Novel role of LLGL2 silencing in autophagy: reversing epithelial-mesenchymal transition in prostate cancer.

PURPOSE: Prostate cancer (PCa) is a major urological disease that is associated with significant morbidity and mortality in men. LLGL2 is the mammalian homolog of Lgl. It acts as a tumor suppressor in breast and hepatic cancer. However, the role of LLGL2 and the underlying mechanisms in PCa have not yet been elucidated. Here, we investigate the role of LLGL2 in the regulation of epithelial-mesenchymal transition (EMT) in PCa through autophagy in vitro and in vivo. METHODS: PC3 cells were transfected with siLLGL2 or plasmid LLGL2 and autophagy was examined. Invasion, migration, and wound healing were assessed in PC3 cells under autophagy regulation. Tumor growth was evaluated using a shLLGL2 xenograft mouse model. RESULTS: In patients with PCa, LLGL2 levels were higher with defective autophagy and increased EMT. Our results showed that the knockdown of LLGL2 induced autophagy flux by upregulating Vps34 and ATG14L. LLGL2 knockdown inhibits EMT by upregulating E-cadherin and downregulating fibronectin and α-SMA. The pharmacological activation of autophagy by rapamycin suppressed EMT, and these effects were reversed by 3-methyladenine treatment. Interestingly, in a shLLGL2 xenograft mouse model, tumor size and EMT were decreased, which were improved by autophagy induction and worsened by autophagy inhibition. CONCLUSION: Defective expression of LLGL2 leads to attenuation of EMT due to the upregulation of autophagy flux in PCa. Our results suggest that LLGL2 is a novel target for alleviating PCa via the regulation of autophagy.

Enhanced Postsurgical Cancer Treatment Using Methacrylated Glycol Chitosan Hydrogel for Sustained DNA/Doxorubicin Delivery and Immunotherapy.

Background: Cancer recurrence and metastasis are major contributors to treatment failure following tumor resection surgery. We developed a novel implantable drug delivery system utilizing glycol chitosan to address these issues. Glycol chitosan is a natural adjuvant, inducing dendritic cell activation to promote T helper 1 cell immune responses, macrophage activation, and cytokine production. Effective antigen production by dendritic cells initiates T-cell-mediated immune responses, aiding tumor growth control. Methods: In this study, we fabricated multifunctional methacrylated glycol chitosan (MGC) hydrogels with extended release of DNA/doxorubicin (DOX) complex for cancer immunotherapy. We constructed the resection model of breast cancer to verify the anticancer effects of MGC hydrogel with DNA/DOX complex. Results: This study demonstrated the potential of MGC hydrogel with extended release of DNA/DOX complex for local and efficient cancer therapy. The MGC hydrogel was implanted directly into the surgical site after tumor resection, activating tumor-related immune cells both locally and over a prolonged period of time through immune-reactive molecules. Conclusions: The MGC hydrogel effectively suppressed tumor recurrence and metastasis while enhancing immunotherapeutic efficacy and minimizing side effects. This biomaterial-based drug delivery system, combined with cancer immunotherapy, can substantial improve treatment outcomes and patient prognosis.

Lipid nanoparticle-based mRNA delivery systems for cancer immunotherapy.

Cancer immunotherapy, which harnesses the power of the immune system, has shown immense promise in the fight against malignancies. Messenger RNA (mRNA) stands as a versatile instrument in this context, with its capacity to encode tumor-associated antigens (TAAs), immune cell receptors, cytokines, and antibodies. Nevertheless, the inherent structural instability of mRNA requires the development of effective delivery systems. Lipid nanoparticles (LNPs) have emerged as significant candidates for mRNA delivery in cancer immunotherapy, providing both protection to the mRNA and enhanced intracellular delivery efficiency. In this review, we offer a comprehensive summary of the recent advancements in LNP-based mRNA delivery systems, with a focus on strategies for optimizing the design and delivery of mRNA-encoded therapeutics in cancer treatment. Furthermore, we delve into the challenges encountered in this field and contemplate future perspectives, aiming to improve the safety and efficacy of LNP-based mRNA cancer immunotherapies.

