Causal effect of parental reading on later development of children: Demonstrating a Bayesian approach.

This study examined the relationship between early parental treatment, specifically reading to young children and later cognitive development with a Bayesian perspective. Previous research established a positive link between parental reading to infants and their cognitive development, such as receptive vocabulary, reading comprehension and motivation to read. Using data from the Millennium Cohort Study, this study analysed individuals aged 9 months to 14 years to investigate the effects of early reading to young children on nine cognitive variables. Bayesian statistical analysis controlled for pre-existing differences and covariates to establish a causal association between reading and cognitive development. The results indicated that reading to infants and toddlers positively impacted their cognitive development beyond reading skills. These findings demonstrate the usefulness of the Bayesian approach in determining scientific significance and underscore the importance of early literacy interventions in promoting cognitive development.

A Rare Case of Coronary Involvement in IgG4-Related Disease.

Although cardiovascular involvement in immunoglobulin G4-related disease is uncommon, it can lead to life-threatening events. We report a patient with multiple coronary aneurysms that were diagnosed by multimodal imaging. The patient had been treated with prednisolone for more than 15 years for immunoglobulin G4-related disease.

Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome.

OBJECTIVES: To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance. METHODS: We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases, and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The Presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electric medical records. RESULTS: PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs. CONCLUSION: Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement.

Significance of anti-transcobalamin receptor antibodies in cutaneous arteritis revealed by proteome-wide autoantibody screening.

Cutaneous arteritis (CA) is a single-organ vasculitis that exclusively affects the small to medium-sized arteries of the skin. Diagnosis depends on a histological investigation with skin biopsy, which could be burdensome for both patients and clinicians. Moreover, the pathogenesis of CA remains unstudied, and treatment has not yet been established. Herein, we applied our proteome-wide autoantibody screening method to explore autoantibodies in the serum of CA patients. As a result, anti-transcobalamin receptor (TCblR) antibodies (Abs) were specifically detected in 24% of CA patients. Patients with positive anti-TCblR Abs were spared from peripheral neuropathy compared to those with negative anti-TCblR Abs, showing characteristics as CA confined to the skin. In addition, we revealed that anti-TCblR Abs trigger the autocrine loop of interleukin-6 mediated by tripartite motif-containing protein 21 in human endothelial cells and induce periarterial inflammation in murine skin. Furthermore, we demonstrated that methylcobalamin, a ligand of TCblR, ameliorates inflammation caused by anti-TCblR Abs both in vitro and in vivo. Collectively, our investigation unveils the pathologic significance of anti-TCblR Abs in CA and their potential as a diagnostic marker and a pathophysiology-oriented therapeutic target.

The Effects of the Presence of Others on Risky Betting in a Laboratory Gambling Task Among High-Risk Gamblers: A Cross-over Randomized Controlled Trial.

We explored the effects of the presence of and cooperation with others on risky betting in a laboratory-based gambling task among high-risk gamblers. Specifically, we compared risky betting under solo, parallel, and cooperation conditions using a stratified randomized, cross-over design. Stratification was conducted according to participant age and gender. The participants were 40 Japanese adults (20 women, 20 men; mean age = 46, SD = 12.80). In the experiment, each participant conducted the Game of Dice Task (GDT) individually (solo condition), in parallel with another participant (parallel condition), and working together with another participant (cooperation condition). Linear mixed modeling results showed that when we controlled for previously specified covariates, there were no significant differences among the solo, parallel, and cooperation conditions regarding risky betting (parallel: estimates = 0.10, SE = 0.79, p = .900; cooperation: estimates = 0.95, SE = 0.79, p = .232). However, post-hoc analysis showed a significant difference between the solo and cooperation conditions regarding the number of times participants chose the riskiest bet (parallel: estimates = 0.18, SE = 0.52, p = .739; cooperation: estimates = 1.13, SE = 0.53, p = .035). Thus, we found that neither the presence of nor cooperation with others decreased risky betting in the GDT among high-risk gamblers. However, we did observe that participants displayed the riskiest betting behavior (i.e., selecting the single choice) in the GDT during the cooperation condition, compared with the solo condition.

Rheumatoid arthritis in a patient with compound heterozygous variants in the COL11A2 gene and progressive hearing loss: A case report.

