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Four commercially available penicillin preparations (benzylpenicillin, aminobenzylpenicillin, carbenicillin and sulbenicillin) and two kinds of the new semisynthetic penicillin preparations (mezlocillin and piperacillin) evoked systemic anaphylactic reactions in guinea pigs immunized with one of the following penicillin- Ascaris extract (As) conjugates in aluminum hydroxide gel (alum), i.e., benzylpenicilloyl (BPO)-As, aminobenzylpenicilloyl (ABPO)-As, carbenicilloyl (CBPO)-As, sulbenicilloyl (SBPO)-As, meziocillin-As conjugate (MEZ-As) and piperacillin-As conjugate (PIP-As). The tracheal chains prepared from the tracheas of the guinea pigs immunized with BPO-As, MEZ-As, or PIP-As revealed anaphylactic contractions in vitro on addition of benzylpenicillin, meziocillin, or piperacillin preparations. These results indicated that the semisynthetic penicillin preparations as well as benzylpenicillin preparation have enough antigenicity to evoke systemic anaphylactic reactions in guinea pigs immunized with penicillin-As conjugate. Such guinea pigs seem to be suitable animals for investigation of penicillin allergy. [ABSTRACT FROM AUTHOR]

Cefotiam (CTM) is one of the most popular cephem antibiotics in Japan. Recently we experienced two cases of nurses with CTM-induced contact anaphylaxis. When they were preparing drip infusions of antibiotics or working around other nurses doing so. they suddenly fell into shock with other symptoms such as flushing, urticaria, abdominal distress, vomiting, dyspnoea and or loss of consciousness. The symptoms never occurred after they avoided exposure to CTM. Passive cutaneous or open patch tests were positive for CTM. Histamine release was induced by CTM from washed leucocytes. RAST analysis using CTM-human serum albumin-coupled discs showed high % RAST count, suggesting that these reactions were mediated by IgE-antibodies. A RAST inhibition lest suggested that the methyl-thiotetrazol side-chain was the main antigenic determinant. Both patients had hand dermatitis that had appeared preceding the episodes of anaphylaxis. Although the dermatitis had been resistant to treatments, it also disappeared after they avoided exposure to CTM. It seemed likely that it was also induced or exacerbated by CTM and facilitated the penetration of CTM to cause anaphylaxis. The literature is also reviewed. [ABSTRACT FROM AUTHOR]

The article presents a study of the incidence and the type of reaction produced by a given drug in Japan, and the factors that predispose a person to the drug hypersensitivity reaction. Mass surveys on drug hypersensitivities were done on four occasions. Each group consisted of white collar workers belonging to companies in Tokyo, Japan. All companies had their own clinical offices and physicians serving the employees. A questionnaire was delivered to each member of the group through the clinical office of that company. The contents of the questionnaire included age, sex, use of drugs in the past, and past and family histories of allergic diseases.

Abstract Background Since equine influenza A virus (H3N8) was transmitted to dogs in the United States in 2004, the causative virus, which is called canine influenza A virus (CIV), has become widespread in dogs. To date, it has remained unclear whether or not CIV-infected dogs could transmit CIV to horses. To address this, we tested whether or not close contact between horses and dogs experimentally infected with CIV would result in its interspecies transmission. Methods Three pairs of animals consisting of a dog inoculated with CIV (108.3 egg infectious dose50/dog) and a healthy horse were kept together in individual stalls for 15 consecutive days. During the study, all the dogs and horses were clinically observed. Virus titres in nasal swab extracts and serological responses were also evaluated. In addition, all the animals were subjected to a gross pathological examination after euthanasia. Results All three dogs inoculated with CIV exhibited clinical signs including, pyrexia, cough, nasal discharge, virus shedding and seroconversion. Gross pathology revealed lung consolidations in all the dogs, and Streptococcus equi subsp. zooepidemicus was isolated from the lesions. Meanwhile, none of the paired horses showed any clinical signs, virus shedding or seroconversion. Moreover, gross pathology revealed no lesions in the respiratory tracts including the lungs of the horses. Conclusions These findings may indicate that a single dog infected with CIV is not sufficient to constitute a source of CIV infection in horses.

