bluuebunny/crossref_metadata_2025 huggingface dataset:
Creation of a Knowledge Management System for QT Analyses
Authors: Tornøe Christoffer W. , Garnett Christine E. , Wang Yaning , Florian Jeffry , Li Michael , Gobburu Jogarao V.
Published: October 2010

An increasing number of thorough QT (TQT) reports are being submitted to the US Food and Drug Administration's interdisciplinary review team for QT (IRT‐QT), requiring time‐intensive quantitative analyses by a multidisciplinary review team within 45 days. This calls for systematic learning to guide future trials and policies by standardizing and automating the QT analyses to improve review efficiency, provide consistent advice, and enable pooled data analyses to answer key regulatory questions. The QT interval represents the time from initiation of ventricular depolarization to completion of ventricular repolarization recorded by electrocardiograph (ECG) and is used in the proarrhythmic risk assessment. The developed QT knowledge management system is implemented in the R package “QT.” Data from 11 crossover TQT studies including time‐matched ECGs and pharmacokinetic measurements following single doses of 400 to 1200 mg moxifloxacin were used for the QT analysis example. The automated workflow was divided into 3 components (data management, analysis, and archival). The generated data sets, scripts, tables, and graphs are automatically stored in a queryable repository and summarized in an analysis report. More than 100 TQT studies have been analyzed using the system since 2007. This has dramatically reduced the time needed to review TQT studies and has made the IRT‐QT reviews consistent across reviewers. Furthermore, the system enables leveraging prior knowledge through pooled data analyses to answer policy‐related questions and to understand the various effects that influence study results.
Analyses of heat recovery devices in the HVAC system in an operating theatre in the tropics
Authors: Yau YH
Published: October 2010

The air-conditioning system is the major electricity consumption for the non-domestic buildings. A significant part of energy savings can be achieved if heat recovery technologies such as run-around coils, plate-to-plate heat exchangers, heat recovery wheels and heat pipe heat exchangers are incorporated into the ACMV system of these buildings. Non-domestic buildings, such as hospitals, expense even more energy as the supply of fresh air into the space is deemed necessary. For example, air must be changed at least 25 times hourly and recirculation of RA is prohibited for the operating theatres. Therefore, an operating theatre of a hospital in a tropical climate country was chosen for this research. The performance of the existing air-conditioning system has been thoroughly studied to investigate the potential in energy savings in the building. The transient system simulation program (TRNSYS) was used to analyse the air-conditioning system incorporated with heat recovery devices. Generally, there are eight heat recovery systems analysed using TRNSYS, which divided into two groups: the heat recovery ventilating system and heat recovery dehumidification system. The energy savings, payback period, dehumidification enhancement, stability of indoor air conditions and preventing the cross contamination, for each of the systems, were analysed in comparison to each other. Based on this study, it is recommended that the heat recovery systems should be installed to enhance moisture removal and reduce energy usage of HVAC system operating in hospitals.

Practical application: The good amount of technical information of real application conducted on heat recovery devices installed in HVAC systems in operating theatres in the tropics could be used as a comprehensive guide for building services engineers and researchers who are intending to apply heat recovery devices as ‘coolness’ recovery and dehumidification devices in HVAC systems operating in tropical countries.
How the internet is changing the implementation of traditional research methods, people’s daily lives, and the way in which developmental scientists conduct research
Authors: Denissen Jaap J.A. , Neumann Linus , van Zalk Maarten
Published: October 2010

Recent years have seen an impressive increase in web-based research, of which we review and discuss two main types. First, researchers can create online versions of traditional questionnaires. Using the internet in this way usually does not compromise the psychometric properties of such measures, and participants are typically not less representative of the general population than those of traditional studies. Technical guidelines are provided to set up such studies, and thorny issues such as participants’ anonymity are discussed. We will also discuss issues regarding the assessment of minors and the repeated assessment of participants to assess developmental changes via the web. Second, the internet has changed the way people interact with each other. The study of the psychosocial consequences of this development is called cyberpsychology. We review emerging findings from this young discipline, with a focus on developmentally-relevant implications such as the use of the internet by adolescents to disclose personal information.
Schizophrenia, reification and deadened life
Authors: Morgan Alastair
Published: October 2010

Recent debates concerning the abolition of the schizophrenia label in psychiatry have focused upon problems with the scientific status of the concept. In this article, I argue that rather than attacking schizophrenia for its lack of scientific validity, we should focus on the conceptual history of this label. I reconstruct a specific tradition when exploring the conceptual history of schizophrenia. This is the concern with the question of the sense of life itself, conducted through the confrontation with schizophrenia as a form of life that does not live, or as Robert Jay Lifton termed it ‘lifeless life’ (1979: 222—39). I conclude by arguing that the contemporary attempt to deconstruct or abolish the schizophrenia concept involves a fundamental shift in concern. The attempt both to normalize psychotic experiences, and to conceive them purely in terms of cognitive processes that can be mapped onto brain function, results in a fundamental move away from the attempt to understand the experience of madness.
The Las Vegas Thesis
Authors: Sughrua William
Published: October 2010

