NFIA in adipocytes reciprocally regulates mitochondrial and inflammatory gene program to improve glucose homeostasis.

Adipose tissue is central to regulation of energy homeostasis. Adaptive thermogenesis, which relies on mitochondrial oxidative phosphorylation (Ox-Phos), dissipates energy to counteract obesity. On the other hand, chronic inflammation in adipose tissue is linked to type 2 diabetes and obesity. Here, we show that nuclear factor I-A (NFIA), a transcriptional regulator of brown and beige adipocytes, improves glucose homeostasis by upregulation of Ox-Phos and reciprocal downregulation of inflammation. Mice with transgenic expression of NFIA in adipocytes exhibited improved glucose tolerance and limited weight gain. NFIA up-regulates Ox-Phos and brown-fat-specific genes by enhancer activation that involves facilitated genomic binding of PPARγ. In contrast, NFIA in adipocytes, but not in macrophages, down-regulates proinflammatory cytokine genes to ameliorate adipose tissue inflammation. NFIA binds to regulatory region of the Ccl2 gene, which encodes proinflammatory cytokine MCP-1 (monocyte chemoattractant protein-1), to down-regulate its transcription. CCL2 expression was negatively correlated with NFIA expression in human adipose tissue. These results reveal the beneficial effect of NFIA on glucose and body weight homeostasis and also highlight previously unappreciated role of NFIA in suppressing adipose tissue inflammation.

VAV1 mutations contribute to development of T-cell neoplasms in mice.

Activating mutations in the Vav guanine nucleotide exchange factor 1 (VAV1) gene are reported in various subtypes of mature T-cell neoplasms (TCNs). However, oncogenic activities associated with VAV1 mutations in TCNs remain unclear. To define them, we established transgenic mice expressing VAV1 mutants cloned from human TCNs. Although we observed no tumors in these mice for up to a year, tumors did develop in comparably aged mice on a p53-null background (p53-/-VAV1-Tg), and p53-/-VAV1-Tg mice died with shorter latencies than did p53-null (p53-/-) mice. Notably, various TCNs with tendency of maturation developed in p53-/-VAV1-Tg mice, whereas p53-/- mice exhibited only immature TCNs. Mature TCNs in p53-/-VAV1-Tg mice mimicked a subtype of human peripheral T-cell lymphoma (PTCL-GATA3) and exhibited features of type 2 T helper (Th2) cells. Phenotypes seen following transplantation of either p53-/-VAV1 or p53-/- tumor cells into nude mice were comparable, indicating cell-autonomous tumor-initiating capacity. Whole-transcriptome analysis showed enrichment of multiple Myc-related pathways in TCNs from p53-/-VAV1-Tg mice relative to p53-/- or wild-type T cells. Remarkably, amplification of the Myc locus was found recurrently in TCNs of p53-/-VAV1-Tg mice. Finally, treatment of nude mice transplanted with p53-/-VAV1-Tg tumor cells with JQ1, a bromodomain inhibitor that targets the Myc pathway, prolonged survival of mice. We conclude that VAV1 mutations function in malignant transformation of T cells in vivo and that VAV1-mutant-expressing mice could provide an efficient tool for screening new therapeutic targets in TCNs harboring these mutations.

Nutrient infusion evoked magnetic resonance imaging signal in the human hypothalamus.

BACKGROUND: The hypothalamus receives ingested nutrient information via ascending gut-related projections and plays a significant role in the regulation of food intake. Human neuroimaging studies have observed changes in the activity or connectivity of the hypothalamus in response to nutrient ingestion. However, previous neuroimaging studies have not yet assessed differences in temporal changes of hypothalamic responses to various nutrients in humans. Thus a repeated measures functional magnetic resonance imaging (fMRI) study using 30-min scans was designed to examine differences in hypothalamic responses to various nutrients. METHODS: In this study, 18 healthy adults (mean age, 22.4 years; standard deviation, 4.8; age range, 19-39 years; 11 males and seven females) underwent fMRI sessions. On the day of each session, one of the four solutions (200 ml of monosodium glutamate, glucose, safflower oil emulsion, or saline) was administered to participants while fMRI scanning. RESULTS: Infused amino acid and glucose, but not lipid emulsion, increased lateral hypothalamic responses as compared to a saline infusion ([x, y, z] = [4, -4, -10], z = 2.96). In addition, only hypothalamic responses to saline, but not those to the infusion of other nutrients, elicited a subjective sensation of hunger. CONCLUSION: These findings suggest that lateral hypothalamic responses to ingested nutrients may mediate homeostatic sensations in humans.

