Comparison of SGLT2 inhibitors vs. DPP4 inhibitors for patients with metabolic dysfunction associated fatty liver disease and diabetes mellitus.

PURPOSE: This study aimed to examine the potential benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with metabolic dysfunction-associated fatty liver disease (MAFLD) and diabetes mellitus (DM) using a real-world database. METHODS: We analyzed individuals with MAFLD and DM newly initiated on SGLT2 or dipeptidyl peptidase 4 (DPP4) inhibitors from a large-scale administrative claims database. The primary outcome was the change in the fatty liver index (FLI) assessed using a linear mixed-effects model from the initiation of SGLT2 or DPP4 inhibitors. A propensity score-matching algorithm was used to compare the change in FLI among SGLT2 and DPP4 inhibitors. RESULTS: After propensity score matching, 6547 well-balanced pairs of SGLT2 and 6547 DPP4 inhibitor users were created. SGLT2 inhibitor use was associated with a greater decline in FLI than DPP4 inhibitor use (difference at 1-year measurement, - 3.8 [95% CI - 4.7 to - 3.0]). The advantage of SGLT2 inhibitor use over DPP4 inhibitor use for improvement in FLI was consistent across subgroups. The relationship between SGLT2 inhibitors and amelioration of FLI was comparable between individual SGLT2 inhibitors. CONCLUSIONS: Our analysis using large-scale real-world data demonstrated the potential advantage of SGLT2 inhibitors over DPP4 inhibitors in patients with MAFLD and DM.

Different changes in the biomarker C-terminal telopeptides of type II collagen (CTX-II) following intra-articular injection of high molecular weight hyaluronic acid and oral non-steroidal anti-inflammatory drugs in patients with knee osteoarthritis: a multi-center randomized controlled study.

OBJECTIVES: We previously reported, based on a multicenter randomized-control study, that the efficacy of intra-articular injections of hyaluronic acid (IA-HA) was not inferior to that of oral non-steroidal anti-inflammatory drugs (NSAIDs) in patients with knee osteoarthritis (OA). However, the molecular effects on the pathophysiology of knee OA remain unclear. C-terminal telopeptides of type II collagen (CTX-II) is reported to primarily originate from the interface between articular cartilage and subchondral bone, which is a site of potential remodeling in OA. We performed a predefined sub-analysis of the previous study to compare the changes of urinary CTX-II (uCTX-II) in response to IA-HA to those in response to NSAID for knee OA. DESIGN: A total of 200 knee OA patients were registered from 20 hospitals and randomized to receive IA-HA (2,700 kDa HA, 5 times at 1-week intervals) or NSAID (loxoprofen sodium, 180 mg/day) for 5 weeks. The uCTX-II levels were measured before and after treatment. RESULTS: The uCTX-II levels were significantly increased by IA-HA treatment (337.7 ± 193.8 to 370.7 ± 234.8 ng/µmol Cr) and were significantly reduced by NSAID treatment (423.2 ± 257.6 to 370.3 ± 250.9 ng/µmol Cr). The %changes of uCTX-II induced by IA-HA (11.6 ± 29.5%) and NSAID (-9.0 ± 26.7%) was significantly different (between-group difference: 20.6, 95% confidence intervals: 10.6 to 30.6). CONCLUSIONS: While both IA-HA and NSAID improved symptoms of knee OA, uCTX-II levels were increased by IA-HA and reduced by NSAIDs treatment, suggesting these treatments may improve symptoms of knee OA through different modes of action.

Laparoscopic and open liver resection for hepatocellular carcinoma with Child-Pugh B cirrhosis: multicentre propensity score-matched study.

