The Role of Cerebral Hypoperfusion in Multiple Sclerosis (ROCHIMS) Trial in Multiple Sclerosis:Insights From Negative Results

Background:Accumulating evidence indicates that mitochondrial energy failure is involved in the progressive axonal degeneration in multiple sclerosis (MS). In patients with MS, it has been shown that both levels of N-acetylaspartate (NAA), which is a marker of axonal mitochondrial energy, and cerebral blood flow (CBF) are reduced in cerebral normal appearing white matter (NAWM). The latter is likely due to the vasoconstrictive action of endothelin-1 (ET-1) produced by reactive astrocytes, which is triggered by local proinflammatory cytokines. A preliminary study in patients with MS showed that CBF could be restored to normal values after a single dose of 62.5 mg of the ET-1 antagonist bosentan. Objective:To investigate whether restoring CBF in patients with relapsing remitting MS (RRMS) increases levels of NAA in cerebral NAWM and improves clinical symptoms. Methods:27 RRMS patients were included in a 4 weeks proof-of-concept, randomized, double-blind placebo-controlled trial (ROCHIMS) to investigate whether bosentan 62.5 mg twice daily could increase the NAA/creatine (NAA/Cr) ratio in NAWM of the centrum semiovale. Magnetic resonance imaging (MRI) assessing CBF and NAA/Cr, and clinical evaluations were performed at baseline and at end of study. Separately from the clinical trial, 10 healthy controls underwent the same baseline multimodal brain MRI protocol as the MS patients. Results:Eleven patients in the bosentan arm and thirteen patients in the placebo arm completed the study. Bosentan did not increase CBF. However, we found that CBF in the patients was not different from that of the healthy controls. There were no effects on NAA levels and clinical symptoms. Conclusions:Our study showed that CBF in RRMS patients is not always decreased and that bosentan has no effect when CBF values are within the normal range. We hypothesize that in our patients there was no significant astrocytic production of ET-1 because they had a mild disease course, with minimal local inflammatory activity. Future studies with bosentan in MS should focus on patients with elevated ET-1 levels in cerebrospinal fluid or blood

Pengaruh Brand Trust dan Brand Equity terhadap Loyalitas Konsumen pada Produk Kosmetik Wardah (Survey Konsumen pada PT. Paragon Technology And Innovation Cabang Pekanbaru)

The purpose of this study was to determine the influence of brand trust ( X1 ) and brand equity ( X2 ) customer loyalty ( Y ) in cosmetic products Wardah ( consumer survey on PT . Paragon technology and innovation branches pekanbaru ) . The method in this research is quantitatively using SPSS 21 program , where samples were used that consumers using cosmetic products Wardah by respondents as many as 100 people sampling technique is accidental sampling using the formula slovin . The results showed that the test results simultaneously obtained from the F count was 34.888 while the value of F table 3.090 . This means that F count> F table and significant value 0,000 < alpha of 0.05 . This means that brand trust and brand equity simultaneously significant effect on consumer loyalty to cosmetic products Wardah

Post-stroke infections associated with spleen volume reduction: A pilot study.

BACKGROUND:Spleen volume reduction followed by re-expansion has been described in acute ischemic stroke in both animal and human studies. Splenic contraction might be partially due to sympathetic hyperactivity and might be accompanied by release of splenocytes in the peripheral circulation, leading to immunodepression. AIMS:To investigate whether spleen volume changes in the first week after stroke are associated with post-stroke infections, changes in lymphocytes count and autonomic dysfunction. METHODS:In patients with acute ischemic stroke, spleen sizes were calculated from abdominal CT images on day one and day seven. Spleen size reduction was defined as > 10% spleen size reduction between day one and day seven. Post stroke infections were diagnosed during the first seven days after stroke onset using the modified criteria of the US Center of Disease Control and Prevention. We assessed the time course of leukocyte subsets and analysed pulse rate variability (PRV) indices. RESULTS:Post-stroke infections occurred in six out of 11 patients (55%) with spleen size reduction versus in five out of 27 patients (19%) without spleen size reduction (p = 0,047). Spleen size reduction was associated with a drop in lymphocytes and several lymphocyte subsets from admission to day one, and a higher NIHSS at admission and at day three (p = 0,028 and p = 0,006 respectively). No correlations could be found between spleen volume change and PRV parameters. CONCLUSION:Post-stroke infections and a drop in lymphocytes and several lymphocyte subsets are associated with spleen volume reduction in acute ischemic stroke

