bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine release is impaired in a mouse model of DYT1 dystonia
Authors: Balcioglu Aygul , Kim Mee‐Ohk , Sharma Nutan , Cha Jang‐Ho , Breakefield Xandra O. , Standaert David G.
Published: May 2007

Early onset torsion dystonia, the most common form of hereditary primary dystonia, is caused by a mutation in the TOR1A gene, which codes for the protein torsinA. This form of dystonia is referred to as DYT1. We have used a transgenic mouse model of DYT1 dystonia [human mutant‐type (hMT)1 mice] to examine the effect of the mutant human torsinA protein on striatal dopaminergic function. Analysis of striatal tissue dopamine (DA) and metabolites using HPLC revealed no difference between hMT1 mice and their non‐transgenic littermates. Pre‐synaptic DA transporters were studied using in vitro autoradiography with [3H]mazindol, a ligand for the membrane DA transporter, and [3H]dihydrotetrabenazine, a ligand for the vesicular monoamine transporter. No difference in the density of striatal DA transporter or vesicular monoamine transporter binding sites was observed. Post‐synaptic receptors were studied using [3H]SCH‐23390, a ligand for D1 class receptors, [3H]YM‐09151‐2 and a ligand for D2 class receptors. There were again no differences in the density of striatal binding sites for these ligands. Using in vivo microdialysis in awake animals, we studied basal as well as amphetamine‐stimulated striatal extracellular DA levels. Basal extracellular DA levels were similar, but the response to amphetamine was markedly attenuated in the hMT1 mice compared with their non‐transgenic littermates (253 ± 71% vs. 561 ± 132%, p < 0.05, two‐way anova). These observations suggest that the mutation in the torsinA protein responsible for DYT1 dystonia may interfere with transport or release of DA, but does not alter pre‐synaptic transporters or post‐synaptic DA receptors. The defect in DA release as observed may contribute to the abnormalities in motor learning as previously documented in this transgenic mouse model, and may contribute to the clinical symptoms of the human disorder.
In vivo targeting of antibody fragments to the nervous system for Alzheimer’s disease immunotherapy and molecular imaging of amyloid plaques
Authors: Poduslo Joseph F. , Ramakrishnan Muthu , Holasek Silvina S. , Ramirez‐Alvarado Marina , Kandimalla Karunya K. , Gilles Emily J. , Curran Geoffry L. , Wengenack Thomas M.
Published: May 2007

Targeting therapeutic or diagnostic proteins to the nervous system is limited by the presence of the blood–brain barrier. We report that a F(ab′)2 fragment of a monoclonal antibody against fibrillar human Aβ42 that is polyamine (p)‐modified has increased permeability at the blood–brain barrier, comparable binding to the antigen, and comparable in vitro binding to amyloid plaques in Alzheimer’s disease (AD) transgenic mouse brain sections. Intravenous injection of the pF(ab′)24.1 in the AD transgenic mouse demonstrated efficient targeting to amyloid plaques throughout the brain, whereas the unmodified fragment did not. Removal of the Fc portion of this antibody derivative will minimize the inflammatory response and cerebral hemorrhaging associated with passive immunization and provide increased therapeutic potential for treating AD. Coupling contrast agents/radioisotopes might facilitate the molecular imaging of amyloid plaques with magnetic resonance imaging/positron emission tomography. The efficient delivery of immunoglobulin G fragments may also have important applications to other neurodegenerative disorders or for the generalized targeting of nervous system antigens.
Agonist‐mediated regulation of presynaptic receptor function during development of rat septal neurons in culture
Authors: Ehret Andreas , Birthelmer Anja , Rutz Susanne , Riegert Céline , Rothmaier Anna Katharina , Jackisch Rolf
Published: May 2007

Presynaptic receptors modulating the release of acetylcholine (ACh) were studied in fetal septal neurons cultured in a growth medium to which various drugs were added from day 3 in vitro (DIV 3) to DIV 14. The influence of these drugs on the function of the presynaptic muscarinic (M‐) autoreceptor was determined at DIV 14 by measuring the inhibitory effect of the M‐agonist oxotremorine on the electrically‐evoked release of [³H]ACh from cultures pre‐incubated with [³H]choline. The presence of the M‐agonists oxotremorine (100 μmol/L) or carbachol (100 μmol/L) from DIV 3 to DIV 14, or from DIV 13 to DIV 14, abolished M‐autoreceptor function at DIV 14, whereas the presence of the M‐antagonist atropine (10 μmol/L from DIV 3 to DIV 14) during growth left M‐autoreceptor function unaltered. Inhibition of ACh esterase by donepezil (1 μmol/L from DIV 3 to DIV 14) weakly decreased M‐autoreceptor function at DIV 14; inhibition of neuronal firing by 0.1 tetrodotoxin (0.1 μmol/L from DIV 3 to DIV 14) did not tend to affect M‐autoreceptor function at DIV 14. Co‐cultivation of fetal septal and raphe neurons for 2 weeks yielded cell cultures containing both vesicular ACh transporter‐ and tryptophan hydroxylase‐immunopositive cells. From these cultures, the release of both [³H]ACh and [³H]5‐HT could be induced by electrical field stimulation. In co‐cultured neurons versus septal‐only ones the inhibitory effect of oxotremorine on the evoked release of [³H]ACh appeared almost normal, whereas that of the selective 5‐HT1B agonist 3‐(1,2,5,6‐tetrahydropyrid‐4‐yl)pyrrollo[3,2‐b]pyrid‐5‐one (CP‐93,129) was completely abolished. The effects of CP‐93,129 were also absent on DIV 14 in septal mono‐cultures grown in the presence of CP‐93,129 (10 μmol/L) from DIV 3 to DIV 14. It is therefore concluded that the regulation of presynaptic receptor function strongly depends on the concentrations of endogenous transmitters in the neuronal environment.
An alternatively spliced cytochrome P4501A1 in human brain fails to bioactivate polycyclic aromatic hydrocarbons to DNA‐reactive metabolites
Authors: Kommaddi Reddy P. , Turman Cheri M. , Moorthy Bhagavatula , Wang Lihua , Strobel Henry W. , Ravindranath Vijayalakshmi
Published: May 2007

