bluuebunny/crossref_metadata_2025 huggingface dataset:
Implementing Smoke-Free Policies in Mental Health Inpatient Units: Learning from Unsuccessful Experience
Authors: Campion Jonathan , Lawn Sharon , Brownlie Andrew , Hunter Ernest , Gynther Bruce , Pols Rene
Published: March 2008

Objective: The aim of this paper is to describe the introduction, trial and termination of a smoke-free policy in an acute mental health unit of a regional hospital, and to consider factors that may contribute to the success of such policies in other settings.

Methods: This analysis is based on key informant interviews and review of correspondence related to the trial, and examination of the relevant incident-reporting database.

Results: Planning for implementation is described. The trial itself was terminated after 6 weeks due to perceived increases in aggression by patients towards staff working in the high dependency unit. Staff perceived that these episodes were directly related to these patients not being allowed to smoke. While there was an increase in events during the trial relating to two seriously ill individuals, examination of formal incident reports over a period of 2 years suggests little change in the overall number of incidents.

Conclusions: Despite clear public health benefits, implementation of a smoke-free policy may have untoward behavioural effects in institutional mental health settings. In addition, staff expectations and perceptions are critical. Salient factors appear to be preparation of staff and patients, appropriate training, avoidance of exceptions and inconsistency, considering alternatives to smoking to fill the gap created by the policy, and a culture of critical evaluation in practice. Such processes will facilitate understanding and cooperation so that mental health services are able to participate in important policy processes with implications for the health of patients and staff.
An Outline of the Planned Work of the Royal Australian and New Zealand College of Psychiatrists' Board of Education
Authors: Boyce Phillip , Burnett Peter , Crawshaw John , Cutbush Jimsie , Handrinos Dennis , Hay Phillippa , Mellsop Graham , Newton Richard , Whyte Sally
Published: March 2008

Objective: The aim of this paper is to inform College Fellows, trainees and other stakeholders about the structure, principles and functioning of the new Board of Education.

Conclusion: The educational activities of the College are likely to evolve and to be developed over the next 5 years by a process taking account of the views of key stakeholders. In the short term, there will be no changes to training or examination processes which would disadvantage trainees.
Human embryonic stem cells in culture possess primary cilia with hedgehog signaling machinery
Authors: Kiprilov Enko N. , Awan Aashir , Desprat Romain , Velho Michelle , Clement Christian A. , Byskov Anne Grete , Andersen Claus Y. , Satir Peter , Bouhassira Eric E. , Christensen Søren T. , Hirsch Rhoda Elison
Published: March 2008

Human embryonic stem cells (hESCs) are potential therapeutic tools and models of human development. With a growing interest in primary cilia in signal transduction pathways that are crucial for embryological development and tissue differentiation and interest in mechanisms regulating human hESC differentiation, demonstrating the existence of primary cilia and the localization of signaling components in undifferentiated hESCs establishes a mechanistic basis for the regulation of hESC differentiation. Using electron microscopy (EM), immunofluorescence, and confocal microscopies, we show that primary cilia are present in three undifferentiated hESC lines. EM reveals the characteristic 9 + 0 axoneme. The number and length of cilia increase after serum starvation. Important components of the hedgehog (Hh) pathway, including smoothened, patched 1 (Ptc1), and Gli1 and 2, are present in the cilia. Stimulation of the pathway results in the concerted movement of Ptc1 out of, and smoothened into, the primary cilium as well as up-regulation of GLI1 and PTC1. These findings show that hESCs contain primary cilia associated with working Hh machinery.
Integrin-linked kinase stabilizes myotendinous junctions and protects muscle from stress-induced damage
Authors: Wang Hao-Ven , Chang Ling-Wei , Brixius Klara , Wickström Sara A. , Montanez Eloi , Thievessen Ingo , Schwander Martin , Müller Ulrich , Bloch Wilhelm , Mayer Ulrike , Fässler Reinhard
Published: March 2008

Skeletal muscle expresses high levels of integrin-linked kinase (ILK), predominantly at myotendinous junctions (MTJs) and costameres. ILK binds the cytoplasmic domain of β1 integrin and mediates phosphorylation of protein kinase B (PKB)/Akt, which in turn plays a central role during skeletal muscle regeneration. We show that mice with a skeletal muscle–restricted deletion of ILK develop a mild progressive muscular dystrophy mainly restricted to the MTJs with detachment of basement membranes and accumulation of extracellular matrix. Endurance exercise training enhances the defects at MTJs, leads to disturbed subsarcolemmal myofiber architecture, and abrogates phosphorylation of Ser473 as well as phosphorylation of Thr308 of PKB/Akt. The reduction in PKB/Akt activation is accompanied by an impaired insulin-like growth factor 1 receptor (IGF-1R) activation. Coimmunoprecipitation experiments reveal that the β1 integrin subunit is associated with the IGF-1R in muscle cells. Our data identify the β1 integrin–ILK complex as an important component of IGF-1R/insulin receptor substrate signaling to PKB/Akt during mechanical stress in skeletal muscle.
Myoblasts and macrophages share molecular components that contribute to cell–cell fusion
Authors: Pajcini Kostandin V. , Pomerantz Jason H. , Alkan Ozan , Doyonnas Regis , Blau Helen M.
Published: March 2008

