bluuebunny/crossref_metadata_2025 huggingface dataset:
Enzastaurin‐induced apoptosis in glioma cells is caspase‐dependent and inhibited by BCL‐XL
Authors: Rieger Johannes , Lemke Dieter , Maurer Gabriele , Weiler Markus , Frank Brigitte , Tabatabai Ghazaleh , Weller Michael , Wick Wolfgang
Published: July 2008

The novel protein kinase C‐β inhibitor enzastaurin (ENZA) induced apoptosis in LNT‐229 and T98G cells whereas A172 cells were resistant. Further, ENZA reduced proliferation in glioblastoma‐initiating cells T 269 and T 323 but did not induce apoptosis. ENZA‐induced apoptosis involved cleavage of caspases 3, 8, and 9 and led to mitochondrial cytochrome c release and was strongly suppressed by the broad spectrum caspase inhibitor zVAD‐fmk but only slightly by the expression of the viral caspase 1/8 inhibitor cytokine response modifier‐A. ENZA did not reduce the phosphorylation of protein kinase B (Akt), but of p70 S6 kinase and of its substrate S6 protein in T98G cells. Inhibition of the phosphatidylinositol 3 kinase signaling pathway did not restore sensitivity of A172 cells towards ENZA, and constitutively active Akt did not protect LNT‐229 and T98G cells from ENZA‐induced apoptosis. Dephosphorylation of glycogen synthase kinase 3β, a biomarker of ENZA action, and cell death induction by ENZA were separately regulated. Inhibition or activation of Akt only weakly modulated ENZA‐induced dephosphorylation of glycogen synthase kinase 3β. In ENZA‐resistant A172 cells, apoptosis ligand 2 (Apo2L.0)‐induced cleavage of caspases 3, 8, and 9 was increased by ENZA, resulting in synergistic activity of ENZA and Apo2L.0.
Altered pharmacology in the intensive care unit patient
Authors: Zagli Giovanni , Tarantini Francesca , Bonizzoli Manuela , Di Filippo Alessandro , Peris Adriano , De Gaudio Angelo Raffaele , Geppetti Pierangelo
Published: July 2008

Critically ill patients, not infrequently present alterations of physiological parameters that determine the success/failure of therapeutic interventions as well as the final outcome. Sepsis and polytrauma are two of the most common and complex syndromes occurring in Intensive Care Unit (ICU) and affect drug absorption, disposition, metabolism and elimination. Pharmacological management of ICU patients requires consideration of the unique pharmacokinetics associated with these clinical conditions and the likely occurrence of drug interaction. Rational adjustment in drug choice and dosing contributes to the appropriateness of treatment of those patients.
Dysfunction of astrocytes in senescence‐accelerated mice SAMP8 reduces their neuroprotective capacity
Authors: García‐Matas Silvia , Gutierrez‐Cuesta Javier , Coto‐Montes Ana , Rubio‐Acero Raquel , Díez‐Vives Cristina , Camins Antoni , Pallàs Mercè , Sanfeliu Coral , Cristòfol Rosa
Published: July 2008

Early onset increases in oxidative stress and tau pathology are present in the brain of senescence‐accelerated mice prone (SAMP8). Astrocytes play an essential role, both in determining the brain's susceptibility to oxidative damage and in protecting neurons. In this study, we examine changes in tau phosphorylation, oxidative stress and glutamate uptake in primary cultures of cortical astrocytes from neonatal SAMP8 mice and senescence‐accelerated‐resistant mice (SAMR1). We demonstrated an enhancement of abnormally phosphorylated tau in Ser199 and Ser396 in SAMP8 astrocytes compared with that of SAMR1 control mice. Gsk3β and Cdk5 kinase activity, which regulate tau phosphorylation, was also increased in SAMP8 astrocytes. Inhibition of Gsk3β by lithium or Cdk5 by roscovitine reduced tau phosphorylation at Ser396. Moreover, we detected an increase in radical superoxide generation, which may be responsible for the corresponding increase in lipoperoxidation and protein oxidation. We also observed a reduced mitochondrial membrane potential in SAMP8 mouse astrocytes. Glutamate uptake in astrocytes is a critical neuroprotective mechanism. SAMP8 astrocytes showed a decreased glutamate uptake compared with those of SAMR1 controls. Interestingly, survival of SAMP8 or SAMR1 neurons cocultured with SAMP8 astrocytes was significantly reduced. Our results indicate that alterations in astrocyte cultures from SAMP8 mice are similar to those detected in whole brains of SAMP8 mice at 1–5 months. Moreover, our findings suggest that this in vitro preparation is suitable for studying the molecular and cellular processes underlying early aging in this murine model. In addition, our study supports the contention that astrocytes play a key role in neurodegeneration during the aging process.
Repression of the SUMO‐specific protease Senp1 induces p53‐dependent premature senescence in normal human fibroblasts
Authors: Yates Kristin E. , Korbel Gregory A. , Shtutman Michael , Roninson Igor B. , DiMaio Daniel
Published: July 2008

The proliferative lifespan of normal somatic human cells in culture terminates in a permanent growth‐arrested state known as replicative senescence. In this study, we show that RNA interference‐mediated repression of the genes encoding the small ubiquitin‐related modifier (SUMO)‐specific proteases, Senp1, Senp2, and Senp7, induced low passage primary human fibroblasts to senesce rapidly. Following Senp1 repression, we observed a global increase in sumoylated proteins and in the number and size of nuclear SUMO‐containing promyelocytic leukemia (PML) bodies. SUMO/PML bodies also increased during replicative senescence. p53 transcriptional activity was enhanced towards known p53 target genes following repression of Senp1, and inhibition of p53 function prevented senescence after Senp1 repression. These data indicate that Senp1 repression induces p53‐mediated premature senescence and that SUMO proteases may thus be required for proliferation of normal human cells.
Different rates of telomere attrition in peripheral lymphocytes in a pair of dizygotic twins with hematopoietic chimerism
Authors: Brüderlein Silke , Müller Kathrin , Melzner Julia , Högel Josef , Wiegand Peter , Möller Peter
Published: July 2008

