bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical constituents of ambient particulate air pollution and biomarkers of inflammation, coagulation and homocysteine in healthy adults: A prospective panel study
Authors: Wu Shaowei , Deng Furong , Wei Hongying , Huang Jing , Wang Hongyi , Shima Masayuki , Wang Xin , Qin Yu , Zheng Chanjuan , Hao Yu , Guo Xinbiao
Published: December 2012

Background

Ambient air pollution has been associated with activation of systemic inflammation and hypercoagulability and increased plasma homocysteine, but the chemical constituents behind the association are not well understood. We examined the relations of various chemical constituents of fine particles (PM2.5) and biomarkers of inflammation, coagulation and homocysteine in the context of traffic-related air pollution.

Methods

A panel of 40 healthy college students underwent biweekly blood collection for 12 times before and after their relocation from a suburban campus to an urban campus with changing air pollution contents in Beijing. Blood samples were measured for circulatory biomarkers of high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor alpha (TNF-α), fibrinogen, plasminogen activator inhibitor type 1 (PAI-1), tissue-type plasminogen activator (t-PA), von Willebrand factor (vWF), soluble platelet selectin (sP-selectin), and total homocysteine (tHcy). Various air pollutants were measured in a central air-monitoring station in each campus and 32 PM2.5 chemical constituents were determined in the laboratory. We used three different mixed-effects models (single-constituent model, constituent-PM2.5 joint model and constituent residual model) controlling for potential confounders to estimate the effects of PM2.5 chemical constituents on circulatory biomarkers.

Results

We found consistent positive associations between the following biomarkers and PM2.5 chemical constituents across different models: TNF-α with secondary organic carbon, chloride, zinc, molybdenum and stannum; fibrinogen with magnesium, iron, titanium, cobalt and cadmium; PAI-1 with titanium, cobalt and manganese; t-PA with cadmium and selenium; vWF with aluminum. We also found consistent inverse associations of vWF with nitrate, chloride and sodium, and sP-selectin with manganese. Two positive associations of zinc with TNF-α and of cobalt with fibrinogen, and two inverse associations of nitrate with vWF, and of manganese with sP-selectin, were independent of the other constituents in two-constituent models using constituent residual data. We only found weak air pollution effects on hs-CRP and tHcy.

Conclusions

Our results provide clues for the potential roles that PM2.5 chemical constituents may play in the biological mechanisms through which air pollution may influence the cardiovascular system.
Identification of new cell size control genes in S. cerevisiae
Authors: Dungrawala Huzefa , Hua Hui , Wright Jill , Abraham Lesley , Kasemsri Thivakorn , McDowell Anthony , Stilwell Jessica , Schneider Brandt L
Published: December 2012

Cell size homeostasis is a conserved attribute in many eukaryotic species involving a tight regulation between the processes of growth and proliferation. In budding yeast S. cerevisiae, growth to a “critical cell size” must be achieved before a cell can progress past START and commit to cell division. Numerous studies have shown that progression past START is actively regulated by cell size control genes, many of which have implications in cell cycle control and cancer. Two initial screens identified genes that strongly modulate cell size in yeast. Since a second generation yeast gene knockout collection has been generated, we screened an additional 779 yeast knockouts containing 435 new ORFs (~7% of the yeast genome) to supplement previous cell size screens. Upon completion, 10 new strong size mutants were identified: nine in log-phase cells and one in saturation-phase cells, and 97% of the yeast genome has now been screened for cell size mutations. The majority of the logarithmic phase size mutants have functions associated with translation further implicating the central role of growth control in the cell division process. Genetic analyses suggest ECM9 is directly associated with the START transition. Further, the small (whi) mutants mrpl49Δ and cbs1Δ are dependent on CLN3 for cell size effects. In depth analyses of new size mutants may facilitate a better understanding of the processes that govern cell size homeostasis.
Amyloidosis cutis dyschromica
Authors: Qiao Jianjun , Fang Hong , Yao Hongtian
Published: December 2012

Background

Amyloidosis cutis dyschromica is a rarely documented variant of cutaneous amyloidosis. To date, only 26 cases have been reported.

Objective

The purpose of this study was to improve the clinical and histopathological data for this variant of amyloidosis and to highlight the immunohistochemical features of the disease. The published cases were also reviewed.

Methods

We performed a retrospective review of patients with amyloidosis cutis dyschromica in a single centre. The clinical, histopathological and immunohistochemical features were documented and analysed.

Observations

We described 10 cases of amyloidosis cutis dyschromica. Six of them were female. Five patients were from the same family, and the other 5 were sporadic. The distinguishing features of the clinical presentation included generalised mottled hyper- and hypopigmented macules, which were asymptomatic or mild pruritic. The typical onset of the lesions occurred in childhood (n = 7) and occasionally after puberty (n = 3). No evidence of systemic amyloidosis deposition was observed in these cases of amyloidosis cutis dyschromica. Amyloid deposits were observed in the papillary dermis and were positive for the Congo red stain. An immunohistochemical study showed that the amyloid expresses cytokeratins CK34βE12 and CK5/6.