Low-Dose Bevacizumab for the Treatment of Focal Radiation Necrosis of the Brain (fRNB): A Single-Center Case Series

Focal radiation necrosis of the brain (fRNB) is a late adverse event that can occur following the treatment of benign or malignant brain lesions with stereotactic radiation therapy (SRT) or stereotactic radiosurgery (SRS). Recent studies have shown that the incidence of fRNB is higher in cancer patients who received immune checkpoint inhibitors. The use of bevacizumab (BEV), a monoclonal antibody that targets the vascular endothelial growth factor (VEGF), is an effective treatment for fRNB when given at a dose of 5–7.5 mg/kg every two weeks. In this single-center retrospective case series, we investigated the effectiveness of a low-dose regimen of BEV (400 mg loading dose followed by 100 mg every 4 weeks) in patients diagnosed with fRNB. A total of 13 patients were included in the study; twelve of them experienced improvement in their existing clinical symptoms, and all patients had a decrease in the volume of edema on MRI scans. No clinically significant treatment-related adverse effects were observed. Our preliminary findings suggest that this fixed low-dose regimen of BEV can be a well-tolerated and cost-effective alternative treatment option for patients diagnosed with fRNB, and it is deserving of further investigation

Population pharmacokinetic approach applied to positron emission tomography: Computed tomography for tumor tissue identification in patients with glioma

Background and Aims 18F-fluoro-ethyl-tyrosine (FET) is a radiopharmaceutical used in positron emission tomography (PET)-computed tomography in patients with glioma. We propose an original approach combining a radiotracer-pharmacokinetic exploration performed at the voxel level (three-dimensional pixel) and voxel classification to identify tumor tissue. Our methodology was validated using the standard FET-PET approach and magnetic resonance imaging (MRI) data acquired according to the current clinical practices. Methods FET-PET and MRI data were retrospectively analyzed in ten patients presenting with progressive high-grade glioma. For FET-PET exploration, radioactivity acquisition started 15 min after radiotracer injection, and was measured each 5 min during 40 min. The tissue segmentation relies on population pharmacokinetic modeling with dependent individuals (voxels). This model can be approximated by a linear mixed-effects model. The tumor volumes estimated by our approach were compared with those determined with the current clinical techniques, FET-PET standard approach (i.e., a cumulated value of FET signal is computed during a time interval) and MRI sequences (T1 and T2/fluid-attenuated inversion recovery [FLAIR]), used as references. The T1 sequence is useful to identify highly vascular tumor and necrotic tissues, while the T2/FLAIR sequence is useful to isolate infiltration and edema tissue located around the tumor. Results With our kinetic approach, the volumes of tumor tissue were larger than the tissues identified by the standard FET-PET and MRI T1, while they were smaller than those determined with MRI T2/FLAIR. Conclusion Our results revealed the presence of suspected tumor voxels not identified by the standard PET approach

Brain volume loss can occur at the rate of normal aging in patients with multiple sclerosis who are free from disease activity