Interpretations of SARS-CoV-2 IgM and IgG antibody titers in the seroepidemiological study of asymptomatic healthy volunteers.

INTRODUCTION: The usefulness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody tests in asymptomatic individuals has not been well validated, although they have satisfied sensitivity and specificity in symptomatic patients. In this study, we investigated the significance of IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects. METHODS: From June 2020, we recruited 10,039 participants to the project named the University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS), and measured iFlash-SARS-CoV-2 IgM and IgG (YHLO IgM and IgG) titers in the collected serum. For the samples with increased IgM or IgG titers, we performed additional measurements using Elecsys Anti-SARS-CoV-2 Ig (Roche total Ig) and Architect SARS-CoV-2 IgG (Abbott IgG) and investigated the reactivity to N, S1, and receptor binding domain (RBD) proteins. RESULTS: After setting the cutoff value at 5 AU/mL, 61 (0.61%) were positive for YHLO IgM and 104 (1.04%) for YHLO IgG. Few samples with elevated YHLO IgM showed reactivity to S1 or RBD proteins, and IgG titers did not increase during the follow-up in any samples. The samples with elevated YHLO IgG consisted of two groups: one reacted to S1 or RBD proteins and the other did not, which was reflected in the results of Roche total Ig. CONCLUSIONS: In SARS-CoV-2 seroepidemiological studies of asymptomatic participants, sufficient attention should be given to the interpretation of the results of YHLO IgM and IgG, and the combined use of YHLO IgG and Roche total Ig might be more reliable.

Changing trends in lipid profile and biomarkers of renal function and bone metabolism before and after switching from tenofovir disoproxil fumarate to tenofovir alafenamide: a prospective observational study.

BACKGROUND: Antiretrovirals, including tenofovir, can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate it. Patients with HIV infection are administered antiretroviral drugs over a long term; thus, managing consequent adverse drug reactions, such as renal dysfunction and bone mineral loss, is important. Currently, highly sensitive biomarkers that can detect adverse drug reactions early have not been well studied. METHODS: This single-center, prospective, observational study explored changes in the biomarkers of renal function, bone metabolism, and lipid profile before and after switching from tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide (TAF) in patients with HIV infection. RESULTS: All 31 enrolled patients had been treated with antiretrovirals for more than 5 years. The rate of proteinuria decreased significantly after starting TAF-containing antiretroviral regimen. The urinary liver-type fatty acid binding protein (L-FABP)/creatinine ratio was significantly decreased at 3 and 6 months after switching to TAF compared with that before switching to TAF (- 0.5 µg/g Cr at 3 months, and - 0.8 µg/g Cr at 6 months; p < 005 for both at 3 and 6 months). The urinary N-terminal telopeptide (NTx)/creatinine ratio decreased over the study period, and the ratios were significantly different between 3 and 6 months (- 11 nmol/mmol Cr at 3 months, - 15.2 nmol/mmol Cr at 6 months; p = 0.0069 at 3 months, p < 0.0001 at 6 months). Low density lipoprotein-cholesterol level significantly increased at 3 (+ 26 mg/dL) and 6 months (+ 13 mg/dL) compared with that at the baseline (p < 0.0001). CONCLUSIONS: Switching from TDF to TAF decreased the levels of renal and bone biomarkers, such as urinary L-FABP and NTx, but increased low density lipoprotein-cholesterol levels. Future studies should evaluate if these biomarkers, such as urinary L-FABP and NTx, truly detect serious adverse drug reactions early.

