bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of dynamics of intracellular calcium in aluminium‐toxicity syndrome
Authors: Rengel Z. , Zhang W.‐H.
Published: July 2003

This review is concentrating on the role of aluminium (Al)‐calcium (Ca) interactions in Al toxicity syndrome in plants. Disruption of cytoplasmic Ca2+ homeostasis has been suggested as a primary trigger of Al toxicity. Aluminium causes an increase in cytosolic Ca2+ activity, potentially disrupting numerous biochemical and physiological processes, including those involved in the root growth. The source of Ca2+ for the increase in cytosolic Ca2+ activity under Al exposure is partly extracellular (likely to be due to the Al‐resistant portion of the flux through depolarization‐activated Ca2+ channels and fluxes through Ca2+‐permeable nonselective cation channels in the plasma membrane) as well as intracellular (increased cytosolic Ca2+ activity enhances the activity of Ca2+ release channels in the tonoplast and the endoplasmic reticulum membrane). The effect on increased cytosolic Ca2+ activity of possible Al‐related inhibition of the plasma membrane and endo‐membrane Ca2+‐ATPases and Ca2+ exchangers (CaX) that sequester Ca2+ out of the cytosol is insufficiently documented at present. The relationship between Al toxicity, cytoplasmic Ca2+ homeostasis and cytoplasmic pH needs to be elucidated. Technical improvements that would allow measurements of cytosolic Ca2+ activity within the short time after exposure to Al (seconds or shorter) are eagerly awaited.

Contents

I.
Introduction
296

II.
Symptoms of aluminium toxicity
296

III.
Calcium – aluminium interactions
297

IV.
The role of electrical properties of the plasma membrane in calcium–aluminium interactions
306

V.
Oxidative stress
307

VI.
Callose
308

VII.
Cytoskeleton
308

VIII.
Conclusions
309

Acknowledgements
309

References
309
How do some plants tolerate low levels of soil zinc? Mechanisms of zinc efficiency in crop plants
Authors: Hacisalihoglu Gökhan , Kochian Leon V.
Published: July 2003

Researchers are beginning to understand how some plant genotypes can maintain reasonable growth and yields under low soil Zn, a trait termed zinc efficiency (ZE). Several studies have shown no correlation between ZE and root Zn uptake, Zn translocation to shoot, or shoot Zn accumulation. Furthermore, it has not been possible to conclusively link differences in leaf subcellular Zn compartmentation with ZE. However, biochemical Zn utilization, including the ability to maintain the activity of Zn requiring enzymes in response to Zn deficiency may be a key component of ZE. The next logical step in investigations of this trait is research on the genetic and molecular basis for ZE, in order to better understand the relationship between Zn utilization and ZE, and to identify the gene(s) controlling ZE. Progress in this research area could provide the knowledge to facilitate the engineering of Zn‐efficient plant varieties, which could help both crop production on marginal soils as well as possibly improve the micronutrient density of food crops to help address significant human nutrition problems related to micronutrient deficiency.
Ginkgo biloba extracts and cancer: a research area in its infancy
Authors: DeFeudis Francis V. , Papadopoulos Vassilios , Drieu Katy
Published: July 2003

Recent studies conducted with various molecular, cellular and whole animal models have revealed that leaf extracts of Ginkgo biloba may have anticancer (chemopreventive) properties that are related to their antioxidant, anti‐angiogenic and gene‐regulatory actions. The antioxidant and associated anti‐lipoperoxidative effects of Ginkgo extracts appear to involve both their flavonoid and terpenoid constituents. The anti‐angiogenic activity of the extracts may involve their antioxidant activity and their ability to inhibit both inducible and endothelial forms of nitric oxide synthase. With regard to gene expression, a Ginkgo extract and one of its terpenoid constituents, ginkgolide B, inhibited the proliferation of a highly aggressive human breast cancer cell line and xenografts of this cell line in nude mice. cDNA microarray analyses have shown that exposure of human breast cancer cells to a Ginkgo extract altered the expression of genes that are involved in the regulation of cell proliferation, cell differentiation or apoptosis, and that exposure of human bladder cancer cells to a Ginkgo extract produced an adaptive transcriptional response that augments antioxidant status and inhibits DNA damage. In humans, Ginkgo extracts inhibit the formation of radiation‐induced (chromosome‐damaging) clastogenic factors and ultraviolet light‐induced oxidative stress – effects that may also be associated with anticancer activity. Flavonoid and terpenoid constituents of Ginkgo extracts may act in a complementary manner to inhibit several carcinogenesis‐related processes, and therefore the total extracts may be required for producing optimal effects.
Monoamine metabolism changes following the mouse forced swimming test but not the tail suspension test
Authors: Renard Caroline E. , Dailly Eric , David Denis J.P. , Hascoet Martine , Bourin Michel
Published: July 2003

Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. It has been suggested that stress may provoke a modification in dopamine (DA) release in different brain areas and that the forced swimming test (FST), in its own accord as a stressor, may be responsible for this modification. Naive male Swiss mice, receiving saline solution, were used in two animal models of depression, the FST and the tail suspension test (TST). In order to understand the locomotor aspect of each test, groups of mice were studied for effects on locomotor activity. Following each test, mice were killed by cervical dislocation, brains were removed and concentrations of amines in the whole brain were analysed by high‐performance liquid chromatography. DA concentration increased from 5 min of the FST, dihydroxyphénylacetate (DOPAC), from 20 min of FST and serotonin, from 8 min of FST. No modification of noradrenaline was observed during the FST and no modification of the neurotransmitter concentrations was observed during the TST. Following an FST of 2‐min duration, a hypolocomotor effect was observed in the subsequent actimeter test. The same effect was observed after a TST of 8 min and onwards. This study confirms the fact that although these two tests are used to study depression, they involve different neuronal mechanisms.
How should therapeutic information be transferred to users?
Authors: Boissel Jean‐Pierre , Haugh Margaret , Fardeheb Malik , Nony Patrice , Gueyffier François , Strang Nigel
Published: July 2003

Without an efficient solution to the problems that prevent prescribers and consumers having easy access to published and unpublished evidence, Evidence‐Based Medicine will never become a reality. Among the problems, dissemination of the summarized evidence is a major one. It involves representing the summarized evidence in a format that corresponds to the users’ needs and knowledge, interpreting it within the context of other related evidence, putting it in perspective, and then delivering it physically to the users at the appropriate time. The current formats, vehicles and representation models, e.g. those for guidelines or textbooks, do not seem efficient enough to fill in the gap of knowledge. We suggest that a new approach is possible by reducing the transferred information to its core and integrating it through appropriate representation models into the doctor's decision‐making process.
The pros and cons of noninferiority trials
Authors: Pocock Stuart J.
Published: July 2003

Noninferiority trials comparing new treatment with an active standard control are becoming increasingly common. This article discusses relevant issues regarding their need, design, analysis and interpretation: the appropriate choice of control group, types of noninferiority trial, ethical considerations, sample size determination and potential pitfalls to consider.
MDR1 polymorphisms G2677T in exon 21 and C3435T in exon 26 fail to affect rhodamine 123 efflux in peripheral blood lymphocytes
Authors: Oselin Kersti , Gerloff Thomas , Mrozikiewicz Przemyslaw M. , Pähkla Rein , Roots Ivar
Published: July 2003

P‐glycoprotein (Pgp) is a member of the ABC‐transporter family, and in humans, is encoded by the MDR1 gene. Recently, several single‐nucleotide polymorphisms in the MDR1 gene were identified. The aim of the present study was to evaluate the effect of the MDR1 genetic polymorphisms G2677T and C3435T on Pgp activity in CD56+ and CD4+ peripheral blood cells. Using flow cytometry, rhodamine 123 (Rh123) efflux was determined in 46 male healthy volunteers. Median Rh123 fluorescence in control sample, after baseline dye uptake, was set as 100%. Rh123 fluorescence in efflux samples, exposed to different efflux periods, was used to calculate the percentage of Rh123 retained in the cells in comparison with control. There was no significant difference in Rh123 efflux in CD56+ cells after 5, 10, 15, and 30 min efflux between individuals with different MDR1 genotypes. Also, in CD4+ cells after 15, 30, 60, and 90 min, Rh123 efflux did not reveal statistically different results for the three genotypes at 2677 and 3435. Rh123 efflux was not enhanced by a 10‐day rifampin administration, as determined in 15 individuals before and after rifampin treatment. In conclusion, we found no impact of the MDR1 G2677T and C3435T polymorphisms on Pgp activity in CD56+ and CD4+ peripheral blood lymphocytes.
Lipid‐lowering drugs and serum liver enzymes: the effects of body weight and baseline enzyme levels
Authors: Kiortsis Dimitrios N. , Nikas Spyridon , Hatzidimou Katerina , Tsianos Epaminondas , Elisaf Moses S.
Published: July 2003

The most important side effects of fibrate and 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor (statin) treatment are hepatic toxicity and myopathy. Obese individuals may have higher levels of serum transaminases than their lean counterparts. The main purpose of this study was to examine the effects of statins and fibrates on liver enzymes in obese patients and to compare them with their effects on patients with various body mass indexes (BMI). Two hundred and sixty‐three hyperlipidemic patients of both sexes aged 31–74 years were studied for 24 weeks. One hundred and three patients received fluvastatin (40 mg/day), 62 atorvastatin (10–20 mg/day), 45 micronized fenofibrate (200 mg/day), 44 ciprofibrate (100 mg/day) and nine patients received gemfibrozil (900 mg/day). Laboratory determinations were performed at baseline, after 8 weeks of treatment and at the end of the follow‐up period. At baseline, obese patients tended to exhibit elevated liver enzymes more frequently than their lean counterparts (12 of 105 vs. 5 of 67). At the end of the study period, 11 obese, seven overweight and six lean subjects exhibited elevated liver enzymes. Twelve patients who experienced a moderate elevation of serum liver enzymes at baseline had their liver enzyme profile normalized at the end of the study. Furthermore, in 12 patients who had normal serum liver enzyme levels at baseline, abnormal levels of at least one enzyme were observed after 24 weeks of treatment. Fibrates and statins are safe drugs for the treatment of hyperlipidemia in obese patients as well as in those with moderately increased liver enzymes.
Effects of glucose–insulin–potassium on baroreflex sensitivity, left ventricular function and ventricular arrhythmia in the subacute phase of myocardial infarction in rats
Authors: Liu Jian‐Guo , Shu He , Shen Fu‐Ming , Miao Chao‐Yu , Su Ding‐Feng
Published: July 2003

