Apple-shaped obesity: A risky soil for cytokine-accelerated severity in COVID-19.

Obesity has been recognized as one of the most significant risk factors for the deterioration and mortality associated with COVID-19, but the significance of obesity itself differs among ethnicity. Multifactored analysis of our single institute-based retrospective cohort revealed that high visceral adipose tissue (VAT) burden, but not other obesity-associated markers, was related to accelerated inflammatory responses and the mortality of Japanese COVID-19 patients. To elucidate the mechanisms how VAT-dominant obesity induces severe inflammation after severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection, we infected two different strains of obese mice, C57BL/6JHamSlc-ob/ob (ob/ob), C57BLKS/J-db/db (db/db), genetically impaired in the leptin ligand and receptor, respectively, and control C57BL/6 mice with mouse-adapted SARS-CoV-2. Here, we revealed that VAT-dominant ob/ob mice were extremely more vulnerable to SARS-CoV-2 due to excessive inflammatory responses when compared to SAT-dominant db/db mice. In fact, SARS-CoV-2 genome and proteins were more abundant in the lungs of ob/ob mice, engulfed in macrophages, resulting in increased cytokine production including interleukin (IL)-6. Both an anti-IL-6 receptor antibody treatment and the prevention of obesity by leptin replenishment improved the survival of SARS-CoV-2-infected ob/ob mice by reducing the viral protein burden and excessive immune responses. Our results have proposed unique insights and clues on how obesity increases the risk of cytokine storm and death in patients with COVID-19. Moreover, earlier administration of antiinflammatory therapeutics including anti-IL-6R antibody to VAT-dominant patients might improve clinical outcome and stratification of the treatment for COVID-19, at least in Japanese patients.

Diverse pro-inflammatory ability of mutated spike protein derived from variant strains of SARS-CoV-2.

The severity of COVID-19 has been reported to differ among SARS-CoV-2 mutant variants. The overactivation of macrophages is involved in severe COVID-19, yet the effects of SARS-CoV-2 mutations on macrophages remain poorly understood. To clarify the effects, we examined whether mutations of spike proteins (S-proteins) affect macrophage activation. CD14+ monocyte-derived macrophages were stimulated with the recombinant S-protein of the wild-type, Delta, and Omicron strains or live viral particles of individual strains. Regarding IL-6 and TNF-α, Delta or Omicron S-protein had stronger or weaker pro­inflammatory ability, respectively, than the wild-type. Similar trends were observed between S-proteins and viral particles. S-protein mutations could be related to the diversity in macrophage activation and severity rates in COVID-19 caused by various SARS-CoV-2 strains.

Influence of denture surface roughness and host factors on dental calculi formation on dentures: a cross-sectional study.

BACKGROUND: Dental calculi formation on dentures can worsen the oral cavity environment by complicating oral hygiene. However, few studies have investigated the effect of how patients use and manage their dentures, denture surface roughness, and host factors such as oral cavity dryness and saliva properties on denture cleanliness and denture dental calculi formation. Accordingly, we conducted the present survey to evaluate these factors to clarify the strength of the influence of each factor. METHODS: We enrolled 53 patients who had used dentures for at least 3 months and used a dental prosthesis that covered at least the six front teeth including the left and right mandibular canines. After staining the dentures, we divided the participants into a group that was positive for dental calculi (DCP group) and a group that was negative for dental calculi (DCN group). After removing all the stains, we evaluated the surface roughness of the dentures. A questionnaire was used to survey how the participants used and managed their dentures. Oral cavity dryness was evaluated, and resting saliva samples were collected to assess saliva properties. Correlations between the presence or absence of dental calculi and denture use and management were evaluated using a chi-square test. Correlations with denture surface roughness, oral cavity dryness, and saliva properties were evaluated using the Mann-Whitney U test. Correlations between the presence or absence of dental calculi and all factors were analyzed using multivariate analysis (quantification II). RESULTS: Surface roughness was significantly greater in the DCP group (p < 0.01), and the DCP group members wore their dentures during sleep significantly more often and used a denture cleaner when storing their dentures significantly less often (both p < 0.01). No significant differences were observed for oral cavity dryness or saliva properties. The multivariate analysis showed significant correlations of dental calculi formation with denture surface roughness and items related to denture use and management, but not for oral cavity dryness or saliva properties. CONCLUSIONS: Our findings indicate that dental calculi formation is influenced by how dentures are used and managed and by denture surface roughness, but not by oral cavity dryness and saliva properties.

Dairy consumption, bone turnover biomarkers, and osteo sono assessment index in Japanese adults: A cross-sectional analysis of data from the Iwaki Health Promotion Project.

