bluuebunny/crossref_metadata_2025 huggingface dataset:
Anion exchanger 2 is essential for spermiogenesis in mice
Authors: Medina Juan F. , Recalde Sergio , Prieto Jesús , Lecanda Jon , Sáez Elena , Funk Colin D. , Vecino Paola , van Roon Marian A. , Ottenhoff Roelof , Bosma Piter J. , Bakker Conny T. , Elferink Ronald P. J. Oude
Published: December 2003

Na
+
-independent anion exchangers (AE) mediate electroneutral exchange of Cl
-
for

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ions across cell membranes, being involved in intracellular pH and cell volume regulation and in transepithelial hydroionic fluxes. Bicarbonate activation of adenylyl cyclase is known to be necessary for sperm motility and sperm capacitation, and a few studies have suggested a possible role of AE carriers in reproduction. Among the four AE genes identified in mammals thus far, only
Ae2
(
Slc4a2
) has been determined to be expressed in the male reproductive system, especially in developing spermatozoa and in epididymal epithelium. Most AE genes drive alternative transcription, which in mouse
Ae2
results in several Ae2 isoforms. Here, we generated mice carrying a targeted disruption of
Ae2
that prevents the expression of the three AE2 isoforms (Ae2a, Ae2b
1
, and Ae2b
2
) normally found in mouse testes. Male
Ae2
-/-
mice (but not female
Ae2
-/-
mice) are infertile. Histopathological analysis of
Ae2
-/-
testes shows an interruption of spermiogenesis, with only a few late spermatids and a complete absence of spermatozoa in the seminiferous tubules. The number of apoptotic bodies is increased in the seminiferous tubules and in the epididymis, which also shows squamous metaplasia of the epididymal epithelium. Our findings reveal an essential role of
Ae2
in mouse spermiogenesis and stress the recently postulated involvement of bicarbonate in germ-cell differentiation through the bicarbonate-sensitive soluble-adenylyl-cyclase pathway.
Chemical chaperone therapy for brain pathology in G
M1
-gangliosidosis
Authors: Matsuda Junichiro , Suzuki Osamu , Oshima Akihiro , Yamamoto Yoshie , Noguchi Akira , Takimoto Kazuhiro , Itoh Masayuki , Matsuzaki Yuji , Yasuda Yosuke , Ogawa Seiichiro , Sakata Yuko , Nanba Eiji , Higaki Katsumi , Ogawa Yoshimi , Tominaga Lika , Ohno Kousaku , Iwasaki Hiroyuki , Watanabe Hiroshi , Brady Roscoe O. , Suzuki Yoshiyuki
Published: December 2003

We synthesized a galactose derivative,
N-
octyl-4-epi-β-valienamine (NOEV), for a molecular therapy (chemical chaperone therapy) of a human neurogenetic disease, β-galactosidosis (G
M1
-gangliosidosis and Morquio B disease). It is a potent inhibitor of lysosomal β-galactosidase
in vitro
. Addition of NOEV in the culture medium restored mutant enzyme activity in cultured human or murine fibroblasts at low intracellular concentrations, resulting in a marked decrease of intracellular substrate storage. Short-term oral administration of NOEV to a model mouse of juvenile G
M1
-gangliosidosis, expressing a mutant enzyme protein R201C, resulted in significant enhancement of the enzyme activity in the brain and other tissues. Immunohistochemical stain revealed a decrease in the amount of G
M1
and G
A1
in neuronal cells in the fronto-temporal cerebral cortex and brainstem. However, mass biochemical analysis did not show the substrate reduction observed histochemically in these limited areas in the brain probably because of the brief duration of this investigation. Chemical chaperone therapy may be useful for certain patients with β-galactosidosis and potentially other lysosomal storage diseases with central nervous system involvement.
Gene expression analysis of plant host–pathogen interactions by SuperSAGE
Authors: Matsumura Hideo , Reich Stefanie , Ito Akiko , Saitoh Hiromasa , Kamoun Sophien , Winter Peter , Kahl Günter , Reuter Monika , Krüger Detlev H. , Terauchi Ryohei
Published: December 2003

The type III restriction endonuclease EcoP15I was used in isolating fragments of 26 bp from defined positions of cDNAs. We call this substantially improved variant to the conventional serial analysis of gene expression (SAGE) procedure “SuperSAGE.” By applying SuperSAGE to
Magnaporthe grisea
(blast)-infected rice leaves, gene expression profiles of both the rice host and blast fungus were simultaneously monitored by making use of the fully sequenced genomes of both organisms, revealing that the
hydrophobin
gene is the most actively transcribed
M. grisea
gene in blast-infected rice leaves. Moreover, SuperSAGE was applied to study gene expression changes before the so-called hypersensitive response in INF1 elicitor-treated
Nicotiana benthamiana
, a “nonmodel” organism for which no DNA database is available. Again, SuperSAGE allowed rapid identification of genes up- or down-regulated by the elicitor. Surprisingly, many of the down-regulated genes coded for proteins involved in photosynthesis. SuperSAGE will be especially useful for transcriptome profiling of two or more interacting organisms like hosts and pathogens, and of organisms, for which no DNA database is available.
The
Drosophila
homolog of Down's syndrome critical region 1 gene regulates learning: Implications for mental retardation
Authors: Chang Karen T. , Shi Yi-Jun , Min Kyung-Tai
Published: December 2003

