Showing papers by "Newcastle University published in 2004"
TL;DR: In this article, a systematic review of the effectiveness and costs of different guideline development, dissemination and implementation strategies was carried out with key informants from primary and secondary care in the UK.
Abstract: OBJECTIVES: To undertake a systematic review of the effectiveness and costs of different guideline development, dissemination and implementation strategies. To estimate the resource implications of these strategies. To develop a framework for deciding when it is efficient to develop and introduce clinical guidelines. DATA SOURCES: MEDLINE, Healthstar, Cochrane Controlled Trial Register, EMBASE, SIGLE and the specialised register of the Cochrane Effective Practice and Organisation of Care (EPOC) group. REVIEW METHODS: Single estimates of dichotomous process variables were derived for each study comparison based upon the primary end-point or the median measure across several reported end-points. Separate analyses were undertaken for comparisons of different types of intervention. The study also explored whether the effects of multifaceted interventions increased with the number of intervention components. Studies reporting economic data were also critically appraised. A survey to estimate the feasibility and likely resource requirements of guideline dissemination and implementation strategies in UK settings was carried out with key informants from primary and secondary care. RESULTS: In total, 235 studies reporting 309 comparisons met the inclusion criteria; of these 73% of comparisons evaluated multifaceted interventions, although the maximum number of replications of a specific multifaceted intervention was 11 comparisons. Overall, the majority of comparisons reporting dichotomous process data observed improvements in care; however, there was considerable variation in the observed effects both within and across interventions. Commonly evaluated single interventions were reminders, dissemination of educational materials, and audit and feedback. There were 23 comparisons of multifaceted interventions involving educational outreach. The majority of interventions observed modest to moderate improvements in care. No relationship was found between the number of component interventions and the effects of multifaceted interventions. Only 29.4% of comparisons reported any economic data. The majority of studies only reported costs of treatment; only 25 studies reported data on the costs of guideline development or guideline dissemination and implementation. The majority of studies used process measures for their primary end-point, despite the fact that only three guidelines were explicitly evidence based (and may not have been efficient). Respondents to the key informant survey rarely identified existing budgets to support guideline dissemination and implementation strategies. In general, the respondents thought that only dissemination of educational materials and short (lunchtime) educational meetings were generally feasible within current resources. CONCLUSIONS: There is an imperfect evidence base to support decisions about which guideline dissemination and implementation strategies are likely to be efficient under different circumstances. Decision makers need to use considerable judgement about how best to use the limited resources they have for clinical governance and related activities to maximise population benefits. They need to consider the potential clinical areas for clinical effectiveness activities, the likely benefits and costs required to introduce guidelines and the likely benefits and costs as a result of any changes in provider behaviour. Further research is required to: develop and validate a coherent theoretical framework of health professional and organisational behaviour and behaviour change to inform better the choice of interventions in research and service settings, and to estimate the efficiency of dissemination and implementation strategies in the presence of different barriers and effect modifiers.
2,733 citations
TL;DR: The present review summarizes the impact structural biology has had on the understanding of the mechanisms by which CBMs bind to their target ligands.
Abstract: The enzymic degradation of insoluble polysaccharides is one of the most important reactions on earth. Despite this, glycoside hydrolases attack such polysaccharides relatively inefficiently as their target glycosidic bonds are often inaccessible to the active site of the appropriate enzymes. In order to overcome these problems, many of the glycoside hydrolases that utilize insoluble substrates are modular, comprising catalytic modules appended to one or more non-catalytic CBMs (carbohydrate-binding modules). CBMs promote the association of the enzyme with the substrate. In view of the central role that CBMs play in the enzymic hydrolysis of plant structural and storage polysaccharides, the ligand specificity displayed by these protein modules and the mechanism by which they recognize their target carbohydrates have received considerable attention since their discovery almost 20 years ago. In the last few years, CBM research has harnessed structural, functional and bioinformatic approaches to elucidate the molecular determinants that drive CBM–carbohydrate recognition. The present review summarizes the impact structural biology has had on our understanding of the mechanisms by which CBMs bind to their target ligands.
1,817 citations
01 Jan 2004
TL;DR: This paper presents a meta-modelling framework for estimating the profit and loss characteristics of the City of London stock market over a 10-year period and some of the strategies used to estimate these losses have been found to be profitable.
Abstract: Copyright & reuse City University London has developed City Research Online so that its users may access the research outputs of City University London's staff. Copyright © and Moral Rights for this paper are retained by the individual author(s) and/ or other copyright holders. All material in City Research Online is checked for eligibility for copyright before being made available in the live archive. URLs from City Research Online may be freely distributed and linked to from other web pages.
