Characteristics and Significance of Tertiary Lymphoid Structures Based on Molecular Subtypes in Endometrial Cancer.

The purpose of this study is to investigate the characteristics and significance of tertiary lymphoid structures (TLSs) in endometrial cancer (EC) based on molecular subtypes. A total of 220 patients with EC were retrospectively enrolled, including 20 with polymerase epsilon ultramutated (POLE-mut), 63 with mismatch repair deficient, 32 with p53 abnormal, and 105 with no specific molecular profile. The presence and maturity of TLSs were determined by immunohistochemical markers (CD3, CD20, CD21, and Bcl6). Disease-free survival served as the endpoint event. TLSs were found in 91 out of 220 patients (41.1%), with 68 located in peritumoral tissues and 37 exhibiting well-formed germinal center structures. The presence and different maturity of TLSs were closely associated with tumor-infiltrating lymphocytes and the programmed cell death ligand-1 expression. Moreover, TLSs displayed heterogeneity across different molecular subtypes. Notably, the TLSs, tumor-infiltrating lymphocytes, and expression of the programmed cell death ligand-1 were significantly enriched in POLE-mut EC. Multivariate logistic regression analysis showed the presence of TLSs (odds ratio: 3.483, 95% CI: 1.044-11.623, P = 0.042) as a potential predictor of POLE-mut EC. Kaplan-Meier survival curves revealed that molecular subtypes significantly stratified prognosis in patients with EC (P = 0.002), whereas TLSs did not. Multivariate Cox regression analysis indicated that The International Federation of Gynecology and Obstetrics stage and Ki-67 expression were independent prognostic factors affecting disease-free survival in patients with EC, and TLSs were not included. In conclusion, TLSs in EC exhibit heterogeneity based on molecular subtypes, necessitating further exploration to determine their clinical application value.

Intracranial Atherosclerotic Disease and Incident Dementia: The ARIC Study (Atherosclerosis Risk in Communities).

BACKGROUND: Studies of the neurovascular contribution to dementia have largely focused on cerebral small vessel disease (CSVD), but the role of intracranial atherosclerotic disease (ICAD) remains unknown in the general population. The objective of this study was to determine the risk of incident dementia from ICAD after adjusting for CSVD and cardiovascular risk factors in a US community-based cohort. METHODS: We acquired brain magnetic resonance imaging examinations from 2011 through 2013 in 1980 Black and White participants in the ARIC study (Atherosclerosis Risk in Communities), a prospective cohort conducted in 4 US communities. Magnetic resonance imaging examinations included high-resolution vessel wall magnetic resonance imaging and magnetic resonance angiography to identify ICAD. Of these participants, 1590 without dementia, without missing covariates, and with adequate magnetic resonance image quality were followed through 2019 for incident dementia. Associations between ICAD and incident dementia were assessed using Cox proportional hazard ratios adjusted for CSVD (characterized by white matter hyperintensities, lacunar infarctions, and microhemorrhages), APOE4 genotype (apolipoprotein E gene ε4), and cardiovascular risk factors. RESULTS: The mean age (SD) of study participants was 77.4 (5.2) years. ICAD was detected in 34.6% of participants. After a median follow-up of 5.6 years, 286 participants developed dementia. Compared with participants without ICAD, the fully adjusted hazard ratios (95% CIs) for incident dementia in participants with any ICAD, with ICAD only causing stenosis ≤50%, and with ICAD causing stenosis >50% in ≥1 vessel were 1.57 (1.17-2.11), 1.41 (1.02-1.95), and 1.94 (1.32-2.84), respectively. ICAD was associated with dementia even among participants with low white matter hyperintensities burden, a marker of CSVD. CONCLUSIONS: ICAD was associated with an increased risk of incident dementia, independent of CSVD, APOE4 genotype, and cardiovascular risk factors. The increased risk of dementia was evident even among participants with low CSVD burden, a group less likely to be affected by vascular dementia, and in participants with ICAD causing only low-grade stenosis. Our results suggest that ICAD may partially mediate the effect that cardiovascular risk factors have on the brain leading to dementia. Both ICAD and CSVD must be considered to understand the vascular contributions to cognitive decline.

Vessel Wall Imaging Features of Spontaneous Intracranial Carotid Artery Dissection.

