bluuebunny/crossref_metadata_2025 huggingface dataset:
Model‐based treatment optimization of a novel VEGFR inhibitor
Authors: Keizer Ron J. , Gupta Anubha , Shumaker Robert , Beijnen Jos H. , Schellens Jan H. M. , Huitema Alwin D. R.
Published: February 2012

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Drugs targeting the VEGF‐pathway often show increase in blood pressure (BP) and proteinuria as dose limiting toxicity. However, high dose levels are also considered crucial for anti‐tumour activity. In preclinical models, lenvatinib affects tumour cell proliferation and tumour vascularization, while therapeutic effects were observed in phase I and II trials.

WHAT THIS STUDY ADDS

• Adverse event guided dose titration, including treatment with anti‐hypertensive treatment and dose de‐escalations can be expected to keep about 80% of patients on treatment with lenvatinib for 16 weeks. Additionally, within subject dose escalation in subjects not experiencing toxicity can considerably increase dose intensity.

AIM To evaluate dosing and intervention strategies for the phase II programme of a VEGF receptor inhibitor using PK–PD modelling and simulation, with the aim of maximizing (i) the number of patients on treatment and (ii) the average dose level during treatment.

METHODS A previously developed PK–PD model for lenvatinib (E7080) was updated and parameters were re‐estimated (141 patients, once daily and twice daily regimens). Treatment of lenvatinib was simulated for 16 weeks, initiated at 25 mg once daily. Outcome measures included the number of patients on treatment and overall drug exposure. A hypertension intervention design proposed for phase II studies was evaluated, including antihypertensive treatment and dose de‐escalation. Additionally, a within‐patient dose escalation was investigated, titrating up to 50 mg once daily unless unacceptable toxicity occurred.

RESULTS Using the proposed antihypertension intervention design, 82% of patients could remain on treatment, and the mean dose administered was 21.5 mg day−1. The adverse event (AE) guided dose titration increased the average dose by 4.6 mg day−1, while only marginally increasing the percentage of patients dropping out due to toxicity (from 18% to 20.8%).

CONCLUSIONS The proposed hypertension intervention design is expected to be effective in maintaining patients on treatment with lenvatinib. The AE‐guided dose titration with blood pressure as a biomarker yielded a higher overall dose level, without relevant increases in toxicity. Since increased exposure to lenvatinib seems correlated with increased treatment efficacy, the adaptive treatment design may thus be a valid approach to improve treatment outcome.
Burkitt lymphoma: staging and response evaluation
Authors: Sandlund John T.
Published: February 2012

The refinements in both the staging and response evaluation of children with Burkitt lymphoma (BL) have contributed to the improvements in treatment outcome observed over the past 40 years. Ziegler and Magrath designed a staging system in the 1970s for children with BL in equatorial Africa. Currently, the most widely used staging system around the world is that described by Murphy in 1980, which was developed for children with non‐Hodgkin lymphoma (NHL) of any histology. There are opportunities for refinement in this system, particularly with respect to certain extra‐nodal sites, such as skin and bone. The findings obtained at diagnosis with novel technologies (functional imaging [e.g., positron emission tomography [PET]] and minimal residual disease [MRD] technology), which are more sensitive with respect to disease detection than historic modalities, also need to be considered. Technological advances have also had impact on the assessment of response evaluation. Standard x‐rays were routinely used in the 1960s; nuclear imaging became widely used in the 1970s; computerized axial tomography was incorporated in the 1980s; PET imaging was incorporated and, in many cases, has replaced gallium/bone scans since 2000; and MRD technology has been explored in some of the most recent clinical trials. There is clearly a need for more clinical data on the use of PET and MRD technology in the determination of response evaluation of children with BL as well as other histological subtypes of NHL. An international working group is currently addressing the refinement of both disease staging and response evaluation in children with NHL.
A 15q24 microdeletion in transient myeloproliferative disease (TMD) and acute megakaryoblastic leukaemia (AMKL) implicates PML and SUMO3 in the leukaemogenesis of TMD/AMKL
Authors: Haemmerling Susanne , Behnisch Wolfgang , Doerks Tobias , Korbel Jan O. , Bork Peer , Moog Ute , Hentze Sabine , Grasshoff Ute , Bonin Michael , Rieß Olaf , Janssen Johannes W. G. , Jauch Anna , Bartram Claus R. , Reinhardt Dirk , Koch Karin A. , Bandapalli Obul R. , Kulozik Andreas E.
Published: February 2012

Transient myeloproliferative disorder (TMD) of the newborn and acute megakaryoblastic leukaemia (AMKL) in children with Down syndrome (DS) represent paradigmatic models of leukaemogenesis. Chromosome 21 gene dosage effects and truncating mutations of the X‐chromosomal transcription factor GATA1 synergize to trigger TMD and AMKL in most patients. Here, we report the occurrence of TMD, which spontaneously remitted and later progressed to AMKL in a patient without DS but with a distinct dysmorphic syndrome. Genetic analysis of the leukaemic clone revealed somatic trisomy 21 and a truncating GATA1 mutation. The analysis of the patient's normal blood cell DNA on a genomic single nucleotide polymorphism (SNP) array revealed a de novo germ line 2·58 Mb 15q24 microdeletion including 41 known genes encompassing the tumour suppressor PML. Genomic context analysis of proteins encoded by genes that are included in the microdeletion, chromosome 21‐encoded proteins and GATA1 suggests that the microdeletion may trigger leukaemogenesis by disturbing the balance of a hypothetical regulatory network of normal megakaryopoiesis involving PML, SUMO3 and GATA1. The 15q24 microdeletion may thus represent the first genetic hit to initiate leukaemogenesis and implicates PML and SUMO3 as novel components of the leukaemogenic network in TMD/AMKL.
Modelling approaches for relating effects of change in river flow to populations of Atlantic salmon and brown trout
Authors: ARMSTRONG J. D. , NISLOW K. H.
Published: February 2012

