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Abstract Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer’s disease (AD), also known as “type 3 diabetes”. Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.

Abstract Background Blood adiponectin and leptin are adipokines that emerged as potential biomarkers for predicting Alzheimer’s disease (AD) owing to their strong connection with obesity. Although obesity affects the relation between beta-amyloid (Aβ) aggregation and cognitive decline, the longitudinal interactive effect of adipokines and Aβ on cognition and brain structures in humans remains unexplored. Hence, we investigated whether plasma levels of adiponectin and leptin are associated with future cognitive decline and cortical thinning across Aβ conditions (Aβ [+] and Aβ [−]) in individuals with mild cognitive impairment (MCI). Methods Of 156 participants with MCI from the longitudinal cohort study of Alzheimer’s Disease Neuroimaging Initiative (ADNI), 31 were Aβ (−) and 125 were Aβ (+) as determined by CSF analysis. The Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores and the thickness of the parahippocampal and entorhinal cortices were used to evaluate cognition and brain structure, respectively. After stratifying groups by Aβ conditions, the association of cognitive and brain structural changes with baseline plasma levels of adiponectin and leptin was examined. Results Of the total 156 participants, 51 were women (32.7%). The mean age of participants was 74.5 (standard deviation 7.57), and the mean follow-up period was 54.3 months, without a difference between the Aβ (+) and (−) groups. After adjustment for confounders, higher plasma adiponectin levels were associated with a faster increase in ADAS-Cog scores, indicating faster cognitive decline under the Aβ (+) condition (beta = 0.224, p = 0.018). Likewise, participants with higher plasma adiponectin presented faster cortical thinning in the bilateral parahippocampal cortices under the Aβ (+) condition (beta = − 0.004, p = 0.012 for the right side; beta = − 0.004, p = 0.025 for the left side). Interestingly, plasma adiponectin levels were not associated with longitudinal ADAS-Cog scores or cortical thickness in the Aβ (−) condition. Plasma leptin levels were not predictive of cognition or cortical thickness regardless of Aβ status. Conclusion Plasma adiponectin can be a potential biomarker for predicting the speed of AD progression in individuals with Aβ (+) MCI.

Abstract Metformin reduces insulin resistance, which constitutes a pathophysiological connection of diabetes with Alzheimer’s disease (AD), but the evidence of metformin on AD development was still insufficient and conflicting. We investigated AD risk in patients with newly diagnosed type 2 DM treated with metformin. This retrospective, observational, nested case–control study included patients with newly diagnosed type 2 DM obtained from the Korean National Health Insurance Service DM cohort (2002–2017). Among 70,499 dementia-free DM patients, 1675 AD cases were matched to 8375 controls for age, sex, and DM onset and duration. The association between AD and metformin was analyzed by multivariable regression analyses, adjusted for comorbidities and cardiometabolic risk profile. Metformin use was associated with an increased odds of AD (adjusted odds ratio [AOR] 1.50; 95% CI 1.23–1.83). The risk of AD was higher in patients with a longer DM duration. Furthermore, AD risk was significantly high in DM patients with depression (AOR 2.05; 95% CI 1.02–4.12). Given the large number of patients with DM who are taking metformin worldwide, a double-blinded, prospective study is required to determine the long-term cognitive safety of metformin.

(1) Background: Milnacipran is a typical serotonin–norepinephrine reuptake inhibitor and has been shown to have analgesic effects in several pain models. However, its antihyperalgesic effect in cisplatin-induced neuropathy remains unknown. We examined the effects of intraperitoneal (IP) milnacipran on allodynia in cisplatin-induced peripheral neuropathic mice. (2) Methods: Peripheral neuropathy was induced by injecting cisplatin (2.3 mg/kg/day, IP) six times, on every other day. Saline or milnacipran (10, 30, 50 mg/kg, IP) were then administered to the neuropathic mice. We examined mechanical allodynia using von Frey hairs at preadministration and at 30, 60, 90, 120, 180, 240 min and 24 h after drug administration. We also measured the dorsal root ganglion (DRG) activating transcription factor 3 (ATF3) to confirm the analgesic effects of milnacipran. (3) Results: For the milnacipran groups, the decreased paw withdrawal thresholds to mechanical stimuli were significantly reversed when compared to the preadministration values and the values in the saline-injected control group (p < 0.0001). Milnacipran administration to cisplatin-induced peripheral neuropathic mice resulted in a significant suppression of neuronal ATF3 activation (p < 0.01). (4) Conclusions: Milnacipran given via IP injection attenuates mechanical allodynia in mouse models of cisplatin-induced poly-neuropathic pain. These effects were confirmed by significant suppression of neuronal ATF3 activation in the DRG.