Glucose–insulin–potassium (GIK) is clinically used for reducing mortality in acute myocardial infarction (MI). It is known that ventricular arrhythmia, left ventricular dysfunction and impaired baroreflex sensitivity (BRS) are the three major determinants for predicting the mortality after acute MI. The present work was designed to study the effects of GIK on BRS, ventricular arrhythmia, and left ventricular function in rats with coronary artery ligature. Sprague–Dawley rats were used and the myocardial infarction was produced by ligature of the left anterior descending artery. Five weeks after coronary artery ligation, BRS was measured in conscious state with a computerized blood pressure monitoring system and left ventricular function and electrocardiogram were determined in the anaesthetized state in the subacute phase of myocardial infarction. It was found that GIK did not affect the blood pressure and heart period in both conscious and anaesthetized rats. GIK did not enhance BRS, but reduced ventricular arrhythmia and improved left ventricular function by reducing left ventricular end diastolic pressure in anaesthetized rats with MI. It is proposed that reducing ventricular arrhythmia and improving left ventricular function contribute to the effect of GIK on reducing the mortality after MI.
Molecular characterization of the high‐affinity [3H]neuropeptide Y‐binding component from the venom of Conus anemone
Authors: Le Minh Tam , Vanderheyden Patrick M. L. , Fierens Frederik L. P. , Vauquelin George
Published: July 2003

The venom of the marine snail Conus anemone contains the ‘ANPY toxin’ which binds neuropeptide Y (NPY) and related insect peptides with nanomolar affinity. This toxin has initially been proposed to be a major 18.5 kDa component of the venom. Here we demonstrate that the 18.5 kDa proteins of venom produce at least five different bands in native electrophoresis and that none of them binds [3H]NPY. Instead, the ANPY toxin migrates as a distinct band on native electrophoresis and is only present as a minor component in the venom. Its approximate molecular weight is 17.5 kDa and its [3H]NPY binding activity is extremely stable below 37 °C, even in the absence of protease inhibitors.
Extracting numerical data from published reports of pharmacokinetics investigations: method description and validation
Authors: de Oliveira Irismar Reis , Santos‐Jesus Rogério , Po Alain Li Wan , Poolsup Nalinee
Published: July 2003

A method has been proposed for extracting numerical data when only graphical results are presented. Reports with both graphical and tabular data were identified and the graphs were electronically scanned. The coordinates of each point were read using the cross‐hair facility of Adobe Photoshop 7.0. To improve the precision of these coordinates, each point was read at 1600% magnification. The agreement between the observers was almost perfect (R > 0.99). The proposed method makes possible use of data in meta‐analyses that, would otherwise be discarded.
Filling the gaps: identifying nursing research priorities through the analysis of completed systematic reviews
Authors: Averis Andrea , Pearson Alan
Published: July 2003

Executive summary

Background  This report describes the results of a study designed to identify research priorities in nursing arising out of the analysis of 22 systematic review reports published by the Joanna Briggs Institute (JBI) from 1998 to 2002. A feature of the systematic review of evidence is the noticeable lack of high‐quality evidence to support a large proportion of nursing interventions and activities. Systematic review topics are selected as areas of concern about practice by nurses comprising the individual and corporate membership of JBI at Professional Advisory Forums and meetings held annually throughout Australia and internationally in conjunction with JBI's collaborating centres. Such selection prioritises nurses’ views about what ‘matters in their daily practice’.

Objective and Methods  The study comprised a content analysis of the 22 systematic review reports and set out to:

• identify any striking gaps in evidence for frequently used practices;

• generate research questions to address the gaps; and

• suggest research approaches appropriate to the research questions generated.

Results  The results of the analysis identified in excess of 200 important gaps in the evidence base available for nursing practice in relation to the 22 discrete areas of practice examined. Recommendations included the wide dissemination of this report to promote the results of systematic reviews as an important resource in setting research priorities. Policy makers, the Commonwealth Government, State and Territory Governments, research funding bodies, organisations and individuals involved in decision‐making and the funding of research in health care have received little substantive direction in setting priorities for nursing research. This lack of well founded advice is evidenced by the incredibly low level of support for nursing research in Australia and the large number of gaps in evidence for nursing practice.

Conclusions  Knowledge transfer – of evidence into practice – has the potential to improve health outcomes, but the delivery of ‘best practice’ care based on sound evidence is dependant upon the generation of evidence to fill systematically identified gaps.
Molecular cloning and sequence analysis of an ascidian egg β‐N‐acetylhexosaminidase with a potential role in fertilization
Authors: Koyanagi Ryo , Honegger Thomas G.
Published: July 2003

