Alternating mealtimes during pregnancy and weaning triggers behavioral changes in adult offspring.

In brief: Mealtime changes in pregnant mice revealed impaired neurobehavioral development in mouse offspring. This study is the basis for investigating diseases associated with neurobehavioral development of adult offspring of pregnant shift-working women. Abstract: Most organisms on Earth have a biological clock, and their physiological processes are regulated by a 1-day cycle. In modern society, several factors can disturb these biological clocks in humans; in particular, individuals working in shifts are exposed to stark environmental changes that interfere with their biological clock. They have a high risk of various diseases. However, there are scarce experimental approaches to address the reproductive and health consequences of shift work in the offspring of exposed individuals. In this study, considering the fact that shift workers usually have their meals during their adjusted working time, we aimed to examine the effects of a 12-h shift with usual mealtime as a plausible night work model on the neurobehavioral development of adult mouse offspring. In these offspring, early exposure to this mealtime shift differentially affected circadian rhythmic variables and total locomotor activity depending on the timing and duration of restrictive feeding. Moreover, neurobehavioral alterations such as declined short-term memory and depressive-like behavior were observed in adulthood. These results have implications for the health concerns of shift-working women and their children.

Mealtime shift delays conception in mice.

The physiological processes of organisms in this rotating planet can adjust according to the time of day via built-in circadian clocks. However, more people are having different shift works, which can increase the risk of pathological conditions including altered reproductive function. Thus, circadian rhythm disturbance has become prevalent in the modern society. Specifically, epidemiological evidence has shown that shift-working women are at high risk of spontaneous abortions, irregular menstrual cycles, and low-birth-weight babies. The current study aimed to investigate the effects of circadian rhythm disturbances on the reproductive function of mice caused by dietary time shift, which is common among night-shift workers. According to the schedule of restricted feeding, the mice were classified into the free feeding, daytime feeding, and night feeding groups. The fertility indices of each group were then evaluated. Activity monitoring was performed to determine whether pregnancy delay might be attributed to mealtime shift. Moreover, the estrous cycle of female mice and the reproductive phenotype of male mice were investigated. Results showed that a 12-h mealtime shift significantly delayed successful conception, which could be attributed to a disrupted estrous cycle, in adult female mice.

Relationship between the appropriateness of antibiotic treatment and clinical outcomes/medical costs of patients with community-acquired acute pyelonephritis: a multicenter prospective cohort study.

BACKGROUND: Inappropriate use of antibiotics not only increases antibiotic resistance as collateral damage but also increases clinical failure rates and medical costs. The purpose of this study was to determine the relationship between the appropriateness of antibiotic prescription and outcomes of community-acquired acute pyelonephritis (CA-APN). METHODS: A multicenter prospective cohort study was conducted at eight hospitals in Korea between September 2017 and August 2018. All hospitalized patients aged ≥ 19 years who were diagnosed with CA-APN on admission were recruited. The appropriateness of empirical and definitive antibiotics, as well as the appropriateness of antibiotic treatment duration and route of administration, was evaluated in accordance with the guideline and expert opinions. Clinical outcomes and medical costs were compared between patients who were administered antibiotics 'appropriately' and 'inappropriately.' RESULTS: A total of 397 and 318 patients were eligible for the analysis of the appropriateness of empirical and definitive antibiotics, respectively. Of them, 10 (2.5%) and 18 (5.7%) were administered 'inappropriately' empirical and definitive antibiotics, respectively. Of the 119 patients whose use of both empirical and definitive antibiotics was classified as 'optimal,' 57 (47.9%) received antibiotics over a longer duration than that recommended; 67 (56.3%) did not change to oral antibiotics on day 7 of hospitalization, even after stabilization of the clinical symptoms. Patients who were administered empirical antibiotics 'appropriately' had shorter hospitalization days (8 vs. 10 days, P = 0.001) and lower medical costs (2381.9 vs. 3235.9 USD, P = 0.002) than those who were administered them 'inappropriately.' Similar findings were observed for patients administered both empirical and definitive antibiotics 'appropriately' and those administered either empirical or definitive antibiotics 'inappropriately'. CONCLUSIONS: Appropriate use of antibiotics leads to better outcomes, including reduced hospitalization duration and medical costs.