Nanoparticles have useful functions due to the characteristics conferred on them by an increase in their specific surface area, and they have already been put into practical use in products in various industrial fields. Although exposure to nanoparticles in daily life is unavoidable for pregnant women, studies that evaluate the toxicity of nanoparticles in pregnant women are lacking. To redress this, we have focused on the placenta and have previously revealed that nanoparticles can show placental toxicity. However, there is still little knowledge regarding the behavior of nanoparticles within placental cells, which would enable us to understand their mode of action. Here, we tried to clarify the intracellular localization of silica nanoparticles in placental cells and how this affects placental toxicity. We analyzed the uptake of silica nanoparticles with a diameter of 10 nm (nSP10) into JEG-3 cells, a human choriocarcinoma cell line. Flow cytometry analysis showed that nSP10 labelled with red fluorescence were taken up into JEG-3 cells, and that pre-treatment with the endocytosis inhibitor cytochalasin D inhibited their uptake, suggesting that nSP10 are taken up into JEG-3 cells by the endocytic pathway. Moreover, confocal microscopy revealed that nSP10 are prominently localized in lysosomes. Staining with LysoTracker showed that nSP10 treatment increased the acidic compartment of JEG-3 cells, suggesting lysosome accumulation and swelling. These results indicate that nSP10 taken into placental cells are transferred to lysosomes and may cause lysosomal dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Not only gray matter lesions (GMLs) but also white matter lesions (WMLs) can play important roles in the pathology of Alzheimer's disease (AD). The progression of cognitive impairment (CI) and behavioral and psychological symptoms of dementia (BPSD) might be caused by a concerted effect of both GML and WML., Objective: This study aimed to investigate the association between GML and WML and how they are involved in the symptoms of CI and BPSD in dementia patients by means of imaging technology., Methods: Patients in our memory clinic, who were diagnosed with AD-type dementia or amnestic mild cognitive impairment (aMCI) and had undergone both single-photon emission computed tomography (SPECT) and brain MRI, were consecutively enrolled ( n = 156; 61 males and 95 females; 79.8 ± 7.4 years old). Symptoms of CI and BPSD were obtained from patients' medical records. For the analysis of GMLs and WMLs, SPECT data and MRI T1-weighted images were used, respectively. This study followed the Declaration of Helsinki, and all procedures were approved by the institutional ethics committee., Results: According to a multivariate analysis, disorientation and disturbed attention demonstrated a relationship between the precuneus and WMLs in both hemispheres. Hyperactivity in BPSD showed multiple correlations between GMLs on both sides of the frontal cortex and WMLs. Patients with aMCI presented more multiple correlations between GMLs and WMLs compared with those with AD-type dementia regarding dementia symptoms including BPSD., Conclusion: The interaction between GMLs and WMLs may vary depending on the symptoms of CI and BPSD. Hyperactivity in BPSD may be affected by the functional relationship between GMLs and WMLs in the left and right hemispheres. The correlation between GMLs and WMLs may be changing in AD-type dementia and aMCI.

Introduction: Present study was to investigate hs-CRP concentration, brain structural alterations, and cognitive function in the context of AD [Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and AD]., Methods: We retrospectively included 313 patients (Mean age = 76.40 years, 59 SCD, 101 MCI, 153 AD) in a cross-sectional analysis and 91 patients (Mean age = 75.83 years, 12 SCD, 43 MCI, 36 AD) in a longitudinal analysis. Multivariable linear regression was conducted to investigate the relationship between hs-CRP concentration and brain structural alterations, and cognitive function, respectively., Results: Hs-CRP was positively associated with gray matter volume in the left fusiform (β = 0.16, p FDR = 0.023) and the left parahippocampal gyrus (β = 0.16, p FDR = 0.029). Post hoc analysis revealed that these associations were mainly driven by patients with MCI and AD. The interaction of diagnosis and CRP was significantly associated with annual cognitive changes (β = 0.43, p = 0.008). Among these patients with AD, lower baseline CRP was correlated with greater future cognitive decline ( r = -0.41, p = 0.013)., Conclusion: Our study suggests that increased hs-CRP level may exert protective effect on brain structure alterations and future cognitive changes among patients already with cognitive impairment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Tatewaki, Nakase, Liu, Tomita, Thyreau, Zheng, Muranaka, Takano, Nagasaka and Taki.)

