Insufficient anti-spike RBD IgA responses after triple vaccination with intramuscular mRNA BNT162b2 vaccine against SARS-CoV-2.

Objectives: This study aims to examine whether the parenterally administered mRNA-based COVID-19 vaccines can induce sufficient mucosal-type IgA responses to prevent SARS-CoV-2 transmission. Methods: We examined the longitudinal kinetics of SARS-CoV-2 spike RBD-specific IgA and IgG responses in sera of Japanese healthcare workers (HCWs) after receiving two doses and the third dose of BNT162b2 mRNA vaccines. During the prospective cohort study, Omicron breakthrough infections occurred in 62 participants among 370 HCWs who had received triple doses of the vaccine. Pre-breakthrough sera of infected HCWs and non-infected HCWs were examined for the levels of anti-RBD IgA and IgG titers. Results: The seropositivity of anti-RBD IgA at 1 M after the second vaccine (2D-1M) and after the third dose (3D-1M) was 65.4% and 87.4%, respectively, and wanes quickly. The boosting effect on anti-RBD Ab titers following breakthrough infections was more notable for anti-RBD IgA than for IgG. There were partial cause-relationships between the lower anti-RBD IgA or IgG at pre-breakthrough sera and the breakthrough infection. Conclusions: Parenterally administered COVID-19 vaccines do not generate sufficient mucosal-type IgA responses despite strong systemic IgG responses to SARS-CoV-2. These results demonstrate the necessity and importance of reevaluating vaccine design and scheduling to efficiently increase oral or respiratory mucosal immunity against SARS-CoV-2.

The appearance of anti-spike receptor binding domain immunoglobulin G4 responses after repetitive immunization with messenger RNA-based COVID-19 vaccines.

OBJECTIVES: It is crucial to analyze the consequences of repeated messenger RNA (mRNA)-based COVID-19 vaccinations on SARS-CoV-2 spike receptor binding domain (RBD)-specific immunoglobulin (Ig)G subclass and the possible causal relationship with breakthrough infection. METHODS: We examined the longitudinal kinetics of RBD-specific IgG subclass antibodies in sera after receiving the second, third, and fourth doses of mRNA-based COVID-19 vaccines in Japanese healthcare workers. Anti-RBD IgG subclass in sera of patients with COVID-19-infected who had not received the COVID-19 vaccine were also examined. We compared anti-RBD IgG subclass antibody titers in the serum of pre-breakthrough-infected vaccinees and non-infected vaccinees. RESULTS: The seropositivity of anti-RBD IgG4 after the vaccination was 6.76% at 1 month after the second dose, gradually increased to 50.5% at 6 months after the second dose, and reached 97.2% at 1 month after the third dose. The seropositivity and titers of anti-RBD IgG1/IgG3 quickly reached the maximum at 1 month after the second dose and declined afterward. The elevated anti-RBD IgG4 Ab levels observed after repeated vaccinations were unlikely to increase the risk of breakthrough infection. CONCLUSIONS: Repeated vaccinations induce delayed but drastic increases in anti-RBD IgG4 responses. Further functional investigations are needed to reveal the magnitude of the high contribution of spike-specific IgG4 subclasses after repeated mRNA-based COVID-19 vaccinations.

Elevation in white blood cell count and development of hyper LDL cholesterolemia.

