bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of forest management on epiphytic lichen diversity in Mediterranean forests
Authors: Aragón Gregorio , Martínez I. , Izquierdo P. , Belinchón R. , Escudero A.
Published: November 2009

Question: What are the responses of epiphytic lichens to the intensity of management along a large environmental gradient in Mediterranean Quercus forests?

Location: Central Spain.

Methods: This study was carried out on 4590 trees located in 306 forest stands dominated by Quercus faginea or Quercus ilex ssp. ballota. The effect of forest management and other predictor variables on several species diversity indicators were studied. Variables modelled were total species richness, cyanolichen richness and community composition. A large number of predictor variables were included: forest fragmentation (patch size, stand variability), climate and topographic (altitude, slope, sun radiation, annual rainfall and mean annual temperature) and intensity of management. General linear models and constrained ordination techniques were used to model community traits and species composition, respectively.

Results: Total richness and especially cyanolichens richness were significantly and negatively affected by the intensity of management. Lichen composition was influenced by management intensity, climatic and topographic variables and stand variability.

Conclusions: In Mediterranean forests, human activities related to forestry, agricultural and livestock use cause impoverishment of lichen communities, including the local disappearance of the most demanding species. The conservation of unmanaged forests with a dense canopy is crucial for lichen diversity.
The role of intramuscular connective tissue in meat texture
Authors: NISHIMURA Takanori
Published: November 2009

The structure, composition and amount of intramuscular connective tissue (IMCT) vary tremendously between muscles, species and breeds, and certainly contribute to meat texture. With animal growth, collagen crosslinks become more stable, and the structural integrity of IMCT increases. These changes increase the mechanical properties of IMCT, contributing to the toughening of meat. Intramuscular fat deposits, mainly in the perimysium between muscle fiber bundles, result in marbling. This causes the remodeling of IMCT structures and reduces the mechanical strength of IMCT, contributing to the tenderization of beef. The IMCT has been thought to be rather immutable compared to myofibrils during postmortem ageing of meat. However, recent studies have shown the disintegration of IMCT during postmortem ageing of meat and its relationship to tenderization of raw meat, although its contribution to cooked meat is still controversial. Given the large influence of IMCT on meat texture, further elucidations of molecular mechanisms which change the structural integrity of IMCT during chronological ageing of animals and postmortem ageing of meat are needed.
Interaction between myostatin and extracellular matrix components
Authors: MIURA Takayuki , KISHIOKA Yasuhiro , WAKAMATSU Jun‐ichi , HATTORI Akihito , NISHIMURA Takanori
Published: November 2009

Myostatin, a member of the TGF‐β superfamily, is a negative regulator of skeletal muscle mass. We have recently demonstrated that decorin binds to myostatin in vitro, and that immobilized decorin within the collagen matrix prevents myostatin‐mediated inhibition of myoblast proliferation. However, little is known about other ECM molecules that bind to myostatin and modulate its activity. Thus, in the present study, we investigated the interaction of several other ECM molecules with myostatin. We here show that fibromodulin, fibronectin and laminin bind to myostatin in the presence of Zn2+ with a dissociation constant (KD) of 10−10∼10−8 mol/L. Fibromodulin shows the highest affinity for myostatin among them. These results suggest that these ECM molecules may modulate myostatin activity like decorin does.
Effects of high potassium chloride supplementation on water intake, urine volume and nitrogen balance in mice
Authors: MURAI Iori , SUGIMOTO Miki , IKEDA Shuntaro , KUME Shin‐ichi
Published: November 2009

Sixteen ICR male mice were assigned to a control diet group or a KCl diet group in metabolic cages to clarify the effects of KCl supplementation on water intake, urine volume and N balance, and 5% of KCl was supplemented in KCl diets for 4 or 8 weeks. Bodyweight of KCl supplemented mice was significantly higher than that of control mice from 24 to 28 days after treatment. Feed intake, water intake and urine volume of KCl supplemented mice were significantly higher than those of control mice, and the increased water intake and urine volume in KCl supplemented mice were 4.49 and 4.15 g, respectively. Urinary N, K and Cl excretion were significantly higher in KCl supplemented mice. Although N retention was not significantly different between control and KCl supplemented mice, N retention in KCl supplemented mice tended to be lower. Serum creatinine concentration at 8 weeks after treatment was lower in KCl supplemented mice. Histological alteration using hematoxylin‐eosin and Sirius red staining was not found in the kidney of each mouse at 4 and 8 weeks after treatment. These results suggest that high KCl supplementation increases water intake, urine volume and urinary N excretion in mice.
The T allele at the g.1471620G>T in the EDG1 gene associated with high marbling in Japanese Black cattle is at a low frequency in breeds not selected for marbling
Authors: WATANABE Naoto , YAMADA Takahisa , YOSHIOKA Sachiyo , ITOH Masayuki , SATOH Youichi , FURUTA Masako , KOMATSU Shigeki , SUMIO Yoshihiko , FUJITA Tatsuo , SASAKI Yoshiyuki
Published: November 2009