Risk estimation for idiopathic normal-pressure hydrocephalus: development and validation of a brain morphometry-based nomogram.

OBJECTIVES: To develop and validate a nomogram based on MRI features for predicting iNPH. METHODS: Patients aged ≥ 60 years (clinically diagnosed with iNPH, Parkinson's disease, or Alzheimer's disease or healthy controls) who underwent MRI including three-dimensional T1-weighted volumetric MRI were retrospectively identified from two tertiary referral hospitals (one hospital for derivation set and the other for validation set). Clinical and imaging features for iNPH were assessed. Deep learning-based brain segmentation software was used for 3D volumetry. A prediction model was developed using logistic regression and transformed into a nomogram. The performance of the nomogram was assessed with respect to discrimination and calibration abilities. The nomogram was internally and externally validated. RESULTS: A total of 452 patients (mean age ± SD, 73.2 ± 6.5 years; 200 men) were evaluated as the derivation set. One hundred eleven and 341 patients were categorized into the iNPH and non-iNPH groups, respectively. In multivariable analysis, high-convexity tightness (odds ratio [OR], 35.1; 95% CI: 4.5, 275.5), callosal angle < 90° (OR, 12.5; 95% CI: 3.1, 50.0), and normalized lateral ventricle volume (OR, 4.2; 95% CI: 2.7, 6.7) were associated with iNPH. The nomogram combining these three variables showed an area under the curve of 0.995 (95% CI: 0.991, 0.999) in the study sample, 0.994 (95% CI: 0.990, 0.998) in the internal validation sample, and 0.969 (95% CI: 0.940, 0.997) in the external validation sample. CONCLUSION: A brain morphometry-based nomogram including high-convexity tightness, callosal angle < 90°, and normalized lateral ventricle volume can help accurately estimate the probability of iNPH. KEY POINTS: • The nomogram with MRI findings (high-convexity tightness, callosal angle, and normalized lateral ventricle volume) helped in predicting the probability of idiopathic normal-pressure hydrocephalus. • The nomogram may facilitate the prediction of idiopathic normal-pressure hydrocephalus and consequently avoid unnecessary invasive procedures such as the cerebrospinal fluid tap test, drainage test, and cerebrospinal fluid shunt surgery.

Nanoparticle-Based Chimeric Antigen Receptor Therapy for Cancer Immunotherapy.

Adoptive cell therapy with chimeric antigen receptor (CAR)-engineered T cells (CAR-Ts) has emerged as an innovative immunotherapy for hematological cancer treatment. However, the limited effect on solid tumors, complex processes, and excessive manufacturing costs remain as limitations of CAR-T therapy. Nanotechnology provides an alternative to the conventional CAR-T therapy. Owing to their unique physicochemical properties, nanoparticles can not only serve as a delivery platform for drugs but also target specific cells. Nanoparticle-based CAR therapy can be applied not only to T cells but also to CAR-natural killer and CAR-macrophage, compensating for some of their limitations. This review focuses on the introduction of nanoparticle-based advanced CAR immune cell therapy and future perspectives on immune cell reprogramming.

Reprogramming the tumor microenvironment with biotechnology.

