bluuebunny/crossref_metadata_2025 huggingface dataset:
Coadministration of the fungal immunomodulatory protein FIP‐Fve and a tumour‐associated antigen enhanced antitumour immunity
Authors: Ding Ying , Seow See Voon , Huang Chiung Hui , Liew Lee Mei , Lim Yaw Chyn , Kuo I. Chun , Chua Kaw Yan
Published: March 2009

Fve is a fungal protein isolated from the golden needle mushroom Flammulina velutipes and has previously been reported to trigger immunological responses in both mouse and human lymphocytes. In this study, we evaluated the potential application of Fve as an adjuvant for tumour immunotherapy and examined the underlying mechanism(s). When the human papillomavirus (HPV)‐16 E7 oncoprotein was used as a model antigen, mice coimmunized with HPV‐16 E7 and Fve showed enhanced production of HPV‐16 E7‐specific antibodies as well as expansion of HPV‐16 E7‐specific interferon (IFN)‐γ‐producing CD4+ and CD8+ T cells as compared with mice immunized with HPV‐16 E7 alone. Tumour protection assays showed that 60% of mice coimmunized with HPV‐16 E7 plus Fve, as compared with 20% of those immunized only with HPV‐16 E7, remained tumour‐free for up to 167 days after challenge with the tumour cells. Tumour therapeutic assays showed that HPV‐16 E7 plus Fve treatment significantly prolonged the survival of tumour‐bearing mice as compared with those treated only with HPV‐16 E7. In vivo cell depletion and adoptive T‐cell transfer assays showed that CD4+ and CD8+ T cells and IFN‐γ played critical roles in conferring the antitumour effects. Interestingly, Fve could stimulate the maturation of splenic dendritic cells in vivo and induce antigen‐specific CD8+ T‐cell immune responses. In summary, Fve has potent adjuvant properties that enhance T helper type 1 antigen‐specific humoral and cellular immune responses which confer strong antitumour effects. The use of Fve as an adjuvant could be an attractive alternative to the current vaccination strategy for cancer immunotherapy.
Mesangial cell complement receptor 1‐related protein y limits complement‐dependent neutrophil accumulation in immune complex glomerulonephritis
Authors: Bao Lihua , Wang Ying , Chen Peili , Sarav Menaka , Haas Mark , Minto Andrew W. , Petkova Miglena , Quigg Richard J.
Published: March 2009

The absence of complement receptor 1 (CR1) related gene/protein y (Crry) leads to embryonic lethality as a result of unrestricted complement activation and concomitant neutrophil infiltration. Here we used Crry−/−C3+/− mice to investigate the role of Crry in the pathogenesis of immune complex glomerulonephritis (GN). After 3 weeks of immunization with horse spleen apoferritin, six of nine Crry−/− C3+/− mice and none of the six control C3+/− mice developed proliferative GN (P = 0·010). After 5 weeks of immunization, GN scores in Crry−/− C3+/− mice were 0·67 ± 0·22 mean ± standard error of the mean (SEM), compared with 0·32 ± 0·16 in C3+/− mice. Glomerular hypercellularity was attributable to neutrophil infiltration in mice with GN (1·7 ± 0·3/glomerulus) compared with those without GN (0·4 ± 0·1/glomerulus) (P = 0·001). Absent staining for α‐smooth muscle actin and proliferating cell nuclear antigen suggested that mesangial cell proliferation did not play a significant role in this model. Serum C3 levels in Crry−/− C3+/− mice were approximately 20% and 30% those of wild‐type mice and C3+/− mice, respectively. To determine whether this acquired hypocomplementaemia was relevant to this GN model system, Crry−/− C3+/− mouse kidneys were transplanted into wild‐type mice followed by immunization with apoferritin for 1 or 2 weeks. Surprisingly, none of the Crry−/− C3+/− mouse kidneys developed GN at these early time‐points, indicating that increasing circulating C3 levels several‐fold did not increase susceptibility to GN. Renal expression of decay‐accelerating factor was not different among any of the groups studied. Thus, our data indicate that mesangial cell Crry limits complement activation and subsequent neutrophil recruitment in the setting of local immune complex deposition.
Binding immunoglobulin protein‐treated peripheral blood monocyte‐derived dendritic cells are refractory to maturation and induce regulatory T‐cell development
Authors: Corrigall Valerie M. , Vittecoq Olivier , Panayi Gabriel S.
Published: March 2009

Binding immunoglobulin protein (BiP) has been shown previously to have immunomodulatory functions. Herein we investigated whether BiP could affect the differentiation of monocytes into dendritic cells (DCs) and thence the development of regulatory T cells. Peripheral blood monocyte‐derived DCs were matured with lipopolysaccharide in the presence or absence of BiP. DC development and T‐cell changes were monitored by flow cytometry and regulatory T‐cell function was measured by uptake of tritiated thymidine. More BiP‐treated DCs (DC(BiP)s) expressed amounts of intracellular indoleamine 2,3‐dioxygenase (IDO) and cell surface leucocyte immunoglobulin‐like receptor subfamily B member 1 (LILRB1), retained CD14 expression but down‐regulated expression of human leucocyte antigen (HLA)‐DR and CD86, and produced copious amounts of interleukin (IL)‐10, when compared with control DCs. T cells co‐cultured with DC(BiP)s developed regulatory function with increased surface expression of CD4+ CD25hi CD27hi but with no concomitant increase in forkhead box P3 (Foxp3). These T cells also showed significantly higher levels of intracellular cytotoxic T‐lymphocyte antigen (CTLA)‐4. The latter could be inhibited by the presence of the IDO inhibitor 1 methyl tryptophan. The addition of neutralizing anti‐IL‐10 antibody or the specific mitogen‐activated protein kinase (MAPK) p38 inhibitor SB203580 reversed the inhibition of DC differentiation by BiP. In conclusion, BiP is an immunomodulator able to arrest inflammation through induction of tolerogenic DCs and subsequent generation of T regulatory cells.
Chronic Exposure to Low Levels of Oestradiol‐17β Affects Oestrous Cyclicity, Hypothalamic Norepinephrine and Serum Luteinising Hormone in Young Intact Rats
Authors: Kasturi B. S. , MohanKumar S. M. J. , Sirivelu M. P. , MohanKumar P. S.
Published: March 2009

