Systolic Blood Pressure Is Associated with Increased Brain Amyloid Load in Mild Cognitively Impaired Participants: Alzheimer's Disease Neuroimaging Initiatives Study.

BACKGROUND: Cardiovascular disease (CVD), including elevated blood pressure (BP), is known to promote Alzheimer's disease (AD) risk. Although brain amyloid load is a recognized hallmark of pre-symptomatic AD, its relationship to increased BP is less known. The objective of this study was to examine the relationship of BP to brain estimates of amyloid-ß (Aß) and standard uptake ratio (SUVr). We hypothesized that increased BP is associated with increased SUVr. METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we stratified BP according to the Seventh Joint National Committee (JNC) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Classification (JNC VII). Florbetapir (AV-45) SUVr was derived from the averaged frontal, anterior cingulate, precuneus, and parietal cortex relative to the cerebellum. A linear mixed-effects model enabled the elucidation of amyloid SUVr relationships to BP. The model discounted the effects of demographics, biologics, and diagnosis at baseline within APOE genotype groups. The least squares means procedure was used to estimate the fixed-effect means. All analyses were performed using the Statistical Analysis System (SAS). RESULTS: In non-ɛ4 carrier MCI subjects, escalating JNC categories of BP was associated with increasing mean SUVr using JNC-4 as a reference point (low-normal (JNC1) p = 0.018; normal (JNC-1) p = 0.039; JNC-2 p = 0.018 and JNC-3 p = 0.04). A significantly higher brain SUVr was associated with increasing BP despite adjustment for demographics and biological variables in non-ɛ4 carriers but not in ɛ4-carriers. This observation supports the view that CVD risk may promote increased brain amyloid load, and potentially, amyloid-mediated cognitive decline. CONCLUSION: Increasing levels of JNC classification of BP is dynamically associated with significant changes in brain amyloid burden in non-ɛ4 carriers but not in ɛ4-carrier MCI subjects. Though not statistically significant, amyloid burden tended to decrease with increasing BP in ɛ4 homozygote, perhaps motivated by increased vascular resistance and the need for higher brain perfusion pressure.

Deregulation of lysophosphatidic acid metabolism in oral cancer promotes cell migration via the up-regulation of COX-2.

Oral squamous cell carcinoma (OSCC) is the sixth most common cancer worldwide and accounts for 300,000 new cases yearly. The five-year survival rate is approximately 50% and the major challenges to improving patient prognosis include late presentation, treatment resistance, second primary tumours and the lack of targeted therapies. Therefore, there is a compelling need to develop novel therapeutic strategies. In this study, we have examined the effect of lysophosphatidic acid (LPA) on OSCC cell migration, invasion and response to radiation, and investigated the contribution of cyclooxygenase-2 (COX-2) in mediating the tumour promoting effects of LPA. Using the TCGA data set, we show that the expression of the lipid phosphate phosphatases (LPP), LPP1 and LPP3, was significantly down-regulated in OSCC tissues. There was no significant difference in the expression of the ENPP2 gene, which encodes for the enzyme autotaxin (ATX) that produces LPA, between OSCCs and control tissues but ENPP2 levels were elevated in a subgroup of OSCCs. To explore the phenotypic effects of LPA, we treated OSCC cell lines with LPA and showed that the lipid enhanced migration and invasion as well as suppressed the response of the cells to irradiation. We also show that LPA increased COX-2 mRNA and protein levels in OSCC cell lines and inhibition of COX-2 activity with the COX-2 inhibitor, NS398, attenuated LPA-induced OSCC cell migration. Collectively, our data show for the first time that COX-2 mediates some of the pro-tumorigenic effects of LPA in OSCC and identifies the ATX-LPP-LPA-COX-2 pathway as a potential therapeutic target for this disease.

Exercise Training Induced Changes In Nuclear Magnetic Resonance-Measured Lipid Particles In Mild Cognitively Impaired Elderly African American Volunteers: A Pilot Study.

