bluuebunny/crossref_metadata_2025 huggingface dataset:
DAG Lipase Involvement in Depolarization-Induced Suppression of Inhibition: Does Endocannabinoid Biosynthesis Always Meet the Demand?
Authors: Min Rogier , Di Marzo Vincenzo , Mansvelder Huibert D.
Published: September 2010

Hippocampal depolarization-induced suppression of inhibition (DSI) is a robust form of short-term synaptic plasticity. DSI is mediated by endocannabinoid signaling. Since this discovery, pinning down the endogenous cannabinoid receptor ligand that mediates DSI has been problematic. Blocking degradation of the endocannabinoid 2-arachidonoyl glycerol (2-AG) lengthens DSI, which seems to indicate that 2-AG mediates DSI. In contrast, pharmacological inhibition of the 2-AG—synthesizing enzyme diacylglycerol lipase (DAGL) has yielded conflicting results: DAGL inhibitors often fail to block hippocampal DSI. Recently, 2 studies seem to have cornered this problem using DAGL knockout mice. Hippocampal DSI is absent in DAGL-α knockout mice, pointing to a key role for 2-AG in DSI. However, these studies do not reconcile the discrepancy with pharmacological experiments. Here, we argue that the seeming contradiction between results from pharmacological and genetic approaches may be explained in several ways. We suggest that the contradiction may be resolved by taking a different perspective on endocannabinoid signaling: in some forms of endocannabinoid-mediated signaling endocannabinoids might not be necessarily produced “on demand” but presynthesized and stored until needed.
Single-chip heat-pump control system based on an MCS-51 microcontroller core
Authors: Chiang Tung-Chien , Chang Cheng-Yuan , Wang Yi-Wei
Published: September 2010

Heat pumps are typically controlled by a programmable logic controller (PLC). However, PLCs are generally expensive and large. This work uses an MCS-51-based controller to control a heat pump, so that the size of the controller of a heat-pump system can be reduced markedly. Moreover, the proposed MCS-51-based controller can detect the status of each heat pump’s sensor automatically, so that a user can know whether a sensor is normal or abnormal, thereby protecting the heat-pump compressor. Knowing the number of a faulty sensor also helps during maintenance. Experimental results demonstrate that the proposed MCS-51-based controller can replace a PLC-based controller and control a heat pump successfully, achieving an inexpensive and effective solution for controlling heat pumps.
Ephemeralization as Environmentalism: Rereading R. Buckminster Fuller’s Operating Manual for Spaceship Earth
Authors: Luke Timothy W.
Published: September 2010

This study critically surveys the environmental thinking and design philosophy Of R. Buckminster Fuller by revisiting two of his major theoretical works, Operating Manual for Spaceship Earth and Utopia or Oblivion. It highlights Fuller’s fascination with economic efficiency and environmental justice in his own pursuit of the practices of industrial design, urban planning, and vernacular engineering. In addition, the analysis stresses how the optimism and energy that Fuller gave to rethinking environmentalism so radically during the 1960s are vital qualities that contemporary green thinkers need to rekindle in their works today.
A Physical Activity Program Improves Behavior and Cognitive Functions in Children With ADHD
Authors: Verret Claudia , Guay Marie-Claude , Berthiaume Claude , Gardiner Phillip , Béliveau Louise
Published: September 2010

Objective: The objective of this study is to explore the effects of a moderate- to high-intensity physical activity program on fitness, cognitive functions, and ADHD-related behavior in children with ADHD. Method: Fitness level, motor skills, behaviors, and cognitive functions are assessed by standardized tests before and after a 10-week training or control period. Results: Findings show that participation in a physical activity program improves muscular capacities, motor skills, behavior reports by parents and teachers, and level of information processing. Conclusion: A structured physical activity program may have clinical relevance in the functional adaptation of children with ADHD. This supports the need for further research in the area of physical activity with this population.
Understanding the Effect Size of Lisdexamfetamine Dimesylate for Treating ADHD in Children and Adults
Authors: Faraone Stephen V.
Published: September 2010

Objective: An earlier meta-analysis of pediatric clinical trials indicated that lisdexamfetamine dimesylate (LDX) had a greater effect size than other stimulant medications. This work tested the hypothesis that the apparent increased efficacy was artifactual. Method: The authors assessed two potential artifacts: an unusually high precision of measurement and an unusually low placebo effect. The authors evaluated generalizability from children of adults. Results: The LDX effect sizes for children were significantly larger than the pooled stimulant effect sizes from studies using the same outcome measures. However, although no other individual stimulant study had an effect size greater than LDX, there was overlap between the 95% confidence intervals for some of these studies and the LDX study. The high LDX effect sizes were not due measurement or placebo effect artifacts. LDX effect sizes for adults were not larger than the stimulant effect sizes from other studies. Conclusion: The high LDX effect size for children could not attributed to measurement artifacts. The superiority of LDX in the pediatric clinical trial reflected the greater efficacy of amphetamine products, compared with methylphenidate products but required replication in children because (a) the results were based on only one trial of LDX in children, and (b) the finding did not generalize to adults.
Exploring the Gender Gap in Referrals for Children With ADHD and Other Disruptive Behavior Disorders
Authors: Coles Erika K. , Slavec Janine , Bernstein Melissa , Baroni Elizabeth
Published: September 2010

