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Abstract Background Hemoplasma infections in cattle are caused by Mycoplasma wenyonii and Candidatus Mycoplasma haemobos and induce asymptomatic or chronic infections but occasionally lead to life-threatening hemolytic anemia. Despite the global distribution of bovine hemoplasmas, information regarding their transmission vectors and prevalence is still lacking in the Republic of Korea. Therefore, this study aims to investigate the infection rate of bovine hemoplasma in cattle and houseflies and to assess the risk factors associated with hemoplasma infection in cattle. Methods Overall, 376 blood samples were collected from Korean indigenous cattle (male, 10−13 months old), along with 2,690 houseflies (Musca domestica) from the same farm where the cattle were raised. PCR assays targeting the 16S rRNA gene were performed to detect hemoplasmas, and positive samples were sequenced. Results The infection rate of bovine hemoplasmas was 50.8% (191/376) in cattle and 7.4% in pooled houseflies. Among cattle, 18.6% (70/376) and 20.0% (75/376) tested positive for M. wenyonii and Candidatus M. haemobos, respectively. Conversely, in houseflies, Candidatus M. haemobos was more frequently detected (5.9%) than M. wenyonii (0.7%). Co-infection was 12.2% (46/376) in cattle and 0.7% in flies. Furthermore, hemoplasma infection was significantly associated with the grazing experience of their dams. Cattle born to cows with grazing experience exhibited a higher risk for M. wenyonii infection (odds ratio [OR] = 1.62; 95% confidence interval [CI]: 1.03−2.55; P = 0.045), whereas these cattle had a lower risk for Candidatus M. haemobos infection (OR = 0.32, 95% CI: 0.19−0.74; P = 0.000) than animals born to cows without grazing experience. The sequences obtained from houseflies were confirmed as Candidatus M. haemobos, which displayed high similarity (98.2−100%) to those from cattle obtained in this study. Conclusions To our knowledge, this study represents the first report of bovine hemoplasmas identified in houseflies. This molecular evidence suggests that houseflies may be possible vectors for Candidatus M. haemobos.

Formononetin is a major isoflavone contained in propolis and is reported to exhibit various pharmacological effects. However, the use of formononetin in pharmaceutical industry is limited due to its low bioavailability and solubility. There had been several efforts on formononetin formulation development, but further study is required to acquire optimal formulation. The aim of this study is to conduct pharmacokinetic (PK) evaluations after the oral administration of three formononetin formulations (20 mg/kg) in male Sprague Dawley rats. Then, a parent-metabolite PK model for formononetin was developed and evaluated for the first time. To do this, a simultaneous analysis method for formononetin and its active metabolites, daidzein, dihydrodaidzein and equol in rat plasma was developed using ultra-performance liquid chromatography tandem mass spectrometry. The separation was performed using a gradient elution of water and acetonitrile and a Kinetex C18 column (2.1 mm × 100 mm, 1.7 µm particle size) at a temperature of 30 ± 5 °C. The simultaneous analytical method developed in this study was validated according to international guidance and was successfully applied for the pharmacokinetic study. The time-plasma concentrations of formononetin and daidzein were well described by a two-compartment model combined with a metabolite compartment. Additionally, plasma protein binding assay was conducted in male rat plasma. The findings from the study could be used as a fundamental for the future development of formononetin as a pharmaceutical product.

Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger approved for the treatment of amyotrophic lateral sclerosis, a fatal neuromuscular disease. Edaravone is administered as an intravenous infusion over 60 min for several treatment cycles. To ease the burden of patients and caregivers, the oral formulation of edaravone has been developed. The purpose of this study was to evaluate pharmacokinetics and tissue distribution of TEJ-1704, an edaravone oral prodrug, in male Sprague Dawley rats and beagle dogs. Animal experiments were conducted using Sprague Dawley rats and beagle dogs to evaluate pharmacokinetics, tissue distribution, and excretion of TEJ-1704. Blood, tissues, cerebrospinal fluid, urine, and feces samples were collected at designated sampling time after intravenous (IV) or oral (PO) administration of edaravone or TEJ-1704. A modified bioanalysis method was developed to quantify edaravone in samples including plasma, tissues, cerebrospinal fluid, urine, and feces. The bioanalysis method was validated and successfully applied to pharmacokinetics, tissue distribution, and excretion studies of the novel edaravone prodrug. Although plasma Cmax of TEJ-1704 was low, groups administered with TEJ-1704 had high AUCinf, suggesting continuous metabolism of TEJ-1704 into edaravone. Groups treated with TEJ-1704 also showed lower CSF distribution than the control groups. After the administration of TEJ-1704, the majority of edaravone was distributed to the heart, lung, and kidney. It was excreted equally via urine and feces. The pharmacokinetics, tissue distribution, and excretion of TEJ-1704, a novel edaravone oral prodrug, were successfully characterized. Additional studies are needed to fully understand the difference between TEJ-1704 and edaravone and determine the potency of TEJ-1704.

Abstract Objective In comparison with amyotrophic lateral sclerosis (ALS), the contribution of neuroinflammation in spinobulbar muscular atrophy (SBMA) has been less explored. We investigated the role of neuroinflammation in the pathogenesis of ALS and SBMA by analyzing systemic inflammatory markers and osteopontin (Spp1). Methods This study involved 105 ALS, 77 SBMA, and 55 healthy controls. We measured their systemic inflammatory markers, serum Spp1, and cytokine levels (interferon‐γ, interleukin [IL]‐1β, IL‐6, IL‐8, IL‐10, tumor necrosis factor‐α, and IL‐17A), investigated correlations between Spp1 levels and clinical features, and evaluated ALS survival rates according to Spp1 levels. Results In the ALS group, systemic inflammatory markers were significantly higher than in the control and SBMA groups. Spp1 levels were observed to be higher in ALS patients, but the difference was not statistically significant among the study groups. Cytokine profiles were comparable. In ALS, higher Spp1 levels were correlated with lower ALS Functional Rating Scale‐Revised (ALSFRS‐R) scores (r = −0.25, p = 0.02) and faster disease progression rate (r = 0.37, p

Background: The brain–gut axis has emerged as a potential target in neurodegenerative diseases, including dementia, as individuals with dementia exhibit distinct gut microbiota compositions. Fecal microbiota transplantation (FMT), the transfer of fecal solution from a healthy donor to a patient, has shown promise in restoring homeostasis and cognitive enhancement. Objective: This study aimed to explore the effects of FMT on specific cognitive performance measures in Alzheimer’s dementia (AD) patients and investigate the relationship between cognition and the gut microbiota by evaluating changes in gene expression following FMT. Methods: Five AD patients underwent FMT, and their cognitive function [Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating Scale Sum of Boxes (CDR-SOB)] was assessed before and after FMT. The patients’ fecal samples were analyzed with 16S rRNA to compare the composition of their gut microbiota. We also assessed modifications in the serum mRNA expression of patients’ genes related to lipid metabolism using serum RNA sequencing and quantitative real-time polymerase chain reaction. Results: Significant improvements in cognitive function, as measured by the MMSE (pre- and post-FMT was 13.00 and 18.00) and MoCA were seen. The MoCA scores at 3 months post-FMT (21.0) were the highest (12.0). The CDR-SOB scores at pre- and post-FMT were 10.00 and 5.50, respectively. Analysis of the gut microbiome composition revealed changes via 16S rRNA sequencing with an increase in Bacteroidaceae and a decrease in Enterococcaceae. Gene expression analysis identified alterations in lipid metabolism-related genes after FMT. Conclusion: These findings suggest a link between alterations in the gut microbiome, gene expression related to lipid metabolism, and cognitive function. The study highlights the importance of gut microbiota in cognitive function and provides insights into potential biomarkers for cognitive decline progression. FMT could complement existing therapies and show potential as a therapeutic intervention to mitigate cognitive decline in AD.

