In vivo retinal imaging is associated with cognitive decline, blood-brain barrier disruption and neuroinflammation in type 2 diabetic mice.

Introduction: Type 2 diabetes (T2D) is associated with chronic inflammation and neurovascular changes that lead to functional impairment and atrophy in neural-derived tissue. A reduction in retinal thickness is an early indicator of diabetic retinopathy (DR), with progressive loss of neuroglia corresponding to DR severity. The brain undergoes similar pathophysiological events as the retina, which contribute to T2D-related cognitive decline. Methods: This study explored the relationship between retinal thinning and cognitive decline in the LepR db/db model of T2D. Diabetic db/db and non-diabetic db/+ mice aged 14 and 28 weeks underwent cognitive testing in short and long-term memory domains and in vivo retinal imaging using optical coherence tomography (OCT), followed by plasma metabolic measures and ex vivo quantification of neuroinflammation, oxidative stress and microvascular leakage. Results: At 28 weeks, mice exhibited retinal thinning in the ganglion cell complex and inner nuclear layer, concomitant with diabetic insulin resistance, memory deficits, increased expression of inflammation markers and cerebrovascular leakage. Interestingly, alterations in retinal thickness at both experimental timepoints were correlated with cognitive decline and elevated immune response in the brain and retina. Discussion: These results suggest that changes in retinal thickness quantified with in vivo OCT imaging may be an indicator of diabetic cognitive dysfunction and neuroinflammation.

Peripheral metabolism of lipoprotein-amyloid beta as a risk factor for Alzheimer's disease: potential interactive effects of APOE genotype with dietary fats.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by brain parenchymal abundance of amyloid-beta (Aß) and the accumulation of lipofuscin material that is rich in neutral lipids. However, the mechanisms for aetiology of AD are presently not established. There is increasing evidence that metabolism of lipoprotein-Aß in blood is associated with AD risk, via a microvascular axis that features breakdown of the blood-brain barrier, extravasation of lipoprotein-Aß to brain parenchyme and thereafter heightened inflammation. A peripheral lipoprotein-Aß/capillary axis for AD reconciles alternate hypotheses for a vascular, or amyloid origin of disease, with amyloidosis being probably consequential. Dietary fats may markedly influence the plasma abundance of lipoprotein-Aß and by extension AD risk. Similarly, apolipoprotein E (Apo E) serves as the primary ligand by which lipoproteins are cleared from plasma via high-affinity receptors, for binding to extracellular matrices and thereafter for uptake of lipoprotein-Aß via resident inflammatory cells. The epsilon APOE ε4 isoform, a major risk factor for AD, is associated with delayed catabolism of lipoproteins and by extension may increase AD risk due to increased exposure to circulating lipoprotein-Aß and microvascular corruption.

Short-term consumption of alcohol (vodka) mixed with energy drink (AMED) attenuated alcohol-induced cerebral capillary disturbances and neuroinflammation in adult wild-type mice.

Background: The ingestion of combinatory Alcohol Mixed with Energy Drink (AMED) beverages continues to increase markedly, particularly among young adults. Some studies suggest detrimental health effects related to the combination of alcohol with energy drink formulations; however, the consumption of AMED has not been investigated in context of the cerebral microvasculature or neuroinflammation. We hypothesized that cerebral capillary integrity and glial cells are particularly vulnerable to the combination of AMED.Methods:12-week old wild-type C57BL/6J mice were orally gavaged with either vehicle (water), alcohol (vodka), an energy drink (MotherTM), or a combination AMED, daily for five days. Thereafter, mice were sacrificed, blood alcohol concentrations were analysed and cryosections of brain specimens were subjected to confocal immunofluorescent analysis for measures of cerebral capillary integrity via immunoglobulin G (IgG), and markers of neuroinflammation, ionized-calcium-binding-adaptor-molecule 1 (Iba1) and Glial-Fibrillary-Acidic-Protein (GFAP). Proinflammatory cytokines, IL-2, IL-17A, IFN-ϒ, and anti-inflammatory cytokines, IL-4, IL-6 and IL-10, were also measured in serum.Results: Consistent with previous studies, cerebral capillary dysfunction and astroglial cell activation were markedly greater in the alcohol-only group (AO); however, the AO-induced effects were profoundly attenuated with the AMED combination. Mice maintained on AO and AMED interventions exhibited a moderate increase in microglial recruitment. There were no significant changes in pro-inflammatory nor anti-inflammatory cytokines in ED or AMED treated mice.Conclusion: This study suggests that paradoxically the acute detrimental effects of alcohol on cerebral capillary integrity and astrogliosis are counteracted with the co-provision of an ED, rich in caffeine and taurine and containing B-group vitamins.

