Impact of the COVID-19 pandemic on the surveillance of antimicrobial resistance.

BACKGROUND: The impact of the coronavirus disease (COVID-19) pandemic on antimicrobial resistance (AMR) is a major concern. AIM: To compare the number of patients and isolation rate of antimicrobial-resistant bacteria before and after the beginning of the COVID-19 pandemic using the comprehensive national surveillance data. METHODS: We utilized comprehensive surveillance data, collected in the Japan Nosocomial Infections Surveillance programme, which included a total of 16.7 million samples of 5.9 million tested patients from >1300 hospitals. We compared the number of patients and isolation rate of five bacteria between 2019 and 2020, including antimicrobial-susceptible and -resistant bacteria of Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa. FINDINGS: The number of patients and isolation rate of S. aureus and meticillin-resistant S. aureus decreased slightly; those of S. pneumoniae and penicillin-resistant S. pneumoniae decreased by 60%; and those of third-generation cephalosporin-resistant K. pneumoniae increased. The isolation rate of the remaining bacteria apparently increased, although the number of patients decreased. This was due to a substantial decrease in the total number of tested patients (the denominator of the isolation rate), which was larger than that of the number of patients (the numerator of the isolation rate). Consistent results were obtained when the same data were re-aggregated using the procedure of the World Health Organization Global Antimicrobial Resistance Surveillance System, demonstrating the general importance of this problem. CONCLUSION: Surveillance data during the COVID-19 pandemic must be carefully interpreted based on examination of the numerator, denominator and background factors that affect the denominator.

The first multi-centre point-prevalence survey in four Japanese university hospitals.

BACKGROUND: The Japanese government adopted a national action plan on antimicrobial resistance, which aims to reduce drug-resistant pathogens and antimicrobial use. A point-prevalence survey (PPS) is a useful surveillance method to gain information about hospital epidemiology; however, no multi-centre PPS has previously been performed in Japan. AIM: To investigate general information about hospital epidemiology, healthcare-associated infections (HCAIs), and antimicrobial use in multiple Japanese university hospitals. METHODS: In July 2016, a multi-centre PPS was conducted using a standardized protocol at four university hospitals in Japan. FINDINGS: A total of 3199 patients were included. Median age and duration of hospital stay were 64 years and 10 days, respectively. A total of 246 (7.7%; 95% confidence interval (CI): 6.8-8.7) patients had 256 active HCAIs, and 933 (29.2%; 95% CI: 27.6-30.8) patients received 1318 antimicrobials. Pneumonia and gastrointestinal system infection were the most common HCAIs (N = 42, 16.4%), and Enterobacteriaceae (N = 49, 30.8%) were the predominant causative organisms. Carbapenems (N = 52, 17.8%), anti-MRSA medications, and cephems with antipseudomonal activity were the most frequently prescribed antimicrobials for HCAIs. As surgical prophylaxis, 46 of 278 antimicrobials (16.5%) were administered orally. Proportions of HCAI and antimicrobial use in each hospital ranged from 4.8% to 9.5% and 19.3%-35.0%, respectively. CONCLUSION: This multi-centre PPS recorded detailed HCAI data and distinct antimicrobial use in Japanese university hospitals. Further surveillance is necessary to reduce HCAIs and formulate feasible plans to achieve the national action plan on antimicrobial resistance.

Neural correlates of electrointestinography: insular activity modulated by signals recorded from the abdominal surface.

Although the neural correlates that underlie abdominal pain have been investigated, so-called brain processes involved in modulating "gut feelings" remain unclear. In the current study, we used electrointestinography (EIG) to measure intestinal activity of healthy humans at rest. EIG measured myoelectrical activity of intestinal smooth muscles from the abdominal surface and was simultaneously conducted along with brain activity measurement using functional magnetic resonance imaging (fMRI). Correlations between the frequency powers of EIG and fMRI signals during 30min of rest were then examined to elucidate gut-brain interactions. Neural activity correlating with 0.14- to 0.21-Hz EIG (suggested to reflect intestinal activity) was observed in the right anterior and middle insula. Moreover, this EIG frequency band correlated with anxiety scores along with resting-state functional connectivity between the insula and dorsal anterior cingulate cortex. These findings suggest that the insular cortex could be the core region involved in central visceral processes associated with subjective feelings.

Surface curvatures of trabecular bone microarchitecture.