Mental retardation is the most common phenotypic abnormality seen in Down's syndrome (DS) patients, yet the underlying mechanism remains mysterious. DS critical region 1 (DSCR1), located on chromosome 21, is overexpressed in the brain of DS fetus and encodes an inhibitor of calcineurin, but its physiological significance is unknown. To study its functional importance and role in mental retardation in DS, we generated
Drosophila
mutants of
nebula
, an ortholog of human DSCR1. Here, we report that both
nebula
loss-of-function and overexpression mutants exhibit severe learning defects that are attributed by biochemical perturbations rather than maldevelopment of the brain. These results, combined with our data showing that the same biochemical signaling pathway is altered in human DS fetal brain tissue overexpressing DSCR1, suggest that alteration of DSCR1 expression could contribute to mental retardation in DS.
Arf
tumor suppressor promoter monitors latent oncogenic signals
in vivo
Authors: Zindy Frederique , Williams Richard T. , Baudino Troy A. , Rehg Jerold E. , Skapek Stephen X. , Cleveland John L. , Roussel Martine F. , Sherr Charles J.
Published: December 2003

Induction of the
Arf
tumor suppressor gene by elevated thresholds of mitogenic signals activates a p53-dependent transcriptional response that triggers either growth arrest or apoptosis, thereby countering abnormal cell proliferation. Conversely,
Arf
inactivation is associated with tumor development. Expression of
Arf
in tissues of adult mice is difficult to detect, possibly because its induction leads to the arrest or elimination of incipient tumor cells. We replaced coding sequences of exon 1β of the mouse cellular
Arf
gene with a cDNA encoding GFP, thereby producing
Arf
-null animals in which GFP expression is driven by the intact
Arf
promoter. The
Arf
promoter was induced in several biologic settings previously shown to elicit mouse p19
Arf
expression. Inactivation of
Arf
in this manner led to the outgrowth of tumor cells expressing GFP, thereby providing direct evidence that the
Arf
promoter monitors latent oncogenic signals
in vivo
.
MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation
Authors: Wang Yi , Qin Jun
Published: December 2003

The mismatch repair proteins function upstream in the DNA damage signaling pathways induced by the DNA methylating agent
N
-methyl-
N
′
-
nitro-
N
-nitrosoguanidine (MNNG). We report that MSH2 (MutS homolog 2) protein interacts with the ATR (ATM- and Rad3-related) kinase to form a signaling module and regulate the phosphorylation of Chk1 and SMC1 (structure maintenance of chromosome 1). We found that phosphorylation of Chk1 by ATR also requires checkpoint proteins Rad17 and replication protein A. In contrast, phosphorylation of SMC1 by ATR is independent of Rad17 and replication protein A, suggesting that the signaling pathway leading to SMC1 phosphorylation is distinct from that mediated by the checkpoint proteins. In addition, both MSH2 and Rad17 are required for the activation of the S-phase checkpoint to suppress DNA synthesis in response to MNNG, and phosphorylation of SMC1 is required for cellular survival. These data support a model in which MSH2 and ATR function upstream to regulate two branches of the response pathway to DNA damage caused by MNNG.
Systematic, genome-wide identification of host genes affecting replication of a positive-strand RNA virus
Authors: Kushner David B. , Lindenbach Brett D. , Grdzelishvili Valery Z. , Noueiry Amine O. , Paul Scott M. , Ahlquist Paul
Published: December 2003

Positive-strand RNA viruses are the largest virus class and include many pathogens such as hepatitis C virus and the severe acute respiratory syndrome coronavirus (SARS). Brome mosaic virus (BMV) is a representative positive-strand RNA virus whose RNA replication, gene expression, and encapsidation have been reproduced in the yeast
Saccharomyces cerevisiae
. By using traditional yeast genetics, host genes have been identified that function in controlling BMV translation, selecting BMV RNAs as replication templates, activating the replication complex, maintaining a lipid composition required for membrane-associated RNA replication, and other steps. To more globally and systematically identify such host factors, we used engineered BMV derivatives to assay viral RNA replication in each strain of an ordered, genome-wide set of yeast single-gene deletion mutants. Each deletion strain was transformed to express BMV replicase proteins and a BMV RNA replication template with the capsid gene replaced by a luciferase reporter. Luciferase expression, which is dependent on viral RNA replication and RNA-dependent mRNA synthesis, was measured in intact yeast cells. Approximately 4,500 yeast deletion strains (≈80% of yeast genes) were screened in duplicate and selected strains analyzed further. This functional genomics approach revealed nearly 100 genes whose absence inhibited or stimulated BMV RNA replication and/or gene expression by 3- to >25-fold. Several of these genes were shown previously to function in BMV replication, validating the approach. Newly identified genes include some in RNA, protein, or membrane modification pathways and genes of unknown function. The results further illuminate virus and cell pathways. Further refinement of virus screening likely will reveal contributions from additional host genes.
Channel gating forces govern accuracy of mechano-electrical transduction in hair cells
Authors: van Netten Sietse M. , Dinklo Theo , Marcotti Walter , Kros Corné J.
Published: December 2003

