Effect of degalactosylated bovine glycoprotein formulations MAF and M сapsules on lymphopenia and clinical outcomes in hospitalized COVID-19 patients: a randomized clinical trial.

BACKGROUND: Targeting mucosal immunity of the gut, which is known to provide antigen processing, while avoiding excessive or unnecessary inflammation, was tested as a way to modulate COVID-19 severity. METHODS: Randomized open-label trial in 204 adults hospitalized with non-critical COVID-19 who received for 14 days in addition to standard of care (SOC) degalactosylated bovine glycoproteins formulations of either MAF capsules (MAF group) or M capsules (M group) or SOC only (control group). RESULTS: Median recovery time when patients did not require supplemental oxygen was 6 days in both study groups compared to 9 days in the control (MAF vs. control; P = 0.020 and M vs. control; P = 0.004). A greater reduction in mortality was seen in the MAF group compared to the control by day 14 (8.3% vs. 1.6%; P = 0.121) and by day 29 (15.3% vs. 3.2%; P = 0.020), and similarly in the M group by day 14 (8.3% vs. 2.9%; P = 0.276) and by day 29 (15.3% vs. 2.9%; P = 0.017). The proportion of those who had baseline absolute lymphocyte count (ALC) lower than 0.8 × 109/L was 13/63 (20.6%), 17/69 (24.6%), and 18/72 (25.0%) of patients in MAF, M, and control group respectively. Day 29 mortality among these lymphopenic patients was three times higher than for the intent-to-treat population (21% vs. 7%) and consisted in above subgroups: 2/13 (15%), 2/17 (12%), and 6/18 (33%) of patients. The decreased mortality in both study subgroups correlated with greater ALC restoration above 0.8 × 109/L level seen on day 14 in 91% (11/12) and 87.5% (14/16) of survivors in MAF and M subgroups respectively compared to 53.3% (8/15) of survivors in control subgroup. Incidences of any ALC decrease below the baseline level on day 14 occurred in 25.4% of patients in the MAF group and 29.0% of patients in the M group compared to 45.8% in control and ALC depletion by ≥ 50% from the baseline level consisted of 7.9%, 5.8%, and 15.3% of cases in these groups respectively. CONCLUSION: This study showed that both study agents prevented ALC depletion and accelerated its restoration, which is believed to be one of the mechanisms of improved crucial clinical outcomes in hospitalized COVID-19 patients. TRIAL REGISTRATION: The trial was registered after the trial start in ClinicalTrials.gov NCT04762628, registered 21/02/2021, https://www. CLINICALTRIALS: gov/ct2/show/NCT04762628 .

Post hoc analysis of the characteristics and treatment needs of patients with dementia with Lewy bodies (DLB) and their caregivers and their physicians' awareness of those treatment needs according to the duration after diagnosis of DLB.