Conclusions

We described the largest series of amyloidosis cutis dyschromica to date and reviewed the published patients. This rare disease is featured by generalised mottled hyper- and hypopigmented lesions, and it is a rare variant of primary cutaneous amyloidosis without evidence of systemic amyloid deposition. Positive staining for the cytokeratins CK34βE12 and CK5/6 in amyloidosis cutis dyschromica suggests that the amyloid is derived from keratinocytes.
PCDq: human protein complex database with quality index which summarizes different levels of evidences of protein complexes predicted from H-Invitational protein-protein interactions integrative dataset
Authors: Kikugawa Shingo , Nishikata Kensaku , Murakami Katsuhiko , Sato Yoshiharu , Suzuki Mami , Altaf-Ul-Amin Md , Kanaya Shigehiko , Imanishi Tadashi
Published: December 2012

Background

Proteins interact with other proteins or biomolecules in complexes to perform cellular functions. Existing protein-protein interaction (PPI) databases and protein complex databases for human proteins are not organized to provide protein complex information or facilitate the discovery of novel subunits. Data integration of PPIs focused specifically on protein complexes, subunits, and their functions. Predicted candidate complexes or subunits are also important for experimental biologists.

Description

Based on integrated PPI data and literature, we have developed a human protein complex database with a complex quality index (PCDq), which includes both known and predicted complexes and subunits. We integrated six PPI data (BIND, DIP, MINT, HPRD, IntAct, and GNP_Y2H), and predicted human protein complexes by finding densely connected regions in the PPI networks. They were curated with the literature so that missing proteins were complemented and some complexes were merged, resulting in 1,264 complexes comprising 9,268 proteins with 32,198 PPIs. The evidence level of each subunit was assigned as a categorical variable. This indicated whether it was a known subunit, and a specific function was inferable from sequence or network analysis. To summarize the categories of all the subunits in a complex, we devised a complex quality index (CQI) and assigned it to each complex. We examined the proportion of consistency of Gene Ontology (GO) terms among protein subunits of a complex. Next, we compared the expression profiles of the corresponding genes and found that many proteins in larger complexes tend to be expressed cooperatively at the transcript level. The proportion of duplicated genes in a complex was evaluated. Finally, we identified 78 hypothetical proteins that were annotated as subunits of 82 complexes, which included known complexes. Of these hypothetical proteins, after our prediction had been made, four were reported to be actual subunits of the assigned protein complexes.

Conclusions

We constructed a new protein complex database PCDq including both predicted and curated human protein complexes. CQI is a useful source of experimentally confirmed information about protein complexes and subunits. The predicted protein complexes can provide functional clues about hypothetical proteins. PCDq is freely available at http://h-invitational.jp/hinv/pcdq/.
Alpha B-crystallin is a new prognostic marker for laryngeal squamous cell carcinoma
Authors: Mao Yuan , Zhang Da-Wei , Lin Hong , Xiong Lin , Liu Ying , Li Qing-Dong , Ma Jun , Cao Qing , Chen Ren-Jie , Zhu Jin , Feng Zhen-Qing
Published: December 2012

Background

Alpha B-crystallin (αB-crystallin) has been suggested to play an important role in the development of solid tumors. However, the association between αB-crystallin expression and clinicopathological characteristics of human laryngeal carcinoma is not well defined. This study aimed to examine the expression of αB-crystallin in human laryngeal squamous cell carcinoma (LSCC) and investigate the relationship between its expression and the prognosis of LSCC.

Methods

Real-time polymerase chain reaction (six LSCC samples, six tumor-adjacent normal samples) and immunohistochemistry by tissue microarrays (109 LSCC samples and 28 tumor-adjacent normal samples) were performed to characterize expression of the αB-crystallin gene in LSCC. Kaplan-Meier survival and Cox regression analyses were carried out to evaluate the prognosis of LSCC.

Results

Real-time polymerase chain reaction and immunohistochemistry analysis showed that the expression of αB-crystallin in LSCC was significantly higher than that in tumor-adjacent normal tissues. Moreover, the expression level of αB-crystallin protein in LSCC was significantly related to alcohol consumption (P = 0.022), tumor differentiation (P = 0.007), pTNM stage (P = 0.041) and 5 years’ survival (P =0.030). COX multi-factor analysis showed that αB-crystallin (P = 0.013), as well as pTNM stage (P =0.027) and lymphatic metastasis (P = 0.015) were independent prognosis factors for LSCC.

Conclusions

The data suggest that αB-crystallin expression is correlated with malignant phenotypes of LSCC and it may serve as a novel prognostic factor for LSCC.
Bevacizumab in Stage II-III Colon Cancer: 5-Year Update of the National Surgical Adjuvant Breast and Bowel Project C-08 Trial
Authors: Allegra Carmen J. , Yothers Greg , O'Connell Michael J. , Sharif Saima , Petrelli Nicholas J. , Lopa Samia H. , Wolmark Norman
Published: December 2012

Purpose

The National Surgical Adjuvant Breast and Bowel Project trial C-08 was designed to investigate the safety and efficacy of adding bevacizumab to fluorouracil, leucovorin, and oxaliplatin (FOLFOX6) for the adjuvant treatment of patients with stage 2-3 colon cancer. Our report summarizes the primary and secondary end points of disease-free and overall survival, respectively, with 5 years median follow-up time.

