bluuebunny/crossref_metadata_2025 huggingface dataset:
Public Values for River Restoration Options on the Middle Rio Grande
Authors: Weber Matthew A. , Stewart Steven
Published: July 2008

River restoration is a widespread phenomenon. This reflects strong public values for conservation, though missing are studies explicitly justifying restoration expenditures. Public restoration benefits are not well quantified, nor are public preferences among diverse activities falling into the broad category “restoration.” Our study estimates public values for restoration on the Middle Rio Grande, New Mexico. Stakeholder meetings and public focus groups guided development of a restoration survey mailed to Albuquerque area households. Four restoration categories were defined: fish and wildlife; vegetation density; tree type; and natural river processes. Survey responses supplied data for both choice experiment (CE) and contingent valuation (CV) analyses, two established environmental economics techniques for quantifying public benefits of conservation policies. Full restoration benefits are estimated at over $150 per household per year via the CE and at nearly $50 per household per year via CV. The CE allows value disaggregation among different restoration categories. The most highly valued category was tree type, meaning reestablishing native tree dominance for such species as Cottonwood (Populus deltoides) and eradicating non‐native trees such as Saltcedar (Tamarix ramosissma). The high public values we have found for restoration offer economic justification for intensive riparian management, particularly native plant‐based restoration in the Southwest.
Impacts of Herbicide Application and Mechanical Cleanings on Growth and Mortality of Two Timber Species inSaccharum spontaneumGrasslands of the Panama Canal Watershed
Authors: Craven Dylan , Hall Jefferson , Verjans Jean‐Marc
Published: July 2008

Reforestation has been suggested as a strategy to controlSaccharum spontaneum, an invasive grass that impedes regeneration in disturbed areas of the Panama Canal Watershed (PCW). In this study, the effects of different intensities of herbicide application and mechanical cleanings on the growth and mortality ofTerminalia amazoniaandTectona grandissaplings were evaluated inS. spontaneumgrasslands within the PCW. Both species exhibited greater height, basal diameter, wood volume index, wider crown diameters, deeper live crowns, and lower mortality with increasing intensity of mechanical cleanings and herbicide application. Height and competition ofS. spontaneumcorrelated negatively with intensity of mechanical cleanings and herbicide application. Grass control costs did not differ between tree species but did increase significantly with intensity of mechanical cleanings and herbicide application. We recommend fire suppression, annual herbicide application, and at least four mechanical cleanings per year inTec. grandisplantations during the first 3 years of plantation establishment. Given the slower initial growth and mortality patterns ofTer. amazonia, aggressive grass control treatments should be continued until individuals are sufficiently large to effectively shadeS. spontaneum. Results from this study suggest that reforestation with commercial timber species can rapidly establish and controlS. spontaneumgrowth in the PCW. Reforestation of areas already invaded or at risk of being invaded byS. spontaneumappears to be a viable strategy to reduce its abundance and subsequent negative ecological effects in the PCW.
Wetland Restoration in the Mancha Occidental Aquifer, Spain: A Critical Perspective on Water, Agricultural, and Environmental Policies
Authors: Martínez‐Santos Pedro , De Stefano Lucia , Llamas Manuel Ramón , Martínez‐Alfaro Pedro E.
Published: July 2008

Conflicts between intensive groundwater use and wetland conservation are widespread throughout arid and semiarid regions worldwide. These have become more significant wherever there has been a synchronism between pumping‐based human development and the awakening of an environmental awareness in society. The Mancha Occidental aquifer provides an example of such an occurrence, which has given rise to noteworthy social conflicts. This paper presents a cross‐policy analysis for wetland restoration measures, establishing the main reasons why funding‐intensive agricultural, environmental, and water policies have only attained marginal success in recovering the area’s aquatic ecosystems.
Ophthalmoplegic Migraine and Infundibular Dilatation of a Cerebral Artery
Authors: Vieira José Pedro , Castro Jorge , Gomes Leonor Bastos , Jacinto Sandra , Dias Ana
Published: July 2008

Ophthalmoplegic migraine (OM) is a childhood disorder of uncertain etiology manifesting recurrent unilateral headache associated with a transitory oculomotor (usually IIIrd nerve) palsy. Recent publications emphasize the finding on MRI of contrast enhancement in the IIIrd nerve suggesting that OM may be a recurrent inflammatory neuropathy.

We report the case of a 7‐year‐old boy with typical symptoms of this disorder. Angio MR and Angio CT revealed the presence of an infundibular dilatation of a perforating branch of the posterior cerebral artery adjacent to the symptomatic IIIrd nerve. We speculate that this and perhaps other cases of OM may have a different pathophysiology related to compression of the IIIrd nerve by an adjacent vascular structure that could activate the trigeminovascular system and produce migrainous pain.
Diabetic neuropathies: components of etiology
Authors: Tomlinson David R. , Gardiner Natalie J.
Published: June 2008