OBJECTIVES: To investigate the differences in patient/caregiver characteristics, their treatment needs, and the attending physician's understanding of those treatment needs according to the duration after diagnosis of dementia with Lewy bodies (DLB). METHODS: This was a post hoc analysis of a multicenter, cross-sectional, questionnaire survey study. A total of 263 patient-caregiver pairs were reclassified into two groups according to the median duration after diagnosis of DLB as follows: short (<24 months; S-group) and long (≥24 months; L-group) post-DLB diagnosis duration. Treatment need was defined as the symptom domain that caused the patient or caregiver the most distress. Concordance rates between patient-physician and caregiver-physician were calculated for physicians' understanding of treatment needs. RESULTS: In this analysis, 126 pairs (32 physicians) and 137 pairs (34 physicians) were classified as the S- and L-groups, respectively. Patient and caregiver characteristics were broadly similar between groups (mean age for patients 78.7 ± 6.6 vs. 79.8 ± 6.7, for caregivers 64.7 ± 12.9 vs. 64.9 ± 12.8; number of male/female for patients 61/65 vs. 67/70, for caregivers 34/92 vs. 38/99), but the prevalence of parkinsonism (82.5% vs. 66.7%) and autonomic dysfunction (49.6% vs. 33.3%), severity of parkinsonism (MDS-UPDRS Part III total scores, 29.2 ± 22.6 vs. 18.0 ± 16.4; Part II total score, 14.6 ± 12.0 vs. 7.6 ± 7.9), and caregiver burden (J-ZBI_8 score, 9.1 ± 6.7 vs. 7.5 ± 5.8) were higher in the L-group than the S-group. Regarding treatment needs, the invalid answer rates for patients were 34.9% and 46.8%, and those for caregivers were 28.6% and 34.9% in the S- and L groups, respectively. Patients' treatment needs did not significantly differ (p = 0.056), but S-group patients were more likely to select cognitive impairment (p = 0.045) as their treatment need, whereas L-group patients were more likely to select parkinsonism (p = 0.003). Caregivers' treatment needs significantly differed (p = 0.032) between groups. S-group caregivers were more likely to select cognitive impairment (p = 0.001), whereas L-group caregivers were more likely to select other symptom domains such as parkinsonism (S-group vs. L-group: 10.3% vs. 16.7%), psychiatric symptoms (20.6% vs. 24.6%), sleep-related disorder (4.0% vs. 7.1%), and autonomic dysfunction (4.8% vs. 9.5%). Concordance rates between patient-physician and caregiver-physician were low in both groups. CONCLUSIONS: There were some differences in characteristics according to the duration after diagnosis of DLB. Cognitive dysfunction may be a particular concern for patients and caregivers soon after diagnosis of DLB. Treatment needs of patients and caregivers for parkinsonism, psychiatric symptoms, sleep-related disorder, or autonomic dysfunction were different according to the duration after diagnosis of DLB. Physicians' perception of patients'/caregivers' treatment needs was poor regardless of the duration after diagnosis of DLB. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry (UMIN000041844).

A body shape index is useful for BMI-independently identifying Japanese patients with obesity at high risk of cardiovascular disease.

BACKGROUND AND AIM: Obesity with multiple metabolic syndrome (MetS) components and/or with skeletal muscle loss is at high risk of cardiovascular disease (CVD). This study aimed to clarify the utility of anthropometric indices for identifying patients with overweight/obese at high risk of CVD based on having multiple MetS components and skeletal muscle loss. METHODS & RESULTS: This cross-sectional study included 188 overweight/obese (BMI ≥25 kg/m2, Japanese patients; 73 men and 115 women, mean age 55.7 years). First, we performed correlation analysis among seven anthropometric indices, body mass index (BMI), percentage body fat, waist circumference (WC), waist-to-hip ratio (WHpR), waist-to-height ratio (WHtR), a body shape index (ABSI), and body roundness index (BRI). Unlike the others, only ABSI was not correlated with BMI. Then, we conducted receiver operating characteristic analysis to assess the predictive abilities of anthropometric indices for having multiple MetS components. WC, WHpR, WHtR, BRI, and ABSI had significant predictive abilities for having multiple MetS components. Furthermore, multiple regression analysis showed that only ABSI had significantly negative associations with all sarcopenia-evaluated indices (skeletal muscle mass index [SMI], handgrip strength [HGS], and muscle quality [MQ]), irrespective of sex and age. Finally, an analysis of covariance showed that the high ABSI group had significantly lower SMI and HGS than the low ABSI group, irrespective of sex and age. CONCLUSION: ABSI was deemed useful for BMI-independently identifying Japanese patients with overweight/obese at high risk of CVD based on having multiple MetS components and skeletal muscle loss. Clinical trials (the unique trial number and the name of the registry) ID: UMIN000042726.

Eating problems in people with dementia with Lewy bodies: Associations with various symptoms and the physician's understanding.

