Search

Abstract Background Elevated serum immunoglobulin G4 (IgG4) concentrations are one of the characteristic findings in IgG4-related disease (IgG4-RD). This study investigated the frequency of elevated serum IgG4 levels and associated factors in a general Japanese population. Methods Serum IgG4 concentrations were measured in 1,201 residents of Ishikawa prefecture who underwent general medical examinations. Factors associated with elevated serum IgG4 concentrations were assessed by logistic regression analysis. Participants with elevated serum IgG4 were subjected to secondary examinations. Results The mean serum IgG4 concentration was 44 mg/dL, with 42 (3.5%) participants having elevated serum IgG4 levels. Age- and sex-adjusted logistic regression analyses showed that male sex, older age, and lower intake of lipids and polyunsaturated fatty acids and higher intake of carbohydrates in daily diet were associated with elevated serum IgG4 concentration. Subgroup analyses in men showed that older age, lower estimated glomerular filtration rates based on serum cystatin C (eGFR-cysC) levels, and higher hemoglobin A1c (HbA1c) levels were associated with elevated serum IgG4 concentration. Analyses in women showed that lower intake of lipids and fatty acids and higher intake of carbohydrates were significantly associated with elevated serum IgG4 concentration. One of the 15 participants who underwent secondary examinations was diagnosed with possible IgG4-related retroperitoneal fibrosis. Conclusions Elevated serum IgG4 levels in a Japanese general population were significantly associated with older age, male gender, and dietary intake of nutrients, with some of these factors identical to the epidemiological features of IgG4-RD.

Abstract Background Multiple joint arthritis patterns require a comprehensive understanding to optimize patient management. This study aimed to present a patient cohort that deviated from known definitions of coxitis knee (CK), identifying and characterizing this atypical group. Methods Patients undergoing both total hip arthroplasty and total knee arthroplasty between January 2008 and December 2018 were retrospectively reviewed. The patients were classified into a typical coxitis knee group (classic, long leg arthropathy, and windswept deformity) and an atypical coxitis knee group. Leg-length discrepancy, body mass index (BMI), and radiographic parameters of the groups were compared and analyzed. Results A total of 31 patients were allocated to the typical coxitis knee group (n = 10), and atypical coxitis knee group (n = 21). In the atypical group, 27 hips were involved, of which 21 had acetabular dysplasia, 5 exhibited subchondral insufficiency fracture-like changes, and only 1 had classic osteoarthritis. Among the 27 knees undergoing total knee arthroplasty, 26 showed varus alignment, 1 was within the normal range, and none was valgus. Acetabular dysplasia involved ipsilateral (n = 1), contralateral (n = 14), and bilateral (n = 6) hips, showing atypical coxitis knee. Patients with acetabular dysplasia were more likely to exhibit atypical CK. Conclusion Most patients in the cohort displayed acetabular dysplasia and contralateral varus knees, constituting a pattern referred to as acetabular dysplasia-associated gonarthritis. Identifying this novel subtype may have important clinical implications for regions with high risk factors, where acetabular dysplasia and constitutional genu varum are prevalent. Graphical Abstract

Purpose: Kneeling is often difficult after a total knee arthroplasty. However, the reasons behind kneeling difficulties are not yet fully understood. According to several studies, a lateral incision reduces perceptual deficits and improves kneeling performance. This study compared two different skin incisions (lateral and midline) as they relate to postoperative perceptual deficits, as well as kneeling on a mat or in daily life following TKA, and demonstrates the advantage of the lateral incision in postoperative kneeling ability. Methods: This study included 99 patients with lateral incisions and 104 patients with midline incisions. Sensory disturbance was evaluated with a brush on the nine subdivisions of the kneeling area. Patients were tested in the outpatient clinic to determine whether they could kneel on a mat. The level of discomfort in the kneeling area was assessed using a visual analog scale. Questionnaires were used to assess kneeling ability. Results: Compared to a midline incision, a lateral incision significantly reduced the perceptual deficits in the center of the kneeling area and the discomfort associated with kneeling on a mat. There was no significant difference between the two groups in kneeling on a mat in the clinic or kneeling in daily activities. However, less than 30% of patients in both groups could kneel in daily living. The reasons for being unable to kneel were mainly anxiety and pain, rather than numbness. Conclusion: Lateral incisions alone did not improve kneeling in patients' daily living following TKA.

