bluuebunny/crossref_metadata_2025 huggingface dataset:
Testing of dynamically substructured, base‐isolated systems using adaptive control techniques
Authors: Tu J. Y. , Lin P. Y. , Stoten D. P. , Li G.
Published: October 2009

Experimental techniques for testing dynamically substructured systems are currently receiving attention in a wide range of structural, aerospace and automotive engineering environments. Dynamic substructuring enables full‐size, critical components to be physically tested within a laboratory (as physical substructures), while the remaining parts are simulated in real‐time (as numerical substructures). High quality control is required to achieve synchronization of variables at the substructuring interfaces and to compensate for additional actuator system(s) dynamics, nonlinearities, uncertainties and time‐varying parameters within the physical substructures. This paper presents the substructuring
approach and associated controller designs for performance testing of an aseismic, base‐isolation system, which is comprised of roller‐pendulum isolators and controllable, nonlinear magnetorheological dampers. Roller‐pendulum isolators are typically mounted between the protected structure and its foundation and have a fundamental period of oscillation far‐removed from the predominant periods of any earthquake. Such semi‐active damper systems can ensure safety and performance requirements, whereas the implementation of purely active systems can be problematic in this respect. A linear inverse dynamics compensation and an adaptive controller are tailored for the resulting nonlinear synchronization problem. Implementation results favourably compare the effectiveness of the adaptive substructuring method against a conventional shaking‐table technique. A 1.32% error resulted compared with the shaking‐table response. Ultimately, the accuracy of the substructuring method compared with the response of the shaking‐table is dependent upon the fidelity of the numerical substructure. Copyright © 2009 John Wiley & Sons, Ltd.
Unfavorable prognosis of CRTC1‐MAML2 positive mucoepidermoid tumors with CDKN2A deletions
Authors: Anzick Sarah L. , Chen Wei‐Dong , Park Yoonsoo , Meltzer Paul , Bell Diana , El‐Naggar Adel K. , Kaye Frederic J.
Published: October 2009

The CRTC1‐MAML2 fusion oncogene underlies the etiology of mucoepidermoid salivary gland carcinoma (MEC) where it confers a favorable survival outcome as compared with fusion‐negative MEC. While these analyses suggested that detection of CRTC1‐MAML2 serves as a useful prognostic biomarker, we recently identified outlier cases of fusion‐positive MEC associated with advanced‐staged lethal disease. To identify additional genetic alterations that might cooperate with CRTC1‐MAML2 to promote disease progression, we performed a pilot high‐resolution oligonucleotide array CGH (aCGH) and PCR‐based genotyping study on 23 MEC samples including 14 fusion‐positive samples for which we had clinical outcome information. Unbiased aCGH analysis identified inactivating deletions within CDKN2A as a candidate poor prognostic marker which was confirmed by PCR‐based analysis (CDKN2A deletions in 5/5 unfavorable fusion‐positive cases and 0/9 favorable fusion‐positive cases). We did not detect either activating EGFR mutations, nor copy number gains at the EGFR or ERBB2 loci as poor prognostic features for fusion‐positive MEC in any of the tumor specimens. Prospective studies with larger case series will be needed to confirm that combined CRTC1‐MAML2 and CDKN2A genotyping will optimally stage this disease. © 2009 Wiley‐Liss, Inc.
FAU regulates carboplatin resistance in ovarian cancer
Authors: Moss Esther L. , Mourtada‐Maarabouni Mirna , Pickard Mark R. , Redman Charles W. , Williams Gwyn T.
Published: October 2009

The development of chemotherapy resistance by cancer cells is complex, using different mechanisms and pathways. The gene FAU (Finkel‐Biskis‐Reilly murine sarcoma virus (FBR‐MuSV)‐associated ubiquitously expressed gene) was identified through functional expression cloning and previous data have shown that overexpression enhances apoptosis in several cell types. We demonstrate that the expression of FAU was reduced in the A2780cis (cisplatin resistant subclone of A2780) cell line compared with the A2780 ovarian cancer cell line, and was directly related to the cell line's sensitivity to carboplatin. Downregulation of FAU in the A2780 cell line by transfection with two predesigned short‐interfering RNAs (siRNAs) to FAU resulted in a significant increase in resistance to carboplatin‐induced cell death. Downregulation resulted in increased cell viability and reduced apoptosis after 72 hr of drug treatment compared with the negative controls (Kruskal‐Wallis P = 0.0002). Transfection of the A2780cis cell line with the pcDNA3 plasmid containing FAU was associated with increased sensitivity to carboplatin‐induced apoptosis, with decreased cell viability and increased apoptosis (Mann Whitney P < 0.0001). The expression of FAU was examined by quantitative real‐time reverse transcriptase polymerase chain reaction in normal and malignant ovarian tissue. A significant reduction in the expression of FAU was seen in the malignant compared with normal ovarian samples (Kruskal‐Wallis P = 0.0261). These data support a role for FAU in the regulation of platinum‐resistance in ovarian cancer. Further research is needed into the apoptotic pathway containing FAU to investigate the potential for targeted therapies to increase or restore the platinum sensitivity of ovarian cancer. © 2009 Wiley‐Liss, Inc.
Mapping quantitative traits in unselected families: algorithms and examples
Authors: Dupuis Josée , Shi Jianxin , Manning Alisa K. , Benjamin Emelia J. , Meigs James B. , Cupples L. Adrienne , Siegmund David
Published: October 2009