Epidemiological study using IgM and IgG antibody titers against SARS-CoV-2 in The University of Tokyo, Japan (UT-CATS).

INTRODUCTION: The worldwide pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to date. Given that some of the patients with coronavirus disease 2019 (COVID-19) are asymptomatic, antibody tests are useful to determine whether there is a previous infection with SARS-CoV-2. In this study, we measured IgM and IgG antibody titers against SARS-CoV-2 in the serum of asymptomatic healthy subjects in The University of Tokyo, Japan. METHODS: From June 2020, we recruited participants, who were students, staff, and faculty members of The University of Tokyo in the project named The University of Tokyo COVID-19 Antibody Titer Survey (UT-CATS). Following blood sample collection, participants were required to answer an online questionnaire about their social and health information. We measured IgG and IgM titers against SARS-CoV-2 using iFlash-SARS-CoV-2 IgM and IgG detection kit which applies a chemiluminescent immunoassay (CLIA) for the qualitative detection. RESULTS: There were 6609 volunteers in this study. After setting the cutoff value at 10 AU/mL, 32 (0.48%) were positive for IgG and 16 (0.24%) for IgM. Of six participants with a history of COVID-19, five were positive for IgG, whereas all were negative for IgM. The median titer of IgG was 0.40 AU/mL and 0.39 AU/mL for IgM. Both IgG and IgM titers were affected by gender, age, smoking status, and comorbidities. CONCLUSIONS: Positive rates of IgG and IgM titers were relatively low in our university. Serum levels of these antibodies were affected by several factors, which might affect the clinical course of COVID-19.

Diagnostic accuracy of urine dipstick for proteinuria category in Japanese workers.

BACKGROUND: Urine dipstick tests are often used to evaluate proteinuria during health checkups. We examined the dipstick's accuracy in assessing the proteinuria levels among Japanese workers. METHODS: We assessed subjects aged ≥ 18 years who had a health checkup at the University of Tokyo in 2016 or 2017 (n = 5383). Proteinuria was stratified by urine protein-to-creatinine ratio (PCR): A1, < 150 mg/gCre; A2, 150-499 mg/gCre; and A3, ≥ 500 mg/gCre. The accuracy of a dipstick result of ± or higher to detect a PCR level of ≥ A2 was examined. We compared changes in dipstick results and PCR level in 136 subjects evaluated twice with a median interval of 119 days. RESULTS: The subjects' mean age was 40 years, and half were women. The dipstick results were - in 94.9%, ± in 4.1%, and ≥ 1 + in 1.0%. The PCR level was A1, A2, A3 in 98.6%, 1.2%, and 0.2% of the subjects, respectively. The sensitivity, specificity, and positive and negative predictive values of a ± or higher dipstick result to detect A2 or higher were 66.2%, 95.6%, 17.5%, and 99.5%, respectively. Among the 136 subjects examined twice, 134 (98.5%) had no change in PCR level (A1 in all cases) despite a decrease or increase in dipstick results. CONCLUSION: Urine dipstick results of ± or above had a high specificity but low sensitivity and positive predictive value to detect PCR proteinuria of A2 or higher. Confirmation by quantitative protein measurement should be recommended for individuals at high risk of chronic kidney disease.

Pleural thickening on screening chest X-rays: a single institutional study.

Although pleural thickening is a common finding on routine chest X-rays, its radiological and clinical features remain poorly characterized. Our investigation of 28,727 chest X-rays obtained from annual health examinations confirmed that pleural thickening was the most common abnormal radiological finding. In most cases (92.2%), pleural thickening involved the apex of the lung, particularly on the right side; thus, it was defined as a pulmonary apical cap. Pleural thickening was more common in males than in females and in current smokers or ex-smokers than in never smokers. The prevalence increased with age, ranging from 1.8% in teenagers to 9.8% in adults aged 60 years and older. Moreover, pleural thickening was clearly associated with greater height and lower body weight and body mass index, suggesting that a tall, thin body shape may predispose to pleural thickening. These observations allowed us to speculate about the causative mechanisms of pleural thickening that are attributable to disproportionate perfusion, ventilation, or mechanical forces in the lungs.

