bluuebunny/crossref_metadata_2025 huggingface dataset:
Determinants of the range of drugs prescribed in general practice: a cross-sectional analysis
Authors: de Bakker Dinny H , Coffie Dayline SV , Heerdink Eibert R , van Dijk Liset , Groenewegen Peter P
Published: August 2007

Background

Current health policies assume that prescribing is more efficient and rational when general practitioners (GPs) work with a formulary or restricted drugs lists and thus with a limited range of drugs. Therefore we studied determinants of the range of drugs prescribed by general practitioners, distinguishing general GP-characteristics, characteristics of the practice setting, characteristics of the patient population and information sources used by GPs.

Methods

Secondary analysis was carried out on data from the Second Dutch Survey in General Practice. Data were available for 138 GPs working in 93 practices.

ATC-coded prescription data from electronic medical records, census data and data from GP/practice questionnaires were analyzed with multilevel techniques.

Results

The average GP writes prescriptions for 233 different drugs, i.e. 30% of the available drugs on the market within one year. There is considerable variation between ATC main groups and subgroups and between GPs. GPs with larger patient lists, GPs with higher prescribing volumes and GPs who frequently receive representatives from the pharmaceutical industry have a broader range when controlled for other variables.

Conclusion

The range of drugs prescribed is a useful instrument for analysing GPs' prescribing behaviour. It shows both variation between GPs and between therapeutic groups. Statistically significant relationships found were in line with the hypotheses formulated, like the one concerning the influence of the industry. Further research should be done into the relationship between the range and quality of prescribing and the reasons why some GPs prescribe a greater number of different drugs than others.
Low density lipoprotein from patients with Type 2 diabetes increases expression of monocyte matrix metalloproteinase and ADAM metalloproteinase genes
Authors: Worley Joanna R , Hughes David A , Dozio Nicoletta , Gavrilovic Jelena , Sampson Mike J
Published: August 2007

Aims

Type 2 diabetes is characterised by increased plasma concentrations of pro-inflammatory cytokines [such as tumour necrosis factor – alpha; TNF-α] and soluble forms of adhesion molecules involved in leukocyte – endothelial interactions. These molecules are synthesised as transmembrane proteins and the plasma soluble forms are generated by ectodomain cleavage from the cell surface by members of the ADAM [a
d isintegrin a nd m etalloproteinase] proteinase family. We hypothesised that plasma low density lipoprotein [LDL] from subjects with Type 2 diabetes would influence in vitro monocytic ADAM and matrix metalloproteinase [MMP] gene expression differently compared to control LDL.

Methods

We examined relative mRNA expression by real time PCR in a monocytic cell line [THP-1] cultured for 4, 8 and 24 hrs with human plasma LDL derived from subjects with [n = 5] or without [n = 4] Type 2 diabetes. Gene expression for MMP-1 and 9, and ADAM – 8, 15, 17 and 28 was studied.

Results

Type 2 diabetes LDL significantly increased gene expression of MMP – 1 [p < 0.01] MMP – 9 [p < 0.001], and ADAM 17 [p < 0.05], – 28 [p < 0.01] and – 15 [p < 0.01] compared to control LDL. Type 2 diabetes LDL had disparate effects on inhibitors of MMP.

Conclusion

These data suggest that Type 2 diabetes LDL could lead to increased adhesion molecule and TNF alpha cell surface shedding, and vascular plaque instability, by promoting increased expression of ADAM and MMP genes.
Association of the Growth Hormone Receptor d3-Variant and Catch-up Growth of Preterm Infants with Birth Weight of Less Than 1500 Grams
Authors: Schreiner Felix , Stutte Sonja , Bartmann Peter , Gohlke Bettina , Woelfle Joachim
Published: August 2007

Background: Preterm infants with very low birth weight frequently exhibit impaired longitudinal growth during the first years of life. Recently, the d3-isoform (genomic deletion of exon 3) of the GH receptor (GHR) has been linked to an increased responsiveness to GH.

Objective: Our objective was to test whether the GHRd3 isoform is associated with postnatal catch-up growth in very low birth weight preterm infants.

Design and Patients: We compared the postnatal growth pattern of 77 otherwise healthy preterm infants (mean gestational age, 28.5 wk; range, 23–35 wk) with a birth weight below 1500 g (mean birth weight, 941 g) to their GHR exon 3 genotype, which was analyzed by multiplex PCR. On examination, mean age of the children was 6.0 yr (range, 4.2–8.0 yr).

Results: Children homozygous or heterozygous for the GHRd3 allele showed a significantly higher rate of postnatal catch-up, compared with those homozygous for the full-length allele.