Following “reflexive ethnography” and utilizing an approach of “performative narrative” and “layered text”, this article explores how Bachelor of Arts students in the Teaching of English as a Foreign Language program at a public university in Mexico successfully manage the writing of an inductive-oriented thesis in English by resisting bibliographic research. This becomes the theme that is “enacted” or “dramaticized” through a crossover narrative of fictionalization, classroom action research, autobiography, and Camusian philosophy.
Perpetrators of Intimate Partner Sexual Violence: Are There Unique Characteristics Associated With Making Partners Have Sex Without a Condom?
Authors: Purdie Michele Parkhill , Abbey Antonia , Jacques-Tiura Angela J.
Published: October 2010

This study examined correlates of making an intimate partner engage in unprotected sex among perpetrators of sexual violence. Based on the Confluence Model, we hypothesized that power and impersonal sex motives would be higher among perpetrators who made a dating partner have unprotected sex. Among a subsample of 78 male college students, significant differences were found for acceptance of verbal pressure, positive attitudes about casual sex, frequency of sexual intercourse, and physical injuries to dating partners. These findings highlight the importance of integrating theories and interventions directed at sexual assault and sexual risk reduction.
Domestic Violence and Sexual Assault Agency Directors’ Perspectives on Services That Help Survivors
Authors: Macy Rebecca J. , Giattina Mary C. , Montijo Natalie Johns , Ermentrout Dania M.
Published: October 2010

Community-based domestic violence and sexual assault service providers need sound knowledge regarding services that work well to improve the lives of survivors. This exploratory, qualitative research aimed to help provide such knowledge by investigating domestic violence and sexual assault agency executive directors’ ( n = 14) opinions regarding what services are most helpful for survivors. In-depth interviews with directors provided findings about (a) critical services for survivors; (b) essential service delivery practices; (c) ideal services that are challenging to deliver because of funding and other barriers; and (d) areas of service delivery practice uncertainty due to a lack of best practices.
Reading Performance as a Function of Treatment With Lisdexamfetamine Dimesylate in Elementary School Children Diagnosed With ADHD
Authors: Wigal Sharon B. , Maltas Stephanie , Crinella Francis , Stehli Annamarie , Steinhoff Kenneth , Lakes Kimberley , Schuck Sabrina
Published: October 2010

Background: Medication treatment studies of ADHD have typically not assessed effects on reading performance, although reading difficulties frequently co-occur in children with ADHD. The current study characterizes the effects of lisdexamfetamine dimesylate (LDX; Vyvanse®, Shire US Inc.), at peak efficacy, on reading performance in children with ADHD. Method: Children (ages 6-12; N = 26) with ADHD enrolled in a modified laboratory school study with an open-label, dose-optimization phase of LDX (30-70 mg/d). The Gray Oral Reading Test-4 (GORT-4) with measures of rate, accuracy, and comprehension was administered at baseline and 3-4 hr postdose, following 4 to 5 weeks of optimal dose titration. Results: Treatment reduced ADHD symptoms. Reading rate was improved, especially among children with higher verbal fluid reasoning without additional symptoms of neurodevelopmental delay. No differences were observed for reading accuracy or comprehension. Conclusion: Endophenotypical profiles may predict drug effects in specific skill areas, such as reading rate.
Personality Disorders and Clinical Syndromes in ADHD Prisoners
Authors: Gudjonsson Gisli H. , Wells June , Young Susan
Published: October 2010

Objective: The main objective of this article is to investigate the type of personality disorders and clinical syndromes (CSs) that were best related to ADHD symptoms among prisoners. Method: The authors screened for childhood and adult ADHD symptoms and administered the Millon Clinical Multiaxial Inventory–III (MCMI-III) to 196 serving prisoners. Results: Childhood and adult ADHD symptoms were most strongly related to the compulsive (negative relationship) and borderline (positive relationship) scales on the MCMI-III with large and medium effect sizes, respectively. Hierarchical multiple regressions revealed that the absence of compulsive personality disorder traits (i.e., a low score as a dimension) was the single best Axis II predictor of childhood and adult ADHD symptoms. CSs did not add significantly to the variance in childhood ADHD beyond that of the personality disorder dimensions, but it did so for current ADHD symptoms in relation to alcohol dependence. Conclusion: The findings demonstrate the relative absence of compulsive personality disorder traits in prisoners with ADHD symptoms as core maladaptive traits involving disorganization.
Depression and Anxiety Among Transitioning Adolescents and College Students With ADHD, Dyslexia, or Comorbid ADHD/Dyslexia
Authors: Nelson Jason M. , Gregg Noel
Published: October 2010

Objective: To investigate depressive and anxious symptomatology among transitioning adolescents and college students with ADHD, dyslexia, or comorbid ADHD/dyslexia. Method: Transitioning adolescents and college students with these disorders along with a non-ADHD/dyslexia college sample completed self-report measures of depression and anxiety. Results: Results indicated no differences between the college-level groups, although a main effect for gender was found and trended toward females with dyslexia reporting more symptoms of depression and anxiety than did males with dyslexia. Internalizing symptomatology differences were not found for subtypes of ADHD. Transitioning high school students with ADHD, dyslexia, or ADHD/dyslexia reported fewer symptoms of anxiety and depression than did college underclassmen with these disorders. Conclusion: The unique characteristics and experiences of the college population of individuals with ADHD and/or dyslexia are discussed relative to the general adult population with these disorders.
The Impact of the Year-Round School Calendar on the Family Vacation: An Exploratory Case Study
Authors: Peercy Margaret A. , McCleary Ken W.
Published: October 2010