BACKGROUND AND OBJECTIVES: Intracranial dissection is an important cause of stroke often with nonspecific angiographic features. Vessel wall imaging (VWI) can detect dissections, but intracranial applications remain unvalidated by pathologic specimens. We sought to determine the ability of VWI to identify the rarely reported spontaneous intracranial carotid dissection (sICD) guided by postmortem validation. METHODS: VWI features of sICD, validated by postmortem specimen analysis in 1 patient, included luminal enhancement within a hypoenhancing outer wall, narrowing the mid to distal ophthalmic (C6) segment, relatively sparing the communicating (C7) segment. VWI examinations were reviewed to identify patients (1) with matching imaging features, (2) no evidence of other vasculopathies (i.e., inflammatory, intracranial atherosclerotic disease [ICAD]), and (3) adequate image quality. These sICD VWI features were compared with those in patients with known ICAD causing similar narrowing of C6 and relative sparing of C7 by a Fisher exact test accounting for multiple samples. RESULTS: Among 407 VWI examinations, 8 patients were identified with 14 sICDs, all women aged 30-56 years, 6 (75%) bilateral. All patients with sICD had risk factors of dissection (e.g., recently postpartum, fibromuscular dysplasia, and hypertension) and 3 (37.5%) had intracranial dissections elsewhere. Seven (87.5%) were diagnosed as moyamoya syndrome on initial angiography. Enhancing lesions varied from thin flap-like defects (n = 6) to thick tissue along the superolateral wall of the internal carotid artery, within the hypoenhancing outer wall. Compared with 10 intracranial carotid plaques in 8 patients with ICAD, sICD demonstrated stronger (84.6% vs 20.0%, p = 0.003-0.025) and more homogeneous (61.5% vs 0.0%, p = 0.005-0.069) enhancement and less positive remodeling (0.0% vs 60.0%, p = 0.004-0.09). T1 hyperintensity was identified in 5 sICDs in 3 patients but not identified in ICAD. Three patients with serial imaging (8- to 39.8-month maximum intervals) revealed little to no changes in stenosis, wall thickening, or enhancement. DISCUSSION: sICD is distinguishable on VWI from ICAD by enhancement characteristics, less positive remodeling, and clinical parameters. These VWI features should raise suspicion especially in young women with risk factors of dissection. Temporal stability and a lack of T1 hyperintensity should not discourage diagnosing sICD.

Epidemiology, Pathophysiology, and Imaging of Atherosclerotic Intracranial Disease.

Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide. Among people with stroke, those of East Asia descent and non-White populations in the United States have a higher burden of ICAD-related stroke compared with Whites of European descent. Disparities in the prevalence of asymptomatic ICAD are less marked than with symptomatic ICAD. In addition to stroke, ICAD increases the risk of dementia and cognitive decline, magnifying ICAD societal burden. The risk of stroke recurrence among patients with ICAD-related stroke is the highest among those with confirmed stroke and stenosis ≥70%. In fact, the 1-year recurrent stroke rate of >20% among those with stenosis >70% is one of the highest rates among common causes of stroke. The mechanisms by which ICAD causes stroke include plaque rupture with in situ thrombosis and occlusion or artery-to-artery embolization, hemodynamic injury, and branch occlusive disease. The risk of stroke recurrence varies by the presumed underlying mechanism of stroke, but whether techniques such as quantitative magnetic resonance angiography, computed tomographic angiography, magnetic resonance perfusion, or transcranial Doppler can help with risk stratification beyond the degree of stenosis is less clear. The diagnosis of ICAD is heavily reliant on lumen-based studies, such as computed tomographic angiography, magnetic resonance angiography, or digital subtraction angiography, but newer technologies, such as high-resolution vessel wall magnetic resonance imaging, can help distinguish ICAD from stenosing arteriopathies.

Central arterial stiffening and intracranial atherosclerosis: the atherosclerosis risk in communities neurocognitive study (ARIC-NCS): Aortic stiffness & intracranial atherosclerosis.

