bluuebunny/crossref_metadata_2025 huggingface dataset:
Spinal Glucocorticoid Receptors Contribute to the Development of Morphine Tolerance in Rats
Authors: Lim Grewo , Wang Shuxing , Zeng Qing , Sung Backil , Mao Jianren
Published: March 2005

Background

Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine.

Methods

In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test.

Results

The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance.

Conclusions

The results indicate an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats and may have significant implications in clinical opioid therapy.
A Bacterial Toxin that Causes DNA Damage to Modulate Cellular Responses
Authors: Lara-Tejero Maria
Published: March 2005

Campylobacter jejuni constitutes the leading cause of bacterial diarrhea in the U.S. and all around the world [1]. This common bacterium produces a toxin known as cytolethal distending toxin (CDT) [2] which causes intoxicated cells to enlarge and to stop dividing with a double DNA content characteristic of G2/M arrest [3]. The effect of the toxin on the cell is so striking that it captivated scientists for a long time. However, its mechanism of action had remained elusive.
Trapping of Organochlorine Compounds in High Mountain Lakes
Authors: Grimalt Joan O. , Fernandez Pilar , Vilanova Rosa M.
Published: March 2005

High mountain areas have recently been observed to be polluted by organochlorine compounds (OC) despite their isolation. These persistent pollutants arrive at these remote regions through atmospheric transport. However, the mechanisms involving the accumulation of these compounds from the atmospheric pool to the lacustrine systems still need to be elucidated. These mechanisms must be related to the processes involving the transfer of these pollutant from low to high latitudes[1] as described in the global distillation effect[2].
Sex-Change Chemicals and their Influence on the Brain
Authors: Harris Catherine A.
Published: March 2005

The potential for man-made chemicals to mimic or antagonise natural hormones is a controversial issue, but one for which increasing amounts of evidence are being gathered worldwide. The controversy surrounds not so much the matter of whether these chemicals can mimic hormones invitro— this phenomenon has been widely accepted in the scientific world — but more whether, as a result, they can disrupt reproduction in a wildlife situation. It has, nevertheless, been acknowledged that many wildlife populations are exhibiting reproductive and/or developmental abnormalities such as intersex gonads in wild roach populations in the U.K.[1] and various reproductive disorders in alligators in Lake Apopka, Florida[2]. However, the causative agents for many of these effects are difficult to specify, due to the extensive mixtures of chemicals — each of which may act via different pathways — to which wild populations are exposed, together with the wide variability observed even in natural (uncontaminated) habitats. As a result, any information detailing fundamental mechanism of action of the so-called endocrine disrupting chemicals (EDCs) is of use in determining whether or not these chemicals, as they are present in the environment, may in fact be capable of causing some of the effects observed in wildlife over recent years.
Overview of Calcitonin Gene-Related Peptide and Its Receptor
Authors: Aiyar Nambi
Published: March 2005

Calcitonin Gene-Related Peptide (CGRP), a 37 amino acid peptide identified as the alternately spliced gene product of calcitonin gene, is a sensory neuropeptide with potent cardiovascular effects. CGRP is distributed throughout the central and peripheral nervous systems and possesses diverse biological actions. CGRP has been suggested to play a role in diseases such as migraine, diabetes, pain, and inflammation. Two forms of CGRP (alpha and beta) that differ in three amino acids have been identified and are encoded by different genes. Based on the differential biological activities of various CGRP analogs, the CGRP receptors have been classified into CGRP1 and CGRP2. Structure-activity studies of CGRP analogs showed that the C- and N-terminal regions of the peptide interact independently with their receptors. While C-terminal peptide, CGRP (8-37) behaves as a CGRP1 receptor antagonist, N-terminal peptide CGRP (1-12) behaves as a weak agonist. Structural modifications of CGRP(28-37) have yielded micromolar to nanomolar affinity ligands. CGRP receptor belongs to the calcitonin receptor like receptor (CRLR) family of G-protein-coupled receptors and has been shown to require a single transmembrane domain protein called receptor activity modifying protein-1 (RAMP1) for its functional expression as well as activity. Human, rat, and porcine CRLRs have been cloned and characterized. Currently, the major focus is on the identification of potent and specific nonpeptide antagonists for this receptor in order to understand the physiological and pathophysiological role of this peptide.
Calcitonin Gene-Related Peptide (Cgrp), Adrenomedullin (Am), Amylin, And Calcitonin (Ct) Receptors And Overlapping Biological Actions
Authors: Fischer J.A. , Born W. , Muff R.
Published: March 2005

