bluuebunny/crossref_metadata_2025 huggingface dataset:
Thermosensitive TRP channel pore turret is part of the temperature activation pathway
Authors: Yang Fan , Cui Yuanyuan , Wang KeWei , Zheng Jie
Published: March 2010

Temperature sensing is crucial for homeotherms, including human beings, to maintain a stable body core temperature and respond to the ambient environment. A group of exquisitely temperature-sensitive transient receptor potential channels, termed thermoTRPs, serve as cellular temperature sensors. How thermoTRPs convert thermal energy (heat) into protein conformational changes leading to channel opening remains unknown. Here we demonstrate that the pathway for temperature-dependent activation is distinct from those for ligand- and voltage-dependent activation and involves the pore turret. We found that mutant channels with an artificial pore turret sequence lose temperature sensitivity but maintain normal ligand responses. Using site-directed fluorescence recordings we observed that temperature change induces a significant rearrangement of TRPV1 pore turret that is coupled to channel opening. This movement is specifically associated to temperature-dependent activation and is not observed during ligand- and voltage-dependent channel activation. These observations suggest that the turret is part of the temperature-sensing apparatus in thermoTRP channels, and its conformational change may give rise to the large entropy that defines high temperature sensitivity.
HuR regulates the expression of stress-sensitive genes and mediates inflammatory response in human umbilical vein endothelial cells
Authors: Rhee Won Jong , Ni Chih-Wen , Zheng Zhilan , Chang Kyunghwa , Jo Hanjoong , Bao Gang
Published: March 2010

An important aspect of vascular biology is the identification of regulators of stress-sensitive genes that play critical roles in mediating inflammatory response. Here, we show that expression of HuR in human umbilical vein endothelial cells is regulated by shear stress and statin treatment; HuR, in turn, regulates other stress-sensitive genes such as Kruppel-like factor 2 (Klf2), endothelial nitric oxide synthase (eNOS), and bone morphogenic protein 4 (BMP-4). We found that siRNA knockdown of HuR-inhibited inflammatory responses in endothelial cells, including ICAM-1 and VCAM-1 up-regulation, NFκB phosphorylation, and adhesion of monocytes. Tissue staining of the mouse aorta revealed increased HuR expression in the lesser curvature region of the arch that is exposed to disturbed flow, consistent with our in vitro data. Taken together, these results suggest that HuR plays a critical role in inducing inflammatory response of endothelial cells under mechanical and biochemical stresses.
A rice high-affinity potassium transporter (HKT) conceals a calcium-permeable cation channel
Authors: Lan Wen-Zhi , Wang Wei , Wang Suo-Min , Li Le-Gong , Buchanan Bob B. , Lin Hong-Xuan , Gao Ji-Ping , Luan Sheng
Published: March 2010

Plant
h
igh-affinity

K
+

t
ransport (HKT) proteins are so named because of their relation to bacterial and fungal transporters that mediate high-affinity K
+
uptake. The view that HKT family members are sodium-selective uniporters or sodium-potassium symporters is widely held. We have found that one of the rice HKT proteins also functions as a Ca
2+
-permeable cation channel that conducts current carried by a wide range of monovalent and divalent cations. The
HKT
rice gene, named
OsHKT2;4
, is expressed in several cell types, including root hairs and vascular parenchyma cells. The protein is localized to the plasma membrane, thereby providing a mechanism for cation uptake and extrusion. This finding goes against firmly entrenched dogma in showing that HKT proteins can function as both ion carriers and channels. The study further extends the function of HKT proteins to Ca
2+
-linked processes and, in so doing, defines a previously undescribed type of Ca
2+
-permeable cation channels in plants. The work also raises questions about the evolutionary changes in this protein family following the divergence of monocots and dicots.
Vicinal dihalonium ions: diprotonated and dimethylated chlorine [H2Cl22+, (CH3)2Cl22+] and bromine [H2Br22+, (CH3)2Br22+] dications
Authors: Olah George A. , Surya Prakash G. K. , Rasul Golam
Published: March 2010

High level ab initio calculations at the MP2/cc-pVTZ, CCSD(T)/cc-pVTZ, and CASSCF(6,6)/cc-pVTZ levels were performed to investigate geometries and energies of superelectrophilic diprotonated, and dimethylated molecular chlorine (

Cl
2

) and bromine (

Br
2

) dications. Diprotonated chlorine and diprotonated bromine dications
3a
and
6a
, respectively, were found to be lowest energy minima. The isomeric dications,
3b
and
6b
, are also minima on the potential energy surfaces but they are significantly less stable than the structures
3a
and
6a
by 33.6 and 30.9 kcal/mol, respectively. On the basis of computed G2 energies, proton affinities and related thermodynamic parameters were also calculated. Dications
3a
and
6a
have substantial kinetic barriers for deprotonation. Their homolytic dissociation are however facile. Dimethylated molecular chlorine and bromine dications
3g
and
6g
, respectively, were also found to be global energy minima. These vicinal dihalonium or the corresponding protosolvated species are expected to form either in the superacidic media or in the gas phase.
Cell pole–specific activation of a critical bacterial cell cycle kinase
Authors: Iniesta Antonio A. , Hillson Nathan J. , Shapiro Lucy
Published: March 2010

