Effect of Regional Brain Activity Following Repeat Transcranial Magnetic Stimulation in SCA3: A Secondary Analysis of a Randomized Clinical Trial.

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32-55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26-58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.

Two undescribed benzopyran derivatives from Ranunculus sceleratus L. with their in vitro anti-inflammatory activity in lipopolysaccharide-activated RAW 264.7 cells.

Previous studies on Ranunculus sceleratus L. have shown the existence of coumarins and their anti-inflammatory effect. Phytochemical work was conducted to investigate the bioactive compounds, leading to the isolation of two undescribed benzopyran derivatives, namely ranunsceleroside A (1) and B (3), together with two known coumarins (2, 4) from the whole plant of R. sceleratus L. All compounds were structurally identified by extensive spectroscopic analysis and then investigated for their inhibitory effect on nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) production induced by lipopolysaccharide (LPS) in RAW 264.7 murine macrophages, repectively. As a result, compound 1-4 presented inhibitory effects on the production of NO, TNF-α, IL-1ß, and IL-6 in a concentration-dependent manner, which provides a potential chemical basis for the traditional use of R. sceleratus L. as an anti-inflammatory plant.

Altered brain white matter structural motor network in spinocerebellar ataxia type 3.

OBJECTIVES: Spinocerebellar ataxia type 3 is a disorder within the brain network. However, the relationship between the brain network and disease severity is still unclear. This study aims to investigate changes in the white matter (WM) structural motor network, both in preclinical and ataxic stages, and its relationship with disease severity. METHODS: For this study, 20 ataxic, 20 preclinical SCA3 patients, and 20 healthy controls were recruited and received MRI scans. Disease severity was quantified using the SARA and ICARS scores. The WM motor structural network was created using probabilistic fiber tracking and was analyzed using graph theory and network-based statistics at global, nodal, and edge levels. In addition, the correlations between network topological measures and disease duration or clinical scores were analyzed. RESULTS: Preclinical patients showed increasing assortativity of the motor network, altered subnetwork including 12 edges of 11 nodes, and 5 brain regions presenting reduced nodal strength. In ataxic patients assortativity of the motor network also increased, but global efficiency, global strength, and transitivity decreased. Ataxic patients showed a wider altered subnetwork and a higher number of reduced nodal strengths. A negative correlation between the transitivity of the motor network and SARA and ICARS scores was observed in ataxic patients. INTERPRETATION: Changes to the WM motor network in SCA3 start before ataxia onset, and WM motor network involvement increases with disease progression. Global network topological measures of the WM motor network appear to be a promising image biomarker for disease severity. This study provides new insights into the pathophysiology of disease in SCA3/MJD.

Contrast-enhanced ultrasonography with intra-glandular contrast injection can improve the diagnostic accuracy of central compartment lymph node metastasis of thyroid cancer / 南方医科大学学报

OBJECTIVE@#To investigate the value of lymphatic contrast-enhanced ultrasound (LCEUS) with intra-glandular injection of contrast agent for diagnosis of central compartment lymph node metastasis of thyroid cancer.@*METHODS@#From November, 2020 to May, 2022, the patients suspected of having thyroid cancer and scheduled for biopsy at our center received both conventional ultrasound and LCEUS examinations of the central compartment lymph nodes before surgery. All the patients underwent surgical dissection of the lymph nodes. The perfusion features in LCEUS were classified as homogeneous enhancement, heterogeneous enhancement, regular/irregular ring, and non-enhancement. With pathological results as the gold standard, we compared the diagnostic ability of conventional ultrasound and LCEUS for identifying metastasis in the central compartment lymph nodes.@*RESULTS@#Forty-nine patients with 60 lymph nodes were included in the final analysis. Pathological examination reported metastasis in 34 of the lymph nodes, and 26 were benign lymph nodes. With ultrasound findings of heterogeneous enhancement, irregular ring and non-enhancement as the criteria for malignant lesions, LCEUS had a diagnostic sensitivity, specificity and accuracy of 97.06%, 92.31% and 95% for diagnosing metastatic lymph nodes, respectively, demonstrating its better performance than conventional ultrasound (P < 0.001). Receiver-operating characteristic curve analysis showed that LCEUS had a significantly greater area under the curve than conventional ultrasound for diagnosing metastatic lymph nodes (94.7% [0.856-0.988] vs 78.2% [0.656-0.878], P=0.003).@*CONCLUSION@#LCEUS can enhance the display and improve the diagnostic accuracy of the central compartment lymph nodes to provide important clinical evidence for making clinical decisions on treatment of thyroid cancer.