BACKGROUND: Laparoscopic liver resection for hepatocellular carcinoma (HCC) in Child-Pugh A cirrhosis has been demonstrated as beneficial. However, the role of laparoscopy in Child-Pugh B cirrhosis is undetermined. The aim of this retrospective cohort study was to compare open and laparoscopic resection for HCC with Child-Pugh B cirrhosis. METHODS: Data on liver resections were gathered from 17 centres. A 1 : 1 propensity score matching was performed according to 17 predefined variables. RESULTS: Of 382 available liver resections, 100 laparoscopic and 100 open resections were matched and analysed. The 90-day postoperative mortality rate was similar in open and laparoscopic groups (4.0 versus 2.0 per cent respectively; P = 0.687). Laparoscopy was associated with lower blood loss (median 110 ml versus 400 ml in the open group; P = 0.004), less morbidity (38.0 versus 51.0 per cent respectively; P = 0.041) and fewer major complications (7.0 versus 21.0 per cent; P = 0.010), and ascites was lower on postoperative days 1, 3 and 5. For laparoscopic resections, patients with portal hypertension developed more complications than those without (26 versus 12 per cent respectively; P = 0.002), and patients with a Child-Pugh B9 score had higher morbidity rates than those with B8 and B7 (7 of 8, 10 of 16 and 21 of 76 respectively; P < 0.001). Median hospital stay was 7.5 (range 2-243) days for laparoscopic liver resection and 18 (3-104) days for the open approach (P = 0.058). The 5-year overall survival rate was 47 per cent for open and 65 per cent for laparoscopic resection (P = 0.142). The 5-year disease-free survival rate was 32 and 37 per cent respectively (P = 0.742). CONCLUSION: Patients without preoperative portal hypertension and Child-Pugh B7 cirrhosis may benefit most from laparoscopic liver surgery.

Autoantibodies to killer cell immunoglobulin-like receptor 3DL1 in patients with systemic lupus erythematosus.

A genetic variant of the killer immunoglobulin-like receptor 3DL1 (KIR3DL1) has been found in patients with systemic lupus erythematosus (SLE). Herein, we investigated the presence of autoantibodies to KIR3DL1 in a cohort of patients with SLE. We tested sera from 28 patients with SLE, 11 patients with rheumatoid arthritis (RA) and 17 healthy control subjects for anti-KIR3DL1 activity by an enzyme-linked immunosorbent assay (ELISA) using recombinant KIR3DL1-enhanced green fluorescent protein (EGFP) and EGFP proteins. Anti-KIR3DL1 antibodies were detected in 22 (79%) of the 28 patients with SLE, whereas they were present in only three (27%) of the 11 patients with RA examined. Notably, 10 (91%) of the 11 samples from patients with SLE prior to therapy had anti-KIR3DL1 antibodies. None of the samples from healthy donors were positive for the antibodies. Here, we report the presence of anti-KIR3DL1 antibodies in the sera of patients with SLE for the first time. Anti-KIR3DL1 autoantibodies may be involved in the pathogenesis of autoimmune diseases.

Delayed lupus nephritis in the course of systemic lupus erythematosus is associated with a poorer treatment response: a multicentre, retrospective cohort study in Japan.

OBJECTIVE: The objective of this study was to investigate possible differences in treatment responses between two categories for the onset of lupus nephritis. METHODS: We performed a multicentre, retrospective cohort study of class III-V lupus nephritis patients diagnosed between 1997 and 2014. The renal responses to initial induction therapy were compared between patients who developed lupus nephritis within one year from diagnosis of systemic lupus erythematosus (early (E-) LN) and the remainder (delayed (D-) LN) using the Kaplan-Meier method. We determined the predictors of renal response as well as renal flares and long-term renal outcomes using multivariate Cox regression analyses. RESULTS: A total of 107 E-LN and 70 D-LN patients were followed up for a median of 10.2 years. Log-rank tests showed a lower cumulative incidence of complete response in D-LN compared with E-LN patients. Multivariate analysis identified D-LN (hazard ratio (HR) 0.48, 95% confidence interval (CI) 0.33-0.70), nephrotic syndrome at baseline, and a chronicity index greater than 2 as negative predictors of complete response. D-LN patients were more likely to experience renal flares. D-LN (HR 2.54, 95% CI 1.10-5.83) and decreased renal function were significant predictors of chronic kidney disease at baseline. CONCLUSION: D-LN was a predictor of poorer treatment outcomes, in addition to renal histology and severity of nephritis at lupus nephritis onset.

The effect of resveratrol on the developmental competence of porcine oocytes vitrified at germinal vesicle stage.