OBJECTIVES: Previous studies suggest an association between central arterial stiffness (CAS) and intracranial atherosclerotic disease (ICAD) among Asian participants with stroke or hypertension; this association has not been evaluated in United States populations. We assessed the cross-sectional association of CAS with ICAD presence and burden in late-life, and differences in association by age, sex, and race. MATERIALS AND METHODS: We conducted a cross-sectional analysis of 1,285 Atherosclerosis Risk in Communities Study participants [mean age 75 (standard deviation: 5) years, 38 % male, 20  % Black] at Visit 5 (2011-2013). CAS was measured as carotid-femoral pulse wave velocity (cfPWV) using the Omron VP-1000 Plus. ICAD was assessed using high-resolution vessel wall MRI and MR angiography. We evaluated associations of a 1 standard deviation (SD) cfPWV (3.02 m/s) and high vs. non-high cfPWV (≥ 13.57 m/s vs. < 13.57 m/s) with presence of plaques (yes/no) and plaque number (0, 1-2, and >2) using multivariable logistic and ordinal logistic regression models adjusted for covariates. RESULTS: Each one SD greater cfPWV was associated with higher odds of plaque presence (odds ratio (OR)=1.32, 95 % confidence interval (CI): 1.22, 1.43), and an incrementally higher odds of number of plaques (OR 1-2 vs. 0 plaques = 1.21, 95 % CI: 1.10, 1.33; OR >2 vs. 0 plaques = 1.51, 95 % CI: 1.33,1.71). Results suggested differences by race, with greater magnitude associations among Black participants. CONCLUSIONS: CAS was positively associated with ICAD presence and burden; cfPWV may be a useful subclinical vascular measure for identification of individuals who are at high risk for cerebrovascular disease.

Detection of Dolichoectasia and Atherosclerosis by Automated MRA Tortuosity Metrics in a Population-Based Study.

BACKGROUND: Intracranial vessel tortuosity is a key component of dolichoectasia and has been associated with atherosclerosis and adverse neurologic outcomes. However, the evaluation of tortuosity is mainly a descriptive assessment. PURPOSE: To compare the performance of three automated tortuosity metrics (angle metric [AM], distance metric [DM], and distance-to-axis metric [DTA]) for detection of dolichoectasia and presence of segment-specific plaques. STUDY TYPE: Observational, cross-sectional metric assessment. POPULATION: 1899 adults from the general population; mean age = 76 years, female = 59%, and black = 29%. FIELD STRENGTH/SEQUENCE: 3-T, three-dimensional (3D) time-of-flight MRA and 3D vessel wall MRI. ASSESSMENT: Tortuosity metrics and mean luminal area were quantified for designated segments of the internal carotid artery, middle cerebral artery, anterior cerebral artery, posterior cerebral artery, vertebral artery, and entire length of basilar artery (BA). Qualitative interpretations of BA dolichoectasia were assessed based on Smoker's visual criteria. STATISTICAL TESTS: Descriptive statistics (2-sample t-tests, Pearson chi-square tests) for group comparisons. Receiver operating characteristics area under the curve (AUC) for detection of BA dolichoectasia or segment-specific plaque. Model inputs included 1) tortuosity metrics, 2) mean luminal area, and 3) demographics (age, race, and sex). RESULTS: Qualitative dolichoectasia was identified in 336 (18%) participants, and atherosclerotic plaques were detected in 192 (10%) participants. AM-, DM-, and DTA-calculated tortuosity were good individual discriminators of basilar dolichoectasia (AUCs: 0.76, 0.74, and 0.75, respectively), with model performance improving with the mean lumen area: (AUCs: 0.88, 0.87, and 0.87, respectively). Combined characteristics (tortuosity and mean luminal area) identified plaques with better performance in the anterior (AUCs ranging from 0.66 to 0.78) than posterior (AUCs ranging from 0.54 to 0.65) circulation, with all models improving by the addition of demographics (AUCs ranging from 0.62 to 0.84). DATA CONCLUSION: Quantitative vessel tortuosity metrics yield good diagnostic accuracy for the detection of dolichoectasia. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 2.

Correlated Hybrid DNA Structures Explored by the oxDNA Model.

Thermodynamically, perfect DNA hybridization can be formed between probes and their corresponding targets due to the favorable energy. However, this is not the case dynamically. Here, we use molecular dynamics (MD) simulations based on the oxDNA model to investigate the process of DNA microarray hybridization. In general, correlated hybrid DNA structures are formed, including one probe associated with several targets as well as one target hybrid with multiple probes leading to the target-mediated hybridization. The formation of these two types of correlated structures largely depends on the surface coverage of the DNA microarray. Moreover, DNA sequence, DNA length, and spacer length have an impact on the structural formation. Our findings shed light on the dynamics of DNA hybridization, which is important for the application of DNA microarray.

Association of brain arterial diameters with demographic and anatomical factors in a multi-national pooled analysis of cohort studies.

