bluuebunny/crossref_metadata_2025 huggingface dataset:
Viral vectors for targeting the canine retina: a review
Authors: Petersen‐Jones Simon M.
Published: August 2012

Clinical trials are currently underway using gene therapy to treat retinal disease such as Leber congenital amaurosis (LCA). Viral vectors that have been utilized to target retinal cells include adenoviruses, lentiviruses, and recombinant adeno‐associated viruses (rAAV). Of the three classes, rAAV vectors show the greatest promise for retinal gene therapy. Recent developments in virus technology such as the development of hybrid and capsid mutant rAAV vectors mean that specific retinal cells can be targeted and faster stronger transgene expression is now possible compared to that achieved with the first generation of vectors. Gene therapy trials in dogs have been very important in the development of therapy for RPE65 LCA which is currently in phase I/II clinical trials in humans. Recent successes in using gene therapy to treat canine achromatopsia, X‐linked progressive retinal atrophy (PRA) and the more severe rapid degenerations such as rod‐cone dysplasia type 3 may lead also to the translation to human clinical trials. Dogs have played and continue to play an important role as animal models for proof‐of‐concept studies of retinal gene therapy. As modifications and improvements in gene therapy protocols are made from experience gathered from human clinical trials perhaps gene therapy for the treatment of canine clinical patients will become available to veterinary ophthalmologists.
Beyond ‘Constitutionalism Beyond the State’
Authors: Anderson Gavin W.
Published: August 2012

For contemporary constitutional theory, the key challenge posed by globalization undermines the traditional link between constitutionalism and the state: in response to multi‐level governance, theories of constitutionalism beyond the state have been advanced. This focus on levels obscures more fundamental epistemological questions raised by globalization about the nature of constitutionalism itself. Critical analysis of three leading schools of constitutionalism beyond the state – supranational, societal, and new constitutionalism – highlights their shared assumptions with state‐based thought regarding the separation between economics and politics, and the necessarily hegemonic character of constitutionalism. However, globalization intensifies critique of these assumptions, and questions their translation to the transnational context. An alternative scholarly fault line to the state/non‐state cleavage emerges between working within and transcending the politics of constitutional knowledge produced during the nation‐state era. A broader globalization perspective reveals the extent to which such processes of constitutional rethinking are under way through developments in the global South.
Inheritance: A Gendered and Intergenerational Dimension of Poverty
Authors: Cooper Elizabeth , Bird Kate
Published: August 2012

This collection of articles contains new and important findings concerning the scale and significance of asset transfers through inheritance among different populations, as well as the ways in which inheritance affects economic and social status and mobility. Evidence exists of women commonly losing access to assets when properties are redistributed following a spouse's death. This and the household effects of gaining or losing access to heritable property highlight the gendered and intergenerational dimensions of inheritance. As an introduction to the collection, this article provides an overview of how inheritance has been understood in poverty‐related policy and research up to now. We then synthesise what the new findings presented in this collection tell us about inheritance as a crucial factor in women's poverty and the intergenerational transmission of poverty, highlighting what other researchers and policy‐makers can take from this research to address the gendered and intergenerational dimensions of inheritance in different contexts.
Widowhood and Asset Inheritance in Sub‐Saharan Africa: Empirical Evidence from 15 Countries
Authors: Peterman Amber
Published: August 2012

Widows in sub‐Saharan Africa (SSA) are perceived to face discrimination in asset inheritance, leading to poverty for themselves and their children. However, large‐sample empirical research supporting this claim is scarce. This article explores asset inheritance among widows using two data sources: (i) nationally representative demographic and health survey (DHS) data from 15 SSA countries, and (ii) a 13‐year longitudinal panel from the Kagera region in north‐west Tanzania. Results indicate that, across the 15 DHS countries, less than half of widows report inheriting any assets; the proportion reporting inheriting the majority of assets is lower. Findings from Kagera indicate that the value of inheritance is significant in determining changes in long‐term household welfare.
Women, Marriage and Asset Inheritance in Uganda
Authors: Doss Cheryl , Truong Mai , Nabanoga Gorrettie , Namaalwa Justine
Published: August 2012

Using a unique dataset which collected individual‐level asset ownership data and women's life histories regarding assets, this article examines the relationships between inheritance, marriage and asset ownership in Uganda. Land is the most important asset in rural Uganda. The majority of couples (both married and those in consensual unions) report owning land jointly. Men who report owning a parcel of land are much more likely than women to say they inherited the land. Inheritance is not an important means of acquisition of other assets, including livestock, business assets, financial assets and consumer durables. These items are acquired through purchase, by both men and women.
Women and Inheritance in Sub‐Saharan Africa: What Can Change?
Authors: Cooper Elizabeth
Published: August 2012

This article analyses how inheritance is being addressed to enhance socio‐economic equity and opportunities in five sub‐Saharan African countries: Ghana, Kenya, Mozambique, Rwanda and Uganda. Based on interviews with governmental and non‐governmental actors, as well as policy analysis and reviews of the literature, it considers how inheritance is understood as a public policy issue, and focuses attention on three areas that offer opportunities for safeguarding women's inheritance: marriage; customary land governance; and local arbitration. Initiatives to change policies and practices related to these areas are discussed, together with the lessons that can be learned.
DISCOVERING ROBUST EMBEDDINGS IN (DIS)SIMILARITY SPACE FOR HIGH‐DIMENSIONAL LINGUISTIC FEATURES
Authors: Mu Tingting , Miwa Makoto , Tsujii Junichi , Ananiadou Sophia
Published: August 2012

