bluuebunny/crossref_metadata_2025 huggingface dataset:
Marked Hippocampal Neuronal Damage without Motor Deficits after Mild Concussive‐like Brain Injury in Apolipoprotein E‐deficient Mice
Authors: HAN SEOL‐HEUI , CHUNG SEUNG‐YUN
Published: January 2006

Abstract: Of various biological factors, only allele ɛ 4 of apolipoprotein E (apoE, protein; APOE4, gene) has been thus far suggested as a major determinant of genetic risk for sporadic and late‐onset familial Alzheimer's disease (AD). Environmental influences such as lack of education, traumatic brain injury, oxidative stress, environmental toxins, hormonal imbalances, and alterations in immune or inflammatory responses may also contribute to the pathogenesis of AD. Thus genetic susceptibility and environmental risk factors may have synergistic effects on the development of AD. The purpose of present report was to assess whether the gene (APOE) and the environmental risk factor (traumatic brain injury) could interact in hippocampal neuronal degeneration. We investigated the histopathological changes of hipoccampal regions after mild concussive‐like brain injury without motor deficits in apoE‐deficient mice using the recently described novel weight‐drop device. Control mice revealed minimal neurodegenerative changes limited to CA2 and CA3, while apoE‐deficient mice showed widespread neuronal degeneration throughout hippocampal subfields and part of dentate gyrus. We also observed widespread glial fibrillary acidic protein (GFAP) immunoreactivity throughout the hippocampus, which was more intense in apoE‐deficient mice. The results of this study indicate that even very mild traumatic brain injury could result in widespread hippocampal damage in apoE‐deficient mice. This again supports the hypothesis that apoE might play a neurotrophic or neuroprotective function in the central nervous system.
Critically Attained Threshold of Cerebral Hypoperfusion: Can It Cause Alzheimer's Disease?
Authors: DE LA TORRE J. C.
Published: January 2006

Abstract: After nearly a century of inquiry, the cause of sporadic Alzheimer's disease (AD) remains to be found. On the subject of AD pathogenesis, recent basic and clinical evidence strongly argues in favor of the concept that AD is linked to brain circulatory pathology. This concept, when viewed from many different medical disciplines and from close pre‐morbid similarities to vascular dementia, assembles and hypothetically explains most of the key pathologic events associated with the development of AD. These pathologic events are triggered in AD by impaired cerebral perfusion originating in the microvasculature which affects the optimal delivery of glucose and oxygen and results in an energy metabolic breakdown of brain cell biosynthetic and synaptic pathways. We propose that two factors converge to initiate cognitive dysfunction and neurodegeneration as expressed in AD brain: (1) advanced aging, and (2) the presence of a condition that lowers cerebral perfusion. The first factor introduces a normal but potentially deconstructing process that lowers cerebral blood flow in proportion to increased aging, whereas the second factor adds a crucial burden that further lowers brain perfusion to a critical threshold that triggers neuronal metabolic compromise. When age and a condition that lowers cerebral perfusion converge, critically attained threshold of cerebral hypoperfusion (CATCH) results. CATCH is a cyclical and progressive cerebrovascular insufficiency that will destabilize neurons, synapses, neurotransmission, and cognitive ability, eventually evolving into a neurodegenerative process characterized by the formation of senile plaques, neurofibrillary tangles, and amyloid angiopathy. The concept of impaired cerebral perfusion as the cause of this dementia also explains the heterogeneic profile observed in AD patients, because an extensive list of risk factors for AD are also reported to significantly diminish blood flow to the aging brain.
Neurocardiovascular Instability, Hypotensive Episodes, and MRI Lesions in Neurodegenerative Dementia
Authors: BALLARD CLIVE , O'BRIEN JOHN , BARBER BOB , SCHELTENS PHILIP , SHAW FIONA , MCKEITH IAN , KENNY ROSE ANNE
Published: January 2006

Abstract: We investigated whether carotid sinus hypersensitivity (CSH) and orthostatic hypotension (OH) were associated with a greater severity of hyperintensities on MRI scan in 30 patients with neurodegenerative dementia (17 dementia with Lewy bodies, 13 Alzheimer's disease), who had a detailed evaluation of OH and CSH during active standing and head‐up tilt. Patients also underwent a 1.0 Tesla MRI scan, from which hyperintensities were rated on a standardized scale. A blood pressure (BP) drop >30 mm Hg during carotid sinus massage or active standing was significantly associated with the severity of MRI hyperintensities in the deep white matter (OR 10.0, 95%; CI 1.8–55.7) and in the basal ganglia (OR 11.0, 95%; CI 1.2–99.5) but not in periventricular areas (OR 1.4, 95%; CI 0.3–1.8). Patients with the cardio‐inhibitory form of CSH with the largest BP drops were the most at risk. Further longitudinal studies need to investigate the direction of causality to determine whether CSH or OH predispose to MRI hyperintensities and accelerate cognitive decline.
Relevance of White Matter Changes to Pre‐ and Poststroke Dementia
Authors: PASQUIER FLORENCE , HÉNON HILDE , LEYS DIDIER
Published: January 2006