β‐N‐Acetylhexosaminidase, which is found almost ubiquitously in sperm of invertebrates and vertebrates, supposedly mediates a carbohydrate‐based transient sperm–egg coat binding. In ascidians and mammals, β‐hexosaminidase released at fertilization from eggs has been proposed to modify sperm receptor glycoproteins of the egg envelope, thus setting up a block to polyspermy. Previously, it was shown that in potential sperm receptor glycoproteins of the ascidian Phallusia mammillata, N‐acetylglucosamine is the prevailing glycoside residue and that the egg harbors three active molecular forms of β‐hexosaminidase. In the present study, P. mammillataβ‐hexosaminidase cDNA was isolated from an ovarian cDNA library and characterized. The deduced amino acid sequence showed a high similarity with other known β‐hexosaminidases; however, P. mammillataβ‐hexosaminidase had a unique potential N‐glycosylation site. A phylogenetic analysis suggested that P. mammillataβ‐hexosaminidase developed independently after having branched off from the common ancestor gene of the chordate enzyme before two isoforms of the mammalian enzyme appeared. In situ hybridization revealed stage‐specific expression of β‐hexosaminidase mRNA during oogenesis in the oocyte and in the accessory test and follicle cells. This suggests that the three egg β‐hexosaminidase forms are specific for the oocyte, test cells and follicle cells.
Morphological asymmetry in dividing retinal progenitor cells
Authors: Saito Kanako , Kawaguchi Ayano , Kashiwagi Saori , Yasugi Sadao , Ogawa Masaharu , Miyata Takaki
Published: July 2003

For the understanding of histogenetic events in the 3‐D retinal neuroepithelium, direct observation of the progenitor cells and their morphological changes is required. A slice culture method has been developed by which the behavior of single progenitor cells can be monitored. Although it has been believed that each retinal progenitor cell loses its basal process while it is in M phase, it is reported here that the process is retained throughout M phase and is inherited by one daughter cell, which can be a neuron or a progenitor cell. Daughter neurons used an inherited process for neuronal translocation and positioning. In divisions that produced two mitotic daughters, both of which subsequently divided to form four granddaughter cells, only one daughter cell inherited the original basal process while the other extended a new process. Interestingly, behavioral differences were often noted between such mitotic sisters in the trajectory of interkinetic nuclear movement, cell cycle length, and the composition of the granddaughter pair. Therefore, ‘symmetric’ (progenitor → progenitor + progenitor) divisions are in fact morphologically asymmetric, and the behavior of the mitotic daughters can often be asymmetric, indicating the necessity for studying possible associations between the process inheritance and the cell fate choice.
Deltex/Dtx mediates NOTCH signaling in regulation of Bmp4 expression in cranial neural crest formation during avian development
Authors: Endo Yukinori , Osumi Noriko , Wakamatsu Yoshio
Published: July 2003

NOTCH signaling plays a key role in cell fate determination in both vertebrates and invertebrates. It is well known that Su(H)/RBP‐J is a major mediator of NOTCH signaling. In a previous study, it was shown that NOTCH signaling was involved in cranial neural crest formation in avian embryos. However, Su(H)/RBP‐J activity did not appear to be required in this process. In this study, the Deltex/Dtx gene was focussed on as a potential mediator of NOTCH signaling in neural crest formation. At the time of neural crest formation, quail Deltex2 was expressed throughout the ectoderm. Misexpression of a dominant‐negative form of Deltex in the ectoderm caused reduced expression of Slug, a neural crest marker. Dominant‐negative Deltex expression reduced the expression of Bmp4, a neural crest inducer, whereas co‐transfection of Bmp4 with dominant‐negative Deltex rescued Slug expression. In parallel, Hairy2 expression in the epidermis was regulated by a Su(H)‐dependent pathway. These results indicate that NOTCH signaling has dual functions mediated by either Su(H) or Deltex in the avian embryonic ectoderm.
Microarray analysis of embryonic retinoic acid target genes in the ascidian Ciona intestinalis
Authors: Ishibashi Tomoko , Nakazawa Masumi , Ono Hiroaki , Satoh Nori , Gojobori Takashi , Fujiwara Shigeki
Published: July 2003

Many chordate‐ and vertebrate‐specific characteristics develop depending on retinoic acid (RA). Because the gene encoding the RA receptor exists only in chordates, RA function seems to be involved in chordate evolution. A cDNA microarray analysis of 9287 non‐redundant cDNA clones was used to screen for RA target genes in the ascidian Ciona intestinalis. In addition, the spatial expression pattern of 94 candidate RA target genes was examined by in situ hybridization in RA‐treated and control embryos. Strong RA‐induced upregulation of Hox‐1 and Cyp26 was observed, as is the case in vertebrates. In addition, a number of novel candidate target genes was identified. These included transcription factors and signaling molecules, suggesting that various differentiation and/or morphogenetic pathways are modulated by RA. The expression of cell adhesion molecules, cytoskeletal proteins and extracellular matrix components was affected by RA. Changes in the expression pattern of these genes may be a direct cause of abnormal morphogenesis of the anterior neural tissues. RA also affected the expression of genes that seemed to be involved in neuronal functions. Although obvious homeotic transformation has not been observed, the function of various neural cell types seemed to be impaired by RA. The microarray data are reliable and will contribute to comprehensive understanding of RA action in the development and evolution of chordates.
Signaling pathway from [Ca2+]i transients to ooplasmic segregation involves small GTPase rho in the ascidian egg
Authors: Yoshida Manabu , Horiuchi Yuji , Sensui Noburu , Morisawa Masaaki
Published: July 2003

