Search

The strength of performance incentives differs for employees within an organization. We describe how differences in incentive strength can lead to pay dispersion because employees facing stronger incentives work harder and earn more pay than those facing weaker incentives. We then conduct four experiments examining how the lower-paid employees respond to such pay dispersion. Consistent with our hypothesis derived from referent cognitions theory, we find that such pay dispersion decreases the lower-paid employees' perceived fairness and thus their effort. These results hold whether the employees are assigned to or self-select into the job with weaker incentives and whether they have more explicit or less explicit information about the economic rationale for the difference in incentive strength. Our findings are inconsistent with conventional economic reasoning and refine the conclusions from prior pay dispersion studies. The robustness of our results demonstrates their generalizability to a range of actual employment settings. Data Availability: Data and experimental instruments are available upon request. JEL Classifications: M41; M52; M55.

Early disease diagnosis is key to the effective treatment of diseases. Histopathological analysis of human biopsies is the gold standard to diagnose tissue alterations. However, this approach has low resolution and overlooks 3D (three-dimensional) structural changes resulting from functional alterations. Here, we applied multiphoton imaging, 3D digital reconstructions and computational simulations to generate spatially resolved geometrical and functional models of human liver tissue at different stages of non-alcoholic fatty liver disease (NAFLD). We identified a set of morphometric cellular and tissue parameters correlated with disease progression, and discover profound topological defects in the 3D bile canalicular (BC) network. Personalized biliary fluid dynamic simulations predicted an increased pericentral biliary pressure and micro-cholestasis, consistent with elevated cholestatic biomarkers in patients’ sera. Our spatially resolved models of human liver tissue can contribute to high-definition medicine by identifying quantitative multiparametric cellular and tissue signatures to define disease progression and provide new insights into NAFLD pathophysiology. A combination of high-resolution imaging and modeling approaches facilitates the study of the mechanisms and clinical progression of non-alcoholic fatty liver disease in humans.

The developmental effects of chemicals that co-occur in vulnerable populations with elevated psychological stress are of increasing concern to the public. To investigate these concerns, we developed a rodent model of co-occurring perinatal manipulations and conducted a series of cognitive assessments in male and female offspring. Manganese (Mn), a neurodevelopmental toxicant when exceeding physiological requirements, was delivered in the drinking water (0, 2, or 4 mg Mn/mL) of rats from gestational day (GD) 7 to postnatal day (PND) 22. A variable perinatal stress paradigm was applied to half of the animals from GD13 to PND9. Novel object recognition (NOR), Morris water maze (MWM), differential reinforcement of low-rates procedure (DRL) and cued and uncued choice reaction time (CRT) tests were used to assess cognitive functions in offspring. Mn (4 mg/mL) and stress impaired NOR in adolescent males but facilitated NOR performance in females. However, when stress and Mn were combined these effects were attenuated in both sexes. During training for the DRL, Mn (2 mg/mL) facilitated, while stress impaired, lever press learning in both sexes. Few effects related to the treatments were found on DRL or MWM. During cued CRT, Mn (2 and 4 mg/mL) and stress reduced accuracy in males, while stress and Mn (2 mg/mL) increased anticipatory responding and slowed decision time in both sexes. Stress combined with Mn (2 mg/mL) improved cued accuracy and decision time, and Mn attenuated the effect of stress on anticipatory responding in both sexes. Stress slowed female movement time but when combined with Mn (4 mg/mL) the effect of stress was attenuated. During uncued CRT, except for decision time (which replicated effects observed with the cued task), no other effects of Mn or its combination with stress occurred. Females remained negatively affected by stress in most uncued CRT performance measures, while stressed improved male uncued accuracy. Taken together these data do not support increased cognitive impairment produced by Mn when combined with stress. However, the effects of perinatal stress alone, on these cognitive functions may hinder the detection of effects due to chemical exposures and underscores the need to consider the psychological health and wellbeing of the mother and her environment in risk assessment for developmental neurotoxicity of chemicals.

