bluuebunny/crossref_metadata_2025 huggingface dataset:
Platelet count and function at high altitude and in high-altitude pulmonary edema
Authors: Lehmann T. , Mairbäurl H. , Pleisch B. , Maggiorini M. , Bärtsch P. , Reinhart W. H.
Published: January 2006

Platelet aggregation is the key process in primary hemostasis. Certain conditions such as hypoxia may induce platelet aggregation and lead to platelet sequestration primarily in the pulmonary microcirculation. We investigated the influence of high-altitude exposure on platelet function as part of a larger study on 30 subjects with a history of high-altitude pulmonary edema (HAPE) and 10 healthy controls. All participants were studied in the evening and the next morning at low altitude (450 m) and after an ascent to high altitude (4,559 m). Platelet count, platelet aggregation (platelet function analyzer PFA100; using epinephrine and ADP as activators), plasma soluble P (sP)-selectin, and the coagulation parameters prothrombin fragments 1+2 and thrombin-antithrombin complex were measured. High-altitude exposure decreased the platelet count, shortened the platelet function analyzer closure time by ∼20%, indicating increased platelet aggregation, increased sP-selectin levels to ∼250%, but left plasma coagulation unaffected. The HAPE-susceptible subjects were prophylactically treated with either tadalafil (a phosphodiesterase 5 inhibitor), dexamethasone, or placebo in a double-blind way. Subgroup analyses between these different treatments and comparisons of the seven placebo-treated individuals developing HAPE and controls revealed no differences in platelet count, platelet aggregation, or sP-selectin values. We conclude that exposure to high altitude activates platelets, which leads to platelet aggregation, platelet consumption, and decreased platelet count. These effects are, however, not more pronounced in individuals with a history of HAPE or actually suffering from HAPE than in controls and therefore may not be a pathophysiological mechanism of HAPE.
Reactive oxygen species: influence on cerebral vascular tone
Authors: Faraci Frank M.
Published: January 2006

Reactive oxygen species have multiple effects on vascular cells. Defining the sources and the impact of the various reactive oxygen species within the vessel wall has emerged as a major area of study in vascular biology. This review will focus on recent findings related to effects of reactive oxygen species on cerebral vascular tone. Effects of superoxide radical, hydrogen peroxide, and the reactive nitrogen species peroxynitrite are summarized. Although higher concentrations may be important for cerebral vascular biology in disease, relatively low concentrations of reactive oxygen species may function as signaling molecules involved with normal regulation of cerebral vascular tone. The mechanisms by which reactive oxygen species affect vascular tone may be quite complex, and our understanding of these processes is increasing. Additionally, the role of reactive oxygen species as mediators of endothelium-dependent relaxation is addressed. Finally, the consequences of the molecular interactions of superoxide with nitric oxide and arachidonic acid are discussed.
Reporter gene recombination in juxtaglomerular granular and collecting duct cells by human renin promoter-Cre recombinase transgene
Authors: Castrop H. , Oppermann M. , Weiss Y. , Huang Y. , Mizel D. , Lu H. , Germain S. , Schweda F. , Theilig F. , Bachmann S. , Briggs J. , Kurtz A. , Schnermann J.
Published: January 2006

To assess the feasibility of using the renin promoter for expressing Cre recombinase in juxtaglomerular (JG) cells only, we generated five independent transgenic mouse lines (designated hRen-Cre) expressing Cre recombinase under control of a 12.2-kb human renin promoter. In the kidneys of adult mice Cre mRNA (RT-PCR) was found in the renal cortex, with Cre protein (immunohistochemistry) being localized in afferent arterioles and to a lower degree in interlobular arteries. Cre mRNA levels were regulated in a renin-typical fashion by changes in oral salt intake, water restriction, or isoproterenol infusion, indicating the presence of key regulatory elements within 12.2 kb of the 5′-flanking region of the human renin gene. hRen-Cre mice were interbred with both the ROSA26-EGFP and ROSA26-lacZ reporter strains to assess renin promoter activity from Cre-mediated excision of a floxed stop cassette and subsequent enhanced green fluorescent protein (EGFP) and β-galactosidase (β-gal) detection. In adult mice, β-gal staining and EGFP were observed in afferent arterioles and interlobular arteries, overlapping with Cre protein expression. In addition, intense β-gal staining was found in cortical and medullary collecting ducts where Cre expression was minimal. In embryonic kidneys, β-gal staining was detected in the developing collecting duct system beginning at embryonic day 12, showing substantial activity of the human renin promoter in the branching ureteric bud. Our data indicate that besides its well-known activity in JG cells and renal vessels the human renin promoter is transiently active in the collecting duct system during kidney development, complicating the use of this approach for JG cell-specific excision of floxed targets.
Workplace Democracy: Why Bother?
Authors: Foley Janice R. , Polanyi Michael
Published: January 2006

