bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacological activity of a Bv8 analogue modified in position 24
Authors: Lattanzi R , Sacerdote P , Franchi S , Canestrelli M , Miele R , Barra D , Visentin S , DeNuccio C , Porreca F , De Felice M , Guida F , Luongo L , de Novellis V , Maione S , Negri L
Published: November 2011

BACKGROUND AND PURPOSE

The amphibian peptide Bv8 induces potent nociceptive sensitization in rodents. Its mammalian homologue, prokineticin 2 (PROK2), is strongly up‐regulated in inflamed tissues and is a major determinant in triggering inflammatory pain. Bv8 and PROK2 activate two closely related GPCRs, PK1 and PK2, in a relatively non‐selective fashion. To characterize better the roles of the two receptors in hyperalgesia and to obtain ligands whose binding affinity and efficacy differed for the two receptors, we modified the Bv8 molecule in regions essential for receptor recognition and activation.

EXPERIMENTAL APPROACH

We modified the Bv8 molecule by substituting Trp in position 24 with Ala (A‐24) and compared it with Bv8 for binding and activating PK1 and PK2 receptors in cell preparations and in affecting nociceptive thresholds in rodents.

KEY RESULTS

A‐24 preferentially bound to PK2 receptors and activated them with a lower potency (5‐fold) than Bv8. When systemically injected, A‐24 induced Bv8‐like hyperalgesia in rats and in mice, at doses 100 times higher than Bv8. Locally and systemically injected at inactive doses, A‐24 antagonized Bv8‐induced hyperalgesia. In rat and mouse models of inflammatory and post‐surgical pain, A‐24 showed potent and long‐lasting anti‐hyperalgesic activity. Unlike Bv8, A‐24 increased β‐endorphin levels in mouse brain.

CONCLUSIONS AND IMPLICATIONS

A‐24 induced its anti‐hyperalgesic effect in rodents by directly blocking nociceptor PK1 receptors and by activating the central opioid system and the descending pain control pathway through brain PK2 receptors.
Interplay between temperature, fish partial migration and trophic dynamics
Authors: Brodersen Jakob , Nicolle Alice , Nilsson P. Anders , Skov Christian , Brönmark Christer , Hansson Lars‐Anders
Published: November 2011

Whereas many studies have addressed the mechanisms driving partial migration, few have focused on the consequences of partial migration on trophic dynamics, and integrated studies combining the two approaches are virtually nonexistent. Here we show that temperature affects seasonal partial migration of cyprinid fish from lakes to predation refuges in streams during winter and that this migration in combination with temperature affects the characteristics and phenology of lower trophic levels in the lake ecosystem. Specifically, our six‐year study showed that the proportion of fish migrating was positively related to lake temperature during the pre‐migration growth period, i.e. during summer. Migration from the lake occurred later when autumn water temperatures were high, and timing of return migration to the lake occurred earlier at higher spring water temperatures. Moreover, the winter mean size of zooplankton in the lake increased with the proportion of fish being away from the lake, likely as a consequence of decreased predation pressure. Peak biomass of phytoplankton in spring occurred earlier at higher spring water temperatures and with less fish being away from the lake. Accordingly, peak zooplankton biomass occurred earlier at higher spring water temperature, but relatively later if less fish were away from the lake. Hence, the time between phyto‐ and zooplankton peaks depended only on the amount of fish being away from the lake, and not on temperature. The intensity of fish migration thereby had a major effect on plankton spring dynamics. These results significantly contribute to our understanding of the interplay between partial migration and trophic dynamics, and suggest that ongoing climate change may significantly affect such dynamics.
Service user involvement in research
Authors: Szmukler George , Staley Kristina , Kabir Thomas
Published: November 2011

Involving service users as research partners is likely to be one of themajor developments in research management and conduct in thetwenty‐first century. We outline the reasons why we believe this willmake for better research, citing examples. Some of the many waysin which service users can be involved are described, but thereremains plenty of scope for innovation and creativity. There aresignificant challenges, but the evidence from experience in this fieldindicates they can be overcome.
Course‐dependent response of brain functional alterations in men with acute and chronic post‐traumatic stress disorder: A follow‐up functional magnetic imaging study
Authors: Zhang Li , Zheng Huirong , Li Lingjiang , Li Weihui , Zhang Yan , Hou Cailan , Li Zexuan , Zhou Jiansong , He Zhong , Liu Jun , Yin Yan , Jiang Tianzi , Shan Baoci , Zhang Zhijun
Published: November 2011

Introduction

The aim of this study was to investigate the neurofunctional alterations in both acute and chronic post‐traumatic stress disorder (PTSD) resulting from the same stress experience.

Methods

Brain responses to emotional trauma‐related and neutral pictures with a symptom provocation task were measured using functional magnetic resonance imaging (fMRI). Twenty‐four PTSD patients resulting from a mining accident and 14 controls exposed to the same accident without PTSD two months post‐trauma were recruited. In the follow‐up study 20 PTSD patients and 14 controls were also recruited after 24 months post‐trauma. Correlations were conducted in PTSD between altered fMRI blood oxygenation level‐dependent (BOLD) signals of areas extracted as regions of interest and three Clinician‐Administered PTSD Scale (CAPS) subscores respectively.

