Anisotropy of T2 and T1ρ relaxation time in articular cartilage at 3 T.

PURPOSE: The anisotropy of R2 and R1ρ relaxation rates in articular cartilage contains information about the collagenous structure of the tissue. Here we determine and study the anisotropic and isotropic components of T2 and T1ρ relaxation parameters in articular cartilage with a clinical 3T MRI device. Furthermore, a visual representation of the topographical variation in anisotropy is given via anisotropy mapping. METHODS: Eight bovine stifle joints were imaged at 22 orientations with respect to the main magnetic field using T2, continuous-wave (CW) T1ρ, and adiabatic T1ρ mapping sequences. Relaxation rates were separated into isotropic and anisotropic relaxation components using a previously established relaxation anisotropy model. Pixel-wise anisotropy values were determined from the relaxation-time maps using Michelson contrast. RESULTS: The relaxation rates obtained from the samples displayed notable variation depending on the sample orientation, magnetization preparation, and cartilage layer. R2 demonstrated significant anisotropy, whereas CW-R1ρ (300 Hz) and CW-R1ρ (500 Hz) displayed a low degree of anisotropy. Adiabatic R1ρ was largely isotropic. In the deep cartilage regions, relaxation rates were generally faster and more anisotropic than in the cartilage closer to the tissue surface. The isotropic relaxation rate components were found to have similar values regardless of measurement sequence. CONCLUSIONS: The fitted relaxation model for T2 and T1ρ demonstrated varying amounts anisotropy, depending on magnetization preparation, and studied the articular cartilage layer. Anisotropy mapping of full joints showed varying amounts of anisotropy depending on the quantitative MRI parameter and topographical location, and in the case of T2, showed systematic changes in anisotropy across cartilage depth.

Axon fiber orientation as the source of T1 relaxation anisotropy in white matter: A study on corpus callosum in vivo and ex vivo.

PURPOSE: Recent studies indicate that T1 in white matter (WM) is influenced by fiber orientation in B0 . The purpose of the study was to investigate the interrelationships between axon fiber orientation in corpus callosum (CC) and T1 relaxation time in humans in vivo as well as in rat brain ex vivo. METHODS: Volunteers were scanned for relaxometric and diffusion MRI at 3 T and 7 T. Angular T1 plots from WM were computed using fractional anisotropy and fiber-to-field-angle maps. T1 and fiber-to-field angle were measured in five sections of CC to estimate the effects of inherently varying fiber orientations on T1 within the same tracts in vivo. Ex vivo rat-brain preparation encompassing posterior CC was rotated in B0 and T1 , and diffusion MRI images acquired at 9.4 T. T1 angular plots were determined at several rotation angles in B0 . RESULTS: Angular T1 plots from global WM provided reference for estimated fiber orientation-linked T1 changes within CC. In anterior midbody of CC in vivo, where small axons are dominantly present, a shift in axon orientation is accompanied by a change in T1 , matching that estimated from WM T1 data. In CC, where large and giant axons are numerous, the measured T1 change is about 2-fold greater than the estimated one. Ex vivo rotation of the same midsagittal CC region of interest produced angular T1 plots at 9.4 T, matching those observed at 7 T in vivo. CONCLUSION: These data causally link axon fiber orientation in B0 to the T1 relaxation anisotropy in WM.

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months. METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812. FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups. INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale. FUNDING: Fonds NutsOhra.

Psoriatic epidermis is associated with upregulation of CDK2 and inhibition of CDK4 activity.

BACKGROUND: The cyclin-dependent kinases (CDKs) CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. CDK inhibitory proteins (CKIs) such as p16INK 4A (p16) bind CDK4/6 kinases and prevent their interaction with D-type cyclins. CKIs such as p21Cip1 (p21) and p27Kip1 (p27) associate with CDK-cyclin complexes and prevent their activation. OBJECTIVES: To gain insight into the molecular implication of CDK2 and CDK4 kinases in psoriasis, we sought to characterize expression of these kinases and associated cyclins, as well as of CKIs, and addressed the status of CDK2 and CDK4 activity in human psoriatic epidermis. METHODS: A cohort of 24 patients with psoriasis participated in the study. Biopsies were removed from a chronic plaque and from nonlesional skin. CDK2, CDK4, cyclin D1, cyclin E and CKI protein expression was assessed by immunoblotting, immunohistochemistry and immunofluorescence. CDK4 and CDK2 mRNA expression was determined by real-time polymerase chain reaction. Specific kinase activities of CDK2 and CDK4 were evaluated using fluorescent peptide biosensors. RESULTS: CDK2-cyclin E expression and activity were significantly increased in psoriatic epidermis compared with uninvolved adjacent skin. In contrast, CDK4-cyclin D1 activity was inhibited, although its expression was increased in psoriatic epidermis and its transcription slightly inhibited. p27 expression was reduced, while p16 and p21 expression was induced in psoriatic epidermis. CONCLUSIONS: Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. What's already known about this topic? Cyclin-dependent kinases (CDKs) are involved in cell-cycle progression. The levels of cyclin partners and CDK inhibitors regulate their activity. Psoriasis is a chronic T-cell-driven inflammatory skin disease characterized by hyperproliferation of basal epidermal cells. What does this study add? Thanks to fluorescent peptide biosensors, this study demonstrates that epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations involve post-translational control mediated by decreased expression of p27, and p16 overexpression, respectively. What is the translational message? CDK2 and CDK4 are involved in regulation of cell-cycle progression, and psoriasis is characterized by hyperproliferation of basal epidermal cells. Epidermal CDK2 activity is increased in psoriatic epidermis while CDK4 activity is completely inhibited. These alterations are not associated with changes in CDK transcription and instead involve post-translational control mediated by decreased expression of p27 and p16 overexpression, respectively. Pharmacological modulation of CDK2 and CDK4 may constitute a promising therapeutic strategy.

