Liliana Gonzalez

Microvascular injury and blood–brain barrier leakage in Alzheimer's disease

Thinning and discontinuities within the vascular basement membrane (VBM) are associated with leakage of the plasma protein prothrombin across the blood-brain barrier (BBB) in Alzheimers disease (AD). Prothrombin immunohistochemistry and ELISA assays were performed on prefrontal cortex. In severe AD, prothrombin was localized within the wall and neuropil surrounding microvessels. Factor VIII staining in severe AD patients indicated that prothrombin leakage was associated with shrinkage of endothelial cells. ELISA revealed elevated prothrombin levels in prefrontal cortex AD cases that increased with the Braak stage (Control=1.39, I-II=1.76, III-IV=2.28, and V-VI=3.11 ng prothrombin/mg total protein). Comparing these four groups, there was a significant difference between control and Braak V-VI (p=0.0095) and also between Braak stages I-II and V-VI (p=0.0048). There was no significant difference in mean prothrombin levels when cases with versus without cerebral amyloid angiopathy (CAA) were compared (p-value=0.3627). When comparing AD patients by APOE genotype (ApoE3,3=2.00, ApoE3,4=2.49, and ApoE4,4=2.96 ng prothrombin/mg total protein) an analysis of variance indicated a difference between genotypes at the 10% significance level (p=0.0705). Tukeys test indicated a difference between the 3,3 and 4,4 groups (p=0.0607). These studies provide evidence that in advanced AD (Braak stage V-VI), plasma proteins like prothrombin can be found within the microvessel wall and surrounding neuropil, and that leakage of the blood-brain barrier may be more common in patients with at least one APOE4 allele.

Hippocampal RAGE Immunoreactivity in Early and Advanced Alzheimer’s Disease

Microvascular accumulation and neuronal overproduction of amyloid-beta peptide (Abeta) are pathologic features of Alzheimers disease (AD). In this study, we examined the receptor for advanced glycation endproducts (RAGE), a multi-ligand receptor found in both neurons and cerebral microvascular endothelia that binds Abeta. RAGE expression was assessed in aged controls (n = 6), patients with early AD-like pathology (n = 6), and severe, Braak V-VI AD (n = 6). Human hippocampi were stained with a specific polyclonal antibody directed against RAGE (Research Diagnostics, Flanders, NJ). Immunoreactivity was localized in both neurons and cerebral endothelial cells. Quantitative image-analyses were performed on grayscale images to assess the total surface area of endothelial RAGE immunoreaction product in cross sections of cerebral microvessels (5-20 microm). Confocal images were acquired for confirmation of RAGE immunoreactivity in both microvessels and neurons by coupling RAGE with CD-31 and neurofilament, respectively. A significant increase in endothelial RAGE immunoreactivity was found in severe Braak V-VI AD patients when compared to aged controls (p < 0.001), and when compared to patients with early AD pathology (p = 0.0125). In addition, a significant increase in endothelial RAGE immunoreactivity was witnessed when comparing aged controls having no reported AD pathology with patients having early AD-like pathology (p = 0.038). Our data suggest that microvascular RAGE levels increase in conjunction with the onset of AD, and continue to increase linearly as a function of AD pathologic severity (p < 0.0001).

Cerebral Cortical Arteriolar Angiopathy, Vascular Beta-Amyloid, Smooth Muscle Actin, Braak Stage, and APOE Genotype

Background and Purpose— We examined the associations among the vascular &bgr;-amyloid levels, smooth muscle actin, wall thickness, and lumen diameter to achieve greater understanding of the arteriolar changes that accompany Alzheimer disease (AD). Methods— Post-mortem pathology brain specimens from 76 patients with AD and 19 non-AD age control subjects were studied. We analyzed arterioles of the frontal cortex (Brodmann area 10) by immunohistochemistry and morphometry, and derived measures of vascular &bgr;-amyloid level, smooth muscle actin (SMA) volume, and arteriolar wall thickness and lumen diameter. APOE genotype was determined for each case. Results— Overall, there was a striking reciprocal relationship between arteriolar &bgr;-amyloid volume and smooth muscle actin (P<0.0001). In addition, there was a strong positive association between progressively accumulating vascular &bgr;-amyloid and augmentations in both wall thickness (P<0.0001) and lumen width (P<0.0001). In comparison with non-AD control subjects, smooth muscle actin was decreased in patients clinically diagnosed with AD and was reduced >10-fold in cases with AD pathology (Braak I to VI) compared with those lacking AD neuropathology. Significantly altered composition and structure of cortical vessels in pre-Braak stages corroborated our hypothesis that arterioles are devastated early in the AD pathological process. Smooth muscle actin, arteriolar wall thickness, and luminal diameter did not vary with Braak stage severity (P>0.05), indicating that substantial arteriolar damage may precede at least some of the interstitial plaques and neuronal tangles. Moreover, the structural and biochemical arteriolar abnormalities did not vary as a function of APOE genotype (P>0.05). Conclusion— We postulate that in elderly patients, the continually progressing &bgr;-amyloid-associated angiopathy, at the arteriolar level, harms the contractile apparatus and cerebral blood flow autoregulation, thereby making the downstream capillaries vulnerable to damage. Collectively, our observations lend further support to the idea that microvascular damage has a role, perhaps relatively early, in the onset of major AD pathology.