Cell–cell fusion is critical to the normal development of certain tissues, yet the nature and degree of conservation of the underlying molecular components remains largely unknown. Here we show that the two guanine-nucleotide exchange factors Brag2 and Dock180 have evolutionarily conserved functions in the fusion of mammalian myoblasts. Their effects on muscle cell formation are distinct and are a result of the activation of the GTPases ARF6 and Rac, respectively. Inhibition of ARF6 activity results in a lack of physical association between paxillin and β1-integrin, and disruption of paxillin transport to sites of focal adhesion. We show that fusion machinery is conserved among distinct cell types because Dock180 deficiency prevented fusion of macrophages and the formation of multinucleated giant cells. Our results are the first to demonstrate a role for a single protein in the fusion of two different cell types, and provide novel mechanistic insight into the function of GEFs in the morphological maturation of multinucleated cells.
Inhibition of “self” engulfment through deactivation of myosin-II at the phagocytic synapse between human cells
Authors: Tsai Richard K. , Discher Dennis E.
Published: March 2008

Phagocytosis of foreign cells or particles by macrophages is a rapid process that is inefficient when faced with “self” cells that display CD47—although signaling mechanisms in self-recognition have remained largely unknown. With human macrophages, we show the phagocytic synapse at cell contacts involves a basal level of actin-driven phagocytosis that, in the absence of species-specific CD47 signaling, is made more efficient by phospho-activated myosin. We use “foreign” sheep red blood cells (RBCs) together with CD47-blocked, antibody-opsonized human RBCs in order to visualize synaptic accumulation of phosphotyrosine, paxillin, F-actin, and the major motor isoform, nonmuscle myosin-IIA. When CD47 is functional, the macrophage counter-receptor and phosphatase-activator SIRPα localizes to the synapse, suppressing accumulation of phosphotyrosine and myosin without affecting F-actin. On both RBCs and microbeads, human CD47 potently inhibits phagocytosis as does direct inhibition of myosin. CD47–SIRPα interaction initiates a dephosphorylation cascade directed in part at phosphotyrosine in myosin. A point mutation turns off this motor's contribution to phagocytosis, suggesting that self-recognition inhibits contractile engulfment.
Important role of matrix metalloproteinase 9 in epileptogenesis
Authors: Wilczynski Grzegorz M. , Konopacki Filip A. , Wilczek Ewa , Lasiecka Zofia , Gorlewicz Adam , Michaluk Piotr , Wawrzyniak Marcin , Malinowska Monika , Okulski Pawel , Kolodziej Lukasz R. , Konopka Witold , Duniec Kamila , Mioduszewska Barbara , Nikolaev Evgeni , Walczak Agnieszka , Owczarek Dorota , Gorecki Dariusz C. , Zuschratter Werner , Ottersen Ole Petter , Kaczmarek Leszek
Published: March 2008

Temporal lobe epilepsy (TLE) is a devastating disease in which aberrant synaptic plasticity plays a major role. We identify matrix metalloproteinase (MMP) 9 as a novel synaptic enzyme and a key pathogenic factor in two animal models of TLE: kainate-evoked epilepsy and pentylenetetrazole (PTZ) kindling–induced epilepsy. Notably, we show that the sensitivity to PTZ epileptogenesis is decreased in MMP-9 knockout mice but is increased in a novel line of transgenic rats overexpressing MMP-9. Immunoelectron microscopy reveals that MMP-9 associates with hippocampal dendritic spines bearing asymmetrical (excitatory) synapses, where both the MMP-9 protein levels and enzymatic activity become strongly increased upon seizures. Further, we find that MMP-9 deficiency diminishes seizure-evoked pruning of dendritic spines and decreases aberrant synaptogenesis after mossy fiber sprouting. The latter observation provides a possible mechanistic basis for the effect of MMP-9 on epileptogenesis. Our work suggests that a synaptic pool of MMP-9 is critical for the sequence of events that underlie the development of seizures in animal models of TLE.
Enhancing therapeutic vaccination by blocking PD-1–mediated inhibitory signals during chronic infection
Authors: Ha Sang-Jun , Mueller Scott N. , Wherry E. John , Barber Daniel L. , Aubert Rachael D. , Sharpe Arlene H. , Freeman Gordon J. , Ahmed Rafi
Published: March 2008

Therapeutic vaccination is a potentially promising strategy to enhance T cell immunity and viral control in chronically infected individuals. However, therapeutic vaccination approaches have fallen short of expectations, and effective boosting of antiviral T cell responses has not always been observed. One of the principal reasons for the limited success of therapeutic vaccination is that virus-specific T cells become functionally exhausted during chronic infections. We now provide a novel strategy for enhancing the efficacy of therapeutic vaccines. In this study, we show that blocking programmed death (PD)-1/PD-L1 inhibitory signals on exhausted CD8+ T cells, in combination with therapeutic vaccination, synergistically enhances functional CD8+ T cell responses and improves viral control in mice chronically infected with lymphocytic choriomeningitis virus. This combinatorial therapeutic vaccination was effective even in the absence of CD4+ T cell help. Thus, our study defines a potent new approach to augment the efficacy of therapeutic vaccination by blocking negative signals. Such an approach may have broad applications in developing treatment strategies for chronic infections in general, and perhaps also for tumors.
CD94-NKG2A recognition of human leukocyte antigen (HLA)-E bound to an HLA class I leader sequence
Authors: Petrie Emma J. , Clements Craig S. , Lin Jie , Sullivan Lucy C. , Johnson Darryl , Huyton Trevor , Heroux Annie , Hoare Hilary L. , Beddoe Travis , Reid Hugh H. , Wilce Matthew C.J. , Brooks Andrew G. , Rossjohn Jamie
Published: March 2008