Fucosylated proteins are widely used as biomarkers of cancer and inflammation. Fucosylated alpha-fetoprotein (AFP-L3) is a specific biomarker for hepatocellular carcinoma. We previously showed that increases in serum AFP-L3 levels depend on increased expression of fucosylation-regulatory genes and abnormal transport of fucosylated proteins in cancer cells. In normal hepatocytes, fucosylated proteins are selectively secreted in the bile duct but not blood. In cases of cancer cells without cellular polarity, this selective secretion system is destroyed. Here, we aimed to identify cargo proteins involved in the selective secretion of fucosylated proteins, such as AFP-L3, into bile duct-like structures in HepG2 hepatoma cells, which have cellular polarity like, in part, normal hepatocytes. α1-6 Fucosyltransferase (FUT8) is a key enzyme to synthesize core fucose and produce AFP-L3. Firstly, we knocked out the FUT8 gene in HepG2 cells and investigated the effects on the secretion of AFP-L3. AFP-L3 accumulated in bile duct-like structures in HepG2 cells, and this phenomenon was diminished by FUT8 knockout, suggesting that HepG2 cells have cargo proteins for AFP-L3. To identify cargo proteins involved in the secretion of fucosylated proteins in HepG2 cells, immunoprecipitation and the proteomic Strep-tag system experiments followed by mass spectrometry analyses were performed. As a result of proteomic analysis, seven kinds of lectin-like molecules were identified, and we selected vesicular integral membrane protein gene VIP36 as a candidate of the cargo protein that interacts with the α1-6 fucosylation (core fucose) on N -glycan according to bibliographical consideration. Expectedly, the knockout of the VIP36 gene in HepG2 cells suppressed the secretion of AFP-L3 and other fucosylated proteins, such as fucosylated alpha-1 antitrypsin, into bile duct-like structures. We propose that VIP36 could be a cargo protein involved in the apical secretion of fucosylated proteins in HepG2 cells.

Background and Purpose: Ginkgo biloba extract (GBE) reportedly ameliorates cognitive function in patients with chronic cerebrovascular insufficiency. However, its efficacy in healthy adults is ambiguous. It was reported that concentrations of terpene lactones, active components of GBE that are present in very low concentrations in the brain, were significantly increased following administration of a mixture of GBE, sesame seed, and turmeric (GBE/MST) in mice. This study aims to investigate the effectiveness of GBE/MST on the cognitive function of healthy adults by comparing it with that of GBE alone., Methods: Altogether, 159 participants providing informed consent will be recruited from a population of healthy adults aged 20-64 years. Normal cognitive function at baseline will be confirmed using the Japanese version of the Montreal Cognitive Assessment battery. Participants will be randomly assigned in a double-blind manner to the GBE/MST, GBE, and placebo groups in a 1:1:1 ratio. The Wechsler Memory Scale, Trail Making Test, and Stroop Color and Word Test will be used to assess the memory and executive functions at baseline and at the endpoint (24 weeks). For biological assessment, resting state functional magnetic resonance imaging (rs-fMRI) will be performed simultaneously with the neuropsychological tests., Discussion: This study aims to obtain data that can help compare the profile changes in memory and executive functions among participants consuming GBE/MST, GBE alone, and placebo for 24 weeks. Alterations in the default mode network will be evaluated by comparing the rs-fMRI findings between baseline and 24 weeks in the aforementioned groups. Our results may clarify the impact of GBE on cognitive function and the functional mechanism behind altered cognitive function induced by GBE components., Trial Registration: This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; registration number: UMIN000043494). This information can be searched on the website of the International Clinical Trials Registry Platform Search Portal of the World Health Organization under the Japan Primary Registries Network., Competing Interests: TN is paid a part of salary by the founder. This does not alter our adherence to PLOS ONE policies on sharing data and materials. YTat, IM, KK, HI, HA, RE, MM, TM, and YTak do not have any COI., (Copyright: © 2023 Nakase et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Flunixin meglumine (FM), a nonselective cyclooxygenase (COX) inhibitor, is most frequently selected for the treatment of equine systemic inflammatory response syndrome (SIRS)/endotoxemia. However, FM has considerable adverse effects on gastrointestinal function. The aims of this study were to compare the effect of meloxicam (MX), a COX-2 selective inhibitor commonly used in equine clinical practice, with FM, and to investigate the potential for clinical application in horses with SIRS/endotoxemia. Fifteen horses were divided into three groups of five and orally administered MX (0.6 mg/kg), FM (1.1 mg/kg), or saline as placebo at 30 minutes after LPS challenge. Clinical parameters, including behavioral pain scores, were recorded and blood for clinical pathological data was collected at various times from 60 minutes before to 420 minutes after LPS infusion. The pain score were significantly lower in both the MX and FM groups than in the placebo group, with no significant difference between them. Body temperature was significantly lower in the MX and FM groups than in the placebo group. Heart rates and respiratory rates, hoof wall surface temperature, and leukocyte counts changed similarly between the MX and FM groups. TNF-α and cortisol were lower in the FM group than in the MX group. The results suggest that MX suppresses the inflammatory response after LPS infusion and has an analgesic effect similar to that of FM. Given the adverse effects of nonselective COX inhibitors, clinical application of MX may be beneficial in horses with SIRS/endotoxemia., (Copyright © 2022. Published by Elsevier Inc.)

