Multimodal Imaging Findings of Cerebral Amyloid Angiopathy Related Inflammation With Unusual Clinical Manifestation: A Case Report

Cerebral amyloid angiopathy-related inflammation (CAA-RI) is a rare encephalopathy characterized by the coexistence of a perivascular inflammatory reaction in patients with cerebral amyloid angiopathy. CAA-RI diagnosis is challenging as its final diagnosis requires invasive procedures such as autopsy or brain biopsy. Therefore, multimodal imaging approaches with clinical considerations are essential for the probable diagnosis of CAA-RI. In particular, in the case of CAA-RI presented with uncommon clinical symptoms, the need for imaging in diagnosis is further highlighted by difficulties of clinical approaches. Herein, we report a case of CAA-RI with unusual clinical manifestation diagnosed using multimodal imaging including magnetic resonance imaging (MRI) and amyloid positron emission tomography-computed tomography (PET-CT). Multimodal imaging approaches using adequate MRI sequences and PET-CT scans could facilitate the diagnosis of CAA-RI without requiring invasive pathological confirmation.

Prediction of Microsatellite Instability in Colorectal Cancer Using a Machine Learning Model Based on PET/CT Radiomics

Purpose@#We investigated the feasibility of preoperative 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/ computed tomography (CT) radiomics with machine learning to predict microsatellite instability (MSI) status in colorectal cancer (CRC) patients. @*Materials and Methods@#Altogether, 233 patients with CRC who underwent preoperative FDG PET/CT were enrolled and divided into training (n=139) and test (n=94) sets. A PET-based radiomics signature (rad_score) was established to predict the MSI status in patients with CRC. The predictive ability of the rad_score was evaluated using the area under the receiver operating characteristic curve (AUROC) in the test set. A logistic regression model was used to determine whether the rad_score was an independent predictor of MSI status in CRC. The predictive performance of rad_score was compared with conventional PET parameters. @*Results@#The incidence of MSI-high was 15 (10.8%) and 10 (10.6%) in the training and test sets, respectively. The rad_score was constructed based on the two radiomic features and showed similar AUROC values for predicting MSI status in the training and test sets (0.815 and 0.867, respectively; p=0.490). Logistic regression analysis revealed that the rad_score was an independent predictor of MSI status in the training set. The rad_score performed better than metabolic tumor volume when assessed using the AUROC (0.867 vs. 0.794, p=0.015). @*Conclusion@#Our predictive model incorporating PET radiomic features successfully identified the MSI status of CRC, and it also showed better performance than the conventional PET image parameters.

A study of job stress, suicidal ideation and suicide attempts in display manufacturing workers: a crosssectional study

Background@#This study aimed to investigate the association between job stress and suicide ideation/attempts among display manufacturing workers. @*Methods@#Data were collected from 836 workers in a display manufacturing company who participated in health screenings from May 22 to June 16, 2017. The data included general characteristics, night work, job tenure, previous physician-diagnosed chronic diseases, suicidal ideation/suicide attempts, and job stress. We investigated suicidal ideation/suicide attempts that covered the past year by using a self-reported questionnaire. Job stress was measured using the 43-item Korean Occupational Stress Scale. Multiple logistic regression analysis was used to investigate the association between job stress and suicidal ideation/ suicide attempts. The mediator effect of depression on suicidal ideation/suicide attempts was tested using a series of logistic regression by applying Baron and Kenny's mediation method. @*Results@#In the model adjusting for variables (e.g., age, body mass index, smoking, alcohol consumption, regular exercise, shift work, job tenure, chronic disease and depression), physical environment (OR: 3.60, 95% CI: 1.08–12.02), lack of reward (OR: 5.31, 95% CI:1.54–18.34), and occupation climate (OR: 7.36, 95% CI: 2.28–23.72) were correlated with suicidal ideation/suicide attempts in women. However, all subscales of job stress were not significantly correlated with suicidal ideation/suicide attempts in men. In mediation analysis, job instability and occupational climate were correlated with suicidal ideation/suicide attempts and were mediated by depression in men workers. @*Conclusions@#In women workers, the experiences of suicidal ideation/suicide attempts were significantly correlated with the physical environment, lack of reward, and occupational climate that were subscales of job stress. In men workers, depression rather than job stress was correlated with experiences of suicidal ideation/suicide attempts.