The tumor microenvironment (TME) is a unique environment that is developed by the tumor and controlled by tumor-induced interactions with host cells during tumor progression. The TME includes immune cells, which can be classified into two types: tumor- antagonizing and tumor-promoting immune cells. Increasing the tumor treatment responses is associated with the tumor immune microenvironment. Targeting the TME has become a popular topic in research, which includes polarizing macrophage phenotype 2 into macrophage phenotype 1 using Toll-like receptor agonists with cytokines, anti-CD47, and anti-SIPRα. Moreover, inhibiting regulatory T cells through blockades and depletion restricts immunosuppressive cells in the TME. Reprogramming T cell infiltration and T cell exhaustion improves tumor infiltrating lymphocytes, such as CD8+ or CD4+ T cells. Targeting metabolic pathways, including glucose, lipid, and amino acid metabolisms, can suppress tumor growth by restricting the absorption of nutrients and adenosine triphosphate energy into tumor cells. In conclusion, these TME reprogramming strategies exhibit more effective responses using combination treatments, biomaterials, and nanoparticles. This review highlights how biomaterials and immunotherapy can reprogram TME and improve the immune activity.

Gold nanostructure-integrated conductive microwell arrays for uniform cancer spheroid formation and electrochemical drug screening.

Cancer spheroids, which mimic distinct cell-to-cell and cell-extracellular matrix interactions of solid tumors in vitro, have emerged as a promising tumor model for drug screening. However, owing to the unique characteristics of spheroids composed of three-dimensionally densely-packed cells, the precise characterizations of cell viability and function with conventional colorimetric assays are challenging. Herein, we report gold nanostructure-integrated conductive microwell arrays (GONIMA) that enable both highly efficient uniform cancer spheroid formation and precise electrochemical detection of cell viability. A nanostructured gold on indium tin oxide (ITO) substrate facilitated the initial cell aggregation and further 3D cell growth, while the non-cytophilic polymer microwell arrays restricted the size and shape of the spheroids. As a result, approximately 150 human glioblastoma spheroids were formed on a chip area of 1.13 cm2 with an average diameter of 224 µm and a size variation of only 5% (±11.36 µm). The high uniformity of cancer spheroids contributed to the stability of electrical signals measuring cell viability. Using the fabricated GONIMA, the effects of a representative chemotherapeutic agent, hydroxyurea, on the glioblastoma spheroids were precisely monitored under conditions of varying drug concentrations (0-0.3 mg/mL) and incubation times (24-48 h). Therefore, we conclude that the newly developed platform is highly useful for rapid and precise in vitro drug screening, as well as for the pharmacokinetic analyses of specific drugs using 3D cellular cancer models.

Risk of dementia according to the smoking habit change after ischemic stroke: a nationwide population-based cohort study.

There is a paucity of research regarding the association between the risk of incident dementia and changes in smoking habits in the acute ischemic stroke population. We aimed to investigate the effects of smoking habit change on the risk of incident dementia in an ischemic stroke population using data from the Korean National Health Insurance Services Database. This nationwide population-based cohort study included 197,853 patients with ischemic stroke. The patients were divided into never smokers, former smokers, smoking quitters, sustained smokers, and new smokers, based on the 2-year change in smoking status between the two consecutive health examinations before and after the index stroke. The patients were followed up from the index date to 2018 to assess the development of dementia. Dementia was further categorized into Alzheimer's, vascular, and other types of dementia according to the International Classification of Diseases, Tenth Revision diagnosis. Multivariable Cox proportional hazards models were used to assess the association between changes in smoking habits and the risk of dementia. After a median of 4.04 years of follow-up, 19,595 (9.9%) dementia cases were observed. Among them, 15,189 (7.7%) were diagnosed with Alzheimer's disease dementia and 2719 (1.4%) were diagnosed with vascular dementia. After adjusting for covariates, including age, sex, alcohol intake habits, cigarette pack-year, regular physical activity, income, history of hypertension, diabetes mellitus, dyslipidemia, and chronic kidney disease, new smokers, sustained smokers, and smoking quitters were significantly associated with a higher risk of all-cause dementia than never smokers (adjusted hazard ratio [aHR] 1.395, 95% confidence interval [CI] 1.254-1.552; aHR 1.324, 95% CI 1.236-1.418; and aHR 1.170, 95% CI 1.074-1.275, respectively). Similar trends were observed for both Alzheimer's dementia and vascular dementia, but the association between new smokers and vascular dementia was not significant. The impact of smoking habit change was more prominent in the 40-65-year-old group. New and sustained smokers had a substantially higher risk of incident dementia after ischemic stroke than never smokers. Smoking quitters also had an elevated risk of incident dementia, but the detrimental effects were lower than those in new and sustained smokers.