1,603 citations
TL;DR: It is observed that hysteresis in their adsorption and desorption kinetics above the supercritical temperature of H2 that reflects the dynamical opening of the “windows” between pores, which would allow H2 to be adsorbed at high pressures but stored at lower pressures.
Abstract: Adsorption and desorption of hydrogen from nanoporous materials, such as activated carbon, is usually fully reversible. We have prepared nanoporous metal-organic framework materials with flexible linkers in which the pore openings, as characterized in the static structures, appear to be too small to allow H2 to pass. We observe hysteresis in their adsorption and desorption kinetics above the supercritical temperature of H2 that reflects the dynamical opening of the "windows" between pores. This behavior would allow H2 to be adsorbed at high pressures but stored at lower pressures.
1,093 citations
University of Tennessee Health Science Center1, University of Washington2, Creighton University3, George Mason University4, Semmelweis University5, University of Arkansas System6, University of Murcia7, Neuroscience Research Australia8, University of South Florida9, University of California, Irvine10, University of Auckland11, Johns Hopkins University12, City University of New York13, Ruhr University Bochum14, California State University, Long Beach15, Oregon Health & Science University16, St. John's University17, University of California, Los Angeles18, Bowling Green State University19, Duke University20, Newcastle University21, University of Chicago22
TL;DR: The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is reviewed, with a rationale for each name change and evidence for any homologies implied by the new names.
Abstract: The standard nomenclature that has been used for many telencephalic and related brainstem structures in birds is based on flawed assumptions of homology to mammals. In particular, the outdated terminology implies that most of the avian telencephalon is a hypertrophied basal ganglia, when it is now clear that most of the avian telencephalon is neurochemically, hodologically, and functionally comparable to the mammalian neocortex, claustrum, and pallial amygdala (all of which derive from the pallial sector of the developing telencephalon). Recognizing that this promotes misunderstanding of the functional organization of avian brains and their evolutionary relationship to mammalian brains, avian brain specialists began discussions to rectify this problem, culminating in the Avian Brain Nomenclature Forum held at Duke University in July 2002, which approved a new terminology for avian telencephalon and some allied brainstem cell groups. Details of this new terminology are presented here, as is a rationale for each name change and evidence for any homologies implied by the new names. Revisions for the brainstem focused on vocal control, catecholaminergic, cholinergic, and basal ganglia-related nuclei. For example, the Forum recognized that the hypoglossal nucleus had been incorrectly identified as the nucleus intermedius in the Karten and Hodos (1967) pigeon brain atlas, and what was identified as the hypoglossal nucleus in that atlas should instead be called the supraspinal nucleus. The locus ceruleus of this and other avian atlases was noted to consist of a caudal noradrenergic part homologous to the mammalian locus coeruleus and a rostral region corresponding to the mammalian A8 dopaminergic cell group. The midbrain dopaminergic cell group in birds known as the nucleus tegmenti pedunculopontinus pars compacta was recognized as homologous to the mammalian substantia nigra pars compacta and was renamed accordingly; a group of gamma-aminobutyric acid (GABA)ergic neurons at the lateral edge of this region was identified as homologous to the mammalian substantia nigra pars reticulata and was also renamed accordingly. A field of cholinergic neurons in the rostral avian hindbrain was named the nucleus pedunculopontinus tegmenti, whereas the anterior nucleus of the ansa lenticularis in the avian diencephalon was renamed the subthalamic nucleus, both for their evident mammalian homologues. For the basal (i.e., subpallial) telencephalon, the actual parts of the basal ganglia were given names reflecting their now evident homologues. For example, the lobus parolfactorius and paleostriatum augmentatum were acknowledged to make up the dorsal subdivision of the striatal part of the basal ganglia and were renamed as the medial and lateral striatum. The paleostriatum primitivum was recognized as homologous to the mammalian globus pallidus and renamed as such. Additionally, the rostroventral part of what was called the lobus parolfactorius was acknowledged as comparable to the mammalian nucleus accumbens, which, together with the olfactory tubercle, was noted to be part of the ventral striatum in birds. A ventral pallidum, a basal cholinergic cell group, and medial and lateral bed nuclei of the stria terminalis were also recognized. The dorsal (i.e., pallial) telencephalic regions that had been erroneously named to reflect presumed homology to striatal parts of mammalian basal ganglia were renamed as part of the pallium, using prefixes that retain most established abbreviations, to maintain continuity with the outdated nomenclature. We concluded, however, that one-to-one (i.e., discrete) homologies with mammals are still uncertain for most of the telencephalic pallium in birds and thus the new pallial terminology is largely devoid of assumptions of one-to-one homologies with mammals. The sectors of the hyperstriatum composing the Wulst (i.e., the hyperstriatum accessorium intermedium, and dorsale), the hyperstriatum ventrale, the neostriatum, and the archistriatum have been renamed (respectively) the hyperpallium (hypertrophied pallium), the mesopallium (middle pallium), the nidopallium (nest pallium), and the arcopallium (arched pallium). The posterior part of the archistriatum has been renamed the posterior pallial amygdala, the nucleus taeniae recognized as part of the avian amygdala, and a region inferior to the posterior paleostriatum primitivum included as a subpallial part of the avian amygdala. The names of some of the laminae and fiber tracts were also changed to reflect current understanding of the location of pallial and subpallial sectors of the avian telencephalon. Notably, the lamina medularis dorsalis has been renamed the pallial-subpallial lamina. We urge all to use this new terminology, because we believe it will promote better communication among neuroscientists. Further information is available at http://avianbrain.org
1,061 citations
TL;DR: Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.