Abstract  This review examines the putative role of glucose in the etiology of diabetic neuropathies. Excessive glucose generates several secondary metabolic anomalies — principally oxidative stress (via both the polyol pathway and glucoxidation) and non‐enzymic glycation of macromolecules. The latter is also facilitated by glucoxidation. These metabolic deviations trigger cellular responses that are inappropriate to normal function. Principal among these are neurotrophic deficits and phosphorylation of mitogen‐activated protein kinases (MAPK). Downstream of these events are aberrant ion channel function and disordered gene expression, leading to changes in cellular phenotype. This leads directly to disordered nerve conduction, a recognised early clinical sign, and indirectly, via as yet undisclosed links, to sensory loss and axonopathy. Recent work also links MAPK activation to the development of neuropathic pain.
Novel signals controlling embryonic Schwann cell development, myelination and dedifferentiation
Authors: Mirsky Rhona , Woodhoo Ashwin , Parkinson David B. , Arthur‐Farraj Peter , Bhaskaran Ambily , Jessen Kristján R.
Published: June 2008

Abstract Immature Schwann cells found in perinatal rodent nerves are generated from Schwann cell precursors (SCPs) that originate from the neural crest. Immature Schwann cells generate the myelinating and non‐myelinating Schwann cells of adult nerves. When axons degenerate following injury, Schwann cells demyelinate, proliferate and dedifferentiate to assume a molecular phenotype similar to that of immature cells, a process essential for successful nerve regeneration. Increasing evidence indicates that Schwann cell dedifferentiation involves activation of specific receptors, intracellular signalling pathways and transcription factors in a manner analogous to myelination. We have investigated the roles of Notch and the transcription factor c‐Jun in development and after nerve transection.In vivo, Notch signalling regulates the transition from SCP to Schwann cell, times Schwann cell generation, controls Schwann cell proliferation and acts as a brake on myelination. Notch is elevated in injured nerves where it accelerates the rate of dedifferentiation. Likewise, the transcription factor c‐Jun is required for Schwann cell proliferation and death and is down‐regulated by Krox‐20 on myelination. Forced expression of c‐Jun in Schwann cells prevents myelination, and in injured nerves, c‐Jun is required for appropriate dedifferentiation, the re‐emergence of the immature Schwann cell state and nerve regeneration. Thus, both Notch and c‐Jun are negative regulators of myelination. The growing realisation that myelination is subject to negative as well as positive controls and progress in molecular identification of negative regulators is likely to impact on our understanding of demyelinating disease and mechanisms that control nerve repair.
Outcome measures in immune‐mediated neuropathies: the need to standardize their use and to understand the clinimetric essentials
Authors: Van Nes Sonja I. , Faber Catharina G. , Merkies Ingemar S. J.
Published: June 2008

Abstract  Peripheral neurological disorders like neuropathies may cause impairments (such as weakness and sensory deficits), which may lead to problems in daily life and social functioning with a possible decrement in quality of life expectations. Choosing the proper outcome measure to evaluate the therapeutic efficacy of an intervention at one of these levels of outcome should therefore be considered as fundamental to the design of randomized trials in peripheral neurological disorders. However, these choices are dependent not only on the proposed research purposes but also, and perhaps more importantly, on the fulfillment of the scientific needs of these measures. With an increasing demand for accuracy, a thorough and comprehensive evaluation of an outcome measure is needed to determine its simplicity, communicability, validity, reliability, and responsiveness before being clinically applicable, techniques that are being captured by the science of clinimetrics. Most neurologists are still unfamiliar with these rigorous methodological essentials or overlook some of them in their trial preparations because these are considered time consuming and mind numbing. This review will highlight, against the background of the international classification framework and clinimetric needs for outcome measures, the selected scales applied in published randomized controlled trials in patients with Guillain‐Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy, and gammopathy‐related neuropathies. The need for comparison responsiveness studies between equally valid and reliable measures and to standardize their use is emphasized in these conditions. Finally, specific recommendations are given to move from classic to modern clinimetric approach when constructing, evaluating, and selecting outcome measures using new methods like Rasch analysis, accentuating the need of shifting toward a more modern era.
Specific Reduction of Alcohol’s Motivational Properties by the Positive Allosteric Modulator of the GABAB Receptor, GS39783—Comparison With the Effect of the GABAB Receptor Direct Agonist, Baclofen
Authors: Maccioni Paola , Fantini Noemi , Froestl Wolfgang , Carai Mauro A. M. , Gessa Gian Luigi , Colombo Giancarlo
Published: July 2008

Background:  Activation of the GABAB receptor—either by means of direct agonists (like baclofen) or positive allosteric modulators (like GS39783)—has been observed to suppress alcohol drinking and reinforcement in rats and mice. The present study was conducted to assess and compare the effect of baclofen and GS39783 on the motivational properties of alcohol.

Methods:  Selectively bred Sardinian alcohol‐preferring (sP) rats were initially trained to respond on a lever (on an fixed ratio 4 schedule of reinforcement) to orally self‐administer alcohol (15%, v/v) or sucrose (3%, w/v) in daily 30‐minute sessions. Once lever‐responding reached stable levels, rats were exposed to sessions with a progressive ratio schedule of reinforcement. The effect of nonsedative doses of baclofen (0, 1, and 3 mg/kg, i.p.) and GS39783 (0, 25, 50, and 100 mg/kg, i.g.) on breakpoint for alcohol and sucrose (defined as the lowest response requirement not achieved by each rat and used as index of the motivational strength of alcohol and sucrose) was determined.

Results:  Baclofen administration resulted in a dose‐dependent decrease in breakpoint for alcohol; this effect was not specific, as baclofen also reduced—to a comparable extent—breakpoint for sucrose. Conversely, GS39783 administration resulted in a dose‐dependent and completely specific reduction in breakpoint for alcohol.