Abstract  Modelling approaches for relating discharge to the biology of Atlantic salmon, Salmo salar L., and brown trout, Salmo trutta L., growing in rivers are reviewed. Process‐based and empirical models are set within a common framework of input of water flow and output of characteristics of fish, such as growth and survival, which relate directly to population dynamics. A continuum is envisaged incorporating various contributions of process and empirical structure as practical and appropriate to specific goals. This framework is compared with, and shown to differ from, approaches whose output is in the form of quantity and form of habitat (or usable area) based on its frequency of use by fish, which then is assumed to have some relationship with fish performance. A simple conceptual modelling approach is also developed to relate water flow to fish population characteristics to assess the likelihood of simple relationships between flow and usable area thresholds. Basic predictions of the model are tested against empirical data from a long‐term individual‐based study of juvenile S. salar and resident brook trout, Salvelinus fontinalis (Mitchell), in West Brook, Massachusetts. For this system, growth rates of both species increased linearly with flow during spring, summer and autumn months and bore no relation to Q95 or wetted‐width discontinuities. Winter is identified as a season during which water might be abstracted most safely, but cautiously given sparse knowledge of wild salmonid fish at this time of year. These results, together with the fundamental conceptual problems inherent in usable area‐based approaches, suggest that models that relate directly to fish performance outcomes may be more robust as a basis for flow prescriptions. However, this utility will depend strongly on our ability to generalise from a limited set of empirical studies and to use the results of these studies of management actions to inform and improve future models.
Improved clonality detection in Hodgkin lymphoma using the BIOMED‐2‐based heavy and kappa chain assay: a paraffin‐embedded tissue study
Authors: Tapia Gustavo , Sanz Carolina , Mate José L , Muñoz‐Mármol Ana M , Ariza Aurelio
Published: February 2012

Tapia G, Sanz C, Mate J L, Muñoz‐Mármol A M & Ariza A  (2012) Histopathology 60, 768–773 Improved clonality detection in Hodgkin lymphoma using the BIOMED‐2‐based heavy and kappa chain assay: a paraffin‐embedded tissue study

Aims:  Although BIOMED‐2 polymerase chain reaction (PCR) standardization protocols allow clonality detection in nearly 100% of non‐Hodgkin B cell lymphomas, they have not been widely validated for Hodgkin lymphoma (HL). Our aim was to assess BIOMED‐2 protocol sensitivity when using non‐microdissected, formalin‐fixed, paraffin‐embedded (FFPE) tissue from HL cases.

Methods and results:  We studied 69 consecutive HL cases, of which 61 corresponded to classic HL (cHL) and eight to nodular lymphocyte‐predominant HL (NLPHL). CD30‐positive cell numbers (<10, 10–25 or >25 per ×200 field), background CD20‐positive cell density (low or high) and tumour cell immunophenotype were evaluated. IGH and IGK clonality was assessed on FFPE tissue following BIOMED‐2 protocols. Of the 58 assessable cHL cases, 15 (25.9%) exhibited IGH and/or IGK clonality; IGH clonality was shown by nine (15.5%) and IGK clonality by 12 (20.7%). Clonality detection rates in cHL improved as CD30‐positive Reed–Sternberg (RS) cell density increased and CD20‐positive B cell density decreased, although these correlations did not reach statistical significance. Of the eight NLPHL cases studied, none showed clonal rearrangement.

Conclusions:  Combined study of IGH and IGK rearrangement according to BIOMED‐2 protocols improves clonality detection rate (up to 25% of cases) in HL, even when working on non‐microdissected FFPE tissue.
‘You need to let your voice be heard’: research participants' views on research
Authors: McDonald K. E. , Kidney C. A. , Patka M.
Published: February 2012

Background  Persons with intellectual and developmental disabilities have had regrettably few opportunities to voice their opinions on aspects of research with which they have had direct experience. Understanding and responding to these views can contribute to policies and practices that increasingly treat people as they desire to be treated.

Methods  We conducted individual interviews and focus groups with 16 adults with intellectual and developmental disabilities to examine their perspectives on participating in research.

Results  Our analysis indicates that adults with intellectual and developmental disabilities want to engage in research to improve their quality of life and to have greater access to a worthwhile activity through more active participation. Our results also highlight trust as a critical ingredient in the success of research with this group.

Conclusions  Our findings suggest that despite ethical challenges, researchers can and should pursue research that has the potential to improve the lives of persons with intellectual and developmental disabilities. Such research is more likely to be both ethical and successful if researchers pay attention to enhancing autonomy and person‐centredness, while at the same time engendering participant trust.
Event sequencing of forced intramuscular medication in England
Authors: BOWERS L. , ROSS J. , OWITI J. , BAKER J. , ADAMS C. , STEWART D.
Published: February 2012

Accessible summary

In many countries staff are allowed to inject psychiatric inpatients against their will with psychotropic medication.