Catheter-related bloodstream infection caused by Kodamaea ohmeri: A case report and literature review.

Kodamaea ohmeri is a rare yeast pathogen that has recently emerged as an important cause of fungemia in immunocompromised patients. However, appropriate therapy for this infection remains unclear. We report a case of catheter-related blood stream infection caused by K. ohmeri in a 58-year-old patient who improved after removal of the central venous catheter and administration of micafungin. Considering the antibiotic susceptibility of this pathogen and reviewing literature, echinocandins may be the first choice for an empiric therapy for this pathogen.

The incidence and risk factors of asymptomatic primary spontaneous pneumothorax detected during health check-ups.

BACKGROUND: Patients with primary spontaneous pneumothorax (PSP) usually complain of sudden-onset dyspnea and pleuritic chest pain. However, asymptomatic PSP has been incidentally detected on chest X-rays. In this study, we analyzed the incidence, characteristics, risk factors, and prognosis of asymptomatic PSP detected during regular medical check-ups in university students. METHODS: In this study, 101,709 chest X-rays were performed during medical check-ups for students at the University of Tokyo between April 2011 and March 2016. Among them, 43 cases of asymptomatic PSP (0.042%) were detected. We calculated the lung collapse rate of pneumothorax using Kircher's method. We also analyzed risk factors associated with asymptomatic PSP using characteristics inspected in medical check-ups. RESULTS: The incidence of asymptomatic PSP was significantly higher in men than in women (0.050% vs 0.018%). Multivariate analysis revealed an association of younger age, greater height, lower body mass index, and greater height growth per year with an increased risk of asymptomatic PSP in male students. Mild lung collapse (<10%) was present in 22 of 43 students with asymptomatic PSP; among these, eight students eventually underwent an invasive therapy. CONCLUSIONS: The prevalence of asymptomatic PSP among university students was as high as 0.042%. In addition to known risk factors for conventional PSP, greater height growth was a risk factor for asymptomatic PSP. Careful follow-up is very important because a considerable number of patients with mild lung collapse eventually require an invasive medical procedure.

A pathologically proven case of adult-onset HIV-related lymphocytic interstitial pneumonia with acute exacerbation treated with steroid and antiretroviral therapy.

Lymphocytic interstitial pneumonia (LIP) is a rare opportunistic illness in human immunodeficiency virus (HIV)-infected adults, although it is relatively common among HIV-infected children. Most adult cases have been reported in African and Afro-Caribbean patients and few cases have been reported from Asia. Acute exacerbation of HIV-related LIP has not been well described. Here we report a pathologically proven case of acute exacerbation of adult-onset HIV-related LIP. The patient was an African immigrant living in Japan who presented with chronic dyspnea and diffuse bilateral pulmonary infiltrates. His clinical, radiological, and pathological findings were consistent with those of LIP. After a diagnostic surgical lung biopsy, his hypoxemia and pulmonary infiltrates exacerbated rapidly over a few days, although his condition had not progressed during the previous year. LIP may be an important differential diagnosis among adult patients in Asian countries, especially patients of non-Asian ethnicity.

Quantitative evaluation model of variable diagnosis for chest X-ray images using deep learning.

The purpose of this study is to demonstrate the use of a deep learning model in quantitatively evaluating clinical findings typically subject to uncertain evaluations by physicians, using binary test results based on routine protocols. A chest X-ray is the most commonly used diagnostic tool for the detection of a wide range of diseases and is generally performed as a part of regular medical checkups. However, when it comes to findings that can be classified as within the normal range but are not considered disease-related, the thresholds of physicians' findings can vary to some extent, therefore it is necessary to define a new evaluation method and quantify it. The implementation of such methods is difficult and expensive in terms of time and labor. In this study, a total of 83,005 chest X-ray images were used to diagnose the common findings of pleural thickening and scoliosis. A novel method for quantitatively evaluating the probability that a physician would judge the images to have these findings was established. The proposed method successfully quantified the variation in physicians' findings using a deep learning model trained only on binary annotation data. It was also demonstrated that the developed method could be applied to both transfer learning using convolutional neural networks for general image analysis and a newly learned deep learning model based on vector quantization variational autoencoders with high correlations ranging from 0.89 to 0.97.

