bluuebunny/crossref_metadata_2025 huggingface dataset:
INDUCTIVE RISK AND JUSTICE IN KIDNEY ALLOCATION
Authors: SCARANTINO ANDREA
Published: July 2009

How should UNOS deal with the presence of scientific controversies on the risk factors for organ rejection when designing its allocation policies? The answer I defend in this paper is that the more undesirable the consequences of making a mistake in accepting a scientific hypothesis, the higher the degree of confirmation required for its acceptance. I argue that the application of this principle should lead to the rejection of the hypothesis that ‘less than perfect’ Human Leucocyte Antigen (HLA) matches are an important determinant of kidney graft survival. The scientific community has been divided all along on the significance of partial antigen matches. Yet reliance on partial matches has emerged as one of the primary factors leading blacks to spend a much longer time than whites on the waiting list for kidneys, thereby potentially impacting the justice of the kidney allocation policy. My case study illustrates one of the legitimate roles non‐epistemic values can play in science and calls into question the ideal of a value‐free science.
IN DEFENCE OF PRIORITY REVIEW VOUCHERS
Authors: SONDERHOLM JORN
Published: July 2009

Infectious and parasitic diseases cause enormous health problems in the developing world whereas they leave the developed one relatively unscathed. Research and development (R&D) of drugs for diseases that mainly affect people in developing countries is limited. The problem that relatively few drugs are available for diseases that cause an enormous burden of disease in the developing world is called the ‘availability problem’. In recent years, the availability problem has received quite a bit of attention. A number of proposals have been fielded as to how this problem might be minimized. Wild‐card patent extensions, advance market commitments, cash prizes and the Health Impact Fund are prominent examples of such proposals. These proposals can be thought of as pull‐mechanisms for R&D of drugs for neglected diseases. What has been coined a ‘priority review voucher’ is another pull‐mechanism. This paper is a critical discussion of this pull‐mechanism. First, the original priority review voucher scheme, as proposed by Ridley et al. (2006), is described. A number of objections to this scheme are thereafter presented. A few amendments to the original scheme are then suggested, and it is argued that with these amendments in place, the priority review voucher scheme constitutes an attractive way of stimulating R&D of drugs for neglected diseases.
Estimation and Inference Based on Neumann Series Approximation to Locally Efficient Score in Missing Data Problems
Authors: CHEN HUA YUN
Published: July 2009

Abstract. Theory on semi‐parametric efficient estimation in missing data problems has been systematically developed by Robins and his coauthors. Except in relatively simple problems, semi‐parametric efficient scores cannot be expressed in closed forms. Instead, the efficient scores are often expressed as solutions to integral equations. Neumann series was proposed in the form of successive approximation to the efficient scores in those situations. Statistical properties of the estimator based on the Neumann series approximation are difficult to obtain and as a result, have not been clearly studied. In this paper, we reformulate the successive approximation in a simple iterative form and study the statistical properties of the estimator based on the reformulation. We show that a doubly robust locally efficient estimator can be obtained following the algorithm in robustifying the likelihood score. The results can be applied to, among others, parametric regression, marginal regression and Cox regression when data are subject to missing values and the data are missing at random. A simulation study is conducted to evaluate the performance of the approach and a real data example is analysed to demonstrate the use of the approach.
Goodness‐of‐Fit Tests for Multiplicative Models with Dependent Data
Authors: DETTE HOLGER , PARDO‐FERNÁNDEZ JUAN CARLOS , KEILEGOM INGRID VAN
Published: July 2009

Abstract.  Several classical time series models can be written as a regression model between the components of a strictly stationary bivariate process. Some of those models, such as the ARCH models, share the property of proportionality of the regression function and the scale function, which is an interesting feature in econometric and financial models. In this article, we present a procedure to test for this feature in a non‐parametric context. The test is based on the difference between two non‐parametric estimators of the distribution of the regression error. Asymptotic results are proved and some simulations are shown in the paper in order to illustrate the finite sample properties of the procedure.
Troubling biographical disruption: narratives of unconcern about hepatitis C diagnosis
Authors: Harris Magdalena
Published: July 2009

This paper explores the impact of hepatitis C diagnosis among participants of a recent qualitative study based in New Zealand and Australia. The findings of this research were unique with regard to the small amount of existing literature on the topic. Whilst most social research indicates that diagnosis with hepatitis C is a disruptive or distressing experience, study participants were almost evenly divided between those who reported being distressed by diagnosis and those who described contracting hepatitis C as ‘no big deal’. The varied nature of participants’ narratives about their hepatitis C diagnosis indicates that the experience of biographical disruption is contextual: dependent upon previous experiences of illness, marginalisation or hardship, and the extent to which hepatitis C is an unknown entity or normalised within community networks. This paper draws on the theoretical frameworks of biographical disruption, normalisation and dys‐appearance to illuminate these and other contextual issues informing participants’ narratives of unconcern about hepatitis C diagnosis.
Minimum Distance Estimation and Testing of DSGE Models from Structural VARs*
Authors: Fève Patrick , Matheron Julien , Sahuc Jean‐Guillaume
Published: July 2009

