Helminth-induced impairment of humoral immunity differently contribute to their anti-arthritic effects in mice: Comparison of Schistosoma mansoni and Trichinella spiralis.

AIMS: We have previously reported reduction of anti-type II collagen (IIC) IgG levels in collagen-induced arthritis (CIA) by Schistosoma mansoni (Sm) and Trichinella spiralis (Ts). To clarify the contribution of the impairment of humoral immunity to their anti-arthritic activities, we herein investigated the relationship between anti-IIC IgG levels and arthritic swelling in Sm- or Ts-infected mice. METHODS AND RESULTS: Male DBA/1J mice were infected with Sm cercariae or Ts muscle larvae prior to the IIC immunization. In the Sm-infected mice, paw swelling and anti-IIC IgG levels were continuously lower than those of non-infected control group. In contrast, arthritic swelling in the Ts-infected mice only decreased in the early phase of CIA progression, despite the continued impairment of anti-IIC IgG production throughout the experimental period. Correlation coefficients between residual paw swelling and anti-IIC IgG titers were similar or higher in the Sm group than in the control group, but were similar or lower in the Ts group than in the control group. CONCLUSION: The down-modulations of anti-IIC IgG levels by the two parasitic infections and the correlation analyses suggest that the anti-arthritic activity of Sm was primarily attributed to the modulation of IgG-independent arthritogenic mechanisms and secondarily to the impairment of anti-IIC IgG production. In contrast, Ts could alleviate CIA mainly via the impairment of antibody production.

Fractional excretion of total protein in patients with nephrotic syndrome.

BACKGROUND: The urine protein to creatinine ratio (UPCR) correlates well with the 24-h urine protein test (24-h UPT) and is a reliable indicator of proteinuria. However, in nephrotic syndrome, the correlation between the UPCR and the 24-h UPT tends to decrease. To address this, we introduced the fractional excretion of total protein (FETP), which reflects serum total protein and creatinine levels because severe hypoproteinemia and/or elevated serum creatinine levels tend to occur under these conditions. The 24-h UPT corrected for body surface area (BSA) (24-h UPT/BSA) was used to take body size into consideration. The correlation coefficients for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR were calculated. The statistical significance of the differences between these coefficients was also calculated. METHODS: Thirty-six pediatric patients with nephrotic syndrome were included in this study. The FETP was calculated as total protein clearance/creatinine clearance (%). Correlation coefficients were calculated for 24-h UPT/BSA and FETP and 24-h UPT/BSA and UPCR. The statistical significance of the differences between these coefficients was also calculated. RESULTS: The mean ± standard error of FETP was 0.11% ± 0.013%. The correlation coefficients of FETP and UPCR with 24-h UPT/BSA were 0.91 and 0.81, respectively. The FETP demonstrated a significantly stronger correlation with 24-h UPT/BSA than with UPCR (p = 0.01). CONCLUSIONS: The FETP correlated more strongly with 24-h UPT/BSA than with UPCR in patients with nephrotic syndrome. The FETP is a reliable indicator of proteinuria in nephrotic syndrome, especially in patients with severe hypoproteinemia or elevated serum creatinine levels.

A delayed diagnosis of fascioliasis: The importance of appropriate fecal diagnostic method.

Fascioliasis, a zoonotic helminthiasis, occurs sporadically in Japan. In this report, we describe a case of fascioliasis that was initially difficult to diagnose because the fecal examination method was negative for the Fasciola sp. eggs. A 64-year-old man living in Shimonoseki City, Japan, presented with fatigue and anorexia. Laboratory tests showed hepatic dysfunction and eosinophilia. Abdominal dynamic contrast-enhanced computed tomography and magnetic resonance cholangiopancreatography suggested intrahepatic biliary cysts. Thereafter, fever and night sweats persisted, and positron emission tomography and biopsy of the porta hepatis lymph node were performed on suspicion of malignancy. However, histopathological diagnosis found non-specific inflammation. As fascioliasis was suspected due to eosinophilia and the multiple hepatic masses, fecal egg examination was performed by an external private laboratory, which adopted the flotation method and reported the absence of parasite eggs. However, fecal examination was retried in our laboratory using the formalin-ether concentration method, and we detected Fasciola sp. eggs. This case suggests that misdiagnosis may occur depending on the fecal examination method; thus, it is necessary to choose a suitable method for certain parasite species.