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and degenerative disorder of the central nervous system. Accelerated brain volume loss (BVL) has emerged as a promising magnetic resonance imaging marker (MRI) of neurodegeneration, correlating with present and future clinical disability. We have systematically selected MS patients fulfilling ‘no evidence of disease activity-3′ (NEDA-3) criteria under high-efficacy disease-modifying treatment (DMT) from the database of two Belgian MS centers. BVL between both MRI scans demarcating the NEDA-3 period was assessed and compared with a group of prospectively recruited healthy volunteers who were matched for age and gender. Annualized whole brain volume percentage change was similar between 29 MS patients achieving NEDA-3 and 24 healthy controls (−0.25 ± 0.49 versus −0.24 ± 0.20, p = 0.9992; median follow-up 21 versus 33 months; respectively). In contrast, we found a mean BVL increase of 72%, as compared with the former, in a second control group of MS patients (n = 21) whom had been excluded from the NEDA-3 group due to disease activity (p = 0.1371). Our results suggest that neurodegeneration in MS can slow down to the rate of normal aging once inflammatory disease activity has been extinguished and advocate for an early introduction of high-efficacy DMT to reduce the risk of future clinical disability

Reliability of measuring regional callosal atrophy in neurodegenerative diseases

The Corpus Callosum (CC) is an important structure connecting the two brain hemispheres. As several neurodegenerative diseases are known to alter its shape, it is an interesting structure to assess as biomarker. Yet, currently, the CC-segmentation is often performed manually and is consequently an error prone and time-demanding procedure. In this paper, we present an accurate and automated method for corpus callosum segmentation based on T1-weighted MRI images. After the initial construction of a CC atlas based on healthy controls, a new image is subjected to a mid-sagittal plane (MSP) detection algorithm and a 3D affine registration in order to initialise the CC within the extracted MSP. Next, an active shape model is run to extract the CC. We calculated the reliability of most popular CC features (area, circularity, corpus callosum index and thickness profile) in healthy controls, Alzheimer's Disease patients and Multiple Sclerosis patients. Importantly, we also provide inter-scanner reliability estimates. We obtained an intra-class correlation coefficient (ICC) of over 0.95 for most features and most datasets. The inter-scanner reliability assessed on the MS patients was remarkably well and ranged from 0.77 to 0.97. In summary, we have constructed an algorithm that reliably detects the CC in 3D T1 images in a fully automated way in healthy controls and different neurodegenerative diseases. Although the CC area and the circularity are the most reliable features (ICC > 0.97); the reliability of the thickness profile (ICC > 0.90; excluding the tip) is sufficient to warrant its inclusion in future clinical studies

Inter- and intra-scanner variability of automated brain volumetry on three magnetic resonance imaging systems in Alzheimer's disease and controls

Magnetic Resonance Imaging (MRI) has become part of the clinical routine for diagnosing neurodegenerative disorders. Since acquisitions are performed at multiple centers using multiple imaging systems, detailed analysis of brain volumetry differences between MRI systems and scan-rescan acquisitions can provide valuable information to correct for different MRI scanner effects in multi-center longitudinal studies. To this end, five healthy controls and five patients belonging to various stages of the AD continuum underwent brain MRI acquisitions on three different MRI systems (Philips Achieva dStream 1.5T, Philips Ingenia 3T, and GE Discovery MR750w 3T) with harmonized scan parameters. Each participant underwent two subsequent MRI scans per imaging system, repeated on three different MRI systems within 2 h. Brain volumes computed by icobrain dm (v5.0) were analyzed using absolute and percentual volume differences, Dice similarity (DSC) and intraclass correlation coefficients, and coefficients of variation (CV). Harmonized scans obtained with different scanners of the same manufacturer had a measurement error closer to the intra-scanner performance. The gap between intra- and inter-scanner comparisons grew when comparing scans from different manufacturers. This was observed at image level (image contrast, similarity, and geometry) and translated into a higher variability of automated brain volumetry. Mixed effects modeling revealed a significant effect of scanner type on some brain volumes, and of the scanner combination on DSC. The study concluded a good intra- and inter-scanner reproducibility, as illustrated by an average intra-scanner (inter-scanner) CV below 2% (5%) and an excellent overlap of brain structure segmentation (mean DSC &gt; 0.88)