Spinosin Attenuates Alzheimer’s Disease-Associated Synaptic Dysfunction via Regulation of Plasmin Activity

Hippocampal synaptic dysfunction is a hallmark of Alzheimer’s disease (AD). Many agents regulating hippocampal synaptic plasticity show an ameliorative effect on AD pathology, making them potential candidates for AD therapy. In the present study, we investigated spinosin as a regulating agent of synaptic plasticity in AD. Spinosin attenuated amyloid β (Aβ)-induced long-term potentiation (LTP) impairment, and improved plasmin activity and protein level in the hippocampi of 5XFAD mice, a transgenic AD mouse model. Moreover, the effect of spinosin on hippocampal LTP in 5XFAD mice was prevented by 6-aminocaproic acid, a plasmin inhibitor. These results suggest that spinosin improves synaptic function in the AD hippocampus by regulating plasmin activity.

Hydrangeae Dulcis Folium Attenuates Physical Stress by Supressing ACTH-Induced Cortisol in Zebrafish / 中国结合医学杂志

OBJECTIVE@#To determine the effects of Hydrangeae Dulcis Folium (EHDF) on physical stress, changes in the whole-body cortisol level and behaviour in zebrafish (Danio rerio).@*METHODS@#One hundred and seventy-four fish were randomly divided into 4 [adrenocorticotropin hormone (ACTH) challenge test: 4 fish per group] or 6 groups (behavioural test: 10-12 fish per group, whole-body cortisol: 4 fish per group). Net handling stress (NHS) was used to induce physical stress. Fish were treated with vehicle or EHDF (5-20 mg/L) for 6 min before they were exposed to stress. And then, fish were sacrificed for collecting body fluid from whole-body or conducted behavioural tests, including novel tank test and open field test, and were evaluated to observe anxiety-like behaviours and locomotion. In addition, to elucidate the mode of action of the anti-stress effects of EHDF, ACTH (0.2 IU/g, i.p.) challenge test was performed.@*RESULTS@#The increased anxiety-like behaviours in novel tank test and open field test under stress were prevented by treatment with EHDF at 5-20 mg/L (P <0.05). Moreover, compared with the unstressed group, which was not treated with NHS, the whole-body cortisol level was significantly increased by treatment with NHS (P <0.05). Compared with the NHS-treated stressed control group, pre-treatment with EHDF at concentrations of 5-20 mg/L for 6 min significantly prevented the NHS-increased whole-body cortisol level (<0.05). In addition, ACTH challenge test showed that EHDF completely blocked the effects of ACTH on cortisol secretion (P <0.05).@*CONCLUSION@#EHDF may be a good antistress candidate and its mechanism of action may be related to its positive effects on cortisol release.

A study of job stress, suicidal ideation and suicide attempts in display manufacturing workers: a crosssectional study

Background@#This study aimed to investigate the association between job stress and suicide ideation/attempts among display manufacturing workers. @*Methods@#Data were collected from 836 workers in a display manufacturing company who participated in health screenings from May 22 to June 16, 2017. The data included general characteristics, night work, job tenure, previous physician-diagnosed chronic diseases, suicidal ideation/suicide attempts, and job stress. We investigated suicidal ideation/suicide attempts that covered the past year by using a self-reported questionnaire. Job stress was measured using the 43-item Korean Occupational Stress Scale. Multiple logistic regression analysis was used to investigate the association between job stress and suicidal ideation/ suicide attempts. The mediator effect of depression on suicidal ideation/suicide attempts was tested using a series of logistic regression by applying Baron and Kenny's mediation method. @*Results@#In the model adjusting for variables (e.g., age, body mass index, smoking, alcohol consumption, regular exercise, shift work, job tenure, chronic disease and depression), physical environment (OR: 3.60, 95% CI: 1.08–12.02), lack of reward (OR: 5.31, 95% CI:1.54–18.34), and occupation climate (OR: 7.36, 95% CI: 2.28–23.72) were correlated with suicidal ideation/suicide attempts in women. However, all subscales of job stress were not significantly correlated with suicidal ideation/suicide attempts in men. In mediation analysis, job instability and occupational climate were correlated with suicidal ideation/suicide attempts and were mediated by depression in men workers. @*Conclusions@#In women workers, the experiences of suicidal ideation/suicide attempts were significantly correlated with the physical environment, lack of reward, and occupational climate that were subscales of job stress. In men workers, depression rather than job stress was correlated with experiences of suicidal ideation/suicide attempts.