Background: Atrial fibrillation (AF) is a strong risk factor for Alzheimer's disease (AD) independent of ischemic stroke. However, the clinicopathological impact of AF on the severity of AD has not been well elucidated. We aimed to investigate the clinical differences between dementia patients with AF and those without AF by means of imaging data., Methods: Following approval from the institutional ethics committee, patients with newly diagnosed AD or amnestic mild cognitive impairment (aMCI) were retrospectively screened (n = 170, 79.5 ± 7.4 years old). Cognitive function was assessed using the Mini-Mental State Examination (MMSE). Based on the MRI data, the cerebral volume, cerebral microbleeds (CMBs), periventricular white matter lesions (WMLs), and deep WMLs were evaluated. The regional cerebral blood flow (rCBF) was measured using 123 I-IMP SPECT., Results: Of the patients, 14 (8.2%) and 156 (91.8%) had AF (AF group) and sinus rhythm (SR group), respectively. The AF group had significantly lower MMSE scores than the SR group (average [standard deviation (SD)]: 19.4 [4.4] and 22.0 [4.4], respectively; p = 0.0347). Cerebral volume and CMBs did not differ between the two groups. The periventricular WMLs, but not the deep WMLs, were significantly larger in the AF group than in the SR group (mean [SD] mL: 6.85 [3.78] and 4.37 [3.21], respectively; p = 0.0070). However, there was no significant difference in rCBF in the areas related to AD pathology between the two groups., Conclusion: AD and aMCI patients with AF showed worse cognitive decline along with larger periventricular WMLs compared to those with SR, although the reduction of rCBF was not different between patients with AF and SR. The white matter lesions may be a more important pathology than the impairment of cerebral blood flow in dementia patients with AF. A larger study is needed to confirm our findings in the future., (© 2023. The Author(s).)