1,010 citations
TL;DR: The objective was to critically appraise six prominent systems for grading levels of evidence and the strength of recommendations as a basis for agreeing on characteristics of a common, sensible approach.
Abstract: A number of approaches have been used to grade levels of evidence and the strength of recommendations. The use of many different approaches detracts from one of the main reasons for having explicit approaches: to concisely characterise and communicate this information so that it can easily be understood and thereby help people make well-informed decisions. Our objective was to critically appraise six prominent systems for grading levels of evidence and the strength of recommendations as a basis for agreeing on characteristics of a common, sensible approach to grading levels of evidence and the strength of recommendations. Six prominent systems for grading levels of evidence and strength of recommendations were selected and someone familiar with each system prepared a description of each of these. Twelve assessors independently evaluated each system based on twelve criteria to assess the sensibility of the different approaches. Systems used by 51 organisations were compared with these six approaches. There was poor agreement about the sensibility of the six systems. Only one of the systems was suitable for all four types of questions we considered (effectiveness, harm, diagnosis and prognosis). None of the systems was considered usable for all of the target groups we considered (professionals, patients and policy makers). The raters found low reproducibility of judgements made using all six systems. Systems used by 51 organisations that sponsor clinical practice guidelines included a number of minor variations of the six systems that we critically appraised. All of the currently used approaches to grading levels of evidence and the strength of recommendations have important shortcomings.
975 citations
TL;DR: In this paper, the authors examine the role of knowledge stocks and flows in establishing competitive advantage for clusters and firms, and specifically address knowledge development at the firm and the cluster level.
Abstract: Researchers in international strategy are increasingly investigating the role of regional clusters as features of international industry, most concerned with the competitive role of clusters and the competitive interactions among cluster firms. We look instead at knowledge sharing between firms through the medium of untraded interdependencies—knowledge exchanged informally and without explicit compensation. We specifically address knowledge development at the firm and the cluster level and examine the role of knowledge stocks and flows in establishing competitive advantage for clusters and firms.
945 citations
TL;DR: NICE has to make both scientific and social value judgments when appraising health technologies and developing clinical guidelines for the NHS, according to its chair and previous vice chair.
Abstract: NICE has to make both scientific and social value judgments when appraising health technologies and developing clinical guidelines for the NHS. Here, its chair and previous vice chair explain the rationale behind the decisions
790 citations
TL;DR: In this article, a small population of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously identified as a marker of stem cells in prostate epithelia.
Abstract: Stem cells are clonogenic cells with self-renewal and differentiation properties, which may represent a major target for genetic damage leading to prostate cancer and benign prostatic hyperplasia. Stem cells remain poorly characterised because of the absence of specific molecular markers that permit us to distinguish them from their progeny, the transit amplifying cells, which have a more restricted proliferative potential. Human CD133 antigen, also known as AC133, was recently identified as a haematopoietic stem cell marker. Here we show that a small population (approximately 1%) of human prostate basal cells express the cell surface marker CD133 and are restricted to the alpha(2)beta(1)(hi) population, previously shown to be a marker of stem cells in prostate epithelia. alpha(2)beta(1)(hi)/CD133(+) cells exhibit two important attributes of epithelial stem cells: they possess a high in vitro proliferative potential and can reconstitute prostatic-like acini in immunocompromised male nude mice.
783 citations
TL;DR: There is convincing evidence, collectively from human intervention studies, epidemiological studies, animal studies and experimental studies, for an association between the amount and frequency of free sugars intake and dental caries.