To investigate the relationship between white blood cell (WBC) count and incidence of hyper-low-density lipoprotein (LDL) cholesterolemia in a population-based longitudinal study. This is a retrospective study using data of annual health check-ups for residents of Iki City, Japan. A total of 3312 residents (≥ 30 years) without hyper-LDL cholesterolemia at baseline were included in this analysis. Primary outcome was incidence of hyper-LDL cholesterolemia (LDL cholesterol levels ≥ 3.62 mmol/L and/or use of lipid lowering drugs). During follow-up (average 4.6 years), 698 participants development of hyper-LDL cholesterolemia (incidence 46.8 per 1000 person-years). Higher incidence of hyper-LDL cholesterolemia was observed among participants with higher leukocyte count (1st quartile group: 38.5, 2nd quartile group: 47.7, 3rd quartile group: 47.3, and 4th quartile group: 52.4 per 1,000 person-years, P = 0.012 for trend). Statistically significant relation was observed even after adjustment for age, gender, smoking, alcohol intake, leisure-time exercise, obesity, hypertension and diabetes: hazard ratio 1.24 (95% confidence interval 0.99 to 1.54) for 2nd quartile group, 1.29 (1.03-1.62) for 3rd quartile group and 1.39 (1.10-1.75) for 4th quartile group, compared with 1st quartile group (P for trend = 0.006). Increased WBC count was related to incidence of hyper-LDL cholesterolemia in general Japanese population.

Predictive Factors for the Necessity of Hospitalization of Patients With Acute Alcohol Intoxication.

Background: The aim of the study was to identify factors related to the need for hospitalization due to acute alcohol intoxication. Methods: The data of 42 patients with acute alcohol intoxication who visited our hospital from April 1, 2014 to September 30, 2015 were available for analysis. Factors related to outcome included hospitalization or release to home, Glasgow coma scale (GCS), temperature, pulse rate, blood pressure, oxygen saturation of the peripheral artery (SpO2), and respiratory rate. A retrospective survey was done that included estimated blood alcohol concentration, osmotic pressure, and serum lactate level. The following formula was used to estimate blood alcohol concentration: (measured osmotic pressure - estimated osmotic pressure × 4.6 mg/dL). Univariate analysis of each variable was done for the two outcome groups, hospital admission or release to home, then statistically significant items were subjected to multivariate analysis. Results: Of the 42 patients (average age 22.8 ± 8.6 years, 33 men, six women), 29 were admitted and 13 were released to home. There was a weak correlation between estimated blood alcohol concentration and GCS. There was no significant difference in alcohol concentration or GCS between the hospitalized and released to home groups. In multivariate analysis using the outcome as the objective variable, a serum lactate level of 26 mg/dL or higher was associated with the need for hospitalization (odds ratio: 6.7). Conclusion: A serum lactate level of 26 mg/dL would be useful for deciding if hospitalization is necessary for patients with acute alcohol intoxication.

Antibody acquisition after second and third SARS-CoV-2 vaccinations in Japanese kidney transplant patients: a prospective study.

BACKGROUND: Kidney transplant patients have lower antibody acquisition after SARS-CoV-2 vaccination. The efficacy of vaccines in Japanese kidney transplant patients with specific characteristics, such as predominant living-donor, ABO-incompatible kidney transplant, and low-dose immunosuppression, requires verification. METHODS: We conducted a prospective study to estimate anti-SARS-CoV-2 antibody levels in 105 kidney transplant patients and 57 controls. Blood samples were obtained before vaccination, 1, 3, and 6 months after second vaccination, and 1 month after third vaccination. We investigated antibody acquisition rates, antibody levels, and factors associated with antibody acquisition. RESULTS: One month after second vaccination, antibody acquisition was 100% in the controls but only 36.7% in the kidney transplant group (P < 0.001). Antibody levels in positive kidney transplant patients were also lower than in the controls (median, 4.9 arbitrary units vs 106.4 arbitrary units, respectively, P < 0.001). Years after kidney transplant (odds ratio 1.107, 95% confidence interval 1.012-1.211), ABO-incompatible kidney transplant (odds ratio 0.316, 95% confidence interval 0.101-0.991) and mycophenolate mofetil use (odds ratio 0.177, 95% confidence interval 0.054-0.570) were significant predictors for antibody acquisition after second vaccination. After third vaccination, antibody positivity in the kidney transplant group increased to 75.3%, and antibody levels in positive patients were 71.7 arbitrary units. No factors were associated with de novo antibody acquisition. CONCLUSIONS: In Japanese kidney transplant patients, years after kidney transplant, ABO-incompatible kidney transplant and mycophenolate mofetil use were predictors for antibody acquisition after second vaccination. Third vaccination improves antibody status even in patients who were seronegative after the second vaccination.

