Evolutionary insights into sequence modifications governing chitin recognition and chitinase inactivity in YKL-40 (HC-gp39, CHI3L1).

YKL-40, also known as human cartilage glycoprotein-39 (HC-gp39) or CHI3L1, shares structural similarities with chitotriosidase (CHIT1), an active chitinase, but lacks chitinase activity. Despite being a biomarker for inflammatory disorders and cancer, the reasons for YKL-40's inert chitinase function have remained elusive. This study reveals that the loss of chitinase activity in YKL-40 has risen from multiple sequence modifications influencing its chitin affinity. Contrary to the common belief associating the lack of chitinase activity with amino acid substitutions in the catalytic motif, attempts to activate YKL-40 by creating two amino acid mutations in the catalytic motif (MT-YKL-40) proved ineffective. Subsequent exploration that included creating chimeras of MT-YKL-40 and CHIT1 catalytic domains (CatDs) identified key exons responsible for YKL-40 inactivation. Introducing YKL-40 exons 3, 6, or 8 into CHIT1 CatD resulted in chitinase inactivation. Conversely, incorporating CHIT1 exons 3, 6, and 8 into MT-YKL-40 led to its activation. Our recombinant proteins exhibited properly formed disulfide bonds, affirming a defined structure in active molecules. Biochemical and evolutionary analysis indicated that the reduced chitinase activity of MT-YKL-40 correlates with specific amino acids in exon 3. M61I and T69W substitutions in CHIT1 CatD diminished chitinase activity and increased chitin binding. Conversely, substituting I61 with M and W69 with T in MT-YKL-40 triggered chitinase activity while reducing the chitin-binding activity. Thus, W69 plays a crucial role in a unique subsite within YKL-40. These findings emphasize that YKL-40, though retaining the structural framework of a mammalian chitinase, has evolved to recognize chitin while surrendering chitinase activity.

Demonstration of differential ventricular overdrive pacing during long RP' supraventricular tachycardia.

We described the differential ventricular overdrive pacing during long RP' supraventricular tachycardia and discussed about its response leading to the dianosis.

Complete atrioventricular block following internal electrical cardioversion during atrial fibrillation ablation.

BACKGROUND: Complete atrioventricular block (C-AVB) following internal electrical cardioversion (IEC) during atrial fibrillation (AF) ablation has not been fully investigated. We aimed to determine the prevalence and predictors of C-AVB following IEC during AF ablation. METHODS: C-AVB (non-conducted sinus impulse after IEC) and ventricular pause (VP) (the interval between IEC and the QRS complex) following the first attempt of IEC, and baseline electrocardiographic parameters were investigated in patients who underwent first-time AF ablation. RESULTS: We investigated the first attempt of IEC in 124 patients (mean age:70 ± 11 years, 81 men, 99 non-paroxysmal AF). AF was terminated in 109/124 (88%) patients, with a VP of 1590 [1014-2208] (maximum, 8780) ms. Transient C-AVB following IEC occurred in 14/109 (13%) patients. The VP was longer in patients with transient C-AVB than in those without transient C-AVB (2418 [1693-4425] vs. 1530 [876-2083] ms, p = 0.002). In multivariate analysis, the left atrial diameter (Odds ratio [OR]:1.21; 95% confidence interval (95%CI):1.06-1.39; p = 0.005) and preexisting intraventricular conduction abnormality (OR:9.22; 95%CI:1.60-53.3; p = 0.013) were predictors of transient C-AVB following IEC. CONCLUSION: Left atrial diameter and preexisting intraventricular conduction abnormalities were predictors of transient C-AVB following IEC during AF ablation.

Post-settlement dynamics of Japanese flounder Paralichthys olivaceus in Tango Bay: Seasonal patterns in growth, mortality, and recruitment potential.

Japanese flounder Paralichthys olivaceus is one of the most valuable coastal flatfish species in East Asia. To investigate post-settlement growth and mortality, juveniles were sampled in Tango Bay (Japan) weekly throughout the settlement period in 2007 and 2008. Otolith (lapillus) microstructure analysis enabled the categorization of juveniles into six biweekly cohorts each year. Later cohorts exhibited higher growth rates possibly because of higher water temperatures. A key observation was the direct relationship between high mortality and high density in mid-season cohorts in both years, pointing to density-dependent mortality. This increased mortality may be attributed to predation, including cannibalism by earlier cohorts. Furthermore, growth-selective mortality was evident soon after settlement, underscoring the vulnerability of slow growers to predation during the early juvenile stage. Although earlier and later cohorts were less abundant but showed promising recruitment potential, the prospective contribution of mid-season cohorts to the adult population remained uncertain. The results clearly highlight the importance of density-dependent mortality in population regulation in post-settlement Japanese flounder.

Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort.

BACKGROUND AND PURPOSE: Atherosclerotic burden increases the risk of both extracranial internal carotid artery stenosis (ICS) and intracranial large artery disease (ICAD). However, the differences in risk profiles have not been thoroughly investigated. METHODS: Participants were recruited from the Nagahama study cohort in Japan. Individuals over 60 years old who underwent 1.5-T head and neck magnetic resonance angiography (MRA) between July 2013 and February 2017 were included. ICAD was defined as WASID ≥ 50 %, and ICS was defined as NSCET ≥ 30 %. The prevalence and association of risk factors, including proatherogenic and proinflammatory factors, and the p.R4810K variant in the RNF213 gene, were investigated. Multivariable logistic regression analyses were performed. RESULTS: A total of 3089 individuals participated in the study, with a mean age of 68.1 ± 5.3 years, and 36.0 % were males. Among them, 52 (1.7 %) had ICS, 119 (3.8 %) had ICAD, and 15 (0.49 %) had both conditions. Alopecia areata was an independent predictor for both ICS (Odds ratio [OR] 3.5; 95 % CI 1.3-8.3) and ICAD (OR 2.1; 95 % CI 1.0-3.9). Diabetes (OR 3.7; 95 % CI 2.0-7.0) and older age (OR 2.4; 95 % CI 1.2-4.5) were associated only with ICS, while the RNF213 variant was associated with only ICAD (OR 5.7; 95 % CI 1.6-16.0). ICS and ICAD were also independently associated with each other. CONCLUSIONS: In this MRA-based large scale study, alopecia areata, known as a systemic inflammatory disease, was shown to be a common risk factor for ICS and ICAD. While conventional atherosclerotic factors were associated with ICS, non-atherosclerotic factors appear to contribute to ICAD in Japan.

Sex-specific associations between air pollutants and asthma prevalence in Japanese adults: a population-based study.

This study investigated the association between air pollutants and asthma prevalence in male and female Japanese adults. In this retrospective cross-sectional analysis, annual mean exposure levels of air pollutants, specifically nitrogen dioxide (NO2) and particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5), were assessed at a local monitoring site. Multivariable logistic regression models, adjusted for genetic and/or lifestyle factors, were used to explore the association between air pollutants and asthma, with stratification by sex. A total of 1,497 participants aged ≥40 years were included. Their mean age was 65.9 ± 12.4 years, with 847 being women. Overall, 91 participants were diagnosed with asthma. In the multivariable model, ambient exposure levels of NO2 and PM2.5 were significantly associated with asthma in women but not in men. This study highlights sex as a significant determinant of the link between air pollutants and asthma exacerbation, particularly among female Japanese adults.

Longitudinal relationship between screen-based sedentary behavior and nutrient intake in Japanese children: an observational epidemiological cohort study.