OBJECTIVES: Eating problems frequently occur in people with dementia with Lewy bodies (DLB), but few studies have investigated the clinical background of this phenomenon. This study examined the relationship between eating problems and various symptoms of DLB and the relation between the treatment needs for DLB people with eating problems and the understanding of their eating problems by caregivers and physicians. DESIGN, MEASUREMENTS, AND PARTICIPANTS: This was a subanalysis of a cross-sectional, questionnaire-based survey study. Two hundred sixty-one subjects with DLB were divided into subjects with or without eating problems. Logistic or linear regression analysis was used to investigate the factors influencing eating problems. The treatment needs of DLB people for their eating problems and the understanding of these needs by caregivers and physicians were calculated as participant-caregiver and participant-physician kappa coefficient. RESULTS: Of the 261 participants, 27% suffered from eating problems. The presence of eating problems in participants with DLB was related to depression (p = 0.01, OR : 2.19, 95% CI: 1.23-3.91) and apathy (p = 0.01, OR 2.15, 95% CI: 1.20-3.87), while the worsening of eating problems was related to dysphagia (ß = 0.24, p = 0.03), apathy (ß = 0.23, p = 0.05), and nighttime behavior (ß = 0.24, p = 0.04). The participant-physician kappa coefficient for physician understanding of constipation, weight loss, dysphagia, weight gain, and increase in appetite was significantly lower than the corresponding participant-caregiver kappa coefficient (p-value of five symptoms < 0.01). CONCLUSIONS: Physicians need to pay more attention to eating problems and their neuropsychiatric background in the long-term support and management of DLB subjects.

Impact of coronavirus disease 2019 on medical practice in endocrine and metabolic diseases in Japan: a nationwide surveillance study conducted by the Japan Endocrine Society.

We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.

Differences in metabolic characteristics between Metabolically Healthy Obesity (MHO) and Metabolically Unhealthy Obesity (MUO) in weight reduction therapy.

Metabolically Healthy Obesity (MHO) is generally recognized as the absence of any metabolic disorders and cardiovascular diseases, including type 2 diabetes, dyslipidemia, and hypertension, in obese individuals; however, it is not clearly defined. Therefore, the present study investigated differences in metabolic characteristics between individuals with MHO and Metabolically Unhealthy Obesity (MUO) during weight reduction therapy. The key factors defining MHO and the importance of weight reduction therapy for MHO were also examined. Cohort data from the Japan Obesity and Metabolic Syndrome (JOMS) study were analyzed. Subjects were divided into the MHO (n = 25) and MUO (n = 120) groups. Prior to weight reduction therapy, serum adiponectin levels were significantly higher in the MHO group than in the MUO group. Serum adiponectin levels also negatively correlated with the area of subcutaneous adipose tissue (SAT) and Homeostasis model assessment (HOMA)-R in the MHO group, but not in the MUO group. Collectively, the present results suggest the importance of adiponectin for maintaining metabolic homeostasis in the MHO group. On the other hand, no significant differences were observed in inflammatory markers between the MHO and MUO groups, suggesting the presence of chronic inflammation in both groups. Furthermore, a positive correlation was noted between changes in serum cystatin C levels and waist circumference in the MHO group, which indicated that despite the absence of metabolic disorders, the MHO group exhibited anti-inflammatory responses during weight reduction therapy. These results underscore the significance of weight reduction even for individuals with MHO.

Questionnaire survey of satisfaction with medication for five symptom domains of dementia with Lewy bodies among patients, their caregivers, and their attending physicians.

BACKGROUND: The real-world status of satisfaction with medication for dementia with Lewy bodies (DLB) has not been elucidated. We assessed the satisfaction of patients with DLB, their caregivers, and their attending physicians (trios) with medication according to the clinical symptom domains of DLB. METHODS: This was a subanalysis of a cross-sectional, questionnaire-based, survey study of trios. The subanalysis set comprised analysis populations for cognitive impairment, parkinsonism, psychiatric symptoms, sleep-related disorders, and autonomic dysfunction (orthostatic hypotension, constipation, and dysuria). These analysis populations included trios of patients who had any symptom domain and took medication for each symptom domain, and for which all trio data on satisfaction with medication for the symptom domain were available. The degrees of satisfaction with medication were classified as 'satisfied', 'neutral', or 'dissatisfied'. RESULTS: The analysis set for this study included 110 trios for cognitive impairment, 62 for parkinsonism, 47 for psychiatric symptoms, 29 for sleep-related disorders, none for orthostatic hypotension, 11 for constipation, and seven for dysuria. There were no statistically significant differences in the degree of satisfaction with medication for symptom domains other than parkinsonism and dysuria between patients-caregivers, patients-physicians, and caregivers-physicians. Regarding satisfaction with medication for parkinsonism, significantly more physicians than patients answered 'satisfied' (75.8% vs. 51.6%), and significantly more patients than physicians answered 'neutral' (35.5% vs. 14.5%) (P = 0.013). Regarding satisfaction with medication for dysuria, significantly more caregivers than physicians answered 'satisfied' (100% vs. 28.6%, P = 0.038). CONCLUSIONS: Satisfaction with medication for symptom domains other than parkinsonism and dysuria was similar among trios. Our results suggest that physicians should pay more attention to patients' satisfaction with medication for parkinsonism, and to caregivers' satisfaction with medication for dysuria to help prevent undermedication.