North American business corporations are currently facing competitive challenges as well as rising public demand for more participative and accountable forms of governance. While they have responded to the competitive challenge by implementing new lean and .exible organizational processes to improve productivity, they have made few changes in governance, and employees continue to have little input into decisions that fundamentally affect them. This article outlines the conventional arguments for workplace democracy and proposes a new, health-based argument. The grounds for an emerging employee rights movement are then presented. The article concludes that while the evidence backing up the conventional arguments for workplace democracy may be equivocal, there are still compelling reasons, both economic and non-economic, to democratize workplaces.
The Working Conditions and Health of Non-Permanent Employees: Are There Differences between Private and Public Labour Markets?
Authors: Virtanen Pekka , Saloniemi Antti , Vahtera Jussi , Kivimaäki Mika , Virtanen Marianna , Koskenvuo Markku
Published: January 2006

Increasing levels of non-permanent employment have raised concern about quality of working life in the public sector. This Finnish study examines whether the public sector can be characterized as a ‘model employer’ with regard to the working conditions and well-being of fixed-term employees. Compared to the private sector, the difference in the physical load between non-permanent and permanent employees is significantly smaller in the public sector. Comparison of psychosocial strain shows a difference in favour of non-permanent employees, particularly among women working in the public sector. The association between type of employment contract and health is similar in both sectors. The equality between permanent and nonpermanent employees gives reason to benchmark the public sector as a model, even if the present findings may be due partly to sectorspecific occupational structures.
Transnational Institutions in Developing Countries: The Case of Iranian Civil Aviation
Authors: Carney Michael , Farashahi Mehdi
Published: January 2006

The proliferation of transnational institutions in the form of protocols, conventions, regimes and standards is a growing influence on organizational practice. Recent work on the origins and impact of transnational institutions focuses upon processes in ‘core’ states, but their influence in developing countries has not received much attention. In this paper we narrate a case study of the diffusion of two institutional regimes represented by the International Civil Aviation Organization (ICAO) and the International Air Transport Association (IATA) in Iranian civil aviation. The case study describes a seemingly frictionless and uncontested embedding of the emergent international aviation regime in post-World War II Iran and a severe challenge to those institutions in the years following Iran's Islamic revolution. We characterize the rise and decline of these regimes as a double process of institutionalization and de-institutionalization, and identify political and technical factors that drive institutional change. We discuss several theoretical and policy implications stemming from the experience of transnational aviation institutions in Iran.
Mental health and higher education: mapping field, consciousness and legitimation
Authors: Baker Sally , Brown B. J. , Fazey John A.
Published: January 2006

Some UK academics have declared that they do not want higher education to become part of the social welfare system. In this article we review aspects of policy and practice that suggest that this has already happened. Explicit encouragement of people with mental health problems to undertake courses has proceeded alongside a number of initiatives to make higher education institutions better able to support students in difficulty, and new responsibilities are being unfolded for the staff. There is growing evidence that students’ mental health problems are increasing. To make sense of the transformations in the topography of policy and in the consciousness it encourages, we make use of theoretical frameworks such as Bourdieu's notion of field and the generative work of Foucault and Rose, to examine the implications this has for the conceptualization of politics under New Labour and the implications this has for a newly recapitalized notion of responsible individuals.
Antisocial families and withholding welfare support
Authors: Rodger John J.
Published: January 2006

The attempt to introduce the principle of withholding housing benefit from people deemed to be antisocial, together with recent antisocial behaviour legislation, marks a subtle change in the role of the welfare state. The argument favouring a welfare contract in which benefits are conditional on citizens behaving in a socially acceptable way is critically appraised as is the view that incivility is the product of a deficit in appropriate value orientations. The paper concludes by offering a broader perspective on incivility incorporating an understanding of culture as a set of ‘tool kits’ rather than value orientations and, on the basis of a distinction between human capital and cultural capital, argues for social policies that build social solidarity as being equally important as those aimed at improving the educability and civility of the individual.
Application of a Classical Lamination Theory Model to the Design of Piezoelectric Composite Unimorph Actuators
Authors: Webber Kyle G. , Hopkinson David P. , Lynch Christopher S.
Published: January 2006

This work presents the design, development, and characterization of unimorphtype laminated piezoelectric actuators. The actuators consist of a piezoelectric lead zirconate titanate (PZT) layer sandwiched between unidirectional Kevlar 49 and epoxy composite layers. Differential thermal expansion during processing places the ceramic plate in a state of residual compression and results in a curved actuator. Modified classical lamination theory (MCLT) (modified to include piezoelectricity) was used to design the actuators. Three layups were fabricated and characterized: [90/PZT/90/0], [902/PZT/90/02], and [903/PZT/90/03]. Results were compared to a commercially available unimorph-type actuator made from layers of metal, adhesive, and piezoelectric material. The classical lamination theory predictions were in good agreement with the measured response of the PZT composite actuators and provide a useful design tool for these actuators.
Two Approaches to Structural Damage Identification: Model Updating versus Soft Computing
Authors: Kolakowski Przemyslaw , Mujica Luis E. , Vehi Josep
Published: January 2006