Abstract: Oral health is related to diet in many ways, for example, nutritional influences on craniofacial development, oral cancer and oral infectious diseases. Dental diseases impact considerably on self-esteem and quality of life and are expensive to treat. The objective of this paper is to review the evidence for an association between nutrition, diet and dental diseases and to present dietary recommendations for their prevention. Nutrition affects the teeth during development and malnutrition may exacerbate periodontal and oral infectious diseases. However, the most significant effect of nutrition on teeth is the local action of diet in the mouth on the development of dental caries and enamel erosion. Dental erosion is increasing and is associated with dietary acids, a major source of which is soft drinks. Despite improved trends in levels of dental caries in developed countries, dental caries remains prevalent and is increasing in some developing countries undergoing nutrition transition. There is convincing evidence, collectively from human intervention studies, epidemiological studies, animal studies and experimental studies, for an association between the amount and frequency of free sugars intake and dental caries. Although other fermentable carbohydrates may not be totally blameless, epidemiological studies show that consumption of starchy staple foods and fresh fruit are associated with low levels of dental caries. Fluoride reduces caries risk but has not eliminated dental caries and many countries do not have adequate exposure to fluoride. It is important that countries with a low intake of free sugars do not increase intake, as the available evidence shows that when free sugars consumption is ,15‐20 kg/yr (,6‐10% energy intake), dental caries is low. For countries with high consumption levels it is recommended that national health authorities and decision-makers formulate country-specific and community-specific goals for reducing the amount of free sugars aiming towards the recommended maximum of no more than 10% of energy intake. In addition, the frequency of consumption of foods containing free sugars should be limited to a maximum of 4 times per day. It is the responsibility of national authorities to ensure implementation of feasible fluoride programmes for their country.
TL;DR: Antibodies against alternatively spliced products on cancer cells are currently in clinical trials, and competitive reverse transcription-PCR across regions of alternative splicing is being used as a simple diagnostic test.
Abstract: Pre-mRNA splicing is a sophisticated and ubiquitous nuclear process, which is a natural source of cancer-causing errors in gene expression. Intronic splice site mutations of tumor suppressor genes often cause exon-skipping events that truncate proteins just like classical nonsense mutations. Also, many studies over the last 20 years have reported cancer-specific alternative splicing in the absence of genomic mutations. Affected proteins include transcription factors, cell signal transducers, and components of the extracellular matrix. Antibodies against alternatively spliced products on cancer cells are currently in clinical trials, and competitive reverse transcription-PCR across regions of alternative splicing is being used as a simple diagnostic test. As well as being associated with cancer, the nature of the alternative gene products is usually consistent with an active role in cancer; therefore, the alternative splicing process itself is a potential target for gene therapy.
TL;DR: The results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation and blocks TGF‐β‐induced growth arrest by indirectly reducing T GF‐β/ALK5 signalling.
Abstract: Endoglin is a transmembrane accessory receptor for transforming growth factor-β (TGF-β) that is predominantly expressed on proliferating endothelial cells in culture and on angiogenic blood vessels in vivo. Endoglin, as well as other TGF-β signalling components, is essential during angiogenesis. Mutations in endoglin and activin receptor-like kinase 1 (ALK1), an endothelial specific TGF-β type I receptor, have been linked to the vascular disorder, hereditary haemorrhagic telangiectasia. However, the function of endoglin in TGF-β/ALK signalling has remained unclear. Here we report that endoglin is required for efficient TGF-β/ALK1 signalling, which indirectly inhibits TGF-β/ALK5 signalling. Endothelial cells lacking endoglin do not grow because TGF-β/ALK1 signalling is reduced and TGF-β/ALK5 signalling is increased. Surviving cells adapt to this imbalance by downregulating ALK5 expression in order to proliferate. The ability of endoglin to promote ALK1 signalling also explains why ectopic endoglin expression in endothelial cells promotes proliferation and blocks TGF-β-induced growth arrest by indirectly reducing TGF-β/ALK5 signalling. Our results indicate a pivotal role for endoglin in the balance of ALK1 and ALK5 signalling to regulate endothelial cell proliferation.
TL;DR: A special profile of six papers demonstrating the development in methodology used in species distribution modelling can be found in this paper, where information-theoretic approaches based on Akaike's information criterion allow the selection of a best approximation model or a subset of models from a set of candidates.
Abstract: 1The management of both desirable and undesirable species requires an understanding of the factors determining their distribution. Quantitative distribution models offer simple methods for formulating the species–habitat link and the means not only for predicting where species should occur, but also for understanding the factors involved. Generalized linear modelling, in particular, links the incidence of species to habitat variables, and has increasingly formed the backbone of the modelling approaches used. New ‘data technologies’, such as remote sensing and geographical information systems, have further broadened these modelling applications to almost any ecological system and any species for which there are distribution data.2Many previous approaches have aimed to identify the most parsimonious model with the best suite of predictors, selected on the basis of null hypothesis testing. However, information-theoretic approaches based on Akaike's information criterion allow the selection of a best approximating model or a subset of models from a set of candidates. Information-theoretic approaches require a deeper understanding of the biology of the system modelled and may well become an improved paradigm for species distribution modelling.3Synthesis and applications. This special profile of six papers demonstrates the development in methodology used in species distribution modelling. The papers show how information-theoretic approaches can be coupled with emerging data technologies to address issues of conservation significance. With conservation biology and applied ecology at the forefront of many of the basic science developments so far, we expect these methods to pervade other areas of ecological research more fully in future.
