The efficacy of different vitamin D supplementation delivery methods on serum 25(OH)D: A randomised double-blind placebo trial.

BACKGROUND: The use of vitamin D supplementation has increased due to greater recognition of widespread deficiency. AIMS: There has been little research on the effectiveness of different delivery methods and therefore the aim of was to test the efficacy of different delivery methods on serum 25(OH)D. METHODS: Using a randomised repeated measures double-blind placebo design (registered under ClinicalTrials.gov Identifier no. NCT03463642), changes in serum 25(OH)D over a 4-week period using a capillary spot method were monitored. 62 female participants blindly chose a number related to a supplementation delivery method: pill placebo, pill, oral liquid, oral liquid placebo, Skin oil application (SOA) placebo, SOA plus vitamin D3 suspension, or SOA plus vitamin D3 suspension with essential oil enhancer; active vitamin D supplements contained 100,000IU. Participants took their allocated supplements over a 24-hr period with serum 25(OH)D retested 4 weeks later. Liquid chromatography-tandem mass spectrometry method was applied to dried blood spot samples by an independent laboratory. RESULTS: ANCOVA reported a significant difference between the groups (F1,6 = 146.68; p < 0.001, eta2 = 0.51). Separate analysis within the delivery methods (pill, SOA, oral liquid) indicated significant differences between the active and placebo supplementation groups (p < 0.01). Post hoc analysis of absolute changes indicated vit D pill and SOA + vit D + essential oil had significant increases (p < 0.05) in serum 25(OH)D compared to all other interventions with no significant difference between them. CONCLUSIONS: In human participants vitamin D oral pill has the greatest effect on serum 25(OH)D levels. Skin oil application delivery of vitamin D using a penetrator enhancer has also been shown to be an effective method of delivery.

Potential impurities in drug substances: Compound-specific toxicology limits for 20 synthetic reagents and by-products, and a class-specific toxicology limit for alkyl bromides.

This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 µg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-linear dose-response. Several compounds evaluated have been previously incorrectly assumed to be mutagenic, or to be mutagenic carcinogens, but the evidence reported here for such compounds indicates a lack of mutagenicity, and a non-mutagenic mode of action for tumor induction. For non-mutagens with insufficient data to develop a toxicology limit, the ICH Q3A qualification thresholds are recommended. The compound- and class-specific toxicology limits described here may be adjusted for an individual drug substance based on treatment duration, dosing schedule, severity of the disease and therapeutic indication.

Temporal and geospatial trends of pediatric cancer incidence in Nebraska over a 24-year period.

BACKGROUND: Data from the Surveillance, Epidemiology, and End Results (SEER) revealed that the incidence of pediatric cancer in Nebraska exceeded the national average during 2009-2013. Further investigation could help understand these patterns. METHODS: This retrospective cohort study investigated pediatric cancer (0-19 years old) age adjusted incidence rates (AAR) in Nebraska using the Nebraska Cancer Registry. SEER AARs were also calculated as a proxy for pediatric cancer incidence in the United States (1990-2013) and compared to the Nebraska data. Geographic Information System (GIS) mapping was also used to display the spatial distribution of cancer in Nebraska at the county level. Finally, location-allocation analysis (LAA) was performed to identify a site for the placement of a medical center to best accommodate rural pediatric cancer cases. RESULTS: The AAR of pediatric cancers was 173.3 per 1,000,000 in Nebraska compared to 167.1 per 1,000,000 in SEER. The AAR for lymphoma was significantly higher in Nebraska (28.1 vs. 24.6 per 1,000,000; p = 0.009). For the 15-19 age group, the AAR for the 3 most common pediatric cancers were higher in Nebraska (p < 0.05). Twenty-three counties located >2 h driving distance to care facilities showed at least a 10% higher incidence than the overall state AAR. GIS mapping identified a second potential treatment site that would alleviate this geographic burden. CONCLUSIONS: Regional differences within Nebraska present a challenge for rural populations. Novel use of GIS mapping to highlight regional differences and identify solutions for access to care issues could be used by similar states.

Standardized cell sources and recommendations for good cell culture practices in genotoxicity testing.