Results

In response to picture stimulus (traumatic negative pictures versus neutral pictures), the acute PTSD group showed greater activation in the bilateral posterior cingulate gyri, left precuneus, right fusiform and left parahippocampal gyrus than the chronic PTSD group (P < 0.001, cluster size > 20 voxels). In the acute PTSD group, BOLD signals of either posterior cingulate gyrus correlated positively with CAPS intrusion subscores. There was also no significant correlation between BOLD signals of five regions mentioned above in the chronic PTSD group and three CAPS subscores.

Discussion

These findings suggested that brain circuits affected in acute PTSD may be more extended than chronic PTSD. The reason may due to the formation of traumatic memory in the acute phase of PTSD.
Postnatal depression and associated parenting indicators among Vietnamese women
Authors: Suzuki Yuriko , Goto Aya , Vinh Nguyen Quang , Van Nguyen Thi Tu , Minh Pham Nghiem , Thuy Chung Thi Mong , Phuc Trinh Huu , Thanh Pham Viet , Yasumura Seiji
Published: November 2011

Introduction

Postnatal depression is a serious mental health problem. In low‐income countries, there has been only limited research investigating the direct link between childrearing attitude and maternal mood. The present study sought to determine the prevalence of probable depressive state among mothers in Vietnam, and to examine its risk factors with respect to social support and maternal childrearing attitude.

Methods

A questionnaire survey was conducted in 299 consecutive mothers who visited Tu Du Obstetrical and Gynecological Hospital, a tertiary hospital, for regular check‐up between one and three months postpartum. The questionnaire was administered by trained pediatricians in October through December 2007. Depression was assessed using a two‐question case‐finding instrument for depression.

Results

Sixty‐eight of the 294 (23.1%) mothers of singletons were assessed as having probable depressive state. Parental and familial conflict and recent moving was strongly associated with probable depressive state. In terms of childrearing attitude, the following factors increased risk of probable depressive state of mothers; lack of confidence (adjusted odds ratio = 2.74, 95% confidence interval: 1.40–5.38), and less relaxed feeing (adjusted odds ratio = 2.85, 95% confidence interval: 1.21–6.71) after controlling for subjective health.

Discussion

Mothers who felt unconfident and were less relaxed in childrearing were more likely to report a probable depressive state. Social support factors may have played a role in the depression. A brief screening tool for depression is useful to identify mothers in need of additional support in childrearing.
It Is Time to Dance with Dragons
Authors: Niles Damayanthi M.A.
Published: November 2011

How can we live today between what is unknown (the dragon) and what is known or familiar, between comprehension and mystery? Three concepts that have figured prominently in the IRM are critically examined here – “ecumenical,” “salvation history” and missio Dei. Originally richly open terms pointing to God and God's whole world, through the years they have been domesticated in order to fit with what is known, thereby reducing their fullness and mystery. They need to be creatively and dialogically expanded amid the plurality in which we live today.
God's Mission as Praxis for Healing and Reconciliation
Authors: Isaak Paul John
Published: November 2011

In the first part I address the missional church and its praxis: what God in Jesus Christ together with the Holy Spirit is doing in the world to bring about healing, reconciliation, wholeness, liberation and salvation. In the second section I address the issue of healing from contextual and holistic perspectives. The third part is on reconciling mission and mission as reconciliation. Mission as reconciliation should continually seek to correspond to the specifics of a given context. In short, God's mission as praxis for healing and reconciliation means serving, healing, and reconciling a wounded and broken humanity.
High-Temperature Reactive Flow of Combustion Gases in an Expansion Turbine
Authors: Godin T. , Harvey S. , Stouffs P.
Published: November 2011

The analysis of the chemical behavior of the working fluid in gas turbines is usually restricted to the combustion chamber sections. However, the current trend toward higher Turbine Inlet Temperatures (TIT), in order to achieve improved thermal efficiency, will invalidate the assumption of frozen composition of the gases in the first stages of the expansion process. It will become necessary to consider the recombination reactions of the dissociated species, resulting in heat release during expansion. In order to quantify the influence of this reactivity on the performance of high TIT gas turbines, a one-dimensional model of the reactive flow has been developed. Preliminary results were reported in a previous paper. The authors concluded that, in the case of expansion of combustion gases in a subsonic static uncurved distributor nozzle, the residual reactivity must be taken into account above a temperature threshold of around 2000 K. The present study extends these results by investigating the reactive flow in a complete multistage turbine set, including a transonic first-stage nozzle. A key result of this study is that heat release during the expansion process itself will be considerable in future high-temperature gas turbines, and this will have significant implications for turbine design techniques. Furthermore, we show that, at the turbine exit, the fractions of NO and CO are very different from the values computed at the combustor outlet. In particular, NO production in the early part of the expansion process is very high. Finally, the effects of temperature fluctuations at the turbine inlet are considered. We show that residual chemical reactivity affects the expansion characteristics in gas turbines with TITs comparable to those attained by modern high-performance machines.
Commissioning a small‐field biological irradiator using point, 2D, and 3D dosimetry techniques
Authors: Newton Joseph , Oldham Mark , Thomas Andrew , Li Yifan , Adamovics John , Kirsch David G. , Das Shiva
Published: November 2011

Purpose

: To commission a small‐field biological irradiator, the XRad225Cx from Precision x‐Ray, Inc., for research use. The system produces a 225 kVp x‐ray beam and is equipped with collimating cones that produce both square and circular radiation fields ranging in size from 1 to 40 mm. This work incorporates point, 2D, and 3D measurements to determine output factors (OF), percent‐depth‐dose (PDD) and dose profiles at multiple depths.

