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The Japanese Society of Hypertension updated guidelines for hypertension management (JSH2019), changing the blood pressure (BP) classification. However, evidence is sparse regarding the association of the classification with cardiovascular disease (CVD) events among young to middle-aged workers in Japan. We examined this issue using longitudinal data from Japan Epidemiology Collaboration on Occupational Health Study with a prospective cohort design. Participants were 81,876 workers (aged 20-64 years) without taking antihypertensive medication at baseline. BP in 2011 or 2010 was used as exposure. CVD events that occurred from 2012 to 2021 were retrieved from a within-study registry. Cox regression was used to calculate multivariable-adjusted hazard ratios of CVD events. During 0.5 million person-years of follow-up, 334 cardiovascular events, 75 cardiovascular deaths, and 322 all-cause deaths were documented. Compared with normal BP (systolic BP [SBP] < 120 mmHg and diastolic BP [DBP] < 80 mmHg), multivariable-adjusted hazard ratios (95% confidence intervals) of cardiovascular events were 1.98 (1.49-2.65), 2.10 (1.58-2.77), 3.48 (2.33-5.19), 4.12 (2.22-7.64), and 7.81 (3.99-15.30) for high normal BP (SBP120-129 mmHg and DBP < 80 mmHg), elevated BP (SBP130-139 mmHg and/or DBP80-89 mmHg), stage 1 hypertension (SBP140-159 mmHg and DBP90-99 mmHg), stage 2 hypertension (SBP160-179 mmHg and/or DBP100-109 mmHg), and stage 3 hypertension (SBP ≥ 180 mmHg and/or DBP ≥ 110 mmHg), respectively. The highest population attributable fraction was observed in elevated BP (17.8%), followed by stage 1 hypertension (14.1%). The present data suggest that JSH2019 may help identify Japanese workers at a higher cardiovascular risk., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

We aimed to assess the association between heated tobacco product (HTP) use and high-density lipoprotein cholesterol (HDL-C) concentration. Our study included 12,268 workers from five companies (Study I) and 36,503 workers from another large company (Study II). Participants were categorized into five groups: never smokers, past smokers, exclusive HTP users, dual users of cigarettes and HTPs, and exclusive cigarette smokers. We analyzed the data of Studies I and II separately and then pooled these estimates using a fixed-effect model. Of the 48,771 participants, 9.3% were exclusive HTP users, and 6.0% were dual users. Exclusive HTP users had modestly but significantly lower concentrations of HDL-C than never smokers, with the pooled mean difference being - 1.1 (95% CI - 1.5 to - 0.6) mg/dL. Dual users showed a further reduction (mean difference - 3.7 (- 4.2 to - 3.2) mg/dL), which was comparable to that of exclusive cigarette smokers versus never smokers (mean difference - 4.3 (- 4.7 to - 3.9) mg/dL). The pooled odds ratios (95% CIs) of having low HDL-C (< 40 mg/dL for men and 50 mg/dL for women) were 1, 0.99 (0.90-1.11), 1.25 (1.09-1.43), 2.02 (1.76-2.32), and 2.09 (1.88-2.32) for never smokers, past smokers, exclusive HTP users, dual users, and exclusive cigarette smokers, respectively. In conclusion, exclusive HTP users had lower HDL-C concentrations than never smokers, although higher than exclusive cigarette smokers. Moreover, dual users had HDL-C concentrations similar to those in exclusive cigarette smokers., (© 2022. The Author(s).)

Increased visit-to-visit variability (VVV) of blood pressure, which is calculated based on several readings, has been suggested to be a significant predictor of cardiovascular events and mortality, independent of mean blood pressure. This study examined associations between the VVV of systolic blood pressure (SBP) measured annually and cardiovascular disease (CVD) events among 72,617 Japanese subjects. Data were obtained from the Japan Epidemiology Collaboration on Occupational Health Study, which is an ongoing epidemiological survey of workers in Japan. VVV was calculated as the coefficient of variation of SBP readings from 2008 to 2011; information on fatal and nonfatal CVD events was collected from registries of specific outcomes between April 2012 and March 2019. A Cox proportional hazards model was applied to investigate associations after adjusting for mean SBP between 2008 and 2011 and covariates. During the 7-year follow-up period, there were 63 CVD fatalities and 314 CVD events (combining fatal and nonfatal events). The results showed that a one-standard deviation increase in VVV was associated with a significant increase in the risk of CVD mortality (hazard ratio [HR] = 1.42; 95% confidence interval [CI] = 1.32-1.54); those in the highest tertile had a 3.20 times (95% CI = 1.26-8.17) higher risk of CVD mortality than those in the lowest tertile. We found less pronounced associations regarding CVD events (HR = 1.08, 95% CI = 1.02-1.15). In conclusion, VVV was significantly associated with CVD mortality in our Japanese working population., (© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