CGRP, AM, amylin, and CT have in common N-terminal 6-7 amino acid ring structures linked by disulfide bridges and amidated C-termini required for biological activity. For the related bioactive peptides, receptor-binding sites linked to cAMP stimulation and to a lesser extent to the phospholipase C signaling pathway have been identified in tissue specific manner. The highest density of CGRP receptors has been recognized in the cerebellum and the spinal cord. There photoaffinity-labeled N-glycosylated 60,000 and 54,000 Mr proteins are converted to 46,000 and 41,000 Mr components following endoglycosidase F/N-glycosidase F treatment. The same proteins were specifically labeled with [125I]-hCGRP-I(1-37) and -(8-37). Some cross-reaction between the CGRP receptor and AM was evident whereas amylin and CT were only recognized at over 10-7 M. A different AM receptor localized predominantly in the lung recognized CGRP at low, and amylin and calcitonin at equally high concentrations. CT receptor binding sites have been identified in osteoclasts and in the periventricular region of the brain. They cross-reacted with amylin at low concentrations and with CGRP and AM at over 10-7 M. Amylin receptor binding sites cross-reacting with salmon CT and CGRP but not with hCT and adrenomedullin to any great extent were originally described by Sexton in the nucleus accumbens and may represent a second CGRP receptor. The structure of a CT receptor was elucidated by the group of Goldring in 1991 through molecular cloning, and of a 60% homologous human CT receptor-like receptor (CRLR) shortly thereafter here. The latter was an orphan receptor until the discovery of the receptor-activity-modifying proteins (RAMP) by Foord which upon coexpression yield a CGRP receptor with RAMP1 and an AM receptor with RAMP2. Coexpression of the hCT receptor isotype 2 revealed a CGRP/amylin receptor with RAMP1 and an amylin receptor isotype with RAMP3. The CRLR/RAMP1 receptor antagonized by CGRP(8-37) corresponds to the CGRP1 receptor defined by Quirion, whereas his CGRP2 receptor remains to be identified. Another CGRP receptor isotype remains to be discovered in the cerebellum with no detectable CRLR encoding mRNA. Overlapping biological actions include inhibition of bone resorption obtained predominantly with CT, but also at high concentrations with CGRP, AM, and amylin. CGRP and AM are potent vasodilators, an effect shared with CT at pharmacological concentrations. Biological actions of amylin include suppression of insulin secretion, stimulation of glycogenolysis and inhibition of glycogen synthesis. In conclusion, the hCT2 receptor or the CRLR are associated with one of three RAMPs to bind to CGRP, AM, or amylin.
Alterations in Neurogenic Inflammatory Responses in Mice Lacking αCGRP
Authors: Lee Jongho , Emeson Ronald B.
Published: March 2005

a-Calcitonin gene-related peptide (aCGRP) is a pleiotropic peptide neuromodulator that is widely expressed throughout the central and peripheral nervous systems. Although CGRP has been implicated in numerous physiological processes (including peripheral vasodilatation, acetylcholine receptor biosynthesis, nociception, and neurogenic inflammation), the precise physiological roles of CGRP remain to be elucidated. To provide a better understanding of the physiological role(s) mediated by this peptide neurotransmitter, we have generated aCGRP-null mice by targeted modification in embryonic stem cells.
CGRP Receptor Family and Accessory Protein Localization: Implications for Predicted Function
Authors: Oliver K.R.
Published: March 2005

Calcitonin gene-related peptide (CGRP), adrenomedullin, amylin, and calcitonin are functionally related neuropeptides. Certain of these peptides mediate their action through receptors which have common components, such as the receptor activity modifying proteins (RAMPs) and CGRP-receptor component protein, as well as possibly through other distinct receptors. Specifically, the molecular pharmacology of CGRP and adrenomedullin is determined by coexpression of one of three receptor activity-modifying proteins (RAMPs) with calcitonin receptor-like receptor (CRLR). Additionally, through formation of another hetero-oligomer, RAMPs also govern the pharmacology of the calcitonin receptor, which in association with RAMP1 or RAMP3, binds amylin with high affinity. We have used multiple approaches to discern the regional and cellular expression of these various receptor components and binding sites for the above neuropeptides in multiple species and in different tissues. Techniques applied include in situ hybridization, immunohistochemistry and radioligand autoradiography. These data allow further understanding of both the complexity of receptor-receptor component and receptor-ligand interactions in vivo. Interestingly, these localization data suggest that RAMPs may interact with receptors additional to those already identified for the CGRP family and may be involved in binding innate neuropeptides or other neurotransmitters which are not members of the calcitonin gene-related peptide fam
Targeted Regulation Of Cgrp Gene Expression
Authors: Russo A. F. , Durham P. L.
Published: March 2005