The purpose of this study is to identify the structural relationships among online class related factors, zoom fatigue, learning engagement, perceived achievement, and class satisfaction in a university distance learning context. The study analyzed 265 responses from K University in Korea. The key findings of the study are first, situational factors of online class usage, personal factors of online class attitudes, agreeableness and conscientiousness, technical issue of environmental factors, and non-verbal overload (cognitive) factors of interaction factors had significant effects on zoom fatigue. Second, personal characteristics directly affect the study's outcome variables, perceived achievement and class satisfaction in online classes. Third, online class attitude, agreeableness, conscientiousness, technical issue, and non-verbal overload (cognitive) had significant indirect effects on perceived achievement and class satisfaction through the dual mediation of zoom fatigue and learning engagement. Fourth, zoom fatigue did not have a direct effect on perceived achievement and class satisfaction, but had a negative and significant effect on learning engagement, and learning engagement had a positive and significant direct effect on perceived achievement and class satisfaction. Fifth, learning engagement fully mediated the relationship between zoom fatigue, perceived achievement, and class satisfaction. Zoom fatigue has a negative and significant effect on learning engagement, and learning engagement has a positive and significant effect on perceived achievement and class satisfaction. Based on these findings, the study discusses implications for university instructors on effective design and implementation of real-time video lectures and proposes avenues for future research, considering the study's significance and limitations.

Abstract Reliable and reproducible assessment of animal learning and behavior is a central aim of basic and translational neuroscience research. Recent developments in automated operant chamber technology have led to the possibility of universal standard protocols, in addition to increased translational potential, reliability and accuracy. However, the impact of regional and national differences in the supplies of available reinforcers in this system on behavioural performance and inter-laboratory variability is an unknown and at present uncontrolled variable. Therefore, we aimed to identify which constituent(s) of the reward determines reinforcer strength to enable improved standardization of this parameter across laboratories. Male C57BL/6 mice were examined in the touchscreen-based fixed ratio (FR) and progressive ratio (PR) schedules, reinforced with different kinds of milk-based reinforcers to directly compare the incentive values of plain milk (PM, high-calorie: high-fat/low-sugar), strawberry-flavored milk (SM, high-calorie: low-fat/high-sugar), and semi-skimmed low-fat milk (LM, low-calorie: low-fat/low-sugar) on the basis of differences in caloric content, sugar/fat content, and flavor. Use of a higher caloric content reward was effective in increasing operant training acquisition rate. Total trial number completed in FR and breakpoint in PR were higher using the two isocaloric milk products (PM and SM) than the lower caloric LM, with comparable outcomes between PM and SM conditions, suggesting that total caloric content determines reward strength. Analysis of within-session changes in response rate revealed that overall outputs in FR and PR primarily depend on the response rate at the initial phase of a session, which itself was dependent on reinforcer caloric content. Interestingly, the rate of satiation, indicated by decay in response rate within a FR session, was highest when reinforced with SM, suggesting a rapid satiating effect of sugar. The key contribution of reward caloric content to operant performance was confirmed in a multi-laboratory study using the touchscreen 5-choice serial reaction time task (5-CSRTT) reinforced by two isocaloric milk-based liquid rewards with different countries of origin, which yielded consistent performance parameters across sites. Our results indicate that milk-based liquid reinforcer standardization can be facilitated by matching caloric content across laboratories despite regional or national differences in other non-caloric aspects of the reinforcers.

The global increase in livestock production has correspondingly intensified farm odors due to harmful bacteria, reduced immunity, and disease progression. In this study, we treated feces with Biomagic-Enzyme complex for 4 months to understand the relationship between farm odor, immunity against common viral diseases, immune cytokines, and changes in the microbiota. A gas meter (MultiRAE) was used to measure ammonia (NH3) and hydrogen sulfide (H2S) while odor intensity and offensiveness were characterized by the non-objective scaling method. A complete blood count was performed and plasma was obtained after blood centrifugation at 3,000 rpm for 20 minutes. The cytokine profile was evaluated using commercial kits. Microbial DNA was extracted and purified from fecal samples to analyze the microbiota. Microbial DNA and viral RNA/DNA were obtained from fecal samples and amplified to determine the expression of transmissible gastroenteritis virus (TGEV), porcine reproductive and respiratory syndrome (PRRS), and porcine circovirus type 2 (PCV2). Our results indicated that Biomagic reduced odor nuisance by decreasing ammonia levels, resulting in faint and fairly offensive odor intensity. After the enzyme treatment, Escherichia coli populations significantly reduced across all 3 farms. In contrast, beneficial Lactobacillus spp. levels remained stable, indicating the enzyme selectively targeted harmful bacteria while preserving beneficial ones. The beneficial Lachnospiraceae, Spirochaetaceae, and Bacteroidaceae were found to be higher in the third month of treatment. TGEV was not detected, while PRRS and non-pathogenic PCV2 showed a positive infection rate. In conclusion, Biomagic reduced ammonia, prevented viral infection from pig farms, and improved gut-beneficial bacteria and microbiota. [ABSTRACT FROM AUTHOR]

