Major Impact (major + impact)

Distribution by Scientific Domains
Distribution within Medical Sciences

Selected Abstracts

Books and Multimedia Reviews

Article first published online: 26 JAN 2010
Book reviewed in this article: Chemical Dynamics in Extreme Environments, Volume 11 of Advanced Series in Physical Chemistry edited by Rainer A. Dressler. Storms in Space by John Freeman. Major Impacts and Plate Tectonics: A Model for the Phanerozoic Evolution of the Earth's Lithosphere by Neville J. Price. Meteorite Hunter: The Search For Siberian Meteorite Craters by Roy A. Gallant. [source]

Control of muscle blood flow during exercise: local factors and integrative mechanisms

I. Sarelius
Abstract Understanding the control mechanisms of blood flow within the vasculature of skeletal muscle is clearly fascinating from a theoretical point of view due to the extremely tight coupling of tissue oxygen demands and blood flow. It also has practical implications as impairment of muscle blood flow and its prevention/reversal by exercise training has a major impact on widespread diseases such as hypertension and diabetes. Here we analyse the role of mediators generated by skeletal muscle activity on smooth muscle relaxation in resistance vessels in vitro and in vivo. We summarize their cellular mechanisms of action and their relative roles in exercise hyperaemia with regard to early and late responses. We also discuss the consequences of interactions among mediators with regard to identifying their functional significance. We focus on (potential) mechanisms integrating the action of the mediators and their effects among the cells of the intact arteriolar wall. This integration occurs both locally, partly due to myoendothelial communication, and axially along the vascular tree, thus enabling the local responses to be manifest along an entire functional vessel path. Though the concept of signal integration is intriguing, its specific role on the control of exercise hyperaemia and the consequences of its modulation under physiological and pathophysiological conditions still await additional analysis. [source]

A History of Dermatologic Surgery in the United States

William P. Coleman III MD
Background. Dermatologic surgery has a long and distinguished history in the United States. Objective. To examine the specific contributions of American dermatologic surgeons. Method. The medical literature on cutaneous reconstructive and cosmetic surgery for the last century and a half was researched. Results. Numerous American dermatologic surgeons have had a major impact on scientific and technological discoveries in cutaneous surgery. Dermatologic surgeons have been significantly involved in cutaneous surgery since the second half of the 19th century. Dermatologic surgeons have contributed many important advances to the fields of chemical peeling, cryosurgery, dermabrasion, electrosurgery, hair transplantation, soft tissue augmentation, tumescent liposuction, laser surgery, phlebology, Mohs chemosurgery, cutaneous reconstruction, wound healing, botulium toxin, blepharoplasty, and rhytidectomy. Conclusion. Dermatologic surgeons in the United States have contributed significantly to the history of reconstructive and cosmetic surgery. Dermatologic surgeons have been leaders in advancing this field and are poised to continue in the future. [source]

Organ-specific lymphangiectasia, arrested lymphatic sprouting, and maturation defects resulting from gene-targeting of the PI3K regulatory isoforms p85,, p55,, and p50,

Carla Mouta-Bellum
Abstract The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85,, p55,, and p50, impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. Pik3r1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the Pik3r1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor-, co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that Pik3r1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis. Developmental Dynamics 238:2670,2679, 2009. © 2009 Wiley-Liss, Inc. [source]

Incidence and characteristics of lower limb amputations in people with diabetes

S. Fosse
Abstract Aims To estimate the incidence, characteristics and potential causes of lower limb amputations in France. Methods Admissions with lower limb amputations were extracted from the 2003 French national hospital discharge database, which includes major diagnoses and procedures performed during hospital admissions. For each patient, diabetes was defined by its record in at least one admission with or without lower limb amputation in the 2002,2003 databases. Results In 2003, 17 551 admissions with lower limb amputation were recorded, involving 15 353 persons, which included 7955 people with diabetes. The crude incidence of lower limb amputation in people with diabetes was 378/100 000 (349/100 000 when excluding traumatic lower limb amputation). The sex and age standardized incidence was 12 times higher in people with than without diabetes (158 vs. 13/100 000). Renal complications and peripheral arterial disease and/or neuropathy were reported in, respectively, 30% and 95% of people with diabetes with lower limb amputation. Traumatic causes (excluding foot contusion) and bone diseases (excluding foot osteomyelitis) were reported in, respectively, 3% and 6% of people with diabetes and lower limb amputation, and were 5 and 13 times more frequent than in people without diabetes. Conclusions We provide a first national estimate of lower limb amputation in France. We highlight its major impact on people with diabetes and its close relationship with peripheral arterial disease/neuropathy and renal complications in the national hospital discharge database. We do not suggest the exclusion of traumatic causes when studying the epidemiology of lower limb amputation related to diabetes, as diabetes may contribute to amputation even when the first cause appears to be traumatic. [source]

How much of a priority is treating erectile dysfunction?