Conclusions:  The present results (i) confirm previous data on baclofen’s capacity to suppress, although nonspecifically, alcohol’s motivational properties, and (ii) extend to alcohol’s motivational properties the capacity of GS39783 to inhibit alcohol drinking and reinforcement in rats.
Salivary Acetaldehyde Concentration According to Alcoholic Beverage Consumed and Aldehyde Dehydrogenase‐2 Genotype
Authors: Yokoyama Akira , Tsutsumi Eri , Imazeki Hiromi , Suwa Yoshihide , Nakamura Chizu , Mizukami Takeshi , Yokoyama Tetsuji
Published: July 2008

Background:  Acetaldehyde is suspected of playing a critical role in cancer development in the upper aerodigestive tract (UADT). The high salivary acetaldehyde levels after alcohol drinking are partly due to acetaldehyde production by oral bacteria. Some alcoholic beverages, especially Calvados and shochu, contain very high levels of acetaldehyde. Inactive heterozygous aldehyde dehydrogenase‐2 (ALDH2) increases the risk of UADT cancer in drinkers.

Methods:  In a randomized cross‐over design study, 19 healthy Japanese volunteers ingested 0.6 g ethanol/kg body weight in the form of 13% ethanol Calvados, 13% ethanol shochu, 13% ethanol red wine, and 5% ethanol beer under the fasting conditions at 3‐week intervals. We monitored blood and salivary acetaldehyde concentrations immediately after drinking, and 30, 60, 90, 120, and 180 minutes after completion of drinking.

Results:  The acetaldehyde concentration of each beverage was: Calvados 0.60 mM (1.86 mM in 40% undiluted solution), shochu 0.60 mM (1.16 mM in 25% undiluted solution), red wine 0.25 mM, and beer 0.14 mM. The salivary acetaldehyde concentration immediately after drinking wine was significantly lower than the other beverages, and it was significantly lower immediately after drinking beer than Calvados. The acetaldehyde concentrations 30 to 180 minutes after drinking were unrelated to the beverage type. Throughout the observation period the salivary acetaldehyde concentrations were much higher than the blood acetaldehyde concentrations in all 12 active ALDH2 homozygotes (24 to 53 μM in saliva vs. 2 to 5 μM in blood) and in all 7 inactive ALDH2 heterozygotes (37 to 76 μM in saliva vs. 12 to 25 μM in blood), and they were 13 to 25 μM higher in the ALDH2 heterozygotes than in the ALDH2 homozygotes after adjusting for age, body weight, sex, smoking and drinking habits, and time since the last toothbrushing. The values after subtracting the blood acetaldehyde concentration from the salivary acetaldehyde concentration were also higher in the ALDH2 heterozygotes than in the ALDH2 homozygotes.

Conclusions:  There are differences in exposure of the UADT to high salivary acetaldehyde concentrations according to the type of alcoholic beverage and ALDH2 genotype, and the differences partly explain the differences in the cancer susceptibility of the UADT according to alcoholic beverage and ALDH2 genotype.
DNA‐Based Methods for the Identification of Commercial Fish and Seafood Species
Authors: Rasmussen Rosalee S. , Morrissey Michael T.
Published: July 2008

ABSTRACT:  The detection of species substitution has become an important topic within the food industry and there is a growing need for rapid, reliable, and reproducible tests to verify species in commercial fish and seafood products. Increases in international trade and global seafood consumption, along with fluctuations in the supply and demand of different fish and seafood species, have resulted in intentional product mislabeling. The effects of species substitution are far‐reaching and include economic fraud, health hazards, and illegal trade of protected species. To improve detection of commercial seafood fraud, a variety of DNA‐based techniques have been developed, including Multiplex PCR, FINS, PCR‐RFLP, PCR‐RAPD, PCR‐AFLP, and PCR‐SSCP, which are all based on polymorphisms in the genetic codes of different species. These techniques have been applied in the differentiation of many types of fish and seafood species, such as gadoids, salmonids, scombroids, and bivalves. Some emerging technologies in this field include the use of real‐time PCR, lab‐on‐a‐chip, and DNA microarray chips. In this review article, the major DNA‐based methods currently employed in the authentication of commercial fish and seafood species are discussed and future trends are highlighted. Examples of commercial applications and the use of online database resources are also considered.
Ventriculo‐peritoneal shunt infection in a patient on hemodialysis
Authors: THET Yupar , MYINT Wynne , HUGHES David , CROWE Alex V. , BANERJEE Anindya
Published: July 2008

Sepsis is an important and serious complication in hemodialysis (HD) patients. Here we report on a case of spina bifida with ventriculo‐peritoneal (VP) shunt infection who was on HD and underwent at least 5 months of investigations before a source of the infection was found and eventually treated successfully. We believe this to be the first reported case of VP shunt‐associated sepsis in a patient on HD.
Toward the wearable artificial kidney
Authors: RONCO Claudio , DAVENPORT Andrew , GURA Victor
Published: July 2008

The evolution of technology in hemodialysis has gone through several steps including the feasibility phase, the search for reliability, the implementation of automation to improve efficiency and the quest towards increased tolerance and treatment adequacy. Today, a new challenge is appearing on the scene and it concerns miniaturization, transportability, wearability and the possibility of developing implantable devices for renal replacement therapies. Although we are not there yet, a new series of papers have recently been published disclosing interesting and promising results on the application of wearable ultrafiltration systems (WUF) and wearable artificial kidneys (WAK). Some of these use extracorporeal blood cleansing as a method of blood purification while others use peritoneal dialysis as a treatment modality. This manuscript presents the initial results with these new devices and proposes an effort to make a quantum leap in technology making the wearable artificial kidney a reality rather than a dream.
What limits the expansion of self‐care dialysis at home?
Authors: LEDEBO Ingrid
Published: July 2008