The recognition of human leukocyte antigen (HLA)-E by the heterodimeric CD94-NKG2 natural killer (NK) receptor family is a central innate mechanism by which NK cells monitor the expression of other HLA molecules, yet the structural basis of this highly specific interaction is unclear. Here, we describe the crystal structure of CD94-NKG2A in complex with HLA-E bound to a peptide derived from the leader sequence of HLA-G. The CD94 subunit dominated the interaction with HLA-E, whereas the NKG2A subunit was more peripheral to the interface. Moreover, the invariant CD94 subunit dominated the peptide-mediated contacts, albeit with poor surface and chemical complementarity. This unusual binding mode was consistent with mutagenesis data at the CD94-NKG2A–HLA-E interface. There were few conformational changes in either CD94-NKG2A or HLA-E upon ligation, and such a “lock and key” interaction is typical of innate receptor–ligand interactions. Nevertheless, the structure also provided insight into how this interaction can be modulated by subtle changes in the peptide ligand or by the pairing of CD94 with other members of the NKG2 family. Differences in the docking strategies used by the NKG2D and CD94-NKG2A receptors provided a basis for understanding the promiscuous nature of ligand recognition by NKG2D compared with the fidelity of the CD94-NKG2 receptors.
Pea–Fusarium solani Interactions Contributions of a System Toward Understanding Disease Resistance
Authors: Hadwiger Lee A.
Published: March 2008

This mini-review points to the usefulness of the pea–Fusarium solani interaction in researching the biochemical and molecular aspects of the nonhost resistance components of peas. This interaction has been researched to evaluate the resistance roles of the phytoalexin, pisatin, the cuticle barrier, and the activation of the nonhost resistance response. Concurrently, evaluations of associated signaling processes and the tools possessed by the pathogen to contend with host obstacles were included. The properties of some pathogenesis-related genes of pea and their regulation and contribution to resistance are discussed. A proposed action of two biotic elicitors on both chromatin conformation and the architectural transcription factor, HMG A, is presented and includes time lines of events within the host immune response.
Nocturnal activity positively correlated with auditory sensitivity in noctuoid moths
Authors: ter Hofstede Hannah M , Ratcliffe John M , Fullard James H
Published: March 2008

We investigated the relationship between predator detection threshold and antipredator behaviour in noctuoid moths. Moths with ears sensitive to the echolocation calls of insectivorous bats use avoidance manoeuvres in flight to evade these predators. Earless moths generally fly less than eared species as a primary defence against predation by bats. For eared moths, however, there is interspecific variation in auditory sensitivity. At the species level, and when controlling for shared evolutionary history, nocturnal flight time and auditory sensitivity were positively correlated in moths, a relationship that most likely reflects selection pressure from aerial-hawking bats. We suggest that species-specific differences in the detection of predator cues are important but often overlooked factors in the evolution and maintenance of antipredator behaviour.
Local song elements indicate local genotypes and predict physiological condition in song sparrowsMelospiza melodia
Authors: Stewart Kathryn A , MacDougall-Shackleton Elizabeth A
Published: March 2008

Geographical variation in birdsong is taxonomically widespread and behaviourally salient, with females often preferring local over non-local song. However, the benefits associated with this preference remain poorly understood. One potential explanation is that song may reflect a male's place of origin and thus allow females to obtain genes well adapted to the local environment. We studied naturally occurring variation in the degree to which the elements of a male's song repertoire matched those of the local population (‘syllable sharing’) in migratory song sparrows (Melospiza melodia melodia). Syllable sharing was correlated with genetic similarity to the local population, suggesting that song reflects population of origin. Males sharing more syllables also had larger testosterone-dependent traits, fewer blood-borne parasites and reduced indicators of stress. Our findings are consistent with locally good genes models. Alternatively, immigrants' condition may suffer due to unfamiliarity with the breeding site or inability to match song elements during territorial interactions. Females preferring ‘local-sounding’ males may thus obtain genetic and/or direct benefits for their offspring.
Specialized shell-breaking crab claws in Cretaceous seas
Authors: Dietl Gregory P , Vega Francisco J
Published: March 2008

Here we report on a large brachyuran crab species from the Late Cretaceous of Mexico that has claws indicative of highly specialized shell-breaking behaviour. This crab possessed dimorphic claws (the right larger than the left), armed with several broad teeth, including a curved tooth structure found at the base of the movable finger of the right claw. The curved tooth is similar to the one observed on claws of many living durophagous crabs that use it as a weapon to peel, crush or chip the edges of hard-shelled prey, particularly molluscs. These morphological traits suggest that specialized shell-breaking crab predators had evolved during the Cretaceous, which contradicts previous findings supporting an Early Cenozoic origin for specialized shell crushers within the brachyuran clade.
Circatidal activity rhythm in the mangrove cricketApteronemobius asahinai
Authors: Satoh Aya , Yoshioka Eiji , Numata Hideharu
Published: March 2008

