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Substantial Evidence (substantial + evidence)
Selected AbstractsCritical Thoughts on Teaching Standard EnglishCURRICULUM INQUIRY, Issue 2 2000Barbara L. Speicher This article exposes four assumptions that underlie most discussions of Standard English. First, spoken English equates to written English. Substantial evidence demonstrates that this equation is both misleading and false. Second, spoken and written English are equally amenable to standardization. This is also fallacious. We will use Prototype Theory (Rosch et al., 1976) and Standard Ideology (Milroy and Milroy, 1991) to explore how broadly shared notions about standard language have led to this belief. Third, Standard English is the language of the workplace and essential for social mobility. While we do not refute this assumption, we do explore the discrimination that stems from it. Fourth, Standard English is the language of the classroom. This assumption has never been systematically tested in the literature by examining the language that teachers use. Nor is it clear that teachers believe they do or should impose an idealized spoken form on their students. [source] PANDAS anorexia nervosa,Endangered, extinct or nonexistent?INTERNATIONAL JOURNAL OF EATING DISORDERS, Issue 1 2008Frances Puxley BSc Abstract Objective: Substantial evidence exists for the concept of pediatric autoimmune neuropsychiatric disorders associated with streptoccoccal infection (PANDAS) such as some cases of obsessive-compulsive disorder and tics/Tourette's syndrome. More recently PANDAS-AN has been described. The aim of this article is to provide a critical review of this concept. Method: The literature was searched using Medline, Psychinfo, and Google. Results: There is some evidence for the entity of PANDAS-AN but this is considerably limited by a wide range of methodological problems, including the seemingly low prevalence, the lack of clarity in diagnostic criteria, and the lack of specificity in the diagnostic tests. Innovative treatment approaches hold promise but require further evaluation. Conclusion: Further research into PANDAS-AN, using more clearly defined and consistent diagnostic criteria is needed, given the potential for enhancing the understanding of the pathogenesis of AN and for more effective treatments. © 2007 by Wiley Periodicals, Inc. Int J Eat Disord 2008 [source] Molecular abnormalities of T-cells in systemic lupus erythematosusINTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, Issue 4 2006Tsutomu TAKEUCHI Abstract Substantial evidence supports that T-cells play a central role in the pathogenesis of systemic lupus erythematosus (SLE). To explore the molecular basis of the defective function of SLE T-cells, we focused on the signal transduction system via T-cell antigen receptor (TCR) in peripheral blood T-cells from SLE patients. Comprehensive analysis to identify the molecules responsible for the defects showed the expression of the TCR , chain was attenuated, or absent in more than half of SLE patients. Moreover, the aberrant transcripts of the TCR , chain, including spliced variants lacking exon 7 and with a short 3,-UTR, were detected in SLE T-cells. Although attenuated expression of the TCR , chain is also observed in patients with cancers, infections, and other autoimmune diseases, sustained attenuation of TCR , expression and aberrant transcripts are only observed in SLE. In this review we discuss the unique features of the TCR , defects in SLE. [source] Scientific rationale for the Finnish Allergy Programme 2008,2018: emphasis on prevention and endorsing toleranceALLERGY, Issue 5 2009L. C. Von Hertzen ,In similarity to many other western countries, the burden of allergic diseases in Finland is high. Studies worldwide have shown that an environment rich in microbes in early life reduces the subsequent risk of developing allergic diseases. Along with urbanization, such exposure has dramatically reduced, both in terms of diversity and quantity. Continuous stimulation of the immune system by environmental saprophytes via the skin, respiratory tract and gut appears to be necessary for activation of the regulatory network including regulatory T-cells and dendritic cells. ,Substantial evidence now shows that the balance between allergy and tolerance is dependent on regulatory T-cells. Tolerance induced by allergen-specific regulatory T-cells appears to be the normal immunological response to allergens in non atopic healthy individuals. Healthy subjects have an intact functional allergen-specific regulatory T-cell response, which in allergic subjects is impaired. Evidence on this exists with respect to atopic dermatitis, contact dermatitis, allergic rhinitis and asthma. Restoration of impaired allergen-specific regulatory T-cell response and tolerance induction has furthermore been demonstrated during allergen-specific subcutaneous and sublingual immunotherapy and is crucial for good therapeutic outcome. However, tolerance can also be strengthened unspecifically by simple means, e.g. by consuming farm milk and spending time in nature. ,Results so far obtained from animal models indicate that it is possible to restore tolerance by administering the allergen in certain circumstances both locally and systemically. It has become increasingly clear that continuous exposure to microbial antigens as well as allergens in foodstuffs and the environment is decisive, and excessive antigen avoidance can be harmful and weaken or even prevent the development of regulatory mechanisms. ,Success in the Finnish Asthma Programme was an encouraging example of how it is possible to reduce both the costs and morbidity of asthma. The time, in the wake of the Asthma Programme, is now opportune for a national allergy programme, particularly as in the past few years, fundamentally more essential data on tolerance and its mechanisms have been published. In this review, the scientific rationale for the Finnish Allergy