Hematopoietic chimerism in dizygotic twins is due to placental vascular anastomoses and arises when hematopoietic stem cells from one twin home to the bone marrow of the other. We report a case of hematopoietic chimerism in a pair of 27‐year‐old dizygotic twins who each had a mixture of 46,XX and 46,XY blood lymphocytes, both with 98% male (XY) lymphocytes and 2% female (XX) lymphocytes. Analysis of telomere length by T/C FISH revealed that the female twin generally had longer telomeres than the male twin. Moreover, in the male sibling, the telomeres within the female lymphocytes were shortened to 87% of their original length, while the telomeres within the male lymphocytes were 33% longer in the female sibling. Thus, telomere length attrition in peripheral lymphocytes is determined mainly by the environment of the cell and less by intracellular factors.
Science–policy guidelines as a benchmark: making the European Water Framework Directive
Authors: Lagacé Emilie , Holmes John , McDonnell Rachael
Published: July 2008

In recent years, a number of governments have made moves towards evidenced‐based policymaking justified by the assertions that scientific understanding makes for better‐informed and more effective legislative and regulatory decisions. Some of these governments have produced generic, almost step‐by‐step recipes, for the use of evidence in policymaking in the form of ‘science–policy guidelines’. The usefulness of these somewhat linear procedures has not been assessed in the actual process of policymaking. Using as a benchmark the guidelines developed by the European Commission, this paper examines the collection and use of scientific advice in the development of the European Water Framework Directive.
Experience and the distribution of portfolio payoffs in the European Commission
Authors: FRANCHINO FABIO
Published: July 2008

Abstract. This article tests four theories of portfolio distribution within the European Commission and assesses whether experience plays a role in the process of allocating policy responsibilities. The share of portfolios that each Member State is assigned, through its Commissioners, is strongly related to its resources and voting power, as predicted by the proportionality norm and bargaining theory, respectively. Additionally, Member States with Commissioners that have experience in the relevant portfolios are assigned shares that are significantly above what one may expect from these two theories. For half of the portfolios, Commissioners have moderate views along the dimension of the policy they manage, but appointed Commissioners also have significantly more experience in both supranational portfolios and similar national portfolios than the median Commissioner. The difference in experience in supranational and, more weakly, national portfolios significantly accounts for the difference in preference between the appointed and the median Commissioner. Finally, salience matters as well. Left/right leaning Commissioners are significantly more likely to be assigned portfolios with a left‐wing/right‐wing ideological profile, but this strong relation disappears for Commissioners with above average experience in the Commission, in the relevant supranational portfolios or in national governments.
Resting Brain Glucose Uptake in Headache‐Free Migraineurs
Authors: Kassab Mounzer , Bakhtar Omid , Wack David , Bednarczyk Edward
Published: July 2008

Background and Objective.— To compare metabolism in the brains of migraineurs during headache‐free periods with those obtained from healthy volunteers.

Methods.— Eleven migraineurs (defined by the International Headache Society's criteria) presented during spontaneous headache‐free intervals to undergo 18FDG PET brain imaging of glucose metabolism. The control group consisted of 14 healthy volunteers. Comparison of images was done using Statistical Parametric Mapping to detect significant (P < .05) differences in brain glucose metabolism between the 2 groups.

Results.— Two regions of significant increase in glucose uptake were identified in migraineurs relative to the control population. The 2 regions were mapped predominantly to the posterior white matter of the cerebrum and cerebellum.

Conclusions.— Our study demonstrates the presence of what may be a primary metabolic disturbance in the posterior white matter of the brain in migraineurs.
Effect of stage 2 kindling on local cerebral blood flow rates in rats with genetic absence epilepsy
Authors: Çarçak Nihan , Ferrandon Arielle , Koning Estelle , Aker Rezzan Gülhan , Özdemir Osman , Onat Filiz Yilmaz , Nehlig Astrid
Published: July 2008

Purpose:  Genetic absence epilepsy rats from Strasbourg (GAERS) are resistant to the progression of kindling seizures. We studied local cerebral blood flow (LCBF) changes in brain regions involved in seizures in both GAERS and nonepileptic rats (NEC) to map the differences that may be related to the resistance to kindling.

Methods:  Electrodes were implanted in the amygdala of adult NEC and GAERS male rats, which were stimulated to reach stage 2. Quantitative autoradiographic measurements of LCBF were performed by the [14C]‐iodoantipyrine ([14C]IAP) autoradiographic technique allowing the precise mapping of regional perfusion changes. LCBF rates were measured bilaterally in 43 brain regions. The tracer infusion lasted for 60 s and started at 15 s before seizure induction.

Results:  Rates of LCBF increased in stimulated GAERS and NEC groups compared to nonstimulated controls. The LCBF increase in stimulated GAERS was larger and more widespread than that observed in stimulated NEC. The LCBF increase in the somatosensory cortex, ventrobasal and anterior thalamic nuclei, hypothalamus, subthalamic nucleus, piriform, entorhinal and perirhinal cortex, amygdala, CA2 region of hippocampus, and substantia nigra was statistically significantly larger in stimulated GAERS compared to stimulated NEC rats.

