Convective infux/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways

Tracers injected into CSF pass into the brain alongside arteries and out again. This has been recently termed the "glymphatic system" that proposes tracers enter the brain along periarterial "spaces" and leave the brain along the walls of veins. The object of the present study is to test the hypothesis that: (1) tracers from the CSF enter the cerebral cortex along pial-glial basement membranes as there are no perivascular "spaces" around cortical arteries, (2) tracers leave the brain along smooth muscle cell basement membranes that form the Intramural Peri-Arterial Drainage (IPAD) pathways for the elimination of interstitial fluid and solutes from the brain. 2 μL of 100 μM soluble, fluorescent fixable amyloid β (Aβ) were injected into the CSF of the cisterna magna of 6-10 and 24-30 month-old male mice and their brains were examined 5 and 30 min later. At 5 min, immunocytochemistry and confocal microscopy revealed Aβ on the outer aspects of cortical arteries colocalized with α-2 laminin in the pial-glial basement membranes. At 30 min, Aβ was colocalised with collagen IV in smooth muscle cell basement membranes in the walls of cortical arteries corresponding to the IPAD pathways. No evidence for drainage along the walls of veins was found. Measurements of the depth of penetration of tracer were taken from 11 regions of the brain. Maximum depths of penetration of tracer into the brain were achieved in the pons and caudoputamen. Conclusions drawn from the present study are that tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways. The exit route is along IPAD pathways in which Aβ accumulates in cerebral amyloid angiopathy (CAA) in Alzheimer's disease. Results from this study suggest that CSF may be a suitable route for delivery of therapies for neurological diseases, including CAA

Nutrition in cardiovascular disease: salt in hypertension and heart failure

There is much evidence for a causal relationship between salt intake and blood pressure (BP). The current salt intake in many countries is between 9 and 12 g/day. A reduction in salt intake to the recommended level of 5-6 g/day lowers BP in both hypertensive and normotensive individuals. A further reduction to 3-4 g/day has a much greater effect. Prospective studies and outcome trials have demonstrated that a lower salt intake is associated with a decreased risk of cardiovascular disease. Increasing evidence also suggests that a high salt intake is directly related to left ventricular hypertrophy (LVH) independent of BP. Both raised BP and LVH are important risk factors for heart failure. It is therefore possible that a lower salt intake could prevent the development of heart failure. In patients who already have heart failure, a high salt intake aggravates the retention of salt and water, thereby exacerbating heart failure symptoms and progression of the disease. A lower salt intake plays an important role in the management of heart failure. Despite this, currently there is no clear evidence on how far salt intake should be reduced in heart failure. Our personal view is that these patients should reduce their salt intake to <5 g/day, i.e. the maximum intake recommended by the World Health Organisation for all adults. If salt intake is successfully reduced, there may well be a need for a reduction in diuretic dosag

Predictors and outcomes of sustained, intermittent or never achieving remission in patients with recent onset inflammatory polyarthritis:Results from the Norfolk Arthritis Register

Objectives: Early remission is the current treatment strategy for patients with inflammatory polyarthritis (IP) and RA. Our objective was to identify baseline factors associated with achieving remission: sustained (SR), intermittent (IR) or never (NR) over a 5-year period in patients with early IP.  Methods: Clinical and demographic data of patients with IP recruited to the Norfolk Arthritis Register (NOAR) were obtained at baseline and years 1, 2, 3 and 5. Remission was defined as no tender or swollen joints (out of 51). Patients were classified as NR or PR, respectively, if they were in remission at: no assessment or ⩾3 consecutive assessments after baseline, and IR otherwise. Ordinal regression and a random effects model, respectively, were used to examine the association between baseline factors, remission group and HAQ scores over time.  Results: A total of 868 patients (66% female) were included. Of these, 54%, 34% and 12% achieved NR, IR and SR, respectively. In multivariate analysis, female sex (odds ratio, OR 0.47, 95% CI: 0.35, 0.63), higher tender joint count (OR = 0.94, 95% CI: 0.93, 0.96), higher HAQ (OR = 0.59, 95% CI: 0.48, 0.74), being obese (OR = 0.70, 95% CI: 0.50, 0.99), hypertensive (OR = 0.67, 95% CI: 0.50, 0.90) or depressed (OR = 0.74, 95% CI: 0.55, 1.00) at baseline were independent predictors of being in a lower remission group. IR and SR were associated with lower HAQ scores over time and lower DAS28 at year 5.  Conclusion: Women with higher tender joint count and disability at baseline, depression, obesity and hypertension were less likely to achieve remission. This information could help when stratifying patients for more aggressive therapy