How Do Oroxylin A and Spinosin Exert Their Activities on Cognitive Function?

Flavonoids are mainly contained in the vegetables and medicinal herbs. Until now, over 5,000 kinds of flavonoid have been identified and their biological activities have been reported. Among them, we are interested in oroxylin A and spinosin because of their specific structures having bulky group at C-6 of ring A. Oroxylin A is contained in the Scutellaria baicalensis and exhibits cognitive enhancing activity as a GABAA receptor antagonist, which is different from those of mainly contained in the S. baicalenis, baicalein or wogonin. Spinosin is isolated from Zizyphus jujuba var. spinosa and mainly studied as a hypnotic or anxiolytic agent because of traditional knowledge about its original herb. As far as we know, the cognitive function of spinosin was first identified by our group. In this review, we discuss how such flavonoids exert their pharmacological activities associated with cognitive function based on the receptor binding study and behavioral studies. Traditional knowledge and reverse pharmacology may be addressed in the research field of phytochemical pharmacology and useful to unveil the secret of phytochemicals.

Quantitative Proteomic Analysis Reveals Impaired Axonal Guidance Signaling in Human Postmortem Brain Tissues of Chronic Traumatic Encephalopathy

Chronic traumatic encephalopathy (CTE) is a distinct neurodegenerative disease that associated with repetitive head trauma. CTE is neuropathologically defined by the perivascular accumulation of abnormally phosphorylated tau protein in the depths of the sulci in the cerebral cortices. In advanced CTE, hyperphosphorylated tau protein deposits are found in widespread regions of brain, however the mechanisms of the progressive neurodegeneration in CTE are not fully understood. In order to identify which proteomic signatures are associated with CTE, we prepared RIPA-soluble fractions and performed quantitative proteomic analysis of postmortem brain tissue from individuals neuropathologically diagnosed with CTE. We found that axonal guidance signaling pathwayrelated proteins were most significantly decreased in CTE. Immunohistochemistry and Western blot analysis showed that axonal signaling pathway-related proteins were down regulated in neurons and oligodendrocytes and neuron-specific cytoskeletal proteins such as TUBB3 and CFL1 were reduced in the neuropils and cell body in CTE. Moreover, oligodendrocyte-specific proteins such as MAG and TUBB4 were decreased in the neuropils in both gray matter and white matter in CTE, which correlated with the degree of axonal injury and degeneration. Our findings indicate that deregulation of axonal guidance proteins in neurons and oligodendrocytes is associated with the neuropathology in CTE. Together, altered axonal guidance proteins may be potential pathological markers for CTE.

Metabolomic Analysis Identifies Alterations of Amino Acid Metabolome Signatures in the Postmortem Brain of Alzheimer's Disease

Despite significant advances in neuroscience research over the past several decades, the exact cause of AD has not yet fully understood. The metabolic hypothesis as well as the amyloid and tau hypotheses have been proposed to be associated with AD pathogenesis. In order to identify metabolome signatures from the postmortem brains of sporadic AD patients and control subjects, we performed ultra performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer (UPLC-LTQ–Orbitrap-MS). Not only our study identified new metabolome signatures but also verified previously known metabolome profiles in the brain. Statistical modeling of the analytical data and validation of the structural assignments discovered metabolic biomarkers associated with the AD pathogenesis. Interestingly, hypotaurin, myo-inositol and oxo-proline levels were markedly elevated in AD while lutamate and N-acetyl-aspartate were decreased in the postmortem brain tissue of AD patients. In addition, neurosteroid level such as cortisol was significantly increased in AD. Together, our data indicate that impaired amino acid metabolism is associated with AD pathogenesis and the altered amino acid signatures can be useful diagnostic biomarkers of AD. Thus, modulation of amino acid metabolism may be a possible therapeutic approach to treat AD.