Conclusion:  The results show that more brain regions are activated by kindling stimulation in GAERS. This widespread activation in GAERS involves the somatosensory cortex and thalamus, which are both known to be involved in the expression of absence seizures as well as numerous limbic regions thought not to play a role in the expression of absence seizures, suggesting an interaction between corticothalamocortical and limbic circuitries.
EEG‐fMRI study of the ictal and interictal epileptic activity in patients with eyelid myoclonia with absences
Authors: Liu Yonghong , Yang Tianhua , Liao Wei , Yang Xuhong , Liu Iing , Yan Bo , Chen Huafu , Gong Qiyong , Stefan Hermann , Zhou Dong
Published: July 2008

Purpose:  To investigate the blood oxygenation level‐dependent (BOLD) signal changes correlated with ictal and interictal epileptic discharges using electroencephalography‐correlated functional magnetic resonance imaging (EEG‐fMRI) in patients with eyelid myoclonia with absences (EMA) and then to explore the pathophysiological mechanisms of epileptic discharges and their effect on brain function.

Methods:  Four patients with EMA were investigated through the method of EEG‐fMRI. The characteristics of BOLD signal changes linked to ictal and interictal epileptic discharges under different states of consciousness were explored.

Results:  Seven sessions of EEG‐fMRI scanning in the four patients were obtained. The main regions of activation included thalamus, mesial frontal cortex, middle parietal lobe, temporal lobe, insula, midline structures, and cerebellum. Deactivations were mainly in the anterior frontal lobe, posterior parietal lobe, and posterior cingulate gyrus. Thalamic BOLD change was predominantly activation in most of our cases. The distribution of activation associated with ictal epileptic discharges was wider, and the distribution of deactivation was closer to pericortex compared with the BOLD change linked with interictal epileptic discharges.

Conclusions:  The activation in the thalamus may be associated with generalized spike wave in EMA; the combination of different patterns of activation with consistent pattern of deactivations (“default” pattern) in patients with EMA may prognosticate different states of consciousness in response to ictal and interictal epileptic discharges.
PHYLOGEOGRAPHY OF BATRACHOSPERMUM MACROSPORUM (BATRACHOSPERMALES, RHODOPHYTA) FROM NORTH AND SOUTH AMERICA1
Authors: Vis Morgan L. , Cameron Hodge J. , Necchi Jr. Orlando
Published: July 2008

Phylogeographic trends in Batrachospermum macrosporum Mont. were investigated using the mitochondrial intergenic spacer between the cytochrome oxidase subunit 2 and 3 genes (cox2‐3). A total of 11 stream segments were sampled with seven in the coastal plain of North America and four in tropical areas of South America. Fifteen thalli were sampled from seven streams, 14 thalli from two streams, and eight thalli from two streams. There were 16 haplotypes detected using 149 individuals. Of the eight haplotypes from locations in North America, all were 334 base pairs (bp) in length, and of those from South America, five were 344 bp, and three were 348 bp. Two individual networks were produced: one for the haplotypes from North America and another for those from South America, and these could not be joined due to the large number of base pair differences. This split between haplotypes from North and South America was confirmed with sequence data of the rbcL gene. There was very little genetic variation among the haplotypes from the North American locations, leading us to hypothesize that these are fairly recent colonization events along the coastal plain. In contrast, there was high variation among haplotypes from South America, and it would appear that the Amazon serves as a center of diversity. We detected considerable variation in haplotypes among streams, but frequently, a single haplotype in an individual stream segment, which is consistent with data from previous studies of other batrachospermalean taxa, may suggest a single colonization event per stream.
EVALUATION OF ANTIOXIDANT DEFENSE RESPONSES TO LEAD STRESS IN HAPALOSIPHON FONTINALIS‐3391
Authors: Zutshi Sunaina , Choudhary Meenakshi , Bharat Naveen , Abdin Malik Zainul , Fatma Tasneem
Published: July 2008

Lead (Pb) is a heavy metal and a potentially hazardous environmental pollutant. In this study, the potential of lead to induce oxidative stress in biological systems was assessed using the cyanobacterium Hapalosiphon fontinalis‐339 as model test organism. The impact of lead toxicity on the cellular antioxidant system and the biochemical modulations that result in generation of antioxidant defense responses were also studied. To determine the effect of Pb toxicity, the test organism was grown in the presence of various concentrations (0.05, 0.10, 0.20, 0.40, 0.80, 1.0, 1.20, and 1.25 mg · L−1) of exogenous lead chloride (PbCl2), and its effects on growth were observed in terms of the change in chl content. There was a significant increase in metal uptake by the alga with a concomitant decrease in growth. Lead stress appeared to significantly up‐regulate the levels of stress‐related antioxidant enzymes—such as superoxide dismutase (SOD), ascorbate peroxidase (APX), and glutathione reductase (GR)—while a decrease in catalase (CAT) levels was observed. In addition, the levels of nonenzymatic antioxidants, oxidized and total glutathione, were changed. Our results suggest the existence of a potent antioxidant defense machinery in H. fontinalis‐339 and this organism can be employed to monitor lead toxicity in the environment.
INFLUENCE OF IRRADIANCE ON VIRUS–ALGAL HOST INTERACTIONS1
Authors: Baudoux Anne‐Claire , Brussaard Corina P. D.
Published: July 2008