This article explores how the family vacation and the family vacation decision process have changed due to the implementation of year-round school in a Midwestern school system in the United States. A total of 96 families responded to a mail survey that dealt with the characteristics of the family vacation before and after the implementation of year-round school. The results indicate that year-round school has had a significant impact on vacation patterns. Implications for tourism are discussed.
Using Large-Scale Databases in Evaluation: Advances, Opportunities, and Challenges
Authors: Penuel William R. , Means Barbara
Published: October 2010

Major advances in the number, capabilities, and quality of state, national, and transnational databases have opened up new opportunities for evaluators. Both large-scale data sets collected for administrative purposes and those collected by other researchers can provide data for a variety of evaluation-related activities. These include (a) identifying or highlighting issues that invite greater client attention; (b) establishing the plausibility of policy theories of action; and (c) program evaluation. The authors illustrate through examples from the fields of education, social services, and public health both the opportunities provided by higher quality, interoperable data systems and the challenges encountered when using databases to identify issues of concern, test the plausibility of a proposed theory of action, or evaluate an existing program. The authors then explore implications for roles evaluators may need to play to support these uses of databases and for funding and infrastructure to support greater evaluator involvement in program planning and improvement.
Complementary Medicine Use by Middle-aged and Older Women
Authors: Sarris J. , Goncalves D.C. , Robins Wahlin T.-B. , Byrne G.J.
Published: October 2010

This study analysed NEO Five Factor Inventory (NEO-FFI) personality trait data in middle-aged and older Australian women and their CAM usage. Participants were women from the Longitudinal study of Ageing in Women (LAW study) aged 47 to 87 years ( N = 419). Only the NEO-FFI trait of Openness was significantly correlated with cumulative CAM product use. Regression models revealed that number of specialists’ consultations, number of CAM products used and reported level of physical and leisure activities were predictive of CAM therapy use; while age was predictive of CAM product use.
Mixed Methods in Health Psychology
Authors: Dures E. , Rumsey N. , Morris M. , Gleeson K.
Published: October 2010

This article has two purposes: to examine why mixed methods is a legitimate approach particularly well suited to health psychology; and to describe the challenges inherent in conducting mixed methods research. First, arguments justifying the status of mixed methods as a third paradigm alongside solely quantitative and qualitative frameworks are discussed. Second, a qualitatively driven model of mixed methods is illustrated using examples from a research programme exploring the psychosocial impact of a rare, genetic skin disorder. The flexibility of a mixed methods approach enables the researcher to be responsive to a range of issues, but it is important the approach is used thoughtfully and appropriately.
Stimulating Stuff: The Pathological Effects of Cocaine and Amphetamines on the Cardiovascular System
Authors: Macmahon Michael J , Tallentire Vicky R
Published: October 2010

Physicians involved in acute medical take or emergency department work will be well aware of the various acute presentations associated with cocaine and amphetamine use. As the population ages and the heavy users from previous decades accumulate ‘crack years’, the longer term consequences of these drugs on the cardiovascular system are becoming more evident. This article will review the pharmacology of stimulant drugs and discuss acute and chronic problems associated with their use. Management strategies of acute presentations, including the role of vasodilators in cocaine-induced myocardial infarction, the avoidance of beta-blockers in acute toxicity and the potential role of alpha-2 agonists are discussed. The management of chronic cardiac damage associated with cocaine or amphetamine abuse has an insufficient evidence base to suggest anything other than complete abstinence in combination with well established therapies.
First use of thymus transplantation therapy for FOXN1 deficiency (nude/SCID): a report of 2 cases
Authors: Markert M. Louise , Marques José G. , Neven Bénédicte , Devlin Blythe H. , McCarthy Elizabeth A. , Chinn Ivan K. , Albuquerque Adriana S. , Silva Susana L. , Pignata Claudio , de Saint Basile Geneviève , Victorino Rui M. , Picard Capucine , Debre Marianne , Mahlaoui Nizar , Fischer Alain , Sousa Ana E.
Published: October 2010

FOXN1 deficiency is a primary immunodeficiency characterized by athymia, alopecia totalis, and nail dystrophy. Two infants with FOXN1 deficiency were transplanted with cultured postnatal thymus tissue. Subject 1 presented with disseminated Bacillus Calmette-Guérin infection and oligoclonal T cells with no naive markers. Subject 2 had respiratory failure, human herpes virus 6 infection, cytopenias, and no circulating T cells. The subjects were given thymus transplants at 14 and 9 months of life, respectively. Subject 1 received immunosuppression before and for 10 months after transplantation. With follow up of 4.9 and 2.9 years, subjects 1 and 2 are well without infectious complications. The pretransplantation mycobacterial disease in subject 1 and cytopenias in subject 2 resolved. Subject 2 developed autoimmune thyroid disease 1.6 years after transplantation. Both subjects developed functional immunity. Subjects 1 and 2 have 1053/mm3 and 1232/mm3 CD3+ cells, 647/mm3 and 868/mm3 CD4+ T cells, 213/mm3 and 425/mm3 naive CD4+ T cells, and 10 200 and 5700 T-cell receptor rearrangement excision circles per 100 000 CD3+ cells, respectively. They have normal CD4 T-cell receptor β variable repertoires. Both subjects developed antigen-specific proliferative responses and have discon-tinued immunoglobulin replacement. In summary, thymus transplantation led to T-cell reconstitution and function in these FOXN1 deficient infants.
Correlation between sequence conservation and structural thermodynamics of microRNA precursors from human, mouse, and chicken genomes
Authors: Ni Ming , Shu Wenjie , Bo Xiaochen , Wang Shengqi , Li Songgang
Published: October 2010