BACKGROUND: Concerns regarding the impact of screen-based sedentary behavior on health have been increasing. Therefore, the present study investigated the longitudinal relationship between multiple screen time and nutrient intake in children and adolescents. METHODS: The present study was conducted utilizing 3 years longitudinal data. Study subjects were 740 Japanese children aged between 6 and 12 years at baseline and between 9 and 15 years in the follow-up. Screen-based sedentary behavior was assessed using screen time, including television (TV) viewing, personal computer (PC) use, and mobile phone (MP) use. The main outcomes were the intakes of nutrients. Mixed effect multivariate linear regression analyses were used to examine the longitudinal relationship between screen-based sedentary time and nutrient intake. Covariates included in the multivariable analysis consisted of sex, age, solitary eating, skipping breakfast, staying up late, and body weight status, as confounders, and physical inactivity, as mediator. RESULTS: In boys, a longer total screen time longitudinally correlated with higher intake of energy and lower intakes of protein, dietary fiber, minerals, and vitamins. In girls, longer total screen time longitudinally associated with higher intake of sucrose and lower intakes of protein, minerals, and vitamins. In boys, a longer TV viewing time was associated with higher intake of sucrose and lower intakes of protein, minerals, and vitamins. In girls, a longer TV viewing time was associated with higher intake of carbohydrates and lower intakes of protein, fat, minerals, and vitamins. In boys, relationships were observed between a longer PC use time and higher intakes of energy as well as lower intakes of protein, minerals, and vitamins. Relationship was observed between longer PC use time and lower intakes of minerals in girls. An increased MP use time was associated with higher intakes of energy, and lower intakes of protein, sucrose, dietary fiber, minerals, and vitamins in boys. A longer MP use time was associated with higher intakes of fat, and salt as well as lower intakes of carbohydrates, protein, minerals, and vitamins in girls. CONCLUSIONS: The present results revealed that longer screen-based sedentary behaviors were longitudinally associated with nutrient intake in children and adolescents. Future study is needed to elucidate these relationships.

Sensor array design of optically pumped magnetometers for accurately estimating source currents.

An optically pumped magnetometer (OPM) is a new generation of magnetoencephalography (MEG) devices that is small, light, and works at room temperature. Due to these characteristics, OPMs enable flexible and wearable MEG systems. On the other hand, if we have a limited number of OPM sensors, we need to carefully design their sensor arrays depending on our purposes and regions of interests (ROIs). In this study, we propose a method that designs OPM sensor arrays for accurately estimating the cortical currents at the ROIs. Based on the resolution matrix of minimum norm estimate (MNE), our method sequentially determines the position of each sensor to optimize its inverse filter pointing to the ROIs and suppressing the signal leakage from the other areas. We call this method the Sensor array Optimization based on Resolution Matrix (SORM). We conducted simple and realistic simulation tests to evaluate its characteristics and efficacy for real OPM-MEG data. SORM designed the sensor arrays so that their leadfield matrices had high effective ranks as well as high sensitivities to ROIs. Although SORM is based on MNE, the sensor arrays designed by SORM were effective not only when we estimated the cortical currents by MNE but also when we did so by other methods. With real OPM-MEG data we confirmed its validity for real data. These analyses suggest that SORM is especially useful when we want to accurately estimate ROIs' activities with a limited number of OPM sensors, such as brain-machine interfaces and diagnosing brain diseases.

Continuous and Early Progression of Carotid Intima-Media Thickness after Radiotherapy for Head and Neck Cancer: 5-Year Prospective Observational Study.

INTRODUCTION: Radiation-induced carotid artery stenosis (RI-CS) is known as one of long-term side effects of radiotherapy for head and neck cancer (HNC). However, the clinical time course after irradiation has been poorly understood. We aimed to investigate the natural history of radiation-induced carotid atherosclerosis, comparing the patients who received radiotherapy for HNC with the patients who were treated without radiotherapy. METHODS: The patients who received treatment of HNC at Department of Otolaryngology, Head and Neck Surgery of Kyoto University Hospital, from November 2012 to July 2015 were enrolled. The patients were assigned into the RT group and the control group, depending on whether radiotherapy was planned or not. Annual carotid ultrasound was performed from the enrollment to 5 years. The increase of mean intima-media thickness (IMT) at common carotid artery from the enrollment (Δmean IMT) was evaluated. RESULTS: Fifty-six patients in the RT group and 25 patients in the control group were enrolled. From 5-year follow-up data, the significant higher increase of Δmean IMT was consistently observed in the RT group than in the control group after 2 years. The RT group presented a 7.8-fold increase of mean IMT compared to the control group (0.060 mm per year in the RT group and 0.008 mm per year in the control group). Cumulative incidence curves obtained from the analysis of all vessels revealed that the RT group presented higher incidence of Δmean IMT ≥0.25 mm than the control group (p < 0.01). In the RT group, the patients with mean IMT ≥1.0 mm at enrollment exhibited significantly higher incidence of Δmean IMT ≥0.25 mm than the patients with mean IMT <1.0 mm (p < 0.01). DISCUSSION: Radiotherapy for HNC induces continuous carotid mean IMT progression. The irradiated carotid arteries with mean IMT ≥1.0 mm before radiotherapy presented earlier IMT progression than those with mean IMT <1.0 mm.