Purpose: Femoral component rotation (FCR) is crucial in total knee arthroplasty (TKA). Currently, the optimal method to select FCR is unknown due to patient anatomy variation. Addressing the variability of femoral component rotation is critical to optimizing TKA outcomes and patient satisfaction. In this study, we aimed to identify outlier frequency and evaluate malrotation risk reduction by setting anatomic limits for FCR selection. Methods: One hundred patients with end-stage knee osteoarthritis requiring TKA were included and categorized as normal rotation, internal rotation outlier, and external rotation outlier based on their expected FCR calculated intraoperatively using the modified gap balancing technique with a tensioning device. The computed FCR was then referenced to their Posterior Condylar Angle (PCA) and Condylar Twist Angle (CTA). The postoperative FCR and 1, 2-, and 5-years functional scores were also measured. Results: Seventy-one knees (71%) were within the limits of PCA and CTA. The combined outlier frequency is 29%. The mean computed FCRs are 4.4° (±1.5), −1° (±2.6), and 8.0° (±3.4) for the normal, internal rotation, and external rotation groups, respectively. Whereas after setting the limits, the postoperative FCRs are 3.1° (±1.5), 3.9° (±1.7), and 2.5° (±1.4) for the three groups, respectively. The relative risk reduction against malrotation was 65%. At 1, 2, and 5 years post-TKA, all groups showed significant functional improvement, with no significant differences in functional outcomes between the normal and outlier groups. Conclusion: The use of lower and upper limits for selecting the FCR based on CTA and PCA can be a valuable approach to reducing malrotation risk and achieving satisfactory functional outcomes in TKA. Addressing the individual patient's anatomic limits contributes to improved TKA outcomes and patient-specific component alignment, thus enhancing the overall success of the procedure.

Abstract Background In systemic lupus erythematosus (SLE), autoreactive B cells are thought to develop by-passing immune checkpoints and contribute to its pathogenesis. Toll-like receptor (TLR) 7 and 9 signaling have been implicated in their development and differentiation. Although some B cell subpopulations such as T-bet + double negative 2 (DN2) cells have been identified as autoreactive in the past few years, because the upregulated surface markers of those cells are not exclusive to them, it is still challenging to specifically target autoreactive B cells in SLE patients. Methods Our preliminary expression analysis revealed that phospholipase D4 (PLD4) is exclusively expressed in plasmacytoid dendritic cells (pDCs) and B cells in peripheral blood mononuclear cells (PBMCs) samples. Monoclonal antibodies against human PLD4 were generated, and flow cytometry analyses were conducted for PBMCs from 23 healthy donors (HDs) and 40 patients with SLE. In vitro cell culture was also performed to study the conditions that induce PLD4 in B cells from HDs. Finally, recombinant antibodies were synthesized from subpopulations of PLD4 + B cells from a patient with SLE, and their antinuclear activity was measured through enzyme-linked immunosorbent assay. Results pDCs from both groups showed comparable frequency of surface PLD4 expression. PLD4 + B cells accounted for only a few percent of HD B cells, whereas they were significantly expanded in patients with SLE (2.1% ± 0.4% vs. 10.8% ± 1.2%, P

Abstract Background Fat embolism syndrome (FES) is a rare syndrome that typically occurs 12–72 h after long bone or pelvic fractures with a classic triad of respiratory distress, neurologic changes, and petechial rash. Although Gurd’s criteria for FES include anuria or oliguria, the mechanism of acute kidney injury (AKI) remain unknown. Here, we present a case of FES complicated by AKI that required blood purification. Case presentation A 79-year-old woman was admitted to our hospital because of a right humerus and pelvic fracture caused by a traffic accident. On the second day of hospitalization, she developed impaired consciousness, respiratory failure, and disseminated intravascular coagulation (DIC). Chest radiography revealed bilateral diffuse alveolar infiltration. Brain magnetic resonance imaging revealed diffuse high signal intensity on diffusion-weighted imaging and diffuse low signal intensity on susceptibility-weighted imaging in the cerebral and cerebellar regions. The diagnosis of FES was confirmed and the patient was treated with methylprednisolone (40 mg/day) and ulinastatin. On the third day of hospitalization, she was admitted to our department because of AKI with oliguria. Although echocardiography showed an elevated right ventricular artery systolic pressure suggestive of pulmonary hypertension (PH), pulmonary congestion was initially considered on chest imaging, and hemodialysis and rapid ultrafiltration were initiated. However, she developed hypovolemic shock and treatment was switched to continuous hemodiafiltration and slow ultrafiltration. Thereafter, her consciousness, hypoxemia, DIC and PH completely improved. She was weaned from blood purification therapy on the 29th day of hospitalization. She had hemolytic anemia that might have been caused by thrombotic microangiopathy (TMA), but it resolved without plasmapheresis. On the 51st day of hospitalization, the patient was transferred to another hospital for rehabilitation. Conclusions FES can be complicated by AKI. In this case, DIC, which was difficult to differentiate from TMA, and/or renal congestion were considered to be a cause of AKI. Chest radiographs of FES may be indistinguishable from pulmonary congestion. In our case, chest radiography showed bilateral diffuse alveolar infiltrates which was not indicative of pulmonary congestion but pulmonary involvement of FES. FES is associated with PH, which may lead to right heart failure. Therefore, the patient could have developed hypovolemic shock due to hemodialysis and rapid ultrafiltration. Clinicians should pay attention to the hemodynamics when blood purification for FES is performed.

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband’s parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH–CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH–CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS.