Body Fat-Reducing Effects of Whey Protein Diet in Male Mice.

This study investigated the mechanism of reducing body fat via whey protein diet. Pregnant mice were fed whey or casein, and their offspring were fed by birth mothers. After weaning at 4 weeks, male pups received the diets administered to their birth mothers (n = 6 per group). At 12 weeks of age, body weight, fat mass, fasting blood glucose (FBG), insulin (IRI), homeostatic model assessment of insulin resistance (HOMA-IR), cholesterol (Cho), triglyceride (TG), the expression levels of lipid metabolism-related genes in liver tissues and metabolomic data of fat tissues were measured and compared between the groups. The birth weights of pups born were similar in the two groups. Compared to the pups in the casein group, at 12 weeks of age, pups in the whey group weighed less, had significantly lower fat mass, HOMA-IR and TG levels (p < 0.01, p = 0.02, p = 0.01, respectively), and significantly higher levels of the antioxidant glutathione and the anti-inflammatory 1-methylnicotinamide in fat tissues (p < 0.01, p = 0.04, respectively). No differences were observed in FBG, IRI, Cho levels (p = 0.75, p = 0.07, p = 0.63, respectively) and expression levels of lipid metabolism-related genes. Whey protein has more antioxidant and anti-inflammatory properties than casein protein, which may be its mechanism for reducing body fat.

[Current status and challenges of supervisory organizations' support for the health and safety of technical intern trainees: Focusing on collaboration with occupational health professionals].

OBJECTIVES: We aimed to clarify the current status and challenges of supervisory organizations' support for the health and safety of technical intern trainees in Japan. We also assessed the effectiveness of collaboration with occupational health professionals at a training site to investigate the potential for such collaboration to help solve related problems. METHODS: In October 2021, we distributed a questionnaire survey by postal mail to 3,262 supervisory organizations. We requested responses from those directly engaged in training technical intern trainees and those connected with training companies. We inquired regarding the frequency and difficulty of providing support for the health and safety of technical intern trainees (based on 22 survey items). Subsequently, we conducted a multiple logistic regression analysis to assess the association between collaboration with occupational health professionals and the difficulty of obtaining support. RESULTS: The analysis included 932 cases (response rate: 28.6%). Vietnam (76.6%) was the most frequent country of origin for trainees, and 10-49 (30.3%) was the most frequent range for the number of trainees. Over the preceding year, 17.0% of the organizations had collaborated with occupational health professionals at the training site. The most frequently indicated items on the survey were "explaining and interpretating for medical checkups," "providing traffic safety education and interpretation," and "accompanying and interpreting for health care facilities." Over 80% of the respondents answered that these actions were easy to implement. In contrast, only 30-40% of respondents answered that "counseling on mental health problems," "counseling on marriage, pregnancy, and childbirth," and "counseling on sexual harassment and power harassment" were easy to implement. The supervisory organizations that had collaborated with occupational health professionals tended to report that "providing traffic safety education and interpretation" (p = .049) and "providing health and safety education and interpretation" (p = .072) were easier than they were for organizations that had no support from occupational health professionals. CONCLUSIONS: The supervisory organizations surveyed faced challenges in dealing with mental health problems, marriage, pregnancy, childbirth, and harassment of technical intern trainees. Those organizations that collaborated with occupational health professionals found it easier to provide education on traffic safety and occupational safety and health education. Thus, the presence of a person in charge of health and safety in the planning of training programs and opportunities for education was considered important for promoting collaboration between supervisory organizations and occupational health professionals.

A Non-Obese Hyperglycemic Mouse Model that Develops after Birth with Low Birthweight.

