Best Medicine for Dementia: The Life-Long Defense of the Brain.

This review deals with an unwelcome reality about several forms of dementia, including Alzheimer's disease- that these dementias are caused, in part or whole, by the aging of the vasculature. Since the vasculature ages in us all, dementia is our fate, sealed by the realit!ies of the circulation; it is not a disease with a cure pending. Empirically, cognitive impairment before our 7th decade is uncommon and considered early, while a diagnosis in our 11th decade is late but common in that cohort (>40%). Projections from earlier ages suggest that the prevalence of dementia in people surviving into their 12th decade exceeds 80%. We address the question why so few of many interventions known to delay dementia are recognized as therapy; and we try to resolve this few-and-many paradox, identifying opportunities for better treatment, especially pre-diagnosis. The idea of dementia as a fate is resisted, we argue, because it negates the hope of a cure. But the price of that hope is lost opportunity. An approach more in line with the evidence, and more likely to limit suffering, is to understand the damage that accumulates with age in the cerebral vasculature and therefore in the brain, and which eventually gives rise to cognitive symptoms in late life, too often leading to dementia. We argue that hope should be redirected to delaying that damage and with it the onset of cognitive loss; and, for each individual, it should be redirected to a life-long defense of their brain.

Differences in Physical Demands Among Offensive and Defensive Players in Elite Men Bandy.

Purpose: This study examined the physiological sport-specific demands (total distance, mean velocity, effective game time, and time in five velocity zones) in elite bandy players of offensive and defensive playing positions. Method: Data were collected with 10 Hz GPS-units in the Swedish Elite League during the season 2015/16. Ten male elite bandy players were examined during 13 matches. Data were analyzed with Independent Samples Test and with descriptive statistics. Result: Analysis showed that defensive positions covered a significantly longer (p < .001) total distance (23.2 ± 2.4 km vs 21.1 ± 3.5 km) compared to the offensive positions. Significantly higher (p < .001) mean velocity was found in offensive positions (17.8 ± 1.0 km/h vs 15.5 ± 1.6 km/h) in relation to defensive positions. In variable effective game time analysis exposed significant differences (p < .001) between offensive positions and defensive positions (90.4 ± 3.5 min vs 71.3 ± 11.9 min). Furthermore, in easy and moderate skating defensive positions spent significantly (p < .001) more time and in fast, very fast, and sprint skating offensive positions spent significantly (p < .001) more time in relation to each other. The descriptive analysis of positions indicates that libero, defender, and half have the longest game time, half skate the longest distance, and forward have the highest mean velocity during the game. Conclusion: From a practical perspective, the result can provide coaches knowledge when planning the setup in training drills. Thus, the training sessions could be more specific to the playing position, which could maximize the player's physiological outcome in order to optimize performance.

Soft Tissue Integration of Hydroxyapatite-Coated Abutments for Bone Conduction Implants.

PURPOSE: The protocol for bone conduction hearing implant surgery involves reduction of soft tissues around the abutment to minimize the risk of skin-related complications. The present investigation was undertaken to demonstrate that hydroxyapatite-coated abutments provide improved soft tissue integration compared with conventional (pure titanium) abutments and are suitable for use without surgical removal of subepidermal soft tissues. MATERIALS AND METHODS: Forty-eight implants for bone conduction with two different types of abutments (test and control) were inserted in the skull parietal part of eight sheep. Test abutments had a hydroxyapatite-coated surface and a concave shape. Conventional titanium abutments were used as controls. A follow-up time of 4 weeks was used. Histomorphometric analyses of test and control samples were analyzed, and morphometric results were compared using mixed model analysis. RESULTS: Histological assessment showed healthy soft tissues around the abutments with limited or no signs of inflammation. Hydroxyapatite-coated abutments showed intimate dermal adherence, while less close contact was noted for control abutments. Statistically significant differences in mean pocket depth (0.4 vs 1.6 mm, p = .0013) and epidermal downgrowth (0.6 vs 2.0 mm, p = .0003) between test and control abutments were recorded. CONCLUSION: The study confirms that hydroxyapatite-coated abutments resulted in a significant reduction in pocket depth and improved soft tissue integration compared with conventional titanium abutments, possibly by providing tight adherence at the interface. Statistically significant reduced pocket depth formation and epidermal downgrowth were recorded.

