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Neuroinflammation is often associated with blood-brain-barrier dysfunction, which contributes to neurological tissue damage. Here, we reveal the pathophysiology of Susac syndrome (SuS), an enigmatic neuroinflammatory disease with central nervous system (CNS) endotheliopathy. By investigating immune cells from the blood, cerebrospinal fluid, and CNS of SuS patients, we demonstrate oligoclonal expansion of terminally differentiated activated cytotoxic CD8 + T cells (CTLs). Neuropathological data derived from both SuS patients and a newly-developed transgenic mouse model recapitulating the disease indicate that CTLs adhere to CNS microvessels in distinct areas and polarize granzyme B, which most likely results in the observed endothelial cell injury and microhemorrhages. Blocking T-cell adhesion by anti-α4 integrin-intervention ameliorates the disease in the preclinical model. Similarly, disease severity decreases in four SuS patients treated with natalizumab along with other therapy. Our study identifies CD8 + T-cell-mediated endotheliopathy as a key disease mechanism in SuS and highlights therapeutic opportunities. Susac syndrome is an inflammatory pathology of the brain endothelium. Here the authors show that the pathology is driven by CD8 T cells attacking the endothelium, and that blocking T cell-endothelial adhesion ameliorates the disease in a mouse model, and associates with improved clinical score in 4 patients.

Aims/hypothesis There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA 1c and the risks of vascular complications and death in such patients. Methods Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA 1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA 1c decile were estimated using Cox models. Possible differences in the association between HbA 1c and risks at different levels of HbA 1c were explored using linear spline models. Results There was a non-linear relationship between mean HbA 1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA 1c studied (5.5–10.5%), there was evidence of ‘thresholds’, such that below HbA 1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p  > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA 1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p  < 0.0001). Conclusions/interpretation In patients with type 2 diabetes, HbA 1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm. Trial Registration: ClinicalTrial.gov NCT00145925 Funding: Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281)

Background Transabdominal ultrasonography and transperineal ultrasonography (TPUS) appear correspond to colonoscopy (CS) for evaluating ulcerative colitis (UC) activity, but their utility in UC diagnosis remains unclear. This research compared the accuracy of TPUS and CS for assessing rectal activity and differentiating noninflammatory bowel disease proctitis from UC in pediatric cases. Methods The study is a blinded, prospective, and controlled trial. Prospectively, values of fecal calprotectin (FCP) and findings of the TPUS and CS were compared between child cases of UC and non-IBD proctitis. Findings of rectal wall thickening (RWT), rectal wall flow (RWF) on power Doppler, and microvascular signal at wall circumference (MSWC) on monochrome superb microvascular imaging assessed using TPUS were compared with the CS. Results Thirty patients with Mayo endoscopic subscore (MES) 0 to 1 UC, 57 with MES 2 to 3 UC, and 44 with proctitis were registered. Fecal calprotectin, RWF, and MSWC indicated significant differences among the groups (P < .05). Rectal wall thickening showed no significant difference between MES 0–1 and proctitis (P = .76). Rectal wall thickening and MSWC were independent predictors of endoscopic activity of UC, resulting in a sensitivity and specificity of 100% for RWT ≥4.5 mm and positive MSWC. Fecal calprotectin and RWF were independent predictors for differentiating MES 0 to 1 and proctitis, and FCP and RWT were independent predictors for differentiating MES 2 to 3 and proctitis. Sensitivity and specificity were 77.2% and 80.9%, respectively, for FCP >242.5 μg/g and RWF negative; and they were both 100% for RWT >4.1 mm and MSWC positive. Conclusions Transperineal ultrasonography with mSMI may enable the evaluation of rectal activity and differentiation of UC from non-IBD proctitis with accuracy comparable to endoscopy. Lay Summary Transperineal ultrasonography with superb microvascular imaging can differentiate ulcerative colitis from noninflammatory bowel disease proctitis and is therefore useful in distinguishing whether diarrhea and bloody stool during the treatments of ulcerative colitis are due to recurrence or infection.