Background: This cadaveric study aimed to analyze injectate spread to target nerves during a single-injection, ultrasound-guided intertransverse process block. Methods: An ultrasound-guided intertransverse process block with three different injectate volumes was administered to 12 cadavers. Each hemithorax was subjected to computer-generated random allocation of 10, 15, or 20 mL ultrasound-guided, single-injection intertransverse process block at the T2 vertebral level. Latex dye solution was injected into each hemithorax in accordance with the allocated volume. The presence of dye at the nerve root in the sympathetic chain and intercostal nerves at various injection levels was examined via dissection. Results: Injectate spread into the dorsal rami was observed in seven of eight (87.5%), seven of eight (87.5%), and all eight (100%) of the 10, 15, and 20 mL specimens, respectively. In all 20 mL specimens, consistent staining of the dorsal rami, spinal nerve, and dorsal root ganglion was observed. Conclusions: An injectate volume of 20 mL was required for consistent staining of the dorsal rami, spinal nerve, and dorsal root ganglion in an intertransverse process block. Although an augmented injectate volume was associated with an increased likelihood of target nerve staining, consistent staining of the sympathetic ganglion, rami communicans, and ventral ramus was not observed, even at a volume of 20 mL. The current study presents initial findings suggesting that as opposed to a sympathetic ganglion block, a 20 mL intertransverse process block may act as a feasible substitute for dorsal root ganglion, spinal nerve, and medial branch blocks within a clinical context. [ABSTRACT FROM AUTHOR]

Background: Healthcare-associated infections (HAI) caused by multidrug-resistant organisms have emerged as a significant global issue, posing substantial challenges to healthcare systems. Low- and intermediate-level disinfectants are extensively utilized for cleaning and disinfecting surfaces in hospitals to mitigate environmental transmission of HAI. Therefore, the need for more effective and environmentally safe disinfectants is increasing. This study aimed to assess the effect of antimicrobial wipes used for surface cleaning and disinfection in healthcare environments. Materials and Methods: A microbe library comprising 188 bacterial and fungal isolates, including multidrug-resistant strains, was established and used to evaluate the antimicrobial effect of three types of antimicrobial wipes: A (didecyldimethylammonium chloride [DDAC] 0.31% and 3-(trimethoxysilyl)-propyldimethyloctadecyl ammonium chloride [Si-QAC] 0.45%); B (benzalkonium chloride [BAK] 0.63%); and C (DDAC 0.5% and BAK 0.9%). The antimicrobial effect of the wipes was assessed and compared in three assays: rapid bactericidal effect assay of the three wipes, minimum inhibitory concentration (MIC) assay of DDAC and BAK, and a time-kill assay of the DDAC and Si-QAC combination. Results: The rapid antimicrobial effect evaluation showed that both wipes A and C, which contain a combination of two quaternary ammonium compounds (QACs), exhibited similar antimicrobial effect (P=0.8234). Antimicrobial wipe A demonstrated better effect against Gram-positive bacteria and fungi than wipe C (P <0.05). The antimicrobial efficacy of the A wipe against Mycobacterium strains was superior to that of both the B and C wipes. Moreover, DDAC exhibited MIC50 values that were 2 to 3-fold lower than those of BAK for Gram-negative bacteria and fungi. The time-kill assay results for the DDAC and Si-QAC combination exhibited a growth reduction of >3 logs for Staphylococcus aureus and Enterococcus faecium, whereas approximately 2 logs of reduction was observed for Escherichia coli and Pseudomonas aeruginosa at 3 hour. Conclusion: The results suggest that antimicrobial wipes containing relatively lower concentrations of QAC (wipe A) achieve similar rapid bactericidal effect as that of those with higher concentrations (wipe C). For Gram-negative bacteria, including multidrug-resistant strains and fungal isolates, DDAC presented lower MICs compared with BAK. Furthermore, the combination therapy with DDAC and Si-QAC demonstrated enhanced efficacy compared to treatment with either agent alone, except in the case of Klebsiella strains. Further research is needed to develop antimicrobial wipes that minimize the environmental impact while ensuring effective disinfection. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to establish baseline morphological and functional data for normal mouse kidneys via a clinical 33 MHz ultra-high-frequency (UHF) transducer, compare the data with the findings from fibrotic mice, and assess correlations between ultrasonography (US) parameters and fibrosis-related markers. Methods: This retrospective study aggregated data from three separate experiments (obstructive nephropathy, diabetic nephropathy, and acute-to-chronic kidney injury models). Morphological parameters (kidney size, parenchymal thickness [PT]) and functional (shear-wave speed [SWS], stiffness, resistive index [RI], and microvascular imaging-derived vascular index [VI]) were assessed and compared between normal and fibrotic mouse kidneys. Semi-quantitative histopathologic scores were calculated and molecular markers (epithelial cadherin), Collagen 1A1 [Col1A1], transforming growth factor-β, and α-smooth muscle actin [α-SMA]) were evaluated using western blots. Correlations with US parameters were explored. Results: Clinical UHF US successfully imaged the kidneys of the experimental mice. A three-layer configuration was prevalent in the normal mouse kidney parenchyma (34/35) but was blurred in most fibrotic mouse kidneys (33/40). US parameters, including size (11.14 vs. 10.70 mm), PT (2.07 vs. 1.24 mm), RI (0.64 vs. 0.77), VI (22.55% vs. 11.47%, only for non-obstructive kidneys), SWS (1.67 vs. 2.06 m/s), and stiffness (8.23 vs. 12.92 kPa), showed significant differences between normal and fibrotic kidneys (P<0.001). These parameters also demonstrated strong discriminative ability in receiver operating characteristic curve analysis (area under the curve, 0.76 to 0.95; P<0.001). PT, VI, and RI were significantly correlated with histological fibrosis markers (ρ=-0.64 to -0.68 for PT and VI, ρ=0.71-0.76 for RI, P<0.001). VI exhibited strong negative correlations with Col1A1 (ρ=-0.76, P=0.006) and α-SMA (ρ=-0.75, P=0.009). Conclusion: Clinical UHF US effectively distinguished normal and fibrotic mouse kidneys, indicating the potential of US parameters, notably VI, as noninvasive markers for tracking fibrosis initiation and progression in mouse kidney fibrosis models. [ABSTRACT FROM AUTHOR]