Good cell culture practice and characterization of the cell lines used are of critical importance in in vitro genotoxicity testing. The objective of this initiative was to make continuously available stocks of the characterized isolates of the most frequently used mammalian cell lines in genotoxicity testing anywhere in the world ('IVGT' cell lines). This project was organized under the auspices of the International Life Sciences Institute (ILSI) Health and Environmental Sciences Institute (HESI) Project Committee on the Relevance and Follow-up of Positive Results in In Vitro Genetic Toxicity (IVGT) Testing. First, cell isolates were identified that are as close as possible to the isolate described in the initial publications reporting their use in genotoxicity testing. The depositors of these cell lines managed their characterization and their expansion for preparing continuously available stocks of these cells that are stored at the European Collection of Cell Cultures (ECACC, UK) and the Japanese Collection of Research Bioresources (JCRB, Japan). This publication describes how the four 'IVGT' cell lines, i.e. L5178Y TK+/- 3.7.2C, TK6, CHO-WBL and CHL/IU, were prepared for deposit at the ECACC and JCRB cell banks. Recommendations for handling these cell lines and monitoring their characteristics are also described. The growth characteristics of these cell lines (growth rates and cell cycles), their identity (karyotypes and genetic status) and ranges of background frequencies of select endpoints are also reported to help in the routine practice of genotoxicity testing using these cell lines.

Laparoscopy, computerised tomography and fluorodeoxyglucose positron emission tomography in the management of gastric and gastro-oesophageal junction cancers.

BACKGROUND: The staging laparoscopy has been used in the management of gastrointestinal cancers. The aim of this study was to evaluate the role of staging laparoscopy, in comparison with computed tomography (CT) and fluorodeoxyglucose positron emission tomography (FDG-PET) imaging in staging patients with gastro-oesophageal junction (GOJ) and gastric cancers. METHODS: The data were collected for patients between 1996 and 2013 undergoing investigation and treatment for GOJ and gastric cancers at a single institute. The pre-operative data (staging data), intraoperative details, post-operative course and follow-up were analysed for individual cases. RESULTS: Staging laparoscopy altered management plan in 64 (17 %) of 387 patients with negative staging CT and FDG-PET scan. Twenty-seven (7 %) patients with GOJ cancer (types I, II and III) were identified with pathological intraperitoneal nodes, 15 (4 %) gastric cancer with metastatic intraperitoneal deposits and liver metastases and 3 % gastric cancers with positive ascitic fluid for cancer cells. Ten (3 %) of patients were downstaged and were offered curative resection. Patients with metastatic disease were referred for palliative chemotherapy. The overall sensitivity of staging laparoscopy in diagnosing intraabdominal pathology was 86 % in comparison with CT (81 %) and FDG-PET (78 %). CONCLUSIONS: The diagnostic laparoscopy is useful for detecting and confirming nodal involvement and distant metastatic disease not evident on the staging CT scan and FDG-PET. This could potentially alter treatment and prognosis in patients with upper gastrointestinal cancer. The diagnostic laparoscopy should be performed as part of investigation and treatment planning for patients suffering from GOJ and gastric cancers. This can help to avoid surgery in patients with advanced disease.

T-lymphocyte populations following a period of high volume training in female soccer players.

PURPOSE: To investigate the T-lymphocyte response to a period of increased training volume in trained females compared to habitual activity in female controls. METHODS: Thirteen trained female (19.8 ± 1.9 yrs) soccer players were monitored during a two-week long high volume training period (increased by 39%) and thirteen female untrained (20.5 ± 2.2 yrs) controls were monitored during two-weeks of habitual activity. Blood lymphocytes, collected at rest, were isolated before and after the two-week period. Isolated lymphocytes were assessed for the cell surface expression of the co-receptor CD28, a marker of T-lymphocyte naivety, and CD57 a marker used to identify highly-differentiated T-lymphocytes. Co-expression of these markers was identified on helper CD4(+) and cytotoxic CD8(+) T-lymphocytes. In addition a further population of γδ(+) T-lymphocytes were identified. Plasma was used to determine Cytomegalovirus (CMV) serostatus. RESULTS: No difference was observed in the T-lymphocyte populations following the two-week period of increased volume training. At baseline the number of total CD3(+), cytotoxic CD8(+), naïve (CD8(+) CD28(+) CD57(-)), intermediate (CD8(+) CD28(+) CD57(+)) T-lymphocytes and the number and proportion of γδ(+) T-lymphocytes were greater in the trained compared to the untrained females (p<0.05). The proportion of CD4(+)T-lymphocytes was greater in the untrained compared to the trained (p<0.05), in turn the CD4(+):CD8(+) ratio was also greater in the untrained females (p<0.05). Inclusion of percentage body fat as a covariate removed the main effect of training status in all T-lymphocyte sub-populations, with the exception of the γδ(+) T-lymphocyte population. 8% of the untrained group was defined as positive for CMV whereas 23% of the trained group was positive for CMV. However, CMV was not a significant covariate in the analysis of T-lymphocyte proportions. CONCLUSION: The period of high volume training had no effect on T-lymphocyte populations in trained females. However, baseline training status differences were evident between groups. This indicates that long-term exercise training, as opposed to short-term changes in exercise volume, appears to elicit discernible changes in the composition of the blood T-lymphocyte pool.