The aim of this paper is to complement the minimum distance estimation–structural vector autoregression approach when the weighting matrix is not optimal. In empirical studies, this choice is motivated by stochastic singularity or collinearity problems associated with the covariance matrix of impulse response functions. Consequently, the asymptotic distribution cannot be used to test the economic model's fit. To circumvent this difficulty, we propose a simple simulation method to construct critical values for the test statistics. An empirical application with US data illustrates the proposed method.
Revascularization in acute ischaemic stroke using the penumbra system: the first single center experience
Authors: Grunwald I. Q. , Walter S. , Papanagiotou P. , Krick C. , Hartmann K. , Dautermann A. , Faßbender K. , Haass A. , Bolar L. J. , Reith W. , Roth C.
Published: July 2009

Background and purpose:  This is the first single center experience illustrating the effectiveness of the penumbra system (PS) in the treatment of large vessel occlusive disease in the arena of acute ischaemic stroke. The PS is an innovative mechanical thrombectomy device, employed in the revascularization of large cerebral vessel occlusions in patients via the utilization of an aspiration platform.

Methods:  This is a prospective, non‐randomized controlled trial evaluating the clinical and functional outcome in 29 patients with acute intra‐cranial occlusions consequent to mechanical thrombectomy by the PS either as mono‐therapy or as an adjunct to current standard of care. Patients were evaluated by a neurologist and treated by our in house interventional neuro‐radiologists. Primary end‐points were revascularization of the occluded target vessel to TIMI grade 2 or 3 and neurological outcome as measured by an improvement in the NIH Stroke Scale (NIHSS) score after the procedure.

Results:  Complete revascularization (TIMI 3) was achieved in 21/29 (72.4%) of patients. Partial revascularization (TIMI 2) was established in 4/29 (13.8%) of patients. Revascularization failed in four (13.8%) patients. Nineteen (19) patients (65.5%) had at least a four‐point improvement in NIHSS scores. Modified Rankin scale scores of ≤2 were seen in 37.9% of patients. There were no device‐related adverse events. Symptomatic intra‐cranial hemorrhage occurred in 7% of patients.

Conclusions:  The PS has the potential of exercising a significant impact in the interventional treatment of ischaemic stroke in the future.
Elevated cerebrospinal fluid and plasma homocysteine levels in ALS
Authors: Valentino F. , Bivona G. , Butera D. , Paladino P. , Fazzari M. , Piccoli T. , Ciaccio M. , La Bella V.
Published: July 2009

Background:  High cerebrospinal fluid (CSF) and plasma levels of homocysteine (HC) have been reported in certain neurodegenerative disorders, such as Alzheimer’s, Parkinson’s diseases and, recently, amyotrophic lateral sclerosis (ALS).

Objectives:  To assay the CSF and plasma levels of HC in ALS patients and controls, and to evaluate the relationship between HC levels and clinical variables of the disease.

Methods:  Cerebrospinal fluid from sixty‐nine (M/F 1.87) and plasma from sixty‐five ALS patients (M/F 1.83) were taken and stored at −80°C until use. Controls (CSF = 55; plasma = 67) were patients admitted to our hospital for neurological disorders with no known relationship to HC changes. CSF and plasma from ALS patients and controls were obtained as a necessary step of the diagnostic workup. HC levels in CSF and plasma were assayed using a high performance liquid chromatograph (HPLC) and a fluorimeter detector.

Results:  The median level of total HC in the CSF of ALS patients was 0.46 μM, significantly higher than that of the controls (0.24 μM, +91.6%, P < 0.001). A similar trend was observed when HC was assayed in plasma (ALS, 12.4 μM vs. controls, 7.26 μM, +70.8%, P < 0.001). The CSF and plasma HC levels showed no relationship with the disease progression, age at onset, and the site of onset.

Conclusions:  Homocysteine is a biochemical marker in ALS, and it might be related to the pathophysiology of the disease.
Use of cerebrospinal fluid biomarkers in diagnosis of dementia across Europe
Authors: Hort J. , Bartos A. , Pirttilä T. , Scheltens P.
Published: July 2009

Background and purpose:  Cerebrospinal fluid (CSF) biomarkers have been reported to be useful in dementia diagnosis. Not much is known about their use in clinical practice in Europe.

Methods:  We analyzed data from a survey on the use of CSF biomarkers in the diagnosis of dementia across Europe using a questionnaire which was filled out by representatives of the 25 member countries of the European Federation of Neurological Societies (EFNS).

Results:  Cerebrospinal fluid beta‐amyloid, total tau, and phosphorylated tau proteins are frequently evaluated in the majority of the countries (in 18 out of 23 countries). No major technical or ethical issues were found that would hamper the procedure’s ability to become routine in early and differential diagnostics of Alzheimer’s disease. Cut‐off values for beta‐amyloid (median 500, range 300–849 pg/ml), total tau (367; 195–450 pg/ml) and phosphorylated tau (60; 40–85 pg/ml) varied considerably amongst countries and even within every country.