Sensory hair cells are known for the exquisite displacement sensitivity with which they detect the sound-evoked vibrations in the inner ear. In this article, we determine a stochastically imposed fundamental lower bound on a hair cell's sensitivity to detect mechanically coded information arriving at its hair bundle. Based on measurements of transducer current and its noise in outer hair cells and the application of estimation theory, we show that a hair cell's transducer current carries information that allows the detection of vibrational amplitudes with an accuracy on the order of nanometers. We identify the transducer channel's molecular gating force as the physical factor controlling this accuracy in proportion to the inverse of its magnitude. Further, we show that the match of stochastic channel noise to gating-spring noise implies that the gating apparatus operates at the threshold of negative stiffness.
Primitive adult hematopoietic stem cells can function as osteoblast precursors
Authors: Olmsted-Davis Elizabeth A. , Gugala Zbigniew , Camargo Fernando , Gannon Francis H. , Jackson KathyJo , Kienstra Kirsten Anderson , Shine H. David , Lindsey Ronald W. , Hirschi Karen K. , Goodell Margaret A. , Brenner Malcolm K. , Davis Alan R.
Published: December 2003

Osteoblasts are continually recruited from stem cell pools to maintain bone. Although their immediate precursor is a plastic-adherent mesenchymal stem cell able to generate tissues other than bone, increasing evidence suggests the existence of a more primitive cell that can differentiate to both hematopoietic and mesenchymal cells. We show here that the “side population” (SP) of marrow stem cells, defined by their ability to rapidly expel a DNA-binding dye and to regenerate the hematopoietic compartment, can differentiate to osteoblasts through a mesenchymal intermediate. When transplanted into lethally irradiated mice, single gene-marked murine SP cells reconstituted depleted osteoprogenitor pools, such that a large proportion of the osteogenic cells in the epiphysis of long bone carried the donor SP cell marker. These findings suggest that the developmental capacity of SP cells is not restricted to the hematopoietic lineages but extends to osteogenic differentiation. This property not only elucidates a previously unrecognized step in osteoblast development, but also has intriguing implications for the use of SP cells in clinical orthopedics and stem cell-based disorders of bone.
A discrete water exit pathway in the membrane protein cytochrome
c
oxidase
Authors: Schmidt Bryan , McCracken John , Ferguson-Miller Shelagh
Published: December 2003

By using the non-redox-active Mg
2+
/Mn
2+
site of cytochrome
c
oxidase as a probe, water access from the outside of the enzyme and water escape from the buried active site were studied. Water movement was time-resolved by monitoring the magnetic interaction of the oxygen isotope
17
O with the Mn
2+
by using a rapid freeze-quench–electron spin echo envelope modulation technique. Rapid (msec) access of water from the bulk phase to the Mn
2+
was demonstrated by mixing cytochrome
c
oxidase with H
2
17
O. To determine whether a channel involving the Mn
2+
was used for water exit from the active site, samples incubated in
17
O
2
were allowed to turn over approximately five times before freezing. The
17
O, now in the form of H
2
17
O, was detected at the Mn
2+
. The significant broadening of the Mn
2+
signal after the limited number of turnovers strongly suggests that the water exits the protein by means of one discrete pathway, not by random diffusion.
Trophoblast expression of fms-like tyrosine kinase 1 is not required for the establishment of the maternal–fetal interface in the mouse placenta
Authors: Hirashima Masanori , Lu Yong , Byers Lois , Rossant Janet
Published: December 2003

Fms-like tyrosine kinase 1 (Flt1)/vascular endothelial growth factor (VEGF) receptor 1, a receptor for VEGF-A and placental growth factor, is expressed in the spongiotrophoblast layer that segregates the maternal and fetal vasculature in the mouse placenta. A soluble form of Flt1 (sFlt1) produced in the mouse and human placenta can also be detected in the maternal blood. Levels of maternal sFlt1 are elevated in preeclampsia, suggesting that placental sFlt1 plays roles in regulating the maternal vasculature during pregnancy. However, it remains to be determined whether placental Flt1/sFlt1 serves as a regulator of VEGF-A activity in the placenta
per se
. Here, we investigated the placental development in
Flt1
-deficient mice. Flt1 is expressed in a subpopulation of ectoplacental cone cells and later marks the spongiotrophoblast cells, peri/endovascular trophoblast cells, and trophoblast glycogen cells. The labyrinth of

Flt1
lacZ/lacZ

placentae lacked the fetal capillary network because of a defect in allantoic mesoderm invasion. To address whether the absence of
Flt1
in the trophoblast alone affects placental development, we investigated chimeric placentae comprised of

Flt1
lacZ/lacZ

trophoblast and
Flt1
+

/

+
mesoderm, generated by tetraploid aggregation. Fetal growth was supported normally, and no defect in the formation of placental circulation into the maternal spiral artery or invasion of peri/endovascular trophoblast was detected. These findings indicate that trophoblast-derived Flt1/sFlt1 is dispensable for the initial establishment of the maternal–fetal interface in the mouse placenta. Targeting maternal sFlt1 levels for treatment of preeclampsia may thus be possible without affecting the proper formation of the placenta.
Cell surface expression of an endoplasmic reticulum resident heat shock protein gp96 triggers MyD88-dependent systemic autoimmune diseases
Authors: Liu Bei , Dai Jie , Zheng Hong , Stoilova Diliana , Sun Shaoli , Li Zihai
Published: December 2003

Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Without tissue distress or death, these intracellular molecules are inaccessible to surface receptor(s) on DCs, possibly to avoid uncontrolled DC activation and breakdown of immunologic tolerance. We herein addressed this hypothesis in transgenic mice by enforcing cell surface expression of gp96, a ubiquitous heat shock protein of the endoplasmic reticulum. Although a pan-specific promoter is used for transgene expression, neither the expression level nor the tissue distribution of the endogenous gp96 was altered by this maneuver. However, cell surface gp96 induced significant DC activations and spontaneous lupus-like autoimmune diseases, even though the development/functions of lymphocytic compartments were unaltered. Using a bone marrow chimera approach, we further demonstrated that both DC activation and autoimmunity elicited by cell surface gp96 are dependent on the downstream adaptor protein MyD88 for signaling by Toll/IL-1 receptor family. Our study not only established the proinflammatory property of cell surface gp96
in vivo
, but also suggested a chronic stimulation of DCs by gp96 as a pathway to initiate spontaneous autoimmune diseases.
Reversing cerebellar long-term depression
Authors: Lev-Ram Varda , Mehta Samar B. , Kleinfeld David , Tsien Roger Y.
Published: December 2003

The discovery of a postsynaptically expressed form of cerebellar parallel fiber–Purkinje cell long-term potentiation (LTP) raises the question whether this is the long-sought resetting mechanism for long-term depression (LTD). Extracellular monitoring of PC spikes enables stable prolonged recordings of parallel fiber–Purkinje cell synaptic efficacy. LTD, saturated by repeated induction protocols, can be reversed by a single round of postsynaptic LTP or nitric oxide (NO), enabling LTD to be reinduced. Conversely, after postsynaptic LTP has been saturated, one round of LTD permits fresh postsynaptic LTP. By contrast, after saturation of LTD, induction of presynaptic LTP or application of forskolin leaves LTD still saturated. Likewise, presynaptic LTP cannot be reversed by LTD. Therefore postsynaptic LTP mediated by NO without postsynaptic Ca
2+
elevation, unlike presynaptic LTP mediated by cAMP, is a true counterbalance to LTD mediated by coincidence of NO plus postsynaptic Ca
2+
Cation–chloride cotransporters mediate neural computation in the retina
Authors: Gavrikov Konstantin E. , Dmitriev Andrey V. , Keyser Kent T. , Mangel Stuart C.
Published: December 2003

The ability of directionally selective (DS) retinal ganglion cells to respond selectively to stimulus motion in one direction is a classic unresolved example of computation in a local neural circuit. Recent evidence indicates that DS responses occur first in the retina in the dendrites of starburst amacrine cells (interneurons presynaptic to the ganglion cells). We report that the directional responses of starburst-cell dendrites and DS ganglion cells are highly sensitive to the polarity of the transmembrane chloride gradient. Reducing the transmembrane chloride gradient by ion substitution or by blocking the K–Cl cotransporter resulted in the starburst cells responding equally to light moving in opposite directions. Conversely, increasing the chloride gradient by blocking the Na–K–Cl cotransporter eliminated responses to light moving in either direction. Moreover, in each case, blocking the chloride cotransporters or reducing the transmembrane chloride gradient eliminated the directional responses of DS ganglion cells in a manner opposite that of the starburst cells. These results indicate that chloride cotransporters play a key role in the generation of direction selectivity and that the directional responses of starburst cells and DS ganglion cells are exquisitely sensitive to the chloride equilibrium potential. The findings further suggest that the directional responses of DS ganglion cells are mediated in part by the directional release of γ-aminobutyric acid from starburst dendrites and that the asymmetric distribution of the two cotransporters along starburst-cell dendrites mediates direction selectivity. A model of direction selectivity in the retina that incorporates these and other findings is discussed.
Unemployment Trends in Some American Cities with Living Wage Ordinances
Authors: Buss James A. , Franceschi Dina
Published: December 2003

By early 2003, more than 90 American cities and counties have passed laws, called Living Wage Ordinances, which require companies that have contracts with these municipalities and/or receive tax subsidies to pay their workers a wage above the federal minimum rate. The levels of these wages and the types of workers who are affected by these living wage ordinances are reviewed. Also examined are the major arguments for and against these laws. This study looks at the trends in unemployment rates in 40 cities that have enacted Living Wage Ordinances. Each city's unemployment rate is compared to that in its metropolitan area, its state, and the nation. The study reveals that experiences are mixed. Some cities with living wage ordinances have experienced an improvement in their relative employment situation. Other cities have experienced just the opposite.
Trust and Networking in Inter-firm Relations: the Case of Eco-industrial Development
Authors: Gibbs David
Published: December 2003

Despite much rhetoric concerning the implementation of sustainable development within local and regional economic development strategies, very few concrete examples exist of projects that combine economic, social and environmental aims. However, recently, a number of developments have occurred, based around ideas drawn from industrial ecology. These ecoindustrial parks seek to reduce environmental impacts, while at the same time improving business competitiveness and creating jobs. Eco-industrial parks rely upon creating networks of material and by-product flows between participating firms. However, it is frequently assumed that the trust and cooperation between firms that this involves will arise automatically. In this paper it is argued that a much more nuanced approach is needed, drawing upon work in economic geography and regional economics on trust, networking and untraded interdependencies.
Individual Differences in Deductive Reasoning
Authors: Newstead Stephen E. , Handley Simon J. , Harley Clare , Wright Helen , Farrelly Daniel
Published: December 2003