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype.

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

Automated Quantitative Analysis of ex vivo Blood-Brain Barrier Permeability Using Intellesis Machine-Learning.

BACKGROUND: An increase in blood brain barrier permeability commonly precedes neuro-inflammation and cognitive impairment in models of dementia. Common methods to estimate capillary permeability have potential confounders, or require laborious and subjective semi-manual analysis. NEW METHOD: Here we used snap frozen mouse and rat brain sections that were double-immunofluorescent labeled for immunoglobulin G (IgG; plasma protein) and laminin-α4 (capillary basement membrane). A Machine Learning Image Analysis program (Zeiss ZEN Intellisis) was trained to recognize and segment laminin-α4 to equivocally identify blood vessels in large sets of images. An IgG subclass based on a threshold intensity was segmented and quantitated only in extravascular regions. The residual parenchymal IgG fluorescence is indicative of blood-to-brain extravasation of IgG and was accurately quantitated. RESULTS: Automated machine-learning and threshold based segmentation of only parenchymal IgG extravasation accentuates otherwise indistinct capillary permeability, particularly frequent in minor BBB leakage. Comparison with Existing Methods: Large datasets can be processed and analyzed quickly and robustly to provide an overview of vascular permeability throughout the brain. All human bias or ambiguity involved in classifying and measuring leakage is removed. CONCLUSION: Here we describe a fast and precise method of visualizing and quantitating BBB permeability in mouse and rat brain tissue, while avoiding the confounding influence of unphysiological conditions such as perfusion and eliminating any human related bias from analysis.

The Consumption of Energy Drinks Induces Blood-Brain Barrier Dysfunction in Wild-Type Mice.

Energy drinks containing significant quantities of caffeine and sugar are increasingly consumed, particularly by adolescents and young adults. Chronic ingestion of energy drinks may potentially regulate vascular risk factors. This study investigated the effects of chronic ingestion of energy drinks on blood-brain barrier (BBB) integrity and neuroinflammation. Male C57BL/6J mice were maintained on water (control), MotherTM (ED), sugar-free MotherTM (sfED), or Coca ColaTM soft drink (SD) for 13 weeks. The BBB integrity and neuroinflammation were analyzed with semi-quantitative immunofluorescent microscopy. Blood pressure, plasma inflammatory cytokine levels and blood glucose were also considered. Following 13 weeks of intervention, mice treated with ED, sfED, and SD showed significant disruption of BBB. However, marked neuroinflammation was observed only in sfED group mice. The consumption of ED and sfED significantly altered the blood pressure and plasma concentrations of inflammatory cytokines, TNF-a, IL-4, IL-6, and IL-10, and both increased plasma glucose. Correlation analyses showed significant associations between BBB dysfunction and hypotension, hyperglycaemia and cytokine dyshomeostasis. The intake of energy drink, particularly the sugar free formulation, may compromise the integrity of BBB and induce neuroinflammation via hypotension, hyperglycaemia and inflammatory pathways.

Blood-brain barrier disruption and ventricular enlargement are the earliest neuropathological changes in rats with repeated sub-concussive impacts over 2 weeks.

