bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematically characterizing and prioritizing chemosensitivity related gene based on Gene Ontology and protein interaction network
Authors: Chen Xin , Jiang Wei , Wang Qianghu , Huang Teng , Wang Peng , Li Yan , Chen Xiaowen , Lv Yingli , Li Xia
Published: October 2012

Background

The identification of genes that predict in vitro cellular chemosensitivity of cancer cells is of great importance. Chemosensitivity related genes (CRGs) have been widely utilized to guide clinical and cancer chemotherapy decisions. In addition, CRGs potentially share functional characteristics and network features in protein interaction networks (PPIN).

Methods

In this study, we proposed a method to identify CRGs based on Gene Ontology (GO) and PPIN. Firstly, we documented 150 pairs of drug-CCRG (curated chemosensitivity related gene) from 492 published papers. Secondly, we characterized CCRGs from the perspective of GO and PPIN. Thirdly, we prioritized CRGs based on CCRGs’ GO and network characteristics. Lastly, we evaluated the performance of the proposed method.

Results

We found that CCRG enriched GO terms were most often related to chemosensitivity and exhibited higher similarity scores compared to randomly selected genes. Moreover, CCRGs played key roles in maintaining the connectivity and controlling the information flow of PPINs. We then prioritized CRGs using CCRG enriched GO terms and CCRG network characteristics in order to obtain a database of predicted drug-CRGs that included 53 CRGs, 32 of which have been reported to affect susceptibility to drugs. Our proposed method identifies a greater number of drug-CCRGs, and drug-CCRGs are much more significantly enriched in predicted drug-CRGs, compared to a method based on the correlation of gene expression and drug activity. The mean area under ROC curve (AUC) for our method is 65.2%, whereas that for the traditional method is 55.2%.

Conclusions

Our method not only identifies CRGs with expression patterns strongly correlated with drug activity, but also identifies CRGs in which expression is weakly correlated with drug activity. This study provides the framework for the identification of signatures that predict in vitro cellular chemosensitivity and offers a valuable database for pharmacogenomics research.
Molecular mapping of the Pi2/9 allelic gene Pi2-2 conferring broad-spectrum resistance to Magnaporthe oryzae in the rice cultivar Jefferson
Authors: Jiang Nan , Li Zhiqiang , Wu Jun , Wang Yue , Wu Liqun , Wang Suhua , Wang Dan , Wen Ting , Liang Yi , Sun Pingyong , Liu Jinling , Dai Liangying , Wang Zhilong , Wang Chao , Luo Meizhong , Liu Xionglun , Wang Guo-Liang
Published: October 2012

Background

Utilization of broad-spectrum resistance (R) genes is an effective and economical strategy to control the fungal pathogen Magnaporthe oryzae, the causal agent of the rice blast disease. Among the cloned blast resistance genes, Pi9, Pi2 and Piz-t confer broad-spectrum resistance to diverse M. oryzae isolates and were isolated from the Pi2/9 locus on chromosome 6. Identification and isolation of additional R genes with different resistance spectra from this locus will provide novel genetic resources for better control of this important rice disease.

Results

In this study, we identified a dominant R gene, Pi2-2, at the Pi2/9 locus from Jefferson, an elite U.S. rice cultivar, through genetic and physical mapping. Inoculation tests showed that Jefferson has different resistant specificities to M. oryzae isolates compared rice lines with the Pi9, Pi2 and Piz-t genes. Fine mapping delimited Pi2-2 to a 270-kb interval between the markers AP5659-3 and RM19817, and this interval contains three nucleotide-binding site-leucine-rich repeat (NBS-LRR) genes in the Nipponbare genome. Five bacterial artificial chromosome (BAC) clones spanning the region were identified, and a BAC contig covering the Pi2-2 locus was constructed.

Conclusions

We identified a new allelic gene at the Pi2/9 locus and fine-mapped the gene within a 270-kb region. Our results provide essential information for the isolation of the Pi2-2 gene and tightly linked DNA markers for rice blast resistance breeding.
Metformin overdose causes platelet mitochondrial dysfunction in humans
Authors: Protti Alessandro , Lecchi Anna , Fortunato Francesco , Artoni Andrea , Greppi Noemi , Vecchio Sarah , Fagiolari Gigliola , Moggio Maurizio , Comi Giacomo Pietro , Mistraletti Giovanni , Lanticina Barbara , Faraldi Loredana , Gattinoni Luciano
Published: October 2012

Introduction

We have recently demonstrated that metformin intoxication causes mitochondrial dysfunction in several porcine tissues, including platelets. The aim of the present work was to clarify whether it also causes mitochondrial dysfunction (and secondary lactate overproduction) in human platelets, in vitro and ex vivo.

Methods

Human platelets were incubated for 72 hours with saline or increasing doses of metformin (in vitro experiments). Lactate production, respiratory chain complex activities (spectrophotometry), mitochondrial membrane potential (flow-cytometry after staining with JC-1) and oxygen consumption (Clark-type electrode) were then measured. Platelets were also obtained from ten patients with lactic acidosis (arterial pH 6.97 ± 0.18 and lactate 16 ± 7 mmol/L) due to accidental metformin intoxication (serum drug level 32 ± 14 mg/L) and ten healthy volunteers of similar sex and age. Respiratory chain complex activities were measured as above (ex vivo experiments).