TL;DR: The aim of this cross-sectional study was to establish the pattern of cerebral atrophy on MRI in Parkinson's disease patients with dementia, and voxel-based morphometry (VBM) was used to provide an unbiased means of investigating brain volume loss.
Abstract: Parkinson's disease is a common neurodegenerative disorder primarily characterized by rigidity, tremor and bradykinesia. Cognitive impairment and neuropsychiatric symptoms are frequent in Parkinson's disease, with a 70% cumulative incidence of dementia. The aim of this cross-sectional study was to establish the pattern of cerebral atrophy on MRI in Parkinson's disease patients with dementia. We used voxel-based morphometry (VBM) to provide an unbiased means of investigating brain volume loss. Whole brain structural T1-weighted MRI scans from Parkinson's disease patients with dementia (PDD, n = 26), Parkinson's disease patients without dementia (n = 31), Alzheimer's disease patients (n = 28), patients with dementia with Lewy bodies (DLB, n = 17) and control subjects (n = 36) were acquired. Images were analysed using SPM99 and the optimized method of VBM. Reduced grey matter volume in PDD patients compared with controls was observed bilaterally in the temporal lobe, including the hippocampus and parahippocampal gyrus, and in the occipital lobe, the right frontal lobe and the left parietal lobe, as well as some subcortical regions. Parkinson's disease patients without dementia showed reduced grey matter volume in the frontal lobe compared with control subjects. There was significant grey matter atrophy bilaterally in the occipital lobe of PDD patients compared with Parkinson's disease patients. In addition, significant temporal lobe atrophy, including the hippocampus and parahippocampal gyrus was detected in Alzheimer's disease relative to PDD. No significant volumetric differences were observed in PDD compared with DLB. Thus, Parkinson's disease involves grey matter loss in frontal areas. In PDD, this extends to temporal, occipital and subcortical areas, with occipital atrophy in PDD being the only difference between the two groups. This provides important information about the pattern of cerebral atrophy in Parkinson's disease and PDD.
TL;DR: Patients who have marked functional limitation, severe pain, low mental health score, and other comorbid conditions before total knee arthroplasty are more likely to have a worse outcome at one year and two years postoperatively.
Abstract: Background: The relief of pain and the restoration of functional activities are the main outcomes of primary total knee arthroplasty for the treatment of osteoarthritis. This paper examines the preoperative predictors of pain and functional outcome at one and two years following total knee arthroplasty.
Methods: Patients were recruited for a prospective observational study of primary total knee arthroplasty for the treatment of osteoarthritis from centers in the United States, the United Kingdom, and Australia. Research assistants recruited the patients and collected the clinical history and physical examination data preoperatively and at three, twelve, and twenty-four months postoperatively. The Western Ontario and McMaster University Osteoarthritis Index (WOMAC), Short Form-36 (SF-36), and demographic data were obtained by self-administered patient questionnaires.
Results: We recruited 860 patients and obtained one-year WOMAC data on 759 patients (88%) and two-year data on 701 (82%). The mean age was seventy years, and 59% of the patients were female. Using hierarchical regression models, we found that the most significant preoperative predictors of worse scores on the pain and function domains of the WOMAC scale and on the physical functioning domain of the SF-36 at one and two years postoperatively were low preoperative scores, a higher number of comorbid conditions, and a low SF-36 mental health score. After adjusting for these predictors, we found that the functional status of the patients from the United Kingdom was significantly worse than that of the patients from the other countries and the difference was clinically important at both the one-year and two-year follow-up examination (p < 0.0005). The mean WOMAC pain scores for the three countries were not significantly different at one year, and, although they were significantly different at two years (p = 0.025), the difference was not clinically important.
Conclusions: Patients who have marked functional limitation, severe pain, low mental health score, and other comorbid conditions before total knee arthroplasty are more likely to have a worse outcome at one year and two years postoperatively. After adjusting for these predictors, it was found that patients from the United Kingdom had significantly worse functional outcomes but similar pain relief compared with those from the United States and Australia.
Level of Evidence: Prognostic study, Level I-1 (prospective study). See Instructions to Authors for a complete description of levels of evidence.
TL;DR: Histone deacetylase 1 (HDAC1) is a co‐repressor involved in differentiation and proliferation control and targets a number of transcription factors including p53.
Abstract: BACKGROUND
Histone deacetylase 1 (HDAC1) is a co-repressor involved in differentiation and proliferation control. It is upregulated in malignant compared to benign tissue, and targets a number of transcription factors including p53.