Linkage analysis has been widely used to identify from family data genetic variants influencing quantitative traits. Common approaches have both strengths and limitations. Likelihood ratio tests typically computed in variance component analysis can accommodate large families but are highly sensitive to departure from normality assumptions. Regression‐based approaches are more robust but their use has primarily been restricted to nuclear families. In this paper, we develop methods for mapping quantitative traits in moderately large pedigrees. Our methods are based on the score statistic, which in contrast to the likelihood ratio statistic can use nonparametric estimators of variability to achieve robustness of the false‐positive rate against departures from the hypothesized phenotypic model. Because the score statistic is easier to calculate than the likelihood ratio statistic, our basic mapping methods utilize relatively simple computer code that performs statistical analysis on output from any program that computes estimates of identity by descent. This simplicity also permits development and evaluation of methods to deal with multivariate and ordinal phenotypes, and with gene‐gene and gene‐environment interaction. We demonstrate our methods on simulated data and on fasting insulin, a quantitative trait measured in the Framingham Heart Study. Genet. Epidemiol. 33:617–627, 2009. © 2009 Wiley‐Liss, Inc.
Extracapsular spread in oral squamous cell carcinoma
Authors: Shaw Richard J. , Lowe Derek , Woolgar Julia A. , Brown James S. , Vaughan E. David , Evans Christopher , Lewis‐Jones Huw , Hanlon Rebecca , Hall Gillian L. , Rogers Simon N.
Published: October 2009

Background

Extracapsular spread (ECS) in the cervical lymph nodes represents the most significant adverse prognostic indicator in oral squamous cell carcinoma (OSCC).

Methods

In a consecutive cohort of OSCC treated by primary surgery, ECS was seen in 25% (101) of 400 patients.

Results

ECS doubled the incidence of local recurrence and distant metastases, but tripled regional failure. The recurrences occurred sooner in ECS than in non‐ECS cases (206 vs 334 days, p = .04). Patients with macroscopic ECS had a 5‐year overall survival (OS) of 19% compared with 31% in microscopic ECS. MRI neck staging offered poor sensitivity, especially in microscopic ECS. Age >75 years, smoking, and heavy use of alcohol were independent predictors of ECS, which may implicate a failure of immunosurveillance by the host as much as adverse biology of the tumor.

Conclusions

Reporting of ECS is essential in accurate prognostication, and we advocate that all patients with OSCC and ECS should be grouped as pN3 on the basis of their prognosis. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Impact of comorbidity on short‐term mortality and overall survival of head and neck cancer patients
Authors: Datema Frank R. , Ferrier Marciano B. , van der Schroeff Marc P. , Baatenburg de Jong Robert J.
Published: October 2009

Background

In 2001, we presented a Cox regression model that is able to predict survival of the newly diagnosed patient with head and neck squamous cell carcinoma (HNSCC). This model is based on the TNM classification and other important clinical variables such as age at diagnosis, sex, primary tumor site, and prior malignancies. We aim to improve this model by including comorbidity as an extra prognostic variable. Accurate prediction of the prognosis of the newly diagnosed patient with head and neck cancer can assist the physician in patient counseling, clinical decision‐making, and quality maintenance.

Methods

All patients with HNSCC of the oral cavity, pharynx, and larynx diagnosed in the Leiden University Medical Centre between 1981 and 1998 were included. From these 1371 patients, data on primary tumor site, age at diagnosis, sex, TNM classification, and prior malignancies were already available. Comorbidity data were collected retrospectively according to the ACE27 manual. The prognostic value of each variable on overall survival was studied univariately by Kaplan–Meier curves and the log‐rank test. The Cox regression model was used to investigate the impact of these variables on overall survival simultaneously. Furthermore, univariate analyses were performed to investigate the impact of comorbidity severity on short‐term mortality and to investigate the impact of organ‐specific‐comorbidity on short‐term mortality.

Results

Comorbidity was present in 36.4% of our patients. Mild decompensation was seen in 17.4%, moderate decompensation in 13.5%, and severe decompensation in 5.5%. Most frequently observed ailments were cardiovascular, respiratory, and gastrointestinal. In univariate analyses, all prognostic variables, including comorbidity, contributed significantly to overall survival. Their contribution (except sex) remained significant in the multivariate Cox model. Internal validation of this model showed a concordance index of 0.73, indicating a good predictive value. Short‐term mortality was seen in 5.7% of our patients. Cardiovascular comorbidity, respiratory comorbidity, gastrointestinal comorbidity, and diabetes showed a significant relationship with short‐term mortality.

Conclusions

Comorbidity impacts overall survival of the newly diagnosed patient with HNSCC. There is a clear distinction between the impact of the 4 ACE27 severity grades. The impact of an ACE27 grade 3 is comparable to the impact of a T4 tumor or an N2 neck. Comorbidity impacts short‐term mortality as well. Especially cardiovascular comorbidity, respiratory comorbidity, gastrointestinal comorbidity, and diabetes show a strong relationship. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Clinical grading of oral mucosa by curve‐fitting of corrected autofluorescence using diffuse reflectance spectra
Authors: Mallia Rupananda Jayachandra , Subhash Narayanan , Mathews Anitha , Kumar Rejnish , Thomas Shiny Sara , Sebastian Paul , Madhavan Jayaprakash
Published: October 2009

Background

Laser‐induced autofluorescence (LIAF) and diffuse reflectance (DR) were collectively used in this clinical study to improve early oral cancer diagnosis and tissue grading.

