in Patients with Rheumatoid Arthritis.

PURPOSE: This study sought to investigate the associations between personality traits and medication adherence and to identify predictors of good medication adherence in rheumatoid arthritis (RA) patients. MATERIALS AND METHODS: A total of 207 RA patients using disease-modifying anti-rheumatic drugs were invited for an interview and questionnaire study. Medication adherence was measured using the Compliance Questionnaire for Rheumatology (CQR). Personality traits were analyzed with the five-factor model of the Korean version of the Big Five Inventory 10. Psychological factors were assessed with the Patient Health Questionnaire-9, Generalized Anxiety Disorder-7, and British Columbia Cognitive Inventory. Health-related Quality of Life (HRQoL) and functional disability were evaluated with the EuroQoL-5 dimension questionnaire and Health Assessment Questionnaire. Multivariate logistic regression analyses were performed to investigate predictors of good medication adherence. RESULTS: Nonadherence to medication was reported by 66.7%. The number of daily prescribed pills was higher in the medication adherence group than in the nonadherence group. Concomitant oral glucocorticoid doses were associated with medication adherence. A high level of conscientiousness and diabetes mellitus comorbidity were associated with better medication adherence [odds ratio (OR), 2.11; 95% confidence interval (CI), 1.01-4.38 and OR, 3.00; 95% CI, 1.12-8.07, respectively]. There were no significant differences in psychological factors or HRQoL between medication adherence and nonadherence groups. CONCLUSION: The personality trait of conscientiousness was associated with medication adherence among the five personality traits evaluated. Patients with diabetes mellitus also showed higher medication adherence than those without this comorbidity.

Association between Body Weight Changes and Menstrual Irregularity: The Korea National Health and Nutrition Examination Survey 2010 to 2012.

BACKGROUND: Menstrual irregularity is an indicator of endocrine disorders and reproductive health status. It is associated with various diseases and medical conditions, including obesity and underweight. We aimed to assess the association between body weight changes and menstrual irregularity in Korean women. METHODS: A total of 4,621 women 19 to 54 years of age who participated in the 2010 to 2012 Korea National Health and Nutrition Examination Survey were included in this study. Self-reported questionnaires were used to collect medical information assessing menstrual health status and body weight changes. Odds ratios (ORs) and 95% confidence interval (CI) were calculated to evaluate the association between body weight changes and menstrual irregularity. RESULTS: Significantly higher ORs (95% CI) were observed in the association between menstrual irregularity and both weight loss (OR, 1.74; 95% CI, 1.22 to 2.48) and weight gain (OR, 1.45; 95% CI, 1.13 to 1.86) after adjusting for age, body mass index, current smoking, heavy alcohol drinking, regular exercise, calorie intake, education, income, metabolic syndrome, age of menarche, parity, and stress perception. Of note, significant associations were only observed in subjects with obesity and abdominal obesity, but not in non-obese or non-abdominally obese subjects. U-shaped patterns were demonstrated in both obese and abdominally obese subjects, indicating that greater changes in body weight are associated with higher odds of menstrual irregularity. CONCLUSION: We found a U-shaped pattern of association between body weight changes and menstrual irregularity among obese women in the general Korean population. This result indicates that not only proper weight management but also changes in body weight may influence the regulation of the menstrual cycle.

The impact of kidney transplantation on 24-hour ambulatory blood pressure in end-stage renal disease patients.

In this study, we prospectively investigated the impact of kidney transplantation (KT) on the status of hypertension, including circadian rhythm in end-stage renal disease (ESRD) patients. We performed 24-hour ambulatory blood pressure (BP) monitoring and office BP measurement in 48 patients before and 1 year after KT. According to the nocturnal reduction in systolic BP (ΔSBP), the patients were divided into dippers, non-dippers, and reverse dippers. After KT, the mean BP value in office BP and 24-hour ambulatory BP monitoring did not change, but the proportion of patients taking anti-hypertensive drugs and the pill number significantly decreased. In contrast, the mean ΔSBP significantly decreased, and the proportion of non-dippers and reverse dippers did not decrease. Decrease in ΔSBP after KT was associated with inferior allograft function during follow-up. Our study suggests that KT improved the overall BP level, but it did not affect abnormal circadian rhythm in ESRD patients.

