This study aimed to clarify the optimal value for the unbound cefmetazole concentration to remain above the minimum inhibitory concentration (MIC) (fT ≥ MIC) for efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing Escherichia coli. This double-center retrospective observational study was conducted at Tokyo Bay Urayasu Ichikawa Medical Center and Keio University Hospital from January 2012 to October 2022. Efficacy was determined via clinical evaluation (mortality rate, recurrence rate, vital changes) and bacteriological evaluation, and the optimal fT ≥ MIC was calculated via receiver operating characteristic curve analysis. As a result, the number of patients evaluated were 40 (35 and 5 in the treatment success and treatment failure groups, respectively). Univariate analysis showed that fT ≥ MIC, recurrence rate, and MIC for cefmetazole against bacteria were significantly different for the two groups (p < 0.05). Receiver operating characteristic curve analysis showed that the optimal fT ≥ MIC indicating efficacy was 57% (area under the curve: 0.94, 95% confidence interval: 0.86–1.00, p = 0.002). All patients with fT ≥ MIC ≥ 57% had successful treatment, whereas the frequency of treatment failure was high among those with fT ≥ MIC <57%. The optimal fT ≥ MIC for the clinical efficacy of de-escalation to cefmetazole in patients with bacteremic urinary tract infection by extended-spectrum β-lactamase-producing E. coli was fT ≥ MIC ≥ 57%. This finding would be useful for optimal dosing of cefmetazole.

The central histamine system is involved in several physiological behaviors and neurological disorders, including the sleep–wake cycle, anxiety-related behaviors (both high and low anxiety), and attention deficit hyperactivity disorder (ADHD). Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) and primarily metabolized by histamine-N-methyltransferase (HNMT) in the central nervous system. We previously reported that mice with intermittent sleep deprivation may exhibit impulsive-like symptoms resembling ADHD and low-anxiety behavior. However, the specific role of histaminergic systems in these behaviors remains unclear. In this study, we evaluated HDC expression levels in the hypothalamus as well as the expression of histamine H1 to H4 receptors and HNMT in the hypothalamus and frontal cortex of sleep-deprived mice. Moreover, the effects of administering histidine, a histamine precursor, and inhibitors of each histamine receptor on sleep deprivation-induced low-anxiety and impulsive-like behaviors were examined using an elevated plus maze test. The expressions of HDC and histamine H1 and H3 receptors in the hypothalamus increased, while that of histamine H1 receptors in the frontal cortex of sleep-deprived mice decreased. The low-anxiety and impulsive-like behaviors in intermittent sleep-deprived mice significantly decreased and increased, respectively, following the administration of histamine H1 and H3 receptor blockers and histidine. Collectively, these findings suggest that the low-anxiety behavior and impulsive-like ADHD symptoms induced by intermittent sleep deprivation may result from the overstimulation of histamine H1 and H3 receptors by elevated histamine, together with increased hypothalamic HDC expression. Furthermore, they suggest that sufficient sleep may contribute to ameliorating ADHD symptoms.

Detecting low-frequency genetic mutations is crucial for genetic testing, especially in cancer diagnostics. Wild-type blocking PCR identifies these genetic mutations using a blocking oligonucleotide that is fully complementary to wild-type DNA. The blocking oligonucleotide selectively binds to wild-type DNA, inhibiting its amplification by DNA polymerase and allowing preferential amplification of mutant DNA. Bridged nucleic acids (BNAs), with high binding affinities for cDNA, are often incorporated into the blocking oligonucleotide to enhance inhibition. However, the effects of BNA positioning within the blocking oligonucleotide on wild-type DNA amplification inhibition are poorly understood. To address this issue, we evaluated the effects of different BNA positions on amplification inhibition efficacy by comparing blocking oligonucleotides with varying numbers of BNAs at the 5′ end, 3′ end, and central region. Results indicated that BNAs at the 5′ end enhanced the inhibition efficacy, whereas BNAs at the 3′ end notably diminished the inhibition efficacy. Likewise, increasing the number of BNAs in the central region generally decreased the inhibition efficacy. This is one of the first studies to report the importance of BNA positioning in the amplification inhibition efficacy of blocking oligonucleotides.

Ergothioneine (ERGO) has antioxidant and anti-inflammatory activities in UV-irradiated skin cells in vitro; however, there is no evidence about the effects of dietary ERGO on UV-induced skin damage or ERGO skin distribution in vivo. This study examined the protective effects of ERGO-rich edible mushrooms Pleurotus species against UVB-induced skin damage and the exposure to ERGO in the plasma and skin. Hos : HR-1 hairless mice were fed with or without freeze-dried cross-bred Pleurotus species (PS) or Pleurotus eringii (PE) and were exposed to UVB. Dietary intake of PS or PE significantly alleviated UVB-induced reductions in skin moisture content, increases in transepidermal water loss and oxidative stress markers, and epidermal thickening at plasma ERGO concentrations of 30–40 μM. Additionally, ingestion of PS significantly suppressed UVB-induced expression of pro-inflammatory cytokines. These results suggest that ingesting PS and PE may protect against UVB-induced skin disorders through antioxidant and anti-inflammatory activities at clinically relevant ERGO concentrations. Ingestion of PS and PE led to an increase in epidermal ERGO concentration to levels that were approx. 100 times higher than the ERGO concentration required for significant suppression of UVB-induced intracellular reactive oxygen species in immortalized human keratinocyte HaCaT cells. This suggests that the beneficial effects of PS and PE may be at least partly due to the antioxidant effects of ERGO in murine skin. Overall, ingestion of ERGO-rich Pleurotus species resulted in efficient distribution of ERGO to the skin and protective effects against UVB-induced skin damage, suggesting that these mushrooms may have beneficial effects in humans.

mRNA vaccines have emerged as promising platforms for the prevention of infectious diseases and cancer treatment. The antigenic protein has a signal peptide added to the N-terminus for extracellular secretion. However, it remains unclear whether the optimization of signal peptides has been sufficiently compared and examined for antigen protein secretion and immunogenicity. This study investigated the effects of various signal peptides on the extracellular secretion of a model protein, NanoLuc luciferase (Nluc), in different cell lines. We compared the secretion efficiency of Nluc fused to artificial (#38 and #34) and natural signal peptides (cystatin S, lactotransferrin, and tissue plasminogen activator) in human embryonic kidney 293, C2C12, and HepG2 cells. Luciferase assays and Western blot analysis revealed that the cystatin S signal peptide consistently induced the highest secretion of Nluc among all cell types tested. Notably, the cystatin S signal peptide outperformed previously reported tissue plasminogen activator signal peptides in terms of secretion efficiency. Furthermore, we observed no correlation between Nluc secretion and mRNA expression levels for each signal peptide, suggesting that enhanced secretion was not attributable to increased transcription. Our findings highlight the potential of the cystatin S signal peptide in enhancing the extracellular secretion of antigenic proteins in mRNA vaccines by improving the efficiency of protein translation.