The Role of Multiple Sclerosis as a Risk Factor for the Development of Osteoporosis

Background: Osteoporosis is the most common bone disease in the United States, and it is particularly common among women with multiple sclerosis (MS). However, despite this association, the temporal relationship between these two conditions has not been previously studied. Data from the Women’s Health Initiative provides a unique opportunity to examine the risk of developing osteoporosis over time in individuals diagnosed with MS. Objective: The purpose of this study is to refine the relationship between MS and osteoporosis, clarifying the impact of environmental and pharmacologic factors on each condition, as well as addressing treatment and preventative efforts for a patient population at a greater potential risk for osteoporosis. Methods: The study sample, derived from the Women’s Health Initiative, included 449 women who reported an MS diagnosis at baseline and 161,359 women without MS who comprised a control group. Baseline measures of self-reported osteoporosis, age, smoking status, steroid and anti-inflammatory use, and supplementary as well as dietary calcium and vitamin D were compared. MS patients reporting osteoporosis at baseline were removed, resulting in 355 women with MS to monitor for time to incident osteoporosis. Survival analyses were performed on follow-up data gathered annually between 1993 and 2005 to factor out significant associations of additional factors. Proportions of participants on osteoporosis-related medications as well as latency to use were compared between the multiple sclerosis and control cohorts. Results: At baseline, women with MS are nearly three times as likely to report osteoporosis (p Conclusions: A higher prevalence of osteoporosis at baseline suggests MS may significantly increase the risk of osteoporosis in premenopausal women. In contrast, environmental and pharmacologic variables appear to have a more significant role in the post-menopausal population. While osteoporosis was treated similarly between both groups, the point for intervention or prevention of osteoporosis in MS patients may be earlier in the disease course

Određivanje trans-resveratrola u pokožici grožđa tijekom sazrijevanja i u vinu pomoću metode HPLC

Trans-resveratrol (3,5,4’-trihydroxy-trans-stilbene) is naturally present in the skin of grapes and therefore is expected to occur in grape products. Recently, there has been a renewal of interest in wine as medical treatment for various disorders. In this study, berry skins of five red grape varieties were analysed at weekly intervals for trans-resveratrol production, during 2012 and 2013 harvest. The obtained wines were also evaluated. Quantification of trans resveratrol in grape skin extracts and wines was carried out by high-performance liquid chromatography. Favourable viticultural climate during harvest in 2012 resulted in a higher content of trans-resveratrol. The highest trans-resveratrol content was in Pinot Noir and Feteasca Neagra grape varieties, both in berry skins and wines, while the lowest amounts were identified in Cabernet Sauvignon variety. We can conclude that there was a significant correlation between the content of trans-resveratrol in grape skins and that in the respective wine.Trans-resveratrol (3,5,4\u27-trihidroksi-trans-stilben) je prirodni fenol, koji se nalazi u pokožici grožđa i iz nje dospijeva u proizvode od grožđa. U novije se vrijeme ponovno javlja interes za primjenu vina u liječenju različitih zdravstvenih poremećaja. U ovom je radu tjedno praćen udjel trans-resveratrola u pokožici pet sorata crnog grožđa tijekom uzgoja 2012. i 2013. godine. Nakon toga su analizirana i vina proizvedena iz tih sorata. Za određivanje količine trans-resveratrola u ekstraktu pokožice i vinu upotrijebljena je viskodjelotvorna tekućinska kromatografija. Veći je udjel trans-resveratrola pronađen u grožđu i vinu iz 2012. godine, i to zbog povoljnijih klimatskih uvjeta. Najviše je trans-resveratrola bilo u grožđu i vinu sorata Pinot Noir i Feteasca Neagra, a najmanje u onima sorte Cabernet Sauvignon. Zaključeno je da postoji značajna korelacija između količine trans-resveratrola u pokožici grožđa i u vinu, i to kod svih sorata

Ethernet based time synchronization for Raspberry Pi network improving network model verification for distributed active turbulent flow control

Friction drag primarily determines the total drag of transport systems. A promising approach to reduce drag at high Reynolds numbers (> 104) are active transversal surface waves in combination with passive methods like a riblet surface. For the application in transportation systems with large surfaces such as airplanes, ships or trains, a large scale distributed real-time actuator and sensor network is required. This network is responsible for providing connections between a global flow control and distributed actuators and sensors. For the development of this network we established at first a small scale network model based on Simulink and TrueTime. To determine timescales for network events on different package sizes we set up a Raspberry Pi based testbed as a physical representation of our first model. These timescales are reduced to time differences between the deterministic network events to verify the behavior of our model. Experimental results were improved by synchronizing the testbed with sufficient precision. With this approach we assure a link between the large scale model and the later constructed microcontroller based real-time actuator and sensor network for distributed active turbulent flow control

In vivo characterization of cerebellar microglia activation in multiple sclerosis by combined 11C-PBR28 MR-PET and 7 Tesla MRI.