Recent research has shown the effectiveness of rich feature representation for tasks in natural language processing (NLP). However, exceedingly large number of features do not always improve classification performance. They may contain redundant information, lead to noisy feature presentations, and also render the learning algorithms intractable. In this paper, we propose a supervised embedding framework that modifies the relative positions between instances to increase the compatibility between the input features and the output labels and meanwhile preserves the local distribution of the original data in the embedded space. The proposed framework attempts to support flexible balance between the preservation of intrinsic geometry and the enhancement of class separability for both interclass and intraclass instances. It takes into account characteristics of linguistic features by using an inner product‐based optimization template. (Dis)similarity features, also known as empirical kernel mapping, is employed to enable computationally tractable processing of extremely high‐dimensional input, and also to handle nonlinearities in embedding generation when necessary. Evaluated on two NLP tasks with six data sets, the proposed framework provides better classification performance than the support vector machine without using any dimensionality reduction technique. It also generates embeddings with better class discriminability as compared to many existing embedding algorithms.
MUSIC‐ANN Analysis for Locating Structural Damages in a Truss‐Type Structure by Means of Vibrations
Authors: Osornio‐Rios Roque A , Amezquita‐Sanchez Juan Pablo , Romero‐Troncoso Rene J. , Garcia‐Perez Arturo
Published: August 2012

Abstract:  This article presents a methodology for damage detection, location, and quantification based on vibration signature analysis and a comprehensive experimental study to assess the utility of the proposed structural health monitoring applied to a five‐bay truss‐type structure. The MUSIC algorithm introduced first by Jiang and Adeli for health monitoring of structures in 2007 is fused with artificial neural networks for an automated result. The developed methodology is based on feeding the amplitude of the natural frequencies as input of an artificial neural network, being the novelty of the proposed methodology its ability to identify, locate, and quantify the severity of damages with precision such as: external and internal corrosion and cracks in an automated monitoring process. Results show the proposed methodology is effective for detecting a healthy structure, a structure with external and internal corrosion, and a structure with crack. Therefore, the proposed fusion of MUSIC‐ANN algorithms can be regarded as a simple, effective, and automated tool without requiring sophisticated equipment, toward establishing a practical and reliable structural health monitoring methodology, which will help to evaluate the condition of the structure, in order to detect damages early and to make the corresponding maintenance decisions in the structures.
Structural Analysis with Fuzzy Data and Neural Network Based Material Description
Authors: Graf W. , Freitag S. , Sickert J.‐U. , Kaliske M.
Published: August 2012

Abstract:  In the article, a new approach is presented utilizing artificial neural networks for uncertain time‐dependent structural behavior. Recurrent neural networks (RNNs) for fuzzy data can be trained by uncertain experimental data to describe arbitrary stress–strain–time dependencies. The benefit is a generalized formulation, which can be applied to describe the behavior of several materials without definition of a specific material model. Model‐free material descriptions can be used as numerical efficient material formulations within the finite element method. To perform fuzzy or fuzzy stochastic finite element analyses, a new approach is introduced. An

‐level optimization is utilized for signal computation and training of RNNs for fuzzy data. The applicability is demonstrated by means of examples.
Evidence for a multiple sclerosis epidemic?
Authors: Krone B. , Ramagopalan S. V.
Published: August 2012

Click here to view the accompanying paper in this issue.
Do I Look Like Someone Who Cares? Recruiters’ Ratings of Applicants’ Paid and Volunteer Experience
Authors: Wilkin Christa L. , Connelly Catherine E.
Published: August 2012

Despite the widespread use of resumes, little is known about whether recruiters value applicants’ volunteer experience, and if they value some kinds of volunteer experience more than others. Based on a sample of recruiters (n = 135) who each rated a series of resumes with different amounts and types of paid and volunteer experience, our results suggest that recruiters prefer resumes with relevant experience, and resumes with a combination of volunteer and paid experience. Our results did not suggest significant differences in the ratings given to paid or volunteer experience. We discuss the implications of these findings for researchers and practitioners, with specific advice for human resource professionals and applicants.
Order Effects on Situational Judgment Test Items: A case of construct‐irrelevant difficulty
Authors: Marentette Brian J. , Meyers Lawrence S. , Hurtz Gregory M. , Kuang Daniel C.
Published: August 2012

Situational judgment tests (SJTs) pose unique cognitive demands on test takers in that, when presented in written form, they require a great deal of reading and cognitive effort. Because of this cognitive demand, responses to test items toward the end of the test may be influenced by an order effect produced by responding to a large quantity of previous test items. This construct‐irrelevant order effect may increase measurement error and threaten the validity of SJT scores. To test this phenomenon, data were obtained from 1,089 applicants who had completed a lengthy SJT as part of a selection process for an hourly safety and surveillance job at a large international corporation. Results showed that local item dependence, item difficulty, and the rate of omitted responses all increased when items were placed toward the end. The order effect alone was not strong enough to influence subgroup mean score differences in the second half of the test. However, this effect did vary by race: African‐Americans were most strongly affected by the order effect, followed by Caucasians, in their number of omitted responses. Implications and future research of this effect for SJTs and similar types of assessments are discussed.
Investigating the Cross‐cultural Applicability of the Personnel Reaction Blank Using American and Singaporean Respondent Groups
Authors: Tong Yew Kwan , Arvey Richard D.
Published: August 2012