IntroductionImmunoglobulin G4 (IgG4) is a member of the human immunoglobulin G (IgG) subclass, a protein involved in immunity to pathogens and the body’s resistance system. IgG4-related diseases (IgG4-RD) are intractable diseases in which IgG4 levels in the blood are elevated, causing inflammation in organs such as the liver, pancreas, and salivary glands. IgG4-RD are known to be more prevalent in males than in females, but the etiology remains to be elucidated. This study was conducted to investigate the relationship between gut microbiota (GM) and serum IgG4 levels in the general population.MethodsIn this study, the relationship between IgG4 levels and GM evaluated in male and female groups of the general population using causal inference. The study included 191 men and 207 women aged 40 years or older from Shika-machi, Ishikawa. GM DNA was analyzed for the 16S rRNA gene sequence using next-generation sequencing. Participants were bifurcated into high and low IgG4 groups, depending on median serum IgG4 levels.ResultsANCOVA, Tukey’s HSD, linear discriminant analysis effect size, least absolute shrinkage and selection operator logistic regression model, and correlation analysis revealed that Anaerostipes, Lachnospiraceae, Megasphaera, and [Eubacterium] hallii group were associated with IgG4 levels in women, while Megasphaera, [Eubacterium] hallii group, Faecalibacterium, Ruminococcus.1, and Romboutsia were associated with IgG4 levels in men. Linear non-Gaussian acyclic model indicated three genera, Megasphaera, [Eubacterium] hallii group, and Anaerostipes, and showed a presumed causal association with IgG4 levels in women.DiscussionThis differential impact of the GM on IgG4 levels based on sex is a novel and intriguing finding.

Abstract Mathematical and computational approaches were used to investigate dementia with Lewy bodies (DLB), in which recurrent complex visual hallucinations (RCVH) is a very characteristic symptom. Beginning with interpretative analyses of pathological symptoms of patients with RCVH-DLB in comparison with the veridical perceptions of normal subjects, we constructed a three-module scenario concerning function giving rise to perception. The three modules were the visual input module, the memory module, and the perceiving module. Each module interacts with the others, and veridical perceptions were regarded as a certain convergence to one of the perceiving attractors sustained by self-consistent collective fields among the modules. Once a rather large but inhomogeneously distributed area of necrotic neurons and dysfunctional synaptic connections developed due to network disease, causing irreversible damage, then bottom-up information from the input module to both the memory and perceiving modules were severely impaired. These changes made the collective fields unstable and caused transient emergence of mismatched perceiving attractors. This may account for the reason why DLB patients see things that are not there. With the use of our computational model and experiments, the scenario was recreated with complex bifurcation phenomena associated with the destabilization of collective field dynamics in very high-dimensional state space.

In citrus breeding programs, male sterility is an important trait for developing seedless varieties. Sterility associated with the male sterile cytoplasm of Kishu mandarin (Kishu-cytoplasm) has been proposed to fit the cytoplasmic male sterility (CMS) model. However, it remains undetermined whether CMS in citrus is controlled by interactions between sterile cytoplasm and nuclear restorer-of-fertility (Rf) genes. Accordingly, mechanisms underlying the control of the wide phenotypic variation in pollen number for breeding germplasm should be elucidated. This study aimed to identify complete linkage DNA markers responsible for male sterility at the MS-P1 region based on fine mapping. Two P-class pentatricopeptide repeat (PPR) family genes were identified as candidates for Rf based on predicted mitochondrial localization and higher expression in a male fertile variety/selected strain than in a male sterile variety. Eleven haplotypes (HT1–HT11) at the MS-P1 region were defined based on genotyping of DNA markers. Association analysis of diplotypes at the MS-P1 region and the number of pollen grains per anther (NPG) in breeding germplasms harboring Kishu-cytoplasm revealed that the diplotypes in this region influenced NPG. Among these haplotypes, HT1 is a non-functional restorer-of-fertility (rf) haplotype; HT2, a less-functional Rf; HT3–HT5 are semi-functional Rfs; and HT6 and HT7 are functional Rfs. However, the rare haplotypes HT8–HT11 could not be characterized. Therefore, P-class PPR family genes in the MS-P1 region may constitute the nuclear Rf genes within the CMS model, and a combination of the seven haplotypes could contribute to phenotypic variation in the NPG of breeding germplasms. These findings reveal the genomic mechanisms of CMS in citrus and will contribute to seedless citrus breeding programs by selecting candidate seedless seedlings using the DNA markers at the MS-P1 region.

IntroductionTo allow the identification of IgG4-related disease (IgG4-RD) from a subclinical phase as it is important to understand the risk of elevated serum IgG4 levels. We planned to evaluate serum IgG4 levels in the participants of the Nagasaki Islands Study (NaIS), a large-scale health checkup cohort study.MethodsThis study included 3,240 individuals who participated in the NaIS between 2016 and 2018 and consented to participate in the study. Serum IgG4, IgG, and IgE levels and human leukocyte antigen (HLA) genotyping results of the NaIS subjects as well as lifestyle habits and peripheral blood test results were analyzed. The magnetic bead panel assay (MBA) and the standard nephelometry immunoassay (NIA) were used to measure serum IgG4 levels. The data were evaluated using multivariate analysis to identify lifestyle and genetic factors associated with elevated serum IgG4 levels.ResultsSerum IgG4 levels measured with the NIA and MBA showed a tight positive correlation between the two groups (correlation coefficient 0.942). The median age of the participants in the NaIS was 69 years [63–77]. The median serum IgG4 level was 30.2 mg/dL [IQR 12.5–59.8]. Overall, 1019 (32.1%) patients had a history of smoking. When the subjects were stratified into three groups based on the smoking intensity (pack-year), the serum IgG4 level was significantly higher among those with a higher smoking intensity. Accordingly, the multivariate analysis identified a significant relationship between smoking status and serum IgG4 elevation.ConclusionIn this study, smoking was identified as a lifestyle factor correlating positively with elevated serum IgG4 levels.

