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Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus. Within the circuit, variations in target responses observed for PPI paradigms represent prepulse-induced excitability changes. However, little is known about the mechanism of PPI. Here, we focused on short-latency PPI of the trigeminal blink reflex R1 signal with an oligosynaptic reflex arc through the principal sensory trigeminal nucleus and the facial nucleus. As the facial nucleus is facilitatory to any input, R1 PPI is the phenomenon in the former nucleus. Considering that GABAergic modulation may be involved in PPI, this study investigated whether the PPI mechanism includes GABA-A equivalent inhibition, which peaks at approximately 30 ms in humans. In 12 healthy volunteers, the reflex was elicited by electrical stimulation of the supraorbital nerve, and recorded at the ipsilateral lower eyelid by accelerometer. Stimulus intensity was 1.5 times the R1 threshold for test stimulus and 0.9 times for the prepulse. The prepulse–test interval (PTI) was 5–150 ms. Results showed significant inhibition at 40-and 80–150-ms PTIs but not at 20-, 30-, 50-, 60-, and 70-ms PTIs, yielding two distinct inhibitions of different time scales. This corresponds well to the early and late components of inhibitory post synaptic potentials by GABA-A and GABA-B receptor activation. Thus, the data support the contribution of inhibitory post synaptic potentials elicited by the prepulse to the observed PPI. As inhibitory function-related diseases may impair the different inhibition components to varying degrees, methods deconvoluting each inhibitory component contribution are of clinical importance.

Responses to a sensory stimulus are inhibited by a preceding stimulus; if the two stimuli are identical, paired-pulse suppression (PPS) occurs; if the preceding stimulus is too weak to reliably elicit the target response, prepulse inhibition (PPI) occurs. PPS and PPI represent excitability changes in neural circuits induced by the first stimulus, but involve different mechanisms and are impaired in different diseases, e.g., impaired PPS in schizophrenia and Alzheimer’s disease and impaired PPI in schizophrenia and movement disorders. Therefore, these measures provide information on several inhibitory mechanisms that may have roles in clinical conditions. In the present study, PPS and PPI of the auditory change-related cortical response were examined to establish normative data on healthy subjects (35 females and 32 males, aged 19–70 years). We also investigated the effects of age and sex on PPS and PPI to clarify whether these variables need to be considered as biases. The test response was elicited by an abrupt increase in sound pressure in a continuous sound and was recorded by electroencephalography. In the PPS experiment, the two change stimuli to elicit the cortical response were a 15-dB increase from the background of 65 dB separated by 600 ms. In the PPI experiment, the prepulse and test stimuli were 2- and 10-dB increases, respectively, with an interval of 50 ms. The results obtained showed that sex exerted similar effects on the two measures, with females having stronger test responses and weaker inhibition. On the other hand, age exerted different effects: aging correlated with stronger test responses and weaker inhibition in the PPS experiment, but had no effects in the PPI experiment. The present results suggest age and sex biases in addition to normative data on PPS and PPI of auditory change-related potentials. PPS and PPI, as well as other similar paradigms, such as P50 gating, may have different and common mechanisms. Collectively, they may provide insights into the pathophysiologies of diseases with impaired inhibitory function.

Objective: This study focused on the gastrointestinal (GI) symptoms in the omicron variant infection and the related factors based on digestive health., Methods: A cross-sectional study was conducted on individuals infected with the omicron variant. A structured questionnaire was developed to gather their demographic characteristics, preexisting digestive problems (diseases & symptoms), and clinical manifestations during the infection., Results: 11,484 questionnaires were received from online platforms. 7,929 infected participants were selected based on inclusion and exclusion criteria. Among them, 4,225 (53.3%) were females, and the mean age was 36.0±8.8 years old. In general, the proportion of GI symptoms in the omicron variant infection was 31.4% (62.6% and 25.0% in participants with pre-existing digestive problems and those without, respectively). The participants with pre-existing digestive problems exhibited more severe clinical manifestations during infection compared to those without. Notably, participants with gastrointestinal symptoms during the infection had more severe clinical manifestations, regardless of basic digestive health. Upper, rather than lower GI symptoms were more closely associated with the severity of the clinical manifestations. NSAIDs may increase the occurrence of GI symptoms in participants with a healthy digestive system but not in those with preexisting digestive problems., Conclusion: Patients infected with the omicron variant may experience more severe clinical symptoms if they have gastrointestinal issues. Digestive health strongly influences the occurrence of gastrointestinal symptoms and the severity of clinical manifestations., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Liu 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.)

Background/objective: The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients., Methods: We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI., Results: We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns., Conclusions: Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.

Achalasia, a rare esophageal motility disorder characterized by the inability of the lower esophageal sphincter to relax and loss of esophageal peristalsis, significantly impacts pediatric patient quality of life through symptoms like dysphagia, chest pain, and weight loss. This nationwide retrospective cohort study evaluates the efficacy and safety of peroral endoscopic myotomy (POEM) for pediatric achalasia in Mongolia, contributing to the limited global data on this minimally invasive treatment in children. Conducted between February 2020 and March 2022 at 2 tertiary centers, the study included symptomatic achalasia patients, treatment-naive or those with unsatisfactory outcomes from previous esophageal dilations. The POEM procedure was assessed for its impact on esophageal structure and function, symptom severity via the Eckardt score, and procedure-related safety, with outcomes measured at baseline, 3 days, and 12 months post-procedure. The study demonstrated notable post-procedure improvements across all measured outcomes: abnormal contraction length and esophageal width significantly reduced, underscoring the procedure's effectiveness. More precisely, the integrated relaxation pressure showed a significant improvement from a mean of 26.8 mm Hg (standard deviation [SD], 5.4 mm Hg) pre-procedure to 10.8 mm Hg (SD, 1.1 mm Hg) 12 months (P < .001). Similarly, Eckardt scores, which assess symptom severity, improved significantly from a pre-procedure mean of 7.0 (SD, 1.0) to a substantially lower score post-procedure (P < .001), reflecting enhanced patient quality of life and symptom alleviation. This study underscores POEM's role as an effective, minimally invasive option for pediatric achalasia management within the Mongolian population, offering significant symptomatic relief and improved esophageal function., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction/aims: Paired-pulse stimulation provides clinically useful information regarding sensory inhibition. When supraorbital nerve stimulation is repeated within a short interval, the response to the second stimulation is reduced to varying degrees. This magnitude of change in stimulation response can be monitored by electromyogram (EMG) or by mechanomyogram (MMG) as in this report. MMG has some advantages such as being less time consuming and lacking stimulus artifact. We compared the use of MMG and EMG to validate MMG as an effective method of assessing blink reflex paired-pulse inhibition., Methods: Eight volunteers participated. Participants received electrical stimulation to the supraorbital nerve of each side. A paired-pulse paradigm was employed, varying the conditioning-test interval between 5 and 800 ms. The R1 component of the induced blink reflex was simultaneously recorded by EMG using a pair of electrodes placed on the lower eyelid and by MMG using an accelerometer placed between the electrodes., Results: The correlation coefficient of the R1 amplitude between MMG and EMG of the grand-averaged waveforms was 0.99. The average participant r value was .91 (range .76-.99). Similar analyses were performed for the amplitude variation of the second response relative to the first response. Results correlated well, yielding r values of .97 and .86 for the grand-averaged waveform and the average for each subject., Discussion: The present results demonstrate that MMG could be an alternative to EMG in assessing paired-pulse inhibition of the electrical blink reflex R1 component., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Prepulse inhibition (PPI) is a well-established phenomenon wherein a weak sensory stimulus attenuates the startle reflex triggered by a subsequent strong stimulus. Within the circuit, variations in target responses observed for PPI paradigms represent prepulse-induced excitability changes. However, little is known about the mechanism of PPI. Here, we focused on short-latency PPI of the trigeminal blink reflex R1 signal with an oligosynaptic reflex arc through the principal sensory trigeminal nucleus and the facial nucleus. As the facial nucleus is facilitatory to any input, R1 PPI is the phenomenon in the former nucleus. Considering that GABAergic modulation may be involved in PPI, this study investigated whether the PPI mechanism includes GABA-A equivalent inhibition, which peaks at approximately 30 ms in humans. In 12 healthy volunteers, the reflex was elicited by electrical stimulation of the supraorbital nerve, and recorded at the ipsilateral lower eyelid by accelerometer. Stimulus intensity was 1.5 times the R1 threshold for test stimulus and 0.9 times for the prepulse. The prepulse-test interval (PTI) was 5-150 ms. Results showed significant inhibition at 40-and 80-150-ms PTIs but not at 20-, 30-, 50-, 60-, and 70-ms PTIs, yielding two distinct inhibitions of different time scales. This corresponds well to the early and late components of inhibitory post synaptic potentials by GABA-A and GABA-B receptor activation. Thus, the data support the contribution of inhibitory post synaptic potentials elicited by the prepulse to the observed PPI. As inhibitory function-related diseases may impair the different inhibition components to varying degrees, methods deconvoluting each inhibitory component contribution are of clinical importance., 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 © 2024 Shingaki, Itoh, Borgil, Kida and Inui.)