Interaction between type 2 diabetes polygenic risk and physical activity on cardiovascular outcomes.

AIM: The beneficial effects of exercise on reducing the risk of cardiovascular disease are established. However, the potential interaction between genetic risk for type 2 diabetes and physical activity on cardiovascular outcomes remains elusive. We aimed to investigate the effect of type 2 diabetes genetic risk-physical activity interaction on cardiovascular outcomes in individuals with diabetes. METHODS: Using the UK Biobank cohort, we investigated the effect of type 2 diabetes genetic risk-physical activity interaction on 3-point and 4-point major adverse cardiovascular events (MACE), in 25,701 diabetic participants. We used a polygenic risk score for type 2 diabetes (PRS_T2D) as a measure of genetic risk for type 2 diabetes. RESULTS: We observed significant interaction between PRS_T2D and physical activity on cardiovascular outcomes (3-point MACE: P trend for interaction = 0.0081; 4-point MACE: P trend for interaction = 0.0037). Among participants whose PRS_T2D was in the first or second quartile, but not in the third or fourth quartile, each 10 metabolic equivalents (METs) hours per week of physical activity decreased the risk of 3-point or 4-point MACE. Furthermore, restricted cubic spline analysis indicated that intense physical activity (>80 METs hours per week, which was self-reported by 12.7% of participants) increased the risk of cardiovascular outcomes among participants whose PRS_T2D was in the fourth quartile. Subgroup analysis suggested that negative impact of intense physical activity was observed only in non-insulin users. CONCLUSIONS: The beneficial effect of physical activity on cardiovascular outcomes were disappeared among those with high genetic risk for type 2 diabetes.

The beneficial effects of exercise on reducing the risk of cardiovascular disease are established. However, whether genetic risk for type 2 diabetes influences the effect of physical activity on cardiovascular outcomes in individuals with diabetes remains elusive. We aimed to investigate interaction between genetic risk for type 2 diabetes and physical activity on major adverse cardiovascular events in individuals with diabetes. The beneficial effect of physical activity on cardiovascular outcomes were disappeared among diabetic individuals with high genetic risk for type 2 diabetes, due to significant gene-environment interaction; in this subpopulation, intense physical activity was associated with increased risk of cardiovascular outcomes. Personalized exercise recommendations tailored to avoid excessively intense exercise, in combination with genetic screening of high-risk individuals, would be required.

Anti-neurofascin 155 Antibody-positive Neuropathy in a Human Immunodeficiency Virus-infected Patient.

Human immunodeficiency virus (HIV)-associated neuropathy is a common complication of HIV infection and has several clinical subtypes. HIV-associated chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a demyelinating neuropathy whose clinical features are known to differ from those of CIDP in the HIV-uninfected population. We herein report a case of CIDP in an HIV-infected patient who was finally diagnosed with anti-neurofascin 155 (NF155) antibody-positive neuropathy. The clinical features, including clinical findings and therapeutic responses, were typical of paranodal antibody-mediated neuropathy. To our knowledge, this is the first case of anti-NF155 antibody-associated neuropathy in an HIV-infected patient.

A Comparative Study of Periodontal Health Status between International and Domestic University Students in Japan.