Natural history of horizontal canal benign paroxysmal positional vertigo is truly short.

The objective of the study is to characterize the natural course of positional vertigo and nystagmus in patients with horizontal canal benign paroxysmal positional vertigo (h-BPPV) and to analyze the difference in the natural course between the two variants of h-BPPV. We conducted a prospective study in 106 patients with geotropic type h-BPPV [h-BPPV (Geo)] (n = 43) and apogeotropic type h-BPPV [h-BPPV (Apo)] (n = 63) who agreed and signed the written informed consent of no treatment. All patients were asked to answer a detailed interview about the onset time of positional vertigo and to visit the hospital every 1-3 days. At every visit, they were interviewed about cessation time of positional vertigo and positional nystagmus was assessed. The mean period ± SD between the onset and remission of vertigo in the h-BPPV (Geo) was 6.7 ± 6.3 days, whereas that in the h-BPPV (Apo) was 3.7 ± 4.1 days. In addition, the mean period ± SD from the initial diagnosis to the disappearance of positional nystagmus in the h-BPPV (Geo) was 4.7 ± 3.9 days, whereas that in the h-BPPV (Apo) was 4.4 ± 5.0 days. Although the duration until natural remission of positional nystagmus did not differ between the two variants of h-BPPV, the remission of vertigo occurred faster in h-BPPV (Apo) than h-BPPV (Geo) (p < 0.05). The natural course of h-BPPV is much shorter than that indicated in previous reports. The positional vertigo disappeared faster in the h-BPPV (Apo) compared to the h-BPPV (Geo) unlike the positional nystagmus.

Persistent spontaneous nystagmus following a canalith repositioning procedure in horizontal semicircular canal benign paroxysmal positional vertigo.

IMPORTANCE: Nystagmus can occur spontaneously from multiple causes. Direction-changing positional nystagmus on the supine roll test is a characteristic clinical feature in horizontal semicircular canal benign paroxysmal positional vertigo. One of several mechanisms of spontaneous nystagmus is plugging of the otoconia, which has been described as a canalith jam. OBSERVATIONS: We evaluated a 52-year-old woman with a history of geotropic variant of horizontal semicircular canal benign paroxysmal positional vertigo on the right side who had been treated with a modified Lempert maneuver 3 months earlier. The patient had persistent spontaneous nystagmus, despite a positional change after the canalith repositioning procedure. A bithermal caloric test result demonstrated unilateral canal paresis on the right side. The following day, the patient's symptoms and nystagmus had subsided. On a repeated bithermal caloric test, a normal response was demonstrated on both sides. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first report of a case that shows on video persistent nystagmus findings consistent with a canalith jam. We discuss a possible mechanism underlying this phenomenon.

Benign paroxysmal positional vertigo with simultaneous involvement of multiple semicircular canals.

BACKGROUND AND OBJECTIVES: Benign paroxysmal positional vertigo (BPPV) generally involves a single semicircular canal (single canal BPPV) but it has been reported that more than one semicircular canal on either the same or the opposite side can be involved in 6.8-20% of the cases (multiple canal BPPV). In this study, the clinical characteristics of multiple canal BPPV were analyzed and compared to those of single canal BPPV. MATERIALS AND METHODS: Retrospective analysis was performed on 1054 consecutive patients diagnosed with BPPV. Multiple canal BPPV was diagnosed when the combination of typical nystagmus was provoked by the Dix-Hallpike and supine head roll tests. Canalith repositioning maneuver was performed sequentially starting with the semicircular canal causing more severe nystagmus or symptoms. Clinical characteristics and the treatment course were statistically compared between single canal BPPV and multiple canal BPPV. RESULTS: Among the 1054 patients, single canal BPPV was diagnosed in 1005 patients (95.4%) while multiple canal BPPV was diagnosed in 49 patients (4.6%). BPPV involving semicircular canals on the same side was more common (79.6%) than BPPV with bilateral involvement. The most common combination of the involved canals was ipsilateral posterior and horizontal semicircular canals (63.3%). Multiple canal BPPV was significantly more associated with underlying otologic diseases, especially labyrinthitis. Multiple canal BPPV required more treatment sessions and longer duration of treatment to achieve resolution of nystagmus and symptoms. CONCLUSIONS: As all cases of multiple canal BPPV were treated successfully although a longer duration of treatment and more treatment sessions were required compared to single canal BPPV, the results of our study could aid in making an accurate diagnosis and providing appropriate treatment of multiple canal BPPV.