The Personnel Reaction Blank (PRB) is an important personality‐based instrument for assessing the integrity of individuals. Our study investigated the cross‐cultural applicability of its three psychological factors (Sense of Well‐being, SWB; Prosocial Background, PSB; and Compliance with Social Norms, CSN) using American and Singaporean respondent groups. Based on this three‐factor structure, the PRB demonstrated acceptable cross‐group generalizability. Mean scores for SWB, PSB, and CSN showed differences between male and female respondents, although the factor correlation matrices were invariant across gender. The mean composite score (SWB + PSB + CSN) was also not significantly different across gender.
Namaqua dwarf adders must breed frequently: the problem with being small
Authors: Maritz B. , Alexander G. J.
Published: August 2012

Reproductive frequency is a key component of reproductive output, and has important influences on organismal fitness and population persistence. Viperid snakes, like many other ectothermic vertebrates, generally exhibit a low frequency of reproduction (LFR), as females only reproduce every second year, or even less frequently. However, for small‐bodied species with constrained clutch/litter sizes, and low survival, reproductive frequency cannot be too infrequent if populations are to persist. We assessed whether Bitis schneideri, a small, arid‐adapted viperid snake from southern Africa has the LFR typical of many other viperids, despite having low survival and small litters. We calculated the reproductive frequency required to sustain a population using information gathered from recent studies of the ecology of the species. The small litter size imposed by being small‐bodied, and low annual survival, require B. schneideri to reproduce frequently, probably annually, for populations to persist. We also assessed the reproductive status of all available preserved adult females. A high proportion were reproductive (up to 80% during summer), with developing or mature follicles, or developing young. Such frequent reproduction is atypical, even among closely related species, and might be facilitated through the capacity of B. schneideri to feed year‐round in the aseasonal habitat in which it occurs. We predict that future studies of small‐bodied species from climates that allow for extended periods of feeding will continue to show that frequent reproduction is more widespread among vipers than is currently assumed.
Development and assessment of sensitive immuno‐PCR assays for the quantification of cerebrospinal fluid three‐ and four‐repeat tau isoforms in tauopathies
Authors: Luk Connie , Compta Yaroslau , Magdalinou Nadia , Martí Maria José , Hondhamuni Geshanthi , Zetterberg Henrik , Blennow Kaj , Constantinescu Radu , Pijnenburg Yolande , Mollenhauer Brit , Trenkwalder Claudia , Van Swieten John , Chiu Wan Zheng , Borroni Barbara , Cámara Ana , Cheshire Perdita , Williams David R. , Lees Andrew J. , de Silva Rohan
Published: August 2012

Characteristic tau isoform composition of the insoluble fibrillar tau inclusions define tauopathies, including Alzheimer's disease (AD), progressive supranuclear palsy (PSP) and frontotemporal dementia with parkinsonism linked to chromosome 17/frontotemporal lobar degeneration‐tau (FTDP‐17/FTLD‐tau). Exon 10 splicing mutations in the tau gene, MAPT, in familial FTDP‐17 cause elevation of tau isoforms with four microtubule‐binding repeat domains (4R‐tau) compared to those with three repeats (3R‐tau). On the basis of two well‐characterised monoclonal antibodies against 3R‐ and 4R‐tau, we developed novel, sensitive immuno‐PCR assays for measuring the trace amounts of these isoforms in CSF. This was with the aim of assessing if CSF tau isoform changes reflect the pathological changes in tau isoform homeostasis in the degenerative brain and if these would be relevant for differential clinical diagnosis. Initial analysis of clinical CSF samples of PSP (n = 46), corticobasal syndrome (CBS; n = 22), AD (n = 11), Parkinson's disease with dementia (PDD; n = 16) and 35 controls revealed selective decreases of immunoreactive 4R‐tau in CSF of PSP and AD patients compared with controls, and lower 4R‐tau levels in AD compared with PDD. These decreases could be related to the disease‐specific conformational masking of the RD4‐binding epitope because of abnormal folding and/or aggregation of the 4R‐tau isoforms in tauopathies or increased sequestration of the 4R‐tau isoforms in brain tau pathology.
Coastal geomorphology and culture in the spatiality of whaling in the Faroe Islands
Authors: Fielding Russell
Published: August 2012

This paper explores the suggested relationship between the physical structure of beaches in the Faroe Islands and the spatial history and regulation of the grindadráp – the traditional method of whaling practised by the Faroese in which entire pods of whales are driven ashore by collective effort. Using coastal survey methods, this research shows a lack of strong correlation between beach morphology and the practice and regulation of whaling, except in the case of dramatic near‐shore bathymetric features. The gap between these data points can best be filled through cultural‐historical analysis, which informs our understanding of the dynamics behind the spatiality of Faroese whaling and whale conservation efforts.
Activation of the bile acid receptor GPBAR1 protects against gastrointestinal injury caused by non‐steroidal anti‐inflammatory drugs and aspirin in mice
Authors: Cipriani Sabrina , Mencarelli Andrea , Bruno Angela , Renga Barbara , Distrutti Eleonora , Santucci Luca , Baldelli Franco , Fiorucci Stefano
Published: August 2012

Background and Purpose

Low doses of aspirin (acetylsalicylic acid; ASA) and non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of gastrointestinal bleeding. GPBAR1 is a bile acid receptor expressed in the gastrointestinal tract. Here, we have investigated whether GPBAR1 was required for mucosal protection in models of gastrointestinal injury caused by ASA and NSAIDs.