CYP1A1, a cytochrome P450 enzyme, metabolizes polycyclic aromatic hydrocarbons to genotoxic metabolite(s) that bind to DNA and initiate carcinogenesis. RT‐PCR amplification of the complete open reading frame of CYP1A1 generated an amplicon of 1593 bp having deletion of 87 bp of exon‐6 that translated into functional P450 enzyme. Unlike wild type CYP1A1, exon 6 del CYP1A1 did not metabolize polycyclic aromatic hydrocarbons such as, benzo(a)pyrene to genotoxic, ultimate carcinogens that form DNA adducts. Exon 6 del CYP1A1 metabolized ethoxyresorufin (the classical substrate for CYP1A1) less efficiently compared with wild type CYP1A1 while pentoxy and benzyloxyresorufin (classical substrates for CYP2B) were dealkylated more efficiently. In silico docking showed alteration of the substrate access channel in exon 6 del CYP1A1 such that benzo(a)pyrene does not bind in any orientation that would permit the formation of carcinogenic metabolites. Genotyping revealed that the splice variant was not generated due to differences in genomic DNA sequence and the variant was present only in brain but not in liver, kidney, lung, or heart from the same individual. We provide evidence that unique P450 enzymes, generated by alternate splicing in a histiospecific manner can modify genotoxic potential of carcinogens such as benzo(a)pyrene by altering their biotransformation pathway.
Constitutively active calcineurin mediates delayed neuronal death through Fas‐ligand expression via activation of NFAT and FKHR transcriptional activities in mouse brain ischemia
Authors: Shioda Norifumi , Han Feng , Moriguchi Shigeki , Fukunaga Kohji
Published: May 2007

We recently demonstrated that a constitutively active form of calcineurin (CaN) is generated by calpain‐mediated limited proteolysis following brain ischemia. The calpain‐induced CaN activation mediated delayed neuronal death through translocation of nuclear factor of activated T‐cells (NFAT) into nuclei after brain ischemia. We also previously demonstrated that activation of forkhead in rhabdomyosarcoma (FKHR), a forkhead transcription factor and substrate of protein kinase‐B (Akt), mediated ischemia‐induced neuronal death through Fas‐ligand expression in gerbil hippocampus. FKHR activation occurred through decreased Akt activity and concomitant dephosphorylation mediated by undefined phosphatases. In this study, we show that phosphorylated Ser‐256 of FKHR is dephosphorylated by constitutively active CaN and that in turn FKHR forms a complex with CaN that is translocated into nuclei after brain ischemia. After nuclear translocation of NFAT and FKHR, both NFAT and FKHR stimulated expression of Fas‐ligand by binding to its promoter region. Consistent with activation of the Fas‐ligand promoter by FKHR dephosphorylation, Fas‐ligand expression increased 2 days after ischemia/reperfusion, and treatment with the CaN inhibitor FK506 inhibited that expression. These results suggest that FKHR is a downstream target of CaN and that constitutively active CaN mediates delayed neuronal death through Fas‐ligand expression via up‐regulation of both NFAT and FKHR transcriptional activity in brain ischemia.
Contrasting roles of neuronal Msk1 and Rsk2 in Bad phosphorylation and feedback regulation of Erk signalling
Authors: Clark C. J. , McDade D. M. , O’Shaughnessy C. T. , Morris B. J.
Published: May 2007

Activated extracellular‐signal‐regulated kinase (Erk) phosphorylates and activates downstream kinases including ribosomal S6 kinase 2 (Rsk2/RPS6KA3) and mitogen‐ and stress‐activated kinase 1 (Msk1, RPS6KA5). Rsk2 plays an important role in neuronal plasticity, as patients with Coffin–Lowry syndrome, where Rsk2 is dysfunctional, have impaired cognitive function. However, the relative role of neuronal Rsk2 and Msk1 in activating proteins downstream of Erk is unclear. In PC12 cells and in cortical neurones, the calcium ionophore A23187‐induced phosphorylation of Erk, Msk1, Rsk2 and also the Bcl‐2‐associated death protein (Bad), which protects against neurotoxicity. Specific knockdown of Msk1 with small interfering RNA reduced the ability of A23187 to induce Bad phosphorylation in both PC12 cells and cortical neurones. Conversely, specific knockdown of Rsk2 potentiated Bad phosphorylation following A23187 treatment, and also elevated Erk phosphorylation in both cell types. This indicates that Msk1 rather than Rsk2 mediates neuronal Bad phosphorylation following Ca2+ influx and implicates Rsk2 in a negative‐feedback regulation of Erk activity.
Inhibition of protein phosphatases induces transport deficits and axonopathy
Authors: Yang Ying , Yang Xi‐Fei , Wang Yi‐Peng , Tian Qing , Wang Xiao‐Chuan , Li Hong‐Lian , Wang Qun , Wang Jian‐Zhi
Published: May 2007

