Syntheses, Structures, and Electrochemical Properties of Metallacyclic Oxidovanadium(V) Complexes with Asymmetric Multidentate Linking Ligands.

Trinuclear metallacyclic oxidovanadium(V) complexes, [{VO(L3+2R)}3] (1-3) with asymmetric multidentate linking ligands (H3L3+2R: R = H, Me, Br), were synthesized. The molecular structure of 1 is characterized as a tripod structure, with each V(V) ion coordinated by ONO-atoms from a tridentate Schiff base site and ON-atoms from a bidentate benzoxazole site of two respective H3L3+2H ligands. The intramolecular V⋯V distances range from 8.0683 to 8.1791 Å. Complex 4 is a mononuclear dioxidovanadium(V) complex, (Et3NH)[VO2(HL3+2H)]. Cyclic voltammograms of 1-3 in DMF revealed redox couples attributed to three single-electron transfer processes.

Analysis of Predictive Factors for Diarrhea after the Administration of Naldemedine.

Naldemedine (NAL), a peripherally acting µ-opioid receptor antagonist, is effective for opioid-induced constipation (OIC). However, diarrhea is the most common adverse event. We investigated the incidence of NAL-induced diarrhea in patients who started NAL at Nagasaki University Hospital between June 2017 and March 2019. Predictors of NAL-induced diarrhea were analyzed using a multivariate logistic regression model. Two hundred and forty-two patients were included in the present study, and NAL-induced diarrhea was observed in 17.8% (43 patients). The results of multiple logistic regression analyses identified the administration of opioid analgesics for 8 d or longer before the initiation of NAL (odds ratio (OR): 2.20, 95% confidence interval (95% CI): 1.04-4.64, p = 0.039), the combination of a laxative (OR: 2.22, 95%CI: 1.03-4.81, p = 0.042), and the combination of CYP3A4 inhibitors (strong/moderate) (OR: 2.80, 95%CI: 1.02-7.67, p = 0.045) as risk factors. Therefore, the development of diarrhea needs to be considered in patients with these risk factors. Furthermore, diarrhea may be controlled by the initiation of NAL within 7 d of opioid analgesics and, where possible, the discontinuation of or change in the combination of moderate or strong CYP3A4 inhibitors.

Early-phase Innate Immune Suppression in Murine Severe Sepsis Is Restored with Systemic Interferon-ß.

BACKGROUND: Sepsis is a leading cause of death in the intensive care unit. Immune modulatory therapy targeting sepsis-associated proinflammatory responses has not shown survival benefit. Here, the authors evaluated innate immunity at the early stage of murine mild or severe peritoneal sepsis induced by cecal ligation and puncture, and the effect of systemic interferon-ß, a potent inflammatory mediator, on severe sepsis as well as its mechanism of action. METHODS: Mild and severe sepsis was induced in C57BL/6 mice by cecal ligation and puncture with 22- and 18-gauge needles for puncture, respectively. Interferon-ß (700 U/g) was subcutaneously administered either before or 12 h after cecal ligation and puncture for the severe sepsis group. RESULTS: Severe sepsis resulted in significantly lower 6-day survival rates than mild sepsis (n = 48, 25% vs. n = 11, 81.8%, P = 0.002), significantly less phagocytic capacity of peritoneal exudate cells, and lower CXC chemokine receptor-2 expression on circulating neutrophils at 24 h after cecal ligation and puncture. Interferon-ß administration 12 h after cecal ligation and puncture associated with significantly improved survival (n = 34, 52.9%, P = 0.017) increased the number and function of peritoneal exudate cells, peritoneal/systemic inflammatory cytokine/chemokine concentrations, and CXC chemokine receptor-2 on neutrophils, compared with the severe sepsis controls. However, those responses were not observed in the prophylactic interferon-ß group (n = 24). Interferon-ß increased lipopolysaccharide-induced interleukin-6 messenger RNA/protein expression of lipopolysaccharide-tolerant murine peritoneal macrophages, which was not observed in nontolerant cells. CONCLUSIONS: In severe sepsis, immune suppression occurs within 24 h and is associated with worse mortality. Interferon-ß given after the onset of peritonitis restores impaired innate immunity in vivo and in vitro.

