Metacognition in wild Japanese macaques: cost and stakes influencing information-seeking behavior.

Metacognition allows us to evaluate memories and knowledge, thus enabling us to distinguish between what we know and what we do not. Studies have shown that species other than humans may possess similar abilities. However, the number of species tested was limited. Testing ten free-ranging Japanese macaques (Macaca fuscata) on a task in which they had to find food hidden inside one of the four opaque tubes, we investigated whether these subjects would seek information when needed. The monkeys could look inside the tubes before selecting one. We varied three parameters: the baiting process, the cost that monkeys had to pay to look inside the tubes, and the reward at stake. We assessed whether and how these parameters would affect the monkeys' tendency to look inside the tube before selecting one. When they were not shown which tube contained the reward, nine monkeys looked significantly more frequently in at least one condition. Half of them tended to reduce their looks when the cost was high, but only when they already knew the location of the reward. When a high-quality reward was at stake, four monkeys tended to look more inside the tubes, even though they already knew the reward's location. Our results are consistent with those of rhesus macaques, suggesting that metacognitive-like abilities may be shared by Cercopithecidae, and that, at least some monkeys may be aware of their lack of knowledge.

Metacognition in Japanese macaques (Macaca fuscata): does impulsivity explain unnecessary looks in the tubes task?

Potential metacognitive abilities, such as monitoring and controlling cognitive processes, have been revealed in some primate species. In the tubes task, apes and macaques showed higher content-checking behavior when unaware of a reward's location, but they also periodically inspected the tubes when aware, especially when a more appealing reward was involved. Some attribute this to the pleasure of looking at the reward. This study investigates whether the unnecessary tube-checking behavior observed in nine wild Japanese macaques, previously tested for metacognition using the tubes task, can be solely attributed to impulsivity. The macaques' propensity to look inside a single tube containing food they cannot immediately reach was measured and compared to their behavior in the tubes task. Results indicated that looking inside the baited tube increased as reward quality improved. However, macaques displaying unnecessary tube inspections in metacognitive tests showed less impulsivity to look. This intriguing result counters the notion that excessive looking in the tubes task is solely due to impulsive looking, prompting us to advocate for further research into the relationship between inhibition and metacognitive performance.

Behavioral responses of solicitors after failure to receive grooming in Macaca fuscata.

Grooming is one of the most common cooperative behaviors among several animal species. However, the tactics used to cope with uncooperative partners in grooming interactions remain unclear. Japanese macaques (Macaca fuscata) solicit grooming from partners through postural behaviors, but may not necessarily receive grooming. This study investigated the behavior of female Japanese macaques after they solicited but did not receive grooming. We predicted that unsuccessful solicitors would engage in grooming interactions with uncooperative partners if they were affiliated. If they were not affiliated, the solicitors would not do so and may seek grooming interactions with other grooming partners. We used a focal-animal sampling method, targeting 17 females at Katsuyama, Okayama Prefecture, Japan. We recognized affiliative relationships by measuring close spatial association. After unsuccessful solicitation, females tended to scratch themselves, suggesting that solicitors may experience anxiety or distress when they do not receive grooming. They also tended to be proximate with affiliated partners after solicitation, regardless of whether the solicitors received grooming from their partners. In contrast, when solicitors failed to receive grooming from unaffiliated partners, their subsequent proximity was lower than when they were groomed. Moreover, unsuccessful solicitors were likely to engage in grooming interactions with affiliated partners who were uncooperative (receivers of unsuccessful solicitations). However, they were less likely to engage in grooming interactions with unaffiliated partners and instead engaged in grooming interactions with other nearby partners. These findings indicate that female Japanese macaques decide whether to engage in grooming interactions with uncooperative partners who have not groomed solicitors based on affiliative relationships and the availability of other grooming partners. It is probable that, when the cost of searching for a grooming partner is low, female Japanese macaques are likely to switch partners, potentially leading to an increase in the benefits obtained from grooming interactions.

Diet-related factors strongly shaped the gut microbiota of Japanese macaques.