The activity of protein phosphatase (PP)‐2A and PP‐1 decreased in the brains of Alzheimer’s disease and inhibition of the phosphatases led to spatial memory deficit in rats. However, the molecular basis underlying memory impairment of the phosphatase inhibition is elusive. In the present study, we observed a selective inhibition of PP‐2A and PP‐1 with Calyculin A (CA) not only caused hyperphosphorylation of cytoskeletal proteins, but also impaired the transport of pEGFP‐labeled neurofilament‐M subunit in the axon‐like processes of neuroblastoma N2a cells and resulted in accumulation of neurofilament in the cell bodies. To analyze the morphological alteration of the cells during inhibition of the phosphatases, we established a cell model showing steady outgrowth of axon‐like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA‐treated cells. We conclude suppression of PP‐2A and PP‐1 by CA not only damages intracellular transport but also leads to cell degeneration, which may serve as the functional and structural elements for the memory deficits induced by suppression of the phosphatases.
The lipophilic metal chelators DP‐109 and DP‐460 are neuroprotective in a transgenic mouse model of amyotrophic lateral sclerosis
Authors: Petri Susanne , Calingasan Noel Y. , Alsaied Osama A. , Wille Elizabeth , Kiaei Mahmoud , Friedman Jonathan E. , Baranova Oxana , Chavez Juan C. , Beal M. Flint
Published: May 2007

One of the hypotheses for the development of familial amyotrophic lateral sclerosis (ALS) is that mutations in the superoxide dismutase 1 enzyme lead to aberrant properties of the copper within the active site of the enzyme which then causes increased oxidative damage. The lipophilic metal chelators DP‐109 and DP‐460 which chelate calcium, copper, and zinc were tested in the G93A‐transgenic ALS mouse model. Both compounds significantly extended survival, DP‐109 (5 mg/kg/day) by 10%, DP‐460 (10 mg/kg/day) by 9%. While the effect on survival was relatively small, chelator treatment also improved motor performance, dramatically reduced cell loss in the lumbar spinal cord and decreased reactive astrocytosis and microgliosis. Markers of oxidative damage, tumor necrosis factor (TNF)‐αand α‐synuclein were reduced in the lumbar spinal cord of G93A mice treated with DP‐109 or DP‐460 as compared with vehicle‐treated animals. Furthermore, the treatment induced protein expression of the transcription factor hypoxia inducible factor‐1α and mRNA levels of vascular endothelial growth factor as a corresponding target gene. In line with previous studies using metal chelators in the G93A animal model, our results suggest that these compounds have neuroprotective capacities in ALS.
Brain‐derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte‐enhancer factor 2C through an ERK1/2‐RSK2 signaling cascade
Authors: Wang Yupeng , Liu Lidong , Xia Zhengui
Published: May 2007

Neurotrophin activation of myocyte‐enhancer factor (MEF) 2C is one of the strongest pro‐survival signaling pathways in developing neurons. To date, neurotrophin stimulation of MEF2C has been largely attributed to its direct phosphorylation by extracellular signal‐regulated kinase (ERK) 5. Because MEF2C is not directly phosphorylated by ERK1/2 in vitro, it is generally assumed that the ERK1/2 signaling cascade does not regulate MEF2C. Surprisingly, we discovered that ERK1/2 are required for both the transcriptional and neuroprotective activity of MEF2C in cortical neurons stimulated by brain‐derived neurotrophic factor. ERK1/2 stimulation of MEF2C is mediated by p90 ribosomal S6 kinase 2 (RSK2), a Ser/Thr protein kinase downstream of ERK1/2. RSK2 strongly phosphorylates purified recombinant MEF2C protein in vitro. Furthermore, RSK2 can directly phosphorylate MEF2C on S192, a consensus RSK2‐phosphorylation site located in the transactivation domain of MEF2C. Substitution of S192 with a non‐phosphorylatable alanine diminishes both the transcriptional and neuroprotective activity of MEF2C to an extent similar to mutation on S387, an established activating phosphorylation site. Together, our data identifies ERK1/2‐RSK2 signaling as a novel mechanism by which neurotrophins activate MEF2C and promote neuronal survival.
Isolation and characterization of microsatellite loci in the finless porpoise (Neophocaena phocaenoides)
Authors: CHEN L. , BRUFORD M. , YANG G.
Published: May 2007

Eight dinucleotide microsatellite loci were isolated from the finless porpoise (Neophocaena phocaenoides). Analysis of 30 individuals showed the number of alleles ranged from four to 21 with observed heterozygosity ranging from 0.300 to 0.833, and expected heterozygosity ranging from 0.437 to 0.932. Cross‐species amplification was tested in four other cetacean species. These microsatellite markers would be valuable tools for population genetic studies of finless porpoises and other cetacean species.
Habitat selection by Marsh Tits Poecile palustris in the UK
Authors: HINSLEY SHELLEY A. , CARPENTER JANE E. , BROUGHTON RICHARD K. , BELLAMY PAUL E. , ROTHERY PETER , AMAR ARJUN , HEWSON CHRIS M. , GOSLER ANDREW G.
Published: May 2007