This article presents two approaches for structural damage identification, each based on a different philosophy. The virtual distortion method (VDM) is a model-updating method of damage assessment, utilizing gradient-based optimization techniques to solve the resulting inverse dynamic problem in the time domain. Case-based reasoning (CBR) is a softcomputing method utilizing wavelet transformation for signal processing and neural networks for training a base of damage cases to use for retrieving a similar relevant case. Advantages and drawbacks of each approach are discussed. Successful calibration of a numerical model from experiments has been shown as a sin equa non for the VDM approach. A numerical example of a beam is presented including a demonstration of the complexity of the inverse problem. Qualitative and quantitative comparisons between the two approaches are made.
Design of a Control System using Linear Matrix Inequalities for the Active Vibration Control of a Plate
Authors: Da Silva Samuel , Junior Vicente Lopes , Brennan Michael J.
Published: January 2006

The study of algorithms for active vibration control in smart structures is an area of interest, mainly due to the demand for better performance of mechanical systems, such as aircraft and aerospace structures. Smart structures, formed using actuators and sensors, can improve the dynamic performance with the application of several kinds of controllers. This article describes the application of a technique based on linear matrix inequalities (LMI) to design an active control system. The positioning of the actuators, the design of a robust state feedback controller and the design of an observer are all achieved using LMI. The following are considered in the controller design: limited actuator input, bounded output (energy) and robustness to parametric uncertainties. Active vibration control of a flat plate is chosen as an application example. The model is identified using experimental data by an eigensystem realization algorithm (ERA) and the placement of the two piezoelectric actuators and single sensor is determined using a finite element model (FEM) and an optimization procedure. A robust controller for active damping is designed using an LMI framework, and a reduced model with observation and control spillover effects is implemented using a computer. The simulation results demonstrate the efficacy of the approach, and show that the control system increases the damping in some of the modes.
Gene expression and angiotropism in primary CNS lymphoma
Authors: Rubenstein James L. , Fridlyand Jane , Shen Arthur , Aldape Ken , Ginzinger David , Batchelor Tracy , Treseler Patrick , Berger Mitchel , McDermott Michael , Prados Michael , Karch Jon , Okada Craig , Hyun William , Parikh Seema , Haqq Chris , Shuman Marc
Published: January 2006

Primary CNS lymphoma is an aggressive form of non-Hodgkin lymphoma whose growth is restricted to the central nervous system. We used cDNA microarray analysis to compare the gene expression signature of primary CNS lymphomas with nodal large B-cell lymphomas. Here, we show that while individual cases of primary CNS lymphomas may be classified as germinal center B-cell, activated B-cell, or type 3 large B-cell lymphoma, brain lymphomas are distinguished from nodal large B-cell lymphomas by high expression of regulators of the unfolded protein response (UPR) signaling pathway, by the oncogenes c-Myc and Pim-1, and by distinct regulators of apoptosis. We demonstrate that interleukin-4 (IL-4) is expressed by tumor vasculature as well as by tumor cells in CNS lymphomas. We also identify high expression in CNS lymphomas of several IL-4-induced genes, including X-box binding protein 1 (XBP-1), a regulator of the UPR. In addition, we demonstrate expression of the activated form of STAT6, a mediator of IL-4 signaling, by tumor cells and tumor endothelia in CNS lymphomas. High expression of activated STAT6 in tumors was associated with short survival in an independent set of patients with primary CNS lymphoma who were treated with high-dose intravenous methotrexate therapy.
Endothelial-cell apoptosis induced by cleaved high-molecular-weight kininogen (HKa) is matrix dependent and requires the generation of reactive oxygen species
Authors: Sun Danyu , McCrae Keith R.
Published: January 2006

High–molecular-weight kininogen (HK) is an abundant plasma protein that plays a central role in activation of the kallikrein-kinin system. Cleavage of HK by plasma kallikrein results in release of the nonapeptide bradykinin (BK), leaving behind cleaved high–molecular-weight kininogen (HKa). Previous studies have demonstrated that HKa induces apoptosis of proliferating endothelial cells and inhibits angiogenesis in vivo, activities mediated primarily through its domain 5. However, the mechanisms by which these effects occur are not well understood. Here, we demonstrate that HKa induces apoptosis of endothelial cells cultured on gelatin, vitronectin, fibronectin, or laminin but not collagen type I or IV. The ability of HKa to induce endothelial-cell apoptosis is dependent on the generation of intracellular reactive oxygen species and associated with depletion of glutathione and peroxidation of endothelial-cell lipids, effects that occur only in cells cultured on matrix proteins permissive for HKa-induced apoptosis. Finally, the ability of HKa to induce endothelial-cell apoptosis is blocked by the addition of reduced glutathione or N-acetylcysteine. These studies demonstrate a unique role for oxidant stress in mediating the activity of an antiangiogenic polypeptide and highlight the importance of the extracellular matrix in regulating endothelial-cell survival.
P-selectin binds to the D′-D3 domains of von Willebrand factor in Weibel-Palade bodies
Authors: Michaux Grégoire , Pullen Timothy J. , Haberichter Sandra L. , Cutler Daniel F.
Published: January 2006