This study, conducted in England, found such injections were given to 9% of patients, usually in response to aggressive behaviour or medication refusal.

In most cases the forced injections ended a crisis, but the study concludes that there are opportunities for staff to use alternative approaches.

In most inpatient psychiatric care systems it is permissible in certain situations for staff to forcibly inject patients with psychotropic medication. The aim of this study is to describe what precedes and follows a coerced intramuscular injection within a nursing shift. Data were collected on the sequence of conflict (aggression, absconding, etc.) and containment (seclusion, restraint, etc.) for the first 2 weeks of 522 acute admissions on 84 wards in 31 UK hospitals. Injections were given to 9% of patients. Aggression, regular medication refusal and pro re nata (PRN) medication refusal preceded injections. The giving of coerced medication concluded most crises. Coerced medication effectively resolves crises in the short term. Staff should offer oral PRN as an alternative, unless this is unsafe. Where only verbal violence has occurred staff should try to resolve the crisis without enforcing medication. More research on the best way to respond to inpatients' medication refusal is required.
Managing distressed and disturbed patients: the thoughts and feelings experienced by Italian nurses
Authors: CAMUCCIO C. A. , CHAMBERS M. , VÄLIMÄKI M. , FARRO D. , ZANOTTI R.
Published: February 2012

Accessible summary

The aim of the research was to examine the thoughts and feelings experienced by Italian nurses when caring for distressed and aggressive patients in acute psychiatric settings.

Fear was the prevalent feeling experienced by nurses: fear of being harmed by the patient and fear of harming the patient and fear of damaging the therapeutic relationship.

When managing distressed and aggressive patients, the nursing team have to share similar feelings and be emotionally in tune with each other.

The paper offers clear explanations of nurses' feelings, the reasons for their fear and the importance of effective team working during a crisis.

This paper reports on a qualitative study to identify Italian nurses' feelings and emotions towards the management of distressed and disturbed psychiatric patients in acute inpatient settings. Four focus groups were carried out involving 33 nurses from seven acute psychiatric services in a region of Italy. Data were analysed using content analysis. Findings highlight that fear is the prevailing feeling experienced by nurses in the management of distressed patients. This includes both fear of being physically harmed and concerns about doing harm or damage to patients. The unpredictability of aggressive behaviour from unknown patients was described as especially frightening. Known patients, namely those previously admitted to the unit, induced less fear, as their behaviour was considered more predictable. Patients with dual diagnosis were also a worry for many nurses, who considered themselves lacking in the personal relational skills needed to manage an individual in crisis. Nurses reported that they try to understand the reasons for a patient's aggressive behaviour and are empathetic to his or her suffering. When such empathy is lacking, nurses experience conflicting feelings of counter‐aggressiveness. The paper concludes by emphasizing the need to increase availability of education related to patient management, in particular team working and its internal relationships.
Self‐esteem among German nurses: does academic education make a difference?
Authors: VAN ECKERT S. , GAIDYS U. , MARTIN C. R.
Published: February 2012

Accessible summary

Self‐esteem is not typically associated with nurses.

An academic nurse training can potentially increase self‐esteem.

Promoting self‐esteem in nurses should be part of academic as well as non‐academic education.

Self‐esteem is not typically associated with the nursing profession. However, the concept is indispensible for job satisfaction and good‐quality patient care. Many healthcare systems are confronted with declining numbers of qualified nurses, and desperately seek suitable strategies to recruit and retain sufficient trainees and junior staff. This investigation examined self‐esteem in 212 German nurses using the Rosenberg Self‐Esteem Scale. Nurses with an academic degree displayed a statistically significant higher level of self‐esteem than nurses without academic education (P < 0.01). The type of professional training may therefore have a direct effect on the self‐esteem, thus offering a myriad of potential benefits to both nurses and patients. Self‐esteem is a quality relevant to this profession and, as such, the findings of research in this area should be reflected in the design of nurse training curricula.
A comparison between colonic submucosa and mucosa to detect Lewy pathology in Parkinson’s disease
Authors: Pouclet H. , Lebouvier T. , Coron E. , Des Varannes S. B. , Neunlist M. , Derkinderen P.
Published: February 2012

Background  Lewy bodies and neurites (LN), the two pathological hallmarks of Parkinson’s disease (PD), are found in the enteric nervous system (ENS). Previously, we have shown that whole mounts of submucosa obtained after microdissection of colonic biopsies can be used for the detection of LN in the submucosal plexus (SMP) of PD patients. Recent reports suggest that Lewy pathology may extend beyond the submucosa to involve the digestive mucosa. The aim of the present research was to determine whether the analysis of the mucosa obtained after microdissection may help improve the sensitivity of colonic biopsies to detect Lewy pathology in the colon of PD patients.

Methods  Nine PD patients and 10 controls were included. Four biopsies were taken from the sigmoid/descending colon junction during the course of a rectosigmoidoscopy (short colonoscopy) in PD patients and during a total colonoscopy for colorectal screening in controls. Biopsies were microdissected, the mucosa was separated from the submucosa and both structures were analyzed by immunohistochemistry. Immunohistochemical analysis was performed using antibodies against phosphorylated alpha‐synuclein to detect LN and neurofilaments NF200 kDa to label the neuronal structures.