Neuroprotective Effect of Macrophage Migration Inhibitory Factor (MIF) in a Mouse Model of Ischemic Stroke.

The mechanism of the neuroprotective effect of the macrophage migration inhibitory factor (MIF) in vivo is unclear. We investigated whether the MIF promotes neurological recovery in an in vivo mouse model of ischemic stroke. Transient middle cerebral artery occlusion (MCAO) surgery was performed to make ischemic stroke mouse model. Male mice were allocated to a sham vehicle, a sham MIF, a middle cerebral artery occlusion (MCAO) vehicle, and MCAO+MIF groups. Transient MCAO (tMCAO) was performed in the MCAO groups, and the vehicle and the MIF were administered via the intracerebroventricular route. We evaluated the neurological functional scale, the rotarod test, and T2-weighted magnetic resonance imaging. The expression level of the microtubule-associated protein 2 (MAP2), Bcl2, and the brain-derived neurotrophic factor (BDNF) were further measured by Western blot assay. The Garcia test was significantly higher in the MCAO+MIF group than in the MCAO+vehicle group. The MCAO+MIF group exhibited significantly better performance on the rotarod test than the MCAO+vehicle group, which further had a significantly reduced total infarct volume on T2-weighted MRI imaging than the MCAO vehicle group. Expression levels of BDNF, and MAP2 tended to be higher in the MCAO+MIF group than in the MCAO+vehicle group. The MIF exerts a neuroprotective effect in an in vivo ischemic stroke model. The MIF facilitates neurological recovery and protects brain tissue from ischemic injury, indicating a possibility of future novel therapeutic agents for stroke patients.

Comparison of the clinical characteristics of community-acquired acute pyelonephritis between male and female patients.

BACKGROUND: Community-acquired acute pyelonephritis (CA-APN) is relatively rare in men. This study aimed to compare the clinical characteristics of CA-APN between male and female patients. METHODS: We prospectively collected the clinical and microbiological data of hospitalized CA-APN patients aged ≥19 years in South Korea from March 2010 to February 2011 in 11 hospitals and from September 2017 to August 2018 in 8 hospitals. Only the first episodes of APN of each patient during the study period were included. RESULTS: From 2010 to 2011, 573 patients from 11 hospitals were recruited, and from 2017 to 2018, 340 patients were recruited from 8 hospitals. Among them, 5.9% (54/913) were male. Male patients were older (66.0 ± 15.2 vs. 55.3 ± 19.0 years, P < 0.001), had a higher Charlson comorbidity index (1.3 ± 1.5 vs. 0.7 ± 1.2, P = 0.027), and had a higher proportion of structural problems in the urinary tract (40.7% vs. 6.1%, P < 0.001) than female patients. Moreover, the total duration of antibiotic treatment was longer (21.8 ± 17.8 d vs. 17.3 ± 9.4 d, P = 0.001) and the proportion of carbapenem usage was higher (24.1% vs. 9.5%, P = 0.001) in men than in women. Male patients were hospitalized for longer durations than female patients (median, 10 d vs. 7 d, P < 0.001). CONCLUSIONS: Male CA-APN patients were older and had more comorbidities than female CA-APN patients. In addition, male patients received antibiotic treatment for a longer duration than female patients.

Accelerated Development of Hippocampal Neurons and Limited Adhesion of Astrocytes on Negatively Charged Surfaces.