Aims: This study aimed to investigate the relationship between changes in patellar height and clinical outcomes at a mean follow-up of 7.7 years (5 to 10) after fixed-bearing posterior-stabilized total knee arthroplasty (PS-TKA). Methods: We retrospectively evaluated knee radiographs of 165 knees, which underwent fixed-bearing PS-TKA with patella resurfacing. The incidence of patella baja and changes in patellar height over a minimum of five years of follow-up were determined using Insall-Salvati ratio (ISR) measurement. We examined whether patella baja (ISR < 0.8) at final follow-up affected clinical outcomes, knee joint range of motion (ROM), and Knee Society Score (KSS). We also assessed inter- and intrarater reliability of ISR measurements and focused on the relationship between patellar height reduction beyond measurement error and clinical outcomes. Results: The ISR gradually decreased over five years after TKA, and finally 33 patients (20.0%) had patella baja. Patella baja at the final follow-up was not related to passive knee ROM or KSS. Interestingly, when we divided into two groups - patella baja and patella normal-alta (ISR ≥ 0.8) - the patella baja group already had a lower patellar height before surgery, compared with the patella normal-alta group. The ISR measurement error in this study was 0.17. Both passive knee flexion and KSS were significantly decreased in the group with a decrease in ISR of ≥ 0.17 at final follow-up. Conclusion: Patellar height gradually decreased over five years of follow-up after TKA. The reduction in patellar height beyond measurement error following TKA was associated with lower clinical outcomes. Cite this article: Bone Jt Open 2021;2(12):1075–1081.

Abstract The outcomes of patients with immunoglobulin G4 (IgG4)-related disease (IgG4-RD) who are not treated are unclear. This study aimed to clarify these outcomes and identify the factors related to them. We retrospectively evaluated various clinical features including laboratory data and involved organs at diagnosis in 107 patients with IgG4-RD, who were followed up for more than 6 months, at a single center in Japan. We compared the clinical features of the 27 untreated patients with those of the 80 patients treated with glucocorticoid. The patient outcomes were investigated, and logistic regression analysis was performed to identify factors related to them. The patients comprised 73 men and 34 women (median age 67 years). The untreated patients had significantly lower IgG4-RD responder index (9 vs. 12) and fewer affected organs (1 vs. 3) than did those treated with glucocorticoid. Of these 27 patients, 8 experienced deterioration of IgG4-RD after the diagnosis. In the age- and sex-adjusted logistic regression analysis, serum IgG4 elevation (per 100 mg/dL, odds ratio 1.194, 95% confidence interval 1.017–1.402) was the only significant factor related to disease deterioration in untreated patients with IgG4-RD, whereas not serum IgG4 levels (per 100 mg/dL, odds ratio 0.995, 95% confidence interval 0.921–1.075) but history of allergy (OR 3.134, 95% confidence interval 1.094–8.977, P = 0.033) related to deterioration in patients who underwent treatment. Serum IgG4 levels may be a useful predictor of unfavorable outcomes in untreated patients with IgG4-RD, who tend to have fewer affected organs and lower IgG4-RD responder index.

Abstract This study aimed to clarify the factors underlying the discrepancy that has been noted between estimated glomerular filtration ratio (eGFR) measured using serum creatinine (Cr) and eGFR using serum cystatin C (CysC) in patients with rheumatoid arthritis (RA) and to identify those patients whose renal function should be evaluated using CysC. We retrospectively evaluated clinical features, disease activity, Steinbrocker radiological staging, and co-morbidities (diabetes mellitus, hypertension, dyslipidemia) in 238 RA patients. eGFR using serum creatinine (eGFR-Cr) and eGFR using serum cystatin C (eGFR-CysC) were calculated using the new Japanese coefficient-modified Modification of Diet in Renal Disease study equation. To clarify the cause(s) of differences of 20% or more between the two eGFRs, we divided our RA patients into Group A (eGFR-Cr/eGFR-CysC ≥ 1.2) and Group B (eGFR-Cr/eGFR-CysC

Abstract Background Glucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis. Methods This study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3 years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters. Results The significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis. Conclusions Prolonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.