Patients and Methods

Patients received modified FOLFOX6 once every 2 weeks for a 6-month period (control group) or modified FOLFOX6 for 6 months plus bevacizumab (5 mg/kg) once every 2 weeks for a 12-month period (experimental group). The primary end point of the study was disease-free survival (DFS) and overall survival (OS) was a secondary end point.

Results

Of 2,673 analyzed patients, demographic factors were well-balanced by treatment. With a median follow-up of 5 years, the addition of bevacizumab to mFOLFOX6 did not result in an overall significant increase in DFS (hazard ratio [HR], 0.93; 95% CI, 0.81 to 1.08; P = .35). Exploratory analyses found that the effect of bevacizumab on DFS was different before and after a 1.25-year landmark (time-by-treatment interaction P value <.0001). The secondary end point of OS was no different between the two study arms for all patients (HR, 0.95; 95% CI, 0.79 to 1.13; P = .56) and for those with stage 3 disease (HR, 1.0; 95% CI, 0.83 to 1.21; P = .99).

Conclusion

Bevacizumab for 1 year with modified FOLFOX6 does not significantly prolong DFS or OS in stage 2-3 colon cancer. We observed no evidence of a detrimental effect of exposure to bevacizumab. A transient effect on disease-free survival was observed during bevacizumab exposure in the study's experimental arm.
Feasibility Research on Non-Invasive Analysis of Tanreqing Injection with near Infrared Spectroscopy
Authors: Li Wenlong , Cheng Zhiwei , Wang Yuefei , Qu Haibin
Published: December 2012

A non-invasive analysis method for bottled Tanreqing injection was developed based on near infrared (NIR) spectroscopy. The NIR trans-mission spectra were collected using a home-made accessory. The quality indicators of Tanreqing injection, which include baicalin, ursodesoxycholic acid (UDCA), chenodeoxycholic acid (CDCA), chlorogenic acid (CA), forsythin, total amino acids (TAA) and soluble solid content (SSC), were determined with standard methods. Several outlier samples were eliminated using the Dixon test, leverage and studentised residual test and analogous samples were amalgamated. Partial least squares regression (PLSR) was used for establishing the calibration models with the pre-treated spectra and the reference values. The root mean square errors of prediction ( RMSEP) values of external validation samples were 0.098 g L−1, 0.059 g L−1, 0.140 g L−1, 0.038g L−1, 0.007 g L−1, 0.053 g L−1 and 0.538 gL−1 for baicalin, CA, UDCA, CDCA, forsythin, TAA and SSC, respectively, which indicated that the established models possessed satisfactory predictive abilities. The presented method can reduce the workload of product inspection to a large extent. This will allow the sampling proportion to be increased and enable improved quality control during Tanreqing injection production.
A Feasibility Study on Non-Destructive Determination of Oil Content in Palm Fruits by Visible–Near Infrared Spectroscopy
Authors: Kasemsumran Sumaporn , Thanapase Warunee , Punsuvon Vittaya , Ozaki Yukihiro
Published: December 2012

Palm oil content is the most important factor for quality evaluation of the fresh oil palm fruits. Evaluating the colour of fruits with the naked eye and weighing of fresh fruit bunches are employed as the rapid method for estimating the palm oil content, but may not be accurate. On the other hand, the chemical extraction method yields more reliable results but it is a time-consuming method. Therefore, a reliable and rapid method for the determination of the oil content in oil palms is required. This study investigated the feasibility of non-destructive near infrared (NIR) spectroscopy for the non-destructive determination of palm oil in oil palm fruits. A total of 42 oil palm fruit samples, at varying stages of ripeness, were examined. The samples were scanned by two NIR spectrometers with different modes; one used a diffuse reflectance mode in the long wavelength (LW) region of 1100–2500 nm and the other employed an interactance mode in the visible-short wavelength (vis-SW) region of 665–955 nm. The palm oil content was analysed by soxhlet extraction as a reference method. Partial least squares regression (PLSR) models for the determination of the palm oil content in the oil palm fruits were developed for both the vis-SW- and LW-NIR spectral regions and compared. The results showed that NIR spectroscopy can be applied for the determination of palm oil content in fresh fruits as a reliable, rapid and non-destructive method. The model developed from the LW-NIR region has modestly higher performance for correlation coefficients of determination ( R2) of 0.92, root mean square error of calibration ( RMSEC) of 1.80%w/w, root mean square error of cross-validation ( RMSECV) of 2.81%w/w, the ratio of standard deviation of reference data to RMSECV in the calibration set ( RSC) of 2.19 than those obtained from the vis-SW NIR region.
Prediction of Brix Values of Intact Peaches with Least Squares-Support Vector Machine Regression Models
Authors: Mukarev Mihail I. , Walsh Kerry B.
Published: December 2012