A study of patients' perceptions
Abstract Background Erectile dysfunction (ED) is one complication of diabetes for which the treatment is rationed. Despite considerable public debate there has been no formal assessment of the views of patients and sufferers of the priority of treating ED. Aims To determine the perceptions of diabetic patients of the relative priority of treating ED in comparison with treatments for other diabetic complications and common medical conditions. Methods Psychological measures were used to assess subjects' perceptions of the relative importance of ED in comparison with eight other common problems (blindness, foot ulcers, high blood pressure, impotence, kidney disease, high cholesterol, migraine, mild indigestion and sleeping difficulties). The concept of willingness to pay was used to assess the amount per month participants would be prepared to pay for treatment for ED and other conditions. Four groups (controls, healthy diabetic men, impotent diabetic men and impotent diabetic men not in a sexual relationship) were studied. Results Significant differences were found between the four groups with regard to the ranking of the importance of ED compared with other health problems. Impotent diabetic male patients were prepared to pay more for treatment for their condition than all other conditions except blindness and renal failure. Conclusions Men with diabetes, in particular ED sufferers, believe ED has a major impact on quality of life and is as important to treat as many other conditions associated with diabetes. Diabet. Med. 20, 205,209 (2003) [source]

Evolution of invertebrate nervous systems: the Chaetognatha as a case study

ACTA ZOOLOGICA, Issue 1 2010
Steffen Harzsch
Abstract Harzsch, S. and Wanninger, A. 2010. Evolution of invertebrate nervous systems: the Chaetognatha as a case study. ,Acta Zoologica (Stockholm) 91: 35,43 Although recent molecular studies indicate that Chaetognatha may be one of the earliest Bilaterian offshoots, the phylogenetic position of this taxon still is a matter of ongoing debate. In this contribution, we review recent attempts to contribute phylogenetic information on the Chaetognatha by analysing structure and development of their nervous system (neurophylogeny). Analysing this group of organisms also has a major impact on our understanding of nervous system evolution in Bilateria. We review recent evidence from this field and suggest that Urbilateria already was equipped with the genetic toolkit required to build a complex, concentrated central nervous system (CNS), although this was not expressed phenotypically so that Urbilateria was equipped with a nerve plexus and not a CNS. This implies that in the deep metazoan nodes, concentration of the ancestral plexus occurred twice independently, namely once after the protostome,deuterostome split on the branch leading to the protostomes (resulting in a ventrally positioned nerve cord) and once along the chordate line (with a dorsal nerve cord). [source]

The relation between different dimensions of alcohol consumption and burden of disease: an overview

ADDICTION, Issue 5 2010
Jürgen Rehm
ABSTRACT Aims As part of a larger study to estimate the global burden of disease and injury attributable to alcohol: to evaluate the evidence for a causal impact of average volume of alcohol consumption and pattern of drinking on diseases and injuries; to quantify relationships identified as causal based on published meta-analyses; to separate the impact on mortality versus morbidity where possible; and to assess the impact of the quality of alcohol on burden of disease. Methods Systematic literature reviews were used to identify alcohol-related diseases, birth complications and injuries using standard epidemiological criteria to determine causality. The extent of the risk relations was taken from meta-analyses. Results Evidence of a causal impact of average volume of alcohol consumption was found for the following major diseases: tuberculosis, mouth, nasopharynx, other pharynx and oropharynx cancer, oesophageal cancer, colon and rectum cancer, liver cancer, female breast cancer, diabetes mellitus, alcohol use disorders, unipolar depressive disorders, epilepsy, hypertensive heart disease, ischaemic heart disease (IHD), ischaemic and haemorrhagic stroke, conduction disorders and other dysrhythmias, lower respiratory infections (pneumonia), cirrhosis of the liver, preterm birth complications and fetal alcohol syndrome. Dose,response relationships could be quantified for all disease categories except for depressive disorders, with the relative risk increasing with increased level of alcohol consumption for most diseases. Both average volume and drinking pattern were linked causally to IHD, fetal alcohol syndrome and unintentional and intentional injuries. For IHD, ischaemic stroke and diabetes mellitus beneficial effects were observed for patterns of light to moderate drinking without heavy drinking occasions (as defined by 60+ g pure alcohol per day). For several disease and injury categories, the effects were stronger on mortality compared to morbidity. There was insufficient evidence to establish whether quality of alcohol had a major impact on disease burden. Conclusions Overall, these findings indicate that alcohol impacts many disease outcomes causally, both chronic and acute, and injuries. In addition, a pattern of heavy episodic drinking increases risk for some disease and all injury outcomes. Future studies need to address a number of methodological issues, especially the differential role of average volume versus drinking pattern, in order to obtain more accurate risk estimates and to understand more clearly the nature of alcohol,disease relationships. [source]