Three studies are reported, which examined individual differences in deductive reasoning as a function of intellectual ability and thinking style. Intellectual ability was a good predictor of logical performance on syllogisms, especially where there was a conflict between logic and believability. However, in the first two experiments there was no link between ability and performance on indicative selection tasks, in sharp contrast to previous research. This correlation did, however, return in the final study. Our data are consistent with the claim that the correlation with logical accuracy on abstract selection tasks is found primarily with participants of relatively high ability. At lower levels, pragmatically cued responses are given but those of slightly higher ability divorce the rule from the scenario and respond consistently (though incorrectly) across problems. Self-report questionnaires were generally poor predictors of performance, but a measure of the ability to generate alternative representations proved an excellent predictor. These results are consistent with a mental models approach to reasoning and also have implications for the debate about human rationality.
Anticipated Action Effects Affect the Selection, Initiation, and Execution of Actions
Authors: Kunde Wilfried , Koch Iring , Hoffmann Joachim
Published: December 2003

This study investigated the impact of contingent action effects on response production. In Experiment 1 responses of varying intensity were initiated faster when contingently followed by auditory effects of corresponding rather than of noncorresponding intensity. This response–effect (R–E) compatibility influence was robust with respect to practice, and it was not due to persisting influences of preceding R–E episodes. These results support the conclusion that R–E compatibility reflects the impact of anticipatory effect representations in response production. Experiment 2 showed that anticipatory effect codes have an impact on early processes of response production (response selection) as well as on processes that immediately precede overt responding (response initiation). Finally, they also influence the way the actions are physically performed (response execution). The results support and specify ideo-motor theories of action control that assume movements to be controlled by anticipations of their sensorial effects.
Iono‐Covalent Character of the Metal–Oxygen Bonds in Oxides: A Comparison of Experimental and Theoretical Data
Authors: Lenglet M.
Published: December 2003

The aim of this paper is to review the actual data on the chemical bond in binary and mixed oxides. The electronegativity (χM)
and the acidity pa
scales are the most significant semi‐empirical concepts for predicting
the trend of bonding character in iono‐covalent oxides. A satisfactory correlation between the data issued from the acidity scale and the calculated ionic charges has been established.

The most recent studies show that the hybrid methods such as the B3LYP method lead to more reliable results for the description of structural, energetic and electronic properties of binary oxides than those from standard methods.
Perceptions v. reality: pupils’ experiences of Learning in history and geography at Key Stage 4
Authors: Biddulph Mary , Adey Ken
Published: December 2003

History and geography have been identified as subject areas in which there has been ‘a notable lack of research’ (Lord and Harland, 2000: 29–30). This article builds on the findings of a questionnaire survey of over 1400 Year 9 pupils conducted in 1999 (Adey and Biddulph, 2001). The aim of this survey was to establish pupils’ experiences of learning history and geography at Key Stage 3 and to gain some insights into what they expected these subjects to be like at Key Stage 4. At the time of conducting the survey the message was clear – that pupils had found both subjects to be interesting and enjoyable at Key Stage 3 but many did not expect this interest and enjoyment to continue into GCSE. The data from the questionnaires pointed to trends in pupils’ perceptions of both subjects. In terms of GCSE, pupils were expecting subjects that required a lot of reading and writing, were quite difficult, where lessons would be varied and contain some (although not many) practical elements, and where they would have some opportunity to express their own opinions. It was clear that prior to GCSE pupils had a very insecure understanding of the relevance of learning in both subjects.
The voice of the cultural restorationists: recent trends in RE policy‐making
Authors: Rose David
Published: December 2003

This article considers the nature of RE curriculum policy‐making from 1988–97. It concentrates on the hegemonic intent of cultural restorationists. Cultural restorationism finds expression when current political action is justified by particular interpretations being placed upon the past. This involves particular use of language and a strong emphasis on tradition, culture and the past. It is also related to economics, policy‐making generally and, for this article, is particularly related to RE curriculum policy‐making. The ‘voice’ of the cultural restorationists is explored and the manner in which they proceeded to impact on RE policy‐making. The context of text production is explored, with its public ridicule and derision, also the marginalization of key figures and groups with skilful manipulation being made of the media. Language itself was adapted and used as a tool to achieve a manipulative and ‘ratchet‐like’ effect on education. Many official documents are used positively to effect their agenda, reflecting hegemonic intent. In religious education policy‐making cultural restorationism is aligned closely to a ‘Christianizing’ agenda. This involves the increased use of centralizing powers and the subsequent redefinition of the role for those involved at a local level in RE. Interview data are used from parliamentarians and those seeking to influence the processes. The article concludes that RE is increasingly subject to central control, despite its unique status vis à vis the National Curriculum.
Curriculum change: a study of the implementation of General National Vocational Qualifications
Authors: Higham Jeremy
Published: December 2003