Diagnostic yield of TOF-MRA for detecting incidental vascular lesions in patients with cognitive impairment: An observational cohort study.

Objectives: The role of three-dimensional (3D) TOF-MRA in patients with cognitive impairment is not well established. We evaluated the diagnostic yield of 3D TOF-MRA for detecting incidental extra- or intracranial artery stenosis and intracranial aneurysm in this patient group. Methods: This retrospective study included patients with cognitive impairment undergoing our brain MRI protocol from January 2013 to February 2020. The diagnostic yield of TOF-MRA for detecting incidental vascular lesions was calculated. Patients with positive TOF-MRA results were reviewed to find whether additional treatment was performed. Logistic regression analysis was conducted to identify the clinical risk factors for positive TOF-MRA findings. Results: In total, 1,753 patients (mean age, 70.2 ± 10.6 years; 1,044 women) were included; 199 intracranial aneurysms were detected among 162 patients (9.2%, 162/1,753). A 3D TOF-MRA revealed significant artery stenoses (>50% stenosis) in 162 patients (9.2%, 162/1,753). The overall diagnostic yield of TOF-MRA was 16.8% (294/1,753). Among them, 92 patients (31.3%, 92/294) underwent either medical therapy, endovascular intervention, or surgery. In total, eighty-one patients with stenosis were prescribed with either antiplatelet medications or lipid-lowering agent. In total, fifteen patients (aneurysm: 11 patients, stenosis: 4 patients) were further treated with endovascular intervention or surgery. Thus, the "number needed to scan" was 19 for identifying one patient requiring treatment. Multivariate logistic regression analysis showed that being female (odds ratio [OR] 2.05) and old age (OR 1.04) were the independent risk factors for intracranial aneurysm; being male (OR 1.52), old age (OR 1.06), hypertension (OR 1.78), and ischemic heart disease history (OR 2.65) were the independent risk factors for significant artery stenosis. Conclusions: Our study demonstrated the potential benefit of 3D TOF-MRA, given that it showed high diagnostic yield for detecting vascular lesions in patients with cognitive impairment and the considerable number of these lesions required further treatment. A 3D TOF-MRA may be included in the routine MR protocol for the work-up of this patient population, especially in older patients and patients with vascular risk factors.

Incidence of Amyloid-Related Imaging Abnormalities in Patients With Alzheimer Disease Treated With Anti-ß-Amyloid Immunotherapy: A Meta-analysis.

BACKGROUND AND OBJECTIVES: To assess the incidence of amyloid-related imaging abnormalities (ARIA) in clinical trials of anti-ß-amyloid (Aß) immunotherapy and compare the incidence among different agents and clinical characteristics to identify possible predisposing factors for ARIA. METHODS: The PubMed and Embase databases were searched for clinical trials of anti-Aß immunotherapy published on or before January 12, 2022. Phase 2 or 3 randomized controlled trials reporting detailed data sufficient to assess the incidence of ARIA were selected. The pooled incidences of ARIA and subgroup analyses according to agent and ApoE-4 carrier status were calculated using the DerSimonian-Liard random-effects model. The proportion of symptomatic ARIA cases was also calculated. RESULTS: In total, 19 eligible studies, including 24 cohorts, were identified and 9,429 patients were analyzed. The overall pooled incidence of ARIA-effusion (E) and ARIA-hemorrhage (H) was 6.5% and 7.8%, respectively. In the subgroup analysis, the incidence of ARIA was different according to the anti-Aß immunotherapy agent. The cohorts treated with aducanumab had a significantly higher incidence of ARIA-E and ARIA-H (30.7% and 30.0%, respectively; both p < 0.001) compared with cohorts from other drugs. In subgroup analysis according to ApoE-4 carrier status, the incidences of ARIA-E and ARIA-H were higher in the ApoE-4 carrier group than those in the ApoE-4 noncarrier group, but there was no statistical significance (ApoE-4 carrier vs noncarrier, ARIA-E: 8.6% vs 6.9%, p = 0.663, and ARIA-H: 10.5% vs 6.6%, p = 0.398). The pooled proportion of asymptomatic ARIA, detected by routine scheduled MRI surveillances, was 80.4%. DISCUSSION: The overall incidences of ARIA-E and ARIA-H were 6.5% and 7.8%, respectively, and the pooled proportion of asymptomatic ARIA was 80.4%. The cohorts treated with aducanumab showed a significantly higher incidence of ARIA-E and ARIA-H (30.7% and 30.0%) compared with other drugs.