Caulobacter crescentus
integrates phospho-signaling pathways and transcription factor regulatory cascades to drive the cell cycle. Despite the essential role of the CckA histidine kinase in the control of cell cycle events, the factors that signal its activation at a specific time in the cell cycle have remained elusive. A conditional genetic screen for CckA mislocalization mutants, using automated fluorescence microscopy and an image processing platform, revealed that the essential DivL protein kinase promotes CckA localization, autophosphorylation, and activity at the new cell pole. The transient accumulation of DivL at the new cell pole, but not its kinase activity, is required for the localization and activation of CckA. Because DivL and CckA accumulate at the same cell pole after the initiation of DNA replication and were found to interact in vivo, we propose that DivL recruits CckA to the pole, thereby promoting its autophosphorylation and activity.
Attenuation of Forkhead signaling by the retinal determination factor DACH1
Authors: Zhou Jie , Wang Chenguang , Wang Zhibin , Dampier Will , Wu Kongming , Casimiro Mathew C. , Chepelev Iouri , Popov Vladimir M. , Quong Andrew , Tozeren Aydin , Zhao Keji , Lisanti Michael P. , Pestell Richard G.
Published: March 2010

The
Drosophila
Dachshund (
Dac
) gene, cloned as a dominant inhibitor of the hyperactive growth factor mutant
ellipse
, encodes a key component of the retinal determination gene network that governs cell fate. Herein, cyclic amplification and selection of targets identified a DACH1 DNA-binding sequence that resembles the FOX (
F
orkhead b
ox
–containing protein) binding site. Genome-wide
in silico
promoter analysis of DACH1 binding sites identified gene clusters populating cellular pathways associated with the cell cycle and growth factor signaling. ChIP coupled with high-throughput sequencing mapped DACH1 binding sites to corresponding gene clusters predicted
in silico
and identified as weight matrix resembling the cyclic amplification and selection of targets–defined sequence. DACH1 antagonized FOXM1 target gene expression, promoter occupancy in the context of local chromatin, and contact-independent growth. Attenuation of FOX function by the cell fate determination pathway has broad implications given the diverse role of FOX proteins in cellular biology and tumorigenesis.
Regulation of the polycomb protein Ring1B by self-ubiquitination or by E6-AP may have implications to the pathogenesis of Angelman syndrome
Authors: Zaaroor-Regev Daphna , de Bie Prim , Scheffner Martin , Noy Tahel , Shemer Ruth , Heled Maya , Stein Ilan , Pikarsky Eli , Ciechanover Aaron
Published: March 2010

The polycomb repressive complex (PRC) 1 protein Ring1B is an ubiquitin ligase that modifies nucleosomal histone H2A, a modification which plays a critical role in regulation of gene expression. We have shown that self-ubiquitination of Ring1B generates multiply branched, “noncanonical” polyubiquitin chains that do not target the ligase for degradation, but rather stimulate its activity toward histone H2A. This finding implies that Ring1B is targeted by a heterologous E3. In this study, we identified E6-AP (E6-associated protein) as a ligase that targets Ring1B for “canonical” ubiquitination and subsequent degradation. We further demonstrated that both the self-ubiquitination of Ring1B and its modification by E6-AP target the same lysines, suggesting that the fate of Ring1B is tightly regulated (e.g., activation vs. degradation) by the type of chains and the ligase that catalyzes their formation. As expected, inactivation of E6-AP affects downstream effectors: Ring1B and ubiquitinated H2A levels are increased accompanied by repressed expression of HoxB9, a PRC1 target gene. Consistent with these findings,
E6-AP
knockout mice display an elevated level of Ring1B and ubiquitinated histone H2A in various tissues, including cerebellar Purkinje neurons, which may have implications to the pathogenesis of Angelman syndrome, a neurodevelopmental disorder caused by deficiency of E6-AP in the brain.
Patients as interpreters
Authors: Wulf Stefan , Schmiedebach Heinz-Peter
Published: March 2010

Between 1900 and 1914 many so-called “insane re-migrants” (geisteskranke Rückwanderer) from America were admitted to the psychiatric institution in Hamburg-Friedrichsberg. These patients were mainly East European emigrants who had left Europe via Hamburg, had been classified insane and had been sent back by the US authorities. A total of 446 relevant medical files are available. This article concentrates on the years 1900 through 1903, and focuses on the issue of foreign language interpreting in psychiatric practice. Two cases — two multilingual Friedrichsberg patients who assumed the function of interpreters in each case of a foreign “insane re-migrant” — will be described in detail. The interpreters played a significant role in the reconstruction and documentation of the medical histories of their fellow patients. Conversations and interrogations carried out by them and recorded by their own hand have been passed down in the medical files of the patients they “examined”. The files of the multilingual patients themselves were also found in the archives. Thus, their activity as asylum interpreters can be viewed in the context of their own medical histories, i.e. their own mental condition.
“That is not necessary for you to know!”
Authors: Keselman Olga , Cederborg Ann-Christin , Linell Per
Published: March 2010

