bluuebunny/crossref_metadata_2025_split huggingface dataset:
Animal models in the drug discovery pipeline for Alzheimer's disease
Authors: Van Dam Debby , De Deyn Peter Paul 
Published: March 2011

With increasing feasibility of predicting conversion of mild cognitive impairment to dementia based on biomarker profiling, the urgent need for efficacious disease‐modifying compounds has become even more critical. Despite intensive research, underlying pathophysiological mechanisms remain insufficiently documented for purposeful target discovery. Translational research based on valid animal models may aid in alleviating some of the unmet needs in the current Alzheimer's disease pharmaceutical market, which includes disease‐modification, increased efficacy and safety, reduction of the number of treatment unresponsive patients and patient compliance. The development and phenotyping of animal models is indeed essential in Alzheimer's disease‐related research as valid models enable the appraisal of early pathological processes – which are often not accessible in patients, and subsequent target discovery and evaluation. This review paper summarizes and critically evaluates currently available animal models, and discusses their value to the Alzheimer drug discovery pipeline. Models dealt with include spontaneous models in various species, including senescence‐accelerated mice, chemical and lesion‐induced rodent models, and genetically modified models developed in Drosophila melanogaster, Caenorhabditis elegans, Danio rerio and rodents. Although highly valid animal models exist, none of the currently available models recapitulates all aspects of human Alzheimer's disease, and one should always be aware of the potential dangers of uncritical extrapolating from model organisms to a human condition that takes decades to develop and mainly involves higher cognitive functions.LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Predictive validity of behavioural animal models for chronic pain
Authors: Berge Odd‐Geir 
Published: March 2011

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature‐based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well‐controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue‐4
Constitutive expression of hypoxia‐inducible factor‐1 α in keratinocytes during the repair of skin wounds in horses
Authors: Deschene Karine , Céleste Christophe , Boerboom Derek , Theoret Christine L. 
Published: March 2011

ABSTRACTAs a transient hypoxic state exists within skin wounds in horses and may be important for the healing process, this study sought to identify a molecular hypoxia response occurring in horse limb and body wounds healing by second intention. Hypoxia‐inducible factor 1α (HIF1α) protein expression was studied throughout repair by Western blotting and immunofluorescence. Paradoxically, HIF1α was strongly expressed in intact skin and its expression decreased dramatically following wounding (p<0.01), despite the expected hypoxic state within the wounded tissue. HIF1α levels reincreased in parallel with the epithelialization process, and more rapidly in body wounds than in limb wounds (p<0.01). HIF1α localized predominantly to the keratinocyte layer, in which it was constitutively expressed throughout healing. The HIF1α target gene cyclin‐dependent kinase inhibitor 1A (CDKN1A) showed a pattern of expression similar to HIF1α throughout the healing process and also localized to the keratinocyte layer, suggesting that HIF1α may regulate its constitutive expression. The HIF1α target genes vascular endothelial growth factor A (VEGFA) and solute carrier family 2 (facilitated glucose transporter) member 1 (SLC2A1) however did not have a pattern of expression similar to HIF1α, at the mRNA level. We conclude that HIF1α is expressed in a continuous and hypoxia‐independent manner in equine keratinocytes in both intact and wounded skin, and may regulate the expression of CDKN1A in this cell type.
The reinnervation and revascularization of wounds is temporarily altered after treatment with interleukin 10
Authors: Henderson James , Ferguson Mark W.J. , Terenghi Giorgio 
Published: March 2011

ABSTRACTDenervated wounds fail to heal normally, and hypertrophic scars are abnormally innervated. Wounds can be manipulated with cytokines to reduce subsequent scarring. Wounds treated with the antiscarring cytokine interleukin 10 (IL10) were investigated to assess if the treatment alterered patterns of reinnervation and revascularization as the wounds matured into scars. Thirty CD1 mice underwent intradermal injection of 100 μL phosphate‐buffered saline (PBS) containing 125 ng IL10 or placebo at the margins of 1 cm2 full thickness dorsal skin excisions at the time of wounding and at 24 hours after wounding. Wounds were not dressed. Six IL10‐treated and six control were harvested days 7, 14, 21, 42 and 84 postoperatively. Sections underwent histological scar assessment along with immunohistochemical staining for protein gene product 9.5 (PGP9.5), a pan‐neuronal marker, and the sensory neuropeptides calcitonin gene related peptide (CGRP) and substance P (SP). The endothelial marker von Willebrand factor (VWF) was used to allow co‐localization and quantification of blood vessels. Quantitative analysis was performed on the periphery and center of wounds. Wounds treated with IL10 healed with dermal collagen organized into a pattern more closely resembling normal skin than control wounds. IL10 changed the pattern of CGRP reinnervation during the healing process, but at 84 days, the density levels of all nerve fiber types were similar to controls. Wounds treated with IL10 were more vascular than untreated wounds during healing, but by 84 days, VWF density was that of unwounded skin.
Human hypertrophic scar‐like nude mouse model: Characterization of the molecular and cellular biology of the scar process
Authors: Wang JianFei , Ding Jie , Jiao Haiyan , Honardoust Dariush , Momtazi Moein , Shankowsky Heather A. , Tredget Edward E. 
Published: March 2011