The Marsh Tit Poecile palustris is a small, hole‐nesting woodland passerine whose national population in the UK has declined by more than 50% in the last 25 years. To investigate possible causes for the species long‐term decline, we examined habitat selection by Marsh Tits at three scales. For individual foraging birds, winter time budgets and foraging behaviour, recorded using instantaneous sampling, differed little between Marsh and Blue Tits Cyanistes caeruleus, but Marsh Tits spent more time in the understorey and more time lower down in both the woodland canopy and the understorey. At the scale of breeding territories, the characteristics (numbers by size class, vegetation density, species richness) of trees and shrubs were compared using 100 × 10‐m sample transects of ten territories in each of four woods. The characteristics of the trees differed significantly between woods whilst those of the shrubs did not, suggesting that the characteristics of shrubs were more important in territory selection by Marsh Tits than were those of trees. Furthermore, in one of the four woods (Wytham Woods, Oxfordshire), Marsh Tits were largely absent from areas with dense tree canopy, but poor shrub cover. On a national scale, using data from 157 of the woodlands surveyed by the RSPB/BTO Repeat Woodland Bird Survey, Marsh Tit abundance in 2003/04 was found to be positively related to vegetation cover at heights corresponding to the shrub layer, especially at 2–4 m. These relationships were not apparent in data for the same woods for the 1980s, but shrub cover had increased substantially by 2003/04 and Marsh Tit abundance had increased in woods with the most cover in 2003/04. Thus, factors damaging the shrub layer, such as overgrazing by deer, shading out by canopy closure and managed clearance of shrub cover, may reduce the suitability of woodland for Marsh Tits. Habitat use by a closely related species, Willow Tit Poecile montanus, is also discussed.
The ecology of clutch size variation in Darwin's Small Ground FinchGeospiza fuliginosa: comparison between lowland and highland habitats
Authors: KLEINDORFER S.
Published: May 2007

This study examines the ecology of clutch size variation between two contiguous populations of Small Ground FinchGeospiza fuliginosathat breed in geographically distinct habitats (lowlands, highlands) on Santa Cruz Island of the Galapagos Archipelago. Small clutch size is considered an adaptive response to high predation risk (to reduce behavioural conspicuousness at the nest and lower the energetic costs of re‐nesting), whereas high food abundance is predicted to favour large clutch size. This study has two main objectives: (1) to present descriptive data on clutch size variation inG. fuliginosabetween habitats, and (2) to test life‐history predictions for clutch size variation based on food abundance and nest predation hypotheses. The highlands on Santa Cruz Island were characterized by high nest predation (52%), high annual rainfall and high insect abundance across the year, whereas the lowlands were characterized by low nest predation (5%), seasonal rainfall and high insect abundance during the breeding season. The highland birds had smaller clutch size and a shorter re‐nesting interval. Patterns of nest attendance differed significantly between habitats. The percentage of time incubating per hour was comparable between habitats, but the mean duration per incubation event was longer in the highlands (with fewer events per hour), which is consistent with the prediction of reduced behavioural conspicuousness at nests under conditions of high predation risk. There were no significant differences in nestling feeding levels between habitats, probably becauseG. fuliginosais a multiple prey loader.
Compensation for light loss due to filtering by macular pigment: relation to hue cancellation
Authors: Stringham James M. , Hammond Billy R.
Published: May 2007

Background:  A long‐standing question in colour vision research is how the visual system is able to correct for the significant absorbance of short wave light by the crystalline lens and macular pigment (MP). Such compensation must be required in order to maintain colour constancy across the retina where MP levels are changing quickly and dramatically.

Objective:  We studied this compensation mechanism by measuring MP spatial density profiles and hue cancellation functions across the central retina in a sample of six young healthy subjects.

Method:  Yellow (Y, 575 nm)/blue (B, 440 nm) and red (R, 600 nm)/green (G, 501 nm) cancellation functions were obtained at 0, 1, 1.75, 3 and 7° eccentricity. The MP optical density at 460 nm was measured at these same eccentricities using heterochromatic flicker photometry. One subject was assessed repeatedly over a 4‐month period during daily supplementation with 30 mg of lutein (L).

Results:  Hue cancellation values for the Y/B system did not change across the retina (r = 0.09). In contrast, R/G sensitivity changed as a direct function of MP absorbance (r = 0.99). The Y/B values did not change in the one subject supplemented with 30 mg L daily, despite increases in MP of about 50% over 4 months.

Conclusions:  Despite large variations in MP across the retina, hue cancellation values for the Y‐B system across the central retina were constant. For example, one subject's MP density declined from a central peak of 0.99 to near zero at 7° (near 90% transmission difference) yet thresholds for the Y/B system were unaffected. In contrast, the G lobe of the R/G system was directly correlated with MP density. Taken together, these results confirm that the Y/B system compensates for MP density, but the R/G system does not.
Objective refraction from monochromatic wavefront aberrations via Zernike power polynomials
Authors: Robert Iskander D. , Davis Brett A. , Collins Michael J. , Franklin Ross
Published: May 2007

With the increased popularity of wavefront sensor devices there has been significant interest in relating the subjectively measured sphero‐cylindrical refractive error to the objectively measured wavefront aberrations. We investigate the applicability of four different measures for objective refraction assessment that are derived from a set of estimated Zernike wavefront coefficients. Two of the measures are based on the second‐ and higher‐order Zernike polynomials while the other two measures are based on the estimated dioptric power representations. For the latter, closed‐form expressions for dioptric powers based on the estimated focal length and the wavefront curvature are derived. We call these two new representations the ‘refractive Zernike power polynomials’ and ‘curvature Zernike power polynomials’. Data from 120 eyes from 60 normal subjects were used to assess the correlation between the subjective and objective refractions. The results indicate that the objective sphero‐cylindrical refraction calculated from the estimated refractive power map via the Zernike power polynomials is superior to the other considered representations and achieves best correlation with subjective sphero‐cylindrical refraction.
Changes in astigmatism with accommodation
Authors: Radhakrishnan Hema , Charman W. Neil
Published: May 2007