This article is a study of how the participation status of asylum-seeking children is interactively constructed in interpreter-mediated asylum hearings. We have undertaken a discourse analysis of 50 non-repair side-sequences from 26 hearings with Russian-speaking, asylum-seeking children in Sweden. A side-sequence is here defined as a monolingual sequence conducted in only one of the languages involved in the interviews. It involves the interpreter and only one of the primary interlocutors. In this article, four extracts are chosen for a micro-analysis in order to elucidate how interpreters can challenge asylum-seeking children’s participant statuses. We show that the right of the child to make his or her voice heard can be challenged, especially when the interpreters exclude, distort, discredit and guide the voices of the children, which is often done with the tacit approval of caseworkers.
Computer-Based Demonstrations in Cognitive Psychology: Benefits and Costs
Authors: Copeland David E. , Scott Jenna R. , Houska Jeremy Ashton
Published: March 2010

This study examined the costs and benefits of using demonstrations in an upper level psychology course. For 6 topics, half of the class read a chapter that explained the concept and theoretical explanations for the described effects, and the other half participated in a demonstration in addition to the reading. Students overwhelmingly reported higher enjoyment of their learning experience when they participated in the demonstrations. However, measures of learning based on essays, quizzes, and exam questions showed that students did not always benefit from participating in the demonstrations. In fact, for 2 of the 3 measures, results indicated that participating in the demonstrations significantly worsened performance.
Alumni Perceptions of Workforce Readiness
Authors: Landrum R. Eric , Hettich Paul I. , Wilner Abby
Published: March 2010

We surveyed psychology alumni (N = 78) about (a) their preparedness and competency on 54 areas of workforce readiness, (b) changes since graduation on 33 adjectives describing emotional states and personality qualities, and (c) suggestions for universities about how to provide opportunities that enhance workforce success. Among the highest rated qualities expected in the workplace were self-discipline and responsibility, and among the greatest changes in emotional qualities were increased confidence, independence, and maturity. Respondents also provided revealing open-ended suggestions for improving workplace readiness and success. We discuss these results in light of recent, national attention to workforce readiness, the American Psychological Association's (APA) Guidelines for the Undergraduate Psychology Major (APA, 2007), and future steps for psychology educators to help current students make the transition to successful alumni.
BMP-induced REST regulates the establishment and maintenance of astrocytic identity
Authors: Kohyama Jun , Sanosaka Tsukasa , Tokunaga Akinori , Takatsuka Eriko , Tsujimura Keita , Okano Hideyuki , Nakashima Kinichi
Published: March 2010

Once they have differentiated, cells retain their individual character and repress genes that are specifically expressed in other cell lineages, but how alternative fate choice is restricted during and/or after differentiation remains unclear. In the mammalian central nervous system, neurons, astrocytes, and oligodendrocytes are generated throughout life from common tripotent neural progenitor cells (NPCs). Bone morphogenetic proteins (BMPs) are well-known astrocyte-inducing cytokines. We show here that the expression of a transcriptional repressor, RE1 silencer of transcription (REST)/neuron-restrictive silencer factor (NRSF), is up-regulated and sustained by BMP signal activation in the course of astrocytic differentiation of NPCs, and restricts neuronal differentiation. We further show that, in differentiated astrocytes, endogenous REST/NRSF associates with various neuronal genes and that disruption of its function resulted in their derepression, thereby explaining how ectopic neuronal gene expression is prevented in cells with astrocytic traits. Collectively, our results suggest that REST/NRSF functions as a molecular regulator of the nonneuronal phenotype in astrocytes.
Energetics of gating at the apo–acetylcholine receptor transmitter binding site
Authors: Purohit Prasad , Auerbach Anthony
Published: March 2010

Acetylcholine receptor channels switch between conformations that have a low versus high affinity for the transmitter and conductance for ions (R↔R*; gating). The forward isomerization, which begins at the transmitter binding sites and propagates ∼50 Å to the narrow region of the pore, occurs by approximately the same sequence of molecular events with or without agonists present at the binding sites. To pinpoint the forces that govern the R versus R* agonist affinity ratio, we measured single-channel activation parameters for apo-receptors having combinations of mutations of 10 transmitter binding site residues in the α (Y93, G147, W149, G153, Y190, C192, and Y198), ε (W55 and P121), or δ (W57) subunit. Gating energy changes were largest for the tryptophan residues. The αW149 energy changes were coupled with those of the other aromatic amino acids. Mutating the aromatic residues to Phe reduces the R/R* equilibrium dissociation constant ratio, with αY190 and αW149 being the most sensitive positions. Most of the mutations eliminated long-lived spontaneous openings. The results provide a foundation for understanding how ligands trigger protein conformational change.
Bayesian profile regression with an application to the National survey of children's health
Authors: Molitor John , Papathomas Michail , Jerrett Michael , Richardson Sylvia
Published: March 2010

Standard regression analyses are often plagued with problems encountered when one tries to make inference going beyond main effects using data sets that contain dozens of variables that are potentially correlated. This situation arises, for example, in epidemiology where surveys or study questionnaires consisting of a large number of questions yield a potentially unwieldy set of interrelated data from which teasing out the effect of multiple covariates is difficult. We propose a method that addresses these problems for categorical covariates by using, as its basic unit of inference, a profile formed from a sequence of covariate values. These covariate profiles are clustered into groups and associated via a regression model to a relevant outcome. The Bayesian clustering aspect of the proposed modeling framework has a number of advantages over traditional clustering approaches in that it allows the number of groups to vary, uncovers subgroups and examines their association with an outcome of interest, and fits the model as a unit, allowing an individual's outcome potentially to influence cluster membership. The method is demonstrated with an analysis of survey data obtained from the National Survey of Children's Health. The approach has been implemented using the standard Bayesian modeling software, WinBUGS, with code provided in the supplementary material available at Biostatistics online. Further, interpretation of partitions of the data is helped by a number of postprocessing tools that we have developed.
Implicit Memory Formation during Routine Anesthesia in Children
Authors: Pham Xiuzhi , Smith Katherine R. , Sheppard Suzette J. , Bradshaw Carolyn , Lo Eric , Davidson Andrew J.
Published: March 2010