In neonatal intensive care units (NICUs), 87.5% of alarms by the monitoring system are false alarms, often caused by the movements of the neonates. Such false alarms are not only stressful for the neonates as well as for their parents and caregivers, but may also lead to longer response times in real critical situations. The aim of this project was to reduce the rates of false alarms by employing machine learning algorithms (MLA), which intelligently analyze data stemming from standard physiological monitoring in combination with cerebral oximetry data (in-house built, OxyPrem).Four popular MLAs were selected to categorize the alarms as false or real: (i) decision tree (DT), (ii) 5-nearest neighbors (5-NN), (iii) naïve Bayes (NB) and (iv) support vector machine (SVM). We acquired and processed monitoring data (median duration (SD): 54.6 (± 6.9) min) of 14 preterm infants (gestational age: 26 6/7 (± 2 5/7) weeks). A hybrid method of filter and wrapper feature selection generated the candidate subset for training these four MLAs.A high specificity of99% was achieved by all four approaches. DT showed the highest sensitivity (87%). The cerebral oximetry data improved the classification accuracy.Despite a (as yet) low amount of data for training, the four MLAs achieved an excellent specificity and a promising sensitivity. Presently, the current sensitivity is insufficient since, in the NICU, it is crucial that no real alarms are missed. This will most likely be improved by including more subjects and data in the training of the MLAs, which makes pursuing this approach worthwhile.

Background and aims Carriage of rs738409:G in patatin-like phospholipase domain containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with carriage of PNPLA3 rs738409:G. This study explores the risk associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. Approach and results Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including 1,031 with alcohol-related cirrhosis and HCC, 1,653 with alcohol-related cirrhosis without HCC, 2,588 alcohol misusers with no liver disease, and 899 healthy controls. Genetic associations with the risks for developing alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for developing both cirrhosis (odds ratio [OR], 0.79; 95% confidence interval [CI], 0.72-0.88; P = 8.13 × 10-6 ) and HCC (OR, 0.77; 95% CI, 0.68-0.89; P = 2.27 × 10-4 ), whereas carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR, 1.70; 95% CI, 1.54-1.88; P = 1.52 × 10-26 ) and HCC (OR, 1.77; 95% CI, 1.58-1.98; P = 2.31 × 10-23 ). These associations remained significant after adjusting for age, sex, body mass index, type 2 diabetes, and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women, but the protective effect against the subsequent development of HCC was only observed in men (ORallelic , 0.75; 95% CI, 0.64-0.87; P = 1.72 × 10-4 ). Conclusions Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of HCC in this population.

It seems that the issues of periodization do not feature amongst the popular topics of discussion in the science of history. However, important accounts of this subject have been published. It has been made clear in the process that periodization is bound to certain spaces. The periodization of European history is different from the one of Chinese or African history. Furthermore, periodizations are didactic necessities: every account requires a temporal structuring. The most important aspects of periodization theories will be pointed out, followed by an analysis of their application in new Swiss syllabi and teaching materials.

Background Antibiotic resistance is now a global emergency. An increasing number of infections are becoming difficult to treat and lead to longer hospitalizations, higher medical costs and increased mortality. The aim of this study is to assess, in a population at low prevalence of use of antibiotics, whether a previous use of these drugs is associated with the occurrence of clinically relevant resistance of E.coli to fluoroquinolones (FQs), one of the most widespread and critical bacteria resistance in Italy. Methods Through a data linkage of databases of the health information systems of the Province of Bolzano (Italy) a case-control study was carried out using 2016 data. All subjects for which the resistance of E. coli to FQs was tested by the regional microbiology reference laboratory were included in the study. Those with a positive FQs-resistant E.coli isolate were defined as cases (n = 409), while the others were considered controls (n = 933). For each subject the total number of prescriptions of any antibiotics and the total number of prescriptions of FQs in the previous year were detected through a record linkage with the drug prescription database. Information on potential confounding factors (age, gender, number of hospital admissions, days of hospitalization, number of surgeries, diagnosis of chronic diseases) were obtained from the database of hospital admissions. Multivariate logistic regression analysis was used to study the association between previous use of antibiotics (any and FQs only) and development of E.coli resistance to FQs. Results It was observed that for each unit increase in the number of prescriptions of any antibiotic, the probability for E.coli to develop FQs resistance significantly rises by 16%. This probability is much higher (45%) if the prescribed antibiotic is a FQ. Conclusions This study confirms the association between previous consumption of antibiotics and the onset of resistance even in an area with a low prevalence of use. Key messages The results of this study reiterate the need to prescribe and dispense antibiotics only when they are really needed. Health information systems allows to study the role of antibiotic use in the development of bacterial resistance, providing useful information for audit interventions among healthcare professionals.