Conclusions:  Cerebrospinal fluid analysis of beta‐amyloid, tau, and phosphorylated tau is frequently used in Europe. However, the use of various cut off values seriously hampers comparability and yields a potential threat to an interpretation and balanced use in clinical practice. We recommend that each laboratory establishes normative data and that multi‐centered studies should be organized to explore the reasons for any differences.
Vitamin D and cognitive performance in adults: a systematic review
Authors: Annweiler C. , Allali G. , Allain P. , Bridenbaugh S. , Schott A.‐M. , Kressig R. W. , Beauchet O.
Published: July 2009

Chronic low serum 25‐hydroxyvitamin D (25OHD) concentrations are common in adults and are associated with numerous non‐skeletal diseases. Vitamin D receptors (VDR) are located in the human cortex and hippocampus, which are key areas for cognition. The objective of this study was to systematically review all published data from the past 30 years which examined the association between serum 25OHD concentrations and cognitive performance in adults. An English and French Medline, PsycINFO® and Cochrane Library search ranging from 1979 to 2008 indexed under the Medical Subject Heading (MeSH) terms ‘Vitamin D’ or ‘Hydroxycholecalciferols’ combined with the terms ‘Dementia’ or ‘Cognition’ or ‘Cognition Disorders’ or ‘Delirium’ or ‘Memory’ or ‘Memory Disorders’ or ‘Orientation’ or ‘Executive Functions’ or ‘Attention’ or ‘Brain’ or ‘Neuropsychological Tests’ was performed. Of the 99 selected studies, five observational studies met the selection criteria and were included in the final analysis. No prospective cohort study was found. The number of participants ranged from 32 to 9556 community‐dwelling older adults (45–65% women). Three studies showed four significant positive associations between serum 25OHD concentrations and global cognitive functions, whereas three other studies exploring specific aspects of cognition showed 11 non‐significant associations. This systematic review shows that the association between serum 25OHD concentrations and cognitive performance is not yet clearly established. The inconclusive results of the reviewed studies could be due to methodology, types of the cognitive tasks used and/or the cellular mechanisms of vitamin D.
A study of F‐waves in patients with unilateral lumbosacral radiculopathy
Authors: Pastore‐Olmedo C. , González O. , Geijo‐Barrientos E.
Published: July 2009

Background and purpose:  The F wave, a late response of low amplitude, is widely used in the study of peripheral nerve lesions, and its persistence and latencies are the main parameters that are usually considered. The analysis of repeater F‐waves, which are commonly observed in association with focal or generalized motor neuropathy, is not always performed as a standard electrodiagnostic protocol.

Methods:  We recorded and quantified the F waves from 13 healthy subjects and 22 patients with unilateral lumbosacral radiculopathy (ULSR) affecting the L5 or S1 roots.

Results:  We found differences between the injured and normal sides of patients with ULSR in several F‐wave parameters. Taking into consideration the normalized and pooled values of tibial and peroneal nerves in the injured side of patients with ULSR, the minimum and mean latencies were higher (1.05 and 1.04 with respect to 1.00; P < 0.01), the relative amplitude of the F waves was higher (1.95 with respect to 1.00; P < 0.001), and the percentage of repeater F‐waves was also higher (4.19 with respect to 1.00; P < 0.001). This latter parameter was the most sensitive to detect lateral differences as indicated by the percentage of change and its high z score.

Conclusions:  Our results show that the use of F‐waves may improve the electrodiagnosis of the ULSR if the number of repeater waves is evaluated given the clear and consistent increase of this variable in patients with lumbosacral root injury.
The Reduced Folate Carrier (SLC19A1) c.80G>A Polymorphism is Associated with Red Cell Folate Concentrations Among Women
Authors: Stanisławska‐Sachadyn Anna , Mitchell Laura E. , Woodside Jayne V. , Buckley Peter T. , Kealey Carmel , Young Ian S. , Scott John M. , Murray Liam , Boreham Colin A. , McNulty Helene , Strain J. J. , Whitehead Alexander S.
Published: July 2009

Low folate status may be a consequence of suboptimal intake, transport or cellular utilization of folate and, together with elevated homocysteine, is a recognized risk factor or marker for several human pathologies. As folate transport across cell membranes is mediated in part by the reduced folate carrier (RFC1), variants within SLC19A1, the gene that encodes RFC1, may influence disease risk via an effect on folate and/or homocysteine levels. The present study was undertaken to assess the association between the SLC19A1 c.80G>A polymorphism and folate/homocysteine concentrations in healthy young adults from Northern Ireland.

The SLC19A1 c.80G>A polymorphism was not strongly associated with either serum folate or homocysteine concentrations in either men or women. However, in women, but not in men, this polymorphism explained 5% of the variation in red blood cell (RBC) folate levels (P= 0.02). Relative to women with the SLC19A1 c.80GG genotype, women with the GA and AA genotypes had higher RBC folate concentrations. Consequently, compared to women with the SLC19A1 c.80GA and AA genotypes, women who are homozygous for the 80G allele may be at increased risk of having a child affected with a neural tube defect and of developing pathologies that have been associated with folate insufficiency, such as cardiovascular disease.
Stimulus‐hand correspondence and direct response activation: An electromyographic analysis
Authors: Hasbroucq Thierry , Burle Boris , Vidal Franck , PossamaÏ Camille‐Aime
Published: July 2009