Background

Previous studies have shown that microRNA precursors (pre-miRNAs) have considerably more stable secondary structures than other native RNAs (tRNA, rRNA, and mRNA) and artificial RNA sequences. However, pre-miRNAs with ultra stable secondary structures have not been investigated. It is not known if there is a tendency in pre-miRNA sequences towards or against ultra stable structures? Furthermore, the relationship between the structural thermodynamic stability of pre-miRNA and their evolution remains unclear.

Results

We investigated the correlation between pre-miRNA sequence conservation and structural stability as measured by adjusted minimum folding free energies in pre-miRNAs isolated from human, mouse, and chicken. The analysis revealed that conserved and non-conserved pre-miRNA sequences had structures with similar average stabilities. However, the relatively ultra stable and unstable pre-miRNAs were more likely to be non-conserved than pre-miRNAs with moderate stability. Non-conserved pre-miRNAs had more G+C than A+U nucleotides, while conserved pre-miRNAs contained more A+U nucleotides. Notably, the U content of conserved pre-miRNAs was especially higher than that of non-conserved pre-miRNAs. Further investigations showed that conserved and non-conserved pre-miRNAs exhibited different structural element features, even though they had comparable levels of stability.

Conclusions

We proposed that there is a correlation between structural thermodynamic stability and sequence conservation for pre-miRNAs from human, mouse, and chicken genomes. Our analyses suggested that pre-miRNAs with relatively ultra stable or unstable structures were less favoured by natural selection than those with moderately stable structures. Comparison of nucleotide compositions between non-conserved and conserved pre-miRNAs indicated the importance of U nucleotides in the pre-miRNA evolutionary process. Several characteristic structural elements were also detected in conserved pre-miRNAs.
Polyploid genome of Camelina sativarevealed by isolation of fatty acid synthesis genes
Authors: Hutcheon Carolyn , Ditt Renata F , Beilstein Mark , Comai Luca , Schroeder Jesara , Goldstein Elianna , Shewmaker Christine K , Nguyen Thu , De Rocher Jay , Kiser Jack
Published: October 2010

Background

Camelina sativa, an oilseed crop in the Brassicaceae family, has inspired renewed interest due to its potential for biofuels applications. Little is understood of the nature of the C. sativa genome, however. A study was undertaken to characterize two genes in the fatty acid biosynthesis pathway, fatty acid desaturase (FAD) 2 and fatty acid elongase (FAE) 1, which revealed unexpected complexity in the C. sativa genome.

Results

In C. sativa, Southern analysis indicates the presence of three copies of both FAD2 and FAE1 as well as LFY, a known single copy gene in other species. All three copies of both CsFAD2 and CsFAE1 are expressed in developing seeds, and sequence alignments show that previously described conserved sites are present, suggesting that all three copies of both genes could be functional. The regions downstream of CsFAD2 and upstream of CsFAE1 demonstrate co-linearity with the Arabidopsis genome. In addition, three expressed haplotypes were observed for six predicted single-copy genes in 454 sequencing analysis and results from flow cytometry indicate that the DNA content of C. sativa is approximately three-fold that of diploid Camelina relatives. Phylogenetic analyses further support a history of duplication and indicate that C. sativa and C. microcarpa might share a parental genome.

Conclusions

There is compelling evidence for triplication of the C. sativa genome, including a larger chromosome number and three-fold larger measured genome size than other Camelina relatives, three isolated copies of FAD2, FAE1, and the KCS17-FAE1 intergenic region, and three expressed haplotypes observed for six predicted single-copy genes. Based on these results, we propose that C. sativa be considered an allohexaploid. The characterization of fatty acid synthesis pathway genes will allow for the future manipulation of oil composition of this emerging biofuel crop; however, targeted manipulations of oil composition and general development of C. sativa should consider and, when possible take advantage of, the implications of polyploidy.
Association of methylenetetrahydrofolate reductase C677T polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations
Authors: Zhang Lin , Yin Rui-Xing , Liu Wan-Ying , Miao Lin , Wu Dong-Feng , Aung Lynn Htet Htet , Hu Xi-Jiang , Cao Xiao-Li , Wu Jin-Zhen , Pan Shang-Ling
Published: October 2010

Background

The association of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and serum lipid profiles is still controversial in diverse ethnics. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The aim of the present study was to eveluate the association of MTHFR C677T polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.

Methods

A total of 780 subjects of Bai Ku Yao and 686 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the MTHFR C677T was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.