We tested the effects of resveratrol both as a pre-treatment and as a recovery treatment after warming during in vitro maturation (IVM) on the viability and developmental competence of porcine oocytes vitrified at the germinal vesicle stage. Pre-treatment before vitrification of oocytes for 3 hr with 2 µM resveratrol did not affect survival, oocyte maturation and embryo developmental competence to the blastocyst stage after parthenogenetic activation. However, supplementation of the medium with resveratrol during subsequent IVM after vitrification and warming significantly improved the ability of surviving oocytes to develop to the blastocyst stage, and this effect was observed only on vitrified, but not on non-vitrified oocytes. The intracellular levels of glutathione and hydrogen peroxide in oocytes were not affected by vitrification and resveratrol treatment. Also, there was no significant difference in the occurrence of apoptosis measured by annexin V binding between vitrified and non-vitrified oocytes, regardless of the resveratrol treatment. In conclusion, resveratrol did not prevent the cellular damages in immature porcine oocytes during vitrification; however, when added to the IVM medium, it specifically improved the developmental competence of vitrified oocytes. Further research will be necessary to clarify the mechanisms of action of resveratrol on the recovery of vitrified oocytes from vitrification-related damages.

Bone marrow lesions, subchondral bone cysts and subchondral bone attrition are associated with histological synovitis in patients with end-stage knee osteoarthritis: a cross-sectional study.

OBJECTIVE: The aim of this study was to examine the osteoarthritis (OA)-related structural changes associated with histological synovitis in end-stage knee OA patients. METHODS: Forty end-stage knee OA patients (female: 88%, mean age: 71.8 y) were enrolled. All participants underwent 3.0-T MRI. The structural changes, such as cartilage morphology, subchondral bone marrow lesion (BML), subchondral bone cyst (SBC), subchondral bone attrition (SBA), osteophytes, meniscal lesion and synovitis, were scored using the whole-organ MRI scoring (WORMS) method. Synovial samples were obtained from five regions of interest (ROIs) of the knee joint during total joint replacement surgery. The associations between the histological synovitis score (HSS) and WORMS or the synovial expression levels of cyclooxygenase (COX)-2, interleukin (IL)-1ß, IL-6 and transforming growth factor (TGF)-ß were examined using Spearman's correlation coefficient. RESULTS: Among the seven OA-related structural changes, the BML, SBC, SBA and synovitis were significantly associated with the HSS (r = 0.33, 0.35, 0.48 and 0.36, respectively), while other morphological changes were not. Although synovial COX-2, IL-1ß or IL-6 expression levels were not associated with the HSS, the synovial TGF-ß expression levels were associated with the HSS. CONCLUSION: The presence of BML, SBC and SBA was associated with histological synovitis in end-stage knee OA patients.

The degeneration and destruction of femoral articular cartilage shows a greater degree of deterioration than that of the tibial and patellar articular cartilage in early stage knee osteoarthritis: a cross-sectional study.

OBJECTIVE: The aim of the present study was to examine whether the degenerative and morphological changes of articular cartilage in early stage knee osteoarthritis (OA) occurred equally for both femoral- and tibial- or patellar- articular cartilage using magnetic resonance imaging (MRI)-based analyses. DESIGN: This cross-sectional study was approved by the ethics committee of our university. Fifty patients with early stage painful knee OA were enrolled. The patients underwent 3.0 T MRI on the affected knee joint. Healthy volunteers who did not show MRI-based OA changes were also recruited as controls (n = 19). The degenerative changes of the articular cartilage were quantified by a T2 mapping analysis, and any structural changes were conducted using Whole Organ Magnetic Resonance Imaging Score (WORMS) technique. RESULTS: All patients showed MRI-detected OA morphological changes. The T2 values of femoral condyle (FC) (P < 0.0001) and groove (P = 0.0001) in patients with early stage knee OA were significantly increased in comparison to those in the control, while no significant differences in the T2 values of patellar and tibial plateau (TP) were observed between the patients and the control. The WORMS cartilage and osteophyte scores of the femoral articular cartilage were significantly higher than those in the patellar- (P = 0.001 and P = 0.007, respectively) and tibial- (P = 0.0001 and P < 0.0001, respectively) articular cartilage in the patients with early stage knee OA. CONCLUSIONS: The degradation and destruction of the femoral articular cartilage demonstrated a greater degree of deterioration than those of the tibial- and patellar- articular cartilage in patients with early stage knee OA.

Chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis exacerbation in a patient with systemic lupus erythematosus.

Chronic active Epstein-Barr virus infection (CAEBV) is characterized by chronic infectious mononucleosis-like symptoms. We report a very rare case with autoimmune hepatitis (AIH) complicated by CAEBV. A 50-year-old woman with systemic lupus erythematosus (SLE) complicated by AIH began to suffer from acute respiratory failure and her clinical symptoms improved rapidly in response to steroid treatment. However, during the gradual tapering of the steroid dose, a steady increase of the serum hepatobiliary enzyme levels subsequently was observed and the patient began to have continuous fever. Moreover, upper gastrointestinal endoscopy revealed multiple intractable gastric ulcers. When EBER-ISH was performed on liver biopsy and gastric mucosal biopsy specimens, EBER-positive lymphocytes were observed. When peripheral blood was examined, 2.1 × 10(6) copies/µg of EBV-DNA were observed in the CD4-positive T cells, confirming the diagnosis of CAEBV. A cooling therapy was started by steroid and cyclosporine. Thereafter, despite the start of CHOP therapy, she developed a malignant lymphoma (PTCL-NOS) and died of hepatic failure. When treatment-resistant AIH patients are encountered, not only AIH exacerbation but also CAEBV should be considered in the differential diagnosis.

The factors associated with pain severity in patients with knee osteoarthritis vary according to the radiographic disease severity: a cross-sectional study.

OBJECTIVES: Knee osteoarthritis (OA) pain is suggested to be associated with inflammation and detrimental mechanical loading across the joint. In this cross-sectional study, we simultaneously examined the inflammation and alignment of the lower limb and examined how the pain components varied depending on the disease progression. DESIGN: One-hundred sixty female medial type of early- [n = 74 in Kellgren-Lawrence (K/L) 2] to advanced-stage (n = 96 in K/L >2) knee OA subjects (70.5 years on average) were enrolled. Knee pain was evaluated using a pain visual analog scale (VAS) and the pain-related subcategory of the Japanese Knee Osteoarthritis Measure (JKOM-pain). The serum interleukin (sIL)-6 level reflecting synovitis, and the high sensitivity C-reactive protein (hs-CRP) level were measured to evaluate the severity of inflammation. The anatomical axis angle (AAA) was measured as an alignment index. The ß-coefficient was estimated after adjusting for age and the body mass index (BMI) using a multiple linear regression analysis. RESULTS: Multiple linear regression analyses showed that the sIL-6 levels, but not AAA, associated with the pain VAS [ß = 10.77 (95% confidence interval (CI): 4.14-17.40), P < 0.01] and JKOM-pain scores [ß = 3.19 (95% CI: 1.93-4.44), P < 0.001] in the early stage. Conversely, AAA, but not the sIL-6 levels, was found to be associated with the pain VAS [ß = -1.29 (95% CI: -2.51 to -0.08), P < 0.05] and JKOM-pain scores [ß = -0.49 (95% CI: -0.82 to -0.16), P < 0.01] in the advanced stage. CONCLUSIONS: The presence of a higher level of sIL-6 and the varus alignment of the joint is associated with pain in early- and advanced-stage knee OA patients, respectively.

Risk factors for infantile atopic dermatitis and recurrent wheezing.