In a common version of the Simon task, the subjects respond by a left‐ or a right‐hand key press to the color of a stimulus (S) presented to the left or right of a fixation point. Albeit S location is irrelevant, the incorrect response is more often activated when the required response is contralateral to the S (incongruent) than when it is ipsilateral to the S (congruent). The aim of the present study was to decipher the respective contributions of S‐response key location correspondence and S‐hand correspondence to such incorrect activations (IAs). The subjects were required to perform a Simon task with the arms not crossing and crossing the median plane. Present for both arm placements, the difference in the frequency of IAs between incongruent and congruent responses was smaller when the arms were crossed. IAs are (i) essentially due to S‐key location correspondence and (ii) less influenced by S‐hand correspondence. Latency analyses further suggest that intra‐hemispheric processing mediates the influence of S‐hand correspondence.
Peroxisomal and mitochondrial status of two murine oligodendrocytic cell lines (158N, 158JP): potential models for the study of peroxisomal disorders associated with dysmyelination processes
Authors: Baarine Mauhamad , Ragot Kevin , Genin Emmanuelle C. , El Hajj Hammam , Trompier Doriane , Andreoletti Pierre , Ghandour M. Said , Menetrier Franck , Cherkaoui‐Malki Mustapha , Savary Stephane , Lizard Gerard
Published: July 2009

In some neurodegenerative disorders (leukodystrophies) characterized by myelin alterations, the defect of peroxisomal functions on myelin‐producing cells (oligodendrocytes) are poorly understood. The development of in vitro models is fundamental to understanding the physiopathogenesis of these diseases. We characterized two immortalized murine oligodendrocyte cell lines: a normal (158N) and a jimpy (158JP) cell line mutated for the proteolipid protein PLP/DM20. Fluorescence microscopy, flow cytometry, and western blotting analysis allow to identify major myelin proteins (PLP colocalizing with mitochondria; myelin basic protein), oligodendrocyte (CNPase and myelin oligodendrocyte glycoprotein), and peroxisomal markers [adrenoleukodystrophy protein, PMP70, acyl‐CoA oxidase 1 (ACOX1), l‐peroxisomal bifunctional enzyme, and catalase]. Using electron microscopy, peroxisomes were identified in the two cell lines. Gene expression (ATP‐binding cassette, Abcd1, Abcd2, Abcd3, and Acox1) involved in peroxisomal transport or β‐oxidation of fatty acids was evaluated using quantitative PCR. 4‐phenylbutyrate treatment increases expression of ACOX1, l‐peroxisomal bifunctional enzyme, PLP, myelin oligodendrocyte glycoprotein, and CNPase, mainly in 158N cells. In both cell lines, 4‐phenylbutyrate‐induced ACOX1 and catalase activities while only Abcd2 gene was up‐regulated in 158JP. Moreover, the higher mitochondrial activity and content observed in 158JP were associated with higher glutathione content and increased basal production of reactive oxygen species revealing different redox statuses. Altogether, 158N and 158JP cells will permit studying the relationships between peroxisomal defects, mitochondrial activity, and oligodendrocyte functions.
Retinoid X receptor‐α mediates (R )‐flurbiprofen’s effect on the levels of Alzheimer’s β‐amyloid
Authors: You Xiaoqing , Zhang Yun‐wu , Chen Yaomin , Huang Xiumei , Xu Raymond , Cao Xihua , Chen Jiebo , Liu Yun , Zhang Xiaokun , Xu Huaxi
Published: July 2009

Alzheimer’s disease (AD) is characterized by the formation of extracellular senile plaques in the brain, whose major component is a small peptide called β‐amyloid (Aβ). Long‐term use of non‐steroidal anti‐inflammatory drugs (NSAIDs) has been found beneficial for AD and several reports suggest that NSAIDs reduce the generation of Aβ, especially the more amyloidogenic form Aβ42. However, the exact mechanism underlying NSAIDs’ effect on AD risk remains largely inconclusive and all clinical trials using NSAIDs for AD treatment show negative results so far. Recent studies have shown that some NSAIDs can bind to certain nuclear receptors, suggesting that nuclear receptors may be involved in NSAID’s effect on AD risk. Here we find that (R)‐flurbiprofen, the R‐enantiomer of the racemate NSAID flurbiprofen, can significantly reduce Aβ secretion, but at the same time, increases the level of intracellular Aβ. In addition, we find that a nuclear receptor, retinoid X receptor α (RXRα), can regulate Aβ generation and that down‐regulation of RXRα significantly increases Aβ secretion. We also show that (R)‐flurbiprofen can interfere with the interaction between RXRα and 9‐cis‐retinoid acid, and that 9‐cis‐retinoid acid decreases (R)‐flurbiprofen’s reduction of Aβ secretion. Moreover, the modulation effect of (R)‐flurbiprofen on Aβ is abolished upon RXRα down‐regulation. Together, these results suggest that RXRα can regulate Aβ generation and is also required for (R)‐flurbiprofen‐mediated Aβ generation.
Pharmacokinetics of rituximab associated with CHOP chemotherapy in B‐cell non‐Hodgkin lymphoma
Authors: Blasco Hélène , Chatelut Etienne , De Bretagne Isabelle Benz , Congy‐Jolivet Nicolas , Le Guellec Chantal
Published: July 2009