Alkaline comet assay in liver and stomach, and micronucleus assay in bone marrow, from rats treated with 2-acetylaminofluorene, azidothymidine, cisplatin, or isobutyraldehyde.

As part of the Japanese Center for the Validation of Alternative Methods (JaCVAM) initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined the ability of the assay to determine the genotoxicity of 2-acetylaminofluorene (AAF), azidothymidine (AZT), cisplatin (CPN), and isobutyraldehyde (IBA) in liver and glandular stomach of male Sprague-Dawley rats. Rats were given oral doses of test compound or control once daily for three days. High dose levels were approximately maximum tolerated doses and were based on preliminary range-finding studies. Tissues were harvested 3h after the final dose (48h after the initial dose). A bone marrow micronucleus assay (MN) was also conducted on the rats treated with AZT, CPN, and IBA. Acute toxic effects of treatment were determined primarily through histomorphologic analysis of liver and stomach but also by body weight and serum liver enzyme changes. The comet assay was conducted on fresh tissue preparations but frozen samples from two studies were also assayed. Statistically significant dose-related differences in comet % DNA in tail were found in liver and stomach for the genotoxin AZT and in liver for the genotoxin CPN, but not in liver or stomach for the non-genotoxin IBA. Statistically significant differences in % DNA in tail were measured in liver for the low and mid dose of the genotoxin AAF, but not the high dose. The comet assays of frozen liver suspensions from CPN- and AAF-treated rats yielded comparable results to the assays of fresh preparations. There were no indications of significant toxicity induced by any treatment. The micronucleus assay was positive for CPN and AZT and negative for IBA. In conclusion, the in vivo comet assay is capable of detecting genotoxic effects of a variety of chemicals and may fill an important role in the genotoxicity test battery.

Equine Odontoclastic Tooth Resorption and Hypercementosis: Histopathologic Features.

Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a painful progressive condition of older horses that involves multiple teeth, including canines and incisors. EOTRH is uncommonly recognized by veterinary pathologists and in some cases may be misdiagnosed as cementoblastoma. The cause is unknown. The goals of this study were to describe the histopathologic features of EOTRH in 17 affected horses from the United States and to increase awareness of this condition. Samples ranged from affected tooth to the entire rostral mandible and maxilla. Affected teeth exhibited cemental hyperplasia and lysis. The marked proliferation of cementum in severe cases caused bulbous enlargement of the intra-alveolar portions of affected teeth. Several teeth contained necrotic debris, bacteria, and plant material in the regions of cemental lysis. All horses exhibited dentinal lysis in at least affected tooth, and several contained necrotic debris in these regions. Endodontic disease was often present with inflammation, lysis, necrotic debris, fibrosis, and/or a thin rim of atubular mineralized tissue in the pulp cavity. Periodontal disease was a common feature that was primarily characterized by moderate lymphoplasmacytic inflammation. Resorption with secondary hypercementosis appears to begin on the external surface of the teeth rather than within the pulp cavity. Distinguishing EOTRH from other diseases requires a complete history that includes the number and location of affected teeth, a gross description of regional hard/soft tissue health, and radiographic findings.

The Ingestion of 39 or 64 g·h(-1) of Carbohydrate is Equally Effective at Improving Endurance Exercise Performance in Cyclists.