Repeated sub-concussive impact (e.g. soccer ball heading), a significantly lighter form of mild traumatic brain injury, is increasingly suggested to cumulatively alter brain structure and compromise neurobehavioural function in the long-term. However, the underlying mechanisms whereby repeated long-term sub-concussion induces cerebral structural and neurobehavioural changes are currently unknown. Here, we utilised an established rat model to investigate the effects of repeated sub-concussion on size of lateral ventricles, cerebrovascular blood-brain barrier (BBB) integrity, neuroinflammation, oxidative stress, and biochemical distribution. Following repeated sub-concussion 3 days per week for 2 weeks, the rats showed significantly enlarged lateral ventricles compared with the rats receiving sham-only procedure. The sub-concussive rats also presented significant BBB dysfunction in the cerebral cortex and hippocampal formation, whilst neuromotor function assessed by beamwalk and rotarod tests were comparable to the sham rats. Immunofluorescent and spectroscopic microscopy analyses revealed no significant changes in neuroinflammation, oxidative stress, lipid distribution or protein aggregation, within the hippocampus and cortex. These data collectively indicate that repeated sub-concussion for 2 weeks induce significant ventriculomegaly and BBB disruption, preceding neuromotor deficits.

Chronic high fat feeding paradoxically attenuates cerebral capillary dysfunction and neurovascular inflammation in Senescence-Accelerated-Murine-Prone Strain 8 mice.

Background: A body of epidemiological, clinical and preclinical studies suggest increased risk for cerebro- and cardio-vascular disease associated with dietary ingestion of long-chain saturated fatty acids (LCSFA). In wild-type rodent models, chronic ingestion of LCSFA diets are associated with increased cerebral capillary permeability, heightened neurovascular inflammation and poorer cognitive performance. However, recent studies suggest that diets enriched in fat may paradoxically attenuate elements of the ageing phenotype via a caloric support axis.Objective: The purpose of this study was to explore the effects of dietary LCSFA on cerebral capillary integrity and neurovascular inflammation in an established model of accelerated ageing, Senescence-Accelerated-Murine-Prone Strain 8 (SAMP8) mice.Methods: From 6 weeks of age, SAMP8 mice and age-matched controls were randomised to either normal chow, or to an LCSFA-enriched diet, for either 12 or 34 weeks. An additional group of SAMP8 mice were provided the LCSFA-enriched diet for 12 weeks followed by the provision of ordinary low-fat chow for 22 weeks. Ex vivo measures of cerebrovascular integrity, neurovascular inflammation and astrocytic activation, were determined via 3-dimensional immunofluorescent confocal microscopy methodologies.Results: LCSFA-fed SAMP8 mice had markedly attenuated cerebral capillary dysfunction concomitant with reduced microglial activation. In SAMP8 mice transiently maintained on an LCSFA diet for 12 weeks, suppression of neurovascular inflammation persisted. Marked hippocampal astrogliosis was evident in LCSFA-fed mice when compared to SAMP8 mice maintained on ordinary chow.Conclusion: The findings from this study support the notion that high-fat, potentially ketogenic diets, may confer neuroprotection in SAMP8 mice through a vascular-support axis.

Repeated Long-Term Sub-concussion Impacts Induce Motor Dysfunction in Rats: A Potential Rodent Model.

Whilst detrimental effects of repeated sub-concussive impacts on neurophysiological and behavioral function are increasingly reported, the underlying mechanisms are largely unknown. Here, we report that repeated sub-concussion with a light weight drop (25 g) in wild-type PVG rats for 2 weeks does not induce detectable neuromotor dysfunction assessed by beamwalk and rotarod tests. However, after 12 weeks of repeated sub-concussion, the rats exhibited moderate neuromotor dysfunction. This is the first study to demonstrate development of neuromotor dysfunction following multiple long-term sub-concussive impacts in rats. The outcomes may offer significant opportunity for future studies to understand the mechanisms of sub-concussion-induced neuropsychological changes.

Minimal required PDT light dosimetry for nonmuscle invasive bladder cancer.