Mangrove forests are influenced by tidal flooding and ebbing for a period of approximately 12.4 hours (tidal cycle). Mangrove crickets (Apteronemobius asahinai) forage on mangrove forest floors only during low tide. Under constant darkness, most crickets showed a clear bimodal daily pattern in their locomotor activity for at least 24 days; the active phases of approximately 10 hours alternated with inactive phases of approximately 2 hours, which coincided with the time of high tide in the field. The free-running period was 12.56±0.13 hours (mean±s.d.,n=11). This endogenous rhythm was not entrained by the subsequent 24 hours light–dark cycle, although it was suppressed in the photophase; the active phase in the scotophase continued from the active phase in the previous constant darkness, with no phase shift. The endogenous rhythm was assumed to be a circatidal rhythm. On the other hand, the activity under constant darkness subsequent to a light–dark cycle was more intense in the active phase continuing from the scotophase than from the photophase of the preceding light–dark cycle; this indicates the presence of circadian components. These results suggest that two clock systems are involved in controlling locomotor activity in mangrove crickets.
Top-down causation by information control: from a philosophical problem to a scientific research programme
Authors: Auletta G , Ellis G.F.R , Jaeger L
Published: March 2008

It has been claimed that different types of causes must be considered in biological systems, including top-down as well as same-level and bottom-up causation, thus enabling the top levels to be causally efficacious in their own right. To clarify this issue, the important distinctions between information and signs are introduced here and the concepts of information control and functional equivalence classes in those systems are rigorously defined and used to characterize when top-down causation by feedback control happens, in a way that is testable. The causally significant elements we consider are equivalence classes of lower level processes, realized in biological systems through different operations having the same outcome within the context of information control and networks.
Fluid–particle dynamics in canalithiasis
Authors: Obrist Dominik , Hegemann Stefan
Published: March 2008

The semicircular canals (SCCs; located in the inner ear) are the primary sensors for angular motion. Angular head movements induce a fluid flow in the SCCs. This flow is detected by afferent hair cells inside the SCCs. Canalithiasis is a condition where small particles disturb this flow, which leads to benign paroxysmal positional vertigo (top-shelf vertigo).

The present work investigates the interaction between the fluid flow and the particles on the basis of an idealized analytical model. Numerical solutions of the full model and a thorough analytical study of the linearized model reveal the principal mechanisms of canalithiasis. We propose a set of dimensionless numbers to characterize canalithiasis and derive explicit expressions connecting these dimensionless numbers directly to the typical clinical symptoms.
Function of bright coloration in the wasp spider
Argiope bruennichi
(Araneae: Araneidae)
Authors: Bush Alex A , Yu Douglas W , Herberstein Marie E
Published: March 2008

There are two major competing explanations for the counter-intuitive presence of bright coloration in certain orb-web spiders. Bright coloration could lure insect prey to the web vicinity, increasing the spider's foraging success. Alternatively, the markings could function as disruptive camouflage, making it difficult for the insect prey to distinguish spiders from background colour variation. We measured the prey capture rates of wasp spiders,
Argiope bruennichi
, that were blacked out, shielded from view using a leaf fragment, or left naturally coloured. Naturally coloured spiders caught over twice the number of prey as did either blacked-out or leaf-shielded spiders, and almost three times as many orthopteran prey. Spectrophotometer measurements suggest that the bright yellow bands on the spider's abdomen are visible to insect prey, but not the banding on the legs, which could disguise the spider's outline. Thus, our results provide strong support for the hypothesis that bright coloration in the wasp spider acts as a visual lure for insect prey and weak support for the hypothesis that the arrangement of the banding pattern across the spider's body disguises the presence of the spider on the web.
Informational conflicts created by the waggle dance
Authors: Grüter Christoph , Balbuena M. Sol , Farina Walter M
Published: March 2008

The honeybee (Apis mellifera) waggle dance is one of the most intriguing animal communication signals. A dancing bee communicates the location of a profitable food source and its odour. Followers may often experience situations in which dancers indicate an unfamiliar location but carry the scent of a flower species the followers experienced previously at different locations. Food scents often reactivate bees to resume food collection at previously visited food patches. This double function of the dance creates a conflict between the social vector information and the private navigational information. We investigated which kind of information followers with field experience use in this situation and found that followers usually ignored the spatial information encoded by the waggle dance even if they followed a dance thoroughly (five waggle runs or more). They relied on private information about food source locations instead (in 93% of all cases). Furthermore, foragers preferred to follow dancers carrying food odours they knew from previous field trips, independently of the spatial information encoded in the dance. Surprisingly, neither odour identity nor the location indicated by the dancer was an important factor for the reactivation success of a dance. Our results contrast with the assumption that (i) followers usually try to decode the vector information and (ii) dances indicating an unfamiliar location are of little interest to experienced foragers.
Topological modelling of large networks
Authors: Mondragón Raúl J
Published: March 2008