A deeper epigenomic understanding of spatial organization of cells in human tissues is an important challenge. Here we report the first combined positional analysis of transcriptomes and methylomes across three micro-dissected zones (pericentral, intermediate and periportal) of human liver. We identify pronounced anti-correlated transcriptional and methylation gradients including a core of 271 genes controlling zonated metabolic and morphogen networks and observe a prominent porto-central gradient of DNA methylation at binding sites of 46 transcription factors. The gradient includes an epigenetic and transcriptional Wnt signature supporting the concept of a pericentral hepatocyte regeneration pathway under steady-state conditions. While donors with non-alcoholic fatty liver disease show consistent gene expression differences corresponding to the severity of the disease across all zones, the relative zonated gene expression and DNA methylation patterns remain unchanged. Overall our data provide a wealth of new positional insights into zonal networks controlled by epigenetic and transcriptional gradients in human liver., Spatial mapping of genomic programs in tissue cells is an important step in the understanding of organ function and disease. Here, the authors provide a spatially resolved epigenomic and transcriptomic map of human liver and show porto-central gradients in metabolic and morphogen networks and transcription factor binding sites as a basis to better understand liver regeneration and function.

Shareholder litigation is an important part of the regulation of securities markets that can influence corporate managers' reporting behavior. Prior research shows that conventional economic factors affect investors' litigation decisions. We use experimental markets to examine whether investors engage in costly litigation even without a direct financial incentive to do so and whether this affects managers' reporting decisions and managers' and investors' welfare. We find that investors frequently litigate when they can impose a financial penalty on managers for misreporting even though they cannot recover their legal fees or receive restitution for their losses. Moreover, this deters managers' shirking and misreporting and improves managers' and investors' welfare almost as effectively as when investors can recover their legal fees and receive restitution for their losses. Overall, our results indicate that, in addition to financial incentives, investors' desire to punish misreporting plays an important role in their litigation decisions, and that may yield substantial welfare benefits.

Although managers’ green investments have no impact on future cash flows in our experimental markets, investors respond favorably when managers make and disclose an investment and highlight the societal benefits rather than the cost to the company. Managers anticipate investors’ reaction and therefore often disclose their investment and the associated societal benefits. Managers and other shareholders benefit from investors’ reaction, but the investment cost always exceeds this benefit, demonstrating that managers make green investments because they value the societal benefits. Collectively, our findings show that both investors and managers tradeoff wealth for societal benefits and help explain managers’ corporate social responsibilty disclosures.

This article is based on a panel discussion of accounting and sustainability at the AAA 2014 Management Accounting Section Midyear Meeting. It first provides background and motivation for the original panel and then presents the three panelists' remarks, which have been further extended in developing this article. The article therefore consists primarily of three essays. The first essay discusses the information on which CSR decisions could be based, emphasizing the role of regulation in promoting the production of new types of information. The second essay discusses how to assess the rationality of CSR investments. The third essay approaches the question of the rationality of CSR initiatives by first drawing an analogy to investments in customer satisfaction and quality improvement and then by considering the role of incentives and performance measures in driving sustainability. The latter two essays also provide specific guidance for experimental, archival, and field researchers interested in researching sustainability.

Firms have increasingly adopted open work environments. Although openness is thought to have benefits, it could also expose firms to an unanticipated cost. An open (closed) internal reporting environment makes it more (less) likely that managers will observe a colleague's communications with senior executives. This increase in what one manager knows about another manager's communication to senior executives could facilitate employee collusion to extract resources from the firm. To test whether internal reporting openness results in more collusion, we conduct an experiment in which two managers each make separate reports to the firm about cost information they know in common but that remains unknown by the firm. Because both managers face the same truth-inducing contract, conventional economic theory predicts that they will not collude to misreport costs regardless of reporting openness. However, using behavioral theory involving trust and reciprocity, we predict and find that managers honor their nonbinding collusive agreements and successfully collude more often in an open versus closed internal reporting environment, leading to lower firm welfare in the open environment. These results suggest that firms should consider how the cost of collusion compares to the benefits of openness.