Programme 2008,2018 is outlined. The focus is on tolerance and how to endorse tolerance at the population level. [source] Premature translation of transition protein 2 mRNA causes sperm abnormalities and male infertilityMOLECULAR REPRODUCTION & DEVELOPMENT, Issue 3 2007Khailun Tseden Abstract During mammalian spermiogenesis somatic histones are replaced at first by transition proteins, which are in turn replaced by the protamines, forming the sperm nucleoprotamines. It is believed that transition protein 2 (Tnp2) is necessary for maintaining the normal processing of protamines and, consequently, the completion of chromatin condensation. The transition protein mRNAs are stored in translationally inert messenger ribonucleoprotein particles for up to 7 days until translational activation in elongated spermatids. Substantial evidence suggests an involvement of 3,untranslated region (UTR) in the translational regulation of the Tnp2 mRNAs. In order to determine the role of Tnp2 3,UTR in translational regulation and to study whether the translational repression of Tnp2 mRNA is necessary for normal spermatid differentiation in mice, we generated transgenic mice that carry a Tnp2-hGH transgene. In this transgene, 3,UTR of Tnp2 gene was replaced by 3, 3,UTR of human growth hormone gene. In these transgenic animals, transcription and translation of Tnp2 occur simultaneously in round spermatids which is an evidence for involvement of Tnp2 3,UTR in its translation repression. Premature translation of Tnp2 mRNA caused abnormal head morphogenesis, reduced sperm motility and male infertility. These results show clearly that a strict temporal and stage-specific Tnp2 translation is necessary for the correct differentiation of round spermatids into mature spermatozoa and for male fertility. Mol. Reprod. Dev. © 2006 Wiley-Liss, Inc. [source] Discovery of Potent Vascular Endothelial Growth Factor Receptor-2 InhibitorsCHEMMEDCHEM, Issue 1 2010Athanasios Papakyriakou Dr. Abstract Substantial evidence over the last decades has implicated uncontrolled angiogenesis with various pathological states, including cancer. Vascular endothelial growth factor (VEGF) plays a critical role in its regulation. Because the tyrosine kinase VEGF receptor-2 (VEGFR-2) is the major mediator of the mitogenic, angiogenic, and permeability-enhancing effects of VEGF, it has become one of the most profound anti-angiogenesis targets. Inspired by the anthranilamide class of VEGFR-2 inhibitors, we performed a computational analysis of some potent representative members, using docking and molecular dynamics calculations. Based on the observations drawn from introducing the effect of the receptor's flexibility in implicit aqueous environment, we designed, synthesized, and characterized several new analogues of related scaffolds with modifications in their steric and electronic characteristics. In,vitro evaluation of these compounds revealed several novel VEGFR-2 inhibitors that are less cytotoxic and more potent than the parent compounds. [source] Critical role of Nitric Oxide on Nicotine-Induced Hyperactivation of Dopaminergic Nigrostriatal System: Electrophysiological and Neurochemical evidence in RatsCNS: NEUROSCIENCE AND THERAPEUTICS, Issue 3 2010Vincenzo Di Matteo Nicotine, the main psychoactive ingredient in tobacco, stimulates dopamine (DA) function, increasing DA neuronal activity and DA release. DA is involved in both motor control and in the rewarding and reinforcing effects of nicotine; however, the complete understanding of its molecular mechanisms is yet to be attained. Substantial evidence indicates that the reinforcing properties of drugs of abuse, including nicotine, can be affected by the nitric oxide (NO) system, which may act by modulating central dopaminergic function. In this study, using single cell recordings in vivo coupled with microiontophoresis and microdialysis in freely moving animals, the role of NO signaling on the hyperactivation elicited by nicotine of the nigrostriatal system was investigated in rats. Nicotine induced a dose-dependent increase of the firing activity of the substantia nigra pars compacta (SNc) DA neurons and DA and 3,4-dihydroxyphenylacetic acid (DOPAC) release in the striatum. Pharmacological manipulation of the NO system did not produce any change under basal condition in terms of neuronal discharge and DA release. In contrast, pretreatments with two NO synthase (NOS) inhibitors, N-,-nitro- l -arginine methyl ester (l -NAME) and 7-nitroindazole (7-NI) were both capable of blocking the nicotine-induced increase of SNc DA neuron activity and DA striatal levels. The effects of nicotine in l -NAME and 7-NI-pretreated rats were partially restored when rats were pretreated with the NO donor molsidomine. These results further support the evidence of an important role played by NO on modulation of dopaminergic function and drug addiction, thus revealing new pharmacological possibilities in the treatment of nicotine dependence and other DA dysfunctions. [source] THE EARNINGS EFFECT OF EDUCATION AT COMMUNITY COLLEGESCONTEMPORARY ECONOMIC POLICY, Issue 1 2010DAVE E. MARCOTTE In this paper, I make use of data from the 2000 follow-up of the National Education Longitudinal Survey postsecondary education transcript files to extend what is known about the value of education at community colleges. I examine the effects of enrollment in community colleges on students' subsequent earnings. I estimate the effects of credits earned separately from credentials because community colleges are often used as a means for students to engage in study not necessarily leading to a degree or certificate. I find consistent evidence of wage and salary effects of both credits and degrees, especially for women. There is no substantial evidence that enrollment in vocational rather than academic coursework has a particularly beneficial effect, however. (JEL I2, J24) [source] Integrated psychodynamic therapy for bulimia nervosa and binge eating disorder: theory, practice and preliminary findingsEUROPEAN EATING DISORDERS REVIEW, Issue 6 2005Susan Murphy Abstract While there is a substantial evidence base for the use of more recently developed therapeutic approaches, there is very little evidence that psychodynamically based treatments are effective in treating bulimia nervosa or binge-eating disorder. Clinicians have suggested that such an approach should be supplemented with behavioural foci and that it should be time-limited. This paper outlines an integrative approach to the outpatient treatment of these eating disorders, where psychodynamic principles and practice are used in tandem with behavioural strategies, and presents preliminary data on behavioural changes among patients who undertake this programme. A case series design was used, employing this approach with a selected group of 21 female patients. Data are presented on failure to complete the programme, as well as changes in body mass index and frequency of bingeing and vomiting. All of the 21 patients completed the programme, though 5 were lost to the study by the last follow-up point. Those who completed the programme had a stable body mass index, but showed clinically and statistically significant reductions in bulimic symptoms. These preliminary findings indicate that the bulimic disorders can be treated effectively using a psychodynamic approach that is integrated with behavioural techniques and that has time limits. While further research is needed to support this conclusion, it appears to be important to use a more integrative psychodynamic approach than is commonly used. Copyright © 2005 John Wiley & Sons, Ltd and Eating Disorders Association. [source] The use of brief interventions adapted from motivational interviewing across behavioral domains: a systematic reviewADDICTION, Issue 12 2001Chris Dunn Aims. To examine the effectiveness of brief behavioral interventions adapting the principles and techniques of Motivational Interviewing (MI) to four behavioral domains: substance abuse, smoking, HIV risk and diet/exercise. Design. We conducted a systematic review of 29 randomized trials of MI interventions. Data on methodological quality were extracted and tabulated. Between-group behavior change effect sizes and confidence intervals were calculated for each study. Findings. Due to varying intervention time lengths, targeted problem behaviors, settings and interventionists' backgrounds and skill levels, outcomes were not combined meta-analytically. Sixty per cent of the 29 studies yielded at least one significant behavior change effect size. No significant association between length of follow-up time and magnitude of effect sizes was found across studies. There was substantial evidence that MI is an effective substance abuse intervention method when used by clinicians who are non-specialists in substance abuse treatment, particularly when enhancing entry to and engagement in more intensive substance abuse treatment treatment-as-usual. Data were inadequate to judge the effect of MI in the other domains. Client attribute-treatment interactions were understudied and the sparse and inconsistent findings revealed little about the mechanism by which MI works or for whom it works best. Conclusion. To determine more effectively how well MI works in domains other than substance abuse and for whom it works best in all domains, researchers should study MI with risk behaviors other than substance abuse, while examining both interactions and the theoretical components of MI. [source] Synaptically released 5-HT modulates the activity of tonically discharging neuronal populations in the rostral ventral medulla (RVM)EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 8 2000Pascale Piguet Abstract There is substantial evidence for an important modulating role of monoamines (catecholamines and serotonin, 5-HT) in the rostral ventral medulla (RVM), a region which plays an important role in cardiovascular and nociceptive functions. We investigated in slices the role of endogenous monoamines in the synaptic control of the activity of rat RVM neuronal populations using intracellular recordings in the lateral RVM plus lateral aspect of nucleus paragigantocellularis lateralis. A triple-labelling protocol allowed us to identify the location of impaled neurons and their eventual monoaminergic phenotype within the serotonergic and catecholaminergic populations of the RVM. Focal electrical stimulation revealed the existence of a functional monoaminergic input onto RVM neurons which was mediated by endogenous 5-HT acting at inhibitory 5-HT1A receptors but did not involve noradrenergic neurotransmission. The slow 5-HT-mediated inhibitory postsynaptic potential (IPSP) was only observed in the regularly discharging neurons, which were found to be neither catecholaminergic nor serotonergic. The synaptic release of 5-HT was, itself, under an inhibitory control involving GABAA (,-aminobutyric acid) receptors. Moreover, we characterized the effect of the 5-HT-releasing agent fenfluramine on this functional 5-HT-mediated synaptic transmission. Our results show that the effect of fenfluramine is biphasic consisting of an initial prolongation of the serotonergic IPSP followed by a decrease in amplitude. Our data provide a basis for the previously reported inhibitory effects of exogenously applied serotonin agonists/antagonists on the autonomic functions controlled by the RVM. This 5-HT pathway, which functionally links the serotonergic and catecholaminergic regions, might play an important role in cardiovascular and nociceptive functions. [source] Helicobacter pylori, coccoid forms and biofilm formationFEMS IMMUNOLOGY & MEDICAL MICROBIOLOGY, Issue 2 2009Leif Percival Andersen Abstract Electron microscopic studies have shown that Helicobacter pylori occurs in three stages: spiral forms, coccoid forms and degenerative forms. The spiral forms are viable, culturable, virulent and can colonize experimental animals and induce inflammation. The