The number of low birthweight (LBW) infants weighing below 2500 g has not decreased in Japan. This study aimed to develop an adult non-obese hyperglycemic mouse model born with LBW to study the pathogenesis. At 16.5 days of gestation, transient intrauterine ischemia (blocked blood flow in both uterine arteries for 15 min) was performed in a subgroup of pregnant mice (group I). Non-occluded dams were used as sham controls (group C). After birth, female pups in each group were weaned at 4 weeks of age and reared on the normal diet until 8 weeks of age (n = 7). Fasting blood glucose levels, serum immunoreactive insulin (IRI), and body composition were then measured. Metabolite analyses was performed on the liver tissues. Birthweight was significantly lower in group I compared with group C. Pups from group I remained underweight with low fat-free mass and showed hyperglycemia with high serum IRI and homeostasis model assessment of insulin resistance levels, indicating insulin resistance. Metabolite analyses showed significantly reduced adenosine triphosphate and nicotinamide adenine dinucleotide production and increased lactic acid in group I. The pathogenesis of our non-obese hyperglycemic mouse model may be due to increased myogenic insulin resistance based on mitochondrial dysfunction and reduced lean body mass.

Case Report: Successful Treatment With Anti-C5 Monoclonal Antibody in a Japanese Adolescent Who Developed Thrombotic Microangiopathy After Autologous Bone Marrow Transplantation for Malignant Lymphoma.

Background: Transplant-associated thrombotic microangiopathy (TA-TMA) is a serious complication of bone marrow transplantation (BMT). Recently, abnormalities in the complement system have been identified in the pathogenesis of TA-TMA, and there are series of reports stating that anti-C5 monoclonal antibody (eculizumab) is effective in patients with high levels of the membrane attack complex (C5b-9). Case Presentation: A 12-year-old boy underwent autologous BMT after receiving high-dose chemotherapy for malignant lymphoma. The patient was engrafted on day 19 after transplantation; however, hemolytic anemia and non-immune thrombocytopenia persisted, and haptoglobin decreased on day 46. Moreover, on day 83, the patient developed pulmonary hemorrhage, hypertension, severe proteinuria, hematuria, and acute kidney injury (AKI). Pulmonary bleeding stopped with daily platelet transfusion and hemostatic agents, but reappeared on day 100. Based on the presence of destruction of red blood cells, elevated lactate dehydrogenase levels, negative direct and indirect Coombs tests, normal ADAMTS13 levels, hemolytic anemia, non-immune thrombocytopenia, and AKI, the patient was diagnosed with systemic TA-TMA and we initiated plasma exchange (PE) and continuous hemodialysis for AKI. High C5b-9 levels were identified at the start of the series of PE, therefore we decided to administer eculizumab. After three courses of eculizumab, no pulmonary hemorrhage was observed, and anemia, thrombocytopenia, renal dysfunction, hematuria, and proteinuria all tended to improve. Three years after transplantation, the patient is alive and does not require eculizumab. Discussion: Eculizumab is a humanized monoclonal antibody that binds complement protein C5, preventing cleavage C5 and the formation of C5b-9. In this case, TA-TMA could not be controlled with PE alone. We therefore decided to use eculizumab relatively early based on the high C5b-9 level and could resolve the momentum of TA-TMA. Conclusion: In previous reports, TA-TMA typically occurred in early post-allogeneic BMT of patients with lymphoma or in post-autologous BMT of patients with neuroblastoma and was treated with eculizumab. We here reported that eculizumab could be successful treatment for TA-TMA in post-autologous BMT of patient with lymphoma.

Effectiveness of Infection Preventive Behaviors on COVID-19-Like Illness Symptoms During the Winter Third Wave of the Epidemic in Japan: A 2-Month Follow-up Nationwide Cohort Study.

Although multilayered strategies including preventive behaviors should be adopted to mitigate coronavirus disease 2019 (COVID-19) transmission, evidence on the effectiveness of preventive behaviors against COVID-19 remains limited. This Internet-based prospective cohort study collected baseline data in November 2020 and follow-up data in February 2021, during the third wave of the epidemic in Japan. Among the 19 941 included participants, the percentages reporting that they always used a face mask, practiced hand washing/disinfection, gargling, and ensuring proper room ventilation were 85.4%, 36.0%, 51.1%, and 44.6%, respectively. Multiple logistic regression analyses revealed that less frequently practicing hand washing/disinfection (odds ratio [OR] = 1.20), gargling (OR = 1.20), and ensuring proper room ventilation (OR = 1.38) were significantly associated with self-reported COVID-19-like illness (CLI). These results suggest that personal preventive behaviors may be effective in reducing CLI, even when universal masking is practiced.