Abstract Background Global warming will expand the range of new and invasive pathogens in orchards, and subsequently increase the risk of disease epidemics and economic losses. The development of new resistant plant varieties can help to reduce the impact of pathogens, however, the breeding speed can be extremely slow, due to the growth rates of the plants, and the availability of resistance genes. Citrus trees are suffering immense damage from serious diseases such as citrus canker (XCC), huanglongbing (HLB), and citrus tristeza virus (CTV). A fast-track breeding system, that aimed at shortening the duration for disease resistance breeding by incorporating the resistance genes from related species to commercial varieties, has been developed using the integration of precocious transgenic trifoliate orange with the overexpression of CiFT and MAS. It was applied here to incorporate CTV resistance of trifoliate orange into citrus germplasm. Results One generation of backcrossed breeding, that would normally take at least 5 years, was achieved in a single year by fast-track breeding system. Linkage analysis using the corresponding DNA markers revealed that CTV resistance and T-DNA integrated regions were found in different linkage groups, and they were independently segregated in the BC progenies. The CTV resistant null segregants, in which the T-DNA integrated region was removed from their genome, were feasibly obtained by MAS in each generation of the BC progenies, and their CTV resistance was confirmed by immunological analysis. Several BC3 null segregants, whose genetic backgrounds had been substituted into citrus germplasm, except for the haplotype block of CTV resistance, were successfully obtained. CGH and NGS analyses revealed that the T-DNA integrated region was safely segregated out in null segregants. Conclusion Fast-track breeding systems are expected to shorten the required breeding time by more than one-fifth in comparison with conventional cross breeding techniques. Using this system, we obtained BC3–8, whose genetic background was successfully substituted except for the CTV resistance locus, and could be a novel mandarin breeding material. The fast-track breeding system will be useful to introduce important traits from related species to citrus germplasm while also drastically reducing the time required for breeding.

Autoantibodies against endothelium have been recognized in Takayasu arteritis (TAK). Here the authors identify endothelial protein C receptor and scavenger receptor class B type 1 as major autoantigens in TAK, and find autoantibodies inhibit the negative regulation of endothelial activation.

Abstract A 30‐year‐old man with severe hypoalbuminemia (serum albumin: 0.9 g/dL) was admitted with severe bilateral leg edema and unilateral pleural effusion. Serum anti‐SS‐A and SS‐B antibody levels were abnormally elevated, and his symptoms fulfilled the diagnostic criteria for Sjögren's syndrome. Technetium‐99m albumin scintigraphy revealed protein leakage from a large area of the small intestine. Immunohistochemistry revealed perivascular deposition of C1q, C3d, and immunoglobulin G in the duodenal mucosa. The patient was diagnosed with protein‐losing gastroenteropathy associated with Sjögren's syndrome. Within 2 months of treatment with oral prednisolone and mycophenolate mofetil, the clinical symptoms of hypoalbuminemia and Sjögren's syndrome disappeared completely.

Abstract Background Understanding the relationship between serotype epidemiology and antimicrobial susceptibility of Streptococcus pneumoniae is essential for the effective introduction of pneumococcal conjugate vaccines (PCVs) and control of antimicrobial-resistant pneumococci. Methods We conducted a community-based study in Nha Trang, central Vietnam, to clarify the serotype distribution and pattern of S. pneumoniae antimicrobial susceptibility in children under 5 years of age and to identify risk factors for carrying antimicrobial-resistant strains. Nasopharyngeal swabs collected from children with acute respiratory infections (ARIs) hospitalized between April 7, 2008, and March 30, 2009, and from healthy children randomly selected in July 2008 were subjected to bacterial culture. Minimum inhibitory concentrations (MICs) against S. pneumoniae were determined, and multiplex-polymerase chain reaction (PCR) serotyping assays were performed. Logistic regression was applied to identify risk factors. Results We collected 883 samples from 331 healthy children and 552 ARI cases; S. pneumoniae was isolated from 95 (28.7%) healthy children and 202 (36.6%) ARI cases. Age and daycare attendance were significantly associated with pneumococcal carriage. In total, 18.0, 25.8 and 75.6% of the isolates had high MICs for penicillin (≥4 μg/ml), cefotaxime (≥2 μg/ml) and meropenem (≥0.5 μg/ml), respectively. The presence of pneumococci non-susceptible to multiple beta-lactams was significantly associated with serotype 19F (Odds Ratio: 4.23) and daycare attendance (Odds Ratio: 2.56) but not ARIs, age or prior antimicrobial use. The majority of isolates non-susceptible to multiple beta-lactams (90%) were PCV13 vaccine serotypes. Conclusions S. pneumoniae serotype 19F isolates non-susceptible to multiple beta-lactams are widely prevalent among Vietnamese children. Vaccine introduction is expected to significantly increase drug susceptibility.

Farnesoid X receptor (FXR) is mainly present in enterohepatic tissues and regulates cholesterol, lipid, and glucose homeostasis in coordination with target genes such as SHP and FABP6. Although FXR has been revealed to be expressed in reproductive tissues, FXR function and expression levels in the ovary remain unknown. In this study, we investigated FXR expression in mouse ovaries and its target genes in ovarian granulosa cells. In situ hybridization and immunohistochemical staining showed that FXR was mainly distributed in secondary and tertiary follicles. The agonist-induced activation of FXR in cultured granulosa cells induced the expression of SHP and FABP6, while siRNA targeting of FXR decreased CYP19a1 and HSD17b1 expression. Upon examination of the roles of SHP and FABP6 in granulosa cells, we found that SHP overexpression significantly decreased StAR, CYP11a1, and HSD3b gene expression. In addition, siRNA targeting of FABP6 decreased CYP19a1 and HSD17b1 expression, while FABP6 overexpression increased CYP19a1 expression. In conclusion, the present study demonstrates the presence of FXR signaling in the ovary and reveals that FXR signaling may have a role in function of granulosa cells.