Abstract: White matter changes are often associated with stroke, risk factors for stroke, and dementia. From a theoretical point of view, they may be associated with an increased risk of pre‐ or poststroke dementia because (i) they are linked with subtle cognitive decline, which may add to the consequences of the stroke lesions and of associated Alzheimer pathology; and (ii) they indicate an increased risk of stroke recurrence. The aim of this study was to evaluate the contribution of white matter changes to pre‐ and poststroke dementia. The relationship between preexisting dementia and white matter changes was evaluated in the Lille stroke‐dementia cohort. We assessed the cognitive functioning prior to stroke in 202 consecutive patients with ischemic or hemorrhagic stroke, by means of the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). We classified in the dementia group patients with IQ‐CODE scores of 104 or more. White matter changes were rated on CT with the Blennow's rating scale. Thirty‐three of 202 patients were demented before stroke (16.3%; 95% confidence interval: 11.2–21.4); the logistic regression analysis found that female sex, family dementia, white matter changes, and cerebral atrophy were independently associated with prestroke dementia. White matter changes were also associated with an increased risk of poststroke dementia, 2 years after stroke onset. Thus, white matter changes contribute to dementia occurring in stroke patients.
Contrast‐enhanced MRI of White Matter Lesions in Patients with Blood‐Brain Barrier Dysfunction
Authors: WAHLUND LARS‐OLOF , BRONGE LENA
Published: January 2006

Abstract: White matter lesions (WMLs) and blood‐brain barrier (BBB) dysfunction are common in dementia. Both conditions may be a consequence of small‐vessel disease, in which case the BBB damage could be suspected to be located to the WMLs. Magnetic resonance imaging (MRI) can be used to show WMLs as well as to detect BBB damage when using an intravenous contrast agent, gadolinium. We examined 10 demented patients with WMLs, including 5 cases with BBB (elevated CSF/serum albumin ratios). Results showed no significant changes in MR signal in the WMLs after contrast administration. We conclude that WMLs are not related to BBB damage to such a degree that is detectable with this method and that the elevated CSF albumin might have another origin.
The Association between White Matter Lesions on Magnetic Resonance Imaging and Noncognitive Symptoms
Authors: O'BRIEN JOHN , PERRY ROBERT , BARBER ROBERT , GHOLKAR ANIL , THOMAS ALAN
Published: January 2006

Abstract: A number of studies have suggested that cerebral changes, particularly deep white matter lesions (WML) visualized on magnetic resonance imaging(MRI), may be involved in the genesis of late life depression. This has been confirmed in a prospective study which also found a relationship between the presence of WML and poor 3‐year outcome in elderly depressed subjects. Most studies find these lesions to predominate in frontal lobe and basal ganglia, supporting the hypothesis of “fronto‐striatal” dysfunction in depression. To investigate whether WML are associated with mood disturbance in dementia, proton density and T2‐weighted images were obtained in 80 subjects with dementia (dementia with Lewy bodies, n= 27; Alzheimer's disease, n= 28; vascular dementia, n= 25) and 26 age‐matched normal controls. Periventricular lesions (PVL), white matter lesions (WML), and basal ganglia hyperintensities (BG) were visually rated blind to diagnosis using a semiquantitative scale. Frontal WML were associated with higher depression scores in patients with dementia, implying a common pathophysiology of depression irrespective of diagnosis. Further study of the neurobiological basis of WML is needed. This can best be achieved by serial clinical assessment combined with in vivo and in vitro MRI and neuropathological examination.
Neuropathological Findings in the Very Old: Results from the First 101 Brains of a Population‐based Longitudinal Study of Dementing Disorders
Authors: XUEREB J. H. , BRAYNE C. , DUFOUIL C. , GERTZ H. , WISCHIK C. , HARRINGTON C. , MUKAETOVA‐LADINSKA E. , McGEE M. A. , O'SULLIVAN A. , O'CONNOR D. , PAYKEL E. S. , HUPPERT F. A.
Published: January 2006

Abstract: We report a unique longitudinal epidemiological study of cognitive decline in the elderly population of the city of Cambridge, UK. A population sample of people aged 75 and over was surveyed between 1984–1996 (n= 2,616) and followed 2.4, 6, and 9 years later. CAMDEX diagnostic criteria were used for clinical assessment, and the neuropathological protocol (in 101 cases) was based on the CERAD method, with additional features to allow Braak staging of neurofibrillary pathology. The main findings are of the heterogeneity of lesions to be found in very old populations, and the existence of considerable overlap in the pathologies found in the demented and nondemented. It seems that white matter (ischemic) pallor an amyloid angiopathy, as well as neuritic plaques, neurofibrillary tangles and Lewy body formation are all lesions that increase the likelihood of dementia.
Spatial organisation and dynamics of the pine marten Martes martes population in Białowieza Forest (E Poland) compared with other European woodlands
Authors: Zalewski Andrzej , Jędrzejewski Włodzimierz
Published: January 2006