ß2-microglobulin measurement with dried urine spots for congenital anomalies of the kidney and urinary tract screening in 3-year-old children.

BACKGROUND: Screening using dipstick urinalysis has long been performed in 3-year-old children; however, it is ineffective in detecting congenital anomalies of the kidney and urinary tract (CAKUT). Measurement of the urinary ß2-microglobulin (ß2MG)/creatinine (Cr) ratio may be more effective for this purpose. Analysis of dried urine spots (DUS) on filter paper is suitable for mass screening since operational costs are low and samples are easy to collect and transport. We examined the accuracy of measuring the urinary ß2MG/Cr ratio in DUS on filter paper. METHODS: We collected 2,623 urine samples from 3-year-old children. ß2MG and Cr levels were measured in DUS on filter paper. We examined the correlation between the ß2MG/Cr ratios measured in DUS and using the conventional method in 640 samples using the coefficient of determination test. Children with high ß2MG/Cr ratios (>0.6 µg/mg Cr) in DUS samples were further examined to establish a definitive diagnosis. RESULTS: There was strong correlation between the two methods for determination of ß2MG levels (r2 = 0.68; P < 0.001) and ß2MG/Cr ratios (r2 = 0.69; P < 0.001). Of the 2,623 children, 38 (1.45%) had ß2MG/Cr ratios >0.6. Thirty-five children were subsequently examined, resulting in findings of renal hypodysplasia (n = 2, 0.08%), horseshoe kidney (n = 1, 0.04%), renal tubular dysfunction with hepatoblastoma (n = 1, 0.04%), data abnormality (high urine ß2MG level, n = 6, 0.23%; high serum Cr level, n = 1, 0.04%), and normal values (n = 24, 0.91%). CONCLUSIONS: We evaluated a practical method for measuring ß2MG/Cr ratios in DUS as a screening method to detect CAKUT in 3-year-old children.

Non-lethal rodent malarial infection prevents collagen-induced arthritis in mice via anti-arthritic immunomodulation.

AIMS: Immunomodulatory effects of parasitic infections on the outcomes of allergic or autoimmune disorders have been addressed in many experimental studies. We examined the effects of Plasmodium yoelii 17X NL (Py) infection on collagen-induced arthritis (CIA). METHODS AND RESULTS: Male DBA/1J mice were immunized with bovine type II collagen (IIC). Py inoculation was induced at three different time points (1, 4 weeks after or 4 weeks before the immunization). Only the inoculation at 4 weeks after IIC immunization significantly inhibited arthritis development. Non-malarial anaemia induced by phenylhydrazine hydrochloride (PHZ) did not affect arthritis development. In the infected mice, anti-IIC IgG levels were transiently reduced. In addition, splenic production of pro-arthritic cytokines (IL-17 and TNF-α) and IFN-γ decreased, whereas IL-10 production increased. Flow cytometric analysis clarified that the main IL-10 producers in Py-infected mice had the CD4+ CD25- Foxp3- phenotype, presumably Tr1 cells. CONCLUSION: We demonstrated that experimental malarial infection alleviated autoimmune arthritis via immunomodulation, suggesting the importance of malaria in the hygiene hypothesis and the significance of searching for therapeutic immunomodulatory molecules from malarial parasites.

Characteristics of Kawasaki Disease Patients during the COVID-19 Pandemic in Japan: A Single-Center, Observational Study.

BACKGROUND: Under the Coronavirus disease 2019 (COVID-19) pandemic, manifestations in children with Kawasaki disease (KD) are different between the Western and the Eastern countries. Particularly, there has not been a report comparing a series of KD in Japan, where KD was originally discovered and has a large number of registered cases. METHODS: We compared patients with KD under the period of the COVID-19 pandemic in Japan with the report from Italy during its reported period by a retrospective, cohort, observational study in a Japanese single center. RESULTS: Thirty-two patients with typical KD were treated during the study period, while the Italian study reported 10 patients with the signs of KD. Concerning the proof of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) infection, none (0%) of our KD cases showed a positive result and one and no patients developed the macrophage activation syndrome (MAS) and Kawasaki disease shock syndrome (KDSS), respectively; however, eight (80%) patients in the Italian series were confirmed with SARS-CoV-2 infection. MAS and KDSS developed in six and five patients, respectively. CONCLUSIONS: Cases reported as COVID-19 pandemic-related KD in Italy showed significantly different clinical characteristics from the typical KD symptoms known in Japan. Although they show KD-like manifestations, we cannot conclude that SARS-CoV-2 has the same etiology of our 'classic' KD at the present stage.