LARGE-SCALE DIVERSITY PATTERNS OF CEPHALOPODS IN THE ATLANTIC OPEN OCEAN AND DEEP SEA

Although the oceans cover 70% of the Earths surface and the open ocean is by far the largest ecosystem on the planet, our knowledge regarding diversity patterns of pelagic fauna is very scarce. Here, we examine large-scale latitudinal and depth-related patterns of pelagic cephalopod richness in the Atlantic Ocean in relation to ambient thermal and productive energy availability. Diversity, across 17 biogeochemical regions in the open ocean, does not decline monotonically with latitude, but is positively correlated to the availability of oceanic resources. Mean net primary productivity (NPP), determined from ocean color satellite imagery, explains 37% of the variance in species richness. Outside the poles, the range in NPP explains over 40% of the variability. This suggests that cephalopods are well adapted to the spatial patchiness and seasonality of open-ocean resources. Pelagic richness is also correlated to sea surface temperature, with maximum richness occurring around 15 degrees C and decreasing with both colder and warmer temperatures. Both pelagic and benthos-associated diversities decline sharply from sublittoral and epipelagic regions to the slope and bathypelagic habitats and then steadily to abyssal depths. Thus, higher energy availability at shallow depths seems to promote diversification rates. This strong depth-related trend in diversity also emphasizes the greater influence of the sharp vertical thermal gradient than the smoother and more seasonal horizontal (latitudinal) one on marine diversity.

Estimating pediatric inpatient medication use in the United States

We demonstrated the feasibility of developing national estimates of pediatric inpatient medication use by analyzing data from a large administrative database.

Comparing data mining and logistic regression for predicting IVF outcome

Design We utilized Quinlan’s C5.0 decision tree data mining algorithm to retrospectively investigate the predictive power of the 100 parameters that we track for each IVF cycle. The parameters investigated include patient demographics, stimulation regime, response properties, oocyte and embryo parameters and embryo transfer variables. To validate our findings from a statistical point of view we also constructed a statistical model based on logistic regression.

Trace element concentrations in follicular fluid of small follicles differ from those in blood serum, and may represent long-term exposure

OBJECTIVE To determine the levels of elements in follicular fluid (FF) of patients undergoing IVF and evaluate the relationship between the concentration of elements in FF, follicular volume, and blood. DESIGN Prospective blinded study. SETTING University-based IVF center. PATIENT(S) Follicular fluid/blood samples from 6/3 patients, respectively, undergoing IVF. INTERVENTION(S) Single follicular aspirations of 33 follicles were performed. Blood samples ( approximately 5 mL) were drawn at the time of oocyte retrieval from 3/6 patients only. The concentrations 26 elements were measured by inductively coupled plasma mass spectroscopy. MAIN OUTCOME MEASURE(S) Trace elements concentrations in follicular fluid and blood. RESULT(S) [1] Calcium and magnesium were the most abundant, followed by Cu, Zn, Fe, Cr, Rb. The elements V, Sr, Se, B, As, Pb, Al, Mo, Mn, and Cs were found in trace amounts. The elements Li, Be, Ag, Cd, Ba, Ti, Bi, U were not detected. [2] Element concentrations in small follicles frequently differed from those of large follicles. [3] Element concentrations in large follicles more closely resembled those in blood. CONCLUSION(S) Concentrations of elements in FF of small follicles can differ from those of large follicles in the same woman and from those of blood serum. When follicles grow they become filled with fluid of an elemental composition similar to blood. Concentrations of elements in small follicles may represent longer term element exposure, whereas those of growing follicles represents the coincident blood concentrations.