This article focuses on curriculum change, in particular on course team responses to the introduction of a new curriculum and on the implications of empirical findings for our understanding of curriculum implementation and change. The case discussed is that of the second version of GNVQ. The discussion is based on an analysis of data collected across twenty‐two course teams in ten schools and colleges over a two‐year period as part of an ESRC‐funded project. The model of comprehensive assessment of the second version of the GNVQ is one in which the curriculum reinforcement role of assessment related to the coverage and standards of the qualification but not to the design of courses. Theoretically, significant scope was accorded to course teams to develop and provide courses that responded to local contexts. The article explores how patterns of difference and similarity in course team responses to the introduction of this curriculum might be explained and indicates three broad approaches: implementation, adaptation and assimilation, relating these responses to the existing experience and expertise of members of the various course teams. The article draws on concepts from the field of linguistics to put forward the notions of ‘curricular fields’ and ‘sub‐curricular fields’ and suggests that curriculum implementation needs to take greater account of the sub‐curricular fields of course teams.
Substance use and the prediction of young offender recidivism
Authors: PUTNIŅŠ ALDIS L.
Published: December 2003

The problem considered is whether self‐reported substance use can be used in the estimation of recidivism risk among youths placed in secure care. The Secure Care Psychosocial Screening (SECAPS) and offending records of 447 youths admitted to detention centres in South Australia were examined. The target outcome was any new offending within 6 months of release. Use of a psychoactive substance at the time of committing the most recent offence was not a significant predictor of subsequent offending, nor was acknowledging having a problem with drug or alcohol use. In relation to the recent use of alcohol, marijuana, hallucinogens, sedatives/hypnotics, narcotics, stimulants and inhalants, only the use of alcohol and inhalants appeared to have significant relationships with recidivism. While the relationships were too small to permit using these items on their own to estimate re‐offending risk, recent alcohol and inhalant use could be included as part of a broader recidivism risk assessment.
Health and well‐being outcomes for drug‐dependent offenders on the NSW Drug Court programme
Authors: FREEMAN KAREN
Published: December 2003

Given the centrality of drug treatment to the drug court framework, the proliferation of drug courts in the United States, and their emergence more recently in Australia, it is surprising that such little attention has been given to assessing their therapeutic effect. This evaluation aimed to assess the health and well‐being of drug‐dependent offenders diverted to the New South Wales Drug Court, and monitor changes in their health and well‐being throughout 12 months of programme participation. The study consisted of baseline interviews with 202 offenders accepted into the programme between February 1999 and April 2000, and follow‐up interview at 4, 8 and 12 months with participants who remained on the programme. Health and well‐being was assessed at each follow‐up using the Short Form‐36 Health Survey (SF‐36) the OTI social functioning scale, and self‐reported spending as a proxy for illicit drug use. The health of male Drug Court participants prior to commencing the programme was significantly poorer than Australian population norms. The results provided evidence of significant and sustained improvements in health and well‐being for the 51 participants who competed each follow‐up interview. Furthermore, significant improvements were found for offenders who remained on the programme for at least 4 months but less than 12 months. However, the positive health outcomes are limited by the low programme retention rate. These results indicate that significant health outcomes can be achieved for at least some heavily drug‐dependent, recidivist offenders through the drug court model.
General practitioners' diagnostic skills and referral practices in managing patients with drug and alcohol‐related health problems: implications for medical training and education programmes
Authors: FUCITO USA M. , GOMES BRUNO S. , MURNION BRIDIN , HABER PAUL S.
Published: December 2003

The aim of this study was to determine the current practices of established general practitioners in managing patients with drug and alcohol‐related problems and identify gaps in training. A random sample of general practitioners completed a survey assessing diagnostic skills and referral practices concerning alcohol and illicit drug use in general practices in February 1999, comprising 110 general practitioners registered with the Central Sydney Division of General Practice. The main outcome measures were competent skills and knowledge, willingness to treat. The majority (96%) of GPs provided clinically appropriate responses for at least one drug category, although none received this rating for all six. Most general practitioners reported that they were unwilling to treat heroin and cocaine problems themselves but expressed willingness to refer patients appropriately. More than a quarter of general practitioners were unaware of the safe drinking levels for men and women or the appropriate treatment for patients consuming above such levels. Age, years in practice, type of practice, willingness to obtain drug use histories and post‐graduate training were all significantly associated with general practitioners' willingness to treat and competence in managing drug and alcohol‐related problems. In this study, general practioners reported low levels of skills and referrals for treatment of illicit drug use and suboptimal skills in the management of alcohol problems. The results suggest that a more comprehensive approach to education and training is required to bring about a change in practice behaviour.
Dexamethasone‐induced and estradiol‐induced CREB activation and annexin 1 expression in CCRF‐CEM lymphoblastic cells: evidence for the involvement of cAMP and p38 MAPK
Authors: Castro-caldas M. , Mendes A. F. , Duarte C. B. , Lopes M. C. F.
Published: December 2003

Aims: Annexin 1 (ANXA1), a member of the annexin family of calcium‐binding and phospholipid‐binding proteins, is a key mediator of the anti‐inflammatory actions of steroid hormones. We have previously demonstrated that, in the human lymphoblastic CCRF‐CEM cell line, both the synthetic glucocorticoid hormone, dexamethasone (Dex), and the estrogen hormone, 17β‐estradiol (E2β), induce the synthesis of ANXA1, by a mechanism independent of the activation of their nuclear receptors. Recently, it was reported that the gene coding for ANXA1 contains a cAMP‐responsive element (CRE). In this work, we investigated whether Dex and E2β were able to induce the activation of CRE binding proteins (CREB) in the CCRF‐CEM cells. Moreover, we studied the intracellular signalling pathways involved in CREB activation and ANXA1 synthesis in response to Dex and E2β; namely, the role of cAMP and the p38 mitogen‐activated protein kinase (MAPK).