The accurate and prompt diagnosis of SARS-CoV-2 infection is required for the control and treatment of the coronavirus infection disease 2019 (COVID-19). In this study, we aimed to investigate the time courses of the anti-severe acute corona respiratory syndrome coronavirus 2 (SARS-CoV-2) IgM and IgG titers and to evaluate the sensitivity and specificity of such tests according to the specific day after the onset of COVID-19 among a patient population in Japan. We measured the titers of SARS-CoV-2 IgM and IgG in sera from 105 subjects, including 26 symptomatic COVID-19 patients, using chemiluminescent immunoassay (CLIA) methods utilizing magnetic beads coated with SARS-CoV-2 nucleocapsid protein and spike protein. The results of a ROC analysis suggested the possibility that the cutoff values in Japan might be lower than the manufacturer's reported cutoff (10 AU/mL): 1  AU/mL for IgM and 5  AU/mL for IgG. The sensitivity of the test before Day 8 after symptom onset was less than 50%; at Days 9-10, however, we obtained a much higher sensitivity of 81.8% for both IgM and IgG. At 15 days or later after symptom onset, the SARS-CoV-2 IgG test had a sensitivity of 100%. These results suggest that if the number of days since disease onset is taken into consideration, these antibody tests could be very useful for the diagnosis of COVID-19 and similar diseases.

Pressure dependence of the electronic and crystal structures of KxFe2-ySe2, which has pressure-induced two superconducting domes of SC I and SC II, was investigated by x-ray emission spectroscopy and diffraction. X-ray diffraction data show that compressibility along the c-axis changes around 12 GPa, where a new superconducting phase of SC II appears. This suggests a possible tetragonal to collapsed tetragonal phase transition. X-ray emission spectroscopy data also shows the change in the electronic structure around 12 GPa. These results can be explained by the scenario that the two SC domes under pressure originate from the change of Fermi surface topology. Our results here show the pronounced increase of the density of states near the Fermi surface under pressure with a structural phase transition, which can help address our fundamental understanding for the appearance of the SC II phase.

Objective: To validate reported energy intake (rEI) with a self-administered diet history questionnaire (DHQ) against total energy expenditure (TEE) by the doubly labeled water (DLW) method., Subjects: A total of 140 healthy Japanese adults (67 men and 73 women) aged 20-59 years living in four areas in Japan., Methods: Energy intake was assessed twice with DHQ over a 1-month period before and after TEE measurement (rEI(DHQ1) and rEI(DHQ2), respectively). TEE was measured by DLW during 2 weeks (TEE(DLW))., Results: Mean rEI(DHQ1) was lower than those of TEE(DLW) by 1.9+/-2.4 MJ/day (16.4%, P<0.001) for men and 0.6+/-1.9 MJ/day (6.0%, P<0.01) for women. In men and women together, 62 subjects (44%) were defined as underreporters (rEI(DHQ1)/TEE(DLW) <0.84), 58 (41%) as acceptable reporters (0.84-1.16) and 20 (14%) as over-reporters (>1.16). Pearson correlation coefficient was 0.34 for men and 0.22 for women. After adjustment for the dietary and non-dietary factors related to rEI(DHQ1)/TEE(DLW), the correlation coefficient improved to 0.42 and 0.37, respectively., Conclusion: The energy intake assessed with DHQ correlated low to modestly with TEE measured by DLW. In addition, DHQ underestimated energy intake at a group level. Caution is needed when energy intake was evaluated by DHQ at both individual and group levels.