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38+CD43+ B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFNα on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFNα promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFNα preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon α. This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.

To enrich carotenoids, especially β-cryptoxanthin, in juice sac tissues of fruits via molecular breeding in citrus, allele mining was utilized to dissect allelic variation of carotenoid metabolic genes and identify an optimum allele on the target loci characterized by expression quantitative trait (eQTL) analysis. SNPs of target carotenoid metabolic genes in 13 founders of the Japanese citrus breeding population were explored using the SureSelect target enrichment method. An independent allele was determined based on the presence or absence of reliable SNPs, using trio analysis to confirm inheritability between parent and offspring. Among the 13 founders, there were 7 PSY alleles, 7 HYb alleles, 11 ZEP alleles, 5 NCED alleles, and 4 alleles for the eQTL that control the transcription levels of PDS and ZDS among the ancestral species, indicating that some founders acquired those alleles from them. The carotenoid composition data of 263 breeding pedigrees in juice sac tissues revealed that the phenotypic variance of carotenoid composition was similar to that in the 13 founders, whereas the mean of total carotenoid content increased. This increase in total carotenoid content correlated with the increase in either or both β-cryptoxanthin and violaxanthin in juice sac tissues. Bayesian statistical analysis between allelic composition of target genes and carotenoid composition in 263 breeding pedigrees indicated that PSY-a and ZEP-e alleles at PSY and ZEP loci had strong positive effects on increasing the total carotenoid content, including β-cryptoxanthin and violaxanthin, in juice sac tissues. Moreover, the pyramiding of these alleles also increased the β-cryptoxanthin content. Interestingly, the offset interaction between the alleles with increasing and decreasing effects on carotenoid content and the epistatic interaction among carotenoid metabolic genes were observed and these interactions complexed carotenoid profiles in breeding population. These results revealed that allele composition would highly influence the carotenoid composition in citrus fruits. The allelic genotype information for the examined carotenoid metabolic genes in major citrus varieties and the trio-tagged SNPs to discriminate the optimum alleles (PSY-a and ZEP-e) from the rest would promise citrus breeders carotenoid enrichment in fruit via molecular breeding.

A 45-year-old man presented with severe left shoulder pain that was not associated with trauma. Plain radiography with the arm in an elevated position and ultrasonography demonstrated calcium deposits at the anterior acromial insertion site of left deltoid muscle. Conservative management could successfully relieve pain. At the 3-year follow-up, the calcification completely disappeared. To the best of our knowledge, calcium deposits at the acromial insertion site of the deltoid have not been reported in the literature. Clinicians who suspect calcific tendinitis but do not observe calcification around the rotator cuff should carefully palpate and examine other sites, such as the deltoid origin, and use ultrasonography or radiography.

Abstract Background Somatic embryogenesis in nucellar tissues is widely recognized to induce polyembryony in major citrus varieties such as sweet oranges, satsuma mandarins and lemons. This capability for apomixis is attractive in agricultural production systems using hybrid seeds, and many studies have been performed to elucidate the molecular mechanisms of various types of apomixis. To identify the gene responsible for somatic embryogenesis in citrus, a custom oligo-DNA microarray including predicted genes in the citrus polyembryonic locus was used to compare the expression profiles in reproductive tissues between monoembryonic and polyembryonic varieties. The full length of CitRKD1, which was identified as a candidate gene responsible for citrus somatic embryogenesis, was isolated from satsuma mandarin and its molecular function was investigated using transgenic ‘Hamlin’ sweet orange by antisense-overexpression. Results The candidate gene CitRKD1, predominantly transcribed in reproductive tissues of polyembryonic varieties, is a member of the plant RWP-RK domain-containing protein. CitRKD1 of satsuma mandarin comprised two alleles (CitRKD1-mg1 and CitRKD1-mg2) at the polyembryonic locus controlling embryonic type (mono/polyembryony) that were structurally divided into two types with or without a miniature inverted-repeat transposable element (MITE)-like insertion in the upstream region. CitRKD1-mg2 with the MITE insertion was the predominant transcript in flowers and young fruits where somatic embryogenesis of nucellar cells occurred. Loss of CitRKD1 function by antisense-overexpression abolished somatic embryogenesis in transgenic sweet orange and the transgenic T1 plants were confirmed to derive from zygotic embryos produced by self-pollination by DNA diagnosis. Genotyping PCR analysis of 95 citrus traditional and breeding varieties revealed that the CitRKD1 allele with the MITE insertion (polyembryonic allele) was dominant and major citrus varieties with the polyembryonic allele produced polyembryonic seeds. Conclusion CitRKD1 at the polyembryonic locus plays a principal role in regulating citrus somatic embryogenesis. CitRKD1 comprised multiple alleles that were divided into two types, polyembryonic alleles with a MITE insertion in the upstream region and monoembryonic alleles without it. CitRKD1 was transcribed in reproductive tissues of polyembryonic varieties with the polyembryonic allele. The MITE insertion in the upstream region of CitRKD1 might be involved in regulating the transcription of CitRKD1.