An experiment is described in which changes in ocular astigmatism were recorded over an accommodation stimulus range of 0–4 D, in the right eyes of a group of 31 normal subjects aged 17–37 years. The visual axes were horizontal and the observation conditions were monocular. Although subjects had a range of spherical ametropia, all had initial astigmatism of 1.0 DC or less. It was found that, for most subjects in the group, astigmatism changed in the with‐the‐rule direction, the mean change being −0.036 DC at axis 176 deg for each dioptre of accommodation response. It is speculated that these changes might reflect increases in lens tilt about a horizontal axis, caused by the combined effects of a slacker zonule and gravity.
Magnification and accommodation with phakic intraocular lenses
Authors: Langenbucher Achim , Szentmáry Nóra , Seitz Berthold
Published: May 2007

Background and Purpose:  The calculation of phakic lenses (PL) was described by van der Heijde et al. [Klin. Monatsbl. Augenheilkd (1988) Vol. 193, pp. 99–102], but a formalism for estimating relative magnification compared with spectacle correction and accommodation effects are not yet published. The purpose of this study was to describe a mathematical strategy for calculating PL and relative magnification as a function of object vergence (phakic accommodation).

Methods:  Parameters used for the calculations are the spectacle refraction before and after (target refraction) surgery, the vertex distance, corneal refraction, and the predicted position of the phakic intraocular lens. The lens power is determined as the difference in vergences between the spectacle‐corrected eye and the uncorrected eye at the reference plane of the predicted lens position. If we simplify the crystalline lens to a single refracting surface located at the principal plane of the crystalline lens, the vergence of the eye with spectacle correction and with PL is determined as a function of object distance [object vergence 0 D (infinity) to 10 D (object at a distance of 10 cm)] to evaluate accommodation effects of the crystalline lens.

Results:  The method was applied to two clinical examples. In example 1 we calculated the power of a PL for correction of a 10‐D myopia and determined the relative magnification and the vergence at the principal plane of the crystalline lens as a function of object vergence. Magnification gain increases with objects at near from 17% to 26%, whereas the vergence at the principal plane of the crystalline lens changes by 3.04 D less than in the spectacle‐corrected eye. In example 2, a 20‐D myopia was corrected with a PL. The gain in magnification changed from 33% to 58% with nearer objects. The change in vergence at the principal plane of the crystalline lens with objects at near was much higher with the PL compared with the spectacle correction, which implies that the refractive change necessary for focusing objects at near distance is much higher in the PL correction.

Conclusions:  Even if the predictability of postoperative refraction with PL is comparable or better than in other methods of correcting high or excessive ametropia, the effects of lateral magnification change and accommodation have to be considered to avoid image‐size disparities (aniseikonia) and to maintain binocular vision, especially with monocular PL implantation and anisometropia.
Circular polarization biomicroscopy: a method for determining human corneal stromal lamellar organization in vivo
Authors: Misson Gary P.
Published: May 2007

The theory of polarization biomicroscopy is explored using Stokes vectors and Mueller matrices. It is established that circular polarization can be used to simultaneously detect birefringent elements at any orientation unlike orientation‐sensitive techniques using linear polarized light alone. A method of biomicroscopy using circular polarized light is described and tested in a physical model. The method is then used to investigate the lamellar structure of human corneas in vivo in pairs of eyes of 38 subjects. An approximate confocal elliptic/hyperbolic distribution of stromal fibrils, presumed to be collagen, is clearly identified within central and intermediate areas of the cornea. All subjects tested demonstrate approximate mirror symmetry between pairs of eyes typically with a preferred orientation of central fibrils at approximately 15° to the horizontal in a superotemporal–inferonasal direction.
Pediatric Patient Safety Events during Hospitalization: Approaches to Accounting for Institution‐Level Effects
Authors: Slonim Anthony D. , Marcin James P. , Turenne Wendy , Hall Matt , Joseph Jill G.
Published: May 2007

Objective. To determine the rates, patient, and institutional characteristics associated with the occurrence of patient safety indicators (PSIs) in hospitalized children and the degree of statistical difference derived from using three approaches of controlling for institution level effects.

Data Source. Pediatric Health Information System Dataset consisting of all pediatric discharges (<21 years of age) from 34 academic, freestanding children's hospitals for calendar year 2003.

Methods. The rates of PSIs were computed for all discharges. The patient and institutional characteristics associated with these PSIs were calculated. The analyses sequentially applied three increasingly conservative methods to control for the institution‐level effects robust standard error estimation, a fixed effects model, and a random effects model. The degree of difference from a “base state,” which excluded institution‐level variables, and between the models was calculated. The effects of these analyses on the interpretation of the PSIs are presented.

Principal Findings. PSIs are relatively infrequent events in hospitalized children ranging from 0 per 10,000 (postoperative hip fracture) to 87 per 10,000 (postoperative respiratory failure). Significant variables associated PSIs included age (neonates), race (Caucasians), payor status (public insurance), severity of illness (extreme), and hospital size (>300 beds), which all had higher rates of PSIs than their reference groups in the bivariable logistic regression results. The three different approaches of adjusting for institution‐level effects demonstrated that there were similarities in both the clinical and statistical significance across each of the models.