Key Results  Lewy neurites were present in the SMP of four patients and in the mucosa of three patients. Remarkably, among the patients who displayed LN within their mucosa, one was devoid of Lewy pathology in his SMP. No LN were observed in the mucosa and the SMP of controls.

Conclusions & Inferences  The parallel analysis of colonic mucosa, along with the SMP, can help detect Lewy pathology in PD.
Magnetic mineral transport and sorting in the swash‐zone: northern Lake Erie, Canada
Authors: GALLAWAY ERIC , TRENHAILE ALAN S. , CIOPPA MARIA T. , HATFIELD ROBERT G.
Published: February 2012

A combined field and laboratory study in northern Lake Erie has provided new insights into the origin and dynamics of heavy mineral placer deposits on beaches consisting primarily of non‐magnetic sediment. Work was conducted on the cross‐shore and longshore transport of heavy magnetic minerals using magnetic susceptibility and fluorescent paints to trace the movement, in the field, of samples of magnetic (magnetite) and non‐magnetic (quartz and calcite) grains, respectively. Laboratory experiments examined how the burial of small, dense magnetic minerals is affected by the grain size of the non‐magnetic host material, and how grain burial affects magnetic susceptibility measurements at the surface. The field experiments demonstrated that the magnetic mineral tracers were buried rapidly beneath coarser, non‐magnetic grains under low to moderate wave conditions, and subsequently were unable to move in the longshore or cross‐shore directions. The laboratory experiments showed that the magnetic susceptibility rapidly decreased with the rate and depth of burial of the magnetic minerals, and that magnetic grain burial was most effective beneath coarser rather than finer non‐magnetic sand and, for the latter sediments, under less rather than more energetic conditions. The results imply that magnetic mineral concentrations develop in this area through magnetic grain burial under fairly mild conditions, and subsequent settling, exposure and concentration in the upper swash zone during more energetic periods, when the non‐magnetic grains are eroded. It is probably during these erosional periods, when the magnetic minerals are exposed in fairly homogeneous deposits, that longshore and cross‐shore transport takes place.
Suboptimal patterns of provider initiated HIV testing and counselling, antiretroviral therapy eligibility assessment and referral in primary health clinic attendees in Blantyre, Malawi*
Authors: MacPherson Peter , Lalloo David G. , Choko Augustine T. , Mann Gillian H. , Squire Stephen Bertel , Mwale Daniel , Manda Eddie , Makombe Simon D. , Desmond Nicola , Heyderman Robert , Corbett Elizabeth L.
Published: February 2012

Objective:  To understand reasons for suboptimal and delayed uptake of antiretroviral therapy (ART) by describing the patterns of HIV testing and counselling (HTC) and outcomes of ART eligibility assessments in primary clinic attendees.

Methods:  All clinic attendances and episodes of HTC were recorded at two clinics in Blantyre. A cohort of newly diagnosed HIV‐positive adults (>15 years) was recruited and exit interviews undertaken. Logistic regression models were constructed to investigate factors associated with referral to start ART. Qualitative interviews were conducted with providers and patients.

Results:  There were 2398 episodes of HTC during 18 021 clinic attendances (13.3%) between January and April 2011. The proportion of clinic attendees undergoing HTC was lowest in non‐pregnant women (6.3%) and men (8.5%), compared with pregnant women (47.2%). Men had more advanced HIV infection than women (79.7% WHO stage 3 or 4 vs. 56.4%). Problems with WHO staging and access to CD4 counts affected ART eligibility assessments; only 48% completed ART eligibility assessment, and 54% of those reporting WHO stage 3/4 illnesses were not referred to start ART promptly. On multivariate analysis, HIV‐positive pregnant women were significantly less likely to be referred directly for ART initiation (adjusted OR: 0.29, 95% CI: 0.13–0.63).

Conclusions:  These data show that provider‐initiated testing and counselling (PITC) has not yet been fully implemented at primary care clinics. Suboptimal ART eligibility assessments and referral (reflecting the difficulties of WHO staging in primary care) mean that simplified eligibility assessment tools are required to reduce unnecessary delay and attrition in the pre‐ART period. Simplified initiation criteria for pregnant women, as being introduced in Malawi, should improve linkage to ART.
Training community care workers to provide comprehensive TB/HIV/PMTCT integrated care in KwaZulu‐Natal: lessons learnt
Authors: Uwimana J. , Zarowsky C. , Hausler H. , Jackson D.
Published: February 2012

Objective  To describe a participatory approach to implement and evaluate ways to integrate and train community care workers (CCWs) to enhance collaborative TB/HIV/PMTCT activities, and home‐based HIV counseling and testing (HCT) at community level.

Methods  The intervention study was conducted in Sisonke, a rural district of KwaZulu Natal, South Africa. A baseline household (HH) survey was conducted in 11 villages. Six villages were randomly selected into intervention and control clusters. Training was provided first to CCWs from the intervention cluster (IC) followed by the control cluster (CC). Routine monthly data from CCWs were collected from March–December 2010. The data was subjected to bivariate tests.