This work examines the development of primary neurons and astrocytes on thoroughly controlled functional groups. Negatively charged surfaces presenting carboxylate (COO-) or sulfonate (SO3-) groups prove beneficial to neuronal behavior, in spite of their supposed repulsive electrostatic interactions with cellular membranes. The adhesion and survival of primary hippocampal neurons on negatively charged surfaces are comparable to or slightly better than those on positively charged (poly-d-lysine-coated) surfaces, and neuritogenesis and neurite outgrowth are accelerated on COO- and SO3- surfaces. Moreover, such favorable influences of the negatively charged surfaces are only seen in neurons but not for astrocytes. Our results indicate that the in vitro developmental behavior of primary hippocampal neurons is sophisticatedly modulated by angstrom-sized differences in chemical structure or the charge density of the surface. We believe that this work provides new implications for understanding neuron-material interfaces as well as for establishing new ways to fabricate neuro-active surfaces.

Effect of providing drug utilization review information on tricyclic antidepressant prescription in the elderly.

Tricyclic antidepressants are known as potentially inappropriate medications in the elderly. A notification issued in July 2015 in South Korea recommended caution while prescribing tricyclic antidepressants to the elderly. Further, since October 2015, the nationwide computerized drug utilization review monitoring system provides a pop-up window, on a real-time basis, whenever tricyclic antidepressants are prescribed to elderly outpatients. Therefore, we evaluated whether providing drug utilization review information was effective in reducing tricyclic antidepressant prescription to elderly outpatients. We used the Health Insurance Review and Assessment Service-Adult Patient Sample data from 2014 to 2016. Data related to the prescription of tricyclic antidepressants to outpatients aged 65 years or more were extracted. We determined the number of prescriptions per day per 100,000 elderly patients in each month, compared the average number of prescriptions before and after the drug utilization review information was provided, and evaluated the changes in the number of prescriptions by using an interrupted time series analysis. The average number of tricyclic antidepressant prescriptions per day per 100,000 elderly patients decreased from 76.6 (75.5 to 77.6) to 65.7 (64.5 to 66.9), a 14.2% reduction after the provision of drug utilization review information started. Following initiation of provision of drug utilization review information, there was an immediate drop of 9.2 tricyclic antidepressant prescriptions per day per 100,000 elderly patients, whereas there was no statistically significant change in trends. Providing the drug utilization review information on tricyclic antidepressant prescription for the elderly contributed to the reduction in tricyclic antidepressant prescriptions.

Cytoprotective Encapsulation of Individual Jurkat T Cells within Durable TiO2 Shells for T-Cell Therapy.

Lymphocytes, such as T cells and natural killer (NK) cells, have therapeutic promise in adoptive cell transfer (ACT) therapy, where the cells are activated and expanded in vitro and then infused into a patient. However, the in vitro preservation of labile lymphocytes during transfer, manipulation, and storage has been one of the bottlenecks in the development and commercialization of therapeutic lymphocytes. Herein, we suggest a cell-in-shell (or artificial spore) strategy to enhance the cell viability in the practical settings, while maintaining biological activities for therapeutic efficacy. A durable titanium oxide (TiO2 ) shell is formed on individual Jurkat T cells, and the CD3 and other antigens on cell surfaces remain accessible to the antibodies. Interleukin-2 (IL-2) secretion is also not hampered by the shell formation. This work suggests a chemical toolbox for effectively preserving lymphocytes in vitro and developing the lymphocyte-based cancer immunotherapy.

Control over Neurite Directionality and Neurite Elongation on Anisotropic Micropillar Arrays.

Control over neurite orientation in primary hippocampal neurons is achieved by using interrupted, anisotropic micropillar arrays as a cell culture platform. Both neurite orientation and neurite length are controlled by a function of interpillar distance.

Increased use in propofol and reported patterns of adverse events among anesthetics in Korea.