The pharmacokinetics of rituximab administered alone at a dose of 375 mg/m2 once a week have been widely studied but few data are available for the administration of rituximab in combination with other agents. We carried out a pilot pharmacokinetic study in 10 patients with B‐cell non‐Hodgkin lymphoma treated with rituximab associated with chemotherapy on a three‐weekly basis. Patients received four courses of rituximab (375 mg/m2) associated with CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) at 21‐day intervals. Blood samples were collected from each patient at selected times throughout the treatment period and analysed using a validated enzyme‐linked immunosorbent assay. The nonmem software was used to obtain population and post hoc estimates of rituximab pharmacokinetic parameters and to study possible time‐dependent variation during treatment. Pharmacokinetic parameters obtained from 10 patients were similar to those described for studies in the absence of chemotherapy. We did not observe any intra‐subject variation in pharmacokinetic parameters over the treatment period. Our results suggest that rituximab pharmacokinetics is not affected by combination with CHOP chemotherapy. Nevertheless, the substantial intersubject variability observed in this small sample size highlights the need for further study of the determinants of rituximab pharmacokinetic variability.
Preclinical evaluation of a monoclonal antibody targeting the epidermal growth factor receptor as a radioimmunodiagnostic and radioimmunotherapeutic agent
Authors: Ray GL , Baidoo KE , Wong KJ , Williams M , Garmestani K , Brechbiel MW , Milenic DE
Published: July 2009

Background and purpose:  The studies described here are the first to evaluate the in vitro and in vivo properties of 111In‐CHX‐A″‐panitumumab for radioimmunotherapy (α‐ and β‐‐emitters) and radioimmunoimaging (single photon emission computed tomography and positron emission tomography).

Experimental approach:  Twenty‐seven human carcinoma cell lines were analysed for expression of epidermal growth factor receptors by flow cytometry. Panitumumab was conjugated with CHX‐A″‐DTPA (diethylenetriamine‐pentaacetic acid) and radiolabelled with 111In. Immunoreactivity of the CHX‐A″‐DTPA‐panitumumab and 111In‐CHX‐A″‐DTPA‐panitumumab was evaluated by radioimmunoassays. Tumour targeting was determined in vivo by direct quantitation of tumour and normal tissues and by γ‐scintigraphy.

Key results:  For 26 of 27 human tumour cell lines, 95% of the cells expressed epidermal growth factor receptors over a range of intensity. Immunoreactivity of panitumumab was retained after modification with CHX‐A″‐DTPA. Radiolabelling of the immunoconjugate with 111In was efficient with a specific activity of 19.5 ± 8.9 mCi·mg−1 obtained. Immunoreactivity and specificity of binding of the 111In‐panitumumab was shown with A431 cells. Tumour targeting by 111In‐panitumumab was demonstrated in athymic mice bearing A431, HT‐29, LS‐174T, SHAW or SKOV‐3 s.c. xenografts with little uptake observed in normal tissues. The 111In‐panitumumab was also evaluated in non‐tumour‐bearing mice. Pharmacokinetic studies compared the plasma retention time of the 111In‐panitumumab in both non‐tumour‐bearing and A431 tumour‐bearing mice. Tumour targeting was also visualized by γ‐scintigraphy.

Conclusions and implications:  Panitumumab can be efficiently radiolabelled with 111In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.
Dual functionality of interleukin‐1 family cytokines: implications for anti‐interleukin‐1 therapy
Authors: Luheshi NM , Rothwell NJ , Brough D
Published: July 2009

Dysregulated inflammation contributes to disease pathogenesis in both the periphery and the brain. Cytokines are coordinators of inflammation and were originally defined as secreted mediators, released from expressing cells to activate plasma membrane receptors on responsive cells. However, a group of cytokines is now recognized as having dual functionality. In addition to their extracellular effects, these cytokines act inside the nuclei of cytokine‐expressing or cytokine‐responsive cells. Interleukin‐1 (IL‐1) family cytokines are key pro‐inflammatory mediators, and blockade of the IL‐1 system in inflammatory diseases is an attractive therapeutic goal. All current therapies target IL‐1 extracellular actions. Here we review evidence that suggests IL‐1 family members have dual functionality. Several IL‐1 family members have been detected inside the nuclei of IL‐1‐expressing or IL‐1‐responsive cells, and intranuclear IL‐1 is reported to regulate gene transcription and mRNA splicing. However, further work is required to determine the impact of IL‐1 intranuclear actions on disease pathogenesis. The intranuclear actions of IL‐1 family members represent a new and potentially important area of IL‐1 biology and may have implications for the future development of anti‐IL‐1 therapies.
Emerging cardiovascular actions of the incretin hormone glucagon‐like peptide‐1: potential therapeutic benefits beyond glycaemic control?
Authors: Grieve David J , Cassidy Roslyn S , Green Brian D
Published: July 2009

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide‐ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP‐1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP‐1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP‐1 receptors (GLP‐1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP‐1R agonists have wide‐ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP‐1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP‐1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP‐1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP‐1 as a novel treatment for CVD.
Guidelines for EEG in encephalopathy related to ESES/CSWS in children
Authors: Scheltens‐de Boer Marjan
Published: July 2009