Although knowledge of the functions of the gut microbiome has increased greatly over the past few decades, our understanding of the mechanisms governing its ecology and evolution remains obscure. While host genetic distance is a strong predictor of the gut microbiome in large-scale studies and captive settings, its influence has not always been evident at finer taxonomic scales, especially when considering among the recently diverged animals in natural settings. Comparing the gut microbiome of 19 populations of Japanese macaques Macaca fuscata across the Japanese archipelago, we assessed the relative roles of host genetic distance, geographic distance and dietary factors in influencing the macaque gut microbiome. Our results suggested that the macaques may maintain a core gut microbiome, while each population may have acquired some microbes from its specific habitat/diet. Diet-related factors such as season, forest, and reliance on anthropogenic foods played a stronger role in shaping the macaque gut microbiome. Among closely related mammalian hosts, host genetics may have limited effects on the gut microbiome since the hosts generally have smaller physiological differences. This study contributes to our understanding of the relative roles of host phylogeography and dietary factors in shaping the gut microbiome of closely related mammalian hosts.

Central fibrous area in the glomerular vascular pole consists of fibrous collagens and is associated with advanced age: a cross-sectional study.

BACKGROUND: For the optimal management of patients with both allograft kidneys and native kidney diseases, the recognition of the histological features associated with older age is important. This is because most pathological findings are non-specific. Central fibrous areas (CFAs) have recently been proposed to be age-related. However, the components of CFAs and whether CFAs are observed in various kidney diseases remain undetermined. This cross-sectional study was undertaken to clarify the histological features, epidemiology, and clinicopathological features of CFAs. METHODS: One hundred and one consecutive kidney needle biopsy specimens were retrospectively collected from seven facilities in the Hokuriku region and diagnosed at the Kanazawa University Hospital in 2015. First, the components of CFAs were analyzed using normal histostaining, immunostaining, and electron microscopy. Second, the patients were divided into two groups (CFA [+] or CFA [-]) according to the presence of CFA in the obtained samples. Clinical and histological features were compared between the two groups, and factors associated with CFA formation were determined using univariate and multivariate analyses. The number of CFAs per specimen was counted in the CFA (+) group. Third, the presence of myofibroblasts in CFA was examined by immunostaining. RESULTS: CFAs were observed in 56 of 101 patients (55.4%) with various kidney diseases. CFAs consist of fibrillar collagens (collagen I and III) in addition to non-fibrillar collagens (collagen IV and VI), as confirmed by electron microscopy. Clinically, the CFA (+) group was older and had a significantly higher prevalence of hypertension and hyperlipidemia than the CFA (-) group. Histologically, elastofibrosis of the interlobular artery, arteriolar hyalinosis, and membranous nephropathy were significantly more evident in the CFA (+) group than in the CFA (-) group. Multivariate analysis revealed that older age was the sole factor associated with CFA formation. Finally, 27 of 58 (46.6%) CFA-containing glomeruli in 26 cases included alpha-smooth muscle actin-positive cells in or adjacent to the CFA. CONCLUSIONS: CFAs consist of fibrous collagens in addition to matrix collagens. CFA formation is associated with older age and was observed in various kidney diseases.

Urinary abnormality in mixed connective tissue disease predicts development of other connective tissue diseases and decrease in renal function.

OBJECTIVE: To clarify the clinical significance of development of urinary abnormality in mixed connective tissue disease (MCTD). METHODS: Forty-one patients with an initial diagnosis of MCTD, followed at five hospitals between April 1, 2000 and December 31, 2013, were included. The relationship between urinary abnormality and various clinical parameters were retrospectively analyzed. Urinary abnormality was defined as proteinuria and/or hematuria detected by urinalysis. Development of other connective tissue diseases (CTDs) was defined as satisfaction of the criteria of each respective disease. RESULTS: Of 41 patients (34 females, 7 males, mean age at diagnosis 42.2 ± 15.2 years), 16 developed urinary abnormality (UrA(+) patients). The total incidences of development of other CTDs were higher in the UrA(+) patients than UrA(-) (62.5% versus 16.0%, p = .01). In the comparison between UrA(+) and UrA(-) patients, there were no significant differences in follow-up duration or last determined estimated glomerular filtration rate (eGFR), although eGFR decreased more significantly in the UrA(+) patients than UrA(-). (-20.2 ± 17.2 vs -6.1 ± 13.8 ml/min/1.73m2, p = .01; -21.0 ± 18.9 vs -6.7 ± 14.1%, p = .03). CONCLUSION: Urinary abnormality during the clinical course in MCTD is predictive of a higher incidence of developing other CTDs. Furthermore, it might also predict long-term renal prognosis in patients with an initial diagnosis of MCTD.