It has recently been shown that the ultralarge platelet–recruiting von Willebrand factor (VWF) strings formed immediately at exocytosis from endothelial cells may be anchored to the cell surface by interaction with the integral membrane protein P-selectin. This finding of a new binding partner for VWF immediately prompts the question which domains of VWF bind to P-selectin. We have exploited the fact that VWF expression in HEK293 cells triggers the formation of Weibel-Palade body–like structures that can recruit P-selectin. A suitably modified version of this assay using coexpressed truncations of VWF, together with P-selectin variants in HEK293 cells, allowed us to determine which domains of VWF would recruit P-selectin within a physiologically appropriate intracellular environment. Confirming the results of such a cellular assay by conventional coimmunoprecipitation, we concluded that the lumenal domain of P-selectin interacts with the D′-D3 domains of VWF.
Significance of circulating T-cell clones in Sézary syndrome
Authors: Ortonne Nicolas , Huet Delphine , Gaudez Caroline , Marie-Cardine Anne , Schiavon Valérie , Bagot Martine , Musette Philippe , Bensussan Armand
Published: January 2006

Identification of malignant Sézary cells by T-cell receptor (TCR) clonality studies is routinely used for the diagnosis of Sézary syndrome, but T-cell clones expressed in a single patient have never been accurately characterized. We previously reported that CD158k expression delineates Sézary syndrome malignant cells, and, more recently, we identified vimentin at the surface membranes of Sézary cells and normal activated lymphocytes. In the present study, T-cell clones from 13 patients with Sézary syndrome were identified by immunoscopy and further characterized in the blood according to their TCR Vβ, CD158k, and vimentin cell-surface expression. We found in most patients a unique malignant T-cell clone that coexpressed CD158k and vimentin and that, when patients were tested, was also present in the skin. However, in some patients we detected the presence of a nonmalignant circulating clone expressing high amounts of vimentin and lacking CD158k. These results indicate that clonal expansion may originate from circulating malignant and nonmalignant CD4+ T cell populations in patients with Sézary syndrome. Identification of the malignant cells in Sézary syndrome cannot be achieved by T-cell clonality studies or by TCR Vβ monoclonal antibody (mAb) analysis alone; it also relies on CD158k phenotyping.
Randomized Trial of Long-Term Follow-Up for Early-Stage Breast Cancer: A Comparison of Family Physician Versus Specialist Care
Authors: Grunfeld Eva , Levine Mark N. , Julian Jim A. , Coyle Doug , Szechtman Barbara , Mirsky Doug , Verma Shailendara , Dent Susan , Sawka Carol , Pritchard Kathleen I. , Ginsburg David , Wood Marjorie , Whelan Tim
Published: January 2006

Purpose

Most women with breast cancer are diagnosed at an early stage and more than 80% will be long-term survivors. Routine follow-up marks the transition from intensive treatment to survivorship. It is usual practice for routine follow-up to take place in specialist clinics. This study tested the hypothesis that follow-up by the patient's family physician is a safe and acceptable alternative to specialist follow-up.

Patients and Methods

A multicenter, randomized, controlled trial was conducted involving 968 patients with early-stage breast cancer who had completed adjuvant treatment, were disease free, and were between 9 and 15 months after diagnosis. Patients may have continued receiving adjuvant hormonal therapy. Patients were randomly allocated to follow-up in the cancer center according to usual practice (CC group) or follow-up from their own family physician (FP group). The primary outcome was the rate of recurrence-related serious clinical events (SCEs). The secondary outcome was health-related quality of life (HRQL).

Results

In the FP group, there were 54 recurrences (11.2%) and 29 deaths (6.0%). In the CC group, there were 64 recurrences (13.2%) and 30 deaths (6.2%). In the FP group, 17 patients (3.5%) compared with 18 patients (3.7%) in the CC group experienced an SCE (0.19% difference; 95% CI, −2.26% to 2.65%). No statistically significant differences (P < .05) were detected between groups on any of the HRQL questionnaires.

Conclusion

Breast cancer patients can be offered follow-up by their family physician without concern that important recurrence-related SCEs will occur more frequently or that HRQL will be negatively affected.
ARAP3 is essential for formation of lamellipodia after growth factor stimulation
Authors: Krugmann Sonja , Andrews Simon , Stephens Len , Hawkins Phillip T.
Published: January 2006

Rho and Arf family small GTPases control dynamic actin rearrangements and vesicular trafficking events. ARAP3 is a dual GAP for RhoA and Arf6 that is regulated by phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P3], a product of the phosphoinositide 3-kinase (PI3K) signalling pathway. To investigate the physiological function of ARAP3, we used an RNAi-based approach in an endothelial cell model. ARAP3-deficient cells showed increased activities of RhoA and Arf6. Phenotypically, they were more rounded than control counterparts and displayed very fine stress fibres. ARAP3-deficient cells were not capable of producing lamellipodia upon growth factor stimulation, a process known to depend on PI3K and Rac activities. Rac was transiently activated in stimulated ARAP3 RNAi cells although its cellular localisation was altered, a likely consequence of increased Arf6 activity. We conclude that ARAP3 recruitment to sites of elevated PtdIns(3,4,5)P3 is crucial to allow localised inactivation of RhoA and cycling of Arf6, both of which are necessary to allow growth factor-stimulated formation of lamellipodia.
Localised PtdIns(3,4,5)P3 or PtdIns(3,4)P2 at the phagocytic cup is required for both phagosome closure and Ca2+ signalling in HL60 neutrophils
Authors: Dewitt Sharon , Tian Wei , Hallett Maurice B.
Published: January 2006