BACKGROUND: Propofol is an addictive drug, and the problem of its abuse and dependence has occurred. To compare the safety profiles of propofol and other similar anesthetics such as diazepam, lorazepam, and midazolam, we evaluated their uses and related adverse drug reactions (ADRs) using Korean Adverse Event Reporting System (KAERS) data. METHODS: The domestic consumption data and the ADR reports of four anesthetics from 2008 to 2012 were retrieved. ADR proportions were calculated using defined daily dose/1000 inhabitants/day (DID) for the denominator. The patient's characteristics were compared among the four drugs statistically, and the types of ADRs were analyzed. RESULTS: The consumption and ADR reports increased during the study period, particularly in the cases of propofol and midazolam. Lorazepam showed the highest overall and serious ADR proportions (220.81 reports/DID, 58.47 reports/DID, respectively); however, with respect to death proportion, propofol was the first (19.21 reports/DID). Also, ADRs related to drug addiction were mainly observed in the propofol group. CONCLUSIONS: Four anesthetics were different with regard to the consumption and proportion or the type of ADRs. The use of propofol increased more than 2 times, and propofol showed the highest ADR proportions in death and drug addiction cases among the four anesthetics.

Prescribing patterns of the four most commonly used sedatives in endoscopic examination in Korea: propofol, midazolam, diazepam, and lorazepam.

As the sedative use increases due to the effectiveness and relatively safe profile, the abuse potential is also increasing. This study was conducted to examine the usage of four sedative agents in endoscopic examination and to compare the propofol use with the other three sedatives. Using National Health Insurance claims data from 2008 to 2012, we identified the number of cases of conscious sedation during endoscopy using one or more of the following agents: propofol, midazolam, diazepam, and lorazepam. The general characteristics of patients and medical service providers were analyzed, and the regional and annual distributions of frequency of use were compared. We also identified patient cases with excessive number of endoscopic examinations. Among the total of 3,156,231 sedatives users, midazolam was the most commonly used agent (n=2,845,250, 90.1%). However, the largest increase in patient number, which increased from 11,410 in 2008 to 28,170 in 2012, was observed with propofol. While the majority of patients received an annual endoscopy, we identified several suspected abuse cases of patients receiving endoscopies repetitively as many as 114 times in five years. The rise of sedative use in endoscopic examinations and several patient cases of repeated sedative administration suggest a potential risk for abuse. Medical service providers should be cautious when using sedatives and carefully review each patient's medical history prior to the procedure.

Prevalence of antibiotic use for pediatric acute upper respiratory tract infections in Korea.

This study was conducted to estimate the prevalence of antimicrobial prescribing for acute upper respiratory tract infections (URI) among pediatric outpatients and to identify the national patterns of its use from 2009 to 2011 in Korea. Using National Patients Sample database from 2009 to 2011, we estimated the frequency of antibiotics prescribing for URI in pediatric outpatients with diagnoses of acute nasopharyngitis (common cold), acute sinusitis, acute pharyngitis, acute tonsillitis, acute laryngitis/tracheitis, acute obstructive laryngitis/epiglottitis, and acute upper respiratory infections of multiple and unspecified sites. The proportions of each antibiotic class were calculated by year and absolute and relative differences were estimated. Also, we investigated daily amount of prescribed antibiotics per defined population according to the type of medical care institution, physician specialty, and geographic region. The overall antibiotic prescribing proportion was 58.7% and its annual proportion slightly decreased (55.4% in 2011 vs. 60.5% in 2009; adjusted odds ratio, 0.82; 95% confidence interval, 0.82-0.83). Variations by the type of medical care institution were observed. Tertiary hospitals (45.0%) were less likely to prescribe antibiotics than primary care clinics (59.4%), hospitals (59.0%), and general hospitals (61.2%); they showed different tendencies in choosing antibiotics. Variations by physician specialty and region were also observed. Prevalence of antimicrobial prescribing for pediatric URI is still considered higher than that of western countries and varies by the type of medical care institution, physician specialty, and geographic region.

Dramatic decrease in fluoroquinolones in the pediatric population in Korea.