Our previous study detected a single nucleotide polymorphism (SNP), g.1471620G>T, in the 5′ flanking region of the endothelial differentiation sphingolipid G‐protein‐coupled receptor 1 (EDG1) gene, which has been considered as a positional functional candidate for the gene responsible for marbling, and showed association of the g.1471620G>T SNP with marbling in Japanese Black beef cattle. In the present study, we investigated the allele frequency distribution of the g.1471620G>T SNP among the 5 cattle breeds, Japanese Black, Japanese Brown, Japanese Short Horn, Holstein, and Brown Swiss breeds. The T allele at the g.1471620G>T SNP associated with high marbling was found at high frequency in Japanese Black breed that has been subjected to a strong selection for high marbling, while the allele was absent or at very low frequencies in the other breeds that have not been strongly selected for high marbling. Based on this finding, we hypothesized that the pressure of the strong selection for high marbling in Japanese Black breed has increased the frequency of the T allele at the g.1471620G>T SNP in the EDG1.
Prevalence of porcine reproductive and respiratory syndrome virus and porcine circovirus type 2 in piglets after weaning on a commercial pig farm in Japan
Authors: SASAKI Kenichi , TSUKAHARA Takamitsu , TAIRA Osamu , TSUCHIYA Kotaro , ITOH Mitsugi , USHIDA Kazunari
Published: November 2009

To investigate the transition in concentration of porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) and antibody for these viruses in serum, serum samples were collected from 29 pigs on weaning day and at 7, 14, 21, 28, 53, 84, and 120 days after weaning. The concentration of circulated PRRSV and PCV2 in serum was measured by real‐time RT‐PCR and real‐time PCR, respectively. The specific antibody for PRRSV and PCV2 was measured using ELISA. PRRSV was not detected on 0 days post‐weaning (dpw). The specific antibody for PRRSV began to increase as the concentration of PRRSV in serum increased, and the level of PRRSV then tended to decrease. PCV2 was detected in 12 of 28 pigs on 0 dpw. The concentration of PCV2 and the specific antibody for PCV2 showed a similar tendency to those of PRRSV. The correlation analysis suggests that a decline in the daily weight gain coincided with an increase in the PRRSV concentration. Pigs with a higher antibody titer against PRRSV or PCV2 on 0 dpw showed the lower level of PRRSV or PCV2, respectively.
Protein Biomarker Analysis of Primary Peyronie’s Disease Cells
Authors: De Young Ling X. , Bella Anthony J. , O’Gorman David B. , Gan Bing S. , Lim Kok B. , Brock Gerald B.
Published: November 2009

Introduction

The molecular pathogenesis of Peyronie’s Disease (PD) remains unclear more than 250 years after its initial description. Because of this, no test is currently available to accurately predict PD progression among those affected.

Aim

To investigate the expression of wound healing and fibrosis-associated proteins in primary cell cultures of PD fibroblasts to determine whether altered protein expression patterns can be used as predictors of clinical course and natural history.

Methods

Primary cell cultures derived from normal Tunica albuginea tissue and PD plaque tissue were examined by immuno-cytochemistry. Protein expression profiles were analyzed by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (SELDI-TOF-MS) and Western immunoblotting.

Main Outcome Measures

Expression of wound healing and fibrosis-associated proteins and protein expression patterns were assessed.

Results

Statistically significant increases in smooth muscle α-actin, β-catenin, and Heat shock proteins (Hsp47) were identified in cells derived from PD relative to cells derived from normal Tunica albuginea tissue. Changes in TGFβ-1 receptor and Fibronectin were also observed. In addition, altered expression of additional as yet unidentified proteins at 4.7, 8.9, 10.8, 16.8, and 76.8 kDa were detected by complementary SELDI-TOF-MS approaches.

Conclusions

Primary cells derived from PD plaques display up-regulated expression of several proteins that are established components of fibrosis and wound healing. In addition, changes in other, as yet unidentified proteins were measured. It will be of interest to conduct further studies to see whether these dysregulated protein peaks represent potential biological markers of disease progression.
Immature Defense Mechanisms Are Associated with Lesser Vaginal Orgasm Consistency and Greater Alcohol Consumption before Sex
Authors: Costa Rui Miguel , Brody Stuart
Published: November 2009

Introduction

Disturbances of emotional and physical awareness can impair female sexual function. Previous research revealed that immature psychological defense mechanisms (impairing emotional awareness) are associated specifically with impaired vaginal orgasm (orgasm triggered solely by penile–vaginal stimulation). Alcohol consumed before sex (ACBS) might impair vaginal orgasm or lead to avoiding the opportunity for it, but research examining immature defenses, ACBS, and specific sexual behaviors has been lacking.

Aim

To test the hypothesis that greater use of immature defenses and greater ACBS are inversely associated with vaginal orgasm consistency, but unrelated or positively correlated with greater frequency of other sexual behaviors.

Methods

Three hundred twenty-three coitally experienced women (predominantly Scottish) responded to an online survey reporting their frequency of various sexual activities (and corresponding orgasms) and their ACBS, and completed the Defense Style Questionnaire DSQ-40.

Main Outcome Measures

Univariate and multivariate correlations of immature defenses, ACBS, and various sexual behaviors.

Results

Both immature defenses and ACBS were associated with less vaginal orgasm consistency, but unrelated or positively correlated with frequency of other sexual behaviors (including clitoral masturbation during penile–vaginal intercourse). Immature defenses were associated with more ACBS. Immature defenses explained the association between ACBS and both lack of vaginal orgasm and greater frequency of other sexual behaviors.