BACKGROUND AND PURPOSE: Brain arterial diameters are markers of cerebrovascular disease. Demographic and anatomical factors may influence arterial diameters. We hypothesize that age, sex, height, total cranial volume (TCV), and persistent fetal posterior cerebral artery (fPCA) correlate with brain arterial diameters across populations. METHODS: Participants had a time-of-flight MRA from nine international cohorts. Arterial diameters of the cavernous internal carotid arteries (ICA), middle cerebral arteries (MCA), and basilar artery (BA) were measured using LAVA software. Regression models assessed the association between exposures and brain arterial diameters. RESULTS: We included 6,518 participants (mean age: 70 ± 9 years; 41% men). Unilateral fPCA was present in 13.2% and bilateral in 3.2%. Larger ICA, MCA, and BA diameters correlated with older age (Weighted average [WA] per 10 years: 0.18 mm, 0.11 mm, and 0.12 mm), male sex (WA: 0.24 mm, 0.13 mm, and 0.21 mm), and TCV (WA: for one TCV standard deviation: 0.24 mm, 0.29 mm, and 0.18 mm). Unilateral and bilateral fPCAs showed a positive correlation with ICA diameters (WA: 0.39 mm and 0.73 mm) and negative correlation with BA diameters (WA: -0.88 mm and -1.73 mm). Regression models including age, sex, TCV, and fPCA explained on average 15%, 13%, and 25% of the ICA, MCA, and BA diameter interindividual variation, respectively. Using height instead of TCV as a surrogate of head size decreased the R-squared by 3% on average. CONCLUSION: Brain arterial diameters correlated with age, sex, TCV, and fPCA. These factors should be considered when defining abnormal diameter cutoffs across populations.

Chromosome 10q24.32 Variants Associate With Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

BACKGROUND: Brain arterial diameters (BADs) are novel imaging biomarkers of cerebrovascular disease, cognitive decline, and dementia. Traditional vascular risk factors have been associated with BADs, but whether there may be genetic determinants of BADs is unknown. METHODS AND RESULTS: The authors studied 4150 participants from 6 geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). Brain arterial diameters for 13 segments were measured and averaged to obtain a global measure of BADs as well as the posterior and anterior circulations. A genome-wide association study revealed 14 variants at one locus associated with global BAD at genome-wide significance (P<5×10-8) (top single-nucleotide polymorphism, rs7921574; ß=0.06 [P=1.54×10-8]). This locus mapped to an intron of CNNM2. A trans-ancestry genome-wide association study meta-analysis identified 2 more loci at NT5C2 (rs10748839; P=2.54×10-8) and AS3MT (rs10786721; P=4.97×10-8), associated with global BAD. In addition, 2 single-nucleotide polymorphisms colocalized with expression of CNNM2 (rs7897654; ß=0.12 [P=6.17×10-7]) and AL356608.1 (rs10786719; ß=-0.17 [P=6.60×10-6]) in brain tissue. For the posterior BAD, 2 variants at one locus mapped to an intron of TCF25 were identified (top single-nucleotide polymorphism, rs35994878; ß=0.11 [P=2.94×10-8]). For the anterior BAD, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). CONCLUSIONS: The current study reveals 3 novel risk loci (CNNM2, NT5C2, and AS3MT) associated with BADs. These findings may help elucidate the mechanism by which BADs may influence cerebrovascular health.

A Novel Window Into Human Vascular Remodeling and Diagnosing Carotid Flow Impairment: The Petro-Occipital Venous Plexus.