Background

Implicit memory cannot be consciously recalled but may be revealed by changes in behavior. There is evidence for implicit memory formation during anesthesia in adults, but several studies in children have found no evidence for implicit memory. This may be due to insensitive testing. Also many of these tests were undertaken under controlled conditions. It remains unknown whether implicit memory is formed during routine pediatric anesthesia. The aim of this study was to determine whether there is evidence of implicit memory formation during routine anesthesia in children, using a degraded auditory stimulus recognition task.

Methods

Three hundred and twelve children, aged 5-12 yr, were randomly assigned to be played either a sheep sound or white noise continuously through headphones during general anesthesia. No attempt was made to standardize the anesthetic. On recovery, children were played a sheep sound degraded by a white noise mask that progressively decreased over 60 s, with the outcome being the time taken to correctly recognize the sheep sound.

Results

Three hundred children completed the task. A comparison of the distribution of recognition times between the two groups found little evidence that exposure to a sheep sound during anesthesia was associated with postoperative time to recognition of a degraded sheep sound (hazard ratio 1.14, 95% CI of 0.90-1.43, P = 0.28).

Conclusion

No implicit memory formation during routine anesthesia was demonstrated in children. It is increasingly likely that the potential clinical implications of implicit memory formation are less of a concern for pediatric anesthetists.
Acute stress enhances contact dermatitis by promoting nuclear factor‐κB DNA‐binding activity and interleukin‐18 expression in mice
Authors: ZHANG Jing , LI Lingjiang , LU Qianjin , XIAO Rong , WEN Haiquan , YAN Kailin , LI Yan , ZHOU Ying , SU Yuwen , ZHANG Guiying , LI Weihui , ZHOU Jiansong
Published: March 2010

Psychological stress adversely affects the immune system, and aggravates various skin diseases, such as psoriasis, alopecia areata and atopic dermatitis. However, the precise underlying mechanisms remain to be elucidated. The goal of this study was to use a murine restraint stress model to determine the mechanisms by which psychological stress modulates immune response in contact dermatitis. In the present study, mice were sensitized and challenged on the skin with 2,4‐dinitrofluorobenzene. Acute restraint stress was administrated to healthy or sensitized mice before challenge, and nuclear factor (NF)‐κB DNA‐binding activation of nuclear protein and expression of interleukin (IL)‐18 mRNA in murine spleen lymphocytes was detected. Chemical sympathectomy was performed using the neurotoxin 6‐hydroxy‐dopamine to determine the effect of the sympathetic nervous system. The experiment showed that restraint stress induced a series of changes which include increasing of NF‐κB DNA‐binding activity and IL‐18 mRNA expression in spleen lymphocytes and enhancement of contact hypersensitivity response, and these changes may be mediated by the sympathetic nervous system. These findings provide new insights into the roles of the nervous system in the aggravation of skin diseases.
Radiotelemetry reveals variation in fever and sickness behaviours with latitude in a free‐living passerine
Authors: Adelman James S. , Córdoba‐Córdoba Sergio , Spoelstra Kamiel , Wikelski Martin , Hau Michaela
Published: March 2010

1. The acute phase immune response, which includes fever and sickness behaviours, carries high costs in energy and time, but enhances pathogen clearance in diverse hosts. Hypotheses based upon pathogen pressures and life‐history trade‐offs predict that costly immune responses will decrease in strength as latitude increases. However, whether the acute phase response shows latitudinal patterns among free‐living, wild populations remains unknown.

2. Here, we studied fever and sickness behaviours during the early breeding season in free‐living song sparrows (Melospiza melodia) along a latitudinal gradient in southern California (CA), Washington (WA), and Alaska (AK). In 2007 and 2008, we injected males with lipopolysaccharide and assessed sickness behaviour by measuring changes in territorial aggression. In 2008, we monitored fever and sickness behaviour in CA and WA birds using a novel telemetric technique: skin‐mounted radiotransmitters with temperature sensors.

3. In 2007, territorial defence varied by latitude, with a lower probability of territorial response at 24 h after injection in CA, but not in WA or AK. Radiotelemetry in 2008 revealed that CA birds showed pronounced and prolonged lethargy and fever (c. 2 °C above control males throughout the night), whereas WA birds showed only moderate lethargy and fever (c. 1 °C, returning to control levels during the night).