The impact of subthreshold levels of amyloid deposition on conversion to dementia in patients with amyloid-negative amnestic mild cognitive impairment.

BACKGROUND: About 40-50% of patients with amnestic mild cognitive impairment (MCI) are found to have no significant Alzheimer's pathology based on amyloid PET positivity. Notably, conversion to dementia in this population is known to occur much less often than in amyloid-positive MCI. However, the relationship between MCI and brain amyloid deposition remains largely unknown. Therefore, we investigated the influence of subthreshold levels of amyloid deposition on conversion to dementia in amnestic MCI patients with negative amyloid PET scans. METHODS: This study was a retrospective cohort study of patients with amyloid-negative amnestic MCI who visited the memory clinic of Asan Medical Center. All participants underwent detailed neuropsychological testing, brain magnetic resonance imaging, and [18F]-florbetaben (FBB) positron emission tomography scan (PET). Conversion to dementia was determined by a neurologist based on a clinical interview with a detailed neuropsychological test or a decline in the Korean version of the Mini-Mental State Examination score of more than 4 points per year combined with impaired activities of daily living. Regional cortical amyloid levels were calculated, and a receiver operating characteristic (ROC) curve for conversion to dementia was obtained. To increase the reliability of the results of the study, we analyzed the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset together. RESULTS: During the follow-up period, 36% (39/107) of patients converted to dementia from amnestic MCI. The dementia converter group displayed increased standardized uptake value ratio (SUVR) values of FBB on PET in the bilateral temporal, parietal, posterior cingulate, occipital, and left precuneus cortices as well as increased global SUVR. Among volume of interests, the left parietal SUVR predicted conversion to dementia with the highest accuracy in the ROC analysis (area under the curve [AUC] = 0.762, P < 0.001). The combination of precuneus, parietal cortex, and FBB composite SUVRs also showed a higher accuracy in predicting conversion to dementia than other models (AUC = 0.763). Of the results of ADNI data, the SUVR of the left precuneus SUVR showed the highest AUC (AUC = 0.596, P = 0.006). CONCLUSION: Our findings suggest that subthreshold amyloid levels may contribute to conversion to dementia in patients with amyloid-negative amnestic MCI.

Changes in the Plasma Apurinic/Apyrimidinic Endonuclease 1/Redox Factor-1(APE1/Ref-1) Level during Cancer Surgery: An Observational Study.

Background and Objectives: Propofol-based total intravenous anesthesia (TIVA) is presumed to have more favorable effects on the prognosis of patients with cancer compared with volatile inhaled anesthesia (VIA). We hypothesized that these anesthetics target plasma apurinic apyrimidinic endonuclease/redox effector factor-1 (APE1/Ref-1) as a possible mechanism of action. Materials and Methods: The plasma APE1/Ref-1 level was evaluated three times during surgery for cancer, i.e., before anesthesia, immediately after cancer resection, and finally, in the recovery room. Blood (3 cc) was drawn from the radial artery catheter, and plasma APE1/Ref-1 levels were compared according to measurement time and between the two groups. Spearman's Rho correlation analysis was performed to determine relationships among body mass index, American Society of Anesthesiologists classification, age, sex, cancer type, and tumor-node-metastasis (TNM) stage. A total of 166 patients (VIA: 129; TIVA: 37) were enrolled. Results: Plasma APE1/Ref-1 level increased significantly (p = 0.028) after cancer resection compared with before surgery, but no significant difference was observed between anesthetics (p = 0.134). The post-resection plasma APE1/Ref-1 level showed a positive correlation with the NM stages, but not the T stage. Conclusions: The plasma APE1/Ref-1 level increased during surgery with more severe lymph node invasion, but there were no significant differences according to the anesthetics used.