Electrical status epilepticus during slow sleep (ESES) or continuous spikes and waves during slow sleep (CSWS) is a phenomenon characterized by strong activation of epileptiform activity in the electroencephalogram (EEG) during sleep. The literature contains several small series of patients and many case reports. Large prospective studies are lacking. Definitions of the syndromes and EEG criteria and methods vary, as does their classification. The fluctuating clinical course and EEG findings complicate the diagnostic process and evaluation of effect of therapy. Studies describing quantitative aspects of the epileptiform abnormalities in EEG are overrepresented in literature, whereas qualitative aspects are relatively undervalued. Guidelines for evaluation of the EEG in these syndromes, which focus on both aspects, are presented.
Corticosteroids as treatment of epileptic syndromes with continuous spike‐waves during slow‐wave sleep
Authors: Buzatu Marga , Bulteau Christine , Altuzarra Cécilia , Dulac Olivier , Van Bogaert Patrick
Published: July 2009

To assess the efficacy and tolerability of steroids in epileptic syndromes with continuous spike‐waves during slow‐wave sleep (CSWS), charts of 44 children (25 boys) who received corticosteroids for cognitive and/or behavioral deterioration associated with CSWS were retrospectively reviewed. Awake and sleep electroencephalography (EEG) records, clinical and neuropsychological assessments were available before, during, and after corticosteroid therapy. Evaluation focused on effects on EEG, behavior, and cognition. All but two patients received hydrocortisone (initial dose of 5 mg/kg/day). The treatment was slowly tapered with a total duration of 21 months. There were 18 symptomatic and 26 cryptogenic cases. Mean age was 7 years and mean intelligence quotient/developmental quotient (IQ/DQ) was 65. Mean CSWS duration before corticosteroid treatment was 1.7 years. Twenty patients had tried more than two antiepileptic drugs (AEDs) before steroids. Positive response to steroids was found during the first 3 months of treatment in 34 of 44 patients (77.2%), with normalization of the EEG in 21 patients. Relapse occurred in 14 of them. Hence, 20 patients (45.4%) were long‐term responders after a single but prolonged trial of steroids, including all four cases of Landau‐Kleffner syndrome. Positive response to steroids was highly significantly associated with higher IQ/DQ. Shorter CSWS duration, but not age, etiology, or previous AED trials, was associated with positive response to steroids. Early discontinuation of the treatment for side effects was encountered in seven patients. We conclude that corticosteroids are safe and efficient for treatment of epilepsy with CSWS. Poor responders are patients with very low IQ and long duration of CSWS.
Do Muscle Mass, Muscle Density, Strength, and Physical Function Similarly Influence Risk of Hospitalization in Older Adults?
Authors: Cawthon Peggy Mannen , Fox Kathleen M. , Gandra Shravanthi R. , Delmonico Matthew J. , Chiou Chiun‐Fang , Anthony Mary S. , Sewall Ase , Goodpaster Bret , Satterfield Suzanne , Cummings Steven R. , Harris Tamara B. ,   for the Health, Aging and Body Composition Study
Published: July 2009

OBJECTIVES: To examine the association between strength, function, lean mass, muscle density, and risk of hospitalization.

DESIGN: Prospective cohort study.

SETTING: Two U.S. clinical centers.

PARTICIPANTS: Adults aged 70 to 80 (N=3,011) from the Health, Aging and Body Composition Study.

MEASUREMENTS: Measurements were of grip strength, knee extension strength, lean mass, walking speed, and chair stand pace. Thigh computed tomography scans assessed muscle area and density (a proxy for muscle fat infiltration). Hospitalizations were confirmed by local review of medical records. Negative binomial regression models estimated incident rate ratios (IRRs) of hospitalization for race‐ and sex‐specific quartiles of each muscle and function parameter separately. Multivariate models adjusted for age, body mass index, health status, and coexisting medical conditions.

RESULTS: During an average 4.7 years of follow‐up, 1,678 (55.7%) participants experienced one or more hospitalizations. Participants in the lowest quartile of muscle density were more likely to be subsequently hospitalized (multivariate IRR=1.47, 95% confidence interval (CI)=1.24–1.73) than those in the highest quartile. Similarly, participants with the weakest grip strength were at greater risk of hospitalization (multivariate IRR=1.52, 95% CI=1.30–1.78, Q1 vs. Q4). Comparable results were seen for knee strength, walking pace, and chair stands pace. Lean mass and muscle area were not associated with risk of hospitalization.

CONCLUSION: Weak strength, poor function, and low muscle density, but not muscle size or lean mass, were associated with greater risk of hospitalization. Interventions to reduce the disease burden associated with sarcopenia should focus on increasing muscle strength and improving physical function rather than simply increasing lean mass.
Human epicardium: ultrastructural ancestry of mesothelium and mesenchymal cells
Authors: Gherghiceanu Mihaela , Popescu L.M.
Published: July 2009

The human sub‐epicardial area contains an unexplored cellular population under a layer of mesothelial cells. Transmission electron microscopy revealed the existence of interstitial Cajal‐like cells (ICLCs), isolated smooth muscle cells (iSMC) and mesenchymal cells besides other well‐known cells. The presence of iSMC in the sub‐epicardial space is quite unique and could explain why epicardial‐derived cells isolated from human epicardium generate smooth muscle cells in culture. Mesenchymal cells, guided by ICLCs, were found migrating from sub‐epicardial area in the mesothelial layer. These findings suggest that epithelial‐mesenchymal transition is not a common process involved in cardiac regeneration in vivo.
A Tale of Two Regions: Diffusion of the Israeli “50 Percent Rule” from the Galilee to the Occupied West Bank
Authors: Forman Geremy
Published: July 2009