Background Adaptive arterial remodeling caused by flow reduction from downstream stenosis has been demonstrated in animal studies. The authors sought to determine whether inward remodeling from downstream stenosis also occurs in humans and is detectable by ex vacuo expansion of the Rektorzik venous plexus (RVP) surrounding the petrous internal carotid artery. Methods and Results The authors analyzed 214 intracranial magnetic resonance imaging examinations that included contrast-enhanced vessel wall imaging. RVP symmetry was qualitatively assessed on vessel wall imaging. RVP thickness (RVPT) was measured on the thicker side if asymmetric or randomly assigned side if symmetric. Maximum stenosis (M1 or intracranial internal carotid artery) was measured. Posterior communicating artery and A1 diameters (>1.0 mm and 1.5 mm, respectively) defined adequate collateral outflow when proximal to the stenosis. Seventy-two patients had stenosis downstream from RVPT measurements. For those without adequate outflow (38 of 72), 95.0% with RVPT ≥1.0 mm had ≥50% stenosis compared with only 5.6% with RVPT <1.0 mm. For these 72 patients, higher RVPT (RVPT ≥1.0 mm versus <1.0 mm) and absent adequate outflow were associated with greater downstream stenosis (P<0.001) using multivariate regression. For patients with downstream stenosis without adequate outflow, asymmetric RVP thickening was associated with greater ipsilateral stenosis (P<0.001, all had ≥46% stenosis) when stenosis was unilateral and greater differences in stenosis between sides (P=0.005) when stenosis was bilateral. Conclusions Inward internal carotid artery remodeling measured by RVPT or RVP asymmetry occurs as downstream stenosis approaches 50%, unless flow is preserved through a sufficiently sized posterior communicating artery or A1, and may serve as a functional measure of substantial flow reduction from downstream stenosis.

Concurrent measurement of perfusion parameters related to small blood vessels and cerebrospinal fluid circulation in the human brain using dynamic dual-spin-echo perfusion MRI.

Accumulating evidence from recent studies has indicated the importance of studying the interaction between the microvascular and lymphatic systems in the brain. To date, most imaging methods can only measure blood or lymphatic vessels separately, such as dynamic susceptibility contrast (DSC) MRI for blood vessels and DSC MRI-in-the-cerebrospinal fluid (CSF) (cDSC MRI) for lymphatic vessels. An approach that can measure both blood and lymphatic vessels in a single scan offers advantages such as a halved scan time and contrast dosage. This study attempts to develop one such approach by optimizing a dual-echo turbo-spin-echo sequence, termed "dynamic dual-spin-echo perfusion (DDSEP) MRI". Bloch simulations were performed to optimize the dual-echo sequence for the measurement of gadolinium (Gd)-induced blood and CSF signal changes using a short and a long echo time, respectively. The proposed method furnishes a T1-dominant contrast in CSF and a T2-dominant contrast in blood. MRI experiments were performed in healthy subjects to evaluate the dual-echo approach by comparing it with existing separate methods. Based on simulations, the short and long echo time were chosen around the time when blood signals show maximum difference between post- and pre-Gd scans, and the time when blood signals are completely suppressed, respectively. The proposed method showed consistent results in human brains as previous studies using separate methods. Signal changes from small blood vessels occurred faster than from lymphatic vessels after intravenous Gd injection. In conclusion, Gd-induced signal changes in blood and CSF can be detected simultaneously in healthy subjects with the proposed sequence. The temporal difference in Gd-induced signal changes from small blood and lymphatic vessels after intravenous Gd injection was confirmed using the proposed approach in the same human subjects. Results from this proof-of-concept study will be used to further optimize DDSEP MRI in subsequent studies.

Association of leisure-time physical activity and sedentary behavior with carotid atherosclerosis morphology: The ARIC carotid-MRI study.

Objective: We evaluated the prospective association of midlife leisure-time physical activity (LTPA) and sedentary behavior (SB), and their temporal patterns, with MRI-measured carotid atherosclerotic morphology. Methods: Participants enrolled in the Carotid MRI substudy (2004-2006) of the Atherosclerosis Risk in Communities (ARIC) Study and with self-reported assessments of LTPA and SB at visits 1 (1987-1989) and 3 (1993-1995) were included in this study. LTPA was ascertained using the ARIC/Baecke physical activity questionnaire and categorized according to the American Heart Association's metric of poor, intermediate, or ideal physical activity. SB, measured as TV viewing frequency, was categorized as high, medium, and low. We used multivariable adjusted linear and logistic regression models to examine the associations between midlife (visit 3 only) and persistent (visit 1 to 3) LTPA and TV viewing with carotid artery plaque burden and components. Results: Among the 1,582 (mean age: 59 years, 43% male, 18% Black) participants, 45.7%, 21.7%, and 32.6% reported ideal, intermediate, or poor LTPA, respectively. High TV viewing was reported in 33.8% of participants, with 46.4% and 19.8% reporting medium or low TV viewing, respectively. Compared to poor LTPA, ideal LTPA in midlife was not associated with total wall volume (ß=0.01, 95% CI: -0.01, 0.03), maximum carotid wall thickness (ß=0.06, 95% CI: -0.08, 0.21), normalized wall index (ß=-0.01, 95% CI: -0.03, 0.01), or maximum stenosis (ß=-0.11, 95% CI: -1.98, 1.76). Low or middle, compared to high, TV viewing was also not associated with carotid artery measures of plaque burden. Compared to poor LTPA or high TV viewing, ideal LTPA (odds ratio (OR): 0.82, 95% CI: 0.55, 1.23) and low TV viewing (OR=0.90, 95% CI: 0.56, 1.44) was not associated with odds of lipid core presence, respectively. Conclusion: Overall, this study does not provide strong evidence for an association between LTPA and SB with carotid plaque measures.