Objective: The current study examined the impact of the gender of children with ADHD on teachers’ perceptions toward inattentive, hyperactive, or oppositional behaviors, and how these perceptions relate to teachers’ ratings of children’s impairment and referral recommendations. Method: Teachers read eight vignettes depicting boys and girls with different subtypes of ADHD, as well as one depicting comorbidity (ADHD + ODD). Teachers then completed measures of impairment, and responded to questions about what services they would likely refer for the child and why. Results: Teachers rated girls as being significantly more impaired and more in need of services than boys. Regardless of gender, teachers overwhelmingly reported preferring the use of behavior modification for the described child. Also, children who were described with symptoms of ADHD-predominately inattentive subtype were rated as being the least impaired, while girls described as hyperactive and impulsive were rated by teachers as being the most impaired. Conclusion: The current study adds to previous literature on gender bias in ADHD referrals by providing evidence for the differential referral of ADHD boys and girls to treatment based on presentation of symptoms.
Parental Functioning in Families of Children With ADHD
Authors: Gerdes Alyson C. , Haack Lauren M. , Schneider Brian W.
Published: September 2010

Objective/Method: Statistically significant and clinically meaningful effects of behavioral parent training on parental functioning were examined for 20 children with ADHD and their parents who had successfully completed a psychosocial treatment for ADHD. Results/Conclusion: Findings suggest that behavioral parent training resulted in statistically significant improvements in some domains of parenting behavior for both mothers and fathers and in reductions in most domains of parenting stress for mothers. Importantly, clinically meaningful change also was noted for these parental functioning areas, as well as for other domains of parental functioning that did not result in statistically significant findings. Clinical implications are discussed.
When ‘good’ conflicts go bad: Testing a frame-building model on embeds’ attitudes toward government news management in the Iraq War
Authors: Johnson Thomas J. , Fahmy Shahira
Published: September 2010

Scholars have debated how successful the government was in managing coverage of the ground war in Iraq through the embed system, but few have surveyed the embedded journalists themselves to discover the degree they believe their press freedom was restricted. This study compares results from a survey conducted of embedded journalists in late 2005 and early 2006 to one conducted in early 2004 to examine whether embeds’ opinions toward press freedom have changed over time and whether they believe government news management has increased as criticism of the Iraq War has increased and public support has declined. It also tests the hierarchy-of-influences model by examining the degree to which individual, journalism routines, external and cultural factors significantly predict attitudes toward press freedom and perceptions of censorship after controlling for demographics and political ideology.
Genomic encyclopedia of sugar utilization pathways in the Shewanella genus
Authors: Rodionov Dmitry A , Yang Chen , Li Xiaoqing , Rodionova Irina A , Wang Yanbing , Obraztsova Anna Y , Zagnitko Olga P , Overbeek Ross , Romine Margaret F , Reed Samantha , Fredrickson James K , Nealson Kenneth H , Osterman Andrei L
Published: September 2010

Background

Carbohydrates are a primary source of carbon and energy for many bacteria. Accurate projection of known carbohydrate catabolic pathways across diverse bacteria with complete genomes constitutes a substantial challenge due to frequent variations in components of these pathways. To address a practically and fundamentally important challenge of reconstruction of carbohydrate utilization machinery in any microorganism directly from its genomic sequence, we combined a subsystems-based comparative genomic approach with experimental validation of selected bioinformatic predictions by a combination of biochemical, genetic and physiological experiments.

Results

We applied this integrated approach to systematically map carbohydrate utilization pathways in 19 genomes from the Shewanella genus. The obtained genomic encyclopedia of sugar utilization includes ~170 protein families (mostly metabolic enzymes, transporters and transcriptional regulators) spanning 17 distinct pathways with a mosaic distribution across Shewanella species providing insights into their ecophysiology and adaptive evolution. Phenotypic assays revealed a remarkable consistency between predicted and observed phenotype, an ability to utilize an individual sugar as a sole source of carbon and energy, over the entire matrix of tested strains and sugars.

Comparison of the reconstructed catabolic pathways with E. coli identified multiple differences that are manifested at various levels, from the presence or absence of certain sugar catabolic pathways, nonorthologous gene replacements and alternative biochemical routes to a different organization of transcription regulatory networks.

Conclusions

The reconstructed sugar catabolome in Shewanella spp includes 62 novel isofunctional families of enzymes, transporters, and regulators. In addition to improving our knowledge of genomics and functional organization of carbohydrate utilization in Shewanella, this study led to a substantial expansion of our current version of the Genomic Encyclopedia of Carbohydrate Utilization. A systematic and iterative application of this approach to multiple taxonomic groups of bacteria will further enhance it, creating a knowledge base adequate for the efficient analysis of any newly sequenced genome as well as of the emerging metagenomic data.
Identification of two Amino Acids in the C-terminal Domain of Mouse CRY2 Essential for PER2 Interaction
Authors: Ozber Natali , Baris Ibrahim , Tatlici Gulnaz , Gur Ibrahim , Kilinc Seda , Unal Evrim B , Kavakli Ibrahim H
Published: September 2010

Background

Cryptochromes (CRYs) are a class of flavoprotein blue-light signaling receptors found in plants and animals, and they control plant development and the entrainment of circadian rhythms. They also act as integral parts of the central circadian oscillator in humans and other animals. In mammals, the CLOCK-BMAL1 heterodimer activates transcription of the Per and Cry genes as well as clock-regulated genes. The PER2 proteins interact with CRY and CKIε, and the resulting ternary complexes translocate into the nucleus, where they negatively regulate the transcription of Per and Cry core clock genes and other clock-regulated output genes. Recent studies have indicated that the extended C-termini of the mammalian CRYs, as compared to photolyase proteins, interact with PER proteins.