Chronic exposure to oestrogens is known to inhibit the secretion of luteinising hormone (LH) in rats, leading to anovulation. Hypothalamic catecholamines, norepinephrine and dopamine play an important role in LH regulation. However, the effects of chronic exposure to low levels of oestradiol on hypothalamic catecholamines have not been investigated thoroughly. In the present study, adult female Sprague–Dawley rats were either sham implanted or implanted with 17β‐oestradiol (E2) pellets (20 ng/day) for 30 (E‐30), 60 (E‐60) or 90 (E‐90) days. E2 exposure affected oestrous cyclicity and ovarian morphology in a duration‐dependent manner. There was no change in oestrous cyclicity in E‐30 rats; however, 75% of E‐60 and 95% of E‐90 rats were acyclic (P < 0.05). Cycling rats from E‐30 or the control group were killed at different time points on the afternoon of pro‐oestrous. E‐30 rats in oestrous, constant oestrous rats in the E‐60 and E‐90 groups and a group of old constant oestrous (OCE) rats were killed at 12.00 h. LH was measured in the serum by radioimmunoassay. Individual hypothalamic nuclei that are involved in LH regulation were microdissected and analysed for norepinephrine and dopamine levels using high‐performance liquid chromatography/electrochemical detection. Norepinephrine levels in the hypothalamic nuclei increased significantly in control and E‐30 groups during the afternoon of pro‐oestrous, which was accompanied by a rise in LH levels (P < 0.05). On the day of oestrous, norepinephrine concentrations in hypothalamic nuclei and serum LH were significantly lower in E‐60, E‐90 and OCE rats compared to E‐30 and control rats. On the other hand, dopamine levels declined significantly in one hypothalamic nucleus. These results indicate that chronic E2 exposure affects hypothalamic catecholamine and serum LH levels in a duration‐dependent manner. This coincides well with the loss of cyclicity observed in these animals. These results suggest that repeated exposure to endogenous oestrogens could play a role in reproductive senescence.
Differential Expression of Oestrogen Receptor α Following Reproductive Experience in Young and Middle‐Aged Female Rats
Authors: Byrnes E. M. , Babb J. A. , Bridges R. S.
Published: March 2009

Reproductive experience (i.e. pregnancy and lactation) alters a number of physiological and behavioural endpoints, many of which are related to reproductive function and are regulated by oestrogen. For example, reproductive experience significantly attenuates the oestradiol‐induced prolactin surge on the afternoon of pro‐oestrous and circulating oestradiol levels are reduced at this time. Although parity‐related effects on oestrogen receptor (ER) α have been observed within the anterior pituitary, there are currently no data regarding possible parity‐induced alterations in ERα in the brain. Thus, the present study aimed to examine the effect of parity on the expression of ERα in reproductively relevant brain regions. Moreover, because previous findings have demonstrated that the long‐term effects of reproductive experience are often oestrous cycle‐dependent, ERα was examined at two stages of the oestrous cycle (i.e. dioestrous and pro‐oestrous). Finally, because the expression of ERα is significantly influenced by age, both young and middle‐aged females were included in the present study. ERα status was determined using immunohistochemistry in select brain regions involved in the regulation of reproductive behaviour in age‐matched, cycling primiparous (i.e. one pregnancy and lactation) and nulliparous females as well as in age‐matched, noncycling (i.e. persistent oestrous) 12 month‐old primiparous and nulliparous females. Significant shifts in ERα cell numbers were observed in the medial preoptic area and medial amygdala as a consequence of reproductive experience in an oestrous‐dependent manner. These findings indicate that significant changes in ERα activity occur in the brain as a function of reproductive experience.
The sensitivity of a PDA‐based psychomotor vigilance task to sleep restriction in 10‐year‐old girls
Authors: PETERS JACQUELINE D. , BIGGS SARAH N. , BAUER KATIE M. M. , LUSHINGTON KURT , KENNEDY DECLAN , MARTIN JAMES , DORRIAN JILLIAN
Published: March 2009

The impact of sleep restriction on sustained attention in children has not been well quantified. To address this shortcoming, this study tested the sensitivity of a 5‐min personal digital assistant‐psychomotor vigilance task (PDA‐PVT) to sleep restriction in 14 female children [mean (SD) age = 10.6 ± 0.3 years]. The children underwent PDA‐PVT trials at regular intervals both before and after a sleep restriction (5 h time‐in‐bed) and a control (10 h time‐in‐bed) condition. Sleep restriction was associated with longer mean response times and increased number of lapses. These results are consistent with findings in the adult literature suggesting an association between inadequate sleep and impaired functioning. In conclusion, the 5‐min PDA‐PVT is sensitive to sleep restriction in pre‐adolescent female children supporting the utility of the PDA‐PVT for examining the impact of sleep deprivation on daytime functioning in children.
Conservation of hepatitis C virus nonstructural protein 3 amino acid sequence in viral isolates during liver transplantation
Authors: Mello I. M. V. G. C. , Thumann C. , Schvoerer E. , Soulier E. , Pinho J. R. R. , Silvestre D. A. M. M. , Queiroz A. T. L. , Wolf P. , Baumert T. F. , Keller F. S. , Pereira C. A.
Published: March 2009