Intracellular Ca2+ transients occur at fertilization in the eggs of all animal species and are thought to be critical for the initiation of several events in egg activation. The rho family of small GTPases are known to organize and maintain the actin filament‐dependent cytoskeleton, and rho is involved in the control mechanism of cytokinesis. In the ascidian Ciona savignyi, the first step of ooplasmic segregation observed just after fertilization is cortical contraction with egg deformation, mediated by the cortical actin filaments. C3 exoenzyme, a rho‐specific inhibitor, did not affect the pattern of [Ca2+]i transients in the ascidian egg, but inhibited ooplasmic segregation and cytokinesis at the first cleavage. Injection of inositol 1,4,5‐trisphosphate or treatment of Ca2+ ionophore induced deformation of the egg and extrusion of the first polar body, but these phenomena did not occur in the C3 exoenzyme‐injected egg. These results suggest that rho proteins are involved in egg deformation, ooplasmic segregation and cytokinesis downstream of the [Ca2+]i transients.
Mr 25 000 protein, a substrate for protein serine/threonine kinases, is identified as a part of Xenopus laevis vitellogenin B1
Authors: Yoshitome Satoshi , Nakamura Hiroyasu , Nakajo Nobushige , Okamoto Kengo , Sugimoto Isamu , Kohara Hiromi , Kitayama Kaori , Igarashi Kazuaki , Ito Susumu , Sagata Noriyuki , Hashimoto Eikichi
Published: July 2003

A phosphorylated protein with a molecular mass of 25 000 (pp25) previously purified from the cytosolic fraction of Xenopus laevis oocytes is an effective phosphate acceptor for casein kinases and protein kinase C. In this study, based on the partial amino acid sequence of pp25, a cDNA was isolated that encodes a new yolk precursor protein, Xenopus vitellogenin B1, which contained the sequence encoding pp25. Both mRNA and protein of vitellogenin B1 were expressed in all of the female organs examined. In agreement with a previous report, the amount of vitellogenin B1 protein in the liver increased after stimulation with estrogen. These results suggest that pp25 is a cytosolic non‐crystallized yolk protein nutrient source, but it might also play a role in rapid development.
Changes in causes of death and mortality rates among children in Greenland from 1987 - 91 to 1992 - 99
Authors: Aaen-Larsen Birger , Bjerregaard Peter
Published: July 2003

Aims: This study analysed the spontaneous trends in mortality among children in Greenland from 1987 - 91 to 1992 - 99 and describes the changes in the causes of death, mortality rates, and variation between regions. Methods: The data are based on the Greenland Registry of Causes of Death and the birth registry of the Medical Office of Health in Greenland. The causes of death and relevant mortality rates, the trends over time and the differences between regions were analysed epidemiologically for 1992 - 99 and compared with those for 1987 - 91. Results: From 1992 to 1999, 8,709 children were born in Greenland. The data include information on 313 child deaths during this period: 64 stillbirths, 158 deaths before one year of age (infants) and 91 deaths between one and 14 years of age. There were fewer stillbirths due to placenta previa, abruptio placentae, and prematurity, fewer infants died from birth asphyxia and infectious diseases and fewer children aged 1 - 14 years died from accidents in 1992 - 99 compared with 1987 - 91. Infant mortality in Greenland declined from 25.2 per 1,000 live births to 18.3 and mortality among children 1 - 14 years old from 122.7 per 100,000 person-years to 80.4 between 1987 - 91 and 1992 - 99. Mortality dropped proportionally more in East Greenland. Conclusion: The decline in child mortality in all age groups probably resulted from general societal trends and general improvement in the healthcare system. Child mortality is still unacceptably high, and it is recommended that sectors other than healthcare become aware of their responsibility for preventing the high rate of child mortality.
The Finnmark Intervention Study: is it possible to change CVD risk factors by community-based intervention in an Arctic village in crisis?
Authors: Lupton Beate Søholt , Fønnebø Vinjar , Søgaard Anne Johanne
Published: July 2003

Aims: Owing to high cardiovascular mortality, the Norwegian Government introduced the programme ``Health and Inequalities in Finnmark'' in 1988. One of the projects in this programme was aimed at changing cardiovascular risk factors through community-based intervention in a fishing community in the Norwegian Arctic. Methods: The intervention community Båtsfjord and the three control communities were selected from the same coastal area. The intervention was based on a quasi-experimental design, and evaluated by population surveys before (1987) and after (1993) the invention. The attending cohort was analysed. The intervention method was based on empowerment and cooperation between different organizations, and the primary healthcare system. Results: From 1987-93, the male cohort in Båtsfjord had a more favourable development when compared with changes in the control communities regarding the 8.6% increase in physical activity (p=0.047), the reduction in systolic blood pressure by 0.01 mmHg (p=0.002), and the reduction in diastolic blood pressure by 2.1 mmHg (p<0.001). The female cohort in Båtsfjord had a more favourable development when compared with changes in the control communities regarding the 11.2% increase in use of low-fat milk (p=0.046), the increase in systolic blood pressure by 2.1 mmHg (p=0.024), and the reduction in diastolic blood pressure by 2.1 mmHg (p<0.001). Conclusion: Despite a difficult economic situation for the Arctic coastal communities, the study found it possible for voluntary organizations, local public administration, and local health personnel to promote change in lifestyle and blood pressure using a community intervention approach.
To seek or not to seek? Care-seeking behaviour among people with low-back pain
Authors: Mortimer Monica ,   the MUSIC-Norrtälje study group, Ahlberg Gunnel
Published: July 2003