Introduction Cerebellar involvement occurs early in multiple sclerosis (MS), and is associated with neurological impairment and disease progression. Neuropathological cerebellar examinations in MS reported heterogeneous processes including demyelination, neurodegeneration and microglia activation. The role of microglia in the pathogenesis of cerebellar pathology is unknown. Activated microglia upregulate expression of the 18kDa translocator protein (TSPO), which can be imaged in vivo using the 11C-PBR28 radioligand. Objectives We investigated, using integrated 3 Tesla (3T) magnetic resonance-positron emission tomography (MR-PET) imaging with 11C-PBR28, TSPO expression in lesional and non lesional white and grey matter (WM, GM) in the cerebellum of a heterogeneous MS cohort, and its association with cerebellar lesions, atrophy and clinical parameters. Cerebellar lesions were characterized using ultra high resolution 7 Tesla (7T) MRI. Methods Twenty-seven patients with MS (13 relapsing-remitting, RRMS, 14 secondary progressive, SPMS) and 18 healthy controls (HC) matched for age and PBR28 affinity, were included in the study. All subjects underwent 90-min 11C-PBR28 MR-PET. Anatomical 3T images of the cerebellum for regions of interest segmentation were also acquired. A manual segmentation was performed to extract whole cerebellum (WHC) masks on Freesurfer (Figure 1A). In patients, normal appearing WHC (NAWHC) was obtained by subtracting the lesion masks to the WHC mask using FSL. Cerebellar WM and GM were segmented using Volbrain (Figure 1B), and volumes were normalized by total intracranial volume in Freesurfer. In patients, cerebellar lesions were segmented on 7 T T1-weighted images (0.6x0.6x1.5 mm3) obtained on a separate session by using Slicer v 4.2 (Figure 2). Quantification of 11C-PBR28 uptake in the WHC, NAWHC, GM, WM and cerebellar lesions (CL) was performed using 60-90 minutes standardized uptake values normalized by a pseudoreference region in the normal appearing basal ganglia. Tracer uptake was extracted in cerebellar lesions that have been grouped according to localization in cortical (CCL), leukocortical (LCL), deep grey matter (DGML), and purely WM lesions (WML). All patients underwent neurological and cognitive assessment by Expanded Disability Status Scale (EDSS) and Symbol Digit Modality Test (SDMT). Linear regression models were used to compare cerebellar 11C-PBR28 uptake in MS patients versus controls, and to assess their relationship with EDSS. Age and binding affinity were included as covariates of no interest. Spearman correlation coefficient was used to assess the association between clinical parameters (EDSS, SDMT) and uptake values. Matched-pair T-test was performed to search for differences in lesion uptake between different regions of interest. Results Mean age for patients was 48±10, EDSS ranged from 1.5 to 7.5 (median 3.5, mean 4.0). Mean age for HC was 49±12. Cerebellar lesions were found in 13 out of 14 SPMS and in 10 out of 13 RRMS. In RRMS, most of the lesions are localized in the WM; in progressive patients, a majority of leucocortical lesions has been detected. No significant differences in the uptake were found in lesions affecting different regions in the cerebellum, when considering all patients as one group, and after separating SPMS and RRMS patients. Compared to controls, MS subjects showed significantly higher PBR28 uptake in all examined regions: WHC (p=0.04), NAWHC (p=0.05), GM (p=0.04), WM (p=0.03). Within patients, the mean uptake was higher in lesions then in the rest of the parenchyma (1.45 versus 1.39) though not significantly. There was a significative difference between global lesion uptake and the uptake in the cerebellum of HC (p=0.02, Figure 3D). No differences in uptake were found in SPMS versus RRMS. Tracer uptake in the WM correlated positively with EDSS (p=0.03), and negatively with SDMT z-scores (p<0.01). When corrected for age and tracer binding affinity, this significance became a trend for EDSS (p=0.07) but was maintained for SDMT (p=0.04), being the age a determinant for motor and cognitive performance reduction. There was no correlation between cerebellar volume, cerebellar lesion load and tracer uptake in any of the regions examined. Discussion Our data provide in vivo evidence for the presence of diffuse microglia activation in the cerebellum in MS. Interestingly, the highest increase in microglia activation was detected in lesions that were mainly concentrated in WM in RRMS, while they extensively involved the cortical cerebellar GM in SPMS. Abnormal microglia activation in the WM was related to worse neurological disability and cognitive performance in the whole MS cohort. Conclusions MR-PET is a valid tool to estimate cerebellar neuroinflammation in patients with MS. Future studies will assess its longitudinal evolution in relation to structural pathology and clinical outcome

Microglia activation in cerebellum increases with proximity to the fourth ventricle in progressive MS.