4. This study establishes radiotelemetry as a powerful method for quantifying fever and sickness behaviours in small, free‐living vertebrates. Moreover, our data suggest that latitude predicts the strength of these responses. These results can provide insight into disease susceptibility and spread among wild populations.
Influence of crack distribution of rocks on P‐wave velocity anisotropy – a laboratory and field scale study‡
Authors: Vilhelm Jan , Rudajev Vladimír , Živor Roman , Lokajíček Tomáš , Pros Zdeněk
Published: March 2010

The purpose of this paper is the comparison of P‐wave velocity and velocity anisotropy, measured at different scales under laboratory and field conditions. A shallow seismic refraction survey with shot/receiver spacing of up to 10 m was carried out on a flat outcrop of lhertzolite in the southern part of the Balmuccia massif. Oriented rock samples were also obtained from the locality. The particular advantage of the laboratory method used is the possibility of measuring velocity in any direction under controlled conditions. Laboratory tests were made on spherical peridotite samples, 50 mm in diameter, by ultrasonic velocity measurements in 132 directions (meridian and parallel networks) under confining stress ranging from atmospheric to 400 MPa. The mean P‐wave velocity of the field and laboratory data differed by between 20–30%. In addition, P‐wave velocity anisotropy of 25% was detected in the field data. Whereas the anisotropy in the laboratory samples in the same orientation as the field surveys was less than 2%. This observed scaling factor is related to the different sampling sizes and the difference in frequencies of applied elastic waves. With an ultrasonic wavelength of 10 mm, laboratory samples represent a continuum. The field velocities and velocity anisotropy reflect the presence of cracks, which the laboratory rock samples do not contain. Three sub‐vertical fracture sets with differing strikes were observed in the field outcrop. Estimates of fracture stiffness from the velocity anisotropy data are consistent with other published values. These results highlight the difficulty of using laboratory velocity estimates to interpret field data.
Comparison of margin assessment by radial and shave sections in wide local excision specimens for invasive carcinoma of the breast
Authors: Hodi Zsolt , Ellis Ian O , Elston Christopher W , Pinder Sarah E , Donovan Glynn , Macmillan R Douglas , Lee Andrew H S
Published: March 2010

Hodi Z, Ellis I O, Elston C W, Pinder S E, Donovan G, Macmillan R D & Lee A H S (2010) Histopathology56, 573–580Comparison of margin assessment by radial and shave sections in wide local excision specimens for invasive carcinoma of the breast

Aims:  Standard margin assessment of breast carcinoma surgical specimens uses radial sections perpendicular to the margin. Shave sections assess a larger surface area of margin than radial sections. The aim was to assess the value of additional shave sections of the margin.

Methods and results:  Both types of section were used to assess 471 wide local excision specimens for invasive carcinoma. One hundred and seventy‐nine specimens had positive margins: only radial margins were involved (tumour within 5 mm of margin) in 76, only shave margins in 45, and both shave and radial margins in 58. Residual carcinoma was found in re‐excision specimens (immediate or later) in 43% when the closest distance to the radial margin was 0–1 mm, 25% for 2–4 mm, 18% for 5–9 mm and 13% for >9 mm. Residual carcinoma was found in 44% of specimens if any shave section was positive and in 9% if all shaves were negative. Residual carcinoma was found in 32% if either radial or shave sections were positive and in 4% if neither was positive.

Conclusions:  The combination of radial and shave sections appears to be good at separating patients into two groups with high and low risk of residual carcinoma.
Hyalinizing trabecular tumour of the thyroid—differential expression of distinct miRNAs compared with papillary thyroid carcinoma
Authors: Sheu Sien‐Yi , Vogel Esther , Worm Karl , Grabellus Florian , Schwertheim Suzan , Schmid Kurt Werner
Published: March 2010

Sheu S‐Y, Vogel E, Worm K, Grabellus F, Schwertheim S & Schmid K W (2010) Histopathology56, 632–640

Hyalinizing trabecular tumour of the thyroid—differential expression of distinct miRNAs compared with papillary thyroid carcinoma

Aims:  To compare the expression pattern of five microRNAs (miRNAs) (146b, ‐181b, ‐21, ‐221, ‐222) of papillary thyroid carcinoma (PTC) and hyalinizing trabecular tumour of the thyroid (HTT).

Methods and results:  The expression pattern of five miRNAs known to be up‐regulated in PTC was retrospectively analysed in 18 HTTs, adjacent normal thyroid tissue, 10 PTCs, 10 follicular adenomas and 10 non‐toxic multinodular goitres (MNG) by reverse transcriptase‐polymerase chain reaction using the TaqMan miRNA assay. Furthermore, the two common genetic alterations characteristic for PTC, the V600E mutation of the BRAF gene and RET/PTC 1 and 3 rearrangements, were determined in all HTTs. All miRNAs were significantly up‐regulated in PTCs, whereas all miRNAs in HTT, normal thyroid tissue, adenomas, and MNGs were down‐regulated. Calculating relative changes in gene expression, a 510‐fold change of miRNA 146b between PTC and HTT could be observed followed by fold changes between 6.4 and 29 in the remaining miRNAs (P < 0.001). All HTTs lacked BRAF mutations and RET/PTC rearrangements.