Methods

: Three independent dosimetry systems were used: ion‐chambers (a farmer chamber and a micro‐ionisation chamber), 2D EBT2 radiochromic film, and a novel 3D dosimetry system (DLOS/PRESAGE®). Reference point dose rates and output factors were determined from in‐air ionization chamber measurements for fields down to ∼13 mm using the formalism of TG61. PDD, profiles, and output factors at three separate depths (0, 0.5, and 2 cm), were determined for all field sizes from EBT2 film measurements in solid water. Several film PDD curves required a scaling correction, reflecting the challenge of accurate film alignment in very small fields. PDDs, profiles, and output factors were also determined with the 3D DLOS/PRESAGE® system which generated isotropic 0.2 mm data, in scan times of 20 min.

Results:

Surface output factors determined by ion‐chamber were observed to gradually drop by ∼9% when the field size was reduced from 40 to 13 mm. More dramatic drops were observed for the smallest fields as determined by EBT∼18% and ∼42% for the 2.5 mm and 1 mm fields, respectively. PRESAGE® and film output factors agreed well for fields <20 mm (where 3D data were available) with mean deviation of 2.2% (range 1%–4%). PDD values at 2 cm depth varied from ∼72% for the 40 mm field, down to ∼55% for the 1 mm field. EBT and PRESAGE® PDDs agreed within ∼3% in the typical therapy region (1–4 cm). At deeper depths the EBT curves were slightly steeper (2.5% at 5 cm). These results indicate good overall consistency between ion‐chamber, EBT2 and PRESAGE® measured OFs, PDDs, and profiles.

Conclusions:

The combination of independent 2D and 3D measurements was found to be valuable to ensure accurate and comprehensive commissioning. Film measurements were time consuming and challenging due to the difficulty of film alignment in small fields. PRESAGE® 3D measurements were comprehensive and efficient, because alignment errors are negligible, and all parameters for multiple fields could be obtained from a single dosimeter and scan. However, achieving accurate superficial data (within 4 mm) is not yet feasible due to optical surface artifacts.
Role of Intracellular Proteases in the Antibiotic Resistance, Motility, and Biofilm Formation of Pseudomonas aeruginosa
Authors: Fernández Lucía , Breidenstein Elena B. M. , Song Diana , Hancock Robert E. W.
Published: November 2011

Pseudomonas aeruginosa
possesses complex regulatory networks controlling virulence and survival under adverse conditions, including antibiotic pressure, which are interconnected and share common regulatory proteins. Here, we screen a panel of 13 mutants defective in intracellular proteases and demonstrate that, in addition to the known alterations in Lon and AsrA mutants, mutation of three protease-related proteins PfpI, ClpS, and ClpP differentially affected antibiotic resistance, swarming motility, and biofilm formation.
Changes in the Use of Broad-Spectrum Antibiotics after Cefepime Shortage: a Time Series Analysis
Authors: Plüss-Suard C. , Pannatier A. , Ruffieux C. , Kronenberg A. , Mühlemann K. , Zanetti G.
Published: November 2011

The original cefepime product was withdrawn from the Swiss market in January 2007 and replaced by a generic 10 months later. The goals of the study were to assess the impact of this cefepime shortage on the use and costs of alternative broad-spectrum antibiotics, on antibiotic policy, and on resistance of
Pseudomonas aeruginosa
toward carbapenems, ceftazidime, and piperacillin-tazobactam. A generalized regression-based interrupted time series model assessed how much the shortage changed the monthly use and costs of cefepime and of selected alternative broad-spectrum antibiotics (ceftazidime, imipenem-cilastatin, meropenem, piperacillin-tazobactam) in 15 Swiss acute care hospitals from January 2005 to December 2008. Resistance of
P. aeruginosa
was compared before and after the cefepime shortage. There was a statistically significant increase in the consumption of piperacillin-tazobactam in hospitals with definitive interruption of cefepime supply and of meropenem in hospitals with transient interruption of cefepime supply. Consumption of each alternative antibiotic tended to increase during the cefepime shortage and to decrease when the cefepime generic was released. These shifts were associated with significantly higher overall costs. There was no significant change in hospitals with uninterrupted cefepime supply. The alternative antibiotics for which an increase in consumption showed the strongest association with a progression of resistance were the carbapenems. The use of alternative antibiotics after cefepime withdrawal was associated with a significant increase in piperacillin-tazobactam and meropenem use and in overall costs and with a decrease in susceptibility of
P. aeruginosa
in hospitals. This warrants caution with regard to shortages and withdrawals of antibiotics.
CHARACTERIZATION OF SURFACE RUPTURE AND STRUCTURAL DAMAGE IN HONGKOU TOWN DURING WENCHUAN EARTHQUAKE
Authors: TAI J. J. , DENG J. H. , CHEN F. , WEI J. B.
Published: November 2011

Hongkou Town is located north of Dujiangyan City, around 27 km away to the northeast of the epicenter of Wenchuan Earthquake on May 12, 2008. The middle segment of the central fault, that is the Yingxiu-Beichuan Fault of the Longmenshan Fault belt, passes through the town, along which almost every form of surface ruptures is developed. The quake also resulted in 73 of the town's residents dead or missing and 95% of its buildings or infrastructures damaged, including the collapse of Gaoyuan Bridge. Its estimated intensity was around XI. On the other hand, in Shenxigou Village and Gaoyuan Village, many houses successfully withstood the quake.