Objective: We have previously shown that neutrophil extracellular traps (NETs) are present on the ocular surface of patients with ocular graft versus host disease (oGVHD), contributing to inflammation and surface disease. Therefore, we performed a clinical trial using deoxyribonuclease I (DNAase) eye drops to test the hypothesis that reducing the abundance of NETs from the ocular surface will reduce signs and symptoms of oGVHD., Methods: A prospective, phase I or II, randomized, placebo-controlled, double-masked clinical trial was performed to determine the safety and preliminary efficacy of DNAase (0.1%) eye drops four times daily for 8 weeks in patients with oGVHD (n=58). Intent-to-treat analysis was performed to determine the change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (ocular surface disease index [OSDI] score and corneal staining) between baseline and week 8., Results: Tolerability and adverse events were similar in the vehicle and DNAase groups. Within the DNAase group (but not the vehicle group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 (3.50 [2.75; 5.00]) compared with baseline (5.00 [3.00; 7.00]). The OSDI score also showed a statistically significant clinically meaningful reduction of 18.4 (9.16; 33.1) ( P <0.001) at week 8 compared with baseline (45.5 [31.8; 50.0]) within the DNAase group. The proportion of eyes that had improvement in subjective global assessment (SGA) and mucous discharge was significantly greater in the DNAase group (55.6% and 57.7% at weeks 4 and 8, respectively; P <0.0001 at both time points) as compared with the vehicle group (35.7% and 34.0% at weeks 4 and 8, respectively)., Conclusions: Treatment of patients with oGVHD using DNAase eye drops is safe and demonstrates preliminary efficacy. Deoxyribonuclease I eye drops can potentially reduce the severity of signs and symptoms of ocular surface disease in patients with oGVHD., Competing Interests: S. Jain, MD: Consultant, Ocugen, Inc., Neutrolis, Inc., GlaxoSmithKline; Stock Ownership, Advaite Inc., Selagine Inc.; Patent application, UIC. Other authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)

Objective: To perform a longitudinal study for determining the development of ocular graft-versus-host disease (oGVHD) after allogeneic hematopoietic stem cell transplant (HSCT) and report cases that illustrate the "window of opportunity" concept in oGVHD treatment., Methods: Patients (n=61) were examined at prescheduled clinic visits before HSCT and three-month intervals after HSCT for 2 years. The presence or absence of oGVHD was determined using the international chronic oGVHD consensus group diagnostic criteria. Ocular surface washings (OSW) were obtained at each visit and analyzed for cytokine levels., Results: In the longitudinal study, 26.2% (n=16; progressed group) developed either probable (11.5%, n=7) or definite oGVHD (14.8%, n=9). In the progressed group, clinically significant changes in signs (corneal staining and Schirmer I test) and symptoms at the post-HSCT visit as compared with the pre-HSCT visit occurred at 9 months. Significant differences in clinical signs and symptoms (whether average post-HSCT values or changes in values over pre-HSCT levels) between the progressed and nonprogressed groups occurred at a 9-month visit or later. In the progressed group, 55.6% of eyes that had negative matrix metalloproteinase 9 (MMP-9) test at pre-HSCT turned MMP-9 positive at 3 to 6 months post-HSCT. In the progressed group, interleukin 8 levels in OSW were significantly increased at 6 months post-HSCT. In the case reports, the "window of opportunity" was detected by MMP-9 turning positive, early corneal staining, interleukin 8 increase in OSW, and peripheral corneal epithelial thinning, which resolved with treatment initiation., Conclusions: A "window of opportunity" exists before patients developing symptomatic tear-deficient dry eye after HSCT for initiating treatment that may preempt oGVHD development; however, larger-scale longitudinal studies are needed for definitive recommendations., Competing Interests: S. Jain, MD: Consultant, Ocugen Inc, Neutrolis Inc, GSK; Stock Ownership, Advaite Inc; Selagine Inc; Patent application: UIC. The remaining authors have no funding or conflicts of interest to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Contact Lens Association of Opthalmologists.)

Responses to a sensory stimulus are inhibited by a preceding stimulus; if the two stimuli are identical, paired-pulse suppression (PPS) occurs; if the preceding stimulus is too weak to reliably elicit the target response, prepulse inhibition (PPI) occurs. PPS and PPI represent excitability changes in neural circuits induced by the first stimulus, but involve different mechanisms and are impaired in different diseases, e.g., impaired PPS in schizophrenia and Alzheimer's disease and impaired PPI in schizophrenia and movement disorders. Therefore, these measures provide information on several inhibitory mechanisms that may have roles in clinical conditions. In the present study, PPS and PPI of the auditory change-related cortical response were examined to establish normative data on healthy subjects (35 females and 32 males, aged 19-70 years). We also investigated the effects of age and sex on PPS and PPI to clarify whether these variables need to be considered as biases. The test response was elicited by an abrupt increase in sound pressure in a continuous sound and was recorded by electroencephalography. In the PPS experiment, the two change stimuli to elicit the cortical response were a 15-dB increase from the background of 65 dB separated by 600 ms. In the PPI experiment, the prepulse and test stimuli were 2- and 10-dB increases, respectively, with an interval of 50 ms. The results obtained showed that sex exerted similar effects on the two measures, with females having stronger test responses and weaker inhibition. On the other hand, age exerted different effects: aging correlated with stronger test responses and weaker inhibition in the PPS experiment, but had no effects in the PPI experiment. The present results suggest age and sex biases in addition to normative data on PPS and PPI of auditory change-related potentials. PPS and PPI, as well as other similar paradigms, such as P50 gating, may have different and common mechanisms. Collectively, they may provide insights into the pathophysiologies of diseases with impaired inhibitory function., 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 © 2024 Inui, Takeuchi, Borgil, Shingaki, Sugiyama, Taniguchi, Nishihara, Watanabe, Suzuki, Motomura and Kida.)

Background: There is a lack of evidence regarding 24-hour movement behaviors of young children from low- and middle-income countries. This study examined Mongolian preschoolers' adherence to the World Health Organization's guidelines for physical activity, sedentary behavior, and sleep; their associations with health indicators, and the feasibility of the SUNRISE International study in Mongolia., Methods: Preschool-aged children were recruited from 5 kindergartens in urban and rural areas of Ulaanbaatar city and Tuv province in Mongolia. Physical activity and sedentary behavior were measured by an ActiGraph accelerometer worn for 5 consecutive days. Screen time and sleep were reported by parents. The National Institute of Health and Early Years Toolboxes were used to assess motor skills and executive function, respectively., Results: One hundred and one children participated in the study (mean age = 4.82 y, boys = 58), with 88% (n = 89) having complete data for analysis. The proportion of children who met the recommendations for physical activity, sedentary screen time, and sleep was 61%, 23%, and 82%, respectively. Only 7% met all recommendations. Meeting the sleep recommendation individually (P = .032) and in combination with the physical activity recommendation was associated with better gross (P = .019) and fine (P = .042) motor skills. Spending more time in physical activity was positively correlated with motor development. Results confirmed that the SUNRISE study protocol was feasible, age-appropriate, and enjoyable for children., Conclusions: The results of the SUNRISE pilot study will help inform the SUNRISE Mongolia main study and lay the groundwork for future research into children's 24-hour movement behaviors in Mongolia.