We provide a list of points to consider (PTCs) to help researchers self-assess whether they have addressed certain common issues that arise frequently in accounting research seminars and in reviewers’ and editors’ comments on papers submitted to journals. Anticipating and addressing such issues can help accounting researchers, especially doctoral students and junior faculty members, convert an initial empirical accounting research idea into a thoughtful and carefully designed study. Doing this also allows outside readers to provide more beneficial feedback rather than commenting on the common issues that could have been dealt with in advance. The list, provided in the appendix, consists of five sections: Research Question; Theory; Contribution; Research Design and Analysis; and Interpretation of Results and Conclusions. In each section, we include critical items that readers, journal referees, and seminar participants are likely to raise and offer suggestions for how to address them. The text elaborates on some of the more challenging items, such as how to increase a study's contribution, and provides examples of how such issues have been effectively addressed in previous accounting studies

We conduct an experiment to examine investment professionals’ use of corporate social responsibility (CSR) disclosures when making personal investment decisions or Investment recommendations to clients. We predict and find that investment professionals are more willing to personally invest and recommend investment to a client when a firm discloses positive CSR performance than when it makes no CSR disclosures. Investment professionals’ decisions and recommendations are influenced by CSR disclosures both because, on average, they believe that better CSR performance results in better current and longer-term financial performance and because they value the societal benefits of CSR activities. We also find that Investment professionals’ general beliefs regarding whether CSR activities benefit society affect how they assess firms’ CSR performance and their view of the relation between CSR performance and financial performance. Finally, investment professionals’ experience appears to protect them from the potential biasing effect of appealing pictures that accompany many CSR disclosures.

Conventional economics assumes workers provide the same effort under penalty contracts and economically equivalent bonus contracts. However, prior research finds that although workers prefer bonus contracts, they provide more effort under penalty contracts. Given these findings, the prevalence of bonus contracts in practice is puzzling. If penalty contracts yield more worker effort, why would employers not use them more often? We conduct experimental labor markets to test whether the prior finding of more effort under penalty contracts than bonus contracts (i.e., the contract frame effect) persists when workers can choose their contract and know that their employer intentionally offered the contract they choose. As predicted, these features of labor markets eliminate the difference in effort between penalty and bonus contracts reported in prior studies. This finding suggests employers may use bonus contracts more often than penalty contracts because they can offer the contract most workers prefer without sacrificing worker effort.

Prior research suggests that pay dispersion among employees can cause lower-paid employees to feel unfairly treated and thus lower their effort. Recently, some firms have reduced pay dispersion by raising lower-paid employee’s wages in an attempt to mitigate this effect. However, popular press articles suggest that reducing pay dispersion could also cause higher-paid employees to leave the firm. We conduct a series of experiments to examine the effect of reduced pay dispersion on lower-paid employees’ effort and higher-paid employees’ turnover intentions. In Experiment 1, we find that reducing pay dispersion can increase lower-paid employees’ effort by increasing their perceived pay fairness. We also show that it is the reduction in pay dispersion rather than merely the increase in the lower-paid employees’ wages that yields these results. In Experiment 2, we replicate the results of our first experiment without collecting data on perceptions of pay fairness to ensure that the results of the first experiment were not the result of demand effects. Finally, in Experiment 3 we find that, contrary to concerns expressed in the popular press, higher-paid employees indicate that they are not more likely to leave the firm for a comparable job when lower-paid employees’ wages are increased, and may even be less likely to leave. Our results suggest that firms should consider whether the benefit of increased effort from the lower-paid employees is worth the extra cost they incur by increasing their wages.