Methods

LIAF and DR emission from oral mucosa were recorded on a fiber‐optic spectrometer by illumination with a 404‐nm diode laser and tungsten halogen lamp in 36 healthy volunteers and 40 lesions of 20 patients.

Results

Absorption dips in LIAF spectra at 545 and 575 nm resulting from changes in oxygenated hemoglobin were corrected using DR spectra of the same site. These corrected spectra were curve‐fitted using Gaussian spectral functions to determine constituent emission peaks and their relative contribution. The Gaussian peak intensity and area ratios F500/F635 and F500/F685 were found to be useful indicators of tissue transformation. The diagnostic capability of various ratios in differentiating healthy, hyperplastic, dysplastic, and squamous cell carcinomas (SCCs) were examined using discrimination scatterplots.

Conclusions

The LIAF/DR technique, in conjunction with curve‐fitting, differentiates different grades of dysplasia and SCC in this clinical trial and proves its potential for early detection of oral cavity cancer and tissue grading. © 2009 Wiley Periodicals, Inc. Head Neck, 2010
Upregulation of interleukin‐1 by Epstein–Barr virus latent membrane protein 1 and its possible role in nasopharyngeal carcinoma cell growth
Authors: Huang Yu‐Tzu , Liu Mei‐Ying , Tsai Ching‐Hwa , Yeh Te‐Huei
Published: October 2009

Background

Nasopharyngeal carcinoma (NPC) is associated with Epstein–Barr virus (EBV) infection. We previously found that interleukin (IL)‐1α and IL‐1β significantly increased in NPC tissues. This study investigated what EBV‐encoded proteins were involved in such IL‐1 production.

Methods and Results

IL‐1α and IL‐1β messenger ribonucleic acids (mRNAs) were detected in the EBV latent membrane protein 1 (LMP1) transfectant (LMP135) only by reverse transcriptase–polymerase chain reaction (RT‐PCR). LMP1‐mediated IL‐1α and IL‐1β production could be enhanced by tumor necrosis factor alpha (TNF‐α), determined by enzyme‐linked immunosorbent assay (ELISA). Moreover, IL‐1α and IL‐1β mRNAs and proteins were increased in a dose‐dependent manner in epithelial cells transiently transfected by an LMP1 plasmid. Besides, immortalized human epidermal keratinocyte (RHEK‐1) epithelial cells could be enhanced to proliferate by IL‐1α and IL‐1β determined by water‐soluble tetrazolium salt (WST‐1) assay.

Conclusions

EBV LMP1 is capable of upregulating IL‐1α and IL‐1β secretions from epithelial cells and positively modulated by TNF‐α. This may consequently contribute to tumor growth in patients with NPC. © 2009 Wiley Periodicals, Inc. Head Neck, 2009
Ammonia and the Neutrophil in the Pathogenesis of Hepatic Encephalopathy in Cirrhosis
Authors: Shawcross Debbie L. , Shabbir Shabnam S. , Taylor Nicholas J. , Hughes Robin D.
Published: October 2009

Hepatic encephalopathy (HE) constitutes a neuropsychiatric syndrome which remains a major clinical problem in patients with cirrhosis. In the severest form of HE, cirrhotic patients may develop varying degrees of confusion and coma. Ammonia has been regarded as the key precipitating factor in HE, and astrocytes have been the most commonly affected cells neuropathologically. Although the evidence base supporting a pivotal role of ammonia is robust, in everyday clinical practice a consistent correlation between the concentration of ammonia in the blood and the manifest symptoms of HE is not observed. More recently the synergistic role of inflammation and infection in modulating the cerebral effects of ammonia has been shown to be important. Furthermore, it has been recognized that infection impairs brain function both in the presence and absence of liver disease. Thus it could be postulated that in the presence of ammonia, the brain is sensitized to a systemic inflammatory stimulus and is able to elicit an inflammatory response involving both proinflammatory and neurotransmitter pathways. Ammonia is not only directly toxic to astrocytes but induces neutrophil dysfunction with the release of reactive oxygen species, which contribute to oxidative stress and systemic inflammation. This may further exacerbate the cerebral effects of ammonia and potentially reduce the capacity of the neutrophil to fight microbial attack, thus inducing a vicious circle. This evidence supports the neutrophil in addition to ammonia as being culpable in the pathogenesis of HE, making the neutrophil a target for future anti-inflammatory therapeutic strategies in addition to ammonia lowering therapies. (Hepatology 2010.)
Emergency Adult-to-Adult Living-Donor Liver Transplantation for Acute Liver Failure in A Hepatitis B Virus Endemic Area
Authors: Park Soo Jung , Lim Young-Suk , Hwang Shin , Heo Nae Yun , Lee Han Chu , Suh Dong Jin , Yu Eunsil , Lee Sung Gyu
Published: October 2009

The outcomes of patients with acute liver failure (ALF) vary greatly according to etiology. Emergency adult-to-adult living-donor liver transplantation (adult LDLT) would help address the shortage of available organs for patients with ALF, especially in hepatitis B virus (HBV)-endemic areas. We analyzed a prospective database of 110 consecutive adult patients with ALF. ALF was defined as sudden development of severe coagulopathy and encephalopathy within 26 weeks of onset of symptoms. In about 90% of patients, ALF was caused by etiologies that usually result in poor outcomes, including HBV infection (37%). Three cases (3%) were associated with acetaminophen overdose. Of the 99 patients listed for emergency liver transplantation, four (4%) underwent deceased-donor liver transplantation (DDLT), and 40 (40%) underwent adult LDLT. The 1-year survival rate of adult LDLT patients was 85%. Of the 55 patients listed but not transplanted, 45 (82%) died within a median of 7 days (range, 1-90 days). Multivariate analysis showed that adult LDLT (hazard ratio [HR] 0.10,

P

< 0.01) and DDLT (HR 0.12,

P

= 0.04) were associated with decreased mortality, whereas older age (HR 1.03,

P

= 0.01) and higher Model for End-stage Liver Disease (MELD) (HR 1.03,

P

= 0.04) was associated with increased mortality of patients. There was no living donor mortality. Eight (17.8%) and three (6.7%) living donors experienced grade 1 and 2 complications, respectively.