Background: A nationwide vaccination program against coronavirus disease 2019 (COVID-19) was started in Mongolia 4 months after the first local transmission, which occurred in November 2020. Previous studies have reported that two doses of COVID-19 vaccine result in increased antibody against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A study was conducted in Mongolia 2 weeks after the second vaccine dose. In the present study, the serum levels of antibodies of individuals 6 months after natural SARS-CoV-2 infection were compared with those of individuals who had not been infected or had been infected but had received two doses of vaccine, including BNT162b2, ChAdOx1 n-CoV-19, Gam-COVID-Vac, and BBIBP-CorV, which were used for COVID-19 in Mongolia., Methods: Of the 450 participants in this study, 237 (52.66%) were female and 213 (47.33%) were male. Four hundred people with or without SARS-CoV-2 infection who received two doses of 4 different COVID-19 vaccine participated in the vaccine groups and vaccine plus SARS-CoV-2 infection groups (50 in each group) and 50 individuals previously infected with SARS-CoV-2 participated in the unvaccinated group. Total antibody against SARS-CoV-2 infection, anti-SARS-CoV-2 N and S protein human IgG, and antibody inhibiting RBD-ACE2 binding were tested., Results: In the BNT162b2 vaccine group, total antibody against SARS-CoV-2 remained constant until 6 months, while the other vaccine groups showed a significant decrease, as compared to the unvaccinated group. The level of anti-SARS-CoV-2 S-RBD protein IgG was significantly increased in the ChAdOx1 n-CoV-19, Gam-COVID-Vac, and BNT162b2 vaccines groups as compared to the unvaccinated group. Participants in the BNT162b2 vaccine group had higher ACE2 inhibition efficiency compared to the other vaccine groups as well as the unvaccinated group., Conclusions: The BNT162b2 vaccine showed the highest level of antibody against SARS-CoV-2, followed by the BBIBP-CorV, Gam-COVID-Vac, and ChAdOx1 n-CoV-19 vaccines. The level of antibodies was increased in people infected with SARS-CoV-2 after vaccination, as compared to uninfected but vaccinated individuals., (© 2023 Published by Elsevier Ltd on behalf of International Society for Infectious Diseases.)

Purpose: The burden of diabetes in Mongolia has risen tremendously over the last three decades, and an individually tracked, national registry of diabetes is lacking. Therefore, we aim to investigate diabetes prevalence in Mongolia and analyze some associated factors., Materials and Methods: A cross-sectional, nationally representative, population-based survey was carried out in Mongolia. We recruited participants from randomly selected six different clusters for the required 3113 ± 311 sample size. We collected detailed demographics, diabetes condition and medications, anthropometric measurements, body composition, and glucose profiles. Oral glucose tolerance tests were used to diagnose diabetes using the International Diabetes Federation algorithm. Chi-square and multinomial logistic regression tests were used to determine associated factors. Age-standardized prevalence rates were estimated., Results: We recruited 3272 participants in the study between June and October 2019. Crude prevalence rates for prediabetes and diabetes were 10.8% (95% CI; 9.8-11.9) and 11.2% (95% CI; 10.1-12.3), respectively. Sixty-one adults were newly diagnosed with diabetes. Age-standardized prediabetes and diabetes prevalence rates were 9.8% (95% CI; 8.5-11.1) and 10.0% (95% CI; 8.7-11.3) among adults 30 or older. Higher BMI, central obesity, diabetes inheritance, sedentary habitus, and hypertension are significantly associated with diabetes in adjusted analysis for sex and age group., Conclusion: The prevalence of diabetes has increased at least threefold since 1999 in Mongolia. In addition, numerous modifiable risk factors were associated with diabetes. Therefore, future investigations and programs should focus on combating obesity and sedentary lifestyles and propose dietary recommendations in the context of expanding diabetes in Mongolia., Competing Interests: The authors declare no conflicts of interest in this work., (© 2023 Dayan et al.)

Despite the clinical significance of prepulse inhibition (PPI), the mechanisms are not well understood. Herein, we present our investigation of PPI in the R1 component of electrically induced blink reflexes. The effect of a prepulse was explored with varying prepulse test intervals (PTIs) of 20-600 ms in 4 females and 12 males. Prepulse-test combinations included the following: stimulation of the supraorbital nerve (SON)-SON [Experiment (Exp) 1], sound-sound (Exp 2), the axon of the facial nerve-SON (Exp 3), sound-SON (Exp 4), and SON-SON with a long trial-trial interval (Exp 5). Results showed that (1) leading weak SON stimulation reduced SON-induced ipsilateral R1 with a maximum effect at a PTI of 140 ms, (2) the sound-sound paradigm resulted in a U-shaped inhibition time course of the auditory startle reflex (ASR) peaking at 140 ms PTI, (3) facial nerve stimulation showed only a weak effect on R1, (4) a weak sound prepulse facilitated R1 but strongly inhibited SON-induced late blink reflexes (LateRs) with a similar U-shaped curve, and (5) LateR in Exp 5 was almost completely absent at PTIs >80 ms. These results indicate that the principal sensory nucleus is responsible for R1 PPI. Inhibition of ASR or LateR occurs at a point in the startle reflex circuit where auditory and somatosensory signals converge. Although the two inhibitions are different in location, their similar time courses suggest similar neural mechanisms. As R1 has a simple circuit and is stable, R1 PPI helps to clarify PPI mechanisms. SIGNIFICANCE STATEMENT Prepulse inhibition (PPI) is a phenomenon in which the startle response induced by a startle stimulus is suppressed by a preceding nonstartle stimulus. This study demonstrated that the R1 component of the trigeminal blink reflex shows clear PPI despite R1 generation within a circuit consisting of the trigeminal and facial nuclei, without startle reflex circuit involvement. Thus, PPI is not specific to the startle reflex. In addition, PPI of R1, the auditory startle reflex, and the trigeminal late blink reflex showed similar time courses in response to the prepulse test interval, suggesting similar mechanisms regardless of inhibition site. R1 PPI, in conjunction with other paradigms with different prepulse-test combinations, would increase understanding of the underlying mechanisms., (Copyright © 2023 Inui et al.)

Objective:  Mongolia is a sparsely populated country; however, almost fifty percent of the population lives in the capital city. Medical care services and exceptionally well-organized cervical cancer screening tests are limited in remote areas. To improve cervical cancer screening test coverage, we compared the interest between physicians taking samples and self-sampling among the attendees in this study., Methods: A total of 175 women participated in this study. The hundred twelve women visited the Gynecology ward, and the sixty-three women were provided with the cervical self-sampling test kit and filled out a questionnaire. Subsequently, the acceptability of physician taking and self-sampling were evaluated using a questionnaire. All specimens were processed using the TACAS LBC system, and the quality of samples was tested by cytology., Results: Regarding the acceptability of self-sampling, the selections for subsequent screening were 36% self-sampling and 64% gynecologist-sampling methods. The acceptability rates were higher in the remote areas than the urban areas. However, 64% of the participants lacked knowledge that the causative agent of cervical cancer is the human papillomavirus, and 66.9% mainly were sexually transmitted. In addition, 82.3% of the women surveyed were unaware that there was a vaccine to prevent cervical cancer, but 88.6% wanted to be vaccinated. Of most women, 44.4% chose self-sampling due to no embarrassment in the gynecological examination. The self-sampling preferences were dominant in the old age group (61.6%). The cytology satisfaction rate in physician-sampling (99.1%) was higher than in the self-sampling group (69.8%)., Conclusion: The Implementation of the self-sampling tool may be considered a primary screening. The self-sampling test can adopt into the early screening program and may increase the coverage of the screening program and improve the quality.

Objectives: This study investigated neuronal sources of slow cortical potentials (SCPs) evoked during vagus nerve stimulation (VNS) in patients with epilepsy who underwent routine electroencephalography (EEG) after implantation of the device., Materials and Methods: We analyzed routine clinical EEG from 24 patients. There were 5 to 26 trains of VNS during EEG. To extract SCPs from the EEG, a high-frequency filter of 0.2 Hz was applied. These EEG epochs were averaged and used for source analyses. The averaged waveforms for each patient and their grand average were subjected to multidipole analysis. Patients with at least 50% seizure frequency reduction were considered responders. Findings from EEG analysis dipole were compared with VNS responses., Results: VNS-induced focal SCPs whose dipoles were estimated to be located in several cortical areas including the medial prefrontal cortex, postcentral gyrus, and insula, with a significantly higher frequency in patients with a good VNS response than in those with a poor response., Conclusions: This study suggested that some VNS-induced SCPs originating from the so-called vagus afferent network are related to the suppression of epileptic seizures., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the outcomes of transcanalicular diode laser-assisted dacryocystorhinostomy (TCL-DCR), nonendoscopic endonasal dacryocystorhinostomy (NEN-DCR), and external dacryocystorhinostomy (EXT-DCR) as first-line treatments for functional epiphora., Methods: This multicenter, retrospective, case-control study included 135 eyes of 135 patients with functional epiphora (86 females and 49 males). Functional epiphora was diagnosed based on a patent lacrimal system with a delay in the fluorescein dye disappearance test (FDDT) or dacryoscintigraphy (DSG) and no ocular surface or eyelid abnormalities. The patients were treated with TCL-DCR (2008-2011) or Ext-DCR (2005-2008, 2011-2017) at Beyoglu Eye Research Hospital (Istanbul, Turkey) and NEN-DCR at Carrot Eye Surgery Clinic affiliated with the McMaster University (Hamilton, ON, Canada) (2010-2016). Success was defined as the absence of epiphora and the normalization of an earlier delayed FDDT after surgery., Results: The TCL-DCR, NEN-DCR, and EXT-DCR groups consisted of 38, 47, and 50 eyes with 25.9, 44.2, and 45.9 months of follow-up. The success rate for TCL-DCR was 65.8%, 70.2% for NEN-DCR, and 84.0% for EXT-DCR. During the follow-up period, 13.2% of TCL-DCR cases and 6.4% of NEN-DCR cases developed an anatomic obstruction of the lacrimal system., Conclusion: The EXT-DCR group had a higher success rate in the management of functional epiphora than the NEN-DCR and TCL-DCR groups and was significantly safer in terms of an iatrogenic anatomic block of the lacrimal system., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2022 Can Ozturker et al.)