We studied factors affecting density and spacing patterns in the pine marten Martes martes population inhabiting temperate forests of Białowieza National Park, eastern Poland. From 1985/1986 to 1995/1996 marten densities ranged from 3.63 to 7.57 individuals 10 km−2 (mean 5.4) and were positively correlated with abundance of forest rodents in the previous year. The rate of marten population growth was inversely density‐dependent and positively related to rodent density. Annual mortality rate averaged 0.384 and tended to be negatively related to marten densities. Mean annual home range of males (2.58 km2, SE=0.24) was larger than that of females (1.41 km2, SE=0.20). Seasonal home ranges also differed significantly between males and females. Both sexes held the smallest ranges in December–January. Female ranges increased in April–May, whereas those of males increased in June–September when they were mating. Fidelity of pine martens to their home ranges was very high. The mean shift between arithmetic centres of seasonal ranges was 0.25 km, and the ranges recorded in two consecutive seasons overlapped, on average, by 87–90%. We observed very little home range overlap between neighbouring male (mean 4–6%) or female (mean 6%) marten. Year round the neighbouring individuals of the same sex neither avoided nor attracted each other. Females attracted males only during the spring‐summer mating season. A review of other studies has documented that winter severity and seasonal variation in ecosystem productivity were essential factors shaping the biogeographic variation in pine marten densities between 41o and 68oN. The density of marten populations increased in areas with mild winters and lower seasonality. Maximum population densities (indicative of habitat carrying capacity) were correlated with mean winter temperature. In Europe, male home ranges increased with decreasing forest cover in a study area, whereas female ranges varied positively with rodent abundance.
Inter‐specific competition from fallow deer Dama dama reduces habitat quality for the Italian roe deer Capreolus capreolus italicus
Authors: Focardi Stefano , Aragno Paola , Montanaro Paolo , Riga Francesco
Published: January 2006

The roe deer of Mediterranean habitats in the central and southern parts of Italy has recently been recognised as a distinct subspecies, Capreolus capreolus italicus. A population of this endangered subspecies has been monitored in the Preserve of Castelporziano, near Rome, since 1988. We observed an abrupt population decline in 2000, which may severely threaten the sustainability of this population. We evaluated the hypothesis that competition by fallow deer may be a principal cause of this decline. By a new and innovative methodology, we modelled the spatial distribution of fallow deer density (FDD) in the study area to show that 1) habitat quality for roe deer was an inverse function of FDD, 2) habitat apportionment between fallow and roe deer increased as a function of FDD and – by applying structural equation modelling – 3) FDD was superior to habitat composition in explaining observed variations in home range size and probably in habitat quality for roe deer. This analysis is the first to document that inter‐specific competition may influence the spatial behaviour of a deer species leading to poor phenotypic performance in the inferior competitor. We conclude that the conservation of this relict population would benefit by reducing fallow deer numbers at Castelporziano and from other measures aimed to decrease the level of inter‐specific competition.
Dynamic Performance Analysis of a Compressor Driven Metal Hydride Cooling System
Authors: Mazumdar Sagnik , Gopal M. Ram , Bhattacharyya Souvik
Published: January 2006

Though several studies have been reported to show that compressor driven metal hydride cooling systems are competitive with conventional vapor compression systems, an elaborate computational model that takes into account the transient nature of the compressor and the conditioned space is still unreported. The results presented here are obtained for a room air conditioner with Zr0.9Ti0.1Cr0.55Fe1.45 as the hydrogen absorbing material and employing standard heat exchanger configurations. Though previous thermodynamic and transient studies predicted attainment of significant coefficients of performance, the present results indicate that even with the optimal design the maximum coefficient of performance and specific power will be around 2.38 and 750kJ∕kg-alloy.h, respectively. This indicates a need for better materials and effective control strategies so that these systems can become commercially viable.
A Two-Layer Paraffin Deposition Structure Observed and Used to
Explain the Removal and Aging of Paraffin Deposits in Wells and
Pipelines
Authors: Toma Peter , Ivory John , Korpany Gerard , deRocco Mario , Holloway Larry , Goss Chris , Ibrahim Jamal , Omar Ismail
Published: January 2006

Paraffin fouling of pipelines and wells is a dynamic process involving deposition and removal. Deposited wax growth and hardening have been observed in the field. They must be properly evaluated at the design stage in order to develop a suitable and economic flow assurance strategy. Laboratory studies and direct observations on the nature and composition of the deposited wax have been made possible with the aid of a novel, axial wax deposition apparatus. This study resulted in an improved understanding and calculation of wax removal and aging rates. A turbulent burst mechanism was used to explain experimental observations made during this study as well as results recently published by other laboratories and field knowledge of wax removal and the aging/hardening process. Direct observations of the wax deposit nature and composition which were performed on samples removed from the deposited wax, provided essential information on the nature and composition of the deposit resulting from different flow regimes. These observations suggested that two distinct flowing zones (layers) and a wall-attached, thin, solid deposit are part of the flow-related deposition-removal process. A turbulent burst action, which is promoted in the near-wall area by the turbulent flow core zone, was used to explain experimental and field observations suggesting a selective removal of n-paraffin fractions. While the proposed removal mechanism acts selectively depending on the size of nonattached, crystallized wax, the transport of liquid n-alkanes components from the bulk, warmer zone to the near-wall colder region is considered as an overall “n-alkane” transport as accepted and used in calculations so far. The proposed two fluid layer model offers a framework for improving the design and operation (pigging and additive) strategies as well as for revisiting the accepted (safe) ranges of design velocities for waxy crude production and transport limes. This work aims to offer a better tool for estimating the pigging frequency, the optimal flow regime and a better additive testing and application strategy with considerable costs-saving to industry.
Analysis of Homogeneous Charge Compression Ignition (HCCI) Engines for Cogeneration Applications
Authors: Aceves Salvador M. , Martinez-Frias Joel , Reistad Gordon M.
Published: January 2006