Purpose: Dairy foods are nutritional sources of calcium, phosphorus, protein, and other nutrients that improve bone health. However, the effects of dairy consumption on bone biomarkers in the Japanese population remain unclear. This study explored the association between dairy consumption and bone biomarkers in Japanese adults. Methods: This cross-sectional study was conducted as part of the Iwaki Health Promotion Project in Aomori, Japan. In total, 1063 adults were included in the analysis. Bone turnover marker levels were measured in local citizens during their annual medical checkups. The calcaneus osteo sono assessment index (OSI) was calculated using a quantitative ultrasound technique. The dietary intake of foods and nutrients was estimated using a food frequency questionnaire. Linear regression models were established using dairy consumption and bone biomarkers with adjustments. Statistic significance was considered by P < 0.05. Results: In multivariate models, the tartrate-resistant acid phosphatase 5b and parathyroid hormone concentrations were inversely associated with dietary dairy consumption after adjusting for age and sex. The undercarboxylated osteocalcin, a procollagen type I N-terminal peptide to bone alkaline phosphatase ratio, and OSI were the directly associated with dairy consumption in multivariate models with adjustment. Conclusions: Dairy consumption is partially associated with bone turnover biomarkers and OSI in adult Japanese participants. Habitual consumption of dairy foods may contribute to the nutritional supplementation for maintaining bone health, including turnover and structure. Clinical trial registry number and website where it was obtained: The Japanese Clinical Trials Registry (UMIN000040459), https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000046175.

Necroptosis in alveolar epithelial cells drives lung inflammation and injury caused by SARS-CoV-2 infection.

COVID-19, caused by SARS-CoV-2 infection, results in irreversible or fatal lung injury. We assumed that necroptosis of virus-infected alveolar epithelial cells (AEC) could promote local inflammation and further lung injury in COVID-19. Since CD8+ lymphocytes induced AEC cell death via cytotoxic molecules such as FAS ligands, we examined the involvement of FAS-mediated cell death in COVID-19 patients and murine COVID-19 model. We identified the occurrence of necroptosis and subsequent release of HMGB1 in the admitted patients with COVID-19. In the mouse model of COVID-19, lung inflammation and injury were attenuated in Fas-deficient mice compared to Fas-intact mice. The infection enhanced Type I interferon-inducible genes in both groups, while inflammasome-associated genes were specifically upregulated in Fas-intact mice. The treatment with necroptosis inhibitor, Nec1s, improved survival rate, lung injury, and systemic inflammation. SARS-CoV-2 induced necroptosis causes cytokine induction and lung damage, and its inhibition could be a novel therapeutic strategy for COVID-19.

Thrombosis and antiphospholipid antibodies in Japanese COVID-19: based on propensity score matching.

Background: Thrombosis is a unique complication of coronavirus disease 2019 (COVID-19). Although antiphospholipid antibodies (aPL) are detected in COVID-19 patients, their clinical significance remains elusive. We evaluated the prevalence of aPL and serum concentrations of beta-2 glycoprotein I (ß2GPI), a major self-antigen for aPL, in Japanese COVID-19 patients with and without thrombosis. Methods: This retrospective single-center nested case-control study included 594 hospitalized patients with COVID-19 between January 2020 and August 2021. Thrombotic complications were collected from medical records. Propensity score-matching method (PSM) (1:2 matching including age, sex, severity on admission, and prior history of thrombosis) was performed to compare the prevalence and titer of aPL (anti-cardiolipin (aCL) IgG/IgM, anti-ß2GPI IgG/IgM/IgA, and anti-phosphatidylserine/prothrombin antibody (aPS/PT) IgG/IgM) and serum ß2GPI concentration. In addition, PSM (1:1 matching including age and sex) was performed to compare the serum ß2GPI concentration between COVID-19 patients and healthy donors. Results: Among the patients, 31 patients with thrombosis and 62 patients without were compared. The prevalence of any aPLs was indifferent regardless of the thrombosis (41.9% in those with thrombosis vs. 38.7% in those without, p =0.82). The positive rates of individual aPL were as follows: anti-CL IgG (9.7% vs. 1.6%, p =0.11)/IgM (0% vs. 3.2%, p =0.55), anti-ß2GP1 IgG (22.6% vs. 9.7%, p =0.12)/IgA (9.7% vs. 9.7%, p =1.0)/IgM (0% vs. 0%, p =1.0), and anti-PS/PT IgG (0% vs. 1.6%, p =1.0)/IgM (12.9% vs. 21.0%, p =0.41), respectively. The aPL titers were also similar regardless of thrombosis. The levels of ß2GPI in COVID-19 patients were lower than those in the healthy donors. Conclusion: Although aPLs were frequently detected in Japanese COVID-19 patients, their prevalence and titer were irrelevant to thrombotic complications. While COVID-19 patients have lower levels of serum ß2GPI than healthy blood donors, ß2GPI levels were indifferent regardless of thrombosis. Although most of the titers were below cut-offs, positive correlations were observed among aPLs, suggesting that the immune reactions against aPL antigens were induced by COVID-19. We should focus on the long-term thromboembolic risk and the development of APS in the aPL-positive patients with high titer or multiple aPLs.