RATIONALE: Collagen type XI alpha 2 chain is a component of type XI collagen and is expressed in various tissues including articular cartilage and tectorial membrane of the cochlea. Variants in the COL11A2 gene, which encodes collagen type XI alpha 2 chain, has been reported to cause hearing loss and has been associated with osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Despite the importance of type XI collagen in the joints, association of rheumatoid arthritis (RA) with COL11A2 has not been reported. PATIENT CONCERNS: The patient is a 60-year-old female, born to Japanese parents of no known consanguinity. She had progressive hearing loss since childhood. Her father also had progressive hearing loss before middle age. She developed joint pain in the knees and the hips in her forties. When she was 56, she developed polyarthritis. Rheumatoid factor and anti-CCP antibodies were positive. DIAGNOSES: She was diagnosed with osteoarthritis and RA. Whole exome analysis detected 2 rare variants, c.4201C>T, p.(Arg1401Trp) and c4265C>T, p.(Pro1422Leu), in the COL11A2 gene (NM_080680.2). Whole genome analysis with a long insert size confirmed 2 variants that are in trans. INTERVENTIONS AND OUTCOMES: She received a cochlear implant, which improved her hearing. She was treated with methotrexate, golimumab, tocilizumab, and upadacitinib with partial responses for her RA. LESSONS: We herein report a patient with RA with compound heterozygous variants in the COL11A2 gene. Autoantibodies against type XI collagen are detected in the sera of patients with RA, suggesting the possibility that type XI collagen may be involved in the pathogenesis of RA as an autoantigen. The hearing loss and osteoarthritis in this patient may be due to the compound heterozygous variants in the COL11A2 gene, and the conformational changes induced by the variants may have changed the immunogenicity of type XI collagen, leading to the development of RA.

Anti-Ku antibody-positive myositis presenting as a wide range of axial myopathies and myocarditis: A case report and review of the literature.

Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases predominantly affecting proximal muscles; paraspinal muscle involvement is relatively rare. Because paraspinal myopathies do not always cause clinically evident symptoms, the diagnosis of IIMs with axial myopathies can be challenging. Anti-Ku autoantibodies, initially reported in polymyositis/systemic sclerosis overlap syndrome, are myositis-associated antibodies observed in patients with a wide variety of connective tissue diseases. Few reports have been published demonstrating predominant axial myopathy in IIM patients with anti-Ku antibodies. Herein, we investigated a previously healthy Japanese woman in her early 70s who presented with Raynaud's phenomenon, back pain, and exertional dyspnoea. The creatine kinase was elevated and antinuclear antibody staining was positive, but myositis-specific antibodies were negative. Magnetic resonance imaging revealed myocarditis and a wide range of axial muscle inflammation, including bilateral thoracolumbar paraspinal, infraspinatus, and trapezius muscles. The muscle biopsy was consistent with IIM. In addition, anti-Ku antibody was positive. The administration of prednisolone and tacrolimus quickly alleviated the symptoms, and the creatine kinase level returned to normal. The diagnosis of IIM was arduous in this case because she did not present with camptocormia, muscle weakness involving the proximal limbs was not apparent, and myositis-specific antibodies were negative. Whether axial myopathy and myocarditis are more prevalent in IIM patients with than without anti-Ku antibodies is uncertain. Clinicians should suspect axial myopathy and myositis-associated antibodies, such as anti-Ku antibodies, especially in patients in whom muscle weakness of the proximal limbs is not noticeable.

Immature platelet levels correlate with disease activity and predict treatment response of thrombocytopenia in lupus patients.

OBJECTIVE: The immature platelet fraction (IPF) represents recently produced platelets in bone marrow and this parameter is increased in patient with primary immune thrombocytopenia (ITP). We investigated the associations between IPF and absolute immature platelet count (AIPC), and clinical parameters in systemic lupus erythematosus (SLE), which has more complex pathological mechanisms than in primary ITP. METHODS: Patients with SLE were retrospectively reviewed at the University of Tokyo Hospital from May, 2012 to January, 2021. The correlations between clinical parameters and the number of immature platelets were assessed with Spearman's rank correlation coefficients. A multiple logistic regression model was used to identify the independent clinical parameters for IPF and AIPC. The difference in the distribution of time for a complete response (CR) after prednisolone (PSL) administration was also evaluated by log-rank test. RESULTS: A total of 282 SLE patients were enrolled, and 12.41% of those patients showed thrombocytopenia. IPF correlated with clinical parameters such as platelet count (r = -0.58), AIPC (r = 0.64) and systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K) (r = 0.24). SLEDAI-2K [odds ratio (OR) (per unit increase), 1.07; 95% CI, 1.013 - 1.13] and thrombocytopenia (OR, 32.23; 95% CI, 11.072 - 93.80) were independent clinical parameters to account for IPF increase. IPF correlated with the number of bone marrow megakaryocytes (n = 19, r = 0.57). Notably, the probability of CR in response to PSL in AIPC-high patients was higher than in AIPC-low patients (hazard ratio, 4.62; 95% CI, 1.07 - 20.02). CONCLUSION: IPF correlated with disease activity of SLE and represented platelet production in the bone marrow, whereas AIPC predicted a rapid response to steroids in thrombocytopenic patients with SLE.