Objective: To measure total energy expenditure (TEE) for normal healthy Japanese by the doubly labelled water (DLW), and to compare the physical activity level (PAL) among categories classified by the categories used in daily reference intake (DRI), Japan and the International Physical Activity Questionnaire (IPAQ)., Subjects and Methods: A total of 150 healthy Japanese men and women aged 20- to 59-year-old living in four districts of Japan. TEE was measured by the DLW method, and the PAL was calculated from TEE divided by basal metabolic rate. Simultaneously with TEE measurement, the PAL was assessed employing the categories used in DRI, Japan and IPAQ., Results: The average TEE and PAL were 10.78+/-1.67 MJ/day and 1.72+/-0.22 for males and 8.37+/-1.30 MJ/day and 1.72+/-0.27 for females, respectively. The subjects in the highly active categories assessed by both DRI and IPAQ showed significantly higher PAL compared with less active categories. However, PALs among light and moderate categories by DRI, and insufficient and sufficiently active by IPAQ were not significantly different., Conclusions: In developed countries, highly active subjects could be assessed by a simple questionnaire. However, the questionnaire should be improved to clarify the sedentary to moderately active subjects by assessing carefully very light to moderate physical activity.

The prevalence of atrial fibrillation (AF) increases in patients with hypertension. Angiotensin II is involved in structural atrial remodeling, which contributes to the onset and maintenance of AF in paced animal models. We investigated the role of angiotensin II in atrial structural remodeling in rats with hypertension. Ten-week-old male Wistar-Kyoto rats were randomly divided into 4 groups: a control group (no treatment), an Nomega-nitro-L-arginine methyl ester (L-NAME) group (administered L-NAME, an inhibitor of nitric oxide synthase, 1 g/l in drinking water), an L-NAME+candesartan group (L-NAME plus candesartan-an angiotensin II receptor blocker (ARB)-at 0.1 mg/kg/day), and an L-NAME + hydralazine group (L-NAME plus hydralazine at 120 mg/l in drinking water). Eight weeks after treatment, the L-NAME group showed significantly higher systolic blood pressure than the control group (197 +/- 12 vs.138 +/- 5 mmHg, p < 0.05). Candesartan or hydralazine with L-NAME reduced systolic blood pressure to baseline. Chronic inhibition of NO synthesis increased the extent of fibrosis and transforming growth factor-beta expression in atrial tissue, and both of these effects were prevented by candesartan, but not by hydralazine. Cardiac hypertrophy and dysfunction were induced in the L-NAME group, and these effects were also prevented by candesartan, but not by hydralazine. In contrast, the decrease in thrombomodulin expression in the atrial endocardium in hypertensive rats was restored by candesartan and hydralazine. The ARB prevented atrial structural remodeling, a possible contributing factor for the development of AF, in the hearts of rats with hypertension induced by long-term inhibition of NO synthesis.

A novel nonsteroidal aromatase inhibitor, TAN-931, was isolated from the culture filtrate of a soil isolate fungus, No. 8974. The strain was identified as Penicillium funiculosum No. 8974. TAN-931 inhibited human placental and rat ovarian aromatase activity, and the IC50 value was 17.2 and 162 microM, respectively. The inhibition of human placental aromatase was uncompetitive with respect to androstenedione conversion with a Ki value of 40 microM. When TAN-931 was subcutaneously administered at doses of 25, 50 and 100 mg/kg (once/day, x4) to 20-day-old female Sprague-Dawley rats treated with gonadotropin, the plasma estradiol-17 beta level and the weight of ovaries and uterus were markedly reduced in a dose-dependent manner. The in vivo inhibitory activity of TAN-931 was more potent than that of 4-hydroxyandrostenedione. Consecutive administration of TAN-931 (100 mg/kg, sc, twice/day, x 7) to 9-week-old male Sprague-Dawley rats did not induce any adrenal hypertrophy even though administration of aminoglutethimide caused 2-fold enlargement of the adrenal under the same conditions. Specific binding of TAN-931 to the estrogen receptor from a human breast cancer cell line, MCF-7, was not detected.