In an investigator-blind, randomized cross-over design, male cyclists (mean± SD) age 34.0 (± 10.2) years, body mass 74.6 (±7.9) kg, stature 178.3 (±8.0) cm, peak power output (PPO) 393 (±36) W, and VO2max 62 (±9) ml·kg-1·min(-1) training for more than 6 hr/wk for more than 3y (n = 20) completed four experimental trials. Each trial consisted of a 2-hr constant load ride at 95% of lactate threshold (185 ± 25 W) then a work-matched time trial task (~30 min at 70% of PPO). Three commercially available carbohydrate (CHO) beverages, plus a control (water), were administered during the 2-hr ride providing 0, 20, 39, or 64 g·hr-1 of CHO at a fluid intake rate of 1L·hr(-1). Performance was assessed by time to complete the time trial task, mean power output sustained, and pacing strategy used. Mean task completion time (min:sec ± SD) for 39 g·hr(-1) (34:19.5 ± 03:07.1, p = .006) and 64 g·hr(-1) (34:11.3 ± 03:08.5 p = .004) of CHO were significantly faster than control (37:01.9 ± 05:35.0). The mean percentage improvement from control was -6.1% (95% CI: -11.3 to -1.0) and -6.5% (95% CI: -11.7 to -1.4) in the 39 and 64 g·hr(-1) trials respectively. The 20 g·hr(-1) (35:17.6 ± 04:16.3) treatment did not reach statistical significance compared with control (p = .126) despite a mean improvement of -3.7% (95% CI -8.8-1.5%). No further differences between CHO trials were reported. No interaction between CHO dose and pacing strategy occurred. 39 and 64 g·hr-1 of CHO were similarly effective at improving endurance cycling performance compared with a 0 g·hr(-1) control in our trained cyclists.

Perioperative management of patients on new oral anticoagulants.

BACKGROUND: New oral anticoagulants (NOACs) offer an alternative to warfarin for preventing stroke in patients with atrial fibrillation. NOACs are expected to replace warfarin and other vitamin K antagonists for most of their indications in the future. Knowledge of the use of NOACs in the perioperative period is important for optimal care. METHODS: Studies that reported on the use of NOACs were identified, focusing on evidence-based guidance relating to the perioperative period. PubMed was searched for relevant articles published between January 2000 and January 2014. RESULTS: The anticipated expanded clinical use of NOACs such as rivaroxaban (Xarelto™), apixaban (Eliquis™) and dabigatran (Pradaxa™) has the potential to simplify perioperative anticoagulant management because of fewer drug-drug interactions, rapid onset of action, predictable pharmacokinetics and relatively short half-lives. However, coagulation status cannot be monitored by international normalized ratio and no antidotes are currently available. In elective surgery, it is important to discontinue the use of NOACs, with special consideration of renal function as route of elimination. Guidelines for the management of bleeding complications in patients on NOACs are provided, and may be considered for trauma and emergency surgery. Haemodialysis could be considered for bleeding with use of dabigatran. Better options for reversal of the effects of NOACs when bleeding occurs may follow with novel drugs. CONCLUSION: Management of NOACs in elective and emergency conditions requires knowledge of time of last intake of drug, current renal function and the planned procedure in order to assess the overall risk of bleeding. Currently no antidote exists to reverse the effects of these drugs.

A pilot study to investigate the role of thymidylate synthase as a marker of prognosis for neoadjuvant chemotherapy in gastric and gastro-oesophageal junction adenocarcinoma.

Aims and Background. Patients in the United Kingdom with operable gastric and gastro-oesophageal junction (GOJ) tumours receive neoadjuvant chemotherapy. Our aim was to study the expression of thymidylate synthase (TS) enzyme in pre-treatment diagnostic biopsy specimens and investigate its clinical usefulness. Methods. A single-centre study was carried out in 45 patients with gastric and GOJ adenocarcinoma treated with neo-adjuvant chemotherapy according to the MAGIC protocol. TS expression was determined using immunohistochemistry. >10% tumour nuclei expression of TS was used as cut-off for positivity. Results. Forty-one (91%) of the 45 tumours expressed TS. There was no association between TS expression and lymph node status (P = 0.80), histological response (P = 0.30), and recurrence (P = 0.55). On univariate analysis, only N-stage (P = 0.02) and vascular invasion (P = 0.04) were associated with a poor prognosis. Patients with negative tumour TS expression had better outcome than those with positive expression. The overall 5-year survival rate was 100% in the TS negative versus 56% in TS positive group, but the difference was not statistically significant (P = 0.17). Conclusion. TS expression should be studied in a larger series of gastro-oesophageal cancers as a potential prognostic marker of prognosis to neo-adjuvant chemotherapy.

Lakota elders' views on traditional versus commercial/addictive tobacco use; oral history depicting a fundamental distinction.