The neuropeptide calcitonin gene-related peptide (CGRP) is a potent regulator of cerebral vascular tone and contributes to neurogenic inflammation. Clinical studies have shown that CGRP levels are elevated during the painful phase of migraine headache, then restored to baseline by antimigraine 5-HT1 drugs. Conversely, CGRP is depleted in perivascular nerve terminals from patients who have suffered vasospasm following subarachnoid hemorrhage. We have investigated the mechanisms controlling CGRP expression in the trigeminal ganglia neurons, which provide virtually all of the CGRP innervation to the cerebral vasculature. We found that nerve depolarization, inflammatory compounds, and nitric oxide can increase CGRP synthesis and secretion. Using both adenoviral vectors and transfection approaches, we have shown that the increased synthesis is due to activation of a cell-specific MAP kinase-responsive enhancer upstream of the CGRP gene. Interestingly, the 5-HT1 migraine drugs are able to block this up-regulation by a mechanism that involves a very prolonged elevation of calcium. We have shown that the duration of the calcium signal is a key determinant for whether a MAP kinase responsive gene will be stimulated or repressed by calcium-activated pathways. This observation supports the importance of a finely tuned balance of calcium in the trigeminal neuron, which is intriguing in light of genetic evidence for calcium channel mutations in a rare form of inherited migraine. These studies suggest that modulation of MAP kinase control of the cell-specific CGRP gene enhancer may be a useful therapeutic strategy for neurovascular disorders.
LTP in a Culture Dish
Authors: MacDonald J.F. , Ju William , Wang Yu Tian
Published: March 2005

The “aging” of populations in the developed world is rapidly altering demographics and presents a number of challenges for science and medicine. Foremost among these challenges is the need to enhance the quality of life for this “aging” majority. Paradoxically, improved prevention and treatment of diseases will only increase the number of individuals who will lose quality of life because of cognitive deficits in learning and memory. Such cognitive deficits are particularly vexing in societies where the ability to deal with information technology has become an increasing necessity. Understanding how the human brain encodes and stores information becomes critical in designing required therapeutic strategies.
Formation of Neural Precursor Cell Populations by Differentiation of Embryonic Stem Cells In Vitro
Authors: Rathjen Joy , Rathjen Peter D.
Published: March 2005

Recent interest in the generation of neural lineages by differentiation of embryonic stem cells arises from the opportunities represented by a developmentally normal, unlimited source of material that can be manipulated genetically with precision. Several experimental approaches, which differ conceptually, in the route of differentiation and the characteristics of the resulting cell population have been reported. In this review we undertake a comparative analysis of these approaches and their suitability for experimental investigation or implantation.
Organotin Pollution in China
Authors: Zhou Qun-fang , Jiang Gui-bin , Liu Ji-yan
Published: March 2005

A preliminary investigation of the occurrence of butyltin compounds was made in various environmental samples including water, sediment, sea products, and other commodities from China. Detection was carried out by the method of hydrogenation coupled with SPME or Grignard derivatization, followed by GC-FPD analysis. The results showed the universal existence of butyltin compounds in a wide range of tested samples, which was a potential danger for human health. Urgent control or management of organotin compounds is necessary to prevent the underlying hazard caused by this kind of pollutant.
Neural Induction, Neural Fate Stabilization, and Neural Stem Cells
Authors: Moody Sally A. , Je Hyun-Soo
Published: March 2005

The promise of stem cell therapy is expected to greatly benefit the treatment of neurodegenerative diseases. An underlying biological reason for the progressive functional losses associated with these diseases is the extremely low natural rate of self-repair in the nervous system. Although the mature CNS harbors a limited number of self-renewing stem cells, these make a significant contribution to only a few areas of brain. Therefore, it is particularly important to understand how to manipulate embryonic stem cells and adult neural stem cells so their descendants can repopulate and functionally repair damaged brain regions. A large knowledge base has been gathered about the normal processes of neural development. The time has come for this information to be applied to the problems of obtaining sufficient, neurally committed stem cells for clinical use. In this article we review the process of neural induction, by which the embryonic ectodermal cells are directed to form the neural plate, and the process of neural�fate stabilization, by which neural plate cells expand in number and consolidate their neural fate. We will present the current knowledge of the transcription factors and signaling molecules that are known to be involved in these processes. We will discuss how these factors may be relevant to manipulating embryonic stem cells to express a neural fate and to produce large numbers of neurally committed, yet undifferentiated, stem cells for transplantation therapies.
Innovations in the Speciation of Organolead Compounds in Water: Towards a More Rational, Rapid, and Simple Analytical Process
Authors: Baena J.R. , Gallego M. , Valcarcel M.
Published: March 2005

Speciation analysis calls for rapid, simple systems for minimizing errors made in the most troublesome of all steps in the analytical process: sample preparation. In this context, continuous-flow systems are of great help. The evolution in the different methodologies enabled solutions to the main shortcomings occurring from the lack of selectivity of using RP–C18as sorbent material. One solution was a shift to more sensitive and selective, but only partially automated, systems employing C60fullerene and Grignard’s reagent; another was a shift to completely automated systems employing sodium tetrapropylborate; and a final solution was to employ the simplest possible configuration by removing the reagent stream. The analytical methods developed allowed the identification and quantification of different organolead species at the pg/ml levels in rainwater samples, with precision (RSD) of about 5% and recoveries ranging from 92 to 100%.
Sample Preparation and Liquid Chromatography Mass Spectrometry Analysis of Alkylphenolic Compounds and Steroid Sex Hormones in Sediments
Authors: Petrovia Mira , Barcela Damia
Published: March 2005