Vibrio vulnificus sepsis after shrimp shelling in a patient with preexisting primary biliary cholangitis: a case report.

BACKGROUND: Vibrio vulnificus is typically present in seawater, fish, and shellfish, and is known to cause severe sepsis, particularly in patients with liver diseases such as cirrhosis. V. vulnificus is one of the most dangerous waterborne pathogens, and infection mainly occurs in western Japan during the summer, with an increased fatality rate. Herein, we report the case of a patient with primary biliary cholangitis and sepsis caused by V. vulnificus infection sustained through shrimp shelling. CASE PRESENTATION: An 82-year-old Japanese Asian woman with no medical history or underlying disease developed redness, swelling, and pain, which extended from the right fingers to the upper arm. A diagnosis of sepsis due to cellulitis was made. Blood culture detected V. vulnificus; thus, minocycline was administered in addition to meropenem. The disease course was uneventful, and the patient was discharged on day 28 of hospitalization. Symptoms in the right upper arm developed 1 day after the patient shelled a large number of shrimp; therefore, the infection route was assumed to be through wounds sustained during shrimp shelling. We suspected liver disease and measured serum anti-mitochondrial M2 antibody levels, leading to the diagnosis of primary biliary cholangitis. CONCLUSIONS: As in this case, small wounds caused by handling fish and shrimp are a potential source of infection. Patients with severe V. vulnificus infection should be thoroughly assessed for the presence of liver diseases such as primary biliary cholangitis.

Acute Myocarditis with Severe Fever and Thrombocytopenia Syndrome.

A 67-year-old man, hospitalized with fever and pancytopenia, experienced cardiogenic shock on the 3rd day of hospitalization. He complained of chest pain and exhibited cardiac dysfunction, upregulated serum troponin levels, and an ST elevation on electrocardiogram. Severe fever with thrombocytopenia syndrome (SFTS) was suspected based on the symptom course after a tick bite and was definitively diagnosed using the serum polymerase chain reaction (PCR) test. An endomyocardial biopsy performed in the convalescent phase revealed a sign of myocardial inflammation with increases in CD3- and CD68-positive cells. We herein report the first case of acute myocarditis complicated with SFTS.

Longitudinal Dynamics of SARS-CoV-2 IgG Antibody Responses after the Two-Dose Regimen of BNT162b2 Vaccination and the Effect of a Third Dose on Healthcare Workers in Japan.

Analysis of longitudinal dynamics of humoral immune responses to the BNT162b2 COVID-19 vaccine might provide useful information to predict the effectiveness of BNT162b2 in preventing SARS-CoV-2 infection. Herein, we measure anti-RBD IgG at 1, 3 and 6 months (M) after the second dose of BNT162b2, and at 1 M after a third dose of BNT162b2 vaccination in 431 COVID-19-naïve healthcare workers (HCWs) in Japan. All HCWs mounted high-anti-RBD IgG responses after the two-dose regimen of BNT162b2 vaccinations. Older persons and males presented lower anti-RBD IgG responses than younger adults and females, respectively. The decay in anti-RBD IgG started from 1 M after the second dose of BNT162b2 and anti-RBD IgG titers dropped to nearly one-tenth at 6 M after the second vaccination. Subsequently, the participants received a third dose of BNT162b2 at 8 M after the second dose of BNT162b2 vaccine. Anti-RBD antibody titers 1 M after the third dose of BNT162b2 increased seventeen times that of 6 M after the second dose, and was twice higher than the peak antibody titers at 1 M after the second dose of vaccination. The negative effect of age for the male gender on anti-RBD IgG antibody titers was not observed at 1 M after the third dose of BNT162b2 vaccine. There were no notable adverse events reported, which required hospitalization in these participants. These results suggest that the third dose of BNT162b2 safely improves humoral immunity against SARS-CoV-2 with no major adverse events.