Self‐care dialysis at home, whether peritoneal dialysis or hemodialysis, is more cost‐effective than in‐center dialysis and treatment outcome is at least comparable. Still, both self‐care modalities are considered underutilized and we wished to identify the perceived reasons for this underutilization among nephrology professionals. A questionnaire was distributed at 5 international nephrology meetings in 2006. Questions addressed the most important stakeholders and the most important issues for patients and nephrology professionals to enable the expansion of self‐care dialysis and commonly mentioned barriers were given as alternative responses. The proportion of patients considered suitable for self‐care was also investigated. Seven thousand responses were collected. The listed stakeholders, i.e., health care and reimbursement authorities, nurses and physicians, and finally patients and their families, are considered approximately equally important for the process. Nephrology professionals feel that patient motivation for choosing and performing self‐care dialysis is the strongest driver. The need for dedicated resources for self‐care is judged to be vital for the expansion of this modality of treatment. Thirty‐two percent of incident patients are considered able to perform self‐care dialysis at home. This international survey among 7000 nephrology professionals has identified patient motivation as one of the strongest drivers of self‐care dialysis at home. The need for dedicated resources for the staff to devote time to developing such motivation is given as one of the major reasons for the slow adoption. Under ideal conditions, it is felt that one‐third of all patients starting dialysis can be trained to perform self‐care dialysis.
The immune reaction against allogeneic necrotic cells is reduced in Annexin A5 knock out mice whose macrophages display an anti‐inflammatory phenotype
Authors: Frey Benjamin , Munoz Luis E. , Pausch Friederike , Sieber Renate , Franz Sandra , Brachvogel Bent , Poschl Ernst , Schneider Holm , Rödel Franz , Sauer Rolf , Fietkau Rainer , Herrmann Martin , Gaipl Udo S.
Published: July 2008

Proteins of the annexin family bind to phospholipids in a Ca2+ dependent manner. The exposure of phosphatidylserine (PS) by apoptotic as well as necrotic cells is one major eat‐me‐signal for macrophages. Annexin A5 (Anx A5) preferentially binds to PS. The availability of Anx A5 knock out (KO) mice allowed us to investigate for the first time if endogenous Anx A5 modulates the immune response towards allogeneic cells. Furthermore, the effect of Anx A5 gene deletion on the phagocytic process as well as on the inflammatory reaction of macrophages was explored. We found that Anx A5 KO mice have a strongly reduced allogeneic cellular immune reaction against primary as well as secondary necrotic cells. In vivo phagocytosis experiments revealed that macrophages of Anx A5 KO mice displayed an increased uptake of necrotic cells. Additionally, an increased secretion of the anti‐inflammatory cytokine IL‐10 of isolated macrophages of Anx A5 KO mice after contact with necrotic cells was observed. Furthermore, the promoter activity of the Anx A5 gene was enhanced after stimulation of macrophages. The tumour size of an allogeneic tumour regressed faster when endogenous Anx A5 was present. These data demonstrate that endogenous Anx A5 influences the phagocytosis of necrotic cells, modulates the immune response towards allogeneic cells and acts as an inflammatory protein.
GFP‐tagged proteins visualized by freeze‐fracture immuno‐electron microscopy: a new tool in cellular and molecular medicine
Authors: Robenek Horst , Buers Insa , Hofnagel Oliver , Lorkowski Stefan , Severs Nicholas J.
Published: July 2008

GFP‐tagging is widely used as a molecular tool to localize and visualize the trafficking of proteins in cells but interpretation is frequently limited by the low resolution afforded by fluorescence light microscopy. Although complementary thin‐section immunogold electron microscopic techniques go some way in aiding interpretation, major limitations, such as relatively poor structural preservation of membrane systems, low labelling efficiency and the two‐dimensional nature of the images, remain. Here we demonstrate that the electron microscopic technique freeze‐fracture replica immunogold labelling overcomes these disadvantages and can be used to define, at high resolution, the precise location of GFP‐tagged proteins in specific membrane systems and organelles of the cell. Moreover, this technique provides information on the location of the protein within the phospholipid bilayer, potentially providing insight into mis‐orientation of tagged proteins compared to their untagged counterparts. Complementary application of the freeze‐fracture replica immunogold labelling technique alongside conventional fluorescence microscopy is seen as a novel and valuable approach to verification, clarification and extension of the data obtained using fluorescent‐tagged proteins. The application of this approach is illustrated by new findings on PAT‐family proteins tagged with GFP transfected into fibroblasts from patients with Niemann‐Pick type C disease.
Cysteinylation and homocysteinylation of plasma protein thiols during ageing of healthy human beings
Authors: Rossi R. , Giustarini D. , Milzani A. , Dalle‐Donne I.
Published: July 2008