Second derivative of interactance spectra (731–926 nm) of intact peaches and Brix values of extracted juice were used to develop a least squares support vector machine (LS-SVM) regression (based on an RBF kernel) and a PLS regression model. An iterative approach was taken with the LS-SVM regression, involving a grid search with application of a gradient-based optimisation method using a validation set for the tuning of hyperparameters, followed by pruning of the LS-SVM model with the optimised hyperparameters. The grid search approach led to five-fold faster and better determination of hyperparameters. Less than 45% of the initial 1430 calibration samples were kept in the models. In prediction of an independent test set with 120 samples, the pruned LS-SVM models performed better than the PLS model ( RMSEP decreased by 9% to 14%).
Near Infrared Spectroscopy for Estimating Eucalyptus Charcoal Properties
Authors: Andrade Carlos Rogério , Trugilho Paulo Fernando , Hein Paulo Ricardo Gherardi , Lima José Tarcísio , Napoli Alfredo
Published: December 2012

Steel can be produced from vegetable charcoal used as a thermo reducer in steel blast furnaces. Hence, the metallurgical industry requires new solutions for controlling the quality of their charcoal in order to maintain the same quality standard. The objective of this study was to assess the properties of charcoal by near infrared spectroscopy. Partial least square (PLS) regressions were established for estimating fixed-carbon, volatile matter content and gravimetric yield of charcoal. These models were validated by cross-validations and independent test sets and presented similar performance. PLS-R models obtained from untreated NIR spectra for FCC and VMC yielded promissory statistics [ r2p of ∼0.9; root mean squared error of prediction ( RMSEP) of ∼3.3%; and ratio of the standard error of prediction to standard deviation ( RPD)>3] while the statistics of the calibrations for gravimetric yield had relatively lower magnitude ( R2p of ∼0.8, a RMSEP of ∼2.2 and RPD<2). Since new solutions are required for controlling the quality of charcoal with speed and precision, these models can be useful for monitoring charcoal quality in steel industries.
Optimising Sample Preparation and near Infrared Spectra Measurements of Soil Samples to Calibrate Organic Carbon and Total Nitrogen Content
Authors: Miltz Jasmin , Don Axel
Published: December 2012

There is increasing attention in soil science to using near infrared spectroscopy as a fast and cheap method to analyse various soil properties. However, soil chemical components such as carbon and nitrogen are of low concentrations and analysis is exacerbated by a heterogeneous sample matrix. Thus, for soil analysis, the optimisation of sample preparation and measurement protocols is a prerequisite to establish NIR spectroscopy as a soil analytical method. Several methodological aspects, such as sample-grinding and drying, have been identified as important factors, but results on the best methods still remain inconsistent. The objective of this study was to comprehensively investigate the impact of these factors on a common sample set in order to be able to give recommendations for a standard measurement protocol. The examinations were performed on a set of agricultural soils covering a broad range of soil types, texture classes and carbon and nitrogen content. The number of spectra replicates and size of the sample cups (scanning area 6.8 cm2 and 19.6 cm2) had negligible impact on NIR calibration accuracy. Drying (oven-dried vs air-dried) and grinding (grinding vs crushing and sieving) significantly decreased the calibration error for organic carbon when ground and oven-dried samples were used, whereas these influences were smaller for N (grinding) or had hardly any affect on calibrations (drying). Overall, lowest root mean square error of cross-validation ( RMSEC)values were reached for ground, oven-dried samples measured in a large cup (scanning area = 19.6 cm2), with 0.391% for C and 0.028% for N. A factorial analysis on the RMSECV for drying, ring cup and grinding, showed the biggest influence on RMSECV by grinding for C with 35% and for N with 28% of the sum of squares accounted for. The effect of varying the laboratory temperature (20°C, 24°C and 28°C) was small when oven-dried samples were used but might have caused a considerable bias in predictions of air-dried samples. In addition, only oven-dried soil samples showed satisfactory reproducibility of predicted values within nine months when NIR measurements were repeated. Since calibrations of different soil parameters seemed to be affected differently by sample preparation and measurement parameters, this study can be considered as a first step towards a standardised measurement protocol.
Study of component distribution in pharmaceutical binary powder mixtures by near infrared chemical imaging
Authors: Bautista Manel , Cruz Jordi , Blanco Marcelo
Published: December 2012

Near infrared chemical imaging (NIR-CI) has recently emerged as an effective technique for extracting spatial
information from pharmaceutical products in an expeditious, non-destructive and non-invasive manner. These features
have turned it into a useful tool for controlling various steps in drug production processes. Imaging techniques provide a
vast amount of both spatial and spectral information that can be acquired in a very short time. Such a huge amount of data
requires the use of efficient and fast methods to extract the relevant information. Chemometric methods have proved
especially useful for this purpose. In this study, we assessed the usefulness of the correlation coefficient (CC) between
the spectra of samples, the pure spectra of the active pharmaceutical ingredient (API) and we assessed the excipients to
check for correct ingredient distribution in pharmaceutical binary preparations blended in the laboratory. Visual information
about pharmaceutical component distribution can be obtained by using the CC. The performance of this model construction
methodology for binary samples was compared with other various common multivariate methods including partial least
squares, multivariate curve resolution and classical least squares. Based on the results, correlation coefficients are a
powerful tool for the rapid assessment of correct component distribution and for quantitative analysis of pharmaceutical
binary formulations. For samples of three or more components it has been shown that if the objective is only to determine
uniformity of blending, then the CC image map is very good for this, and easy and fast to compute.
Practice Summaries: An Optimization Mathematical Model for Concentrated Solar Power Financing Decisions at Lockheed Martin
Authors: Taber Alan , Nikiforov Andrei , Baveja Alok
Published: December 2012