ABSTRACTHypertrophic scar (HTS) following thermal injury and other forms of trauma is a dermal fibroproliferative disorder that leads to considerable morbidity. Because of the lack of an ideal animal model, research is difficult. We have established an HTS model that involves transplanting human split‐thickness skin graft (STSG) or full‐thickness skin graft (FTSG) onto the backs of nude mice. The animals developed raised, firm, and reddish scars 2 months following transplantation. Histology and micromeasurement indicate raised, thickened engrafted skin with STSG and FTSG. In contrast, thickening was not observed with full‐thickness rat skin grafts used as controls. Masson's trichrome staining demonstrates increased accumulations of collagen fibrils in the dermis in both scars grafted with STSG and FTSG. Staining cells with toludine blue and an antibody for F4/80 showed an increase in the infiltration of mast cells and macrophages. Quantification of fibrocytes reveals increased fibrocytes. Moreover, STSG grafted skin had significantly more macrophages, mast cells, and fibrocytes than FTSG. Real‐time polymerase chain reaction analysis showed significantly elevated mRNA levels for type I collagen, transforming growth factor‐β, connective tissue growth factor and heat shock protein 47 in both types of engrafted skin. These data demonstrate that human skin grafted onto nude mice develops red raised and thickened scars having intrinsic properties that closely resemble HTS formation as seen in humans. Interestingly, STSG developed more scar than FTSG. Furthermore, inflammatory cells and bone marrow‐derived fibrocytes may play a critical role in HTS development in this animal model.
Effects of Membrane Molecular Weight Cutoff on Performance of a Novel Bioartificial Liver
Authors: Shi Xiao‐lei , Zhang Yue , Han Bing , Gu Jin‐yang , Chu Xue‐hui , Xiao Jiang‐qiang , Ren Hao‐zhen , Tan Jiao‐jun , Ding Yi‐tao 
Published: March 2011

AbstractImmunoisolation using semipermeable membranes has been incorporated into bioartificial liver (BAL) devices to separate cellular components of the recipient's immune system from the cells within the BAL device. This study was designed to explore the influence of membrane molecular weight cutoff on performance of the multilayer radial‐flow BAL using porcine hepatocytes cocultured with mesenchymal stem cells. In this study, healthy beagles underwent 6‐h treatment with a BAL containing membrane with 200 kDa retention rating or 1200 kDa retention rating. Functional markers of BAL performance were monitored before and after treatment, as well as cytotoxic immune response to BAL therapy. The results showed that hepatocyte performance levels such as albumin secretion, urea synthesis, and viability were all significantly higher in 200 kDa retention rating group compared with the 1200 kDa retention rating group after treatment (P <  0.05). Significant levels of canine proteins were detected in BAL medium from the 1200 kDa retention rating group. Fluorescence microscopy further verified that heavy deposition of canine IgG, IgM, and complement (C3) on coculture cells was obtained after BAL treatment in the 1200 kDa retention rating group. However, only trace deposits of canine immunoproteins were observed on coculture cells obtained from BAL in the 200 kDa retention rating group. Small membrane molecular weight cutoff of the BAL could reduce the transfer of xenoreactive antibodies into the BAL medium and improve the performance of the BAL.
Development of an Implantable Myoelectric Sensor for Advanced Prosthesis Control
Authors: Merrill Daniel R. , Lockhart Joseph , Troyk Phil R. , Weir Richard F. , Hankin David L. 
Published: March 2011

AbstractModern hand and wrist prostheses afford a high level of mechanical sophistication, but the ability to control them in an intuitive and repeatable manner lags. Commercially available systems using surface electromyographic (EMG) or myoelectric control can supply at best two degrees of freedom (DOF), most often sequentially controlled. This limitation is partially due to the nature of surface‐recorded EMG, for which the signal contains components from multiple muscle sources. We report here on the development of an implantable myoelectric sensor using EMG sensors that can be chronically implanted into an amputee's residual muscles. Because sensing occurs at the source of muscle contraction, a single principal component of EMG is detected by each sensor, corresponding to intent to move a particular effector. This system can potentially provide independent signal sources for control of individual effectors within a limb prosthesis. The use of implanted devices supports inter‐day signal repeatability. We report on efforts in preparation for human clinical trials, including animal testing, and a first‐in‐human proof of principle demonstration where the subject was able to intuitively and simultaneously control two DOF in a hand and wrist prosthesis.
Students’ engagement with their group in a problem‐based learning curriculum
Authors: McHarg J. , Kay E. J. , Coombes L. R. 
Published: March 2011