Hemorrhagic gastric ulcer in a patient with Behcet's disease successfully treated with infliximab.

Behcet's disease (BD) is a multisystem immune-mediated inflammatory disorder that occasionally involves the gastrointestinal tract. Reports on gastrointestinal involvement of BD are relatively rare, of which gastroduodenal involvement is particularly rare. Endoscopic features of gastroduodenal lesions are unknown, and treatment strategies have not been established. In this report, we present the case of a 72-year-old female with gastrointestinal BD who presented with extensive gastroduodenal ulcers and hematemesis that were resistant to colchicine and corticosteroid treatment, which were subsequently successfully treated with infliximab. We also review the current literature on the gastroduodenal involvement of BD. Although rare, the case highlights the importance of being aware of upper gastrointestinal manifestations of BD, as well as demonstrating the potential of infliximab to treat corticosteroid-resistant cases.

A case of toxic epidermal necrolysis comorbid with severe burns.

Toxic epidermal necrolysis (TEN) and severe burns both have high mortality rates, but coexistence is extremely rare. The specificity of developing TEN in burn patients is not well understood and its treatment strategy is not established. Case Presentation: A 68-year-old man was carried to our hospital with severe burns covering 35% of his body surface area. He developed bacteremia during treatment of burns and required antimicrobial therapy. However, erythema appeared on the trunk and upper limbs and rapidly spread to the extremities, leading to a diagnosis of TEN. The rash gradually improved after terminating antimicrobial therapy and administrating of 1,000 mg/day methylprednisolone for 3 days. The rash caused by TEN was confined to non-burned areas, suggesting that TEN may less likely occur at burn sites. Conclusion: It is necessary to pay attention because burn patients can develop TEN concomitantly. Corticosteroids therapy may be effective for TEN even in severe burn patients.

Evidence for the involvement of caspases in establishing proper cerebrospinal fluid hydrodynamics.

A large number of cells undergo apoptosis via caspase activation during and after neural tube closure (NTC) in mammals. Apoptosis is executed by either intrinsic or extrinsic apoptotic pathways, and inhibition of each pathway causes developmental defects around NTC stages, which hampers the physiological roles of apoptosis and caspases after NTC. We generated transgenic mice in which a broad spectrum of caspases could be suppressed in a spatiotemporal manner by pan-caspase inhibitor protein p35 originating from baculovirus. Mice with nervous system-specific expression of p35 (Nestin-Cre (NCre);p35V mice) exhibited postnatal lethality within 1 month after birth. They were born at the expected Mendelian ratio, but demonstrated severe postnatal growth retardation and hydrocephalus. The flow of cerebrospinal fluid (CSF) between the third and fourth ventricles was disturbed, whereas neither stenosis nor abnormality in ciliary morphology was observed in the pathway of CSF flow. Hydrocephalus and growth retardation of NCre;p35V mice were not rescued by the deletion of RIPK3, an essential factor for necroptosis which occurs in the absence of caspase-8 activation during development. The CSF of NCre;p35V mice contained a larger amount of secreted proteins than that of the controls. These findings suggest that the establishment of proper CSF dynamics requires caspase activity during brain development after NTC.

Arterial and Venous Thrombosis Complicated in COVID-19: A Retrospective Single Center Analysis in Japan.