This paper presents an evaluation of the applicability of homogeneous charge compression ignition (HCCI) engines for small-scale cogeneration (<1MWe) in comparison to five previously analyzed prime movers. The five comparator prime movers include stoichiometric spark-ignited (SI) engines, lean burn SI engines, diesel engines, microturbines, and fuel cells. The investigated option, HCCI engines, is a relatively new type of engine that has some fundamental differences with respect to other prime movers. The prime movers are compared by calculating electric and heating efficiency, fuel consumption, nitrogen oxide (NOx) emissions, and capital and fuel costs. Two cases are analyzed. In case 1, the cogeneration facility requires combined power and heating. In case 2, the requirement is for power and chilling. The results show that HCCI engines closely approach the very high fuel utilization efficiency of diesel engines without the high emissions of NOx and the expensive diesel fuel. HCCI engines offer a new alternative for cogeneration that provides a combination of low cost, high efficiency, low emissions, and flexibility in operating temperatures that can be optimally tuned for cogeneration systems. HCCI is the most efficient engine technology that meets the strict 2007 CARB NOx standards for cogeneration engines, and merits more detailed analysis and experimental demonstration.
A Comprehensive Procedure to Estimate Erosion in Elbows for Gas/Liquid/Sand Multiphase Flow
Authors: Chen Xianghui , McLaury Brenton S. , Shirazi Siamack A.
Published: January 2006

A comprehensive procedure that combines mechanistic analysis and numerical simulation approaches is proposed to estimate the erosion in elbows for gas/liquid/sand particle multiphase flow systems. The erosion problem in multiphase flow is approximately transferred to one in single-phase flow by introducing the effective sand mass ratio and a representative single-phase flow to which a single-phase computational-fluid-dynamics-based erosion-prediction model can be applied. Erosion in elbows is calculated for various multiphase flow patterns and compared to experimental data in the literature. Reasonable agreement between the simulations and the literature data is observed. The proposed approach is an effective tool to estimate the erosion in multiphase flow.
Fundamentals of Exergy Cost Accounting and Thermoeconomics. Part I: Theory
Authors: Valero A. , Serra L. , Uche J.
Published: January 2006

These two papers resume the theoretical background supporting the main ideas of the exergy cost accounting and the thermoeconomic approach followed by Valero and co-workers. Part I introduces the basic requirements, with a simple example accompanying the dissertations, to calculate the exergy and thermoeconomic costs and to perform the thermoeconomic analysis of a complex system. The connections with other thermoeconomic approaches and schools are briefly explained. Part II presents, as an illustration of the applications of thermoeconomic analysis, some of the most interesting applications of costs to the operation diagnosis and optimization of a complex system, showing the results on the mentioned example presented in Part I.
The Ensemble Kalman Filter for Continuous Updating of Reservoir Simulation Models
Authors: Gu Yaqing , Oliver Dean S.
Published: January 2006

This paper reports the use of ensemble Kalman filter (EnKF) for automatic history matching. EnKF is a Monte Carlo method, in which an ensemble of reservoir state variables are generated and kept up-to-date as data are assimilated sequentially. The uncertainty of reservoir state variables is estimated from the ensemble at any time step. Two synthetic problems are selected to investigate two primary concerns with the application of the EnKF. The first concern is whether it is possible to use a Kalman filter to make corrections to state variables in a problem for which the covariance matrix almost certainly provides a poor representation of the distribution of variables. It is tested with a one-dimensional, two-phase waterflood problem. The water saturation takes large values behind the flood front, and small values ahead of the front. The saturation distribution is bimodal and is not well modeled by the mean and variance. The second concern is the representation of the covariance via a relatively small ensemble of state vectors may be inadequate. It is tested by a two-dimensional, two-phase problem. The number of ensemble members is kept the same as for the one-dimensional problem. Hence the number of ensemble members used to create the covariance matrix is far less than the number of state variables. We conclude that EnKF can provide satisfactory history matching results while requiring less computation work than traditional history matching methods.
Lactose-over-Glucose Preference inBifidobacterium longumNCC2705:glcP, Encoding a Glucose Transporter, Is Subject to Lactose Repression
Authors: Parche Stephan , Beleut Manfred , Rezzonico Enea , Jacobs Doris , Arigoni Fabrizio , Titgemeyer Fritz , Jankovic Ivana
Published: February 2006