Stripping Analysis at Bismuth Electrodes: A Review

ELECTROANALYSIS, Issue 15-16 2005
Joseph Wang
Abstract For many years mercury electrodes were the transducer of choice in stripping voltammetry of trace metals owing to their high sensitivity, reproducibility, and renewability. However, because of the toxicity of mercury, alternative (,environmentally friendly') electrode materials are highly desired for both centralized and field applications. Recently introduced bismuth electrodes offer a very attractive alternative to commonly used mercury electrodes. Such electrodes display well-defined, undistorted and highly reproducible response, favorable resolution of neighboring peaks, high hydrogen evolution, with good signal-to-background characteristics comparable to those of common mercury electrodes. The attractive stripping behavior of bismuth electrodes reflects the ability of bismuth to form ,fused' multicomponent alloys with heavy metals. Bismuth stripping electrodes thus hold great promise for decentralized metal testing, with applications ranging from continuous remote sensing to single-use measurements. Fundamental studies aimed at understanding the behavior of bismuth film electrodes should lead to rational preparation and operation of reliable alternative (,non,mercury') stripping electrodes that would have a major impact upon electroanalysis of trace metals. This article reviews the development, behavior, scope and prospects of bismuth electrodes for stripping-based electrochemical measurements of trace metals. [source]

Limits of life in MgCl2 -containing environments: chaotropicity defines the window

John E. Hallsworth
Summary The biosphere of planet Earth is delineated by physico-chemical conditions that are too harsh for, or inconsistent with, life processes and maintenance of the structure and function of biomolecules. To define the window of life on Earth (and perhaps gain insights into the limits that life could tolerate elsewhere), and hence understand some of the most unusual biological activities that operate at such extremes, it is necessary to understand the causes and cellular basis of systems failure beyond these windows. Because water plays such a central role in biomolecules and bioprocesses, its availability, properties and behaviour are among the key life-limiting parameters. Saline waters dominate the Earth, with the oceans holding 96.5% of the planet's water. Saline groundwater, inland seas or saltwater lakes hold another 1%, a quantity that exceeds the world's available freshwater. About one quarter of Earth's land mass is underlain by salt, often more than 100 m thick. Evaporite deposits contain hypersaline waters within and between their salt crystals, and even contain large subterranean salt lakes, and therefore represent significant microbial habitats. Salts have a major impact on the nature and extent of the biosphere, because solutes radically influence water's availability (water activity) and exert other activities that also affect biological systems (e.g. ionic, kosmotropic, chaotropic and those that affect cell turgor), and as a consequence can be major stressors of cellular systems. Despite the stressor effects of salts, hypersaline environments can be heavily populated with salt-tolerant or -dependent microbes, the halophiles. The most common salt in hypersaline environments is NaCl, but many evaporite deposits and brines are also rich in other salts, including MgCl2 (several hundred million tonnes of bischofite, MgCl2·6H2O, occur in one formation alone). Magnesium (Mg) is the third most abundant element dissolved in seawater and is ubiquitous in the Earth's crust, and throughout the Solar System, where it exists in association with a variety of anions. Magnesium chloride is exceptionally soluble in water, so can achieve high concentrations (> 5 M) in brines. However, while NaCl-dominated hypersaline environments are habitats for a rich variety of salt-adapted microbes, there are contradictory indications of life in MgCl2 -rich environments. In this work, we have sought to obtain new insights into how MgCl2 affects cellular systems, to assess whether MgCl2 can determine the window of life, and, if so, to derive a value for this window. We have dissected two relevant cellular stress-related activities of MgCl2 solutions, namely water activity reduction and chaotropicity, and analysed signatures of life at different concentrations of MgCl2 in a natural environment, namely the 0.05,5.05 M MgCl2 gradient of the seawater : hypersaline brine interface of Discovery Basin , a large, stable brine lake almost saturated with MgCl2, located on the Mediterranean Sea floor. We document here the exceptional chaotropicity of MgCl2, and show that this property, rather than water activity reduction, inhibits life by denaturing biological macromolecules. In vitro, a test enzyme was totally inhibited by MgCl2 at concentrations below 1 M; and culture medium with MgCl2 concentrations above 1.26 M inhibited the growth of microbes in samples taken from all parts of the Discovery interface. Although DNA and rRNA from key microbial groups (sulfate reducers and methanogens) were detected along the entire MgCl2 gradient of the seawater : Discovery brine interface, mRNA, a highly labile indicator of active microbes, was recovered only from the upper part of the chemocline at MgCl2 concentrations of less than 2.3 M. We also show that the extreme chaotropicity of MgCl2 at high concentrations not only denatures macromolecules, but also preserves the more stable ones: such indicator molecules, hitherto regarded as evidence of life, may thus be misleading signatures in chaotropic environments. Thus, the chaotropicity of MgCl2 would appear to be a window-of-life-determining parameter, and the results obtained here suggest that the upper MgCl2 concentration for life, in the absence of compensating (e.g. kosmotropic) solutes, is about 2.3 M. [source]