Visceral-to-subcutaneous fat ratio is a possible prognostic factor for type 1 endometrial cancer.

BACKGROUND: Associations have been observed between obesity defined by the body mass index (BMI) and the incidence of endometrial cancer. However, the impact of obesity on the prognosis of endometrial cancer is not yet clear. Recently, visceral fat has been considered to have a greater impact on malignant disease in obese patients than subcutaneous fat. In this study, we investigated the association between prognostic factors of type 1 and type 2 endometrial cancer and obesity parameters. METHODS: The impacts of clinical factors on the progression-free survival (PFS) and overall survival (OS) were analyzed retrospectively in 145 primary endometrial cancer patients. The factors included age, BMI, pathological findings, Federation of Gynecology and Obstetrics (FIGO) stage, status of lymph node metastasis, and the amounts of visceral and subcutaneous fat obtained from computed tomography (CT) data. RESULTS: Only the visceral-to-subcutaneous fat ratio (V/S ratio) (cutoff value 0.5) corresponded to a significant difference in OS and PFS in type 1 endometrial cancer (p = 0.0080, p = 0.0053) according to the results of log-rank tests of Kaplan-Meier curves. The COX regression univariate analysis revealed that only the V/S ratio was a significant prognostic factor for PFS, but not OS (p = 0.033 and p = 0.270, respectively). CONCLUSION: A V/S ratio > 0.5 is a possible factor for poor prognosis in type 1 endometrial cancer. Further research is needed to investigate the preventive and therapeutic effects of reducing visceral fat on the prognosis of this type of cancer.

Pleiotropic neuroprotective effects of taxifolin in cerebral amyloid angiopathy.

Cerebral amyloid angiopathy (CAA) results from amyloid-ß deposition in the cerebrovasculature. It is frequently accompanied by Alzheimer's disease and causes dementia. We recently demonstrated that in a mouse model of CAA, taxifolin improved cerebral blood flow, promoted amyloid-ß removal from the brain, and prevented cognitive dysfunction when administered orally. Here we showed that taxifolin inhibited the intracerebral production of amyloid-ß through suppressing the ApoE-ERK1/2-amyloid-ß precursor protein axis, despite the low permeability of the blood-brain barrier to taxifolin. Higher expression levels of triggering receptor expressed on myeloid cell 2 (TREM2) were associated with the exacerbation of inflammation in the brain. Taxifolin suppressed inflammation, alleviating the accumulation of TREM2-expressing cells in the brain. It also mitigated glutamate levels and oxidative tissue damage and reduced brain levels of active caspases, indicative of apoptotic cell death. Thus, the oral administration of taxifolin had intracerebral pleiotropic neuroprotective effects on CAA through suppressing amyloid-ß production and beneficially modulating proinflammatory microglial phenotypes.

Gingival bleeding and pocket depth among smokers and the related changes after short-term smoking cessation.