Results

In vitro, metformin dose-dependently increased lactate production (P < 0.001), decreased respiratory chain complex I activity (P = 0.009), mitochondrial membrane potential (P = 0.003) and oxygen consumption (P < 0.001) of human platelets. Ex vivo, platelets taken from intoxicated patients had significantly lower complex I (P = 0.045) and complex IV (P < 0.001) activity compared to controls.

Conclusions

Depending on dose, metformin can cause mitochondrial dysfunction and lactate overproduction in human platelets in vitro and, possibly, in vivo.

Trial registration

NCT%2000942123.
BSmooth: from whole genome bisulfite sequencing reads to differentially methylated regions
Authors: Hansen Kasper D , Langmead Benjamin , Irizarry Rafael A
Published: October 2012

DNA methylation is an important epigenetic modification involved in gene regulation, which can now be measured using whole-genome bisulfite sequencing. However, cost, complexity of the data, and lack of comprehensive analytical tools are major challenges that keep this technology from becoming widely applied. Here we present BSmooth, an alignment, quality control and analysis pipeline that provides accurate and precise results even with low coverage data, appropriately handling biological replicates. BSmooth is open source software, and can be downloaded from http://rafalab.jhsph.edu/bsmooth.
H2A.Z landscapes and dual modifications in pluripotent and multipotent stem cells underlie complex genome regulatory functions
Authors: Ku Manching , Jaffe Jacob D , Koche Richard P , Rheinbay Esther , Endoh Mitsuhiro , Koseki Haruhiko , Carr Steven A , Bernstein Bradley E
Published: October 2012

Background

The histone variant H2A.Z has been implicated in nucleosome exchange, transcriptional activation and Polycomb repression. However, the relationships among these seemingly disparate functions remain obscure.

Results

We mapped H2A.Z genome-wide in mammalian ES cells and neural progenitors. H2A.Z is deposited promiscuously at promoters and enhancers, and correlates strongly with H3K4 methylation. Accordingly, H2A.Z is present at poised promoters with bivalent chromatin and at active promoters with H3K4 methylation, but is absent from stably repressed promoters that are specifically enriched for H3K27 trimethylation. We also characterized post-translational modification states of H2A.Z, including a novel species dually-modified by ubiquitination and acetylation that is enriched at bivalent chromatin.

Conclusions

Our findings associate H2A.Z with functionally distinct genomic elements, and suggest that post-translational modifications may reconcile its contrasting locations and roles.
A synthetic peptide derived from the parasite Toxoplasma gondii triggers human dendritic cellsˈ migration
Authors: Persat Florence , Mercier Corinne , Ficheux Damien , Colomb Evelyne , Trouillet Sophie , Bendridi Nadia , Musset Karine , Loeuillet Corinne , Cesbron-Delauw Marie-France , Vincent Claude
Published: October 2012

Pep29, a peptide derived from the Toxoplasma GRA5 protein, is responsible for human dendritic cellsˈ migration toward the CCR7 ligand.

The migration of DCs is a critical function, enabling information to be carried to where the immunological response occurs. Parasites are known to weaken host immunity by interfering with the functions of DCs and thus, may be a source of molecules with immunomodulatory properties. Here, we demonstrate that the soluble protein, GRA5, specific to Toxoplasma gondii, is able to increase the migration of human CD34-DCs toward CCL19. A synthetic Pep29 derived from the GRA5 hydrophilic NT region (Pep29) was found to be internalized by macropinocytosis and to trigger in vitro migration of CD34-DCs via CCR7 expression without activating DCs. Pep29 also induced a decrease in the number of LCs from human skin epidermis. As local depletion of DCs and migration of immature DCs lead to a disruption of the specific innate response, our results highlight the potential of using pathogen-derived synthetic peptides as novel cell modulators with a therapeutic potential to reduce symptoms in inflammatory disorders.
Modeling the Change of Paradigm: Non-Bayesian Reactions to Unexpected News
Authors: Ortoleva Pietro
Published: October 2012

Bayes' rule has two well-known limitations: 1) it does not model the reaction to zero-probability events; 2) a sizable empirical evidence documents systematic violations of it. We characterize axiomatically an alternative updating rule, the Hypothesis Testing model. According to it, the agent follows Bayes' rule if she receives information to which she assigned a probability above a threshold. Otherwise, she looks at a prior over priors, updates it using Bayes' rule for second-order priors, and chooses the prior to which the updated prior over priors assigns the highest likelihood. We also present an application to equilibrium refinement in game theory. (JEL D11, D81, D83)
Liquidity, Monetary Policy, and the Financial Crisis: A New Monetarist Approach
Authors: Williamson Stephen D
Published: October 2012

A model of public and private liquidity integrates financial intermediation theory with a New Monetarist monetary framework. Non-passive fiscal policy and costs of operating a currency system imply that an optimal policy deviates from the Friedman rule. A liquidity trap can exist in equilibrium away from the Friedman rule, and there exists a permanent nonneutrality of money, driven by an illiquidity effect. Financial frictions can produce a financial-crisis phenomenon that can be mitigated by conventional open market operations working in an unconventional manner. Private asset purchases by the central bank are either irrelevant or they reallocate credit and redistribute income. (JEL E13, E44, E52, E62, G01)
Sinking, Swimming, or Learning to Swim in Medicare Part D
Authors: Ketcham Jonathan D , Lucarelli Claudio , Miravete Eugenio J , Roebuck M. Christopher
Published: October 2012