The effect of different irradiance levels on the interactions between the algal host and its virus was investigated for two marine phytoplankton, Phaeocystis globosa Scherff. and Micromonas pusilla (Butcher) Manton et Parke. The algal cultures were acclimated at 25, 100, and 250 μmol photons · m−2 · s−1 (LL, ML, and HL, respectively), after which they were infected with a lytic virus (PgV‐07T and MpV‐02T) and monitored under the appropriate irradiance and in darkness. The effect of irradiance levels on the host–virus interactions differed for the two algal host–virus systems examined. For P. globosa, the LL‐acclimated cultures showed a 4 h prolonged latent period (11–16 h), which may be related to the subsaturated growth observed at this irradiance. The burst size was reduced by 50% at LL and HL compared to ML (525 PgV · cell−1). The fraction of infectious viruses, however, remained unchanged. Viral replication was prevented when the LL P. globosa cultures were kept in darkness (up to 48 h) but recovered when placed back into the light. PgV‐07T still replicated in the dark for the ML‐ and HL‐acclimated cultures, but viral yield was reduced by 50%–85%. For M. pusilla, the burst size (285–360 MpV · cell−1), the infectivity, and the latent period of MpV‐02T (7–11 h) remained unaffected by the incident light. Conversely, darkness not only inhibited MpV replication but also resulted in substantial cell lysis of the noninfected cultures. Our study implies that irradiance level is an important factor controlling algal host–virus interactions and hence the dynamics of phytoplankton populations.
Environmental Enrichment Alters Neurotrophin Levels After Fetal Alcohol Exposure in Rats
Authors: Parks Elizabeth A. , McMechan Andrew P. , Hannigan John H. , Berman Robert F.
Published: July 2008

Background:  Prenatal alcohol exposure causes abnormal brain development, leading to behavioral deficits, some of which can be ameliorated by environmental enrichment. As both environmental enrichment and prenatal alcohol exposure can individually alter neurotrophin expression, we studied the interaction of prenatal alcohol and postweaning environmental enrichment on brain neurotrophin levels in rats.

Methods:  Pregnant rats received alcohol by gavage, 0, 4, or 6 g/kg/d (Zero, Low, or High groups), or no treatment (Naïve group), on gestational days 8 to 20. After weaning on postnatal day 21, offspring were housed for 6 weeks in Isolated, Social, or Enriched conditions. Levels of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), and neurotrophin‐3 (NT‐3) were then measured in frontal cortex, occipital cortex, hippocampus, and cerebellar vermis.

Results:  Prenatal alcohol exposure increased NGF levels in frontal cortex (High‐dose group) and cerebellar vermis (High‐ and Low‐dose groups); increased BDNF in frontal cortex, occipital cortex and hippocampus (Low‐dose groups), and increased NT‐3 in hippocampus and cerebellar vermis (High‐dose). Environmental enrichment resulted in lower NGF, BDNF, and NT‐3 levels in occipital cortex and lower NGF in frontal cortex. The only significant interaction between prenatal alcohol treatment and environment was in cerebellar vermis where NT‐3 levels were higher for enriched animals after prenatal alcohol exposure, but not for animals housed under Isolated or Social conditions.

Conclusions:  Both prenatal alcohol exposure and postweaning housing conditions alter brain neurotrophin levels, but the effects appear to be largely independent. Although environmental enrichment can improve functional outcomes, these results do not provide strong support for the hypothesis that rearing in a complex environment ameliorates prenatal alcohol effects on brain neurotrophin levels in rats.
Role of Acetaldehyde in Ethanol‐Induced Elevation of the Neuroactive Steroid 3α‐Hydroxy‐5α‐Pregnan‐20‐One in Rats
Authors: Boyd Kevin N. , O’Buckley Todd K. , Leslie Morrow A.
Published: July 2008

Background:  Systemic ethanol administration increases neuroactive steroid levels that increase ethanol sensitivity. Acetaldehyde is a biologically active compound that may contribute to behavioral and rewarding effects of ethanol. We investigated the role of acetaldehyde in ethanol‐induced elevations of 3α‐hydroxy‐5α‐pregnan‐20‐one (3α,5α‐THP) levels in cerebral cortex.

Methods:  Male Sprague–Dawley rats were administered ethanol, and plasma acetaldehyde concentrations were measured by gas chromatography to determine relevant concentrations. Rats were then administered acetaldehyde directly, acetaldehyde plus cyanamide to block its degradation, or ethanol in the presence of inhibitors of ethanol metabolism, to determine effects on 3α,5α‐THP levels in cerebral cortex.

Results:  Ethanol administration (2 g/kg) to rats results in a peak acetaldehyde concentration of 6‐7 μM at 10 minutes that remains stable for the duration of the time points tested. Direct administration of acetaldehyde eliciting this plasma concentration does not increase cerebral cortical 3α,5α‐THP levels, and inhibition of ethanol‐metabolizing enzymes to modify acetaldehyde formation does not alter ethanol‐induced 3α,5α‐THP levels. However, higher doses of acetaldehyde (75 and 100 mg/kg), in the presence of cyanamide to prevent its metabolism, are capable of increasing cortical 3α,5α‐THP levels.

Conclusions:  Physiological concentrations of acetaldehyde are not responsible for ethanol‐induced increases in 3α,5α‐THP, but a synergistic role for acetaldehyde with ethanol may contribute to increases in 3α,5α‐THP levels and ethanol sensitivity.
Age‐ and Sex‐Dependent Effects of Footshock Stress on Subsequent Alcohol Drinking and Acoustic Startle Behavior in Mice Selectively Bred for High‐Alcohol Preference
Authors: Chester Julia A. , Barrenha Gustavo D. , Hughes Matthew L. , Keuneke Kelly J.
Published: July 2008

Background: Exposure to stress during adolescence is known to be a risk factor for alcohol‐use and anxiety disorders. This study examined the effects of footshock stress during adolescence on subsequent alcohol drinking in male and female mice selectively bred for high‐alcohol preference (HAP1 lines). Acoustic startle responses and prepulse inhibition (PPI) were also assessed in the absence of, and immediately following, subsequent footshock stress exposures to determine whether a prior history of footshock stress during adolescence would produce enduring effects on anxiety‐related behavior and sensorimotor gating.