Maoto, a traditional herbal medicine, for post-exposure prophylaxis for Japanese healthcare workers exposed to COVID-19: A single center study.

BACKGROUND: Little research has been done on post-exposure prophylaxis (PEP) for COVID-19. This study was done to determine if maoto, a traditional herbal medicine commonly used for diseases with symptoms similar to those of COVID-19, can be repurposed for post-exposure prophylaxis to prevent the spread of nosocomial infection with SARS-CoV-2. METHODS: A cohort analysis was done of the data of 55 health care workers (HCWs) whether to get infected with SARS-CoV-2 in a Japanese hospital experiencing a COVID-19 cluster in April of 2021. Of these subjects, maoto granules for medical use were prescribed for PEP to 42 HCWs and taken for three days in mid-April. Controls were 13 HCWs who rejected the use of maoto. Polymerase chain reaction was performed routinely once or twice a week or when a participant presented with symptoms of COVID-19. RESULT: There were no background differences between the maoto and control groups by profession, sex, or mean age. No severe adverse reactions were observed. During the observation period of 1 week, significantly fewer subjects were diagnosed with COVID-19 in the maoto group (N = 3, 7.1%) than in the control group (N = 6, 46.2%). The prophylactic effectiveness of maoto was 84.5%. CONCLUSION: Oral administration of maoto is suggested to be effective as PEP against nosocomial COVID-19 infection.

Diagnostic error rates and associated factors for lower gastrointestinal perforation.

Lower gastrointestinal perforation is rare and challenging to diagnose in patients presenting with an acute abdomen. However, no study has examined the frequency and associated factors of diagnostic errors related to lower gastrointestinal perforation. This large-scale multicenter retrospective study investigated the frequency of diagnostic errors and identified the associated factors. Factors at the level of the patient, symptoms, situation, and physician were included in the analysis. Data were collected from nine institutions, between January 1, 2015 and December 31, 2019. Timely diagnosis was defined as diagnosis at the first visit in computed tomography (CT)-capable facilities or referral to an appropriate medical institution immediately following the first visit to a non-CT-capable facility. Cases not meeting this definition were defined as diagnostic errors that resulted in delayed diagnosis. Of the 439 cases of lower gastrointestinal perforation identified, delayed diagnosis occurred in 138 cases (31.4%). Multivariate logistic regression analysis revealed a significant association between examination by a non-generalist and delayed diagnosis. Other factors showing a tendency with delayed diagnosis included presence of fever, absence of abdominal tenderness, and unavailability of urgent radiology reports. Initial misdiagnoses were mainly gastroenteritis, constipation, and small bowel obstruction. In conclusion, diagnostic errors occurred in about one-third of patients with a lower gastrointestinal perforation.

Ephedrae Herba and Cinnamomi Cortex interactions with G glycoprotein inhibit respiratory syncytial virus infectivity.

Although respiratory syncytial virus (RSV) is a major cause of respiratory tract infection in children, no effective therapies are available. Recently, RSV G, the attachment glycoprotein, has become a major focus in the development of therapeutic strategies against RSV infection. Treatment of RSV-infected cultured cells with maoto, a traditional herbal medicine for acute febrile diseases, significantly reduced the viral RNA and titers. RSV attachment to the cell surface was inhibited both in the presence of maoto and when RSV particles were pre-treated with maoto. We demonstrated that maoto components, Ephedrae Herba (EH) and Cinnamomi Cortex (CC), specifically interacted with the central conserved domain (CCD) of G protein, and also found that this interaction blocked viral attachment to the cellular receptor CX3CR1. Genetic mutation of CX3C motif on the CCD, the epitope for CX3CR1, decreased the binding capacity to EH and CC, suggesting that CX3C motif was the target for EH and CC. Finally, oral administration of maoto for five days to RSV-infected mice significantly reduced the lung viral titers. These experiments clearly showed the anti-RSV activity of EH and CC mixed in maoto. Taken together, this study provides insights for the rational design of therapies against RSV infection.