A case of labyrinthine fistula by cholesteatoma mimicking lateral canal benign paroxysmal positional vertigo.

Acute peripheral vestibulopathy, of which the chief complaint is positional vertigo, comprises benign paroxysmal positional vertigo (BPPV), labyrinthitis, labyrinthine fistula, and cerebellopontine angle tumors. Since the typical presentation of labyrinthine fistulas may be sensorineural hearing loss, positional vertigo, or disequilibrium, it is often difficult to distinguish from BPPV or Meniere's disease. Herein we report a 61-year-old female patient with typical symptoms and signs attributable to geotropic type variant of the lateral semicircular canal BPPV on the left side, who eventually was confirmed as having a labyrinthine fistula from chronic otitis media with cholesteatoma on the left side. This is another case where, even in the presence of isolated vertigo showing typical findings of acute peripheral vestibulopathy, other otologic symptoms and signs must not be overlooked.

Can the affected semicircular canal be predicted by the initial provoking position in benign paroxysmal positional vertigo?

OBJECTIVES/HYPOTHESIS: The study evaluated the relationship between the position that initially provoked vertigo and the affected semicircular canal (SCC) in patients with benign paroxysmal positional vertigo (BPPV), and aimed to predict the side affected by BPPV through history taking regarding the provoking position. STUDY DESIGN: Prospective study at a tertiary hospital. METHODS: A total of 521 patients with BPPV involving the posterior or horizontal SCCs performed questionnaires at initial visit asking to choose the initial provoking position among the 10 positions corresponding to one of the three planes (roll, pitch, or yaw). After excluding 45 patients showing signs of simultaneous multiple canal or anterior canal involvement, the frequency of the provoking positions and the correlation between the side of the provoking position and the ear affected by BPPV were analyzed. RESULTS: There were 239 patients with posterior SCC BPPV (p-BPPV) and 237 patients with horizontal SCC BPPV (h-BPPV). The waking-up position was the most common provoking position in both types of BPPV. Statistically significant correlation was demonstrated between the side of the provoking position at the onset of vertigo and the affected side by BPPV (P < .01) in patients with p-BPPV as well as h-BPPV (geotropic type [Geo]), but not in patients with h-BPPV (apogeotropic type [Apo]). CONCLUSIONS: History taking regarding the side of provoking position at the onset of vertigo may help predict the side affected by BPPV in p-BPPV and h-BPPV (Geo). When h-BPPV (Apo) is suspected, further detailed examinations using additional localization methods should be performed.

DHS-21, a dicarbonyl/L-xylulose reductase (DCXR) ortholog, regulates longevity and reproduction in Caenorhabditis elegans.

Dicarbonyl/L-xylulose reductase (DCXR) converts l-xylulose into xylitol, and reduces various α-dicarbonyl compounds, thus performing a dual role in carbohydrate metabolism and detoxification. In this study, we identified DHS-21 as the only DCXR ortholog in Caenorhabditis elegans. The dhs-21 gene is expressed in various tissues including the intestine, gonadal sheath cells, uterine seam (utse) cells, the spermathecal-uterus (sp-ut) valve and on the plasma membrane of spermatids. Recombinant DHS-21 was shown to convert L-xylulose to xylitol using NADPH as a cofactor. Dhs-21 null mutants of C. elegans show defects in longevity, reproduction and egg-laying. Knock-down of daf-16 and elt-2 transcription factors affected dhs-21 expression. These results suggest that DHS-21 is a bona fide DCXR of C. elegans, essential for normal life span and reproduction.