In a complex network, there is a strong interaction between the network's topology and its functionality. A good topological network model is a practical tool as it can be used to test ‘what-if’ scenarios and it can provide predictions of the network's evolution. Modelling the topology structure of a large network is a challenging task, since there is no agreement in the research community on which properties of the network a model should be based, or how to test its accuracy. Here we present recent results on how to model a large network, the autonomous system (AS)-Internet, using a growth model. Based on a nonlinear preferential growth model and the reproduction of the network's rich club, the model reproduces many of the topological characteristics of the AS-Internet. We also identify a recent method to visualize the network's topology. This visualization technique is simple and fast and can be used to understand the properties of a large complex network or as a first step to validate a network model.
Optimal resource allocation for multicast sessions in multi-hop wireless networks
Authors: Bui Loc , Srikant R , Stolyar Alexander
Published: March 2008

In this paper, we extend recent results on fair and stable resource allocation in wireless networks to include multicast sessions, in particular multi-rate multicast. The solution for multi-rate multicast is based on scheduling virtual (shadow) ‘traffic’ that ‘moves’ in reverse direction from destinations to sources. This shadow scheduling algorithm can also be used to control delays in wireless networks.
Data, modelling and inference in road traffic networks
Authors: Gibbens Richard.J , Saatci Yunus
Published: March 2008

In this paper, we study UK road traffic data and explore a range of modelling and inference questions that arise from them. For example, loop detectors on the M25 motorway record speed and flow measurements at regularly spaced locations as well as the entry and exit lanes of junctions. An exploratory study of these data helps us to better understand and quantify the nature of congestion on the road network. From a traveller's perspective it is crucially important to understand the overall journey times and we look at methods to improve our ability to predict journey times given access jointly to both real-time and historical loop detector data. Throughout this paper we will comment on related work derived from US freeway data.
Too expensive to meter: the influence of transaction costs in transportation and communication
Authors: Levinson David , Odlyzko Andrew
Published: March 2008

Technology appears to be making fine-scale charging (as in tolls on roads that depend on time of day or even on current and anticipated levels of congestion) increasingly feasible. Such charging also appears to be increasingly desirable, as traffic on roads continues to grow and costs and public opposition limit new construction. Similar incentives towards fine-scale charging also appear to be operating in communications and other areas, such as electricity usage. Standard economic theory supports such measures and technology is being developed and deployed to implement them. But their spread is not very rapid and their prospects for the future are uncertain. This paper presents a collection of sketches, ranging from ancient history to very recent developments, that illustrate the costs that charging imposes. Some of those costs are explicit (in terms of the monetary costs to users and the costs of implementing the charging mechanisms). Others are implicit, such as the time or the mental processing costs of users. These argue that the case for fine-scale charging is not unambiguous and that in many cases such charging may lead to undesirable outcomes.
Mathematical programs with complementarity constraints in traffic and telecommunications networks
Authors: Ralph Daniel
Published: March 2008

Given a suitably parametrized family of equilibrium models and a higher level criterion by which to measure an equilibrium state, mathematical programs with equilibrium constraints (MPECs) provide a framework for improving or optimizing the equilibrium state. An example is toll design in traffic networks, which attempts to reduce total travel time by choosing which arcs to toll and what toll levels to impose. Here, a Wardrop equilibrium describes the traffic response to each toll design. Communication networks also have a deep literature on equilibrium flows that suggest some MPECs. We focus on mathematical programs with complementarity constraints (MPCCs), a subclass of MPECs for which the lower level equilibrium system can be formulated as a complementarity problem and therefore, importantly, as a nonlinear program (NLP). Although MPECs and MPCCs are typically non-convex, which is a consequence of the upper level objective clashing with the users' objectives in the lower level equilibrium program, the last decade of research has paved the way for finding local solutions of MPCCs via standard NLP techniques.
Measurement of tracheal wall pressure: a comparison of three different in vitro techniques
Authors: Horisberger T. , Gerber S. , Bernet V. , Weiss M.
Published: March 2008

We compared three different tracheal wall pressure measuring techniques in vitro. Using a high‐volume, low‐pressure, cuffed tracheal tube with an internal diameter of 7.5 mm and a model trachea, the pressure difference technique, the wall pressure membrane technique and the microchip sensor probe technique with and without lubrication were studied. Wall pressures were measured after sequential injections of 0.5 ml of air into the cuff at cuff pressures ranging from 0 to 50 mmHg. The coefficient of variance was largest for the microchip sensor probe technique with lubrication (29%) and without lubrication (214%), and was lower for the wall pressure membrane technique (22%) and the pressure difference technique (19%). The wall pressure membrane and pressure difference techniques provided comparable results. The microchip sensor probe technique considerably underestimated wall pressure. These findings have an impact on the interpretation of published data on tracheal or pharyngeal wall pressure using the microchip sensor probe technique.
Influence of the CYP2D6*4 polymorphism on dose, switching and discontinuation of antidepressants
Authors: Bijl Monique J. , Visser Loes E. , Hofman Albert , Vulto Arnold G. , Van Gelder Teun , Stricker Bruno H. Ch. , Van Schaik Ron H. N.
Published: March 2008

What is already known about this subject

• Most antidepressants are metabolized by CYP2D6. The variant allele CYP2D6*4 is the main polymorphism resulting in reduced enzyme activity in Caucasians.

• Reduced enzyme activity potentially leads to increased toxicity of antidepressants, but the relevance of genotyping for clinical practice is unclear. Most clinical studies suffer from small numbers of patients.

What this study adds

• This large population‐based cohort study in 1198 elderly Dutch patients examines the influence of the CYP2D6*4 polymorphism on intolerability of antidepressants.