Conclusion:

Emergency adult LDLT can be performed expeditiously and safely for patients with ALF, and greatly improves the survival rate. As the window during which transplantation is possible is limited, emergency adult LDLT should be considered one of the first-line treatment options in patients with ALF, especially in regions in which ALFs are caused by etiologies associated with poor outcome and the supply of organs is severely limited. (Hepatology 2010.)
Area CA3 interneurons receive two spatially segregated mossy fiber inputs
Authors: Cosgrove Kathleen E. , Galván Emilio J. , Meriney Stephen D. , Barrionuevo Germán
Published: October 2009

Area CA3 receives two extrinsic excitatory inputs, the mossy fibers (MF), and the perforant path (PP). Interneurons with somata in str. lacunosum moleculare (L‐M) of CA3 modulate the influence of the MF and PP on pyramidal cell activity by providing strong feed‐forward inhibitory influence to pyramidal cells. Here we report that L‐M interneurons receive two separate MF inputs, one to the dorsal dendrites from the suprapyramidal blade of the dentate gyrus (MFSDG), and a second to ventral dendrites from the str. lucidum (MFSL). Responses elicited from MFSDG and MFSL stimulation sites have strong paired‐pulse facilitation, similar DCG‐IV sensitivity, amplitude, and decay kinetics but target spatially segregated domains on the interneuron dendrites. These data demonstrate that certain interneuron subtypes are entrained by two convergent MF inputs to spatially separated regions of the dendritic tree. This anatomical arrangement could make these interneurons considerably more responsive to the excitatory drive from dentate granule cells. Furthermore, temporal summation is linear or slightly sublinear between PP and MFSL but supralinear between PP and MFSDG. This specific boosting of the excitatory drive to interneurons from the SDG location may indicate that L‐M interneurons could be specifically involved in the processing of the associational component of the recognition memory. © 2009 Wiley‐Liss, Inc.
The association between birth order, sibship size and glioma development in adulthood
Authors: Amirian E. , Scheurer Michael E. , Bondy Melissa L.
Published: October 2009

The etiology of brain tumors is still largely unknown. Previous research indicates that infectious agents and immunological characteristics may influence adult glioma risk. The purpose of our study was to evaluate the effects of birth order and sibship size (total number of siblings), as indicators of the timing and frequency of early life infections, on adult glioma risk using a population of 489 cases and 540 cancer‐free controls from the Harris County Brain Tumor Study. Odds ratios for birth order and sibship size were calculated separately from multivariable logistic regression models, adjusting for sex, family history of cancer, education, and age. Each one‐unit increase in birth order confers a 13% decreased risk of glioma development in adulthood (OR = 0.87, 95% CI = 0.79–0.97). However, sibship size was not significantly associated with adult glioma status (OR = 0.97, 95% CI = 0.91–1.04). Our study indicates that individuals who were more likely to develop common childhood infections at an earlier age (those with a higher birth order) may be more protected against developing glioma in adulthood. More biological and epidemiological research is warranted to clarify the exact mechanisms through which the timing of common childhood infections and the course of early life immune development affect gliomagenesis.
The state of the art of cancer control in 30 European countries in 2008
Authors: Bastos Joana , Peleteiro Bárbara , Gouveia Joaquim , Coleman Michel P. , Lunet Nuno
Published: October 2009

Inequalities in cancer incidence, mortality and survival represent a major challenge for public health. Addressing this challenge requires complex and multidisciplinary approaches. Sharing successful experiences from across Europe may therefore be of benefit. We describe the state of the art of cancer control structures in the 27 European Union countries, plus Iceland, Norway and Switzerland, at the beginning of 2008. Information on cancer plans, cancer registries, cancer screening, Human Papillomavirus (HPV) vaccination and smoking restrictions in each country was identified through PubMed, the official websites of national and international organizations and Google™ searches. Experts and/or health authorities from each country completed and validated the information. Sixteen countries had implemented national cancer plans in 2008. Twenty four countries had population‐based cancer registries with 100% coverage. The exceptions were Greece and Luxembourg (no population‐based registry yet), France, Italy and Spain (<50%), and Switzerland (62%). In 9 countries, population coverage of breast cancer screening was 100% with participation ranging from 26 to 87%; 8 countries did not have organized programmes. Seven countries had cervical cancer screening programmes with 100% coverage with participation ranging from 10 to 80%; 8 countries had no organized programme. Nine countries had announced national HPV vaccination policies by early 2008. Six countries had organized colorectal cancer screening programmes. Five countries had complete bans on smoking in public places. There is wide international heterogeneity in cancer control structures in Europe. This provides considerable scope and motivation for cooperation and sharing of experience.
Does long‐run purchasing power parity hold in Eastern and Southern African countries? Evidence from panel data stationary tests with multiple structural breaks
Authors: Hoarau Jean‐François
Published: October 2009