Coronary flow reserve (CFR) and coronary artery calcium (CAC) represent functional and structural aspects of atherosclerosis. We examined the prevalence of reduced CFR and high CAC scores in three predefined groups of participants without known cardiovascular disease: (1) patients with type 2 diabetes and albuminuria; (2) patients with type 2 diabetes and normoalbuminuria; and (3) non-diabetic controls. In a cross-sectional design, cardiac (82)Rb positron emission tomography/computed tomography was conducted in 60 patients with type 2 diabetes who were free of overt cardiovascular disease and who were stratified by normoalbuminuria (<30 mg/24 h) (n = 30; age [mean ± SD] 60.9 ± 10.1 years) and albuminuria (≥ 30 mg/24 h) (n = 30; age 65.6 ± 4.8 years), and in 30 healthy, non-diabetic controls (age 59.8 ± 9.9 years). In controls, normoalbuminuric and albuminuric patients, CFR was 3.0 ± 0.8, 2.6 ± 0.8 and 2.0 ± 0.5, respectively. Reduced CFR (<2.5) was observed in 16.7%, 40.0% and 83.3% of participants, respectively, and median (interquartile range) CAC scores were 0 (0-81), 36 (1-325) and 370 (152-1,025), respectively (p for trend <0.01). After adjustment, the difference in CFR and CAC between albuminuric patients and controls remained significant (p ≤ 0.001). There were trends towards lower CFR and higher CAC scores in normoalbuminuric patients vs controls (p ≤ 0.023) and towards higher CAC scores in albuminuric vs normoalbuminuric patients (p = 0.026). In multivariate regression analysis, a higher urinary albumin excretion rate (UAER) tended to predict reduced CFR in the total population (p = 0.045). When the CAC score was added, there was also a trend (p = 0.032) towards an inverse association with reduced CFR. Type 2 diabetic patients who were free of overt cardiovascular disease had a high prevalence of coronary microvascular dysfunction, especially with concomitant albuminuria, suggesting a common microvascular impairment occurring in multiple microvascular beds. Prospective studies are needed to show the prognostic significance of this finding.

The presence of atherosclerotic plaque vessels is a critical factor in plaque destabilization. This may be attributable to the leaky phenotype of these microvessels, although direct proof for this notion is lacking. In this study, we investigated molecular and cellular patterns of stable and hemorrhaged human plaque to identify novel drivers of intraplaque vessel dysfunction. From transcriptome data of a human atherosclerotic lesion cohort, we reconstructed a co-expression network, identifying a gene module strongly and selectively correlated with both plaque microvascular density and inflammation. Spectrin Beta Non-Erythrocytic 1 (sptbn1) was identified as one of the central hubs of this module (along with zeb1 and dock1) and was selected for further study based on its predominant endothelial expression. Silencing of sptbn1 enhanced leukocyte transmigration and vascular permeability in vitro, characterized by an increased number of focal adhesions and reduced junctional VE-cadherin. In vivo, sptbn1 knockdown in zebrafish impaired the development of the caudal vein plexus. Mechanistically, increased substrate stiffness was associated with sptbn1 downregulation in endothelial cells in vitro and in human vessels. Plaque SPTBN1 mRNA and protein expression were found to correlate with an enhanced presence of intraplaque hemorrhage and future cardiovascular disease (CVD) events during follow-up. In conclusion, we identify SPTBN1 as a central hub gene in a gene program correlating with plaque vascularisation. SPTBN1 was regulated by substrate stiffness in vitro while silencing blocked vascular development in vivo, and compromised barrier function in vitro. Together, SPTBN1 is identified as a new potential regulator of the leaky phenotype of atherosclerotic plaque microvessels.

Background Microvascular invasion (MVI) is considered to be one of the important prognostic factors that affect postoperative recurrence in patients with hepatocellular carcinoma (HCC) with variable results across their treatment options. This study was carried out to investigate efficacy of postoperative adjuvant RT in HCC patients with MVI. Methods This was single center, prospective study carried out in HCC patients with MVI, aged 35–72 years. All patients were non-randomly allocated to receive standard postoperative treatment of HBV/HCV and nutritional therapy or RT in addition to standard postoperative treatment (1:1). The primary endpoints assessed were relapse-free survival and overall survival. The prognostic factors associated with survival outcomes were also analyzed. The safety events were graded according to NCI-CTCAE v4.03 criteria. Results Of the 115 patients eligible for study, 59 patients were included in analysis. Univariate analysis revealed that MVI classification ( P  = 0.009), post-operative treatment strategies ( P  = 0.009) were prognostic factors for worst RFS; tumor size ( P  = 0.011), MVI classification ( P  = 0.005) and post-operative treatment ( P  = 0.015) were associated for OS. The 1-, 2-, 3-year RFS rates were 86.2, 70.5 and 63.4% for patients in RT group, and 46.4, 36.1, and 36.1% in control group. For OS, corresponding rates were 96.6, 80.7, and 80.7% for patients in RT group and 79.7, 58.3, and 50.0% in control group. Subgroup classification of HCC patients according to low risk MVI showed significantly longer RFS ( P  = 0.035) and OS ( P  = 0.004) in RT group than control group, while for high risk MVI, RT depicted longer OS than control group with no significance ( P  = 0.106). Toxicities were usually observed in acute stage with no grade 4 toxicities. Conclusion Postoperative adjuvant RT following hepatectomy offers better RFS for HCC patients with MVI than with standard postoperative therapy. Also, it will be useful to control microscopic lesions in both M1 (low risk) and M2 (high risk) subgroups of HCC patients with MVI. Trial registration Trial Registration number: ChiCTR1800017371 . Date of Registration: 2018-07-26. Registration Status: Retrospectively registered.