This qualitative study is intended to elucidate Lakota elders' views on traditional tobacco and commercial/addictive tobacco use, capturing the oral history that depict the cultural protocol regarding traditional tobacco, called Cansasa. Commercial tobacco use has significantly impacted the Northern Plains Indians. National surveillance systems report that tobacco use is more prevalent among American Indian/Alaska Natives than any other population, and is notably higher than the national average. Lung cancer among Native Americans is highest in the Northern Plains and Alaska, where smoking prevalence is also the highest, and smoking is responsible for nearly 90 % of all lung cancer cases. Yet, the use of traditional tobacco is largely ignored by surveillance and seems to have a distinct, positive role. Using a community-based participatory research approach, semi-structured interviews, and qualitative analysis tools, the research team, including 2 Lakota tribe elders, Lakota speaking tribal college students, and university faculty, sought to discern tribal elders' distinctions between traditional and the addictive commercial tobacco. The team interviewed thirty Lakota elders, transcribed the interviews and field notes, and analyzed them using immersion/crystallization organizing framework. The research design engaged the Lakota tribal community in all stages, from planning to publication. Analysis revealed a clear distinction between traditional and commercial tobacco: tribal elders conveyed strong positive messages connected to traditional tobacco use (i.e., spirituality, respect, health and wellness, humility, and thoughtfulness) versus strong negative messages linked to addictive tobacco (i.e., crime, loss of control and self-esteem, lack of respect to self and others, sickness and death). These messages, along with stories in the Lakota language that were told and recorded during the interviews, can guide new ways to address addictive tobacco prevention in this community, to enhance cultural pride, and to serve as a cross-generation bridge regarding tobacco use.

Bacterial mutagenicity screening in the pharmaceutical industry.

Genetic toxicity testing is used as an early surrogate for carcinogenicity testing. Genetic toxicity testing is also required by regulatory agencies to be conducted prior to initiation of first in human clinical trials and subsequent marketing for most small molecule pharmaceutical compounds. To reduce the chances of advancing mutagenic pharmaceutical candidates through the drug discovery and development processes, companies have focused on developing testing strategies to maximize hazard identification while minimizing resource expenditure due to late stage attrition. With a large number of testing options, consensus has not been reached on the best mutagenicity platform to use or on the best time to use a specific test to aid in the selection of drug candidates for development. Most companies use a process in which compounds are initially screened for mutagenicity early in drug development using tests that require only a few milligrams of compound and then follow those studies up with a more robust mutagenicity test prior to selecting a compound for full development. This review summarizes the current applications of bacterial mutagenicity assays utilized by pharmaceutical companies in early and late discovery programs. The initial impetus for this review was derived from a workshop on bacterial mutagenicity screening in the pharmaceutical industry presented at the 40th Annual Environmental Mutagen Society Meeting held in St. Louis, MO in October, 2009. However, included in this review are succinct summaries of use and interpretation of genetic toxicity assays, several mutagenicity assays that were not presented at the meeting, and updates to testing strategies resulting in current state-of the art description of best practices. In addition, here we discuss the advantages and liabilities of many broadly used mutagenicity screening platforms and strategies used by pharmaceutical companies. The sensitivity and specificity of these early mutagenicity screening assays using proprietary compounds and their concordance (predictivity) with the regulatory bacterial mutation test are discussed.

Addressing narcissistic personality features in the context of medical care: integrating diverse perspectives to inform clinical practice.

Narcissistic personality disorder (NPD) is characterized by an unrealistic need for admiration, lack of empathy toward others, and feelings of superiority. NPD presents a unique and significant challenge in clinical practice, particularly in medical settings with limited provider contact time, as health professionals treat individuals who often require excessive admiration and have competing treatment needs. This practice review highlights real case examples across three distinct medically oriented clinical settings (inpatient and outpatient behavioral medicine and a Level I trauma center) to demonstrate the difficult and compromising situations that providers face when treating patients with general medical conditions and comorbid narcissistic personality features. The main goal of this article is to discuss the various challenges and obstacles associated with these cases in medical settings and discuss some strategies that may prove successful. A second goal is to bridge diverse conceptualizations of narcissism/NPD through the discussion of theoretical and empirical perspectives that can inform understanding of the clinical examples. Despite differing perspectives regarding the underlying motivation of narcissistic behavior, this practice review highlights that these paradigms can be integrated when sharing the same ultimate goal: to improve delivery of care across medically oriented clinical settings for patients with narcissistic features.