Microstructure of trabecular bone has been examined with a particular emphasis on surface curvatures in two-phase (trabecular and intertrabecular space- i.e., marrow space) structures. Three trabecular bone samples, quantified as "plate-like," "rod-like," and a mixture of these two structural elements according to the structure model index (SMI), were subjected to analysis based on (differential) geometry. A correspondence between the SMI and the mean curvature was found. A method to measure surface curvatures is proposed. The gaussian curvatures averaged over the surfaces for the three analyzed bone structures were all found to be negative, demonstrating their surfaces to be, on average, hyperbolic. In addition, the Euler-Poincaré characteristics and the genus, both characterizing topological features of bone connectivity, were estimated from integral gaussian curvature (Gauss-Bonnet theorem). The three bone microstructures were found to be topologically analogous to spheres with one to three handles.

Functional changes of aorta with massive accumulation of calcium.

The present study was undertaken to elucidate pathophysiological changes and functional alterations of the calcified artery. For this purpose, rats were treated with 500,000 units/kg vitamin D3, and tension development of isolated rat aortae was examined. Treatment of rats with vitamin D3 resulted in an increase (approx. 64-fold) in the tissue calcium. Light microscopic examination of the aorta after staining with hematoxylin-eosin and von Kossa indicated numerous plaques in the aortic media. The results indicate a massive accumulation of calcium in the aortic media. Responsiveness of the calcified tissue to norepinephrine, epinephrine, serotonin, prostaglandin F2 alpha was found to be 11-66% when compared to that of the control. Furthermore, the calcified tissue responded minimally to isoproterenol and acetylcholine, which elicited a relaxation in control aortae. Isoproterenol-induced relaxation of the calcified aorta after 100 mM KCl contracture was also diminished. In the present study we have demonstrated poor responsiveness of the calcified aorta to physiological and pharmacological substances relative to normal tissue, which implies a functional damage of the artery upon massive calcium accumulation.

Synthesis of endothelin-1 in rat uterus during pregnancy.

Endothelin is a potent vasoconstrictive peptide first isolated from the supernatant of cultured porcine aortic endothelial cells. The purpose of this study was to determine the source of endothelin-1 (ET-1) production in rat uterus during pregnancy and to clarify its role in normal pregnancy. ET-1, as recognized by immunohistochemistry, was weakly expressed only in endometrial glandular cells in nonpregnant rats but was intensely expressed in both glandular and myometrial cells in the early postpartum period. In situ hybridization confirmed the localization of prepro-ET-1 mRNA in the cytoplasm of endometrial glandular and myometrial cells but not in stromal cells or in smooth muscle cells of blood vessels. Northern blot analysis detected prepro-ET-1 mRNA in myometrial tissue from pregnant but not nonpregnant rats. In particular, the expression of prepro-ET-1 mRNA was strongest in the early postpartum period compared with the various stages of pregnancy. These results indicate that, in addition to endothelial cells and endometrial glandular cells, myometrial cells also produce ET-1 and its production significantly increases in the early postpartum period. Therefore, ET-1 may play a pivotal role in controlling bleeding from the placental bed through myometrial contraction.

Changes with age of the rat fetuin concentration in serum and its mRNA expression.

Rat fetuin, a counterpart of human alpha2-HS glycoprotein and bovine fetuin, shows strong intermolecular binding and association with other serum proteins. Therefore, to measure its concentration in rat serum, we pretreated serum samples with 1% SDS plus 5% (ca. 0.7 M) 2-mercaptoethanol at 100 degrees C for 3 min, and then subjected them to SDS-PAGE under reducing conditions followed by Western blotting. We found that the fetuin concentrations in normal rat serum determined by Western blotting were 2.5-4.5 mg/ml. These concentrations were three orders of magnitude higher than the previously reported concentrations. We also tried to measure the fetuin concentration in rat serum by means of an enzyme-linked immunosorbent assay after treatment of the samples with 0.1% sodium dodecyl sulfate (SDS) plus 10 mM 2-mercaptoethylamine at 100 degrees C for 3 min, but it gave a value of about 1/4 of that on Western blotting. Rat fetuin is expressed mainly in the liver, with a peak 2-4 weeks after birth, as determined by Northern blot analysis. The fetuin mRNA level in the liver changes almost in parallel with its serum concentration. The tibia also expresses fetuin, but much less than the liver.