PURPOSE: This study was performed to evaluate the change of prescribing patterns after the regulatory action regarding fluoroquinolones in pediatric patients. METHODS: We conducted a time series analysis using the Korea Health Insurance Review and Assessment Service National Patients Sample database. Study subjects consisted of pediatric patients under 18 years of age who were prescribed antibiotics at least once (ATC code, J01) before (January 2009-December 2009) and after implementation (January 2010-December 2011) of the regulation. The use of fluoroquinolones was defined as the use of the following antibiotics for at least once in pediatric patients: ofloxacin, ciprofloxacin, norfloxacin, lomefloxacin, levofloxacin, and gemifloxacin. We calculated the number of pediatric fluoroquinolone users for each month. The difference between proportions before and after the regulation was estimated as relative and absolute reduction of fluoroquinolone use. We calculated 95% confidence intervals (CI). RESULTS: We identified 4, 945, 169 antibiotic prescriptions in 484, 914 pediatric patients. During the 12-month period before implementation, percentage of fluoroquinolone use was 4.81% (95% CI: 4.70-4.91%, N = 8001). We observed a rapid decrease in the monthly number of fluoroquinolone users in pediatric population after the implementation of regulatory action. In the year after regulatory action, the percentage of fluoroquinolone use was only 0.26% (95% CI: 0.24-0.28%, N = 834). Overall, there was a 94.55% relative reduction (95% CI: 88.02-101.56%) in the use of fluoroquinolones. CONCLUSION: Korean regulatory actions regarding fluoroquinolones had an effect of reducing use in pediatric population.

Neurons on nanotopographies: behavioral responses and biological implications.

Neural cells are well known to be affected by the topographical features of the surfaces to which they adhere. There have been numerous reports showing guided neurite extension on microgrooves and micropillar arrays made of a wide range of materials. However, it has recently been disclosed that neural cells on nanotopographies exhibit much more derivatized and complicated responses than just neurite guidance. Nevertheless, the biological mechanisms for these responses are not yet understood. In this review, we categorized the responses of neurons to nanotopographies into three groups (adhesion, neurite guidance, and developmental acceleration). In addition, we also tried to elicit biological implications about the mechanisms for the recognition of nanotopographies. Further investigation of neuronal responses to nanotopographies would highly inspire both fundamental research about neuronal development and practical applications related to neuro-regeneration.

Cytoprotective silica coating of individual mammalian cells through bioinspired silicification.

The cytoprotective coating of physicochemically labile mammalian cells with a durable material has potential applications in cell-based sensors, cell therapy, and regenerative medicine, as well as providing a platform for fundamental single-cell studies in cell biology. In this work, HeLa cells in suspension were individually coated with silica in a cytocompatible fashion through bioinspired silicification. The silica coating greatly enhanced the resistance of the HeLa cells to enzymatic attack by trypsin and the toxic compound poly(allylamine hydrochloride), while suppressing cell division in a controlled fashion. This bioinspired cytocompatible strategy for single-cell coating was also applied to NIH 3T3 fibroblasts and Jurkat cells.

Cytoskeletal actin dynamics are involved in pitch-dependent neurite outgrowth on bead monolayers.

Neurite outgrowth is an important preceding step for the development of nerve systems. Given that the in vivo environments of neurons consist of numerous hierarchical micro/nanotopographies, there have been many efforts to investigate the relationship between neuronal behaviors and surface topography. The acceleration of neurite outgrowth was recently reported on surfaces with a periodic nanotopography, but the biological mechanism has not yet been elucidated. In this work, the initial neurite development of hippocampal neurons on assembled silica beads with diameters ranging from 700 to 1800 nm was explored. The acceleration of neurite outgrowth increased with the surface-pitch size and leveled off after a pitch of 1 µm. Biochemical analysis indicated that cytoskeletal actin dynamics were primarily responsible for the recognition of surface topography. This work contributes to the emerging research field of topographical neurochemistry, as well as applied fields including neuroregeneration and neuroprosthetics.

Molecular and Phenotypic Investigation on Antibacterial Activities of Limonene Isomers and Its Oxidation Derivative against Xanthomonas oryzae pv. oryzae.