Methods: Alcohol‐naïve, adolescent (male,n = 27; female,n = 23) and adult (male,n = 30; female,n = 30) HAP1 mice were randomly assigned to a stress or no stress group. The study consisted of 5 phases: (1) 10 consecutive days of exposure to a 30‐minute footshock session, (2) 1 startle test, (3) one 30‐minute footshock session immediately followed by 1 startle test, (4) 30 days of free‐choice alcohol consumption, and (5) one 30‐minute footshock session immediately followed by 1 startle test.

Results: Footshock stress exposure during adolescence, but not adulthood, robustly increased alcohol drinking behavior in both male and female HAP1 mice. Before alcohol drinking, females in both the adolescent and adult stress groups showed greater startle in phases 2 and 3; whereas males in the adolescent stress group showed greater startle only in phase 3. After alcohol drinking, in phase 5, enhanced startle was no longer apparent in any stress group. Males in the adult stress group showed reduced startle in phases 2 and 5. PPI was generally unchanged, except that males in the adolescent stress group showed increased PPI in phase 3 and females in the adolescent stress group showed decreased PPI in phase 5.

Conclusions: Adolescent HAP1 mice appear to be more vulnerable to the effects of footshock stress than adult mice, as manifested by increased alcohol drinking and anxiety‐related behavior in adulthood. These results in mice suggest that stress exposure during adolescence may increase the risk for developing an alcohol‐use and/or anxiety disorder in individuals with a genetic predisposition toward high alcohol consumption.
The Effects of Patient Function and Dependence on Costs of Care in Alzheimer's Disease
Authors: Zhu Carolyn W. , Leibman Christopher , McLaughlin Trent , Scarmeas Nikolaos , Albert Marilyn , Brandt Jason , Blacker Deborah , Sano Mary , Stern Yaakov
Published: July 2008

OBJECTIVES: To estimate incremental effects of patients' dependence and function on costs of care during the early stages of Alzheimer's disease (AD) and to compare strengths of their relationships with different cost components.

DESIGN: Multicenter, cross‐sectional, observational study.

SETTING: Three university hospitals in the United States.

PARTICIPANTS: One hundred seventy‐nine community‐living patients with probable AD, with modified Mini‐Mental State Examination scores of 30 or higher.

MEASUREMENTS: Patients' dependence was measured using the Dependence Scale (DS). Functional capacity was measured using the Blessed Dementia Rating Scale (BDRS). Total cost was measured by summing direct medical costs and informal costs. Direct medical costs included costs of hospitalization, outpatient treatment and procedures, assistive devices, and medications. Informal costs were estimated from time spent helping with basic and instrumental activities of daily living for up to three caregivers per patient using national average hourly earnings as wage rate.

RESULTS: DS and BDRS were associated with higher total cost; a 1‐point increase in DS was associated with a $1,832 increase in total cost, and a 1‐point increase in BDRS was associated with a $3,333 increase. Examining component costs separately identified potential differences between DS and BDRS. A 1‐point increase in BDRS was associated with a $1,406 increase in direct medical cost. A 1‐point increase in DS was associated with a $1,690 increase in informal cost.

CONCLUSION: Patients' dependence and function related differently to direct medical and informal cost, suggesting that measures of function and dependence provided unique information for explaining variations in cost of care for patients with AD, highlighting the value in measuring both constructs.
Cystatin‐C, Renal Function, and Incidence of Hip Fracture in Postmenopausal Women
Authors: LaCroix Andrea Z. , Lee Jennifer S. , Wu LieLing , Cauley Jane A. , Shlipak Michael G. , Ott Susan M. , Robbins John , Curb J. David , Leboff Meryl , Bauer Douglas C. , Jackson Rebecca D. , Kooperberg Charles L. , Cummings Steven R.
Published: July 2008

OBJECTIVES: To evaluate the association between chronic kidney disease and incident hip fracture using serum cystatin‐C as a biomarker of renal function calculated without reference to muscle mass.

DESIGN: Case‐control study nested within a prospective study.

SETTING: The Women's Health Initiative Observational Study conducted at 40 U.S. clinical centers.

PARTICIPANTS: From 93,676 women aged 50 to 79 followed for an average of 7 years, 397 incident hip fracture cases and 397 matched controls were studied.

MEASUREMENTS: Cystatin‐C levels were measured on baseline serum using a particle‐enhanced immunonepholometric assay. Estimated glomerular filtration rates (eGFRcys‐c) were calculated using a validated equation and categorized into three groups (≥90.0 mL/min per 1.73 m2, 60.0–89.9 mL/min per 1.73 m2, and <60.0 mL/min per 1.73 m2 indicating chronic kidney disease Stages 3 to 4).

RESULTS: The odds ratio (OR) for hip fracture was 2.50 (95% confidence interval (CI)=1.32–4.72) for eGFRcys‐c less than 60 mL/min per 1.73 m2 compared with Stages 0 to 1, after adjustment for body mass, parental hip fracture, smoking, alcohol consumption, and physical function. No association was observed for eGFRcys‐c of 60 to 90 mL/min per 1.73 m2 (OR=1.04, 95% CI=0.66–1.64). Additional adjustment for poor health status, hemoglobin, serum 25‐hydroxy vitamin D, and bone metabolism markers did not affect these associations. Adjustment for plasma homocysteine reduced the OR for eGFRcys‐c less than 60 mL/min per 1.73 m2 to 1.83 (95% CI=0.93–3.61).