The “50 percent rule” is an Israeli judicial doctrine that has played a pivotal role since the early 1960s in deciding disputes between the Israeli government and Palestinian landholders under Article 78 of the Ottoman Land Code. It was first institutionalized during a government land‐claiming campaign aimed at providing state land for settlement‐based Judaization of Israel's predominantly Palestinian Galilee region. Two decades later, during a similar state land‐claiming campaign, the doctrine diffused into the occupied West Bank. Drawing on spatial components of social science diffusion literature and work in the field of legal geography, this article offers a legal‐historical‐geographical analysis of the evolution and diffusion of the 50 percent rule. Its conclusions suggest a new spatialized approach to the study of legal transfers and transplants that conceptualizes law's movement across international borders as one component of a broader process of legal diffusion, in which internal diffusion also plays an important role.
International Legal Rulings on Lustration Policies in Central and Eastern Europe: Rule of Law in Historical Context
Authors: Horne Cynthia M.
Published: July 2009

The transitional justice literature highlights various trade‐offs involved in the choice and implementation of lustration as a transitional justice measure in Central and Eastern Europe. This article examines how international legal body rulings on lustration laws have interpreted rule‐of‐law versus justice concerns. The European Court of Human Rights and the International Labour Organization have explored possible information problems, due process violations, employment discrimination issues, and bureaucratic loyalty concerns within the context of lustration. Three findings emerge from their legal rulings. First, contrary to popular notions, international legal bodies are not antilustration. The institutions are engaging with questions regarding the fair implementation, not the legality, of lustration laws. Second, the prioritizing of justice concerns during the transition efforts is highlighted as a way to lay a strong democratic foundation. Third, the organizations have emphasized the importance of placing rule of law in historical context, thereby situating post‐Communist societies within other posttotalitarian regime‐building narratives.
A Second Look at the Structure of Human Olfactory Memory
Authors: White Theresa L.
Published: July 2009

How do we remember olfactory information? Is the architecture of human olfactory memory unique compared with that of memory for other types of stimuli? Ten years ago, a review article evaluated these questions, as well as the distinction between long‐ and short‐term olfactory memory, with three lines of evidence: capacity differences, coding differences, and neuropsychological evidence, though serial position effects were also considered. From the data available at the time, the article preliminarily suggested that olfactory memory was a two‐component system that was not qualitatively different from memory systems for other types of stimuli. The decade that has elapsed since then has ushered in considerable changes in theories of memory structure and provided huge advances in neuroscience capabilities. Not only have many studies exploring various aspects of olfactory memory been published, but a model of olfactory perception that includes an integral unitary memory system also has been presented. Consequently, the structure of olfactory memory is reevaluated in the light of further information currently available with the same theoretical lines of evidence previously considered. This evaluation finds that the preponderance of evidence suggests that, as in memory for other types of sensory stimuli, the short‐term–long‐term distinction remains a valuable dissociation for conceptualizing olfactory memory, though perhaps not as architecturally separate systems.
Functional Organization of the Rodent Parabrachial Nucleus
Authors: Yamamoto Takashi , Takemura Motohide , Inui Tadashi , Torii Kunio , Maeda Naohiro , Ohmoto Makoto , Matsumoto Ichiro , Abe Keiko
Published: July 2009

The rodent parabrachial nucleus (PBN) is not merely a sensory relay station but also plays an important role in integrating various ascending and descending inputs together with plastic changes of neuronal responses after learning and experience. The limbic and reward systems receive ingestion‐related information via the cortical areas in primates, whereas in rodents the information is sent to these systems mostly via the PBN. To explore how the rat PBN is functionally organized, we detected activation patterns of neurons mainly by means of c‐fos immunohistochemistry to show neuronal activation in different situations of ingestive behavior. The expression pattern was different under nutritionally replete and deficient conditions, perceptually new and familiar conditions, and learned and unlearned conditions. As for the possible functions, the rostral part of the external lateral subnucleus is related to general visceral inputs; the caudal part of the external lateral subnucleus, aversive behavior; the dorsal lateral subnucleus, ingestive behavior; and the central medial subnucleus, taste of NaCl. Because several genes were localized in specific subnuclei, we are trying to correlate the gene expressions with possible functional significance.
Olfaction in Petrels
Authors: Bonadonna Francesco
Published: July 2009

In the 1960s, Betsy Bang unraveled the complexity of the olfactory apparatus of procellariiform seabirds (petrels and albatrosses), suggesting an important role for olfaction in their ecology. Shortly thereafter, Prof. B. Wenzel continued the investigations on petrels’ well‐developed olfactory neuroanatomy as well as their sensitivity to food‐related scents. Later studies demonstrated further that the sense of smell is also critical to these birds when homing to their burrow. Building on these findings, we have demonstrated in several petrel species the importance of the burrow olfactory signature in homing. The nature of this olfactory signature relies predominantly on their mate's odor. Indeed, in our Y‐maze experiments, Antarctic prions (Pachyptila desolata) and blue petrels (Halobaena caerulea) could discriminate between their own and their mates’ odors. However, although they are attracted by their mate odor, they prefer the odor of a conspecific bird to their own. These results have drawn attention to the possible use of chemical signals in birds’ social behaviors, such as individual recognition and/or mate choice. Indeed, petrel life history traits suggest that olfactory‐mediated mate choice may have evolved in this group to ensure genetic compatibility between mates. We have recently shown that a bird's semiochemical profile is more similar to itself, year after year, than to that of a conspecific. As a result, a novel function of olfaction emerges in petrels: the perception of a chemical signal that may broadcast individuals’ identity and quality, thereby contributing to an optimal mate choice.
The Anatomical and Electrophysiological Basis of Peripheral Nasal Trigeminal Chemoreception
Authors: Silver Wayne L. , Finger Thomas E.
Published: July 2009