Results  The baseline HH survey revealed that of 3012 HH members visited by CCWs in 2008, 21% were screened for TB symptoms, 7% were visited for TB adherence support and 2% for ART adherence, and 1.5% were counselled on infant feeding options. A total of 89 CCWs were trained. Data show that during the study period in IC, 684 adults were offered HCT by CCWs, 92% accepted HCT and tested and 7% tested HIV‐positive and were referred to the clinic for further care. Of 3556 adults served in IC, 44% were screened for TB symptoms and 32% for symptoms of sexually transmitted infections (STIs) and 37% of children were traced as TB contact. Out of 6226 adults served in CC, 10% were screened for TB symptoms and 7% for STI symptoms. The differences in uptake of services between IC and CC were statistically significant (p < 0.05).

Conclusion  The findings of this study suggest higher uptake of TB and STI symptoms screening, TB contact tracing and home based HCT in the intervention clusters. This study suggests that up‐skilling CCWs could be one avenue to enhance TB/HIV case finding, TB contact tracing and linkages to care.
Assessment of fitness costs in Cry3Bb1‐resistant and susceptible western corn rootworm (Coleoptera: Chrysomelidae) laboratory colonies
Authors: Oswald K. J. , French B. W. , Nielson C. , Bagley M.
Published: February 2012

Abstract Maize production in the United States is dominated by plants genetically modified with transgenes from Bacillus thuringiensis (Bt). Cry3Bb delta endotoxins expressed by Bt maize specifically target corn rootworms (genus Diabrotica) and have proven highly efficacious. However, development of resistance to Bt maize, especially among western corn rootworm (Diabrotica virgifera virgifera) populations, poses a significant threat to the future viability of this pest control biotechnology. The structured refuge insect resistance management (IRM) strategy implemented in the United States for Bt maize adopts a conservative approach to managing resistance by assuming no fitness costs of Bt resistance, even though these trade‐offs strongly influence the dynamics of Bt resistance within numerous agricultural pest species. To investigate the effects of Bt resistance on fitness components of western corn rootworm, we compared survivorship, fecundity and viability of five Bt‐resistant laboratory lines reared on MON863 (YieldGard Rootworm), a Bt maize product that expresses Cry3Bb1 delta endotoxin, and on its non‐transgenic isoline. Analysis of performance on the isoline maize demonstrated no fitness costs associated with Bt resistance. In fact, resistant lines emerged approximately 2–3 days earlier than control lines when reared on both MON863 and the isoline, indicating that selection for Bt resistance resulted in a general increase in the rate of larval development. In addition, resistant lines reared on Bt maize displayed higher fecundity than those reared on the isoline, which may have significant management implications. These data will be valuable for formulating improved IRM strategies for a principal agricultural pest of maize.
Training opportunities and employee exhaustion in call centres: mediation by psychological contract fulfilment
Authors: Chambel Maria Jose , Castanheira Filipa
Published: February 2012

The aim of this study is to analyse psychological contract fulfilment as a mechanism through which training affects stress in call centres. The hypotheses were tested on a sample of 412 call centre operators, using structural equation modelling to analyse their survey responses. Our results demonstrated that training is negatively related to workers' exhaustion and that the relationship is fully mediated by the fulfilment of socio‐emotional obligations. We found that it was the fulfilment of balanced obligations, and not relational obligations, which mediated the relationship between training and exhaustion. Hence, we verified that training was related to lower levels of employee exhaustion through fulfilment of the balanced psychological contract. Our findings highlight the centrality of psychological contract fulfilment to call centre workers, and the importance of training in constructing positive employment relationships with workers. We discuss implications for human resource management in call centres.
Sources contributing to the average extracellular concentration of dopamine in the nucleus accumbens
Authors: Owesson‐White Catarina A. , Roitman Mitchell F. , Sombers Leslie A. , Belle Anna M. , Keithley Richard B. , Peele Jessica L. , Carelli Regina M. , Wightman R. Mark
Published: February 2012

J. Neurochem. (2012) 121, 252–262.

Mesolimbic dopamine neurons fire in both tonic and phasic modes resulting in detectable extracellular levels of dopamine in the nucleus accumbens (NAc). In the past, different techniques have targeted dopamine levels in the NAc to establish a basal concentration. In this study, we used in vivo fast scan cyclic voltammetry (FSCV) in the NAc of awake, freely moving rats. The experiments were primarily designed to capture changes in dopamine caused by phasic firing – that is, the measurement of dopamine ‘transients’. These FSCV measurements revealed for the first time that spontaneous dopamine transients constitute a major component of extracellular dopamine levels in the NAc. A series of experiments were designed to probe regulation of extracellular dopamine. Lidocaine was infused into the ventral tegmental area, the site of dopamine cell bodies, to arrest neuronal firing. While there was virtually no instantaneous change in dopamine concentration, longer sampling revealed a decrease in dopamine transients and a time‐averaged decrease in the extracellular level. Dopamine transporter inhibition using intravenous GBR12909 injections increased extracellular dopamine levels changing both frequency and size of dopamine transients in the NAc. To further unmask the mechanics governing extracellular dopamine levels we used intravenous injection of the vesicular monoamine transporter (VMAT2) inhibitor, tetrabenazine, to deplete dopamine storage and increase cytoplasmic dopamine in the nerve terminals. Tetrabenazine almost abolished phasic dopamine release but increased extracellular dopamine to ∼500 nM, presumably by inducing reverse transport by dopamine transporter (DAT). Taken together, data presented here show that average extracellular dopamine in the NAc is low (20–30 nM) and largely arises from phasic dopamine transients.
Finding political capital for monetary tightening: Unemployment insurance and partisan monetary cycles
Authors: ALEXIADOU DESPINA
Published: February 2012