Concentrated solar power plants are an alternative to natural gas turbine plants in the portfolios of utilities and independent power producers (IPPs). To obtain financing for a new plant, an IPP must rigorously establish plant production guarantees. We developed an optimization model that maximizes annual profits by generating an optimal hour-by-hour production schedule. We use a fast greedy heuristic to solve this mathematical model. This work has enabled Lockheed Martin and its developer partners to be successful in project negotiations with major utility companies, resulting in 725 megawatts of power plants in development and over $5 billion in predicted sales.
Insulin Pen Misuse by Patient; Diluent Vial Looks like Drug Vial; Full Content cannot be Withdrawn from Istodax Vial; Patients May Fail to Remove Used Fentanyl Patches
Authors: Cohen Michael R. , Smetzer Judy L.
Published: December 2012

These medication errors have occurred in health care facilities at least once. They will happen again—perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs.

Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below.

Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site ( www.ismp.org ), by calling 800-FAIL-SAFE, or via e-mail at ismpinfo@ismp.org . ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications.
Phentermine/Topiramate Extended Release
Authors: Cada Dennis J. , Ingram Kyle T. , Levien Terri L. , Baker Danial E.
Published: December 2012

Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. Subscribers to The Formulary Monograph Service also receive access to a pharmacy bulletin board, The Formulary Information Exchange (The F.I.X.). All topics pertinent to clinical and hospital pharmacy are discussed on The F.I.X. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service or The F.I.X., call The Formulary at 800-322-4349. The December 2012 monograph topics are on linaclotide, teriflunomide, regorafenib tablets, bosutinib, and enzalutamide capsules. The DUE/MUE is on teriflunomide.
Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals
Authors: Baker Danial E.
Published: December 2012

This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at bakerdan@wsu.edu .
Efficacy of Gabapentin for Treatment of Adults with Phantom Limb Pain
Authors: Abbass Kim
Published: December 2012

Objective:

To evaluate the effectiveness of gabapentin in adults with phantom limb pain.

Data Sources:

A PubMed search (1966-September 2012) was conducted using the key words phantom limb pain and gabapentin. Search limits were English language, humans, adult, clinical trials, and randomized controlled trial.

Study Selection and Data Extraction:

Randomized controlled trials that studied the effectiveness of gabapentin in adults with phantom limb pain were identified and selected. Primary outcomes were associated with pain. Pediatric population studies were excluded.

Data Synthesis:

Three studies, with a total of 89 patients, were reviewed. All studies employed a pain rating scale to determine the primary outcome. Results varied. One crossover study reported a significant difference in pain intensity at 6 weeks compared with baseline (p < 0.01) and compared with placebo (p = 0.03). Another crossover study did not find a significant difference for the primary outcome of pain intensity, but did report a significant decrease in a secondary outcome measure related to pain. The third study displayed a decreased use of rescue pain medications by patients in the gabapentin treatment group. Heterogeneity of the study designs precludes a direct comparison of the results. Several confounding factors that may affect the interpretation of these results include the use of rescue pain medication, small sample size, short-term treatment, and different pain scales.

Conclusions:

Given the results of these trials, oral gabapentin in patients aged 18 years or older may decrease phantom limb pain. A strong recommendation for the effectiveness of gabapentin in phantom limb pain cannot be ascertained until more methodologically sound studies are executed in this population.
Dabigatran Effects on the International Normalized Ratio, Activated Partial Thromboplastin Time, Thrombin Time, and Fibrinogen: A Multicenter, In Vitro Study
Authors: Dager William E , Gosselin Robert C , Kitchen Steve , Dwyre Dennis
Published: December 2012

Background:

Patients receiving the direct thrombin inhibitor dabigatran may have selected anticoagulation assays performed as part of routine care. The effect of dabigatran on the international normalized ratio (INR), activated partial thromboplastin time (aPTT), thrombin time (TT), and fibrinogen requires clarification.

Objective:

To describe the effect of dabigatran on selected assays in North America and the United Kingdom.

Methods:

Pooled normal plasma enriched with dabigatran at concentrations of 25, 50, 75, 100, 125, 150, 200, 300, 400, and 500 ng/mL were sent blinded to 19 centers in the US, the UK, and Canada to assess the effect of dabigatran on routine coagulation screening tests, the INR, aPTT, TT, and fibrinogen.

Results:

Data were returned from 16 centers. For effects on INR, Neoplastine CI Plus and Simplastin HTF were the most sensitive and Thromborel S the least sensitive to increasing dabigatran concentrations. For the aPTT, all reagents demonstrated decreasing sensitivity to increasing dabigatran concentrations. Measured fibrinogen either demonstrated no change or factitious decrease with increasing dabigatran concentrations. Commercial TT methods were very sensitive to low concentrations of dabigatran, with 9 of 10 reporting sites exceeding test limits at dabigatran concentrations of 100 ng/mL.