Histidine-rich glycoprotein (HRG) is abundant plasma protein with various effects on angiogenesis, coagulation, and immune responses. Previously, we identified the base and amino acid sequences of equine HRG (eHRG) and revealed that eHRG regulates neutrophil functions. In this study, we first conducted a large-scale gene analysis with DNA samples extracted from 1700 Thoroughbred horses and identified unique insertion/deletion polymorphisms in the histidine-rich region (HRR) of eHRG. Here we report two types of polymorphisms (deletion type 1 [D1] and deletion type 2 [D2]) containing either a 45 bp or 90 bp deletion in the HRR of eHRG, and five genotypes of eHRG (insertion/insertion [II], ID1, ID2, D1D1, and D1D2) in Thoroughbred horses. Allele frequency of I, D1, and D2, was 0.483, 0.480, and 0.037 and the incidence of each genotype was II: 23.4%, ID1: 46.2%, ID2: 3.6%, D1D1: 23.1%, and D1D2: 3.7%, respectively. The molecular weights of each plasma eHRG protein collected from horses with each genotype was detected as bands of different molecular size, which corresponded to the estimated amino acid sequence. The nickel-binding affinity of the D1 or D2 deletion eHRG was reduced, indicating a loss of function at the site. eHRG proteins show a variety of biological and immunological activities in vivo, and HRR is its active center, suggesting that genetic polymorphisms in eHRG may be involved in the performance in athletic ability, productivity, and susceptibility to infectious diseases in Thoroughbred horses., (© 2023. The Author(s).)

We have previously demonstrated the excellent bactericidal activity of josamycin against Staphylococcus aureus isolated from patients with atopic dermatitis (AD), with therapeutic efficacy equal to that of betamethasone. The present study was designed to evaluate the effectiveness of combination therapy with betamethasone and josamycin for AD. Betametasone (0.1%) and josamycin (0.1%) were topically administered to NC/Nga mice with severe AD-like skin lesions. Skin severity scores, histological changes in skin lesions, and serum immunoglobulin E (IgE) levels were assessed as indicators of therapeutic efficacy. Topical treatment with both drugs suppressed the skin severity score to a greater degree than betamethasone alone. This was associated with a reduction of epidermal thickening, a reduced density of dermal cellular infiltration, a decreased mast cell count in the dermis, and a reduced serum IgE level. In addition, both drugs in combination markedly reduced the expression of interferon (IFN)-γ and interleukin (IL)-4 in auricular lymph node cells, as well as the S. aureus count on the lesioned skin. These results show that simultaneous topical application of both drugs can ameliorate severe AD-like skin lesions in NC/Nga mice. It is suggested that combination therapy with betamethasone and josamycin would be beneficial for control of severe AD lesions colonized by S. aureus by inhibiting the development of both T helper (Th) type 1 (Th1) and Th2 cells and also through elimination of superficially located S. aureus.

Background and Purpose: In terms of the gut-brain axis, constipation has been considered to be an important factor of neurodegenerative diseases, although the exact mechanism is still controversial. Herein, we aimed to investigate the contribution of constipation to the progression of dementia in a retrospective study., Methods: Patients of Alzheimer's disease(AD) and amnestic mild cognitive impairment were consecutively screened between January 2015 and December 2020, and those of whom brain MRI and neuropsychological tests were performed twice were enrolled in this study. Participants were classified into with constipation (Cons[+], n = 20) and without constipation (Cons[-], n = 64) groups. Laboratory data at the first visit were used. Regression analysis was performed in MMSE, ADAS-Cog, and the volumes of hippocampus on MRI-MPRAGE images and deep white matter lesions (DWMLs) on MRI-FLAIR images obtained at two different time points., Results: The main finding was that the Cons[+] group showed 2.7 times faster decline in cognitive impairment compared with the Cons[-] group, that is, the liner coefficients of ADAS-Cog were 2.3544 points/year in the Cons[+] and 0.8592 points/year in the Cons[-] groups. Ancillary, changes of DWMLs showed significant correlation with the time span (p < 0.01), and the liner coefficients of DWMLs were 24.48 ml/year in the Cons[+] and 14.83 ml/year in the Cons[-] group, although annual rate of hippocampal atrophy was not different between the two groups. Moreover, serum homocysteine level at baseline was significantly higher in the Cons[+] group than Cons[-] group (14.6 ± 6.4 and 11.5 ± 4.2 nmol/ml, respectively: p = 0.03)., Conclusion: There is a significant correlation between constipation and faster progression of AD symptoms along with expansion of DWMLs., (© 2022 The Authors. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Both objective and perceived social isolations were associated with future cognitive decline and increase risk of Alzheimer's disease (AD). However, the impacts of perceived social isolation depending on different clinical stages of AD have not been elucidated. The aim of this study was to investigate the influence of perceived social isolation or loneliness on brain structure and future cognitive trajectories in patients who are living with or are at risk for AD. A total of 176 elderly patients (mean age of 78 years) who had complaint of memory problems (39 subjective cognitive decline [SCD], 53 mild cognitive impairment [MCI], 84 AD) underwent structural MRI and neuropsychological testing. Loneliness was measured by one binary item question "Do you often feel lonely?." Voxel-based morphometry was conducted to evaluate regional gray matter volume (rGMV) difference associated with loneliness in each group. To evaluate individual differences in cognitive trajectories based on loneliness, subgroup analysis was performed in 51 patients with AD (n = 23) and pre-dementia status (SCD-MCI, n = 28) using the longitudinal scores of Alzheimer's Disease Assessment Scale-cognitive component-Japanese version (ADAS-Jcog). Whole brain VBM analysis comparing lonely to non-lonely patients revealed loneliness was associated with decreased rGMV in bilateral thalamus in SCD patients and in the left middle occipital gyrus and the cerebellar vermal lobules I - V in MCI patients. Annual change of ADAS-Jcog in patients who reported loneliness was significantly greater comparing to these non-lonely in SCD-MCI group, but not in AD group. Our results indicate that perceived social isolation, or loneliness, might be a comorbid symptom of patients with SCD or MCI, which makes them more vulnerable to the neuropathology of future AD progression., (© 2022. The Author(s), under exclusive licence to American Aging Association.)