Conclusions: Our results define the GHR exon 3 genotype as a predictor for the postnatal growth pattern of very low birth weight preterm infants. Those who carry at least one GHRd3 allele are more likely to catch-up.
The muscle-specific microRNAs miR-1 and miR-133 produce opposing effects on apoptosis by targeting HSP60, HSP70 and caspase-9 in cardiomyocytes
Authors: Xu Chaoqian , Lu Yanjie , Pan Zhenwei , Chu Wenfeng , Luo Xiaobin , Lin Huixian , Xiao Jiening , Shan Hongli , Wang Zhiguo , Yang Baofeng
Published: August 2007

The microRNAs miR-1 and miR-133 are preferentially expressed in cardiac and skeletal muscles and have been shown to regulate differentiation and proliferation of these cells. We report here a novel aspect of cellular function of miR-1 and miR-133 regulation of cardiomyocyte apoptosis. miR-1 and miR-133 produced opposing effects on apoptosis, induced by oxidative stress in H9c2 rat ventricular cells, with miR-1 being pro-apoptotic and miR-133 being anti-apoptotic. miR-1 level was significantly increased in response to oxidative stress. We identified single target sites for miR-1 only, in the 3′-untranslated regions of the HSP60 and HSP70 genes, and multiple putative target sites for miR-133 throughout the sequence of the caspase-9 gene. miR-1 reduced the levels of HSP60 and HSP70 proteins without changing their transcript levels, whereas miR-133 did not affect HSP60 and HSP70 expression at all. By contrast, miR-133 repressed caspase-9 expression at both the protein and mRNA levels. The post-transcriptional repression of HSP60 and HSP70 and caspase-9 was further confirmed by luciferase reporter experiments. Our results indicate that miR-1 and miR-133 are involved in regulating cell fate with increased miR-1 and/or decreased miR-133 levels favoring apoptosis and decreased miR-1 and/or miR-133 levels favoring survival. Post-transcriptional repression of HSP60 and HSP70 by miR-1 and of caspase-9 by miR-133 contributes significantly to their opposing actions.
Unexpected high prevalence of herpes simplex virus (HSV) type 2 seropositivity and HSV genital shedding in pregnant women living in an East Paris suburban area
Authors: LeGoff Jérôme , Saussereau Elodie , Boulanger Marie-Christine , Chemin Cécile , Si-Mohamed Ali , Bélec Laurent , Maisonneuve Lydia
Published: August 2007

Both herpes simplex virus type 2 (HSV-2) seroprevalence and the proportion of HSV-1 genital ulcers are increasing in industrialized countries. The consequences of these epidemiological changes, in pregnant women in France, for both the genital shedding of HSV and vertical transmission, have been poorly evaluated. The HSV-1 and HSV-2 seroprevalence and the rate of subclinical genital shedding of herpes close to delivery were evaluated in pregnant women, with no history of genital herpes, living in the East Paris suburban area. HSV-2 antibody prevalence of 26% was significantly associated with country of origin and was higher than that reported in 2002 in French women from the general population (18%). HSV-2 and HSV-1 genital reactivations were observed in 10% of HSV-2 seropositive and in 4% of HSV-1 seropositive and HSV-2 seronegative women, respectively. The high rates of HSV-2 seropositivity and subclinical herpes genital shedding observed in this study should be considered to promote a national survey in pregnant women to propose strategies to prevent the spread of HSV within the population and to the neonate.
Tipranavir/T20-based salvage regimens highly effective and durable against HIV-1 with evidence for genotypic predictability of response in clinical practice
Authors: Gupta R K , Loveday Clive , Kalidindi U , Lechelt M , Skinner Celia , Orkin Chloe
Published: August 2007

Escalating drug resistance in treatment-experienced HIV-1-infected patients has made management increasingly difficult. In clinical trials, tipranavir (TPV) has produced potent and durable responses in such patients, although experience in clinical cohorts is limited. A retrospective clinical case review was undertaken of triple-class experienced HIV-1-infected patients receiving optimized boosted TPV-containing regimens and T20 with up to 108 weeks follow-up. Antiretroviral therapy (ART) resistance profiles were characterized using International Aids Society (IAS)-USA scoring and 'TPV resistance score' (TPV-RS) at baseline and failure. Five of 12 patients had undetectable virus (<50 copies/mL) after median 84 weeks (range 60–108), and 1/12 < had 700 copies/mL after 40 weeks. Six of 12 patients failed after 36 (range 12–48) weeks and were more likely to have ≥3 TPV-RS mutations than non-failures ( P = 0.06). Presence of a major IAS-USA mutation at baseline was strongly associated with absence of a 1 log viral load drop at 24 weeks ( P = 0.02). TPV-containing regimens showed impressive efficacy and tolerability in this heavily experienced cohort.
Molecular epidemiology of genital human papillomavirus and Chlamydia trachomatis among patients attending a genitourinary medicine clinic – will vaccines protect?
Authors: Jalal H , Stephen H , Bibby D F , Sonnex C , Carne C A
Published: August 2007

High-risk subtypes of human papillomavirus (HPV) are the main causative agents of cervical cancer, for which Chlamydia trachomatis (CT) may sometimes be a co-factor. Vaccines have been developed against some subtypes of human papillomavirus and a vaccine against CT is in development. The objective of this study was to determine the prevalence of the subtypes of HPV and CT in genitourinary (GU) medicine clinic attenders. In total, 1000 consecutive patients attending the GU clinic participated in this anonymized point-prevalence study. Urethral swabs from 437 men and urethral plus cervical swabs as a single specimen from 563 women were tested for the subtypes of both organisms. Nested major outer membrane protein (MOMP) polymerase chain reaction detected CT chromosomal DNA in 44/437 (10%) of the men and 73/563 (13%) of the women. Genotypes E, F, and D were the most common. In all, 55/437 (13%) of men and 244/563 (43%) of women were infected with at least one high-risk HPV type. In conclusion, the new HPV vaccines, Gardasil and Cervarix, would have protected against 58% and 45%, respectively, of the high-risk subtypes found in women in this population. The rate of high-risk HPV infection (43%) found in women in this study raises concern.
Preventing falls and fall injuries in hospital: a major risk management challenge
Authors: Oliver David
Published: August 2007