The Impact of Obesity and a High-Fat Diet on Clinical and Immunological Features in Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with multiple organ involvement predominantly affecting women of childbearing age. Environmental factors, as well as genetic predisposition, can cause immunological disturbances that manifest as SLE. A habitual high-fat diet and obesity have recently been reported to play a role in the pathogenesis of autoimmune diseases. The frequency of obesity is higher in patients with SLE than in general populations. Vitamin D and adipokines, such as leptin and adiponectin, are possible mediators connecting obesity and SLE. Serum leptin and adiponectin levels are elevated in patients with SLE and can impact innate and adaptive immunity. Vitamin D deficiency is commonly observed in SLE. Because vitamin D can modulate the functionality of various immune cells, we review vitamin D supplementation and its effects on the course of clinical disease in this work. We also discuss high-fat diets coinciding with alterations of the gut microbiome, or dysbiosis. Contingent upon dietary habits, microbiota can be conducive to the maintenance of immune homeostasis. A high-fat diet can give rise to dysbiosis, and patients who are affected by obesity and/or have SLE possess less diverse microbiota. Interestingly, a hypothesis about dysbiosis and the development of SLE has been suggested and reviewed here.

The effects of ratio and interval schedules on the location variability of pecking responses in pigeons: Application of Bayesian statistical model.

Many studies have investigated how variability in animal behavior is induced by different reinforcement schedules. However, the animal species and experimental settings have varied between these studies. The present study investigated the variability of pigeons' pecking location to operandum under fixed-ratio, fixed-interval, variable-ratio, and variable-interval schedules. A circular response area that was 22.4 cm in diameter was used so that the pecking responses would be effective over a wide range. Pigeons were exposed to a multiple-ratio yoked-interval schedule; the pairs of schedules were fixed-ratio and fixed-interval or variable-ratio and variable-interval. We used a Bayesian statistical approach to probabilistically evaluate the effects of reinforcement schedules on the variability. Bayesian statistical analysis showed the following: (1) interval schedules provided greater variability than did the ratio schedules under the same interreinforcement intervals, (2) fixed schedules provided greater variability than did variable schedules for both the ratio and interval schedule requirements, (3) the larger schedule requirement generated greater variability under the fixed schedules but this effect was not observed on the variable schedules, and (4) the variability did not change as time elapsed in each trial. These results suggested that each reinforcement schedule has a specific effect on the variability of the response location.

The Use of External-beam Radiotherapy for Muscle-invasive Bladder Cancer in Elderly or Medically-fragile Patients.

AIM: To evaluate the clinical results of external-beam radiotherapy (EBRT) for muscle-invasive bladder cancer (MIBC) in elderly or medically-fragile patients. PATIENTS AND METHODS: Twenty-five consecutive patients with MIBC (cT2-4N0-1M0) receiving EBRT were retrospectively analyzed. Their median age was 82 years. Radiotherapy median dose was 60 Gy administered in 30 fractions. RESULTS: Median follow-up period was 14.7 months. Median overall survival (OS) and progression-free survival (PFS) were 14.7 months and 7.8 months, respectively. The OS, cause-specific survival (CSS), and PFS rates at 1-year were 56.0%, 68.5%, and 40.0%, respectively. The local progression-free rates (LPFR) at 6 months and 1 year were 89.3% and 59.5%, respectively. Performance status 3 was a significantly unfavorable factor for OS, CSS, and progression-free survival; clinical N stage was a significantly unfavorable factor for progression-free survival; and lower irradiation dose (≤50.4 Gy) was a significantly unfavorable factor for LPFR. CONCLUSION: EBRT for elderly or medically-fragile patients is feasible, and achieves acceptable local progression-free status.

The effects of fixed-interval schedules on variability of pigeons' pecking location.

Many studies that have investigated performance under reinforcement schedules have measured response rate or interresponse time, which reflect the temporal dimension of responding; however, relatively few studies have examined other dimensions. The present study investigated the effects of fixed-interval schedules on the location of pigeons' pecking response. A circular response area 22.4 cm in diameter was used so that the pecking responses were effective over a wide range. Pigeons were exposed to a fixed-interval schedule whose requirement was systematically varied between conditions. Response location moved closer to the location of the last reinforced response as time elapsed in each trial. Additionally, as the fixed-interval duration requirement increased, response locations shifted to the border of the response area and the variability of response locations increased. These results suggest that fixed-interval schedules systematically control response location.

Fatal Unusual Miliary Tuberculosis in which a Patient Developed Acute Respiratory Distress Syndrome Induced by Infliximab: An Autopsy Case Report.