BACKGROUND: The pathogenic mechanisms of atopic dermatitis (AD) and recurrent wheezing (RW) during infancy are not fully understood. OBJECTIVE: We evaluated immunological markers associated with AD and RW during infancy. METHODS: We followed a cohort (n = 314) from birth to 14 months of age. Some of the participants underwent a physical examination and blood test at 6 and 14 months of age. Univariate and multivariate logistic regression analysis and receiver operating characteristic curve analysis were performed to find which immunological markers could be risk factors for AD and RW. RESULTS: Of 16 immunological markers found in cord blood, only immunoglobulin (Ig) E was associated with AD at 6 months of age (adjusted OR [aOR], 1.607). None of the markers was associated with AD or RW at 14 months of age. Of 23 immunological markers at 6 months of age, total IgE (aOR, 1.018) and sensitization to egg white (aOR, 23.246) were associated with AD at 14 months of age. Phytohemagglutinin (PHA)-induced production of interleukin (IL) 4 from peripheral blood mononuclear cells (PBMCs) (aOR, 1.043) was associated with RW at 14 months of age. CONCLUSION: Cord blood IgE was a risk factor for AD at 6 months of age. Total IgE and sensitization to egg white at 6 months of age were risk factors for AD at 14 months of age. PHA-induced IL-4 production in PBMCs at 6 months of age was a risk factor for RW at 14 months of age.

Possible role of the JAK/STAT pathways in the regulation of T cell-interferon related genes in systemic lupus erythematosus.

Changes in gene expression in CD3+ T cells associated with disease progression in systemic lupus erythematosus (SLE) patients were determined. The genes related to SLE disease-related activities were identified and their gene regulatory networks were investigated. Analyses of gene expression were performed by both DNA microarray and real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). The expression of certain genes including interferon (IFN) regulatory factor (IRF)-related genes, such as IFN-regulated, -related, and -signature genes was increased in the active phase of SLE. Pathway network analyses suggested that these IRF-related genes are regulated through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. JAK/STAT pathway-mediated regulation of IRF-related genes may have an important role in the disease activity of SLE. Inhibitors of JAK/STAT cascade may be useful as therapeutic agents.

Association study of TRAF1-C5 polymorphisms with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese.

OBJECTIVE: The primary aim of this study was to investigate the association of polymorphisms of TRAF1-C5, a newly identified rheumatoid arthritis (RA) risk locus in Caucasians, with susceptibility to RA and systemic lupus erythematosus (SLE) in Japanese populations. Gene expression levels of TRAF1 and C5 to assess the functional significance of genotypes were also analysed. METHODS: A multicentre association study consisting of 4 RA case-control series (4397 cases and 2857 controls) and 3 SLE case-control series (591 cases and 2199 shared controls) was conducted. Genotyping was performed using TaqMan genotyping assay for two single nucleotide polymorphisms (SNPs) that showed the best evidence of association in the previous Caucasian studies. Quantifications of TRAF1 and C5 expression were performed with TaqMan expression assay. RESULTS: Significant differences in allele frequency for both SNPs were observed between RA and control subjects (combined odds ratio = 1.09), while no significant difference was detected between patients with SLE and controls. Interestingly, alleles rs3761847 A and rs10818488 G had increased the risk for RA in the present study, while they decreased the risk in the original studies. A significant difference was found between risk allele carriers and non-carriers of rs10818488 for the expression level of TRAF1 in phorbol myristate acetate-stimulated lymphoblastoid cell lines (p = 0.04). CONCLUSION: Association of TRAF1-C5 locus with RA susceptibility was detected in the Japanese populations with modest magnitude, while no significant association was observed for SLE. Significant positive effect of genotype on the expression of TRAF1 might support the genetic association between TRAF1 and RA.

Nuclear replacement of in vitro-matured porcine oocytes by a serial centrifugation and fusion method.