CONCLUSION: Women with eGFRcys‐c levels less than 60 mL/min per 1.73 m2 have a substantially greater risk of hip fracture. Effects of renal function on homocysteine levels may partially mediate, or accompany, this association.
Self‐Reported Osteoarthritis, Ethnicity, Body Mass Index, and Other Associated Risk Factors in Postmenopausal Women—Results from the Women's Health Initiative
Authors: Wright Nicole C. , Riggs Gail Kershner , Lisse Jeffrey R. , Chen Zhao
Published: July 2008

The objective of this analysis was to assess risk factors for self‐reported osteoarthritis (OA) in an ethnically diverse cohort of women. The participants were postmenopausal women aged 50 to 79 (n=146,494) participating in the clinical trial and observational study of the Women's Health Initiative (WHI). Baseline OA and risk factors were collected from WHI questionnaires. Logistic regression was used to find the association between the risk factors and OA. Risk factor distribution and ethnicity interaction terms were used to assess ethnic differences in OA risk. Forty‐four percent of the participants reported OA. Older age (odds ratio (OR)70–79 vs 50–59=2.69, 95% confidence interval (CI)=2.60–2.78) and higher body mass index (BMI) (ORBMI≥40.0 vs <24.9=2.80, 95% CI=2.63–2.99) were found to be the strongest risk factors associated with self‐reported OA. The prevalence of obesity (BMI≥30.0) was 57.9% in African Americans, 51.0% in American Indians, 41.9% in Hispanic whites, and 32.9% in non‐Hispanic whites. The prevalence of other major OA risk factors was higher in African‐American, American‐Indian, and Hispanic white women than in non‐Hispanic white women. Non‐Hispanic white women who were in the extreme obese category (BMI≥40.0 kg/m2) had a 2.80 times (95% CI=2.63, 2.99) greater odds of self‐reported OA. The odds were even higher in American‐Indian (OR=4.22, 95% CI=1.82, 9.77) and African‐American (OR=3.31, 95% CI=2.79, 3.91) women, indicating a significant interactive effect of BMI and ethnicity on odds of OA. In conclusion, OA is a highly prevalent condition in postmenopausal women, and there are differential effects according to ethnicity.
Health Outcome Priorities Among Competing Cardiovascular, Fall Injury, and Medication‐Related Symptom Outcomes
Authors: Tinetti Mary E. , McAvay Gail J. , Fried Terri R. , Allore Heather G. , Salmon JoAnna C. , Foody Joanne M. , Bianco Luann , Ginter Sandra , Fraenkel Liana
Published: July 2008

OBJECTIVES: To determine the priority that older adults with coexisting hypertension and fall risk give to optimizing cardiovascular outcomes versus fall‐ and medication symptom‐related outcomes.

DESIGN: Interview.

SETTING: Community.

PARTICIPANTS: One hundred twenty‐three cognitively intact persons aged 70 and older with hypertension and fall risk.

MEASUREMENTS: Discrete choice task was used to elicit the relative importance placed on reducing the risk of three outcomes: cardiovascular events, serious fall injuries, and medication symptoms. Risk estimates with and without antihypertensive medications were obtained from the literature. Participants chose between 11 pairs of options that displayed lower risks for one or two outcomes and a higher risk for the other outcome(s), versus the reverse. Results were used to calculate relative importance scores for the three outcomes. These scores, which sum to 100, reflect the relative priority participants placed on the difference between the risk estimates of each outcome.

RESULTS: Sixty‐two participants (50.4%) placed greater importance on reducing risk of cardiovascular events than reducing risk of the combination of fall injuries and medication symptoms; 61 participants did the converse. A lower percentage of participants with chronic obstructive pulmonary disease (P=.02), unsteadiness (P=.02), functional dependency (P=.04), lower cognition (P=.02) and depressive symptoms (P=.03) prioritized cardiovascular outcomes over fall injuries and medication symptoms than did participants without these characteristics.

CONCLUSION: Interindividual variability in the face of competing outcomes supports individualizing decision‐making to individual priorities. In the current example, this may mean forgoing antihypertensive medications or compromising on blood pressure reduction for some individuals.
Olfaction and the 5‐Year Incidence of Cognitive Impairment in an Epidemiological Study of Older Adults
Authors: Schubert Carla R. , Carmichael Lakeesha L. , Murphy Claire , Klein Barbara E. K. , Klein Ronald , Cruickshanks Karen J.
Published: July 2008

OBJECTIVES: To determine whether odor identification ability is associated with the 5‐year incidence of cognitive impairment in a large population of older adults with normal cognition at baseline and whether olfactory impairment contributes to the prediction of cognitive decline.

DESIGN: Population‐based longitudinal study.

SETTING: Beaver Dam, Wisconsin.

PARTICIPANTS: One thousand nine hundred twenty participants in the Epidemiology of Hearing Loss Study (mean age 66.9).

MEASUREMENTS: Olfaction was measured using the San Diego Odor Identification Test (SDOIT). Incident cognitive impairment was defined as a Mini‐Mental State Examination (MMSE) score of less than 24 or reported diagnosis of dementia or Alzheimer's disease (AD) at follow‐up in participants with a MMSE score of 24 or greater and no diagnosis of dementia or AD at baseline.

RESULTS: There was a significant association between olfactory impairment at baseline and 5‐year incidence of cognitive impairment (odds ratio (OR)=6.62, 95% confidence interval (CI)=4.36–10.05). The association remained significant after adjusting for possible confounders (OR=3.72, 95% CI=2.31–5.99). The positive predictive value of the SDOIT was 15.9%, the negative predictive value was 97.2%, the sensitivity was 55.1%, and the specificity was 84.4% for 5‐year incidence of cognitive impairment.