Results

The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of C and T alleles was 77.4% and 22.6% in Bai Ku Yao, and 60.9% and 39.1% in Han (P < 0.001); respectively. The frequency of CC, CT and TT genotypes was 58.7%, 37.3% and 4.0% in Bai Ku Yao, and 32.6%, 56.4% and 11.0% in Han (P < 0.001); respectively. The levels of TC and LDL-C in both ethnic groups were significant differences among the three genotypes (P < 0.05-0.01). The T allele carriers had higher serum TC and LDL-C levels than the T allele noncarriers. The levels of ApoB in Han were significant differences among the three genotypes (P < 0.05). The T allele carriers had higher serum ApoB levels as compared with the T allele noncarriers. The levels of TC, TG and LDL-C in Bai Ku Yao were correlated with genotypes (P < 0.05-0.001), whereas the levels of LDL-C in Han were associated with genotypes (P < 0.001). Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in the both ethnic groups.

Conclusions

The differences in serum TC, TG, LDL-C and ApoB levels between the two ethnic groups might partly result from different genotypic and allelic frequencies of the MTHFR C677T or different MTHFR gene-enviromental interactions.
Spatiotemporal expression of the serine protease inhibitor, SERPINE2, in the mouse placenta and uterus during the estrous cycle, pregnancy, and lactation
Authors: Chern Schu-Rern , Li Sheng-Hsiang , Lu Chung-Hao , Chen Edmund I Tsuen
Published: October 2010

Background

SERPINE2, also known as glia-derived nexin or protease nexin-1, belongs to the serine protease inhibitor (SERPIN) superfamily. It is one of the potent serpins that modulates the activity of the plasminogen activator (PA) and was implicated in tissue remodeling. In this study, we investigated the expression patterns of SERPINE2 in the mouse placenta and uterus during the estrous cycle, pregnancy, and lactation.

Methods

SERPINE2 was purified from mouse seminal vesicle secretion using liquid chromatography (LC) and identified by LC/tandem mass spectrometry. The antiserum against the SERPINE2 protein was raised in rabbits. To reveal the uterine and placental expression of SERPINE2, tissues at various stages were collected for real-time PCR quantification, Western blotting, and immunohistochemical staining.

Results

Serpine2 mRNA was the major PA inhibitor in the placenta and uterus during the estrous cycle, pregnancy, and lactation, although Serpine1 mRNA had higher expression levels than Serpine2 mRNA in the placenta. Plat seemed to be the major PA in the mouse uterus and placenta. Antiserum against the SERPINE2 protein specifically recognized two forms of SERPINE2 and an extra 75-kDa protein, which was probably a complex of SERPINE2 with a certain protease, from among thousands of protein components in the tissue extract as demonstrated by Western blotting. In the uterus, SERPINE2 was primarily localized in luminal and glandular epithelial cells but it also was detected in circular and longitudinal smooth muscle cells during the estrous cycle and lactation. It was prominently expressed in decidual stroma cells, the metrial gland, and endometrial epithelium of the pregnant uterus. In the placenta, SERPINE2 was expressed in trophoblasts of the labyrinth and spongiotrophoblasts. However, its expression was remarkably reduced in giant cells which existed in the giant cell-decidual junction zone. In contrast, prominent expression of SERPINE2 seemed to be detected on clusters of glycogen cells near the junction zone. In addition, yolk sac membranes also showed high expression of SERPINE2.

Conclusions

These findings indicate that SERPINE2 is a major PA inhibitor in the placenta and uterus during the estrous cycle, pregnancy, and lactation. It may participate in the PA-modulated tissue remodeling process in the mouse placenta and uterus.
Fcγ receptors are required for NF-κB signaling, microglial activation and dopaminergic neurodegeneration in an AAV-synuclein mouse model of Parkinson's disease
Authors: Cao Shuwen , Theodore Shaji , Standaert David G
Published: October 2010

Overexpression of alpha-synuclein (α-SYN), a protein which plays an important role in the pathogenesis of Parkinson's disease (PD), triggers microglial activation and adaptive immune responses, and leads to neurodegeneration of dopaminergic (DA) neurons. We hypothesized a link between the humoral adaptive immune response and microglial activation in α-SYN induced neurodegeneration. To test this hypothesis, we employed adeno-associated virus serotype 2 (AAV2) to selectively over-express human α-SYN in the substantia nigra (SN) of wild-type mice and FcγR-/- mice, which lack high-affinity receptors for IgG. We found that in wild-type mice, α-SYN induced the expression of NF-κB p65 and pro-inflammatory molecules. In FcγR-/- mice, NF-κB activation was blocked and pro-inflammatory signaling was reduced. Microglial activation was examined using immunohistochemistry for gp91PHOX. At four weeks, microglia were strongly activated in wild-type mice, while microglial activation was attenuated in FcγR-/- mice. Dopaminergic neurodegeneration was examined using immunohistochemistry for tyrosine hydroxylase (TH) and unbiased stereology. α-SYN overexpression led to the appearance of dysmorphic neurites, and a loss of DA neurons in the SN in wild-type animals, while FcγR-/- mice did not exhibit neuritic change and were protected from α-SYN-induced neurodegeneration 24 weeks after injection. Our results suggest that the humoral adaptive immune response triggered by excess α-SYN plays a causative role in microglial activation through IgG-FcγR interaction. This involves NF-κB signaling, and leads to DA neurodegeneration. Therefore, blocking either FcγR signaling or specific intracellular signal transduction events downstream of FcγR-IgG interaction, such as NF-κB activation, may be viable therapeutic strategies in PD.
Appropriation, Property Rights Institutions, and International Trade
Authors: Stefanadis Christodoulos
Published: October 2010