Purpose: The current paradigm for therapy of recalcitrant ocular surface diseases (OSD) consists of a sequential, step-up treatment approach. A combinatorial topical therapy (anti-inflammatory/immunosuppressive [steroid] with immunomodulatory [pooled human immune globulin] and tear substitute [serum]) that simultaneously targets several immunological pathways may be more efficacious. This report evaluates if the combinatorial therapy resulted in clinical benefit in patients with recalcitrant OSD., Methods: We performed a retrospective case study of patients receiving topical, preservative-free, compounded formulations of steroids, pooled human immune globulin, and serum tears. Outcome measures included visual acuity, ocular surface disease index (OSDI), ocular discomfort score, subjective global assessment (SGA), corneal staining, conjunctival redness, and slit lamp photographs., Results: Patients consisted of one male and 11 females ranging in age from 27 to 87 years old. Pathologies included ocular graft-versus-host disease (n = 4), Sjögren's syndrome (n = 3), ocular cicatricial pemphigoid (n = 1), pemphigus vulgaris (n = 1), peripheral ulcerative keratitis (n = 1), Stevens-Johnson syndrome (n = 1), and giant papillary conjunctivitis (n = 1). All patients were "improved" or "much improved" on SGA after combinatorial therapy. There was a clinically meaningful reduction in OSDI, ocular discomfort, corneal staining, and conjunctival injection. Additionally, three patients had improvement in their visual acuity (one from 20/400 to 20/20). Adverse effects included increased intraocular pressure in two patients, presumably due to topical steroid use., Conclusions: Combinatorial therapy provides clinical benefit by reducing the symptoms and signs in recalcitrant OSD. Our study provides the rationale for performing prospective clinical trials to evaluate the efficacy of combinatorial therapy for treating recalcitrant OSD., (Copyright © 2021 Elsevier Inc. All rights reserved.)

To study the affect of anatomical variance of lacrimal sac fossa on dacryocystorhinostomies (DCR) performed by the traditional external (EX-DCR) approach or an endoscopic (EN-DCR) endonasal approach. A total of 292 consecutive cases with primary nasolacrimal obstruction underwent DCR surgery. Orbital computed tomography scan was used to measure lacrimal sac fossa and other related structures and Lac-Q questionnaire was used to compare surgery result. Maxillary portion of lacrimal sac fossa is thicker in failed surgery group than successful surgery group ( P <0.05). Lateral nasal structures (uncinate process, operculum of the middle turbinate, agger nasi) are dominantly adjusting to lacrimal sac fossa in failed surgery group ( P <0.05). Patients who underwent EX-DCR has a 6.0-point and EN-DCR group 11.0-point improvement ( P <0.016) in Lac-Q questionnaire. Patients who have a thick frontal process of the maxilla and uncinate process, operculum of the middle turbinate, ethmoid cells adjusting to lacrimal fossa are prone to have recurrence of nasolacrimal duct obstruction after DCR surgery. The EN-DCR and the EX-DCR approach have an equivalent surgical success rate but improvement in quality of life by using the Lac-Q questionnaire is greater in the endoscopic group when compared with the external.

Background/aims: As the number of colonoscopies and polypectomies performed continues to increase in many Asian countries, there is a great demand for surveillance colonoscopy. The aim of this study was to investigate the adherence to postpolypectomy surveillance guidelines among physicians in Asia., Methods: A survey study was performed in seven Asian countries. An email invitation with a link to the survey was sent to participants who were asked to complete the questionnaire consisting of eight clinical scenarios., Results: Of the 137 doctors invited, 123 (89.8%) provided valid responses. Approximately 50% of the participants adhered to the guidelines regardless of the risk of adenoma, except in the case of tubulovillous adenoma ≥10 mm combined with high-grade dysplasia, in which 35% of the participants adhered to the guidelines. The participants were stratified according to the number of colonoscopies performed: ≥20 colonoscopies per month (high volume group) and <20 colonoscopies per month (low volume group). Higher adherence to the postpolypectomy surveillance guidelines was evident in the high volume group (60%) than in the low volume group (25%). The reasons for nonadherence included concern of missed polyps (59%), the low cost of colonoscopy (26%), concern of incomplete resection (25%), and concern of medical liability (15%)., Conclusions: A discrepancy between clinical practice and surveillance guidelines among physicians in Asia was found. Physicians in the low volume group frequently did not adhere to the guidelines, suggesting a need for continuing education and appropriate control. Concerns regarding the quality of colonoscopy and complete polypectomy were the main reasons for nonadherence.

Background: The indeterminate pulmonary nodule is a common clinical problem. Preoperative tissue diagnosis is not always possible, despite all attempts. The objectives of this study were to determine the frequency of a malignant diagnosis in this scenario and whether attempted preoperative biopsy impacted estimation of the risk of malignancy., Patients and Methods: We reviewed 500 consecutive cases of pulmonary resection without a preoperative tissue diagnosis at a tertiary care center from 2009 to 2013. Age, sex, smoking status, prior malignancy, tumor size, and whether or not tissue diagnosis had been attempted were recorded. Logistic regression models were constructed to determine factors associated with a malignant diagnosis., Results: There were 297 males (59.4%), the mean age was 64.9 years, and 412 had a smoking history (82.4%). Also, 203 patients (40.6%) had a malignancy history, and 36 patients (7.2%) had previous lung cancer. Biopsy was attempted for 102 patients (20.5%). The final diagnosis was lung cancer in 336 patients (67.2%), metastatic cancer in 93 patients (18.6%), and benign tumour in 71 patients (14.2%). Male sex, increasing age, smoking history, and prior lung cancer were positive predictors of lung cancer. Model discrimination was good (c-statistic, 0.83). Attempted biopsy did not alter model discrimination., Conclusion: In this cohort, 86% of resected lesions were malignant. The decision to pursue preoperative tissue diagnosis did not change the predictive ability offered by clinical factors. These findings are reassuring in the scenario when a patient is operable but the diagnosis remains unknown., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Herpes simplex virus-1 (HSV-1) infection leads to varying pathologies including the development of ocular lesions, stromal keratitis and encephalitis. While the role for host immunity in disease progression is well understood, the contribution of genetic variances in generating preferential viral entry receptor usage and resulting immunopathogenesis in humans are not known., Methods: Ocular cultures were obtained from patients presenting distinct pathologies of herpes simplex keratitis (HSK). Next-generation sequencing and subsequent analysis characterized genetic variances among the strains and estimated evolutionary divergence. Murine model of ocular infection was used to assess phenotypic contributions of strain variances on damage to the ocular surface and propagation of innate immunity. Flow cytometry of eye tissue identified differential recruitment of immune cell populations, cytokine array probed for programming of local immune response in the draining lymph node and histology was used to assess inflammation of the trigeminal ganglion (TG). Ex-vivo corneal cultures and in-vitro studies elucidated the role of genetic variances in altering host-pathogen interactions, leading to divergent host responses., Results: Phylogenetic analysis of the clinical isolates suggests evolutionary divergence among currently circulating HSV-1 strains. Mutations causing alterations in functional host interactions were identified, particularly in viral entry glycoproteins which generated a receptor bias to herpesvirus entry mediator, an immune modulator involved in immunopathogenic diseases like HSK, leading to exacerbated ocular surface pathologies and heightened viral burden in the TG and brainstem., Conclusions: Our data suggests receptor bias resulting from genetic variances in clinical strains may dictate disease severity and treatment outcome., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background/aims: The clinical practice pattern of polypectomy is not well-investigated in Asian countries. We aimed to survey Asian endoscopists about their preferred polypectomy techniques for given conditions and images of polyps., Methods: A survey was performed using questionnaires composed of two parts: a scenario-based questionnaire using scenarios of polyps, which were adopted from the European Society of Gastrointestinal Endoscopy guidelines, and an image-based questionnaire using provided endoscopic images of polyps., Results: A total of 154 endoscopists participated in this survey. The most preferred resection techniques for diminutive (≤5 mm), small (6-9 mm), and benign-looking intermediate (10-19 mm) nonpedunculated polyps were cold forceps polypectomy, hot snare polypectomy, and endoscopic mucosal resection (EMR), respectively, in both the scenario- and image-based questionnaires. For benign-looking large (≥20 mm) nonpedunculated polyps, EMR and endoscopic submucosal dissection (ESD) were preferred in the scenario- and image-based surveys, respectively. In case of malignant nonpedunculated polyps, EMR and ESD were preferred for intermediate-sized and large lesions, respectively, according to the scenario-based survey. However, ESD was preferred in both intermediate-sized and large malignant nonpedunculated polyps according to the image-based survey. Trainee endoscopists, endoscopists working in referral centers, and endoscopists in the colorectal cancer-prevalent countries were independently associated with preference of cold snare polypectomy for removing small polyps., Conclusions: The polypectomy practice patterns of Asian endoscopists vary, and cold snare polypectomy was not the most preferred resection method for polyps <10 mm in size, in contrast to recent guidelines.