• The risk of switching to another antidepressant in tricyclic antidepressant users is higher in poor metabolizers (PMs), but not in SSRI users. PMs require a lower maintenance dose of antidepressants compared with extensive metabolizers (EMs).

• Antidepressants were initiated in a relatively low dose, with gradual dose increments thereafter, reducing the risk of adverse drug reactions. Therefore, the question remains whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy.

Aims

To study the effect of CYP2D6*4 on antidepressant dose, switching and discontinuation of therapy.

Methods

The study consisted of all subjects in the Rotterdam Study, who received a first antidepressant prescription between April 1st 1991 and July 1st 2005 and for whom data on CYP2D6 genotype were available. Binary logistic regression was performed to study the association between CYP2D6*4 and switching to any other antidepressant or discontinuation of therapy within 45 days. The difference in mean antidepressant dose was compared between CYP2D6 genotypes using t‐tests and repeated measurements analyses.

Results

In users of tricyclic antidepressants (TCAs) the risk of switching to another antidepressant was significantly higher in poor metabolizers (PMs:*4/*4) compared with extensive metabolizers (EMs:*1/*1), with an adjusted OR of 5.77 (95% CI 1.59, 21.03; P = 0.01). In SSRI users there was no significant difference (OR 0.91; 95% CI 0.20, 4.15; P = 0.90). Heterozygous patients did not have an increased risk of switching in both TCA and SSRI users. The mean TCA dose was significantly lower in PMs than in EMs at the third and fourth prescription (difference 0.11 DDD, P = 0.03). In SSRI users the difference in mean dose between PMs and EMs was significant at the third prescription (0.17 DDD; P = 0.02).

Conclusions

The risk of switching to another antidepressant in TCA users is higher in PMs than in EMs. The maintenance doses of antidepressants were significantly lower in PMs. However, the question whether genotyping prior to the start of antidepressant therapy contributes substantially to the optimization of pharmacotherapy, requires further study.
Determinants of chronic benzodiazepine use in the elderly: A longitudinal study
Authors: Luijendijk Hendrika J. , Tiemeier Henning , Hofman Albert , Heeringa Jan , Stricker Bruno H. Ch.
Published: March 2008

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• The risk of adverse events due to chronic benzodiazepine use is high in the elderly.

• Cross‐sectional studies have shown that increasing age, female gender and poor physical and mental health are associated with benzodiazepine use.

• When users were re‐examined some years later, chronic somatic disease, pain and stress seemed to contribute to the continuation of benzodiazepine use.

WHAT THIS STUDY ADDS

• This is the first longitudinal study that analyzed the determinants of new‐onset chronic benzodiazepine use in community‐dwelling elderly.

• Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new‐onset chronic use. Living alone was found to decrease the risk of chronic use.

AIMS

The risk of adverse events due to chronic benzodiazepine use is high in the elderly. Clinicians need to be able to identify those persons who are at risk of chronic benzodiazepine use, but little is known about the determinants. This study determined social and health related factors that predict new‐onset chronic benzodiazepine use in community‐dwelling elderly.

METHODS

This study was embedded in an ongoing cohort study among 5364 persons aged ≥57 years. Drug‐dispensing medication records were available for the period between 1991 and 2003. We defined chronic benzodiazepine use as use during at least 180 days in a period of 365 consecutive days. The association of various social, psychiatric and somatic variables with new‐onset chronic benzodiazepine use was studied with a Cox proportional hazards analysis.

RESULTS

Symptoms of depression, hypertension, pain related joint complaints and the perception of poor physical health predicted new‐onset chronic use. In the subsample of participants who had filled at least one prescription in the follow‐up period, of these variables only pain related joint complaints increased the risk of new‐onset chronic use. Living alone protected against chronic benzodiazepine use.

CONCLUSIONS

The elderly with poor mental and physical health are at an increased risk of chronic benzodiazepine use. Living alone was found to decrease the risk of chronic use, which suggests that social factors may determine drug usage patterns. Very few characteristics predicted chronic benzodiazepine use once patients had received their first prescription. For clinicians, identification of patients at high risk is therefore not straightforward.
Incidence of fatal adverse drug reactions: a population based study
Authors: Wester Karin , Jönsson Anna K. , Spigset Olav , Druid Henrik , Hägg Staffan
Published: March 2008

What is already known about this subject

• Although drugs generally are safe and effective therapies for numerous diseases, adverse drug reactions do occur and may even be fatal.

• The incidence of fatal adverse drug reactions in hospitalized patients has been estimated to be approximately 5%.

• In previous studies the incidence of fatal adverse drug reactions in hospitalized patients has been reported, but the incidence of fatal adverse drug reactions in the general population is largely unknown.

What this study adds

• Fatal adverse drug reactions account for approximately 3% of all deaths in the general population.

• Haemorrhages amount to almost two‐thirds of the fatal adverse drug reactions and antithrombotic agents are implicated in more than half of the suspected fatal adverse drug reactions.

• Fatal adverse drug reactions are estimated to be the seventh most common cause of death in Sweden.

Aims

To determine the incidence of fatal adverse drug reactions (FADRs) in a Swedish population.