How do governments find the political capital to raise interest rates in pursuit of inflation stabilisation? Against common wisdom, this article shows that the ability of governments to exercise tight monetary policy largely depends on the level of unemployment insurance. Unemployment insurance is particularly useful to social democratic parties since their core constituency – labour – is the hardest hit by economic downturns. Empirical evidence from 17 OECD countries over thirty years demonstrates that high levels of unemployment insurance present a strong incentive for social democratic governments to respond more aggressively to positive changes in inflation. These findings resolve the puzzle of why partisan monetary cycles are not often observed in the literature and have important policy implications, given continued calls for scaling down social insurance.
Novel developmental biology‐based protocol of embryonic stem cell differentiation to morphologically sound and functional yet immature hepatocytes
Authors: Bukong Terence N. , Lo Tracie , Szabo Gyongyi , Dolganiuc Angela
Published: February 2012

Background/Aims

Liver diseases are common in the United States and often require liver transplantation; however, donated organs are limited and thus alternative sources for liver cells are in high demand. Embryonic stem cells (ESC) can provide a continuous and readily available source of liver cells. ESC differentiation to liver cells is yet to be fully understood and comprehensive differentiation protocols are yet to be defined. Here, we aimed to achieve human (h)ESC differentiation into mature hepatocytes using defined recombinant differentiation factors and metabolites.

Methods

Embryonic stem cell H1 line was sub‐cultured on feeder layer. We induced hESCs into endodermal differentiation succeeded by early/late hepatic specification and finally into hepatocyte maturation using step combinations of Activin A and fibroblast growth factor (FGF)‐2 for 7 days; followed by FGF‐4 and bone morphogenic protein 2 (BMP2) for 7 days, succeeded by FGF‐10 + hepatocyte growth factor 4 + epidermal growth factor for 14 days. Specific inhibitors/stimulators were added sequentially throughout differentiation. Cells were analysed by PCR, flow cytometry, microscopy or functional assays.

Results

Our hESC differentiation protocol resulted in viable cells with hepatocyte shape and morphology. We observed gradual changes in cell transcriptome, including up‐regulation of differentiation‐promoting GATA4, GATA6, POU5F1 and HNF4 transcription factors, steady levels of stemness‐promoting SOX‐2 and low levels of Nanog, as defined by PCR. The hESC‐derived hepatocytes expressed alpha‐antitrypsin, CD81, cytokeratin 8 and low density lipoprotein (LDL) receptor. The levels of alpha‐fetoprotein and proliferation marker Ki‐67 in hESC‐derived hepatocytes remained elevated. Unlike stem cells, the hESC‐derived hepatocytes performed LDL uptake, produced albumin and alanine aminotransferase and had functional alcohol dehydrogenase.

Conclusion

We report a novel protocol for hESC differentiation into morphological and functional yet immature hepatocytes as an alternative method for hepatocyte generation.
Cardiac dysfunction in cirrhosis – does adrenal function play a role? A hypothesis
Authors: Theocharidou Eleni , Krag Aleksander , Bendtsen Flemming , Møller Søren , Burroughs Andrew K.
Published: February 2012

Cirrhotic cardiomyopathy (CCM), a condition of unknown pathogenesis, is characterized by suboptimal ventricular contractile response to stress, diastolic dysfunction and QT interval prolongation. It is most often found in patients with advanced cirrhosis. It is clinically relevant during stressful conditions, such as sepsis, bleeding and surgery. CCM reverses after liver transplantation and potentially has a role in the pathogenesis of hepatorenal syndrome. In adrenal insufficiency (AI), cardiac dysfunction is a feature with low ejection fraction, decreased left ventricular chamber size and electrocardiographic abnormalities, including QT interval prolongation. With optimal diagnostic tests, AI is present in approximately 10% of patients with cirrhosis, particularly in those with advanced disease. Down‐regulation and decreased number of beta‐adrenergic receptors, and high catecholamine levels are common to both cardiac conditions. Thus, AI may play a role in CCM. Steroid replacement therapy reverses cardiac changes in AI, and may do so for CCM, with important therapeutic implications; this needs formal evaluation.
Blockage of the afferent sensitive pathway prevents sympathetic atrophy and hemodynamic alterations in rat portal hypertension
Authors: Ezkurdia Nahia , Coll Mar , Raurell Imma , Rodriguez Sarai , Cuenca Silvia , González Antonio , Guardia Jaime , Esteban Rafael , Genescà Joan , Martell María
Published: February 2012

Background and Aims

Portal hypertension causes arterial vasodilation and sympathetic atrophy in the splanchnic area. We aimed to demonstrate a relationship between hemodynamic alterations and sympathetic atrophy by investigating a pathway from sensitive afferent signals to mesenteric sympathetic ganglia.

Methods

Experiments were conducted in sham and portal vein ligated (PVL) adult and neonatal rats treated with vehicle or capsaicin. Hemodynamic parameters, and immunohistochemistry, immunofluorescence and Western blot of different tissues were analysed.