Results

We identified a region on mCRY2 (between residues 493 and 512) responsible for direct physical interaction with mPER2 by mammalian two-hybrid and co-immunoprecipitation assays. Moreover, using oligonucleotide-based degenerate PCR, we discovered that mutation of Arg-501 and Lys-503 of mCRY2 within this C-terminal region totally abolishes interaction with PER2.

Conclusions

Our results identify mCRY2 amino acid residues that interact with the mPER2 binding region and suggest the potential for rational drug design to inhibit CRYs for specific therapeutic approaches.
Synergistic disruptions in seuss cyp85A2 double mutants reveal a role for brassinolide synthesis during gynoecium and ovule development
Authors: Nole-Wilson Staci , Rueschhoff Elizabeth E , Bhatti Huda , Franks Robert G
Published: September 2010

Background

The Arabidopsis SEUSS (SEU) gene encodes a transcriptional adaptor protein that is required for a diverse set of developmental events, including floral organ identity specification, as well as gynoecium, ovule and embryo development. In order to better understand the molecular mechanisms of SEUSS action we undertook a genetic modifier screen to identify seuss-modifier (sum) mutations.

Results

Screening of M2 lines representing approximately 5,000 M1 individuals identified mutations that enhance the seuss mutant phenotypic disruptions in ovules and gynoecia; here we describe the phenotype of the sum63 mutant and enhanced disruptions of ovule and gynoecial development in the seu sum63 double mutant. Mapping and genetic complementation tests indicate that sum63 is allelic to CYP85A2 (AT3G30180) a cytochrome p450 enzyme that catalyzes the final steps in the synthesis of the phytohormone brassinolide.

Conclusions

Our identification of mutations in CYP85A2 as enhancers of the seuss mutant phenotype suggests a previously unrecognized role for brassinolide synthesis in gynoecial and ovule outer integument development. The work also suggests that seuss mutants may be more sensitive to the loss or reduction of brassinolide synthesis than are wild type plants.
A case report of mesenteric mucinous cystoadenoma with review of the literature
Authors: Del Gobbo Alessandro , Bimbatti Manuela , Ferrero Stefano
Published: September 2010

Background

Few cases of primary retroperitoneal mucinous cystoadenoma, a rare benign tumor, have been reported in the literature so far. The pathogenesis of this tumour is not completely understood yet.

Our case is particularly significant since the localization in the mesentery has been described only once before in the literature. Unless biologically benign, this tumour can cause relevant clinical symptoms related to the size and site (compression or obstruction of organs).

Case presentation

We describe the case of a 52-years old woman who had presented with abdominal pain and underwent surgery in order to remove a palpable lump in the mesentery with histological diagnosis of primary mucinous cystoadenoma. The patient was followed-up for two years with no evidence of recurrence.

Conclusions

Mucinous cystoadenoma is more frequent in women, particularly when there is history of one or more pregnancies. A complete preoperative study with abdominal and pelvic tomographic images and an accurate physical examination are essentials for the management of the patient. Surgical resection is the only way to treat mucinous cystoadenomas, and to have the histological confirmation that the removed mass is a benign tumor.
PGF2α-F-prostanoid receptor signalling via ADAMTS1 modulates epithelial cell invasion and endothelial cell function in endometrial cancer
Authors: Keightley Margaret C , Sales Kurt J , Jabbour Henry N
Published: September 2010

Background

An increase in cancer cell invasion and microvascular density is associated with a poorer prognosis for patients with endometrial cancer. In endometrial adenocarcinoma F-prostanoid (FP) receptor expression is elevated, along with its ligand prostaglandin (PG)F2α, where it regulates expression and secretion of a host of growth factors and chemokines involved in tumorigenesis. This study investigates the expression, regulation and role of a disintegrin and metalloproteinase with thrombospondin repeat 1 (ADAMTS1) in endometrial adenocarcinoma cells by PGF2α via the FP receptor.

Methods

Human endometrium and adenocarcinoma tissues were obtained in accordance with Lothian Research Ethics Committee guidance with informed patient consent. Expression of ADAMTS1 mRNA and protein in tissues was determined by quantitative RT-PCR analysis and immunohistochemistry. Signal transduction pathways regulating ADAMTS1 expression in Ishikawa cells stably expressing the FP receptor to levels seen in endometrial cancer (FPS cells) were determined by quantitative RT-PCR analysis. In vitro invasion and proliferation assays were performed with FPS cells and human umbilical vein endothelial cells (HUVECs) using conditioned medium (CM) from PGF2α-treated FPS cells from which ADAMTS1 was immunoneutralised and/or recombinant ADAMTS1. The role of endothelial ADAMTS1 in endothelial cell proliferation was confirmed with RNA interference. The data in this study were analysed by T-test or ANOVA.