Kainic acid (KA) is an excitotoxic glutamate analogue produced by a marine seaweed. It elicits neuronal excitotoxicity leading to epilepsy in rodents. Activation of transient receptor potential vanilloid subfamily 1 (TRPV1), a nonselective cation channel protein, by capsaicin, prevents KA-induced seizures in a mouse model of temporal lobe epilepsy. However, the precise mechanism behind this protective effect of capsaicin remains unclear. In order to analyze the direct effect of KA on TRPV1, we evaluated the ability of KA to activate TRPV1 and analyzed its binding to TRPV1 using a molecular modeling approach. In vitro, KA activates a Ca 2+ influx into TRPV1 expressing HEK293 cells but not in contsrol HEK293 cells. Pretreatment with either capsaicin (1 M) or capsazepine (10 M; TRPV1 antagonist) prevents the effect of KA. Pharmacological inhibition of phospholipase C (PLC) by U73122 or overexpression of phosphatidylinositol 5 phosphatase (Synaptojanin 1; Synj-1) counters the effect of KA. Further, KA treatment causes actin reorganization in HEK TRPV1 cells and PLC inhibition by U73122 prevents this. Molecular modeling data revealed that KA binds to TRPV1 and prebinding with capsaicin prevents the binding of KA to TRPV1. Consistently, the lack of effect of KA in activating chicken TRPV1, which is insensitive to capsaicin, suggests that there is a significant overlap between the sites of KA and capsaicin activation of TRPV1. However, PLC inhibition did not suppress TRPV1 activation by capsaicin. Collectively, our data suggest that KA binds to and activates TRPV1 and causes actin reorganization via PLC-dependent mechanism in vitro. We propose that KA mediates Ca 2+ induced toxicity possibly by activating TRPV1. Therefore, inhibiting TRPV1 will be a beneficial strategy in abating Ca 2+ -induced neurotoxicity.

In Mongolia, horses play important roles, not only in livestock production, but also in terms of culture, tradition, and Mongolian beliefs. Although the presence of non-tsetse-transmitted horse trypanosomoses, which are caused by infections with Trypanosoma evansi (surra) and T. equiperdum (dourine), has been reported in the country, whether there is a nationwide epidemic of these infectious diseases is unknown. In the present study, a nationwide surveillance of horse trypanosomoses was performed. The sample sizes for each province, the whole country, and male and female horses were, respectively, 96, 2,400, and 316 and 306. In total, 3,641 samples of horse sera were collected by simple random sampling. The rTeGM6-4r-based ELISA, which was applied for surra against cattle and water buffalo and dourine against horse, revealed that the overall sero-prevalence of the diseases in Mongolia was 4.8%. Among them, high sero-prevalences were observed in the central provinces (5.2-11.0%, p  < 0.05) of the country. The sero-prevalence was significantly higher in females than in males (6.0% and 4.0%, p  < 0.05, respectively) and in non-castrated males (8.4%, p  < 0.01) compared with castrated males (3.0%). These results suggested that currently, horse trypanosomoses are a nationwide endemic problem in Mongolia. Knowledge of the nationwide endemic status of non-tsetse-transmitted horse trypanosomoses in Mongolia will be useful to prevent these diseases., Competing Interests: The authors declare no competing interests in association with this study., (© 2020 The Authors.)

Purpose: To investigate the role of Anti-Citrullinated Protein autoantibodies (ACPAs) in the pathology of dry eye disease (DED) and the therapeutic potential of pooled human immune globulin-eye drops in these patients., Methods: We investigated the presence of citrullinated proteins and ACPAs in ocular surface wash (OSW) and conjunctival impressions from patients with DED and determined the pathological consequences of OSW with high ACPA using in vitro experiments and in vivo murine models. We performed a randomized, double-masked, pilot clinical trial to determine the safety, tolerability and preliminary efficacy of using pooled human immune globulin-eye drops to treat DED patients with ACPAs in OSW., Results: We found that neutrophils are a source of citrullinated proteins on the ocular surface of DED patients. We detected significantly higher immunoglobulin amount and presence of several species of ACPAs in OSW from DED patients. We also found that OSW with high ACPA contributes to production of NETs, and that ACPAs cause ocular surface disease in murine eyes, both of which are reduced with addition of Immune globulins. As compared to Vehicle treatment, pooled human immune globulin-eye drops (IVIG 4 mg/mL) twice a day for 8 weeks caused significant reduction in signs and symptoms of DED with no difference in tolerability or adverse events., Conclusions: This is the first report demonstrating ACPAs in OSW of DED patients and their contribution to ocular surface disease. The first-in-human clinical trial suggests that pooled immune globulin-eye drops are a potential new class of biologic therapies for Dry Eye patients., Competing Interests: Declaration of competing interest Sandeep Jain, MD: Consultant, Ocugen, Inc; Stock Ownership, Advaite, LLC; Patent application., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Equine piroplasmosis caused by Theileria equi and Babesia caballi is an economically important disease with a worldwide distribution. The objective of the present study was to investigate the seroepidemiology of T. equi and B. caballi in horses reared in various Mongolian provinces. Serum samples prepared from blood collected from horses in 19 Mongolian provinces were screened for antibodies specific to T. equi and B. caballi using enzyme-linked immunosorbent assays based on recombinant forms of T. equi merozoite antigen-2 and the B. caballi 48-kDa merozoite rhoptry protein, respectively. Of 1,282 horses analyzed, 423 (33%) and 182 (14.2%) were sero-positive for T. equi and B. caballi , respectively. Additionally, 518 (40.4%) were positive for at least 1 parasite species, of which 87 (16.8%) were co-infected with both parasites. Both T. equi and B. caballi were detected in all surveyed provinces, and on a per province basis the positive rates ranged from 19.0 to 74.2% and 4.5 to 39.8%, respectively. Theileria equi - and B. caballi -positive rates were comparable between male horses (31.9 and 14.1%, respectively) and female horses (34.5 and 14.3%, respectively). However, the positive rates were higher in the >3-yr-old age group (37.7 and 15.6%, respectively) compared with the 1-3-yr-old age group (19.4 and 10.0%, respectively). These findings confirmed that T. equi and B. caballi infections are widespread among horses all over Mongolia, and that horse age is a risk factor for infection in this country. Our results will be useful for designing appropriate control measures to minimize T. equi and B. caballi infections among Mongolian horses.