This study tests for the long‐run purchasing power parity hypothesis for a panel of 17 African economies, all belonging to the Common Market for Eastern and Southern Africa, over the period 1970–2007. This assumption is considered both in its traditional view, that is, the reversion of the real exchange rate (RER) to a constant mean, and in the Balassa‐Samuelson view, that is, the reversion of the RER to a constant trend. For this purpose, we use the new panel data stationary test advocated by Carrion‐i‐Silvestre et al. that accounts for multiple structural breaks and cross‐sectional dependence. Finally, our results give strong evidence for purchasing power parity when the Balassa‐Samuelson version is considered. This finding supports the view that purchasing power parity is most likely to be found among high inflation less developed countries and non‐CFA countries. Copyright © 2009 John Wiley & Sons, Ltd.
Making trading decisions for financial‐engineered derivatives: a novel ensemble of neural networks using information content
Authors: Leung Mark T. , Chen An‐Sing , Mancha Ruben
Published: October 2009

Over the last decades, there has been a growing interest in applying artificial intelligence techniques to solve a spectrum of financial problems. A number of studies have shown promising results in using artificial neural networks (ANNs) to guide investment trading. Given the expanding role of ANNs in financial trading, this paper proposes the use of a hybrid neural network, which consists of two independent ANN architectures, and comparatively evaluates its performance against independent ANNs and econometric models in the trading of a financial‐engineered (synthetic) derivative composed of options on foreign exchange futures. We examine the financial profitability and the market timing ability of the competing neural network models and statistically compare their attributes with those based on linear and nonlinear statistical projections. A random walk model and the option pricing method are also included as benchmarks for comparison. Our empirical investigation finds that, for each of the currencies analysed, trading strategies guided by the proposed dual network are financially profitable and yield a more stable stream of investment returns than the other models. Statistical results strengthen the notion that diffusion of information contents and cross‐validation between the independent components within the dual network are able to reduce bias and extreme decision making over the long run. Moreover, the results are robust with respect to different levels of transaction costs. Copyright © 2009 John Wiley & Sons, Ltd.
Cytotoxic effects of polychlorinated biphenyl hydroquinone metabolites in rat hepatocytes
Authors: Chan Katie , Lehmler Hans‐Joachim , Sivagnanam Milani , Feng Cynthia Yan , Robertson Larry , O'Brien Peter J.
Published: October 2009

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that exhibit various toxic effects in animals and exposed human populations. The molecular mechanisms of PCB toxicity have been attributed to the toxicological properties of its metabolites, such as hydroquinones, formed by cytochrome‐P‐450 oxidation. The effects of PCB hydroquinone metabolites towards freshly isolated rat hepatocytes were investigated. Hydroquinones can be oxidized to semiquinones and/or quinone metabolites. These metabolites can conjugate glutathione or can oxidize glutathione as a result of redox cycling. This depletes hepatocyte glutathione, which can inhibit cellular defence mechanisms, causing cell death and an increased susceptibility to oxidative stress. However in the following, glutathione‐depleted hepatocytes became more resistant to the hydroquinone metabolites of PCBs. This suggested that their glutathione conjugates were toxic and that there was a third type of quinone toxicity mechanism which involved a hydrogen peroxide‐accelerated autoxidation of the hydroquinones to form toxic electrophilic quinone and semiquinone–glutathione conjugates. Copyright © 2009 John Wiley & Sons, Ltd.
Impediment of NEMO oligomerization inhibits osteoclastogenesis and osteolysis
Authors: Darwech Isra , Otero Jesse , Alhawagri Muhammad , Dai Simon , Abu‐Amer Yousef
Published: October 2009

The transcription factor NF‐κB is essential for osteoclastogenesis and is considered an immune‐modulator of rheumatoid arthritis and inflammatory osteolysis. Activation of NF‐κB subunits is regulated by the upstream IκB kinase (IKK) complex which contains IKKα, IKKβ, and IKKγ; the latter also known as NF‐κB essential modulator (NEMO). The role of IKKα and IKKβ in the skeletal development and inflammatory osteolysis has been described, whereas little is known regarding the role of NEMO in this setting. Typically, signals induced by RANK ligand (RANKL) or TNF prompt oligomerization of NEMO monomers through the coiled‐coil‐2 (CC2) and leucine zipper (LZ) motifs. This step facilitates binding to IKKs and further relaying signal transduction. Given the central role of NF‐κB in osteoclastogenesis, we asked whether NEMO is essential for osteoclastogenesis and whether interruption of NEMO oligomerization impedes osteoclast differentiation in vitro and in vivo. Using cell‐permeable short peptides overlapping the CC2 and LZ motifs we show that these peptides specifically bind to NEMO monomers, prevent trimer formation, and render NEMO monomers susceptible for ubiquitin‐mediated degradation. Further, CC2 and LZ peptides attenuate RANKL‐ and TNF‐induced NF‐κB signaling in bone marrow‐derived osteoclast precursors (OCPs). More importantly, these peptides potently inhibit osteoclastogenesis, in vitro, and arrest RANKL‐induced osteolysis, in mice. To further ascertain its role in osteoclastogenesis, we were able to block osteoclastogenesis using NEMO siRNA knockdown approach. Collectively, our data establish that obstruction of NEMO oligomerization destabilizes NEMO monomers, inhibits NF‐κB activation, impedes osteoclastogenesis and arrests inflammatory osteolysis. Thus, NEMO presents itself as a promising target for anti‐osteolytic intervention. J. Cell. Biochem. 108: 1337–1345, 2009. © 2009 Wiley‐Liss, Inc.
Quantum mechanical studies on model α‐pleated sheets
Authors: Wu Hao , Canfield Alana , Adhikari Jhashanath , Huo Shuanghong
Published: October 2009