New 7-methoxycephem antibiotics were found in culture filtrates of a bacterium isolated from a plant and named cephabacin M1-6. They are the first members of 7-methoxycephem antibiotics of bacterial origin. The producing organism was taxonomically characterized and identified as Xanthomonas lactamgena YK-431; other strains of this species have recently been reported to produce cephabacin F and H group antibiotics. Cephabacin M1-6 exhibited moderate antibacterial activity against Gram-negative and Gram-positive bacteria. Cephabacin M1-6 were as stable as cephamycin C to cephalosporinases. They showed inhibitory activity against a cephalosporinase of Proteus vulgaris GN 4413. The mode of action of cephabacin M1 was examined using Escherichia coli and Bacillus subtilis as test organisms; primary lethal targets of cephabacin M1 are penicillin-binding protein (PBP) 1 in E. coli and PBP 4 in B. subtilis.

The new thiolactone antibiotic, thiolactomycin, is rapidly absorbed in rats when administered either orally or by intramuscular injection. A peak in concentration of the drug is reached in the blood and in various visceral organs within 15 minutes after administration. The concentration decreases rather rapidly and about 51-69% of the drug is excreted in urine during the first 24 hours. Though the in vitro effect of thiolactomycin is moderate, it effectively protected mice challenged intraperitoneally with several strains of S. marcescens and K. pneumoniae and more effective than carbenicillin in treating experimental acute urinary tracts infected with S. marcescens. Also, in mice whom immunodefense was decreased by treatment with cyclophosphamide, thiolactomycin was more effective than carbenicillin against S. marcescens challenge.

A new antibiotic, cyanocycline A, was isolated from the fermentation broth of Streptomyces flavogriseus strain No. 49, a soil isolate. The molecular formula of cyanocycline A was determined to be C22H26N4O5. The antibiotic has a cyano group and a N-heterocyclic quinone moiety in its structure. Cyanocycline A was found to have broad spectrum antimicrobial and antitumor activity.

The structures of six inhibitors of prolyl hydroxylase, fibrostatins A, B, C, D, E and F produced by a strain of Streptomyces, were deduced to be 1, 2, 3, 4, 5 and 6, respectively, from chemical and spectroscopic evidence, especially from extensive 13C NMR studies including selective decoupling and low power selective decoupling experiments monitored by 13C-1H long-range couplings. These compounds are the first naturally occurring 2,6,7- or 3,6,7-tri-substituted or 2,3,6,7-tetra-substituted 5-hydroxy-1,4-naphthoquinone inhibitors possessing N-acetyl-L-cystein-S-yl moieties in the molecule.

Thiotropocin, a new sulfur-containing 7-membered-ring antibiotic, was isolated from a culture broth of Pseudomonas sp. CB-104. The antibiotic occurs as orange or yellowish orange needles and has the molecular formula C8H4O3S2. It is active against Gram-positive and Gram-negative bacteria, some phytopathogens and mycoplasma.

The synthesis and the relationship between in vitro and in vivo activities of 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-3-R1-1-ureido]-2- phenylacetamido]penicillanic acids having C2 approximately 8 alkyl or substituted alkyl groups as the substituents (R1) are described. In this series, 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-3-(3-hydroxypropyl)-1-ureido] -2-phenylacetamido]penicillanic acid (1b, AO-1100) showed the most potent protective effect on mice in experimental Pseudomonas aeruginosa infections, although it did not have the strongest in vitro activity among the penicillins we synthesized.

Fibrostatin C, a novel prolyl hydroxylase inhibitor produced by Streptomyces catenulae subsp. griseospora No. 23924, inhibited the activity of purified chick embryo prolyl hydroxylase by about 50% at a concentration of 2.9 x 10(-5) M. The inhibition was mixed type with respect to (Pro-Pro-Gly)5 with a Ki of 2.1 x 10(-5) M. When an excess of ferrous ions or ascorbate was added to the reaction mixture, the inhibition was negligibly or slightly reversed, respectively. Fibrostatin C, when administered intraperitoneally at 1 mg/kg/day or orally at about 100 mg/kg/day as a dietary admixture, significantly inhibited estradiol-17 beta stimulated collagen biosynthesis in the uterus of the immature rat.