Atom probe tomography investigation of lath boundary segregation and precipitation in a maraging stainless steel.

Lath boundaries in a maraging stainless steel of composition 13Cr-8Ni-2Mo-2Cu-1Ti-0.7Al-0.3Mn-0.2Si-0.03C (at%) have been investigated using atom probe tomography following aging at 475 °C for up to 100 h. Segregation of Mo, Si and P to the lath boundaries was observed already after 5 min of aging, and the amount of segregation increases with aging time. At lath boundaries also precipitation of η-Ni3(Ti, Al) and Cu-rich 9R, in contact with each other, takes place. These co-precipitates grow with time and because of coarsening the area number density decreases. After 100 h of aging a ∼5 nm thick film-like precipitation of a Mo-rich phase was observed at the lath boundaries. From the composition of the film it is suggested that the phase in question is the quasicrystalline R' phase. The film is perforated with Cu-rich 9R and η-Ni3(Ti, Al) co-precipitates. Not all precipitate types present in the matrix do precipitate at the lath boundaries; the Si-containing G phase and γ'-Ni3(Ti, Al, Si) and the Cr-rich α' phase were not observed at the lath boundaries.

Histologic evaluation of soft tissue integration of experimental abutments for bone anchored hearing implants using surgery without soft tissue reduction.

OBJECTIVE: The protocol for bone-anchored hearing implants (e.g., Baha) surgery involves reduction of soft tissues around the abutment to minimize the risk of skin-related complications. It is hypothesized that good soft tissue outcomes may be achieved without performing skin reduction if improved abutment designs and/or materials are used that provide enhanced integration with surrounding soft tissues. The aim of the study was to investigate soft tissue response to different abutment designs/materials. METHODS: Thirty-six Baha implants and abutments were inserted in the skull of six sheep without performing soft tissue reduction. Four different abutments were used: 1) standard Baha abutments, 2) hydroxyapatite-coated standard Baha abutments, 3) concave titanium abutments, and 4) hydroxyapatite-coated concave abutments. Healing times of 1, 2, and 4 weeks were used (2 animals per time point). Samples were analyzed using descriptive histology and morphometric measurements, and results were compared using Wilcoxon's signed-ranked test. RESULTS: Histologic assessment showed healthy soft tissues around the abutments with limited or no signs of inflammation. Hydroxyapatite-coated abutments showed tight adherence with dermis and limited epidermal downgrowth and pocket formation. Weaker adherence, often associated with significant epidermal downgrowth and pocket formation, was noted for noncoated titanium abutments. The mean pocket depth for abutment types A, B, C, and D was 1.38, 0.42, 1.51, and 0.24 mm, respectively. The difference between C and D was statistically significant (p = 0.031). CONCLUSION: The results showed enhanced dermal adherence and reduced epidermal downgrowth and pocket formation for hydroxyapatite-coated abutments, with the most significant effect recorded for the hydroxyapatite-coated abutments with a concave shape.

Fibrinogen adsorption and conformational change on model polymers: novel aspects of mutual molecular rearrangement.

By combining quartz crystal microbalance with dissipation monitoring (QCM-D) and surface plasmon resonance (SPR), the organic mass, water content, and corresponding protein film structure of fibrinogen adsorbed to acrylic polymeric substrates with varying polymer chain flexibility was investigated. Albumin and immunoglobulin G were included as reference proteins. For fibrinogen, the QCM-D model resulted in decreased adsorbed mass with increased polymer chain flexibility. This stands in contrast to the SPR model, in which the adsorbed mass increased with increased polymer chain flexibility. As the QCM-D model includes the hydrodynamically coupled water, we propose that on the nonflexible polymer significant protein conformational change with water incorporation in the protein film takes place. Fibrinogen maintained a more native conformation on the flexible polymer, probably due to polymer chain rearrangement rather than protein conformational change. In comparison with immunoglobulin G and albumin, polymer chain flexibility had only minor impact on adsorbed mass and protein structure. Understanding the adsorption and corresponding conformational change of a protein together with the mutual rearrangement of the polymer chain upon adsorption not only has implications in biomaterial science but could also increase the efficacy of molecular imprinted polymers (MIPs).