In this paper, the authors examine why the latter houses withstood the earthquake well. Based on field investigation and local geology, especially fault configuration in the area, a detailed description is given on the characteristics of surface rupture and structural damage in the two villages and an attempt is made to correlate fault movement with structural damage. The results show that: (1) Fault movement or surface rupture may be affected by local geological configuration and topography. Compression can lead to local strike-slip movement. (2) Structural damage is associated with fault movement. Strike-slip movement causes less damage to structures, while in the adjacent area of fault with thrust movement, the structures in the hanging-wall can be more easily damaged than the ones on the footwall, i.e. hanging-wall effects. An area located on the footwalls of two nearly parallel faults may result in a "safer island," where structural damage is much lighter that those outside the island. (3) Apart from shaking effect, site effects should also be considered in structural design.
EXPERIMENTAL INVESTIGATION OF THE SCOURING OF QUAKE DAMS DURING DAM-BREAK
Authors: XU WEILIN , NIU ZHIPAN , LIANG XU
Published: November 2011

Earthquake can trigger debris flow that can result in formation of quake lakes. The break-up of the quake dams can lead to catastrophic flooding for residents living in lower reaches of the rivers. By using high-speed photography, a set of laboratory tests were conducted to study the processes of downward erosion, head cutting erosion, and the characteristics of dam-break flows with different dam configurations. Experimental observations indicated that the quake dam's evolution was a gradual process during dam failure. In cases wherein flow took place without a discharging channel, head cutting appeared in every test, with the downstream edge of the eroding crest retreating upstream. As flood water overtopped the dam, knick points appeared and moved upstream. The case of flow through a discharging channel with small dam seepage was then studied. It was observed that the bottom erosion leads to a head cutting process in the longitudinal direction, while both sides of the discharge channel collapse gradually into the channel. The alluvial fan enlarges and extends sideway and forward continuously. Finally, the case of flow with a discharging channel and large dam seepage was studied. For this case, the breach development process was similar to that when discharging through a discharging channel with small dam seepage. In addition, cross-sectional depression and slope-break points developed during the scouring process. The discharge channel finally extended to both sides of the flume, with the upstream part deepening and forming a channel with an irregular shape. The amount of post-discharge residual debris of three cases was also measured. After 200 s of the discharging, the model in which flow occurred without discharging channel left behind the smallest amount of residual debris. On the other hand, flow through a discharging channel with large dam seepage led to the largest amount of residual debris. The findings from the experiments can provide useful reference for mitigating the risk of potential dam-break from quake lakes.
The anisotropy of surface roughness measured using a digital photogrammetric technique
Authors: Jessell Mark W. , Cox Simon J. D. , Schwarze Phillip , Power William L.
Published: November 2011

The characterization of fracture surface morphology is important for the understanding of shear and normal deformation behaviour of rock masses, and for their transport properties. It has been suggested that natural fracture surfaces might be fractal. If true, this would have dramatic implications for these rock properties and would provide a sound basis for future modelling.

Evaluating this hypothesis requires measurement of fracture surface morphology over a large range of scales. A software package has been developed that can automatically reconstruct surface morphology information from stereo pairs at any scale, using edge correlation and point matching.

The data derived using this technique compare favourably with results generated from a traditional surface profilometer survey, and results are presented from the analysis of the anisotropy of blasting-induced tensile fractures in granite from Mt Alexander Quarry, Harcourt, Victoria, Australia.
Fractography and fracture characterization in the Permo-Triassic sandstones and the Lower Palaeozoic Basement, West Cumbria, UK
Authors: Ameen Mohammed S.
Published: November 2011

Three distinctive phases of fracturing (mesofractures and macrofaults) are recognized in the Permo-Triassic part of the cover rocks of West Cumbria. The earliest phase caused syn-depositional growth macrofaults with northerly strikes in the lower part of the cover rocks. This phase is not evident in any of the macrofaults and mesofractures which are exposed in the study area. The second phase led to the occurrence of the easterly striking macrofaults and mesofractures and is clearly evident from surface exposures. The latest phase caused the exposed northerly striking macrofaulting and mesofracturing. Some of the latter macrofaults most probably propagated upwards from the tips of the pre-existing (phase 1) northerly macrofaults. Others resulted from the coalescence of mesofractures and propagated downwards.

The fractographic features on both the second and third phase mesofractures suggest that they occurred as Mode I (tensile) fractures and were later modified by shear or mixed-mode loading. The geometry and degree of development of fracture surface morphology are controlled by a combination of factors.

The Lower Palaeozoic basement is characterized by complex meso- and macrofracture patterns, including a large number of local sets with a wide range of orientations. Although ‘statistically’ prominent regional sets are recognized in the basement rocks, these are purely geometrical and include various types of fractures that developed under different stresses. Each local set of mesofractures shows varied attitudes of fractographic features, indicating different dynamic implications of fractures within the same set. Some macrofaults in the cover may have propagated from the basement, or are related to movements on basement faults which controlled the evolution of the sedimentary basin and its subsequent structures.
Spatial change in joint geometry in the Chalk of eastern England
Authors: Goodwin A. M.
Published: November 2011

