In vitro antibacterial activity of FK041, a new orally active cephalosporin.

The in vitro activity of FK041, a new orally active cephem antibiotic, against a wide variety of clinical isolates of bacteria was investigated and compared with those of cefdinir (CFDN) and cefditoren (CDTR). FK041 exhibited broad spectrum activity against reference strains of Gram-positive and Gram-negative aerobes and anaerobes. FK041 was active against clinical isolates of Gram-positive organisms except Enterococcus faecalis with MIC90s less than 1.56 microg/ml. FK041 was more active than CFDN and CDTR against Staphylococcus aureus, Staphylococcus epidermidis, and Streptococcus agalactiae and was comparable to CFDN and CDTR against Streptococcus pyogenes and Streptococcus pneumoniae. FK041 had no activity against methicillin-resistant staphylococci, like CFDN and CDTR. FK041 showed moderate activity against penicillin-resistant S. pneumoniae with an MIC range of 0.05 approximately 3.13 microg/ml, and was superior to CFDN but inferior to CDTR. Against clinical isolates of many Gram-negative organisms such as Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, FK041 had good activity comparable or superior to those of CFDN and CDTR. However, it was inferior to CDTR in activity against Moraxella catarrhalis, Haemophilus influenzae, Morganella morganii, and Serratia marcescens, and was inactive against Pseudomonas aeruginosa. With FK041 a small difference between MIC and MBC against S. aureus, E. coli, K. pneumoniae, and H. influenzae was found, indicating that its action is bactericidal against these species. FK041 was stable to group 2beta-lactamase hydrolysis but was unstable to group 1beta-lactamase hydrolysis. The stability of FK041 to these enzymes was similar to those of CFDN and CDTR. FK041 showed high affinity for the main penicillin-binding proteins (PBPs) of S. aureus (PBP 3, 2, and 1) and E. coli (PBP 3, 4, lbs, 2, and 1a).     

Selection of Human Ovarian Carcinoma Cells with High Dissemination Potential by Repeated Passage of the Cells in vivo into Nude Mice, and Involvement of Lex-determinant in the Dissemination Potential

Cells of the human tumor cell line RMG-1, derived from a clear-cell adenocarcinoma of the ovary, were injected intraperitoneally into nude mice, and the cells obtained from the tumor nodules in the mesenterium were found to form a larger number of, and larger-sized, tumor nodules than the original RMG-1 cells. The RMG-1-h cells, transferred into culture from the tumor nodules after a 4th in vivo passage, showed a dissemination potential as high as that of cells disseminating directly from the tissues, and exceedingly higher than that of RMG-1 cells. To assess the molecular bases of the different biological properties of RMG-1 and RMG-1-h cells, we compared the content and expression of various carbohydrate antigens in both cells. The chromosomal profile of RMG-1-h cells revealed their human origin and was identical to that of the original RMG-1 cells. In contrast to the broad histogram for the Le^x-bearing cells among RMG-1 cells in flow cytometry, the weakly and moderately positive cells toward anti-Le^x antibody were found to be eliminated from the histogram for the RMG-1-h cells, resulting in the enrichment of cells strongly expressing Le^x, which may account for the high dissemination potential. In addition, the adhesion of RMG-1 cells to mesothelial cells was found to be significantly inhibited by pretreatment of the cells with anti-Le^x antibody, indicating Le^x-mediated cell-to-cell interaction between ovarian cancer cells and mesothelial cells. By TLC-immunostaining, two Le^x-glycolipids, III³Fucα-nLc₄Cer and V³Fucα-nLc₆Cer were detected in both RMG-1 and RMG-1-h cells, and their total concentrations were not significantly different from each other. However, the hydrophobic moieties of Le^x-glycolipids in RMG-1-h cells were different from those in RMG-1 cells, suggesting that a difference in the structure of the hydrophobic moieties of Le^x is partly involved in the enhanced reactivity of RMG-1-h cells toward anti-Le^x antibody. Thus, the high dissemination potential of ovarian cancer cells was shown to be mediated by the Le^x-determinant and the Le^x-bearing cells are enriched by repeated in vivo passage of the cells into nude mice.     

Clinical risk factors for poor neonatal outcomes in umbilical cord prolapse

Objectives: To clarify the clinical risk factors associated with poor neonatal outcomes due to umbilical cord prolapse (UCP).