Conclusions:  Our findings do not support the concept that a high proportion of HTT represents a variant of PTC. It is suggested that HTTs lacking both a miRNA expression pattern characteristic for PTC and RET/PTC rearrangements are re‐designated as ‘hyalinizing trabecular adenomas’.
Association of androgen receptor CAG repeat polymorphism with VO2max response to hypoxic training in North China Han men
Authors: Wang H. Y. , Hu Y. , Wang S. H. , Shan Q. L. , Li Y. C. , Nie J. , Yi L. Y. , Bao D. P. , Xu C. Y. , He Z. H.
Published: March 2010

The purposes of this study were to investigate the distribution characteristics of CAG repeat polymorphism in exon 1 of androgen receptor gene and the association of CAG polymorphism with VO2max response to hypoxic training in North China Han men. Sixty‐five healthy young men completed a 30‐day HiHiLo training (living high, exercise high and training low) in a simulated normobaric hypoxic environment. All subjects slept in 14.3–14.8% O2 concentration, and participated in hypoxic training three times a week in 15.4% O2 concentration. VO2max (peak oxygen consumption) and body weight were measured before and after hypoxic training. A total of 15 repeat alleles were observed by CAG genotype analyze, in which (CAG)22 was most common. When using 21 and 22 alleles, respectively, as cut‐off points, we found that the baseline body weight of two shorter genotype groups was significantly lower than that of longer ones, and that the ΔVO2max and ΔrVO2max (Δrelative value of VO2max) of two shorter genotype groups were significantly higher than those of longer ones after hypoxic training. These findings indicated that AR CAG repeat polymorphism was associated with the exercise performance after simulated normobaric hypoxic HiHiLo training in North China Han men, and that the shorter genotypes had a better individual response to hypoxic training.
Genetic isolation of insular populations of the Maghrebian bat, Myotis punicus, in the Mediterranean Basin
Authors: Biollaz François , Bruyndonckx Nadia , Beuneux Grégory , Mucedda Mauro , Goudet Jérôme , Christe Philippe
Published: March 2010

Aim  We investigate the population genetic structure of the Maghrebian bat, Myotis punicus, between the mainland and islands to assess the island colonization pattern and current gene flow between nearby islands and within the mainland.

Location  North Africa and the Mediterranean islands of Corsica and Sardinia.

Methods  We sequenced part of the control region (HVII) of 79 bats across 11 colonies. The phylogeographical pattern was assessed by analysing molecular diversity indices, examining differentiation among populations and estimating divergence time. In addition, we genotyped 182 bats across 10 colonies at seven microsatellite loci. We used analysis of molecular variance and a Bayesian approach to infer nuclear population structure. Finally, we estimated sex‐specific dispersal between Corsica and Sardinia.

Results  Mitochondrial analyses indicated that colonies between Corsica, Sardinia and North Africa are highly differentiated. Within islands there was no difference between colonies, while at the continental level Moroccan and Tunisian populations were highly differentiated. Analyses with seven microsatellite loci showed a similar pattern. The sole difference was the lack of nuclear differentiation between populations in North Africa, suggesting a male‐biased dispersal over the continental area. The divergence time of Sardinian and Corsican populations was estimated to date back to the early and mid‐Pleistocene.

Main conclusions  Island colonization by the Maghrebian bats seems to have occurred in a stepping‐stone manner and certainly pre‐dated human colonization. Currently, open water seems to prevent exchange of bats between the two islands, despite their ability to fly and the narrowness of the strait of Bonifacio. Corsican and Sardinian populations are thus currently isolated from any continental gene pool and must therefore be considered as different evolutionarily significant units (ESU).
Causality, mathematical models and statistical association: dismantling evidence‐based medicine
Authors: Thompson R. Paul
Published: March 2010

From humble beginnings, largely at the medical school at McMaster University, Canada, the evidence‐based medicine (EBM) movement has enjoyed a spectacular rise in international acceptance over the last 25 years. Randomized controlled trials (RCTs) and systematic reviews based on them have pride of place (the gold standard) in EBM's hierarchy of evidence; models and theories are relegated to the bottom of the hierarchy. In the last decade, RCTs have been extensively criticized. I briefly rehearse those criticisms because they are an important backdrop to the criticism of EBM developed in this paper. In essence, the argument developed here is that RCTs use mathematics solely as a tool of analysis rather than as the language of the science and that this fundamentally affects the validity of causal claims. As EBM gives pride of place to RCTs and devalues theoretical models – a devaluation that would be incomprehensible to a physicist or biologist – the validity of EBM's causal claims and knowledge claims are weak and far from a ‘gold standard’.
Health, health care and the problem of intrinsic value
Authors: Duncan Peter
Published: March 2010

Philosophical conceptual attempts to clarify the nature of health frequently alight on the idea that its value is intrinsic. It is asserted that health is a value in itself and as such can be abstracted from thoughts of preference or utility (subjective or instrumental value). In contrast, I argue here that it is highly problematic to conceive of the value of health in terms other than the instrumental. We value health for what it leads us to. The mistaken idea that health has essential intrinsic value is very often associated with attempts to justify the production of ‘more health’ through health promotion and public health interventions, possibly by authoritarian means. I argue that seeing health as properly instrumental in value supports liberal interpretations of the purpose and methods of health care (including public health and health promotion) and weakens justifications for authoritarian policy and practice. However, such liberal interpretations may pose real difficulties for occupational or professional direction in the field, and for the disadvantaged within health care systems.
The concept of health: beyond normativism and naturalism
Authors: Hamilton Richard P.
Published: March 2010