Under Medicare Part D, senior citizens choose prescription drug insurance offered by numerous private insurers. We examine nonpoor enrollees' actions in 2006 and 2007 using panel data. Our sample reduced overspending by $298 on average, with gains by 81 percent of them. The greatest improvements were by those who overspent most in 2006 and by those who switched plans. Decisions to switch depended on individuals' overspending in 2006 and on individual-specific effects of changes in their current plans. The oldest consumers and those initiating medications for Alzheimer's disease improved by more than average, suggesting that real-world institutions help overcome cognitive limitations. (JEL D14, G22, H51, I13, I18)
Reset Price Inflation and the Impact of Monetary Policy Shocks
Authors: Bils Mark , Klenow Peter J , Malin Benjamin A
Published: October 2012

Many business cycle models use a flat short-run Phillips curve, due to time-dependent pricing and strategic complementarities, to explain fluctuations in real output. But, in doing so, these models predict unrealistically high persistence and stability of US inflation in recent decades. We calculate “reset price inflation”—based on new prices chosen by the subsample of price changers—to dissect this discrepancy. We find that the models generate too much persistence and stability both in reset price inflation and in the way reset price inflation is converted into actual inflation. Our findings present a challenge to existing explanations for business cycles. (JEL E31, E52)
Is the Volatility of the Market Price of Risk Due to Intermittent Portfolio Rebalancing?
Authors: Chien YiLi , Cole Harold , Lustig Hanno
Published: October 2012

Our paper examines whether the failure of unsophisticated investors to rebalance their portfolios can help to explain the countercyclical volatility of aggregate risk compensation in financial markets. To answer this question, we set up a model in which a large mass of investors do not rebalance their portfolio shares in response to aggregate shocks, while a smaller mass of active investors do. We find that intermittent rebalancers more than double the effect of aggregate shocks on the time variation in risk premia by forcing active traders to sell more shares in good times and buy more shares in bad times. (JEL D14, E32, G11, G12)
Credit Market Consequences of Improved Personal Identification: Field Experimental Evidence from Malawi
Authors: Giné Xavier , Goldberg Jessica , Yang Dean
Published: October 2012

We implemented a randomized field experiment in Malawi examining borrower responses to being fingerprinted when applying for loans. This intervention improved the lender's ability to implement dynamic repayment incentives, allowing it to withhold future loans from past defaulters while rewarding good borrowers with better loan terms. As predicted by a simple model, fingerprinting led to substantially higher repayment rates for borrowers with the highest ex ante default risk, but had no effect for the rest of the borrowers. We provide unique evidence that this improvement in repayment rates is accompanied by behaviors consistent with less adverse selection and lower moral hazard. (JEL D14, D82, G21, O12, O16)
Testing Models of Consumer Search Using Data on Web Browsing and Purchasing Behavior
Authors: Santos Babur De los , Hortaçsu Ali , Wildenbeest Matthijs R
Published: October 2012

Using a large dataset on web browsing and purchasing behavior we test to what extent consumers are searching in accordance to various search models. We find that the benchmark model of sequential search with a known price distribution can be rejected based on recall patterns found in the data as well as the absence of dependence of search decisions on prices. Our findings suggest fixed sample size search provides a more accurate description of search behavior. We then utilize the fixed sample size search model to estimate demand elasticities of online bookstores in an environment where store preferences are heterogeneous. (JEL D12, D83, L81)
The Colonial Origins of Comparative Development: An Empirical Investigation: Comment
Authors: Albouy David Y
Published: October 2012

Acemoglu, Johnson, and Robinson's (2001) seminal article argues property-rights institutions powerfully affect national income, using estimated mortality rates of early European settlers to instrument capital expropriation risk. However, 36 of the 64 countries in the sample are assigned mortality rates from other countries, often based on mistaken or conflicting evidence. Also, incomparable mortality rates from populations of laborers, bishops, and soldiers—often on campaign—are combined in a manner that favors the hypothesis. When these data issues are controlled for, the relationship between mortality and expropriation risk lacks robustness, and instrumental-variable estimates become unreliable, often with infinite confidence intervals. (JEL D02, E23, F54, I12, N40, O43, P14)
The Colonial Origins of Comparative Development: An Empirical Investigation: Reply
Authors: Acemoglu Daron , Johnson Simon , Robinson James A
Published: October 2012

Acemoglu, Johnson, and Robinson (2001) established that economic institutions today are correlated with expected mortality of European colonialists. David Albouy argues this relationship is not robust. He drops all data from Latin America and much of the data from Africa, making up almost 60 percent of our sample, despite much information on the mortality of Europeans in those places during the colonial period. He also includes a “campaign” dummy that is coded inconsistently; even modest corrections undermine his claims. We also show that limiting the effect of outliers strengthens our results, making them robust to even extreme versions of Albouy's critiques. (JEL D02, E23, F54, I12, N40, O43, P14)
Levoleucovorin as Replacement for Leucovorin in Cancer Treatment
Authors: Chuang Victor Tuan Giam , Suno Manabu
Published: October 2012

Objective:

To comprehensively review the literature regarding the efficacy, safety, and costs associated with the use of levoleucovorin in cancer treatment and to assess whether levoleucovorin would be a reasonable alternative to the use of racemic leucovorin.