Two Different Ways of Stress Release in Supercoiled DNA Minicircles under DNA Nick.

It is generally believed that DNA nick is an effective way to release stress in supercoiled DNA, resulting from the twisting motion that individual strands rotate around the axis of the DNA helix. Here, we use MD simulations based on the oxDNA model to investigate the relaxation of 336 bp supercoiled minicircular DNA under DNA nick. Our simulations show that stress release, characterized by the abrupt decrease in linking number, may be induced by two types of DNA motion depending on the nick position. Except for the twisting motion, there is a writhing motion, that is, double strands collectively rotating with one plectoneme removal, which may occur in the process of DNA relaxation with the nick position in the loop region. Moreover, the writhing motion is more likely to occur in the DNA with relatively high hardness, such as C-G pairs. Our simulation results uncover the relationship between structural transformation, stress release, and DNA motion during the dynamic process under DNA nick, indicating the influence of nick position on the relaxation of the supercoiled DNA.

Chromosome 10q24.32 Variants Associate with Brain Arterial Diameters in Diverse Populations: A Genome-Wide Association Study.

Background: Brain arterial diameters are novel imaging biomarkers of cerebrovascular disease, cognitive decline and dementia. Traditional vascular risk factors have been associated with brain arterial diameters but whether there may be genetic determinants of brain arterial diameters is unknown. Results: We studied 4150 participants from six geographically diverse population-based cohorts (40% European, 14% African, 22% Hispanic, 24% Asian ancestries). We measured brain arterial diameters for 13 segments and averaged them to obtain a global measure of brain arterial diameters as well as the posterior and anterior circulations. A genome-wide association study (GWAS) revealed 14 variants at one locus associated with global brain arterial diameter at genome-wide significance (P<5×10-8) (top SNP, rs7921574; ß =0.06, P=1.54×10-8). This locus mapped to an intron of CNNM2. A trans-ancestry GWAS meta-analysis identified two more loci at NT5C2 (rs10748839; P=2.54×10-8) and at AS3MT (rs10786721; P=4.97×10-8), associated with global brain arterial diameter. In addition, two SNPs co-localized with expression of CNNM2 (rs7897654, ß=0.12, P=6.17×10-7) and AL356608.1 (rs10786719, ß =-0.17, P=6.60×10-6) in brain tissue. For the posterior brain arterial diameter, two variants at one locus mapped to an intron of TCF25 were identified (top SNP, rs35994878; ß =0.11, P=2.94×10-8). For the anterior brain arterial diameter, one locus at ADAP1 was identified in trans-ancestry genome-wide association analysis (rs34217249; P=3.11×10-8). Conclusion: Our study reveals three novel risk loci (CNNM2, NT5C2 and AS3MT) associated with brain arterial diameters. Our finding may elucidate the mechanisms by which brain arterial diameters influence the risk of stroke and dementia.

[Influence of electroacupuncture of"Zusanli"(ST36)on mast cells/TRPV1 signaling pathway in visceral hypersensitivity rats with functional dyspepsia].