Theracurmin Ameliorates Cognitive Dysfunctions in 5XFAD Mice by Improving Synaptic Function and Mitigating Oxidative Stress

As the elderly population is increasing, Alzheimer's disease (AD) has become a global issue and many clinical trials have been conducted to evaluate treatments for AD. As these clinical trials have been conducted and have failed, the development of new theraphies for AD with fewer adverse effects remains a challenge. In this study, we examined the effects of Theracurmin on cognitive decline using 5XFAD mice, an AD mouse model. Theracurmin is more bioavailable form of curcumin, generated with submicron colloidal dispersion. Mice were treated with Theracurmin (100, 300 and 1,000 mg/kg) for 12 weeks and were subjected to the novel object recognition test and the Barnes maze test. Theracurmin-treated mice showed significant amelioration in recognition and spatial memories compared those of the vehicle-treated controls. In addition, the antioxidant activities of Theracurmin were investigated by measuring the superoxide dismutase (SOD) activity, malondialdehyde (MDA) and glutathione (GSH) levels. The increased MDA level and decreased SOD and GSH levels in the vehicle-treated 5XFAD mice were significantly reversed by the administration of Theracurmin. Moreover, we observed that Theracurmin administration elevated the expression levels of synaptic components, including synaptophysin and post synaptic density protein 95, and decreased the expression levels of ionized calcium-binding adapter molecule 1 (Iba-1), a marker of activated microglia. These results suggest that Theracurmin ameliorates cognitive function by increasing the expression of synaptic components and by preventing neuronal cell damage from oxidative stress or from the activation of microglia. Thus, Theracurmin would be useful for treating the cognitive dysfunctions observed in AD.

Neuroprotective effect of the ethanol extract of Artemisia capillaris on transient forebrain ischemia in mice via nicotinic cholinergic receptor / 中国天然药物

Artemisia capillaris Thunberg is a medicinal plant used as a traditional medicine in many cultures. It is an effective remedy for liver problems including hepatitis. Recent pharmacological reports have indicated that Artemisia species can exert various neurological effects. Previously, we reported a memory-enhancing effect of Artemisia species. However, the mechanisms underlying the neuroprotective effect of A. capillaris (AC) are still unknown. In the present study, we investigated the effect of an ethanol extract of AC on ischemic brain injury in a mouse model of transient forebrain ischemia. The mice were treated with AC for seven days, beginning one day before induction of transient forebrain ischemia. Behavioral deficits were investigated using the Y-maze. Nissl and Fluoro-jade B staining were used to indicate the site of injury. To determine the underlying mechanisms for the drug, we measured acetylcholinesterase activity. AC (200 mg·kg) treatment reduced transient forebrain ischemia-induced neuronal cell death in the hippocampal CA1 region. The AC-treated group also showed significant amelioration in the spontaneous alternation of the Y-maze test performance, compared to that in the untreated transient forebrain ischemia group. Moreover, AC treatment showed a concentration-dependent inhibitory effect on acetylcholinesterase activity in vitro. Finally, the effect of AC on forebrain ischemia was blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor antagonist. Our results suggested that in a model of forebrain ischemia, AC protected against neuronal death through the activation of nicotinic acetylcholine receptors.

Tau Positron Emission Tomography Imaging in Degenerative Parkinsonisms

In recent years, several radiotracers that selectively bind to pathological tau proteins have been developed. Evidence is emerging that binding patterns of in vivo tau positron emission tomography (PET) studies in Alzheimer's disease (AD) patients closely resemble the distribution patterns of known neurofibrillary tangle pathology, with the extent of tracer binding reflecting the clinical and pathological progression of AD. In Lewy body diseases (LBD), tau PET imaging has clearly revealed cortical tau burden with a distribution pattern distinct from AD and increased cortical binding within the LBD spectrum. In progressive supranuclear palsy, the globus pallidus and midbrain have shown increased binding most prominently. Tau PET patterns in patients with corticobasal syndrome are characterized by asymmetrical uptake in the motor cortex and underlying white matter, as well as in the basal ganglia. Even in the patients with multiple system atrophy, which is basically a synucleinopathy, ¹⁸F-flortaucipir, a widely used tau PET tracer, also binds to the atrophic posterior putamen, possibly due to off-target binding. These distinct patterns of tau-selective radiotracer binding in the various degenerative parkinsonisms suggest its utility as a potential imaging biomarker for the differential diagnosis of parkinsonisms.