Results

ADAMTS1 mRNA and protein expression is elevated in endometrial adenocarcinoma tissues compared with normal proliferative phase endometrium and is localised to the glandular and vascular cells. Using FPS cells, we show that PGF2α-FP signalling upregulates ADAMTS1 expression via a calmodulin-NFAT-dependent pathway and this promotes epithelial cell invasion through ECM and inhibits endothelial cell proliferation. Furthermore, we show that CM from FPS cells regulates endothelial cell ADAMTS1 expression in a rapid biphasic manner. Using RNA interference we show that endothelial cell ADAMTS1 also negatively regulates cellular proliferation.

Conclusions

These data demonstrate elevated ADAMTS1 expression in endometrial adenocarcinoma. Furthermore we have highlighted a mechanism whereby FP receptor signalling regulates epithelial cell invasion and endothelial cell function via the PGF2α-FP receptor mediated induction of ADAMTS1.
Determining the role of external beam radiotherapy in unresectable intrahepatic cholangiocarcinoma: a retrospective analysis of 84 patients
Authors: Chen Yi-Xing , Zeng Zhao-Chong , Tang Zhao-You , Fan Jia , Zhou Jian , Jiang Wei , Zeng Meng-Su , Tan Yun-Shan
Published: September 2010

Background

Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary liver cancer. Only few studies have focused on palliative radiotherapy used for patients who weren't suitable for resection by surgery. This study was conducted to investigate the effect of external beam radiotherapy (EBRT) for patients with unresectable ICC.

Methods

We identified 84 patients with ICC from December 1998 through December 2008 for retrospective analysis. Thirty-five of 84 patients received EBRT therapy five times a week (median dose, 50 Gy; dose range, 30-60 Gy, in fractions of 1.8-2.0 Gy daily; EBRT group); the remaining 49 patients comprised the non-EBRT group. Tumor response, jaundice relief, and survival rates were compared by Kaplan-Meier analysis. Patient records were reviewed and compared using Cox proportional hazard analysis to determine factors that affect survival time in ICC.

Results

After EBRT, complete response (CR) and partial response (PR) of primary tumors were observed in 8.6% and 28.5% of patients, respectively, and CR and PR of lymph node metastases were observed in 20% and 40% of patients. In 19 patients with jaundice, complete and partial relief was observed in 36.8% and 31.6% of patients, respectively. Median survival times were 5.1 months for the non-EBRT group and 9.5 months for the EBRT group (P= 0.003). One-and two-year survival rates for EBRT versus non-EBRT group were 38.5% versus 16.4%, and 9.6% versus 4.9%, respectively. Multivariate analysis revealed that clinical symptoms, larger tumor size, no EBRT, multiple nodules and synchronous lymph node metastases were associated with poorer prognosis.

Conclusions

EBRT as palliative care appears to improve prognosis and relieve the symptom of jaundice in patients with unresectable ICC.
The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells
Authors: Dasari Bhanu , Prasanthi Jaya RP , Marwarha Gurdeep , Singh Brij B , Ghribi Othman
Published: September 2010

Background

Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including β-amyloid (Aβ) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD.

Methods

ARPE-19 cells were treated with 0, 10 or 25 μM 27-OHC for 24 hours. Levels of Aβ peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca2+ homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays.

Results

27-OHC dose-dependently increased Aβ peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca2+ dyshomeostasis, increased levels of the nuclear factor κB (NFκB) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death.

Conclusions

The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from Aβ accumulation to oxidative cell damage. Our results suggest that high levels of 27-OHC may represent a common pathogenic factor for both AMD and AD.
A comparative summary of expression systems for the recombinant production of galactose oxidase
Authors: Spadiut Oliver , Olsson Lisbeth , Brumer Harry
Published: September 2010

Background

The microbes Escherichia coli and Pichia pastoris are convenient prokaryotic and eukaryotic hosts, respectively, for the recombinant production of proteins at laboratory scales. A comparative study was performed to evaluate a range of constructs and process parameters for the heterologous intra- and extracellular expression of genes encoding the industrially relevant enzyme galactose 6-oxidase (EC 1.1.3.9) from the fungus Fusarium graminearum. In particular, the wild-type galox gene from F. graminearum, an optimized variant for E. coli and a codon-optimized gene for P. pastoris were expressed without the native pro-sequence, but with a His-tag either at the N- or the C-terminus of the enzyme.