In producer-friendly economies—economies that are ruled by productive agents and have strong property rights institutions—international trade causes an institutional improvement and an aggregate shift of talent towards production, and away from socially wasteful appropriation. However, in predator-friendly economies—economies that are ruled by rent seekers and have weak institutions—international trade leads to an institutional deterioration, and a more unfavorable talent allocation. (JEL D72, F12, K11)
Domestic Institutions and the Bypass Effect of Financial Globalization
Authors: Ju Jiandong , Wei Shang-Jin
Published: October 2010

This paper proposes a simple model to study how domestic institutions affect patterns of international capital flows. Inefficient financial system, and poor corporate governance, may be bypassed by two-way capital flows in which domestic savings leave the country in the form of financial capital outflows but domestic investment takes place via inward FDI. While financial globalization always improves the welfare of a developed country with a good financial system, its effect is ambiguous for a developing country with an inefficient financial sector or poor corporate governance. Interestingly, financial and property rights institutions can have opposite effects on capital flows. (JEL D02, E21, F21, F32, G34)
Sharing Demographic Risk—Who Is Afraid of the Baby Bust?
Authors: Ludwig Alexander , Reiter Michael
Published: October 2010

We model the reaction of a PAYG pension system to demographic shocks. We compare the ex ante first best and second best solution of a Ramsey planner with full commitment to the outcome under simple third best rules. The model is calibrated to the German economy. We find that the German system comes relatively close to the second-best solution, and that the recent baby-boom/baby-bust cycle leads to welfare losses of about 5 percent of lifetime consumption for some cohorts. We argue that it is crucial for all our results to correctly model the labor market distortions arising from the pension system. (JEL D91, E62, H55, J11)
High-efficiency siRNA-based gene knockdown in human embryonic stem cells
Authors: Ma Yinghong , Jin Jianyu , Dong Chunsheng , Cheng Ee-Chun , Lin Haifan , Huang Yingqun , Qiu Caihong
Published: October 2010

Loss-of-function studies in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) via nonviral approaches have been largely unsuccessful. Here we report a simple and cost-effective method for high-efficiency delivery of plasmids and siRNAs into hESCs and iPSCs. Using this method for siRNA delivery, we achieve >90% reduction in the expression of the stem cell factors Oct4 and Lin28, and observe cell morphological and staining pattern changes, characteristics of hESC differentiation, as a result of Oct4 knockdown.
Increased Aripiprazole Concentrations in an HIV-Positive Male Concurrently Taking Duloxetine, Darunavir, and Ritonavir
Authors: Aung Gregory L , O'Brien John G , Tien Pamela G , Kawamoto Laura S
Published: October 2010

Objective:

To report a case of increased aripiprazole concentrations during coadministration with darunavir, ritonavir, and duloxetine.

Case Summary:

A 43-year-old HIV-positive Hispanic man received darunavir/ritonavir-based antiretroviral therapy (ART) in addition to aripiprazole and duloxetine for depression and anxiety. A month after the aripiprazole dosage was increased to 50 mg dailry, the patient developed confusion and loss of coordination. Weeks later, he presented to the emergency department with fever, cough, headache, neck stiffness, back pain, and blurred vision and was admitted for possible meningitis. Because symptoms improved with pain control and intravenous fluids during hospitalization, he was discharged within a couple days after admission. One month later he was readmitted for worsening symptoms, and the resulting diagnostic workup showed unremarkable findings except for lymphadenopathy (LAD). This finding was attributed to discontinuing ARTs after his first admission, He was discharged on aripiprazole 50 mg daily, darunavir 800 mg daily, ritonavir 100 mg daily, and duloxetine 60 mg daily. A random steady-state concentration of aripiprazole was 1100 ng/mL (therapeutic concentration 100-200 ng/mL) obtained 49 days after discharge.

Discussion:

The Horn Drug Interaction Probability Scale demonstrated a possible relationship between the increased aripiprazole concentration and coadministration of darunavir/ritonavir and duloxetine, which inhibit CYP3A4 and 2D6. Potential confounders to the increased concentration include duloxeline inhibition of CYP2D6 polymorphism, possible 2D6 polymorphism, and exceeding aripiprazole's maximum dose. The initial presentation of confusion and loss of coordination may have been early signs of aripiprazole toxicity, which relapsed as shown by his symptoms prior to admission.