Philosophical discussions of health and disease have traditionally been dominated by a debate between normativists, who hold that health is an inescapably value‐laded concept and naturalists, such as Christopher Boorse, who believe that it is possible to derive a purely descriptive or theoretical definition of health based upon biological function. In this paper I defend a distinctive view which traces its origins in Aristotle's naturalistic ethics. An Arisotelian would agree with Boorse that health and disease are ubiquitous features of the natural world and thus not mere projections of human interests and values. She would differ from him in rejecting the idea that value is a non‐natural quality. I conclude my discussion with some comments of the normative character of living systems.
Are there different spheres of conscience?
Authors: Sutton Erica J. , Upshur Ross E. G.
Published: March 2010

Interest in understanding the meaning of conscience and conscientious objection in medicine has recently emerged in the academic literature. We would like to contribute to this debate in four ways: (1) to underscore and challenge the existing hierarchy of conscientious objection in health care; (2) to highlight the importance of considering the lay public when discussing the role of conscientious objection in medicine; (3) to critique the numerous proposals put forth in favour of implementing review boards to assess whether appeals to conscience are justifiable, reasonable and sincere; and (4) to introduce the Universal Declaration of Human Rights and the Siracusa Principles into the dialogue around conscience and suggest that perhaps conscientious objection is a human right.
Abortion and conscientious objection
Authors: Hill Daniel J.
Published: March 2010

In this article I do not seek to discuss when, if ever, abortion is morally permissible. Rather I seek to analyse the precise legal status of the exemptions afforded under British law to those with a conscientious objection to abortion. I then argue that the legal status quo in Britain is not morally satisfactory, and that the law urgently needs to be changed.
The challenge of evidence in clinical medicine
Authors: Tonelli Mark R.
Published: March 2010

The primary goal of evidence‐based medicine (EBM) has been to change the way clinicians make decisions. But EBM has inappropriately privileged the results of clinical research for medical decision making and has undermined the importance of other kinds of medical knowledge, pathophysiologic understanding and clinical experience, to clinical practice. Here, the specific advantages and limitations of each kind of medical knowledge are examined. No particular kind of medical knowledge is necessarily more compelling than the others when it comes to making specific patient care decisions. Several cases where medical knowledge is conflicting are examined to demonstrate the weighting and negotiation necessary for sound clinical judgement. Expert clinicians must utilize a variety of reasons and methods of reasoning in arriving at the best clinical decision or recommendation for an individual patient. The process can be formalized and made explicit, but it cannot be narrowed, simplified and focused only on the results of clinical research.
Ethics and EBM: acknowledging bias, accepting difference and embracing politics
Authors: Kerridge Ian
Published: March 2010

Evidence‐based medicine (EBM) has been effective because it confers both epistemic and moral authority, promising that both individual patient care and public health interventions are effective, safe and efficient, that these decisions and standards can be determined (and therefore judged) in a transparent manner and that this form of decision making is reliable, objective and value‐free. The problem is that EBM refers to particular, ideologically and philosophically specific concepts of evidence, medicine and the relationship between them. The analysis of the ‘ethics’ of EBM, therefore, requires not only a critique of its philosophical naïvety and its attachment to modernism and positivism, but a critique of its social, cultural and political implications.
Treatment of hepatitis C virus (HCV) infection in patients coinfected with HIV in the HIV Outpatient Study (HOPS), 1999–2007
Authors: Vellozzi C. , Buchacz K. , Baker R. , Spradling P. R. , Richardson J. , Moorman A. , Tedaldi E. , Durham M. , Ward J. , Brooks J. T. ,   the HOPS Investigators
Published: March 2010

Summary.  Liver disease due to hepatitis C virus (HCV) infection is a leading cause of non‐AIDS‐related morbidity and mortality in patients infected with HIV. We assessed the frequency of and predictors for initiation of treatment for HCV infection among patients coinfected with HCV/HIV enrolled in the HIV Outpatient Study (HOPS) during 1999–2007. We included patients with confirmed HCV infection, at least 1 year of subsequent follow‐up, and no evidence of prior HCV treatment. We assessed predictors of HCV treatment initiation using Cox proportional hazards analyses. During 1999–2007, 103 (20%) HOPS patients coinfected with HCV/HIV initiated HCV treatment during a median of 4.3 years of follow‐up (interquartile range: 2.7, 6.7). In multivariable analysis, non‐Hispanic black race/ethnicity (hazard ratio HR] 0.3; 95% confidence interval [CI] = 0.2, 0.6) was independently associated with a lower likelihood of HCV treatment. Elevated alanine aminotransferase (ALT; HR 3.5; 95% CI = 2.2, 5.6) and CD4+ cell count ≥500 cells/mm3 (HR 1.8; 95% CI = 1.2, 2.8) at the start of observation were independently associated with higher likelihood of HCV treatment. For patients starting observation in 1999–2001, 2002–2004 and 2005–2007, 5%, 11% and 21% of patients initiated treatment during the first year of follow‐up, respectively. Between 1999 and 2007, despite a stable low fraction of patients coinfected with HCV/HIV initiating treatment for HCV infection, an increasing proportion initiated treatment within the first year after the infection was confirmed. Treatment of HCV infection in patients coinfected with HCV/HIV should be considered a priority, given the increased risk of accelerated end‐stage liver disease.
Alopecia in a black Labrador retriever associated with focal sub‐follicular panniculitis and sebaceous adenitis
Authors: Varjonen Katarina , Rest Joan , Bond Ross
Published: March 2010