Conclusions. Institution‐level effects can be appropriately controlled for by using a variety of methods in the analyses of administrative data. Whenever possible, resource‐conservative methods should be used in the analyses especially if clinical implications are minimal.
Quality by Any Other Name?: A Comparison of Three Profiling Systems for Assessing Health Care Quality
Authors: Kerr Eve A. , Hofer Timothy P. , Hayward Rodney A. , Adams John L. , Hogan Mary M. , McGlynn Elizabeth A. , Asch Steven M.
Published: May 2007

Objective. Many performance measurement systems are designed to identify differences in the quality provided by health plans or facilities. However, we know little about whether different methods of performance measurement provide similar answers about the quality of care of health care organizations. To examine this question, we used three different measurement approaches to assess quality of care delivered in veteran affairs (VA) facilities.

Data Sources/Study Setting. Medical records for 621 patients at 26 facilities in two VA regions.

Study Design. We examined agreements in quality conclusions using: focused explicit (38 measures for six conditions/prevention), global explicit (372 measures for 26 conditions/prevention), and structured implicit review physician‐rated care (a single global rating of care for three chronic conditions and overall acute, chronic and preventive care). Trained nurse abstractors and physicians reviewed all medical records. Correlations between scores from the three systems were adjusted for measurement error in each using multilevel regression models.

Results. Intercorrelations of scores were generally moderate to high across all three systems, and rose with adjustment for measurement error. Site‐level correlations for prevention and diabetes care were particularly high. For example, adjusted for measurement error at the site level, prevention quality was correlated at 0.89 between the implicit and global systems, 0.67 between implicit and focused, and 0.73 between global and focused systems.

Conclusions. We found moderate to high agreement in quality scores across the three profiling systems for most clinical areas, indicating that all three were measuring a similar construct called “quality.” Adjusting for measurement error substantially enhanced our ability to identify this underlying construct.
Muslim‐Christian Relations in Medieval Southern Italy
Authors: Taylor Julie Anne
Published: May 2007

Abstract:  This article examines the nature of relations between Muslims and Christians in southern Italy during the thirteenth century. In response to uprisings in Sicily, the emperor Frederick II transferred an estimated 20,000 Muslims to the city of Lucera in Apulia. Outside the Iberian Peninsula, Lucera came to have the largest Muslim population of any city in western Europe. Although the formation of the colony led to competition for resources between its inhabitants and the local Christian population, the members of the two religious communities often traded and collaborated. Social mobility was possible for the Lucerine Muslims, particularly through military service. Like Christians and Jews living in the dar al‐Islam, the Muslims of Lucera had a protected status, and they paid a tax called the jizya. They remained free to practice their religion. The heavy taxes paid by the Muslim colony at Lucera during its almost eighty‐year existence made it a valuable asset to the Hohenstaufen and Angevin crowns. Nevertheless, the settlement was dismantled in 1300 on the order of the Angevin king, Charles II, who gave a religious justification. The colony's history provides insight into the complex relations between Muslims and Christians in medieval Mediterranean Europe.
Mild donor liver steatosis has no impact on hepatitis C virus fibrosis progression following liver transplantation
Authors: Botha Jean F. , Thompson Eric , Gilroy Richard , Grant Wendy J. , Mukherjee Sandeep , Lyden Elizabeth R. , Fox Ira J , Sudan Debra L. , Shaw Byers W. , Langnas Alan N.
Published: May 2007

Background: This study examines the impact of donor liver macrovesicular steatosis on recurrence of hepatitis C virus (HCV) disease after liver transplantation.

Methods: Between 1998 and 2004, 113 patients underwent liver transplantation for HCV‐related cirrhosis. Time to histologic recurrence (fibrosis score ≥2) was the primary endpoint of the study. Recurrence was graded according to the system of Ludwig and Batts. A Cox's proportional hazard regression model was used to analyse the association between donor liver steatosis and HCV recurrence.

Results: Recurrence‐free survival for patients who received steatotic grafts was 82% and 47% at 1 and 4 years, respectively, and 81% and 52% for patients who received a non‐steatotic liver. Donor macrovesicular steatosis (5–45%) was found to have no impact on HCV recurrence (P=0.47). Donor age (P=0.02) and cold ischaemia time (P=0.01) were found to increase the relative risk of HCV recurrence. The estimated risk of HCV recurrence increased by 23% for every 10‐year increase in donor age. Similarly the risk of recurrence increased by 13% for every 1‐h increase in cold ischaemia time.

Conclusion: Mild‐moderate donor liver macrovesicular steatosis has no impact on HCV recurrence after liver transplantation for HCV‐related cirrhosis. Cold ischaemia time and donor age increased the likelihood of HCV recurrence.
Documenting a transfusion: how well is it done?
Authors: Rock Gail , Berger Ray , Filion Diane , Touche Donna , Neurath Doris , Wells George , ElSaadany Susie , Afzal Mohammed
Published: May 2007

BACKGROUND: Current practice in transfusion medicine promotes clear documentation of transfusion‐related events including the fact that the patient has been informed of the related risks and benefits.

STUDY DESIGN AND METHODS: A retrospective review of 1005 patient charts was carried out to determine documentation.

RESULTS: Most patients were from general surgery (10.8%) and cardiac surgery (14.1%). In 75 percent of cases the physician had not documented that any discussion had occurred regarding the risks and/or benefits or alternatives. Only 12 percent of charts included information that the patient was subsequently told what blood components were given to them. The discharge summary recorded transfusion information in 32.1 percent of cases whereas the consult note had this information in 26.3 percent. Chart records matched the transfusion medicine records in 60.6 percent of cases. The most common error was in the blood unit identification number.