Effects of Repetitive Transcranial Magnetic Stimulation on Cerebellar Metabolism in Patients With Spinocerebellar Ataxia Type 3.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia, and, thus far, effective treatment remains low. Repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of spinal cerebellar ataxia, but the mechanism is unclear; in addition, whether any improvement in the symptoms is related to cerebellar metabolism has not yet been investigated. Therefore, the purpose of this study was to investigate the effects of low-frequency rTMS on local cerebellar metabolism in patients with SCA3 and the relationship between the improvement in the symptoms and cerebellar metabolism. Methods: A double-blind, prospective, randomized, sham-controlled trial was carried out among 18 SCA3 patients. The participants were randomly assigned to the real stimulation group (n = 9) or sham stimulation group (n = 9). Each participant in both the groups underwent 30 min of 1 Hz rTMS stimulation (a total of 900 pulses), differing only in terms of stimulator placement, for 15 consecutive days. To separately compare pre- and post-stimulation data (magnetic resonance spectroscopy (MRS) data and the International Cooperative Ataxia Rating Scale (ICARS) score) in the real and sham groups, paired-sample t-tests and Wilcoxon's signed-rank tests were used in the analyses. The differences in the ICARS and MRS data between the two groups were analyzed with independent t-tests and covariance. To explore the association between the changes in the concentration of cerebellar metabolism and ICARS, we applied Pearson's correlation analysis. Results: After 15 days of treatment, the ICARS scores significantly decreased in both the groups, while the decrease was more significant in the real stimulation group compared to the sham stimulation group (p < 0.001). The analysis of covariance further confirmed that the total ICARS scores decreased more dramatically in the real stimulation group after treatment compared to the sham stimulation group (F = 31.239, p < 0.001). The values of NAA/Cr and Cho/Cr in the cerebellar vermis, bilateral dentate nucleus, and bilateral cerebellar hemisphere increased significantly in the real stimulation group (p < 0.05), but no significant differences were found in the sham stimulation group (p > 0.05). The analysis of covariance also confirmed the greater change in the real stimulation group. This study also demonstrated that there was a negative correlation between NAA/Cr in the right cerebellar hemisphere and ICARS in the real stimulation group (r = - 0.831, p = 0.02). Conclusion: The treatment with rTMS over the cerebellum was found to induce changes in the cerebellar local metabolism and microenvironment in the SCA3 patients. The alterations may contribute to the improvement of the symptoms of ataxia in SCA3 patients.

Role of PI3K/Akt signaling pathway in reduction of acute lung injury by bone marrow mesenchymal stem cells-conditioned medium in rats / 中华麻醉学杂志

Objective:To evaluate the role of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling pathway in reduction of acute lung injury (ALI) by bone marrow mesenchymal stem cells (MSCs)-conditioned medium in rats.Methods:Thirty-two healthy male Sprague-Dawley rats, aged 6-8 weeks, weighing 200-250 g, were divided into 4 groups ( n=8 each) according to the random number table method: control group (group C), group ALI, ALI + bone marrow MSCs-conditioned medium group (group M), and ALI + bone marrow MSCs-conditioned medium + LY294002 group (group L). A rat model of ALI was developed by endotracheal inhalation of aerosolized lipopolysaccharide (LPS) 5 mg/kg in anesthetized animals in group ALI, group M and group L. At 1 h after LPS administration, serum-free DMEM medium 1 ml was intravenously injected in group C and group ALI, bone marrow MSCs-conditioned medium 1 ml was intravenously injected in group M, PI3K inhibitor LY294002 30 mg/kg was intraperitoneally injected at 2 h before the model was developed, and bone marrow MSCs-conditioned medium 1 ml was intravenously injected at 1 h after the model was developed in group L. The blood samples were taken from the heart at 24 h after LPS administration, and serum was isolated for determination of the serum levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) (by enzyme-linked immunosorbent assay). Then the rats were sacrificed and lung tissues were obtained for determination of the lung wet/dry weight ratio (W/D ratio), expression of Akt and phosphorylated Akt (p-Akt) (by Western blot) and for microscopic examination of the pathological changes which were scored.The p-Akt/Akt ratio was calculated. Results:Compared with group C, the W/D ratio, lung injury score and serum levels of TNF-α and IL-6 were significantly increased, the expression of p-Akt in lung tissues was down-regulated, the ratio of p-Akt/Akt was decreased ( P<0.05), and pathological changes were found in lung tissues in group ALI.Compared with group ALI, the W/D ratio, lung injury score and serum levels of TNF-α and IL-6 were significantly decreased, the expression of p-Akt in lung tissues was up-regulated, the ratio of p-Akt/Akt was increased ( P<0.05), and pathological changes were significantly attenuated in group M, and no significant change was found in the parameters mentioned above in group L ( P>0.05). Compared with group M, the W/D ratio, lung injury score and serum levels of TNF-α and IL-6 were significantly increased, the expression of p-Akt in lung tissues was down-regulated, the ratio of p-Akt/Akt was decreased ( P<0.05), and pathological changes were accentuated in group L. There were no significant differences in the expression of Akt in lung tissues between the four groups ( P>0.05). Conclusions:PI3K/Akt signaling pathway is involved in reduction of ALI by bone marrow MSCs-conditioned medium in rats.