Aim: The present study sought to identify potential differences between subjects who seek care for their low-back pain problems and those who do not with respect to pain intensity, grade of disability, physical or psychosocial working conditions, individual physical and physiological factors, and lifestyle factors. Material and methods: The study population was obtained from a population-based, case-referent study, the MUSIC-Norrtälje study. All persons with low-back pain among cases as well as ``referents'' were compared according to care-seeking behaviour. In all 727 cases with low-back pain who had sought care by any of 75 caregivers in the region, including all physicians and physiotherapists as well as chiropractors, osteopaths, and homeopaths, 721 referents with low-back pain who did not seek care participated. All participants underwent a clinical examination, and filled in a questionnaire about personal and occupational data, pain and disability, pain history, psychosomatic complaints, and present psychosocial situation. Results: High disability and high pain intensity were strongly related to care seeking among men and women with low-back pain. The odds ratios for high disability were 7.4 (CI 5.0 - 11.0) for women and 4.9 (CI 3.3 - 7.1) for men respectively. The odds ratios for high pain intensity were 3.7 (CI 2.2 - 6.0) for women and 1.7 (CI 1.1 - 2.8) for men. A more strained economic situation and use of passive coping strategies significantly increased the probability of women not seeking care. Neither previous pain history, high physical workload, nor jobstrain, poor job satisfaction, or life style factors (high body weight, smoking, and exercise) or psychosomatic complaints affected care-seeking behaviour. Conclusions: The most decisive factors for seeking care were disability and pain. However, numerous individuals with low disability and low pain intensity also seek care for their pain problems. Better information and advice on the common course of low-back pain may make those individuals less frightened of their pain and, as a result, reduce the consumption of care and social costs for society. The majority of people seek care for pain without wanting a medical prescription. The fact that economic factors seemed to be of importance indicates that costs for healthcare must be kept low if the goal is to give healthcare on equal terms for all.
Frequency and perceived credibility of reported sources of reproductive health information among primary school adolescents in Arusha, Tanzania
Authors: Masatu Melkiory C. , KvÅle Gunnar , Klepp Knut-Inge
Published: July 2003

Aims: To describe adolescents' sources of reproductive health information and perceived credibility of these sources. Methods: A questionnaire survey was conducted among 1247 seventh grade pupils in Arusha district; enquiring their sources of reproductive health information and perceived credibility of these sources. Mean scores were computed for each type of information in relation to frequency of source and credibility, and scales for reproductive health information sources and credibility constructed. Analysis of covariance was used to compare mean scores by demographic and sexual behaviour variables. Results: Mass media ranked first as sources of reproductive health information, followed by teachers and health workers. Health workers ranked first in credibility followed by parents, while credibility rating for media was low. Religious leaders and respondents' friends played a rather minor role as sources of reproductive health information, and their credibility ratings were also low. Conclusion: Mass media were the most frequent sources of reproductive health information for primary school adolescents, but parents and health workers were regarded as more credible sources. Programmes seeking to promote reproductive health of young people should take into account the diverse arenas through which young people currently obtain reproductive health information, and strive to tap into and strengthen the full range of these arenas. Increased involvement of parents and health workers in providing reproductive health information to young people seem indispensable.
The role of benzodiazepines in elderly suicides
Authors: Carlsten Anders , Waern Margda , Holmgren Per , Allebeck Peter
Published: July 2003

Aims: In Sweden, suicides by drug poisoning have decreased in the population at large during the past two decades. However, drug poisoning suicides increased among the elderly during this period. Suicides by benzodiazepine poisoning increased in this age group despite a reduction in prescription sales of these drugs. This study aims therefore to determine the role of benzodiazepines in suicide late in life. Methods: Information concerning all definite suicides and deaths due to ``undetermined'' causes recorded among Swedish citizens aged 65 and above during 1992 - 96 was obtained from the Cause-of-Death Register. Death certificates were scrutinized to determine the type of drug employed in drug-related suicides. Results of the post mortem screening for drugs and alcohol were then examined. Results: A benzodiazepine was implicated in 216/548 (39%) of the drug poisoning suicides recorded among the elderly. Death certificates revealed that a benzodiazepine was the sole agent in 72% of these cases. Flunitrazepam or nitrazepam were implicated in 90% of the single benzodiazepine suicides. In addition to the suicides classified as drug poisonings, 82 cases were found in which a drug may have contributed to the cause of death. Benzodiazepines predominated. The terminal cause of death was drowning, often in the victim's own bathtub, in three-quarters of these cases. The annual fatality ratios for the newer benzodiazepine-like hypnotics zopiclone and zolpidem appear to be on the rise. Conclusion: Benzodiazepines, especially the hypnotics flunitrazepam and nitrazepam, are common in drug poisoning suicides in the elderly and should be prescribed with caution for this age group.
Sunbed use among Swedish adolescents in the 1990s: a decline with an unchanged relationship to health risk behaviors
Authors: Boldeman Cecilia , Jansson Bjarne , Dal Henrik , Ullén Henrik
Published: July 2003