The purpose of the present study was to determine the relative amount of S‐thiolated proteins (i.e. S‐homocysteinylated, S‐cysteinylglycinylated, S‐glutathionylated and S‐cysteinylated proteins) to the total protein thiols (i.e. the sum of reduced protein sulphydryl groups (PSHs) and protein mixed disulphides with homocysteine [HcySH], cysteinylglycine, cysteine [CysSH] and glutathione) in the plasma of healthy individuals aged 20 to 93. After plasma separation, total protein thiols, S‐thiolated proteins, as well as CysSH, cystine, HcySH and homocystine were measured by high‐performance liquid chromatography (HPLC) with fluorescence determination of the thiol‐monobromobimane conjugate. Determination of plasma levels of protein thiols was performed by spectrophotometry with 5,5′‐dithiobis(2‐nitrobenzoic acid) as a titrating agent. The present study demonstrates an age‐dependent reduction in the amount of PSHs, and an age‐dependent increase in cysteinylated and homocysteinylated plasma proteins in healthy human beings. This indicates that the efficiency of the reduced protein thiol pool as an antioxidant defence system decreases with age, possibly causing an increased risk of irreversible oxidation (i.e. further oxidation to sulphinic and sulphonic acids, which are usually not reducible by thiol reducing agents) of sulphydryl groups of plasma proteins. The drop in the plasma level of protein sulphydryl groups suggests depletion and/or impairment of the antioxidant capacity of plasma, likely related to an alteration of the delicate balance between the different redox forms of thiols.
microRNAs and prostate cancer
Authors: Shi Xu‐Bao , Tepper Clifford G. , White Ralph W. deVere
Published: July 2008

Introduction

miRNAs and human cancer

Aberrant expression of miRNAs in prostate cancer

Biological function of prostate cancer‐related miRNAs

Identification of targets of prostate cancer‐related miRNAs

Regulation of miRNAs in prostate cancer

Potential application of miRNAs in prostate cancer

Conclusions

Prostate cancer (CaP) is the most frequently diagnosed malignant tumour and the second leading cause of cancer deaths in American men. One of the most troubling aspects of this disease is that, after androgen ablation therapy, androgen‐dependent cancer cells inevitably progress to an androgen‐independent status, for which no effective treatment has yet been developed. To date, the mechanisms that underlie the occurrence and progression of CaP remain largely unknown. Recent studies suggest that microRNAs (miRNAs) are involved in human tumourigenesis. Some aberrantly expressed miRNAs have been discovered in CaP cell lines, xenografts and clinical tissues and these CaP‐related miRNAs may play critical roles in the pathogenesis of CaP. This review provides an overview of current findings about aberrantly expressed miRNAs in CaP. Although a number of CaP‐related miRNAs were discovered, to date, only five are characterized for their functionalities: three as oncogenes and two as tumour suppressors. To understand the mechanisms of miRNA action as oncogenes or tumour suppressors, mRNA targets of miRNAs were characterized. Oncogenic miRNAs down‐regulate the expression of apoptosis‐related genes, and tumour suppressor miRNAs target the proliferation‐related genes. Importantly, there is evidence that CaP‐related miRNAs are regulated through androgen signalling and that this regulation may contribute to the development of androgen independence. Due to the oncogenic or tumour‐suppressive properties of CaP‐related miRNAs, they are highly likely to be of clinical use first as biomarkers but more importantly as therapeutic targets for prostate cancer treatment in the near future.
E2F1 represses β‐catenin/TCF activity by direct up‐regulation of Siah1
Authors: Xie Wei , Jin Lei , Mei Yide , Wu Mian
Published: July 2008

Transcription factor E2F1 is a key regulator of cell proliferation and apoptosis. Its activity is strictly controlled by the pRB/E2F pathway. In the majority of cancer cells, however, this pathway is frequently found deregulated, and the underlying mechanism involving transcriptional control by E2F1 has not yet been fully elucidated. Here we report the identification of two putative E2F1‐binding sites located upstream from Siah1 transcription start site (+1). Chromatin immunoprecipitation assay reveals that transcription factor E2F1 is capable of binding to the putative sites, and luciferase reporter assay shows that E2F1 can activate transcription from the Siah1 promoter. Ectopic expression of E2F1 elevates the Siah1 level, hence suppressing the β‐catenin/TCF activity. Consistently, knock‐down of endogenous E2F1 by a shRNA strategy results in reduced expression of Siah1. Moreover, repression of β‐catenin/TCF activity by E2F1 can be attenuated by shRNA‐based repression of endogenous Siah1, implying that Siah1 is a bona fide E2F1 target gene, which at least partly, mediates the suppression of β‐catenin/TCF signalling pathway.
The natural compound atraric acid is an antagonist of the human androgen receptor inhibiting cellular invasiveness and prostate cancer cell growth
Authors: Papaioannou Maria , Schleich Sonja , Prade Ina , Degen Stephanie , Roell Daniela , Schubert Undine , Tanner Tamzin , Claessens Frank , Matusch Rudolf , Baniahmad Aria
Published: July 2008