Enhancing Mass spectrometry-based tumor immunopeptide identification: machine learning filter leveraging HLA binding affinity, aliphatic index and retention time deviation.

Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer. Machine learning was utilized to evaluate Mascot identifications through the prediction of MS/MS spectral consistency, and four descriptors for each candidate sequence: the max Mascot ion score, predicted HLA binding affinity, aliphatic index and retention time deviation, were selected as important features in filtering out identifications with inadequate fragmentation consistency. This suggests that incorporating rescoring filters based on peptide physicochemical characteristics could enhance the identification rate of MS-based immunopeptidomics compared to the traditional Mascot approach predominantly used for proteomics, indicating the potential for optimizing neoantigen identification pipelines as well as clinical applications.

[Analysis of a case of oxaliplatin - induced persistence sensory neuropathy].

Thirty-seven patients with advanced or recurrent colorectal cancer were treated with mFOLFOX6 or mFOLFOX6 with a Bevacizumab regimen between September 2008 and March 2009. Then, we evaluated persistent neuropathy using the National Cancer Institute Common Terminology Criteria for Adverse Events (ver. 3). As a result of the research, grade 1-3 sensory neuropathy was observed in 5.6% after 3 cycles, 44. 4% after 5 cycles, 83. 3% after 8 cycles, and 83. 4% after 10 cycles. The average dose of L-OHP (mg/m2) until persistent sensory neuropathy appeared was grade 1: 399.7+/-157. 0 (17/ 37 patients); grade 2: 418.0+/-214. 1 (5/37 patients); and grade 3: 498.0+/-152. 8 (3/37 patients). As has been shown in international clinical trials, the severity and frequency of L-OHP-induced neurotoxicity are associated with the cumulative dose and duration of L-OHP administration. Further research is necessary to develop strategies for preventing or treating this side effect.

Diversity in genes responsible for lifestyle-related diseases in Asia-Pacific region.

In Asia-Pacific countries, both environmental modernization and hereditary traits of Mongoloid reported to cause rapid increase in lifestyle-related diseases (LRD). However, reproducibility of reported responsive-factors is low. To examine this, a decision-tree method of complexity-model was applied to select LRD-responsive-factors. Genomic DNA was collected from Asia-Pacific regions. Single nucleotide polymorphisms (SNPs) on genomic DNA were determined as hereditary-trait-factor. Three indices of LRD (BMI, body fat, and serum leptin levels) were classified according to published criteria. WEKA Machine-learning system was used as decision-tree software. Age was added as a factor with different dimension. Selected factors were validated by other statistical methods. In Thai-males, GLUT) (glucose-transporter 1)-SNP was most-responsive to body fat, followed by USF1-SNP (transcription-factor for lipid metabolism). Differences between genotypes were validated (P = .002 for GLUT1 by Levene's, P = .071 for USF1 by ANOVA). Responsive-factors of Thai-females, Palau-males and Palau-females, were consisted with SNPs and age, and varied by groups. Convincing responsive-factors were not selected from mixed-data. Decision-tree-analysis successfully selected the convincing results. Responsive-factors differed by ethnic group and gender.

Pharmacokinetic and Pharmacodynamic Analyses of Drug-Drug Interactions between Iguratimod and Warfarin.