AbstractIntroduction:  In a new enquiry‐based learning dental curriculum, problem‐based learning (PBL) was chosen as a central methodology because it promotes a collaborative and constructive approach to learning. However, inevitably, some groups function worse than others. This study explores the relationship between group functionality and individuals’ results on knowledge‐based assessment. It also sought to establish whether using the Belbin team role theory could improve group functionality.Methods:  Students completed the Belbin team role inventory that assigns individuals to a team role type and were allocated to either an ideal Belbin group or a control group. To evaluate the functionality of the groups, Macgowan’s group engagement measure was completed after 18 and 31 weeks for each student by their group facilitator. The scores were summed and averaged giving a group engagement score for each group. Relationships between group engagement, individual performance in assessment in weeks 18 and 31 and Belbin and non‐Belbin teams were investigated.Results:  Individual group engagement scores and performance in the knowledge tests had a statistically significant positive relationship despite the small number of students involved (62). However, no correlation was shown between Belbin groups and group engagement scores.Conclusions:  Those students who engaged most with the PBL process performed markedly better in assessments of knowledge. Using Belbin’s team role theory to place students in PBL groups in an effort to increase group functionality had no effect when compared with non‐Belbin control groups.
Chronic Administration of Udenafil, A Selective Phosphodiesterase Type 5 Inhibitor, Promotes Erectile Function Recovery in an Animal Model of Bilateral Cavernous Nerve Crush Injury
Authors: Lee Chan-Ho , Kim Hae-Sun , Goo Moon-Jung , Kang Kyung-Koo , Ahn Byoung-Ok , Kim Soon Hoe , Yang Dae-Yul 
Published: March 2011

ABSTRACT

Introduction
Preservation of the cavernous nerves (CNs) during radical prostatectomy is crucial for the patient's erectile function. Despite advances in operative technique, the majority of men report compromised erectile function postprostatectomy or complete loss of potency due to CN trauma even with nerve-sparing modifications.

Aim
This study was designed to investigate whether repeated dosing of udenafil, a phosphodiesterase type 5 inhibitor, helps to improve erectile function after CN injury.

Methods
Using the CN crush injury model, 8-week-old male Sprague Dawley rats were divided into the following groups; sham-operated group, bilateral CN crush injury exposed to either no udenafil (vehicle) or udenafil (5, 20 mg/kg) daily for two different durations (4 and 8 weeks, p.o.).

Main Outcome Measures
At both time points, CN electrical stimulation was used to assess erectile function by measuring the intracavernous pressure. The expressions of hypoxia-inducible factor 1-alpha (HIF-1α), transforming growth factor-beta (TGF-β1), nerve growth factor (NGF), endothelin B receptor (ETB), endothelial nitric oxide synthase (eNOS), neuronal nitric oxide synthase (nNOS), and sonic hedgehog homolog (SHH) in penile tissue were examined. Immunohistochemical antibody staining was performed for NGF, eNOS, nNOS, CD31, and alpha-smooth muscle actin (α-SMA). Additionally, terminal deoxynucleotidyl transferase-mediated nick-end labeling assay was performed to quantify apoptosis and the tissue slides were stained for Masson's trichrome to assess the smooth muscle/collagen ratio.

Results
Udenafil improved erectile function in a dose- and time-dependent manner with the maximum erectile function recovery achieved by 20 mg/kg udenafil at an 8-week time point. CN injury increased the expression of HIF-1α, TGF-β1, NGF, and ETB, however, decreased the expression of eNOS, nNOS, and SHH. Udenafil significantly suppressed these alterations. The results from the histological analyses show that udenafil markedly reduces apoptosis induced by CN injury and augments the smooth muscle/collagen ratio.

Conclusions
CN injury induces significantly impaired erectile function and altered gene/protein expression. Chronic administration of udenafil preserves erectile function and has a beneficial role against the pathophysiological consequences of CN injury.
Characterization ofBacillus subtilisHC8, a novel plant‐beneficial endophytic strain from giant hogweed
Authors: Malfanova Natalia , Kamilova Faina , Validov Shamil , Shcherbakov Andrey , Chebotar Vladimir , Tikhonovich Igor , Lugtenberg Ben 
Published: March 2011