Pauling and Corey proposed a pleated‐sheet configuration, now called α‐sheet, as one of the protein secondary structures in addition to α‐helix and β‐sheet. Recently, it has been suggested that α‐sheet is a common feature of amyloidogenic intermediates. We have investigated the stability of antiparallel β‐sheet and two conformations of α‐sheet in solution phase using the density functional theoretical method. The peptides are modeled as two‐strand acetyl‐(Ala)2‐N‐methylamine. Using stages of geometry optimization and single point energy calculation at B3LYP/cc‐pVTZ//B3LYP/6‐31G* level and including zero‐point energies, thermal, and entropic contribution, we have found that β‐sheet is the most stable conformation, while the α‐sheet proposed by Pauling and Corey has 13.6 kcal/mol higher free energy than the β‐sheet. The α‐sheet that resembles the structure observed in molecular dynamics simulations of amyloidogenic proteins at low pH becomes distorted after stages of geometry optimization in solution. Whether the α‐sheets with longer chains would be increasingly favorable in water relative to the increase in internal energy of the chain needs further investigation. Different from the quantum mechanics results, AMBER parm94 force field gives small difference in solution phase energy between α‐sheet and β‐sheet. The predicted amide I IR spectra of α‐sheet shows the main band at higher frequency than β‐sheet. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010
Fetal thickened nuchal soft tissues may first appear in the second trimester in Down syndrome
Authors: Zimmer Etan Z. , Blazer Shraga , Linn Shai , Bronshtein Moshe
Published: October 2009

Purpose.

To describe a series of cases of late‐onset fetal nuchal translucency in Down syndrome.

Method.

In our practice area, most pregnant women usually undergo 3 different sonographic examinations: a fetal nuchal translucency examination in the 1st trimester and 2 detailed surveys of all fetal organs in the early 2nd trimester and in midpregnancy.

Result.

During the study period (2003–2008), we detected 11 fetuses with new appearance of severe thickened nuchal soft tissues (≥6 mm) at 14–16 weeks' gestation after a normal nuchal screening in the 1st trimester. All of these fetuses had trisomy 21. Associated structural anomalies were observed in 10/11 of the cases. In addition, there were 12 fetuses with new appearance of thickened nuchal soft tissues (<4 mm); all these fetuses had a normal karyotype and were normal at delivery.

Conclusion.

Obstetricians should be aware that a nuchal abnormality may first appear only at 14–16 weeks' gestation. Fetal karyotyping is advocated in these cases because of the high probability of Down syndrome. © 2009 Wiley Periodicals, Inc. J Clin Ultrasound, 2010
Patient and physician predictors of inappropriate acid‐suppressive therapy (AST) use in hospitalized patients
Authors: Nachnani Jagdish S. , Bulchandani Deepti , Moormeier Jill , Foxworth John
Published: October 2009

BACKGROUND:

The use of acid suppressive therapy (AST) in prevention of stress ulcers has been well defined in critical care patients, though its use has become increasingly common in general medicine patients, with little to no supportive evidence. None of the previous studies has examined the patient and physician characteristics of inappropriate AST initiation and use in hospitalized patients. The aim of our study was to identify: (1) the appropriateness of AST in hospitalized patients and the cost associated with inappropriate use; and (2) patient and physician characteristics predicting inappropriate initiation and use of AST.

METHODS:

All discharges over a period of 8 consecutive days were selected.

RESULTS:

There were 207 patients discharged over a period of 8 days. AST was inappropriately initiated in 92 of 133 (69.2%) patients included in our study. On univariate analysis, higher hemoglobin value, postgraduate year 1 (PGY‐1) residents, physicians with an MD degree, international medical graduates (IMGs), and internal medicine physicians were more likely to prescribe AST inappropriately. On multivariate analysis, a higher hemoglobin value, PGY‐1 residents, and MD physicians were factors associated with inappropriate AST use. The total direct patient cost for this inappropriate use was $8026, with an estimated annual cost of approximately $366,000.

CONCLUSIONS:

AST was inappropriately initiated in 69.2% of patients with increased direct costs of $8026. Residents in their first year of training as well physicians with a MD degree are more likely to initiate AST inappropriately. Curtailing the inappropriate use of AST therapy may reduce overall costs for the patient and institution. Journal of Hospital Medicine 2009;4:E10–E14. © 2009 Society of Hospital Medicine.
Inpatient thromboprophylaxis use in U.S. hospitals: Adherence to the seventh American College of Chest Physician's recommendations for at‐risk medical and surgical patients
Authors: Amin Alpesh N. , Stemkowski Stephen , Lin Jay , Yang Guiping
Published: October 2009

BACKGROUND:

The clinical venous thromboembolism (VTE) burden remains high in the United States, despite guidelines recommending that safe and effective VTE prophylaxis be available. This study assesses the real‐world rate of appropriate inpatient VTE prophylaxis in hospitalized U.S. medical and surgical patients at risk of VTE, in accordance with the seventh American College of Chest Physicians, (ACCP) guidelines.

METHODS:

Medical and surgical discharges from Premier's Perspective™ database between January 1, 2005 and December 31, 2006 were considered. Discharges aged ≥40 years, with a length of stay ≥6 days, at risk of VTE due to the presence of ≥1 VTE risk factors identified by the seventh ACCP guidelines, and without contraindications for anticoagulation, were included in the analysis. Appropriate prophylaxis was determined by comparing the daily use, dosage, and duration of anticoagulants and compression devices with the seventh ACCP recommendations for each medical condition or surgical procedure.