MAFFT online service: multiple sequence alignment, interactive sequence choice and visualization.

This article describes several features in the MAFFT online service for multiple sequence alignment (MSA). As a result of recent advances in sequencing technologies, huge numbers of biological sequences are available and the need for MSAs with large numbers of sequences is increasing. To extract biologically relevant information from such data, sophistication of algorithms is necessary but not sufficient. Intuitive and interactive tools for experimental biologists to semiautomatically handle large data are becoming important. We are working on development of MAFFT toward these two directions. Here, we explain (i) the Web interface for recently developed options for large data and (ii) interactive usage to refine sequence data sets and MSAs.

Tertiary lymphoid tissue in early-stage IgG4-related tubulointerstitial nephritis incidentally detected with a tumor lesion of the ureteropelvic junction: a case report.

BACKGROUND: IgG4-related kidney disease causes renal impairment of unknown pathogenesis that may progress to kidney failure. Although ectopic germinal centers contribute to the pathogenesis of the head and neck lesions of IgG4-related disease, the presence of tertiary lymphoid tissue (TLT) containing germinal centers in IgG4-RKD has rarely been reported. CASE PRESENTATION: We report a 72-year-old Japanese man who had IgG4-related tubulointerstitial nephritis (TIN) with TLT formation incidentally detected in a resected kidney with mass lesion of IgG4-related ureteritis in the ureteropelvic junction. During follow-up for past surgical resection of a bladder tumor, renal dysfunction developed and a ureter mass was found in the right ureteropelvic junction, which was treated by nephroureterectomy after chemotherapy. Pathology revealed no malignancy but abundant IgG4-positive cell infiltration, obliterative phlebitis and storiform fibrosis, confirming the diagnosis of IgG4-related ureteritis. In the resected right kidney, lymphoplasmacytes infiltrated the interstitium with focal distribution in the renal subcapsule and around medium vessels without storiform fibrosis, suggesting the very early stage of IgG4-TIN. Lymphocyte aggregates were also detected at these sites and consisted of B, T, and follicular dendritic cells, indicating TLT formation. IgG4-positive cells infiltrated around TLTs. CONCLUSIONS: Our case suggests that TLT formation is related with the development of IgG4-TIN and our analysis of distribution of TLT have possibility to elucidate IgG4-TIN pathophysiology.

Significance of kidney biopsy in autosomal dominant tubulointerstitial kidney disease-UMOD: is kidney biopsy truly nonspecific?