Conclusions

The results provide further evidence that difficulty in having a vaginal orgasm is associated with immature defenses (and associated disturbances of sensibility), among other indicators of poorer health and relatedness. ACBS might impair vaginal orgasm or increase the likelihood of choosing other sexual activities, but this effect might be somewhat contingent on immature defenses. Based on various empirical studies, we call for examination of the possibility that lack of vaginal orgasm (given an adequate man) should qualify as a female sexual dysfunction.
Application of Direct Push Methods to Investigate Uranium Distribution in an Alluvial Aquifer
Authors: McCall Wesley , Christy Thomas M. , Christopherson Thomas , Issacs Howard
Published: November 2009

The U.S. EPA 2000 Radionuclide Rule established a maximum contaminant level (MCL) for uranium of 30 µg/L. Many small community water supplies are struggling to comply with this new regulation. At one such community, direct push (DP) methods were applied to obtain hydraulic profiling tool (HPT) logs and install small diameter wells in a section of alluvial deposits located along the Platte River. This work was conducted to evaluate potential sources of elevated uranium in the Clarks, Nebraska drinking water supply. HPT logs were used to understand the hydrostratigraphy of a portion of the aquifer and guide placement of small diameter wells at selected depth intervals. Low‐flow sampling of the wells provided water quality parameters and samples for analysis to study the distribution of uranium and variations in aquifer chemistry. Contrary to expectations, the aquifer chemistry revealed that uranium was being mobilized under anoxic and reducing conditions. Review of the test well and new public water supply well construction details revealed that filter packs extended significantly above the screened intervals of the wells. These filter packs were providing a conduit for the movement of groundwater with elevated concentrations of uranium into the supply wells and the community drinking water supply. The methods applied and lessons learned here may be useful for the assessment of unconsolidated aquifers for uranium, arsenic, and many other drinking water supply contaminants.
Polar Compounds from the Dissolution of Weathered Diesel
Authors: Lang Dale A. , Bastow Trevor P. , Van Aarssen Ben G.K. , Warton Ben , Davis Greg B. , Johnston Colin D.
Published: November 2009

Hydrocarbon and nonhydrocarbon components dissolving in water from fresh diesel and field samples of highly weathered diesel (spilled up to 50 years ago) from two sites were investigated. The fresh and weathered diesels were equilibrated with water using a slow‐stirring method, and the product and equilibrated aqueous water samples analyzed by a range of analytical procedures. The water phase equilibrated with weathered diesels had higher total dissolved organics concentrations (96 and 8.6 mg/L at the two sites) compared to the water phase equilibrated with fresh diesel (average of 3.4 mg/L). Compound class characterization of dissolved organics in water from the weathered diesel showed that polar components were a significant compound class (98% and 42% at the two sites) and appeared largely as an unresolved complex mixture (UCM) in the total ion chromatograms (TICs). Identification of 1‐adamantanol in the polar fraction of both weathered diesel samples (3.6 and 0.3 μg/L at the two sites) suggested that at least some of the associated polar components are from a petroleum source. The analysis of total petroleum hydrocarbons (TPH) is aimed at measuring only dissolved carbon and hydrogen‐containing compounds, and dissolved polar compounds present as a UCM are often assumed to be from natural organic matter (NOM) and removed. This may result in a gross underestimation of the total soluble organic material in water associated with weathered diesels. In addition, the risk posed by these fuel‐derived polar compounds is unknown.
Alzheimer's disease: Seeing the signs early
Authors: Leifer Bennett P.
Published: November 2009

Purpose: Many patients with early symptoms of Alzheimer's disease (AD) first seek help from their primary care providers (PCPs). PCPs must therefore be watchful for signs and symptoms of AD, and should screen elderly patients who complain of memory and cognitive problems for dementia.

Data sources: Published literature on case detection, diagnosis, and treatment of AD.

Conclusions: There are a number of simple, accurate, and fast tools to facilitate case detection, including the Mini‐Mental State Examination. Once a diagnosis has been made, healthcare providers, patients, and caregivers can evaluate treatment options. Several medications are available for symptomatic treatment of AD, including the cholinesterase inhibitors donepezil, galantamine, and rivastigmine, and for later stage disease, the N‐methyl D‐aspartate (NMDA) receptor antagonist, memantine.

Implications for Practice: Early intervention is critical because a delay in treatment is associated with nonreversible symptom progression. Realistic treatment expectations include reduction in symptom severity and slowed decline in cognition, function, and behavior. Treatment may allow patients to retain independence longer and reduce the burden that advanced AD places on caregivers.
Patient satisfaction with nurse practitioner‐delivered primary healthcare services
Authors: Agosta Lucie J.
Published: November 2009

Purpose: To identify levels of satisfaction with nurse practitioner (NP)‐delivered primary healthcare services and to determine demographic differences in degrees of general satisfaction reported by patients.

Data sources: The Nurse Practitioner Satisfaction Survey (NPSS), a 28‐item, 5‐point, Likert‐type survey instrument was developed; data from 300 female and male clients over 18 years of age presenting for primary healthcare visits at the employee health department of a not‐for‐profit hospital in the Southern United States were analyzed.