Conclusions:

The INR, aPTT, and TT rise as dabigatran concentrations increase. Both the INR and aPTT increase in a linear pattern with marginal slopes, creating challenges in using these assays as reliable means for assessing the amount of dabigatran present. The commercial TT assay is very sensitive at low concentrations of dabigatran. Fibrinogen test results may be either unaffected or lower in the presence of dabigatran.
Intraventricular Daptomycin and Intravenous Linezolid for the Treatment of External Ventricular-Drain–Associated Ventriculitis Due to Vancomycin-Resistant Enterococcus faecium
Authors: Mueller Scott W , Kiser Tyree H , Anderson Tracey A , Neumann Robert T
Published: December 2012

Objective:

To report the successful treatment of external ventricular-drain (EVD)– associated infection due to vancomycin-resistant Enterococcus faecium (VRE) with intraventricular daptomycin and intravenous linezolid.

Case Summary:

A 64-year-old white male with a complicated medical history was admitted to the neurosurgical unit with Scedosporium apiospermum meningitis and hydrocephalus requiring management with a right and left EVD. On day 28, cerebrospinal fluid cultures from the right EVD grew VRE. Despite initiation of intravenous linezolid, cultures from the right EVD remained positive. Intraventricular daptomycin 5 mg daily was initiated and administered into the right EVD for 7 days. Cerebrospinal fluid was collected from EVD outputs and analyzed for daptomycin concentrations. VRE in cultures from the EVD cleared after 1 day of therapy and no adverse effects were noted. Right and left EVD daptomycin concentrations were discordant throughout therapy by at least a 3-fold difference. First-dose peak and trough daptomycin concentrations in the cerebrospinal fluid were 112.2 and 1.34 μg/mL, respectively, for the right EVD and 37.4 and 0.37 μg/mL, respectively, for the left EVD. Daptomycin accumulation was evident after 3 days of therapy.

Discussion:

Varying doses and frequencies of intraventricular daptomycin have been reported effective for VRE ventriculitis. Intraventricular drug distribution may not be homogeneous throughout the central nervous system. Therefore, daptomycin minimum inhibitory concentration for VRE, cerebrospinal fluid communication throughout the central nervous system, EVD output, and the potential for drug accumulation should be considered when selecting a dose and frequency.

Conclusions:

Intraventricular daptomycin may be an option for EVD-associated VRE infections that do not respond to conventional therapy. Intraventricular daptomycin 5 mg is a reasonable initial dose in adults with VRE ventriculitis, based on our experience in this patient.
MNAzyme qPCR with Superior Multiplexing Capacity
Authors: Mokany Elisa , Tan Yee Lee , Bone Simon M , Fuery Caroline J , Todd Alison V
Published: December 2012

BACKGROUND

MNAzymes (nucleic acid enzymes formed from multiple partial enzymes) can be linked to PCR to provide a highly specific method for target detection and quantification. We investigated the feasibility of multiplexing MNAzyme quantitative PCR (qPCR) methods.

METHODS

We combined MNAzyme components with PCR primers and standard qPCR reagents to perform MNAzyme qPCR and reverse-transcription qPCR (RT-qPCR) assays with a set of universal reporter probes. Assays were performed on single targets and in multiplex formats that combined up to 5 different targets in a single reaction.

RESULTS

A comparison of 3 targets amplified in single and triplex formats showed no significant differences with respect to detection limit or amplification efficiency. Likewise, we successfully converted single-target assays for 11 transcripts of interest to triplex assays containing 2 reference transcripts without having to optimize or modify the conditions. A quintuplex RT-qPCR that simultaneously quantified 5 transcripts with 5 universal probes produced high amplification efficiencies and r2 values for all transcripts. Despite the large numbers of oligonucleotides in the reactions, we observed no false-positive signals, owing to the requirement of 4 target-specific binding events to produce a signal. A quadruplex assay that combined MNAzymes with methylation-specific PCR to measure epigenetic biomarkers of prostate cancer was capable of detecting a single methylated DNA allele in a BACKGROUND of 1000–10 000 unmethylated alleles. The MNAzyme qPCR was compatible with a rapid-cycling protocol.

CONCLUSIONS

MNAzymes offer a flexible and unique approach to qPCR that is specific, sensitive, and easily multiplexed. The universal nature of MNAzyme reporter probes removes the need for target-specific probes, thereby making the development of new assays easier and cheaper.
Identification and Characterization of a Sleep-Active Cell Group in the Rostral Medullary Brainstem
Authors: Anaclet Christelle , Lin Jian-Sheng , Vetrivelan Ramalingam , Krenzer Martina , Vong Linh , Fuller Patrick M. , Lu Jun
Published: December 2012