Blood interactions with noble metals: coagulation and immune complement activation.

Noble metals are interesting biomaterials for a number of reasons, e.g., their chemical inertness and relative mechanical softness, silver's long known antimicrobial properties, and the low allergenic response shown by gold. Although important for the final outcome of biomaterials, little is reported about early events between pure noble metals and blood. In this article, we used whole blood in the "slide chamber model" to study the activation of the immune complement activation, generation of thrombin/antithrombin (TAT) complexes, and platelet depletion from blood upon contact with silver (Ag), palladium (Pd), gold (Au), titanium (Ti), and Bactiguard, a commercial nanostructured biomaterial coating comprised of Ag, Pd, and Au. The results show the highest TAT generation and platelet depletion on Ti and Au and lower on Pd, Ag, and the Bactiguard coating. The immune complement factor 3 fragment (C3a) was generated by the surfaces in the following order: Ag > Au > Pd > Bactiguard > Ti. Quartz crystal microbalance adsorption studies with human fibrinogen displayed the highest deposition to Ag and the lowest onto the Bactiguard coating. The adsorbed amounts of fibrinogen did not correlate with thrombogenicity in terms of TAT formation and platelet surface accumulation in blood. The combined results suggest, hence, that noble metal chemistry has a different impact on the protein adsorption properties and general blood compatibility. The low thrombogenic response by the Bactiguard coating cannot be explained by any of the single noble metal properties but is likely a successful combination of the nanostructure, nanogalvanic effects, or combinatory chemical and physical materials properties.

Competitive adsorption of water soluble plasma proteins from egg yolk at the oil/water interface.

Water soluble plasma proteins were fractionated from hen's egg yolk, and the molecular weight and pI of the most abundant protein species were characterized with gel electrophoresis. The proteins were identified by mass spectrometry. The protein fraction was used to produce oil-in-water emulsions, both at various protein concentrations and at various pH values, and the surface load was determined through serum depletion. The competitive adsorption was studied through the determination of nonadsorbing species with gel electrophoresis. The results show that it was possible to form an oil-in-water emulsion for which droplet size and maximum surface load depended on the protein concentration and pH. Serum albumin and YGP40 adsorbed selectively at the oil/water interface throughout the pH range investigated, and for albumin the selectivity increased close to its pI. It is suggested that this selective adsorption is due to long hydrophobic stretches in the polypeptide chain, which are present in the selectively adsorbing species but absent in less adsorbing species.

Quartz crystal microbalance-with dissipation monitoring (QCM-D) for real time measurements of blood coagulation density and immune complement activation on artificial surfaces.

A recently developed variant of quartz crystal microbalance (QCM) called QCM-with dissipation monitoring (QCM-D) allows simultaneous and simple measurements of changes in adsorbed mass as well as the viscoelastic property (D-factor) of deposited protein layers on the sensor surface. We have taken the QCM-D technology a step further and demonstrated its advantages in the study of protein assembly as a consequence of surface induced immune complement activation, or contact activated blood coagulation. In the present study we have continued our QCM-D investigations of surface assembly of fibrin clot formation and complement activation and incubated differently modified quartz sensor surfaces in blood plasma and sera. Polymer surfaces used were spin-coated polyethylene, poly(ethylene terephtalate), poly(methylmetacrylate) and poly(dimethylsiloxane). Also used were sputtered titanium and heparin grafted surfaces. In this investigation we found that we could describe the surface induced coagulation with four independent parameters: (1) Time of onset of coagulation, (2) fibrin deposition rate, (3) total frequency shift at stable plateau, and (4) fibrin clot density. The most important finding was that the blood plasma clot density can be assessed with the use of D determinations and that the clot density varied significantly with the chemical composition of the surface. However, the D-factor did not give any new analytical information about the possible complement activation mechanisms. Nevertheless, the QCM-D was found to be a reliable tool for the analysis of surface induced complement activation. We also compared the QCM-D technique with traditional enzyme immuno assay (EIA) measurements of soluble products from the surface activation of the complement and coagulation systems. We found that the results from EIA and QCM-D measurements corresponded well for the complement activation but not for the coagulation, probably due to the biological complexity of the coagulation system.

Immune complement activation on polystyrene and silicon dioxide surfaces. Impact of reversible IgG adsorption.