Novel calcineurin interacting protein-2: the functional characterization of CNP-2 in Caenorhabditis elegans.

Calcineurin (Cn) is a serine/threonine phosphatase implicated in a wide variety of biological responses. To identify proteins that mediate Cn signaling pathway effects, we used yeast two-hybrid assays to screen for Cn interacting proteins, discovering a protein encoded by the gene, cnp-2 (Y46G5A.10). Utilizing serially deleted forms of Cn as baits, we demonstrated that the catalytic domain of Cn (TAX-6) binds with CNP-2, and this physical interaction was able to be reconstituted in vitro, supporting our yeast two-hybrid results. cnp-2 is a nematode-specific novel gene found in C. elegans as well as its closest relative, C. briggsae. CNP-2 was strongly expressed in the intestine of C. elegans. To study the function of cnp-2, we performed cnp-2 RNAi knock-down and characterized phenotypes associated with Cn mutants. However, no gross defects were revealed in these RNAi experiments. CNP-2 was proven to be a Cn binding protein; however, its role remains to be elucidated.

A novel calcineurin-interacting protein, CNP-3, modulates calcineurin deficient phenotypes in Caenorhabditis elegans.

Calcineurin (Cn) is a calcium/calmodulin-dependent serine/threonine protein phosphatase that has diverse functions in different cell types and organisms. We screened proteins interacting with the C. elegans CnA homolog, TAX-6, by the yeast two-hybrid system. CNP-3 (Calcineurin interacting protein-3) is a novel protein that physically interacts with the catalytic domain of TAX-6. It is strongly expressed in the nuclei of intestine, hypodermis, dorsal uterine regions and spermatheca. Expression begins around the 60-cell stage and proceeds during all larval stages and the adult. To elucidate the biological function of cnp-3 we isolated a cnp-3 deletion mutant. Since CNP-3 binds CnA, we looked at factors associated with calcineurin loss-of-function mutants, such as brood size, body size, serotonin- and levamisole-mediated egg-laying behavior. The cnp-3(jh145) single mutant had no gross defects compared to wild-type animal. However, the phenotypes of the double mutants, tax-6(p675);cnp-3(jh145) and cnb-1(jh103);cnp-3(jh145), were more severe in terms of brood size, body size and serotonin-mediated egg-laying defects than tax-6(p675) and cnb-1(jh103), respectively. These results suggest that dysfunction of cnp-3 enhances certain calcineurin loss-of-function phenotypes in C. elegans.

PYP-1, inorganic pyrophosphatase, is required for larval development and intestinal function in C. elegans.

Inorganic pyrophosphatase (PPase) catalyzes the hydrolysis of inorganic pyrophosphate (PPi) into phosphate (Pi), which provides a thermodynamic driving force for important biosynthetic reactions. The nematode Caenorhabditis elegans gene C47E12.4 encodes a PPase (PYP-1) which shows 54% amino acid identity with human PPase. PYP-1 exhibits specific enzyme activity and is mainly expressed in the intestinal and nervous system. A null mutant of pyp-1 reveals a developmental arrest at early larval stages and exhibits gross defects in intestinal morphology and function. The larval arrest phenotype was successfully rescued by reintroduction of the pyp-1 gene, suggesting that PYP-1 is required for larval development and intestinal function in C. elegans.

Membrane proteomic analysis of human mesenchymal stromal cells during adipogenesis.