Prominent NE and NW striking joint sets previously recognized in southern England have been traced northwards in the Chalk of eastern England. Both sets change their geometry northwards, defining two joint continua, from steep conjugate hybrid joints in Norfolk to a sub-vertical single joint set in Humberside. This spatial change is consistent both with the observed northward increase in rock strength of the Chalk and a possible northward decrease in differential stress across eastern England.
Mixed-order compositing for 3D paintings
Authors: Baran Ilya , Schmid Johannes , Siegrist Thomas , Gross Markus , Sumner Robert W.
Published: November 2011

We present a method for rendering 3D paintings by compositing brush strokes embedded in space. The challenge in compositing 3D brush strokes is reconciling conflicts between their
z
-order in 3D and the order in which the strokes were painted, while maintaining temporal and spatial coherence. Our algorithm smoothly transitions between compositing closer strokes over those farther away and compositing strokes painted later over those painted earlier. It is efficient, running in
O
(
n
log
n
) time, and simple to implement. We demonstrate its effectiveness on a variety of 3D paintings.
Sketch-based Dynamic Illustration of Fluid Systems
Authors: Zhu Bo , Iwata Michiaki , Haraguchi Ryo , Ashihara Takashi , Umetani Nobuyuki , Igarashi Takeo , Nakazawa Kazuo
Published: November 2011

This paper presents a lightweight sketching system that enables interactive illustration of complex fluid systems. Users can sketch on a 2.5-dimensional (2.5D) canvas to design the shapes and connections of a fluid circuit. These input sketches are automatically analyzed and abstracted into a hydraulic graph, and a new hybrid fluid model is used in the background to enhance the illustrations. The system provides rich simple operations for users to edit the fluid system incrementally, and the new internal flow patterns can be simulated in real time. Our system is used to illustrate various fluid systems in medicine, biology, and engineering. We asked professional medical doctors to try our system and obtained positive feedback from them.
Interactive hybrid simulation of large-scale traffic
Authors: Sewall Jason , Wilkie David , Lin Ming C.
Published: November 2011

We present a novel, real-time algorithm for modeling large-scale, realistic traffic using a hybrid model of both continuum and agent-based methods for traffic simulation. We simulate individual vehicles in regions of interest using state-of-the-art agent-based models of driver behavior, and use a faster continuum model of traffic flow in the remainder of the road network. Our key contributions are efficient techniques for the dynamic coupling of discrete vehicle simulation with the aggregated behavior of continuum techniques for traffic simulation. We demonstrate the flexibility and scalability of our interactive visual simulation technique on extensive road networks using both real-world traffic data and synthetic scenarios. These techniques demonstrate the applicability of hybrid techniques to the efficient simulation of large-scale flows with complex dynamics.
Can Tissue PCR Augment the Diagnostic Accuracy in Genitourinary Tract Tuberculosis?
Authors: Chawla Arun , Chawla Kiran , Reddy Sreedhar , Arora Nitika , Bairy Indira , Rao Sugandhi , Hegde Padmaraj , Thomas Joseph
Published: November 2011

Purpose: Conventional methods like smear and culture for Mycobacterium tuberculosis are of limited sensitivity and specificity. Histopathological examination (HPE) for the tissues obtained gives inconclusive diagnosis in the absence of caseous necrosis or stained acid-fast bacilli. This study was conducted to determine the utility of tissue PCR for diagnosing tuberculosis of the genitourinary tract (GUTB) and its comparative evaluation with HPE. Patients and Methods: A prospective study was conducted from January 2006 to August 2009 with 78 tissue specimens (renal, prostate, epididymis, penile and soft tissue) from patients with clinically suspected GUTB. All the samples were processed for both PCR and histopathology. Results: In 68 (87.1%) samples, results for both PCR and HPE were coinciding. False positivity and false negativity was observed in 5.1% (4/78) and 7.6% (6/78) samples, respectively. With HPE as the gold standard, PCR has shown sensitivity of 87.5% (95% CI 80.1; 91.9) and specificity of 86.7% (95% CI 74.9; 93.8) and positive agreement between two tests was observed as significant (0.7). PCR results were obtained within a mean period of 3.4 days while those of HPE were obtained in 7.2 days. Conclusions: Tissue PCR is a sensitive and specific method for obtaining early and timely diagnosis of GUTB. Application of tissue PCR results can augment the diagnostic accuracy in histopathologically labelled granulomatous inflammations.
Pretreatment with Oral Contraceptive Pills Does Not Influence the Pregnancy Rate in the Long Leuprolide Acetate Protocol
Authors: Bozdag Gurkan , Esinler Ibrahim , Yaralı Hakan
Published: November 2011