Once-weekly epoetin beta therapy in patients with solid tumours and chemotherapy-induced anaemia: a randomized, double-blind, dose-finding study

P. HERAS md, phd
Anaemia is common in patients receiving chemotherapy, causing symptoms that have a major impact on quality of life (QoL). Epoetin beta rapidly increases haemoglobin (Hb) levels and improves QoL in anaemic patients with a variety of tumours. This was a randomized, double-blind, parallel-group, dose-finding study assessing the efficacy and safety of once-weekly epoetin beta in patients with solid tumours receiving chemotherapy. Adult patients with anaemia (Hb < 11 g/dL) were randomized to receive epoetin beta 30 000 IU or 20 000 IU once weekly for 12 weeks. All patients received oral iron supplementation. Haemoglobin levels, transfusion need and QoL [Functional Assesment of Cancer Therapy-fatigue (FACT-F) subscale score] were assessed at regular intervals. Fifty patients were randomized; 30 patients received epoetin beta 30 000 IU once weekly and 20 received 20 000 IU once weekly. Mean (± SD) increase in Hb from baseline to week 12 was 1.75 ± 2.15 g/dL in the 30 000 IU group (P = 0.008 vs. baseline) and 1.04 ± 1.75 g/dL in the 20 000 IU group (non-significant). Haemoglobin response (increase in Hb ,2 g/dL from baseline) was observed in 78.3% of patients receiving epoetin beta 30 000 IU and 66.7% receiving epoetin beta 20 000 IU. Improvements in FACT-F subscale score were significantly (P < 0.001) correlated with increases in Hb level. Transfusion use was low during the study in both groups. Both epoetin beta regiments were well tolerated and there were no dose-dependant adverse events. Epoetin beta 30 000 IU once weekly is an effective and well-tolerated treatment of anaemia in patients with solid tumours. [source]

The impact of HLA-B micropolymorphism outside primary peptide anchor pockets on the CTL response to CMV

Abstract The factors controlling epitope selection in the T cell response to persistent viruses are not fully understood, and we have examined this issue in the context of four HLA-B*35-binding peptides from the pp65 antigen of human cytomegalovirus, two of which are previously undescribed. Striking differences in the hierarchy of immunodominance between these four epitopes were observed in healthy virus carriers expressing HLA-B*3501 versus B*3508, two HLA-B allotypes that differ by a single amino acid at position 156 (HLA-B*3501, 156Leucine; HLA-B*3508, 156Arginine) that projects from the ,2 helix into the centre of the peptide-binding groove. While HLA-B*3501+ individuals responded most strongly to the 123IPSINVHHY131 and 366HPTFTSQY373 epitopes, HLA-B*3508+ individuals responded preferentially to 103CPSQEPMSIYVY114 and 188FPTKDVAL195. By comparing peptide-MHC association and disassociation rates with peptide immunogenicity, it was clear that dissociation rates correlate more closely with the hierarchy of immunodominance among the four pp65 peptides. These findings demonstrate that MHC micropolymorphism at positions outside the primary anchor residue binding pockets can have a major impact on determinant selection in antiviral T cell responses. Such influences may provide the evolutionary pressure that maintains closely related MHC molecules in diverse human populations. [source]

Institutions, distributional concerns, and public sector reform

As in otherWestern countries, a wave of reform has swept the Danish public sector. The record of these reforms is mixed and paradoxical; an ambiguous delegation of executive authority and radical privatization have been successfully implemented, while other measures, especially contracting out and user democracy or the introduction of greater choice, turn out to have failed. The paper argues that this experience offers two general lessons. First, shortterm costs and benefits are decisive to those who enact and implement public sector reform. Second, institutional factors specific to each type of reorganization have a major impact on the political distribution of costs and benefits. [source]


Forrest S. MostenArticle first published online: 7 DEC 200
Family lawyers are major beneficiaries of the reforms set out in the Family Law Education Reform Project (FLER) Report. This commentary from a veteran family law practitioner explores the needs of the family law bar for the training of law students in practical, interdisciplinary, client-centered lawyering that goes beyond the traditional case method. I trace many of the current innovations evolving in family law practice and how FLER reforms will not only benefit law schools but also have a major impact in the courts and private practice sector. [source]