Conclusions: Although many studies using a variety of healthcare‐related patient satisfaction instruments have demonstrated acceptable patient satisfaction with NPs, few have investigated patient satisfaction with NPs in the outpatient primary care occupational health arena. Overall the population seeking health care was satisfied with NP services. In particular, married or cohabitating subjects reported general satisfaction scores that were statistically significantly higher than those who were single and never married. No other differences were found.

Implications for practice: The provision of on‐site, employer‐sponsored NP primary healthcare services that are perceived as acceptable and satisfactory to employees and families affords significant opportunity and advantage to both employee and employer. Such benefits include enhanced employee and family wellness, facilitated health promotion, enhanced access to care, reduced illness related to time away from work, improved employee productivity, and reduced overall organizational healthcare costs. Knowledge regarding those characteristics contributing to general satisfaction with NP‐delivered care serves to facilitate practice pattern changes within the profession that further enhances the visibility, utilization, and acceptability of NPs as primary care providers.
Understanding, recognizing, and managing chronic critical illness syndrome
Authors: Bellar Ann , Kunkler Kathleen , Burkett Mary
Published: November 2009

Purpose: No evidence‐based guidelines exist for the care of patients with chronic critical illness syndrome (CCIS), a growing population of patients being cared for by nurse practitioners (NPs). The purpose of this article is to provide NPs with a beginning physiological framework, allostasis, to guide their understanding and management of patients with CCIS.

Data sources: Scientific publications, related clinical guidelines.

Conclusions: Patients with CCIS are a distinct group of critically ill patients whose care needs are different from those of patients who are acutely critically ill. These patients demonstrate widespread tissue and organ damage. The widespread tissue and organ damage results in a syndrome of interrelated elements, which include neuroendocrine problems, severe malnutrition, wounds, infections, bone loss, polyneuropathy and myopathy, delirium and depression, and suffering.

Implications for practice: In caring for patients with CCIS, NPs need to focus on treating the elements of the syndrome as a cohort of interrelated elements and on re‐establishing normalcy for the patient.
Incretin‐based therapies: Therapeutic rationale and pharmacological promise for type 2 diabetes
Authors: Wick Allison , Newlin Kelley
Published: November 2009

Purpose: To highlight the therapeutic promise of the incretin hormone glucagon‐like peptide‐1 (GLP‐1), the consequent rationale for therapies acting through GLP‐1‐mediated pathways in type 2 diabetes mellitus (T2DM), and the emerging clinical role of the dipeptidyl peptidase‐4 (DPP‐4) inhibitors and GLP‐1 receptor agonists.

Data sources: The PubMed database was searched (using terms including incretins, GLP‐1, GIP, DPP‐4), along with recent ADA and EASD abstracts.

Conclusions: Many traditional drugs used for T2DM fail to achieve and maintain glycemic control, and possess limitations such as risk for hypoglycemia and weight gain. GLP‐1 is a gut‐derived hormone that glucose‐dependently stimulates insulin secretion while simultaneously reducing gastric emptying and appetite. Other physiological actions of GLP‐1 may benefit the cardiovascular system and beta‐cell function. Recently developed drug therapies that mimic or prolong the action of this hormone, therefore, have great promise in the treatment of T2DM.

Implications for practice: The GLP‐1 receptor agonists and DPP‐4 inhibitors are incretin‐based therapies that are now becoming established as effective therapies for T2DM to be used either as monotherapy or added to other antidiabetes drugs. They enable improvements to be made in glycemic control without weight gain, with a low risk for hypoglycemia, and with potential additional clinical benefits.
Fellowship in the American Academy of Nurse Practitioners
Authors: Hicks Rodney W. , Bray Christell O. , Green Roger , Olson Karen Koozer
Published: November 2009

The purpose of this column is to describe the process of application and selection for fellowship in the Fellows of the American Academy of Nurse Practitioners (FAANP). Fellows are invited and selected based on their accomplishments in four priority areas: research, practice, education, and policy. Based on the 10‐year history of the FAANP, current members provide guidance for potential applicants on the steps necessary for making a successful application.
Multidrug‐resistant and extensively drug‐resistant tuberculosis: The new face of an old disease
Authors: Ferguson Laurie Anne , Rhoads Jacqueline
Published: November 2009

Purpose: To provide an overview of tuberculosis (TB), especially the persistent threat of multidrug‐resistant (MDR) and extensively drug‐resistant (XDR), and the role of the nurse practitioner (NP) in diagnosis, treatment, and public health surveillance.

Data sources: Public health sources such as the World Health Organization and the Centers for Disease Control as well as current literature.

Conclusions: One hundred twenty‐five years after the discovery of Mycobacterium tuberculosis, the disease remains a persistent threat and a leading cause of death worldwide. Medication adherence and prevention are critical to successfully treating and ultimately eradicating this killer disease. Healthcare providers need to be knowledgeable in the detection and diagnosis of TB and to understand that they assume responsibility for public health by monitoring treatment adherence and/or appropriate referral.

Implications for practice: The persistent and increasing threat of MDR‐TB and XDR‐TB is a significant public health threat. Healthcare providers need to be knowledgeable and vigilant in diagnosing and treating this disease.
Acute atrial arrhythmogenesis in murine hearts following enhanced extracellular Ca2+entry depends on intracellular Ca2+stores
Authors: Zhang Y. , Fraser J. A. , Schwiening C. , Zhang Y. , Killeen M. J. , Grace A. A. , Huang C. L.‐H.
Published: November 2009

Aim: To investigate the effect of increases in extracellular Ca2+entry produced by the L‐type Ca2+channel agonist FPL‐64176 (FPL) uponacuteatrial arrhythmogenesis in intact Langendorff‐perfused mouse hearts and its dependence upon diastolic Ca2+release from sarcoplasmic reticular Ca2+stores.