Analysis of culture supernatants obtained fromBifidobacterium longumNCC2705 grown on glucose and lactose revealed that glucose utilization is impaired until depletion of lactose. Thus, unlike many other bacteria,B. longumpreferentially uses lactose rather than glucose as the primary carbon source. Glucose uptake experiments withB. longumcells showed that glucose transport was repressed in the presence of lactose. A comparative analysis of global gene expression profiling using DNA arrays led to the identification of only one gene repressed by lactose, the putative glucose transporter geneglcP. The functionality of GlcP as glucose transporter was demonstrated by heterologous complementation of a glucose transport-deficientEscherichia colistrain. Additionally, GlcP exhibited the highest substrate specificity for glucose. Primer extension and real-time PCR analyses confirmed that expression ofglcPwas mediated by lactose. Hence, our data demonstrate that the presence of lactose in culture medium leads to the repression of glucose transport and transcriptional down-regulation of the glucose transporter geneglcP.This may reflect the highly adapted life-style ofB. longumin the gastrointestinal tract of mammals.
The
dltABCD
Operon of
Bacillus anthracis
Sterne Is Required for Virulence and Resistance to Peptide, Enzymatic, and Cellular Mediators of Innate Immunity
Authors: Fisher Nathan , Shetron-Rama Lynne , Herring-Palmer Amy , Heffernan Brian , Bergman Nicholas , Hanna Philip
Published: February 2006

In the environment, the gram-positive bacterium
Bacillus anthracis
persists as a metabolically dormant endospore. Upon inoculation into the host the endospores germinate and outgrow into vegetative bacilli able to cause disease. The dramatic morphogenic changes to the bacterium during germination and outgrowth are numerous and include major rearrangement of and modifications to the bacterial surface. Such modifications occur during a time in the
B. anthracis
infectious cycle when the bacterium must guard against a multitude of innate immune mediators. The
dltABCD
locus of
B. anthracis
encodes a cell wall
d
-alanine esterification system that is initiated by transcriptional activation during endospore outgrowth. The level of transcription from the
dltABCD
operon determined
B. anthracis
resistance to cationic antibacterial peptides during vegetative growth and cationic peptide, enzymatic, and cellular mediators of innate immunity during outgrowth. Mutation of
dltABCD
was also attenuating in a mouse model of infection. We propose that the
dltABCD
locus is important for protection of endosporeforming bacteria from environmental assault during outgrowth and that such protection may be critical during the establishment phase of anthrax.
Novel Organic Hydroperoxide-Sensing and Responding Mechanisms for OhrR, a Major Bacterial Sensor and Regulator of Organic Hydroperoxide Stress
Authors: Panmanee Warunya , Vattanaviboon Paiboon , Poole Leslie B. , Mongkolsuk Skorn
Published: February 2006

Xanthomonas campestris
pv. phaseoli OhrR belongs to a major family of multiple-cysteine-containing bacterial organic hydroperoxide sensors and transcription repressors. Site-directed mutagenesis and subsequent in vivo functional analyses revealed that changing any cysteine residue to serine did not alter the ability of OhrR to bind to the P1
ohrR-ohr
promoter but drastically affected the organic hydroperoxide-sensing and response mechanisms of the protein.
Xanthomonas
OhrR requires two cysteine residues, C22 and C127, to sense and respond to organic hydroperoxides. Analysis of the free thiol groups in wild-type and mutant OhrRs under reducing and oxidizing conditions indicates that C22 is the organic hydroperoxide-sensing residue. Exposure to organic hydroperoxides led to the formation of an unstable OhrR-C22 sulfenic acid intermediate that could be trapped by 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole and detected by UV-visible spectral analysis in an oxidized C127S-C131S mutant OhrR. In wild-type OhrR, the cysteine sulfenic acid intermediate rapidly reacts with the thiol group of C127, forming a disulfide bond. The high-performance liquid chromatography-mass spectrometry analysis of tryptic fragments of alkylated, oxidized OhrR and nonreducing polyacrylamide gel electrophoresis analyses confirmed the formation of reversible intersubunit disulfide bonds between C22 and C127. Oxidation of OhrR led to cross-linking of two OhrR monomers, resulting in the inactivation of its repressor function. Evidence presented here provides insight into a new organic hydroperoxide-sensing and response mechanism for OhrRs of the multiple-cysteine family, the primary bacterial transcription regulator of the organic hydroperoxide stress response.
Positive Selection of the Hrp Pilin HrpE of the Plant Pathogen
Xanthomonas
Authors: Weber Ernst , Koebnik Ralf
Published: February 2006

The plant-pathogenic bacterium
Xanthomonas campestris
pv. vesicatoria possesses a type III secretion (TTS) system which is encoded by the 23-kb
hrp
(
h
ypersensitive
r
esponse and
p
athogenicity) gene cluster. The TTS system is necessary for pathogenicity in susceptible hosts and induction of the hypersensitive response in resistant plants. At the cell surface, the TTS system is associated with an extracellular filamentous structure, the Hrp pilus, which serves as a conduit for the transfer of bacterial proteins into the plant cell cytosol. The major pilus component, the HrpE pilin, is unique to xanthomonads. Previous work showed that HrpE contains two regions: a hypervariable surface-exposed domain, including the N-terminal secretion signal, and a C-terminal polymerization domain. In this study, the evolutionary rate of the
hrpE
gene was analyzed. Twenty-one alleles were cloned, sequenced, and compared with five known
hrpE
alleles. The ratio of synonymous (

K
s

) and nonsynonymous (

K
a

) substitution rates shows that parts of the HrpE N terminus are subjected to positive selection and the C terminus is subjected to purifying selection. The trade-off between positive and purifying selection at the very-N terminus allowed us to ascertain the amphipathic α-helical nature of the TTS signal. This is the first report of a surface structure from a plant-pathogenic bacterium that evolved under the constraint of positive selection and hints to the evolutionary adaptation of this extracellular appendage to avoid recognition by the plant defense surveillance system.
Identification of a Gene Encoding a Functional Reverse Transcriptase within a Highly Variable Locus in the P2-Like Coliphages
Authors: Odegrip Richard , Nilsson Anders S. , Haggård-Ljungquist Elisabeth
Published: February 2006