BACKGROUND: In our previous study, international university students showed a significantly higher dental caries morbidity rate than domestic students. On the other hand, the periodontal health status of international university students has not been clarified yet. In this study, we compared the periodontal health status of international and domestic university students in Japan. METHODS: We conducted a retrospective review of the clinical data of the university students that visited a dental clinic in the division for health service promotion at a university in Tokyo for screening between April 2017 and March 2019. Bleeding on probing (BOP), calculus deposition and probing pocket depth (PPD) were investigated. RESULTS: The records of 231 university students (79 international and 152 domestic university students) were analyzed; 84.8% of international students were from Asian countries (n = 67). The international university students showed a higher percentage of BOP than domestic students (49.4% and 34.2%, respectively: p < 0.05) and they showed more extensive calculus deposition (calculus grading score [CGS]) than domestic university students (1.68 and 1.43, respectively: p < 0.01), despite no significant difference in PPD. CONCLUSIONS: The current study shows that international university students have poorer periodontal health than domestic students in Japan, even though the result might include many uncertainties and possible biases. To prevent severe periodontitis in the future, regular checkups and thorough oral health care are essential for the university students, especially those from foreign countries.

Waning cellular immune responses and predictive factors in maintaining cellular immunity against SARS-CoV-2 six months after BNT162b2 mRNA vaccination.

Several clinical trials have shown that the humoral response produced by anti-spike antibodies elicited by coronavirus disease 2019 (COVID-19) vaccines gradually declines. The kinetics, durability and influence of epidemiological and clinical factors on cellular immunity have not been fully elucidated. We analyzed cellular immune responses elicited by BNT162b2 mRNA vaccines in 321 health care workers using whole blood interferon-gamma (IFN-γ) release assays. IFN-γ, induced by CD4 + and CD8 + T cells stimulated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike epitopes (Ag2), levels were highest at 3 weeks after the second vaccination (6 W) and decreased by 37.4% at 3 months (4 M) and 60.0% at 6 months (7 M), the decline of which seemed slower than that of anti-spike antibody levels. Multiple regression analysis revealed that the levels of IFN-γ induced by Ag2 at 7 M were significantly correlated with age, dyslipidemia, focal adverse reactions to full vaccination, lymphocyte and monocyte counts in whole blood, Ag2 levels before the second vaccination, and Ag2 levels at 6 W. We clarified the dynamics and predictive factors for the long-lasting effects of cellular immune responses. The results emphasize the need for a booster vaccine from the perspective of SARS-CoV-2 vaccine-elicited cellular immunity.

Chronic hepatitis B in patients coinfected with human immunodeficiency virus in Japan: a retrospective multicenter analysis.

A nationwide survey in Japan revealed that about 6 % of human immunodeficiency virus (HIV)-positive patients are coinfected with hepatitis B virus (HBV). To further analyze the features of liver disease in HIV/HBV-coinfected patients, we analyzed 252 patients from six hospitals in the HIV/AIDS (acquired immunodeficiency syndrome) Network of Japan. The mean age was 39.5 years, and the proportion of male patients was very high (243 of 252; 96 %). The main transmission route was male homosexual contact (186 of 252; 74 %), followed by heterosexual contact. The HBV genotype was determined in 77 patients. Among them, genotype A HBV was the most frequent (58 of 77; 75 %) and was detected almost exclusively in homosexual patients. Acute hepatitis B was documented in 21 patients (8 %). Three of the 252 HIV/HBV-coinfected patients developed advanced liver disease with the complication of ascites, hepatic encephalopathy, or hepatocellular carcinoma. A comparison between patients not treated and those treated with antiretroviral drugs including anti-HBV drugs revealed that the baseline liver function was worse in treated patients. However, the serum albumin levels and platelet counts in both groups increased after treatment and were similar. Liver disease-associated death was not observed. Here, we characterize the clinical features of liver disease in HIV/HBV-coinfected patients in Japan for the first time. The findings suggest that antiretroviral therapy with anti-HBV drugs may retard the progression of a liver disease and prevent liver disease-associated death in such patients.

Systemic Disorders Closely Associated with Malocclusion in Late Adolescence: A Review and Perspective.

Oral diseases such as dental caries and periodontal disease are reported to be associated with various systemic diseases such as heart disease, respiratory disease, diabetes, rheumatism, and metabolic syndrome, thus increasing the importance of prevention and early treatment [...].