Methods

Every seventh randomly selected deceased in three counties in South‐east Sweden during 1 January 2001–31 December 2001 was identified in the Cause of Death Register. Relevant case records (hospitals and/or primary care centres and medicolegal files) were reviewed to identify suspected drug‐related fatalities.

Results

Of 1574 deceased study subjects, 49 (3.1%; 95% CI 2.2%, 4.0%) were suspected to have died from FADRs. The most common suspected FADRs were gastrointestinal haemorrhages (n = 18; 37%), central nervous system haemorrhages (n = 14; 29%), cardiovascular disorders (n = 5; 10%), other haemorrhages (n = 4; 8%) and renal dysfunction (n = 3; 6%). The drugs most commonly implicated in FADRs were antithrombotic drugs (n = 31; 63%), followed by nonsteroidal anti‐inflammatory drugs (NSAIDs) (n = 9; 18%), antidepressants (n = 7; 14%) and cardiovascular drugs (n = 4; 8%). Of all the 639 fatalities in hospital 41 (6.4%; 95% CI 4.5%, 8.3%) were suspected to be due to FADRs.

Conclusions

The medical burden of FADRs is significant. Haemorrhages were seen in a majority of the FADRs; antithrombotic agents or NSAIDs were implicated in most of these events. These results suggest that preventive measures should be taken to reduce the number of deaths caused by drugs.
Effect of maraviroc on the pharmacokinetics of midazolam, lamivudine/ zidovudine, and ethinyloestradiol/ levonorgestrel in healthy volunteers
Authors: Abel Samantha , Russell Deborah , Whitlock Lyndsey A. , Ridgway Caroline E. , Muirhead Gary J.
Published: March 2008

AIMS

To assess the effect of maraviroc on the pharmacokinetics of midazolam, a sensitive probe CYP3A4 substrate; lamivudine/zidovudine, a combination of nucleoside reverse transcriptase inhibitors (NRTIs); and ethinyloestradiol/levonorgestrel, a combination oral contraceptive.

METHODS

Three randomized, double‐blind, placebo‐controlled studies were conducted in healthy subjects to assess the effect of maraviroc on pharmacokinetics of other drugs. Two, two‐period crossover studies were conducted to assess (i) the effect of steady‐state maraviroc (300 mg b.i.d.) on pharmacokinetics of midazolam; and (ii) the effect of steady‐state maraviroc (300 mg b.i.d.) on the pharmacokinetics of lamivudine/zidovudine. A third two‐way crossover study was conducted to evaluate the effect of steady‐state maraviroc (100 mg b.i.d.) on the pharmacokinetics of 30 μg ethinyloestradiol/150 μg levonorgestrel (Microgynon®).

RESULTS

The geometric mean ratios for Cmax and AUC for each of the compounds tested in the presence and absence of maraviroc were between 92% and 121%. There were no notable differences in Tmax, t1/2 or CLR (where measured) for any of the compounds.

CONCLUSIONS

Maraviroc had no clinically relevant effects on the pharmacokinetics of the CYP3A4 substrate midazolam, the NRTIs zidovudine/lamivudine, or the oral contraceptive steroids ethinyloestradiol and levonorgestrel.
A novel probe drug interaction study to investigate the effect of selected antiretroviral combinations on the pharmacokinetics of a single oral dose of maraviroc in HIV‐positive subjects
Authors: Pozniak Anton L. , Boffito Marta , Russell Deborah , Ridgway Caroline E. , Muirhead Gary J.
Published: March 2008

AIMS

Maraviroc (UK‐427 857), an antagonist of the CCR5 receptor with potent anti‐HIV activity, was recently approved for use in treatment‐experienced patients infected with CCR5‐tropic HIV‐1. The aim of this study was to evaluate the effect of selected commonly used antiretroviral therapy (ART) combinations on the pharmacokinetics of a single oral dose of maraviroc 300 mg in HIV‐positive subjects compared with historical controls.

METHODS

In this study, four cohorts of HIV‐positive patients (n = 8 each) receiving one of the following combination therapies were recruited: cohort 1 – efavirenz + Combivir® (lamivudine/zidovudine); cohort 2 – efavirenz + didanosine + tenofovir; cohort 3 – nevirapine + lamivudine + tenofovir; cohort 4 – Kaletra® (lopinavir/ritonavir) + stavudine + lamivudine. Subjects continued on their prescribed ART and also received a single oral dose of maraviroc 300 mg. Serial blood samples and urine for determination of maraviroc pharmacokinetics were collected over 12 h postdose. Plasma pharmacokinetic parameters from this study were compared with historical data generated in HIV‐positive subjects receiving maraviroc monotherapy in a Phase IIa study.

RESULTS

A total of 29 subjects were recruited (eight each in cohorts 1–3, and five in cohort 4). The geometric mean ratios for AUC12 and Cmax for each treatment group compared with maraviroc monotherapy were: 47% and 67% (cohort 1); 48% and 76% (cohort 2); 101% and 154% (cohort 3); and 265% and 180% (cohort 4), respectively. Tmax was similar in all treatment groups. Mean values for renal clearance ranged from 8.2 l h−1 (cohort 1) to 13.2 l h−1 (cohort 4). There were no renal clearance data collected in the comparator study.