BACKGROUND: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare hereditary disease caused by a variety of genetic mutations. Carriers of a mutation in the responsible genes are at risk of reaching end-stage kidney disease typically in middle age. The frequency of this disease is assumed to be underestimated because of a lack of disease-specific signs. Pathological findings obtained from kidney of uromodulin related ADTKD (ADTKD-UMOD) patients are regarded as non-specific and less-informative for its diagnosis. This research was undertaken to evaluate the significance of kidney biopsy in ADTKD-UMOD patients. METHODS: Thirteen patients from 10 families with nine identified uromodulin (UMOD) gene mutations who underwent kidney biopsy in the past were studied. Their kidney tissues were stained with anti-UMOD antibody in addition to conventional methods such as PAS staining. When positive, the numbers of tubules with visible UMOD protein accumulations were calculated based on the total numbers of UMOD expressing tubules. Pathological findings such as tubulointerstitial fibrosis, atrophy, inflammation and glomerulosclerosis were also evaluated and analyzed. RESULTS: Interstitial fibrosis and tubular atrophy were present in all 13 patients. Most atrophic tubules with thickening and lamellation of tubular basement membranes showed negative UMOD staining. In all but two patients with C94F mutations, massive accumulation of UMOD proteins was observed in the renal endoplasmic reticulum. UMOD accumulations were also detectable by PAS staining as polymorphic unstructured materials in the 11 patients at frequencies of 2.6-53.4%. 80.4% of the UMOD accumulations were surrounded by halos. The detection rate of UMOD accumulations positively correlated with eGFR. Glomerulosclerosis was detected in 11/13 patients, with a frequency of 20.0 to 61.1%, while no cystic dilatations of glomeruli were detected. CONCLUSIONS: Massively accumulated UMOD proteins in ADTKD-UMOD kidneys are detectable not only by immunostaining using anti-UMOD antibody but also by conventional methods such as PAS staining, although their detection is not easy. These findings can provide important clues to the diagnosis of ADTKD-UMOD. Kidney biopsy in ADTKD-UMOD may be more informative than assumed previously.

Hypocomplementemia is related to elevated serum levels of IgG subclasses other than IgG4 in IgG4-related kidney disease.

OBJECTIVES: This study investigated the clinical features of IgG4-RKD patients with hypocomplementemia compared with those without it, so as to clarify the factors related to hypocomplementemia. METHODS: In this single-center retrospective study, we analyzed the clinical features of 25 patients with IgG4-RKD according to the presence/absence of hypocomplementemia. Additionally, we validated the results of a single-center study in a separate large multicenter cohort of 328 patients with IgG4-RD, and searched for factors related to hypocomplementemia. RESULTS: Serum IgG levels (p < .001), non-IgG4 IgG levels, calculated as the total IgG minus IgG4 (p < .001), serum IgG1 levels (p = .017), and the number of involved organs (p = .018) were significantly higher in the hypocomplementemia group. At relapse of renal lesions in four patients, all had serum IgG4 re-elevation, with the three with hypocomplementemia presenting worsening of hypocomplementemia and re-elevation of non-IgG4 IgG levels. In a validation cohort of 328 patients with IgG4-RD, multivariate logistic regression analysis indicated elevation of non-IgG4 IgG levels to be an independent factor related to hypocomplementemia in the patients with IgG4-RKD. CONCLUSION: The present study suggests that hypocomplementemia is associated with elevation of IgG subclasses other than IgG4 including IgG1 in IgG4-RKD.

Different factors underlie recurrent and de novo organ involvement in immunoglobulin G4-related disease.

OBJECTIVES: In IgG4-related disease (IgG4-RD), relapse including recurrent organ involvement (ROI) and de novo organ involvement (DNOI) occurs frequently during the clinical course. This study aimed to clarify the differences between the risk factors underlying ROI and DNOI in IgG4-RD. METHODS: We retrospectively investigated factors related to ROI and DNOI in 86 IgG4-RD patients. For assessment of factors related to ROI and DNOI, we performed uni- and multivariate Cox regression analyses. On stepwise multivariate analysis, we applied the variables with P < 0.1 in the univariate analysis and the predictors of relapse suggested in past reports. RESULTS: During the mean follow-up period of 63.1 months, ROI was detected at 1.0-120 months after diagnosis in 20 patients, 4 of whom were not receiving glucocorticoid (GC) at the time of ROI. In contrast, DNOI was detected at 5.0-120 months after diagnosis in 15 patients, 8 of whom were not receiving GC at the time of DNOI. In the multivariate analysis, blood eosinophil counts at diagnosis [per 100/µl; hazard ratio (HR) 1.072 (95% CI 1.018, 1.129)] and continuation of GC [vs discontinuation or observation without GC; HR 0.245 (95% CI 0.076, 0.793)] had a significant impact on the time to DNOI, whereas age [HR 0.942 (95% CI 0.899, 0.986)] and ANA positivity [vs negativity; HR 6.632 (95% CI 1.892, 23.255)] had a significant impact on the time to ROI. CONCLUSION: The present study suggests that the risk factors of ROI and DNOI are different in IgG4-RD, highlighting the need for different preventative strategies.