Neuroprotective effect of the ethanol extract of Artemisia capillaris on transient forebrain ischemia in mice via nicotinic cholinergic receptor / 中国天然药物

Artemisia capillaris Thunberg is a medicinal plant used as a traditional medicine in many cultures. It is an effective remedy for liver problems including hepatitis. Recent pharmacological reports have indicated that Artemisia species can exert various neurological effects. Previously, we reported a memory-enhancing effect of Artemisia species. However, the mechanisms underlying the neuroprotective effect of A. capillaris (AC) are still unknown. In the present study, we investigated the effect of an ethanol extract of AC on ischemic brain injury in a mouse model of transient forebrain ischemia. The mice were treated with AC for seven days, beginning one day before induction of transient forebrain ischemia. Behavioral deficits were investigated using the Y-maze. Nissl and Fluoro-jade B staining were used to indicate the site of injury. To determine the underlying mechanisms for the drug, we measured acetylcholinesterase activity. AC (200 mg·kg) treatment reduced transient forebrain ischemia-induced neuronal cell death in the hippocampal CA1 region. The AC-treated group also showed significant amelioration in the spontaneous alternation of the Y-maze test performance, compared to that in the untreated transient forebrain ischemia group. Moreover, AC treatment showed a concentration-dependent inhibitory effect on acetylcholinesterase activity in vitro. Finally, the effect of AC on forebrain ischemia was blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor antagonist. Our results suggested that in a model of forebrain ischemia, AC protected against neuronal death through the activation of nicotinic acetylcholine receptors.

Increased Uptake of AV-1451 in a Subacute Infarction Lesion

¹⁸F-AV-1451 is a tau PET ligand that has high affinity for paired helical filament tau. However, various off-target bindings unrelated to tau have also been reported. Herein, we report a case of 83-year-old woman, who showed abnormal uptake of AV-1451 that was shown to be subacute infarction. Clinicians should recognize that increased uptake of AV-1451 may be related to stroke.

Astrocytic proBDNF and Tonic GABA Distinguish Active versus Reactive Astrocytes in Hippocampus

Astrocytes are the most abundant cell type in the brain and they make close contacts with neurons and blood vessels. They respond dynamically to various environmental stimuli and change their morphological and functional properties. Both physiological and pathological stimuli can induce versatile changes in astrocytes, as this phenomenon is referred to as ‘astrocytic plasticity’. However, the molecular and cellular mechanisms of astrocytic plasticity in response to various stimuli remain elusive, except for the presence of hypertrophy, a conspicuous structural change which is frequently observed in activated or reactive astrocytes. Here, we investigated differential characteristics of astrocytic plasticity in a stimulus-dependent manner. Strikingly, a stab wound brain injury lead to hypertrophy of astrocytes accompanied by increased GABA expression and tonic GABA release in mouse CA1 hippocampus. In contrast, the mice experiencing enriched environment exhibited astrocytic hypertrophy with enhanced proBDNF immunoreactivity but without GABA signal. Based on the results, we define proBDNF-positive/GABA-negative hypertrophic astrocytes as ‘active’ astrocytes and GABA-positive hypertrophic astrocytes as ‘reactive’ astrocytes, respectively. We propose for the first time that astrocytic proBDNF can be a bona fide molecular marker of the active astrocytes, which are distinct from the reactive astrocytes which show hypertrophy but with aberrant GABA.

Risk Factors Associated with Mortality of Patients with Pelvic Fractures and Hemodynamic Instability in a Korean Trauma Center

PURPOSE: The aim of this study is to evaluate treatment outcomes and mortality risks associated with hemodynamic instability caused by severe pelvic fracture in a regional trauma center. METHODS: The medical charts of 44 patients with hemodynamic instability due to pelvic fractures who were admitted to a regional trauma center from January 2014 to May 2017 were analyzed retrospectively. RESULTS: The mean age was 61.8 years, and the mean injury severity score was 39.1. Twenty-six patients (59.1%) were transferred from other hospitals, and the median time from injury to emergency room arrival was 115.5 minutes. Preperitoneal pelvic packing, pelvic angiography, and external pelvic fixation were performed in 38 patients (86.4%) for hemostasis. The mortality rate was 52.3%, and 15 patients (34.1%) died from hemorrhage. Logistic regression analysis showed that initial low systolic blood pressure and packed red blood cell (PRBC) requirement were independent risk factors associated with mortality. PRBC requirement for four hours and application of emergent hemostatic procedures were independent factors associated with hemorrhage-induced mortality. CONCLUSION: Emergency procedures for hemostasis should be performed immediately for patients with hemodynamic instability due to pelvic fracture, and they should be transferred to a regional trauma center as soon as possible.