Mesenchymal stromal cells (MSCs) have proven useful for cell and immune therapy, but the molecular constituents responsible for their functionalities, in particular, those on the plasma membrane, remain largely unknown. Here we employed both gel and nongel based MS to analyze human MSCs' membrane proteome before and after adipogenesis. 2-DE of cells that were pretreated with membrane impermeable fluorescent dyes revealed that both the whole cell proteome and the cell surface subproteome were independent of donors. LC coupled with tandem MS analysis of the plasma membrane-containing fraction allowed us to identify 707 proteins, approximately half of which could be annotated as membrane-related proteins. Of particular interest was a subset of ectodomain-containing membrane-bound proteins that encompass most known surface markers for MSCs, but also contain a multitude of solute carriers and ATPases. Upon adipogenic differentiation, this proteomic profile was amended to include several proteins involved in lipid metabolism and trafficking, at the expense of, most noticeably, ectoenzymes. Our results here provide not only a basis for future studies of MSC-specific molecular mechanisms, but also a molecular inventory for the development of antibody-based cell isolation and identification procedures.

Functional importance of polymerization and localization of calsequestrin in C. elegans.

Dual roles of calsequestrin (CSQ-1) being the Ca2+ donor and Ca2+ acceptor make it an excellent Ca2+-buffering protein within the sarcoplasmic reticulum (SR). We have isolated and characterized a calsequestrin (csq-1)-null mutant in Caenorhabditis elegans. To our surprise, this mutant csq-1(jh109) showed no gross defects in muscle development or function but, however, is highly sensitive to perturbation of Ca2+ homeostasis. By taking advantage of the viable null mutant, we investigated the domains of CSQ-1 that are important for polymerization and cellular localization, and required for its correct buffering functions. In transgenic animals rescued with various CSQ-1 constructs, the in vivo patterns of polymerization and localization of several mutated calsequestrins were observed to correlate with the structure-function relationship. Our results suggest that polymerization of CSQ-1 is essential but not sufficient for correct cellular localization and function of CSQ-1. In addition, direct interaction between CSQ-1 and the ryanodine receptor (RyR) was found for the first time, suggesting that the cellular localization of CSQ-1 in C. elegans is indeed modulated by RyR through a physical interaction.

Genome-wide differential gene expression profiling of human bone marrow stromal cells.

Bone marrow stromal cells (BMSCs) reside in bone marrow and provide a lifelong source of new cells for various connective tissues. Although human BMSCs are regarded as highly suitable for the development of cell therapeutics and regenerative medicine, the molecular factors and the networks of signaling pathways responsible for their biological properties are as yet unclear. To gain a comprehensive understanding of human BMSCs at the transcriptional level, we have performed DNA microarray-based, genome-wide differential gene expression analysis with the use of peripheral blood-derived mononuclear cells (MNCs) as a baseline. The resulting molecular profile of BMSCs was revealed to share no meaningful overlap with those of other human stem cell types, suggesting that the cells might express a unique set of genes for their stemness. By contrast, the distinct molecular signature, consisting of 92 different genes whose expression strengths are at least 50-fold higher in BMSCs compared with MNCs, was shown to encompass largely a gene subset of umbilical cord blood-derived adherent cells, suggesting that adherent cells derived from bone marrow and umbilical cord blood may be defined by a common set of genes, regardless of their origin. Intriguingly, a large number of these genes, particularly ones for extracellular matrix products, coincide with normal or tumor endothelium-specific markers. Taken together, our results here provide a BMSC-specific genetic catalog that may facilitate future studies on molecular mechanisms governing core properties of these cells.

Caenorhabditis elegans PMR1, a P-type calcium ATPase, is important for calcium/manganese homeostasis and oxidative stress response.

The Caenorhabditis elegans PMR1, a P-type Ca2+/Mn2+ ATPase, is expressed in hypodermal seam cells, intestinal cells and spermatheca; localized in Golgi complex. Knock down of pmr-1 as well as overexpression of truncated Caenorhabditis elegans PMR1, which mimics dominant mutations observed in human Hailey-Hailey disease, renders the worm highly sensitive to EGTA and Mn2+. Interestingly, pmr-1 knock down not only causes animals to become resistant to oxidative stress but also suppresses high reactive oxygen species sensitivity of smf-3 RNA-mediated interference and daf-16 worms. These findings suggest that C. elegans PMR1 has important roles in Ca2+ and Mn2+ homeostasis and oxidative stress response.