Effects of exercise intensity and altered substrate availability on cardiovascular and metabolic responses to exercise after oral carnitine supplementation in athletes.

The effects of 15 d of supplementation with L-carnitine L-tartrate (LC) on metabolic responses to graded-intensity exercise under conditions of altered substrate availability were examined. Fifteen endurance-trained male athletes undertook exercise trials after a 2-d high-carbohydrate diet (60% CHO, 25% fat) at baseline (D0), on Day 14 (D14), and after a single day of high fat intake (15% CHO, 70% fat) on Day 15 (D15) in a double-blind, placebo-controlled, pair-matched design. Treatment consisted of 3 g LC (2 g L-carnitine/d; n = 8) or placebo (P, n = 7) for 15 d. Exercise trials consisted of 80 min of continuous cycling comprising 20-min periods at each of 20%, 40%, 60%, and 80% VO2peak. There was no significant difference between whole-body rates of CHO and fat oxidation at any workload between D0 and D14 trials for either the P or LC group. Both groups displayed increased fat and reduced carbohydrate oxidation between the D14 and D15 trials (p < .05). During the D15 trial, heart rate (p < .05 for 20%, 40%, and 60% workloads) and blood glucose concentration (p < .05 for 40% and 60% workloads) were lower during exercise in the LC group than in P. These responses suggest that LC may induce subtle changes in substrate handling in metabolically active tissues when fatty-acid availability is increased, but it does not affect whole-body substrate utilization during short-duration exercise at the intensities studied.

A linkage map of sheep chromosome X (OARX) aligned to human chromosome X (HSAX).

We have constructed a genetic linkage map of the sheep X chromosome (OARX) containing 22 new gene loci from across the human X chromosome (HSAX). The female OARX linkage map has a total length of 152.6 cM with average gene spacing of 5.5 cM. Comparison with HSAX confirms one previously reported major breakpoint and inversion, and other minor rearrangements between OARX and HSAX. Comparison of the linkage map with sheep sequence data OAR 1.0 reveals a different arrangement of markers on the q arm, which may more accurately reflect the genuine arrangement of this region.

Dietary fats, cerebrovasculature integrity and Alzheimer's disease risk.

An emerging body of evidence is consistent with the hypothesis that dietary fats influence Alzheimer's disease (AD) risk, but less clear is the mechanisms by which this occurs. Alzheimer's is an inflammatory disorder, many consider in response to fibrillar formation and extracellular deposition of amyloid-beta (Abeta). Alternatively, amyloidosis could notionally be a secondary phenomenon to inflammation, because some studies suggest that cerebrovascular disturbances precede amyloid plaque formation. Hence, dietary fats may influence AD risk by either modulating Abeta metabolism, or via Abeta independent pathways. This review explores these two possibilities taking into consideration; (i) the substantial affinity of Abeta for lipids and its ordinary metabolism as an apolipoprotein; (ii) evidence that Abeta has potent vasoactive properties and (iii) studies which show that dietary fats modulate Abeta biogenesis and secretion. We discuss accumulating evidence that dietary fats significantly influence cerebrovascular integrity and as a consequence altered Abeta kinetics across the blood-brain barrier (BBB). Specifically, chronic ingestion of saturated fats or cholesterol appears to results in BBB dysfunction and exaggerated delivery from blood-to-brain of peripheral Abeta associated with lipoproteins of intestinal and hepatic origin. Interestingly, the pattern of saturated fat/cholesterol induced cerebrovascular disturbances in otherwise normal wild-type animal strains is analogous to established models of AD genetically modified to overproduce Abeta, consistent with a causal association. Saturated fats and cholesterol may exacerbate Abeta induced cerebrovascular disturbances by enhancing exposure of vessels of circulating Abeta. However, presently there is no evidence to support this contention. Rather, SFA and cholesterol appear to more broadly compromise BBB integrity with the consequence of plasma protein leakage into brain, including lipoprotein associated Abeta. The latter findings are consistent with the concept that AD is a dietary-fat induced phenotype of vascular dementia, reflecting the extraordinary entrapment of peripherally derived lipoproteins endogenously enriched in Abeta. Rather than being the initiating trigger for inflammation in AD, accumulation of extracellular lipoprotein-Abeta may be a secondary amplifier of dietary induced inflammation, or possibly, simply be consequential. Clearly, delineating the mechanisms by which dietary fats increase AD risk may be informative in developing new strategies for prevention and treatment of AD.