SIGNIFICANCE: Photodynamic therapy (PDT) could become a treatment option for nonmuscle invasive bladder cancer when the current high morbidity rate associated with red light PDT and variable PDT dose can be overcome through a combination of intravesical instillation of the photosensitizer and the use of green light creating a steep PDT dose gradient. AIM: To determine how a high PDT selectivity can be maintained throughout the bladder wall considering other efficacy determining parameters, in particular, the average optical properties of the mucosal layer governing the fluence rate multiplication factor, as well as the bladder shape and the position of the emitter in relationship to the bladder wall. APPROACH: We present three irradiance monitoring systems and evaluate their ability to enable selective bladder PDT considering previously determined photodynamic threshold values for the bladder cancer, mucosa and urothelium in a preclinical model, and the photosensitizer's specific uptake ratio. Monte Carlo-based light propagation simulations performed for six human bladders at the time of therapy for a range of tissue optical properties. The performance of one irradiance sensing device in a clinical phase 1B trial is presented to underline the impact of irradiance monitoring, and it is compared to the Monte Carlo-derived dose surface histogram. RESULTS: Monte Carlo simulations showed that irradiance monitoring systems need to comprise at least three sensors. Light scattering inside the bladder void needs to be minimized to prevent increased heterogeneity of the irradiance. The dose surface histograms vary significantly depending on the bladder shape and bladder volume but are less dependent on tissue optical properties. CONCLUSIONS: We demonstrate the need for adequate irradiance monitoring independent of a photosensitizer's specific uptake ratio.

Chronic Consumption of Bovine Dairy Milk Attenuates Dietary Saturated Fatty Acid-Induced Blood-Brain Barrier Dysfunction.

Ingestion of Western-diets enriched in long chain saturated fatty acids (LCSFA) are associated with increased risk of blood-brain barrier (BBB) dysfunction and neurovascular inflammation. Potential mechanisms include vascular insult as a consequence of metabolic aberrations, or changes in capillary permeability resulting in brain parenchymal extravasation of pro-inflammatory molecules. Bovine dairy milk (BDM) is potentially a significant source of dietary LCSFA, however, BDM contains an array of bioactive molecules purported to have vascular anti-inflammatory properties. This study investigated the effects of full cream (4% total fat) and delipidated (skim) BDM on BBB integrity and neuroinflammation in wild-type mice. Mice consuming substantial amounts of full cream or skim BDM with LCSFA-enriched chow were dyslipidemic compared to control mice provided with standard chow and water. However, there was no evidence of BBB dysfunction or neuroinflammation indicated by parenchymal abundance of immunoglobulin G and microglial recruitment, respectively. Positive control mice maintained on an LCSFA-enriched diet derived from cocoa-butter and water, had marked BBB dysfunction, however, co-provision of both full cream and skim milk solutions effectively attenuated LCSFA-induced BBB dysfunction. In mice provided with low-fat chow and full cream BDM drinking solutions, there were substantial favorable changes in the concentration of plasma anti-inflammatory cytokines. This study suggests that consumption of BDM may confer potent vascular benefits through the neuroprotective properties exuded by the milk-fat globule membrane moiety of BDM.

The differential effects of fatty acids on enterocytic abundance of amyloid-beta.

BACKGROUND: Consumption of a Western-styled diet enriched in saturated fatty acids (SFA) relative to polyunsaturated fatty acids is positively associated with risk for Alzheimer's disease. Whilst potential causal mechanism are unclear, there is increasing evidence that chronic ingestion of SFA enriched diets promote increase the plasma levels of lipoprotein-associated amyloid-ß (Aß). However, the effects of dietary mono- and poly-unsaturated fats (MUFA/PUFA) on nascent lipoprotein Aß abundance have not been previously reported. METHODS: Wild-type C57BL/6 J mice were maintained on low-fat control chow (LF) or diets enriched in either SFA, MUFA, or PUFA for 9 months. Enterocytic abundance of Aß was determined with quantitative immunofluorescent microscopy and plasma Aß was measured by ELISA. RESULTS: The chronic ingestion of SFA-enriched diet increased the enterocytic abundance and plasma concentration of Aß compared to LF control mice. The mice maintained on MUFA or PUFA diet showed comparable enterocytic and plasma Aß levels to the LF control mice. CONCLUSIONS: The data indicates that a diet enriched in SFA significantly increases the enterocytic Aß production and secretion into the circulation, whilst MUFA and PUFA enriched diet do not exert such effects.