Neptunium uptake by serum transferrin

FEBS JOURNAL, Issue 7 2005
Isabelle Llorens
Although of major impact in terms of biological and environmental hazards, interactions of actinide cations with biological molecules are only partially understood. Human serum transferrin (Tf) is one of the major iron carriers in charge of iron regulation in the cell cycle and consequently contamination by actinide cations is a critical issue of nuclear toxicology. Combined X-ray absorption spectroscopy (XAS) and near infrared absorption spectrometry were used to characterize a new complex between Tf and Np (IV) with the synergistic nitrilotriacetic acid (NTA) anion. Description of the neptunium polyhedron within the iron coordination site is given. [source]

A socio-economic perspective on gear-based management in an artisanal fishery in south-west Madagascar

Abstract, Artisanal fisheries are important socially, nutritionally and economically. Poverty is common in communities dependent on such fisheries, making sustainable management difficult. Poverty based on material style of life (MSL) was assessed, livelihoods surveyed and the relationship between these factors and fishery data collected using a fish landing study were examined. Species richness, diversity, size and mean trophic level of catches were determined for six fishing gears in an artisanal fishery in south-west Madagascar. There was little livelihood diversification and respondents were highly dependent on the fishery. No relationship was found between poverty and gear use. This suggests that poverty does not have a major impact on the nature of the fishery; however, this study was dominated by poor households, so it remains possible that communities with more variation in wealth might show differences in fishing methods according to this parameter. The fishery was heavily exploited with a predominance of small fish in the catches. Beach seines caught some of the smallest fish, overlapped in selectivity with gill nets and also had the highest catch per fishers. Thus, a reduction in the number of beach seines could help reduce the catch of small fish and the overlap in selectivity among gears. [source]

Alitretinoin in the treatment of hand eczema

Dr John English Consultant Dermatologist
Hand eczema is an umbrella term for dermatoses of different clinical sub-types involving the hands. It varies in severity from mild changes affecting a few fingers to a severe blistering, itchy eruption involving the entire hand.1 Hand eczema has a major impact on earnings and quality of life, often resulting in repeated con-sultations, unemployment, time off work and interference with leisure activities.2,3 Copyright © 2008 John Wiley & Sons, Ltd. [source]

Rituximab in advanced rheumatoid arthritis

Michael Guida BSc
Rheumatoid arthritis (RA) continues to have a major impact on public health. Costs to the individual and to the NHS are high, and treatment options for RA are by no means perfect. This article reviews rituximab, an agent that interrupts inflammatory events via a novel mode of action, and shows promise as a new intervention in cases of moderate to severe RA. Copyright © 2006 John Wiley & Sons, Ltd. [source]

The formation and sedimentary infilling of the Cave of Hearths and Historic Cave complex, Makapansgat, South Africa

A.G. Latham
The archaeology of caves is best served by including a study of natural effects prior to and during anthropogenic input. This is especially true for the Cave of Hearths because not only has erosion determined the area of occupation, but also subsequent undermining has caused collapse of some of the rearward parts of the site during Early Stone Age (Acheulian) and later times; and this had a major impact on excavation. The key to understanding the nature of the collapsed layers was the rediscovery of a lower part of the cavern below the whole site. This lower cavern is no longer accessible, but the evidence for it was revealed in a swallow hole by R.J. Mason, and in archived material at the Department of Archaeology, University of Witwatersrand. The creation and dissolution of dolomite fragments in the upper layers has resulted in the formation of thick, carbonate-cemented breccia that has preserved underlying layers and prevented further collapse. We agree with Mason that further archaeological and hominid finds await excavation under the proximate Historical Cave west entrance. This area has the potential for archaeological and palaeoanthropological material that predates the layers in the Cave of Hearths. © 2004 Wiley Periodicals, Inc. [source]

Automobility and the Geographies of the Car

Peter Merriman
The motor car or automobile has had a profound impact on global mobility, settlement patterns, the global economy, and the environment. Transport policy-makers and environmentalists highlight the unsustainable nature of contemporary petrol-car usage, yet despite widespread calls to rethink contemporary automobility and move towards more sustainable forms of public and private travel, it is only in recent years that social scientists have started to examine the social and cultural geography of the motor car, driving and the spaces of the street, road and motorway in any depth. In this article, I outline some of the research which has been undertaken on the geographies and sociologies of the spaces and practices of driving, focusing in particular on the UK. First, the article outlines the major impact the motor car has had on the geographies of road space. It examines how motor roads have shaped our experience of space and place, and outlines studies of their design, inhabitation, and regulation. Second, this article discusses embodied inhabitations of the spaces of the car: how motor cars have been consumed; how they have shaped our embodied apprehensions of our surroundings; and how they facilitate social and cultural relations. Finally, this article concludes by examining the innovative methods which are increasingly being utilised and developed by social scientists to explore the socialities of automotive spaces. [source]