Methods: A postal questionnaire survey was attempted in Japan. The clinical risk factors and managements associated with poor neonatal outcomes were analyzed in cases of UCP treated in Japan.

Results: A total of 267 cases of UCP (out of 2?037?460 total deliveries) were analyzed. The rates of intrauterine death, neonatal death and survival with disability were 3.4%, 5.6% and 7.1%, respectively. The multivariate regression analysis for these poor neonatal outcomes revealed that the significant risk factors included a prolapsed amniotic sac (adjusted odds ratio (aOR), 4.49), preterm labor (aOR, 2.99) and replacement of the prolapsed umbilical cord into the uterus (aOR, 2.87). However, UCP that occurred during labor (aOR, 0.28) and emergency cesarean section (aOR, 0.11) were associated with a reduction in the rates of poor outcomes. The interval between the diagnosis of UCP and delivery was significantly longer in the infants with a poor outcome than intact survival (median 30 versus 24?min, p?=?0.048).

Conclusion: An emergency cesarean section should be carried out immediately to ensure a better outcome for the infant.     

Lipopolysaccharide-induced platinum accumulation in the cerebral cortex after cisplatin administration in mice: Involvement of free radicals

The relationship between the accumulation of platinum in the cerebral cortex following cisplatin administration and injury to the blood-brain barrier after lipopolysaccharide (LPS) treatment was investigated. The appearance of intravenously injected fluorescein in the brain was significantly increased 10–24 h after LPS treatment, the effect being dose-dependent. Platinum was detectable in the cerebral cortex of cisplatin-treated mice 24 h after LPS treatment, but not without LPS treatment. In mice pretreated with -tocopherol, LPS administration did not significantly augment fluorescein penetration into the brain, whereas pretreatment with either allopurinol or ascorbic acid did not modify the LPS-induced increase in fluorescein penetration. In contrast, platinum in the cerebral cortex after cisplatin administration was still detectable in the allopurinol-, ascorbic acid-, and -tocopherol-pretreated groups, and the levels of platinum in these groups were not significantly different from those in the group treated with LPS only. Administration of superoxide dismutase (SOD), but not of catalase, tended to inhibit the penetration of fluorescein. Both SOD and catalase significantly lowered platinum content in the cerebral cortex following cisplatin administration in mice treated with LPS. Thus, free radicals may injure the blood-brain barrier in mice challenged with LPS, and allow cisplatin to penetrate into the cerebral cortex, resulting in platinum accumulation.     

PAX5 alterations in an infant case of KMT2A‐rearranged leukemia with lineage switch

Lineage switch is a rare event at leukemic relapse. While mostly known to occur in KMT2A‐rearranged infant leukemia, the underlying mechanism is yet to be depicted. This case report describes a female infant who achieved remission of KMT2A‐MLLT3‐rearranged acute monocytic leukemia, but 6 months thereafter, relapsed as KMT2A‐MLLT3‐rearranged acute lymphocytic leukemia. Whole exome sequencing of the bone marrow obtained pre‐post lineage switch revealed two somatic mutations of PAX5 in the relapse sample. These two PAX5 alterations were suggested to be loss of function, thus to have played the driver role in the lineage switch from acute monocytic leukemia to acute lymphocytic leukemia.     

Precise immunological evaluation rationalizes the design of a self-adjuvanting vaccine composed of glycan antigen,TLR1/2 ligand,and T-helper cell epitope

Sialyl-Tn (STn), overexpressed on various tumors, has been investigated for its application in anti-cancer vaccine therapy. However, Theratope, an STn-based vaccine, failed in the phase III clinical trial due to poor immunogenicity and epitope suppression by the foreign carrier protein. We therefore developed a self-adjuvanting STn based-vaccine, a conjugate of clustered STn (triSTn) antigen, TLR1/2 ligand (Pam₃CSK₄), and T-helper (Th) cell epitope, and found that this three-component self-adjuvanting vaccine effectively resulted in the production of anti-triSTn IgG antibodies. We herein analyzed immune responses induced by this self-adjuvanting vaccine in detail. We newly synthesized two-component vaccines, i.e., Pam₃CSK₄- or Th epitope-conjugated triSTn, as references to evaluate the immune-stimulating functions of Pam₃CSK₄ and Th epitope. Immunological evaluation of the synthesized vaccine candidates revealed that Pam₃CSK₄ was essential for antibody production, indicating that the uptake of triSTn antigen by antigen-presenting cells (APCs) was promoted by the recognition of Pam₃CSK₄ by TLR1/2. The function of the Th epitope was also confirmed. Th cell activation was important for boosting antibody production and IgG subclass switching. Furthermore, flow cytometric analyses of immune cells, including T cells, B cells, dendritic cells, and other monocytes, were first employed in the evaluation of self-adjuvanting vaccines and revealed that the three-component vaccine was able to induce antigen-specific immune responses for efficient antibody production without excessive inflammatory responses. Importantly, the co-administration of Freund''s adjuvants was suggested to cause excessive myeloid cell accumulation and decreased plasma cell differentiation. These results demonstrate that vaccines can be designed to achieve the desired immune responses via the bottom-up construction of each immune element.