Accidental falls are the commonest patient safety incident in hospital and are especially common in older patients. They are associated with physical and psychological harm, functional impairment, prolonged hospital stay, cost and opportunity cost. Falls often cause concern and anger from patients' relatives, are a frequent cause of complaints and inquests, and may lead to claims in clinical negligence - albeit that the financial risk from these claims is low. As such, falls and related injuries should be a major concern in risk management and governance for institutions. In reality, falls are often a marker of patients' underlying medical illness and frailty and their occurrence does not necessarily mean that there has been a failure in the duty of care or that anyone or any system is to blame. Falls rates are also dependent on the case-mix and frailty of patients on the unit, so that crude unadjusted comparison of falls rates should not be used in isolation as an indicator of care quality. Nonetheless, there appear to be large variations in falls rates. It may be that some falls are essentially inevitable or unpreventable, but that others are avoidable and unacceptable, especially as we must balance falls prevention against the duty to promote rehabilitation, respect patients' autonomy and avoid an excessively custodial, ageist or risk-averse approach to care. Even though all parties may feel that 'something should be done' to manage the risk, it is not always clear what the interventions should be. This in turn means that institutions may implement interventions or assessments which are neither effective nor evidence-based. The starting point for falls prevention programmes should always be a critical review of such evidence. In this review, we discuss the underlying causes of falls, the potential for learning from incident reporting and claims analysis and, in particular, the academic literature on falls risk assessment tools (for which the evidence base is limited) and on falls prevention interventions. Evidence from clinical trials has shown that it is possible to produce modest reductions in falls rates (if not the number of 'fallers') from whole systems interventions which incorporate a variety of approaches to falls prevention. These interventions are described in detail as well as the limitations of performing research in such a frail and unstable patient group.
Wrongful existence claims: the 'McFarlane Approach', trends in policy and ethics, and the future
Authors: Troke Ben
Published: August 2007

This is the third article of a three-part review of the development of case law on 'wrongful existence' claims. An initial article examined the increasing prominence of policy considerations in our jurisprudence more generally, often dressed as 'distributive justice', and considered the apparent trend toward preference for autonomy over more traditional views of the sanctity of life in recent years. A second article described the development of case law on 'wrongful existence' in some detail, and looked briefly at the solutions in other jurisdictions. This third article will pick out the key elements of the leading authority (McFarlane, 1999), and ask whether any predictions can be made in this specific field or more widely.
Treatment of cancer
Authors: Barley Victor
Published: August 2007

The second in a series of three articles. This article describes the management of cancer by surgery, radiotherapy and drugs. The beneficial and harmful effects of radiation are described, and the planning and delivery of radiotherapy are outlined. Potential errors such as incorrect or delayed diagnosis, failure to obtain informed consent, errors in planning, identification, or dose of radiation given are discussed. Chemotherapy and its side effects are explained and the potential harm from error in prescription or delivery is described.
Clinical practice guidelines and risk management: a medicolegal perspective
Authors: Samanta Jo , Samanta Ash
Published: August 2007

Clinical guidelines are systematically developed statements created to assist clinicians in making decisions about the treatment and management of specific conditions. They are linked to the medical evidence base and aim to reduce unnecessary variations in treatment processes, thereby maintaining consistently high quality clinical care. Healthcare risk management is concerned with preventing harm to patients and this goal can be facilitated by clinical guidelines which enhance the quality of care. This paper explores the relationship between clinical guidelines and risk management from a medicolegal perspective.
Periodising neoliberalism?
Authors: Craig David , Cotterell Gerry
Published: August 2007

English

The last decade has seen a number of attempts to periodise neoliberalism and the wider liberal project into different phases. While acknowledging the difficulties any periodisation approach entails, this article proposes a number of core factors against which periodisation might be considered. In its main body, it describes recent and current developments in factors including strategy; labour market policy; institutional reform; disciplinary inclusion and exclusion; and other geopolitical and social aspects of reaction, regendering and re-embedding. In concluding, the article evaluates both the prospects for periodisation as method, and the extent to which a significant, recent period shift in the neoliberal project has emerged.
‘Citizen governance’: opportunities for inclusivity in policy and policy making?
Authors: Simmons Richard , Birchall Johnston , Doheny Shane , Powell Martin
Published: August 2007

English

The term ‘citizen governance’ (CG) is currently attracting attention in policy circles. Yet there is no universally agreed definition, and the term is used in different ways. This article identifies key tensions between citizen governors’ ‘representation’ and ‘steering’ roles, and presents a framework that attempts to make these tensions more explicit. Case study evidence suggests that the effectiveness of CG structures is contextual rather than universalistic, and that different sets of assumptions are often conflated in governance. We argue that if inclusivity in policy making is a genuine goal, these assumptions need to be made more explicit and accommodated in structures that work.
Sharing God’s love or meeting government goals? Local churches and public policy implementation
Authors: Cairns Ben , Harris Margaret , Hutchison Romayne
Published: August 2007