Effects of cerivastatin sodium, a new HMG-CoA reductase inhibitor, on biliary lipid metabolism in patients with hypercholesterolemia.

The use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has become common in the treatment of hypercholesterolemia. The present uncontrolled study was undertaken to determine the effect of cerivastatin sodium (BAY w 6228), a new HMG-CoA reductase inhibitor, on biliary lipid levels in patients with hypercholesterolemia. Twenty-one hypercholesterolemic patients (World Health Organization type IIa = 16 patients; type IIb = 5 patients) received placebo during a 4- to 6-week observation period, after which they received cerivastatin sodium 0.2 mg/d for 12 weeks. Fasting blood samples were drawn for the measurement of serum lipid levels early in the morning before the start of treatment and once a month for each of the 12 weeks of cerivastatin sodium treatment. Gallbladder bile samples were aspirated with a duodenal tube by cerulein stimulation to assess bile lithogenicity. Serum total cholesterol levels decreased markedly after 12 weeks. However, no significant difference was found in the molar percentage composition of biliary lipids (e.g., cholesterol, phospholipids, and total bile acids) or in individual biliary bile acids. Consequently, no significant change in bile cholesterol saturation index was found. The index values before and after 12 weeks of treatment were 0.81 +/- 0.38 and 0.80 +/- 0.47, respectively, whereas when patients were grouped by type of hypercholesterolemia, there was a tendency toward decreased lithogenicity in patients with type IIb but not type IIa hypercholesterolemia. We concluded that cerivastatin sodium was an effective cholesterol-lowering drug that did not appear to worsen biliary lipid metabolism and that may decrease lithogenicity in patients with type IIb hypercholesterolemia.

Bilirubin overload modulates bile canalicular membrane fluidity in rats: association with disproportionate reduction of biliary lipid secretion.

We recently demonstrated that several organic anions cause dissociation of biliary lipid secretion from that of bile acids; namely, the "uncoupling phenomenon," in association with changes in the phospholipid molecular species in the canalicular membrane lipid bilayer. Because of the uncoupling phenomenon, transcytotic vesicles are retained inside cells, resulting in the accumulation of substances normally excreted in the bile. In the present study, bilirubin ditaurate (BDT; synthetic bilirubin) was used to investigate the effect of bilirubin overload on biliary lipid secretion and the lipid composition of hepatic subcellular fractions, as well as canalicular membrane packing density and fluidity. Male Sprague-Dawley rats underwent cannulation of the bile duct and femoral vein. Sodium taurocholate was infused intravenously at 100 nmol/min per 100 g body weight. Then BDT (50 nmol/min per 100 g body weight) was infused concomitantly, followed by periodic bile collection for analysis of lipids. Bile acid secretion was not significantly affected by the infusion of BDT. In contrast, the secretion of cholesterol and phospholipids was decreased by 56.7% and 49.2%, respectively, compared with control. The phosphatidylcholine hydrophobicity of canalicular membrane vesicles, estimated by the molar ratio of saturated to unsaturated fatty acids (S/U ratio) was decreased, but not significantly by BDT infusion. With BDT infusions, the biliary cholesterol/phospholipid (C/P) ratio was increased by 19%; canalicular membrane vesicle fluidity was decreased by 5.8%, whereas P-glycoprotein expression was unchanged. As P-glycoprotein expression was not altered, our findings suggested that the reduced canalicular membrane vesicle fluidity was a crucial regulator of canalicular membrane transporter function.

Expression of hepatocyte growth factor/scatter factor and c-Met in human dental papilla and fibroblasts from dental papilla.

Hepatocyte growth factor/scatter factor (HGF/SF), a broad-spectrum and multifunctional cytokine, is essential for the development of tissues including tooth. Here it was found that the HGF/SF content of human dental papillae obtained from 8 to 16-year-old individuals decreased significantly with age. Cultured fibroblasts prepared from the dental papillae of individuals of different ages produced HGF/SF at almost the same rate, but the sensitivities of the cells to interleukin-1alpha and tumour necrosis factor-alpha for the production of HGF/SF increased with age. Generally, mesenchymal cells such as fibroblasts produce HGF/SF but do not express c-Met, a receptor for HGF/SF, yet fibroblasts in dental papilla and cultured fibroblasts prepared from dental papilla did express c-Met, as determined by immunohistochemistry, in situ hybridization and reverse transcription-polymerase chain reaction. Recombinant human [125I]iodo-HGF/SF specifically bound to cell-surface macromolecules with a mol. wt of 146,000, which is the same as that of the beta-subunit of c-Met. The physiological role of c-Met on fibroblasts in dental papilla is unknown, but the addition of 2 ng of HGF/SF per ml to the culture medium significantly stimulated DNA synthesis in the cells, as determined by pulse labelling with [3H]thymidine. Exogenous HGF/SF also stimulated secretion by the cells of vascular endothelial growth factor, a cytokine that induces blood vessel-formation. These results suggest that HGF/SF may be involved in tooth development via autocrine mechanisms.