Lactivicin is moderately active against a wide range of Gram-negative bacteria and highly active against Gram-positive bacteria. It shows various biological activities commonly observed with beta-lactam antibiotics, such as higher activity against beta-lactam hypersensitive mutants than against their parents, sensitivity to beta-lactamases, inhibitory activity against beta-lactamases and ability to induce beta-lactamase activity. The primary lethal target of lactivicin in Escherichia coli is highly likely to be penicillin-binding protein (PBP) 1; lactivicin strongly lysed E. coli cells with induction of spheroplasts at its MIC, and showed high affinity for PBPs 1A and 1B. At concentrations above x 5 MIC, however, lactivicin dominantly exhibited secondary antibacterial action possibly owing to inhibition of crucial SH proteins engaged in the fundamental membrane functions. In contrast, against Bacillus subtilis, lactivicin showed the typical beta-lactam action under a wide range of concentrations. It showed high affinity for PBPs 1, 2 and 4, the possible lethal targets of beta-lactam antibiotics in this organism. In conclusion, lactivicin is the first non-beta-lactam antibiotic showing beta-lactam action through binding to PBPs.

Cyanocycline A was cytotoxic against Meth A cells in vitro, and also showed marked activity against the same cell line grown as an experimental ascites tumor. This antibiotic inhibited nucleic acid synthesis in Escherichia coli and Meth A cells. The antimicrobial activity of the antibiotic was reversed by addition of exogenous herring sperm DNA. Cytofluorometric analysis of cyanocycline A-treated Meth A cells showed an unusual pattern of the relative content of DNA and RNA per cell. These results suggested that cyanocycline A binds to DNA, and that it inhibits nucleic acid synthesis.

New monocyclic beta-lactam antibiotics, formadicins A, B, C and D, were isolated from the culture filtrate of Flexibacter alginoliquefaciens sp. nov. YK-49 by various types of column chromatography and preparative reverse-phase HPLC. Their structures were determined by spectroscopic analyses and degradation studies. They have a nocardicin-type skeleton and a formylamino group at the 3- or 12-position. Formadicins A and B each have a D-glucuronide moiety and give formadicins C and D, respectively, upon hydrolysis using beta-D-glucuronidase.

The antibiotic thiolactomycin inhibits the growth of Escherichia coli K-12 and Pseudomonas aeruginosa 507 (beta-lactam supersensitive mutant). A micrograph of E. coli cells, which were grown at a sublethal concentration of thiolactomycin (20 micrograms/ml), revealed the morphological change with cell elongation. The effects of the antibiotic on syntheses of cellular constituents were studied by measuring the incorporation of labeled precursors into lipids and macromolecules. This antibiotic preferentially inhibited the incorporation of [14C]acetate into fatty acids and lipids. Addition of both palmitate and oleate, but not of either fatty acid alone, reversed the growth inhibition of P. aeruginosa by thiolactomycin. These findings support the conclusion that the effects of thiolactomycin are due to a specific inhibition of fatty acid synthetase.

Three Gram-negative bacteria produce new cephem antibiotics, named cephabacins, with unique 3-side chains. Cephabacins include F group antibiotics with a 7-formylamino substituent and H group antibiotics without the substituent. The producing bacteria were taxonomically characterized and designated as Lysobacter lactamgenus sp. nov. YK-90 and Xanthomonas lactamgena sp. nov. YK-278 and YK-280.

Fifteen components of new antibiotics, cephabacins, were isolated from the culture filtrates of Lysobacter lactamgenus YK-90, Xanthomonas lactamgena YK-280 and X. lactamgena YK-278. They were purified by column chromatography using cation-exchange resins, activated carbon, high porous resins and cation-exchange Sephadex and by preparative reverse-phase HPLC. The basic, water-soluble antibiotics were characterized as having a cephem skeleton and oligopeptide(s) as a side chain constituent from their spectroscopic analyses and amino acid analyses.

Thiolactomycin is a new broad-spectrum antibiotic, active in vitro against many species of Gram-positive cocci, Enterobacteriaceae, Haemophilus, acid-fast bacteria and anaerobic bacteria. However, the activity is generally moderate and bacteriostatic in action. This antibiotic eludes cross resistance with any of the known antibacterial drugs such as ampicillin, carbenicillin or cycloserine. The effect on Gram-negative bacilli in vitro is little affected by the inoculum size, the presence of horse serum, the pH of the medium or the type of medium. When thiolactomycin was added to the assay medium, the minimum inhibitory concentration of ampicillin against inducible beta-lactamase producing strains of Staphylococcus aureus and Pseudomonas aeruginosa was reduced. Thiolactomycin inhibited the production of inducible beta-lactamase in several organisms.