Experimental Approch

GPBAR1+/+ and GPBAR1−/− mice were given ASA (10–50 mg.kg−1) or naproxen. Gastric and intestinal mucosal damage was assessed by measuring lesion scores.

Key Results

Expression of GPBAR1, mRNA and protein, was detected in mouse stomach. Mice lacking GPBAR1 were more sensitive to gastric and intestinal injury caused by ASA and NSAIDs and exhibited a markedly reduced expression of cystathionine‐γ‐liase (CSE), cystathionine‐β‐synthase (CBS) and endothelial NOS enzymes required for generation of H2S and NO, in the stomach. Treating GPBAR1+/+ mice with two GPBAR1 agonists, ciprofloxacin and betulinic acid, rescued mice from gastric injury caused by ASA and NSAIDs. The protective effect of these agents was lost in GPBAR1−/− mice. Inhibition of CSE by DL‐propargylglycine completely reversed protection afforded by ciprofloxacin in wild type mice, whereas treating mice with an H2S donor restored the protective effects of ciprofloxacin in GPBAR1−/− mice. Deletion of GPBAR1 altered the morphology of the small intestine and increased sensitivity to injury caused by naproxen.

Conclusion and Implications

GPBAR1 is essential to maintain gastric and intestinal mucosal integrity. GPBAR1 agonists protect against gastrointestinal injury caused by ASA and NSAIDs by a COX‐independent mechanism.
Endosomal proteolysis regulates calcitonin gene‐related peptide responses in mesenteric arteries
Authors: McNeish AJ , Roux BT , Aylett S‐B , Van Den Brink AM , Cottrell GS
Published: August 2012

Background and Purpose

Calcitonin gene‐related peptide (CGRP) is a potent vasodilator, implicated in the pathogenesis of migraine. CGRP activates a receptor complex comprising, calcitonin receptor‐like receptor (CLR) and receptor activity‐modifying protein 1 (RAMP1). In vitro studies indicate recycling of CLR●RAMP1 is regulated by degradation of CGRP in early endosomes by endothelin‐converting enzyme‐1 (ECE‐1). However, it is not known if ECE‐1 regulates the resensitization of CGRP‐induced responses in functional arterial tissue.

Experimental Approach

CLR, ECE‐1a‐d and RAMP1 expression in rat mesenteric artery smooth muscle cells (RMA‐SMCs) and mesenteric arteries was analysed by RT‐PCR and by immunofluorescence and confocal microscopy. CGRP‐induced signalling in cells was examined by measuring cAMP production and ERK activation. CGRP‐induced relaxation of arteries was measured by isometric wire myography. ECE‐1 was inhibited using the specific inhibitor, SM‐19712.

Key Results

RMA‐SMCs and arteries contained mRNA for CLR, ECE‐1a‐d and RAMP1. ECE‐1 was present in early endosomes of RMA‐SMCs and in the smooth muscle layer of arteries. CGRP induced endothelium‐independent relaxation of arteries. ECE‐1 inhibition had no effect on initial CGRP‐induced responses but reduced cAMP generation in RMA‐SMCs and vasodilation in mesenteric arteries responses to subsequent CGRP challenges.

Conclusions And Implications

ECE‐1 regulated the resensitization of responses to CGRP in RMA‐SMCs and mesenteric arteries. CGRP‐induced relaxation did not involve endothelium‐derived pathways. This is the first report of ECE‐1 regulating CGRP responses in SMCs and arteries. ECE‐1 inhibitors may attenuate an important vasodilatory pathway, implicated in primary headaches and may represent a new therapeutic approach for the treatment of migraine.
ONO‐2506 inhibits spike–wave discharges in a genetic animal model without affecting traditional convulsive tests via gliotransmission regulation
Authors: Yamamura Satoshi , Hoshikawa Masamitsu , Dai Kato , Saito Hiromitsu , Suzuki Noboru , Niwa Osamu , Okada Motohiro
Published: August 2012

This article is commented on by Onat, pp. 1086‐1087 of this issue.
Music during after‐death care: a focus group study
Authors: Holm Marianne S , Fålun Nina , Gjengedal Eva , Norekvål Tone M
Published: August 2012

Background: The intensive care unit (ICU) is not only a place to recover from injuries incurred during accidents and from serious illness. For many patients, it is also a place where they might die. Nursing care does not stop when a patient dies; rather, it continues with the care of the deceased and with family support. The aims of this study were (1) to explore the experiences and attitudes of nurses towards the use of ambient music in the ICU during after‐death care and (2) to describe the feedback nurses received from relatives when music was used during the viewing.

Method: A qualitative design employing focus group interviews was used. Three focus group interviews with 15 nurses were conducted. All the interviews were audiotaped, transcribed verbatim and analysed using qualitative content analysis.