Impaired expression of innate immunity-related genes in IgG4-related disease: A possible mechanism in the pathogenesis of IgG4-RD.

Background: IgG4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and tissue infiltration by IgG4-positive plasma cells. The pathogenesis of this disease is not clear. Transcriptome analysis was performed to identify genes over- and under-expressed in patients with IgG4-RD.Method: DNA microarray analysis was performed using RNA from peripheral blood mononuclear cells of two patients with IgG4-RD and four healthy individuals. Genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy were identified. Four genes related to innate immunity such as transcobalamin I (TCN1), secretory leukocyte peptidase inhibitor (SLPI), bactericidal/permeability-increasing protein (BPI) and lactotransferrin (LTF) were assessed by real-time PCR in 15 IgG4-RD patients and 13 healthy individuals.Result: DNA microarray analysis identified 30 genes showing a greater than threefold change in expression in IgG4-RD patients following steroid therapy. Real-time RT-PCR showed that the levels of mRNAs encoding TCNI and SLPI, except for BPI and LTF, were significantly lower in patients with IgG4-RD than in healthy people. The levels of all four mRNAs in patients with IgG4-RD were significantly increased after steroid treatment.Conclusion: These results indicate that reduction in expression of innate immunity-related genes may participate in the pathogenesis of IgG4-RD that steroid treatment may rectify impaired innate immunity as well as acquired immunity.

Parallelization of MAFFT for large-scale multiple sequence alignments.

Summary: We report an update for the MAFFT multiple sequence alignment program to enable parallel calculation of large numbers of sequences. The G-INS-1 option of MAFFT was recently reported to have higher accuracy than other methods for large data, but this method has been impractical for most large-scale analyses, due to the requirement of large computational resources. We introduce a scalable variant, G-large-INS-1, which has equivalent accuracy to G-INS-1 and is applicable to 50 000 or more sequences. Availability and implementation: This feature is available in MAFFT versions 7.355 or later at https://mafft.cbrc.jp/alignment/software/mpi.html. Supplementary information: Supplementary data are available at Bioinformatics online.

Abundant a proliferation-inducing ligand (APRIL)-producing macrophages contribute to plasma cell accumulation in immunoglobulin G4-related disease.

BACKGROUND: This study aimed to investigate the contribution of a proliferation-inducing ligand (APRIL), a member of the tumor necrosis factor (TNF) superfamily implicated in plasma cell survival, to the development of plasma cell-rich lesions in immunoglobulin G4-related disease (IgG4-RD). METHODS: We performed immunohistochemical staining for APRIL with Stalk-1 and Aprily-8 antibodies specifically recognizing APRIL-producing cells and secreted APRIL, respectively, in renal and submandibular lesions of IgG4-RD in comparison with those of Sjögren's syndrome and sialolithiasis. RESULTS: Numerous Stalk-1-positive APRIL-producing cells were detectable in lesions of IgG4-RD. These cells, identified as CD163-positive M2 macrophages, secreted APRIL that distributed close to and even on infiltrating plasma cells. In contrast, APRIL-producing cells and the secreted form of APRIL were rarely detectable in lesions of Sjögren's syndrome or sialolithiasis. Notably, APRIL expression decreased concomitantly with the level of plasma cell infiltration after successful glucocorticoid treatment. CONCLUSIONS: Abundant infiltration into tissue lesions of APRIL-producing M2 macrophages and retention of secreted APRIL in plasma-cell-rich areas support a role for APRIL in the pathogenesis of plasma cell-rich lesions in IgG4-RD.

A case of IgG4-related tubulointerstitial nephritis and membranous glomerulonephritis during the clinical course of gastric cancer: Imaging features of IgG4-related kidney disease.