Hepatocyte growth factor in gingival crevicular fluid and the distribution of hepatocyte growth factor-activator in gingival tissue from adult periodontitis.

Hepatocyte growth factor (HGF), also known as scatter factor, is a broad-spectrum and multifunctional cytokine required for the development, growth and regeneration of various organs and tissues. The expression of HGF in human gingival fibroblasts is induced by inflammatory cytokines such as interleukin 1. Thus, although it is possible that content of HGF in gingival crevicular fluid (GCF) in periodontitis is increased, this has not so far been reported because the volume of GCF is too small to determine HGF by the available enzyme-linked immunosorbent assay (ELISA). A recently developed, highly sensitive ELISA for HGF, with a detection limit of 1 pg/ml sample, has now enabled HGF to be measured in GCF.The mean HGF content in GCF from sites with clinically healthy gingiva, defined by the absence of overt signs of gingival inflammation and a probing depth (PD) <3 mm, was 1.7 ng/ml, and that of periodontitis, defined by obvious alveolar bone loss detected by radiographic examination and a PD> or =3 mm, was 3.23 ng/ml. Although treating the periodontitis did not significantly decrease the HGF concentration despite significantly improved clinical scores such as PD and Gingival Index, the total amount of HGF in GCF did decrease significantly after treatment. HGF was expressed by gingival fibroblasts and inflammatory cells as determined by in situ hybridization. HGF-activator (HGFA), which converts inactive pro-HGF to active mature HGF, was detected in gingival epithelial cells by immunostaining. The expression of HGFA was also confirmed in gingival tissue by reverse transcription-polymerase chain reaction (RT-PCR). These findings indicate that HGF is synthesized and activated in gingiva that is clinically healthy or associated with periodontitis.

Interfacial and topological measurements of bicontinuous polymer morphologies.

Bicontinuous morphologies are ubiquitous in nature and occur at various length scales. Topological features of two such morphologies arising in an ordered block copolymer at equilibrium and a polymer blend during spinodal decomposition are measured from three-dimensional images. Interfacial curvature, coordination number, and interjunction distance distributions exhibit remarkable similarity in these systems, despite vastly different length scales. A channel coordination of 3 is dominant in both morphologies, and topological measurements such as the Euler-Poincaré characteristic and genus are reported.

The blood supply of the lateral epiphyseal arteries in Perthes' disease.

We performed superselective angiography in 28 hips in 25 patients with Perthes' disease in order to study the blood supply of the lateral epiphyseal arteries (LEAs). Interruption of the LEAs at their origin was observed in 19 hips (68%). Revascularisation in the form of numerous small arteries was seen in ten out of 11 hips in the initial stage of Perthes' disease, in seven of eight in the fragmentation stage and in five of nine in the healing stage. Penetration of mature arteries into the depths of the epiphysis was seen in four of nine hips in the healing stage. Vascular penetration was absent in the weight-bearing portion of the femoral head below the acetabular roof. Interruption of the posterior column artery was seen where it passed through the capsule in seven hips when they lay either in internal rotation or in abduction with internal rotation. We suggest that in Perthes' disease the blood supply of the LEAs is impaired at their origin and that revascularisation occurs from this site by ingrowth of small vessels into the femoral epiphysis. This process may be the result of recurrent ischaemic episodes.

[Toxicokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate (NS-21), a novel drug for urinary frequency and incontinence, in mice and rats during 13-week dietary administration].