Results: The results show that Dex and E2β were as effective as the cAMP analogue, dBcAMP, in inducing CREB activation. On the other hand, dBcAMP induced ANXA1 synthesis as effectively as these steroid hormones. Furthermore, the cAMP antagonist, Rp‐8‐Br‐cAMPS, and the specific p38 MAPK inhibitor, SB203580, effectively prevented Dex‐induced, E2β‐induced and dBcAMP‐induced CREB activation and ANXA1 synthesis.

Conclusions: Taken together, our results suggest that, in CCRF‐CEM cells, Dex‐induced and E2β‐induced ANXA1 expression requires the activation of the transcription factor CREB, which in turn seems to be mediated by cAMP and the p38 MAPK. These findings also suggest that, besides the nuclear steroid hormone receptors, other transcription factors, namely CREB, may play important roles in mediating the anti‐inflammatory actions of glucocorticoids and oestrogen hormones.
Levels of serum IL‐1β, IL‐2, IL‐8 and tumor necrosis factor‐α in patients with unstable angina pectoris
Authors: Ozeren Ali , Aydin Mustafa , Tokac Mehmet , Demircan Nejat , Unalacak Murat , Gurel Ahmet , Yazici Mehmet
Published: December 2003

Objectives: Inflammation is the most important mechanism of plaque disruption playing an essential role in acute coronary syndromes. It is controversial whether the inflammatory mediators are the cause or the result in the development of plaque rupture. Stimulation of interleukins increases adhesion molecules, fibrinogen and plasminogen activator inhibitors, which cause the activation of inflammation and thrombosis. However, the importance of interleukins in acute coronary syndromes has not been clearly defined. We did not find any article concerning relations between the levels of serum interleukin (IL)‐1β, IL‐2, IL ‐8 and tumor necrosis factor (TNF)‐α in patients with unstable angina pectoris (UAP). So the aim of this study was to determine the levels of serum IL‐1β, IL‐2, IL‐8 and TNF‐α during the early stage of UAP.

Methods and results: Thirty‐seven patients with UAP (12 females and 25 males; mean age, 57.5±9.7 years) within 6 h of admission and 20 healthy volunteers (eight females and 12 males; mean age, 51.3±6.3 years) were included in the study. IL‐1β, IL‐2, IL‐8 and TNF‐α levels were measured using the enzyme‐linked immunosorbent assay method. Patients with acute or chronic inflammation, renal failure or chronic heart failure were excluded from the study. The age, gender and risk factors of the study and control groups were similar. The levels of IL‐1β, IL‐8 and TNF‐α were significantly increased (p < 0.0001, p < 0.001 and p < 0.016, respectively) in patients with UAP. There was no difference of IL‐2 levels between the UAP group and controls.

Conclusion: We detected high levels of IL‐1β, IL‐8 and TNF‐α in patients with UAP during early phase. We suggest that proinflammatory cytokines (e.g. IL‐1β, IL‐8, TNF‐α) may play an important role in the development of atherosclerosis and its complications.
Basis for the Age‐related Decline in Intestinal Mucosal Immunity
Authors: Schmucker Douglas L. , Owen Robert L. , Outenreath Robert , Thoreux Karine
Published: December 2003

The elderly are characterized by mucosal immunosenescence and high rates of morbidity and mortality associated with infectious diseases of the intestinal tract. Little is known about how the differentiation of immunoglobulin A (IgA) plasma cells in Peyer′s patches (PPs) and their subsequent homing to the small intestinal lamina propria (LP) is affected by aging. Quantitative immunohistochemical analyses demonstrated a 2‐fold increase in the number of IgA+ cells in the PPs, coupled with significant declines in the numbers of IgA+ and antibody‐positive cells in the intestinal LP of senescent rats compared to young adult animals. These data suggest that aging diminishes the emigration of IgA immunoblasts from these lymphoid aggregates, as well as their migration to the intestinal LP. Flow cytometry and lymphocyte adoptive transfer studies showed 3‐ to 4‐fold age‐related declines in the homing of antibody‐containing cells and mesenteric lymph node lymphocytes to the small intestines of rhesus macaques and rats, respectively. The number of peripheral blood IgA immunoblasts expressing the homing molecule α4β7 declined 30% in senescent rats. This was accompanied by a >17% decrease in the areal density of LP blood vessels staining positive for the cell adhesion molecule MAdCAM‐1. Cumulatively, declines in expression of these homing molecules constitute a substantial age‐related diminution of IgA immunoblast homing potential. In vitro antibody secretion by LP plasma cells, i.e. antibody secreted per antibody‐positive cell, remains unchanged as a function of donor age. Intestinal mucosal immunosenescence is a consequence of reduced homing of IgA plasma cells to the intestinal LP as a result of declines in homing molecule expression.
The Effects of Alpha Interferon on the Development of Autoimmune Thyroiditis in the NOD H2h4 Mouse
Authors: Oppenheim Yael , Kim Grace , Ban Yoshiyuki , Unger Pamela , Concepcion Erlinda , Ando Takao , Tomer Yaron
Published: December 2003