We have studied aspects of the molecular background to immune complement activation on solid surfaces. Quartz crystal microbalance with dissipation monitoring (QCM-D) sensor surfaces were modified by means of spin coating with polystyrene (PS) or sputtering of silicon dioxide (SiO2). The IC activation on modified QCM-D surfaces was investigated by incubation in serum, followed by determinations of the amounts of bound C3 fragments (C3c) at the surface. Determinations of soluble C3a and soluble C5b-9 complex (sC5b-9) were made with enzyme immunoassay (EIA) method. We found that IC activation was high on PS surfaces, independent of the method used for measurements. On the SiO2 surfaces, IC activation was generally lower, but still detectable with anti-C3c as well as sC5b-9 and C3a determinations. Pre-coating the surfaces with a layer of IgG resulted in that IC activation became very high on PS surface, while the IC response remained low on SiO2 surfaces. The lower level of IC activation on the SiO2 surfaces was explained by a low surface concentration of IgG as measured with QCM-D. This was a result of the high reversibility of the IgG protein adsorption as well as absence of sufficient conformational changes of adsorbed IgG molecules. The QCM-D method was as sensitive as the C3a and sC5b-9 determinations to reveal surface associated IC-activation on these model surfaces. Additional advantages of the QCM-D method are the broad dynamic measurement window, i.e. the high precision and the ability to perform time resolved measurements and the ease of making different surface modifications.

The effect of substrate molecular mobility on surface induced immune complement activation and blood plasma coagulation.

Changing the length of the alkyl ester side chain in poly(alkyl methacrylates) provides a unique opportunity to systematically vary the mobility of the polymer chains, or in other words vary the glass transition temperature (T(g)), without greatly affect the solid surface energy (gamma(s)) of the polymer. A series of poly(alkyl methacrylate) coatings was therefore analysed with regard to the human immune complement (IC) activation and the surface associated blood plasma coagulation cascade (CC) properties. For the IC and CC measurements we used a quartz crystal microbalance (QCM) where we modified the chemistry of the sensor surface by applying 10-30 nm thick poly(alkyl methacrylate) coatings. The surface energy was calculated from water contact angles and small differences between the coatings were observed. The surface chemistry of the coatings, as determined with X-ray photoelectron spectroscopy (XPS), showed no deviation from expected compositions. Tapping mode atomic force microscopy (TM-AFM) measurements revealed that all coatings displayed similar morphology and the roughness was in the range of 0.7-0.9 nm. Increased polymer mobility correlated with a decrease in IC activation, measured as a decreased C3c deposition at the surface. The surface induced CC, measured as fibrin clot formation at the surface, was different between the different coatings but no correlation with molecular mobility was observed. Thus, the molecular mobility of the polymer chains had a major effect on both the IC and the CC and it seems that different aspects of the chemistry of the solid surface regulate activation of the IC and the CC.

Acoustics of blood plasma on solid surfaces.

We have quantified surface associated coagulation of human blood plasma with a recently developed methodological system consisting of a Quartz Crystal Microbalance with Dissipation monitoring (QCM-D), a method that measures the weight of adsorbed molecules on surfaces as a function of frequency shifts of a quartz crystal. Further, it measures the damping energy (i.e. viscoelasticity) of the adsorbed layer. Four different surfaces where studied: Heparin (Hep) surface as an active inhibitor of clot formation, titanium (Ti) surfaces that are known to activate the intrinsic pathway, polystyrene (PS) surfaces and poly(urethane urea) (PUUR) surfaces. The experiments were initiated by applying citrated human plasma at the sensor surfaces; calcium was then added toinitiate coagulation. The Hep surfaces showed no apparent indication of clot formation during one hour of incubation at room temperature. However, on Ti surfaces we observed an early and rapid change in both frequency shift and viscoelastic properties of the coagulating plasma. We inhibited the intrinsic pathway activation by using corn trypsin inhibitor (CTI), which is specific for factor FXIIa in the bulk phase, which prolonged the coagulation times for all non-heparinized surfaces. We have also found a peculiar initial plasma protein interaction phenomenon on Ti surfaces. The described methodology would be very efficient for basic studies of surface associated coagulation and as a screening method for new biomaterials.