Revisiting exit block after entrance block: Investigation of ablation index-guided pulmonary vein isolation.

INTRODUCTION: Unidirectional block, left atrium to pulmonary vein (LA-PV) entrance block without PV-LA exit block, has not been fully investigated in the setting of ablation index (AI)-guided pulmonary vein (PV) isolation (PVI). The aim of this study was to investigate unidirectional blocks during AI-guided PVI. METHODS: After achieving entrance block, exit block was evaluated by pacing from the catheter placed in the PV. Local PV musculature capture without conduction to the LA was necessary to prove exit block. RESULTS: In total, 441 PVs (including nine left common PVs) from 113 consecutive patients (mean age: 71 ± 12 years, 77 men, 61 paroxysmal atrial fibrillation cases) who underwent initial AI-guided PVI for atrial fibrillation were studied. Entrance block was achieved in all PVs. of the 247/441 (56%) PVs showing local PV musculature capture, 5/247 (2.0%) showed unidirectional blocks. Three of the five PVs (left superior and inferior PVs in one patient; right superior PV in another patient) showed LA-PV reconnection, requiring additional ablation to achieve bidirectional block during the procedure. Two of the five PVs (left superior and inferior PVs in one patient) showed LA-PV reconnection, and thereafter, LA-PV conduction became blocked again spontaneously, leading to bidirectional block without further ablation during the procedure. CONCLUSION: AI-guided PVI presented a low prevalence of unidirectional block (2%), using entrance block alone as the endpoint of PVI could therefore be justified.

Performance of the onstructural 1 Antigen Rapid Test for detecting all four DENV serotypes in clinical specimens from Bangkok, Thailand.

BACKGROUND: Dengue is an arboviral disease that has a large effect on public health in subtropical and tropical countries. Rapid and accurate detection of dengue infection is necessary for diagnosis and disease management. We previously developed highly sensitive immunochromatographic devices, the TKK 1st and TKK 2nd kits, based on dengue virus (DENV) nonstructural protein 1 detection. However, these TKK kits were evaluated mainly using DENV type 2 clinical specimens collected in Bangladesh, and further validation using clinical specimens of other serotypes was needed. METHODS: In the present study, one of the TKK kits, TKK 2nd, was evaluated using 10 DENV-1, 10 DENV-2, 4 DENV-3, 16 DENV-4, and 10 zika virus-infected clinical specimens collected in Bangkok, Thailand. RESULTS: The TKK 2nd kit successfully detected all four DENV serotypes in patient serum specimens and did not show any cross-reactivities against zika virus serum specimens. The IgM and/or IgG anti-DENV antibodies were detected in seven serum specimens, but did not seem to affect the results of antigen detection in the TKK 2nd kit. CONCLUSION: The results showed that the TKK 2nd kit successfully detected all four DENV serotypes in clinical specimens and confirmed the potential of the kit for dengue diagnosis in endemic countries.

A retrospective cohort study on the association between poor sleep quality in junior high school students and high hemoglobin A1c level in early adults with higher body mass index values.

BACKGROUND: Few epidemiological studies have been performed to clarify the association between glucose metabolism disorders in early adults (20 years old) and physiological and environmental factors, including body mass index (BMI) in junior high school days. Therefore, we examined the association between hemoglobin A1c (HbA1c) level and body size (BMI) in early adulthood and lifestyles, including sleep habits and BMI in junior high school days in Shika town, a small town in Japan, by conducting a retrospective cohort study. METHODS: We examined the HbA1c levels and body size (BMI) of 99 early adults who turned 20 years old between 2016 and 2020 and were residing in Shika town, Ishikawa Prefecture. We obtained the information on lifestyles and living environment factors, including BMI, from a questionnaire survey conducted among the subjects during their junior high school days (13-15 years old) from 2009 to 2013. RESULTS: No correlations were observed between the HbA1c levels and the BMI values of the early adults. A two-way analysis of covariance (with the HbA1c levels and BMI values of the early adults as main factors) of the body size and lifestyle habits of the junior high school students revealed that "sleep quality in junior high school" was significantly poorer in the high HbA1c group than in the low HbA1c group in the early adults with high BMI values only. This result was also supported by the logistic regression analysis result. CONCLUSIONS: The present results indicate that poor sleep quality in junior high school was associated with the high HbA1c levels of the early adults with higher BMI values, which suggests that good sleep quality in junior high school prevents the development of hyperglycemia. However, the present study did not find any relationship between early-adult BMI and HbA1c level.