OBJECTIVE: To explore the interventional mechanism of electroacupuncture (EA) of "Zusanli"(ST36)based on the involvement of mast cells/ transient receptor potential vanilloid type1 (TRPV1) signaling pathway in relieving visceral hypersensitivity in functional dyspepsia (FD) rats. METHODS: Sixty SD rats (half male and half female, 10 days in age) were randomly divided into normal control, model, medication (ketotifen) and EA groups, with 15 rats in each group. The FD model was established by gavage of iodoacetamide combined with tail clamping (stress stimulation). Rats of the medication group received intraperitoneal injection of ketotifen (1 mg·kg-1·d-1) for 14 d, and those of the EA group received EA of ST36 for 20 min, once a day for 14 d. An air-balloon was inserted into the rat's stomach for recording changes of the intragastric pressure (mL/mm Hg) via a pressure transducer. The visceral hypersensitivity was assessed using abdominal withdrawal reflex (AWR) score and the number and degranulation of mast cells of gastric mucosa were observed using toluidine blue staining. The expression levels of TRPV1 and proteinase activated receptor 2 (PAR2) in the stomach were observed using immunofluorescence histochemistry and Western blot, separately, and the contents of SP and CGRP in the stomach detected using ELISA. RESULTS: When the intragastric pressure was at 50, 60 and 70 mm Hg, the gastric compliance was significantly decreased (P<0.01), and the levels of visceral sensitivity increased in the model group （P<0.01）。 TRPV1 immunofluorescence tensity, expression of PAR2 and TRPV1 proteins, and contents of SP and CGRP in the stomach were considerably up-regulated in the model group compared with the normal control group (P<0.01). In comparison with the model group, under intragastric pressure of 50，60 and 70 mm Hg, the gastric compliance was obviously increased, and the visceral hypersensitivity decreased in the EA group （P<0.01,P<0.05）. TRPV1 immunofluorescence intensity, expression levels of PAR2 and TRPV1 proteins, and the contents of SP and CGRP in the stomach were considerably down-regulated in both medication and EA groups compared with the model group (P<0.01, P<0.05). The therapeutic effect of EA was significantly superior to that of medication in up-regulating the gastric compliance （at 70 mm Hg）, and down-regulating the contents of SP and CGRP (P<0.05). No significant differences were found between the EA and medication groups in up-regulating gastric compliance at intragastric pressure of 50 and 60 mm Hg, and in down-regulating the visceral sensitivity, TRPV1 fluorescence intensity, and expression of PAR2 and TRPV1 proteins (P>0.05). Toluidine blue staining showed an apparent increase of mast cell number with obvious degranulation in the gastric mucosa of rats in the model group, which was milder in the EA and medication groups. CONCLUSION: EA of ST36 can suppress visceral hypersensitivity and increase the gastric compliance in FD rats, which may be related with its effects in inhibiting the activation of gastric mast cells, and down-regulating the expression of gastric PAR2 and TRPV1 proteins and SP and CGRP contents.

Non-contrast hemodynamic imaging of Moyamoya disease with MR fingerprinting ASL: A feasibility study.

PURPOSE: MR Fingerprinting (MRF) Arterial Spin Labeling (ASL) is a non-contrast technique to estimate multiple brain hemodynamic and structural parameters in a single scan. The purpose of this study is to examine the feasibility and initial utility of MRF-ASL in Moyamoya disease. METHODS: MRF-ASL, conventional single-delay ASL, Time-of-flight (TOF) MR angiography, and contrast-based dynamic-susceptibility-contrast (DSC) MRI were prospectively collected from a group of Moyamoya patients in North America (N = 21, 4 men and 17 women). Sixteen healthy subjects (7 men and 9 women) also underwent an MRF-ASL scan. Cerebral blood flow (CBF), bolus arrival time (BAT), and tissue T1 were compared between Moyamoya patients and healthy controls. Perfusion parameters from MRF-ASL were compared to those from other MRI sequences. Multi-linear regression was used for comparisons of parameter values between Moyamoya and control groups. Linear mixed-effects models was used when comparing MRF-ASL to PCASL and DSC parameters. Spearman's Rank Correlation Coefficient was calculated when comparing MRF-ASL to and MRA grades. A P value of 0.05 or less was considered significant. RESULTS: BAT in stenotic internal carotid artery (ICA) territories was prolonged (P < 0.001) in Moyamoya patients, when compared with healthy controls. CBF in stenotic ICA territories of Moyamoya patients was not different from CBF in healthy controls; but in the PCA territories, CBF in Moyamoya patients was higher (P < 0.01) than controls. Quantitative T1 values in the stenotic ICA territories was longer (P < 0.05) than that in controls. Hemodynamic parameters estimated from MRF-ASL were significantly correlated with single-delay ASL and DSC. Longer BAT was associated with more severe intracranial artery stenosis in ICA. CONCLUSIONS: MRF-ASL is a promising technique to assess perfusion and structural abnormalities in Moyamoya patients.

Chemical composition of essential oils from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare and their acaricidal effects on Haemaphysalis longicornis (Acari: Ixodidae).