MRI-Based Grading of Clear Cell Renal Cell Carcinoma Using a Machine Learning Classifier.

OBJECTIVE: To develop a machine learning (ML)-based classifier for discriminating between low-grade (ISUP I-II) and high-grade (ISUP III-IV) clear cell renal cell carcinomas (ccRCCs) using MRI textures. MATERIALS AND METHODS: We retrospectively evaluated a total of 99 patients (with 61 low-grade and 38 high-grade ccRCCs), who were randomly divided into a training set (n = 70) and a validation set (n = 29). Regions of interest (ROIs) of all tumors were manually drawn three times by a radiologist at the maximum lesion level of the cross-sectional CMP sequence images. The quantitative texture analysis software, MaZda, was used to extract texture features, including histograms, co-occurrence matrixes, run-length matrixes, gradient models, and autoregressive models. Reproducibility of the texture features was assessed with the intra-class correlation coefficient (ICC). Features were chosen based on their importance coefficients in a random forest model, while the multi-layer perceptron algorithm was used to build a classifier on the training set, which was later evaluated with the validation set. RESULTS: The ICCs of 257 texture features were equal to or higher than 0.80 (0.828-0.998. Six features, namely Kurtosis, 135dr_RLNonUni, Horzl_GLevNonU, 135dr_GLevNonU, S(4,4)Entropy, and S(0,5)SumEntrp, were chosen to develop the multi-layer perceptron classifier. A three-layer perceptron model, which has 229 nodes in the hidden layer, was trained on the training set. The accuracy of the model was 95.7% with the training set and 86.2% with the validation set. The areas under the receiver operating curves were 0.997 and 0.758 for the training and validation sets, respectively. CONCLUSIONS: A machine learning-based grading model was developed that can aid in the clinical diagnosis of clear cell renal cell carcinoma using MRI images.

Role of Nrf2∕HO-1 signaling pathway in bone marrow mesenchymal stem cells-induced reduction of endotoxin-induced acute lung injury in rats / 中华麻醉学杂志