Summary.  As a consequence of selective pressure exerted by the immune response during hepatitis C virus (HCV) infection, a high rate of nucleotide mutations in the viral genome is observed which leads to the emergence of viral escape mutants. The aim of this study was to evaluate the evolution of the amino acid (aa) sequence of the HCV nonstructural protein 3 (NS3) in viral isolates after liver transplantation. Six patients with HCV‐induced liver disease undergoing liver transplantation (LT) were followed up for sequence analysis. Hepatitis C recurrence was observed in all patients after LT. The rate of synonymous (dS) nucleotide substitutions was much higher than that of nonsynonymous (dN) ones in the NS3 encoding region. The high values of the dS/dN ratios suggest no sustained adaptive evolution selection pressure and, therefore, absence of specific NS3 viral populations. Clinical genotype assignments were supported by phylogenetic analysis. Serial samples from each patient showed lower mean nucleotide genetic distance when compared with samples of the same HCV genotype and subtype. The NS3 samples studied had an N‐terminal aa sequence with several differences as compared with reference ones, mainly in genotype 1b‐infected patients. After LT, as compared with the sequences before, a few reverted aa substitutions and several established aa substitutions were observed at the N‐terminal of NS3. Sites described to be involved in important functions of NS3, notably those of the catalytic triad and zinc binding, remained unaltered in terms of aa sequence. Rare or frequent aa substitutions occurred indiscriminately in different positions. Several cytotoxic T lymphocyte epitopes described for HCV were present in our 1b samples. Nevertheless, the deduced secondary structure of the NS3 protease showed a few alterations in samples from genotype 3a patients, but none were seen in 1b cases. Our data, obtained from patients under important selective pressure during LT, show that the NS3 protease remains well conserved, mainly in HCV 3a patients. It reinforces its potential use as an antigenic candidate for further studies aiming at the development of a protective immune response.
Adaptive microclimatic structural and expressional dehydrin 1 evolution in wild barley, Hordeum spontaneum, at ‘Evolution Canyon’, Mount Carmel, Israel
Authors: YANG ZUJUN , ZHANG TAO , BOLSHOY ALEXANDER , BEHARAV ALEXANDER , NEVO EVIATAR
Published: March 2009

‘Evolution Canyon’ (ECI) at Lower Nahal Oren, Mount Carmel, Israel, is an optimal natural microscale model for unravelling evolution in action highlighting the twin evolutionary processes of adaptation and speciation. A major model organism in ECI is wild barley, Hordeum spontaneum, the progenitor of cultivated barley, which displays dramatic interslope adaptive and speciational divergence on the ‘African’ dry slope (AS) and the ‘European’ humid slope (ES), separated on average by 200 m. Here we examined interslope single nucleotide polymorphism (SNP) sequences and the expression diversity of the drought resistant dehydrin 1 gene (Dhn1) between the opposite slopes. We analysed 47 plants (genotypes), 4–10 individuals in each of seven stations (populations) in an area of 7000 m2, for Dhn1 sequence diversity located in the 5′ upstream flanking region of the gene. We found significant levels of Dhn1 genic diversity represented by 29 haplotypes, derived from 45 SNPs in a total of 708 bp sites. Most of the haplotypes, 25 out of 29 (= 86.2%), were represented by one genotype; hence, unique to one population. Only a single haplotype was common to both slopes. Genetic divergence of sequence and haplotype diversity was generally and significantly different among the populations and slopes. Nucleotide diversity was higher on the AS, whereas haplotype diversity was higher on the ES. Interslope divergence was significantly higher than intraslope divergence. The applied Tajima D rejected neutrality of the SNP diversity. The Dhn1 expression under dehydration indicated interslope divergent expression between AS and ES genotypes, reinforcing Dhn1 associated with drought resistance of wild barley at ‘Evolution Canyon’. These results are inexplicable by mutation, gene flow, or chance effects, and support adaptive natural microclimatic selection as the major evolutionary divergent driving force.
Dual localization of fumarase is dependent on the integrity of the glyoxylate shunt
Authors: Regev‐Rudzki Neta , Battat Emil , Goldberg Israel , Pines Ophry
Published: March 2009

Fumarase and aconitase in yeast are dual localized to the cytosol and mitochondria by a similar targeting mechanism. These two tricarboxylic acid cycle enzymes are single translation products that are targeted to and processed by mitochondrial processing peptidase in mitochondria prior to distribution. The mechanism includes reverse translocation of a subset of processed molecules back into the cytosol. Here, we show that either depletion or overexpression of Cit2 (cytosolic citrate synthase) causes the vast majority of fumarase to be fully imported into mitochondria with a tiny amount or no fumarase in the cytosol. Normal dual distribution of fumarase (similar amounts in the cytosol and mitochondria) depends on an enzymatically active Cit2. Glyoxylate shunt deletion mutations (Δmls1, Δaco1 and Δicl1) exhibit an altered fumarase dual distribution (like in Δcit2). Finally, when succinic acid, a product of the glyoxylate shunt, is added to the growth medium, fumarase dual distribution is altered such that there are lower levels of fumarase in the cytosol. This study suggests that the cytosolic localization of a distributed mitochondrial protein is governed by intracellular metabolite cues. Specifically, we suggest that metabolites of the glyoxylate shunt act as ‘nanosensors’ for fumarase subcellular targeting and distribution. The possible mechanisms involved are discussed.
Fungicide sensitivity in Swedish isolates of Phaeosphaeria nodorum
Authors: Blixt E. , Djurle A. , Yuen J. , Olson Å.
Published: March 2009