The trigeminal nerve (TN) provides sensory information from the eyes, nose, and mouth. A subset of trigeminal nerve fibers, particularly those containing the neuropeptides substance P and calcitonin gene‐related peptide (CGRP), responds to chemical irritants in the environment. Axons in the ethmoid and nasopalatine branches of the trigeminal nerve innervate the nasal mucosa where they ramify repeatedly. TN endings extend close to the nasal epithelial surface stopping at the line of tight junctions only a few micrometers from the surface. A single ethmoid nerve axon may send branches to the nasal mucosa, olfactory bulb, and the spinal trigeminal complex. Traditionally, irritants are thought to stimulate free TN endings in the nasal epithelium. Recently, however, solitary chemoreceptor cells (SCCs) have been found scattered throughout the nasal cavity. The SCCs are contacted by TN fibers and may express T2R ‘‘bitter‐taste’’ receptors alpha‐gustducin, and TRPM5. Peripheral trigeminal electrophysiological recordings in response to irritants have been obtained from the mucosa (negative mucosal potential, NMP) and the nerve to analyze characteristics of trigeminal stimuli. Responses to a wide variety of irritants have been recorded from the ethmoid nerve. In general, the more lipid soluble the compound, the lower the threshold. Nerve recordings have also suggested several mechanisms by which irritants elicit responses. Bitter substances elicit responses from the ethmoid nerve and cause a change in respiration indicating stimulation via SCCs. SCCs themselves respond to chemical stimuli and may be contributing to the detection of nasal irritants.
Computing with Dendrodendritic Synapses in the Olfactory Bulb
Authors: Urban Nathaniel N. , Arevian Armen C.
Published: July 2009

Decades of work in vivo and in vitro have provided a wealth of data on the properties of the reciprocal dendrodendritic synapses that connect olfactory bulb mitral and granule cells. However, hypotheses about the function of these connections have changed relatively little. These synapses are believed to mediate recurrent and lateral inhibition and thus, by analogy with lateral inhibition in other systems, have been proposed to play a role in sharpening mitral cell receptive fields and in generating oscillatory spiking in mitral cells. This description is likely to be partially accurate, but is likely to be a rather simplified and incomplete account of the function of these connections. In particular, current hypotheses about the function of dendrodendritic circuits do not account for some of the unusual features of reciprocal synapses that may allow olfactory bulb circuits to perform special functions. Here we review recent work on the physiology and function of olfactory bulb circuits and try to link the physiological properties of reciprocal synapses particular computations that the olfactory bulb may perform.
Multiple Receptor Systems for Umami Taste in Mice
Authors: Yoshida Ryusuke , Yasumatsu Keiko , Shirosaki Shinya , Jyotaki Masashi , Horio Nao , Murata Yoshihiro , Shigemura Noriatsu , Nakashima Kiyohito , Ninomiya Yuzo
Published: July 2009

Recent molecular studies proposed that the T1r1/T1r3 heterodimer, mGluR1 and mGluR4 might function as umami taste receptors in mice. However, the roles of each of these receptors in umami taste are not yet clear. In this paper, we summarize recent data for T1r3, mGluR1, and mGluR4 as umami taste receptors and discuss receptor systems responsible for umami detection in mice.
The Role of the Parabrachial Nucleus in Taste Processing and Feeding
Authors: Scott Thomas R. , Small Dana M.
Published: July 2009

The parabrachial nucleus (PBN) was identified as a taste relay in rodents in 1971. Early recordings suggested that the PBN transmitted a faithful representation of taste activity from the nucleus of the solitary tract (NTS). However, its role assumed greater significance as its subnuclei were shown to deal with different aspects of taste, visceral sensations, hedonics, and conditioned aversions. The discovery of parallel projections from PBN to the thalamus and to ventral forebrain, and evidence that the former carried sensory information while the latter signaled hedonics, conferred on PBN a central role in guiding feeding. Thus, it was surprising to discover that the PBN is not a taste relay in primates. So arose a distinction between rodents, in which parallel processing of taste and hedonic information is the rule, and primates, where serial processing through the cortex precedes a hedonic assessment. Where does the integration of taste and hedonics occur, and how does this affect feeding? Neurons in both NTS and PBN of rodents are modified by changing physiological conditions. That altered activity parallels and perhaps directs the rodent's feeding behavior. Information from primate NTS implies no such modification. These interactions are reserved for orbitofrontal cortex and ventral forebrain. The implication is that in rodents, hindbrain alterations not only control the reflexes associated with taste, but also direct food selection through the PBN–ventral forebrain projections. In primates, the apparatus is in place for an independent cognitive analysis unaltered by physiological state, upon which a hedonic assessment is subsequently overlaid.