Results

cFos expression in the brain supraoptic nuclei was used to confirm abrogation of the afferent signal in capsaicin‐treated PVL rats (effectively afferent blocked). Neonatal and adult PVL afferent blocked rats showed simultaneous prevention of hemodynamic alterations and sympathetic atrophy (measured by tyrosine hydroxylase expression in nerve structures of splanchnic vasculature). Not effectively afferent blocked rats showed none of these effects, behaving as PVL vehicle. All capsaicin treated animals presented loss of calcitonin gene‐related peptide in superior mesenteric artery and ganglia, whereas neuronal nitric oxide synthase remained unaffected. Neuronal markers semaphorin‐3A, nerve growth factor, its precursor and p75 neurotrophic receptor, were significantly over‐expressed in the PVL sympathetic ganglia compared with sham, but not in effectively afferent blocked rats. Semaphorin‐3A staining in mesenteric ganglia co‐localized with vesicular acetylcholine transporter, but not with adrenergic, nitrergic and sensory axons, suggesting that semaphorin‐3A might originate in preganglionic neurons.

Conclusion

These results indicate that the nervous system has a central role in the genesis of the circulatory abnormalities of portal hypertension, and support that mesenteric sympathetic atrophy contributes to splanchnic arterial vasodilation.
Early Patient Experience with an Electro‐Anatomic Navigation System Dedicated to Device Lead Implantation: Feasibility and Safety
Authors: MANLUCU JAIMIE , YEE RAYMOND , SKANES ALLAN C. , GARDESKI KENNETH C. , NEIDERT MICHAEL R. , KELLEY JAMES F. , KLEIN GEORGE J. , KRAHN ANDREW D. , GULA LORNE J. , LEONG‐SIT PETER , VERARD LAURENT G. , WU KEVIN T.
Published: February 2012

Introduction:
 Fluoroscopy‐guided pacing lead placement has well‐recognized limitations and risks. We studied the safety and feasibility of using a novel electromagnetic navigation system specifically designed to guide pacemaker and implantable cardioverter defibrillator lead placement.

Methods:
 Twenty‐four patients (mean age of 54 ± 34 years) underwent the study protocol; 16 before electrophysiology study and eight before device implantation. The navigational deflectable sheath assembly was introduced via the subclavian vein and advanced to seven prespecified targets within the right heart chambers. The time taken to reach each target site was measured.

Results:
 All seven prespecified targets were successfully reached by 21 of 24 patients (88%). The total time required to complete the study protocol ranged from 3.21 to 15.25 minutes (average 8.9 minutes), with an associated mean fluoroscopy time of 50 ± 36 seconds. In three of the 24 patients, this navigation system was successfully used to guide right ventricular pacing lead placement. The average total procedure time for these devices was 97.8 minutes (excluding the study protocol), with an average associated fluoroscopy time of 6.93 minutes. These procedures were well tolerated and no periprocedural complications were noted.

Conclusions:
 This study suggests that this novel electro‐anatomic navigation system is a viable and safe alternative to traditional fluoroscopy‐guided lead implantation. Further studies are required to determine the absolute reduction in radiation exposure and increased efficiency relative to current standard fluoroscopic techniques. PACE 2012; 35:385–391)
Oral health attitudes and behaviours of final‐year dental students
Authors: Messer L. B. , Calache H.
Published: February 2012

Objectives:  The objectives of this study of final‐year dental students in 10 classes (1997, 2001—2009) were to examine their self‐reported oral health attitudes and behaviours and describe any trends in these attributes.

Participants and methods:  Students were surveyed in final semester via an anonymous questionnaire (34 behaviour questions; eight attitude statements). Distributions, trends over time and attitude–behaviour associations were examined.

Results:  Of 583 students, 459 responded (79%). All tooth‐brushed with fluoride toothpaste; 80% brushed ≥2/day. Overall, 85% flossed; over time flossing behaviour increased significantly (P < 0.05), and those flossing 1—2/day increased (P < 0.005). Over time, significant decreases occurred in those taught toothbrushing (P < 0.001) and flossing (P < 0.05), and in use of mouth rinses (P < 0.05) and tooth cleansing sticks/picks (P < 0.001). Almost all (96%) had received a dental examination; 77% attended a dentist 1—3/year. Between‐meal snacking was common (84%); 71% chewed gum. Although 18% had ever smoked, 5% currently smoked. Most strongly agreed they expected to keep most of their teeth for all their life (76%); their future needs for fillings would be minimal (61%); smoking could adversely affect their teeth or gums (85%); and regular dental attendance was important for their dental health (51%). Congruent attitudes and behaviours favouring oral health were widely held concerning dental attendance, flossing and smoking.