Regularly irregular atrial rhythm after superior vena cava isolation: Another manifestation of sinoatrial node injury?

The present case described an unusual clinical manifestation of the sinoatrial node (or sinoatrial junction) injury during superior vena cava isolation.

Niclosamide downregulates LOX-1 expression in mouse vascular smooth muscle cells and changes the composition of atherosclerotic plaques in ApoE-/- mice.

Genetic lineage tracing studies have shown that phenotypic switching of vascular smooth muscle cells (VSMCs) results in less-differentiated cells, including macrophage-like cells that lack traditional VSMC markers. This switching contributes to the formation of necrotic core in plaques and promotes atherosclerosis, which is important for plaque stability. Niclosamide, a commonly used anti-helminthic drug, has recently attracted attention as an anti-cancer drug that inhibits multiple signaling pathways. The expression of the S100A4 protein is upregulated in synthetic VSMCs and inhibited by niclosamide on metastatic progression in colon cancer. We aimed to test the effect of niclosamide on VSMC phenotype switching and plaque stability. To examine murine atherosclerosis, we induced experimental lesions by blood flow cessation in apolipoprotein E knockout mice fed a high-fat diet. Oral administration of niclosamide changed 4-week-old plaques to collagen-rich and less-necrotic core phenotypes and downregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in vivo. In vitro analysis indicated that niclosamide reduced LOX-1 expression in VSMCs in a concentration-dependent and S100A4-independent manner. The inhibitory effect of niclosamide on LOX-1 and collagen type I was associated with the inactivation of the nuclear factor-κB signaling pathway. We demonstrated that the administration of niclosamide reduced LOX-1 expression and altered the composition of murine carotid plaques. Our results highlight the potential of niclosamide as an atheroprotective agent that enhances atherosclerotic plaque stability.

Validation of the correlation between angiosome-based target arterial path, mid-term limb-based patency, and the global limb anatomical staging system.

This study aimed to validate the correlation between the Global Limb Anatomical Staging System (GLASS) and limb-based patency (LBP) and angiosome-based target arterial path (TAP) and to detect the predictors of LBP loss. After the publication of the Global Vascular Guidelines in 2019, the evaluation of GLASS and identification of TAP have been recommended. However, there are few reports regarding GLASS. Eighty-three patients with chronic limb-threatening ischemia (CLTI) and tissue loss from 2016 to 2020 were evaluated. The correlation between GLASS and LBP and successful revascularization of angiosome-based TAP was analyzed. We also investigated the predictors of LBP loss. The number of patients in each GLASS stage was as follows: GLASS I, 6 patients; GLASS II, 15 patients; GLASS III, 62 patients. At 6 months, the Kaplan-Meier estimate of LBP was 66.7% in GLASS I, 41.6% in GLASS II, and 16.4% in GLASS III, respectively (p = 0.034). The rate of successful revascularization of angiosome-based TAP was 100% in GLASS I, 86.7% in GLASS II, and 46.8% in GLASS III, respectively (p = 0.002). Multivariate analysis showed that the Wound, Ischemia, and foot Infection (WIfI) stage [hazard ratio (HR) 1.58; 95% confidence interval (CI) 1.07-2.33; p = 0.021] and GLASS infrapopliteal (IP) grade (HR 1.96; 95% CI 1.31-2.95; p = 0.001) were the independent predictors of LBP loss. The GLASS stage was significantly correlated with successful revascularization of angiosome-based TAP and mid-term LBP. The WIfI stage and GLASS IP grade were the independent predictors of loss of LBP.

Atrial activation sequence changes during ventricular overdrive pacing: What is the mechanism?

We describe atrial activation sequence changes during ventricular overdrive pacing in a patient with a concealed left-sided accessory pathway and discuss its potential mechanism.

True Brugada syndrome ECG or Brugada phenocopy ECG? Can the ECG itself tell us the diagnosis?

We described a type 1 Brugada electrocardiogram and discussed about the potential diagnostic electrocardiographic indicators to differentiate true Brugada syndrome and Brugada phenocopy.