Detailed analysis of a three-component self-adjuvanting vaccine revealed that conjugate vaccines can be designed to achieve the desired immune responses via bottom-up construction of the necessary immune elements.     

Secondary arteriovenous malformation due to subclavian vein occlusion

An 80-year-old man underwent rectal resection and insertion of a central venous catheter through the left subclavian vein 16 years earlier. Following surgery, he developed edema of his left upper limb that became exacerbated and infected. Computed tomography showed occlusion of the subclavian vein and multiple arteriovenous shunts from the branches of the axillary artery to the venous sac of the axillary vein. Angiography confirmed numerous shunts between the branches of the axillary artery and vein and dilated collateral veins. Embolization of the venous sac was performed using coils, alcohol, and glue. Postprocedural angiography showed complete eradication of the nidus.     

Mealtime Regularity Is Associated with Dietary Balance among Preschool Children in Japan—A Study of Lifestyle Changes during the COVID-19 Pandemic

The novel coronavirus-19 (COVID-19) pandemic has considerably impacted children’s lives. The aim of this study was to determine whether the pandemic affected mealtime regularity among preschool children and whether maintaining regular mealtimes or changes in mealtime regularity during the pandemic were related to dietary balance, including chronological relationships. This online cross-sectional survey involving individuals registered with a company that provides meals to children aged 2−6 years was conducted in February 2021. Using a 40-point scale, a healthy diet score (HDS) was developed to evaluate children’s dietary balance. The participants were divided into four groups based on their responses, and multiple regression analyses were performed with the HDS as the dependent variable. Maintaining regular mealtimes was associated with practices such as waking and going to bed earlier, less snacking, and eating breakfast every day. Even after adjusting for basic attributes, lifestyle habits, household circumstances, and other factors, regular mealtimes were still positively correlated with the HDS. These findings indicate that maintaining regular mealtimes is associated with higher HDS scores and better lifestyle habits. Furthermore, as the changed HDS was higher in the group whose mealtimes became regular during the pandemic, adopting regular mealtimes may lead to a more balanced diet.     

Increased insulin sensitivity and hypoinsulinemia in APS knockout mice

A tyrosine kinase adaptor protein containing pleckstrin homology and SH2 domains (APS) is rapidly and strongly tyrosine phosphorylated by insulin receptor kinase upon insulin stimulation. The function of APS in insulin signaling has heretofore remained unknown. APS-deficient (APS(-/-)) mice were used to investigate its function in vivo. The blood glucose-lowering effect of insulin, as assessed by the intraperitoneal insulin tolerance test, was increased in APS(-/-) mice. Plasma insulin levels during fasting and in the intraperitoneal glucose tolerance test were lower in APS(-/-) mice. APS(-/-) mice showed an increase in the whole-body glucose infusion rate as assessed by the hyperinsulinemic-euglycemic clamp test. These findings indicated that APS(-/-) mice exhibited increased sensitivity to insulin. However, overexpression of wild-type or dominant-negative APS in 3T3L1 adipocytes did not affect insulin receptor numbers, phosphorylations of insulin receptor, insulin receptor substrate-1, or Akt and mitogen-activated protein kinase. The glucose uptake and GLUT4 translocation were not affected by insulin stimulation in these cells. Nevertheless, the insulin-stimulated glucose transport in isolated adipocytes of APS(-/-) mice was increased over that of APS(+/+) mice. APS(-/-) mice also showed increased serum levels of leptin and adiponectin, which might explain the increased insulin sensitivity of adipocytes.