SummaryThirty endophytic bacteria were isolated from various plant species growing near Saint‐Petersburg, Russia. Based on a screening for various traits, including plant‐beneficial properties and DNA fragment patterns, potential siblings were removed. The remaining isolates were taxonomically identified using 16S rDNA sequences and potential human and plant pathogens were removed. The remaining strains were tested for their ability to promote radish root growth and to protect tomato plants against tomato foot and root rot. One strain,Bacillus subtilisHC8, isolated from the giant hogweedHeracleum sosnowskyiManden, significantly promoted plant growth and protected tomato against tomato foot and root rot. Metabolites possibly responsible for these plant‐beneficial properties were identified as the hormone gibberellin and (lipo)peptide antibiotics respectively. The antibiotic properties of strain HC8 are similar to those of the commercially available plant‐beneficial strainBacillus amyloliquefaciensFZB42. However, thin layer chromatography profiles of the two strains differ. It is speculated that endophytes such asB. subtilisHC8 contribute to the fast growth of giant hogweed.
Challenges and prospects of international marine bunker fuels demand
Authors: Mazraati Mohammad 
Published: March 2011

AbstractThe international marine bunker demand faces many challenges with regard to regulation on fuel quality by the International Maritime Organization (IMO). This paper reviews the most recent challenges and evolutions related to fuel demand and development in international maritime transportation. By developing a simple recursive econometric model, the future demand is forecast under the no‐policy change scenario. In the alternative scenario, the impacts of Annex VI of IMO's marine pollution convention on spread price between the high‐sulphur and low‐sulphur fuel oil are elaborated, and eventually, the impacts on future bunker demand are evaluated. The low price elasticity of bunker demand confirms minimal impacts on demand albeit considerable impacts on running cost of vessels. Bunker demand elasticity with regard to international maritime transportation is estimated at 0.55, showing that inevitable international transportation requirement is the key driver for bunker demand. Implementation of Annex VI would certainly change the mixture of bunker fuel, which mainly depends on the penetration of SO2 scrubbers on‐board of vessels and/or fuel switching. However, due to discrepancy in the level of fuel consumption and uncertain mixture of bunker fuels in the future, the refinery sector and the international maritime transportation sector would face huge uncertainties.
Impact of alternative fuels and advanced technology vehicles on oil demand in the United States up to 2030
Authors: Mazraati Mohammad , Shelbi Haithem 
Published: March 2011

AbstractThe increasingly high oil consumption in US road transportation sector, coupled with its significant contribution to greenhouse gases emission, resulted in the implementation of many policies geared towards addressing both challenges. Aiming to enhance the US energy security, the Energy Policy Act encourages the use of alternative fuels and has set forth the requirements for the acquisition of alternative fuels vehicles (AFVs) by Federal Agencies. This paper applies a hybrid, top‐down, two‐stage model to forecast the share of AFVs in the United States until 2030 and the resulting impact on the US oil demand. In the first stage, a logistic model is being estimated by econometric techniques to forecast the stock of vehicles as a function of socio‐economic variables, i.e. population, gross domestic product and saturation point. The second stage applies an S‐shape function to forecast the annual share of AFVs based on a trend variable that encompasses inherently fuel cost, cost of AFVs, discount rate and consumer's choice and three different AFV saturation level scenarios (2 per cent, 3 per cent, 4 per cent). The impact of AFV and advanced technologies on oil demand was calculated based on average vehicle miles driven and corporate average fuel economy possible trends for both AFVs and total vehicle stock. The paper concludes that under the 4 per cent saturation level scenario for AFVs, the oil saving is forecasted at 196,000 b/d or 1.8 per cent of total transport fuel requirements in 2030. Furthermore, it was determined that marginal increase of 1 per cent in AFVs saturation level in 2030 results in oil saving of around 49,000 b/d which represents 0.5 per cent of total fuel requirement. Overall, it was concluded that unless stringent policy measures are introduced, or a sustainable level of high oil prices is reached, there is a limited impact of AFVs on the US oil demand.
How are proliferation and differentiation of melanocytes regulated?
Authors: Hirobe Tomohisa 
Published: March 2011

SummaryCoat colors are determined by melanin (eumelanin and pheomelanin). Melanin is synthesized in melanocytes and accumulates in special organelles, melanosomes, which upon maturation are transferred to keratinocytes. Melanocytes differentiate from undifferentiated precursors, called melanoblasts, which are derived from neural crest cells. Melanoblast/melanocyte proliferation and differentiation are regulated by the tissue environment, especially by keratinocytes, which synthesize endothelins, steel factor, hepatocyte growth factor, leukemia inhibitory factor and granulocyte‐macrophage colony‐stimulating factor. Melanocyte differentiation is also stimulated by alpha‐melanocyte stimulating hormone; in the mouse, however, this hormone is likely carried through the bloodstream and not produced locally in the skin. Melanoblast migration, proliferation and differentiation are also regulated by many coat color genes otherwise known for their ability to regulate melanosome formation and maturation, pigment type switching and melanosome distribution and transfer. Thus, melanocyte proliferation and differentiation are not only regulated by genes encoding typical growth factors and their receptors but also by genes classically known for their role in pigment formation.