This is the first report of variability in sensitivity of Phaeosphaeria nodorum to the fungicide azoxystrobin, and also reports on sensitivity to propiconazole, prothioconazole and cyprodinil. An in vitro sensitivity test of 42 isolates from five Swedish winter wheat fields, collected in 2003–2005, was performed on malt extract agar amended with six concentrations of each fungicide. Four isolates collected during the early 1990s, before azoxystrobin had been commercially used in agriculture, were used as references. Fragments of DNA from 231 isolates, including the reference isolates, were sequenced for the genes of cytochrome b and CYP51 in search for amino acid substitutions known to cause loss of sensitivity to strobilurins and triazoles, respectively. The majority of the P. nodorum isolates possessed the amino acid substitution G143A, associated with loss of sensitivity in fungi to strobilurins, except in one field where only half of the isolates had the substitution. The EC50 values varied between 0·66 mg L−1 to estimations far above 1000 mg L−1, with an estimated median value of 366 mg L−1. The EC50 values of the reference isolates ranged from 0·02 to 80·72 mg L−1. The P. nodorum population is still sensitive to propiconazole, prothioconazole and cyprodinil, even though some isolates varied in sensitivity to triazoles. Part of the CYP51 gene, a possible target for triazole sensitivity, was sequenced but no nonsynonymous substitutions were found.
Developmental complexity of arabinan polysaccharides and their processing in plant cell walls
Authors: Verhertbruggen Yves , Marcus Susan E. , Haeger Ash , Verhoef René , Schols Henk A. , McCleary Barry V. , McKee Lauren , Gilbert Harry J. , Paul Knox J.
Published: March 2009

Plant cell walls are constructed from a diversity of polysaccharide components. Molecular probes directed to structural elements of these polymers are required to assay polysaccharide structures in situ, and to determine polymer roles in the context of cell wall biology. Here, we report on the isolation and the characterization of three rat monoclonal antibodies that are directed to 1,5‐linked arabinans and related polymers. LM13, LM16 and LM17, together with LM6, constitute a set of antibodies that can detect differing aspects of arabinan structures within cell walls. Each of these antibodies binds strongly to isolated sugar beet arabinan samples in ELISAs. Competitive‐inhibition ELISAs indicate the antibodies bind differentially to arabinans with the binding of LM6 and LM17 being effectively inhibited by short oligoarabinosides. LM13 binds preferentially to longer oligoarabinosides, and its binding is highly sensitive to arabinanase action, indicating the recognition of a longer linearized arabinan epitope. In contrast, the binding of LM16 to branched arabinan and to cell walls is increased by arabinofuranosidase action. The presence of all epitopes can be differentially modulated in vitro using glycoside hydrolase family 43 and family 51 arabinofuranosidases. In addition, the LM16 epitope is sensitive to the action of β‐galactosidase. Immunofluorescence microscopy indicates that the antibodies can be used to detect epitopes in cell walls, and that the four antibodies reveal complex patterns of epitope occurrence that vary between organs and species, and relate both to the probable processing of arabinan structural elements and the differing mechanical properties of cell walls.
Stability of floral specialization in Trollius europaeus in contrasting ecological environments
Authors: IBANEZ S. , DUJARDIN G. , DESPRÉS L.
Published: March 2009

Specialization of some plants on seed‐eating pollinators is intriguing, especially when co‐pollinators exclusively feeding on nectar are also present. We examined the stability of the morphological specialization of Trollius europaeus (L.) globeflowers with respect to Chiastocheta (Pokorny) flies by artificially opening the flowers. In the montane and subalpine environments studied, other visitors contributed 2% and 28% of all the visits, respectively, and visited open flowers nearly eight times more often than closed flowers, but in both environments their contribution to pollination did not compensate for Chiastocheta aversion against open phenotypes. Net seed set (female success) was slightly higher (+4%) and pollen export (male success) was much higher (+85%) for closed than open flowers. Selection in favour of the closed phenotype was even more intense in patches where open phenotypes were most common, precluding the evolution of open flowers in the study populations.
ASTRAGALOSIDE IV ATTENUATES HYPOXIA‐INDUCED CARDIOMYOCYTE DAMAGE IN RATS BY UPREGULATING SUPEROXIDE DISMUTASE‐1 LEVELS
Authors: Hu Jiong‐Yu , Han Jian , Chu Zhi‐Gang , Song Hua‐Pei , Zhang Dong‐Xia , Zhang Qiong , Huang Yue‐Sheng
Published: March 2009

Astragaloside IV (AST‐IV) is purified from a natural plant product. Previous studies have shown that AST‐IV has anti‐oxidant activity. In the present study, we investigated the effect and mechanism of action AST‐IV on rat cardiomyocytes subjected to hypoxic conditions (up to 12 h).