Multimodal Imaging Analyses of Brain Hippocampal Formation Reveal Reduced Cu and Lipid Content and Increased Lactate Content in Non-Insulin-Dependent Diabetic Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is reported to increase the risk of cognitive impairment and dementia. However, the underlying mechanisms are not fully understood. While the brain homeostasis of metals and lipids is pivotal to maintaining energy metabolism and redox homeostasis for healthy brain function, no studies have reported hippocampal metal and biochemical changes in NIDDM. Therefore, we here utilized direct spectroscopic imaging to reveal the elemental distribution within the hippocampal subregions of an established murine model of NIDDM, db/db mice. In 26-week-old insulin resistant db/db mice, X-ray fluorescence microscopy revealed that the Cu content within the dentate gyrus and CA3 was significantly greater than that of the age-matched nondiabetic control mice. In addition, Fourier transform infrared (FTIR) spectroscopy analysis indicated a significant increase in the abundance of lactate within the corpus callosum (CC), dentate gyrus, CA1, and CA3 regions of diabetic db/db mice compared to that of the control, indicating altered energy metabolism. FTIR analysis also showed a significant decrease in the level of lipid methylene and ester within the CC of db/db mice. Furthermore, immunomicroscopy analyses demonstrated the increase in the level of glial fibrillary acidic protein expression and peri-vascular extravasation of IgG, indicating astrogliosis and blood-brain barrier dysfunction, respectively. These data suggest that astrogliosis-induced alterations in the supply of Cu, lipids, and energy substrates may be involved in the mechanisms of NIDDM-associated cognitive decline.

Probucol prevents blood-brain barrier dysfunction and cognitive decline in mice maintained on pro-diabetic diet.

An emerging body of evidence consistently suggests that compromised blood-brain barrier integrity may be causally associated with cognitive decline induced by type-2 diabetes. Our previous studies demonstrated that selected anti-inflammatory/anti-oxidative agents can preserve the integrity of blood-brain barrier and prevent neuroinflammation in mouse models of dysfunctional blood-brain barrier. Therefore, we have tested whether the previously proven blood-brain barrier protective agent, probucol, can prevent blood-brain barrier breakdown and cognitive decline in a dietary-induced murine model of diabetic insulin resistance. After 6-month chronic ingestion of a diet high in fat and fructose, the mice became insulin resistant. The high-fat and high-fructose-fed mice showed significant cognitive decline assessed by Morris water maze, concomitant with significant elevations in cortical and hippocampal glial acidic fibrillary protein and Fluoro Jade-C staining, indicating heightened neuroinflammation and neurodegeneration, respectively. The integrity of blood-brain barrier in high-fat and high-fructose-fed mice was substantially compromised, and this showed a significant association with heightened neurodegeneration. Co-provision of probucol with high-fat and high-fructose diet completely prevented the cognitive decline and blood-brain barrier dysfunction. Similarly, metformin was able to restore the cognitive function in high-fat and high-fructose-fed mice, while its blood-brain barrier protective effects were modest. These data suggest that probucol may prevent cognitive decline induced by insulin resistance by preserving the integrity of blood-brain barrier, whereas metformin's neuroprotective effects may be mediated through a separate pathway.

The Effects of a Combination of Ion Channel Inhibitors in Female Rats Following Repeated Mild Traumatic Brain Injury.