coccoid forms may also be viable but are nonculturable, less virulent and are less likely to colonize and induce inflammation in experimental animals than the spiral forms. The degenerative forms are pyknotic, nonculturable, coccoid forms of dead H. pylori. These forms cannot be cultured and the cell membrane has disintegrated but gene material can be detected by PCR in water supplies. There is no substantial evidence for viable H. pylori persisting in water supplies. Epidemiological studies suggest that environmental water is a risk factor for H. pylori infection when compared with tap water, and formation of H. pylori biofilm cannot be excluded. Helicobacter pylori does not seem to take part in biofilm formation in the oral cavity even though the bacterium may be detected. [source] Mean and Variance Causality between Official and Parallel Currency Markets: Evidence from Four Latin American CountriesFINANCIAL REVIEW, Issue 2 2002Angelos Kanas This paper examines the issue of mean and variance causality across four Latin American official and black markets for foreign currency using monthly data for the period 1976,1993. We apply a recent test developed by Cheung and Ng (1996) in order to test for mean and variance spillovers. The main findings are: (1) In contrast to the findings of previous studies, EGARCH-M processes characterize each bilateral exchange rate series in both markets; (2) There is substantial evidence of causality in both mean and variance with the causality in mean largely being driven by the causality in variance; and (3) The results indicate that the major exporter of causality is the Mexican black market with the black market of Argentina and the black and official markets of Brazil being the smallest contributors. [source] Permeability of the continental crust: dynamic variations inferred from seismicity and metamorphismGEOFLUIDS (ELECTRONIC), Issue 1-2 2010S. E. INGEBRITSEN Geofluids (2010) 10, 193,205 Abstract The variation of permeability with depth can be probed indirectly by various means, including hydrologic models that use geothermal data as constraints and the progress of metamorphic reactions driven by fluid flow. Geothermal and metamorphic data combine to indicate that mean permeability (k) of tectonically active continental crust decreases with depth (z) according to log k , ,14,3.2 log z, where k is in m2 and z in km. Other independently derived, crustal-scale k,z relations are generally similar to this power-law curve. Yet there is also substantial evidence for local-to-regional-scale, transient, permeability-generation events that entail permeabilities much higher than these mean k,z relations would suggest. Compilation of such data yields a fit to these elevated, transient values of log k , ,11.5,3.2 log z, suggesting a functional form similar to that of tectonically active crust, but shifted to higher permeability at a given depth. In addition, it seems possible that, in the absence of active prograde metamorphism, permeability in the deeper crust will decay toward values below the mean k,z curves. Several lines of evidence suggest geologically rapid (years to 103 years) decay of high-permeability transients toward background values. Crustal-scale k,z curves may reflect a dynamic competition between permeability creation by processes such as fluid sourcing and rock failure, and permeability destruction by processes such as compaction, hydrothermal alteration, and retrograde metamorphism. [source] Conflict resolution strategies in joint purchase decisions for major household consumer durables: a cross-cultural investigationINTERNATIONAL JOURNAL OF CONSUMER STUDIES, Issue 3 2009Rina Makgosa Abstract Previous studies on joint purchase decisions have investigated the types of conflict resolution strategies used by spouses, the usage frequency of different conflict resolution strategies, and the effects of demographics and various other variables, on the uses of conflict resolution strategies. Despite efforts to address this largely unexplored area, the role that culture plays in the use of conflict resolution strategies has been significantly ignored. Using a cross-cultural perspective, this study addresses the gap in our understanding of the joint purchase decisions in the family by examining how husbands and wives of three ethnic groups in Britain , British Whites, Indians and African Blacks , use different conflict resolution strategies while jointly purchasing major household consumer products. The total sample comprised 583 husbands and wives of British White, Indian and African Black origin residing in London and Manchester in Britain. Our results showed that three conflict resolution strategies are used by both husbands and wives: bargaining, assertiveness and playing on an emotion. In addition, disengagement emerged as a strategy for husbands, whereas supplication emerged for wives. The study presented in this paper also provides substantial evidence of differences in the use of conflict resolution strategies by husbands and wives from the three ethnic groups, which greatly improves our knowledge on a cross-cultural perspective of joint purchase decisions. [source] Neutrophils: key mediators of tumour angiogenesisINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 3 2009Simon Tazzyman Summary It is now well known that most malignant tumours contain a significant amount of leucocytic infiltrates the presence of which has, on many occasions, been linked to poor patient prognosis. These leucocyte populations are recruited to tumours by chemotactic factors released by either viable or necrotic tumour cells, or by cells within the tumour stroma. In recent times, most studies have analysed the role that tumour-associated macrophages (TAM) have on tumour progression. However, there is now increasing evidence to show that neutrophils also actively participate in this process. Whilst there are some data to suggest that neutrophil-derived factors can promote genetic