Genetic Ablation of EWS RNA Binding Protein 1 (EWSR1) Leads to Neuroanatomical Changes and Motor Dysfunction in Mice

A recent study reveals that missense mutations of EWSR1 are associated with neurodegenerative disorders such as amyotrophic lateral sclerosis, but the function of wild-type (WT) EWSR1 in the central nervous system (CNS) is not known yet. Herein, we investigated the neuroanatomical and motor function changes in Ewsr1 knock out (KO) mice. First, we quantified neuronal nucleus size in the motor cortex, dorsal striatum and hippocampus of three different groups: WT, heterozygous Ewsr1 KO (+/−), and homozygous Ewsr1 KO (−/−) mice. The neuronal nucleus size was significantly smaller in the motor cortex and striatum of homozygous Ewsr1 KO (−/−) mice than that of WT. In addition, in the hippocampus, the neuronal nucleus size was significantly smaller in both heterozygous Ewsr1 KO (+/−) and homozygous Ewsr1 KO (−/−) mice. We then assessed motor function of Ewsr1 KO (−/−) and WT mice by a tail suspension test. Both forelimb and hindlimb movements were significantly increased in Ewsr1 KO (−/−) mice. Lastly, we performed immunohistochemistry to examine the expression of TH, DARPP-32, and phosphorylated (p)-DARPP-32 (Thr75) in the striatum and substantia nigra, which are associated with dopaminergic signaling. The immunoreactivity of TH and DARPP-32 was decreased in Ewsr1 KO (−/−) mice. Together, our results suggest that EWSR1 plays a significant role in neuronal morphology, dopaminergic signaling pathways, and motor function in the CNS of mice.

Protection Against Electroshock- and Pentylenetetrazol-induced Seizures by the Water Extract of Rehmannia glutinous can be Mediated through GABA Receptor-chloride Channel Complexes

Epilepsy is a brain disorder that affects millions of people worldwide. It is characterized by recurrent and unpredictable seizures that are usually controlled with antiepileptic/anticonvulsive drugs. However, most antiepileptic drugs produce various side effects such as tolerance and sedation. Thus, there is a growing interest for alternative anticonvulsive drugs, preferably from natural or herbal sources. In this study, we evaluated the anticonvulsive effects of Rehmannia glutinosa (RG). The anticonvulsive effect of RG extract was evaluated using electroshock- and chemical-induced seizure tests in mice. To identify its probable mechanism of action, the effects of RG extract on Cl− influx was measured in vitro. We found that RG extract has anticonvulsive effects against electroshock-induced seizures, as indicated by an increased seizure threshold in mice. The RG extract also decreased the percentage of seizure responses induced by the GABAergic antagonist, pentylenetetrazole. These results suggest that the anticonvulsive effects of RG extract are mediated through a GABAergic mechanism. In support of this mechanism, our in vitro test showed that RG extract increases intracellular Cl− influx. Furthermore, RG extract did not show sedative and/or muscle relaxant effects in the open-field and rota-rod tests. Altogether, these results confirm that RG extract could be a herbal anticonvulsant and a potential alternative for clinical use.

Combined Effect of Initial and Longitudinal Increases in γ-Glutamyltransferase on Incident Metabolic Syndrome: ARIRANG Study

PURPOSE: Although γ-glutamyltransferase (GGT) is well known to be associated with metabolic syndrome (MS), prospective data on baseline and longitudinal changes in GGT levels and incident cases of MS are limited. We aimed to examine prospective associations between changes in GGT levels over time, as well as at baseline, and incident MS in Korean adults. MATERIALS AND METHODS: A total of 2579 Korean adults free of MS were followed up for 2.6 years. Data were collected from 2005–2008 (baseline) and from 2008–2011 (follow-up). Serum GGT levels were determined by enzymatic methods. RESULTS: During follow-up, 558 participants (21.6%) developed MS. A gradual increase in the incidence of MS was observed across GGT quartiles. After adjustment for confounding factors, the odds ratio and 95% confidence interval (CI) for new onset MS, comparing the highest to the lowest quartiles of baseline GGT, was 2.07 (95% CI: 1.52–2.80). The odds ratio for the highest GGT changes (>4 IU/L increase) in comparison to the lowest GGT changes (<-5 IU/L decrease) was 1.75 (95% CI: 1.32–2.33). Among participants with baseline GGT concentrations

Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.