A new methodology, based on the use of accelerated solvent extraction (ASE) and highly selective cleanup using restricted access material (RAM) on-line coupled with liquid chromatography–mass spectrometry (LC–MS), is presented for the simultaneous and unequivocal determination of alkylphenol ethoxylates (APEOs), their degradation products and halogenated derivatives, and steroid sex hormones in sediment samples. Using the integrated RAM–LC–MS system, the simultaneous determination of alkylphenolic compounds and sex hormones was achieved, yielding recoveries higher than 60% and producing low MS background noise.
The Use of Antisense-Mediated Inhibition to Delineate The Role of Inflammatory Agents in The Pathophysiology of Spinal Cord Injury
Authors: Pearse Damien D. , Pereira Francisco C. , Chatzipanteli Katina , Dietrich Francisco W. Dalton , Bunge Mary Bartlett
Published: March 2005

Injuries to the central nervous system (CNS) usually lead to a potent and acute inflammatory response[1]. During this period, glia and immune cells respond to chemical cues associated with the debris of lysed neurons, disrupted axons, and a broken blood-brain-barrier by releasing a battery of cytokines including tumor necrosis factor-α(TNF-α) and, interleukin-β (IL-1β) as well as reactive oxygen species such as nitric oxide (NO-)[2]. The secretion of these factors may be primarily responsible for secondary damage to surrounding uninjured tissue that potentiates the initial injury[3]. Antisense oligonucleotides (ASOs) are designed to hybridize to specific regions of specific mRNAs. Hybridization of the oligonucleotide to the mRNA then interferes with the normal processing of that mRNA at the ribosome or targets the RNA duplex for cleavage by the RNA digestive enzyme, ribonuclease H, resulting in greatly reduced expression of the coded protein. This effectively reduces the amount of corresponding translated protein product and experiments can be designed to examine the requirement of particular inflammatory agents in eliciting specific deleterious responses after injury, e.g., cell death.
Rapid Determination of 226Ra and Uranium Isotopes in Solid Samples by Fusion with Lithium Metaborate and Alpha Spectrometry
Authors: Bojanowski R. , Radecki Z. , Piekoś R.
Published: March 2005

A simple and rapid method has been developed to determine226Ra in rocks, soils, and sediments. Samples are decomposed by fusion with lithium metaborate and the melt is dissolved in a solution containing sulfates and citric acid. During the dissolution, a fine suspension of mixed barium and radium sulfates is formed. The microcrystals are collected on a membrane filter (pore size 0.1 μm) and analysed in an alpha spectrometer. Application of a133Ba tracer enables us to assess the loss of the analyte, which only rarely exceeds 10%. All analytical operations, beginning from sample decomposition to source preparation for alpha spectrometry, can be accomplished within 1 or 2 h.

With uranium determination, the filtrate is spiked with a232U tracer and passed through a column loaded with a Dowex AG (1 x 4) anion-exchange resin in the sulfate form. Interfering elements are eluted with dilute sulfuric acid followed by concentrated hydrochloric acid. Uranium is eluted with water, electrodeposited on silver discs, and analysed in the alpha spectrometer. The method was tested on reference soil and sediment materials and was found to be accurate within the estimated uncertainties.
Recent Trends in the Development of Ecological Models Applied on Aquatic Ecosystems
Authors: Jorgensen S.E.
Published: March 2005

This paper presents an overview of the application of models on aquatic ecosystems. More than 17% of the models published in the focal journal in the field, Ecological Modelling, are aquatic ecosystem models. An increasing number of papers are dealing with the theoretical aspects of modeling – new modeling approaches and techniques, how models can be used to reveal ecosystem properties, and how models can better reflect the properties of ecosystems. This development implies that today we have more types of models. The characteristics, the advantages, and the disadvantages of these model types are presented briefly. The selection criteria for the presented model types are discussed, and the application of these types to models for aquatic ecosystems is reviewed. A recent improvement in model calibration of particular interest for aquatic ecosystems is presented, and the perspectives resulting from this new calibration procedure and from possible hybrids of the presented model types are discussed.
A Role for Exocytosis in the Spatial Regulationof Actin Organization
Authors: Gao Xiang-Dong , Albert Stefan
Published: March 2005

The efficient organization of the actin cytoskeleton is important for many cellular functions. However, how the local actin organization is regulated in a cell is not well understood. By using yeast mutants defective in actin organization and secretion, we demonstrated that exocytosis plays a role in the spatial regulation of actin organization. Our findings suggest that the actin cytoskeleton, exocytosis, and perhaps endocytosis, may depend on each other for efficiency and reinforce each other.
Effects of Whole-Body 50-Hz Magnetic Field Exposure on Mouse Leydig Cells
Authors: Forgács Zsolt , Somosy Zoltán , Kubinyi Györgyi , Sinay Hanna , Bakos Jozsef , Thuróczy György , Surján András , Hudák Aranka , Olajos Ferenc , Lázár Péter
Published: March 2005