Conclusions:

The interaction between aripiprazole and darunavir, ritonavir, and duloxetine may be significant. Clinicians should be cognizant of increased risk of aripiprazole toxicity in HIV-positive patients concurrently taking ritonavir-boosted ART and other cytochrome P450 inhibitors like duloxetine. Dose adjustments or monitoring parameters should be an area of research and discussion.
Assessing the Effect of the Surviving Sepsis Campaign Treatment Guidelines on Clinical Outcomes in a Community Hospital
Authors: Patel Gita Wasan , Roderman Nicki , Gehring Hollie , Saad John , Bartek William
Published: October 2010

Background:

Bundles yield a reduction in mortality in patients with sepsis, but the majority of the data is from large academic centers. The ability of a community hospital to implement a sepsis bundle successfully, however, has not been investigated.

Objective:

To examine the effect of a collaborative 2-part sepsis bundle on clinical outcomes and mortality at a community hospital.

Methods:

The study included all patients with severe sepsis/septic shock over the age of 18 years admitted to the intensive care unit (ICU) from 2006 to 2007 who were not treated with a bundle (n = 53) and those who were treated with a bundle (n = 59). Data collected included demographics; initiation of vasopressors; days on vasopressors; blood glucose; use of drotrecogin alfa (activated), steroids, and ventilator; ICU/hospital lengths of stay; ventilator days; time to culture; time to first dose of antibiotics; time to transfer from emergency department to ICU; fluid resuscitation in the first 24 hours; percentage of patients started on dialysis; and mortality.

Results:

Demographics; blood glucose; use of drolrecogin alfa (activated), steroids and ventilator; ICU/hospital lengths of stay; and ventilator days were statistically similar between groups. Median time to cultures, first dose of antibiotics, and transfer to ICU were all reduced with the bundle. Percentage of non-bundle patients on vasopressors was 87% versus 66.7% of bundle patients (p = 0.011) and number of median days on vasopressors was reduced. Fewer bundle patients were initiated on dialysis (0%) versus non-bundle patients (14.8%) (p = 0.02). Median fluid administered in the first 24 hours was 2200 mL (10-13,996 mL) for non-bundle patients and 7143 mL (1000-19,104 mL) for bundle patients (p < 0.001). Mortality was 61.1% in the non-bundle group versus 20% with the bundle (p < 0.001).

Conclusions:

Implementation of a 2-part sepsis bundle based on the Surviving Sepsis Campaign Guidelines can yield a positive impact on clinical outcome and mortality in a nonacademic, community hospital setting.
Spironolactone Management of Resistant Hypertension
Authors: Marrs Joel C
Published: October 2010

Objective:

To review the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and adverse effects of spironolactone in the treatment of resistant hypertension.

Data Sources:

A literature search was conducted using MEDLINE (1966-July 2010), International Pharmaceutical Abstracts (1970-July 2010), and Cochrane database (2009) for the key words spironolactone or resistant hypertension. References cited in the articles were reviewed for additional information.

Study Selection and Data Extraction:

English-language literature reporting pharmacology data from animal studies and clinical trials evaluating the pharmacology, pharmacokinetics, pharmacodynamics, efficacy data, and adverse effects of spironolactone were included.

Data Synthesis:

Spironolactone is a potassium-sparing diuretic with anti-aldosterone effects that are beneficial in the management of hypertension. Spironolactone has shown improvement in 5 prospective studies and 1 retrospective study evaluating its blood pressuring–lowering abilities in patients with resistant hypertension. Specifically, the average blood pressure lowering noted in these trials with the addition of spironolactone in patients with resistant hypertension was 22/10 mm Hg. Trials evaluating spironolactone's role in resistant hypertension treatment have identified hyperkalemia, gynecomastia, and renal insufficiency as the major adverse effects that warrant monitoring.

Conclusions:

Spironolactone is an appropriate antihypertensive medication to add to treatment of patients with resistant hypertension (≥3 antihypertensive medications at optimal doses) not at their blood pressure goal. In patients considered to have resistant hypertension, secondary causes should be ruled out.
Expectation-Driven Changes in Cortical Functional Connectivity Influence Working Memory and Long-Term Memory Performance
Authors: Bollinger Jacob , Rubens Michael T. , Zanto Theodore P. , Gazzaley Adam
Published: October 2010

Expectations generated by predictive cues increase the efficiency of perceptual processing for complex stimuli (e.g., faces, scenes); however, the impact this has on working memory (WM) and long-term memory (LTM) has not yet been investigated. Here, healthy young adults performed delayed-recognition tasks that differed only in stimulus category expectations, while behavioral and functional magnetic resonance imaging data were collected. Univariate and functional-connectivity analyses were used to examine expectation-driven, prestimulus neural modulation, networks that regulate this modulation, and subsequent memory performance. Results revealed that predictive category cueing was associated with both enhanced WM and LTM for faces, as well as baseline activity shifts in a face-selective region of the visual association cortex [i.e., fusiform face area (FFA)]. In addition, the degree of functional connectivity between FFA and right inferior frontal junction (IFJ), middle frontal gyrus (MFG), inferior frontal gyrus, and intraparietal sulcus correlated with the magnitude of prestimulus activity modulation in the FFA. In an opposing manner, prestimulus connectivity between FFA and posterior cingulate cortex, a region of the default network, negatively correlated with FFA activity modulation. Moreover, whereas FFA connectivity with IFJ and the precuneus predicted enhanced expectation-related WM performance, FFA connectivity with MFG predicted LTM improvements. These findings suggest a model of expectancy-mediated neural biasing, in which a single node (e.g., FFA) can be dynamically linked or disconnected from different brain regions depending on prestimulus expectations, and the strength of distinct connections is associated with WM or LTM benefits.
Specialization of Binaural Responses in Ventral Auditory Cortices
Authors: Higgins Nathan C. , Storace Douglas A. , Escabí Monty A. , Read Heather L.
Published: October 2010