Iguratimod (IGU), a disease-modifying antirheumatic drug launched in September 2012, has been reported to carry a risk of severe hemorrhages through a suspected interaction with warfarin (WF) in the all-case surveillance and early postmarketing-phase vigilance. To elucidate possible mechanisms of adverse interaction between IGU and WF, we analyzed the effects of IGU on the pharmacodynamics and pharmacokinetics of WF in rats. IGU was orally administered to male Wistar rats once daily for 5 d at 10 or 30 mg/kg in combination with WF at an oral dose of 0.25 mg/kg. Coadministration of IGU 30 mg/kg enhanced the anticoagulant activity of WF; prolonged blood coagulation time (prothrombin time and activated partial thromboplastin time) and decreased levels of vitamin K (VK)-dependent blood coagulation factors (II, VII, IX, and X) were observed. On the other hand, the pharmacokinetic parameters of WF including maximum plasma concentration (Cmax) and area under the plasma concentration-time curve from 0 to 24 h (AUC0-24 h) were not affected by the combination with IGU. IGU alone did not change blood coagulation time at doses up to 100 mg/kg, while VK-dependent blood coagulation factors decreased slightly at 30 and 100 mg/kg. These results suggest that the pharmacodynamic effect of IGU on VK-dependent blood coagulation factors is involved in the mechanism of drug-drug interaction of IGU with WF.

Lymphatic dysfunction after ligation surgery for varicose vein.

OBJECTIVE: Although the lymphatic complications such as lymphocele sometimes occur after surgery for varicose veins, the lymphatic function of such patients has not been evaluated. In this case report, we present a case of lymphocele after ligation surgery for varicose vein. We also detected subclinical dysfunction in lower limb using indocyanine green (ICG) lymphography. CASE REPORT: A 76 year- old female underwent ligation surgery for right lower leg varicose vein, and she noticed the squashy lesion in the medial side of the right knee. Three years later, she consulted our clinic and we performed ICG lymphography. We observed dermal backflow around the mass, which indicated lymphatic dysfunction. After injecting additional ICG around the knee, we punctured and drained the clear, yellow fluid from the mass and it was contrasted with ICG during the examination and the involvement of the lymphatic system was proven.

Comparison of electrocardiogram findings and lifestyles between urbanized people and ger-living people in Ulaanbaatar, Mongolia.

In Ulaanbaatar, lifestyles differ between urbanized people (group A) and ger (tent)-living people (group B). Group A earn high annual incomes and live in houses or apartments. Group B (who had moved to Ulaanbaatar from nomadic areas) earn low incomes and live in narrow gers. In 2002, we investigated daily food intake, health status, and electrocardiogram (ECG) in these groups. In total, 256 subjects (group A, 142; group B, 114) were enrolled. Group A ate meat, vegetables, and fruits high enough by a Western style. Group B consumed meat but ate only small amounts of vegetables and fruits. They took a lot of fat, however, the serum lipid levels of them were not so high. The fat source as energy was plant oil for cooking rather than meat. Several abnormal ECG findings including left ventricular hypertrophy (LVH) were found in 32 (22.5%) of group A and 50 (43.9%) of group B (P < 0.001). LVH was also found more in group B than in group A. LVH in group A males was accompanied by high body weight (BW), hypertension, and high LDL-cholesterol, whereas LVH in group B males seemed to be related to an unbalanced diet, high salt intake, smoking, and some low socio-economic problems. In order to promote health condition, such risk factors should securely be eliminated from the lifestyles.

Perindopril effects on ambulatory blood pressure: relation to sympathetic nervous activity in subjects with diabetic nephropathy.

BACKGROUND: Few studies have reported the effect of angiotensin-converting enzyme inhibitors on 24-h blood pressure (BP) and regulation of sympathetic nervous activity in hypertensive patients with diabetic nephropathy. Using ambulatory BP monitoring (ABPM) devices equipped with spectral analysis of heart rate variability, we assessed the effects of perindopril on 24-h BP and autonomic nervous activity in these patients. METHODS: Thirty-four hypertensive patients with non-insulin-dependent diabetic nephropathy underwent ABPM before and after treatment with perindopril (final dose: 4.9 +/- 1.8 mg/d). Simultaneously, spectral analysis was performed to calculate the high frequency components (HF) as a marker of parasympathetic nervous activity, and the low frequency components (LF)/HF ratios as an index of the sympathovagal balance. RESULTS: Perindopril significantly and equally decreased the waking and sleeping BP in the diabetic patients. During the sleeping period, the magnitude of change of mean BP induced by perindopril correlated inversely with the sleeping/waking ratio of mean BP before treatment. However, there was no correlation between these parameters during the waking period. Perindopril decreased both waking and sleeping LF/HF ratios, although no differences in HF components were observed between before and after treatment. CONCLUSIONS: In patients with diabetic nephropathy, perindopril decreased 24-h BP. Spectral analysis suggested that this finding was partially related to inhibited sympathetic nervous activity. During sleeping periods, the BP-lowering effect of perindopril was more pronounced in patients showing no nocturnal decrease in BP. Perindopril may be a potent antihypertensive agent to reduce increased nocturnal BP, a risk factor of target organ damage in these patients.