mutations leading to tumourigenesis, or secrete factors that promote tumour cell proliferation; there is now substantial evidence to show that neutrophils, like TAM, significantly affect tumour angiogenesis. In this review, we discuss the likely mechanisms by which neutrophils are recruited into the tumour and then elaborate on how these cells may induce tumour vascularization by the secretion of powerful pro-angiogenic factors. We also discuss possible future chemotherapeutic strategies that are aimed at limiting tumour angiogenesis by inhibiting neutrophil recruitment. [source] Reviews: A review of hereditary and acquired coagulation disorders in the aetiology of ischaemic strokeINTERNATIONAL JOURNAL OF STROKE, Issue 5 2010Lonneke M. L. De Lau The diagnostic workup in patients with ischaemic stroke often includes testing for prothrombotic conditions. However, the clinical relevance of coagulation abnormalities in ischaemic stroke is uncertain. Therefore, we reviewed what is presently known about the association between inherited and acquired coagulation disorders and ischaemic stroke, with a special emphasis on the methodological aspects. Good-quality data in this field are scarce, and most studies fall short on epidemiological criteria for causal inference. While inherited coagulation disorders are recognised risk factors for venous thrombosis, there is no substantial evidence for an association with arterial ischaemic stroke. Possible exceptions are the prothrombin G20210A mutation in adults and protein C deficiency in children. There is proof of an association between the antiphospholipid syndrome and ischaemic stroke, but the clinical significance of isolated mildly elevated antiphospholipid antibody titres is unclear. Evidence also suggests significant associations of increased homocysteine and fibrinogen concentrations with ischaemic stroke, but whether these associations are causal is still debated. Data on other acquired coagulation abnormalities are insufficient to allow conclusions regarding causality. For most coagulation disorders, a causal relation with ischaemic stroke has not been definitely established. Hence, at present, there is no valid indication for testing all patients with ischaemic stroke for these conditions. Large prospective population-based studies allowing the evaluation of interactive and subgroup effects are required to appreciate the role of coagulation disorders in the pathophysiology of arterial ischaemic stroke and to guide the management of individual patients. [source] Turkish women's perceptions of antenatal educationINTERNATIONAL NURSING REVIEW, Issue 3 2010P. Serçeku Serçeku, P. & Mete S. (2010) Turkish women's perceptions of antenatal education. International Nursing Review57, 395,401 Background:, Antenatal education is considered essential for expectant women. Although there are a number of studies on the effects of antenatal education, there are few studies featuring substantial evidence in this area. For this reason, the benefits have not been clearly defined. Aim:, To describe women's perceptions of the effectiveness of antenatal education on pregnancy, childbirth and the post-partum period, and also to describe their impressions on the type of education received. Methods:, A qualitative approach was used. The study featured 15 primipara women who had attended antenatal education. Data were gathered through semi-structured interviews and analysed using the content analysis method. Findings:, The results of this study showed that education provided a basis of knowledge about pregnancy, childbirth and the post-partum period. It was found that education could have positive effects on pregnancy, childbirth, breastfeeding, motherhood and infant care, and that it could at the same time have a positive or negative effect on fear of childbirth. Although different advantages were found to be perceived in both individual and group education, it was discovered that the study participants were much more satisfied with attending group sessions. Key conclusions and implications for practice:, Antenatal education should be planned in such a way that its content and methodology do not increase fear. When the lower costs incurred and the higher satisfaction level attained are considered, group education appears to be the type of antenatal education that should be preferred. [source] Perspective: Postmenopausal Osteoporosis as a Failure of Bone's Adaptation to Functional Loading: A Hypothesis,JOURNAL OF BONE AND MINERAL RESEARCH, Issue 11 2001Lance Lanyon Abstract There is substantial evidence that bones' ability to withstand functional loading without damage depends on the processes of bone modeling and remodeling, which are responsible for establishing and maintaining bone architecture, being influenced by a feedback mechanism related to the control of functional strains. It is probably useful to consider the diminished ability to maintain bone strength in postmenopausal osteoporosis as a failure of this mechanism. Acceptance of this approach would not only increase understanding of the etiology of postmenopausal osteoporosis but also significantly influence the ways in which it is investigated and treated. This would not mean that the many other factors affecting bone mass and bone cell activity will be ignored, but rather these factors will be put in perspective. Research to prevent or treat osteoporosis could be directed usefully to understanding how osteoblasts, lining cells, and osteocytes respond to mechanically derived information and how these responses are converted into stimuli controlling structurally appropriate modeling and remodeling. Evidence suggesting that early strain-related responses of bone cells in males and females involve the estrogen receptor (ER) could explain decreased effectiveness of this pathway when ER levels are low. [source] The effects of immunosuppressive drugs on CD4+CD25+ regulatory T cells: a systematic review of clinical and basic researchJOURNAL