Axonal integrity in the absence of functional peroxisomes from projection neurons and astrocytes

GLIA, Issue 13 2010
Astrid Bottelbergs
Abstract Ablation of functional peroxisomes from all neural cells in Nestin-Pex5 knockout mice caused remarkable neurological abnormalities including motoric and cognitive malfunctioning accompanied by demyelination, axonal degeneration, and gliosis. An oligodendrocyte selective Cnp-Pex5 knockout mouse model shows a similar pathology, but with later onset and slower progression. Until now, the link between these neurological anomalies and the known metabolic alterations, namely the accumulation of very long-chain fatty acids (VLCFA) and reduction of plasmalogens, has not been established. We now focused on the role of peroxisomes in neurons and astrocytes. A neuron-specific peroxisome knockout model, NEX-Pex5, showed neither microscopic nor metabolic abnormalities indicating that the lack of functional peroxisomes within neurons does not cause axonal damage. Axonal integrity and normal behavior was also preserved when peroxisomes were deleted from astrocytes in GFAP-Pex5,/, mice. Nevertheless, peroxisomal metabolites were dysregulated in brain including a marked accumulation of VLCFA and a slight reduction in plasmalogens. Interestingly, despite minor targeting of oligodendrocytes in GFAP-Pex5,/, mice, these metabolic perturbations were also present in isolated myelin indicating that peroxisomal metabolites are shuttled between different brain cell types. We conclude that absence of peroxisomal metabolism in neurons and astrocytes does not provoke the neurodegenerative phenotype observed after deleting peroxisomes from oligodendrocytes. Lack of peroxisomal metabolism in astrocytes causes increased VLCFA levels in myelin, but this has no major impact on neurological functioning. © 2010 Wiley-Liss, Inc. [source]

Immunohistochemical study of epidermal growth factor receptor in adenoid cystic carcinoma of salivary gland origin

Marilena Vered DMD
Abstract Background Epidermal growth factor (EGF) and its receptor (EGFR) are involved in the development of salivary gland tumors. Recently, treatment modalities for EGFR inhibition have shown an enhanced clinical response in carcinomas of different locations. Adenoid cystic carcinoma (ACC) of salivary gland origin is a malignant tumor with a poor long-term outcome. If salivary gland ACC does exhibit EGFR, then immunotherapy could have a major impact on improving its prognosis. Methods The study consisted of 34 samples of formalin-fixed, paraffin-embedded specimens of salivary gland ACC. Specimens were stained with a mouse antihuman monoclonal antibody for immunohistochemical detection of EGFR. Overlying oral mucosa and adjacent normal salivary ducts served as internal controls. Both membrane and cytoplasmic staining were evaluated. Staining score was calculated by multiplying the percentage of positively stained tumor cells by the intensity of the staining. The highest score for a given tumor was equal to 2. Results In the final analysis, 27 of the 34 specimens were included; 7 were excluded, because the internal control did not reveal any staining. Of these 27 specimens, 23 (85%) stained positively for EGFR with a staining score of 0.05 to 1.8. Three palatal tumors attained the highest scores (one tumor, 1.2, and the remaining two, 1.8). Conclusions Most salivary gland ACC stained positively for EGFR, and in some the staining was quite intense. On the basis of the already proven antitumoral effect of agents acting as EGFR inhibitors, it is suggested that patients with ACC might benefit from these agents, especially when surgery has failed or in those with recurrent or metastatic disease. © 2002 Wiley Periodicals, Inc. Head Neck 24: 632,636, 2002 [source]

The health, social care and housing needs of lesbian, gay, bisexual and transgender older people: a review of the literature

Samia Addis MSc
Abstract This paper reports the findings of a literature review of the health, social care and housing needs of older lesbian, gay, bisexual and transgender (LGBT) adults undertaken in 2006 for the Welsh Assembly Government. Peer-reviewed literature was identified through database searches of BNI, PubMed, CINAHL, DARE, ASSIA and PsychInfo. Follow-up searches were conducted using references to key papers and journals as well as specific authors who had published key papers. A total of 187 papers or chapters were retrieved, of which 66 were included in the study; major themes were identified and the findings synthesised using a meta-narrative approach. The main themes that emerged from the review were isolation, health behaviours, mental health and sexual health behaviours. The literature indicates that the health, social care and housing needs of LGBT older people is influenced by a number of forms of discrimination which may impact upon the provision of, access to and take up of health, social care and housing services. Understanding of the health, social care and housing needs of older LGBT people is limited and research in this area is scarce. The research which exists has been criticised for using small samples and for tending to exclude participants from less affluent backgrounds. The focus of research tends to be on gay men and lesbians; consequently, the needs of bisexual and transgender people remain largely unknown. Additionally, research which does exist tends to focus on a narrow range of health issues, often related to the health needs of younger LGBT people. Discrimination in various forms has a major impact on needs and experiences, leading to marginalisation of LGBT people both in the provision of health and social care services and neglect of these groups in public health research. [source]