Prevalence of diego blood group Dia antigen in Mongolians: comparison with that in Japanese.

The Diego blood group is composed of Di(a) and Di(b) antigens. Prevalence of the Di(a) antigen is known to be different among races. The Di(a) antigen is generally found in Oriental people. Thus, it is called a Mongoloid factor. In Japanese, the prevalence of this antigen is 8.78%. However, the prevalence in Mongolians had not previously been examined. In September of 2002, we determined this antigen among inhabitants of Ulaanbaatar. It was found in 24 of 242 subjects (9.92%). This prevalence approximates that in Japanese. The Rh blood group phenotypes also showed patterns similar to those in Japanese. These results are not contrary to the presumption that Mongolians and Japanese may have a common racial background.

A survey of life-style diseases of inhabitants of Thailand.

To elucidate the way to prevent lifestyle-related diseases, such as diabetes mellitus and hypertension, in Asian countries, a comparative study between Mongoloids was conducted at Palau, in Oceania, the Republic of China, Thailand, Mongolia and Japan, from 1998 to October 2002. The survey comprised a social survey, nutrition survey, physical and medical examinations, biomedical analyses, urinalyses, and DNA analyses. This is an interim report for Thailand.

The use of food-frequency questionnaires for various purposes in China.

OBJECTIVE: To compare various food-frequency questionnaires (FFQs) used in nutritional studies in China for various purposes. DESIGN: In Study 1, a simplified FFQ with 17 questions on food was used in a large rural study. In Study 2, a questionnaire consisting of 84 questions on food consumption of 16 food categories was used in a study comparing dietary consumption data and various health indicators of elderly people in four geographical areas in China. In Study 3, a questionnaire with 149 items in 17 food categories is being validated by comparison with data obtained by repeated 24-hour recalls. SETTING: Study 1 was carried out in one southern site and a northern site in 1996 to 1997. Study 2 was conducted in four different geographical sites in 1998. The on-going study, Study 3, has been carried out in Jiangsu and Beijing since 1999. SUBJECTS: Study 1 included 12 234 rural Chinese adults aged 40 years. There were 546 elderly people in Study 2. Study 3 is collecting data from 300 healthy adults. RESULTS: The results of food consumption and nutrient intakes from Study 1 were comparable with those obtained from a previous household dietary survey, in which sensible correlations between diet and diseases were also found. In Study 2, the dietary data from the four geographical areas showed significant differences in food and nutrient intakes among the different areas. The validation of the new FFQ in Study 3 is still going on. CONCLUSION: The FFQ is a useful method for the collection of individual food consumption information. The above FFQ forms could be used in studies with different purposes, especially in studying the relationship between diet, nutrition and chronic diseases.

Improvement in blood lipid levels by dietary sn-1,3-diacylglycerol in young women with variants of lipid transporters 54T-FABP2 and -493g-MTP.