Methods: Confocal microscope studies of Fluo‐3 fluorescence in isolated atrial myocytes were performed in parallel with electrophysiological examination of Langendorff‐perfused mouse hearts.

Results: Atrial myocytes stimulated at 1 Hz and exposed to FPL (0.1 μm) initially showed (<10 min) frequent, often multiple, diastolic peaks following the evoked Ca2+transients whose amplitudes remained close to control values. With continued pacing (>10 min) this reverted to a regular pattern of evoked transients with increased amplitudes but in which diastolic peaks were absent. Higher FPL concentrations (1.0 μm) produced sustained and irregular patterns of cytosolic Ca2+activity, independent of pacing. Nifedipine (0.5 μm), and caffeine (1.0 mm) and cyclopiazonic acid (CPA) (0.15 μm) pre‐treatments respectively produced immediate and gradual reductions in theF/F0peaks. Such nifedipine and caffeine, or CPA pre‐treatments, abolished, or reduced, the effects of 0.1 and 1.0 μmFPL on cytosolic Ca2+signals. FPL (1.0 μm) increased the incidence of atrial tachycardia and fibrillation in intact Langendorff‐perfused hearts without altering atrial effective refractory periods. These effects were inhibited by nifedipine and caffeine, and reduced by CPA.

Conclusion: Enhanced extracellular Ca2+entry exertsacuteatrial arrhythmogenic effects that is nevertheless dependent upon diastolic Ca2+release. These findings complement reports that associate established,chronic, atrial arrhythmogenesis withdecreasedoverall inward Ca2+current.
Biomarkers, Dementia, and Public Health
Authors: Wright C. F. , Hall A. , Matthews F. E. , Brayne C.
Published: November 2009

Public health is defined as the organized efforts of society to improve health. This is often framed in terms of prevention, with primary, secondary, and tertiary prevention representing, respectively, fundamental prevention through understanding of causation, to alteration of natural history, through understanding of pathophysiological mechanisms and palliation. Biomarkers play a role in all of these levels of prevention of dementias. The clearest application of biomarkers from a public health perspective is in the setting of screening. Screening has particular meaning for public health and includes early detection as a core element, coupled with treatments or preventative actions to reduce the burden of disease. Here, we will cover the range of evidence required if biomarkers are to play a part in population prevention of dementia, including scientific and technical aspects together with ethical, legal, and social considerations. Ensuring research activity that addresses these wider perspectives is essential.
CSF Biomarkers
Authors: Mattsson Niklas , Blennow Kaj , Zetterberg Henrik
Published: November 2009

Intense research during the last decades has resulted in an unprecedented accumulation of knowledge regarding the pathogenesis of Alzheimer's disease. Primarily, the focus has been directed toward amyloid and tau pathology and their relations to synaptic and neuronal loss. However, as the complexity of the disease becomes increasingly evident, the importance of other factors, such as inflammation, oxidative stress, and mitochondrial dysfunction, grow apparent. Here, we review available CSF biomarkers for these pathological processes. We also consider their usability in clinical practice and in clinical trials.
Use of Genetic Variation as Biomarkers for Alzheimer's Disease
Authors: Reitz Christiane , Mayeux Richard
Published: November 2009

Late‐onset Alzheimer's disease (LOAD) is the most common cause of late‐onset dementia in western societies. Despite remarkable achievements in human genetics throughout the years, in particular technological advances in gene mapping and in statistical methods that relate genetic variants to disease, to date only a small proportion of the genetic contribution to LOAD can be explained leaving several remaining genetic risk factors to be identified. A possible explanation for the difficulty in gene identification is that LOAD is a multifactorial complex disorder with both genetic and environmental components. Multiple genes with small effects each (“quantitative trait loci”[QTLs]) are likely to contribute to the quantitative traits associated with the disease, such as memory performance, amyloid/tau pathology, or hippocampal atrophy. The motivation for identifying the genetics of LOAD is clear. Not only could it shed light on disease pathogenesis, but it may also provide potential targets for effective treatment, screening, and prevention. Here, we review the usefulness of genetic variation as diagnostic tools and biomarkers in LOAD and discuss the potentials and difficulties researchers face in designing appropriate studies for gene discovery.
Status of Glucocorticoid Alterations in Post‐traumatic Stress Disorder
Authors: Yehuda Rachel
Published: November 2009

The current status of glucocorticoid alterations in post‐traumatic stress disorder (PTSD) will be described in this chapter. Emphasis will be placed on data that suggest that at least some glucocorticoid‐related observations in PTSD reflect pretraumatic glucocorticoid status. Recent observations have provided some evidence that pretraumatic glucocorticoid alterations may arise from genetic, epigenetic, and possibly other environmental influences that serve to increase the likelihood of developing PTSD following trauma exposure, as well as modulate attendant biological alterations associated with its pathophysiology. Current studies in the field of PTSD employ glucocorticoid challenge strategies to delineate effects of exogenously administered glucocorticoids on neuroendocrine, cognitive, and brain function. Results of these studies have provided an important rationale for using glucocorticoid strategies in the treatment of PTSD.
CRH Signaling
Authors: Refojo Damian , Holsboer Florian
Published: November 2009