Data Sources:

A MEDLINE search was conducted for English-language human studies published between January 1980 and April 2012 using the terms I-LV. levoleucovorin, d,I-LV, leucovorin, folinic acid, tolinate, 5-formyltetrahydrofolate, folic acid, folates, methotrexate, 5-fluorouracil, and clinical trials.

Study Selection and Data Extraction:

Articles pertinent to clinical trials (Phase 1, 2, 3) related to evaluating the efficacy, interchangeability, and safety of levoleucovorin were collected and their contents reviewed.

Data Synthesis:

From these pharmacokinetics and clinical studies, information on the use of levoleucovorin as a modulator of fluorouracil as well as when combined with other antitumor agents were scrutinized and extracted for comparison with leucovorin whenever possible. Two randomized Phase 3 clinical studies comparing the efficacy and adverse effect profiles of leucovorin and levoleucovorin demonstrated that levoleucovorin is as effective as leucovorin in terms of response, toxicity, and survival. Six randomized Phase 3 clinical studies demonstrated the safety and efficacy of levoleucovorin as a modulator of fluorouracil in combination with/without other antitumor agents in colorectal cancer patients. Levoleucovorin has been studied in other cancers. These clinical Phase 1/2/3 studies demonstrated efficacy and safety of levoleucovorin in combination chemotherapeutic regimens comprising fluorouracil and other antitumor agents.

Conclusions:

The results of the clinical studies suggest that levoleucovorin is efficacious and can be used safely in combination with fluorouracil and other antitumor agents. Levoleucovorin can be used interchangeably with leucovorin for modulating fluorouracil. The current shortage of the supply of leucovorin centered in North America renders levoleucovorin a reasonable alternative in terms of efficacy and toxicity profile, but from the perspective of cost, leucovorin remains the drug of choice.
Examination of the Relationship Between Antimicrobials and Thrombocytosis
Authors: Forehand Christy C , Cribb Jennifer , May J Russell
Published: October 2012

Objective:

To evaluate whether there is a relationship between antimicrobial therapy and the development of thrombocytosis.

Data Sources:

Literature was accessed through EMBASE (1977-June 2012) and MEDLINE (1977-June 2012) using the terms thrombocytosis and antimicrobial. In addition, reference citations from publications identified were reviewed.

Study Selection and Data Extraction:

All English-language publications identified were evaluated. For case reports, the Naranjo probability scale was used to calculate the likelihood of the drug causing the reaction.

Data Synthesis:

Thrombocytosis occurring during antimicrobial therapy is well documented, with several case reports and clinical trial observations. However, a direct causal relationship is not yet supported by the available literature. Platelets are welt known to be an acute phase reactant, with an elevated count occurring after acute conditions such as blood loss, inflammation, or infection. Thrombocytosis during antimicrobial therapy may be the result of an infectious process and not an adverse drug event.

Conclusions:

Based on the current available literature, a definitive link cannot be established between antimicrobial therapy and occurrence of thrombocytosis.
Paradoxical Reaction of Raynaud Phenomenon following the Repeated Administration of Lloprost in a Patient with Diffuse Cutaneous Systemic Sclerosis
Authors: Barreira Rebeca Iglesias , García Belén Bardán , López Mónica Granero , Legazpi Iria Rodríguez , Díaz Hortensia Álvarez , Penín Isaura Rodríguez
Published: October 2012

Objective

TO report a paradoxical reaction of Raynaud phenomenon following the repeated administration of iloprost in a patient with diffuse cutaneous systemic sclerosis with vascular involvement.

Case Summary

In January 2006, a 40-year-old male was diagnosed with diffuse cutaneous systemic sclerosis with pulmonary, esophageal, cutaneous, and vascular involvement (Raynaud phenomenon, with digital ulcers on his hands). In December 2008, treatment with iloprost was started due to worsening disease. Nine cycles of iloprost were administered at a rate of 0.5–1 ng/kg/min (6 hours per day, for 5 days every 6–8 weeks); the patient tolerated this treatment well. However, on the fourth day of cycles 10 and 11, the patient developed paradoxical Raynaud phenomenon in the hand with perfusion when the infusion was increased to 1 ng/kg/min, requiring treatment to be stopped. Treatment was continued during cycles 12 and 13 at 0.5 ng/kg/min; the patient tolerated the treatment well, although paradoxical Raynaud phenomenon occurred when the rate of infusion was increased.

Discussion

Raynaud phenomenon is extremely common in patients with scleroderma, and often is severe. Iloprost has vasodilating, antiplatelet, cytoprotective, and immunomodulating properties, and has been found to be an efficacious alternative to nifedipine for the treatment of Raynaud phenomenon in patients with scleroderma. The Naranjo probability scale indicated that iloprost was the probable cause of the paradoxical Raynaud phenomenon in this patient.