RESULTS:

A total of 390,024 discharges met the inclusion criteria, of which 201,224 (51.6%) were medical discharges and 188,800 (48.4%) were surgical discharges. Overall, 65.9% of medical discharges and 77.7% of surgical discharges received at least 1 order for VTE prophylaxis during hospitalization. However, only 12.7% of medical discharges and 16.4% of surgical discharges received appropriate prophylaxis when the recommended prophylaxis type, dose, and duration from the seventh ACCP guidelines were taken into account.

CONCLUSIONS:

Few medical and surgical patients at high risk of VTE receive appropriate inpatient prophylaxis in accordance with guideline recommendations. It is important for individual hospitals to improve VTE prophylaxis practices to meet national performance initiatives. Journal of Hospital Medicine 2009;4:E15–E21. © 2009 Society of Hospital Medicine.
Effect of hospitalist attending physicians on trainee educational experiences: A systematic review
Authors: Natarajan Pradeep , Ranji Sumant R. , Auerbach Andrew D. , Hauer Karen E.
Published: October 2009

BACKGROUND:

Trainees receive much of their inpatient education from hospitalists.

PURPOSE:

To characterize the effects of hospitalists on trainee education.

DATA SOURCES:

MEDLINE, Database of Reviews of Effectiveness (DARE), National Health Service (NHS) Economic Evaluation Database (EED), Health Technology Assessment (HTA), and the Cochrane Collaboration Database (last searched October 2008) databases using the term “hospitalist”, and meeting abstracts from the Society of Hospital Medicine (SHM) (2002‐2007), Society of General Internal Medicine (SGIM) (2001‐2007), and Pediatric Academic Societies (PAS) (2000‐2007).

STUDY SELECTION:

Original English language research studies meeting all of the following: involvement of hospitalists; comparison to nonhospitalist attendings; evaluation of trainee knowledge, skills, or attitudes. 711 articles were reviewed, 32 retrieved, and 6 included; 7,062 meeting abstracts were reviewed, 9 retrieved, and 2 included.

DATA EXTRACTION:

Two authors reviewed articles to determine study eligibility. Three authors independently reviewed included articles to abstract data elements and classify study quality.

DATA SYNTHESIS:

Seven studies were quasirandomized one was a noncontemporaneous comparison. All citations only measured trainee attitudes. In all studies comparing hospitalists to nonhospitalists, trainees were more satisfied with hospitalists overall, and with other aspects of their teaching, but ratings were high for both groups. One of 2 studies that distinguished nonhospitalist general internists from specialists showed that trainees preferred hospitalists, but the other did not demonstrate a hospitalist advantage over general internists.

CONCLUSIONS:

Trainees are more satisfied with inpatient education from hospitalists. Whether the increased satisfaction translates to improved learning is unclear. Journal of Hospital Medicine 2009;4:490–498. © 2009 Society of Hospital Medicine.
Communication and documentation considerations for electronic health records
Authors: Gaffey Ann D.
Published: October 2009

Electronic health records (EHRs) are here to stay, and their use is expected to grow significantly in the future. It is incumbent on risk managers to ensure their use does not inhibit good provider‐to‐patient communication. Providing education and strategies on how to make the patient encounter meaningful while the provider uses an EHR may increase patient satisfaction and may contribute to a favorable professional liability loss experience. Risk managers also need to have an understanding of the capabilities of each specific EHR system in the facility, the implications of the ability to cut‐and‐paste information from one provider entry to another, and knowledge of how to control the risk that comes with both copying forward and delayed EHR documentation.
The mathematics of geographic profiling
Authors: O'Leary Mike
Published: October 2009

We begin by describing some of the mathematical foundations of the geographic profiling problem. We then present a new mathematical framework for the geographic profiling problem based on Bayesian statistical methods that makes explicit connections between assumptions on offender behaviour and the components of the mathematical model. It also can take into account local geographic features that either influence the selection of a crime site or influence the selection of an offender's anchor point. Copyright © 2009 John Wiley & Sons, Ltd.
Degenerative abnormalities in transgenic neocortical neuropeptide Y interneurons expressing tau‐green fluorescent protein
Authors: Rancillac Armelle , Lainé Jeanne , Perrenoud Quentin , Geoffroy Hélène , Ferezou Isabelle , Vitalis Tania , Rossier Jean
Published: October 2009