The aim of the present study was to characterize and evaluate the anti-cancer activity of proanthocyanidin-enriched fractions from adzuki beans. For this purpose, we concentrated proanthocyanidins from adzuki beans (Vigna angularis) into five fractions using Amberlite XAD-1180N, Toyopearl HW40F, and Sepacore C-18 reverse-phase flash column chromatography. Proanthocyanidin-enriched fractions were characterized as (epi)catechin hexamer, heptamer, and octamer, epigallocatechin-(epi)catechin pentamer, and epigallocatechin-(epi)catechin hexamer using electrospray ionization time-of-flight mass spectrometry and thiolytic degradation. These fractions showed significant anti-cancer activity against the human PC-3 prostate cancer cell line. They also significantly suppressed the expression of the fatty acid-binding protein 5 gene, which plays critical roles in cell growth and metastasis in prostate cancer.

Abstract Since procyanidins (oligomeric catechin or epicatechin) were reported to exhibit health benefits, much attention has been paid to the synthesis of these compounds, especially those that are longer than trimers. In the present study, syntheses of cinnamtannin A3 (epicatechin pentamer), A4 (epicatechin hexamer), catechin tetramer, pentamer, arecatannin A2 (epicatechin-epicatechin-epicatechin-catechin) and A3 (epicatechin-epicatechin-epicatechin-epicatechin-catechin) were achieved. The key reaction was a Lewis acid mediated equimolar condensation. The antitumor effects of these synthesized compounds against a human prostate cancer cell line (PC-3) were investigated. Among the tested compounds, cinnamtannin A3, A4 and arecatannin A3, which possess epicatechin oligomers longer than tetramers as the basic scaffold, showed significant activities for suppression of cell growth, invasion and FABP5 (fatty acid-binding protein 5) gene expression. Effects on cell cycle distribution showed that cell cycle arrest in the G2 phase was induced. Furthermore, these epicatechin oligomers suppressed significantly the expression of the cancer-promoting gene, FABP5, which is related to cell proliferation and metastasis in various cancer cells. Interestingly, the suppressive activities were associated with the degree of oligomerization of epicatechin. Thus, synthetic studies clearly demonstrate that epicatechin oligomers longer than trimers have significant anti-tumorigenic activities, but not the catechin counterparts.

Abstract Background Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity. Methods Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 μg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. Results The anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice. Conclusions In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.

There has been a great demand for flame stability particularly in low-grade residual oil-fired burners. In order to improve the performance of the residual oil burner, it is required to obtain the stable ignition by the swirler devices which create recirculating combustion gas and rotating fuel spray flows. In the present study, a numerical simulation was made on the flow behaviors of air circulation and droplet streamlines for two types of swirlers with different angles of guide vane. A stereo PIV measurement was also made on the velocity distribution of spray droplets. One type of the swirlers is a former type called “Bent plate swirler” with a constant bending angle of the guide vanes. The air after the guide vane expands to the outer circumferencial direction by centrifugal force and the swirling state abruptly declines. Another is a newly developed type “Wing-curved swirler” in which the bending angle of the guide vane becomes deeper from the center to the outer direction. The air flow maintains the swirling force and the recirculation flow is wider than the former “Bent plate swirler”. The Wing-curved swirler with a high swirl force, a swirl number of 2 or more, not only increases the swirl of the sprayed droplet but also lengthens its trajectories. The flame stability was improved by the burner equipped with the developed Wing-curved swirler. The decrease in dust concentration was demonstrated through the residual oil combustion test of the 10 MW actual burner.

Salicylic acid and jasmonic acid are two important plant hormones that trigger the plant defense responses and regulate the accumulation of bioactive compounds in plants. In the present study, the effects of salicylic acid (SA) and methyl jasmonate (MeJA) on flavonoid and carotenoid accumulation were investigated in the juice sacs of Satsuma mandarin in vitro. The results showed that SA treatment was effective to enhance the contents of eriocitrin, narirutin, poncirin, and β-cryptoxanthin in the juice sacs (p < 0.05). In contrast, the MeJA treatment inhibited flavonoid and carotenoid accumulation in the juice sacs (p < 0.05). Gene expression results showed that the changes of flavonoid and carotenoid contents in the SA and MeJA treatments were highly regulated at the transcriptional level. In addition, a transcriptional factor CitWRKY70 was identified in the microarray analysis, which was induced by the SA treatment, while suppressed by the MeJA treatment. In the SA and MeJA treatments, the change in the expression of CitWRKY70 was consistent with that of flavonoid and carotenoid biosynthetic key genes. These results indicated that CitWRKY70 might be involved in the regulation of flavonoid and carotenoid accumulation in response to SA and MeJA treatments in the juice sacs of citrus fruit.

Here, we present the case of a 29-year-old woman with nasal septal perforation and positive myeloperoxidase- (MPO-) anti-neutrophil cytoplasmic antibody (ANCA). She had been diagnosed with Graves’ disease and had been treated with propylthiouracil (PTU) for 14 months. A biopsy of the nasal septum revealed an infiltration of inflammatory cells, with no evidence of malignancy or granulomatous change. Because of the use of PTU, destructive nasal lesion, and positive MPO-ANCA, she was diagnosed with drug-induced ANCA-associated vasculitis (AAV) and was treated with prednisolone and methotrexate after the cessation of PTU. Although PTU is known to be the medicine that induces drug-induced AAV, the manifestation of nasal septal perforation in drug-induced AAV is poorly identified. This is the rare case of drug-induced AAV which manifested only nasal septal perforation.