Results

The intracellular expression of a codon-optimized gene with an N-terminal His10-tag in E. coli, using the pET16b+ vector and BL21DE3 cells, resulted in a volumetric productivity of 180 U·L-1·h-1. The intracellular expression of the wild-type gene from F. graminearum, using the pPIC3.5 vector and the P. pastoris strain GS115, was poor, resulting in a volumetric productivity of 120 U·L-1·h-1. Furthermore, this system did not tolerate an N-terminal His10-tag, thus rendering isolation of the enzyme from the complicated mixture difficult. The highest volumetric productivity (610 U·L-1·h-1) was achieved when the wild-type gene from F. graminearum was expressed extracellularly in the P. pastoris strain SMD1168H using the pPICZα-system. A C-terminal His6-tag did not significantly affect the production of the enzyme, thus enabling simple purification by immobilized metal ion affinity chromatography. Notably, codon-optimisation of the galox gene for expression in P. pastoris did not result in a higher product yield (g protein·L-1 culture). Effective activation of the enzyme to generate the active-site radical copper complex could be equally well achieved by addition of CuSO4 directly in the culture medium or post-harvest.

Conclusions

The results indicate that intracellular production in E. coli and extracellular production in P. pastoris comprise a complementary pair of systems for the production of GalOx. The prokaryotic host is favored for high-throughput screening, for example in the development of improved enzymes, while the yeast system is ideal for production scale-up for enzyme applications.
t-DARPP regulates phosphatidylinositol-3-kinase-dependent cell growth in breast cancer
Authors: Vangamudi Bhavatarini , Peng Dun-Fa , Cai Qiuyin , El-Rifai Wael , Zheng Wei , Belkhiri Abbes
Published: September 2010

Background

Recent reports have shown that t-DARPP (truncated isoform of DARPP-32) can mediate trastuzumab resistance in breast cancer cell models. In this study, we evaluated expression of t-DARPP in human primary breast tumors, and investigated the role of t-DARPP in regulating growth and proliferation in breast cancer cells.

Results

Quantitative real time RT-PCR analysis using primers specific for t-DARPP demonstrated overexpression of t-DARPP in 36% of breast cancers (13/36) as opposed to absent to very low t-DARPP expression in normal breast tissue (p < 0.05). The mRNA overexpression of t-DARPP was overwhelmingly observed in ductal carcinomas, including invasive ductal carcinomas and intraductal carcinomas, rather than other types of breast cancers. The immunohistochemistry analysis of DARPP-32/t-DARPP protein(s) expression in breast cancer tissue microarray that contained 59 tumors and matched normal tissues when available indicated overexpression in 35.5% of primary breast tumors that were more frequent in invasive ductal carcinomas (43.7%; 21/48). In vitro studies showed that stable overexpression of t-DARPP in MCF-7 cells positively regulated proliferation and anchorage-dependent and -independent growth. Furthermore, this effect was concomitant with induction of phosphorylation of AKTser473 and its downstream target phosphoser9 GSK3β, and increased Cyclin D1 and C-Myc protein levels. The knockdown of endogenous t-DARPP in HCC1569 cells led to a marked decrease in phosphorylation of AKTsser473 and GSK3βser9. The use of PI3K inhibitor LY294002 or Akt siRNA abrogated the t-DARPP-mediated phosphorylation of AKTser473 and led to a significant reduction in cell growth.

Conclusions

Our findings underscore the potential role of t-DARPP in regulating cell growth and proliferation through PI3 kinase-dependent mechanism.
1,2-Dilinoleoyl-sn-glycero-3-phosphoethanolamine ameliorates age-related spatial memory deterioration by preventing neuronal cell death
Authors: Yaguchi Takahiro , Nagata Tetsu , Nishizaki Tomoyuki
Published: September 2010

Background

Accumulating evidence has pointed that a variety of lipids could exert their beneficial actions against dementia including Alzheimer disease and age-related cognitive decline via diverse signaling pathways. Endoplasmic reticulum (ER) stress-induced neuronal apoptosis, on the other hand, is a critical factor for pathogenesis of neurodegenerative diseases such as Alzheimer disease and Parkinson disease, senile dementia, and ischemic neuronal damage. The present study examined the effects of 1,2-dilinoleoyl-sn-glycero-3-phosphoethanolamine (DLPhtEtn), a phospholipid, on ER stress-induced neuronal death and age-related cognitive disorders.

Methods

PC-12 cell viability was assayed before and after treatment with amyloid-β1-40 peptide or thapsigargin in the presence and absence of DLPhtEtn. A series of behavioral tests were performed for senescence-accelerated mouse-prone 8 (SAMP8) mice after 7-month oral administration with polyethylene glycol (PEG) or DLPhtEtn and then, the number of hippocampal neurons was counted.

Results

Amyloid-β1-40 peptide or thapsigargin is capable of causing ER stress-induced apoptosis. DLPhtEtn (30 μM) significantly inhibited PC-12 cell death induced by amyloid-β1-40 peptide or thapsigargin. In the water maze test, oral administration with DLPhtEtn (1 mg/kg) for 7 months (three times a week) significantly shortened the prolonged retention latency for SAMP8 mice. In contrast, DLPhtEtn had no effect on the acquisition and retention latencies in both the open field test and the passive avoidance test for SAMP8 mice. Oral administration with DLPhtEtn (1 mg/kg) for 7 months prevented a decrease in the number of hippocampal neurons for SAMP8 mice.