Cardiomyocytes were prepared from neonatal rats and cultured under normoxic or hypoxic conditions in the absence or presence of AST‐IV (12.5, 25 or 50 µg/mL). Cell viability, malondialdehyde (MDA) levels, activity and expression of superoxide dismutase (SOD)‐1 (mRNA and protein levels determined by reverse transcription–polymerase chain reaction and western blotting, respectively) and reactive oxygen species (ROS; determined by 2′,7′‐dichlorodihydrofluorescein diacetate) were investigated under these culture conditions. Intracellular localization of AST‐IV was tested using fluorescein isothiocyanate‐labelled AST‐IV.

Hypoxic culture reduced the viability of cardiomyocytes, which was improved following treatment with 25 or 50 µg/mL AST‐IV. Under hypoxic conditions, MDA levels were double those under control conditions. Astragaloside IV (25 and 50 µg/mL) dose‐dependently reduced the increase in MDA seen in hypoxic cardiomyocytes.

Fluorescein isothiocyanate‐labelled AST‐IV entered cardiomyocytes and was localized mainly within the cytoplasm.

Under hypoxic conditions, SOD‐1 activity was decreased, but mRNA and protein expression increased, compared with normoxia. Following treatment with 25 µg/mL AST‐IV, SOD‐1 activity and expression were increased under both normoxic and hypoxic conditions. The ROS scavenging effect of AST‐IV was abolished in the presence of the SOD inhibitor sodium diethyl dithiocarbamate (25 µmol/L).

These in vitro results show that AST‐IV protects cardiomyocytes from oxidative stress‐mediated injury under hypoxic conditions. A major part of this action is achieved by upregulation of SOD‐1 content and activity within the cell cytoplasm.
The probability of Gleason score upgrading between biopsy and radical prostatectomy can be accurately predicted
Authors: Capitanio Umberto , Karakiewicz Pierre I , Jeldres Claudio , Briganti Alberto , Gallina Andrea , Suardi Nazareno , Cestari Andrea , Guazzoni Giorgio , Salonia Andrea , Montorsi Francesco
Published: March 2009

The objective of this study was to test the external validity of a previously developed nomogram for the prediction of Gleason score upgrading (GSU) between biopsy and radical prostatectomy (RP). The study population consisted of 973 assessable patients treated with RP at a tertiary care institution. The accuracy of the nomogram was quantified with the receiver operating characteristics curve‐derived area under the curve. The performance characteristics (predicted vs observed rate of GSU) were tested within a calibration plot. Overall, GSU was recorded in 39.8% (n = 387) of patients at RP. Of patients with GSU, 70 (18.1%), 23 (5.9%) and 32 (8.3%), respectively, had extracapsular extension, seminal vesicle invasion and lymph node invasion. The accuracy of the nomogram was 74.9% (confidence interval 72.1–77.6%). The model tended to underestimate the observed rate of GSU and the discordance between the predicted and observed rate of GSU ranged from −7 to +10%. The current tool represents the most accurate method of predicting GSU between biopsy and RP. Nonetheless it is not perfect and its performance characteristics should be known prior to its use in clinical decision‐making.
Urinary calreticulin in the diagnosis of bladder urothelial carcinoma
Authors: Kageyama Susumu , Isono Takahiro , Matsuda Shinjiro , Ushio Yoshihiro , Satomura Shinji , Terai Akito , Arai Yoichi , Kawakita Mutsushi , Okada Yusaku , Yoshiki Tatsuhiro
Published: March 2009

Objectives:  To evaluate the potential suitability of calreticulin (CRT) as a urinary marker for bladder cancer.

Methods:  Urine specimens were collected from patients with histologically confirmed bladder urothelial carcinoma (Group 1; n = 109), urological patients without urothelial carcinoma (Group 2; n = 60), and non‐urological patients (Group 3; n = 40). We developed an enzyme‐linked immunosorbent assay (ELISA) procedure using commercially available anti‐CRT mono/polyclonal antibodies, and then measured the concentration of urinary CRT.

Results:  Urinary CRT concentration of group 1 was significantly higher than group 2 and 3 (Mann–Whitney U‐test, P < 0.001). Groups 2 and 3 were joined together and considered as a non‐bladder cancer group (n = 100), and a cutoff value (2.85 ng/mL) was determined using receiver operating characteristic (ROC) analysis. The sensitivity, specificity, and the area under the curve were 67.9%, 80.0%, and 0.742, respectively. The overall sensitivity of voided urine cytology (VUC) was 39.0% (n = 105), and the sensitivity of urinary CRT was significantly superior to VUC (McNemar test, P < 0.001). Higher sensitivity was observed especially in Ta, G1‐2, and ≤3 cm tumors.

Conclusions:  Urinary CRT may be useful for diagnosis of bladder urothelial cancer. However, given that its specificity is relatively low, further evaluation in larger series is needed to define its clinical usefulness.
Clinical applications of wavefront aberrometry – a review
Authors: Maeda Naoyuki
Published: March 2009

Abstract

One of the most powerful clinical applications of aberrometry is wavefront‐guided refractive surgery. This concept led to a paradigm shift in refractive error correction, and the same ideas were applied to design the power and shape of intraocular and contact lenses. Other applications are the diagnosis of irregular astigmatism and the assessments of the optical quality of the eye. Because the higher‐order aberrations of the eye are expressed as the total root mean square errors, a set of coefficients for the Zernike terms, Strehl ratio, point spread functions, modulation transfer functions, and other types of metrics can be determined, hence the deterioration in the quality of vision can be easily estimated. Simulations of the retinal images are also useful to understand some of the symptoms in patients with irregular astigmatism. With corneal topographic analyses, the origin of irregular astigmatism from the cornea or internally, or both, can be specified by aberrometry.
Optical coherence tomography of the retina and optic nerve – a review
Authors: Sakata Lisandro M , DeLeon‐Ortega Julio , Sakata Viviane , Girkin Christopher A
Published: March 2009