Objective To evaluate the role of nuclear factor erythroid 2-related factor 2 ( Nrf2)∕heme oxygenase-1 ( HO-1) signaling pathway in bone marrow mesenchymal stem cells ( MSCs)-induced re-duction of endotoxin-induced acute lung injury ( ALI) in rats. Methods Thirty-two clean-grade healthy male Sprague-Dawley rats, weighing 180-250 g, were divided into 4 groups ( n=8 each) using a random number table method:control group (group C), ALI group, MSCs group and brusatol plus MSCs group ( group B+MSCs) . Lipopolysaccharide 20 mg∕kg was intravenously infused to establish the model of acute lung injury. Phosphate buffered saline ( PBS) 1 ml was intravenously infused at 1 h after establishing the model in group ALI. The equal volume of sterile saline and PBS was given instead in group C. PBS (1 ml) containing MSCs 1×106 cells was intravenously infused at 1 h after establishing the model in group MSCs. Nrf2 inhibitor brusatol 0. 4 mg∕kg was intraperitoneally injected every other day during 10 days before estab-lishing the model, and MSCs were given at 1 h after establishing the model in group B+MSCs. Bronchoalve-olar lavage fluid ( BALF) was collected and lung tissues were removed at 6 h after establishing the model. The protein concentration and neutrophil count in BALF were determined, and the wet∕dry weight ratio ( W∕D ratio) was calculated. The pathological changes of lung tissues were observed by hematoxylin-eosin staining. The expression of Nrf2 and HO-1 (by Western blot), activities of myeloperoxidase (MPO) and superoxide dismutase ( SOD) and content of malondialdehyde ( MDA) were determined. Results Com-pared with group C, the W∕D ratio and total cell count and protein concentration in BALF were significantly increased, the MPO activity was enhanced, the MDA content was increased, the SOD activity was weak-ened, and the expression of Nrf2 was up-regulated (P<0. 05), and the pathological changes were accentu-ated in group ALI. Compared with group ALI, the W∕D ratio and total cell count and protein concentration in BALF were significantly decreased, the MPO activity was weakened, the MDA content was decreased, the SOD activity was enhanced, the expression of Nrf2 and HO-1 was up-regulated (P<0. 05), and the pathological changes were significantly attenuated in group MSCs. Compared with group MSCs, the total cell count was significantly increased, the MPO activity was enhanced, the MDA content was increased, the expression of Nrf2 and HO-1 was down-regulated ( P<0. 05) , and the pathological changes were accentua-ted in group B+MSCs. Conclusion Nrf2∕HO-1 signaling pathway is involved in bone marrow MSCs-in-duced reduction of endotoxin-induced acute lung injury in rats.

Global cerebrovascular burden and long-term clinical outcomes in Asian elderly across the spectrum of cognitive impairment.

ABSTRACTBackground/Aim:To investigate the predictive ability of the previously established global cerebrovascular disease (CeVD) burden scale on long-term clinical outcomes in a longitudinal study of Asian elderly participants across the spectrum of cognitive impairment. METHODS: A case-control study was conducted over a 2-year period involving participants with no cognitive impairment, cognitive impairment-no dementia (CIND), and Alzheimer's disease (AD). Annually, cognitive function was assessed with a comprehensive neuropsychological battery and the clinical dementia rating (CDR) scale was used to stage disease severity. RESULTS: Of 314 participants, 102 had none/very mild CeVD, 31 mild CeVD, 94 moderate CeVD, and 87 severe CeVD at baseline. There was a 1.14 and 1.42 units decline per year on global cognitive z-scores in moderate and severe CeVD groups, respectively, compared to none/very mild CeVD. Moderate-severe CeVD predicted significant functional deterioration at year 2 (HR = 2.0, 95% CI = 1.2-3.4), and conversion to AD (HR = 6.3, 95% CI = 1.7-22.5), independent of medial temporal atrophy. CONCLUSION: The global CeVD burden scale predicts poor long-term clinical outcome independent of neurodegenerative markers. Furthermore, CeVD severity affects the rate of cognitive and functional deterioration. Hence, cerebrovascular burden, which is potentially preventable, is a strong prognostic indicator, both at preclinical and clinical stages of AD, independent of neurodegenerative processes.

Methylation Status of Transcriptional Modulatory Genes Associated with Colorectal Cancer in Northeast China

BACKGROUND/AIMS: Methylation status plays a causal role in carcinogenesis in targeted tissues. However, the relationship between the DNA methylation status of multiple genes in blood leukocytes and colorectal cancer (CRC) susceptibility as well as interactions between dietary factors and CRC risks are unclear. METHODS: We performed a case-control study with 466 CRC patients and 507 cancer-free controls to investigate the association among the methylation status of individual genes, multiple CpG site methylation (MCSM), multiple CpG site heterogeneous methylation and CRC susceptibility. Peripheral blood DNA methylation levels were detected by performing methylation-sensitive high-resolution melting. RESULTS: Total heterogeneous methylation of CA10 and WT1 conferred a significantly higher risk of CRC (adjusted odds ratio [OR(adjusted)], 5.445; 95% confidence interval [CI], 3.075 to 9.643; OR(adjusted), 1.831; 95% CI, 1.100 to 3.047; respectively). Subjects with high-level MCSM (MCSM-H) status demonstrated a higher risk of CRC (OR(adjusted), 4.318; 95% CI, 1.529 to 12.197). Additionally, interactions between the high-level intake of fruit and CRH, WT1, and MCSM on CRC were statistically significant. CONCLUSIONS: The gene methylation status of blood leukocytes may be associated with CRC risk. MCSM-H of blood leukocytes was associated with CRC, especially in younger people. Some dietary factors may affect hypermethylation status and influence susceptibility to CRC.