Conclusion

The results of the present study show that DLPhtEtn ameliorates age-related spatial memory decline without affecting motor activities or fear memory, possibly by protecting hippocampal neuronal death. DLPhtEtn, thus, might exert its beneficial action against senile dementia and neurodegenerative diseases such as Alzheimer disease.
The pituri story: a review of the historical literature surrounding traditional Australian Aboriginal use of nicotine in Central Australia
Authors: Ratsch Angela , Steadman Kathryn J , Bogossian Fiona
Published: September 2010

The harmful outcomes of nicotine self administration have been the focus of sustained global health education campaigns that have targeted tobacco smoking and to a lesser extent, smokeless tobacco use. 'Smokeless tobacco' infers that the nicotine is not burnt, and administration can be through a range of methods including chewing.

The chewing of wild tobacco plants (Nicotianaspp.) is practiced across a broad inland area of Central Australia by traditional Aboriginal groups. Collectively these plants are known by a variety of names - one common name being 'pituri'. This is the first paper to examine the historical literature and consider the linkage between pituri use and health outcomes. Using a narrative approach, this paper reviews the literature generated since 1770 surrounding the term pituri and the behaviours associated with its use. The review examines the scientific literature, as well as the diaries and journals of nineteenth century explorers, expedition notes, and early Australian novels to expound the scientific evidence and broaden the sense of understanding related to pituri, particularly the behavioural elements. The evaluation considers the complexities of ethnobotany pertaining to language and distance and the ethnopharmacology of indigenous plant usage. The review compares the use of burnt and smokeless tobacco to pituri and establishes the foundation for research into the clinical significance and health outcomes of pituri use. Additionally, this review provides contemporary information for clinicians providing care for patients who chew pituri.
A lifeline to treatment: the role of Indian generic manufacturers in supplying antiretroviral medicines to developing countries
Authors: Waning Brenda , Diedrichsen Ellen , Moon Suerie
Published: September 2010

Background

Indian manufacturers of generic antiretroviral (ARV) medicines facilitated the rapid scale up of HIV/AIDS treatment in developing countries though provision of low‐priced, quality‐assured medicines. The legal framework in India that facilitated such production, however, is changing with implementation of the World Trade Organization Agreement on Trade‐Related Aspects of Intellectual Property Rights, and intellectual property measures being discussed in regional and bilateral free trade agreement negotiations. Reliable quantitative estimates of the Indian role in generic global ARV supply are needed to understand potential impacts of such measures on HIV/AIDS treatment in developing countries.

Methods

We utilized transactional data containing 17,646 donor‐funded purchases of ARV tablets made by 115 low‐ and middle‐income countries from 2003 to 2008 to measure market share, purchase trends and prices of Indian‐produced generic ARVs compared with those of non‐Indian generic and brand ARVs.

Results

Indian generic manufacturers dominate the ARV market, accounting for more than 80% of annual purchase volumes. Among paediatric ARV and adult nucleoside and non‐nucleoside reverse transcriptase inhibitor markets, Indian‐produced generics accounted for 91% and 89% of 2008 global purchase volumes, respectively. From 2003 to 2008, the number of Indian generic manufactures supplying ARVs increased from four to 10 while the number of Indian‐manufactured generic products increased from 14 to 53. Ninety‐six of 100 countries purchased Indian generic ARVs in 2008, including high HIV‐burden sub‐Saharan African countries. Indian‐produced generic ARVs used in first‐line regimens were consistently and considerably less expensive than non‐Indian generic and innovator ARVs. Key ARVs newly recommended by the World Health Organization are three to four times more expensive than older regimens.

Conclusions

Indian generic producers supply the majority of ARVs in developing countries. Future scale up using newly recommended ARVs will likely be hampered until Indian generic producers can provide the dramatic price reductions and improved formulations observed in the past. Rather than agreeing to inappropriate intellectual property obligations through free trade agreements, India and its trade partners ‐ plus international organizations, donors, civil society and pharmaceutical manufacturers ‐ should ensure that there is sufficient policy space for Indian pharmaceutical manufacturers to continue their central role in supplying developing countries with low‐priced, quality‐assured generic medicines.
Health-care cost reduction resulting from primary-care allergy testing in children in Italy
Authors: Zethraeus Niklas , Petersson Carl Johan , Dozzi Massimiliano , Borres Magnus P , Vignati Giulio , Fiocchi Alessandro
Published: September 2010

Background

Allergy places a considerable cost burden on society. Specific immunoglobulin E (spIgE) testing may improve the management of allergy patients. There is therefore a reason to quantify the economic consequences of the use of spIgE testing in the diagnosis of allergic conditions.

Methods

The expected costs of spIgE testing versus no-testing were calculated using a clinical decision model based on a prospective clinical trial performed in primary care.

Results

The expected costs per patient over 2 years decreased from 802 euros in the "no-test strategy" to 560 euros in the spIgE "test strategy". Cost savings persisted even after assumptions about the prevalence of allergy and the prices of medications were changed. The "test strategy" increased the percentage of patients correctly diagnosed from 54 to 87%.