Following mild traumatic brain injury (mTBI), the ionic homeostasis of the central nervous system (CNS) becomes imbalanced. Excess Ca2+ influx into cells triggers molecular cascades, which result in detrimental effects. The authors assessed the effects of a combination of ion channel inhibitors (ICI) following repeated mTBI (rmTBI). Adult female rats were subjected to two rmTBI weight-drop injuries 24 h apart, sham procedures (sham), or no procedures (normal). Lomerizine, which inhibits voltage-gated calcium channels, was administered orally twice daily, whereas YM872 and Brilliant Blue G, inhibiting α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and P2X7 receptors, respectively, were delivered intraperitoneally every 48 h post-injury. Vehicle treatment controls were included for rmTBI, sham, and normal groups. At 11 days following rmTBI, there was a significant increase in the time taken to cross the 3 cm beam, as a sub-analysis of neurological severity score (NSS) assessments, compared with the normal control (p < 0.05), and a significant decrease in learning-associated improvement in rmTBI in Morris water maze (MWM) trials relative to the sham (p < 0.05). ICI-treated rmTBI animals were not different to sham, normal controls, or rmTBI treated with vehicle in all neurological severity score and Morris water maze assessments (p > 0.05). rmTBI resulted in increases in microglial cell density, antioxidant responses (manganese-dependent superoxide dismutase (MnSOD) immunoreactivity), and alterations to node of Ranvier structure. ICI treatment decreased microglial density, MnSOD immunoreactivity, and abnormalities of the node of Ranvier compared with vehicle controls (p < 0.01). The authors' findings demonstrate the beneficial effects of the combinatorial ICI treatment on day 11 post-rmTBI, suggesting an attractive therapeutic strategy against the damage induced by excess Ca2+ following rmTBI.

Sodium alginate capsulation increased brain delivery of probucol and suppressed neuroinflammation and neurodegeneration.

AIM: To enhance the bioavailability and brain uptake of probucol and examine whether it attenuates neuroinflammation and neurodegeneration by utilizing a sodium alginate nanoencapsulation technique. MATERIALS & METHODS: Wild-type mice were given either low-fat standard chow, high-fat (HF) diet to induce neuroinflammation and neurodegeneration, HF diet supplemented with nanocapsuled probucol at a concentration of 0.1% (w/w), HF diet supplemented with noncapsulated probucol at the same concentration of 0.1%, or HF diet supplemented with noncapsulated probucol at higher concentration (1%) for 24 weeks. RESULTS & CONCLUSION: The nanoencapsulation increased the plasma and brain concentration of probucol significantly compared with the mice that was given the same dosage of probucol without capsulation, and significantly suppressed the neuroinflammation and neurodegeneration.

Longitudinal Performance of Senescence Accelerated Mouse Prone-Strain 8 (SAMP8) Mice in an Olfactory-Visual Water Maze Challenge.

Morris water maze (MWM) is widely used to assess cognitive deficits in pre-clinical rodent models. Latency time to reach escape platform is frequently reported, but may be confounded by deficits in visual acuity, or differences in locomotor activity. This study compared performance of Senescence Accelerated Mouse Prone-Strain 8 (SAMP8) and control Senescence Accelerated Mouse Resistant-Strain 1 (SAMR1) mice in classical MWM, relative to performance in a newly developed olfactory-visual maze testing protocol. Performance indicated as the escape time to rescue platform for classical MWM testing showed that SAMP8 mice as young as 6 weeks of age did poorly relative to age-matched SAMR1 mice. The olfactory-visual maze challenge described better discriminated SAMP8 vs. SAMR1 mice than classical MWM testing, based on latency time measures. Consideration of the distance traveled rather than latency time in the classical MWM found no treatment effects between SAMP8 and SAMR1 at 40 weeks of age and the olfactory-visual measures of performance confirmed the classical MWM findings. Longitudinal (repeat) assessment of SAMP8 and SAMR1 performance at 6, 20, 30, and 40 weeks of age in the olfactory-visual testing protocol showed no age-associated deficits in SAMP8 mice to the last age end-point indicated. Collectively, the results from this study suggest the olfactory-visual testing protocol may be advantageous compared to classical MWM as it avoids potential confounders of visual impairment in some strains of mice and indeed, may offer insight into cognitive and behavioral deficits that develop with advanced age in the widely used SAMP8 murine model.

Blood-Brain Barrier Dysfunction Precedes Cognitive Decline and Neurodegeneration in Diabetic Insulin Resistant Mouse Model: An Implication for Causal Link.