Firms frequently attempt to increase profits by replacing some existing workers with new lower-wage workers. However, this strategy may be ineffective in an incomplete-contract environment because the new workers may provide lower effort in response to their lower wages, and hiring new lower-wage workers may damage the remaining original workers' reciprocal relationship with the firm. We conduct an experiment to examine this issue and find that when new lower-wage workers become available, firms hire them to replace original higher-wage workers and pay the new workers lower wages. However, these lower wages do not improve firm profit because the decision to hire new lower-wage workers causes both the new and remaining workers to provide lower effort. Moreover, hiring lower-wage workers reduces new workers' payoffs and, thus, decreases social welfare. These unintended consequences suggest that firms should consider both the wage savings and the potential costs when deciding whether to replace some workers with new lower-wage workers. We discuss the implications of our findings for contract design, hiring practices, and managerial accountants.

Prior research finds that workers prefer bonus contracts, but provide more effort when assigned to penalty contracts. We extend this research by examining an endogenous labor market where employers offer contracts and workers choose a contract and effort level. We also vary whether employers have discretion over contract offers to isolate how employers’ intentions influence the effect of workers having a choice. When employers did not intentionally offer a contract, worker choice did not affect effort, but as in prior studies, effort was higher under the penalty contract. However, in our fully endogenous market that is most like the natural environment, we find that workers provide more effort when they can choose their contract, and that after controlling for worker choice, bonus and penalty contracts do not affect effort differently. Thus, employers may want to provide workers a choice of contracts to achieve higher worker effort at an equivalent cost.

I accepted the invitation to present my thoughts to the American Accounting Association Executive Committee on whether accounting research has become stagnant for several reasons. First, I believe the question is important because the answer has widespread implications, one of which is the extent to which accounting research will remain an important part of the accounting academic profession in the years to come. In order to maintain the current stature of accounting research or to increase its importance, we need to ensure that we produce research that someone cares about. Second, there appears to be a growing sentiment among some accounting researchers that much of the research currently published in the top accounting journals is too similar, with too much emphasis on technique rather than on whether the research addresses an interesting or important question. My final reason was more self-serving. I thought this would provide a good opportunity to reflect on an important issue, and that committing to share my thoughts in a public forum would force me to give the issue the serious consideration it warrants. My comments below describe some conclusions I reached based on what others have written about this issue, discussions with colleagues, and my own reflections.

SYNOPSIS Analytical models can quite naturally complement empirical data, whether archival or experimental. This article begins by discussing the advantages and disadvantages of combining an analytical model with archival or experimental data in a single study. We next describe how models are typically used in empirical research and discuss when including an analytical model is more versus less useful. Finally, we offer examples of more and less successful combinations of analytical models and empirical data, along with a brief discussion of how such studies are likely to fare in the journal review process. JEL Classifications: C02; C51; C99.

M ost companies try to project an image of corporate social responsibility (CSR), often by voluntarily supplementing their annual financial reports with separate CSR reports. Because such CSR reports represent additional disclosures, accounting researchers have become increasingly interested in the role that such disclosures play in firm valuation. The fundamental importance of CSR issues in accounting research is evidenced by the two articles in this Forum (Dhaliwal et al. 2012; Kim et al. 2012), as well as by other recent CSR articles published in The Accounting Review (Dhaliwal et al. 2011; Balakrishnan et al. 2011; Simnett et al. 2009) and other outlets. Traditionally, scholars have considered two broad perspectives on CSR. Economics, finance, and accounting researchers (e.g., Friedman 1970; Shank et al. 2005; Dhaliwal et al. 2011), as well as some writers in the financial press (Karnani 2010), have typically taken the perspective that companies will, or should, only engage in socially responsible activities when doing so maximizes shareholder value. However, there is also a long history of an alternative perspective advocated by

The preferences of students with autism for watching themselves, a familiar adult, or a familiar peer in video recordings were examined. A multi-stimulus video preference assessment was used to evaluate the preferences of five students with autism. Three video options of a preferred activity (e.g., vacuuming) or daily/routine activity (e.g., snack time) were available to students via a computer-based program. Results showed that collectively there was minimal difference between the three video choices across the five students. However, in their individual scores, preferences varied among the students and activities, providing a framework for discussion of individual preference assessments when using video for instructional programs and reinforcement of task performance and behavior.