The introduction of a reporter gene into bacterial artificial chromosome (BAC) constructs allows a rapid identification of the cell type expressing the gene of interest. Here we used BAC transgenic mice expressing a tau‐sapphire green fluorescent protein (GFP) under the transcriptional control of the neuropeptide Y (NPY) genomic sequence to characterize morphological and electrophysiological properties of NPY‐GFP interneurons of the mouse juvenile primary somatosensory cortex. Electrophysiological whole‐cell recordings and biocytin injections were performed to allow the morphological reconstruction of the recorded neurons in three dimensions. Ninety‐six recorded NPY‐GFP interneurons were compared with 39 wild‐type (WT) NPY interneurons, from which 23 and 19 were reconstructed, respectively. We observed that 91% of the reconstructed NPY‐GFP interneurons had developed an atypical axonal swelling from which emerge numerous ramifications. These abnormalities were very heterogeneous in shape and size. They were immunoreactive for the microtubule‐associated protein tau and the lysosomal‐associated membrane protein 1 (LAMP1). Moreover, an electron microscopic analysis revealed the accumulation of numerous autophagic and lysosomal vacuoles in swollen axons. Morphological analyses of NPY‐GFP interneurons also indicated that their somata were smaller, their entire dendritic tree was thickened and presented a restricted spatial distribution in comparison with WT NPY interneurons. Finallly, the morphological defects observed in NPY‐GFP interneurons appeared to be associated with alterations of their electrophysiological intrinsic properties. Altogether, these results demonstrate that NPY‐GFP interneurons developed dystrophic axonal swellings and severe morphological and electrophysiological defects that could be due to the overexpression of tau‐coupled reporter constructs. © 2009 Wiley‐Liss, Inc.
Fear learning and extinction are linked to neuronal plasticity through Rin1 signaling
Authors: Bliss Joanne M. , Gray Erin E. , Dhaka Ajay , O'Dell Thomas J. , Colicelli John
Published: October 2009

The amygdala is known to have a crucial role in both the acquisition and extinction of conditioned fear, but the physiological changes and biochemical mechanisms underlying these forms of learning are only partly understood. The Ras effector Rin1 activates Abl tyrosine kinases and Rab5 GTPases and is highly expressed in mature neurons of the telencephalon including the amygdala, where it inhibits the acquisition of fear memories (Rin1−/− mice show enhanced learning of conditioned fear). Here we report that Rin1−/− mice exhibit profound deficits in both latent inhibition and fear extinction, suggesting a critical role for Rin1 in gating the acquisition and persistence of cue‐dependent fear conditioning. Surprisingly, we also find that depotentiation, a proposed cellular mechanism of extinction, is enhanced at lateral‐basolateral (LA‐BLA) amygdaloid synapses in Rin1−/− mice. Inhibition of a single Rin1 downstream effector pathway, the Abl tyrosine kinases, led to reduced amygdaloid depotentiation, arguing that proper coordination of Abl and Rab5 pathways is critical for Rin1‐mediated effects on plasticity. While demonstrating a correlation between amygdala plasticity and fear learning, our findings argue against models proposing a direct causative relationship between amygdala depotentiation and fear extinction. Taken together, the behavior and physiology of Rin1−/− mice provide new insights into the regulation of memory acquisition and maintenance. In addition, Rin1−/− mice should prove useful as a model for pathologies marked by enhanced fear acquisition and retention, such as posttraumatic stress disorder. © 2009 Wiley‐Liss, Inc.
Fas activation increases neural progenitor cell survival
Authors: Knight Julia C. , Scharf Eugene L. , Mao‐Draayer Yang
Published: October 2009

Although there is a sizable amount of research focusing on adult neural progenitor cells (NPCs) as a therapeutic approach for many neurodegenerative diseases, including multiple sclerosis, little is known about the pathways that govern NPC survival and apoptosis. Fas, a member of the death receptor superfamily, plays a well‐characterized role in the immune system, but its function in neural stem cells remains uncertain. Our study focuses on the effects of Fas on NPC survival in vitro. Activation of Fas by recombinant Fas ligand (FasL) did not induce apoptosis in murine NPCs in culture. In fact, both an increase in the amount of viable cells and a decrease in apoptotic and dying cells were observed with FasL treatment. Our data indicate that FasL‐mediated adult NPC neuroprotection is characterized by a reduction in apoptosis, but not increased proliferation. Further investigation of this effect revealed that the antiapoptotic effects of FasL are mediated by the up‐regulation of Birc3, an inhibitor of apoptosis protein (IAP). Conversely, the observed effect is not the result of altered caspase activation or FLIP (Fas‐associated death domain‐like interleukin‐1beta‐converting enzyme inhibitory protein) up‐regulation, which is known to inhibit caspase‐8‐mediated cell death in T cells. Our data indicate that murine adult NPCs are resistant to FasL‐induced cell death. Activation of Fas increased cell survival by decreasing apoptosis through Birc3 up‐regulation. These results describe a novel pathway involved in NPC survival. © 2009 Wiley‐Liss, Inc.
Ciliary neurotrophic factor enhances nicotinic synaptic transmission in sympathetic neurons
Authors: Nai Qiang , Wang Xiaoyun , Jin Ying , Sun Dongbin , Li Man , Hu Bo , Zhang Xiaotong
Published: October 2009

Nicotinic acetylcholine receptors mediate fast synaptic transmission in both central and peripheral nervous systems. These receptors play important roles in various physiological functions and are involved in different neurological diseases. A disruption in nicotinic receptor‐mediated synaptic transmission due to the loss of nAChRs was detected in the brains of patients with Parkinson's disease and Alzheimer's disease. Although ciliary neurotrophic factor (CNTF) has been reported to promote the cholinergic properties by increasing the production and storage of acetylcholine, it is still unclear whether CNTF can enhance nicotinic synaptic neurotransmission. In this study, we found that CNTF dramatically enhanced the frequency and amplitude of nicotinic excitatory post‐synaptic currents in rat superior cervical ganglion neurons maintained in a medium supplemented with nerve growth factor. Moreover, the number of neurons displaying nicotinic synaptic currents was also significantly increased by CNTF. These results suggest that CNTF could enhance nicotinic synaptic transmission via both presynaptic and postsynaptic mechanisms. The findings of this study reinforce the rationale for the usage of combinations of different neurotrophic factors for the therapy of neurodegenerative diseases. © 2009 Wiley‐Liss, Inc.