PurposeTo investigate the diagnostic values of intereye or intraeye asymmetry of retinal perfused vessel density and neural structure parameters for detection of glaucoma.MethodsIn total, 152 healthy subjects and 72 bilateral primary open-angle glaucoma (POAG) patients were enrolled. Total POAG group contains all glaucoma patients. Early to moderate POAG group contains patients whose binocular mean defect values were larger than −12 dB. The retinal perfused vessel densities were acquired using optic coherence tomography angiography. The neural structure parameters include RNFL, GCC thickness and its derivative indices like focal loss volume percentage (FLV%) and global loss volume percentage (GLV%). Intereye asymmetry equaled to the absolute difference of parameters between paired eyes. Intraeye asymmetry was defined as absolute difference between the inferior and superior hemisphere values from one random selected eye. The areas under the receiver operating characteristic curves (AUROCs) were calculated to evaluate diagnostic ability.ResultsFrom pairwise comparison analysis of ROC curves, the intereye asymmetric parameters with the largest diagnostic accuracy were FLV and GLV% (AUROC = 0.944), which were significantly superior to the intereye asymmetry of perfused vessel density in peripapillary area and parafoveal area (P < 0.05). Particularly, the intereye asymmetry of FLV% (AUROC = 0.926) and GLV% (AUROC = 0.950) showed excellent diagnostic precision for detecting early to moderate glaucoma patients. However, the intraeye asymmetry of microvascular parameters and neural structure parameters showed fair diagnostic ability for identifying POAG patients.ConclusionsThe intereye asymmetry of neural structure parameters, particularly the FLV% and GLV%, outperformed the microvascular parameters for identifying POAG patients.

The long-term outcome of replanted avulsed permanent teeth is frequently compromised by lack of revascularization, resulting in pulp necrosis. The purpose of this study was to evaluate the effects of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) on the revascularization of severed human dental pulps. Tooth slices were prepared from non-carious human molars and treated with 0–50 ng/mL rhVEGF165 or rhFGF-2 for 7 days in vitro. Both angiogenic factors enhanced pulp microvessel density compared with untreated controls (p < 0.05). Tooth slices were also treated with 0 or 50 ng/mL rhVEGF165 for one hour prior to implantation into the subcutaneous space of immunodeficient mice. Treatment with rhVEGF165 increased pulp microvessel density in vivo (p < 0.05). These results demonstrate that rhVEGF165 enhanced neovascularization of severed human dental pulps and suggest that topical application of an angiogenic factor prior to replantation might be beneficial for the treatment of avulsed teeth.

We determined the association between novel and acid-labile skin collagen-linked advanced glycation endproducts (AGEs) and the progression of microvascular and neuropathic complications from baseline to near study closeout in the Diabetes Control and Complications Trial (DCCT). From a skin biopsy obtained near the close of the DCCT, proteolytic collagen digests were analyzed by liquid chromatography/mass spectrometry (LC/MS/MS) for glucosepane (GSPNE), glyoxal and methylglyoxal hydroimidazolones (G-H1 and MG-H1) and the glycation product fructose-lysine (FL) using isotope dilution method. GSPNE and MG-H1 correlated with age and diabetes duration (P<0.02), while GSPNE and FL correlated with the history of glycemia expressed as mean A1c (P≤0.003). Age and duration-adjusted GSPNE and FL levels were lower in intensive (INT) vs. conventional (CONV) treatment subjects in the primary prevention DCCT cohort (P<0.0001), and FL was lower in INT in the secondary intervention cohort (P<0.0001). GSPNE was associated with increased incidence of retinopathy progression (odds ratio (OR) / unit increase in GSPNE: 2.5 for 3 step progression on the ETDRS scale, P=0.003) and sustained≥3 microaneurysms (MA) (OR=4.8, P<0.0001) from DCCT baseline up to the time of the biopsy, and prevalence of microalbuminuria or AER>40mg/24h (OR=5.3, P<0.0001), and confirmed clinical neuropathy (OR=3.4, P=0.015) at the time of the biopsy. GSPNE adjusted for mean A1c remained significant for ≥3 MA (P=0.0252) and AER (P=0.0006). The strong association of complications with A1c was reduced or eliminated when adjusted for GSPNE. Glucosepane is a novel AGE marker of diabetic complications that is robustly associated with nephropathic, retinopathic and neuropathic outcomes despite adjustment for A1c, suggesting that it could be one mediator of these complications with possible diagnostic implications.

High-resolution MRI and histopathological study of the brains of patients who had died from Covid-19 showed punctate hyperintensities and punctate or linear hypointensities, which represented various forms of pauci-inflammatory microvasculopathy. No evidence of active viral infection was found.