Conclusions

spIgE testing of children with respiratory and/or skin problems in primary care in Italy reduces overall costs to society. These cost savings mostly result from a reduction in the use of medications, particularly corticosteroids. The study indicates that spIgE testing of all children with respiratory and/or skin symptoms would be a cost-effective strategy.
Evaluation of Treatment-Effect Heterogeneity Using Biomarkers Measured on a Continuous Scale: Subpopulation Treatment Effect Pattern Plot
Authors: Lazar Ann A. , Cole Bernard F. , Bonetti Marco , Gelber Richard D.
Published: September 2010

The discovery of biomarkers that predict treatment effectiveness has great potential for improving medical care, particularly in oncology. These biomarkers are increasingly reported on a continuous scale, allowing investigators to explore how treatment efficacy varies as the biomarker values continuously increase, as opposed to using arbitrary categories of expression levels resulting in a loss of information. In the age of biomarkers as continuous predictors (eg, expression level percentage rather than positive v negative), alternatives to such dichotomized analyses are needed. The purpose of this article is to provide an overview of an intuitive statistical approach—the subpopulation treatment effect pattern plot (STEPP)—for evaluating treatment-effect heterogeneity when a biomarker is measured on a continuous scale. STEPP graphically explores the patterns of treatment effect across overlapping intervals of the biomarker values. As an example, STEPP methodology is used to explore patterns of treatment effect for varying levels of the biomarker Ki-67 in the BIG (Breast International Group) 1-98 randomized clinical trial comparing letrozole with tamoxifen as adjuvant therapy for postmenopausal women with hormone receptor–positive breast cancer. STEPP analyses showed patients with higher Ki-67 values who were assigned to receive tamoxifen had the poorest prognosis and may benefit most from letrozole.
Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy
Authors: Niitsu Nozomi , Hagiwara Yuki , Tanae Ken , Kohri Mika , Takahashi Naoki
Published: September 2010

Purpose

Recently, there have been reports of hepatitis B virus (HBV) reactivation after rituximab combination chemotherapy in hepatitis B surface antigen (HBsAg) –negative patients with B-cell lymphoma. In this prospective study, the frequency of and risk factors for HBV reactivation in patients who were receiving rituximab chemotherapy were examined.

Patients and Methods

A total of 314 HBsAg-negative patients with diffuse large B-cell lymphoma were treated with rituximab chemotherapy. Antibody to hepatitis B surface antigen (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc) tests were performed in all patients. In patients who were positive for anti-HBs and/or anti-HBc, serum HBV-DNA was measured.

Results

Of the 314 patients, 51 (16.2%) were HBV carriers. HBV reactivation occurred during or after rituximab chemotherapy in six patients (12%). All six patients who developed HBV reactivation were anti-HBc positive, and three of them were also anti-HBs positive. In these six patients, the pretreatment anti-HBs titer was low. Entecavir administration was started when serum HBV DNA became positive, and serum HBV-DNA became negative within 1 to 3 weeks. Rituximab chemotherapy was then continued. Risk factors for HBV reactivation were being male and having a low anti-HBs titer.

Conclusion

HBV reactivation occurred in some patients who had been anti-HBs negative or had a low anti-HBs level. In addition, HBV reactivation occurred at an early stage of rituximab chemotherapy, but rituximab chemotherapy could be continued after entecavir administration reduced the serum HBV-DNA level. Entecavir (BMS 200495) prophylaxis was not performed when rituximab chemotherapy was started, and it was thought that entecavir could be started when serum HBV-DNA increased.
Phase I Study of Vorinostat in Patients With Advanced Solid Tumors and Hepatic Dysfunction: A National Cancer Institute Organ Dysfunction Working Group Study
Authors: Ramalingam Suresh S. , Kummar Shivaani , Sarantopoulos John , Shibata Stephen , LoRusso Patricia , Yerk Mara , Holleran Julianne , Lin Yan , Beumer Jan H. , Harvey R. Donald , Ivy S. Percy , Belani Chandra P. , Egorin Merrill J.
Published: September 2010

Purpose

Vorinostat is the first US Food and Drug Administration–approved histone deacetylase inhibitor and is indicated for the treatment of refractory cutaneous T-cell lymphoma. We conducted a phase I study to determine the maximum-tolerated dose and pharmacokinetics of vorinostat in patients with hepatic dysfunction.

Patients and Methods

Patients had solid malignancies and acceptable bone marrow and renal function. Hepatic dysfunction was categorized as mild, moderate, or severe by the National Cancer Institute Organ Dysfunction Working Group criteria. Fifteen patients with normal liver function were enrolled as controls. All patients received a single 400-mg dose of vorinostat for pharmacokinetic studies. One week later, daily vorinostat dosing was begun and continued until toxicity or disease progression occurred. The daily vorinostat dose was escalated within each hepatic dysfunction category. Vorinostat plasma concentrations were quantitated by a validated liquid chromatography–tandem mass spectrometry assay and modeled noncompartmentally.

Results

Fifty-seven patients were enrolled (median age, 59 years; females, n = 24); 42 patients had hepatic dysfunction (16 mild, 15 moderate, and 11 severe). Eight of nine patients with dose-limiting toxicity had grade 4 thrombocytopenia. The recommended vorinostat doses in mild, moderate, and severe hepatic dysfunction were 300, 200, and 100 mg, respectively, on the daily continuous schedule. There were no significant differences in vorinostat pharmacokinetic parameters among the normal or hepatic dysfunction categories. Disease stabilization was noted in 12 patients. Of five patients with adenoid cystic carcinoma, one patient had a partial response, and four patients had stable disease. A patient with papillary thyroid carcinoma had stable disease for more than 2 years.