Optimal agency contracts pay the lowest wage necessary to induce profit-maximizing effort. Employees could view such contracts as violating reciprocity because, relative to more reciprocal contracts, they offer a lower wage in exchange for higher effort. Consequently, the profit-maximizing effectiveness of optimal contracts could be impaired if employees reject them or reduce their effort. We use experimental labor markets to examine (1) how employees respond to an optimal versus a suboptimal reciprocity-based contract when each contract is the only contract available, (2) how employees respond to these contracts when firms choose which one to offer, (3) whether the firms' contract offers depend on employees' reactions to those offers, and (4) how employees and firms react to a hybrid contract that incorporates features of both contracts. We find that the optimal contract is less effective than agency analysis predicts, the reciprocity-based contract can be equally effective, and the hybrid contract dominates a market in which all three contracts are available. Implications of these results are discussed.

A series of participative budgeting experiments has examined the effect of incentive structures and/or information environments on employees' reporting and production decisions. We analyze the previous experiments in terms of the insights they offer regarding agency theory. We expand the previous analyses of the incentive contracting experiments in three ways. First, we classify the earliest set of participative budgeting experiments based on the type of incentive and information structures examined in each study. Second, from the 21 papers we review, we identify eight specific cases for which the experimental evidence contradicts an agency theory prediction (i.e., anomalies). Third, we develop a classification scheme that can be used to organize hypotheses in terms of whether they rely on an agency theory prediction, a competing behavioral prediction, or a combination of the two. We use this classification to illustrate why we believe that studies that test both an agency theory prediction and a competing behavioral prediction are more likely to advance the development of theory than those that do not.

Monocytes are pluripotent cells of the immune system, circulate in the blood and cross the blood–brain barrier continuously through life. The aim of this study was to explore if primary rat monocytes can adhere and transmigrate at a monolayer of brain capillary endothelial cells (BCEC) and if the monocytes undergo differentiation toward a microglial phenotype at the basolateral side. Monocytes and as a control primary microglia were immunohistochemically stained with markers for CD68 (clone ED-1), CD11b (clone OX-42) or CD11c (clone 8A2). The primary rat monocytes (100,000 cells added) adhered at the BCEC-monolayer (approx. 1200 cells/well) within 30 min and migrated to the basolateral side within 18 h (approx. 40,000 cells/well). The transmigrated monocytes partly differentiated and expressed microglia-markers at the basolateral side. Tumor necrosis factor-alpha as well as conditioned medium derived from BCEC stimulated the differentiation of monocytes in culture. In conclusion, monocytes adhere and migrate through a BCEC-monolayer and express microglia-markers at the basolateral side.

In older adults co-occurrence of multiple diseases often leads to use of multiple medications (polypharmacy). The aim of the present study is to describe how prescription of medications varies across age groups, with specific focus on the oldest old.We performed a cross-sectional study using 2013 data from the OsMed Health-DB database (mean number of medicines and defined daily doses prescribed in 15,931,642 individuals). There were 3,378,725 individuals age 65 years or older (21.2% of the study sample).The mean number of prescribed medications progressively rose from 1.9 in the age group65 years to 7.4 in the age group 80-84 years and then declined, with a more marked reduction in the age group 95 years or older with a mean number of 2.8 medications. A similar pattern was observed for the mean number of defined daily doses. Among participants age ≥65 years, proton pump inhibitors were the most commonly prescribed medication (40.9% of individuals ≥65 years), followed by platelet aggregation inhibitors (32.8%) and hydroxy-methylglutaryl-coenzyme A reductase inhibitors (26.1%). A decline in prescription was observed among individuals age 90 years or older, but this reduction was less consistent for medications used to treat acute conditions (ie, antibiotics and glucocorticoids) rather than preventive medicines commonly used to treat chronic diseases (ie, antihypertensive medications and hydroxy-methylglutaryl-coenzyme A reductase inhibitors).The burden of medication treatment progressively increases till age 85 and substantially declines after age of 90 years. Patterns of medication prescription widely vary across age groups.

Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis in the brain and has recently been shown to possess neuroprotective activity. The aim of the present study was to observe if VEGF can counteract the excitotoxic N-methyl-D-aspartate (NMDA)-induced cell death of cholinergic neurons of the basal nucleus of Meynert in vivo in adult rats. Immunohistochemistry was used to detect vascular structures (RECA-1 or laminin staining) and cholinergic neurons (choline-acetyltransferase). To compare the in vivo VEGF effects also in vitro, VEGF was applied to axotomized cholinergic neurons in organotypic brain slices with or without NMDA. Our data provide evidence that VEGF counteracted cell death in vivo in adult rats but did not protect cholinergic neurons in developing brain slices. Nerve growth factor protected cholinergic neurons in vivo as well as in vitro. In conclusion, VEGF exhibits neuroprotective activity on adult cholinergic neurons of the basal nucleus of Meynert.