We describe an 81-year-old man with immunoglobulin G4-related disease (IgG4-RD) presenting with submandibular gland, lymph node, lung, kidney, aortic wall, and prostate lesions with concomitant gastric cancer. After curative surgical treatment of the gastric cancer, corticosteroid therapy for progressively decreasing renal function was started. Before starting steroid therapy, fluorodeoxyglucose positron emission tomography-computed tomography revealed multiple lesions of IgG4-RD but no metastasis of the cancer. However, the patient died 3 months after initiation of corticosteroid therapy because of recurrence of the gastric cancer. In this case, the imaging features of IgG4-tubulointerstitial nephritis dramatically changed during the clinical course of co-existing gastric cancer. The imaging features of the present case may provide clues to the pattern of spread of IgG4 lesions in the kidney.

De novo profile generation based on sequence context specificity with the long short-term memory network.

BACKGROUND: Long short-term memory (LSTM) is one of the most attractive deep learning methods to learn time series or contexts of input data. Increasing studies, including biological sequence analyses in bioinformatics, utilize this architecture. Amino acid sequence profiles are widely used for bioinformatics studies, such as sequence similarity searches, multiple alignments, and evolutionary analyses. Currently, many biological sequences are becoming available, and the rapidly increasing amount of sequence data emphasizes the importance of scalable generators of amino acid sequence profiles. RESULTS: We employed the LSTM network and developed a novel profile generator to construct profiles without any assumptions, except for input sequence context. Our method could generate better profiles than existing de novo profile generators, including CSBuild and RPS-BLAST, on the basis of profile-sequence similarity search performance with linear calculation costs against input sequence size. In addition, we analyzed the effects of the memory power of LSTM and found that LSTM had high potential power to detect long-range interactions between amino acids, as in the case of beta-strand formation, which has been a difficult problem in protein bioinformatics using sequence information. CONCLUSION: We demonstrated the importance of sequence context and the feasibility of LSTM on biological sequence analyses. Our results demonstrated the effectiveness of memories in LSTM and showed that our de novo profile generator, SPBuild, achieved higher performance than that of existing methods for profile prediction of beta-strands, where long-range interactions of amino acids are important and are known to be difficult for the existing window-based prediction methods. Our findings will be useful for the development of other prediction methods related to biological sequences by machine learning methods.

Post-infectious acute glomerulonephritis with podocytopathy induced by parvovirus B19 infection.

Human parvovirus B19 infection causes a variety of glomerular diseases such as post-infectious acute glomerulonephritis and collapsing glomerulopathy. Although each of these appears independently, it has not been fully determined why parvovirus B19 provokes such a variety of different glomerular phenotypes. Here, we report a 68-year-old Japanese man who showed endocapillary proliferative glomerulonephritis admixed with podocytopathy in association with parvovirus B19 infection. The patient showed acute onset of heavy proteinuria, microscopic hematuria and kidney dysfunction with arthralgia and oliguria after close contact with a person suffering from erythema infectiosum. In the kidney biopsy specimen, glomeruli revealed diffuse and global endocapillary infiltration of inflammatory cells, with some also showing tuft collapse with aberrant vacuolation, swelling, and hyperplasia of glomerular epithelial cells. Immunofluorescence revealed dense granular C3 deposition that resembled the "starry sky pattern". Intravenous glucocorticoid pulse therapy followed by oral prednisolone and cyclosporine combination therapy resulted in considerable amelioration of the kidney dysfunction and urinary abnormalities. The present case reveals that parvovirus B19 infection can induce different glomerular phenotypes even in the same kidney structure. This finding may provide hints useful for the further elucidation of the pathogenesis of parvovirus B19-induced glomerular lesions.

Impact of double positive for anti-centromere and anti-SS-a/Ro antibodies on clinicopathological characteristics of primary Sjögren's syndrome: a retrospective cohort study.