A strain of actinomycetes, isolated from a soil sample, has produced a novel antibiotic (C11H14O2S) containing a unique thiolactone moiety in its molecule. On the basis of taxonomic studies the producing organism was identified as belonging to the genus Nocardia. The antibiotic, named thiolactomycin, exhibits a broad antibacterial spectrum and particularly potent activity against Salmonella, Serratia and Bacteroides. Furthermore, the acute toxicity is weak in experimental animals. These results indicate that thiolactomycin is distinct from other known antibiotics and represents a new type of antibiotic.

A Gram-negative bacterium produces new monocyclic beta-lactam antibiotics with a formylamino substituent, named formadicins A, B, C and D. The producing bacterium was taxonomically characterized and designated as Flexibacter alginoliquefaciens sp. nov. YK-49. Formadicins have narrow antibacterial spectra. They are highly active against some species of Pseudomonas, Proteus and Alcaligenes. Of the four, formadicin C shows the most potent antibacterial activity. Several amino acids such as glycine, D-alanine and D-leucine were antagonistic against formadicins. Formadicins, especially formadicins A and C having the formylamino substituent bound to the 3-position of a beta-lactam nucleus, were highly resistant to hydrolysis by various types of beta-lactamases. Formadicins A and C showed affinity for penicillin-binding proteins (PBPs) 1A and 1B in Pseudomonas aeruginosa IFO 3080, but formadicin B and nocardicin A showed affinity only for PBP 1B. Formadicins A and C did not lyse Escherichia coli LD-2 solely at their MICs, but when combined with mecillinam each induced a rapid lysis of this organism.

Fibrostatins, potent inhibitors of prolyl hydroxylase, were isolated as orange crystals from the culture broth of strain No. 23924, which was identified as Streptomyces catenulae subsp. griseospora. In vitro inhibitory activity (ID50 value) of fibrostatins A, B, C, D, E and F against prolyl hydroxylase of chick embryos was 23, 39, 29, 180, 10 and 14 microM, respectively.

Cephabacin F group antibiotics with a 7-formylamino substituent showed antibacterial activity against a wide variety of bacteria including beta-lactamase-producing clinical isolates and anaerobic bacteria. Cephabacin H group antibiotics without the substituent showed more potent activity against Gram-positive bacteria than cephabacin F group antibiotics, but were not active against Gram-negative bacteria producing beta-lactamases. Cephabacin F group antibiotics were highly resistant to hydrolysis by various types of beta-lactamases and showed strong inhibitory activity against a cephalosporinase of Proteus vulgalis GN 4413 due to the 7-formylamino substituent. Mode of action of cephabacin F1 and H1 was examined using Escherichia coli and Bacillus subtilis as the test organisms. They showed strong lytic activity against these organisms and inhibited their peptidoglycan synthesis. Cephabacin F1 had the highest affinity for penicillin-binding protein (PBP) 1 in E. coli and PBP 4 in B. subtilis. Cephabacins showed a protective effect in experimentally infected mice.

The synthesis and antibacterial activity of new ureidopenicillin derivatives having catechol moieties in the 6-acyl side chain are described. These compounds showed remarkably strong activities against Pseudomonas aeruginosa. Especially, 6-[(R)-2-[3-(3,4-dihydroxybenzoyl)-3-methyl-1-ureido]-2- phenylacetamido]penicillanic acid (7a) had the most potent activity in vitro against Gram-negative bacteria, its activity being 30 approximately 60-fold greater than that of piperacillin against most strains of P. aeruginosa.

In the search for new beta-lactam antibiotics of natural origin, the discoveries of cephamycins and sulfazecins (monobactams) were important turning points in that they accelerated many screening efforts aimed at other new compounds. In our target-directed screening for beta-lactam antibiotics using beta-lactam hypersensitive mutants, we have examined Gram-negative bacteria isolated from natural habitats and have recently reported several types of beta-lactam antibiotics such as cephabacins and formadicins. Here we report a novel antibiotic, lactivicin, found using this system. Although lactivicin has various biological activities commonly observed in beta-lactam antibiotics, it does not possess a beta-lactam ring in its molecule, but has the unique structure of a dicyclic dipeptide.