Toxicokinetics of (+/-)-4-diethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride monohydrate(NS-21), a new drug for the treatment of urinary frequency and incontinence, were studied in mice and rats during a 13-week dietary administration to determine the toxicokinetic profiles of NS-21 and its active metabolite (+/-)-4-ethylamino-1,1-dimethylbut-2-yn-1-yl 2-cyclohexyl-2-hydroxy-2-phenylacetate monohydrochloride (RCC-36) in dietary carcinogenicity studies. Male and female mice were given the drug in the diet at doses of 0(control), 30, 100 and 300 mg/kg/day, and male and female rats were given the drug at doses of 0(control), 10, 30 and 100 mg/kg/day. The chosen doses and means of administration were identical to those of a 78-week dietary carcinogenicity study in mice and 2-year dietary carcinogenicity study in rats. The plasma concentrations were measured on the first and the last day of the administration. For every treatment period, the plasma concentrations of NS-21 and RCC-36 increased with dose in mice and rats. The sum of the area under the concentration-time curve(AUC) of NS-21 and RCC-36 was 2694 to 8614 ng.hr/ml in the maximum dose of mice, and 2232 to 3593 ng.hr/ml in the maximum dose of rats through the administration period. These results show that, when compared with therapeutic dose in humans(682 ng.hr/ml at 10 mg/body/day), the total maximal exposure to NS-21 and RCC-36 in the earlier dietary carcinogenicity studies were estimated to be 4 to 13 times higher in mice, and 3 to 5 times higher in rats.

[Prospective randomized trial comparing modified FAM (5-fluorouracil (5-FU) + adriamycin + mitomycin C) versus 5-FU alone for the treatment of non-resectable pancreatic and biliary tract carcinomas (the 1st trial in non-resectable patients). Study Group of Surgical Adjuvant Therapy for Carcinomas of the Pancreas and Biliary Tract].

The modified FAM (5-fluorouracil (5-FU) + adriamycin (ADR) + mitomycin C (MMC)) therapy (FAM group) was compared with 5-FU mono-therapy (F group) by multi-institutional randomized trial in the patients with cancer of the pancreas or the biliary tract who underwent non-resection. The patients in FAM group received 6 mg/m2 of i.v. MMC during operation, 310 mg/m2 of i.v. 5-FU for 5 days in the 1st and 3rd postoperative weeks and 12 mg/m2 of i.v. ADR in the 2nd postoperative week. Those in F group received only 5-FU course in the administration schedule of FAM group. Among the cases which completed respective whole administration schedules. 35 cases in FAM group and 36 in F group, better effect than partial response (PR) was observed in neither groups, and there was no significant difference between groups with respect to overall/each disease survival duration, progression-suppressed duration and clinical effect. Primary adverse effects were alimentary symptoms and hepatic dysfunction, neither of which was serious, and there was no difference between groups except that hair loss was observed in more cases in FAM group (p less than 0.05). Results in FAM group did not statistically surpass those in F group, but a tendency was observed that FAM group was better than F group in terms of survival duration and clinical effect for cancer of the gall-bladder.

Differential effects of urinary and recombinant chorionic gonadotropin on oxidative stress responses in decidualizing human endometrial stromal cells.

Human chorionic gonadotropin (hCG) is one of the earliest signals secreted by the implanting embryo. In addition to its well-known luteotropic function in early pregnancy, hCG also acts directly on decidualizing endometrium. Recently, we demonstrated that recombinant hCG (rhCG) prevented apoptosis in decidualizing human endometrial stromal cells (HESCs) exposed to oxidative stress. Two hCG preparations are widely used clinically: rhCG, produced by recombinant DNA technology, and urinay hCG (uhCG), extracted from urine of post-menopausal women. However, an analysis of the direct effects of rhCG and uhCG on the decidual phenotype of HESCs has not yet been done. In this study, we investigated the effects of uhCG and rhCG on the morphological and functional profiles of decidualizing HESCs. We demonstrate that neither rhCG nor uhCG alter the morphological appearance of the decidual HESC cultures, although rhCG but not uhCG attenuated prolactin expression, a major decidual marker protein. Moreover, rhCG, but not uhCG, protected decidualizing HESCs from oxidative cell death, mediated at least in part by two major mechanisms. First, rhCG, but not uhCG, enhances the expression of manganese superoxide dismutase, a cardinal enzyme in the cellular defense against oxidative damage. Second, rhCG signaling selectively limits activation of the apoptotic machinery in decidualizing HESCs by enhancing Bcl-2 expression whereas uhCG induces the expression of Fas ligand. Our results suggest that rhCG might be a preferable agent to protect the maternal decidua against oxidative damage in pregnancy, especially at the time of implantation and beyond.