English

Set within the context of the growing expectations on faith organisations in the UK to be involved in public policy implementation, this article considers the capacity of churches to contribute to implementation of the twin public policy themes of delivering public services and encouraging community engagement. Building on an empirical study, it suggests that churches can make an important contribution to the implementation of the twin policy agenda but that their theological underpinnings and organisational characteristics also raise questions about their suitability to play a major role in public policy implementation. The implications of the findings for the broader ‘faith communities’ policy agenda are discussed.
Borders at the edge of the enlarged European Union: barriers or bridges?
Authors: Lawrence Roger
Published: August 2007

English

Borders and borderlands are traditionally seen as barriers. The enlargement of the European Union has changed the nature of borders with some internal borders becoming ‘softer’ and new external borders ‘harder’. This article is a study of the contextual background of transnational collaboration across such changing borders in South East Europe. It identifies trends such as transnational funding programmes and the role of minority ethnic groups, which may change the nature of borders from barriers to bridges.
Clients' experience of case formulation in cognitive behaviour therapy for psychosis
Authors: Pain Christina Morberg. , Chadwick Paul. , Abba Nicola.
Published: August 2007

Objectives. Case formulation (CF) is considered essential to the practice of cognitive behaviour therapy, and crucial when working with more complex problems such as psychosis. Several claims are made for the beneficial impact of CF on clients, although little empirical research has been conducted.

Design. The study used content analysis methodology to assess clients' experience of the CF process in cognitive behaviour therapy for psychosis. In addition, therapists ranked seven documented benefits for them of CF.

Method. Thirteen clients and their respective therapists were interviewed 2–3 weeks after shared written formulation.

Results. Overall, clients' reactions to CF were cognitively, behaviourally, and emotionally complex, and subject to change over time. Therapists reported that they found the CF to be most useful in increasing their understanding of their clients.

Conclusions. Formulation is a complex process for clients, and future research into CF faces methodological challenges.
Distribution of Endothelin-converting Enzyme-1 and Neutral Endopeptidase in Human Endometrium
Authors: Iwase Akira , Ando Hisao , Nagasaka Tetsuro , Goto Maki , Harata Toko , Kikkawa Fumitaka
Published: August 2007

The expression of endothelin-1 (ET-1), which has been proposed to have a potential autocrine/paracrine role, varies during the menstrual cycle, and therefore, ET-1 may be involved in the cyclic change of the human endometrium. However, neither the synthesis nor the degradation of ET-1 in the endometrium has been determined in detail. We investigated endothelin-converting enzyme-1 (ECE-1), which converts big-ET-1 to active ET-1, and neutral endopeptidase (NEP), which cleaves and inactivates ET-1 in human endometrium in vivo and in vitro. Western blot analysis demonstrated that the change in the expression of ECE-1 during the menstrual cycle differed from that of NEP in the endometrium. ECE-1 was expressed by endometrial epithelial cells, whereas NEP was predominantly expressed by stromal cells in vivo and in vitro. In conclusion, our results suggest that spacio-temporal expression of two endopeptidases, ECE-1 and NEP, involved in the synthesis and degradation of ET-1, might regulate ET-1 action in human endometrium.
Human 5-HT Transporter Availability Predicts Amygdala ReactivityIn Vivo
Authors: Rhodes Rebecca A. , Murthy Naga Venkatesha , Dresner M. Alex , Selvaraj Sudhakar , Stavrakakis Nikolaos , Babar Syed , Cowen Philip J. , Grasby Paul M.
Published: August 2007

The amygdala plays a central role in fear conditioning, emotional processing, and memory modulation. A postulated key component of the neurochemical regulation of amygdala function is the neurotransmitter 5-hydroxytryptamine (5-HT), and synaptic levels of 5-HT in the amygdala and elsewhere are critically regulated by the 5-HT transporter (5-HTT). The aim of this study was to directly examine the relationship between 5-HTT availability and amygdala activity using multimodal [positron emission tomography (PET) and functional magnetic resonance imaging (fMRI)] imaging measures in the same individuals. Healthy male volunteers who had previously undergone an [11C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile ([11C]-DASB) PET scan to determine 5-HTT availability completed an fMRI emotion recognition task. [11C]-DASB binding potential values were calculated for the amygdala using arterial input function and linear graphical (Logan) analysis. fMRI was performed on a 3T Philips Intera scanner, and data were analyzed using SPM2 (Wellcome Department Imaging Neuroscience, University College London). Percentage signal change during the task was extracted from the amygdala using MarsBaR (Brett et al., 2002). fMRI analysis revealed significant amygdala activation during the emotion recognition task. Region of interest analyses demonstrated a significant negative correlation between fMRI signal change in the left amygdala and 5-HTT availability in the left amygdala, with 5-HTT availability accounting for ∼42% of the variability in left amygdala activity. Our novelin vivodata highlight the central importance of the serotonergic system in the responsiveness of the human amygdala during emotional processing.
Excitatory Synaptic Transmission Persists Independently of the Glutamate–Glutamine Cycle
Authors: Kam Kaiwen , Nicoll Roger
Published: August 2007