Abstract

Optical coherence tomography (OCT) is a rapid non‐contact method that allows in vivo imaging of the retina, optic nerve head and retinal nerve fibre layer (RNFL). Since its introduction in Ophthalmology approximately a decade ago, the use of this technology has disseminated into the clinical practice. OCT has proven to be a useful ancillary tool for assessing retinal diseases because of its capability to provide cross‐sectional images of the retina, and also to perform quantitative analysis of retinal morphology. In glaucoma, the OCT represents one of the methods capable of documenting and analysing optic disc and RNFL morphology in attempt to diagnose and monitor glaucomatous optic neuropathy. Recently, the spectral domain OCT became available, a new technique that allowed major improvements particularly regarding image acquisition speed and image resolution. Future studies will address how these major technological advances will impact the use of the OCT in research and clinical practice.
Microsurgical varicocelectomy for infertile men with oligospermia: differential effect of bilateral and unilateral varicocele on pregnancy outcomes
Authors: Baazeem Abdulaziz , Boman Jason M. , Libman Jamie , Jarvi Keith , Zini Armand
Published: March 2009

OBJECTIVES

To evaluate the pregnancy outcomes of two groups of oligospermic men with varicocele, one having a varicocelectomy (group 1) and the other electing not to have surgery (group 2), as varicocele represents the most common factor associated with male infertility and most reports indicate that varicocelectomy has a beneficial effect on male fertility and pregnancy outcome.

PATIENTS AND METHODS

We retrospectively reviewed consecutive oligospermic men who had microsurgical varicocelectomy (233, group 1) between September 1996 and January 2002 and a consecutive group of oligospermic men with varicoceles who elected not to have surgery (127, group 2). The outcome measures included changes in semen variables, partner pregnancy rates (assisted and unassisted) and use of assisted reproductive technologies (ART).

RESULTS

The mean sperm concentration and motility increased significantly after varicocelectomy (P < 0.05). The natural pregnancy rate in group 1 (38%) was higher than in group 2 (30%). The use of ART was significantly greater in group 2 than group 1. In the subset of couples with bilateral varicocele, the natural pregnancy rate was significantly higher in group 1 than group 2 (48% vs 15%, respectively, P = 0.008).

CONCLUSIONS

This study suggests that the natural pregnancy rate is higher after varicocelectomy than in those not having surgery, although the difference was not statistically significant. However, in the subset of couples with bilateral varicocele, the spontaneous pregnancy rates were significantly higher after surgery.
“Therefore, Get Wisdom”: What Should the President Know, and How Can He Know It?
Authors: RUDALEVIGE ANDREW
Published: March 2009

The literature on the U.S. presidency offers analysis of how the presidential advice and information support function has been performed. Some studies go further to suggest certain principles for designing the advice‐ and information‐giving process involved in presidential decision making, along with organizational features to implement such principles. A well‐established principle, based on comparative case studies, is that presidents should institutionalize distrust. Implementation of this principle usually involves channeling competing options, along with supporting information, to the Oval Office before a president becomes committed to a course of action or policy choice. In designing how the presidential support function is to operate, the advantages and disadvantages of the institutionalized distrust principle should be carefully examined, taking into account circumstantial conditions. This article examines this practical issue from the perspective of a historically oriented presidency scholar, writing during the transition to the Barack Obama administration.
EFNS guidelines on disease‐specific CSF investigations
Authors: Deisenhammer F. , Egg R. , Giovannoni G. , Hemmer B. , Petzold A. , Sellebjerg F. , Teunissen C. , Tumani H.
Published: March 2009

We reviewed the literature for disease‐specific markers in cerebrospinal fluid (CSF) and evaluated their diagnostic and prognostic relevance in neurological diseases. High tau protein in combination with low amyloid β levels has a high sensitivity (80%) and specificity (90%) for Alzheimer’s disease (AD) against normal aging and can predict conversion of mild cognitive impairment to AD. The detection of 14‐3‐3 has a high sensitivity (80–90%) and specificity (90%) for the diagnosis of CJD. Low or undetectable CSF hypocretin‐1 (orexin‐1) levels constitute a diagnostic biomarker for narcolepsy with cataplexy. Detection of beta‐2‐transferrin indicates CSF contamination in oto‐ and rhinorrhoe with a sensitivity of >79% at a specificity of 95% similar to the beta‐trace protein (sensitivity >90%, specificity 100%). However, beta‐trace protein is faster and cheaper to perform. Possible future biomarkers are: elevated levels of vascular endothelial growth factor are relatively sensitive (51–100%) and specific (73–100%) for leptomeningeal metastases from solid tumors and are associated with a poor prognosis in this condition. Elevated CSF neurofilament (Nf) levels probably reflect acute neuronal degeneration. The prognostic value of CSF Nf levels is highest in acute conditions such as subarachnoid hemorrhage, acute optic neuritis and neuromyelitis optica.
EVIL, ORIGINAL SIN, AND EVOLUTION
Authors: PENDERGAST, S.J. RICHARD J.
Published: March 2009