Early transection and stimulation studies suggested the existence of sleep-promoting circuitry in the medullary brainstem, yet the location and identity of the neurons comprising this putative hypnogenic circuitry remains unresolved. In the present study, we sought to uncover the location and identity of medullary neurons that might contribute to the regulation of sleep. Here we show the following in rats: (1) a delimited node of medullary neurons located lateral and dorsal to the facial nerve—a region we termed the parafacial zone (PZ)—project to the wake-promoting medial parabrachial nucleus; (2) PZ neurons express c-Fos after sleep but not after wakefulness and hence are sleep active; and (3) cell-body-specific lesions of the PZ result in large and sustained increases (50%) in daily wakefulness at the expense of slow-wave sleep (SWS). Using transgenic reporter mice [vesicular GABA/glycine transporter (Vgat)–GFP], we then show that >50% of PZ sleep-active neurons are inhibitory (GABAergic/glycinergic, VGAT-positive) in nature. Finally, we used a Cre-expressing adeno-associated viral vector and conditionalVgatlox/loxmice to selectively and genetically disrupt GABA/glycinergic neurotransmission from PZ neurons. Disruption of PZ GABAergic/glycinergic neurotransmission resulted in sustained increases (40%) in daily wakefulness at the expense of both SWS and rapid eye movement sleep. These results together reveal the location and neurochemical identity of a delimited node of sleep-active neurons within the rostral medullary brainstem.
Rapid Synaptic Vesicle Endocytosis in Cone Photoreceptors of Salamander Retina
Authors: Van Hook Matthew J. , Thoreson Wallace B.
Published: December 2012

Following synaptic vesicle exocytosis, neurons retrieve the fused membrane by a process of endocytosis to provide a supply of vesicles for subsequent release and maintain the presynaptic active zone. Rod and cone photoreceptors use a specialized structure called the synaptic ribbon that enables them to sustain high rates of neurotransmitter release. They must also employ mechanisms of synaptic vesicle endocytosis capable of keeping up with release. While much is known about endocytosis at another retinal ribbon synapse, that of the goldfish Mb1 bipolar cell, less is known about endocytosis in photoreceptors. We used capacitance recording techniques to measure vesicle membrane fusion and retrieval in photoreceptors from salamander retinal slices. We found that application of brief depolarizing steps (<100 ms) to cones evoked exocytosis followed by rapid endocytosis with a time constant ∼250 ms. In some cases, the capacitance trace overshot the baseline, indicating excess endocytosis. Calcium had no effect on the time constant, but enhanced excess endocytosis resulting in a faster rate of membrane retrieval. Surprisingly, endocytosis was unaffected by blockers of dynamin, suggesting that cone endocytosis is dynamin independent. This contrasts with synaptic vesicle endocytosis in rods, which was inhibited by the dynamin inhibitor dynasore and GTPγS introduced through the patch pipette, suggesting that the two photoreceptor types employ distinct pathways for vesicle retrieval. The fast kinetics of synaptic vesicle endocytosis in photoreceptors likely enables these cells to maintain a high rate of transmitter release, allowing them to faithfully signal changes in illumination to second-order neurons.
Cognitive Deficits and Delayed Neuronal Loss in a Mouse Model of Multiple Microinfarcts
Authors: Wang Minghuan , Iliff Jeffrey J. , Liao Yonghong , Chen Michael J. , Shinseki Matthew S. , Venkataraman Arun , Cheung Jessica , Wang Wei , Nedergaard Maiken
Published: December 2012

Microinfarcts are a common clinical feature of the aging brain, particularly in patients with cognitive decline or vascular or Alzheimer's dementia. However, the natural history of these lesions remains largely unexplored. Here we describe a mouse (C57BL/6J) model of multiple diffuse microinfarcts induced by unilateral internal carotid artery injection of cholesterol crystals (40–70 μm). Microinfarcts were spread throughout the deep cortex, subcortical tissue, and hippocampus and were comprised of a core positive for CD68 (a marker for reactive microglia and macrophages), surrounded by large regions of glial fibrillary acidic protein-positive reactive astrogliosis. Widespread reactive gliosis, including mislocalization of the astrocytic water channel aquaporin 4 persisted long after injury, recovering only after 1 month after stroke. Within the cortex, neuronal cell death progressed gradually over the first month, from ∼35% at 3 d to 60% at 28 d after stroke. Delayed demyelination was also observed in lesions, beginning 28 d after stroke. These findings demonstrate that microinfarct development follows a distinct course compared to larger regional infarcts such as those induced by middle cerebral artery occlusion. The long-lasting gliosis, delayed neuronal loss, and demyelination suggest that the therapeutic window for microinfarcts may be much wider (perhaps days to weeks) than for larger strokes.
Musical Expertise Induces Audiovisual Integration of Abstract Congruency Rules
Authors: Paraskevopoulos Evangelos , Kuchenbuch Anja , Herholz Sibylle C. , Pantev Christo
Published: December 2012