Background: To analyze the influence of oral contraceptive pill (OCP) pretreatment in intracytoplasmic sperm injection cycles among normoresponders in whom leuprolide acetate is preferred for that kind of gonadotropin-releasing hormone agonist. Methods: Between March 2001 and January 2010, a total of 821 cycles were pretreated with OCP in luteal-long leuprolide acetate in the IVF Center, Faculty of Medicine, University of Hacettepe. Of these, a total of 169 consecutive patients were selected for the final analyses according to the selection criteria (OCP group) and compared with 349 age-matched controls (Control group). The normoresponders were defined by the presence of 6–15 antral follicles in both ovaries. Results: Female age, body mass index, duration of infertility and antral follicle count were similar among both groups. Although the total dose of FSH used and duration of stimulation were similar, the maximal serum estradiol concentrations were higher in the OCP group than in the Control group (2,630.3 ± 1,568.0 vs. 2,166.5 ± 1,259.7 pg/ml, p = 0.001). The mean numbers of metaphase-II oocytes were 11.0 ± 6.2 versus 9.4 ± 5.2 in the OCP and Control groups, respectively (p = 0.004). The mean number of available day 3 embryos having ≧7 blastomeres was also higher in the OCP group (4.4 ± 3.3 vs. 3.5 ± 3.1, p = 0.013). However, the embryo transfer cancellation rate was noted to be higher in the OCP group, which is mainly due to fertilization failure and arrest during embryogenesis (6.5 vs. 2.9%, p = 0.049). The clinical pregnancy (36.7 vs. 38.3%) and implantation rates (21.8 vs. 20.6%) were comparable. Conclusion: These findings suggest that although pretreatment with an OCP might exaggerate ovarian response, the pregnancy rate does not fluctuate in leuprolide acetate cycles among normoresponders.
Hormonal Management of Complete Androgen Insensitivity Syndrome from Adolescence Onward
Authors: Bertelloni Silvano , Dati Eleonora , Baroncelli Giampiero I , Hiort Olaf
Published: November 2011

Complete androgen insensitivity syndrome (CAIS) represents a main disorder of sex development. Women with CAIS may have their gonads removed before, during or after adolescence, thus requiring hormonal replacement therapy to induce puberty and/or maintain secondary sexual characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Usually estrogens are used for this purpose, but formulations and doses should be better defined in multicentric prospective studies. Some women started testostosterone as hormonal replacement therapy, but this practice remains anecdotal. Bone health remains a crucial aspect in the management of persons with CAIS, but few sound data are available to guide clinical practice.
Hesperetin-7,3'-O-dimethylether selectively inhibits phosphodiesterase 4 and effectively suppresses ovalbumin-induced airway hyperresponsiveness with a high therapeutic ratio
Authors: Yang You-Lan , Hsu Hsin-Te , Wang Kuo-Hsien , Han Cheng-Ying , Chen Chien-Ming , Chen Chi-Ming , Ko Wun-Chang
Published: November 2011

Background

Hesperetin was reported to selectively inhibit phosphodiesterase 4 (PDE4). While hesperetin-7,3'-O-dimethylether (HDME) is a synthetic liposoluble hesperetin. Therefore, we were interested in investigating its selectivity on PDE4 and binding ability on high-affinity rolipram-binding sites (HARBs)in vitro, and its effects on ovalbumin-induced airway hyperresponsivenessin vivo, and clarifying its potential for treating asthma and chronic obstructive pulmonary disease (COPD).

Methods

PDE1~5 activities were measured using a two-step procedure. The binding of HDME on high-affinity rolipram-binding sites was determined by replacing 2 nM [3H]-rolipram. AHR was assessed using the FlexiVent system and barometric plethysmography. Inflammatory cells were counted using a hemocytometer. Cytokines were determined using mouse T helper (Th)1/Th2 cytokine CBA kits, and total immunoglobulin (Ig)E or IgG2alevels were done using ELISA method. Xylazine (10 mg/kg)/ketamine (70 mg/kg)-induced anesthesia was performed.

Results

HDME revealed selective phosphodiesterase 4 (PDE4) inhibition with a therapeutic (PDE4H/PDE4L) ratio of 35.5in vitro.In vivo, HDME (3~30 μmol/kg, orally (p.o.)) dose-dependently and significantly attenuated the airway resistance (RL) and increased lung dynamic compliance (Cdyn), and decreased enhanced pause (Penh) values induced by methacholine in sensitized and challenged mice. It also significantly suppressed the increases in the numbers of total inflammatory cells, macrophages, lymphocytes, neutrophils, and eosinophils, and levels of cytokines, including interleukin (IL)-2, IL-4, IL-5, interferon-γ, and tumor necrosis factor-α in bronchoalveolar lavage fluid (BALF) of these mice. In addition, HDME (3~30 μmol/kg, p.o.) dose-dependently and significantly suppressed total and ovalbumin-specific immunoglobulin (Ig)E levels in the BALF and serum, and enhanced IgG2alevel in the serum of these mice.

Conclusions

HDME exerted anti-inflammatory effects, including suppression of AHR, and reduced expressions of inflammatory cells and cytokines in this murine model, which appears to be suitable for studying the effects of drugs on atypical asthma and COPD, and for screening those on typical asthma. However, HDME did not influnce xylazine/ketamine-induced anesthesia. Thus HDME may have the potential for use in treating typical and atypical asthma, and COPD.
Heritability of physical activity traits in Brazilian families: the Baependi Heart Study
Authors: Horimoto Andréa RVR , Giolo Suely R , Oliveira Camila M , Alvim Rafael O , Soler Júlia P , de Andrade Mariza , Krieger José E , Pereira Alexandre C
Published: November 2011

Background

It is commonly recognized that physical activity has familial aggregation; however, the genetic influences on physical activity phenotypes are not well characterized. This study aimed to (1) estimate the heritability of physical activity traits in Brazilian families; and (2) investigate whether genetic and environmental variance components contribute differently to the expression of these phenotypes in males and females.

Methods

The sample that constitutes the Baependi Heart Study is comprised of 1,693 individuals in 95 Brazilian families. The phenotypes were self-reported in a questionnaire based on the WHO-MONICA instrument. Variance component approaches, implemented in the SOLAR (Sequential Oligogenic Linkage Analysis Routines) computer package, were applied to estimate the heritability and to evaluate the heterogeneity of variance components by gender on the studied phenotypes.