Accurate orientation to sound under challenging conditions requires auditory cortex, but it is unclear how spatial attributes of the auditory scene are represented at this level. Current organization schemes follow a functional division whereby dorsal and ventral auditory cortices specialize to encode spatial and object features of sound source, respectively. However, few studies have examined spatial cue sensitivities in ventral cortices to support or reject such schemes. Here Fourier optical imaging was used to quantify best frequency responses and corresponding gradient organization in primary (A1), anterior, posterior, ventral (VAF), and suprarhinal (SRAF) auditory fields of the rat. Spike rate sensitivities to binaural interaural level difference (ILD) and average binaural level cues were probed in A1 and two ventral cortices, VAF and SRAF. Continuous distributions of best ILDs and ILD tuning metrics were observed in all cortices, suggesting this horizontal position cue is well covered. VAF and caudal SRAF in the right cerebral hemisphere responded maximally to midline horizontal position cues, whereas A1 and rostral SRAF responded maximally to ILD cues favoring more eccentric positions in the contralateral sound hemifield. SRAF had the highest incidence of binaural facilitation for ILD cues corresponding to midline positions, supporting current theories that auditory cortices have specialized and hierarchical functional organization.
Lack of Collagen XV Impairs Peripheral Nerve Maturation and, When Combined with Laminin-411 Deficiency, Leads to Basement Membrane Abnormalities and Sensorimotor Dysfunction
Authors: Rasi Karolina , Hurskainen Merja , Kallio Mika , Stavén Saara , Sormunen Raija , Heape Anthony M. , Avila Robin L. , Kirschner Daniel , Muona Anu , Tolonen Uolevi , Tanila Heikki , Huhtala Pirkko , Soininen Raija , Pihlajaniemi Taina
Published: October 2010

Although the Schwann cell basement membrane (BM) is required for normal Schwann cell terminal differentiation, the role of BM-associated collagens in peripheral nerve maturation is poorly understood. Collagen XV is a BM zone component strongly expressed in peripheral nerves, and we show that its absence in mice leads to loosely packed axons in C-fibers and polyaxonal myelination. The simultaneous lack of collagen XV and another peripheral nerve component affecting myelination, laminin α4, leads to severely impaired radial sorting and myelination, and the maturation of the nerve is permanently compromised, contrasting with the slow repair observed inLama4−/−single knock-out mice. Moreover, theCol15a1−/−;Lama4−/−double knock-out (DKO) mice initially lack C-fibers and, even over 1 year of age have only a few, abnormal C-fibers. TheLama4−/−knock-out results in motor and tactile sensory impairment, which is exacerbated by a simultaneousCol15a1−/−knock-out, whereas sensitivity to heat-induced pain is increased in the DKO mice. Lack of collagen XV results in slower sensory nerve conduction, whereas theLama4−/−and DKO mice exhibit increased sensory nerve action potentials and decreased compound muscle action potentials; x-ray diffraction revealed less mature myelin in the sciatic nerves of the latter than in controls. Ultrastructural analyses revealed changes in the Schwann cell BM in all three mutants, ranging from severe (DKO) to nearly normal (Col15a1−/−). Collagen XV thus contributes to peripheral nerve maturation and C-fiber formation, and its simultaneous deletion from neural BM zones with laminin α4 leads to a DKO phenotype distinct from those of both single knock-outs.
Abl Family Tyrosine Kinases Are Essential for Basement Membrane Integrity and Cortical Lamination in the Cerebellum
Authors: Qiu Zhaozhu , Cang Yong , Goff Stephen P.
Published: October 2010

The Abl family nonreceptor tyrosine kinases, consisting of closely related Abl and Arg (Abl-related gene), play essential roles in mouse neurulation, but their functions in the subsequent development of CNS are poorly understood. Here, we show that conditional deletion ofAblin precursors of neurons and glia on anArgknock-out background leads to striking cerebellar malformations, including defects in anterior cerebellar morphogenesis, granule cell ectopia, and hypoplasia. Time course analyses reveal that the abnormal anterior cerebellar foliation results from local disruptions of the basement membrane (BM) located between radial glial endfeet and the meninges during embryonic cerebellar development. Granule cell ectopia and hypoplasia are also associated with the breaches in the BM and abnormal Bergmann glial networks during postnatal cerebellar development.In vitroculture experiments indicate that Abl/Arg-deficient granule cells can interact with glial processes and proliferate normally in response to sonic hedgehog compared to cells isolated from control mice. Consistent with these findings, selective ablation of Abl family kinases in cerebellar granule cells alone does not cause any abnormality, suggesting that deletion ofAbl/Argfrom glia is likely required for the mutant phenotype. Together, these results provide compelling evidence that Abl and Arg play key redundant roles in BM maintenance and cortical lamination in the cerebellum.