The P2-like coliphages are highly similar; the structural genes show at least 96% identity. However, at two loci they have genes believed to be horizontally transferred. We show that the genetic content at the second loci, the TO region, contains six completely different sequences with high AT contents and with different open reading frames. The product of one of them exhibits reverse transcriptase activity and blocks infection of phage T5.
Does informed consent exempt Japanese doctors from reporting therapeutic deaths?: Table 1
Authors: Ikegaya H , Kawai K , Kikuchi Y , Yoshida K
Published: January 2006

The Japanese Medical Act section 21 states that doctors must report unnatural deaths to the police, even though the term “unnatural death” is not defined by law. However, many doctors are reluctant to report potential therapeutic deaths (PTDs). The Japanese Society of Legal Medicine has submitted guidelines for unnatural death, including PTD. These define a PTD as an unexpected death, the cause of which is unknown, but which is potentially related to medical practice. Such deaths are “reportable” to the coroner in the UK. In this study, we addressed the question of whether physicians would report each of eight hypothetical PTDs. Although the clinical societies (the Japan Society of Internal Medicine and the Japan Surgical Society) declare that doctors must report deaths due to gross negligence, 60% of the participants said that they would not report gross negligence involving an overdose in cases where they had obtained informed consent or had provided an explanation after the death occurred. This can be accounted for by the mistaken belief on the part of the participants that obtaining informed consent exempts Japanese physicians from the duty of reporting PTDs. The attitude of Japanese physicians is caused by the death investigation system, which is designed to discover whether a crime has been committed rather than focusing on the cause of death. Accordingly, the Japanese Government has decided to commission a pilot study from an independent organisation in which medical specialists will investigate PTDs in order to prevent deaths occurring as a result of gross negligence.
On the difficulty of neurosurgical end of life decisions
Authors: Schaller C , Kessler M
Published: January 2006

Objective:To analyse the process of end of life decisions in a neurosurgical environment.

Methods:All 113 neurosurgical patients, who were subject to so called end of life decisions within a one year period were prospectively enrolled in a computerised data bank. Decision pathways according to patient and physician related parameters were assessed.

Results:Leading primary diagnoses of the patients were traumatic brain injury and intracranial haemorrhage. Forty-five patients had undergone an emergency neurosurgical operation prior to end of life decision, N  =  69 were conservatively treated, which included intracranial pressure recording, or they were not offered neurosurgical care because of futile prognosis. N  =  111 died after a median of two (zero to nine) days. Two, in whom the end of life decisions were revised, survived.Cleardecisions to terminate further treatment were made by a senior staff member on call being informed by the senior resident on call (27.4%),difficultdecisions on the basis of extensive round discussions (71.7%), andvery difficultdecision by an interdisciplinary ethical consult (0.9%). Decisions were further substantiated by electrophysiological examinations in N  =  59.

Conclusion:End of life decisions are to be considered standard situations for neurosurgeons. These decisions may reach a high rate of “positive” prediction, if substantiated by electrophysiological examinations as well as on the grounds of clinical experience and respect for the assumed will of the patient. The fact that patients may survive following revision of an end of life decision underlines the necessity for repeated reassessment of these decisions. Ethical training for neurosurgeons is to be encouraged.
Cyborgs and moral identity
Authors: Gillett G
Published: January 2006

Neuroscience and technological medicine in general increasingly faces us with the imminent reality of cyborgs—integrated part human and part machine complexes.

If my brain functions in a way that is supported by and exploits intelligent technology both external and implantable, then how should I be treated and what is my moral status—am I a machine or am I a person? I explore a number of scenarios where the balance between human and humanoid machine shifts, and ask questions about the moral status of the individuals concerned. The position taken is very much in accordance with the Aristotelian idea that our moral behaviour is of a piece with our social and personal skills and forms a reactive and reflective component of those skills.
When psychiatry and bioethics disagree about patient decision making capacity (DMC): Table 1
Authors: Schneider P L , Bramstedt K A
Published: January 2006

The terms “competency” and “decision making capacity” (DMC) are often used interchangeably in the medical setting. Although competency is a legal determination made by judges, “competency” assessments are frequently requested of psychiatrists who are called to consult on hospitalised patients who refuse medical treatment. In these situations, the bioethicist is called to consult frequently as well, sometimes as a second opinion or “tie breaker”. The psychiatric determination of competence, while a clinical phenomenon, is based primarily in legalism and can be quite different from the bioethics approach. This discrepancy highlights the difficulties that arise when a patient is found to be “competent” by psychiatry but lacking in DMC by bioethics. Using a case, this dilemma is explored and guidance for reconciling the opinions of two distinct clinical specialties is offered.
Mental disorder ethics: theory and empirical investigation
Authors: Eastman N , Starling B
Published: January 2006

Mental disorders and their care present unusual problems within biomedical ethics. The disorders themselves invite an ethical critique, as does society’s attitude to them; researching the diagnosis and treatment of mental disorders also presents special ethical issues. The current high profile of mental disorder ethics, emphasised by recent political and legal developments, makes this a field of research that is not only important but also highly topical. For these reasons, the Wellcome Trust’s biomedical ethics programme convened a meeting, “Investigating Ethics and Mental Disorders”, in order to review some current research, and to stimulate topics and methods of future research in the field. The meeting was attended by policy makers, regulators, research funders, and researchers, including social scientists, psychiatrists, psychologists, lawyers, philosophers, criminologists, and others. As well as aiming to inspire a stronger research endeavour, the meeting also sought to stimulate an improved understanding of the methods and interactions that can contribute to “empirical ethics” generally.