Borneol, a novel agent that improves central nervous system drug delivery by enhancing blood-brain barrier permeability.

The clinical application of central nervous system (CNS) drugs is limited by their poor bioavailability due to the blood-brain barrier (BBB). Borneol is a naturally occurring compound in a class of 'orifice-opening' agents often used for resuscitative purposes in traditional Chinese medicine. A growing body of evidence confirms that the 'orifice-opening' effect of borneol is principally derived from opening the BBB. Borneol is therefore believed to be an effective adjuvant that can improve drug delivery to the brain. The purpose of this paper is to provide a comprehensive review of information accumulated over the past two decades on borneol's chemical features, sources, toxic and kinetic profiles, enhancing effects on BBB permeability and their putative mechanisms, improvements in CNS drug delivery, and pharmaceutical forms. The BBB-opening effect of borneol is a reversible physiological process characterized by rapid and transient penetration of the BBB and highly specific brain regional distribution. Borneol also protects the structural integrity of the BBB against pathological damage. The enhancement of the BBB permeability is associated with the modulation of multiple ATP-binding cassette transporters, including P-glycoprotein; tight junction proteins; and predominant enhancement of vasodilatory neurotransmitters. Systemic co-administration with borneol improves drug delivery to the brain in a region-, dose- and time-dependent manner. Several pharmaceutical forms of borneol have been developed to improve the kinetic and toxic profiles of co-administered drugs and enhance their delivery to the brain. Borneol is a promising novel agent that deserves further development as a BBB permeation enhancer for CNS drug delivery.

Identification and determination of myriocin in Isaria cicadae and its allies by LTQ-Orbitrap-HRMS.

A hybrid linear ion trap-quadrupole-Orbitrap high-resolution mass spectrometry (LTQ-Orbitrap-HRMS) was used to qualitatively and quantitatively analyse the myriocin in Isaria cicadae and its allies. The samples were prepared with 95% methanol for 30 min by ultrasonic-assisted extraction. The target compound was purified by ODS solid-phase extraction (SPE) column. The enriched samples were identified by mass spectrometry. The results showed that the contents of myriocin in both wild and artificial Isaria cicadae were below the detection limit, while a strain of Ophiocordyceps longissima and Cordyceps cicadae Shing (Dujiaolong), both closely related to the Isaria cicadae, and its asexual mycelia are rich in myriocin. It suggests that it may be wrong to consider C. cicadae as I. cicadae's teleomorph in Genbank or Mycobank in many published reports based on chemical classification, and the species rich in myriocin is probably not Isaria cicadae.

Cerebral microbleeds and neuropsychiatric symptoms in an elderly Asian cohort.

OBJECTIVES: Neuropsychiatric symptoms (NPS) are commonly found in patients with cerebral small vessel disease such as white matter hyperintensities and lacunar infarcts. However, the association between cerebral microbleeds (CMBs) and NPS has not been examined. Hence the present study sought to investigate the relation between CMBs and NPS in an elderly population. METHODS: This is a cross-sectional study of elderly Asians living in the community, who were assessed on a comprehensive neuropsychological battery and underwent clinical examinations as well as brain MRI scans. The 12-item neuropsychiatric inventory (NPI) was administered to a reliable informant. Total scores for individual symptoms and for NPI global performance were calculated and compared across three groups: no CMB, presence of 1 CMB and presence of multiple CMBs, controlling for demographics, vascular risk factors and other MRI markers. RESULTS: A total of 802 participants were included in the analysis. Participants with multiple CMBs had higher NPI total score compared to those with no CMB (1.06 vs 2.66, p=0.03). On individual symptom scores, higher score on depression (0.16 vs 0.53, p=0.02) and disinhibition (0.01 vs 0.14, p=0.04) was found in those elderly with multiple CMBs, independent of demographic and vascular risk factors, history of stroke, and other small vessel and large vessel disease markers. CONCLUSIONS: The presence of multiple CMBs is associated with high global neuropsychiatric disorder burden, in particular symptoms of depression and disinhibition. Future studies are recommended to investigate the importance of CMBs in the pathogenesis and longitudinal progression of neuropsychiatric disorders in the general elderly population.