The glutamate–glutamine cycle is thought to be integral in continuously replenishing the neurotransmitter pool of glutamate. Inhibiting glial transfer of glutamine to neurons leads to rapid impairment in physiological and behavioral function; however, the degree to which excitatory synaptic transmission relies on the normal operation of this cycle is unknown. In slices and cultured neurons from rat hippocampus, we enhanced the transfer of glutamine to neurons, a fundamental step in this cycle, by adding exogenous glutamine. Although raising glutamine augments synaptic transmission by increasing vesicular glutamate, access to this synthetic pathway by exogenously applied glutamine to neurons is delayed and slow, challenging mechanisms linking the rapid effects of pharmacological inhibitors to decreased vesicular glutamate. We find that pharmacological inhibitors of glutamine synthetase or system A transporters cause an acute depression of basal synaptic transmission that is rapidly reversible, which is unlikely to be attributable to the rapid loss of vesicular glutamate. Furthermore, release of vesicular glutamate remains robust even during the prolonged removal of glutamine from pure neuronal cultures. We conclude that neurons have the capacity to store or produce glutamate for long periods of time, independently of glia and the glutamate–glutamine cycle.
Microarray Analysis of the Cellular Pathways Involved in the Adaptation to and Progression of Motor Neuron Injury in the SOD1 G93A Mouse Model of Familial ALS
Authors: Ferraiuolo Laura , Heath Paul R. , Holden Hazel , Kasher Paul , Kirby Janine , Shaw Pamela J.
Published: August 2007

The cellular pathways of motor neuronal injury have been investigated in the SOD1 G93A murine model of familial amyotrophic lateral sclerosis (ALS) using laser-capture microdissection and microarray analysis. The advantages of this study include the following: analysis of changes specifically in motor neurons (MNs), while still detecting effects of interactions with neighboring cells; the ability to profile changes during disease progression, an approach not possible in human ALS; and the use of transgenic mice bred on a homogeneous genetic background, eliminating the confounding effects arising from a mixed genetic background. By using this rigorous approach, novel changes in key cellular pathways have been detected at both the presymptomatic and late stages, which have been validated by quantitative reverse transcription-PCR.

At the presymptomatic stage (60 d), MNs extracted from SOD1 G93A mice show a significant increase in expression of genes subserving both transcriptional and translational functions, as well as lipid and carbohydrate metabolism, mitochondrial preprotein translocation, and respiratory chain function, suggesting activation of a strong cellular adaptive response. Mice 90 d old still show upregulation of genes involved in carbohydrate metabolism, whereas transcription and mRNA processing genes begin to show downregulation. Late in the disease course (120 d), important findings include the following: marked transcriptional repression, with downregulation of multiple transcripts involved in transcriptional and metabolic functions; upregulation of complement system components; and increased expression of key cyclins involved in cell-cycle regulation. The changes described in the motor neuron transcriptome evolving during the disease course highlight potential novel targets for neuroprotective therapeutic intervention.
Longitudinal Evaluation of theHdh(CAG)150Knock-In Murine Model of Huntington's Disease
Authors: Heng Mary Y. , Tallaksen-Greene Sara J. , Detloff Peter J. , Albin Roger L.
Published: August 2007

Several murine genetic models of Huntington's disease (HD) have been developed. Murine genetic models are crucial for identifying mechanisms of neurodegeneration in HD and for preclinical evaluation of possible therapies for HD. Longitudinal analysis of mutant phenotypes is necessary to validate models and to identify appropriate periods for analysis of early events in the pathogenesis of neurodegeneration. Here we report longitudinal characterization of the murineHdh(CAG)150knock-in model of HD. A series of behavioral tests at five different time points (20, 40, 50, 70, and 100 weeks) demonstrates an age-dependent, late-onset behavioral phenotype with significant motor abnormalities at 70 and 100 weeks of age. Pathological analysis demonstrated loss of striatal dopamine D1and D2receptor binding sites at 70 and 100 weeks of age, and stereological analysis showed significant loss of striatal neuron number at 100 weeks. Late-onset behavioral abnormalities, decrease in striatal dopamine receptors, and diminished striatal neuron number observed in this mouse model recapitulate key features of HD. TheHdh(CAG)150knock-in mouse is a valid model to evaluate early events in the pathogenesis of neurodegeneration in HD.
Sulfatide Storage in Neurons Causes Hyperexcitability and Axonal Degeneration in a Mouse Model of Metachromatic Leukodystrophy
Authors: Eckhardt Matthias , Hedayati Kerstin Khalaj , Pitsch Julika , Lüllmann-Rauch Renate , Beck Heinz , Fewou Simon Ngamli , Gieselmann Volkmar
Published: August 2007

Metachromatic leukodystrophy is a lysosomal storage disorder caused by deficiency in the sulfolipid degrading enzyme arylsulfatase A (ASA). In the absence of a functional ASA gene, 3-O-sulfogalactosylceramide (sulfatide; SGalCer) and other sulfolipids accumulate. The storage is associated with progressive demyelination and various finally lethal neurological symptoms. Lipid storage, however, is not restricted to myelin-producing cells but also occurs in neurons. It is unclear whether neuronal storage contributes to symptoms of the patients. Therefore, we have generated transgenic ASA-deficient [ASA(−/−)] mice overexpressing the sulfatide synthesizing enzymes UDP-galactose:ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST) in neurons to provoke neuronal lipid storage. CGT-transgenic ASA(−/−) [CGT/ASA(−/−)] mice showed an accumulation of C18:0 fatty acid-containing SGalCer in the brain. Histochemically, an increase in sulfolipid storage could be detected in central and peripheral neurons of both CGT/ASA(−/−) and CST/ASA(−/−) mice compared with ASA(−/−) mice. CGT/ASA(−/−) mice developed severe neuromotor coordination deficits and weakness of hindlimbs and forelimbs. Light and electron microscopic analyses demonstrated nerve fiber degeneration in the spinal cord of CGT/ASA(−/−) mice. CGT/ASA(−/−) and, to a lesser extent, young ASA(−/−) mice exhibited cortical hyperexcitability, with recurrent spontaneous cortical EEG discharges lasting 5–15 s. These observations suggest that SGalCer accumulation in neurons contributes to disease phenotype.
The Inhibition Site on Myelin-Associated Glycoprotein Is within Ig-Domain 5 and Is Distinct from the Sialic Acid Binding Site
Authors: Cao Zixuan , Qiu Jin , Domeniconi Marco , Hou Jianwei , Bryson J. Barney , Mellado Wilfredo , Filbin Marie T.
Published: August 2007