CONCLUSION: Olfactory impairment at baseline was strongly associated with 5‐year incidence of cognitive impairment as measured using the MMSE. Odor identification testing may be useful in high‐risk settings, but not in the general population, to identify patients at risk for cognitive decline.
Results, Rhetoric, and Randomized Trials: The Case of Donepezil
Authors: Gilstad John R. , Finucane Thomas E.
Published: July 2008

Whether donepezil provides meaningful benefit to patients with Alzheimer's disease (AD) is controversial, but drug sales annually total billions of dollars. A review of data from published randomized clinical trials (RCTs) found rhetorical patterns that may encourage use of this drug.

To create a reproducible observation, the sentences occurring at five specific text sites in all 18 RCTs of donepezil for AD were tabulated, as were study design, sources of financial support, and outcomes that could be compared between trials.

Rhetoric in the 13 vendor‐supported trials (15 publications) was strongly positive. Three early trials used the motif “efficacious (or effective) … treating … symptoms” four times. “Well‐tolerated and efficacious” or an equivalent motif appeared 11 times in five RCTs. Nine RCTs referred 15 times to previously proven effectiveness. Seven trials encourage off‐label use, for “early” cognitive impairment, severe dementia in advance of the Food and Drug Administration labeling change, or behavioral symptoms. These rhetorical motifs and themes appeared only in the vendor‐supported trials. Trials without vendor support described the drug's effects as “small” or absent; two emphasized the need for better treatments. RCT results were highly consistent in all trials; the small differences do not explain differences in rhetoric.

At these text sites in the primary research literature on donepezil for AD, uniformly positive rhetoric is present in all vendor‐supported RCTs. Reference to the limited benefit of donepezil is confined to RCTs without vendor support. Data in the trials are highly consistent. This observation generates the hypothesis that rhetoric in vendor‐supported published RCTs may promote vendors' products.
Evaluation of the transfusion safety of blood products and determination of plasma concentrations of acitretin and etretinate in patients receiving transfusions
Authors: Park Hyung‐Doo , Kim Hye‐Kyung , Kim Jong‐Won , Kim Dae‐Won , Lee Joo‐Heung , Huh Wooseong , Youn Jai‐Il , Kim Hyung‐Gun , Kim Yoon‐Gyoon , Kim Myung‐Hwa , Lee Soo‐Youn
Published: July 2008

BACKGROUND: Acitretin and etretinate are potentially teratogenic. Many people taking acitretin for psoriasis have donated blood during the deferral period in Korea. Therefore, many of the blood products from these donors treated with acitretin have been circulated in Korea.

STUDY DESIGN AND METHODS: A high‐performance liquid chromatography system (HP 1050, Agilent Technologies) was used to measure the drug concentrations in five blood products and in patients. Sixty patients taking acitretin were enrolled to determine their plasma drug levels. Forty‐one female patients were recruited to investigate the residual plasma levels of acitretin and etretinate in relation to their teratogenicity. We calculated the elimination rate of acitretin and etretinate during the manufacturing process.

RESULTS: Sixty individuals taking acitretin expressed variable acitretin (<2.0‐206.8 ng/mL) and etretinate levels (<2.0‐9.1 ng/mL). All patients that had a transfusion had concentrations of acitretin and etretinate lower than the lower limit of quantification (LLOQ; 2 ng/mL). The concentrations of acitretin and etretinate in five blood products were less than the LLOQ. Approximately 98.84 percent (log value, 1.94) of the acitretin and 99.93 percent (log value, 3.14) of the etretinate was eliminated during the manufacturing process of albumin. More than 99.99 percent (log values, 5.95‐15.76) of acitretin and etretinate was eliminated during the manufacturing processing of immunoglobulin and blood coagulation factors.

CONCLUSIONS: We confirmed the effective manufacturing processing of various blood products. We also demonstrated that individuals receiving transfusions with blood products originating from donors treated with acitretin were not at risk for significant exposure to the acitretin and etretinate.
Bacterial contamination of whole blood–derived platelets: the introduction of sample diversion and prestorage pooling with culture testing in the American Red Cross
Authors: Benjamin Richard J. , Kline Linda , Dy Beth A. , Kennedy Jean , Pisciotto Patricia , Sapatnekar Suneeti , Mercado Rachel , Eder Anne F.
Published: July 2008

BACKGROUND: Bacterial sepsis following whole blood–derived platelet (WBP) transfusion has remained a substantial patient risk, primarily due to a lack of practical and effective means to limit or detect bacterial contamination. We describe the risk of reported septic reactions to WBPs and the introduction of prestorage‐pooled whole blood–derived platelets (PSPs) collected using initial sample diversion and cultured for bacterial contamination.

STUDY DESIGN AND METHODS: Product qualification and quality control (QC) testing with the Acrodose PL system (Pall Medical) were evaluated in four regional blood centers. Bacterial contamination risk was assessed by review of reported septic transfusion reactions to WBPs and by aerobic QC culture of leukoreduced PSPs utilizing automated microbial detection system cultures (BacT/ALERT 3D, bioMérieux).

RESULTS: Before implementing PSPs (January 2003‐December 2006), we distributed 2,535,043 WBP units and received 20 reports of septic reactions including 2 fatalities (7.9 per million [1:126,752] reactions and 0.79 per million [1:1,267,522] fatalities). In October 2006, PSPs were effectively implemented with a product qualification success rate of 99.6 percent and a mean yield of 4.0 × 1011 platelets (PLTs) per pool. Whole blood collection sets with sample diversion technology were introduced during the operational trial and decreased the rate of confirmed‐positive bacterial culture of PSPs from 2111 (1:474) to 965 (1:1036) per million (odds ratio, 0.46; 95% confidence interval, 0.22‐0.95). No septic reactions to PSPs were reported (25,936 PSP units distributed).