Extracts from Pygeum africanum are used in the treatment of prostatitis, benign prostatic hyperplasia and prostate cancer (Pca), major health problems of men in Western countries. The ligand‐activated human androgen receptor (AR) supports the growth of the prostate gland. Inhibition of human AR by androgen ablation therapy and by applying synthetic anti‐androgens is therefore the primary goal in treatment of patients. Here, we show that atraric acid (AA) isolated from bark material of Pygeum africanum has anti‐androgenic activity, inhibiting the transactivation mediated by the ligand‐activated human AR. This androgen antagonistic activity is receptor specific and does not inhibit the closely related glucocorticoid or progesterone receptors. Mechanistically, AA inhibits nuclear transport of AR. Importantly, AA is able to efficiently repress the growth of both the androgen‐dependent LNCaP and also the androgen‐independent C4–2 Pca cells but not that of PC3 or CV1 cells lacking AR. In line with this, AA inhibits the expression of the endogenous prostate specific antigen gene in both LNCaP und C4–2 cells. Analyses of cell invasion revealed that AA inhibits the invasiveness of LNCaP cells through extracellular matrix. Thus, this study provides a molecular insight for AA as a natural anti‐androgenic compound and may serve as a basis for AA derivatives as a new chemical lead structure for novel therapeutic compounds as AR antagonists, that can be used for prophylaxis or treatment of prostatic diseases.
Osteopontin as two‐sided mediator of intestinal inflammation
Authors: Heilmann Katja , Hoffmann Ute , Witte Ellen , Loddenkemper Christoph , Sina Christian , Schreiber Stefan , Hayford Claudia , Holzlbhner Pamela , Wolk Kerstin , Tchatchou Elianne , Moos Verena , Zeitz Martin , Sabat Robert , Giinthert Ursula , Wittig Bianca Maria
Published: July 2008

Osteopontin (OPN) is characterized as a major amplifier of Th1‐immune responses. However, its role in intestinal inflammation is currently unknown. We found considerably raised OPN levels in blood of wild‐type (WT) mice with dextran sodium sulfate (DSS)‐induced colitis. To identify the role of this mediator in intestinal inflammation, we analysed experimental colitis in OPN‐deficient (OPN−/−) mice. In the acute phase of colitis these mice showed more extensive colonic ulcerations and mucosal destruction than WT mice, which was abrogated by application of soluble OPN. Within the OPN−/– mice, infiltrating macrophages were not activated and showed impaired phagocytosis. Reduced mRNA expression of interleukin (IL)‐1 β and matrix metalloproteinases was found in acute colitis of OPN−/– mice. This was associated with decreased blood levels of IL‐22, a Th17 cytokine that may mediate epithelial regeneration. However, OPN–/– mice showed increased serum levels of tumour necrosis factor (TNF)‐α, which could be due to systemically present lipopolysaccharide translocated to the gut. In contrast to acute colitis, during chronic DSS‐colitis, which is driven by a Th1 response of the lamina propria infiltrates, OPN−/– mice were protected from mucosal inflammation and demonstrated lower serum levels of IL‐12 than WT mice. Furthermore, neutralization of OPN in WT mice abrogated colitis. Lastly, we demonstrate that in patients with active Crohn's disease OPN serum concentration correlated significantly with disease activity. Taken together, we postulate a dual function of OPN in intestinal inflammation: During acute inflammation OPN seems to activate innate immunity, reduces tissue damage and initiates mucosal repair whereas during chronic inflammation it promotes the Th1 response and strengthens inflammation.
Follicular streamers (stelae) in scarring and non‐scarring alopecia
Authors: Horenstein Marcelo G. , Jacob Jack S.
Published: July 2008

Background:  Follicular streamers are residual fibrovascular tracts representing the impermanent lower third of the hair follicle below the bulge region. Streamers are generally not counted in transverse alopecia samples as they may represent catagen/telogen (CT) follicles and vellus‐like (VL) follicles, or be mistaken as follicular scars.

Design:  We evaluated 22 non‐scarring alopecia cases, including alopecia areata (AA) and androgenetic alopecia (AGA), and 22 scarring alopecia cases, including follicular degeneration syndrome (FDS)/central centrifugal cicatricial alopecia and other scarring alopecia (OSA) disorders. We counted terminal follicular streamers found at a deep dermal level (L2) and followed them into a mid‐dermal level at the central follicular unit (FU) to determine their precise derivation.

Results:  We found streamers in 8/9 AA, 11/13 AGA, 6/12 FDS and 3/10 OSA cases. We counted a total of 74 streamers at L2, including 61 in non‐scarring alopecia cases (p < 0.001). At the more superficial FU level, 72% of streamers corresponded to CT follicles, 25% to VL follicles and 3% to follicular scars.

Conclusions:  Follicular streamers are found predominantly in non‐scarring alopecia cases. Streamers found at deep dermal or subcutaneous levels should be followed and identified at the FU level in order to obtain accurate follicular counts and follicular ratios needed for non‐scarring alopecia diagnosis.
Capillary gel electrophoresis: a simple method for identification of mutations and polymorphisms in the CEBPA gene in patients with acute myeloid leukaemia
Authors: Juhl‐Christensen Caroline , Bomberg Marianne , Melsvik Dorte , Hokland Peter , Nyvold Charlotte Guldborg
Published: July 2008

Introduction:  The CEBPA gene encodes a transcription factor, CCAAT/enhancer binding protein (C/EBP)α. Expression of the wildtype protein is essential for the lineage specific differentiation of myelocytic haematopoietic precursors into mature neutrophils. Eight percentage of all AML patients harbour at least one mutation in this gene, increasing up to 15% in the group, where standard karyotypic analysis do not reveal chromosomal aberrations.

Objective:  We designed a method, which discriminates as little as single base insertions or deletions accounting for 90% of all CEBPA mutations. The TAD2C length polymorphism was also identified using this set up.

Patients and Methods:  Diagnostic bone marrow or peripheral blood from 446 adults and 39 children diagnosed with AML from 1980 to 2006 was analysed for mutations by PCR and capillary gel electrophoresis.