Myelin-associated glycoprotein (MAG) is a potent inhibitor of axonal regeneration. It contains five Ig-like domains and is a sialic binding protein. Previously, we showed that the sialic acid binding site on MAG maps to arginine 118 in Ig domain 1 (Kelm et al., 1994). However, sialic acid binding was neither necessary nor sufficient for MAG to bring about inhibition of neurite outgrowth. Consistent with this, we now map a distinct inhibition site on MAG to Ig domain 5 (Ig-5). We show that when a truncated form of MAG missing Ig domains 1 and 2 is expressed by Chinese hamster ovary (CHO) cells, it does not bind sialic acid, but still inhibits neurite outgrowth almost as effectively as full-length MAG. To determine whether the inhibition site mapped to Ig-3, Ig-4, or Ig-5, we made chimeric molecules of various combinations of these three MAG Ig domains fused to Ig domains from another Ig family member, sialoadhesin (Sn), which also binds to sialic acid in the same linkage as MAG. The MAG-Sn molecules were expressed in CHO cells and all contained five Ig domains and were able to bind sialic acid. However, only the chimeric molecules containing MAG Ig-5 inhibited neurite outgrowth. Furthermore, peptides corresponding to sequences in MAG Ig-5, but not Ig-4 or Sn Ig-5, are able to block inhibition of neurite outgrowth by both wild-type MAG and CNS myelin. We conclude that the inhibition site on MAG is carried by Ig domain 5 and that this site is distinct from the sialic-acid binding site.
Odorant Category Profile Selectivity of Olfactory Cortex Neurons
Authors: Yoshida Ikue , Mori Kensaku
Published: August 2007

The olfactory cortex receives converging axonal inputs from many mitral and tufted cells in the olfactory bulb. Recent studies indicate that single cortical neurons integrate signals from diverse odorants. However, there remains a basic question, namely, the signals from which kinds of odorants are integrated by the individual cortical neurons? The present study examined the possibility that some cortical neurons integrate signals from distinct component odorants of natural foods because individual foods produce a fixed combination of odorants. Previous psychophysical studies of core odorants emitted by fruits and vegetables suggest that the olfactory images of individual natural foods are basically characterized by the profile of structural and perceptual categories of food-born odorants. The single-unit spike responses of neurons in the dorsoposterior part of rat anterior piriform cortex to a panel of eight food-related categories of odorants were herein examined. The results showed that many cortical neurons in this region are tuned selectively to either a single category or a specific combination of distinct categories. The cortical neurons showed mixture facilitation and mixture inhibition when stimulated with mixtures of distinct categories, thus suggesting that olfactory circuits may play a role in enhancing the category-profile selectivity of individual neurons. These results indicate that signals from distinct categories of food-born odorants are integrated in these cortical neurons. This suggests that these cortical neurons detect the odorant-category profile of foods to distinguish distinct food odors.
The Tau N279K Exon 10 Splicing Mutation Recapitulates Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 Tauopathy in a Mouse Model
Authors: Dawson Hana N. , Cantillana Viviana , Chen Liling , Vitek Michael P.
Published: August 2007

Intracellular tau deposits are characteristic of several neurodegenerative disorders called tauopathies. The tau protein regulates the stability and assembly of microtubules by binding to microtubules through three or four microtubule-binding repeats (3R and 4R). The number of microtubule-binding repeats is determined by the inclusion or exclusion of the second microtubule-binding repeat encoded by exon 10 of theTAUgene.TAUgene mutations that alter the inclusion of exon 10, and hence the 4R:3R ratio, are causal in the tauopathy frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). A mutation located in exon 10 has been identified in several FTDP-17 families that present with increased exon 10 inclusion in both mRNA and protein, parkinsonism, movement disorders, and dementia. We have engineered a human tau minigene construct that was designed to allow alternative splicing of the tau exon 10. Here we demonstrate that transgenic mice expressing human tau protein with this mutation develop neurodegeneration as result of aberrant splicing. The mice recapitulate many of the disease hallmarks that are seen in patients with this mutation, including increased tau exon 10 inclusion in both mRNA and protein, motor and behavioral deficits, and tau protein accumulation in neurons and tufted astrocytes. Furthermore, these mice present with degeneration of the nigrostriatal dopaminergic pathway, suggesting a possible mechanism for parkinsonism in FTDP-17. Additionally, activated caspase-3 immunoreactivity in both neurons and astrocytes implicates the involvement of the apoptotic pathway in the pathology of these mice.
Innovative bankseat for new Highfield Lane Bridge, UK
Authors: Biana I.
Published: August 2007