METHODS
By immunohistochemistry, HDAC1 protein expression was investigated in human prostate specimens and the CWR22 mouse xenograft model. Flow cytometry and deconvolution immunofluorescence were also performed.
RESULTS
HDAC1 was upregulated in pre-malignant and malignant lesions, with the highest increase in expression in hormone refractory (HR) cancer. Using the CWR22 xenograft model we showed androgen dependent regulation of HDAC1. HDAC1 overexpression led to a significant increase in proliferation and a shift towards the undifferentiated cytokeratin (CK) profile in a PC3M derivative clone constitutively expressing HDAC1.
CONCLUSION
This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence. © 2004 Wiley-Liss, Inc.
TL;DR: AG14361 is, to the authors' knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
Abstract: Background: Poly(ADP-ribose) polymerase-1 (PARP-1) facilitates the repair of DNA strand breaks. Inhibiting PARP-1 increases the cytotoxicity of DNA-damaging chemotherapy and radiation therapy in vitro. Because classical PARP-1 inhibitors have limited clinical utility, we investigated whether AG14361, a novel potent PARP-1 inhibitor (inhibition constant <5 nM), enhances the effects of chemotherapy and radiation therapy in human cancer cell cultures and xenografts. Methods: The effect of AG14361 on the antitumor activity of the DNA alkylating agent temozolomide, topoisomerase I poisons topotecan or irinotecan, or x-irradiation or gamma-radiation was investigated in human cancer cell lines A549, LoVo, and SW620 by proliferation and survival assays and in xenografts in mice by tumor volume determination. The specificity of AG14361 for PARP-1 was investigated by microarray analysis and by antiproliferation and acute toxicity assays in PARP-1(-/-) and PARP-1(+/+) cells and mice. After intraperitoneal administration, the concentration of AG14361 was determined in mouse plasma and tissues, and its effect on PARP-1 activity was determined in tumor homogenates. All statistical tests were two-sided. Results: AG14361 at 0.4 muM did not affect cancer cell gene expression or growth, but it did increase the antiproliferative activity of temozolomide (e.g., in LoVo cells by 5.5-fold, 95% confidence interval [CI] = 4.9-fold to 5.9-fold; P = .004) and topotecan (e.g., in LoVo cells by 1.6-fold, 95% CI = 1.3-fold to 1.9-fold; P = .002) and inhibited recovery from potentially lethal gamma-radiation damage in LoVo cells by 73% (95% CI = 48% to 98%). In vivo, nontoxic doses of AG14361 increased the delay of LoVo xenograft growth induced by irinotecan, x-irradiation, or temozolomide by two- to threefold. The combination of AG14361 and temozolomide caused complete regression of SW620 xenograft tumors. AG14361 was retained in xenografts in which PARP-1 activity was inhibited by more than 75% for at least 4 hours. Conclusion: AG14361 is, to our knowledge, the first high-potency PARP-1 inhibitor with the specificity and in vivo activity to enhance chemotherapy and radiation therapy of human cancer.
TL;DR: Genotypes at the codon 620 polymorphism are examined to suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.
Abstract: The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, is a powerful inhibitor of T cell activation. Recently, a single nucleotide polymorphism (SNP), encoding a functional arginine to tryptophan residue change at LYP codon 620 has been shown to be associated with type 1 diabetes and other autoimmune disorders. We have used a PCR-restriction fragment (XcmI) assay to examine genotypes at the codon 620 polymorphism in 549 unrelated probands with Graves' disease, 104 unrelated subjects with autoimmune Addison's disease and 429 controls. The T nucleotide at the SNP, encoding the tryptophan 620 residue, was present in 151 of 1098 (13.8%) Graves' disease alleles compared to 67 of 858 (7.8%) control alleles (chi(2) = 17.2, p = 3.4 x 10(-5)' odds ratio = 1.88, 5-95% confidence intervals [CI] 1.39 to 2.55). Similarly, the T nucleotide at the codon 620 SNP was present in 26 of 208 (12.5%) Addison's disease alleles vs 7.8% of controls (chi(2) = 4.63, p = 0.031; odds ratio = 1.69, 5-95% CI 1.04 to 2.73). These data suggest that this LYP polymorphism is a susceptibility allele for Graves' disease with a major effect, and which is likely to have a role in many other autoimmune conditions.
TL;DR: The TVT procedure appears to be as effective as colposuspension for the treatment of urodynamic stress incontinence at 2 years, and when data were analyzed on an intention-to-treat basis, this study was undertaken to compare tension-free vaginal tape with colpos Suspension as the primary treatment for stressincontinence.
TL;DR: The review suggests that interventions that were previously thought to be ineffective (e.g., dissemination of educational materials) may have modest but worthwhile benefits and that multifaceted interventions were found to be no more effective than single interventions.