This study examines whether constraining experienced auditors’ processing by having them process evidence in a pre-established sequence (an experimental control technique used in previous studies) prevents them from using their usual processing strategies and thereby affects their judgments. We compare the relative attention to evidence and judgments of experienced and inexperienced auditors in a constrained versus an unconstrained processing condition. Consistent with expectations, experienced auditors’ going-concern judgments differed from inexperienced auditors’ judgments only when processing was unconstrained. This difference in judgments was the result of differential attention to evidence. These results demonstrate that the failure to consider how experienced auditors process evidence can result in inadvertently adopting control techniques that limit the generalizability of experimental findings. Although our study used a going-concern task, our conclusions are likely to apply to a variety of ill-structured audit tasks that require a goal-oriented, directed evaluation of evidence.

Angiogenesis plays an important role during development of the brain and under pathological conditions. The aim of the present study was to observe interaction of brain capillaries and cholinergic neurons in organotypic brain slices. Immunohistochemistry was used to visualize brain capillary-like structures (RECA-1 antigen) and cholinergic neurons (choline acetyltransferase). Under normal culture conditions, a very low number of brain capillaries was found in 2- and 4-week-old cortex brain slices. Treatment of slices with acidic medium (pH 6) or hyperthermia (42 degrees C) markedly enhanced the number of brain capillaries. Incubation with 10 ng/mL vascular endothelial growth factor only enhanced angiogenesis in more developed slices. Cholinergic neurons survived in slices of the basal nucleus of Meynert; however, hyperthermia but not acidosis markedly decreased their number. In coslices of the basal nucleus of Meynert and cortex (pretreated with acidic medium), a high number of RECA-1-positive capillaries and cholinergic neurons persisted and displayed strong nerve fibre growth of cholinergic fibres into the cortex. In conclusion, we have demonstrated that RECA-1-positive capillaries and cholinergic neurons can be studied in slice cultures in the absence of blood perfusion, and that this model could provide a system to study mechanisms involved in vascular dementia.

Recent evidence indicates that glial cell line-derived neurotrophic factor (GDNF) may influence microglial survival, proliferation, and activation, but this has not yet been tested on isolated primary microglia. We compared the effects of individual and combined application of 10 ng/ml GDNF and 1 ng/ml transforming growth factor-beta1 (TGF-beta1) on total cell number, 5-bromo-2'-deoxyuridine (BrdU) incorporation, DNA nick-end labelling (TUNEL staining), and nitrite and lactate dehydrogenase (LDH) secretion in serum-free cultures of primary rat microglia. GDNF as well as TGF-beta1 enhanced the total number of lectin-positive cells and decreased the number of TUNEL-positive nuclei, while no effect on proliferation was observed. Both factors suppressed the secretion of nitrite during the first 4 days of culturing, and GDNF but not TGF-beta1 reduced the secretion of LDH in 2-week-old cultures. These findings suggest that GDNF and TGF-beta1 support survival of primary microglia in vitro.

Microglial activation and proliferation occur in nearly all forms of brain injury. The aim of this study was to investigate the influence of glial cell-line derived neurotrophic factor (GDNF) on proliferation and/or survival in a GMIR1 rat microglial cell line, which proliferates in response to granulocyte-macrophage-colony stimulating factor (GM-CSF). Endogenous GDNF and its receptor, GFRalpha-1, were detected in GMIR1 cells by ELISA and immunohistochemistry/Western blot, respectively. Recombinant GDNF strongly enhanced GMIR1 cell numbers and BrdU-incorporation, an effect inhibited by GDNF blocking antibodies. Inhibition of cAMP/cGMP dependent protein kinase enhanced the GDNF-induced GMIR1 cell number. The results suggest that GDNF has synergistic survival promoting effects on microglia potentially via autocrine mechanisms.