UNLABELLED: In a double-blind parallel-group study, serum lipids and visceral fat/total fat ratio in young women (n=49) with variants of lipid transporters, i.e., fatty acid binding protein 2 (FABP2) and microsomal triglyceride transfer protein (MTP), were analyzed by substituting dietary triacylglycerol (TAG) with sn-1,3-diacylglycerol (DAG). All subjects, including some with the hyperlipidemia-prone genotypes Ala54Thr of FABP2 and c-493g of MTP, received DAG or TAG (20 g/day) for 8 weeks. Reductions of serum lipids from weeks 4 to 8 in FABP2-Ala54Thr heterozygotes and MTP -493g homozygotes were significantly different between the DAG and TAG groups (p<0.05, p<0.01). Visceral fat/total fat (%), as determined by computed tomography (CT), was lower in FABP2-Ala54Thr heterozygotes (p<0.05) of the DAG group. The apoCII/CIII ratio was higher in the DAG group than in the TAG group (p<0.01). Other variants of lipid metabolism, including peroxisome proliferator activated receptors (PPARs) alpha and gamma and SREBP cleavage-activating protein (SCAP), were only slightly affected by dietary DAG. CONCLUSION: improvement of serum lipid profiles and visceral fat/total fat ratio (CT) was potentiated by DAG intake in subjects with hyperlipidemia-prone genotypes (Ala54Thr heterozygotes of FABP2 and -493g homozygotes of MTP).

Safety and efficacy of fluvastatin in hyperlipidemic patients with chronic renal disease.

BACKGROUND: There are few reports on the safety and efficacy of long-term treatment with statins in patients with chronic renal disease and hyperlipidemia. We evaluated these subjects treated with fluvastatin. METHODS: After a 4-week run-in period, a total of 80 patients with diabetic nephropathy or chronic glomerulonephritis were randomly allocated to receive dietary therapy and fluvastatin 20 mg/day (n=39), or dietary therapy alone (n=41) for a period of 48 weeks. Lipid parameters, rhabdomyolysis-related indicators, 24-hour urinary albumin excretion and creatinine clearance were measured. The pharmacokinetics of fluvastatin was examined in 8 patients. RESULTS: Creatinine clearance and 24-hour urinary albumin excretion did not differ between the two groups. The peak serum fluvastatin concentration (Cmax) was 141+/-67 microg/L and the mean AUC0-6 h was 341+/-149 microgh/L. Fluvastatin treatment significantly lowered serum total cholesterol, low-density lipoprotein (LDL) cholesterol and apo-lipoprotein B concentrations by 16%, 25%, and 22%, respectively, compared with patients receiving dietary therapy alone. There were no significant differences in serum triglyceride and high-density lipoprotein (HDL) cholesterol concentrations between the two treatment groups. Serum creatine kinase and aldolase concentrations did not change throughout treatment in both groups. CONCLUSIONS: Fluvastatin treatment significantly improved lipid parameters in patients with chronic renal disease. Fluvastatin was well tolerated, with no adverse effects on renal function and no muscular toxicity. However, the drug showed no direct renoprotective effects.

Validity of a self-administered food frequency questionnaire used in the 5-year follow-up survey of the JPHC Study Cohort I to assess fatty acid intake: comparison with dietary records and serum phospholipid level.

We compared fatty acid intake estimated from our 138-item food frequency questionnaire (FFQ) with 28-day weighed dietary records among a subgroup of JPHC Study Cohort I (102 men and 113 women), and with the corresponding two serum phospholipid levels (88 men). Spearman rank correlation coefficients between fatty acid intakes estimated from FFQ and intakes estimated from DR were as follows: saturated fatty acid, r=0.61 and r=0.60; monounsaturated fatty acid, r=0.50 and r=0.44; for energy adjusted value and Eicosapentaenoic acid (EPA), r=0.62 and r=0.55; docosahexaenoic acid (DHA), r=0.61 and r=0.50; for percentage of total fatty acid intake in men and women, respectively. Spearman rank correlation coefficients between fatty acid intakes estimated from FFQ and the corresponding serum phospholipid levels (% of total fatty acid) were as follows: EPA, r=0.43 and r=0.59; DHA, r=0.35 and r=0.49; for crude value (g/day) and percentage of total fatty acid intake, respectively. In conclusion, relatively high correlations were observed for SFA, MUFA and marine-origin n-3 polyunsaturated fatty acid, whereas we must take into account the indicator of each fatty acid intake when using the data of fatty acid intake assessed with FFQ for JPHC study.