Findings: Six main categories of attitudes emerged from the analysis: (1) different attitudes among nurses towards the use of music; (2) music affects the atmosphere; (3) music affects emotions; (4) use of music was situational; (5) special choice of music and (6) positive feedback from the bereaved.

Conclusion: This study demonstrates that music might be helpful for nurses during after‐death care as well as for the care of the relatives.

Relevance to clinical practice: Including ambient music in an after‐death care programme can help nurses show respect for the deceased as the body is being prepared. Music played during the viewing may be a way of helping relatives in their time of grieving. It may ease the situation by making that event special and memorable. However, standardizing this intervention does not seem appropriate. Rather, the individual nurse and the family must decide whether music is to be used in a particular situation.
Development of a Pump Flow Estimator for Rotary Blood Pumps to Enhance Monitoring of Ventricular Function
Authors: Granegger Marcus , Moscato Francesco , Casas Fernando , Wieselthaler Georg , Schima Heinrich
Published: August 2012

Estimation of instantaneous flow in rotary blood pumps (RBPs) is important for monitoring the interaction between heart and pump and eventually the ventricular function. Our group has reported an algorithm to derive ventricular contractility based on the maximum time derivative (dQ/dtmax as a substitute for ventricular dP/dtmax) and pulsatility of measured flow signals. However, in RBPs used clinically, flow is estimated with a bandwidth too low to determine dQ/dtmax in the case of improving heart function. The aim of this study was to develop a flow estimator for a centrifugal pump with bandwidth sufficient to provide noninvasive cardiac diagnostics. The new estimator is based on both static and dynamic properties of the brushless DC motor. An in vitro setup was employed to identify the performance of pump and motor up to 20 Hz. The algorithm was validated using physiological ventricular and arterial pressure waveforms in a mock loop which simulated different contractilities (dP/dtmax 600 to 2300 mm Hg/s), pump speeds (2 to 4 krpm), and fluid viscosities (2 to 4 mPa·s). The mathematically estimated pump flow data were then compared to the datasets measured in the mock loop for different variable combinations (flow ranging from 2.5 to 7 L/min, pulsatility from 3.5 to 6 L/min, dQ/dtmax from 15 to 60 L/min/s). Transfer function analysis showed that the developed algorithm could estimate the flow waveform with a bandwidth up to 15 Hz (±2 dB). The mean difference between the estimated and measured average flows was +0.06 ± 0.31 L/min and for the flow pulsatilities −0.27 ± 0.2 L/min. Detection of dQ/dtmax was possible up to a dP/dtmax level of 2300 mm Hg/s. In conclusion, a flow estimator with sufficient frequency bandwidth and accuracy to allow determination of changes in ventricular contractility even in the case of improving heart function was developed.
Passive Control of a Biventricular Assist Device With Compliant Inflow Cannulae
Authors: Gregory Shaun David , Pearcy Mark John , Timms Daniel
Published: August 2012

Rotary ventricular assist device (VAD) support of the cardiovascular system is susceptible to suction events due to the limited preload sensitivity of these devices. This may be of particular concern with rotary biventricular support (BiVAD) where the native, flow balancing Starling response is diminished in both ventricles. The reliability of sensor and sensorless‐based control systems which aim to control VAD flow based on preload has limitations, and, thus, an alternative solution is desired. This study introduces a compliant inflow cannula (CIC) which could improve the preload sensitivity of a rotary VAD by passively altering VAD flow depending on preload. To evaluate the design, both the CIC and a standard rigid inflow cannula were inserted into a mock circulation loop to enable biventricular heart failure support using configurations of atrial and ventricular inflow, and arterial outflow cannulation. A range of left (LVAD) and right VAD (RVAD) rotational speeds were tested as well as step changes in systemic/pulmonary vascular resistance to alter relative preloads, with resulting flow rates recorded. Simulated suction events were observed, particularly at higher VAD speeds, during support with the rigid inflow cannula, while the CIC prevented suction events under all circumstances. The compliant section passively restricted its internal diameter as preload was reduced, which increased the VAD circuit resistance and thus reduced VAD flow. Therefore, a CIC could potentially be used as a passive control system to prevent suction events in rotary left, right, and biventricular support.
Intracranial EEG‐fMRI analysis of focal epileptiform discharges in humans
Authors: Cunningham Cameron B. J. , Goodyear Bradley G. , Badawy Radwa , Zaamout Fateh , Pittman Daniel J. , Beers Craig A. , Federico Paolo
Published: August 2012

Purpose:  Combining intracranial electroencephalography (iEEG) with functional magnetic resonance imaging (fMRI) is of interest in epilepsy studies as it would allow the detection of much smaller interictal epileptiform discharges than can be recorded using scalp EEG‐fMRI. This may help elucidate the spatiotemporal mechanisms underlying the generation of interictal discharges. To our knowledge, iEEG‐fMRI has never been performed at 3 Tesla (3T) in humans. We report our findings relating to spike‐associated blood oxygen level–dependent (BOLD) signal changes in two subjects.

Methods:  iEEG‐fMRI at 3T was performed in two subjects. Twelve channels of iEEG were recorded from subdural strips implanted on the left posterior temporal and middle frontal lobes in a 20‐year‐old female with bilateral periventricular gray matter heterotopia. Twenty channels of iEEG were recorded bilaterally from two subdural strips laid anterior–posterior along mesial temporal surfaces in a 29‐year‐old woman with bilateral temporal seizures and mild left amygdalar enlargement on MRI. Functional MRI (fMRI) statistical maps were generated and thresholded at p = 0.01.