Abstract: One of the most common findings from health services research is a failure to routinely translate research findings into daily practice. Previous systematic reviews of strategies to promote the uptake of research findings suffered from a range of methodologic problems that have been addressed in a more recent systematic review of guideline dissemination and implementation strategies. Changes in practitioner behavior; in the desired direction, were reported in 86% of the comparisons made. The median effect size overall was approximately 10% improvement in absolute terms. The review suggests that interventions that were previously thought to be ineffective (e.g., dissemination of educational materials) may have modest but worthwhile benefits. Also, multifaceted interventions, previously thought to be more effective than single interventions, were found to be no more effective than single interventions. Overall, there is an imperfect evidence base for decision makers to work from. Many studies had methodologic weaknesses, and reporting of this kind of research is generally poor, making the generalizability of study findings frequently uncertain. A better theoretical underpinning of studies would make this body of research more useful.
TL;DR: The results suggest the depletion of functionally important consumer species by exploitation can indirectly influence coral reef ecosystem structure and function at the scale of islands.
Abstract: Fisheries exploitation provides the opportunity to examine the ecosystem-scale biodiversity consequences of predator removal. We document predatory reef fish densities, coral-eating starfish densities and coral reef structure along a 13-island gradient of subsistence exploitation in Fiji. Along the fishing intensity gradient, predator densities declined by 61% and starfish densities increased by three orders of magnitude. Reefbuilding corals and coralline algae declined by 35% and were replaced by non-reef building taxa (mainly filamentous algae), as a result of starfish predation. Starfish populations exhibited thresholds and Allee-type dynamics: population growth was negative under light fishing intensities and high predator densities, and positive on islands with higher fishing intensities and low predator densities. These results suggest the depletion of functionally important consumer species by exploitation can indirectly influence coral reef ecosystem structure and function at the scale of islands.
TL;DR: Age, number of teeth and cultural background are important variables influencing oral health-related quality of life.
Abstract: – Age and loss of teeth can be expected to have a complex relationship with oral health-related quality of life. This study aimed to explain how age and tooth loss affect the impact of oral health on daily living using the short form, 14-item Oral Health Impact Profile (OHIP-14) on national population samples of dentate adults from the UK (1998 UK Adult Dental Health Survey) and Australia (1999 National Dental Telephone Interview Survey). After correcting for key covariables, increasing age was associated with better mean impact scores in both populations. Those aged 30–49 years in Australia showed the worst (highest) scores. In the UK, those aged under 30 showed the highest scores. In both countries, adults aged 70+ showed much better scores than the rest (P < 0.001). When corrected for age, the independent effect of tooth loss was that the worst scores were found where there were fewer than 17 natural teeth in the UK and fewer than 21 teeth in Australia. People with 25 or more teeth averaged much better scores than all other groups (P < 0.001), although there were differences in pattern between countries. When Australians were analysed by region of birth, the pattern of scores by tooth loss for British/Irish immigrants was strikingly similar to that for the UK sample. First-generation immigrants from elsewhere showed much worse overall scores and a profoundly different pattern to the Australian- and British-born groups. Age, number of teeth and cultural background are important variables influencing oral health-related quality of life.
University of Cambridge1, University of Chicago2, Yale University3, University of California, San Francisco4, University of Illinois at Urbana–Champaign5, University of California, San Diego6, Harvard University7, Vanderbilt University8, Newcastle University9, Baylor College of Medicine10, Kennedy Krieger Institute11
TL;DR: Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
Abstract: The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
TL;DR: The isolation of metabolites indicative of anaerobic hydrocarbon degradation from a large fraction of 77 degraded oil samples from both marine and lacustrine sources from around the world, including the volumetrically important Canadian tar sands are reported, suggesting that anaer aerobic degradation is a common process in biodegraded subsurface oil reservoirs.
Abstract: Biodegradation of crude oil in subsurface petroleum reservoirs is an important alteration process with major economic consequences. Aerobic degradation of petroleum hydrocarbons at the surface is well documented and it has long been thought that the flow of oxygen- and nutrient-bearing meteoric waters into reservoirs was necessary for in-reservoir petroleum biodegradation. The occurrence of biodegraded oils in reservoirs where aerobic conditions are unlikely, together with the identification of several anaerobic microorganisms in oil fields and the discovery of anaerobic hydrocarbon biodegradation mechanisms, suggests that anaerobic degradation processes could also be responsible. The extent of anaerobic hydrocarbon degradation processes in the world's deep petroleum reservoirs, however, remains strongly contested. Moreover, no organism has yet been isolated that has been shown to degrade hydrocarbons under the conditions found in deep petroleum reservoirs. Here we report the isolation of metabolites indicative of anaerobic hydrocarbon degradation from a large fraction of 77 degraded oil samples from both marine and lacustrine sources from around the world, including the volumetrically important Canadian tar sands. Our results therefore suggest that anaerobic hydrocarbon degradation is a common process in biodegraded subsurface oil reservoirs.