Xanthomonas oryzae pv. oryzae (Xoo) causes a devastating bacterial leaf blight in rice. Here, the antimicrobial effects of D-limonene, L-limonene, and its oxidative derivative carveol against Xoo were investigated. We revealed that carveol treatment at ≥ 0.1 mM in liquid culture resulted in significant decrease in Xoo growth rate (> 40%) in a concentration-dependent manner, and over 1 mM, no growth was observed. The treatment with D-limonene and L-limonene also inhibited the Xoo growth but to a lesser extent compared to carveol. These results were further elaborated with the assays of motility, biofilm formation and xanthomonadin production. The carveol treatment over 1 mM caused no motilities, basal level of biofilm formation (< 10%), and significantly reduced xanthomonadin production. The biofilm formation after the treatment with two limonene isomers was decreased in a concentration-dependent manner, but the degree of the effect was not comparable to carveol. In addition, there was negligible effect on the xanthomonadin production mediated by the treatment of two limonene isomers. Field emission-scanning electron microscope (FE-SEM) unveiled that all three compounds used in this study cause severe ultrastructural morphological changes in Xoo cells, showing shrinking, shriveling, and holes on their surface. Moreover, quantitative real-time PCR revealed that carveol and D-limonene treatment significantly down-regulated the expression levels of genes involved in virulence and biofilm formation of Xoo, but not with L-limonene. Together, we suggest that limonenes and carveol will be the candidates of interest in the development of biological pesticides.

Neurofilament light chain and cardiac MIBG uptake as predictors for phenoconversion in isolated REM sleep behavior disorder.

BACKGROUND: Isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD) is considered as a prodromal stage of either multiple system atrophy (MSA) or Lewy body disease (LBD; Parkinson's disease and dementia with Lewy bodies). However, current knowledge is limited in predicting and differentiating the type of future phenoconversion in iRBD patients. We investigated the role of plasma neurofilament light chain (NfL) and cardiac metaiodobenzylguanidine (MIBG) uptake as predictors for phenoconversion. METHODS: Forty patients with iRBD were enrolled between April 2018 and October 2019 and prospectively followed every 3 months to determine phenoconversion to either MSA or LBD. Plasma NfL levels were measured at enrollment. Cardiac MIBG uptake and striatal dopamine transporter uptake were assessed at baseline. RESULTS: Patients were followed for a median of 2.92 years. Four patients converted to MSA and 7 to LBD. Plasma NfL level at baseline was significantly higher in future MSA-converters (median 23.2 pg/mL) when compared with the rest of the samples (median 14.1 pg/mL, p = 0.003). NfL level above 21.3 pg/mL predicted phenoconversion to MSA with the sensitivity of 100% and specificity of 94.3%. Baseline MIBG heart-to-mediastinum ratio of LBD-converters (median 1.10) was significantly lower when compared with the rest (median 2.00, p < 0.001). Heart-to-mediastinum ratio below 1.545 predicted phenoconversion to LBD with the sensitivity of 100% and specificity of 92.9%. CONCLUSIONS: Plasma NfL and cardiac MIBG uptake may be useful biomarkers in predicting phenoconversion of iRBD. Elevated plasma NfL levels may suggest imminent phenoconversion to MSA, whereas low cardiac MIBG uptake suggests phenoconversion to LBD.

Efficient functional delivery of siRNA using mesoporous silica nanoparticles with ultralarge pores.

Among various nanoparticles, mesoporous silica nanoparticles (MSNs) have attracted extensive attention for developing efficient drug-delivery systems, mostly due to their high porosity and biocompatibility. However, due to the small pore size, generally below 5 nm in diameter, potential drugs that are loaded into the pore have been limited to small molecules. Herein, a small interfering RNA (siRNA) delivery strategy based on MSNs possessing pores with an average diameter of 23 nm is presented. The siRNA is regarded as a powerful gene therapeutic agent for treatment of a wide range of diseases by enabling post-transcriptional gene silencing, so-called RNA interference. Highly efficient, sequence-specific, and technically very simple target gene knockdown is demonstrated using MSNs with ultralarge pores of size 23 nm in vitro and in vivo without notable cytotoxicity.