BACKGROUND: Smoking is associated with the deteriorating health of the gingiva and periodontium. The long-term beneficial effects of smoking cessation on oral health are well known. However, the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth are unknown. The purpose of the present study was to determine the effects of short-term smoking cessation on gingival bleeding and periodontal pocket depth. METHODS: Dentate smokers with a mean age of 56.9 ± 14.4 years at an outpatient smoking cessation clinic participated in this study. A professional dentist checked the periodontal pocket depth and gingival bleeding. Patients visited the smoking cessation clinic on their first visit and 2, 4, 8, and 12 weeks (three months). The gingival assessment was re-performed in those who succeeded in smoking cessation 3 months after the baseline. RESULTS: The baseline data of 83 patients showed that an increase in pocket depth was associated with increasing age and the amount of smoking. A significant increase in gingival bleeding (p = .031) and increase in pocket depth (p = .046) were observed 3 months after the baseline in patients who successfully quit smoking (n = 14). CONCLUSION: Short-term smoking cessation increased periodontal pocket depth and gingival bleeding. These findings may reflect healing processes that occur in the healthy gingiva. IMPLICATIONS: Study findings will be useful to advise patients during smoking cessation programs. Dentists can inform patients that an initial increase in gingival bleeding and pocket depth could be associated with smoking cessation. Such advice will prevent patients from any apprehension that may cause them to recommence smoking.

Serum Soluble Triggering Receptor Expressed on Myeloid Cells 2 as a Biomarker for Incident Dementia: The Hisayama Study.

OBJECTIVE: To investigate the association between serum soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a soluble type of an innate immune receptor expressed on the microglia, and the risk of dementia. METHODS: A total of 1,349 Japanese community residents aged 60 and older without dementia were followed prospectively for 10 years (2002-2012). Serum sTREM2 levels were quantified by using an enzyme-linked immunosorbent assay and divided into quartiles. Cox proportional hazards model was used to estimate the hazard ratios (HRs) of serum sTREM2 levels on the risk of dementia. RESULTS: During the follow-up, 300 subjects developed all-cause dementia; 193 had Alzheimer's disease (AD), and 85 had vascular dementia (VaD). The age- and sex-adjusted incidences of all-cause dementia, AD, and VaD elevated significantly with higher serum sTREM2 levels (all p for trend < 0.012). These associations were not altered after adjustment for confounding factors, including high-sensitive C-reactive protein. Subjects with the highest quartile of serum sTREM2 levels had significantly higher multivariable-adjusted risks of developing all-cause dementia, AD, and VaD than those with the lowest quartile (HR = 2.03, 95% confidence interval [CI] = 1.39-2.97, p < 0.001 for all-cause dementia; HR = 1.62, 95% CI = 1.02-2.55, p = 0.04 for AD; HR = 2.85, 95% CI = 1.35-6.02, p = 0.006 for VaD). No significant heterogeneity in the association of serum sTREM2 levels with the development of dementia was observed among the other risk factor subgroups (all p for heterogeneity > 0.11). INTERPRETATION: The present findings suggest a significant association between increased serum sTREM2 levels and the risk of developing all-cause dementia, AD, and VaD in the general elderly Japanese population. ANN NEUROL 2019;85:47-58.

α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

Among dietary fatty acids with immunologic effects, ω-3 polyunsaturated fatty acids, such as α-linolenic acid (ALA), have been considered as factors that contribute to the differentiation of M2-type macrophages (M2 macrophages). In this study, we examined the effect of ALA and its gut lactic acid bacteria metabolites 13-hydroxy-9(Z),15(Z)-octadecadienoic acid (13-OH) and 13-oxo-9(Z),15(Z)-octadecadienoic acid (13-oxo) on the differentiation of M2 macrophages from bone marrow-derived cells (BMDCs) and investigated the underlying mechanisms. BMDCs were stimulated with ALA, 13-OH, or 13-oxo in the presence of IL-4 or IL-13 for 24 h, and significant increases in M2 macrophage markers CD206 and Arginase-1 (Arg1) were observed. In addition, M2 macrophage phenotypes were less prevalent following cotreatment with GPCR40 antagonists or inhibitors of PLC-ß and MEK under these conditions, suggesting that GPCR40 signaling is involved in the regulation of M2 macrophage differentiation. In further experiments, remarkable M2 macrophage accumulation was observed in the lamina propria of the small intestine of C57BL/6 mice after intragastric treatments with ALA, 13-OH, or 13-oxo at 1 g/kg of body weight per day for 3 d. These findings suggest a novel mechanism of M2 macrophage differentiation involving fatty acids from gut lactic acid bacteria and GPCR40 signaling.-Ohue-Kitano, R., Yasuoka, Y., Goto, T., Kitamura, N., Park, S.-B., Kishino, S., Kimura, I., Kasubuchi, M., Takahashi, H., Li, Y., Yeh, Y.-S., Jheng, H.-F., Iwase, M., Tanaka, M., Masuda, S., Inoue, T., Yamakage, H., Kusakabe, T., Tani, F., Shimatsu, A., Takahashi, N., Ogawa, J., Satoh-Asahara, N., Kawada, T. α-Linolenic acid-derived metabolites from gut lactic acid bacteria induce differentiation of anti-inflammatory M2 macrophages through G protein-coupled receptor 40.