There is an urgent need to generate new drugs or improve existing ones in the pharmacology of mood disorders. The corticotropin‐releasing hormone (CRH) system is closely involved in the development and course of depression, and drugs targeting this system arguably offer hope to improve the current tools for drug treatment of depression. Recent clinical studies in depressed patients showed that CRHR1 antagonists improve clinical symptoms of anxiety and depression and reduce stress hormone release following psychosocial stress. These effects of CRHR1 antagonists were not associated with reduced secretory capacity of corticotrophic cells because of CRH receptor abundance at the pituitary level, which contrasts with CRH receptors in the brain. This is in accordance with previous studies showing that CRH injections into the mouse brain activate MAPK pathways in a brain region–specific manner pointing toward differences in signaling pathways beyond the receptor level. We will highlight this and discuss how these brain area–specific differences may offer opportunities for drug discovery. An additional puzzle in the search of new targets for depression is the lack of bona fide animal models helping to discover the antidepressants that are not monoamine based. We recently developed a conditional mouse model that overexpresses CRH in a spatio‐temporal–regulated fashion and permits to dissect precisely the contribution of different brain areas to the CRH‐dependent behaviors. Recent findings obtained with this mouse model and its usefulness in the context of the CRH‐dependent, region‐specific changes in depression will be discussed.
Glucocorticoid Receptor Polymorphisms in Major Depression
Authors: Spijker Anne T. , van Rossum Elisabeth F. C.
Published: November 2009

Previously, it has been suggested that hypothalamic‐pituitary‐adrenal (HPA) axis dysregulation and, as a consequence, increased cortisol levels, is not only a state phenomenon, but may also be a trait phenomenon in mood disorders. Cortisol exerts its effects mainly by binding to the glucocorticoid receptor (GR) and, of particular interest in certain brain regions, the mineralocorticoid receptor (MR). Several GR polymorphisms have been shown to be associated with altered sensitivity of the HPA axis. Recently, the GR polymorphisms BclI and ER22/23EK have been associated with unipolar depression in several studies. In addition, the ER22/23EK polymorphism seems to be associated with a decreased risk of dementia in healthy individuals. Also, during a depressive episode, carriers of this ER22/23EK variant demonstrated a tendency toward better cognition, as measured by divided attention tests. In this overview, currently known clinically relevant GR and MR polymorphisms are discussed in relation to mood disorders (both unipolar depression and bipolar disorder) and cognitive function.
Glucocorticoid Dysregulations and Their Clinical Correlates
Authors: Marques Andrea H. , Silverman Marni N. , Sternberg Esther M.
Published: November 2009

Clinicians have long known that a substantial proportion of patients treated with high‐dose glucocorticoids experience a variety of serious side effects, including metabolic syndrome, bone loss, and mood shifts, such as depressive symptomatology, manic or hypomanic symptoms, and even suicide. The reason for individual variability in expression or severity of these side effects is not clear. However, recent emerging literature is beginning to shed light on possible mechanisms of these effects. As an introduction to this volume, this chapter will review the basic biology of glucocorticoid release and molecular mechanisms of glucocorticoid receptor function, and will discuss how dysregulation of glucocorticoid action at all levels could contribute to such side effects. At the molecular level, glucocorticoid receptor polymorphisms may be associated either with receptor hypofunction or hyperfunction and could thus contribute to differential individual sensitivity to the effects of glucocorticoid treatment. Numerous factors regulate hypothalamic‐pituitary‐adrenal (HPA) axis responsiveness, which could also contribute to individual differences in glucocorticoid side effects. One of these is sex hormone status and the influence of estrogen and progesterone on HPA axis function and mood. Another is immune system activity, in which immune molecules, such as interleukins and cytokines, activate the HPA axis and alter brain function, including memory, cognition, and mood. The effects of cytokines in inducing sickness behaviors, which overlap with depressive symptomatology, could also contribute to individual differences in such symptomatology. Taken together, this knowledge will have important relevance for identifying at‐risk patients to avoid or minimize such side effects when they are treated with glucocorticoids. A framework for assessment of patients is proposed that incorporates functional, physiological, and molecular biomarkers to identify subgroups of patients at risk for depressive symptomatology associated with glucocorticoid treatment, and for prevention of side effects, which in many cases can be life‐threatening.
Role of CRF Receptor Signaling in Stress Vulnerability, Anxiety, and Depression
Authors: Hauger Richard L. , Risbrough Victoria , Oakley Robert H. , Olivares‐Reyes J. Alberto , Dautzenberg Frank M.
Published: November 2009