Genetic variants of human beta-defensin-1 and chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is due to interactions between cigarette smoke exposure and other risk factors. Genetic variations of human beta-defensin-1 (hBD-1), an endogenous antimicrobial peptide in the airway, were investigated in 60 patients and 213 healthy volunteers by single-strand conformation and restriction fragment length polymorphism analysis and DNA sequencing. Four nucleotide variations in the 5' and 3' untranslated regions and two nonsynonymous substitutions in the coding region were identified. Of these, a newly found Ile38 variant was observed in 15.0% of patients but only in 2.8% of healthy individuals and was significantly associated with the disease (OR = 6.1, 95% confidence intervals 2.0-8.3, P = 0.0012). More than 80% of those with Ile38 experienced sputum production for more than 3 months during the follow-up period. Genetic variations in hBD-1 may define a high-risk subgroup of COPD where the component of chronic bronchitis is predominant.

Acetyl-L-carnitine supplementation restores decreased tissue carnitine levels and impaired lipid metabolism in aged rats.

The effects of long-term carnitine supplementation on age-related changes in tissue carnitine levels and in lipid metabolism were investigated. The total carnitine levels in heart, skeletal muscle, cerebral cortex, and hippocampus were approximately 20% less in aged rats (22 months old) than in young rats (6 months old). On the contrary, plasma carnitine levels were not affected by aging. Supplementation of acetyl-l-carnitine (ALCAR; 100 mg/kg body weight/day for 3 months) significantly increased tissue carnitine levels in aged rats but had little effect on tissue carnitine levels in young rats. Plasma lipoprotein analyses revealed that triacylglycerol levels in VLDL and cholesterol levels in LDL and in HDL were all significantly higher in aged rats than in young rats. ALCAR treatment decreased all lipoprotein fractions and consequently the levels of triacylglycerol and cholesterol. The reduction in plasma cholesterol contents in ALCAR-treated aged rats was attributable mainly to a decrease of cholesteryl esters rather than to a decrease of free cholesterol. Another remarkable effect of ALCAR was that it decreased the cholesterol content and cholesterol-phospholipid ratio in the brain tissues of aged rats. These results indicate that chronic ALCAR supplementation reverses the age-associated changes in lipid metabolism.

High prevalence of antibodies to hepatitis A and E viruses and viremia of hepatitis B, C, and D viruses among apparently healthy populations in Mongolia.

The prevalence of infection with hepatitis A virus (HAV), HBV, HCV, HDV, and HEV was evaluated in 249 apparently healthy individuals, including 122 inhabitants in Ulaanbaatar, the capital city of Mongolia, and 127 age- and sex-matched members of nomadic tribes who lived around the capital city. Overall, hepatitis B surface antigen (HBsAg) was detected in 24 subjects (10%), of whom 22 (92%) had detectable HBV DNA. Surprisingly, HDV RNA was detectable in 20 (83%) of the 24 HBsAg-positive subjects. HCV-associated antibodies were detected in 41 (16%) and HCV RNA was detected in 36 (14%) subjects, none of whom was coinfected with HBV, indicating that HBV/HCV carriers account for one-fourth of this population. Antibodies to HAV and HEV were detected in 249 (100%) and 28 (11%) subjects, respectively. Of 22 HBV DNA-positive subjects, genotype D was detected in 21 subjects and genotype F was detected in 1 subject. All 20 HDV isolates recovered from HDV RNA-positive subjects segregated into genotype I, but these differed by 2.1 to 11.4% from each other in the 522- to 526-nucleotide sequence. Of 36 HCV RNA-positive samples, 35 (97%) were genotype 1b and 1 was genotype 2a. Reflecting an extremely high prevalence of hepatitis virus infections, there were no appreciable differences in the prevalence of hepatitis virus markers between the two studied populations with distinct living place and lifestyle. A nationwide epidemiological survey of hepatitis viruses should be conducted in an effort to prevent de novo infection with hepatitis viruses in Mongolia.