A study on indices of apixaban anticoagulation: A single-center prospective study.

BACKGROUND: Depending on the characteristics of patients, the blood concentration of apixaban can unexpectedly increase, possibly leading to bleeding events. Anti-FXa activity reflects the apixaban blood concentration; however, measurement of this activity is both time-consuming and expensive. The current study aimed to evaluate the usefulness of routinely measured coagulation indices as future indicators of the efficacy and safety of apixaban. METHODS: Eighteen nonvalvular atrial fibrillation patients administered apixaban (average, 52.5 days) were prospectively enrolled in our hospital. The prothrombin time (PT) and the activated partial thromboplastin time (APTT) were measured by using the Coagpia® Reagent kits. RESULTS: The PT and the APTT increased significantly after the administration of apixaban (PT: p < 0.001, APTT: p < 0.001). While the apixaban plasma concentration by evaluating anti-FXa activity was not significantly correlated with the APTT after administration of apixaban, the concentration closely correlated with the PT (ß = 0.765, p < 0.001) and the percentage change in the PT from before and after the administration of apixaban (ß = 0.650, p = 0.005). CONCLUSION: The usefulness of routinely monitoring PT in patients administered apixaban during the ordinary clinical medicine should be investigated further by large clinical trials.

Effects of Products Containing Bacillus subtilis var. natto on Healthy Subjects with Neck and Shoulder Stiffness, a Double-Blind, Placebo-Controlled, Randomized Crossover Study.

Neck and shoulder stiffness is a typical subjective symptom in developed countries. This stiffness is caused by factors such as muscle tension and poor blood flow, leading to reduce work efficiency and diminish QOL. NKCP®, a natto-derived dietary food supplement whose main component is bacillopeptidase F, has antithrombotic, fibrinolytic, and blood viscosity-lowering effects. Here, we investigated the effect of NKCP® on neck and shoulder stiffness in a double-blind placebo-controlled randomized crossover study. Thirty subjects with neck and shoulder stiffness were randomly divided into 2 groups and ingested 250 mg of NKCP® or placebo daily for 4 weeks. Headache score significantly improved in the NKCP® group compared to the placebo group. Moreover, NKCP® significantly improved the score of visual analogue scale for neck and shoulder stiffness and pain, reduced muscle stiffness of the neck, and increased the skin surface temperature of neck and shoulders, compared to before ingestion. No adverse effects were observed during this study. These results suggest that NKCP® may alleviate headaches and chronic neck and shoulder stiffness and pain.

Smoking cessation reduces the lectin-like low-density lipoprotein receptor index, an independent cardiovascular risk marker of vascular inflammation.

Vessel wall inflammation promotes the destabilization of atherosclerotic plaques. The lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (LOX-1) expressed by vascular cells and monocytes. LOX index is calculated by multiplying LOX-1 ligand containing apolipoprotein B level with the soluble LOX-1. A high LOX index reflects an increased risk for stroke and myocardial infarction. However, the change in LOX index after smoking cessation and the relationship between smoking-related variables and LOX index are unknown. Relation of the clinical parameters to the LOX index was examined on 180 subjects (135 males and 45 females) at the first visit to our outpatient clinic for smoking cessation. The impact of smoking cessation on the LOX index was also determined in the 94 subjects (62 males and 32 females) who successfully stopped smoking. Sex-adjusted regression analysis and multivariate analysis identified three independent determinants of the LOX index, namely, low-density lipoprotein-cholesterol (LDL-C; ß = 0.311, p < 0.001), high-sensitivity C-reactive protein (ß = 0.358, p < 0.001), and expired carbon monoxide concentration reflecting smoking heaviness (ß = 0.264, p = 0.003). Body mass index (BMI) significantly increased 3 months after the onset of smoking cessation (p < 0.001). However, the LOX index significantly decreased (p < 0.001), regardless of the rate of increase in BMI post-cessation. The LOX index is closely associated with smoking heaviness as well as dyslipidemia and an inflammation marker. Smoking cessation may induce a decrease in this cardiovascular risk marker, independently of weight gain.