Aims: Sunbed use is common among adolescents, and may give an increment to UV exposure and an overall skin cancer risk comparable to that of the sun. Sunbed use was studied among 15- to 19-year-old adolescents in Stockholm County. Methods: Data from two questionnaire surveys (1,252 respondents in 1993, and 2,950 respondents in 1999, survey tool partly revised) were analysed. By stepwise binary logistic regression the occurrence of sunbed use was assessed and analysed versus sunbed erythema, skin type, outdoor tanning, sunscreen use and smoking. Results: Sunbed use declined between the surveys. In 1993, 70% of females, and 44% of males used sunbeds; in 1999, these were 45% and 19% respectively. Sunbeds were used against user recommendations. Of the sunbed users in 1993, 45% and 43% reported sunbed erythema; in 1999, 29% and 19% did so. Sunbed erythema, though related to sun sensitivity, occurred in all skin types. In both surveys, sunbed use was positively related to moderately sensitive skin type (females), outdoor tanning, and smoking (females). Smoking was a strong predictor for sunbed use among females in both surveys. Conclusions: Even though different survey tools were used, and in spite of a decline in sunbed use, sunbed erythema was still common, and the relation to other health risk behaviour remained. Further research on sunbed use and its role in the aggregation of health risk behaviours in vulnerable ages is warranted, particularly its relation to outdoor tanning and smoking. A national and international harmonization of survey tools is also recommended for improved comparability.
ARF6 stimulates clathrin/AP-2 recruitment to synaptic membranes by activating phosphatidylinositol phosphate kinase type Iγ
Authors: Krauss Michael , Kinuta Masahiro , Wenk Markus R. , De Camilli Pietro , Takei Kohji , Haucke Volker
Published: July 2003

Clathrin-mediated endocytosis of synaptic vesicle membranes involves the recruitment of clathrin and AP-2 adaptor complexes to the presynaptic plasma membrane. Phosphoinositides have been implicated in nucleating coat assembly by directly binding to several endocytotic proteins including AP-2 and AP180. Here, we show that the stimulatory effect of ATP and GTPγS on clathrin coat recruitment is mediated at least in part by increased levels of PIP2. We also provide evidence for a role of ADP-ribosylation factor 6 (ARF6) via direct stimulation of a synaptically enriched phosphatidylinositol 4-phosphate 5-kinase type Iγ (PIPKIγ), in this effect. These data suggest a model according to which activation of PIPKIγ by ARF6-GTP facilitates clathrin-coated pit assembly at the synapse.
Lack of GTP-bound Rho1p in secretory vesicles of Saccharomyces cerevisiae
Authors: Abe Mitsuhiro , Qadota Hiroshi , Hirata Aiko , Ohya Yoshikazu
Published: July 2003

Rho1p, an essential Rho-type GTPase in Saccharomyces cerevisiae, activates its effectors in the GTP-bound form. Here, we show that Rho1p in secretory vesicles cannot activate 1,3-β-glucan synthase, a cell wall synthesizing enzyme, during vesicular transport to the plasma membrane. Analyses with an antibody preferentially reacting with the GTP-bound form of Rho1p revealed that Rho1p remains in the inactive form in secretory vesicles. Rom2p, the GDP/GTP exchange factor of Rho1p, is preferentially localized on the plasma membrane even when vesicular transport is blocked. Overexpression of Rom2p results in delocalization of Rom2p and accumulation of 1,3-β-glucan in secretory vesicles. Based on these results, we propose that Rho1p is kept inactive in intracellular secretory organelles, resulting in repression of the activity of the cell wall–synthesizing enzyme within cells.
Function of the p97–Ufd1–Npl4 complex in retrotranslocation from the ER to the cytosol
Authors: Ye Yihong , Meyer Hemmo H. , Rapoport Tom A.
Published: July 2003

Amember of the family of ATPases associated with diverse cellular activities, called p97 in mammals and Cdc48 in yeast, associates with the cofactor Ufd1–Npl4 to move polyubiquitinated polypeptides from the endoplasmic reticulum (ER) membrane into the cytosol for their subsequent degradation by the proteasome. Here, we have studied the mechanism by which the p97–Ufd1–Npl4 complex functions in this retrotranslocation pathway. Substrate binding occurs when the first ATPase domain of p97 (D1 domain) is in its nucleotide-bound state, an interaction that also requires an association of p97 with the membrane through its NH2-terminal domain. The two ATPase domains (D1 and D2) of p97 appear to alternate in ATP hydrolysis, which is essential for the movement of polypeptides from the ER membrane into the cytosol. The ATPase itself can interact with nonmodified polypeptide substrates as they emerge from the ER membrane. Polyubiquitin chains linked by lysine 48 are recognized in a synergistic manner by both p97 and an evolutionarily conserved ubiquitin-binding site at the NH2 terminus of Ufd1. We propose a dual recognition model in which the ATPase complex binds both a nonmodified segment of the substrate and the attached polyubiquitin chain; polyubiquitin binding may activate the ATPase p97 to pull the polypeptide substrate out of the membrane.
A subunit of the dynein regulatory complex in Chlamydomonas is a homologue of a growth arrest–specific gene product
Authors: Rupp Gerald , Porter Mary E.
Published: July 2003