Anti-tumor necrosis factor α (anti-TNFα) agents increase the risk of tuberculosis (TB), but cases are rarely fatal. This report concerns a patient who was undergoing treatment with infliximab and presented with acute respiratory distress syndrome due to miliary TB without a miliary shadow. The findings of a pathological autopsy revealed innumerable granulomas in the organs, and the miliary nodules in the lung consisted of more unstructured granulomas. Anti-TNFα agents are unusual in the presentation of TB. It is important, particularly for patients receiving anti-TNFα agents, to constantly consider the possibility of TB and to prepare for appropriate management.

Interleukin-10-producing LAG3+ regulatory T cells are associated with disease activity and abatacept treatment in rheumatoid arthritis.

BACKGROUND: Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25-LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA). METHODS: LAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays. RESULTS: LAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity. CONCLUSIONS: IL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.

[A CASE OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE COMPLICATED WITH HENOCH-SCHÖNLEIN PURPURA NEPHRITIS].

Purpura nephritis and autosomal dominant polycystic kidney disease are relatively rare kidney disorders. We present a case complicated by these two diseases. A 68 year-old man with polycystic kidney disease was referred to our hospital with a high fever lasting 3 days and pyuria. Pyelonephritis was suspected based on computed tomography findings of bilateral swelling of the kidney. Inflammation subsided gradually after the initiation of antimicrobial therapy. However, approximately 3 weeks later, the patient developed a fever and skin purpura on the extremities, stomach colic pain, gross hematuria, and increased proteinuria was evident. Therefore, we diagnosed Henoch-Schönlein purpura complicated with nephritis based on biopsies of the skin and the kidney. Immunosuppressant therapy was administered; every symptom was relieved and proteinuria decreased for approximately 20 months.

Use of polymerase chain reaction in the diagnosis of Whipple's disease.

Whipple's disease, a systemic, chronic infectious disease caused by Tropheryma whipplei, is extremely rare in Asian populations. A correct diagnosis is necessary due to its high mortality rate. Unfortunately, patients are apt to be misdiagnosed with connective tissue diseases since they typically present with arthritis or arthralgia. There are three diagnostic tools for Whipple's disease using intestinal tissues: 1) periodic acid-Schiff (PAS)-positive macrophages; 2) electron microscopic observation; and 3) polymerase chain reaction (PCR). It is challenging to diagnose this disease in the absence of histological findings, especially in Japan, where the clinical protocol currently used to make the diagnosis needs improvement, although symptomology and PCR results may be sufficient. Herein, we investigated a 24-year-old Japanese woman who had suffered from intermittent fever, migratory arthralgia, and watery diarrhea for several months. Her biopsied intestinal tissue was negative for foamy macrophages and PAS-positive cells, and electron microscopy did not provide diagnostic insight. PCR amplification of the specimens, however, successfully revealed T. whipplei. Whipple's disease was diagnosed based on a positive PCR result and strong clinical suspicion. The patient was treated parenterally with ceftriaxone (2 g daily) for two weeks, followed by oral treatment with 160 mg trimethoprim and 800 mg sulfamethoxazole twice per day. After one month of treatment, her symptoms disappeared and inflammatory markers returned to normal levels. This case illustrates the practicality and effectiveness of a PCR-based diagnostic test in combination with clinical suspicion to correctly diagnose Whipple's disease, especially in cases when a histological examination does not provide insight.

FDG PET Imaging in Pneumocystis Pneumonia.

A 69-year-old woman with rheumatoid arthritis and pleuritis presented with dyspnea. On admission, she was afebrile and had an oxygen saturation of 97% on ambient air. Chest radiography and CT revealed only subtle ground-glass opacities. However, FDG PET revealed pathological uptake in both lungs. A diagnosis of Pneumocystis pneumonia was made based on a positive ß-D-glucan assay and polymerase chain reaction amplification of Pneumocystis jirovecii from the sputum. Posttreatment FDG PET revealed resolution of the previously noted uptake. This case illustrates that FDG PET can be used to diagnose Pneumocystis pneumonia when the CT findings are equivocal.

Applicability to foraging simulation of a reinforcement schedule controlling the response energy of pigeons.

In optimal foraging theory (OFT), energy expenditure is an important variable for predicting foraging behavior. However, early studies, including operant simulations of foraging, did not measure energy expenditure. In the present study, an adjusting energy (AE) schedule was developed to control energy expenditure. Interresponse energy (IRE), a measure of the energy expenditure during a response, was calculated by dividing the square of the elapsed time between two consecutive responses by the square of the straight-line distance between the locations of the same two responses. An adjusting procedure was employed to estimate the indifference point between the requirements of the AE schedule and a fixed ratio (FR) schedule, which has been used in many operant simulations. In the adjusting procedure, pigeons adjusted the requirement of the AE schedule to that of the FR schedule. The results showed a systematic relationship between the requirements of the AE and FR schedules. Moreover, the total IRE per reinforcement systematically increased with the AE requirement. Thus, the present study demonstrates the utility of the AE schedule as a procedure for testing the validity of OFT.