Omega-3 polyunsaturated fatty acids suppress the inflammatory responses of lipopolysaccharide-stimulated mouse microglia by activating SIRT1 pathways.

Obesity and diabetes are known risk factors for dementia, and it is speculated that chronic neuroinflammation contributes to this increased risk. Microglia are brain-resident immune cells modulating the neuroinflammatory state. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major ω-3 polyunsaturated fatty acids (PUFAs) of fish oil, exhibit various effects, which include shifting microglia to the anti-inflammatory phenotype. To identify the molecular mechanisms involved, we examined the impact of EPA, DHA, and EPA+DHA on the lipopolysaccharide (LPS)-induced cytokine profiles and the associated signaling pathways in the mouse microglial line MG6. Both EPA and DHA suppressed the production of the pro-inflammatory cytokines TNF-α and IL-6 by LPS-stimulated MG6 cells, and this was also observed in LPS-stimulated BV-2 cells, the other microglial line. Moreover, the EPA+DHA mixture activated SIRT1 signaling by enhancing mRNA level of nicotinamide phosphoribosyltransferase (NAMPT), cellular NAD+ level, SIRT1 protein deacetylase activity, and SIRT1 mRNA levels in LPS-stimulated MG6. EPA+DHA also inhibited phosphorylation of the stress-associated transcription factor NF-κB subunit p65 at Ser536, which is known to enhance NF-κB nuclear translocation and transcriptional activity, including cytokine gene activation. Further, EPA+DHA increased the LC3-II/LC3-I ratio, an indicator of autophagy. Suppression of TNF-α and IL-6 production, inhibition of p65 phosphorylation, and autophagy induction were abrogated by a SIRT1 inhibitor. On the other hand, NAMPT inhibition reversed TNF-α suppression but not IL-6 suppression. Accordingly, these ω-3 PUFAs may suppress neuroinflammation through SIRT1-mediated inhibition of the microglial NF-κB stress response and ensue pro-inflammatory cytokine release, which is implicated in NAMPT-related and -unrelated pathways.

Prediction of functional profiles of gut microbiota from 16S rRNA metagenomic data provides a more robust evaluation of gut dysbiosis occurring in Japanese type 2 diabetic patients.

We assessed whether gut microbial functional profiles predicted from 16S rRNA metagenomics differed in Japanese type 2 diabetic patients. A total of 22 Japanese subjects were recruited from our outpatient clinic in an observational study. Fecal samples were obtained from 12 control and 10 type 2 diabetic subjects. 16S rRNA metagenomic data were generated and functional profiles predicted using "Phylogenetic Investigation of Communities by Reconstruction of Unobserved States" software. We measured the parameters of glucose metabolism, gut bacterial taxonomy and functional profile, and examined the associations in a cross-sectional manner. Eleven of 288 "Kyoto Encyclopedia of Genes and Genomes" pathways were significantly enriched in diabetic patients compared with control subjects (p<0.05, q<0.1). The relative abundance of almost all pathways, including the Insulin signaling pathway and Glycolysis/Gluconeogenesis, showed strong, positive correlations with hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) levels. Bacterial taxonomic analysis showed that genus Blautia significantly differed between groups and had negative correlations with HbA1c and FPG levels. Our findings suggest a novel pathophysiological relationship between gut microbial communities and diabetes, further highlighting the significance and utility of combining prediction of functional profiles with ordinal bacterial taxonomic analysis (UMIN Clinical Trails Registry number: UMIN000026592).

Serum free thyroxine levels are associated with the efficacy of weight reduction therapy in obese female patients.