The main goal of this study was to evaluate the possible effect of whole-body magnetic field (MF) exposure on the steroidogenic capacity of Leydig cellsin vitro. In four separate experiments, male CFLP mice were exposed to sinusoidal 50-Hz, 100-μT MF. The duration of exposure was 23.5 h/day over a period of 14 days. At the end of the exposure, interstitial (Leydig) cells were isolated from the testicles of the sham-exposed and exposed animals. The cells were cultured for 48 h in the presence or absence of 1, 10, or 100 mIU/ml human chorionic gonadotropin (hCG). The luteinizing hormone (LH) analog hCG was used to check the testosterone (T) response of the sham-exposed controls and to evaluate the possible effect of the whole-body MF exposure on the steroidogenic capacity of Leydig cellsin vitro. Testosterone content of the culture media and blood sera was measured by radioimmunoassay (RIA). In the cultures obtained from MF-exposed animals, the hCG-stimulated T response was significanly higher (p < 0.01) compared with the sham-exposed controls, while the basal T production of cells and the level of serum T remained unaltered. No MF exposurerelated histopathological alterations were found in testicles, epididymes, adrenals, prostates, and pituitary glands. The MF exposure did not affect the animal growth rate and the observed hematologic and serum chemical variables. Our results indicate a presumably direct effect of whole-body MF exposure on the hCG-stimulated steroidogenic response of mouse Leydig cells.
Urinary Tract Infections in Adults
Authors: Cohn Evan B. , Schaeffer Anthony J.
Published: March 2005

Urinary tract infection (UTI) is an exceedingly common problem prompting seven million office visits and one million hospitalizations in the United States each year (1). Advances in the understanding of both host and bacterial factors involved in UTI have led to many improvements in therapy. While there have also been advances in the realm of antimicrobials, there have been numerous problems with multiple drug resistant organisms. Providing economical care while minimizing drug resistance requires appropriate diagnosis, evaluation, and treatment of urinary tract infections.
Microlaparoscopy in Sex Reassignment Surgery
Authors: De Stefani S. , Trombetta C. , Raber M. , Savaco G. , Moro U. , Belgrano E.
Published: March 2005

Sex reassignment (male to female surgery) is a standard operation which is aimed at constructing female genitalia and obtaining a cosmetic and functional result that is similar to that of a normal female subject. The ideal surgical procedure has not yet been described, but the various techniques which have been proposed in the literature are similar. The most cumbersome maneuver of the procedure is that of creating a neovaginal cavity inside the perineum. This step is generally carried out by means of blunt dissection between the rectal wall and the prostate, but most of the surgery is blindly performed without visual control. In these conditions, the risk of rectal injury is high, and may lead to severe intraoperative complications. Microlaparoscopy allows for a direct observation of the perineal dissection from inside the peritoneal cavity, thus avoiding risk of rectal injury. The technique is simple to perform, is non-invasive, and only 15 minutes are added to the operation.
The Role of Oxygen Tension in Penile Erection and Its Relationship to Erectile Dysfunction
Authors: Park Jong-Kwan , Moreland Robert B. , Nehra Ajay
Published: March 2005

The corpus cavernosum of the penis is one of the few vascular beds in which there is a change in oxygen tension with function (blood PO225-40mm Hg in the flaccid state, and 90-100mm Hg in the erect state). This change in oxygen tension exposes the components of the corpus cavernosum to a variety of cytokines, humoral, vasoactive, and growth factors which may affect the structure and function of the endothelial cells, smooth muscle cells, neurons and extracellular matrix. Among these cell types, endothelial cells are the first line of defense to blood-borne stress and can affect the underlying smooth muscle via paracrine mechanisms. Impotence is defined as the inability to obtain or sustain an erection sufficient for vaginal penetration and can result from a variety of pathological conditions, vascular disease, endocrine disease, neurological disease, and psychogenic disorders. The penis is a vascular organ and as such is susceptible to the effects of vascular diseases. This review will discuss the basic etiology of erection and vasculogenic erectile dysfunction and explore the role oxygen tension in regulating various cellular and humoral factors as well as trabecular structure and function.
Tumor necrosis factor family members and inflammatory bowel disease
Authors: Wang Jing , Fu Yang‐Xin
Published: March 2005

Summary:  Tumor necrosis factor (TNF) is one of the most potent effector cytokines in the pathogenesis of inflammatory bowel disease (IBD). Previous studies strongly implicate the critical involvement of several TNF family members in human IBD. This review focuses on the recent studies of TNF family members in IBD development. In particular, we discuss the findings about LIGHT (homologous to lymphotoxins, inducible expression, competes with herpes simplex virus glycoprotein D for herpes viral entry mediator, a receptor expressed on T lymphocytes) in the pathogenesis of IBD, and the potential mechanisms by which LIGHT induces IBD. Such mechanisms may also apply to other TNF family members.
The role of BAFF in immune function and implications for autoimmunity
Authors: Kalled Susan L.
Published: March 2005