PURPOSE: Poor cardiorespiratory fitness (CRF) is linked to cognitive deterioration, but its effects on lipid heterogeneity and functional properties in older African American (AA) subjects with mild cognitive impairment (MCI) need elucidation. This study determined whether exercise training-induced changes in blood lipid particle sizes (LPS) were associated with CRF determined by VO2Max in elderly AAs with MCI. Given the pivotal role of brain-derived neurotrophic factor (BDNF) on glucose metabolism, and therefore, "diabetic dyslipidemia", we also determined whether changes in LPS were associated with the levels of serum BDNF. METHODS: This analysis included 17 of the 29 randomized elderly AAs with MCI who had NMR data at baseline and after a 6-month training. We used Generalized Linear Regression (GLM) models to examine cardiorespiratory fitness (VO2Max) effects on training-induced change in LPS in the stretch and aerobic groups. Additionally, we determined whether the level of BDNF influenced change in LPS. RESULTS: Collectively, mean VO2Max (23.81±6.17) did not differ significantly between aerobic and stretch groups (difference=3.17±3.56, P=0.495). Training-related changes in very low-density lipoprotein, chylomicrons, and total low-density lipoprotein (LDL) particle sizes correlated significantly with VO2Max, but not after adjustment for age and gender. However, increased VO2Max significantly associated with reduced total LDL particle size after similar adjustments (P = 0.046). While stretch exercise associated with increased protective large high-density lipoprotein particle size, the overall effect was not sustained following adjustments for gender and age. However, changes in serum BDNF were associated with changes in triglyceride and cholesterol transport particle sizes (P < 0.051). CONCLUSION: Promotion of stretch and aerobic exercise to increase CRF in elderly AA volunteers with MCI may also promote beneficial changes in lipoprotein particle profile. Because high BDNF concentration may reduce CVD risk, training-related improvements in BDNF levels are likely advantageous. Large randomized studies are needed to confirm our observations and to further elucidate the role for exercise therapy in reducing CVD risk in elderly AAs with MCI.

APOEε4 impacts up-regulation of brain-derived neurotrophic factor after a six-month stretch and aerobic exercise intervention in mild cognitively impaired elderly African Americans: A pilot study.

Possession of the Apolipoprotein E (APOE) gene ε4 allele is the most prevalent genetic risk factor for late onset Alzheimer's disease (AD). Recent evidence suggests that APOE genotype differentially affects the expression of brain-derived neurotrophic factor (BDNF). Notably, aerobic exercise-induced upregulation of BDNF is well documented; and exercise has been shown to improve cognitive function. As BDNF is known for its role in neuroplasticity and survival, its upregulation is a proposed mechanism for the neuroprotective effects of physical exercise. In this pilot study designed to analyze exercise-induced BDNF upregulation in an understudied population, we examined the effects of APOEε4 (ε4) carrier status on changes in BDNF expression after a standardized exercise program. African Americans, age 55years and older, diagnosed with mild cognitive impairment participated in a six-month, supervised program of either stretch (control treatment) or aerobic (experimental treatment) exercise. An exercise-induced increase in VO2Max was detected only in male participants. BDNF levels in serum were measured using ELISA. Age, screening MMSE scores and baseline measures of BMI, VO2Max, and BDNF did not differ between ε4 carriers and non-ε4 carriers. A significant association between ε4 status and serum BDNF levels was detected. Non-ε4 carriers showed a significant increase in BDNF levels at the 6month time point while ε4 carriers did not. We believe we have identified a relationship between the ε4 allele and BDNF response to physiologic adaptation which likely impacts the extent of neuroprotective benefit gained from engagement in physical exercise. Replication of our results with inclusion of diverse racial cohorts, and a no-exercise control group will be necessary to determine the scope of this association in the general population.

Aberrant expression of the S1P regulating enzymes, SPHK1 and SGPL1, contributes to a migratory phenotype in OSCC mediated through S1PR2.

Oral squamous cell carcinoma (OSCC) is a lethal disease with a 5-year mortality rate of around 50%. Molecular targeted therapies are not in routine use and novel therapeutic targets are required. Our previous microarray data indicated sphingosine 1-phosphate (S1P) metabolism and signalling was deregulated in OSCC. In this study, we have investigated the contribution of S1P signalling to the pathogenesis of OSCC. We show that the expression of the two major enzymes that regulate S1P levels were altered in OSCC: SPHK1 was significantly upregulated in OSCC tissues compared to normal oral mucosa and low levels of SGPL1 mRNA correlated with a worse overall survival. In in vitro studies, S1P enhanced the migration/invasion of OSCC cells and attenuated cisplatin-induced death. We also demonstrate that S1P receptor expression is deregulated in primary OSCCs and that S1PR2 is over-expressed in a subset of tumours, which in part mediates S1P-induced migration of OSCC cells. Lastly, we demonstrate that FTY720 induced significantly more apoptosis in OSCC cells compared to non-malignant cells and that FTY720 acted synergistically with cisplatin to induce cell death. Taken together, our data show that S1P signalling promotes tumour aggressiveness in OSCC and identify S1P signalling as a potential therapeutic target.