Effect of chronic kidney disease on the association between hyperuricemia and new-onset hypertension in the general Japanese population: ISSA-CKD study.

We aimed to investigate the association between serum uric acid (SUA) level and development of hypertension as well as the interaction effect of chronic kidney disease (CKD) on this relationship in the general Japanese population. We included 7895 participants aged ≥30 years from the ISSA-CKD study, a population-based retrospective cohort study that used annual health check-up data of residents from Iki Island, Japan. After the exclusion of 1881 with l < 1-year follow-up, 2812 with hypertension at baseline, and 165 with missing information on SUA, a total of 3037 participants were enrolled in this analysis. Participants were divided into four groups according to the quartiles of SUA level at baseline, and multivariable-adjusted hazard ratios for new-onset hypertension were calculated. Stratified analyses were performed for each subgroup (defined by sex, age, alcohol intake, and CKD) to assess the interaction effects. During a mean follow-up period of 4.4 years, 943 participants developed hypertension. The first quartile group was set as the reference group, and the multivariable-adjusted hazard ratios (95% confidence interval) for new-onset hypertension were 1.11 (0.90-1.36) in the second quartile, 1.25 (1.02-1.54) in the third quartile, and 1.35 (1.07-1.70) in the fourth quartile compared with those in the reference group (p = .007 for trend). The stratified analyses showed that the association between SUA and hypertension was significantly stronger in participants with CKD than in those without CKD (p = .035 for interaction). SUA level is an independent risk factor for new-onset hypertension. This tendency was significantly stronger in participants with CKD.

Eating before bed and new-onset hypertension in a Japanese population: the Iki city epidemiological study of atherosclerosis and chronic kidney disease.

The aim of this study was to determine the relationship between eating before bed and the development of hypertension in a general Japanese population. We conducted a population-based retrospective cohort study using annual health check-up data collected from the residents of Iki City, Nagasaki Prefecture, Japan. In total, 2930 participants without hypertension at baseline (mean age 57.0 years, male 42.8%) were included in the present analysis. Eating before bed was defined as eating within 2 h of bedtime. The outcome of this study was incident hypertension (blood pressure ≥140/90 mmHg or initiation of blood pressure-lowering medications). Multivariable-adjusted hazard ratios and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. During an average follow-up of 4.5 years, 909 participants developed hypertension. The incidence (per 1000 person-years) of hypertension in the group of individuals who ate before bed was 82.8, whereas that in the group of individuals who did not eat before bed was 65.8. The association was significant even after adjusting for other risk factors, including age, sex, current smoking status, current alcohol intake, regular exercise, obesity, elevated blood pressure, diabetes mellitus, and dyslipidemia, with a hazard ratio of 1.23 (95% CI: 1.05-1.44) for the group of individuals who ate before bed compared with the group of individuals who did not eat before bed (P = 0.01 for trend). Eating before bed was correlated with a future risk of developing hypertension in the general Japanese population.

Useful clinical findings and simple laboratory data for the diagnosis of seasonal influenza.

BACKGROUND: When using rapid antigen test kits for the diagnosis of influenza, false-negative results may occur if done too soon after the onset of symptoms. The purpose of this study was done to determine clinical laboratory items other than rapid antigen testing are useful for diagnosing influenza. METHODS: The subjects were 915 patients who visited the outpatient clinic of hospital between April 2010 and March 2017 during the influenza epidemic seasons, from December to April, and had both fever of 37.0 degrees or more and cold symptoms. RESULTS: Of the 214 patients who met the inclusion criteria, 176 had influenza. Multivariate analysis extracted patient consultation within four days of onset, fever of 37 degrees or higher, posterior pharyngeal lymphoid follicles, CRP of 0.77 mg/dL or less, and a lymphocyte count of 900/µL less as independent variables. CONCLUSION: In previous study, lymphoid follicles on the posterior pharyngeal wall and decreased lymphocyte count were reported as influenza-specific findings. Both were confirmed with high specificity in our study, indicating that both would be useful when patients with influenza-like symptoms were false-negative for the rapid antigen test.