Electrocardiographic features of paradoxical ventriculophasic response.

BACKGROUND: Paradoxical ventriculophasic response (P-VR), a rare entity, has not been fully investigated. This study sought to compare the electrocardiographic features of P-VR and typical ventriculophasic response (T-VR). METHODS: The 12­lead electrocardiogram (ECG) data recorded before implantation of a cardiac implantable electronic device were analyzed in patients with greater than second-degree atrioventricular block (AVB). P-VR or T-VR was defined as present if the PP interval interposing a QRS complex was prolonged or shortened, respectively, by >3% compared with the preceding PP interval without a QRS complex when a QRS complex occurred within a span of 60% of the preceding PP interval. RESULTS: Of 95 patients (age 80 ± 9 years; 49 men) with heart block, 1868 instances (an instance was defined as a set of PP intervals without a QRS complex and the subsequent PP interval interposing a QRS complex) from 214 ECGs were analyzed: 894 instances from 122 ECGs in 64 patients with complete AVB (cAVB) and 974 instances from 92 ECGs in 43 patients with 2:1 AVB (12 showed both cAVB and 2:1 AVB). P-VR was observed in 48 patients (51%). The position of the interposed QRS complex relative to the preceding PP interval was earlier in P-VR than in T-VR. The PP interval was shorter in P-VR than in T-VR. CONCLUSION: P-VR was present in >50% of patients and was affected by the position of the interposed QRS complex and the PP interval.

MEG current source reconstruction using a meta-analysis fMRI prior.

Magnetoencephalography (MEG) offers a unique way to noninvasively investigate millisecond-order cortical activities by mapping sensor signals (magnetic fields outside the head) to cortical current sources using current source reconstruction methods. Current source reconstruction is defined as an ill-posed inverse problem, since the number of sensors is less than the number of current sources. One powerful approach to solving this problem is to use functional MRI (fMRI) data as a spatial constraint, although it boosts the cost of measurement and the burden on subjects. Here, we show how to use the meta-analysis fMRI data synthesized from thousands of papers instead of the individually recorded fMRI data. To mitigate the differences between the meta-analysis and individual data, the former are imported as prior information of the hierarchical Bayesian estimation. Using realistic simulations, we found out the performance of current source reconstruction using meta-analysis fMRI data to be better than that using low-quality individual fMRI data and conventional methods. By applying experimental data of a face recognition task, we qualitatively confirmed that group analysis results using the meta-analysis fMRI data showed a tendency similar to the results using the individual fMRI data. Our results indicate that the use of meta-analysis fMRI data improves current source reconstruction without additional measurement costs. We assume the proposed method would have greater effect for modalities with lower measurement costs, such as optically pumped magnetometers.

Factors associated with the new appearance of cerebral microbleeds after endovascular treatment for unruptured intracranial aneurysms.

PURPOSE: Endovascular treatment of unruptured intracranial aneurysms may increase cerebral microbleeds (CMBs) in postprocedural T2*-weighted MRIs, which may be a risk for future intracerebral hemorrhage. This study examined the characteristics of postprocedural CMBs and the factors that cause their increase. METHODS: The patients who underwent endovascular treatment for unruptured intracranial aneurysms from April 2016 to February 2018 were retrospectively analyzed. Treatment techniques for endovascular treatment included simple coiling, balloon-assisted coiling, stent-assisted coiling, or flow diverter placement. To evaluate the increase in CMBs, a head MRI including diffusion-weighted imaging and T2*-weighted MRIs was performed on the preprocedural day; the first postprocedural day; and at 1, 3, and 6 months after the procedure. RESULTS: Among the 101 aneurysms that were analyzed, 38 (37.6%) showed the appearance of new CMBs. In the multivariate analysis examining the causes of the CMB increases, chronic kidney disease, a higher number of preprocedural CMBs, and a higher number of diffusion-weighted imaging-positive lesions on the first postprocedural day were independent risk factors. Furthermore, a greater portion of the increased CMBs was found in cortical and subcortical lesions of the treated vascular perfusion area within 1 month after the procedure. CONCLUSION: In endovascular treatment for unruptured intracranial aneurysms, CMBs tended to increase in patients with small vessel disease before the procedure, and it was also implicated in hemorrhagic changes after periprocedural microinfarction.