Immunomagnetic bead-based bioassay for the voltammetric analysis of the breast cancer biomarker HER2-ECD and tumour cells using quantum dots as detection labels.

An electrochemical magnetic immunosensing strategy was developed for the determination of HER2-ECD, a breast cancer biomarker, and breast cancer cells in human serum. A sandwich assay was performed on carboxylic acid-functionalized magnetic beads (MBs) using a screen-printed carbon electrode (SPCE) as transducer surface. The affinity process was detected using electroactive labels; core/shell streptavidin-modified CdSe@ZnS Quantum Dots (QDs). Cd2+ ions, released from the QDs, were determined by differential pulse anodic stripping voltammetry (DPASV). An assay time of 90 min, with an actual hands-on time of about 20 min, a linear range between 0.50-50 ng·mL-1 of HER2-ECD and a limit of detection of 0.29 ng·mL-1 were achieved. Analysis of live breast cancer cells was also performed using the optimized assay. Breast cancer cell lines SK-BR-3 (a HER2-positive cell line), MDA-MB-231 (a HER2-negative cell line) and MCF-7 (a cell line with low HER2 expression) were tested. The selectivity of the assay towards SK-BR-3 cells was confirmed. A concentration-dependent signal that was 12.5× higher than the signal obtained for the HER2-negative cells (MDA-MB-231) and a limit of detection of 2 cells·mL-1 was obtained. Graphical abstractSchematic representation of the electrochemical immunomagnetic assay for the determination of the breast cancer biomarker HER2-ECD and cancer cells using magnetic beads (MBs), a screen-printed carbon electrode (SPCE) as transducer surface and quantum dots (QD) as electroactive labels.

Wake-Up Stroke versus Stroke with Known Onset Time: Clinical and Multimodality CT Imaging Characteristics.

BACKGROUND: Current guidelines for the treatment of acute ischemic stroke are mainly based on the time between symptom onset and initiation of treatment. This time is unknown in patients with wake-up stroke (WUS). We investigated clinical and multimodality CT imaging characteristics on admission in patients with WUS and in patients with a stroke with a known onset time. METHODS: All patients were selected from a large prospective cohort study (Dutch acute stroke study). WUS patients last seen well > 4.5 and ≤4.5 h were separately compared to patients with a known onset time ≤4.5 h. In addition, WUS patients with a proximal occlusion of the anterior circulation last seen well > 6 and ≤6 h were separately compared to patients with a known onset time ≤6 h and a proximal occlusion. National Institute of Health Stroke Score, age, gender, history of atrial fibrillation, non-contrast CT (NCCT) Alberta Stroke Program Early CT Score (ASPECTS), CT-perfusion abnormalities, proximal occlusions, and collateral filling on CT angiography were compared between groups using the Mann-Whitney U test and Fisher's exact test. RESULTS: WUS occurred in 149/1,393 (10.7%) patients. Admission clinical and imaging characteristics of WUS patients last seen well > 4.5 h (n = 81) were not different from WUS patients last seen well ≤4.5 h (n = 68). Although WUS patients last seen well > 4.5 h had a significantly lower NCCT ASPECTS than patients with a known time of stroke symptom onset of ≤4.5 h (n = 1,026), 85.2% had an NCCT ASPECTS > 7 and 75% had a combination of favorable ASPECTS > 7 and good collateral filling. There were no statistically significant differences between the admission clinical and imaging characteristics of WUS patients with proximal occlusions last seen well > 6 h (n = 23), last seen well ≤6 h (n = 40), and patients with a known time to stroke symptom onset ≤6 h (n = 399). Of all WUS patients with proximal occlusions last seen well > 6 h, only 4.3% had severe ischemia (ASPECTS < 5), 13 (56.5%) had ASPECTS > 7 and good collateral filling. CONCLUSIONS: There are only minor differences between clinical and imaging characteristics of WUS patients and patients who arrive in the hospital within the time criteria for intravenous or endovascular treatment. Therefore, CT imaging may help to identify WUS patients who would benefit from treatment and rule out those patients with severe ischemia and poor collaterals.