Summary:  BAFF [B‐cell activating factor belonging to the tumor necrosis factor (TNF) family] is a ligand that is required for peripheral B‐cell survival and homeostasis. In addition to mediating B‐cell survival, BAFF also regulates expression of certain B‐cell‐surface proteins, such as CD21/35. BAFF deficiency results in a reduced number of peripheral B cells and a diminished ability to mount robust humoral immune responses. Overexpression of BAFF has been linked to murine and human autoimmunity, and recent data provide clues as to how excess BAFF may allow the emergence of autoreactive B cells. In vivo animal testing with BAFF inhibitors has generated exciting data that support the pathway as a target for modulating B cells. The role of BAFF in B‐cell biology, T‐cell biology, and autoimmunity is discussed, as well as current efforts to develop BAFF inhibitors for clinical testing in autoimmune disorders.
Pathways to gene identification in rheumatoid arthritis: PTPN22 and beyond
Authors: Gregersen Peter K.
Published: March 2005

Summary:  Rheumatoid arthritis (RA), like other autoimmune diseases, has a complex genetic basis. Rapid technical advances in high‐throughput genotyping and analysis have now reached a point where genes of low‐to‐moderate risk can be identified using a variety of study designs, including whole genome association studies. The availability of large, well‐characterized populations of cases and controls are critical to the success of these efforts. A functional variant (R620W) of the intracellular protein tyrosine phosphatase N22 (PTPN22) has now been conclusively shown to confer approximately two‐fold risk for seropositive RA as well as several other autoimmune disorders. PTPN22 appears to act primarily by setting thresholds for T‐cell receptor signaling, and the current data suggest that the PTPN22 620W allele is likely to be a general risk factor for the development of humoral autoimmunity. PTPN22 is expressed widely in hematopoietic cells, but other than in T cells, its role is unknown. These results provide strong evidence for the longstanding hypothesis that common genes underlie different autoimmune phenotypes and emphasize that finding genes of only moderate risk can provide important insights into disease pathogenesis.
The good turned ugly: immunopathogenic basis for diabetogenic CD8+ T cells in NOD mice
Authors: DiLorenzo Teresa P. , Serreze David V.
Published: March 2005

Summary:  Type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is a T‐cell‐mediated autoimmune disease in which the insulin‐producing pancreatic islet β‐cells are selectively eliminated. As a result, glucose metabolism cannot be regulated unless exogenous insulin is administered. Both the CD4+ and the CD8+ T‐cell subsets are required for T1D development. Approximately 20 years ago, an association between certain class II major histocompatibility complex (MHC) alleles and susceptibility to T1D was reported. This finding led to enormous interest in the CD4+ T cells participating in the development of T1D, while the CD8+ subset was relatively ignored. However, the isolation of β‐cell‐autoreactive CD8+ T‐cell clones from the islets of NOD mice helped to generate interest in the pathogenic role of this subset, as has accumulating evidence that certain class I MHC alleles are additional risk factors for T1D development in humans. Three distinct diabetogenic CD8+ T‐cell populations have now been characterized in NOD mice. Here, we review recent investigations exploring their selection, activation, trafficking, and antigenic specificities. As CD8+ T cells are suspected contributors to β‐cell demise in humans, continued exploration of these critical areas could very possibly lead to tangible benefits for T1D patients and at‐risk individuals.
Role of resistant Drh1 locus in chemical carcinogen‐induced hepatocarcinogenesis in rats: Analysis with a speed congenic strain
Authors: Liu Hongbo , Higashi Ken , Hiai Hiroshi
Published: March 2005

The DRH is an inbred rat strain established by selective mating of the 3′‐Me‐DAB resistant progeny of closed colony Donryu rats over 20 generations. Genetic analysis shows that two semidominant QTLs, Drh1 and Drh2, are responsible for strong resistance to chemical‐induced hepatocarcinogenesis in DRH strain rats. To evaluate the effect of the single Drh1 locus on various stages of liver carcinogenesis, we constructed a speed congenic strain DRH.F344‐Drh1 by transferring a susceptible Drh1 allele of F344 to DRH rats by marker‐assisted backcrossing. The DRH.F344‐Drh1 rats had a ∼43 cM segment of chromosome 1 bearing Drh1 but the Drh2 was of the DRH allele. After oral administration of 3′‐Me‐DAB for 8 weeks, DRH.F344‐Drh1 had as many enzyme altered foci as F344, whereas the quantitative parameters of fibrosis, enzyme altered foci, GST‐P expression and proliferation of liver cells in DRH.F344‐Drh1 rats were intermediate between F344 and DRH. In the liver of carcinogen‐fed DRH rats, there was intensive apoptosis as detected by TUNEL stain, but not in the liver of F344 and DRH.F344‐Drh1 rats. Injection of lead nitrate (100 µmol/kgB.W) induced a wave of liver cell proliferation, as seen by BrdU uptake within a few days in F344 and DRH.F344‐Drh1 rats, but not in DRH rats. Instead, there were numerous TUNEL‐positive nuclei in the DRH liver after lead nitrate injection. Apparently, the hepatocytes were removed by apoptosis during transition from G0 to G1. The major role of Drh1 is effective removal of the hepatocytes newly recruited to proliferate after chemical injury. Resistance to preneoplastic lesions in DRH rats may well be based on similar mechanism. (Cancer Sci 2005; 96: 164–169)
Performance of young people with Down syndrome on the Leiter‐R and British picture vocabulary scales
Authors: Glenn S. , Cunningham C.
Published: March 2005