Bakuchicin attenuates atopic skin inflammation.

Psoralea corylifolia is a medicinal herb that provides advantageous pharmacological effects against vitiligo and skin rash. Former studies have shown that bakuchicin, a furanocoumarin compound from the fruits of P. corylifolia, has therapeutic effects against inflammation, and infection. This study aimed to define the pharmacological effects of bakuchicin on inflammatory responses and lichenification, the major symptoms of atopic dermatitis (AD). To induce AD-like skin inflammation, we exposed the ears of female BALB/c mice to 2, 4-dinitrochlorobenzene (DNCB) and Dermatophagoides farinae (house dust mite) extract (DFE) for 4 weeks. Intragastric administration of bakuchicin attenuated the symptoms of AD-like skin inflammation, as evident by reductions in ear thickness, erythema, and keratosis. Bakuchicin also reversed increases in auricular epidermal and dermal layer thicknesses, and attenuated eosinophil and mast cell infiltration in AD-induced mice. It also suppressed Th2 gene expression as well as that of pro-inflammatory cytokines and chemokines, such as interleukin (IL)-4, IL-13, IL-31, IL-1ß, IL-6, CXCL-1, and CCL-17 in the ear tissue. The levels of total and DFE-specific immunoglobulin (Ig)E, and IgG2a in the mice sera were reduced by the bakuchicin. To investigate the effect of bakuchicin on keratinocytes, experiments were performed using HaCaT cells, the representative cell type used in skin disease studies. Tumor necrosis factor-α and interferon-γ were used to activate keratinocytes. Bakuchicin suppressed Th2 gene expression and that of pro-inflammatory cytokines and chemokines; it also suppressed STAT-1 phosphorylation and the nuclear translocation of NF-κB in activated keratinocytes. These results suggest that bakuchicin attenuated AD symptoms, thus suggesting it as a potential therapeutic agent for the treatment of AD.

Detection of association between periodontitis and polymorphisms of IL-1ß + 3954 and TNF-α -863 in the Korean population after controlling for confounding risk factors.

BACKGROUND AND OBJECTIVE: Interleukin (IL)-1 and tumor necrosis factor (TNF)-α are inflammatory cytokines that play an important role in periodontitis, and their genetic variations have been suggested to be associated with increased risk of periodontitis. Focusing on three single nucleotide polymorphisms (SNPs) of IL-1α + 4845, IL-1ß + 3954, and TNF-α -863, we aimed to investigate the relationship between periodontitis risk and the polymorphisms of IL-1 α/ß and TNF-α in Koreans. MATERIAL AND METHODS: Mouthwash samples from 548 subjects (135 controls without periodontitis, 387 generalized chronic periodontitis patients, and 26 generalized aggressive periodontitis patients) were collected for isolation of genomic DNA. Genotyping of selected SNPs was performed using real-time PCR. Univariable associations between the polymorphisms and periodontitis were assessed by chi-squared test or Fisher's exact test. To evaluate the association after controlling for confounding effects of various risk factors, we stratified the subjects according to the presence or absence of self-reported diseases and employed multiple logistic regression model to adjust for age, smoking status, and oral hygiene indices and behaviors. RESULTS: Significant association of IL-1ß + 3954 and TNF-α -863 polymorphisms with periodontitis was observed after adjusting for the confounding risk factors, but not in univariable association analysis. The significant association between genotype CT of IL-1ß + 3954 and increased risk of advanced periodontitis was consistently detected regardless of the status of self-reported diseases. In the polymorphism of TNF-α -863, the genotype with minor allele (CA + AA) was significantly associated with periodontitis susceptibility, which was observed only in the subjects with self-reported diseases. CONCLUSION: The results suggest that genetic variations of IL-1ß + 3954 and TNF-α -863 are associated with increased risk of periodontitis in Koreans. In addition, our findings underscore the importance of controlling for confounding risk factors to detect significant association between genetic factors and risk of periodontitis. A further well-designed large-scale study is needed to warrant our results.