Markers of hyperactive central corticotropin releasing factor (CRF) systems and CRF‐related single nucleotide polymorphisms (SNPs) have been identified in patients with anxiety and depressive disorders. Designing more effective antagonists may now be guided by data showing that small molecules bind to transmembrane domains. Specifically, CRF1receptor antagonists have been developed as novel anxiolytic and antidepressant treatments. Because CRF1receptors become rapidly desensitized by G protein‐coupled receptor kinase (GRK) and β‐arrestin mechanisms in the presence of high agonist concentrations, neuronal hypersecretion of synaptic CRF alone may be insufficient to account for excessive central CRF neurotransmission in stress‐induced affective pathophysiology. In addition to desensitizing receptor function, GRK phosphorylation and β‐arrestin binding can shift a G protein‐coupled receptor (GPCR) to signal selectively via the extracellular signal‐regulated kinase/mitogen‐activated protein kinase (ERK‐MAPK) or Akt pathways independent of G proteins. Also, Epac‐dependent CRF1receptor signaling via the ERK‐MAPK pathway has been found to potentiate brain‐derived neurotrophic factor (BDNF)‐stimulated TrkB signaling. Thus, genetic or acquired abnormalities in GRK and β‐arrestin function may be involved in the pathophysiology of stress‐induced anxiety and depression.
Glucocorticoid Receptor Polymorphisms in Major Depression
Authors: Claes Stephan
Published: November 2009

Major depressive disorder (MDD) often appears after exposure to acute or chronic stress, and dysfunction of stress response systems, such as the hypothalamic‐pituitary‐adrenal (HPA) axis, is thought to be a key element of MDD neurobiology. The glucocorticoid receptor (GR) is the most important regulator of the HPA axis negative feedback system, and GR sensitivity has been shown to be reduced in MDD in both in vitro and in vivo studies. Transgenic animals with partial impairment of GR function show behavioral changes consistent with MDD. This makes the GR gene a prime candidate for research into the genetic background of MDD. Several single nucleotide polymorphisms (SNPs) have been detected that have specific effects on GR function, metabolic parameters, and HPA axis function in response to stress. Genetic association studies have yielded preliminary evidence for a role of these genetic variations in the genetic vulnerability for MDD. Taken together, the evidence for a role of GR and the GR gene in the neurobiology of MDD is building rapidly.
Proteomics for Brain Disorders—The Promise for Biomarkers
Authors: Ward Malcolm , Güntert Andreas , Campbell James , Pike Ian
Published: November 2009

Biomarkers of brain disorders are urgently needed to aid diagnosis, monitor disease progression, and, as new medicines are introduced, detect the patient's response to treatment. Proteomics provides the opportunity to discover novel biochemical markers based on protein or peptide changes, either in concentration levels or post‐translational modification status. There are many challenges associated with proteomics studies, and this article represents a review of the issues discussed during the proteomics breakout sessions held at the Biomarkers for Brain Disorders conference in Oxford in January 2009. Although to date, there are very few qualified biomarkers that have arisen as a result of proteomics efforts, we remain optimistic that proteomics will deliver biomarkers for brain disorders. To be successful, we need to recognize that such endeavors are likely to require multidisciplinary teams and continued collaboration between academia, the biotechnology industry, and the pharmaceutical sector.
Imaging Biomarkers in Alzheimer's Disease
Authors: Ryan Natalie S. , Fox Nick C.
Published: November 2009

Imaging plays an increasingly important role in both clinical practice and research in Alzheimer's disease. Clinically, there is growing appreciation that imaging provides not just exclusion of alternative pathologies, but also positive predictive, diagnostic, and prognostic information in dementia. Imaging can improve specificity of diagnosis in trial populations, facilitate research on the earlier stages of disease, and provide crucial information regarding drug safety and toxicity. With the advent of disease‐modifying therapies, these properties acquire increasing importance. Furthermore, imaging biomarkers have the potential to serve as outcome measures of disease progression. A whole arsenal of imaging modalities has now been developed, each allowing a different aspect of the disease process to be explored. However, the limitations of each technique must also be appreciated. A multimodal approach, where imaging markers are combined, may be required to maximize the potential of imaging to enhance our understanding of Alzheimer's disease and to help find effective therapies.
MRI Measures of Alzheimer's Disease and the AddNeuroMed Study
Authors: Simmons Andrew , Westman Eric , Muehlboeck Sebastian , Mecocci Patrizia , Vellas Bruno , Tsolaki Magda , Kłoszewska Iwona , Wahlund Lars‐Olof , Soininen Hilkka , Lovestone Simon , Evans Alan , Spenger Christian ,   for the AddNeuroMed Consortium
Published: November 2009

Here we describe the AddNeuroMed multicenter magnetic resonance imaging (MRI) study for longitudinal assessment in Alzheimer's disease (AD). The study is similar to a faux clinical trial and has been established to assess longitudinal MRI changes in AD, mild cognitive impairment (MCI), and healthy control subjects using an image acquisition protocol compatible with the Alzheimer's Disease Neuroimaging Initiative (ADNI). The approach consists of a harmonized MRI acquisition protocol across centers, rigorous quality control, a central data analysis hub, and an automated image analysis pipeline. Comprehensive quality control measures have been established throughout the study. An intelligent web‐accessible database holds details on both the raw images and data processed using a sophisticated image analysis pipeline. A total of 378 subjects were recruited (130 AD, 131 MCI, 117 healthy controls) of which a high percentage (97.3%) of the T1‐weighted volumes passed the quality control criteria. Measurements of normalized whole brain volume, whole brain cortical thickness, and point‐by‐point group‐based cortical thickness measurements, demonstrating the power of the automated image analysis techniques employed, are reported.
AddNeuroMed—The European Collaboration for the Discovery of Novel Biomarkers for Alzheimer's Disease
Authors: Lovestone Simon , Francis Paul , Kloszewska Iwona , Mecocci Patrizia , Simmons Andrew , Soininen Hilkka , Spenger Christian , Tsolaki Magda , Vellas Bruno , Wahlund Lars‐Olof , Ward Malcolm ,   on behalf of the AddNeuroMed Consortium
Published: November 2009