This paper reports on the meeting by describing contributions from individual speakers and discussion sections of the meeting. At the end we describe and discuss the conclusions of the meeting. As a result, the text is referenced less than would normally be expected in a review. Also, in summarising contributions from named presenters at the meeting it is possible that we have created inaccuracies; however, the definitive version of each paper, as provided directly by the presenter, is available athttp://www.wellcome.ac.uk/doc.WTX025116.html.
GENETICS AND BIOCHEMISTRY OF SEED FLAVONOIDS
Authors: Lepiniec Loïc , Debeaujon Isabelle , Routaboul Jean-Marc , Baudry Antoine , Pourcel Lucille , Nesi Nathalie , Caboche Michel
Published: February 2006

Flavonoids are secondary metabolites that accumulate in most plant seeds and are involved in physiological functions such as dormancy or viability. This review presents a current view of the genetic and biochemical control of flavonoid metabolism during seed development. It focuses mainly on proanthocyanidin accumulation in Arabidopsis, with comparisons to other related metabolic and regulatory pathways. These intricate networks and their fine-tuned regulation, once they are determined, should contribute to a better understanding of seed coat development and the control of PA and flavonol metabolism. In addition, flavonoids provide an interesting model to study various biological processes and metabolic and regulatory networks.
Gene transfer of extracellular superoxide dismutase protects against vascular dysfunction with aging
Authors: Brown Kathryn A. , Chu Yi , Lund Donald D. , Heistad Donald D. , Faraci Frank M.
Published: January 2006

Aging is an independent risk factor for cardiovascular disease, but mechanisms leading to vascular dysfunction have not been fully elucidated. Recent studies suggest that oxidative stress may increase in blood vessels during aging. Levels of superoxide are influenced by the activity of SODs. The goal of this study was to examine the effect of extracellular superoxide dismutase (ECSOD) on superoxide levels and vascular function in an animal model of aging. Aortas from young (4–8 mo old) and old (29–31 mo old) Fischer 344 rats were examined in vitro. Relaxation of aorta to ACh was impaired in old rats compared with young rats; e.g., 3 μM ACh produced 57 ± 4% (mean ± SE) and 84 ± 2% relaxation in old and young rats, respectively ( P < 0.0001). Three days after gene transfer of adenovirus expressing human ECSOD (AdECSOD), the response to ACh was not affected in young rats but was improved in old rats. There was no difference in relaxation to the endothelium-independent dilator sodium nitroprusside between young, aged, and AdECSOD-treated old rats. Superoxide levels (lucigenin-enhanced chemiluminescence) were significantly increased in aged rats compared with young rats. After gene transfer of ECSOD to aged rats, superoxide levels in aorta were similar in old and young rats. Gene transfer of an ECSOD with the heparin-binding domain deleted had no effect on vascular function or superoxide levels in old rats. These results suggest that 1) vascular dysfunction associated with aging is mediated in part by increased levels of superoxide, 2) gene transfer of ECSOD reduces vascular superoxide and dysfunction in old rats, and 3) beneficial effects of ECSOD in old rats require the heparin-binding domain of ECSOD.
Evidence for the involvement of myoendothelial gap junctions in EDHF-mediated relaxation in the rat middle cerebral artery
Authors: Sokoya Elke M. , Burns Alan R. , Setiawan Christopher T. , Coleman Harold A. , Parkington Helena C. , Tare Marianne
Published: January 2006

The mechanisms underlying endothelium-dependent hyperpolarizing factor (EDHF) in the middle cerebral artery (MCA) remain largely unresolved. In particular, very little is known regarding the way in which the signal is transmitted from endothelium to smooth muscle. The present study tested the hypothesis that direct communication via myoendothelial gap junctions contributes to the EDHF response in the male rat MCA. EDHF-mediated dilations were elicited in rat MCAs by luminal application of ATP or UTP in the presence of Nω-nitro-l-arginine methyl ester and indomethacin. Maximum dilation to luminal ATP (10−4 M) was reduced significantly after incubation with a gap peptide cocktail (9 ± 4%, n = 6) compared with a scrambled gap peptide cocktail (99 ± 1%, n = 6, P < 0.05). A gap peptide cocktail had no effect on amplitude of endothelial cell hyperpolarization in response to 3 × 10−5 M UTP (22 ± 3 vs. 22 ± 1 mV, n = 4), whereas smooth muscle cell hyperpolarization was significantly attenuated (17 ± 1 vs. 6 ± 1 mV, n = 4, P = 0.004). Connexin (Cx) 37 was localized to smooth muscle and Cx43 to endothelium, whereas Cx40 was found in endothelium and smooth muscle. Electron microscopy revealed the existence of frequent myoendothelial junctions. The total number of myoendothelial junctions per 5 μm of MCA sectioned was 2.5 ± 0.5. Our results suggest that myoendothelial communication contributes to smooth muscle cell hyperpolarization and EDHF dilation in male rat MCA.
Inhibition of sickle red cell adhesion and vasoocclusion in the microcirculation by antioxidants
Authors: Kaul Dhananjay K. , Liu Xiao-du , Zhang Xiaoqin , Ma Li , Hsia Carleton J. C. , Nagel Ronald L.
Published: January 2006