Conclusion

Patients with varying degrees of hepatic dysfunction require appropriate dose reduction even though vorinostat pharmacokinetics are unaltered.
Developmental regulation and extracellular release of a VSG expression-site-associated gene product from Trypanosoma brucei bloodstream forms
Authors: Barnwell Eleanor M. , van Deursen Frederick J. , Jeacock Laura , Smith Katherine A. , Maizels Rick M. , Acosta-Serrano Alvaro , Matthews Keith
Published: September 2010

Trypanosomes evade host immunity by exchanging variant surface glycoprotein (VSG) coats. VSG genes are transcribed from telomeric expression sites, which contain a diverse family of expression-site-associated genes (ESAGs). We have discovered that the mRNAs for one ESAG family, ESAG9, are strongly developmentally regulated, being enriched in stumpy forms, a life-cycle stage in the mammalian bloodstream that is important for the maintenance of chronic parasite infections and for tsetse transmission. ESAG9 gene sequences are highly diverse in the genome and encode proteins with weak similarity to the massively diverse MASP proteins in Trypanosoma cruzi. We demonstrate that ESAG9 proteins are modified by N-glycosylation and can be shed to the external milieu, this being dependent upon coexpression with at least one other family member. The expression profile and extracellular release of ESAG9 proteins represents a novel and unexpected aspect of the transmission biology of trypanosomes in their mammalian host. We suggest that these molecules might interact with the external environment, with possible implications for infection chronicity or parasite transmission.
Plasma concentrations of corticosterone and buprenorphine in rats subjected to jugular vein catheterization
Authors: Goldkuhl Renée , Jacobsen Kirsten R , Kalliokoski Otto , Hau Jann , Abelson Klas S P
Published: September 2010

The present study investigated the postoperative plasma concentrations of corticosterone and buprenorphine in male Wistar and Sprague-Dawley rats, treated with buprenorphine administered either through subcutaneous (SC) injection or through voluntary ingestion (VI). The animals were treated with buprenorphine for pre-emptive analgesia prior to surgical placement of a jugular catheter, followed by automated blood sampling during 96 h. Buprenorphine was administered on a regular basis throughout the experiment, and blood was collected on selected time points. Body weight was measured before and 96 h after surgery. It was found that the two rat stocks responded in a similar manner to both buprenorphine treatments, with the exception of body weight change in Wistar rats, in which body weight was reduced after SC treatment. The plasma concentration of corticosterone was significantly higher in the SC-treated animals than in the VI-treated animals during the first 18 h of the study, while plasma buprenorphine concentration was at least as high and more even over time after VI treatment. The present study shows that buprenorphine administration through VI is suitable for both Wistar and Sprague-Dawley rats, with lower stress response and higher plasma concentrations of buprenorphine than after the traditional SC route of administration.
Investment and Market Structure in Industries with Congestion
Authors: Johari Ramesh , Weintraub Gabriel Y. , Van Roy Benjamin
Published: September 2010

We analyze investment incentives and market structure under oligopoly competition in industries with congestion effects. Our results are particularly focused on models inspired by modern technology-based services such as telecommunications and computing services. We consider situations where firms compete by simultaneously choosing prices and investments; increasing investment reduces the congestion disutility experienced by consumers. We define a notion of returns to investment, according to which congestion models inspired by delay exhibit increasing returns, whereas loss models exhibit nonincreasing returns. For a broad range of models with nonincreasing returns to investment, we characterize and establish uniqueness of pure-strategy Nash equilibrium. We also provide conditions for existence of pure-strategy Nash equilibrium. We extend our analysis to a model in which firms must additionally decide whether to enter the industry. Our theoretical results contribute to the basic understanding of competition in service industries and yield insight into business and policy considerations.
Dynamic Policy Modeling for Chronic Diseases: Metaheuristic-Based Identification of Pareto-Optimal Screening Strategies
Authors: Rauner Marion S. , Gutjahr Walter J. , Heidenberger Kurt , Wagner Joachim , Pasia Joseph
Published: September 2010

We present a risk-group oriented chronic disease progression model embedded within a metaheuristic-based optimization of the policy variables. Policy-makers are provided with Pareto-optimal screening schedules for risk groups by considering cost and effectiveness outcomes as well as budget constraints. The quality of the screening technology depends on risk group, disease stage, and time. As the metaheuristic solution technique, we use the Pareto ant colony optimization (P-ACO) algorithm for multiobjective combinatorial optimization problems, which is based on the ant colony optimization paradigm. Our approach is illustrated by a numerical example for breast cancer. For a 10-year time horizon, we provide cost-effective screening schedules for selected annual and total budgets. We then discuss policy implications of 16 mammography screening scenarios varying the screening schedule (annual, biennial, triennial, quadrennial) and the rate of women tested (25%, 50%, 75%, 100%). Due to the model's flexible structure, interventions for multiple chronic diseases can be considered simultaneously.