Tranexamic acid (TXA) is a synthetic antifibrinolytic agent that has been used for several decades to reduce blood loss during surgery and after trauma. TXA was traditionally used to reduce bleeding in various clinical settings such as menorrhagia, hemophilia, or other bleeding disorder. Numerous studies have demonstrated the efficacy of TXA in reducing blood loss and the need for transfusions. Interest in the potential applications of TXA beyond its traditional use has been growing recently, with studies investigating the use of TXA in postpartum hemorrhage, cardiac surgery, trauma, neurosurgery, and orthopedic surgery. Despite its widespread use and expanding indications, data regarding the safe and appropriate use of TXA is lacking. Recent clinical trials have found various potential risks and limitations in the long-term benefits of TXA. This narrative review summarizes the clinical applications and limitations of TXA. [ABSTRACT FROM AUTHOR]

This study aimed to investigate whether dietary supplementation with heat-inactivated Limosilactobacillus reuteri PSC102 (LR) enhances immunological responses and growth performance in weaned pigs. Twenty-five weaned piglets were randomly allocated to five groups. Each treatment group had separate pens with five pigs each. The pigs were fed a diet supplemented with heat-inactivated LR at a concentration of 1x109 CFU/g for 28 days. Throughout the study period, regular measurements, including body weight, food consumption rate, and diarrhoeal frequency, were conducted. At the end of the experiment, blood samples were collected to assess cytokine and haptoglobin levels. Faecal samples, rectal swabs, and nasal swabs were collected for analysis of pathogenic bacterial growth using selective media. Additionally, faecal samples were analysed to determine the composition of the microbiota. Heat-inactivated LR enhances growth rate and feed efficiency while decreasing diarrheal frequency in weaned piglets. Compared to pigs fed a control diet, diets containing heat-inactivated LR exhibited increased serum levels of cytokines and decreased haptoglobin levels, demonstrating a beneficial effect on the presence of pathogenic microorganisms. Heat-inactivated LR diets alter the microbiota of piglets by enhancing alpha diversity and increasing the composition of beneficial bacteria. Overall, dietary heat-inactivated LR enhanced growth rates, regulated immunological responses in weaned pigs, and reduced post-weaning diarrhoea. Therefore, this suggests its potential as a health functional ingredient for humans and animals. [ABSTRACT FROM AUTHOR]