Results:  We analysed pretreatment samples from 485 AML patients and 57 healthy volunteers and identified sequence variations in 35/446 adults and 1/39 children. We were immediately able to distinguish N‐ and C‐terminal insertions and deletions as well as normally occurring polymorphisms. Abnormal PCR products were reprocessed and analysed by direct sequencing. We found stringent accordance between the two methods and reached the same frequency of mutations and polymorphisms as known from the literature.

Conclusion:  We conclude that capillary gel electrophoresis can be used as an accurate and high throughput diagnostic procedure for mutational status in the CEBPA gene identifying not only the same mutational frequency as in the published reports but also the TAD2C polymorphism in addition.
Targeting lymphocyte activation through the lymphotoxin and LIGHT pathways
Authors: Ware Carl F.
Published: July 2008

Summary: Cytokines mediate key communication pathways essential for regulation of immune responses. Full activation of antigen‐responding lymphocytes requires cooperating signals from the tumor necrosis factor (TNF)‐related cytokines and their specific receptors. LIGHT, a lymphotoxin‐β (LTβ)‐related TNF family member, modulates T‐cell activation through two receptors, the herpesvirus entry mediator (HVEM) and indirectly through the LT‐β receptor. An unexpected finding revealed a non‐canonical binding site on HVEM for the immunoglobulin superfamily member, B and T lymphocyte attenuator (BTLA), and an inhibitory signaling protein suppressing T‐cell activation. Thus, HVEM can act as a molecular switch between proinflammatory and inhibitory signaling. The non‐canonical HVEM–BTLA pathway also acts to counter LTβR signaling that promotes the proliferation of antigen‐presenting dendritic cells (DCs) within lymphoid tissue microenvironments. These results indicate LTβ receptor and HVEM–BTLA pathways form an integrated signaling circuit. Targeting these cytokine pathways with specific antagonists (antibody or decoy receptor) can alter lymphocyte differentiation and activation. Alternately, agonists directed at their cell surface receptors can restore homeostasis and potentially reset immune and inflammatory processes, which may be useful in treating autoimmune and infectious diseases and cancer.
Reprogramming the immune system: co‐receptor blockade as a paradigm for harnessing tolerance mechanisms
Authors: Waldmann Herman , Adams Elizabeth , Cobbold Stephen
Published: July 2008

Summary: The challenge of harnessing tolerance as a therapeutic modality has been greatly influenced by dogmas dictating how self‐tolerance comes about. Deletional strategies popularized from the classical work of Medawar and Owen have always demanded stringent attention to eliminating all antigen‐reactive cells. This was always considered a tough call for the treatment of autoimmune disease, where the number of antigens and their identity were hard to predict. The finding, some 15 years ago, that therapeutic tolerance could be elicited with non‐lytic CD4 monoclonal antibodies using regulatory T cells as major operatives has opened up a new dimension in exploiting tolerance mechanisms for drug minimization in transplantation and for providing short‐term treatments for long‐term benefit in allergy, autoimmunity, transplantation, and other immunopathological conditions. Resolution of the mechanisms underlying tolerance induced by CD4 co‐receptor blockade have provided a general paradigm for how regulatory T cells might be directed to get the upper hand in preventing disease. They have also identified an unexpected role for tissues to contribute to their own protection.
Therapeutic targeting of Janus kinases
Authors: Pesu Marko , Laurence Arian , Kishore Nandini , Zwillich Samuel H. , Chan Gary , O'Shea John J.
Published: July 2008

Cytokines play pivotal roles in immunity and inflammation, and targeting cytokines and their receptors is an effective means of treating such disorders. Type I and II cytokine receptors associate with Janus family kinases (JAKs) to effect intracellular signaling. These structurally unique protein kinases play essential and specific roles in immune cell development and function. One JAK, JAK3, has particularly selective functions. Mutations of this kinase underlie severe combined immunodeficiency, indicative of its critical role in the development and function of lymphocytes. Because JAK3 appears not to have functions outside of hematopoietic cells, this kinase has been viewed as an excellent therapeutic target for the development of a new class of immunosuppressive drugs. In fact, several companies are developing JAK3 inhibitors, and Phase II studies are underway. Mutations of Tyk2 cause autosomal recessive hyperIgE syndrome, and in principle, Tyk2 inhibitors might also be useful as immunosuppressive drugs. JAK2 gain‐of‐function mutations (V617F) underlie a subset of disorders collectively referred to as myeloproliferative diseases and phase 2 trials using JAK inhibitors are underway in this setting. Thus, we are learning a great deal about the feasibility and effectiveness of targeting Janus kinases, and it appears likely that this will be a fruitful strategy in a variety of settings.
The role and therapeutic implications of fibroblast‐like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis
Authors: Noss Erika H. , Brenner Michael B.
Published: July 2008

Summary:Fibroblast‐like synoviocytes (FLS) are resident mesenchymal cells of synovial joints that have been recognized to play an increasingly important role in the pathogenesis of rheumatoid arthritis (RA). Activation of FLS in the setting of RA leads to the production of a broad array of cell surface and soluble mediators that help to recruit, retain, and activate both cells of the immune system and resident joint cells, leading to the promotion of ongoing inflammation and tissue destruction. The ability of FLS to stimulate both inflammation and tissue damage suggests that this cell type may be a unique target for the treatment of inflammatory arthritis. Greater understanding of how FLS are activated and how they interact with other cells in the RA synovium may provide insights that allow development of novel agents for RA therapy.
Periodontal status in patients with pemphigus vulgaris*
Authors: Akman A , Kacaroglu H , Yilmaz E , Alpsoy E
Published: July 2008

Objective:  The aim of this study was to evaluate the periodontal status of pemphigus vulgaris (PV) patients and compare it with that of healthy controls. We also analysed the association between the periodontal condition and the clinical severity of the disease in PV patients.