Key Findings:  No adverse events were noted. A total of 105 interictal discharges were recorded in the posterior middle temporal gyrus of Subject 1. In Subject 2, 478 discharges were recorded from both mesial temporal surfaces (n = 194 left, 284 right). The right and left discharges were modeled separately, as they were independent. Subject 1 showed spike‐associated BOLD signal increases in the left superior temporal region, left middle frontal gyrus, and right parietal lobe. BOLD decreases were seen in the right frontal and parietal lobes. In Subject 2, BOLD signal increases were seen in both mesial temporal lobes, which when left and right spikes were modeled independently, were greater on the side of the discharge. In addition, striking BOLD signal decreases were observed in the thalamus and posterior cingulate gyrus.

Significance:  iEEG‐fMRI can be performed at 3T with low risk. Notably, runs of only 5 or 10 min of EEG‐fMRI were performed as part of our implementation protocol, yet a significant number of epileptiform discharges were recorded, allowing meaningful analyses. With these studies, we have shown that deactivation can be seen in individual subjects with focal epileptiform discharges. These preliminary observations suggest a novel mechanism through which focal interictal discharges may have widespread cortical and subcortical influences.
Genetic variation in dopaminergic activity is associated with the risk for psychiatric side effects of levetiracetam
Authors: Helmstaedter Christoph , Mihov Yoan , Toliat Mohammad R. , Thiele Holger , Nuernberg Peter , Schoch Susanne , Surges Rainer , Elger Christian E. , Kunz Wolfram S. , Hurlemann René
Published: August 2012

Purpose:  Levetiracetam (LEV) is a highly effective antiepileptic agent. A clinically relevant psychiatric complication of LEV treatment, however, is the provocation of irritability and aggression. Recent behavioral research indicates that personality traits may predispose to these side effects. To assess the genetic basis of the adverse psychotropic profile of LEV, a candidate gene‐based two‐stage association study was conducted.

Methods:  Polymorphisms were a priori selected according to their relevance for impulsivity and reactive‐impulsive aggression. Based on data from both stages, a Bonferroni‐corrected joint meta‐analysis was computed.

Key Findings:  Stage 1 analysis included 290 patients with epilepsy and revealed a higher load of adverse psychotropic side effects of LEV in patients carrying genetic variants associated with decreased dopaminergic activity: rs1611115 (dopamine‐β‐hydroxylase, DBH), rs4680 (catechol‐O‐methyltransferase, COMT), and rs1800497 (dopamine receptor D2‐associated ANKK1 TAQ‐1A). Stage II analysis including 100 patients with epilepsy, and joint meta‐analysis confirmed the effect of the rs1800497 polymorphism (Bonferroni corrected significance of the joint meta‐analysis, p = 0.0096).

Significance:  Confirming the suggestion from behavioral observations that patients might be predisposed to develop irritation and aggression under treatment with LEV, the findings provide first evidence of an association of genetic variation in dopaminergic activity and the risk for psychiatric complications of LEV treatment. Replication and further work is required to prove a true causal relationship. Overall, the pharmacogenomic approach to behavioral side effects may provide a future tool to predict adverse psychotropic effects related to antiepileptic drugs.
Insulin Use in Elderly Adults: Risk of Hypoglycemia and Strategies for Care
Authors: Ligthelm Robert J. , Kaiser Marcel , Vora Jiten , Yale Jean‐François
Published: August 2012

Hypoglycemia is a significant problem in elderly adults with diabetes mellitus. Elderly individuals with diabetes mellitus are at greater risk than younger adults for hypoglycemic events. Several factors contribute to this risk, including the high prevalence of comorbidities, polypharmacy, cognitive impairment, and concomitant use of agents that interfere with glucose metabolism. To minimize the risk of hypoglycemia and maximize the benefits of glycemic control, guidelines typically recommend individualizing glycosylated hemoglobin (HbA1c) targets based on life expectancy, functional status, and individual goals. Although many individuals with type 2 diabetes mellitus will ultimately require insulin therapy to achieve and maintain glycemic control, earlier insulin initiation in elderly individuals may be warranted, particularly in those with renal, cardiovascular, or hepatic concerns that could interfere with the use of oral agents. There are few data on the use of insulin—or other glucose‐lowering agents—in elderly adults, but limited evidence suggests that the use of insulin, especially insulin analogs, may be appropriate in this population. Insulin analogs offer a better pharmacokinetic profile, greater convenience, and less variable glycemic control than human insulin. Because of the high prevalence of cognitive impairment and other geriatric syndromes in elderly adults, clinicians should perform a comprehensive assessment of patients' ability to administer and monitor insulin therapy and recognize and treat hypoglycemia.
“Tight Control” in Geriatrics: The Emperor Wears a Thong
Authors: Finucane Thomas E.
Published: August 2012