Experimental models for hepatitis C viral infection,

HEPATOLOGY, Issue 5 2009
Andre Boonstra
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C. (HEPATOLOGY 2009.) [source]

Causes of the first AIDS-defining illness and subsequent survival before and after the advent of combined antiretroviral therapy,

HIV MEDICINE, Issue 4 2008
S Grabar
Objectives To analyse the impact of combined antiretroviral treatment (cART) on survival with AIDS, according to the nature of the first AIDS-defining clinical illness (ADI); to examine trends in AIDS-defining causes (ADC) and non-AIDS-defining causes (non-ADC) of death. Methods From the French Hospital Database on HIV, we studied trends in the nature of the first ADI and subsequent survival in France during three calendar periods: the pre-cART period (1993,1995; 8027 patients), the early cART period (1998,2000; 3504 patients) and the late cART period (2001,2003; 2936 patients). Results The three most frequent initial ADIs were Pneumocystis carinii (jirovecii) pneumonia (PCP) (15.6%), oesophageal candidiasis (14.3%) and Kaposi's sarcoma (13.9%) in the pre-cART period. In the late cART period, the most frequent ADIs were tuberculosis (22.7%), PCP (19.1%) and oesophageal candidiasis (16.2%). The risk of death after a first ADI fell significantly after the arrival of cART. Lower declines were observed for progressive multifocal leukoencephalopathy, lymphoma and Mycobacterium avium complex infection. After an ADI, the 3-year risk of death from an ADC fell fivefold between the pre-cART and late cART periods (39%vs. 8%), and fell twofold for non-ADCs (17%vs. 9%). Conclusions The relative frequencies of initial ADI have changed since the advent of cART. Tuberculosis is now the most frequent initial ADI in France; this is probably the result of the increasing proportion of migrants from sub-Saharan Africa. After a first ADI, cART has a major impact on ADCs and a smaller impact on deaths from other causes. The risk of death from AIDS and from other causes is now similar. [source]

N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel,

HUMAN MUTATION, Issue 5 2008
G.G. Gené
Abstract Over 1,500 cystic fibrosis transmembrane conductance regulator (CFTR) gene sequence variations have been identified in patients with cystic fibrosis (CF) and related disorders involving an impaired function of the CFTR chloride channel. However, detailed structure,function analyses have only been established for a few of them. This study aimed evaluating the impact of eight N-terminus CFTR natural missense changes on channel behavior. By site-directed mutagenesis, we generated four CFTR variants in the N-terminal cytoplasmic tail (p.P5L, p.S50P, p.E60K, and p.R75Q) and four in the first transmembrane segment of membrane-spanning domain 1 (p.G85E/V, p.Y89C, and p.E92K). Immunoblot analysis revealed that p.S50P, p.E60K, p.G85E/V, and p.E92K produced only core-glycosylated proteins. Immunofluorescence and whole cell patch-clamp confirmed intracellular retention, thus reflecting a defect of CFTR folding and/or trafficking. In contrast, both p.R75Q and p.Y89C had a glycosylation pattern and a subcellular distribution comparable to the wild-type CFTR, while the percentage of mature p.P5L was considerably reduced, suggesting a major biogenesis flaw on this channel. Nevertheless, whole-cell chloride currents were recorded for all three variants. Single-channel patch-clamp analyses revealed that the channel activity of p.R75Q appeared similar to that of the wild-type CFTR, while both p.P5L and p.Y89C channels displayed abnormal gating. Overall, our results predict a major impact of the CFTR missense variants analyzed, except p.R75Q, on the CF phenotype and highlight the importance of the CFTR N-terminus on channel physiology. Hum Mutat 29(5), 738,749, 2008. © 2008 Wiley-Liss, Inc. [source]

A novel mutation in the GATA4 gene in patients with Tetralogy of Fallot,,

HUMAN MUTATION, Issue 3 2006
Georges Nemer
Abstract In vertebrates, heart formation which integrates different structures and cell types is a complex process that involves a network of genes regulated by transcription factors. Proper spatiotemporal expression of these factors ensure the highly needed tight control of each step in organogenesis. A mistake at any step from cell-commitment to valve formation will have a major impact on heart morphogenesis and function leading to congenital heart disease (CHD). Cardiac abnormalities occur with an incidence of one per 100 live births and represent 25% of all congenital malformations. As an alternative approach to linkage-analysis of familial cases of CHD, we started screening familial and sporadic cases of CHDs in a highly consanguineous population for mutations in genes encoding cardiac-enriched transcription factors. The evolutionarily conserved role of these proteins in cardiac development suggested a role in CHD. In this study, we report a mutation in the gene encoding GATA4, one of the earliest markers of heart development. This mutation was found in two out of 26 patients with Tetralogy of Fallot (TOF), and in none of the 94 patients with different phenotypes included in the study, nor in 223 healthy individuals. The heterozygous mutation results in an amino acid substitution in the first zinc finger of GATA4 that reduced its transcriptional activation of downstream target genes, without affecting GATA4 ability to bind DNA, nor its interaction with ZFPM2. © 2006 Wiley-Liss, Inc. [source]