CONCLUSIONS: While accepted in theory, the practice of documenting patient information on transfusion is not well done.
Proactive administration of platelets and plasma for patients with a ruptured abdominal aortic aneurysm: evaluating a change in transfusion practice
Authors: Johansson Pär I. , Stensballe Jakob , Rosenberg Iben , Hilsløv Tanja L. , Jørgensen Lisbeth , Secher Niels H.
Published: May 2007

BACKGROUND:Continued hemorrhage remains a major contributor of mortality in massively transfused patients and those who survive have a higher platelet (PLT) count and a shorter prothrombin time and activated partial thromboplastin time (APTT) than nonsurvivors. It was considered that early substitution with PLTs and fresh‐frozen plasma (FFP) would prevent development of coagulopathy and thus improve survival.

STUDY DESIGN AND METHODS:Survival of patients undergoing surgery for a ruptured abdominal aortic aneurysm (rAAA) was compared after implementing a proactive transfusion therapy encompassing two pooled buffy‐coat PLT concentrates (PBPCs) immediately when a rupture of the aorta was suspected and again 30 minutes before aortic unclamping together with FFP administered in a 1:1 ratio to the amount of red blood cells (RBCs) with that of a control group receiving transfusion therapy according to existing recommendations.

RESULTS:The intervention group (n = 50) had a higher PLT count at arrival at the intensive care unit compared to the control group (n = 82; 155 × 109/L vs. 69 × 109/L; p < 0.0001), shorter APTT (39 sec vs. 44 sec; p < 0.001), fewer postoperative transfusions (RBCs, 2 vs. 6; FFP, 2 vs. 4; and PBPCs, 0 vs. 1; p < 0.01), and a higher 30‐day survival rate (66% vs. 44%; p = 0.02).

CONCLUSION:This study suggests that proactive administration of PLTs and FFP improves coagulation competence, reduces postoperative hemorrhage, and increases survival in massively bleeding rAAA patients.
The epidemiology of transfusion‐associated hepatitis C in a children's hospital
Authors: Luban Naomi L.C. , Colvin Camilla A. , Mohan Parvathi , Alter Harvey J.
Published: May 2007

BACKGROUND:Children transfused with blood and blood products before 1992 are at risk for chronic hepatitis C virus (HCV) infection. To determine the prevalence of HCV infection and risks associated with acquisition of HCV, a single‐institution lookback study was performed.

STUDY DESIGN AND METHODS:A total of 5473 infants and children who received transfusions between 1982 and 1992 were identified. A control population of 600 age‐, sex‐, race‐ and zip code–matched children who did not receive transfusions with the same exclusions provided background seroprevalence data. Patients were tested for antibodies to HCV, confirmed with second generation recombinant immunoblot assay (RIBA) and when appropriate quantitative and qualitative HCV RNA by reverse transcription polymerase chain reaction (PCR). Viral persistence was assessed by serial PCR determinations for HCV RNA.

RESULTS:Of the 5473 eligible patients, 4726 were locatable and 2758 were tested. Forty‐three children (1.6%) were persistently anti‐HCV enzyme immunoassay (EIA)–positive, confirmed by RIBA; 39 were positive for the presence of HCV RNA. Four cleared their virus as assessed by two negative HCV PCRs 6 months apart. There was a borderline higher number of children with HCV who received fresh whole blood than those who tested HCV‐negative.

CONCLUSION:Because HCV infection is generally asymptomatic, children are not identified unless they are specifically tested. We identified, enrolled, tested, and confirmed a new diagnosis of HCV infection in 43 patients. As HCV treatments become increasingly effective, it is important to identify silently infected individuals, particularly when the infection was iatrogenically induced.
Successful in vivo recovery and extended storage of additive solution (AS)‐5 red blood cells after deglycerolization and resuspension in AS‐3 for 15 days with an automated closed system
Authors: Bandarenko Nicholas , Cancelas Jose , Snyder Edward L. , Hay Shauna N. , Rugg Neeta , Corda Tammy , Joines Amy D. , Gormas Jennifer F. , Pratt Gayle P. , Kowalsky Richard , Rose Michael , Rose Leslie , Foley Jim , Popovsky Mark A.
Published: May 2007

BACKGROUND: Previously, cryopreserved red blood cell (RBC) units derived from CPD/AS‐5 whole‐blood (WB) collections have been limited to 24 hours postthaw storage (1‐6°C).

STUDY DESIGN AND METHODS: Sixty‐four leukoreduced (LR) and 54 nonleukoreduced (NLR) AS‐5 (n = 118) RBC units from 500‐mL WB collections were stored for 6 days, glycerolized, frozen (−70 ± 5°C) for at least 14 days, thawed, deglycerolized, and stored (1‐6°C) for 15 days resuspended in AS‐3, using an automated closed‐system cell processor (ACP 215, Haemonetics). Frozen units were stored in either ethylene vinyl acetate (EVA) or polyvinylchloride (PVC) bags. In vitro parameters were tested in all units 15 days after deglycerolization. In vivo 24‐hour recovery was measured in 77 of 118 donors.

RESULTS: Postdeglycerolization in vitro RBC mass recoveries (mean ± SD) were 96.8 ± 5.7 and 94.7 ± 5.6% for EVA LR and NLR units, respectively, and 97.3 ± 6.2 and 94.7 ± 6.2% for PVC LR and NLR units, based on unit weight and hematocrit after sampling for in vitro testing, immediately before glycerolization. Hemoglobin content (g/unit, mean ± SD) after deglycerolization was 40.4 ± 5.6 and 42.6 ± 6.0 for EVA LR and NLR units, respectively, and 40.7 ± 4.8 and 43.0 ± 7.7 for PVC LR and NLR units. Hemolysis was 0.61 ± 0.23 and 0.54 ± 0.16% for EVA LR and NLR units, and 0.47 ± 0.14 and 0.43 ± 0.12% for PVC LR and NLR units. In vivo 24‐hour recoveries on Day 15 were 83.0 ± 6.7% (PVC NLR) up to 86.2 ± 5.7% (EVA NLR).