Conclusions

This case demonstrates a probable relationship between the rate of infusion of iloprost and the paradoxical reaction of Raynaud phenomenon.
Drug-Related Problems and Hospital Admissions in Cardiac Transplant Recipients
Authors: Repp Kristin L , Hayes Charles , Woods T Mark , Allen Keith B , Kennedy Kevin , Borkon Michael A
Published: October 2012

Background:

Drug-related problems (DRPs) in the general population account for 15% of all hospital admissions, of which approximately 30% are preventable. Cardiac transplant patients may be at increased risk for DRPs because of their complicated medication regimens that include drugs with a narrow therapeutic index.

Objective:

To determine the incidence and praventability of DRPs causing hospital admission in cardiac transplant patients at a single institution.

Methods:

Between November 2009 and January 2010, a prospective longitudinal study investigated the incidence and preventability of DRPs in a single cardiac transplant center. Three independent reviewers used validated scoring systems to determine the incidence and preventability of drug-related hospital admissions. DRPs were classified by type, pharmacologic class, and impact on length of stay.

Results:

During the 3-month study period, 48 cardiac transplant patients were hospitalized. DRPs accounted for 40% (19/48) of these admissions and 58% (11/19) were adjudicated to be preventable. Common DRPs included supratherapeutic (32%) and subtherapeutic (16%) dosage, adverse drug reaction (32%), drug interaction (5%), and nonadherence (5%). Pharmacologic classes implicated included immunosuppressant (63%), antimicrobial (11%), electrolyte/fluid (11%). and anticoagulant (5%). Average length of stay in drug-related compared to non-drug-related admissions was 11.4 versus 8.5 days (p = 0.458). When annualized, 44 hospitalizations or 500 hospital days may have been prevented.

Conclusions:

Hospital admissions following cardiac transplantation are often drug related (40%) and preventable (58%). Incorporating this insight into the multidisciplinary transplant team may improve outcomes, assist in meeting national quality mandates by the United Network for Organ Sharing and Centers for Medicare Services, and lead to new benchmarks for transplant centers.
Teratogenic Risk of Statins in Pregnancy
Authors: Godfrey Laura M , Erramouspe John , Cleveland Kevin W
Published: October 2012

Objective:

To evaluate the teratogenic potential of statins in women of child-bearing age.

Data Sources:

A PubMed search (1980-September 2012) was performed using the search terms statin and pregnancy, then repealed using statin and teratogenicity. Results were limited to articles published in English reporting on use of statins in humans.

Study Selection and Data Extraction:

All articles presenting data on pregnancy outcomes after statin use during any trimester of pregnancy were included. Three case reports, 2 case series, 2 systematic reviews, 2 registry-based studies, and 1 prospective observational cohort study were reviewed.

Data Synthesis:

Since initial premarketing studies of lovastatin in animals, terato-genesis has been assumed to be a classwide function of statins' mechanism of action. Data from human exposure during pregnancy have been gathered and analyzed in a variety of study formats to formulate useable conclusions on statins' actual teratogenic risk and pattern of associated birth defects. Although the current trend is that actual risk is lower than once thought, the available literature is limited by potential reporting bias, contains overlap in the data, and frequently lacks numbers of total exposures to statins during pregnancy with reported malformations. Additionally, no human studies included data on the 2 newest statins (rosuvastatin, pitavastatin); the more lipophilic statins (lovastatin, simvastatin) have the most experience and thus have more evidence related to teratogenic potential.

Conclusions:

Human teratogenic risk has not been proven nor has it been ruled out by the available data on statin use in pregnancy. Possible differences in risk between individual statins require further evaluation. Additional data, including prospective observational cohorts with inadvertent maternal exposure to statins during early weeks of gestation, should further help to clarify appropriate recommendations for statin use in this population.
Readministration of Calcineurin Inhibitors for Ulcerative Colitis
Authors: Hiraoka Sakiko , Kato Jun , Suzuki Hideyuki , Yamamoto Kazuhide
Published: October 2012

Background:

Calcineurin inhibitors (CNIs) such as cyclosporins and tacrolimus have been shown to be effective for treatment of patients with steroid-dependent or steroid-refractory ulcerative colitis (UC) with moderate to severe activity. However, it has not been determined whether readministration of CNIs is effective in patients who experience relapse after remission induced by CNIs.

Objective:

To determine the effect of readministration of CNIs in patients who had initially responded to CNIs.

Methods:

A review of the medical records of 46 patients with moderate to severe UC who were treated with a CNI at a single tertiary teaching hospital with 840 beds was conducted. Remission was defined as a clinical activity index (CAI) score of 3 or less within 2 months of starting CNI therapy. Response was defined as a CAI score of 4 or higher but had decreased by half from the start of CNI therapy. Relapse was defined as flare-up of symptoms that required an additional treatment or colectomy.

Results:

Of the 46 patients, 37 (80%) achieved clinical remission or response with the initial CNI treatment. Among those 37 patients, 19 experienced relapse (median duration to relapse, 6.4 months), 12 of whom were readministered a CNI. Of the 12 patients, 2 achieved clinical remission, 2 had a response, and the remaining 8 had no response to the CNI. In addition, all patients who responded to CNI readministration experienced relapse within 6 months. CNI readministration was significantly less effective than the initial administration (or treatment of UC (80% vs 33%; p = 0.0014).