CONCLUSION: Sample diversion and bacterial culture are effective methods to reduce bacterial risk with WBP transfusion. Bacterial contamination of PSPs was assessed at 5.8‐fold our current rate for apheresis PLTs utilizing comparable culture protocols.
Proteomic characterization of freeze‐dried human plasma: providing treatment of bleeding disorders without the need for a cold chain
Authors: Steil Leif , Thiele Thomas , Hammer Elke , Bux Jürgen , Kalus Monika , Völker Uwe , Greinacher Andreas
Published: July 2008

BACKGROUND: Transfusion of human plasma is a basic treatment for severe coagulopathies, especially in major bleeding. The required logistics to provide plasma is challenging because of the need to maintain a cold chain. This disadvantage could be overcome by lyophilized plasma. However, it is unknown to what extent lyophilization alters plasma proteins. Quantitative proteomic technologies were applied to monitor protein changes during production of lyophilized, solvent/detergent (S/D)‐treated plasma.

MATERIALS AND METHODS: The impact of S/D treatment and lyophilization on the plasma proteome was evaluated by differential in‐gel electrophoresis (2D‐DIGE), and proteins were characterized by mass spectrometry. Clotting factor activities were determined in lyophilized S/D‐treated plasma after 24 months of storage at room temperature.

RESULTS: By 2D‐DIGE, 600 individual protein spots were compared. Lyophilization did not change any of the 600 spots, whereas pathogen inactivation caused significant changes of 38 spots including α1‐antitrypsin, α1‐antichymotrypsin, and α2‐antiplasmin. Clotting factor activities remained stable over 24 months of storage.

CONCLUSION: Lyophilization of human plasma neither alters its protein composition nor impairs its clotting capacity. It does not require cost‐intensive logistics for storage and transport and can be quickly reconstituted. It is suggested that lyophilized, pathogen‐inactivated plasma is an attractive option to provide the most important basic treatment for severe coagulopathies in areas without cold chain and to provide plasma with reduced time delay in emergency situations.
Synthesis of Hollow Titania Powder by the Hydrothermal Method
Authors: Chung Chia‐Jung , Jean Jau‐Ho
Published: July 2008

A layer‐by‐layer method is used to coat titania on spherical polystyrene (PS) powders in an aqueous solution. To increase surface charge density, a negatively charged PS powder is sequentially adsorbed by a cationic polyethylenimine (PEI)/anionic ammonium salt of poly(acrylic acid)/cationic PEI polyelectrolytes. A precursor of a negatively charged titanium bis‐ammonium lactate dihydroxide (TALH) is then precipitated onto the above positively charged PS. Repeating the coating processes of TALH/PEI in an aqueous solution, a uniform, multilayer TALH/PEI coating on PS powder is formed. A crystalline, spherical, hollow titania powder is then obtained by hydrothermal treatment of the above powder in an aqueous solution at temperatures higher than 350°C.
Microstructure–Property Relationships in Liquid Phase‐Sintered High‐Temperature Bismuth Scandium Oxide‐Lead Titanate Piezoceramics
Authors: Sehirlioglu Alp , Sayir Ali , Dynys Fred
Published: July 2008

High‐temperature piezoelectrics are necessary for aeronautic and aerospace applications. The principal challenge for the insertion of piezoelectric materials is their limitation for upper use temperature, which is due to low Curie temperature and increasing conductivity at high temperatures. We investigated processing, microstructure, and property relationships of (1−x)BiScO3−(x)PbTiO3 composition as a promising high‐temperature piezoelectric. The effects of excess PbO and Bi2O3 and their partitioning in grain boundaries were studied using impedance spectroscopy, ferroelectric, and piezoelectric measurement techniques. Excess Pb addition increased the grain‐boundary conduction and the grain‐boundary area resulting in ceramics with higher AC‐conductivity (tan δ=0.9 and 1.7 for 0 and 5 at.% excess Pb at 350°C and at 10 kHz) that were not resistive enough to pole. Excess Bi addition increased the resistivity (tan δ=0.9 and 0.1 for 0 and 5 at.% excess Pb at 350°C and at 10 kHz), improved poling, and increased the piezoelectric coefficient from 354 to 408 pC/N for 5 at.% excess Bi addition. Thus, excess Bi2O3 proved to be a successful liquid phase forming additive to improve the 0.37BiScO3–0.63PbTiO3 piezoceramics for high‐temperature applications, as a result of increased resistivity and enhanced piezoelectric activity.
Mechanical Properties and Dimensional Effects of ZnO‐ and SnO2‐Based Varistors
Authors: Ramírez Miguel Angel , Rubio‐Marcos Fernando , Fernández José Francisco , Lengauer Markus , Bueno Paulo Roberto , Longo Elson , Varela José Arana
Published: July 2008

A comparison between traditional ZnO‐(modified Matsuoka system, [ZnO]) and SnO2‐based varistors (98.9%SnO2+1%CoO+0.05%Nb2O5+0.05%Cr2O3, [SCNCr]) regarding their mechanical properties, finite element (FE) modeling, and macroscopic response with current pulse is presented in this work. The experimental values of the elastic (static and dynamic) modulus and bending strength are given. Both the static and the dynamic modulus were two times higher for SnO2 (∼200 GPa) with respect to ZnO (∼100 GPa). A similar behavior was found for the bending strength, confirming the superior mechanical properties of SCNCr associated with a homogeneous microstructure. The finite element analyses yielded the most appropriate thickness/diameter aspect ratio (H/D), while thermomechanical stress is minimized. The values of (H/D) were lower for the SCNCr in comparison with the ZnO‐based varistors, allowing the production of smaller pieces that can resist the same thermomechanical stress. Finally, preliminary analyses of the macroscopic failures for samples treated with degradation pulses of 8/20‐μs type allowed to confirm the absence of failures due to cracking and/or puncture in the SCNCr. The absence of these failures originates from the good thermomechanical properties.