Alpha interferon (αIFN) therapy is known to induce thyroid autoimmunity in up to 40% of patients. The mechanism is unknown, but Th1 switching has been hypothesized. The aim of our study was to examine whether αIFN accelerated the development of thyroiditis in genetically susceptible mice. We took advantage of NOD‐H2h4, a genetically susceptible animal model, which develops thyroiditis when fed a high iodine diet. Six to eight week old male NOD H2h4 mice were injected with mouse αIFN (200 units) or with saline three times a week for 8 weeks. All mice drank iodinated water (0.15%). Mice were sacrificed after 8 weeks of injection. Their thyroids were examined for histology and blood was tested for antithyroglobulin antibody levels. T4 and glucose levels were also assessed. In the IFN‐injected group, 6/13 (46.2%) developed thyroiditis and/or thyroid antibodies while in the saline‐injected group, only 4/13 (30.8%) developed thyroiditis and/or thyroid antibodies (p=0.4). The grade of thyroiditis was not different amongst the two groups. None of the mice developed clinical thyroiditis or diabetes mellitus. Our results showed that αIFN treatment did not accelerate thyroiditis in this mouse model. This may imply that αIFN induces thyroiditis in a non‐genetically dependent manner, and this would not be detected in a genetically susceptible mouse model if the effect were small. Alternatively, it is possible that αIFN did not induce thyroiditis in mice because, unlike in humans, in mice αIFN does not induce Th1 switching.
Radiation‐Induced Leiomyosarcoma: Does Antimetabolite ChemotherapyContribute? A Report of Three Cases
Authors: Brockstein Bruce , Mundt Arno , Haraf Daniel J. , Ferguson Mark , Montag Anthony
Published: December 2003

Purpose: Radiation therapy in low and high doses is known to be associated with the occurrence of late secondary sarcomas.
The addition of chemotherapy has not been clearly demonstrated as a contributing factor. We describe three patients with
radiation‐associated leiomyosarcoma who had also received antimetabolite chemotherapy.

Methods: Three cases of leiomyosarcoma occurring 9–27 years after radiation and antimetabolite chemotherapy are
presented, along with histopathological details. A Medline search was used to assess prior reports of leiomyosarcoma after
radiation.

Results: These three cases appear to be the first reported in which leiomyosarcoma followed therapy with radiation and
antimetabolites.

Discussion: With the increasing use of antimetabolite therapy combined with radiation, there is the potential for more
occurrences of leiomyosarcoma or other post‐treatment sarcomas.
Are the ``myths'' of low back pain alive in the general Norwegian population?
Authors: Ihlebæk Camilla , Eriksen Hege R.
Published: December 2003

Aim: The aim of this study was to examine the perception of low back pain care and consequences according to what Deyo refers to as seven ``myths'' about back pain, in the Norwegian population. Methods: In spring 2001, seven questions, corresponding to Deyo's myths, were included in an opinion poll (telephone interviews) of a representative sample (n=1015) of the Norwegian population. Results: In total, 41% of the population held that `If you have a slipped disc you must have surgery'. Approximately 50% believed that `X-ray and newer imaging tests can always identify the cause of pain' and `Most back pain is caused by injury and heavy lifting'. Almost 60% agreed that `Everyone with back pain should have a spine X-ray'. However, only one-quarter believed that `If your back hurts, you should take it easy until the pain goes away', and approximately one-fifth believed that `Back pain is usually disabling'. Only 12% believed that `Bed rest is the mainstay of therapy'. More individuals in the lower- compared with the higher-educated groups believed in the myths. Conclusion: Information concerning current knowledge on healthcare and health consequences of low back pain had reached only a small part of the general population. The most important factor for lack of knowledge was education. Developing effective methods to promote adequate self-care and treatment and reduce the risk of chronicity of low back pain in the lower-educated groups should be a top priority.
Review Article: Establishing a set of mental health indicators for Europe
Authors: Korkeila Jyrki , Lehtinen Ville , Bijl Rob , Dalgard Odd-Steffer , Kovess Viviane , Morgan Antony , Salize Hans Joachim
Published: December 2003

Aims: This review presents the background work for developing a set of mental health indicators as part of a comprehensive health monitoring system in the European Union. The review focuses on the appraisal of mental health at population level with special emphasis on assessments that could be useful for mental health promotion. Methods: A functional model of mental health is used to delineate variables important for a set of mental health indicators. Variables that are not possible to monitor at population level are not discussed here. Literature searches were conducted through the MEDLINE, PSYCHLIT, and SOCIOLOGICAL ABSTRACTS databases and available textbooks. Results: The review presents findings from research seeking associations between mental health and ill health and different individual, social, economic, ecological, and service-related characteristics. Specific domains as key starting points in establishing a set of mental health indicators are outlined according to the research findings. Conclusion: A set of mental health indicators can enhance the visibility of mental health issues in the European context. Ultimately the indicators could be used in estimating how the targets set for health policies are met, and whether there has been a measurable decrease in disability, suffering, and disease.