The Role of a Provider-Sponsored Health Plan in Achieving Scale and Integration.

In pursuit of two primary strategies-to become an integrated delivery network (IDN) on the local level and to achieve additional overall organizational scale to sustain operations-Health First, based in Rockledge, Florida, relies on the success of its provider-sponsored health plan (PSHP) as a critical asset. For Health First, the PSHP serves as an agent for holding and administering financial risk for the health of populations. In addition, we are learning that our PSHP is a critical asset in support of integrating the components of our care delivery system to manage that financial risk effectively, efficiently, and in a manner that creates a unified experience for the customer.Health First is challenged by continuing pressure on reimbursement, as well as by a substantial regulatory burden, as we work to optimize the environments and tools of care and population health management. Even with strong margins and a healthy balance sheet, we simply do not have the resources needed to bring an IDN robustly to life. However, we have discovered that our PSHP can be the vehicle that carries us to additional scale. Many health systems do not own or otherwise have access to a PSHP to hold and manage financial risk. Health First sought and found a not-for-profit health system with complementary goals and a strong brand to partner with, and we now provide private-label health plan products for that system using its strong name while operating the insurance functions under our license and with our capabilities.

Outcome of catheter-directed thrombolysis for lower extremity arterial bypass occlusion.

OBJECTIVE: The purpose of this study was to determine the clinical outcome of patients undergoing catheter-directed thrombolysis (CDT) for lower extremity arterial bypass (LEAB) occlusion. METHODS: A retrospective review was performed of two university-based practices from 1988 to 2001. All patients with LEAB occlusion (<14 days by history) undergoing CDT as initial treatment were included. Technical success, complications, secondary patency, and limb salvage were examined. Additional analysis examined secondary procedures performed for residual lesions or failed CDT and the number of LEABs that were replaced or that became infected. RESULTS: One hundred four patients (77% male; mean age, 65 years) had 109 LEAB occlusions. CDT restored patency in 77%. Of the 25 LEABs that failed initial CDT, 15 underwent surgical thrombectomy/revision, four were replaced, and six underwent no further interventions. Of the 84 LEABs successfully lysed, 51 had residual lesions that underwent revision with interventional (n = 30) or surgical (n = 15) techniques or both (n = 6). Median hospital stay was 8 days with three periprocedural deaths. One quarter of CDT procedures had bleeding or thrombotic complications or both. The mean follow-up period was 45 months. Secondary patency rates on an intention-to-treat basis (attempted thrombolysis) were 32% and 19% at 1 and 5 years, respectively. After successful CDT, the 1-year secondary patency rate was comparable in LEABs with or without residual lesions (42% versus 45%). Overall, the limb salvage rates were 73% and 55% at 1 and 5 years, respectively. The survival rate was 56% at 5 years. Ten of the 54 LEABs (19%) that eventually failed after successful CDT had three or more reocclusive episodes. Seven LEABs (8.3%) salvaged with CDT eventually became infected from recurrent interventions; six of these necessitated major amputation. Twenty LEABs initially salvaged with CDT were replaced (four immediately and 16 after episodes of recurrent ischemia). Two patients died during hospitalization for treatment of recurrent ischemia. CONCLUSION: Despite relatively high initial technical success for LEAB thrombolysis, eventual failure is the rule rather than the exception. Recurrent LEAB occlusions lead to significant morbidity, including recurrent interventions, eventual graft infection/replacement, and limb loss. However, LEAB replacement has substantial problems associated with limited conduit, reoperative anatomy, and subsequent wound complications. We therefore advocate an initial attempt at CDT with liberal use of graft replacement for early and late failures or as an initial strategy in those with favorable remaining conduit.