Study design:  Twenty patients (nine women, 11 men; mean ± s.d. age, 42.9±9.8 years) with PV and 22 healthy subjects (eight women, 14 men; mean ± s.d. age, 40.5 ± 12.1 years) were included in the study. The periodontal status of all subjects was evaluated according to the Community Periodontal Index of Treatment Needs (CPITN). PV patients were also assessed for Clinical Severity Score (CSS).

Results:  The mean CPITN values were observed to be higher in PV patients (2.8 ± 0.7) compared with those of healthy controls (1.0 ± 0.8) (P < 0.001). Nevertheless, there was no statistically significant difference in CPITN values according to the CSS (P = 0.4). The number of carious teeth was significantly higher in PV patients than that in healthy subjects.

Conclusions:  Our results showed that periodontal status is worse in PV patients. Moreover, PV might contribute to the development and / or progression of periodontitis. PV patients should be encouraged for long‐term periodontal follow up.
Genetic susceptibility to obsessive‐compulsive hoarding: the contribution of neurotrophic tyrosine kinase receptor type 3 gene1
Authors: Alonso P. , Gratacòs M. , Menchón J. M. , Segalàs C. , González J. R. , Labad J. , Bayés M. , Real E. , De Cid R. , Pertusa A. , Escaramís G. , Vallejo J. , Estivill X.
Published: July 2008

Recent work suggests that neurotrophic factors may contribute to the genetic susceptibility to obsessive–compulsive disorder (OCD). Among other clinical dimensions, the presence of hoarding obsessions and compulsions has been shown to be correlated with a number of clinical and neuroimaging findings, as well as with a different pattern of genetic inheritance. We used a linkage disequilibrium (LD)‐mapping approach to investigate whether neurotrophic tyrosine kinase receptor type 3 (NTRK3), the high‐affinity receptor of neurotrophin 3 (NT‐3), plays a role in increasing susceptibility to hoarding in OCD. We performed an association study of 52 tag single nucleotide polymorphisms (tagSNPs) covering the whole NTRK3 gene in a sample comprising 120 OCD patients and 342 controls. Single nucleotide polymorphism association and haplotype analysis were performed. Thirty‐six of our patients (30%) exhibited significant hoarding obsessions and compulsions. A significant association of two SNPs in the 3′ downstream region of NTRK3 gene and obsessive–compulsive hoarding was identified: rs1017412 [odds ratio (OR) = 2.16; P = 0.001] and rs7176429 (OR = 2.78; P = 0.0001), although only the latter remained significant after Bonferroni correction. Although the haplotype analysis did not show significant results, a more extended block of LD in the OCD hoarders with respect to the control group was observed, suggesting a lower haplotype diversity in these individuals. Our findings suggest that NTRK3 may contribute to the genetic susceptibility to hoarding in OCD and may constitute an interesting gene to focus on in studies of the genetic basis of obsessive–compulsive hoarding.
Behavioral characterization of P311 knockout mice
Authors: Taylor Gregory A. , Rodriguiz Ramona M. , Greene Robert I. , Daniell Xiaoju , Henry Stanley C. , Crooks Kristy R. , Kotloski Robert , Tessarollo Lino , Phillips Lindsey E. , Wetsel William C.
Published: July 2008

P311 is an 8‐kDa protein that is expressed in many brain regions, particularly the hippocampus, cerebellum and olfactory lobes, and is under stringent regulation by developmental, mitogenic and other physiological stimuli. P311 is thought to be involved in the transformation and motility of neural cells; however, its role in normal brain physiology is undefined. To address this point, P311‐deficient mice were developed through gene targeting and their behaviors were characterized. Mutants displayed no overt abnormalities, bred normally and had normal survival rates. Additionally, no deficiencies were noted in motor co‐ordination, balance, hearing or olfactory discrimination. Nevertheless, P311‐deficient mice showed altered behavioral responses in learning and memory. These included impaired responses in social transmission of food preference, Morris water maze and contextual fear conditioning. Additionally, mutants displayed altered emotional responses as indicated by decreased freezing in contextual and cued fear conditioning and reduced fear‐potentiated startle. Together, these data establish P311 as playing an important role in learning and memory processes and emotional responses.
LUNG RING‐DOWN ARTIFACT AS A SIGN OF PULMONARY ALVEOLAR‐INTERSTITIAL DISEASE
Authors: LOUVET ARNAUD , BOURGEOIS JEAN‐MARIE
Published: July 2008

Three dogs with presumptive cardiogenic pulmonary edema underwent a thoracic ultrasonographic examination. Multiple ring‐down artifacts involving both sides of the thorax emanating from the pleural–lung interface were detected. When clinical and radiographic signs of pulmonary edema were resolved, ring‐down artifacts were not observed. The ring‐down artifact may be a useful diagnostic sign for screening the lung of animals with acute respiratory distress where radiographs are not feasible.