Autoantibodies against integral membrane proteins are usually pathogenic. Although anti-endothelial cell antibodies (AECAs) are considered to be critical, especially for vascular lesions in collagen diseases, most molecules identified as autoantigens for AECAs are localized within the cell and not expressed on the cell surface. For identification of autoantigens, proteomics and expression library analyses have been performed for many years with some success. To specifically target cell-surface molecules in identification of autoantigens, we constructed a serological identification system for autoantigens using a retroviral vector and flow cytometry (SARF). Here, we present an overview of recent research in AECAs and their target molecules and discuss the principle and the application of SARF. Using SARF, we successfully identified three different membrane proteins: fibronectin leucine-rich transmembrane protein 2 (FLRT2) from patients with systemic lupus erythematosus (SLE), intercellular adhesion molecule 1 (ICAM-1) from a patient with rheumatoid arthritis, and Pk (Gb3/CD77) from an SLE patient with hemolytic anemia, as targets for AECAs. SARF is useful for specific identification of autoantigens expressed on the cell surface, and identification of such interactions of the cell-surface autoantigens and pathogenic autoantibodies may enable the development of more specific intervention strategies in autoimmune diseases.

Corticopetal acetylcholine (ACh) is released transiently from the nucleus basalis of Meynert (NBM) into the cortical layers and is associated with top-down attention. Recent experimental data suggest that this release of ACh disinhibits layer 2/3 pyramidal neurons (PYRs) via muscarinic presynaptic effects on inhibitory synapses. Together with other possible presynaptic cholinergic effects on excitatory synapses, this may result in dynamic and temporal modifications of synapses associated with top-down attention. However, the system-level consequences and cognitive relevance of such disinhibitions are poorly understood. Herein, we propose a theoretical possibility that such transient modifications of connectivity associated with ACh release, in addition to top-down glutamatergic input, may provide a neural mechanism for the temporal reactivation of attractors as neural correlates of memories. With baseline levels of ACh, the brain returns to quasi-attractor states, exhibiting transitive dynamics between several intrinsic internal states. This suggests that top-down attention may cause the attention-induced deformations between two types of attractor landscapes: the quasi-attractor landscape (Q-landscape, present under low-ACh, non-attentional conditions) and the attractor landscape (A-landscape, present under high-ACh, top-down attentional conditions). We present a conceptual computational model based on experimental knowledge of the structure of PYRs and interneurons (INs) in cortical layers 1 and 2/3 and discuss the possible physiological implications of our results.

This article discusses a rare case of a 49-year-old woman who developed a specific type of dermatomyositis (DM) after using a medication for rheumatoid arthritis (RA). The article suggests a possible association between the medication and the development of DM. It emphasizes the importance of considering this diagnosis in RA patients who develop interstitial lung disease. The article includes a detailed case presentation with images and laboratory findings. It also mentions that the patient did not receive a COVID-19 vaccine, although there have been reports of similar cases occurring after vaccination. The article was edited by Editage and did not receive any funding. [Extracted from the article]

In citrus breeding programs, male sterility is an important trait for developing seedless varieties. Sterility associated with the male sterile cytoplasm of Kishu mandarin (Kishu-cytoplasm) has been proposed to fit the cytoplasmic male sterility (CMS) model. However, it remains undetermined whether CMS in citrus is controlled by interactions between sterile cytoplasm and nuclear restorer-offertility (Rf) genes. Accordingly, mechanisms underlying the control of the wide phenotypic variation in pollen number for breeding germplasm should be elucidated. This study aimed to identify complete linkage DNA markers responsible for male sterility at the MS-P1 region based on fine mapping. Two P-class pentatricopeptide repeat (PPR) family genes were identified as candidates for Rf based on predicted mitochondrial localization and higher expression in a male fertile variety/selected strain than in a male sterile variety. Eleven haplotypes (HT1-HT11) at the MS-P1 region were defined based on genotyping of DNA markers. Association analysis of diplotypes at the MS-P1 region and the number of pollen grains per anther (NPG) in breeding germplasms harboring Kishu-cytoplasm revealed that the diplotypes in this region influenced NPG. Among these haplotypes, HT1 is a non-functional restorer-of-fertility (rf) haplotype; HT2, a less-functional Rf; HT3-HT5 are semi-functional Rfs; and HT6 and HT7 are functional Rfs. However, the rare haplotypes HT8-HT11 could not be characterized. Therefore, P-class PPR family genes in the MS-P1 region may constitute the nuclear Rf genes within the CMS model, and a combination of the seven haplotypes could contribute to phenotypic variation in the NPG of breeding germplasms. These findings reveal the genomic mechanisms of CMS in citrus and will contribute to seedless citrus breeding programs by selecting candidate seedless seedlings using the DNA markers at the MS-P1 region. [ABSTRACT FROM AUTHOR]

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband's parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH-CFHR genes region have been identified, this is the first report of the combination of a CFH:: CFHR1 fusion gene with CFHR gene duplication. Because the CFH-CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS. [ABSTRACT FROM AUTHOR]