Mutations in the factor IX gene (F9) during the past 150 years have relative rates similar to ancient mutations

HUMAN MUTATION, Issue 1 2002
Jinong Feng
Abstract Pollutants and dietary mutagens have been associated with somatic mutation and cancer, but the extent of their influence on germline mutation is not clear. Since deleterious germline mutations can be transmitted for thousands of years, any influence on germline mutation from the vast increase in man-made chemicals of the past 150 years would be an important public health issue. Observed disease causing mutations in the X-linked factor IX gene (F9) of hemophilia B patients originated predominantly in the past 150 years, since the half-life of these mutations in human populations had been about two generations before effective treatment became available about a generation ago. Recent changes in germline mutational processes may be detected by comparison of the observed hemophilia B causing mutation pattern in F9 with the pattern of neutral polymorphisms which occurred over a much longer period of time. By scanning a total of 1.5 megabases of deep intronic regions of F9 in the genomic DNA from 84 individuals, 42 neutral polymorphisms were found in 23 haplotypes that differed by at least 11 mutations from the ancestral primate haplotype. By sequencing F9 in seven non-human primates, 39 of these polymorphisms were characterized as ancient mutations relative to a unanimous ancestral primate allele. This ancient mutation pattern was compared to the recent pattern of hemophilia B causing mutations. Remarkably, no significant difference was found (P=0.5), suggesting that the vast increase in man-made chemicals during the past 150 years has not had a major impact on the pattern of human germline mutation. This result is consistent with the hypothesis that endogenous processes dominate germline mutation. Hum Mutat 19:49,57, 2002. © 2001 Wiley-Liss, Inc. [source]

Predicting river width, depth and velocity at ungauged sites in England and Wales using multilevel models

D. J. Booker
Abstract Using a dataset of gauged river discharges taken from sites in England and Wales, linear multilevel models (also known as mixed effects models) were applied to quantify the variability in discharge and the discharge-hydraulic geometry relationships across three nested spatial scales. A jackknifing procedure was used to test the ability of the multilevel models to predict hydraulic geometry, and therefore width, mean depth and mean velocity, at ungauged stations. These models provide a framework for making predictions of hydraulic geometry parameters, with associated levels of uncertainty, using different levels of data availability. Results indicate that as one travels downstream along a river there is greater variability in hydraulic geometry than is the case between rivers of similar sizes. This indicates that hydraulic geometry (and therefore hydrology) is driven by catchment area, to a greater extent than by natural geomorphological variations in the streamwise direction at the mesoscale, but these geomorphological variations can still have a major impact on channel structure. Copyright © 2008 John Wiley & Sons, Ltd. [source]

Hydrological versus biogeochemical controls on catchment nitrate export: a test of the flushing mechanism

Carlos J. Ocampo
Abstract Deciphering the connection between streamflows and nitrate (NO,3) discharge requires identification of the various water flow pathways within a catchment, and the different time-scales at which hydrological and biogeochemical processes occur. Despite the complexity of the processes involved, many catchments around the world present a characteristic flushing response of NO,3 export. Yet the controls on the flushing response, and how they vary across space and time, are still not clearly understood. In this paper, the ,flushing response' of NO,3 export from a rural catchment in Western Australia was investigated using isotopic (deuterium), chemical (chloride, NO,3), and hydrometric data across different antecedent conditions and time-scales. The catchment streamflow was at all time-scales dominated by a pre-event water source, and the NO,3 discharge was correlated with the magnitude of areas contributing to saturation overland flow. The NO,3 discharge also appeared related to the shallow groundwater dynamics. Thus, the antecedent moisture condition of the catchment at seasonal and interannual time-scales had a major impact on the NO,3 flushing response. In particular, the dynamics of the shallow ephemeral perched aquifer drove a shift from hydrological controls on NO,3 discharge during the ,early flushing' stage to an apparent biogeochemical control on NO,3 discharge during the ,steady decline' stage of the flushing response. This temporally variable control hypothesis provides a new and alternative description of the mechanisms behind the commonly seen flushing response. Copyright © 2006 John Wiley & Sons, Ltd. [source]