Conclusions:

Readministration of CNIs for relapse after remission with CNI treatment does not seem to be successful. Alternative therapies such as anti-tumor necrosis factor antibody should be used or colectomy should be considered.
Continuous Infusion Vancomycin for Treatment of Methicillin-Resistant Staphylococcus aureus in Cystic Fibrosis Patients
Authors: Fung Lela
Published: October 2012

Objective

To report 3 cases of methiciIlin-resistant Staphylococcus aureus (MRSA) in pediatric patients with cystic fibrosis (CF), all of whom had inadequate serum concentrations of vancomycin with conventional intermittent dosing and who achieved therapeutic serum concentrations with continuous infusions of vancomycin.

Case Summary

In the first case, a 3-year-old patient failed to achieve therapeutic vancomycin trough concentrations despite 2 dose adjustments up to 19 mg/kg every 6 hours. A continuous infusion was initiated and a therapeutic steady-state level was obtained. The remaining case reports describe 2 patients who were readmitted to the hospital after having received intermittent dosing as outpatients. Continuous infusions were started upon readmission, and therapeutic serum concentrations were achieved in both patients.

Discussion

MRSA is a common pathogen in patients with CR. Intravenous vancomycin, a time-dependent antibiotic that is extensively eliminated by the kidneys, is frequently used to treat MRSA infections. Serum trough concentrations of 15–20 mg/L are considered therapeutic, but these levels are difficult to achieve in patients with CF because of increased renal clearance. Continuous infusions of vancomycin were successfully used in the patients described here and resulted in decreased total daily doses of vancomycin, clinical improvement, and no evidence of nephrotoxicity.

Conclusions

Although more extensive studies are necessary, the cases presented here suggest that continuous infusion vancomycin is a safe and convenient therapy for MRSA infections.
Associations Between Patterns of Emerging Sexual Behavior and Young Adult Reproductive Health
Authors: Haydon Abigail A. , Herring Amy H. , Halpern Carolyn Tucker
Published: October 2012

CONTEXT

Identifying young adult outcomes associated with adolescent sexual behavior, including patterns of first oral, vaginal and anal sex, is critical to promoting healthy sexual development.

METHODS

Associations between patterns of emerging sexual behavior, defined using latent class analysis, and young adult sexual and reproductive health were examined among 9,441 respondents to Waves 1 (1994–1995), 3 (2001–2002) and 4 (2008) of the National Longitudinal Study of Adolescent Health. Logistic regression analyses examined associations between class membership and young adult outcomes, and tested for interactions by race and ethnicity.

RESULTS

Compared with respondents who initiated vaginal sex first and reported other sexual behaviors within two years, those who initiated oral and vaginal sex during the same year had similar odds of having had an STD diagnosis ever or in the last year, of having had concurrent sexual partnerships in the last year and of having exchanged sex for money. However, respondents who postponed sexual activity had reduced odds of each outcome (odds ratios, 0.2–0.4); those who initiated vaginal sex and reported only one type of sexual behavior had reduced odds of reporting STD diagnoses and concurrent partnerships (0.4–0.6). Respondents who reported early initiation of sexual activity combined with anal sex experience during adolescence had elevated odds of having had concurrent partnerships (1.6). The data suggest racial and ethnic disparities even when patterns of emerging sexual behavior were the same.

CONCLUSIONS

Patterns of early sexual behavior considered high‐risk may not predict poor sexual and reproductive health in young adulthood.
An Introduction to Proteoglycans and Their Localization
Authors: Couchman John R. , Pataki Csilla A.
Published: October 2012

Proteoglycans comprise a core protein to which one or more glycosaminoglycan chains are covalently attached. Although a small number of proteins have the capacity to be glycanated and become proteoglycans, it is now realized that these macromolecules have a range of functions, dependent on type and in vivo location, and have important roles in invertebrate and vertebrate development, maintenance, and tissue repair. Many biologically potent small proteins can bind glycosaminoglycan chains as a key part of their function in the extracellular matrix, at the cell surface, and also in some intracellular locations. Therefore, the participation of proteoglycans in disease is receiving increased attention. In this short review, proteoglycan structure, function, and localizations are summarized, with reference to accompanying reviews in this issue as well as other recent literature. Included are some remarks on proteoglycan and glycosaminoglycan localization techniques, with reference to the special physicochemical properties of these complex molecules.
Short-term Hypoxia Transiently Increases Dopamine β-Hydroxylase Immunoreactivity in Glomus Cells of the Rat Carotid Body
Authors: Kato Kouki , Yokoyama Takuya , Yamaguchi-Yamada Misuzu , Yamamoto Yoshio
Published: October 2012