Results

The heritability estimates were intermediate (35%) for weekly physical activity among non-sedentary subjects (weekly PA_NS), and low (9-14%) for sedentarism, weekly physical activity (weekly PA), and level of daily physical activity (daily PA). Significant evidence for heterogeneity in variance components by gender was observed for the sedentarism and weekly PA phenotypes. No significant gender differences in genetic or environmental variance components were observed for the weekly PA_NS trait. The daily PA phenotype was predominantly influenced by environmental factors, with larger effects in males than in females.

Conclusions

Heritability estimates for physical activity phenotypes in this sample of the Brazilian population were significant in both males and females, and varied from low to intermediate magnitude. Significant evidence for heterogeneity in variance components by gender was observed. These data add to the knowledge of the physical activity traits in the Brazilian study population, and are concordant with the notion of significant biological determination in active behavior.
The case for conducting first-in-human (phase 0 and phase 1) clinical trials in low and middle income countries
Authors: Kapiriri Lydia , Lavery James V , Singer Peter A , Mshinda Hassan , Babiuk Lorne , Daar Abdallah S
Published: November 2011

Background

Despite the increase in the number of clinical trials in low and middle income countries (LMICs), there has been little serious discussion of whether First in Human (FIH; phase 0 and phase 1) clinical trials should be conducted in LMICs, and if so, under what conditions. Based on our own experience, studies and consultations, this paper aims to stimulate debate on our contention that for products meant primarily for conditions most prevalent in LMICs, FIH trials should preferably be done first in those countries.

Discussion

There are scientific and pragmatic arguments that support conducting FIH trials in LMIC. Furthermore, the changing product-development and regulatory landscape, and the likelihood of secondary benefits such as capacity building for innovation and for research ethics support our argument. These arguments take into account the critical importance of protecting human subjects of research while developing capacity to undertake FIH trials.

While FIH trials have historically not been conducted in LMICs, the situation in some of these countries has changed. Hence, we have argued that FIH should be conducted in LMICs for products meant primarily for conditions that are most prevalent in those contexts; provided the necessary protections for human subjects are sufficient.
Case report of a young child with disseminated histoplasmosis and review of hyper immunoglobulin e syndrome (HIES)
Authors: Robinson Wilson S , Arnold Sandra R , Michael Christie F , Vickery John D , Schoumacher Robert A , Pivnick Eniko K , Ward Jewell C , Nagabhushanam Vijaya , Lew Dukhee B
Published: November 2011

Type 1 hyper IgE syndrome (HIES), also known as Job's Syndrome, is an autosomal dominant disorder due to defects in STAT3 signaling and Th17 differentiation. Symptoms may present during infancy but diagnosis is often made in childhood or later. HIES is characterized by immunologic and non-immunologic findings such as recurrent sinopulmonary infections, recurrent skin infections, multiple fractures, atopic dermatitis and characteristic facies. These manifestations are accompanied by elevated IgE levels and reduced IL-17 producing CD3+CD4+ T cells. Diagnosis in young children can be challenging as symptoms accumulate over time along with confounding clinical dilemmas. A NIH clinical HIES scoring system was developed in 1999, and a more recent scoring system with fewer but more pathogonomonic clinical findings was reported in 2010. These scoring systems can be used as tools to help in grading the likelihood of HIES diagnosis. We report a young child ultimately presenting with disseminated histoplasmosis and a novel STAT3 variant in the SH2 domain.
The acute inflammatory response to intranigral α-synuclein differs significantly from intranigral lipopolysaccharide and is exacerbated by peripheral inflammation
Authors: Couch Yvonne , Alvarez-Erviti Lydia , Sibson Nicola R , Wood Matthew JA , Anthony Daniel C
Published: November 2011

Background

Activated microglia are a feature of the host response to neurodegeneration in Parkinson's disease (PD) and are thought to contribute to disease progression. Recent evidence suggests that extracellular α-synuclein (eSNCA) may play an important role in the pathogenesis of PD and that this may be mediated by a microglial response.

Methods

We wished to discover whether the host response to eSNCA would be sufficient to induce significant cytokine production. In vitro cultured BV-2 microglia were used to determine the basic inflammatory response to eSNCA. In vivo, 8-week old Biozzi mice were subjected to a single intranigral injection of either 3 μg SNCA, lipopolysaccharide (LPS) or serum protein (BSA) and allowed to recover for 24 hours. A second cohort of animals were peripherally challenged with LPS (0.5 mg/kg) 6 hours prior to tissue collection. Inflammation was studied by quantitative real-time PCR for a number of pro-inflammatory genes and immunohistochemistry for microglial activation, endothelial activation and cell death.

Results

In vitro data showed a robust microglial response to SNCA, including a positive NFĸB response and the production of pro-inflammatory cytokines. Direct injection of SNCA into the substantia nigra resulted in the upregulation of mRNA expression of proinflammatory cytokines, the expression of endothelial markers of inflammation and microglial activation. However, these results were significantly different to those obtained after direct injection of LPS. By contrast, when the animals were injected intracerebrally with SNCA and subsequently challenged with systemic LPS, the level of production of IL-1β in the substantia nigra became comparable to that induced by the direct injection of LPS into the brain. The injection of albumin into the nigra with a peripheral LPS challenge did not provoke the production of a significant inflammatory response. Direct injection of LPS into the substantia nigra also induces cell death in a more robust manner than direct injection of either SNCA or BSA.