Background  The British picture vocabulary scales (BPVS‐II) and the Leiter international performance scales (Leiter‐R), both restandardised in 1997, are often used in experimental studies to match individuals with intellectual impairment. Both provide a brief measure of mental age, and cover a wide ability range using a simple format. The BPVS‐II assesses verbal comprehension and the Leiter nonverbal abilities. The issue is which to choose. People with Down syndrome (DS), for example, have particular problems in language and so the BPVS may provide an underestimation of ability.

Method  The present study investigated this by comparing the performance of 46 young people with DS (21 females, 25 males, mean age 19 years 10 months) on the BPVS‐II (verbal mental age – VMA) and the Leiter‐R brief IQ (nonverbal mental age – NVMA).

Results  Contrary to expectations VMAs were significantly higher than NVMAs (6 years 6 months and 5 years 2 months, respectively). There was a significant correlation of 0.61 between the VMA and NVMA, and both discriminated participants at all levels of ability. However, the Leiter‐R brief IQ scores provided poor discrimination at the bottom end of the IQ range (IQ 36).

Conclusion  Both the BPVS‐II and the Leiter‐R provide mental age equivalent scores that are useful for plotting developmental progress, although absolute mental ages may differ.
The association between environmental events and self‐injurious behaviour in Cornelia de Lange syndrome
Authors: Moss J. , Oliver C. , Hall S. , Arron K. , Sloneem J. , Petty J.
Published: March 2005

Background  There has been limited empirical research into the environmental causes of self‐injury in Cornelia de Lange syndrome. The present study examined the variability of self‐injurious behaviour in Cornelia de Lange syndrome across environmental setting events. Additionally, the association between setting events and more specific environmental events was examined.

Method  A descriptive analysis of observational data on eight children with Cornelia de Lange syndrome aged between 4 and 14 years was carried out. The association between self‐injurious behaviour and four environmental setting events and between specific environmental events and setting events was examined using established statistical methods for observational data.

Results  Seven out of eight of the participants showed at least one form of self‐injurious behaviour that was associated with a particular setting event. The study also demonstrated that the relationship between setting events and environmental events is extremely variable across individuals.

Conclusions  Self‐injurious behaviour in some individuals with Cornelia de Lange syndrome is associated with environmental events although the precise nature of the association warrants clarification. Using broad setting events as a methodological tool in isolation provides some insight into the role of specific environmental factors in maintaining self‐injurious behaviour but the integrity of setting events must be established.
Detecting Holocene divergence in the anadromous–freshwater three‐spined stickleback (Gasterosteus aculeatus) system
Authors: RAEYMAEKERS J. A. M. , MAES G. E. , AUDENAERT E. , VOLCKAERT F. A. M.
Published: March 2005

The anadromous–freshwater three‐spined stickleback (Gasterosteus aculeatus) system allows for inferring the role of adaptation in speciation with a high level of accuracy because the freshwater ecotype has evolved multiple times from a uniform anadromous ancestor. A cause for concern is that independent evolution among drainages is not guaranteed in areas with a poorly resolved glacial history. This is the case for the west European great rivers, whose downstream valleys flanked the southern limit of the late Pleistocene ice sheet. We tested for independent and postglacial colonization of these valleys hypothesizing that the relationships among anadromous and freshwater sticklebacks correspond to a raceme structure. We compared the reduction in plate number accompanying this colonization to the genetic differentiation using 13 allozyme and five microsatellite loci in 350 individuals. Overall microsatellite differentiation (FST = 0.147) was twice as large as allozyme differentiation (FST = 0.066). Although habitat‐specific gene flow may mask the ancestral relationships among both ecotypes, levels of microsatellite differentiation supported the hypothesis of raceme‐like divergence, reflecting independent colonizations rather than the presence of two distinct evolutionary clades. Under an infinite alleles model and in the absence of gene flow, the observed freshwater divergence might be reached after 440 (microsatellites) to 4500 (allozymes) generations. Hence, the anadromous–freshwater stickleback system most likely diverged postglacially. We conclude that the reduction in plate number in two freshwater basins probably occurred independently, and that its considerable variation among populations is not in agreement with the time since divergence.
A Signal for Independent Coastal and Continental histories among North American wolves
Authors: WECKWORTH BYRON V. , TALBOT SANDRA , SAGE GEORGE K. , PERSON DAVID K. , COOK JOSEPH
Published: March 2005