OF EVIDENCE BASED MEDICINE, Issue 2 2010Chuntao Zhang Abstract Objective To review the effects of different immunosuppressive drugs on proliferation and function of regulatory T cells (Tregs). Methods We searched MEDLINE, Embase (from inception to September 2009), and the Cochrane Library (Issue 4, 2009) for clinical and basic research about the effects of various immunosuppressive drugs on Tregs. Data were extracted and methodological quality was assessed by two independent reviewers. Outcome measures for clinical research included blood Tregs levels, acute rejection episodes, and graft function. Outcomes for basic research included percentage of Tregs proliferation, function, Tregs phenotype, and evidence for possible mechanisms. We analyzed data qualitatively. Results Forty-two studies, including 19 clinical trials and 23 basic studies, were included. The immunosuppressive drugs studied were calcineurin inhibitors (CNIs), Rapa, anti-metabolism drugs, IL-2 receptor-blocking antibodies, T-cell depleting antibodies, and co-stimulation blockade antibodies. Most of the studies were on Rapa and CNIs. Eight basic studies on Rapa and CNIs showed that Rapa could promote the proliferation and function of Tregs, while CNIs could not. Five clinical trials involving a total of 158 patients showed that patients taking Rapa had higher blood concentration of Tregs than patients taking CNIs, but no difference was found in graft function (6,42 months follow-up). Conclusion There is substantial evidence that Rapa favors Tregs survival and function. However, the higher numbers of blood Tregs in patients treated with Rapa do not show any association with better graft function. Larger clinical studies with longer follow-up are needed to more thoroughly assess the efficacy of immunosuppressive drugs on Tregs, and reveal whether a relationship exists between Tregs and graft function. [source] Increased survival and neuroprotective effects of BN82451 in a transgenic mouse model of Huntington's diseaseJOURNAL OF NEUROCHEMISTRY, Issue 1 2003Peter Klivenyi Abstract There is substantial evidence that excitotoxicity and oxidative damage may contribute to Huntington's disease (HD) pathogenesis. We examined whether the novel anti-oxidant compound BN82451 exerts neuroprotective effects in the R6/2 transgenic mouse model of HD. Oral administration of BN82451 significantly improved motor performance and improved survival by 15%. Oral administration of BN82451 significantly reduced gross brain atrophy, neuronal atrophy and the number of neuronal intranuclear inclusions at 90 days of age. These findings provide evidence that novel anti-oxidants such as BN82451 may be useful for treating HD. [source] Bioenergetics in the pathogenesis of neurodegenerationJOURNAL OF NEUROCHEMISTRY, Issue 2001M. Flint Beal Evidence implicating both mitochondria and bioenergetics as playing a crucial role in necrotic and apoptotic cell death is rapidly accumulating. Mitochondria are essential in controlling specific apoptosis cell death pathways and they are the major source of free radicals in the cell. Direct evidence for a role of mitochondria in neurodegenerative diseases comes from studies in Friedreich's Ataxia. Mutations in frataxin lead to an accumulation of iron within mitochondria. We found a three-fold increase in a marker of oxidative damage to DNA in the urine of patients with Friedreich's Ataxia. There is evidence for mitochondrial defects in patients with amyotrophic lateral sclerosis (ALS). There are mitochondrial abnormalities in liver biopsies and muscle biopsies from individuals with sporadic ALS. Muscle biopsies have shown reduced complex I activity in patients with sporadic ALS. A study of ALS cybrids showed a significant decrease in complex I activity as well as trends towards reduced complex 3 and 4 activities. We found increased levels of 8-hydroxy-2-deoxyguanosine, a marker of oxidative damage to DNA in the plasma, urine and CSF of sporadic ALS patients and increased numbers of point mutations in mtDNA of ALS spinal cord tissue. There is mitochondrial vacuolization in transgenic mouse models of ALS. We found substantial evidence for mitochondrial dysfunction in Huntington's Disease (HD). In HD postmortem brain tissue, there are significant reductions in complex 2, 3 activity. We also demonstrated increased brain lactate concentrations as well as reduced phosphocreatine to inorganic phosphate ratio in the resting muscle of patients with HD. More recent studies have demonstrated that there is abnormal depolarization of mitochondria of HD lymphoblasts, which directly correlates with CAG repeat length. There are reductions in ATP production in muscle are both presymptomatic and symptomatic HD patients. Transgenic mouse models of HD show significant reductions in N-acetylaspartate concentrations, which precede the onset of neuronal degeneration. We investigated a number of therapeutic interventions in both transgenic mouse models of ALS and HD. In transgenic ALS mice we found that oral administration of creatine dose-dependently extends survival and reduces the neuronal degeneration in the spinal cord. We found modest protection with ginkgo biloba and lipoic acid. In the HD mice we found significant improvement with oral administration of creatine in two different transgenic mouse models. Creatine not only extended survival but it also improved motor performance, delayed weight loss and attenuated striatal atrophy. Creatine significantly attenuated reductions in N-acetylaspartate concentrations as assessed using magnetic resonance spectroscopy. We also found significant neuroprotective effects with dichloroacetate, which stimulates pyruvate dehydrogenase. These findings implicate bioenergetic dysfunction in transgenic mouse models of both ALS and HD, and they suggest several novel therapeutic strategies aimed at energy replenishment. [source] Effects of Chronic Oestrogen Replacement on Stress-Induced Activation of Hypothalamic-Pituitary-Adrenal