Dopamine and Dobutamine Use in Preterm or Low Birth Weight Neonates in the Premier 2008 Database

BACKGROUND Dobutamine and dopamine are off-patent drugs prioritized by the National Institute of Child Health and Human Development and US Food and Drug Administration for further study under the Best Pharmaceuticals for Children Act. Both agents are used to manage cardiac insufficiency in preterm neonates and are subject to controversy among neonatologists. Among the controversies are outcome measures (blood pressure vs end organ perfusion) and long-term effects. OBJECTIVES We analyzed retrospective hospitalization data to (1) describe the use of dopamine and dobutamine in low birth weight (LBW) or preterm infants in a large sample and (2) explore the potential of using observational data to describe outcomes in LBW or preterm infants treated with dopamine or dobutamine. METHODS Inpatient data were extracted from the Premier database to calculate the prevalence of use of dopamine and dobutamine among neonates in 2008. Prevalence of use was calculated by categorizing patients as ever or never having received dopamine or dobutamine. We compared mortality in the neonates by using Cox proportional hazards models to identify variables associated with survival and to control for their effects. RESULTS Out of 877,201 pediatric hospitalizations in 2008, 65,216 were neonates and had data available about dopamine and dobutamine use. Of these, 7459 were preterm or LBW and included 1143 very LBW (VLBW) neonates. Dopamine alone was given to 194 VLBW neonates, dobutamine alone was given to 14, and both dopamine and dobutamine were given to 79 neonates. For the VLBW neonates, probability of treatment with dopamine or dobutamine varied almost 10-fold from 4.4% to 38.4% at 11 hospitals and did not differ by 3M APR-DRG (all patient refined diagnosis related group) severity of illness or 3M APR-DRG risk of mortality. CONCLUSIONS Our data suggest the prevalence of dopamine or dobutamine use was 4.9% in preterm or LBW neonates and 25.1% in VLBW neonates. Treatment with dopamine alone was more common than treatment with dobutamine alone. There was no difference in mortality between neonates treated with dopamine compared with treatment with dobutamine, but access to charts and clinical details are required to conduct a comparative effectiveness study.

Volatility prediction during prolonged crises: Evidence from Korean index options

Abstract This paper examines KOSPI200 index option prices in order to investigate whether index option implied volatilities foreshadowed the 1997 economic crisis in Korea. Results indicate the absence of strong fears of an impending market downturn prior to the crisis. Put option implied volatilities rose sharply as the crisis intensified, however, and the difference between put and call implied volatilities reached extreme levels compared to results found in previous studies of financial crises in developed markets. The study indicates that option traders reacted to the crisis rather than predicting its onset, perhaps reflecting the youthfulness of the market. Traders also appear to have learned from the crisis as it intensified.

Morphine Use in Hospitalized Children in the United States: A Descriptive Analysis of Data From Pediatric Hospitalizations in 2008

BACKGROUND Morphine is among the top 10 medications given to children in the inpatient setting. It is not labeled for any pediatric indication, making it one of the drugs most widely used off-label in pediatrics. OBJECTIVES The aims of this study were to describe the epidemiology of morphine use in pediatric inpatients in the United States and to describe the characteristics of patients and hospitals in hospitalizations with morphine use. METHODS Deidentified data from the Premier Perspective Database (2008) were analyzed. Morphine use was defined as any morphine administration during the hospital stay and estimated by patient age in years, sex, race, and type of insurance; and hospital bedsize, teaching status, setting (urban or rural), and geographic location. Proportions (95% CI) were calculated for the entire population and for individual strata. The estimate was applied to national data to calculate the number of pediatric hospitalizations with morphine use in the United States in 2008. Logistic mixed-effects modeling was used to calculate the probability of morphine use by hospital after controlling for hospital and patient effects. RESULTS The database contained records from 877,201 pediatric hospitalizations and 423 hospitals in the United States. Morphine was administered in 54,613 of pediatric hospitalizations (6.2%). Use was higher in boys than girls (6.4% and 6.1%, respectively) and in blacks compared with whites or other racial groups (7.5%, 6.7%, and 5.0%). Use increased from 1.6% in children aged <2 years to 27.4% in those aged 12 to 17 years. Based on these data, morphine may have been administered in 476,205 pediatric hospitalizations in the United States in 2008. The 2 diagnoses most frequently associated with morphine use were appendicitis (14.4%) and fracture (11.1%). On logistic mixed-effects modeling for patients with appendicitis and for patients with fractures, there was hospital variation in morphine use after controlling for variables in the model. CONCLUSIONS Based on the data from this analysis, morphine was used in hospitalized children in all age groups, despite the lack of pediatric labeling. Common conditions such as appendicitis and fracture were leading diagnoses associated with morphine use.