CONCLUSIONS

The results of this study support those previously seen in healthy volunteer studies that showed that efavirenz reduces maraviroc exposure, whereas lopinavir/ritonavir increases maraviroc exposure. These data also suggest that nevirapine does not lead to a clinically significant effect on maraviroc pharmacokinetics.
Transforming growth factor‐β1 regulates the fate of cultured spinal cord‐derived neural progenitor cells
Authors: Park S. M. , Jung J. S. , Jang M. S. , Kang K. S. , Kang S. K.
Published: March 2008

Abstract.  Objectives: We have evaluated the physiological roles of transforming growth factor‐β1 (TGF‐β1) on differentiation, migration, proliferation and anti‐apoptosis characteristics of cultured spinal cord‐derived neural progenitor cells. Methods: We have used neural progenitor cells that had been isolated and cultured from mouse spinal cord tissue, and we also assessed the relevant reaction mechanisms using an activin‐like kinase (ALK)‐specific inhibitory system including an inhibitory RNA, and found that it involved potential signalling molecules such as phosphatidylinositol‐3‐OH kinase (PI3K)/Akt and mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK1/2). Results and Conclusions: Transforming growth factor‐β1‐mediated cell population growth was activated after treatment and was also effectively blocked by an ALK41517‐synthetic inhibitor (4‐(5‐benzo(1,3) dioxol‐5‐yl‐4‐pyridine‐2‐yl‐1H‐imidazole‐2‐yl) benzamide (SB431542) and ALK siRNA, thereby indicating the involvement of SMAD2 in the TGF‐β1‐mediated growth and migration of these neural progenitors cells (NPC). In the present study, TGF‐β1 actively induced NPC migration in vitro. Furthermore, TGF‐β1 demonstrated extreme anti‐apoptotic behaviour against hydrogen peroxide‐mediated apoptotic cell death. At low dosages, TGF‐β1 enhanced (by approximately 76%) cell survival against hydrogen peroxide treatment via inactivation of caspase‐3 and ‐9. TGF‐β1‐treated NPCs down‐regulated Bax expression and cytochrome c release; in addition, the cells showed up‐regulated Bcl‐2 and thioredoxin reductase 1. They also had increased p38, Akt and ERK1/2 phosphorylation, showing the involvement of both the PI3K/Akt and MAPK/ERK1/2 pathways in the neuroprotective effects of TGF‐β1. Interestingly, these effects operate on specific subtypes of cells, including neurones, neural progenitor cells and astrocytes in cultured spinal cord tissue‐derived cells. Lesion sites of spinal cord‐overexpressing TGF‐β1‐mediated prevention of cell death, cell growth and migration enhancement activity have been introduced as a possible new basis for therapeutic strategy in treatment of neurodegenerative disorders, including spinal cord injuries.
Short‐period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K/Akt signalling pathways
Authors: Lee S. H. , Lee M. Y. , Han H. J.
Published: March 2008

Abstract.  Hypoxia plays important roles in some early stages of mammalian embryonic development and in various physiological functions. This study examined the effect of arachidonic acid on short‐period hypoxia‐induced regulation of G1 phase cell‐cycle progression and inter‐relationships among possible signalling molecules in mouse embryonic stem cells. Hypoxia increased the level of hypoxia‐inducible factor‐1α (HIF‐1α) expression and H2O2 generation in a time‐dependent manner. In addition, hypoxia increased the levels of cell‐cycle regulatory proteins (cyclin D1, cyclin E, cyclin‐dependent kinase 2 (CDK2) and CDK4). Maximum increases in the level of these proteins and retinoblastoma phosphorylation were observed after 12–24 h of exposure to hypoxic conditions, and then decreased. Alternatively, the level of the CDK inhibitors, p21Cip1 and p27Kip1 were decreased. These results were consistent with the results of [3H]‐thymidine incorporation and cell counting. Hypoxia also increased the level of [3H]‐arachidonic acid release and inhibition of cPLA2 reduced hypoxia‐induced increase in levels of the cell‐cycle regulatory proteins and [3H]‐thymidine incorporation. The level of cyclooxygenase‐2 (COX‐2) was also increased by hypoxia and inhibition of COX‐2 decreased the levels of cell‐cycle regulatory proteins and [3H]‐thymidine incorporation. Indeed, the percentage of cells in S phase, levels of cell cycle regulatory proteins, and [3H]‐thymidine incorporation were further increased in hypoxic conditions with arachidonic acid treatment compared to normoxic conditions. Hypoxia‐induced Akt and mitogen‐activated protein kinase (MAPK) phosphorylation was inhibited by vitamin C (antioxidant, 10−3 M). In addition, hypoxia‐induced increase of cell‐cycle regulatory protein expression and [3H]‐thymidine incorporation were attenuated by LY294002 (PI3K inhibitor, 10−6 M), Akt inhibitor (10−6 M), rapamycin (mTOR inhibitor, 10−9 M), PD98059 (p44/42 inhibitor, 10−5 M), and SB203580 (p38 MAPK inhibitor, 10−6 M). Furthermore, hypoxia‐induced increase of [3H]‐arachidonic acid release was blocked by PD98059 or SB203580, but not by LY294002 or Akt inhibitor. In conclusion, arachidonic acid up‐regulates short time‐period hypoxia‐induced G1 phase cyclins D1 and E, and CDK 2 and 4, in mouse embryonic stem cells through the cooperation of PI3K/Akt/mTOR, MAPK and cPLA2‐mediated signal pathways.