Several events accompany integrin-mediated phagocytosis by myeloid cells. These include local pseudopod and phagocytic cup formation followed by Ca2+ signalling. However, there is also a role for localised phosphatidylinositol (3,4,5) trisphosphate [PtdIns(3,4,5)P3] production. Here we report that in neutrophilic HL-60 cells expressing PH-Akt-GFP, binding of iC3b-coated zymosan particles (2 μm in diameter) via β2 integrin induces an incomplete phagocytic cup to form before either PtdIns(3,4,5)P3 or phosphatidylinositol (3,4) bisphosphate [PtdIns(3,4)P2] production or Ca2+ signalling. These phosphoinositides then accumulated locally at the site of the phagocytic cup and Ca2+ signalling and phagosome closure follows immediately. Although photobleaching showed that PH-Akt-GFP was freely diffusible in the cytosol and able to dissociate from the phagocytic cup, it was restricted to the plasma membrane of the formed but open phagosome and failed to diffuse into the surrounding plasma membrane or neighbouring phagocytic cups even if connected. Inhibition of phosphoinositide (PI) 3-kinase or depletion of membrane cholesterol inhibited both Ca2+ signalling and phagosome closure, but had no effect on particle binding or phagocytic cup formation. We therefore conclude that PtdIns(3,4,5)P3 or PtdIns(3,4)P2 generation was not required for the events that initiate the formation of the phagocytic cup, but that anchoring of PtdIns(3,4,5)P3 at the phagocytic cup is an essential step for phagosome closure and Ca2+ signalling.
Direct binding of SWAP-70 to non-muscle actin is required for membrane ruffling
Authors: Ihara Sayoko , Oka Tsutomu , Fukui Yasuhisa
Published: January 2006

Membrane ruffling induced by growth factor stimulation is caused by actin remodeling, which is mediated by various signaling molecules including Rac. We have shown that SWAP-70, which binds phosphatidylinositol trisphosphate, is one such molecule required for membrane ruffling in mouse kidney cells. Here, we show that SWAP-70 directly binds to F-actin. The bacterially expressed C-terminal region of SWAP-70 co-sedimented with non-muscle F-actin, suggesting direct binding of SWAP-70 to F-actin. The binding was much weaker in muscle F-actin. A truncated mutant of SWAP-70 containing only the C-terminal region readily colocalizes with F-actin, supporting this idea. Full-length SWAP-70 does not colocalize with F-actin unless cells are stimulated with growth factors, suggesting the presence of a stimuli-dependent regulatory mechanism for actin-binding activity in vivo. Overexpression of the mutant SWAP-70 lacking this binding domain inhibits the membrane ruffling induced by epidermal growth factor stimulation in COS7 cells. This dominant-negative effect is also observed in membrane ruffling induced by a dominant-active Rac, suggesting that SWAP-70 cooperates with Rac. These results suggest that the binding activity of SWAP-70 to non-muscle F-actin is required for membrane ruffling.
Junctional adhesion molecule-A-induced endothelial cell migration on vitronectin is integrin αvβ3 specific
Authors: Naik Meghna U. , Naik Ulhas P.
Published: January 2006

Junctional adhesion molecule-A (JAM-A) is a member of the immunoglobulin superfamily, and is mainly expressed in the tight junctions of both epithelial and endothelial cells. We have recently shown that JAM-A is involved in basic fibroblast growth factor (bFGF)-induced angiogenesis. Here, we show that, when ectopically expressed in human umbilical vein endothelial cells (HUVECs), JAM-A induced enhanced cell migration on vitronectin, but had no effect on fibronectin. Use of antibodies that block integrin function indicated that the migration on vitronectin is specific to integrin αvβ3 and not to integrin αvβ5. JAM-A-induced migration was inhibited by anti-JAM-A antibody. Additionally, overexpression of a JAM-A cytoplasmic domain deletion mutant failed to induce HUVEC migration. Addition of phosphoinositide 3-kinase and protein kinase C inhibitors blocked JAM-A-induced migration, suggesting that these kinases act downstream of JAM-A. Immunoprecipitation analysis showed that JAM-A interacts with integrin αvβ3, and this association was increased by engagement of the ligand-binding site of the integrin by Arg-Gly-Asp-Ser (RGDS) peptide. Furthermore, activation of both focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK) on vitronectin was enhanced by JAM-A overexpression but not by its cytoplasmic domain deletion mutant. Taken together, these results suggest that signaling through JAM-A is necessary for αvβ3-dependent HUVEC migration and implicate JAM-A in the regulation of vascular function.
Hepatitis Associated with Low-Dose Venlafaxine for Postmenopausal Vasomotor Symptoms
Authors: Phillips Beth Bryles , Digmann Rachel R , Beck M Gwen
Published: January 2006

Objective:

To report a case of drug-induced hepatitis associated with low-dose venlafaxine.