Axis Control PathwaysJOURNAL OF NEUROENDOCRINOLOGY, Issue 8 2000C. V. Dayas Abstract Oestrogen replacement therapy reportedly suppresses hypothalamic-pituitary-adrenal (HPA) axis responses to an emotional stressor in postmenopausal women. However, most studies in the rat suggest a facilitatory role for oestrogen in the control of HPA axis function. One explanation for this difference may be the regimen of oestrogen replacement: during oestrogen replacement therapy, oestrogen levels are low and constant whereas most animal studies examined the HPA axis response when oestrogen levels are rising. In the present study, we assessed HPA axis stress responses in mature ovariectomized rats after plasma oestrogen levels had been maintained at physiological levels for a prolonged period (25 or 100 pg/ml for 7 days). In the case of both an emotional stressor (noise) and a physical stressor (immune challenge by systemic interleukin-1, administration), oestrogen replacement suppressed stress-related Fos-like immunolabelling, in hypothalamic neuroendocrine cells and plasma adrenocorticotropin hormone responses. From the present data, and past reports, it appears unlikely that these effects of oestrogen are due to a direct action on corticotropin-releasing factor or oxytocin cells. Therefore, to obtain some indication of oestrogen's possible site(s) of action, Fos-like immunolabelling was mapped in the amygdala and in brainstem catecholamine groups, which are neuronal populations demonstrating substantial evidence of involvement in the generation of HPA axis stress responses. In the amygdala, oestrogen replacement suppressed central nucleus responses to immune challenge, but not to noise. Amongst catecholamine cells, oestrogen replacement was more effective against responses to noise than immune challenge, suppressing A1 and A2 (noradrenergic) and C2 (adrenergic) responses to noise, but only A1 responses to immune challenge. These data suggest that, as in postmenopausal women on oestrogen replacement therapy, chronic low-level oestrogen replacement can suppress HPA axis stress responses in the rat. Moreover, oestrogen appears to exert effects at multiple sites within putative HPA axis control pathways, even though most of the relevant neuronal populations do not contain genomic receptors for this gonadal steroid and the pattern of oestrogen action differs for an emotional vs a physical stressor. [source] The multifaceted influence of gender in career progress in nursingJOURNAL OF NURSING MANAGEMENT, Issue 7 2007CATHERINE TRACEY PhD The complex web of gender influence in the workplace results from a multifaceted interplay of factors [Walby et al. (1994) Medicine and Nursing. Sage Publications, London]. Literature reports that in nursing men's success compared with that of women is disproportionate and substantial evidence of gender-based disadvantage is found [Women in Management Review13 (1998) 184]. However, studies have not addressed the specific reasons for this and little is known of how or what influences nurses' career decisions and developments [Journal of Advanced Nursing25 (1997) 602]. Those studies which examine career developments and patterns are mainly found in the private business sector. [source] Alcoholism Susceptibility Loci: Confirmation Studies in a Replicate Sample and Further MappingALCOHOLISM, Issue 7 2000Tatiana Foroud Background: There is substantial evidence for a significant genetic component to the risk for alcoholism. A previous study reported linkage to chromosomes 1, 2, and 7 in a large data set that consisted of 105 families, each with at least three alcoholic members. Methods: Additional, genotyping in the 105 families has been completed in the chromosomal regions identified in the initial analyses, and a replication sample of 157 alcoholic families ascertained under identical criteria has been genotyped. Two hierarchical definitions of alcoholism were employed in the linkage analyses: (1) Individuals who met both Feighner and DSM-III-R criteria for alcohol dependence represented a broad definition of disease; and (2) individuals who met ICD-10 criteria for alcoholism were considered affected under a more severe definition of disease. Results: Genetic analyses of affected sibling pairs supported linkage to chromosome 1 (LOD = 1.6) in the replication data set as well as in a combined analysis of the two samples (LOD = 2.6). Evidence of linkage to chromosome 7 increased in the combined data (LOD = 2.9). The LOD score on chromosome 2 in the initial data set increased after genotyping of additional markers; however, combined analyses of the two data sets resulted in overall lower LOD scores (LOD = 1.8) on chromosome 2. A new finding of linkage to chromosome 3 was identified in the replication data set (LOD = 3.4). Conclusions: Analyses of a second large sample of alcoholic families provided further evidence of genetic susceptibility loci on chromosomes 1 and 7. Genetic analyses also have identified susceptibility loci on chromosomes 2 and 3 that may act only in one of the two data sets. [source] The immunological basis of psoriasisJOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY & VENEREOLOGY, Issue 2003C E M Griffiths ABSTRACT Evidence that psoriasis is an immune-mediated disorder comes from laboratory studies, clinical observation, and use of targeted therapies. Immunohistochemical studies have shown that the majority of T cells in psoriatic plaques are CD45RO+ memory-effector T cells that migrate into skin in recognition of an as yet undetermined antigen. There is also a predominance of Th1 cytokines, namely interferon gamma, in psoriatic plaques, in contrast to the predominance of Th2 cytokines found in atopic dermatitis. The efficacy of therapeutic agents that target T cells, such as anti-CD4+ monoclonal antibodies, cyclosporin, and interleukin-2 fusion toxin, has provided further substantial evidence that psoriasis is a T-cell-mediated disease. New T-cell targeted approaches and