The dynein regulatory complex (DRC) is an important intermediate in the pathway that regulates flagellar motility. To identify subunits of the DRC, we characterized a Chlamydomonas motility mutant obtained by insertional mutagenesis. The pf2-4 mutant displays an altered waveform that results in slow swimming cells. EM analysis reveals defects in DRC structure that can be rescued by reintroduction of the wild-type PF2 gene. Immunolocalization studies show that the PF2 protein is distributed along the length of the axoneme, where it is part of a discrete complex of polypeptides. PF2 is a coiled-coil protein that shares significant homology with a mammalian growth arrest–specific gene product (Gas11/Gas8) and a trypanosome protein known as trypanin. PF2 and its homologues appear to be universal components of motile axonemes that are required for DRC assembly and the regulation of flagellar motility. The expression of Gas8/Gas11 transcripts in a wide range of tissues may also indicate a potential role for PF2-related proteins in other microtubule-based structures.
Allelic Variation of MHC Structure Alters Peptide Ligands to Induce Atypical Partial Agonistic CD8+ T Cell Function
Authors: Lim Dong-Gyun , Slavik Jacqueline M. , Bourcier Katarzyna , Smith Kathrine J. , Hafler David A.
Published: July 2003

T cell receptors recognize small changes in peptide ligands leading to different T cell responses. Here, we analyzed a panel of HLA-A2–Tax11-19 reactive T cell clones to examine how small allelic variations of MHC molecules could alter the functional outcome of antigen recognition. Similar to the effects induced by antigenic altered peptide ligands, weak or partial agonistic T cell functions were identified in individual T cell clones with the recognition of MHC-altered peptide ligands (MAPLs). Interestingly, one subtype of HLA-A2 molecules induced an unusual type of partial agonistic function; proliferation without cytotoxicity. Modeling of crystallographic data indicated that polymorphic amino acids in the HLA-A2 peptide binding groove, especially the D-pocket, were responsible for this partial agonism. Reciprocal mutations of the Tax peptide side chain engaging the D-pocket indeed restored the agonist functions of the MHC–peptide complex. Whereas early intracellular signaling events were not efficiently induced by these MAPLs, phosphorylated c-Jun slowly accumulated with sustained long-term expression. These data indicate that MAPLs can induce atypical partial agonistic T cell function through structural and biochemical mechanisms similar to altered peptide ligands.
Cellular Prion Protein PromotesBrucellaInfection into Macrophages
Authors: Watarai Masahisa , Kim Suk , Erdenebaatar Janchivdorj , Makino Sou-ichi , Horiuchi Motohiro , Shirahata Toshikazu , Sakaguchi Suehiro , Katamine Shigeru
Published: July 2003

The products of the Brucella abortus virB gene locus, which are highly similar to conjugative DNA transfer system, enable the bacterium to replicate within macrophage vacuoles. The replicative phagosome is thought to be established by the interaction of a substrate of the VirB complex with macrophages, although the substrate and its host cellular target have not yet been identified. We report here that Hsp60, a member of the GroEL family of chaperonins, of B. abortus is capable of interacting directly or indirectly with cellular prion protein (PrPC) on host cells. Aggregation of PrPC tail-like formation was observed during bacterial swimming internalization into macrophages and PrPC was selectively incorporated into macropinosomes containing B. abortus. Hsp60 reacted strongly with serum from human brucellosis patients and was exposed on the bacterial surface via a VirB complex–associated process. Under in vitro and in vivo conditions, Hsp60 of B. abortus bound to PrPC. Hsp60 of B. abortus, expressed on the surface of Lactococcus lactis, promoted the aggregation of PrPC but not PrPC tail formation on macrophages. The PrPC deficiency prevented swimming internalization and intracellular replication of B. abortus, with the result that phagosomes bearing the bacteria were targeted into the endocytic network. These results indicate that signal transduction induced by the interaction between bacterial Hsp60 and PrPC on macrophages contributes to the establishment of B. abortus infection.
Critical Role of the Programmed Death-1 (PD-1) Pathway in Regulation of Experimental Autoimmune Encephalomyelitis
Authors: Salama Alan D. , Chitnis Tanuja , Imitola Jaime , Ansari Mohammed Javeed I. , Akiba Hisaya , Tushima Fumihiko , Azuma Miyuki , Yagita Hideo , Sayegh Mohamed H. , Khoury Samia J.
Published: July 2003

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.
PD-1 Inhibits Antiviral Immunity at the Effector Phase in the Liver
Authors: Iwai Yoshiko , Terawaki Seigo , Ikegawa Masaya , Okazaki Taku , Honjo Tasuku
Published: July 2003

Unlike naive T cells, effector T cells can be activated by either T cell receptor signal or costimulatory signal alone and therefore the absence of costimulatory molecules on tissue cells cannot explain the tolerance mechanism at the effector phase. Here we report that PD-L1, the ligand for the immunoinhibitory receptor PD-1, was expressed on vascular endothelium in peripheral tissues. Liver nonparenchymal cells including sinusoidal endothelial cells and Kupffer cells constitutively expressed PD-L1 and inhibited proliferation and cell division of activated T cells expressing PD-1. The absence of PD-1 induced proliferation of effector T cells in the adenovirus-infected liver and resulted in rapid clearance of the virus. These results indicate that PD-1 plays an important role in T cell tolerance at the effector phase and the blockade of the PD-1 pathway can augment antiviral immunity.