The deep‐seated faith in tight glycemic control for patients with type 2 diabetes mellitus shows signs of moderating, especially for elderly adults, but faith in the importance of a glycosylated hemoglobin goal of 7% retains a strong influence over many clinicians. This faith persists despite weak evidence from randomized controlled trials of any meaningful benefit from “tight control” in any patient group, consistent evidence of lack of benefit for many outcomes, and an almost complete lack of evidence about elderly adults or those with extensive vascular disease. Clinicians who care for these vulnerable individuals face a strong public belief in “tight control” and an orchestrated campaign to increase medication use. Although no benefit has been shown in elderly adults, some harms are clear, and others are likely.
Mentorship in the Context of Interdisciplinary Geriatric Research: Lessons Learned from the RAND/Hartford Program for Building Interdisciplinary Geriatric Research Centers
Authors: Keyser Donna J. , Abedin Zainab , Schultz Dana J. , Pincus Harold Alan
Published: August 2012

In light of the growing trend toward formalized research mentorship for effectively transmitting the values, standards, and practices of science from one generation of researchers to the next, this article provides the results of an exploratory study. It reports on research mentorship in the context of interdisciplinary geriatric research based on experiences with the RAND/Hartford Program for Building Interdisciplinary Geriatric Research Centers. At the end of the 2‐year funding period, staff from the RAND Coordinating Center conducted 60‐ to 90‐minute open‐ended telephone interviews with the co‐directors of the seven centers. Questions focused on interdisciplinary mentorship activities, barriers to implementing these activities, and strategies for overcoming them, as well as a self‐assessment tool with regard to programs, policies, and structures across five domains, developed to encourage research mentorship. In addition, the mentees at the centers were surveyed to assess their experiences with interdisciplinary mentoring and the center. According to the interviewees, some barriers to successful interdisciplinary mentoring included the mentor's lack of time, structural support, and the lack of a clear definition of interdisciplinary research. Most centers had formal policies in place for mentor identification and limited policies on mentor incentives. Mentees uniformly reported their relationships with their mentors as positive. More than 50% of mentees reported having a primary mentor from within their discipline and had more contact with their primary mentor than their secondary mentors. Further research is needed to understand the complexity of institutional levers that emerging programs might employ to encourage and support research mentorship.
Diagnosing Delirium in Older Hospitalized Adults with Dementia: Adapting the Confusion Assessment Method to International Classification of Diseases, Tenth Revision, Diagnostic Criteria
Authors: Thomas Christine , Kreisel Stefan H. , Oster Peter , Driessen Martin , Arolt Volker , Inouye Sharon K.
Published: August 2012

Objectives

To compare performance characteristics of the Confusion Assessment Method (CAM) algorithm for screening and delirium diagnosis with criteria for delirium from the International Classification of Diseases, Tenth Revision (ICD‐10) and Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) in high‐risk individuals.

Design

Prospective cohort study.

Setting

Academic geriatric hospital.

Participants

One hundred two individuals aged 80 to 100 hospitalized for acute medical illness.

Measurements

Complete CAM instrument (nine items), scored using the four‐item CAM diagnostic algorithm. Criterion standard classification of delirium was rated independently according to expert consensus based on DSM‐IV and ICD‐10 criteria for delirium.

Results

In 79 hospitalized participants, the CAM performed well for delirium screening (delirium prevalence of 24% according to DSM‐IV and 14% according to ICD‐10). Of all CAM features, acute onset and fluctuating course are most important for diagnosis (area under the receiver operating characteristic curve (AUC) = 0.92 in DSM‐IV and 0.83 in ICD‐10). The CAM diagnostic algorithm had a sensitivity of 0.74, a specificity of 1.0, and an AUC of 0.88 compared with the DSM‐IV reference standard and a sensitivity of 0.82, a specificity of 0.91, and an AUC of 0.85 compared with the ICD‐10. Compared with the ICD‐10, adding psychomotor change to the CAM algorithm improved specificity to 97%, but sensitivity fell to 55% (AUC = 0.96). Applying psychomotor change sequentially only to the group that the CAM algorithm identified as having no delirium improved sensitivity to 91% with specificity of 85% (AUC = 0.95).

Conclusion

Although the CAM diagnostic algorithm performed well against a DSM‐IV reference standard, adding psychomotor change to the CAM algorithm improved specificity and diagnostic value against ICD‐10 criteria overall in older adults with dementia and improved sensitivity and screening performance when applied sequentially in CAM‐negative individuals.
A Study of Elderly Adults Taking Warfarin Admitted with Prolonged International Normalized Ratio: A Community Hospital's Experience
Authors: Bergman Michael , Ori Yaacov , Blumberger Naava , Brener Zachary Z. , Salman Hertzel
Published: August 2012

Objectives

To assess bleeding complications and outcome of individuals receiving oral anticoagulants who were admitted to the hospital with an international normalized ratio (INR) greater than 4 by comparing them according to age (≤80, >80).

Design

Retrospective cohort study.

Setting

Community hospital.

Participants

All individuals (N = 253) admitted to the Department of Internal Medicine over a period of 4 years with an INR greater than 4: Group I, aged 80 and younger (n = 127); Group II, older than 80 (n = 126). Data included bleeding complications, survival, and quality of INR control before admission and up to 48 months after admission.