Under long-term hypoxia, noradrenaline (NA) content in the carotid body (CB) increases, suggesting that NA plays an important role in CB chemotransduction. However, it is unknown whether short-term hypoxia upregulates NA biosynthesis in CB. Therefore, we examined dopamine β-hydroxylase (DBH) expression in the CB of rats exposed to hypoxia (10% O2) for 0 to 24 hr with immunoblotting and immunohistochemistry. Using immunoblotting, the signal intensity for DBH appeared to be the most intense in rats exposed to hypoxia for 12 hr. Using immunohistochemistry, DBH immunoreactivity was observed in the cytoplasm of some glomus cells and varicosities in controls and rats exposed to hypoxia for 6 hr. In rats exposed to hypoxia for 12 hr, DBH immunoreactive intensities in DBH-positive glomus cells were significantly higher compared with controls ( p<0.05). In the CB of rats exposed to hypoxia for 18 and 24 hr, DBH immunoreactive intensities in DBH-positive glomus cells were significantly lower than that of rats exposed to hypoxia for 12 hr ( p<0.05). These results demonstrate that DBH immunoreactivity is transiently increased in glomus cells by short-term hypoxia, suggesting that NA biosynthesis is transiently facilitated in glomus cells at an early stage of hypoxia.
Renaissance of Korean Film Industry
Authors: Hyun Daiwon
Published: October 2012

For three years, since 1999, when Shiri broke records, the battle for the Korean box office has been really tough. In Spring 2001, a Korean-produced film, Friends, became a new box office record, with over 8 million audience, shattering the records of Shiri and JSA, both of which drew
about 6 million viewers each. In the Summer, another Korean film, Wild Beauty, supplanted Friends as Korea's top-grossing film with one million viewers in only six days. Surely there was competition. A Hollywood blockbuster, Planet of the Apes, premiered almost at the same time, but Wild Beauty
beat it. And still to come is Musa: The Warrior, the most expensive film in Korean history in terms of production cost, which would be expected to outdo Wild Beauty soon. Stephen Short of Time Asia describes the Korean film industry as "Asia's cine-stud right now."
The Effects of Perceived Brand Globalness and Perceived Brand Localness in China: Empirical Evidence on Western, Asian, and Domestic Retailers
Authors: Swoboda Bernhard , Pennemann Karin , Taube Markus
Published: October 2012

Internationalizing retailers have shifted their attention to developing countries in which they pursue different forms of adapted-format transfer strategies to succeed locally. However, little is known about whether such retailers can use their core advantage of a global retail brand and how consumer perceptions of such global retail brands drive retail patronage. To expand knowledge on this issue, the authors use data from 1188 Chinese consumer surveys on 36 Western, Asian, and mainland Chinese retailers. They find that retailers’ perceived brand globalness and perceived brand localness enhance retail patronage only by affecting consumers’ functional and psychological values. These value creation routes to success change according to retailers’ origins. Although Western and Asian retailers draw equally strong benefits from their global perceptions, Asian retailers convince consumers predominantly through functional values, whereas Western retailers also influence consumers emotionally. Chinese retailers gain consumers by being perceived as “glocal” brands. Furthermore, perceived brand globalness enhances retail patronage most strongly for global identity consumers. Thus, retailers in emerging countries benefit from perceived brand globalness depending on retailer- and consumer-specific boundary conditions.
The Impact of Product Recalls on Future Product Reliability and Future Accidents: Evidence from the Automobile Industry
Authors: Kalaignanam Kartik , Kushwaha Tarun , Eilert Meike
Published: October 2012

Although the goal of a product recall program is to enhance safety, little is known about whether firms learn from product recalls. This study tests the direct effect of product recalls on future accidents and future recall frequency and their indirect effect through future product reliability in the automobile industry. The authors test the hypotheses on 459 make/year observations involving 27 automobile makers between 1995 and 2011. The findings suggest that increases in recall magnitude lead to decreases in future number of injuries and recalls. This effect, in turn, is partially mediated by future changes in product reliability. The results also suggest that the positive relationship between recall magnitude and future product reliability is (1) stronger for firms with higher shared product assets and (2) weaker for brands of higher prior quality. The findings are robust across alternate measures and alternate model specifications and offer valuable insights for managerial practice and public policy.
Analysis of Synaptic Growth and Function inDrosophilawith an Extended Larval Stage
Authors: Miller Daniel L. , Ballard Shannon L. , Ganetzky Barry
Published: October 2012

TheDrosophilalarval neuromuscular junction (NMJ) is a powerful system for the genetic and molecular analysis of neuronal excitability, synaptic transmission, and synaptic development. However, its use for studying age-dependent processes, such as maintenance of neuronal viability and synaptic stability, are temporally limited by the onset of pupariation and metamorphosis. Here we characterize larval NMJ growth, growth regulation, structure, and function in a developmental variant with an extended third instar (ETI). RNAi-knockdown of the prothoracicotropic hormone receptor,torso, in the ring gland of developing larvae leaves the timing of first and second instar molts largely unchanged, but triples duration of the third instar from 3 to 9.5 d (McBrayer et al., 2007; Rewitz et al., 2009). During this ETI period, NMJs undergo additional growth (adding >50 boutons/NMJ), and this growth remains under the control of the canonical regulators Highwire and the TGFβ/BMP pathway. NMJ growth during the ETI period occurs via addition of new branches, satellite boutons, and interstitial boutons, and continues even after muscle growth levels off. Throughout the ETI, organization of synapses and active zones remains normal, and synaptic transmission is unchanged. These results establish the ETI larval system as a viable model for studying motor neuron diseases and for investigating time-dependent effects of perturbations that impair mechanisms of neuroprotection, synaptic maintenance, and response to neural injury.
Interleukin-1β Causes Anxiety by Interacting with the Endocannabinoid System
Authors: Rossi Silvia , Sacchetti Lucia , Napolitano Francesco , De Chiara Valentina , Motta Caterina , Studer Valeria , Musella Alessandra , Barbieri Francesca , Bari Monica , Bernardi Giorgio , Maccarrone Mauro , Usiello Alessandro , Centonze Diego
Published: October 2012

Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The synaptic basis of IL-1β-induced emotional disturbances is still unknown. To address the possible involvement of the endocannabinoid system in IL-1β-induced anxiety, we performed behavioral and neurophysiological studies in mice exposed to stress or to intracerebroventricular injections of this inflammatory cytokine or of its antagonist. We found that a single intracerebroventricular injection of IL-1β caused anxiety in mice, and abrogated the sensitivity of cannabinoid CB1 receptors (CB1Rs) controlling GABA synapses in the striatum. Identical behavioral and synaptic results were obtained following social defeat stress, and intracerebroventricular injection of IL-1 receptor antagonist reverted both effects. IL-1β-mediated inhibition of CB1R function was secondary to altered cholesterol composition within membrane lipid rafts, and required intact function of the transient receptor potential vanilloid 1 (TRPV1) channel, another element of the endocannabinoid system. Membrane lipid raft disruption and inhibition of cholesterol synthesis, in fact, abrogated IL-1β–CB1R coupling, and TRPV1−/− mice were indeed insensitive to the synaptic and behavioral effects of both IL-1β and stress. On the other hand, cholesterol enrichment of striatal slices mimicked the synaptic effects of IL-1β on CB1Rs only in control mice, while the same treatment was ineffective in slices prepared from TRPV1−/− mice. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.
p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury
Authors: Floriddia Elisa M. , Rathore Khizr I. , Tedeschi Andrea , Quadrato Giorgia , Wuttke Anja , Lueckmann Jan-Matthis , Kigerl Kristina A. , Popovich Phillip G. , Di Giovanni Simone
Published: October 2012

Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53−/−versus wild-type mice. p53−/−spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss- and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53−/−mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers.In vivoexpression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53−/−mice, while, similarly, p53 expression in p53−/−cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.
A Role for Atypical CadherinCelsr3in Hippocampal Maturation and Connectivity
Authors: Feng Jia , Xu Ying , Wang Meizhi , Ruan Yiwen , So Kwok-Fai , Tissir Fadel , Goffinet Andre , Zhou Libing
Published: October 2012

Atypical cadherin Celsr3, a regulator of planar cell polarity, is critical for the development of the axonal blueprint. We previously showed that expression of Celsr3 is necessary to establish forebrain connections such as the anterior commissure and thalamocortical and corticospinal tracts. The requirement for Celsr3 during hippocampal wiring and its action in the hippocampus remain largely unexplored. Here, we compared the connectivity and maturation of the hippocampal formation inCelsr3|Foxg1andCelsr3|Dlxmice.Celsr3is inactivated in the whole telencephalon, including the hippocampal primordium, inCelsr3|Foxg1mice, and in the early basal telencephalon, including ganglionic eminences and ventral diencephalon, inCelsr3|Dlxmice. Behavioral tests showed that both mutants were hyperactive and had impaired learning and memory. Abnormal cytoarchitecture of CA1, CA3, and dentate gyrus was found in theCelsr3|Foxg1mutant, in which afferent and efferent hippocampal pathways, as well as intrinsic connections, were dramatically disrupted. InCelsr3|Dlxmutant mice, hippocampal cytoarchitecture was mildly affected and extrinsic and intrinsic connectivity moderately disturbed. In both mutants, pyramidal neurons in CA1 harbored atrophic dendritic trees, with decreased synapse density and increased proportion of symmetric versus asymmetric synapses, and long-term potentiation was altered. In contrast, mutant hippocampal neurons extended neurites that were normal, even longer than those of control neurons, indicating that anomaliesin vivoare secondary to defective connections. Postnatal neurogenesis was preserved and mutant interneurons were able to migrate to the hippocampus. Thus, like in neocortex, Celsr3 is required for hippocampal development, connectivity and function, and for pyramidal cell maturation.
Effects of Decision Variables and Intraparietal Stimulation on Sensorimotor Oscillatory Activity in the Human Brain
Authors: Gould Ian C. , Nobre Anna C. , Wyart Valentin , Rushworth Matthew F. S.
Published: October 2012

To decide effectively, information must not only be integrated from multiple sources, but it must be distributed across the brain if it is to influence structures such as motor cortex that execute choices. Human participants integrated information from multiple, but only partially informative, cues in a probabilistic reasoning task in an optimal manner. We tested whether lateralization of alpha- and beta-band oscillatory brain activity over sensorimotor cortex reflected decision variables such as the sum of the evidence provided by observed cues, a key quantity for decision making, and whether this could be dissociated from an update signal reflecting processing of the most recent cue stimulus. Alpha- and beta-band activity in the electroencephalogram reflected the logarithm of the likelihood ratio associated with the each piece of information witnessed, and the same quantity associated with the previous cues. Only the beta-band, however, reflected the most recent cue in a manner that suggested it reflected updating processes associated with cue processing. In a second experiment, transcranial magnetic stimulation-induced disruption was used to demonstrate that the intraparietal sulcus played a causal role both in decision making and in the appearance of sensorimotor beta-band activity.