Isomerisation of nido-[C₂B₁₀H₁₂]²⁻ dianions::Unprecedented rearrangements and new structural motifs in carborane cluster chemistry

We thank the EPSRC for support (DMcK funded by project EP/E02971X/1).Dianionic nido-[C2B10]2- species are key intermediates in the polyhedral expansion from 12- to 13-vertex carboranes and metallacarboranes, and the isomer adopted by these nido intermediates dictates the isomeric form of the 13-vertex product. Upon reduction and metallation of para-carborane up to five MC2B10 metallacarboranes can be produced (Angew. Chem., Int. Ed., 2007, 46, 6706), the structures of which imply the intermediacy of 1,7-, 3,7-, 4,7-, 7,9- and 7,10-isomers of the nido-[C2B10]2- species. In this paper we use density functional theory (DFT) calculations to characterise the reduction of closo-C2B10H12 carboranes and the subsequent isomerisations of the nido-[C2B10H12]2- dianions. Upon reduction para-carborane initially opens to [1,7-nido-C2B10H12]2- (abbreviated to 1,7) and [4,7-nido-C2B10H12]2- (4,7) and isomerisation pathways connecting 1,7 to 7,9, 4,7 to 7,10 and 1,7 to 3,7 have been characterised. For ortho- and meta-carborane the experimental reduction produces 7,9 in both cases and computed pathways for both processes are also defined; with ortho-carborane rearrangement occurs via 7,8, whereas with meta-carborane 7,9 is formed directly. The 7,9 isomer is the global minimum nido-structure. The characterisation of these isomerisation processes uncovers intermediates that adopt new structural motifs that we term basket and inverted nido. Basket intermediates feature a two-vertex basket handle bridging the remaining 10 vertices; inverted nido intermediates are related to known nido species, in that they have 5- and 6-membered belts, but where the latter, rather than the former, is capped, leaving a 5-membered open face. These new intermediates exhibit similar stability to the nido species, which is attributed to their relation to the 13-vertex docosahedron through the removal of 5-connected vertices. Isomerisation pathways starting from nido geometries are most often initiated by destabilisation of the cluster through a DSD process causing the 3-connected C7 vertex to move into a 4-connected site and a neighbouring B vertex to become 3-connected. The ensuing rearrangement of the cluster involves processes such as the pivoting of a 4-vertex diamond about its long diagonal, the pivoting of two 3-vertex triangles about a shared vertex and DSD processes. These processes are all ultimately driven by the preference for carbon to occupy low-connected vertices on the open 6-membered face of the resulting nido species.Publisher PDFPeer reviewe

Micro electrostatic precipitation for air treatment

Micro-Electrostatic precipitation uses combining impulses and dc voltage in order to charge and remove fine, sub-micron particles efficiently. Short impulses are expected to increase the precipitation efficiency and to reduce power consumption

Gold(I)-Catalysed Direct Thioetherifications Using Allylic Alcohols: an Experimental and Computational Study

A gold(I)-catalysed direct thioetherification reaction between allylic alcohols and thiols is presented. The reaction is generally highly regioselective (S(N)2′). This dehydrative allylation procedure is very mild and atom economical, producing only water as the by-product and avoiding any unnecessary waste/steps associated with installing a leaving or activating group on the substrate. Computational studies are presented to gain insight into the mechanism of the reaction. Calculations indicate that the regioselectivity is under equilibrium control and is ultimately dictated by the thermodynamic stability of the products