The aims of this study were to determine if histatin-1 (H1) is present in normal human tears and whether tear levels of H1 varied between normal patients and those with aqueous deficient dry eye disease (ADDE). Patient samples were obtained from 11 normal patients and 11 severe ADDE patients. Relevant patient characteristics, including age, sex, and dry eye disease (DED) diagnostic parameters were collected. Multiple qualitative and quantitative methods were used to compare the concentration of H1 between patient groups. Mixed linear modeling was used to compare H1 levels between groups, and diagnostic performance was assessed using the receiver-operator-characteristic (ROC). ADDE patients had significantly lower H1 concentrations (85.9 ± 63.7 ng/ml) than the normal group (891.6 ± 196.5 ng/ml) (p < 0.001), while controlling for age and sex. ROC analysis indicated that H1 concentration is potentially a biomarker for ADDE (area under curve = 0.96). Reclassification of patients by DED parameters including, Ocular Surface Disease Index (OSDI) (≤13, >13) and Schirmer I (without anesthesia) (<10 mm, ≥10 mm) showed significant differences in H1 level (OSDI, p = 0.004) and Schirmer I ((p = 0.010). In conclusion, this is the first preliminary report of the presence of H1 in human tears. H1 concentrations are lower in ADDE patients and H1 may have diagnostic potential in evaluation ADDE patients.

Purpose: To investigate the role of neutrophil extracellular traps (NETs) and NET-associated proteins in the pathogenesis of oGVHD and whether dismantling of NETs with heparin reduces those changes., Methods: Ocular surface washings from oGVHD patients and healthy subjects were analyzed. Isolated peripheral blood human neutrophils were stimulated to generate NETs and heparinized NETs. We performed in vitro experiments using cell lines (corneal epithelial, conjunctival fibroblast, meibomian gland (MG) epithelial and T cells), and in vivo experiments using murine models, and compared the effects of NETs, heparinized NETs, NET-associated proteins and neutralizing antibodies to NET-associated proteins., Results: Neutrophils, exfoliated epithelial cells, NETs and NET-associated proteins (extracellular DNA, Neutrophil Elastase, Myeloperoxidase, Oncostatin M (OSM), Neutrophil gelatinase-associated lipocalin (NGAL) and LIGHT/TNFSF14) are present in ocular surface washings (OSW) and mucocellular aggregates (MCA). Eyes with high number of neutrophils in OSW have more severe signs and symptoms of oGVHD. NETs (and OSM) cause epitheliopathy in murine corneas. NETs (and LIGHT/TNFSF14) increase proliferation of T cells. NETs (and NGAL) inhibit proliferation and differentiation of MG epithelial cells. NETs enhance proliferation and myofibroblast transformation of conjunctival fibroblasts. Sub-anticoagulant dose Heparin (100 IU/mL) dismantles NETs and reduces epithelial, fibroblast, T cell and MG cell changes induced by NETs., Conclusion: NETs and NET-associated proteins contribute to the pathological changes of oGVHD (corneal epitheliopathy, conjunctival cicatrization, ocular surface inflammation and meibomian gland disease). Our data points to the potential of NET-associated proteins (OSM or LIGHT/TNFSF14) to serve as biomarkers and NET-dismantling biologics (heparin eye drops) as treatment for oGVHD., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dourine is an equine protozoan disease caused by Trypanosoma equiperdum. Dourine-afflicted animals die after developing neurological clinical signs, such as unilateral paresis. The disease has been a problem for many years; however, the pathogenesis regarding the neurological clinical signs of dourine has been unclear. In the present study, we conducted a histopathological examination in order to investigate the mechanisms by which dourine-afflicted horses develop the accompanying neurological clinical signs. Four dourine-afflicted horses in Mongolia were evaluated. An apparently healthy horse exhibited multifocal neuritis without axonal or myelin degeneration. The other horses, which had obvious neurological clinical signs, also exhibited multifocal neuritis. In particular, the nerves that innervated areas associated with neurological clinical signs exhibited neuritis with demyelination in the latter horses. Inflamed, non-demyelinating nerves were infiltrated with B lymphocytes and T lymphocytes; while inflamed, demyelinating nerves were infiltrated with mononuclear phagocytes. Our observations revealed lesion progression in the nerves, such that polyradiculoneuropathy could explain the accompanying neurological clinical signs of dourine. To our knowledge, this is the first report to describe a pathogenic mechanism for the development of the neurological clinical signs found in dourine-afflicted horses., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To determine whether DNase eye drops have the potential to reduce signs and symptoms of dry eye disease (DED)., Methods: A placebo-controlled, randomized clinical trial was performed to compare the safety and efficacy of DNase eye drops 0.1% four times a day for 8 weeks in patients with severe tear deficient DED. The change in safety outcome measures (drug tolerability and proportion of adverse events) and efficacy outcome measures (Ocular Surface Disease Index [OSDI] score, corneal and conjunctival staining) were analyzed between baseline and week 8., Results: Tolerability and adverse events were similar in placebo group and DNase group. Within the DNase group (but not placebo group), corneal staining showed a statistically significant and clinically meaningful reduction at week 8 compared with baseline. The OSDI score also showed a significant median reduction of 27.3 at week 8 compared with baseline within the DNase group. The median reduction in corneal staining and mucoid debris/strands was significantly greater in the DNase group as compared with the placebo group. In the DNase group, the median reduction in OSDI (-20.75) was more than placebo group (-8.43); however, the difference between groups was borderline significant., Conclusions: In this pilot study, treatment of severe tear deficient DED patients with DNase eye drops appears safe, well tolerated, and has the potential to reduce the severity of signs and symptoms., Translational Relevance: Data from this pilot clinical trial demonstrate the therapeutic potential of DNase eye drops in dry eye disease, possibly due to degradation neutrophil extracellular traps (NETs) from the ocular surface.

Objective- Inhibition of HMGCR (3-hydroxy-3-methylglutaryl-coenzyme A reductase) is atheroprotective primarily by decreasing plasma LDL (low-density lipoprotein)-cholesterol. However, it is unknown whether inhibition of HMGCR in myeloid cells contributes to this atheroprotection. We sought to determine the role of myeloid HMGCR in the development of atherosclerosis. Approach and Results- We generated mice with genetically reduced Hmgcr in myeloid cells ( Hmgcr m- /m - ) using LysM (Cre) and compared various functions of their macrophages to those of Hmgcr fl/fl control mice. We further compared the extent of atherosclerosis in Hmgcr m-/ m- and Hmgcr fl/fl mice in the absence of Ldlr (LDL receptor). Hmgcr m-/ m- macrophages and granulocytes had significantly lower Hmgcr mRNA expression and cholesterol biosynthesis than Hmgcr fl/fl cells. In vitro, Hmgcr m-/ m- monocytes/macrophages had reduced ability to migrate, proliferate, and survive compared with Hmgcr fl/fl monocytes/macrophages. However, there was no difference in ability to adhere, phagocytose, store lipids, or polarize to M1 macrophages between the 2 types of macrophages. The amounts of plasma membrane-associated small GTPase proteins, such as RhoA (RAS homolog family member A), were increased in Hmgcr m-/ m- macrophages. In the setting of Ldlr deficiency, Hmgcr m-/ m- mice developed significantly smaller atherosclerotic lesions than Hmgcr fl/fl mice. However, there were no differences between the 2 types of mice either in plasma lipoprotein profiles or in the numbers of proliferating or apoptotic cells in the lesions in vivo. The in vivo migration of Hmgcr m-/ m- macrophages to the lesions was reduced compared with Hmgcr fl/fl macrophages. Conclusions- Genetic reduction of HMGCR in myeloid cells may exert atheroprotective effects primarily by decreasing the migratory activity of monocytes/macrophages to the lesions.

In semiarid regions, deficit and unpredictable precipitation results in yield losses. Uniconazole is a plant growth regulator and its application is beneficial in water saving agriculture and improves maize production in semiarid regions. In order to determine the effects of uniconazole application on seed filling and hormonal changes of maize, a field study was conducted in the summer of 2015 and 2016. Seeds were soaked in uniconazole at concentration of 0 (SCK), 25 (S 25 ), 50 (S 50 ), and 75 (S 75 ) mg kg -1 , while in the second experiment, uniconazole was applied to the foliage at concentration of 0 (FCK), 25 (F 25 ), 50 (F 50 ), and 75 (F 75 ) mg L -1 at the eight-leaf. Uniconazole application significantly improves the seed filling rates by regulating the endogenous hormones contents. Uniconazole seed soaking treatments improved significantly the seed filling rate of superior, middle, and inferior seeds compared with foliar application treatments. Uniconazole improved significantly the zeatin (Z) + zeatin riboside (ZR) and abscisic acid (ABA) contents while reducing the gibberellic acid (GA) content in the seeds during the process of seed filling. The Z + ZR and ABA contents were significantly positively correlated while the GA content was negatively correlated with maximum seed weight, maximum seed filling rates, and mean seed filling rates. Treatments S 25 and F 25 significantly improved the above dry matter accumulation plant -1 , seed filling rates, ABA, Z + ZR contents, characters of ear, and grain yield while reduced the GA content. It is concluded from our results that the uniconazole application at concentration of 25 mg kg -1 as seed soaking or 25 mg L -1 foliar applied at the eight-leaf stage is beneficial to improve the seed filling rates and grain yield of maize in semiarid regions.