Abstract Dysregulation of microRNAs (miRNA) in small extracellular vesicles (sEV) such as exosomes have been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). Although circulating cell-free miRNA have been extensively investigated in ALS, sEV-derived miRNAs have not been systemically explored yet. Here, we performed small RNA sequencing analysis of serum sEV and identified 5 differentially expressed miRNA in a discovery cohort of 12 patients and 11 age- and sex-matched healthy controls (fold change > 2, p

The available quantitative methods for evaluating bulbar dysfunction in patients with amyotrophic lateral sclerosis (ALS) are limited. We aimed to characterize vowel properties in Korean ALS patients, investigate associations between vowel parameters and clinical features of ALS, and analyze subclinical articulatory changes of vowel parameters in those with perceptually normal voices. Forty-three patients with ALS (27 with dysarthria and 16 without dysarthria) and 20 healthy controls were prospectively collected in the study. Dysarthria was assessed using the ALS Functional Rating Scale-Revised (ALSFRS-R) speech subscores, with any loss of 4 points indicating the presence of dysarthria. The structured speech samples were recorded and analyzed using Praat software. For three corner vowels (/a/, /i/, and /u/), data on the vowel duration, fundamental frequency, frequencies of the first two formants (F1 and F2), harmonics-to-noise ratio, vowel space area (VSA), and vowel articulation index (VAI) were extracted from the speech samples. Corner vowel durations were significantly longer in ALS patients with dysarthria than in healthy controls. The F1 frequency of /a/, F2 frequencies of /i/ and /u/, the VSA, and the VAI showed significant differences between ALS patients with dysarthria and healthy controls. The area under the curve (AUC) was 0.912. The F1 frequency of /a/ and the VSA were the major determinants for differentiating ALS patients who had not yet developed apparent dysarthria from healthy controls (AUC 0.887). In linear regression analyses, as the ALSFRS-R speech subscore decreased, both the VSA and VAI were reduced. In contrast, vowel durations were found to be rather prolonged. The analyses of vowel parameters provided a useful metric correlated with disease severity for detecting subclinical bulbar dysfunction in ALS patients.

Abstract Background Myelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Nonetheless, the optimal treatment regimen for preventing relapses in MOG-IgG1-associated disease remains unclear. Case presentation We describe the case of a 45-year-old man with MOG-IgG1-positive highly relapsing optic neuritis who had experienced 5 attacks over 21 months and had monocular blindness despite prednisolone and azathioprine therapy. He began treatment with rituximab, which reduced the rate of relapse markedly. Following discontinuation of rituximab, however, the patient experienced two successive optic neuritis attacks 2 and 4 months after B-lymphocyte restoration. Conclusions Highly relapsing MOG-IgG1-associated disease can be prevented with rituximab even when the MOG-IgG1 titers are relatively stationary. Discontinuation of rituximab and restoration of B-lymphocytes may be associated with the rebound of disease activity.

Purpose This study aimed to explore students’ cognitive patterns while solving clinical problems in 3 different types of assessments—clinical performance examination (CPX), multimedia case-based assessment (CBA), and modified essay question (MEQ)—and thereby to understand how different types of assessments stimulate different patterns of thinking. Methods A total of 6 test-performance cases from 2 fourth-year medical students were used in this cross-case study. Data were collected through one-on-one interviews using a stimulated recall protocol where students were shown videos of themselves taking each assessment and asked to elaborate on what they were thinking. The unit of analysis was the smallest phrases or sentences in the participants’ narratives that represented a meaningful cognitive occurrence. The narrative data were reorganized chronologically and then analyzed according to the hypothetico-deductive reasoning framework for clinical reasoning. Results Both participants demonstrated similar proportional frequencies of clinical reasoning patterns on the same clinical assessments. The results also revealed that the three different assessment types may stimulate different patterns of clinical reasoning. For example, the CPX strongly promoted the participants’ reasoning related to inquiry strategy, while the MEQ strongly promoted hypothesis generation. Similarly, data analysis and synthesis by the participants were more strongly stimulated by the CBA than by the other assessment types. Conclusion This study found that different assessment designs stimulated different patterns of thinking during problem-solving. This finding can contribute to the search for ways to improve current clinical assessments. Importantly, the research method used in this study can be utilized as an alternative way to examine the validity of clinical assessments.