Conclusions:  Final‐year dental students showed well established, favourable oral hygiene attitudes and behaviours, with evidence to suggest this knowledge was developed whilst in dental school. Despite many ceasing smoking, 5% still smoked. All dental students should receive training in motivational counselling and tobacco cessation to ensure this is included in patient care.
Intermittent granulocyte colony‐stimulating factor maintains dose intensity after ABVD therapy complicated by neutropenia
Authors: Ho Prahlad , Sherman Peter , Grigg Andrew
Published: February 2012

Introduction: Granulocyte Colony‐Stimulating Factor (G‐CSF) is commonly used to maintain dose intensity in patients receiving ABVD chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine) for Hodgkin lymphoma. However, the need for growth factor support is unclear, with studies suggesting that dose intensity can be maintained without G‐CSF. Moreover, G‐CSF is expensive (pegfilgrastim: EUR 1540/cycle; 300 μg filgrastim for 7 days: EUR 700/cycle) and is associated with side effects including bone pain and increased risk of bleomycin lung toxicity. Intermittent G‐CSF may be an effective compromise, given that the effect of G‐CSF on granulocyte precursors in vitro persists for 4–5 days after administration. After promising results of a pilot study, this schedule has been used subsequently in the majority of our patients receiving G‐CSF as secondary prophylaxis for ABVD complicated by neutropenia. Methods: Retrospective analysis of the incidence of febrile neutropenia and treatment delay in a variety of different G‐CSF schedules used as secondary prophylaxis in patients receiving ABVD. Results: 848 cycles in 85 consecutive patients were evaluated. Most patients (86%) received G‐CSF, generally commenced prophylactically for neutropenia when cycle 1B was due. Intermittent G‐CSF (typically given on days 4, 8 and 12) was used in 413 cycles compared with daily or pegylated G‐CSF in 99 cycles. In patients receiving intermittent G‐CSF, the median neutrophil count, across all cycles, was 7.3 × 109/L (range: 1.4–47.1) when the next scheduled chemotherapy was due. There were two cases of febrile neutropenia (0.45%) and no treatment delays. One patient developed possible bleomycin toxicity. Conclusions: Intermittent G‐CSF is effective in maintaining dose intensity in patients receiving ABVD.
Comparison of fresh to fixed weights of the vervet monkey (Chlorocebus sabaeus) placenta and its relation to gestational age
Authors: DeMartelly Victoria , Hurley Patrick , Lawrence Mathew , Redmond D. Eugene , Rutherford Julienne
Published: February 2012

Background  Focus on the placenta as an agent of fetal development and offspring health outcomes is growing. Primate research facilities or zoos may collect and fix placental tissue for long‐term storage, but little is known about the effects of formalin fixation on the non‐human primate placenta.

Methods  We obtained 48 vervet monkey placentas from the St. Kitts Biomedical Research Foundation. We investigated via correlation coefficients and ANOVAs the effects of gestational age and original fresh weight on weight change due to fixation. We also used linear regression models to determine whether fixed tissue weight was predictive of fresh weight and gestational age.

Results  Although the vervet monkey placenta is described as bidiscoid, 14.6% of the placentas in this sample were fused into a single mass. A decrease in weight was the most common response to formalin fixation, with the greatest degree of loss experienced by the heaviest placentas (ANOVA, F = 5.99, P = 0.005). Gestational age was unrelated to weight change. Those placentas that increased in weight had the lowest fresh weights. Fixed weights significantly predicted both fresh weight and gestational age (r2 = 0.78, P < 0.00001; r2 = 0.76, P < 0.00001, respectively).

Conclusions  This paper adds to a sparse literature on the vervet monkey placenta. That fixed placentas are excellent predictors of both fresh weight and gestational age suggests that banked tissue may be a valuable resource for reconstructing aspects of individual life history, although caution must be exercised given the variability of weight change as a function of original placental size.
Transportation behaviours of older adults: An investigation into car dependency in urban Australia
Authors: Buys Laurie , Snow Stephen , van Megen Kimberley , Miller Evonne
Published: February 2012

Aim:  Increased car dependency among Australia's ageing population may result in increased social isolation and other health impacts associated with the cessation of driving. While public transport represents an alternative to car usage, patronage remains low among older cohorts. This study investigates the facilitators and barriers to public transport patronage and the nature of car dependence among older Australians.

Methods:  Data were gathered from a sample of 24 adults (mean age = 70 years) through a combination of quantitative (remote behavioural observation) and qualitative (interviews) investigation.

Results:  Findings suggest that relative convenience, affordability and health/mobility may dictate transport mode choices. The car is considered more convenient for the majority of suburban trips irrespective of the availability of public transport.

Conclusion:  Policy attention should focus on providing better education and information regarding driving cessation and addressing older age specific social aspects of public transport including health and mobility issues.
GENERATIVE EXPLANATIONS OF CRIME: USING SIMULATION TO TEST CRIMINOLOGICAL THEORY*
Authors: BIRKS DANIEL , TOWNSLEY MICHAEL , STEWART ANNA
Published: February 2012

This study demonstrates that computational modeling and, in particular, agent‐based modeling (ABM) offers a viable compatriot to traditional experimental methodologies for criminology scholars. ABM can be used as a means to operationalize and test hypothetical mechanisms that offer a potential explanation for commonly observed criminological phenomena. This study tests whether the hypothesized mechanisms of environmental criminology are sufficient to produce several commonly observed characteristics of crime. We present an ABM of residential burglary, simulating a world inhabited by potential targets and offenders who behave according to the theoretical propositions of environmental criminology. A series of simulated experiments examining the impact of these mechanisms on patterns of offending are performed. The outputs of these simulations then are compared with several well‐established findings derived from empirical studies of residential burglary, including the spatial concentration of crime, repeat victimization, and the journey to crime curve. The results from this research demonstrate that the propositions of the routine activity approach, rational choice perspective, and crime pattern theory provide a viable generative explanation for several independent characteristics of crime.