Thyroid function is strongly associated with obesity. The aim of this study is to investigate whether serum free thyroxine (FT4) and/or thyrotropin (TSH) levels are associated with the efficacy of weight reduction therapy in obese patients. We enrolled a total of 283 obese patients and cross-sectionally investigated the association of serum FT4 and/or TSH levels with metabolic features. Furthermore, in 97 obese patients who received 6-month weight reduction therapy, we assessed the relationship of serum FT4 and/or TSH levels to the efficacy of weight reduction therapy. Neither baseline serum FT4 nor TSH levels showed any correlations with body weight (BW) and body mass index (BMI) in these obese patients. However, in 57 obese female patients who underwent weight reduction therapy for six months, serum FT4 levels prior to the therapy was negatively correlated with the degrees of reduction of BW (r = -0.354, p = 0.007) and BMI (r = -0.373, p = 0.004). The correlation between baseline serum FT4 levels with the efficacy of weight reduction therapy was not observed in obese male or postmenopausal female patients. This study demonstrates that baseline serum FT4 levels are associated with weight reduction in obese female premenopausal patients. Therefore, baseline FT4 levels can be used as a clinical, noninvasive, hormonal predictor of weight reduction efficacy in obese patients.

Association between metabolic syndrome and multiple lesions of intracranial atherothrombotic stroke: a hospital-based study.

BACKGROUND: With the increasing trend of metabolic syndrome (MetS) and atherothrombotic stroke (which can manifest as stroke lesion multiplicity), studies on the association between MetS and the clinical aspects of atherothrombotic stroke are of great interest. The present study aimed to investigate the association between MetS and multiple atherothrombotic strokes in patients with intracranial atherothrombotic stroke. METHODS: A retrospective study based on medical charts was conducted among patients (n = 202: 137 men/65 women) who were symptomatically admitted to the hospital with the first-ever atherothrombotic stroke. For the occurrence of multiple lesions of stroke, odds ratio [OR: 95% confidence interval (CI)] of MetS or its respective components was calculated using logistic regression models. RESULTS: Fifty-one percent of the men and 38% of women with stroke presented multiple regions. MetS was a significant factor that was associated with an increased risk of multiple regions in women [OR 4.3 (95% CI 1.4-13.5)], but not in men. According to the components of MetS, dyslipidemia was a significant factor that was positively associated with multiple regions in both men [OR 2.0 (95% CI 1.1-3.7)] and women [OR 3.2 (95% CI 1.1-9.1)]. CONCLUSION: MetS may be pathophysiologically associated with intracranial atherothrombotic stroke multiplicity in women in particular. Future studies are warranted to confirm the findings.

Effects of Statins on Left Ventricular Diastolic Function in Patients with Dyslipidemia and Diastolic Dysfunction (Stat-LVDF Study).

Statins, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors, are potential drugs for chronic heart failure treatment in clinical studies. However, there may be differences in the effects on heart failure between lipophilic and hydrophilic statins. In this study, we investigated whether hydrophilic rosuvastatin (RSV) and lipophilic pitavastatin (PTV) exert different effects on the left ventricular diastolic function. Subjects were hypercholesterolemia patients with left ventricular diastolic dysfunction. This was an open-label, randomized, parallel, comparative, prospective study. The subjects received treatment with RSV or PTV for 24 weeks, and their low density lipoprotein (LDL)-cholesterol levels were controlled by these statins according to the guideline. The primary endpoint was defined as the change in left ventricle (LV) diastolic function (E/E') estimated by echocardiography, and the secondary endpoint was the plasma B-type natriuretic peptide (BNP) level. No serious adverse effects were observed during the entire study period in any patient, nor were there any significant differences in changes in the body mass index, blood pressure, or heart rate. Statin treatment did not significantly alter the primary endpoint, E/E'. The change ratio of BNP was not significantly different between PTV and RSV groups. However, BNP was significantly increased in the RSV (p=0.030) but not the PTV (p>0.999) group. This study revealed that although neither RSV nor PTV improved LV diastolic dysfunction, BNP, a biomarker of LV wall stress, was increased in the RSV but not the PTV group. Observation for a longer period is necessary to clarify the different effects of these statins on LV diastolic dysfunction. (UMIN-ID: UMIN000003571).