Perception of everyday life events relies mostly on multisensory integration. Hence, studying the neural correlates of the integration of multiple senses constitutes an important tool in understanding perception within an ecologically valid framework. The present study used magnetoencephalography in human subjects to identify the neural correlates of an audiovisual incongruency response, which is not generated due to incongruency of the unisensory physical characteristics of the stimulation but from the violation of an abstract congruency rule. The chosen rule—“the higher the pitch of the tone, the higher the position of the circle”—was comparable to musical reading. In parallel, plasticity effects due to long-term musical training on this response were investigated by comparing musicians to non-musicians. The applied paradigm was based on an appropriate modification of the multifeatured oddball paradigm incorporating, within one run, deviants based on a multisensory audiovisual incongruent condition and two unisensory mismatch conditions: an auditory and a visual one. Results indicated the presence of an audiovisual incongruency response, generated mainly in frontal regions, an auditory mismatch negativity, and a visual mismatch response. Moreover, results revealed that long-term musical training generates plastic changes in frontal, temporal, and occipital areas that affect this multisensory incongruency response as well as the unisensory auditory and visual mismatch responses.
Synaptic Kainate Receptors in CA1 Interneurons Gate the Threshold of Theta-Frequency-Induced Long-Term Potentiation
Authors: Clarke Vernon R.J. , Collingridge Graham L. , Lauri Sari E. , Taira Tomi
Published: December 2012

Theta oscillations (4–12 Hz) in neuronal networks are known to predispose the synapses involved to plastic changes and may underlie their association with learning behaviors. The lowered threshold for synaptic plasticity during theta oscillations is thought to be due to decreased GABAergic inhibition. Interneuronal kainate receptors (KARs) regulate GABAergic transmission and are implicated in theta activity; however, the physiological significance of this regulation is unknown. In rat hippocampus, we show that during theta activity, there is excitatory postsynaptic drive to CA1 interneurons mediated by KARs. This promotes feedforward inhibition of pyramidal neurons, raising the threshold for induction of theta-burst long-term potentiation. These results identify a novel mechanism whereby the activation of postsynaptic KARs in CA1 interneurons gate changes in synaptic efficacy to a physiologically relevant patterned stimulation.
Perisynaptic Chondroitin Sulfate Proteoglycans Restrict Structural Plasticity in an Integrin-Dependent Manner
Authors: Orlando Clara , Ster Jeanne , Gerber Urs , Fawcett James W. , Raineteau Olivier
Published: December 2012

During early postnatal development of the CNS, neuronal networks are configured through the formation, elimination, and remodeling of dendritic spines, the sites of most excitatory synaptic connections. The closure of this critical period for plasticity correlates with the maturation of the extracellular matrix (ECM) and results in reduced dendritic spine dynamics. Chondroitin sulfate proteoglycans (CSPGs) are thought to be the active components of the mature ECM that inhibit functional plasticity in the adult CNS. These molecules are diffusely expressed in the extracellular space or aggregated as perineuronal nets around specific classes of neurons. We used organotypic hippocampal slices prepared from 6-d-old Thy1-YFP mice and maintained in culture for 4 weeks to allow ECM maturation. We performed live imaging of CA1 pyramidal cells to assess the effect of chondroitinase ABC (ChABC)-mediated digestion of CSPGs on dendritic spine dynamics. We found that CSPG digestion enhanced the motility of dendritic spines and induced the appearance of spine head protrusions in a glutamate receptor-independent manner. These changes were paralleled by the activation of β1-integrins and phosphorylation of focal adhesion kinase at synaptic sites, and were prevented by preincubation with a β1-integrin blocking antibody. Interestingly, microinjection of ChABC close to dendritic segments was sufficient to induce spine remodeling, demonstrating that CSPGs located around dendritic spines modulate their dynamics independently of perineuronal nets. This restrictive action of perisynaptic CSPGs in mature neural tissue may account for the therapeutic effects of ChABC in promoting functional recovery in impaired neural circuits.
Loss of PAFAH1B2 Reduces Amyloid-β Generation by Promoting the Degradation of Amyloid Precursor Protein C-Terminal Fragments
Authors: Page Richard M. , Münch Anna , Horn Thomas , Kuhn Peer-Hendrik , Colombo Alessio , Reiner Orly , Boutros Michael , Steiner Harald , Lichtenthaler Stefan F. , Haass Christian
Published: December 2012

Amyloid-β peptide (Aβ) is believed to play a central role in the pathogenesis of Alzheimer's disease. In view of the side effects associated with inhibiting the secretases that produce Aβ, new molecular targets are required to provide alternative therapeutic options. We used RNA interference (RNAi) to systematically screen theDrosophilagenome to identify genes that modulate Aβ production upon knockdown. RNAi of 41 genes inDrosophilacells significantly lowered Aβ without affecting general secretion or viability. After the γ-secretase complex components, the most potent effect was observed for platelet activating factor acetylhydrolase α (Paf-AHα), and, in mammalian cells, the effect was replicated for its ortholog PAFAH1B2. Knockdown of PAFAH1B2 strongly reduced Aβ secretion from human cells, and this effect was confirmed in primary cells derived from PAFAH1B2 knock-out mice. Reduced Aβ production was not attributable to altered β-amyloid precursor protein (APP) ectodomain shedding but was a result of an enhanced degradation of APP C-terminal fragments (CTFs) in the absence of PAFAH1B2 but not its close homolog PAFAH1B3. Enhanced degradation of APP CTFs was selective because no such effects were obtained for Notch or E-/N-cadherin. Thus, we have identified an important protein that can selectively modify Aβ generation via a novel mechanism, namely enhanced degradation of its immediate precursor. In view of the absence of a neurological phenotype in PAFAH1B2 knock-out mice, targeted downregulation of PAFAH1B2 may be a promising new strategy for lowering Aβ.