Intrastriatal administration of coenzyme Q10 enhances neuroprotection in a Parkinson's disease rat model.

Parkinson's disease is a neurodegenerative disorder, and no treatment has been yet established to prevent disease progression. Coenzyme Q10, an antioxidant, has been considered a promising neuroprotective agent; however, conventional oral administration provides limited efficacy due to its very low bioavailability. In this study, we hypothesised that continuous, intrastriatal administration of a low dose of Coenzyme Q10 could effectively prevent dopaminergic neuron degeneration. To this end, a Parkinson's disease rat model induced by 6-hydroxydopamine was established, and the treatment was applied a week before the full establishment of this disease model. Behavioural tests showed a dramatically decreased number of asymmetric rotations in the intrastriatal Coenzyme Q10 group compared with the no treatment group. Rats with intrastriatal Coenzyme Q10 exposure also exhibited a larger number of dopaminergic neurons, higher expression of neurogenetic and angiogenetic factors, and less inflammation, and the effects were more prominent than those of orally administered Coenzyme Q10, although the dose of intrastriatal Coenzyme Q10 was 17,000-times lower than that of orally-administered Coenzyme Q10. Therefore, continuous, intrastriatal delivery of Coenzyme Q10, especially when combined with implantable devices for convection-enhanced delivery or deep brain stimulation, can be an effective strategy to prevent neurodegeneration in Parkinson's disease.

Profile of and risk factors for poststroke cognitive impairment in diverse ethnoregional groups.

OBJECTIVE: To address the variability in prevalence estimates and inconsistencies in potential risk factors for poststroke cognitive impairment (PSCI) using a standardized approach and individual participant data (IPD) from international cohorts in the Stroke and Cognition Consortium (STROKOG) consortium. METHODS: We harmonized data from 13 studies based in 8 countries. Neuropsychological test scores 2 to 6 months after stroke or TIA and appropriate normative data were used to calculate standardized cognitive domain scores. Domain-specific impairment was based on percentile cutoffs from normative groups, and associations between domain scores and risk factors were examined with 1-stage IPD meta-analysis. RESULTS: In a combined sample of 3,146 participants admitted to hospital for stroke (97%) or TIA (3%), 44% were impaired in global cognition and 30% to 35% were impaired in individual domains 2 to 6 months after the index event. Diabetes mellitus and a history of stroke were strongly associated with poorer cognitive function after covariate adjustments; hypertension, smoking, and atrial fibrillation had weaker domain-specific associations. While there were no significant differences in domain impairment among ethnoracial groups, some interethnic differences were found in the effects of risk factors on cognition. CONCLUSIONS: This study confirms the high prevalence of PSCI in diverse populations, highlights common risk factors, in particular diabetes mellitus, and points to ethnoracial differences that warrant attention in the development of prevention strategies.

Increased risk of neurodegenerative dementia in women with migraines: A nested case-control study using a national sample cohort.