This article has three sections. The first discusses the problem of evil; the second, the sins of both angels and men that originally introduced evil into the world; the third, a teleological theory of evolution that clarifies the relationship between the first two sections. At present there is a great deal of discussion about the nature of the evolutionary process. Some argue that ultimately it is a strictly random one. But it is quite impossible to prove scientifically that evolution is strictly random. From a Christian point of view the best way to view it is to see it not only as the result of divine intelligence, but also as due to a ferocious conflict between superhuman powers – the biblical angels and demons to whom God in the beginning gave the power to guide and develop his creation.
Tropical Storm Gamma and the Mosquitia of eastern Honduras: a little‐known story from the 2005 hurricane season
Authors: Cochran David M , Reese Carl A , Liu Kam‐biu
Published: March 2009

The 2005 Atlantic hurricane season was unprecedented in terms of storm activity in the United States, Mexico, Central America and Caribbean. Given the impacts of hurricanes Katrina and Rita, the Honduran Mosquitia sparked little attention despite being hit by two hurricanes and a tropical storm in 2005. This article recounts the history of these storms in the Afro‐Caribbean community of Batalla, drawing from public weather advisories and testimony of local residents obtained through participatory research. We contextualise this local history with results from the first paleotempestological study undertaken in the Mosquitia to shed light on long‐term risk of catastrophic storms in the region and to demonstrate the value of integrating these two research approaches. Our findings contribute to recent ethnographic research on hazards by describing how a coastal people understand and respond to tropical cyclones and how landscape change influences the vulnerability of a coastal area. Although residents have not witnessed a storm as intense as those documented in the paleotempestological record, their knowledge and perceptions show how tropical cyclones can be disasters while leaving behind no sedimentary records. The paleotempestological evidence, however, reminds us that catastrophic hurricanes have struck the Mosquitia in the past and will do so again in the future. Understanding the interactions between contemporary human perceptions and responses and long‐term hurricane risk provides insight for emergency managers and local stakeholders to better prepare for such a catastrophic event.
Policy narratives, landholder engagement, and oil palm expansion on the Malaysian and Indonesian frontiers
Authors: MCCARTHY JOHN F , CRAMB R A
Published: March 2009

Over recent decades a structural transformation has affected agriculture in the frontier areas of Malaysian Borneo and Outer Island Indonesia with the rapid conversion of agricultural lands, fallows, and formerly forested areas into oil palm. These frontiers have similar positions in the international political economy of oil palm and have complementary resource endowments. In both cases, state planners face the common challenges of finding a disciplined labour force, delivering land for estate development, maintaining local legitimacy, and dealing with local contestation. Yet there are significant differences in systems of governance and policy frameworks regarding land, shifting capacity of state actors to facilitate the transformation of these agrarian frontiers, and changing degrees of local, national and international contestation. Considering the generic and the specific elements at play in each case, this paper argues that analogous policy narratives have shaped the ways in which landholders have been engaged in the process of oil palm expansion in Malaysia and Indonesia. In both cases, with the shift from state‐led to neoliberal governance approaches to agricultural development, the ‘frontier’ has been created and transformed through policy narratives that facilitate the conversion of whole landscapes into oil palm. This has been achieved by obscuring indigenous forms of agriculture and land tenure, while creating reserves of available ‘state’ or ‘idle’ customary land, and counterpoising smallholder ‘marginality’ and ‘backwardness’ to the modernity of contemporary estate agriculture.
Re‐sensitization of neuropeptide receptors: should we stop the recycling?
Authors: Keeble Julie Elizabeth
Published: March 2009

Neurogenic inflammation, an important component of many disease states, is mediated by the release of neuropeptides from sensory nerves. To date, it has been possible to inhibit neurogenic inflammation using neuropeptide receptor blockers or by prevention of neuropeptide release. In the current edition of the British Journal of Pharmacology, Cattaruzza and co‐workers discuss a novel way of blocking the action of neuropeptides. They have shown that the re‐sensitization of the substance P neurokinin‐1 receptor and the substance P‐induced pro‐inflammatory effects are mediated by the enzyme, endothelin‐converting enzyme 1 (ECE‐1). Therein, they showed that ECE‐1 inhibition could prevent the re‐sensitization process. This is exciting progress in our understanding of neurogenic inflammation, but it remains to be seen how inhibition of receptor recycling via ECE‐1 blockade will affect other inflammatory pathways.
Preclinical characterization of WAY‐211612: a dual 5‐HT uptake inhibitor and 5‐HT1Areceptor antagonist and potential novel antidepressant
Authors: Beyer CE , Lin Q , Platt B , Malberg J , Hornby G , Sullivan KM , Smith DL , Lock T , Mitchell PJ , Hatzenbuhler NT , Evrard DA , Harrison BL , Magolda R , Pangalos MN , Schechter LE , Rosenzweig‐Lipson S , Andree TH
Published: March 2009

Background and purpose: As a combination of 5‐HT selective reuptake inhibitor (SSRI) with 5‐HT1Areceptor antagonism may yield a rapidly acting antidepressant, WAY‐211612, a compound with both SSRI and 5‐HT1Areceptor antagonist activities, was evaluated in preclinical models.

Experimental approach: Occupancy studies confirmed the mechanism of action of WAY‐211612, while itsin vivoprofile was characterized in microdialysis and behavioural models.

Key results: WAY‐211612 inhibited 5‐HT reuptake (Ki = 1.5 nmol·L−1; KB = 17.7 nmol·L−1) and exhibited full 5‐HT1Areceptor antagonist activity (Ki = 1.2 nmol·L−1; KB = 6.3 nmol·L−1; Imax100% in adenyl cyclase assays; KB = 19.8 nmol·L−1; Imax100% in GTPγS). WAY‐211612 (3 and 30 mg·kg−1, po) occupied 5‐HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5‐HT1Areceptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY‐211612 (3–30 mg·kg−1, po) raised levels of cortical 5‐HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg·kg−1, s.c.) and a 5‐HT1Aantagonist (WAY‐100635; 0.3 mg·kg−1, s.c). WAY‐211612 (3.3–30 mg·kg−1, s.c.) decreased aggressive behaviour in the resident‐intruder model, while increasing the number of punished crossings (3–30 mg·kg−1, i.p. and 10–56 mg·kg−1, po) in the mouse four‐plate model and decreased adjunctive drinking behaviour (56 mg·kg−1, i.p.) in the rat scheduled‐induced polydipsia model.