Highfield Lane Bridge in Rotherham, UK is a three-span, road-over-rail bridge that has a number of unusual design features and is also built on poor ground. Durability, buildability, low maintenance and whole-life cost-effectiveness were the main aims of the conceptual design. The use of an integral design was considered to be of paramount importance in meeting these aims to eliminate the bridge engineer's nightmare of movement joints between spans and at end supports. Due to the presence of a shallow worked coal seam and soft made ground, a conventional monolithic integral design or bank pad abutment could not be used. The solution adopted utilised a unique ‘floating’ base form of integral bankseat. In addition, a conventional integral approach slab was incorporated with an innovative pressure relief hinge.
PREDICTING THE ECONOMIC IMPACT OF AN INVASIVE SPECIES ON AN ECOSYSTEM SERVICE
Authors: Cook David C. , Thomas Matthew B. , Cunningham Saul A. , Anderson Denis L. , De Barro Paul J.
Published: August 2007

Quantifying the impact of alien invasive species on ecosystem services is an essential step in developing effective practices and policy for invasive species management. Here we develop a stochastic bioeconomic model that enables the economic impact of an invasive pest to be estimated before its arrival, based on relatively poorly specified ecological and economic parameters. We developed the model by using a hypothetical invasion of the varroa bee mite (Varroa destructor) into Australia and the negative flow‐on effects that it would have on pollination by reducing honey bee populations, giving rise to a loss of pollination services, reduced crop yields, and additional production costs. If the mite were to continue to be prevented from entering the country over the next 30 years, we estimate that the economic costs avoided would be US$16.4–38.8 million (Aus$21.3–50.5 million) per year. We suggest that current invasion response funding arrangements in Australia, which do not acknowledge these avoided damages, require amendment.
IRRUPTIVE POPULATION DYNAMICS IN YELLOWSTONE PRONGHORN
Authors: White P. J. , Bruggeman Jason E. , Garrott Robert A.
Published: August 2007

Irruptive population dynamics appear to be widespread in large herbivore populations, but there are few empirical examples from long time series with small measurement error and minimal harvests. We analyzed an 89‐year time series of counts and known removals for pronghorn (Antilocapra americana) in Yellowstone National Park of the western United States during 1918–2006 using a suite of density‐dependent, density‐independent, and irruptive models to determine if the population exhibited irruptive dynamics. Information‐theoretic model comparison techniques strongly supported irruptive population dynamics (Leopold model) and density dependence during 1918–1946, with the growth rate slowing after counts exceeded 600 animals. Concerns about sagebrush (Artemisia spp.) degradation led to removals of >1100 pronghorn during 1947–1966, and counts decreased from approximately 700 to 150. The best models for this period (Gompertz, Ricker) suggested that culls replaced intrinsic density‐dependent mechanisms. Contrary to expectations, the population did not exhibit enhanced demographic vigor soon after the termination of the harvest program, with counts remaining between 100 and 190 animals during 1967–1981. However, the population irrupted (Caughley model with a one‐year lag) to a peak abundance of approximately 600 pronghorn during 1982–1991, with a slowing in growth rate as counts exceeded 500. Numbers crashed to 235 pronghorn during 1992–1995, perhaps because important food resources (e.g., sagebrush) on the winter range were severely diminished by high densities of browsing elk, mule deer, and pronghorn. Pronghorn numbers remained relatively constant during 1996–2006, at a level (196–235) lower than peak abundance, but higher than numbers following the release from culling. The dynamics of this population supported the paradigm that irruption is a fundamental pattern of growth in many populations of large herbivores with high fecundity and delayed density‐dependent effects on recruitment when forage and weather conditions become favorable after range expansion or release from harvesting. Incorporating known removals into population models that can describe a wide range of dynamics can greatly improve our interpretation of observed dynamics in intensively managed populations.
Reproducibility of Acoustic Rhinometry in the Investigation of Occupational Rhinitis
Authors: Castano Roberto , Thériault Gilles , Gautrin Denyse , Ghezzo Heberto , Trudeau Carole , Malo Jean-Luc
Published: August 2007

Background

To diagnose occupational rhinitis, it is mandatory to conduct an objective assessment of changes in nasal patency during specific inhalation challenge (SIC). The reproducibility of acoustic rhinometry measurements in the setting of occupational challenges has never been examined. This study assessed the reproducibility of acoustic rhinometry during SIC investigation of occupational rhinitis.

Methods

Twenty-four subjects underwent acoustic rhinometry measurements during SIC investigation of occupational rhinitis. Subjects attended 3–6 days of SIC within a week by means of a realistic or closed-circuit apparatus methodology

Results

All of the within-day intraclass correlation coefficients (ICCs) for nasal volume (2–5 cm) and minimum cross-sectional area (MCA) based on a different number of measurements (2–7) were above 0.85; all of the coefficients of variation (CVs) for the same parameters were low (below 10%). The between-day CVs based on different numbers of SIC sessions ranged from 8.0 to 8.8% and from 6.8 to 8.8% for nasal volume and MCA, respectively. The between-day ICCs ranged from 0.80 to 0.88 and from 0.83 to 0.94 for nasal volume and MCA, respectively.