Text: Introduction. Cerebellar pathology contributes to disease progression in multiple sclerosis (MS). Neuroimaging studies show that demyelination in the normal appearing brain and cerebellum tends to occur mainly close to the inner (periventricular) and/or outer (subpial) surfaces, possibly driven by cerebro-spinal fluid inflammatory factors. Aims. To investigate the periventricular distribution of neuroinflammat ion in the cerebellum in relapsing remitting MS (RRMS) and secondary progressive MS (SPMS) relative to healthy controls (HC) using integrated 3 Tesla Magnetic Resonance/Positron Emission Tomography (MR-PET) with C-PBR28, a tracer for activated microglia. Methods. Sixteen RRMS, 15 SPMS and 16 HC underwent 90' C-PBR28 MR-PET scan to obtain 60-90' standardized uptake values normalized by a pseudo-reference region (SUVR), at different distances from the IV ventricle. Fourth ventricle masks were segmented with Freesurfer from anatomical T1 images and concentric periventricular slices were extracted from normal appearing cerebellar tissue underlying the cerebellar cortex at 3-6, 6-9 and 9-12 mm from the IV ventricle. To avoid partial volume effects, the first slice extending 0 to 3 mm from the ventricle was excluded. Mean SUVR values from each slice were obtained with FSL in RRMS, SPMS and HC. Matched pairs t-test was used to estimate uptake differences among the three slices in each group. Multiple linear regression was applied to compare tracer uptake at similar distance among the three groups, age and radiotracer binding affinity being covariates of no interest. Results. Each group (RRMS, SPMS, HC) showed a gradient in PBR SUVR decreasing from the IV ventricle towards the cortex (p< 0.05). At similar distance from IV ventricle, a significant difference in SUVR was present only when comparing SPMS to HC. This difference was more marked close to the IV ventricle (p= 0.03 at 3-6 mm, p= 0.04 at 6-9 mm, p= 0.05 at 9-12 mm). This pattern was present also when comparing SPMS to RRMS though the uptake did not significantly differ between them. Conclusion. Cerebellar C-PBR 28 tracer uptake showed, relative to HC, a mild decreasing gradient from the IV ventricle in SPMS but not in RRMS. This finding suggests that neuroinflammation, although diffuse, tends to be higher near the inner cerebellar surface, at least in progressive disease. Further investigation is needed to clarify the role of neuroinflammation in the pathogenesis of cerebellar demyelination

Evidence of diffuse cerebellar neuroinflammation in multiple sclerosis by 11 C-PBR28 MR-PET

Background: Activated microglia, which can be detected in vivo by 11 C-PBR28 positron emission tomography (PET), represent a main component of MS pathology in the brain. Their role in the cerebellum is still unexplored, although cerebellar involvement in MS is frequent and accounts for disability progression. Objectives: We aimed at characterizing cerebellar neuroinflammation in MS patients compared to healthy subjects by combining 11 C-PBR28 MRI-Positron Emission Tomography (MR-PET) with 7 Tesla (T) MRI and assessing its relationship with brain neuroinflammation and clinical outcome measures. Methods: Twenty-eight MS patients and 16 healthy controls underwent 11 C-PBR28 MR-PET to measure microglia activation in normal appearing cerebellum and lesions segmented from 7 T scans. Patients were evaluated using the Expanded Disability Status Scale and Symbol Digit Modalities Test. 11 C-PBR28 binding was assessed in regions of interest using 60–90 minutes standardized uptake values normalized by a pseudo-reference region in the brain normal appearing white matter. Multilinear regression was used to compare tracer uptake in MS and healthy controls and assess correlations with clinical scores. Results: In all cerebellar regions examined, MS patients showed abnormally increased tracer uptake, which correlated with cognitive and neurological disability. Conclusion: Neuroinflammation is widespread in the cerebellum of patients with MS and related to neurological disability and cognitive impairment