Chemical acaricides are mainly used in traditional tick control, which leads to the emergence of tick resistance and concurrently results in environmental pollution. In the present study, the chemical constituents of essential oils (EOs) from Thymus mongolicus, Cinnamomum verum, and Origanum vulgare was analyzed, and their potential application was evaluated to control the vector tick Haemaphysalis longicornis, which is widely distributed over vast areas of Eurasia, Australia, and New Zealand. Gas chromatography-mass spectrometry analysis revealed that the phenols thymol and carvacrol accounted for 34.66% and 75.72% of the EOs of T. mongolicus and O. vulgare, respectively, whereas trans-cinnamaldehyde (49.42%) was the main constituent of C. verum EO. Immersion tests showed that the EOs of C. verum and O. vulgare had significant acaricidal activity against larval H. longicornis, with the 50% lethal concentration (LC50) being 16.07 and 18.02 mg/mL, respectively, and the 95% lethal concentration (LC95) being 120.37 and 130.09 mg/mL, respectively. The EOs of O. vulgare and T. mongolicus showed significant acaricidal activity against unfed adult H. longicornis, with LC50 being 43.50 and 44.21 mg/mL, respectively, and LC95 being 113.66 and 137.99 mg/mL, respectively. The fumigant toxicity test showed significant acaricidal activity of the three EOs against both unfed and engorged nymphal and adult H. longicornis. Enzyme assays revealed that the EOs of both C. verum and O. vulgare significantly inhibited glutathione S-transferase activity (P < 0.05). In contrast, the activities of carboxylesterase and multifunction oxidases were significantly inhibited by EOs extracted from all three plants (P < 0.05). Taken together, these findings suggest that plant EOs may serve as an environment-friendly alternative for synthetic acaricides in future tick control.

Essentials for Interpreting Intracranial Vessel Wall MRI Results: State of the Art.

Intracranial vessel wall (VW) MRI has become widely available in clinical practice, providing multiple uses for evaluation of neurovascular diseases. The Vessel Wall Imaging Study Group of the American Society of Neuroradiology has recently reported expert consensus recommendations for the clinical implementation of this technique. However, the complexity of the neurovascular system and caveats to the technique may challenge its application in clinical practice. The purpose of this article is to review concepts essential for accurate interpretation of intracranial VW MRI results. This knowledge is intended to improve diagnostic confidence and performance in the interpretation of VW MRI scans. © RSNA, 2021 Online supplemental material is available for this article.

Three-dimensional assessment of brain arterial compliance: Technical development, comparison with aortic pulse wave velocity, and age effect.

PURPOSE: The ability to measure cerebral vascular compliance (VC) is important in the evaluation of vascular diseases. Additionally, quantification of arterial wall pulsation in the brain may be useful for understanding the driving force of the recently discovered glymphatic system. Our goal is to develop an MRI technique to measure VC and arterial wall pulsation in major intracranial vessels. METHODS: A total of 17 healthy subjects were studied on a 3T MRI system. The technique, called VaCom-PCASL, uses pseudo-continuous arterial spin labeling (PCASL) to obtain pure blood vessel signal, uses a 3D radial acquisition, and applies a golden-angle radial sparse parallel (GRASP) algorithm for image reconstruction. The k-space data were retrospectively sorted into different cardiac phases. The GRASP algorithm allows the reconstruction of 5D (three spatial dimensions, one control/label dimension, and one cardiac-phase dimension) data simultaneously. The proposed technique was optimized in terms of reconstruction parameters and labeling duration. Intracranial VC was compared with aortic pulse wave velocity measured with phase-contrast MRI. Age differences in VC were studied. RESULTS: The VaCom-PCASL technique using 10 cardiac phases and GRASP sparsity constraints of λlabel/control = 0.05 and λcardiac = 0.05 provided the highest contrast-to-noise ratio. A labeling duration of 800 ms was found to yield signals comparable to those of longer duration (P > .2), whereas 400 ms yielded significant overestimation (P < .005). A significant correlation was observed between intracranial VC and aortic pulse wave velocity (r = -0.73, P = .038, N = 8). Vascular compliance in the older group was lower than that in the younger group. CONCLUSION: The VaCom-PCASL-MRI technique represents a promising approach for noninvasive assessment of arterial stiffness and pulsatility.

Relationship Between Central Artery Stiffness, Brain Arterial Dilation, and White Matter Hyperintensities in Older Adults: The ARIC Study-Brief Report.

[Figure: see text].