Effect of diltiazem injection on blood pressure control after carotid artery stent implantation / 中国生化药物杂志

Objective To investigate the effect of diltiazem injection on the blood pressure and heart rate of patients with carotid artery stent implantation. Methods 60 patients with carotid artery stent implantation from February 2015 to March 2017 were divided into control group and observation group, with 30 cases in each group. The control group was given conventional medication, the observation group was treated with diltiazem on the basis of routine medication in the control group. The mean arterial pressure (MAP) and heart rate (HR) were measured at 72 hours after operation. The number of patients with low blood pressure was measured. Results The stenosis rate of the two groups was significantly lower than that of the control group, while the observation group was significantly lower than the control group (P<0.05). The blood pressure of the observation group was lower than that of the control group at 72 h after operation, but there was no statistical significance. There was no significant difference between the two groups in the rate of hypotension. Conclusion Application of diltiazem injection can help stabilize the carotid artery stent implantation in patients with blood pressure and heart rate, to avoid the occurrence of accidents.

Effect of diltiazem injection on blood pressure control after carotid artery stent implantation / 中国生化药物杂志

Objective To investigate the effect of diltiazem injection on the blood pressure and heart rate of patients with carotid artery stent implantation. Methods 60 patients with carotid artery stent implantation from February 2015 to March 2017 were divided into control group and observation group, with 30 cases in each group. The control group was given conventional medication, the observation group was treated with diltiazem on the basis of routine medication in the control group. The mean arterial pressure (MAP) and heart rate (HR) were measured at 72 hours after operation. The number of patients with low blood pressure was measured. Results The stenosis rate of the two groups was significantly lower than that of the control group, while the observation group was significantly lower than the control group (P<0.05). The blood pressure of the observation group was lower than that of the control group at 72 h after operation, but there was no statistical significance. There was no significant difference between the two groups in the rate of hypotension. Conclusion Application of diltiazem injection can help stabilize the carotid artery stent implantation in patients with blood pressure and heart rate, to avoid the occurrence of accidents.

Cortical cerebral microinfarcts on 3T MRI: A novel marker of cerebrovascular disease.

OBJECTIVE: We examined the risk factors of cortical cerebral microinfarcts (CMIs) on 3T MRI and their association with cognitive impairment. METHODS: Participants (aged 60 years and older) from the multiethnic Epidemiology of Dementia In Singapore Study underwent detailed neuropsychological testing and 3T brain MRI. Cortical CMIs were graded using a previously validated protocol. Cognitive impairment was categorized into cognitive impairment, no dementia (CIND)-mild, CIND-moderate, and dementia. Cognitive function was summarized as composite and domain-specific z scores. RESULTS: Among 861 participants, 54 (6.3%) had ≥1 cortical CMI. In multivariate-adjusted models, the risk factors of cortical CMIs were increasing age, Malay ethnicity, hypertension, diabetes, history of stroke, and markers of both large (cortical infarcts and intracranial stenosis) and small (lacunar infarcts, white matter hyperintensities, cerebral microbleeds) vessel disease. Presence of cortical CMIs was associated with CIND-moderate (odds ratio: 3.12; 95% confidence interval [CI]: 1.18-8.58), dementia (odds ratio: 16.92; 95% CI: 3.37-85.05), and poorer cognitive function (mean difference in composite z score: -0.42; 95% CI: -0.62 to -0.21). Additional adjustments for vascular risk factors and other MRI markers did not alter these associations. CONCLUSIONS: Cortical CMIs are a novel MRI marker of cerebrovascular disease and are independently associated with cognitive impairment and dementia. These findings provide new insights into the burden of cerebrovascular disease in cognitive impairment. Future research is needed to establish the additional etiologic and prognostic significance of cortical CMIs.

The Diagnostic Utility of the NINDS-CSN Neuropsychological Battery in Memory Clinics.