Results

Atrial fibrillation was the most common indication for warfarin therapy. Its incidence was higher in the older group (88% vs 73%, P = .004). More elderly participants lived in nursing homes (23% vs 9.4%. P = .004) or received in‐home assistance (38.9% vs 20.5%, P = .002). There was no difference in INR upon admission, duration of warfarin treatment, or frequency of INR tests before admission. The incidence of bleeding events was 18.1% in Group I and 12.7% in Group II (P = .30). Major bleeding events occurred in 1.6% of Group I and none of Group II (P = .50). During follow‐up after the first admission, the incidence of INR greater than 4 was higher in Group II (87.3% vs 70%, P = .02), without a difference in the number of additional admissions or bleeding events.

Conclusion

Primary care physicians can safely maintain warfarin treatment in elderly adults, even in those with a history of hospitalization for high INR, using frequent INR measurements.
The Value of the Metabolic Syndrome Concept in Elderly Adults: Is It Worth Less Than the Sum of Its Parts?
Authors: Samaras Katherine , Crawford John , Baune Bernard T. , Campbell Lesley V. , Smith Evelyn , Lux Ora , Brodaty Henry , Trollor Julian N. , Sachdev Perminder
Published: August 2012

Objectives

To determine whether the metabolic syndrome (MetS) or its components were more closely associated with disease states and inflammation in elderly adults.

Design

Sydney Memory and Ageing Study. Cross‐sectional, observational cohort.

Setting

Population‐derived, community‐dwelling elderly adults.

Participants

Nine hundred thirty individuals aged 70 to 90.

Measurements

Age‐ and sex‐adjusted odds ratios (ORs) for disease states; fasting circulating inflammatory markers and oxidative metabolism byproducts.

Results

MetS was associated with diabetes mellitus (OR = 4.1, P < .001) and bowel cancer (OR = 9.1, P = .03) but not in analyses that controlled for component conditions. Models containing component conditions had the strongest associations with heart disease. Disease associations were improved after addition of component conditions to the MetS model. The reverse did not hold: disease associations were not improved when MetS was added to the components model. Low high‐density lipoprotein cholesterol (HDL‐C) was independently associated with myocardial infarction (OR = 2.32) and angina pectoris (OR = 2.59) (both P < .008). Waist circumference was independently associated with cancer (OR = 1.82, P = .008). Although MetS was associated with higher C‐reactive protein, vascular cell adhesion molecule, interleukin‐6, amyloid A, homocysteine, and malondialdehyde, it explained less than half of the variance of models containing its components.

Conclusion

The observation that MetS is associated with disease states and markers of circulating inflammation in the elderly is explained mainly by abdominal obesity and low HDL‐C. Longitudinal data will further clarify these cross‐sectional findings that MetS appears to be less than the sum of its parts in elderly adults.
A Randomized, Prospective Study of Efficacy and Safety of Oral Tramadol in the Management of Post‐Herpetic Neuralgia in Patients from North India
Authors: Saxena Ashok K. , Nasare Namita , Jain Smita , Dhakate Gaurav , Ahmed Rafat S. , Bhattacharya Sambit N. , Mediratta Pramod K. , Banerjee Basu D.
Published: August 2012

Objective:  To evaluate the safety and efficacy of oral tramadol therapy (50 to 200 mg/day) in the treatment for post‐herpetic neuralgia (PHN).

Methods:  The study was a prospective, single‐blind, non‐responder vs. responder, randomized trial conducted in 100 outpatients of PHN after oral administration of tramadol for 4 weeks. Those patients who had achieved 50% or greater pain relief after 14 days of oral tramadol treatment were categorized as responders and those reporting < 50% pain relief were categorized as non‐responders. Rescue analgesia was provided by the topical application of a cream consisting of the combination of 3.33% doxepin and 0.05% capsaicin to the affected areas of PHN patients of both groups for at least 14 days, along with tramadol therapy. The rescue analgesia was extended to 4 weeks in patients of the non‐responder group. The primary endpoints were measured using a Numerical Rating Scale (NRS) at rest and with movement. Secondary endpoints included additional pain ratings such as global perceived effect (GPE), Neuropathic Pain Symptom Inventory scores (NPSI), daily sleep interference score (DSIS), Quality of life (QOL) as per WHO QOL‐BREF Questionnaire scores, patient and clinician ratings of global improvement. The 2 groups were compared on the basis of pain intensity scores, encompassing primary as well as secondary endpoints, and QOL after 28 days of the treatment regimen.

Results:  Pain intensity scores measured by NRS (at resting and with movement), NPSI, and DSIS were consistently reduced (P < 0.001) over 28 days at varying intervals in both the groups, but the magnitude of reduction was higher in responders than non‐responders. A concomitant improvement (P < 0.001) was observed in GPE on days 3, 14, and 28 as compared to the respective baseline scores in both the groups. Although the WHO QOL‐BREF scores showed significant (P < 0.001) improvement in QOL of PHN patients at days 14 and 28 in both the groups, the magnitude of improvement was higher in responders as compared to non‐responders. Significant improvement in pain intensity scores and QOL in non‐responders is mainly attributed to the use of rescue analgesia for 28 days rather than recommended tramadol therapy.

Conclusions:  Treatment with tramadol 50 to 200 mg per day was associated with significant pain reduction in terms of enhanced pain relief, reduced sleep interference, greater global improvement, diminished side‐effect profile, and improved QOL in PHN patients from North India. Further categorization of PHN patients may be helpful so that additional or alternative therapy may be prescribed to non‐responders.