Severe olfactory and gustatory dysfunctions in a Japanese pediatric patient with coronavirus disease (COVID-19).

Coronavirus disease (COVID-19) is often characterized by abnormal olfactory and gustatory symptoms in adults; however, detailed studies on pediatric patients with COVID-19 are extremely limited. A 13-year-old Japanese girl presented with fever and cough, and after 2 days, her olfactory and taste sensations suddenly disappeared. A real-time reverse transcriptase-polymerase chain reaction (RT-PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was performed using a nasopharyngeal swab. Because a positive result was seen, she was admitted on the 7th day of illness. On admission, the visual analogue scale (VAS) score for smell and taste was 0 of 100%. An intravenous olfaction test using prosultiamine (Alinamin test) was performed on the 15th day of illness to evaluate olfaction, and an increase in latency (33 seconds) and a decrease in duration (55 seconds) were observed. In the odor identification test using 12 different odor cards, only 7 odors were correctly identified. On the 18th day of illness, SARS-CoV-2 tested negative in the RT-PCR test; simultaneously, the VAS score for smell and taste fully improved to 100 of 100%. On the 77th day of illness, full recovery was confirmed in the Alinamin test (latency, 7 seconds; duration, 82 seconds). In this present case, an improvement in olfactory and gustatory dysfunctions was observed with negative results in RT-PCR test for SARS-CoV-2.

Malaria cross-sectional surveys identified asymptomatic infections of Plasmodium falciparum, Plasmodium vivax and Plasmodium knowlesi in Surat Thani, a southern province of Thailand.

OBJECTIVES: Malaria cross-sectional surveys are rarely conducted in very low transmission settings. This study aimed to determine the prevalence and risk factors of Plasmodium infection in a near-elimination setting in southern Thailand. METHODS: Two cross-sectional surveys were conducted in areas of active transmission in the Surat Thani province of Thailand in January and May 2019. PCR was used to detect Plasmodium infection. RESULTS: The prevalence of Plasmodium blood infection was 0.45% and 0.61% in January and May 2019, respectively. The major parasite species was Plasmodium falciparum in January and Plasmodium vivax in May. Unexpectedly, Plasmodium knowlesi infections were also detected. Most infections, including those of Plasmodium knowlesi, were asymptomatic. Being male and staying outdoors at night-time were the only significant identified risk factors. Of people infected in January 28.0% were positive in May for the same parasite species, suggesting persistent asymptomatic infections. CONCLUSIONS: Despite the very low incidence rate in Surat Thani, most malaria infections were asymptomatic. Outdoor mosquito biting at night-time is likely an important mode of malaria transmission. Unexpectedly, asymptomatic Plasmodium knowlesi infection was found, confirming previous reports of such infection in mainland Southeast Asia.

Role of complement 3 in renin generation during the differentiation of mesenchymal stem cells to smooth muscle cells.