AIMS: To examine the diagnostic utility of the National Institute of Neurological Disorders and Stroke and the Canadian Stroke Network (NINDS-CSN) neuropsychological battery in memory clinics comparing controls with patients with no cognitive impairment (NCI), patients with cognitive impairment-no dementia (CIND) at varying severity levels (mild/moderate), and patients with dementia. METHODS: A total of 405 participants with NCI, CIND or dementia were assessed with the NINDS-CSN battery. The discriminatory properties of all three protocols (5, 30 and 60 min) before and after education stratification (none/primary vs. secondary/above) were examined by receiver operating characteristic curves. RESULTS: Overall, the shorter protocols are equivalent to the longer protocol in diagnosing dementia, regardless of education. To discriminate between nondementia groups, before education stratification, the 5-min protocol showed varied discriminatory properties between different diagnostic/severity groups. After stratification, the 5-min protocol was broadly equivalent to the longer protocols in lower-education groups [area under the curve (AUC) range: 0.77-0.87] but was less accurate in the higher-education groups (AUC range: 0.68-0.78). The 30- and 60-min protocol constantly showed moderate-to-excellent differentiating capacities regardless of education (AUC range: 0.80-0.90). CONCLUSION: The NINDS-CSN neuropsychological battery can be applied in memory clinics and effectively discriminate between cognitively intact individuals and those with cognitive impairments of varying severity. Furthermore, level of education should be taken into consideration when choosing protocols with different lengths for cognitive assessment.

Hypoxia-stimulated cardiac fibroblast production of IL-6 promotes myocardial fibrosis via the TGF-ß1 signaling pathway.

Interlukin-6 (IL-6) is a multifunctional cytokine produced by several cell types that has a role in fibrosis. Fibroblasts (FBs) maintain this underlying pathogenic change through regulation of IL-6 production; however, its potential functional role in regulating surrounding cellular structural changes during ischemic myocardial remodeling remains unexplored. Here, we generated FBs, cardiomyocytes (CMs), and blood vascular endothelial cells (ECs) from the ventricles of neonatal rats. IL-6 was then overexpressed in FBs and the cells were treated with IL-6 receptor inhibitor (IL6RI), TGF-ß1 receptor inhibitor (TßRI), or MMP2/MMP9 inhibitor (MMPI) using monoculture or coculture models under hypoxic conditions. The results indicate that overexpression of IL-6 is sufficient to induce myofibroblastic proliferation, differentiation, and fibrosis, probably via increased TGF-ß1-mediated MMP2/MMP3 signaling. The use of IL6RI, TßRI, or MMPI diminished these effects. In addition, IL-6 activated the apoptosis-associated factors Caspase3 and Smad3, and decreased the expression of anti-apoptotic factor Bcl2, resulting in apoptosis of CMs under hypoxic coculture: IL6RI or TßRI inhibited these effects. Unexpectedly, IL-6-overexpressing FBs significantly increased the angiogenesis of ECs, which involved significant increases in the expression of proangiogenic growth factors. Treatment of FBs with IL6RI or TßRI in coculture with ECs reduced the levels of secreted proangiogenic growth factors, and the angiogenesis of ECs was significantly downregulated. Thus, IL-6 functions in ischemic myocardial remodeling through multifunctional reprogramming of hypoxia-associated FBs towards fibrosis via upregulation of the TGF-ß1 signaling pathway.

Validation of the Total Cerebrovascular Disease Burden Scale in a Community Sample.

BACKGROUND: A total cerebrovascular disease (CeVD) burden scale was previously constructed and an inverse association of CeVD burden and cognition was found. However, the generalizability of the CeVD scale has not been examined. OBJECTIVE: The objective was to validate the previously constructed total CeVD burden scale by establishing its association with cognitive function and dementia diagnosis in a community sample. METHODS: Eligible participants were assessed on an extensive neuropsychological battery and underwent MRI scans. The total CeVD scale, comprising markers of both small- and large-vessel diseases, was derived according to previously described criteria. Association of total CeVD burden with global and domain-based cognitive performance and dementia diagnostic utility of the scale was established. RESULTS: A total of 863 participants were included in the analysis. A stepwise association of CeVD burden score with global and domain-specific cognitive function was found. Per score increase on the total CeVD burden scale was associated with 3.6 (95% CI = 2.1-6.4) times higher odds of dementia compared to dementia-free. DISCUSSION: The total CeVD burden scale is associated with cognition and dementia in a community sample. Longitudinal studies are required to establish the predictive ability of this scale.