Case Summary:

A 60-year-old white woman receiving venlafaxine 75 mg daily for vasomotor symptoms presented after one month of therapy with nonspecific complaints, including abdominal pain. A series of diagnostic and laboratory tests revealed an enlarged liver and elevated alanine aminotransferase (ALT) up to 372 U/L, aspartate aminotransferase (AST) up to 99 U/L, γ-glutamyl-transferase (GGT) up to 962 U/L, and alkaline phosphatase up to 758 U/L. All potential hepatotoxic medications were discontinued. Within one week after stopping venlafaxine, her liver function test results showed marked improvement. Almost 4 weeks after discontinuing therapy, venlafaxine 37.5 mg was reinitiated. Her ALT, AST, GGT, and alkaline phosphatase again increased to 269, 49, 256, and 263 U/L, respectively, 6 days after resuming therapy. Upon discontinuation of venlafaxine, her liver function abnormalities resolved.

Discussion:

This case is significant due to the severity of symptoms and consequent liver function test results involved in diagnosing drug-induced hepatitis. It is also remarkable because of the hepatotoxicity that occurred initially and on rechallenge with low-dose venlafaxine. The hepatotoxic effects of venlafaxine have been characterized as rare and idiosyncratic. The Naranjo probability scale revealed that the adverse drug event was probable.

Conclusions:

Venlafaxine therapy can lead to drug-induced hepatitis, even when used at low doses. Clinicians should be aware of this possible adverse effect of venlafaxine therapy and monitor patients closely after initiation of therapy.
Miller was (mostly) right: Head injury severity inversely related to simulation
Authors: Greiffenstein Manfred F. , Baker W. John
Published: January 2006

Purpose. British neurologist Henry Miller (1961; Miller & Cartlidge, 1972) provoked controversy by asserting late post‐concussion syndrome (LPCS) is explained by simulation. The present study examines Miller's inverse dose‐response assertion; the more minor the compensable injury, the greater the likelihood of deficit simulation.

Method. We examined the prevalence of three types of simulation (memory, motor, and psychiatric) in two archival cohorts of compensation seekers (N = 391 and 368) representing a broad range of cranio‐cervical injury severity. A moderate‐severe brain injured group provided two sets of performance floors to establish ‘possible’ or ‘probable’ pseudoabnormalities. Instruments included the Rey word recognition list, the Smedley dynamometer, the Test of Memory Malingering, and the MMPI‐2 infrequency scale.

Results. Chronic whiplash and minor head‐injury litigants produced more invalid signs than severely injured persons on measures of simulated memory and motor deficits irrespective of definitional stringency. ANOVA revealed striking inverse linear trends as a function of severity. Under a ‘possible’ rule, at least one pseudoabnormality was present in 80% of LPCS claimants. Memory and motor pseudoabnormalities were more common than psychotic ones.

Conclusions. These findings support Miller and Cartlidge's (1972) observations that embellishment rises as injury severity decreases in a compensable context. Simulating litigants may ‘tailor’ performance to fit aetiological expectations, as we found a low prevalence of psychosis simulation.
Deceptive responses: The impact of verbal and non‐verbal countermeasures
Authors: Caso Letizia , Vrij Aldert , Mann Samantha , De Leo Gaetano
Published: January 2006

Objectives. This experiment investigates the impact of informing participants about verbal and non‐verbal cues to deception on their verbal and non‐verbal responses. Based on the fact that people are more practised in their verbal behaviour than in their non‐verbal behaviour, we predicted that giving participants information about verbal cues would positively affect their verbal accounts resulting in them giving an account that appeared more credible. In contrast, we predicted that informing participants about non‐verbal cues would have no noticeable effect on credibility. We also predicted that focusing on verbal behaviours would impair non‐verbal performance and that, vice versa, concentrating on non‐verbal behaviours would impair verbal performance, particularly in liars.

Method. A total of 128 participants either told the truth or lied about the possession of an object. Prior to these interviews, participants were or were not informed about verbal cues to deception and were or were not informed about non‐verbal cues of deception (these two factors were systematically manipulated).

Results. As predicted, participants were able to adapt their verbal behaviour but were not able to change their non‐verbal behaviour. However, focusing on one aspect (either verbal or non‐verbal behaviour) did not occur at the expense of the other behaviour (either non‐verbal or verbal).

Conclusion. Verbal countermeasures may well be easier to apply than non‐verbal countermeasures.
The extended health belief model applied to the experience of diabetes in young people
Authors: Gillibrand Rachel , Stevenson Jim
Published: January 2006

Objectives The experience of diabetes in young people was investigated within the theoretical framework of the extended health belief model (EHBM). It was anticipated that participant reports of high internal locus of control, high diabetes related empowerment, coping with hypoglycaemia, and diabetes related social support would be associated with good patient adherence to the self‐care regime.

Method 118 participants aged 16–25 years with Type 1 diabetes mellitus were sent a set of questionnaires incorporating previously published scales measuring all variables of the EHBM.