Conclusions and implications: These findings suggest that WAY‐211612 may represent a novel antidepressant.
A role for nitroxyl (HNO) as an endothelium‐derived relaxing and hyperpolarizing factor in resistance arteries
Authors: Andrews Karen L , Irvine Jennifer C , Tare Marianne , Apostolopoulos Jacqueline , Favaloro Joanne L , Triggle Chris R , Kemp‐Harper Barbara K
Published: March 2009

Background and purpose: Nitroxyl (HNO) is emerging as an important regulator of vascular tone as it is potentially produced endogenously and dilates conduit and resistance arteries. This study investigates the contribution of endogenous HNO to endothelium‐dependent relaxation and hyperpolarization in resistance arteries.

Experimental approach: Rat and mouse mesenteric arteries were mounted in small vessel myographs for isometric force and smooth muscle membrane potential recording.

Key results: Vasorelaxation to the HNO donor, Angeli's salt, was attenuated in both species by the soluble guanylate cyclase inhibitor (ODQ, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxaline‐1‐one), the voltage‐dependent K+channel inhibitor, 4‐aminopyridine (4‐AP) and the HNO scavenger,l‐cysteine. In mouse mesenteric arteries, nitric oxide (NO) synthase inhibition (withl‐NAME, Nω‐Nitro‐L‐arginine methyl ester) markedly attenuated acetylcholine (ACh)‐mediated relaxation. Scavenging the uncharged form of NO (NO•) with hydroxocobalamin (HXC) or HNO withl‐cysteine, or 4‐AP decreased the sensitivity to ACh, and a combination of HXC andl‐cysteine reduced ACh‐mediated relaxation, as didl‐NAME alone. ACh‐induced hyperpolarizations were significantly attenuated by 4‐AP alone and in combination withl‐NAME. In rat mesenteric arteries, blocking the effects of endothelium‐derived hyperpolarizing factor (EDHF) (charybdotoxin and apamin) decreased ACh‐mediated relaxation 10‐fold and unmasked a NO‐dependent component, mediated equally by HNO and NO•, as HXC andl‐cysteine in combination now abolished vasorelaxation to ACh. Furthermore, ACh‐evoked hyperpolarizations, resistant to EDHF inhibition, were virtually abolished by 4‐AP.

Conclusions and implications: The factors contributing to vasorelaxation in mouse and rat mesenteric arteries are NO• = HNO > EDHF and EDHF > HNO = NO•respectively. This study identified HNO as an endothelium‐derived relaxing and hyperpolarizing factor in resistance vessels.

British Journal of Pharmacology(2009)157,540–550; doi:10.1111/j.1476‐5381.2009.00150.x; published online 26 March 2009

This article is commented on by Martin, pp. 537–539 of this issue and is part of a themed section on Endothelium in Pharmacology. For a list of all articles in this section see the end of this paper, or visit:http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009
Sorafenib targets dysregulated Rho kinase expression and portal hypertension in rats with secondary biliary cirrhosis
Authors: Hennenberg M , Trebicka J , Stark C , Kohistani AZ , Heller J , Sauerbruch T
Published: March 2009

Background and purpose:  Extrahepatic vasodilation and increased intrahepatic vascular resistance represent attractive targets for the medical treatment of portal hypertension in liver cirrhosis. In both dysfunctions, dysregulation of the contraction‐mediating Rho kinase plays an important role as it contributes to altered vasoconstrictor responsiveness. However, the mechanisms of vascular Rho kinase dysregulation in cirrhosis are insufficiently understood. They possibly involve mitogen‐activated protein kinase/extracellular signal‐regulated kinase (ERK)‐dependent mechanisms in extrahepatic vessels. As the multikinase inhibitor sorafenib inhibits ERK, we tested the effect of sorafenib on haemodynamics and dysregulated vascular Rho kinase in rats with secondary biliary cirrhosis.

Experimental approach:  Secondary biliary cirrhosis was induced by bile duct ligation (BDL). Sorafenib was given orally for 1 week (60 mg·kg−1·d−1). Messenger RNA levels were determined by quantitative real time polymerase chain reaction, protein expressions and protein phosphorylation by Western blot analysis. Aortic contractility was studied by myographic measurements, and intrahepatic vasoregulation by using livers perfused in situ. In vivo, haemodynamic parameters were assessed invasively in combination with coloured microspheres.

Key results:  In BDL rats, treatment with sorafenib decreased portal pressure, paralleled by decreases in hepatic Rho kinase expression and Rho kinase‐mediated intrahepatic vascular resistance. In aortas from BDL rats, sorafenib caused up‐regulation of Rho kinase and an improvement of aortic contractility. By contrast, mesenteric Rho kinase remained unaffected by sorafenib.

Conclusions and implications:  Intrahepatic dysregulation of vascular Rho kinase expression is controlled by sorafenib‐sensitive mechanisms in rats with secondary biliary cirrhosis. Thus, sorafenib reduced portal pressure without affecting systemic blood pressure.