Background: Thrombosis is a characteristic complication in coronavirus disease 2019 (COVID-19). Since coagulopathy has been observed over the entire clinical course, thrombosis might be a clue to understanding the specific pathology in COVID-19. Currently, there is limited epidemiological data of COVID-19-associated thrombosis in the Japanese population and none regarding variant strains of SARS-CoV-2. Here, we elucidate the risk factors and the pattern of thrombosis in COVID-19 patients. Methods: The patients consecutively admitted to Tokyo Medical and Dental University Hospital with COVID-19 were retrospectively analyzed. SARS-CoV-2 variants of concern/interest (VOC/VOI) carrying the spike protein mutants E484K, N501Y, or L452R were identified by PCR-based analysis. All thrombotic events were diagnosed by clinical symptoms, ultrasonography, and/or radiological tests. Results: Among the 516 patients, 32 patients experienced 42 thromboembolic events. Advanced age, severe respiratory conditions, and several abnormal laboratory markers were associated with the development of thrombosis. While thrombotic events occurred in 13% of the patients with a severe respiratory condition, those events still occurred in 2.5% of the patients who did not require oxygen therapy. Elevated D-dimer and ferritin levels on admission were independent risk factors of thrombosis (adjusted odds ratio 9.39 and 3.11, 95% confidence interval 2.08-42.3, and 1.06-9.17, respectively). Of the thrombotic events, 22 were venous, whereas 20 were arterial. While patients with thrombosis received anticoagulation and antiinflammatory therapies with a higher proportion, the mortality rate, organ dysfunctions, and bleeding complications in these patients were higher than those without thrombosis. The incidence of thrombosis in COVID-19 became less frequent over time, such as during the replacement of the earlier strains of SARS-CoV-2 by VOC/VOI and during increased use of anticoagulatory therapeutics. Conclusion: This study elucidated that elevated D-dimer and ferritin levels are useful biomarkers of thrombosis in COVID-19 patients. The comparable incidence of arterial thrombosis with venous thrombosis and the development of thrombosis in less severe patients required further considerations for the management of Japanese patients with COVID-19. Further studies would be required to identify high-risk populations and establish appropriate interventions for thrombotic complications in COVID-19.

Effectiveness of a clinical pathway for complete denture adjustment.

This study was performed to evaluate the usefulness of a developed clinical pathway (CP) to determine the sequence of dental treatment in patients who are edentulous and use maxillary and mandibular complete dentures. Sixty-two edentulous patients with maxillary and mandibular complete dentures were randomly allocated either to with (31 subjects) or without (31 subjects) a CP. The main categories of the CP were the examination, instructions, practice, idle time, evaluation sheet, preparation, and other steps. The subcategories were made with respect to the main categories. The participants were categorized as dentists, assistants, or patients. There was no significant difference in mean chair time between with a CP (27.5 min) and without a CP (28.0 min). The CP led to a significant reduction in idle time (waiting in the chair or no treatment) of dentists, assistants, and patients. In contrast, the instances of medical examination, patients' instructions, and the number of patients reporting improvement of symptoms significantly increased. These results indicated that there is an opportunity to improve the complete denture treatment with a CP.

Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy. We constructed two different tetracycline (tet)-on-based regulatable HSV vectors, one expressing NT-3 and the other expressing IL-10, in which the transactivator expression in the tet-on system was under the control of HSV latency-associated promoter 2 (LAP-2), and expression of the transgene was controlled by doxycycline (DOX). We examined the therapeutic effect of intermittent expression of the transgene in animals with paclitaxel-induced peripheral neuropathy modeled by intraperitoneal injection of paclitaxel (16 mg/kg) once a week for 5 weeks. Intermittent expression of either NT-3 or IL-10 3 days before and 1 day after paclitaxel administration protected animals against paclitaxel-induced peripheral neuropathy over the course of 5 weeks. These results suggest the potential of regulatable vectors for prevention of chemotherapy-induced peripheral neuropathy.

Computed tomography findings of complications resulting from cardiopulmonary resuscitation.

INTRODUCTION: This retrospective study was conducted to evaluate injuries related to cardiopulmonary resuscitation (CPR) and their associated factors using postmortem computed tomography (PMCT) and whole body CT after successful resuscitation. METHODS: The inclusion criteria were adult, non-traumatic, out-of-hospital cardiac arrest patients who were transported to our emergency room between April 1, 2008 and March 31, 2013. Following CPR, PMCT was performed in patients who died without return of spontaneous circulation (ROSC). Similarly, CT scans were performed in patients who were successfully resuscitated within 72h after ROSC. The injuries associated with CPR were analysed retrospectively on CT images. RESULTS: During the study period, 309 patients who suffered out-of hospital cardiac arrest were transported to our emergency room and received CPR; 223 were enrolled in the study. The CT images showed that 156 patients (70.0%) had rib fractures, and 18 patients (8.1%) had sternal fractures. Rib fractures were associated with older age (78.0 years vs. 66.0 years, p<0.01), longer duration of CPR (41min vs. 33min, p<0.01), and lower rate of ROSC (26.3% vs. 55.3%, p<0.01). All sternal fractures occurred with rib fractures and were associated with a greater number of rib fractures, higher age, and a lower rate of ROSC than rib fractures only cases. Bilateral pneumothorax was observed in two patients with rib fractures. CONCLUSIONS: PMCT is useful for evaluating complications related to chest compression. Further investigations with PMCT are needed to reduce complications and improve the quality of CPR.