Effects of Weight Gain after 20 Years of Age and Incidence of Hyper-Low-Density Lipoprotein Cholesterolemia: The Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD).

The aim of this study was to investigate the effects of long-term weight gain from the age of 20 on incidence of hyper-low-density-lipoprotein (LDL) cholesterolemia in the general population of Japanese people. METHODS: We conducted a population-based retrospective cohort study using annual health checkup data for residents of Iki City, Nagasaki Prefecture, Japan. A total of 3179 adult (≥30 years old) men and women without hyper-LDL cholesterolemia at baseline, who underwent two or more health checkups were included in the analysis. Information on weight gain (≥10 kg) after 20 years of age was obtained using questionnaire. The outcome of this study was development of hyper-LDL cholesterolemia defined as LDL-cholesterol level ≥3.62 mmol/L and/or initiation of lipid-lowering medications. RESULTS: During a mean follow-up period of 4.53 years, 665 of the 3179 participants developed hyper-LDL cholesterolemia (46.5/1000 person-years). The incidence of hyper-LDL cholesterolemia was higher in participants with a weight gain of ≥10 kg (55.3/1000 person-years) than among those with a weight gain of <10 kg (41.8/1000 person-years). This association remained statistically significant even after adjustment for age, sex, smoking, daily drinking, exercise, obesity, hypertension, and diabetes (multivariable hazard ratio 1.31, 95% confidence interval 1.08-1.58, p = 0.006). CONCLUSION: A weight gain of ≥10 after 20 years of age affected the development of hyper-LDL cholesterol regardless of age, sex, and obesity in a general population of Japanese.

Eating Speed and Incidence of Diabetes in a Japanese General Population: ISSA-CKD.

BACKGROUND: We investigated whether eating speed was associated with the incidence of diabetes in a Japanese general population. METHODS: A total of 4853 Japanese individuals without diabetes at baseline were analyzed. Self-reported eating speed was categorized as slow, medium, and fast on the basis of questionnaire responses. The study outcome was the incidence of diabetes. RESULTS: After an average follow-up period of 5.1 years, 234 individuals developed diabetes. The incidence of diabetes per 1000 person-years was 4.9 in the slow eating speed group, 8.8 in the medium eating speed group, and 12.5 in the fast eating speed group, respectively (*** p < 0.001 for trend). The HRs were 1.69 (95%CI 0.94-3.06) for the medium eating speed and 2.08 (95%CI 1.13-3.84) for the fast eating speed, compared to the slow eating speed (* p = 0.014 for trend) after adjustment for age, gender, smoking status, drinking, exercise, obesity, hypertension, and dyslipidemia. CONCLUSION: Faster eating speed increased a risk for the incidence of diabetes in a general Japanese population.

Human T-Cell Leukemia Virus Type 1 Infection Is a Risk Factor for Atherosclerosis.

BACKGROUND: Infection, such as by human immunodeficiency virus (HIV), has been reported to cause atherosclerosis by inducing inflammation. Because human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus, as is HIV, we investigated the possible influence of HTLV-1 on the pathogenesis of atherosclerosis by use of established atherosclerosis parameters. METHODS: The study was done on Iki Island, Fukuoka, an area endemic for HTLV-1. The data of 1,424 residents who reported to an annual health check were available for analysis. Anti-HTLV-1 antibody status and factors associated with atherosclerosis were examined, including maximum intima-media thickness (Max-IMT) and brachial-ankle pulse wave velocity (PWV). RESULTS: HTLV-1 positive participants had significantly higher Max-IMT (1.15 ± 0.55 vs. 1.08 ± 0.61 mm, P = 0.04) and PWV (1,760.6 ± 414.5 vs. 1,657.1 ± 425.5 cm/s, P < 0.01) values than did those negative. Moreover, in multiple regression analysis (odds ratio: 1.39, P < 0.01) of participants with Max-IMT 1.1 mm or over, HTLV-1 was extracted as an independent factor for the development of atherosclerosis. CONCLUSION: Our results indicate that HTLV-1 infection confers a high risk of atherosclerosis, although its opposite relation is also possible. It is important to carefully follow the health status of HTLV-1 carriers.