cytokine modulation are advancing basic science in providing an understanding of the evidence for the importance of the immune process in the biology of psoriasis. [source] Clinical trial: cyclophosphamide pulse therapy , a promising therapeutic alternative in refractory Crohn's diseaseALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 12 2009K. J. SCHMIDT Summary Background, In severe steroid-refractory Crohn's disease (CD), established therapies fail in a relevant proportion of patients. Recent pilot studies indicated the efficacy of cyclophosphamide pulse therapy in these patients. Aim, To provide further and substantial evidence for the rationale to apply cyclophosphamide pulse therapy as therapeutic option in severe courses of CD. Methods, Fifteen patients with steroid-refractory (n = 13) or steroid-dependent (n = 2) CD received 2,6 (median 3) monthly pulses of 750 mg cyclophosphamide in an open-label fashion. Eleven patients were on concomitant immunosuppression (azathioprine/mercaptopurine n = 9; methotrexate n = 2). Results, Thirteen of 15 patients (87%) had a clinical response (CDAI decrease >100). Ten patients (67%) went into remission (CDAI <150) after 8 weeks. Steroid-free remission was achieved in eight patients (54%). Two patients (13%) failed to respond. Median CDAI decreased from 420 (245,550) to 100 (26,538) at week 8. Remission lasted 16 months (median, range 4,40). In three patients, arthritis, erythema nodosum and episcleritis completely resolved. Cyclophosphamide pulse therapy administration was well tolerated in all subjects. Conclusions, Cyclophosphamide pulse therapy is safe and highly effective for induction and maintenance of remission in steroid-refractory/-dependent CD. There is a strong need for additional experience to improve the setting of the encouraging cyclophosphamide treatment in CD. [source] Review article: management of patients with chronic hepatitis C virus infection and ,normal' alanine aminotransferase activityALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 8 2006S. ZEUZEM Summary Background Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. Aim To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. Methods This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). Results Current limits defining normal serum alanine aminotransferase activity are not representative of a ,healthy' status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (,F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (,20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. Conclusions A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity. [source] Genetic differentiation and reproductive isolation of a naturally occurring floral homeotic mutant within a wild-type population of Capsella bursa-pastoris (Brassicaceae)MOLECULAR ECOLOGY, Issue 12 2009STEFFEN HAMEISTER Abstract Apart from the common floral architecture in Brassicaceae, variation in flower morphology occurs in several genera within the family and is considered to affect speciation processes. We analysed genetic differentiation and flowering time variation of two floral variants of Capsella bursa-pastoris, the Spe variant and the wild-type, which occur sympatrically in a vineyard in southwest Germany. The Spe variant is characterized by an additional whorl of stamens instead of petals and was formerly classified as an independent taxon ,Capsella apetala' Opiz. Amplified fragment length polymorphism and allozyme analysis revealed a substantial genetic differentiation of the two floral variants and a higher genetic variation within the wild-type subpopulation compared with the Spe subpopulation. The low genetic variation in the mutant provided evidence of a recent local origin or recent introduction. Flowering time analysis indicated that, within the analysed population, the Spe variant flowers significantly later than the wild-type (P < 0.001). We conclude that the evolution and persistence of Spe within a wild-type population is facilitated by high selfing rates and been enhanced by a shift in flowering phenology. Hence, our data provide substantial evidence that the Spe phenotype has established itself as an isolated entity within a wild-type population and may thus serve as a model for the analysis of the evolutionary significance of homeotic mutants in wild populations. [source] Insights into the function of the WhiB-like protein of mycobacteriophage TM4 , a transcriptional inhibitor of WhiB2MOLECULAR MICROBIOLOGY, Issue 3 2010Jan Rybniker Summary WhiB-like proteins of actinomycetes are known to co-ordinate iron-sulfur (Fe-S) clusters and are believed to have regulatory functions in many essential bacterial processes. The systematic determination of the genome sequences of mycobacteriophages has revealed the presence of several whiB -like genes in these viruses. Here we focussed on the WhiB-like protein of mycobacteriophage TM4, WhiBTM4. We provide evidence that this viral protein is capable of co-ordinating a Fe-S cluster. The UV-visible absorption spectra obtained from freshly purified and reconstituted WhiBTM4 were consistent with the presence of an oxygen sensitive [2Fe-2S] cluster. Expression of WhiBTM4 in the mycobacterial host led to hindered septation resembling a WhiB2 knockout phenotype whereas basal expression of WhiBTM4 led to superinfection exclusion. The quantification of mRNA-levels during phage infection showed that whiBTM4 is a highly transcribed early phage gene and a dominant negative regulator of WhiB2. Strikingly, both apo-WhiB2 of Mycobacterium tuberculosis and apo-WhiBTM4 were capable of binding to the conserved promoter region upstream of the whiB2 gene indicating that WhiB2 regulates its own synthesis which is inhibited in the presence of WhiBTM4. Thus, we provide substantial evidence supporting the hypothesis of viral and bacterial WhiB proteins being important Fe-S containing transcriptional regulators with DNA-binding capability. 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