There is an urgent need for Alzheimer's disease (AD) biomarkers—especially in the context of clinical trials. Biomarkers for early diagnosis, disease progression, and prediction are most critical, and disease‐modification therapy development may depend on the discovery and validation of such markers. AddNeuroMed is a cross European, public/private consortium developed for AD biomarker discovery. We report here the development and design of AddNeuroMed and the progress toward the development of plasma markers. Despite the obstacles to such markers, we have identified a range of markers including CFH and A2M, both of which have been independently replicated. The experience of AddNeuroMed leads us to three overall conclusions. First, collaboration is essential. Second, design is paramount and combining modalities, such as imaging and proteomics, may be informative. Third, animal models are valuable in biomarker research. Most importantly, we have learned that plasma markers are feasible.
IS NORMALISING HAEMOGLOBIN IN PATIENTS WITH CKD HARMFUL AND IF SO, WHY?
Authors: Littlewood T. J.
Published: November 2009

Symptomatic anaemia is found in patients with chronic kidney disease. Correction of anaemia by erythropoiesis stimulating agents improves quality of life and life expectancy. Data from patients with both dialysis dependent and nondialysis dependent chronic kidney disease now show that the mortality from cardiovascular disease increases if the haemoglobin concentration is corrected above 13.0g/dl. The mechanism for this increased risk is uncertain.
GOING UPSTREAM: THE IMPLICATION AND OPPORTUNITIES OF EARLY DETECTION
Authors: O’Donoghue Donal J
Published: November 2009

Chronic kidney disease (CKD) is common, harmful and treatable but has, until recently not been recognised in its early stages. The British National Health Service (NHS) provides a unique opportunity to study CKD because it is in effect a closed‐managed care system. This single healthcare system for the United Kingdom is funded by the Government and paid for by general taxation. All UK citizens are registered with primary care physicians who control access to secondary care services. As a managed care system it should be able to offer integrated care across the whole patient pathway—allowing early identification of CKD, interventions to reduce risk and prompt management of complications. In reality, there are professional, organisational and institutional barriers to coordination and delivery of care in the NHS. The establishment of general‐practice‐based disease registers linked to a quality and outcomes framework in 2004 provides a basis for implementing the chronic disease model of care. The publication of the National Service Framework for renal services complemented by these changes in primary care has resulted in a paradigm shift from kidney disease being viewed as a secondary care condition to being a primary care priority as part of vascular control and management.

In the first two years of the initiative, over 40% of the expected CKD stage 3 to 5 population has been registered in primary care. Kidney disease is now recognised as a public health problem in the United Kingdom, preventative strategies are being integrated into comprehensive vascular risk assessments and management programmes and kidney disease has become an NHS priority area.
Malignant pilomatricoma in a soft‐coated Wheaten Terrier
Authors: Jackson Karen , Boger Lore , Goldschmidt Michael , Walton Raquel M.
Published: November 2009

Abstract: A 3‐year‐old, castrated male, soft‐coated Wheaten Terrier was presented for evaluation of mild lameness, fecal incontinence, lumbosacral pain, and lack of anal tone. Magnetic resonance imaging scan showed a large (8 × 6 × 5 cm) mass invading and expanding the pelvic bones, sacrum, and associated structures. A fine‐needle aspirate of the mass contained many neoplastic cells with high nuclear to cytoplasmic ratios and rare spindle and inflammatory cells. The neoplastic cells were 12–16 μm in diameter, round to cuboidal, basaloid in appearance, and arranged both individually and in loosely cohesive clusters with variably distinct cell borders. Given the location, signalment, and cytologic findings, differential interpretations included a primitive embryonal tumor (eg, neuroblastoma or nephroblastoma in an atypical location) or poorly differentiated carcinoma. The owner elected euthanasia due to the poor prognosis. Abnormal gross findings on necropsy included the pelvic mass and multiple firm, pale, pink‐tan nodules in the lung, which proved to be metastases. On histologic examination, the mass and nodules were composed of irregular islands, lobules, and nests of basaloid cells, which transitioned abruptly into large lakes of “ghost” cells with areas of ossification and calcification, consistent with a diagnosis of malignant pilomatricoma. This unusual presentation of a pilomatricoma adds to our knowledge of expected cytologic findings for this tumor.
MODELING THE GLOBAL FISHMEAL AND FISH OIL MARKETS
Authors: MULLON C. , MITTAINE J‐F. , THÉBAUD O. , PÉRON G. , MERINO G. , BARANGE M.
Published: November 2009

Abstract To explore the drivers of change in the complex system relating small pelagic fisheries and fishmeal/fish oil markets, to identify the interactions between these drivers and their overall impacts, we propose a bio‐economic model, coupling the ecological and the economic dynamics of these global commodities. The model enables an analysis of the consequences of both global and local changes in the environment of production systems. Through sensitivity analysis of specific input parameters, we evaluate the robustness of the overall system to such changes and show that local responses of production systems and markets cannot be considered in isolation from the set of interactions at global level.