Conclusion

Acoustic rhinometry showed good within- and between-day reproducibility and can be recommended for the objective monitoring of nasal patency during SIC investigating occupational rhinitis.
Effects of the Cottle's Maneuver on the Nasal Valve as Assessed by Acoustic Rhinometry
Authors: Tikanto Jukka , Pirilä Tapio
Published: August 2007

Backround

The nasal valve is the narrowest segment of the nasal cavity and plays an essential role in breathing. There has been plenty of discussion in the literature concerning the location and function of the nasal valve. The Cottle's maneuver (CM) is a test in which the cheek on the side to be evaluated is gently pulled laterally with one to two fingers to open the valve. This test is used to determine if the most significant site of nasal obstruction is at the valve or farther inside the nasal cavity. The aim of this study was to determine the dimensional changes caused by the CM in the nose as measured by acoustic rhinometry (AR).

Methods

Eight adult volunteers with no nasal symptoms were recruited and their nasal cavities were measured by AR. The measurements were done with and without the CM both before and after decongestion with a mixture of 1:1000 epinephrine and 4% lidocaine in cotton pledgets. The MCA1 and MCA2 and their distances from the nostril, as well as the volume—measured from the zero point to the MCA2 point—were determined.

Results

The main effect of the CM was a mean increase in MCA1 by 33% (p = 0.001) and 44% (p < 0.001) before and after decongestion, respectively. The distance of MCA1 increased significantly, because of the CM, by 12% (p = 0.006) before and 7% (p = 0.008) after decongestion. The percentage increases in volume were 33% (p = 0.001) and 44% (p < 0.001), respectively. Decongestion of the nasal mucosa induced a statistically significant (p = 0.001) increase in both MCA1 (by 21%) and MCA2 (by 28%).

Conclusion

The CM significantly increased MCA1 in AR, and the increase was more evident after decongestion of the nasal mucosa. The changes in MCA2 were nonsignificant. We conclude that the value of the CM in investigating a possible valve insufficiency may be greater if the nose is studied both before and after decongestion of the nasal mucosa.
Dose-Dependent Effects of Topical Tobramycin in an Animal Model of Pseudomonas Sinusitis
Authors: Antunes Marcelo B. , Feldman Michael D. , Cohen Noam A. , Chiu Alexander G.
Published: August 2007

Background

Topical antimicrobials are commonly used to treat Pseudomonas sinusitis after endoscopic sinus surgery. Despite their popularity, there is limited data in the literature to support its use. This study is the first to examine the effects of topical tobramycin in an animal model of Pseudomonas sinusitis.

Methods

Pseudomonas aeruginosa sinusitis was induced in the maxillary sinus of New Zealand white rabbits. Study groups received various concentrations of topical tobramycin instilled through a single lumen catheter embedded within the maxillary sinus for 7 consecutive days. A control group received normal saline irrigation. Bacterial counts were measured from the nasal lavage after irrigation. The sinonasal complex was analyzed and a histological grading system was used to score the degree of infection at study end.

Results

Nasal lavage bacterial counts of the saline control group remained persistently elevated throughout the study. Introduction of increasing concentrations of topical tobramycin caused the bacterial counts to fall to zero by study end. There was a dose-dependent histological response in which increasing concentrations of tobramycin led to a marked reduction but not total elimination of inflammation within the mucosa and underlying bone.

Conclusion

As opposed to normal saline irrigations, topical tobramycin led to a significant improvement in the degree of infection within an animal model of P. aeruginosa sinusitis. Despite the elimination of bacteria within the nasal lavage, there was a suggestion of a residual indolent infection as evidenced by persistent inflammation within the mucosa and underlying bone.
Allergic Fungal Sinusitis Associated with Allergic Bronchopulmonary Aspergillosis: An Uncommon Sinobronchial Allergic Mycosis
Authors: Braun Jean Jacques , Pauli Gabrielle , Schultz Philippe , Gentine André , Ebbo David , de Blay Frédéric
Published: August 2007

Background

The identification of allergic fungal sinusitis (AFS) is still controversial and much more recent than that of allergic bronchopulmonary aspergillosis (ABPA). Their association has been reported very rarely in the literature.

Methods

The aim of this study was to present a review of 6 cases of AFS associated with ABPA from a series of 12 cases of AFS and to compare AFS associated with ABPA and isolated AFS.

Results

All cases of AFS presented with chronic rhinosinusitis. The six cases with AFS and ABPA were atopic, asthmatic, with pulmonary infiltrates (five cases), central bronchiectasis (four cases), and both (three cases). The mycological and immunoallergological features of isolated AFS and AFS associated with ABPA were similar: eosinophilic allergic mucin with noninvasive fungi hyphae, high levels of blood eosinophils, total IgE, specific IgE, IgG, and positive skin tests to Aspergillus. The association of AFS and ABPA was concomitant (two cases) or remote in time (four cases). The treatment with oral corticosteroids and sinus surgery (six cases) associated with antifungal drugs (four cases) led to resolution in three cases, considerable improvement in one case, and therapeutic failure in two cases (follow-up longer than 5 years in all cases).

Conclusion

Independently of the signs linked to the organs involved (sinuses and bronchi) the mycological and immunoallergological features were similar for AFS and AFS associated with ABPA. AFS and ABPA can be isolated or associated in a sinobronchial allergic mycosis.