We showed that increased expression of complement 3 (C3) induces dedifferentiation of mesenchymal cells and epithelial mesenchymal transition, which activate the local renin-angiotensin system (RAS) that contributes to cardiovascular and renal remodeling in spontaneously hypertensive rats (SHRs). In the present study, to investigate contributions of C3 to the development of the pathogenesis of hypertension, we evaluated the formation of renin-producing cells and roles of C3 in renin generation during differentiation of primary bone marrow-mesenchymal stem cells (MSCs) from C57BL/6 mice, Wistar-Kyoto (WKY) rats, and SHRs to smooth muscle cells (SMCs) with transforming growth factor-ß1. The expression of renin transiently increased with increases in transcription factor liver X receptor α (LXRα), and expression of C3 and Krüppel-like factor 5 (KLF5) increased during differentiation of MSCs from C57BL/6 mice, WKY rats, and SHRs to SMCs. Exogenous C3a stimulated renin and LXRα expression accompanied by nuclear translocation of LXRα. C3a receptor antagonist SB290157 suppressed renin and LXRα expression, with inhibition of nuclear translocation of LXRα during the differentiation of mouse MSCs to SMCs. The expression of C3 and KLF5 was significantly higher in the differentiated cells from SHRs compared with the cells from WKY rats during differentiation. Renin-producing cells were formed during differentiation of MSCs to SMCs, and renin generation was observed in undifferentiated SMCs, in which transient expression of renin in the differentiated cells with lower differentiation stage was stronger from SHRs than that from WKY rats. Expression and nuclear localization of LXRα in the differentiated cells from SHRs were stronger than that from WKY rats. C3 was important in forming and maintaining this undifferentiated state of SMCs from MSCs to generate renin with increases in transcription factor LXRα and KLF5. Increases in C3 expression maintain the undifferentiated state of SMCs from MSCs to generate renin that activates RAS and contributes to the pathogenesis of hypertension in SHRs.

A Consensus on Immunization Recommendations for Healthcare and Other Workers at the Tokyo 2020 Olympic and Paralympic Games: A Delphi Survey.

This study aimed to build a consensus on recommendations of immunity requirements for vaccine-preventable diseases among healthcare and non-healthcare workers, including volunteers, at the Tokyo 2020 Olympic and Paralympic Games. We used a two-round Delphi method with a group of 17 Japanese medical doctors involved in vaccination or public health administration. We asked them to rank the importance of immunity to each vaccine-preventable disease as mandatory, recommended, considered if possible, or standard precautions only. The response rate was 88.2% (15/17) for the first questionnaire and 100% (17/17) for the second. All respondents considered that immunity to measles, rubella, varicella, mumps, and hepatitis B should be mandatory for healthcare workers, and 15 of 17 respondents considered that immunity to influenza should also be mandatory. Seven, three, two, and two respondents thought that immunity to pertussis, meningococcal disease, diphtheria, and tetanus should be mandatory, and ten, 11, seven, and seven thought it should be recommended. For non-healthcare workers, immunity to measles, rubella, and varicella was considered mandatory by 17, 15, and 15 respondents. Ten and eight respondents thought that immunity to mumps and influenza should be mandatory, and seven thought that it should be recommended. In conclusion, the consensus was that immunity to measles, rubella, and varicella should be mandatory for both healthcare and non-healthcare workers. Immunity to mumps, hepatitis B, and influenza was also considered mandatory for healthcare workers. Further discussions may be needed to develop a consensus on other vaccine-preventable diseases, especially if vaccination is not routine for adolescents or adults in Japan.

Instant Strong Adhesive Behavior of Nanocomposite Gels toward Hydrophilic Porous Materials.

We investigated the adhesion behavior of nanocomposite hydrogels (NC gels), consisting of unique organic (polymer)-inorganic (clay) network structures, toward inorganic and organic materials. The NC gels exhibit instant and strong adhesion to inorganic and organic substrates with hydrophilic porous surfaces. The NC gels instantly adhere to hydrophilic porous substrates (e.g., unglazed ceramic surfaces and polymer membranes) through simple light contact. In addition, a small piece of NC gel effectively joined two substrate samples (e.g., concrete blocks and bricks) through lamination of the interposing NC gel. The resulting conjoined materials were unable to be separated at the gel-substrate interface; rather, the gel itself fractured upon separation, which indicates that the adhesive strength at the interface is greater than the tensile strength of the NC gel. With the exception of NC gels with very high clay concentrations ( Cclay's), instant strong adhesion and cohesive failure by subsequent stretching were observed for almost all NC gels composed of different polymers or different Cclay values. A thermoresponsive NC gel was reversibly adhered and could be peeled from the surface by stretching (adhesive failure) at a temperature above its transition temperature. The mechanism of instant strong adhesion or reversible adhesion is discussed based on dangling chains that exist on the surfaces of the NC gels composed of polymer-clay networks. The cut surface of an NC gel generally exhibited a higher adhesive strength than the as-prepared surface because of longer dangling chains.