Diabetic insulin resistance and pro-diabetic diet are reported to increase dementia risk through unknown mechanisms. Emerging evidence suggests that the integrity of blood-brain barrier (BBB) is central to the onset and progression of neurodegeneration and cognitive impairment. Therefore, the current study investigated the effect of pro-diabetic diets on cognitive dysfunction in association to BBB integrity and its putative mechanisms. In C57BL/6J mice chronically ingested with a diet enriched in fat and fructose (HFF), Morris Water Maze (MWM) test indicated no significant cognitive decline after 4 weeks of HFF feeding compared to low-fat (LF) fed control. However, at this stage, BBB dysfunction accompanied by heightened neuroinflammation in cortex and hippocampal regions was already evident. After 24 weeks, HFF fed mice showed significantly deteriorated cognitive function concomitant with substantial neurodegeneration, which both showed significant associations with increased BBB permeability. In addition, the data indicated that the loss of BBB tight junctions was significantly associated with heightened inflammation and leukocyte infiltration. The data collectively suggest that in mice maintained on pro-diabetic diet, the dysfunctional BBB associated to inflammation and leukocyte recruitment precedes the neurodegeneration and cognitive decline, possibly indicating causal association.

Chlorhexidine gluconate mouthwashes as a surfactant for addition-reaction silicone impressions.

Addition-reaction silicone impression (PVS) materials are hydrophobic. Hydrophobicity of the impression material may interfere with the wetting of the tooth, resulting in void formation. The study investigates whether conditioning teeth with Chlorhexidine-gluconate based mouthwashes can reduce the hydrophobicity and the number of voids on PVS impressions. Impression material contact angle specimens on bovine tooth surfaces were measured using a Reflex Microscope. PVS impressions (President) were made of untreated bovine teeth in three groups (1, 2 and 3) and fourth group used Impregum polyether impression material: Group I was used as a control group, and original and mint flavoured Corsodyl (Chlorhexidine) mouthwashes were used as clinical surfactants in Groups 2 and 3, respectively. Contact angle readings were recorded on each side of every impression in each of the four groups and compared by an analysis of variance. In the second part of the study, the numbers of air voids on impression surfaces were visually recorded. The proportions of air voids in the groups were compared using a Chi-squared test. The mean angle for Group 3 with mint flavoured Corsodyl mouthwash was significantly smaller than that of any of the other groups (P < 0.05). The only statistically significant (P < 0.01) comparisons of the proportions of air voids were between Group 4 and each of the other experimental groups, with the percentage of voids being significantly greater in Group 4. Although Corsodyl mint significantly reduced the mean contact angle it did not significantly reduce the percentage of voids on impression surfaces.

The effect of engaging the screw access channel of an implant abutment with a cement-retained restoration.

PURPOSE: Factors affecting the retention of fixed prostheses to natural abutments are well understood. In contrast, little is known concerning the factors influencing the retention of fixed prostheses cemented to implant abutments. The purpose of this study was to investigate the effect that extending a casting into the screw access channel of an implant abutment has on the retention when cemented using Temp Bond. MATERIALS AND METHODS: Replace Select Straight abutments received set modifications (buccal wall removal at 15 degrees , 22 degrees , and 30 degrees ) using a milling machine; controls were unmodified. Two castings were fabricated for each of the modified abutments, one with and one without an extension into the screw access channel. Following cementation with Temp Bond under standardized conditions, the castings were removed from the abutments using an Instron machine, and the peak removal force was recorded. RESULTS: Extending the casting into the screw access channel significantly (p < 0.001) increased the peak load of removal. Significant differences (p < 0.05) were found between no modification and 30 degrees modification, 15 degrees and 30 degrees modification, and 22 degrees and 30 degrees modification in the groups when the casting extended into the abutment. In the group where the casting did not extend into the abutment, all groups were significantly different (p < 0.001) with the exception of 22 degrees and 30 degrees modification. CONCLUSIONS: The increased load required to remove a casting that extends into the screw access channel of an implant abutment may compensate for loss in retention, which occurs through unfavorable modification of the abutment.