A 6‐year‐old entire male black Labrador retriever was presented with nonpruritic multicentric, well‐demarcated alopecia of 12‐weeks duration. Skin biopsies from the margins of alopecic regions showed sebaceous adenitis and sub‐follicular panniculitis. Biopsies from alopecic areas showed severe follicular atrophy with residual fibrous tracts, loss of sebaceous glands and lymphohistiocytic panniculitis beneath individual atrophic hair follicle groups. These features differed from previous reports of pilosebaceous diseases of dogs and appeared to extend the spectrum of inflammatory patterns in presumed immune‐mediated adnexal diseases of this species. During the 12‐month follow‐up, there was partial hair regrowth without treatment but alopecia was permanent in the centre of larger lesions.
A convenient and sensitive allergy test: IgE crosslinking‐induced luciferase expression in cultured mast cells
Authors: Nakamura R. , Uchida Y. , Higuchi M. , Nakamura R. , Tsuge I. , Urisu A. , Teshima R.
Published: March 2010

To cite this article:Nakamura R, Uchida Y, Higuchi M, Nakamura R, Tsuge I, Urisu A, Teshima R. A convenient and sensitive allergy test: IgE crosslinking–induced luciferase expression in cultured mast cells.Allergy2010;65: 1266–1273.

Background: For the detection of allergen‐specific IgE in sera, solid‐phase IgE‐binding assays like the CAP test are commonly used. Although such immunochemical methods are very sensitive, they frequently produce false positives. Degranulation of the human IgE receptor (FcεRI)‐transfected rat mast cell (RBL) lines seems to be a possible indicator for human IgE, but spontaneous mediator release from these cells in the presence of human sera is not negligible.

Methods: The nuclear factor of activated T‐cells (NFAT)‐responsive luciferase reporter gene was stably transfected into human FcεRI‐expressing RBL‐SX38 cells. One established clone (RS‐ATL8) was sensitized with 1 : 100 dilution of sera from patients with egg white allergy and then stimulated with purified or a crude extract of egg white allergen.

Results: Sensitization with 15 pg/ml IgE was sufficient to detect IgE crosslinking–induced luciferase expression (EXiLE) by anti‐IgE stimulation. Allergen‐specific EXiLE was elicited by as little as 1 fg/ml of egg white protein without cytotoxicity. There was a good correlation between results with EXiLE and oral food challenge tests on patients with egg allergy (P = 0.001687, Fisher’s exact test). The measured values of EXiLE and the CAP test also correlated well (R = 0.9127, Spearman’s test).

Conclusion: The EXiLE test using RS‐ATL8 cells is a promisingin vitroIgE test to evaluate the biological activity of the binding between IgE and allergens.
Results of WCR monitoring plans and evaluation of an eradication programme using GIS and Indicator Kriging
Authors: De Luigi V. , Furlan L. , Palmieri S. , Vettorazzo M. , Zanini G. , Edwards C.R. , Burgio G.
Published: March 2010

This paper presents 3 years of GIS‐based monitoring of western corn rootworm (WCR –Diabrotica virgifera virgifera LeConte), a pest which invaded Northern Italy in 1998. The Veneto Region established a regional monitoring network to detect this important quarantine pest and to employ an eradication programme. Data were collected by means of sex pheromone PAL traps and analysed by Indicator Kriging, a geostatistics tool that determines the probability of data values in a given area being greater than a defined threshold value. Geostatistical analysis proved to be effective in mapping the spread of WCR. The temporal sequence of the probability maps was useful in interpreting the expansion of the insect. The detailed description of the pattern of WCR presence in 2006–2008 proves the temporary and local efficacy of the eradication programme carried out up to the 2006 season in Venezia province. An interpretation of the spatial pattern of WCR between the 2006 and 2008 seasons suggests that the pest colonized the eradication area coming from other invasion fronts. The large‐scale pattern of WCR dispersion can be accurately described by the spatial approach, thus optimizing the monitoring and subsequent control of this important insect pest of Northern Italy. Other data analyses, based on stochastic interpolations and a demographical approach are in progress. An interesting perspective would be to build predictive simulation models based on climatic and agronomic data taking into account the spatial representation of WCR patterns.
Anti‐oxidant properties of high‐density lipoprotein and atherosclerosis
Authors: Podrez Eugene A
Published: March 2010

1. High‐density lipoprotein (HDL) is one of the major carriers of cholesterol in the blood. It attracts particular attention because, in contrast with other lipoproteins, many physiological functions of HDL influence the cardiovascular system in favourable ways unless HDL is modified pathologically.

2. The best known function of HDL is the capacity to promote cellular cholesterol efflux from peripheral cells and deliver cholesterol to the liver for excretion, thereby playing a key role in reverse cholesterol transport. The functions of HDL that have recently attracted attention include anti‐inflammatory and anti‐oxidant activities. High anti‐oxidant and anti‐inflammatory activities of HDL are associated with protection from cardiovascular disease.

3. Atheroprotective activities, as well as a functional deficiency of HDL, ultimately depend on the protein and lipid composition of HDL. Conversely, these activities are compromised in many pathological states associated with inflammation.

4. The focus of the present review is on the anti‐oxidant and anti‐inflammatory functions of HDL and its individual components in relation to protection from atherosclerosis.