Objective: We investigated whether vagus nerve stimulation (VNS) induces a positive shift of slow cortical potentials (SCPs) in patients with >50% seizure reduction (responders) but not in non-responders., Methods: We analyzed routine clinical electroencephalograms (EEGs) from 24 patients who were undergoing seizure treatment by VNS. The patients were divided into 2 groups by hardware time constant (TC) of EEG: the TC 10-s group (10 patients) and TC 2-s group (14 patients). We compared SCPs at 5 electrodes (Cz and adjacent ones) between the 2 states of VNS: during stimulation and between stimulations. Seizure reduction was independently judged. Correlation between SCP (positivity or not) and seizure reduction (>50% or not) was estimated., Results: In the TC 10-s group, the correlation between SCP and seizure reduction was significant (p<0.05) (i.e., both good results in 4 and both negative results in 5). In TC 2-s group, the correlation between SCP and seizure reduction was not significant (p=0.209)., Conclusions: A positive shift of SCP recorded by using a TC of 10s could be a surrogate marker for VNS response., Significance: SCP could be a biomarker of good responders to VNS., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Copper (Cu), an essential nutrient, promotes wound healing, however, target of Cu action and underlying mechanisms remain elusive. Cu chaperone Antioxidant-1 (Atox1) in the cytosol supplies Cu to the secretory enzymes such as lysyl oxidase (LOX), while Atox1 in the nucleus functions as a Cu-dependent transcription factor. Using mouse cutaneous wound healing model, here we show that Cu content (by X-ray Fluorescence Microscopy) and nuclear Atox1 are increased after wounding, and that wound healing with and without Cu treatment is impaired in Atox1 -/- mice. Endothelial cell (EC)-specific Atox1 -/- mice and gene transfer of nuclear-target Atox1 in Atox1 -/- mice reveal that Atox1 in ECs as well as transcription factor function of Atox1 are required for wound healing. Mechanistically, Atox1 -/- mice show reduced Atox1 target proteins such as p47phox NADPH oxidase and cyclin D1 as well as extracellular matrix Cu enzyme LOX activity in wound tissues. This in turn results in reducing O 2 - production in ECs, NFkB activity, cell proliferation and collagen formation, thereby inhibiting angiogenesis, macrophage recruitment and extracellular matrix maturation. Our findings suggest that Cu-dependent transcription factor/Cu chaperone Atox1 in ECs plays an important role to sense Cu to accelerate wound angiogenesis and healing.

Background: Report of three patients with pseudophakic angle-closure from a Soemmering ring. Three mechanisms of the Soemmering ring induced pseudophakic angle-closure in three patients were demonstrated by meticulous anterior segment examination and ultrasound biomicroscopic (UBM) analysis., Case Presentation: In the first case, the Soemmering-capsule-IOL complex caused relative pupillary block similar to a phakic eye and was successfully treated with laser iridotomy alone. In the second case, an enlarged Soemmering ring provided posterior iris support in apposition to the anterior chamber angle. We performed a laser capsulotomy through the iridotomised hole. The last, a protruding Soemmering content causing absolute pupillary block became resolved after laser iridotomy and total Soemmering ring content removal., Conclusion: Angle-closure in pseudophakic eyes is uncommon. Several causes have been reported in the literatures including Soemmering ring. This is the first report on three different mechanisms of Soemmering ring related angle-closure in pseudophakic eyes. Ultrasound biomicroscopic analysis plays a crucial role as a diagnostic tool.

Background: To report the results of the International Nosocomial Infection Control Consortium (INICC) multicenter study conducted in Mongolia from September 2013-March 2015., Methods: A device-associated health care-associated infection prospective surveillance study in 3 adult intensive care units (ICUs) from 3 hospitals using the U.S. Centers for Disease Control and Prevention (CDC) and National Healthcare Safety Network (NHSN) definitions and INICC methods., Results: We documented 467 ICU patients for 2,133 bed days. The central line-associated bloodstream infection (CLABSI) rate was 19.7 per 1,000 central line days, the ventilator-associated pneumonia (VAP) rate was 43.7 per 1,000 mechanical ventilator days, and the catheter-associated urinary tract infection (CAUTI) rate was 15.7 per 1,000 urinary catheter days; all of the rates are higher than the INICC rates (CLABSI: 4.9; VAP: 16.5; and CAUTI: 5.3) and CDC-NHSN rates (CLABSI: 0.8; VAP: 1.1; and CAUTI: 1.3). Device use ratios were also higher than the CDC-NHSN and INICC ratios, except for the mechanical ventilator device use ratio, which was lower than the INICC ratio. Resistance of Staphylococcus aureus to oxacillin was 100%. Extra length of stay was 15.1 days for patients with CLABSI, 7.8 days for patients with VAP, and 8.2 days for patients with CAUTI. Extra crude mortality in the ICUs was 18.6% for CLABSI, 17.1% for VAP, and 5.1% for CAUTI., Conclusion: Device-associated health care-associated infection rates and most device use ratios in our Mongolian hospitals' ICUs are higher than the CDC-NSHN and INICC rates., (Copyright © 2015 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Elsevier Inc. All rights reserved.)

Genetic studies of plasma TG levels have identified associations with multiple candidate loci on chromosome11q23.3, which harbors a number of genes, including BUD13, ZNF259, and APOA5-A4-C3-A1. This study aimed to examine whether these multiple candidate genes on the 11q23.3 regions exert independent effects on TG levels or whether their effects are confounded by linkage disequilibrium (LD). We performed a genome-wide association study and consequent fine-mapping analyses on TG levels in two Korean population-based cohorts: the Korea Association Resource study (n = 8,223) and the Healthy Twin study (n = 1,735). A total of 301 loci reached genome-wide significance level in pooled analysis, including 10 SNPs with weak LD (r(2) < 0.06) clustered on 11q23.3: ApoA5 (rs651821, rs2075291); ZNF259 (rs964184, rs603446); BUD13 (rs11216126); Apoa4 (rs7396851); SIK3 (rs12292858); PCSK7 (rs199890178); PAFAH1B2 (rs12420127), and SIDT2 (rs2269399). When the inter-dependence between alleles was examined using conditional models, five loci on BUD13, ZNF259, and ApoA5 showed possible independent associations. A haplotype analysis using five SNPs revealed both hyper- and hypotriglyceridemic haplotypes, which are relatively common in Koreans (haplotype frequency 0.08-0.22). Our findings suggest the presence of multiple functional loci on 11q23.3, which might exert their effects on plasma TG level independently or through complex interactions between functional loci., (Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.)

Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.

The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.

We assessed the association between frequency of heavy binge drinking and mortality from oropharynx and esophagus cancer after controlling for the total volume of alcohol intake among Korean men. The cohort comprised 2,677 male residents in Kangwha County, aged 55 or older in March 1985, for their upper digestive tract cancer mortality for 20.8 years up to December 31, 2005. For daily binge drinkers versus non-drinkers, the hazard ratios (95% Cls) for mortality were 4.82 (1.36, 17.1) and 6.75 (1.45, 31.4) for oropharyngeal and esophageal cancers, respectively. Even after adjusting for the volume of alcohol intake, we found the hazard ratios for frequency of binge drinking and mortality of oropharyngeal or esophageal cancer to not change appreciably: the hazard ratios were 4.90 (1.00, 27.0) and 7.17 (1.02, 50.6), respectively. For esophageal cancer, there was a strong dose-response relationship. The frequency of heavy binge drinking and not just the volume of alcohol intake may increase the risk of mortality from upper digestive tract cancer, particularly esophageal cancer in Korean men. These findings need to be confirmed in further studies with a larger sample size.