Conclusion

These results suggest that the presence of eSNCA protein 'primes' microglia, making them susceptible to environmental proinflammatory challenge. For this reason, we hypothesise that where 'inflammation' contributes to the disease progression in PD, it does so in a punctuate manner (on-off) as a result of systemic events.
Comparison of collapsing methods for the statistical analysis of rare variants
Authors: Dering Carmen , Ziegler Andreas , König Inke R , Hemmelmann Claudia
Published: November 2011

Novel technologies allow sequencing of whole genomes and are considered as an emerging approach for the identification of rare disease-associated variants. Recent studies have shown that multiple rare variants can explain a particular proportion of the genetic basis for disease. Following this assumption, we compare five collapsing approaches to test for groupwise association with disease status, using simulated data provided by Genetic Analysis Workshop 17 (GAW17). Variants are collapsed in different scenarios per gene according to different minor allele frequency (MAF) thresholds and their functionality. For comparing the different approaches, we consider the family-wise error rate and the power. Most of the methods could maintain the nominal type I error levels well for small MAF thresholds, but the power was generally low. Although the methods considered in this report are common approaches for analyzing rare variants, they performed poorly with respect to the simulated disease phenotype in the GAW17 data set.
Seroprevalence of Toxoplasma gondii infection in household and stray cats in Lanzhou, northwest China
Authors: Wu Song-Ming , Zhu Xing-Quan , Zhou Dong-Hui , Fu Bao-Quan , Chen Jia , Yang Jian-Fa , Song Hui-Qun , Weng Ya-Biao , Ye De-He
Published: November 2011

Background

Toxoplasma gondii is an important protozoan parasite infecting humans and almost all warm-blooded animals. As the only definitive host, cats play a crucial role in the transmission of T. gondii infection by shedding parasite oocysts in their feces. However, little information on T. gondii infection in cats was available in Lanzhou, northwest China. This study was performed to determine the seroprevalence of T. gondii infection in household and stray cats in Lanzhou, northwest China.

Results

A total of 221 (179 households and 42 strays) blood samples were collected from clinically healthy cats admitted to several pet hospitals located in Lanzhou City, between November 2010 and July 2011 for the serological detection of T. gondii infection. The majority (207) of these cats represented Chinese Lihua cats. 47 of 221 (21.3%) examined cats were seropositive for T. gondii infection using the modified agglutination test (MAT) at the cut-off of 1:25. The seroprevalence in household and stray cats was assessed to be 15.6% and 45.2%, respectively, and the difference was statistically significant (P < 0.05). The seroprevalence ranged from 15.1% to 25.8% among different age groups, but the differences were not statistically significant (P > 0.05). Studies showed that there was no relationship between seroprevalence and the gender (P > 0.05).

Conclusions

The present survey indicated the high seroprevalence of T. gondii in cats in Lanzhou, northwest China, which poses a threat to animal and human health. Therefore, measures should be taken to control and prevent toxoplasmosis of cats in this area.
BEAM: A Randomized Phase II Study Evaluating the Activity of Bevacizumab in Combination With Carboplatin Plus Paclitaxel in Patients With Previously Untreated Advanced Melanoma
Authors: Kim Kevin B. , Sosman Jeffrey A. , Fruehauf John P. , Linette Gerald P. , Markovic Svetomir N. , McDermott David F. , Weber Jeffrey S. , Nguyen Hoa , Cheverton Peter , Chen Daniel , Peterson Amy C. , Carson William E. , O'Day Steven J.
Published: November 2011

Purpose

Metastatic melanoma, a highly vascularized tumor with strong expression of vascular endothelial growth factor, has an overall poor prognosis. We conducted a placebo-controlled, double-blind phase II study of carboplatin plus paclitaxel with or without bevacizumab in patients with previously untreated metastatic melanoma.

Patients and Methods

Patients were randomly assigned in a two-to-one ratio to carboplatin (area under the curve, 5) plus paclitaxel (175 mg/m2) and bevacizumab (15 mg/kg; CPB) or placebo (CP) administered intravenously once every 3 weeks. Progression-free survival (PFS) was the primary end point. Secondary end points included overall survival (OS) and safety.

Results

Two hundred fourteen patients (73% with M1c disease) were randomly assigned. With a median follow-up of 13 months, median PFS was 4.2 months for the CP arm (n = 71) and 5.6 months for the CPB arm (n = 143; hazard ratio [HR], 0.78; P = .1414). Overall response rates were 16.4% and 25.5%, respectively (P = .1577). With 13-month follow-up, median OS was 8.6 months in the CP arm versus 12.3 months in the CPB arm (HR, 0.67; P = .0366), whereas in an evaluation 4 months later, it was 9.2 versus 12.3 months, respectively (HR, 0.79; P = .1916). In patients with elevated serum lactate dehydrogenase (n = 84), median PFS and OS were longer in the CPB arm (PFS: 4.4 v 2.7 months; HR, 0.62; OS: 8.5 v 7.5 months; HR, 0.52). No new safety signals were observed.

Conclusion

The study did not meet the primary objective of statistically significant improvement in PFS with the addition of bevacizumab to carboplatin plus paclitaxel. A larger phase III study will be necessary to determine whether there is benefit to the addition of bevacizumab to carboplatin plus paclitaxel in this disease setting.