In sickle cell anemia (SCA), inflammatory (i.e., intravascular sickling and transient vasoocclusive) events result in chronic endothelial activation. In addition to sickling behavior, sickle (SS) red blood cells exhibit abnormal interaction with the vascular endothelium, which is considered to have an important role in initiation of vasoocclusion. Upregulation of endothelial adhesion molecules caused by oxidants (and cytokines) may lead to increased SS red cell adhesion. We hypothesize that endothelial activation is indispensable in SS red cell adhesion to the endothelium and that antioxidants will have an inhibitory effect on this interaction. We examined the effect of selected antioxidants in ex vivo mesocecum vasculature, a well-established model that allows measurement of hemodynamic parameters and, by intravital microscopy, can allow quantification of adhesion. We tested antioxidant enzymes (SOD and catalase) and an intravascular SOD mimetic, polynitroxyl albumin (PNA), in the presence of platelet-activating factor (PAF); the latter causes endothelial oxidant generation and endothelial activation, which characterize SCA. In ex vivo preparations, PAF not only induced marked endothelial oxidant generation, it also enhanced SS red cell adhesion, resulting in frequent blockage of small-diameter venules. The adhesion, inversely related to venular diameter, and vasoocclusion were markedly inhibited by antioxidants, resulting in improved hemodynamics. PNA, the most effective antioxidant, also abolished SS red cell adhesion in non-PAF-activated preparations. Thus SS red cell adhesion and related vasoocclusion may be ameliorated by antioxidant therapy with a stable and long-acting molecule (e.g., PNA).
Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury
Authors: Hataishi Ryuji , Rodrigues Ana Clara , Neilan Tomas G. , Morgan John G. , Buys Emmanuel , Shiva Sruti , Tambouret Rosemary , Jassal Davinder S. , Raher Michael J. , Furutani Elissa , Ichinose Fumito , Gladwin Mark T. , Rosenzweig Anthony , Zapol Warren M. , Picard Michael H. , Bloch Kenneth D. , Scherrer-Crosbie Marielle
Published: January 2006

To learn whether nitric oxide (NO) inhalation can decrease myocardial ischemia-reperfusion (I/R) injury, we studied a murine model of myocardial infarction (MI). Anesthetized mice underwent left anterior descending coronary artery ligation for 30, 60, or 120 min followed by reperfusion. Mice breathed NO beginning 20 min before reperfusion and continuing thereafter for 24 h. MI size and area at risk were measured, and left ventricular (LV) function was evaluated using echocardiography and invasive hemodynamic measurements. Inhalation of 40 or 80 ppm, but not 20 ppm, NO decreased the ratio of MI size to area at risk. NO inhalation improved LV systolic function, as assessed by echocardiography 24 h after reperfusion, and systolic and diastolic function, as evaluated by hemodynamic measurements 72 h after reperfusion. Myocardial neutrophil infiltration was reduced in mice breathing NO, and neutrophil depletion prevented inhaled NO from reducing myocardial I/R injury. NO inhalation increased arterial nitrite levels but did not change myocardial cGMP levels. Breathing 40 or 80 ppm NO markedly and significantly decreased MI size and improved LV function after ischemia and reperfusion in mice. NO inhalation may represent a novel method to salvage myocardium at risk of I/R injury.
GPI-linked endothelial CD14 contributes to the detection of LPS
Authors: Lloyd Katie L. , Kubes Paul
Published: January 2006

The inflammatory endothelial response to LPS is critical to the host's surviving a gram-negative bacterial infection. In this study we investigated whether human endothelial cells express the functional coreceptor for LPS, CD14, and most importantly whether it is glycosylphosphatidylinositol (GPI) linked. We also examined whether plasma proteins could reconstitute an LPS response in CD14-inhibited endothelium. RT-PCR- and CD14-specific MAbs demonstrated CD14 expression on primary human umbilical vein endothelial cells (HUVEC) but not passaged HUVEC. The amino acid sequence of endothelial CD14 was 99% homologous to CD14 on monocytes. Endothelium responded to relatively low levels of LPS in the absence of plasma, and this was entirely dependent on CD14. Removal of GPI-linked proteins with phosphatidylinositol-phospholipase C prevented LPS detection and subsequent protein synthesis (E-selectin expression). Endothelial CD14 was sufficient to initiate functional leukocyte recruitment, an event inhibited by blocking its LPS binding epitope and also by removing CD14 from the endothelial surface. Plasma proteins restored only ∼30% of the LPS response in CD14-inhibited endothelium. In conclusion, our results strongly support an important role for endothelial membrane CD14 in the activation of endothelium for leukocyte recruitment.