Results High levels of family support and low locus of control beliefs in powerful others to control their diabetes reduce the young person's perception of severity and vulnerability to diabetes related complications. High internal locus of control beliefs and high levels of self‐efficacy predicted the benefits of adhering to the self‐care regime as outweighing the costs of doing so. Adherence to self‐care regime was predicted by high levels of family support.

Conclusion The final model explained 12% of the variance in the young person's adherence to diabetes self‐care regime. It is proposed that the EHBM is an adequate model for understanding the socio‐psychological factors present in the young person's appraisal of their diabetes, which, in turn, influences adherence to the diabetes self‐care regime.
Dispositional optimism and health behaviour in community‐dwelling older people: Associations with healthy ageing
Authors: Steptoe Andrew* , Wright Caroline , Kunz‐Ebrecht Sabine R. , Iliffe Steve
Published: January 2006

Objective Dispositional optimism measured with the Life Orientation Test has been associated with a variety of health outcomes. We assessed whether optimism was related to indices of healthy ageing, and if effects were mediated through health behaviours.

Method A community sample of 128 men and women aged 65 to 80 years was recruited from general practice lists. Optimism and health behaviours were assessed by questionnaire, and healthy ageing indexed by physical health summary scores from the Short Form 36, and by self‐rated health.

Results Optimism was associated with not smoking, moderate alcohol consumption, brisk walking, and vigorous physical activities (women only), independently of socio‐demographic factors and clinical condition. Physical health status was associated with optimism, independently of socio‐demographic factors, clinical condition, negative affectivity, and body mass. This effect was attenuated when health behaviours were taken into account. Self‐rated health was also positively related to optimism, and this association was not mediated by health behaviours. Neither the optimism nor pessimism subscales of the Life Orientation Test showed as consistent effects as the full scale.

Conclusions We conclude that dispositional optimism is associated with healthy ageing. The relationship between optimism and healthy ageing was only partly mediated by the health behaviours assessed in this sample.
Action plans and coping plans for physical exercise: A longitudinal intervention study in cardiac rehabilitation
Authors: Sniehotta Falko F. , Scholz Urte , Schwarzer Ralf
Published: January 2006

Objectives The aim of the present study was to test two brief planning interventions designed to encourage cardiac patients to engage in regular physical exercise following discharge from rehabilitation. The interventions comprised action plans on (a) when, where, and how to act, and (b) coping plans on how to deal with anticipated barriers.

Design and method An experimental longitudinal trial was conducted to test two interventions that either focused on action planning alone, or on a combination of action planning and coping planning. A total of 211 participants completed assessments at baseline and 2 months after discharge. Participants were randomly assigned to either one of the intervention groups or a standard‐care control group.

Results Participants in the combined planning group did significantly more physical exercise 2 months post‐discharge than those in the other groups.

Conclusions The theoretical distinction between action planning and coping planning as introduced in the present study has proven useful in explaining changes in health‐related behaviour. The combined planning intervention can be applied in the context of cardiac rehabilitation programmes.
Dorsolateral Prefrontal Cortex Promotes Long-Term Memory Formation through Its Role in Working Memory Organization
Authors: Blumenfeld Robert S. , Ranganath Charan
Published: January 2006

Results from neuroimaging studies have shown that the dorsolateral prefrontal cortex (DLPFC) implements processes critical for organizing items in working memory (WM). Based on its role in WM, we hypothesized that the DLPFC should contribute to long-term memory (LTM) formation by strengthening associations among items that are organized in WM. We conducted an event-related functional magnetic resonance imaging (fMRI) study to test this hypothesis by investigating prefrontal activity during performance of two different WM tasks: on “rehearse” trials, participants actively maintained triplets of words during a brief delay, whereas on “reorder” trials, participants actively organized each triplet during the delay. After scanning, subjects performed an LTM test on words presented during both WM conditions. Behavioral results showed that WM processing in the reorder condition enhanced LTM by strengthening inter-item associations. fMRI results showed that DLPFC activity specifically during reorder trials was predictive of subsequent LTM. In contrast, activity in the posterior ventrolateral prefrontal cortex was predictive of LTM for words studied on both reorder and rehearse trials. These results support the view that the DLPFC contributes to LTM formation through its role in organization of information in WM.
Neuroanatomical Dissociation of Encoding Processes Related to Priming and Explicit Memory
Authors: Schott Björn H. , Richardson-Klavehn Alan , Henson Richard N. A. , Becker Christine , Heinze Hans-Jochen , Düzel Emrah
Published: January 2006