CONCLUSION: With processing on the ACP 215 system, CPD/AS‐5 LR and NLR thawed RBC units can be stored for up to 14 days after frozen storage at −65°C or colder in EVA or PVC bags with acceptable in vivo and in vitro RBC quality.
Elastic Properties of the Ascending Aorta in Patients with β‐Thalassemia Major
Authors: Gedikli Omer , Altinbas Ahmet , Orucoglu Aslihan , Dogan Abdullah , Ozaydin Mehmet , Aslan Suleyman Murat , Acar Gurkan , Canatan Duran
Published: May 2007

Background: β‐thalassemia major (β‐TM) is a congenital hemolytic disorder characterized by impaired left ventricular and endothelial function. However, elastic properties of the aorta have not been sufficiently investigated in patients with β‐TM. We investigated whether β‐TM is related to impaired ascending aortic elastic properties. Methods: We studied 36 patients with β‐TM (age: 15.8 ± 2.6 years) and 30 age‐ and sex‐matched control subjects by echocardiography. Aortic elastic indexes, aortic strain (%), distensibility (cm2 dyn−1 10−3), and stiffness index were calculated from the echocardiographically derived thoracic aortic diameters (mm/m2), and the measurement of pulse pressure obtained by cuff sphygmomanometry. Results: Patients versus control subjects had increased aortic diameters (P < 0.001), lower mean aortic strain (9 ± 3.6 vs. 14.9 ± 3.2, P < 0.001) and distensibility (0.6 ± 0.36 vs. 0.8 ± 0.2, P < 0.012), and higher mean stiffness index (5.3 ± 2.4 vs. 2.8 ± 0.6, P < 0.001). Aortic elastic indexes were significantly associated with ferritin level, while stiffness index was significantly related to platelet count. Conclusion: Elastic properties of ascending aorta are impaired in patients with β‐TM. Impaired functions of aorta may lead to deterioration of left ventricular function.
Plasmacytoma of the mandible associated with a dental implant failure: a clinical report
Authors: Poggio Carlo E.
Published: May 2007

Abstract: The case report of a patient is presented who had been suffering from a plasmacytoma of the spine several years back, and who had developed a new plasmacytoma of the mandible, 3 years subsequent to the insertion of a dental implant. This second solitary lesion occurred 15 years after the first one, and without signs of conversion to multiple myeloma. Research in animal models has shown multinucleated giant cells, belonging to the monocyte–macrophage lineage, persisting between the titanium surface and the lymphohemopoietic compartment, at least 1.5 years after implant insertion. Factors that increase the proliferative activity of precursor B cells, for example a protracted macrophage activation, are likely to increase the risk of B cell oncogenesis. A possible role of the titanium surface in an increase of precursor B cell proliferative activity, thus facilitating a new localization, was evaluated.
Managing the curriculum – for a change
Authors: Manogue M. , Brown G.
Published: May 2007

Abstract: This article reports the model used to design a new dental curriculum, the design process used and its underlying rationale. The evidence base for the process is reviewed and discussed. Some suggestions are offered for those engaged in developing new curricula. The main conclusions drawn are that the design process needs to be managed openly and democratically; the alignment model is the most appropriate for designing dental curricula; the process of curriculum design is inextricably linked to organisational development; and the concepts of learning organisations, communities of practice and culture all have their part to play in the process of introducing deep innovations, such as new curricula’.
In vitro differentiation of epithelial cells cultured from human periodontal ligament
Authors: Shimonishi M. , Hatakeyama J. , Sasano Y. , Takahashi N. , Uchida T. , Kikuchi M. , Komatsu M.
Published: May 2007

Background and Objective:  Alkaline phosphatase and noncollagenous bone proteins are produced prior to cementum formation. While it has been suggested that epithelial rests of Malassez are involved in cementum formation, little is known about the relationship between epithelial rests of Malassez and cementum formation. The purpose of the present study was to determine whether the epithelial rests of Malassez cells cultured from human periodontal ligament can produce alkaline phosphatase and noncollagenous bone proteins, such as osteopontin, osteocalcin and bone sialoprotein.

Material and Methods:  An outgrowth of putative epithelial rests of Malassez cells was produced from periodontal ligament explant, and second passage cultures were used in the experiments. Human gingival epithelial cells and periodontal ligament fibroblasts were used as controls. The expression levels of amelogenin were analyzed by immunostaining and in situ hybridization. Furthermore, the expression levels of alkaline phosphatase and noncollagenous bone proteins were assessed by immunostaining and reverse transcription–polymerase chain reaction.

Results:  Amelogenin, alkaline phosphatase and osteopontin proteins and their corresponding mRNAs were detected at high levels in putative epithelial rests of Malassez cells. Osteocalcin and bone sialoprotein were not expressed in putative epithelial rests of Malassez cells. Alkaline phosphatase and noncollagenous bone proteins were seen in periodontal ligament fibroblasts, but not in gingival epithelial cells.

Conclusion:  Our results suggest that putative epithelial rests of Malassez cells cultured alone do not transform into maturing cells to form the cementum, but may play a potential role in the mineralization process.