Relatively little genetic variation has been uncovered in surveys across North American wolf populations. Pacific Northwest coastal wolves, in particular, have never been analysed. With an emphasis on coastal Alaska wolf populations, variation at 11 microsatellite loci was assessed. Coastal wolf populations were distinctive from continental wolves and high levels of diversity were found within this isolated and relatively small geographical region. Significant genetic structure within southeast Alaska relative to other populations in the Pacific Northwest, and lack of significant correlation between genetic and geographical distances suggest that differentiation of southeast Alaska wolves may be caused by barriers to gene flow, rather than isolation by distance. Morphological research also suggests that coastal wolves differ from continental populations. A series of studies of other mammals in the region also has uncovered distinctive evolutionary histories and high levels of endemism along the Pacific coast. Divergence of these coastal wolves is consistent with the unique phylogeographical history of the biota of this region and re‐emphasizes the need for continued exploration of this biota to lay a framework for thoughtful management of southeast Alaska.
Old fish in a young lake: stone loach (Pisces: Barbatula barbatula) populations in Lake Constance are genetically isolated by distance
Authors: BARLUENGA MARTA , MEYER AXEL
Published: March 2005

The genetic structure of 10 populations (453 individuals) of stone loach (Barbatula barbatula L.), a small bottom‐dwelling cyprinid fish, in the littoral zone of Lake Constance, central Europe, was investigated by analysing the mitochondrial control region sequences and five microsatellite loci. An unexpectedly high degree of genetic diversity (up to 0.36%) and old estimated age of these populations (> 150 000 years) based on mitochondrial DNA (mtDNA) was found. These findings contrast with the relatively young age of the lake, which could be colonized by fish only after the last ice age around 15 000 bp. Stone loach appears to be an old species in a young lake. Both types of molecular markers showed population genetic structure pronounced in mtDNA (overall FST = 0.15) but moderate in microsatellites (FST = 0.03). As predicted by its life history, philopatry, and limited capacity for dispersal, stone loach populations of Lake Constance show a clear pattern of isolation by distance. Geographic distances along the shores are the best explanation for the observed geographical distribution of genetic differentiation (r = 0.88), indicating that open water represents a barrier for the dispersal of the stone loach. The colonization of Lake Constance might have occurred initially at one location and then populations spread throughout the lake in a stepwise manner following the shoreline, and subsequently remained largely genetically isolated as suggested by the large observed differences among them.
Genetic control of weediness traits and the maintenance of sympatric crop–weed polymorphism in pearl millet (Pennisetum glaucum)
Authors: MIURA R. , TERAUCHI R.
Published: March 2005

Pearl millet (Pennisetum glaucum), a diploid outcrossing crop widely grown in semiarid tropics, provides a unique extant material for the study of crop–weed interactive evolution. Co‐occurrence of a weedy, shattering type of pearl millet with the cultivated one is the rule in the traditional agro‐ecosystem in the Sahel zone of Africa. Selfed progeny of weed‐type plants invariably segregated into distinct weed and crop types in an approximately 3:1 ratio. Genetic analysis using a cleaved amplified polymorphic sequence (CAPS) marker strongly suggested that a series of differences between the crop and the weed types are determined by a single putative supergene that has two allelic types, C and W. The crop‐type plants are CC homozygotes, and the weed‐type plants are CW heterozygotes. WW homozygotes are sterile and rare in the field. Thus, the CW weed plants recurrently arise from crosses between the crop and the weed, as well as from crosses among the weed‐type plants. The weed type appears to have a sufficiently high fitness to maintain the W allele in the pearl millet population, resulting in the perpetuation of this unique crop–weed polymorphism.
Phylogeographical footprints of the Strait of Gibraltar and Quaternary climatic fluctuations in the western Mediterranean: a case study with the greater white‐toothed shrew, Crocidura russula (Mammalia: Soricidae)
Authors: COSSON JEAN‐FRANÇOIS , HUTTERER RAINER , LIBOIS ROLAND , SARÀ MAURIZIO , TABERLET PIERRE , VOGEL PETER
Published: March 2005

We used mitochondrial cyt b sequences to investigate the phylogenetic relationships of Crocidura russula (sensu lato) populations across the Strait of Gibraltar, western Europe, Maghreb, and the Mediterranean and Atlantic islands. This revealed very low genetic divergence between European and Moroccan populations. The application of a molecular clock previously calibrated for shrews suggested that the separation of European from Moroccan lineages occurred less than 60 000 bp, which is at least 5 million years (Myr) after the reopening of the Strait of Gibraltar. This means that an overwater dispersal event was responsible for the observed phylogeographical structure. In contrast, genetic analyses revealed that Moroccan populations were highly distinct from Tunisian ones. According to the molecular clock, these populations separated about 2.2 million years ago (Ma), a time marked by sharp alternations of dry and humid climates in the Maghreb. The populations of the Mediterranean islands Ibiza, Pantelleria, and Sardinia were founded from Tunisian populations by overwater dispersal. In conclusion, overwater dispersal across the Strait of Gibraltar, probably assisted by humans, is possible for small terrestrial vertebrates. Moreover, as in Europe, Quaternary climatic fluctuations had a major effect on the phylogeographical structure of the Maghreb biota.