Priming is a facilitation of cognitive processing with stimulus repetition that can occur without explicit memory. Whereas the functional neuroanatomy of perceptual priming at retrieval is established, encoding processes that initiate priming and explicit memory have not yet been anatomically separated, and we investigated them using event-related functional magnetic resonance imaging. Activations predicting later explicit memory occurred in the bilateral medial temporal lobe (MTL) and left prefrontal cortex (PFC). Activity predicting later priming did not occur in these areas, but rather in the bilateral extrastriate cortex, left fusiform gyrus, and bilateral inferior PFC, areas linked with stimulus identification. Surprisingly, these regions showed response reductions. Our results demonstrate that priming and explicit memory have distinct functional neuroanatomies at encoding, with MTL activations being specific for explicit memory, and suggest that priming is initiated by sharpness of neural responding in stimulus identification areas, consistent with recent electrophysiological evidence regarding priming-related neural oscillations at encoding. We tentatively suggest that this sharpened responding at encoding may set the stage for increased neural processing efficiency at retrieval, with these different neural mechanisms both leading to observed priming-related hemodynamic decreases, and argue that neural measurements at encoding, and not just at retrieval, will be critical in resolving the debate about the neural mechanisms of learning that underlie priming.
Essential Contribution of the Ligand-Binding βB/βC Loop of PDZ1 and PDZ2 in the Regulation of Postsynaptic Clustering, Scaffolding, and Localization of Postsynaptic Density-95
Authors: Nonaka Mio , Doi Tomoko , Fujiyoshi Yoshinori , Takemoto-Kimura Sayaka , Bito Haruhiko
Published: January 2006

Postsynaptic density-95 (PSD-95), a PSD-95/Discs large/zona occludens-1 (PDZ) domain-containing scaffold protein, clusters many signaling molecules near NMDA-type glutamate receptors in the postsynaptic densities. Although the synaptic localization of PSD-95 requires palmitoylation of two cysteines at the N terminus and the presence of at least one PDZ domain, how the clustering of PSD-95 is initiated and regulated remains essentially unknown. To address this issue, we examined PSD-95 clustering in primary cultured hippocampal neurons expressing full-length PSD-95 mutant proteins lacking the ligand-binding ability of PDZ1, PDZ2, and/or PDZ3. The formation of either excitatory or inhibitory synapses was unaffected. Combinations of individual mutations, however, significantly reduced the PSD-95 clustering index, in an approximately additive manner. The sensitivity to 2-bromo-palmitate and latrunculin A, reagents known to affect PSD-95 turnover, was also augmented. Furthermore, the synaptic recruitment of a PSD-95 ligand, synaptic GTPase-activating protein (synGAP), was significantly impaired, whereas the clustering of other scaffolding proteins, such as Homer 1c, Shank/Synamon, and PSD-93/Chapsin-110 was spared. Intriguingly, overexpression of the PSD-95 PDZ1/2/3 mutants caused the PSD-95 clusters to localize away from the dendritic shaft, resulting in the formation of elongated spines, in an inverse correlation with the overall PDZ-ligand affinity. Expression of a mutant synGAP lacking the PDZ-binding motif replicated both the clustering and spine morphology phenotypes. In conclusion, the ligand-binding affinity of the PDZ domains of PSD-95, contributed in part via its interaction with the C-terminal end of synGAP, plays a critical role in titrating the synaptic clustering of PSD-95 and controlling its tight association with the PSD scaffold, thereby affecting synapse maturation.
Myelin-Associated Inhibitors Regulate Cofilin Phosphorylation and Neuronal Inhibition through LIM Kinase and Slingshot Phosphatase
Authors: Hsieh Sidney H.-K. , Ferraro Gino B. , Fournier Alyson E.
Published: January 2006

Myelin-associated inhibitors (MAIs) signal through a tripartate receptor complex on neurons to limit axon regeneration in the CNS. Inhibitory influences ultimately converge on the cytoskeleton to mediate growth cone collapse and neurite outgrowth inhibition. Rho GTPase and its downstream effector Rho kinase are key signaling intermediates in response to MAIs; however, the links between Rho and the actin cytoskeleton have not been fully defined. We found that Nogo-66, a potent inhibitory fragment of Nogo-A, signals through LIM (LIM is an acronym of the three gene products Lin-11, Isl-1, and Mec-3) kinase and Slingshot (SSH) phosphatase to regulate the phosphorylation profile of the actin depolymerization factor cofilin. Blockade of LIMK1 activation and subsequent cofilin phosphorylation circumvents myelin-dependent inhibition in chick dorsal root ganglion neurons, suggesting that phosphorylation and inactivation of cofilin is critical for neuronal inhibitory responses. Subsequent activation of SSH1 phosphatase mediates cofilin dephosphorylation and reactivation. Overexpression of SSH1 does not mimic the neurite outgrowth inhibitory effects of myelin, suggesting an alternative role in MAI inhibition. We speculate that SSH-mediated persistent cofilin activation may be responsible for maintaining an inhibited neuronal phenotype in response to myelin inhibitors.
Multiple Eph Receptors and B-Class Ephrins Regulate Midline Crossing of Corpus Callosum Fibers in the Developing Mouse Forebrain
Authors: Mendes Shannon W. , Henkemeyer Mark , Liebl Daniel J.
Published: January 2006

Agenesis of the corpus callosum (CC) is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. Our studies shed light on which B-class ephrins and Eph receptors function to regulate CC midline growth and how these molecules interact with important guideposts during development. We show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knock-out mice. Defects are most pronounced in the combination double knock-out mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis revealed that Probst's bundle formation may reflect aberrant glial formations and/or altered sensitivity of CC axons to other guidance cues. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing and human disorder.