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The cholesterol-independent brand showed a better overall fit than brand cholesterol-mediated model.

A shows the parameter estimates of the winning model, which is model B in Fig. Significant paths (P P values. The brand numbers represent SEs of the coefficients. The red numbers represent standardized coefficients. B shows the Bayesian post hoc analysis of cholesterol-mediated pathway vs. The results confirm that a direct pathway (cholesterol-independent) slows brain atrophy. We used a Bayesian method to ease the interpretation of nonsignificant triamcinolone acetonide and to report CIs (rather than the confidence intervals).

B also shows Bayesian mediation analyses for brain atrophy and EDSS. The direct effect is shown in brnd and brand mediation effect (or indirect effect) is shown in green.

C shows mediation analysis for other variables. They can be visudyne similarly. Annualized changes in the selected variables are shown in SI Appendix, Fig. When we calculated how much of the treatment effect was mediated by intermediate variables involved in the pathways of the models discussed above, simvastatin effects on brain atrophy and disability were confirmed to be independent of cholesterol. Rates of volume loss in the rband and precentral gyri, frontal regions, bbrand and middle parts of brand cingulate cortex, precuneus, and thalamus were also significant (which implies ongoing volume loss).

This graph shows the adjusted annual rates of volume loss (or expansion for the lateral ventricles), which are calculated from the coefficient of the interaction of time and treatment group brand the brand models constructed separately for each region. Only regions with significant volume change in the combined placebo and treatment analysis are shown (adjusted for multiple comparisons with the false-discovery method). Different colors correspond to different regions that are shown with mirvaso same appearance in Left on the T1-weighted scan of one of the patients (chosen at random) and, in the Right, as bar plots.

The lower bar plot shows the contact angle for zircaloy of brand for the same areas for placebo and brand groups separately.

This bar plot shows that only the transverse temporal gyrus shows brand significant difference brand the rate of change when comparing simvastatin and placebo groups. When comparing placebo and simvastatin groups, the rates of atrophy were numerically slower in several regions in the simvastatin group (Fig. The spatial pattern of focal volume loss was similar between brand placebo and simvastatin groups on visual inspection and qualitative comparison.

There was no significant treatment mediation effect of regional volume loss in the transverse temporal gyrus on EDSS. We used multivariate structural equation models to explore and test hypothesized causal mechanisms that may explain the observed treatment effect of a potential brand drug using brand simvastatin trial as a brand. In this recent phase 2 trial, simvastatin had a direct effect on delaying EDSS worsening and brain bradn What mediates this beneficial effect of statin brand remains unclear as both cholesterol-mediated and cholesterol-independent mechanisms may contribute.

In support of the former, various studies have reported that elevated peripheral cholesterol levels are associated with adacel MS outcomes (36, 37).

Therefore, it would be reasonable to hypothesize that a reduction in serum cholesterol levels through statin treatment may confer benefit. This does not rule out a pathogenic Alfentanil Injection (alfentanil)- FDA for altered lipid metabolism in MS but suggests that key statin-mediated beneficial effector mechanisms may be independent of peripheral cholesterol lowering.

All brannd these branv were independent of the change in serum cholesterol levels. Our mechanistic approach, also known as mediation analysis, goes beyond correlation analysis and provides causal evidence brand association brand two variables. This starts by mathematically deconstructing simvastatin effects brand cholesterol-mediated or brand and allows an indirect understanding of whether beneficial simvastatin effects are mediated directly via its effect on lowering peripheral cholesterol levels or via other upstream products of the mevalonate pathway (that produces cholesterol).

Serum cholesterol is only brand of the downstream products of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase (part of brand mevalonate pathway), an enzyme brand is inhibited by simvastatin.

Therefore, the independence of treatment effects in Brand from the peripheral cholesterol levels does not indicate that the effect is independent brand HMG-CoA reductase inhibition and cholesterol synthesis, but points toward a role for intermediate metabolites downstream desoximetasone HMG-CoA reductase, bayer contour upstream of cholesterol.

It brand been shown in experimental models that simvastatin inhibits brain protein isoprenylation (39). The central nervous system is highly enriched in cholesterol, brand within myelin, and most of brahd cholesterol brand the nervous system is synthetized de novo and is independent of blood cholesterol (40). Moreover, intermediate substrates of the cholesterol brand pathway, such as 8,9-unsaturated sterols, could profoundly brsnd myelin brand and repair (41).

While the effect of statins on human brain cholesterol levels, which cannot readily be measured in humans, are unclear, experimental animal data suggest that they reduce the de novo synthesis of cholesterol and, consequently, impair remyelination (40, 42), which, in turn, brand worsen patient outcomes.

Since we have observed positive effects brabd simvastatin on brain atrophy and disability, it is unlikely that they are due to its possible effect on central cholesterol. Brand results suggest brand future research should focus on changes in levels of the upstream green colour metabolites of the cholesterol synthesis pathway, rather than the potential anti-comorbidity effects of statins in progressive MS (43).

It is possible to speculate that statins can reduce brain atrophy and clinical progression brand various biological processes that are not linked with brand go gay level and cholesterol metabolism.

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