The objective of the present study was to establish a method for nuclear replacement in metaphase-II (M-II) stage porcine oocytes. Karyoplasts containing M-II chromosomes (K) and cytoplasts without chromosomes (C) were produced from in vitro-matured oocytes by a serial centrifugation method. The oocytes were then reconstructed by fusion of one karyoplast with 1, 2, 3 or 4 cytoplasts (K + 1C, K + 2C, K + 3C and K + 4C, respectively). Reconstructed oocytes, karyoplasts without fusion of any cytoplast (K) and zona-free M-II oocytes (control) were used for experiments. The rates of female pronucleus formation after parthenogenetic activation in all groups of reconstructed oocytes (58.2-77.4%) were not different from those of the K and control groups (58.2% and 66.0%, respectively). In vitro fertilization was carried out to assay the fertilization ability and subsequent embryonic development of the reconstructed oocytes. The cytoplast : karyoplast ratio did not affect the fertilization status (penetration and male pronuclear formation rates) of the oocytes. A significantly high monospermy rate was found in K oocytes (p < 0.05, 61.6%) compared with the other groups (18.2-32.8%). Blastocyst formation rates increased significantly as the number of the cytoplasts fused with karyoplasts increased (p < 0.05, 0.0-15.3%). The blastocyst rate in the K + 4C group (15.3%) was comparable with that of the control (17.8%). Total cell numbers in both the K + 3C and K + 4C groups (16.0 and 15.3 cells, respectively) were comparable with that of the control (26.2 cells). Our results demonstrate that a serial centrifugation and fusion (Centri-Fusion) is an effective method for producing M-II chromosome transferred oocytes with normal fertilization ability and in vitro development. It is suggested that the number of cytoplasts fused with a karyoplast plays a critical role in embryonic development.

Reactivated triton-extracted models o paramecium: modification of ciliary movement by calcium ions.

Triton-extracted models of Paramecium were reactivated to swim in solutions of adenosine triphosphate and magnesium ions. The cilia beat in the normal direction (toward the rear) when the calcium ion concentration was less than 10-(6)M, and they beat in the "reversed" direction (toward the front) when calcium ion concentration was raised above 10-(6)M. These results support the proposal that ciliary reversal, hence backward swimming, of live paramecia is mediated by an increased cytoplasmic calcium concentration around the ciliary system by calcium-dependent membrane responses to external stimuli.

Changes in the gene expression of peripheral blood mononuclear cells during the menstrual cycle of females is associated with a gender bias in the incidence of systemic lupus erythematosus.

OBJECTIVE: The incidence of systemic lupus erythematosus (SLE) is far higher in females than in males and the onset and/or disease activity is influenced by pregnancy and the menstrual cycle. Sex hormones seem to influence the pathogenesis of SLE, therefore, changes in gene expression in peripheral blood mononuclear cells (PBMC) were examined during the menstrual cycle in females, under the comparison of gene expression of patients with SLE. METHODS: The detection and a quantitative analysis of the gene expression was performed by DNA microarray or real-time quantitative polymerase chain reaction (RQ-PCR) method. RESULTS: There were thirteen known genes which showed significant quantitative changes during the menstrual cycles of females, but not in males. Among these genes, statistical quantitative differences between normal controls and SLE patients were observed in six genes. CONCLUSION: Based on these findings, certain genes (such as the tumor necrosis factor receptor superfamily, member 14; TNFRSF14, and signal regulatory protein, gamma; SIRPG) appear to contribute to gender difference of SLE.

Rheodielectric study on shear-induced structural change in the smectic-A phase of 4-n-octyl-4'-cyanobiphenyl (8CB).

Simultaneous measurements of rheological and dielectric properties are made to investigate shear-induced structural change in the smectic-A phase of 8CB (4-n-octyl-4'-cyanobiphenyl). With increasing the shear rate, the fluidity changes from non-Newtonian to Newtonian flow via an unstable flow region, accompanied by a characteristic change in the dielectric permittivity. In the non-Newtonian flow region, a dielectric dispersion, which can be ascribed to an undulation motion of smectic layer, is recognized. On the basis of these results, it is suggested that with increasing the shear rate the undulation changes to a chaotic structure, which is followed by a more simple structure with the layer normal along the neutral axis, and that these structural changes are responsible for the fluidity change.

Baculovirus-mediated interferon alleviates dimethylnitrosamine-induced liver cirrhosis symptoms in a murine model.

The wild-type baculovirus Autographa californica multiple nuclear polyhedrosis virus (AcMNPV) infects a range of mammalian cell types in vitro but does not replicate in these cells. The current study investigated the in vivo effect of AcMNPV in the mouse model of liver cirrhosis induced by the mutagen dimethylnitrosamine. Intraperitoneal injection of AcMNPV induced an immune response. The baculovirus was taken up by the liver and spleen where it suppressed liver injury and fibrosis through the induction of interferons. This study presents the first evidence of the feasibility of using baculovirus to treat liver cirrhosis.