TL;DR: This review summarizes current knowledge of the prevalence of human mitochondrial disorders--data that has important implications for the provision of health care and adequate resources for research into the pathogenesis and treatment of these disorders.
TL;DR: Carnitine palmitoyl transferase I exerts approximately 80% of control over pathway flux under normal conditions, but when one or more enzyme activities are attenuated because of a mutation, the major site of flux control will change.
Abstract: Mitochondrial beta-oxidation is a complex pathway involving, in the case of saturated straight chain fatty acids of even carbon number, at least 16 proteins which are organized into two functional subdomains; one associated with the inner face of the inner mitochondrial membrane and the other in the matrix. Overall, the pathway is subject to intramitochondrial control at multiple sites. However, at least in the liver, carnitine palmitoyl transferase I exerts approximately 80% of control over pathway flux under normal conditions. Clearly, when one or more enzyme activities are attenuated because of a mutation, the major site of flux control will change.
TL;DR: In this paper, the authors apply DEA windows analysis to a sample of the worlds major container ports in order to deduce their relative efficiency, concluding that existing programming methods for estimating efficiency are inadequate in capturing the long-term increased efficiency and competitiveness that accrue from significant investments.
Abstract: There have been various analyses of the efficiency of container port (or terminal) production using Data Envelopment Analysis (DEA) based on cross-sectional data. When time is not considered, the efficiency results derived using this approach can be biased. In order to overcome this problem, this paper applies DEA windows analysis, utilising panel data, to a sample of the worlds major container ports in order to deduce their relative efficiency. The results suggest that estimates of container port efficiency fluctuate over time. The paper concludes that existing programming methods for estimating efficiency are inadequate in capturing the long-term increased efficiency and competitiveness that accrue from significant investments.
TL;DR: The dex/CRH test is abnormal in both remitted and non-remitted patients with bipolar disorder, and is possibly indicative of the core pathophysiological process in this illness.
Abstract: Background Hypothalamic-pituitary-adrenal (HPA) axis function, as variously measured by the responses to the combined dexamethasone/corticotrophin-releasing hormone (dex/CRH) test, the dexamethasone suppression test (DST) and basal cortisol levels, has been reported to be abnormal in bipolar disorder.
Aims To test the hypothesis that HPA axis dysfunction persists in patients in remission from bipolar disorder.
Method Salivary cortisol levels and the plasma cortisol response to the DST and dex/CRH test were examined in 53 patients with bipolar disorder, 27 of whom fulfilled stringent criteria for remission, and in 28 healthy controls. Serum dexamethasone levels were measured.
Results Patients with bipolar disorder demonstrated an enhanced cortisol response to the dex/CRH test compared with controls ( P =0.001). This response did not differ significantly between remitted and non-remitted patients. These findings were present after the potentially confounding effects of dexamethasone levels were accounted for.
Conclusions The dex/CRH test is abnormal in both remitted and non-remitted patients with bipolar disorder. This measure of HPA axis dysfunction is a potential trait marker in bipolar disorder and thus possibly indicative of the core pathophysiological process in this illness.
TL;DR: Dopamine transporter loss can be detected in vivo using FP-CIT SPECT in DLB and both region of interest analysis and visual ratings provided good separation between DLBs and AD.
Abstract: Background Dementia with Lewy bodies (DLB) is a common form of late-life dementia that can be difficult to differentiate from other disorders, especially Alzheimer disease (AD), during life. At autopsy the striatal dopaminergic transporter is reduced. Objectives To examine the extent and pattern of dopamine transporter loss using iodine I 123–radiolabeled 2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT) with single-photon emission computed tomography (SPECT) in DLBs compared with other dementias and to assess its potential to enhance a differential diagnosis. Design Cohort study comparing FP-CIT with criterion standard of consensus clinical diagnosis. Setting General hospital. Participants One hundred sixty-four older subjects (33 healthy older control subjects, 34 with NINCDS/ADRDA [National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association]-confirmed AD, 23 with consensus guideline–confirmed DLB, 38 with United Kingdom's Parkinson Disease Society Brain Bank–confirmed Parkinson disease [PD], and 36 with PD and dementia). Interventions Injection of123I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane with SPECT scan performed at 4 hours. Main Outcome Measures Visual ratings of scans and region of interest analysis. Results Significant reductions (P Conclusions Dopamine transporter loss can be detected in vivo using FP-CIT SPECT in DLB. Further studies, especially of subjects with DLB without PD, are required to fully establish use in clinical practice.