Effects of maoto (ma-huang-tang) on host lipid mediator and transcriptome signature in influenza virus infection.

Maoto, a traditional kampo medicine, has been clinically prescribed for influenza infection and is reported to relieve symptoms and tissue damage. In this study, we evaluated the effects of maoto as an herbal multi-compound medicine on host responses in a mouse model of influenza infection. On the fifth day of oral administration to mice intranasally infected with influenza virus [A/PR/8/34 (H1N1)], maoto significantly improved survival rate, decreased viral titer, and ameliorated the infection-induced phenotype as compared with control mice. Analysis of the lung and plasma transcriptome and lipid mediator metabolite profile showed that maoto altered the profile of lipid mediators derived from ω-6 and ω-3 fatty acids to restore a normal state, and significantly up-regulated the expression of macrophage- and T-cell-related genes. Collectively, these results suggest that maoto regulates the host's inflammatory response by altering the lipid mediator profile and thereby ameliorating the symptoms of influenza.

A case of transient global amnesia with hippocampal infarction due to infective endocarditis.

Transient global amnesia (TGA) is an uncommon disease characterized by sudden onset anterograde amnesia that typically improves within 24 hours. A 35-year-old woman presented with complete disruption of memory that had started on the previous day. She had fever and heart murmur and was diagnosed as having infective endocarditis with Staphylococcus lugdunensis, a coagulase-negative staphylococcus. Septic embolizations were found in the spleen and kidney on CT scan. The patient underwent aortic valve replacement. MRI susceptibility-weighted imaging showed a dotted low intensity area in the right hippocampus. Recently, etiology of TGA is reported to be related to hippocampal disorder. We report a rare case of TGA with hippocampal infarction due to septic embolism from infective endocarditis.

Deconstructing the traditional Japanese medicine "Kampo": compounds, metabolites and pharmacological profile of maoto, a remedy for flu-like symptoms.

Pharmacological activities of the traditional Japanese herbal medicine (Kampo) are putatively mediated by complex interactions between multiple herbal compounds and host factors, which are difficult to characterize via the reductive approach of purifying major bioactive compounds and elucidating their mechanisms by conventional pharmacology. Here, we performed comprehensive compound, pharmacological and metabolomic analyses of maoto, a pharmaceutical-grade Kampo prescribed for flu-like symptoms, in normal and polyI:C-injected rats, the latter suffering from acute inflammation via Toll-like receptor 3 activation. In total, 352 chemical composition-determined compounds (CCDs) were detected in maoto extract by mass spectrometric analysis. After maoto treatment, 113 CCDs were newly detected in rat plasma. Of these CCDs, 19 were present in maoto extract, while 94 were presumed to be metabolites generated from maoto compounds or endogenous substances such as phospholipids. At the phenotypic level, maoto ameliorated the polyI:C-induced decrease in locomotor activity and body weight; however, body weight was not affected by individual maoto components in isolation. In accordance with symptom relief, maoto suppressed TNF-α and IL-1ß, increased IL-10, and altered endogenous metabolites related to sympathetic activation and energy expenditure. Furthermore, maoto decreased inflammatory prostaglandins and leukotrienes, and increased anti-inflammatory eicosapentaenoic acid and hydroxyl-eicosapentaenoic acids, suggesting that it has differential effects on eicosanoid metabolic pathways involving cyclooxygenases, lipoxygenases and cytochrome P450s. Collectively, these data indicate that extensive profiling of compounds, metabolites and pharmacological phenotypes is essential for elucidating the mechanisms of herbal medicines, whose vast array of constituents induce a wide range of changes in xenobiotic and endogenous metabolism.