Background: Inspiratory muscle fatigue (IMF) may impair performance in a subsequent exercise. A few studies have reported that IMF decreased swimming performance in submaximal intensity or severe intensity domain. However, the impact of IMF on high-intensity short-duration swimming is not clear. The purpose of this study was to clarify the effect of preinduced IMF on extreme intensity domain swimming., Methods: Seven male competitive swimmers swam two 100-meter all-out front crawl swimming trials with and without preinduced IMF. Maximal inspiratory and expiratory mouth pressure (PImax and PEmax, respectively) was used as indicators of inspiratory and expiratory muscle strength before and after swimming, and stroke parameters during swimming were measured. IMF was achieved by having the subjects breathe against an inspiratory pressure threshold load while generating 40% of their predetermined PImax for 10 minutes., Results: After the induction of IMF, swimming time (55.94±1.15 s) was significantly slower compared with that in control swimming without IMF (54.09±0.91 s) (P<0.05). During swimming followed IMF, a significant decrease in stroke rate and a significant increase in stroke length were observed in the latter half of the 100-meter swimming trial. In addition, the sense of dyspnea was significantly higher in swimming in the IMF condition than in control condition., Conclusions: IMF prior to swimming negatively affects swimming performance in the extreme intensity domain. It is suggested that due to the dual use of respiration and generate propulsion in accessory respiratory muscles, IMF affected swimmers' ability to maintain swimming velocity.

Background: Although Clostridioides difficile -associated diseases (CDAD) is considered to be associated with colitis in horses, few studies have been performed with a focus on the characteristics of CDAD in thoroughbred racehorses., Methods: Between 2010 and 2018, a test for C. difficile was performed using faecal samples from 137 thoroughbred racehorses with colitis presenting with diarrhoea and fever. The mortality rate, clinical findings, predisposing factors and the selected treatments were investigated in a retrospective manner., Results: Twenty-four cases were diagnosed as CDAD and 113 as non-CDAD. The mortality rate was significantly higher in the CDAD group (83 per cent) than that in the non-CDAD group (34 per cent). The levels of serum amyloid A, blood urea nitrogen and packed cell volume at initial presentation were also significantly higher, and those of total protein and albumin were significantly lower in the CDAD group. The development of CDAD was associated with the administration of antimicrobials, surgery and hospitalisation. No significant improvement in mortality was observed for any of the selected treatment in both groups., Conclusion: CDAD in thoroughbred racehorses was identified as a high mortality disease with rapid progression of systemic inflammation and deterioration of the circulatory state. Further investigation is required to improve the treatment., Competing Interests: Competing interests: None declared., (© British Veterinary Association 2020. No commercial re-use. See rights and permissions. Published by BMJ.)