OBJECTIVES: The purpose of our study was to define the clinical characteristics of anti-centromere antibody and anti-SS-A/Ro antibody (ACA/SS-A) double positive Sjögren's syndrome (SS) and to clarify the clinical impact of these antibodies. METHODS: We examined 108 patients (6 males, mean age 57.9 years) with SS who underwent labial salivary gland biopsy. The patients were divided into four groups by ACA and anti-SS-A/Ro antibody positivity. Symptoms, laboratory and pathological data, and scleroderma-related data were compared among the groups. RESULTS: The cohort consisted of 16 ACA/SS-A double positive, 20 ACA single positive, 67 SS-A single positive, and 5 ACA/SS-A double negative SS. ACA/SS-A double positive SS were significantly older than SS-A single positive SS (mean age 71.1 vs. 53.1 years). They had higher EULAR Sjögren's syndrome disease activity index (ESSDAI) at diagnosis (mean 3.81 vs. 0.50) and higher serum IgG (mean 2009 vs. 1389 mg/dL) than ACA single positive SS. No patients developed skin sclerosis during a mean follow-up period of 45.6 months (range: 1-178). CONCLUSION: These results demonstrate that ACA/SS-A double positive SS is distinct from ACA single positive and SSA single positive SS. The combination of ACA and anti-SS-A/Ro antibody in SS should deserve greater attention in clinical practice.

Diagnostic sensitivity of cutoff values of IgG4-positive plasma cell number and IgG4-positive/CD138-positive cell ratio in typical multiple lesions of patients with IgG4-related disease.

OBJECTIVES: This study aimed to investigate the diagnostic sensitivity of the cutoff values of IgG4-positive plasma cell (PC) number and IgG4-positive/CD138-positive cell ratio proposed by the International consensus statement (ICS) on the pathology of IgG4-related disease (IgG4-RD) in typical multiple lesions of patients with IgG4-RD. METHODS: We evaluated IgG4-positive PC number and IgG4-positive/CD138-positive cell ratio in 39 samples from 18 IgG4-RD patients having more than two typical lesions of IgG4-RD. RESULTS: We evaluated 12 submandibular, 12 ophthalmic, six skin, five kidney, two pancreatic, and one bronchus and prostate lesion each in 18 patients with typical clinical, serological, and radiographic features. Concerning IgG4 + PC number per high-power field, most ophthalmic (11/12), kidney (5/5), pancreatic (2/2), and bronchial lesions (1/1) fulfilled the cutoff value of ICS, whereas many of the submandibular (6/12) and skin lesions (0/6) did not. In contrast to the absolute number, all lesions fulfilled the cutoff value of IgG4+/CD138 + cell ratio. In eight cases, only one or two lesions in the same patient fulfilled the cutoff value of ICS, while the others did not. CONCLUSIONS: These results suggest that ICS criteria have different sensitivities among the affected organs for the diagnosis of IgG4-RD.

Changes in serum interleukin-6 levels as possible predictor of efficacy of tocilizumab treatment in rheumatoid arthritis.

OBJECTIVES: We aimed to evaluate the association between the change in serum IL-6 during the clinical course of tocilizumab (TCZ) therapy and rheumatoid arthritis (RA) disease activity or occurrence of adverse events. METHODS: General laboratory data including serum IL-6 levels and physical findings were obtained every 4 weeks, and, in addition, at the time when any adverse events occurred. RESULTS: The proportion achieving Clinical Disease Activity Index (CDAI) remission at 52 weeks was significantly lower in 20 patients with serum IL-6 ≥ 30 pg/ml at 12 weeks than 24 patients with serum IL-6 < 30 pg/ml. In 17 patients with serum IL-6 ≥ 30 pg/ml at 24 weeks, the proportion achieving CDAI remission was also significantly lower than 27 patients with serum IL-6 < 30 pg/ml then. In these 17 patients, Disease Activity Score (DAS) 28-ESR and CDAI at 52 weeks were significantly higher than those with serum IL-6 < 30 pg/ml. Age- and sex-adjusted logistic regression analysis showed logIL-6 at 12 weeks to be a predictive factor for DAS28-ESR remission at 52 weeks. CONCLUSION: Serum IL-6 levels from 12 to 24 weeks after TCZ initiation better reflect the efficacy of TCZ at 52 weeks.