Background: Although binge drinking and high resting heart rate independently affect cardiovascular and all-cause mortality risk, the combined effect of these two risk factors and their interaction has rarely been studied. This study examined the association between binge drinking and cardiovascular and all-cause mortality and evaluated the potential modifying effect on this association of resting heart rate in Korean men., Methods: Men aged 55 years or older in 1985 (n = 2600) were followed for cardiovascular and all-cause mortality for 20.8 years, until 2005. We estimated hazard ratios (HRs) for cardiovascular and all-cause mortality by binge drinking and resting heart rate using the Cox proportional hazard model., Results: Heavy binge drinkers (≥12 drinks on one occasion) with elevated resting heart rate (≥80 bpm) had a HR of 2.25 (95% confidence interval [CI], 1.47-3.45) for death from cardiovascular disease and 1.37 (95% CI, 0.87-2.14) for all-cause mortality compared to the reference group (non-drinking and resting heart rate 61-79 bpm). The HRs of dying from cardiovascular disease increased linearly from 1.36 to 1.52, 1.71, and 2.25 among individuals with resting heart rate greater than or equal to 80 bpm within the four alcohol consumption categories (non-drinking, non-binge, moderate binge, and heavy binge), respectively., Conclusions: Our findings suggest that, among older Korean men, heavy binge drinkers with an elevated resting heart rate are at high risk for cardiovascular and all-cause mortality.

Despite the need to provide evidence-based health policy, most developing countries suffer from a lack of resources for sound epidemiologic evidence. Most twin registers have been established in developed countries and there are relatively fewer twin registers in developing countries. Considering the immense potential of twin research, it will be worthwhile to attempt to establish a new twin register in Mongolia, where biomedical studies are still scarce. Our objectives were to initiate the process of establishing a nation-wide twin register in Mongolia, based on a nation-wide, population-based database. With the approval and support of the Ministry of Population Development and Social Welfare of Mongolia, we were able to access an initial list of 411 twin pairs who live in the district of Ulaanbaatar, the capital city of Mongolia. By developing a questionnaire to estimate zygosity, we conducted a pilot survey. Those who registered consisted of 822 individuals or 411 twin pairs (same sex: male - 178; female - 157; different sex - 76), two sets of triplets (same sex: female - 2). The age of twins ranged from 1 to 81 (mean age 7.3 ± 11.3), and 52.4% were males. The first twin survey in Mongolia not only resulted in interim data for the Mongolian Twin Register, but has the potential for establishing a larger register by using the national database. It has been proven possible to establish a twin register for research purposes in Mongolia.

The Healthy Twin Study, Korea (HT) is an ongoing multi-center cohort study that was initiated in 2005, based on a nation-wide twin and family database. Since its inception, the HT has recruited 815 pairs of adult twins and a total of 3,690 individual twins and their families as of July 2012. Here we summarize updates since the previous report in 2006. Besides the increase in size, the HT has been enriched in several aspects: a biobank was constructed for ongoing and future omics studies; and genome-wide single nucleotide polymorphism markers (Affymetrix GeneChip version 6.0, 1 M probes) have been analyzed for 2,200 individuals, which enabled gene identification studies for measured phenotypes. In addition, longitudinal study protocols were established through the HT and a second wave survey was finished in 2010 with >70% follow-up rate. The parallel genome research projects were recently launched, which would expedite multi-omics studies maximizing the twin potentials such as metagenomics and epigenetics studies, and endow us with resources for recruiting more participants. We submit this report to share updates and research opportunities from the HT.

Insulin stimulates glucose transporter 4 (GLUT4) vesicle recruitment from its intracellular storage site to the plasma membrane. Cysteine string protein 1 (CSP1) is a SNARE-binding protein involved in the vesicular trafficking of neurotransmitters and other exocytic processes. In this study, we investigated the involvement of CSP1 in insulin-dependent GLUT4 recruitment in 3T3-L1 adipocytes. Over-expression of wild-type CSP1 led to attenuated insulin-stimulated glucose uptake without any change in GLUT4 content in the plasma membrane, rather it inhibits docking by blocking the association of VAMP2 with syntaxin 4. In contrast, knockdown of CSP1 enhanced insulin-stimulated glucose uptake. The mRNA and protein expression of CSP1 was elevated in 3T3-L1 adipocytes in insulin resistant states caused by high levels of palmitate and chronic insulin exposure. Taken together, the results of this study suggest that CSP1 is involved in insulin resistance by interrupting GLUT4 vesicle docking with the plasma membrane.

Objective: We examined gender-specific combined effects of smoking and hypertension on risk of mortality from cardiovascular disease in elderly Korean men and women., Study Design: This study followed a cohort of 6097 residents (2593 men, 3504 women) in the general population of Kangwha County, aged ≥55 years in March 1985 and examined their cause-specific mortality for 20.8 years, up to December 31, 2005. All participants were followed up more than once after the 1985 survey., Main Outcome Measures: We calculated hazard ratios for mortality for the combined sets of smoking habits and blood pressure levels using the Cox proportional-hazard model. The set of non-smokers with normal blood pressure served as a reference group., Results: During the 20.8 years of follow-up, 759 people died from cardiovascular disease. The risk of mortality from cardiovascular disease and stroke according to smoking or hypertension was not different between men and women. However, the risk among smokers combined with hypertension was higher in men than in women; the multivariable-adjusted hazard ratios (95% CI) for mortality from cardiovascular disease and stroke were 4.52 (1.67-12.21) and 6.37 (1.57-25.85) in men and 2.11 (1.37-3.24) and 2.41 (1.44-4.01) in women, respectively., Conclusions: The magnitude of the joint effects of smoking and hypertension on cardiovascular disease and stroke mortality was different between men and women. This study suggests that combining quitting smoking with lowering blood pressure could contribute to preventing cardiovascular disease and stroke, especially in men., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: As well as biomedical risk factors, psychological factors have been reported to be related to mortality rate. The purpose of this study was to examine the relationship between life satisfaction and mortality in elderly people through an 11.8-year follow-up study of a prospective cohort., Methods: Among 3,600 participants of the Kangwha Cohort Study who survived in 1994, 1,939 respondents of the Life Satisfaction Index (LSI)-A questionnaire were included (men, 821; women, 1118). The mortality risk for the period up to December 2005 was measured using the Cox Proportional Hazard Model., Results: When the relationship between LSI and mortality was evaluated in men, the unsatisfied group with lower LSI scores showed a significantly higher risk of all-cause mortality (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.11-1.83) than the satisfied group with higher LSI scores. In women, the unsatisfied group showed a significantly higher risk of all-cause mortality (HR, 1.51; 95% CI, 1.18-1.92) and cardiovascular mortality (HR, 2.23; 95% CI, 1.30-3.85) than the satisfied group., Conclusion: We found that elderly people with a lower LSI score, regardless of gender, were at risk of increased mortality from all causes, and low LSI score was also associated with cardiovascular mortality.

Insulin-responsive aminopeptidase (IRAP) and GLUT4 are two major cargo proteins of GLUT4 storage vesicles (GSVs) that are translocated from a postendosomal storage compartment to the plasma membrane (PM) in response to insulin. The cytoplasmic region of IRAP is reportedly involved in retention of GSVs. In this study, vimentin was identified using the cytoplasmic domain of IRAP as bait. The validity of this interaction was confirmed by pull-down assays and immunoprecipitation in 3T3-L1 adipocytes. In addition, it was shown that GLUT4 translocation to the PM by insulin was decreased in vimentin-depleted adipocytes, presumably due to dispersing GSVs away from the cytoskeleton. These findings suggest that the IRAP binding protein, vimentin, plays an important role in retention of GSVs., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Previous studies have shown links between cognitive impairment and hypertension as well as mortality. However, combined effects of these two conditions on mortality have not been fully explored., Objective: To assess the combined effect of cognitive impairment and hypertension on all-cause mortality among the elderly people., Methods: We followed a cohort of 2,496 residents in Kangwha County, ranging in age from 64 to 101 years as of March 1994, for all-cause mortality for 11.8 years up to December 31, 2005. We calculated hazard ratios (HR) for all-cause mortality by cognitive status and blood pressure using the Cox proportional hazards model after having controlled for confounding factors., Results: 1,189 people (47.6%) died during the 11.8 years of follow-up. The HR associated with severe cognitive impairment increased from 2.15 (95% CI: 1.30, 3.54) for prehypertension over 2.68 (95% CI: 1.60, 4.48) for stage 1 hypertension to 3.60 (95% CI: 1.99, 6.49) for stage 2 hypertension in women. A mortality risk of 3.67 (95% CI: 2.05, 6.57) was observed among men who had both mild cognitive impairment and stage 2 hypertension., Conclusion: Individuals with coexisting cognitive impairment and hypertension are at an increased risk of all-cause mortality compared with those with cognitive impairment or hypertension alone., (Copyright © 2011 S. Karger AG, Basel.)