The present study aimed to evaluate the association between migraines and dementia.Data were collected from 11,438 dementia participants who were 1:4 matched by age, sex, income, region of residence, hypertension, diabetes, and dyslipidemia with 45,752 controls from the Korean National Health Insurance Service-National Sample Cohort from 2002 to 2013. Dementia was diagnosed using the International Classification of Disease-10 (ICD-10) codes (G30 or F00). For the integrity of diagnoses, we included only participants ≥60 years old who had been diagnosed with an ICD-10 code twice or more during ambulatory visits for the same episode. For migraine (ICD-10 code, G43), we included participants who had visited outpatient clinics twice or more for the same episode. In both dementia and control groups, a previous history of migraine was investigated.Approximately 7.7% (881/11,438) of patients in the dementia group and 6.3% (2888/45,752) of those in the control group had a history of migraine (P < .001). The crude and adjusted odds ratios (ORs) for migraine with dementia was 1.22 (95% confidence interval [CI] = 1.13-1.32, P < .001) and 1.13 (95% CI = 1.05-1.23, P = .002), respectively. In the subgroup analyses according to age and sex, women demonstrated a significantly higher adjusted OR for migraine with dementia, whereas men did not exhibit an association between migraine and dementia.In a nested case-control study using a national sample cohort, migraine increased the risk of dementia in women.

Longitudinal Cerebral Perfusion Change in Transient Global Amnesia Related to Left Posterior Medial Network Disruption.

BACKGROUND: The pathophysiology of transient global amnesia (TGA) is not fully understood. Previous studies using single photon emission computed tomography (SPECT) have reported inconclusive results regarding cerebral perfusion. This study was conducted to identify the patterns of regional cerebral blood flow (rCBF) in TGA patients via longitudinal SPECT analysis. An association between the observed SPECT patterns and a pathophysiological mechanism was considered. METHODS: Based on the TGA registry database of Seoul National University Bundang Hospital, 22 TGA patients were retrospectively identified. The subjects underwent initial Tc-99m-ethyl cysteinate dimer (ECD) SPECT within 4 days of an amnestic event and underwent follow-up scans approximately 6 months later. The difference in ECD uptake between the two scans was measured via voxel-based whole brain analysis, and the quantified ECD uptake was tested using a paired t-test. RESULTS: The TGA patients had significantly decreased cerebral perfusion at the left precuneus (P<0.001, uncorrected) and at the left superior parietal and inferior temporal gyrus according to the voxel-based whole brain analysis (P<0.005, uncorrected). A difference in the quantified ECD uptake between the 2 scans was also found at the left precuneus among the 62 cortical volumes of interest (P = 0.018, Cohen's d = -0.25). CONCLUSION: We identified left hemispheric lateralized hypoperfusion that may be related to posterior medial network disruption. These findings may be a contributing factor to the pathophysiology of TGA.

Allopurinol Protects against Ischemia/Reperfusion-Induced Injury in Rat Urinary Bladders.

Bladder ischemia-reperfusion (I/R) injury results in the generation of reactive oxygen species (ROS) and markedly elevates the risk of lower urinary tract symptoms (LUTS). Allopurinol is an inhibitor of xanthine oxidase (XO) and thus can serve as an antioxidant that reduces oxidative stress. Here, a rat model was used to assess the ability of allopurinol treatment to ameliorate the deleterious effects of urinary bladder I/R injury. I/R injury reduced the in vitro contractile responses of longitudinal bladder strips, elevated XO activity in the plasma and bladder tissue, increased the bladder levels of tumor necrosis factor-α (TNF-α), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase, reduced the bladder levels of extracellular regulated kinase (ERK), and decreased and increased the bladder levels of Bcl-2 and Bax, respectively. I/R injury also elevated lipid peroxidation in the bladder. Allopurinol treatment in the I/R injury was generated significantly ameliorating all I/R-induced changes. Moreover, an in situ fluorohistological approach also showed that allopurinol reduces the generation of intracellular superoxides enlarged by I/R injury. Together, the beneficial effects of allopurinol reducing ROS production may be mediated by normalizing the activity of the ERK, JNK, and Bax/Bcl-2 pathways and by controlling TNF-α expression.