bluuebunny/crossref_metadata_2025 huggingface dataset:
Angiopoietin‐1 and ‐2 expression in recurrent squamous cell carcinoma of the oral cavity
Authors: Chien Chih‐Yen , Su Chih‐Ying , Chuang Hui‐Ching , Fang Fu‐Min , Huang Hsuan‐Ying , Chen Ching‐Mei , Chen Chang‐Han , Huang Chao‐Cheng
Published: December 2007

Background and Objectives

Our objective was to evaluate the clinical significance of angiopoietin‐1 (Ang‐1) and Ang‐2 expression in recurrent but operable squamous cell carcinoma of the oral cavity (OCSCC).

Patients and Methods

Formalin‐fixed, paraffin‐embedded tissues from 40 patients who underwent surgical intervention for local or local‐regional recurrent OCSCC between 1995 and 2005 were immunohistochemically analyzed for Ang‐1 and Ang‐2 expression.

Results

The recurrent TNM staging classified 5 patients as stage I, 4 as stage II, 2 as stage III, and 29 as stage IV. The actuarial 3‐year disease‐free survival rate was 43.1% with a mean follow‐up of 18.4 months (ranged 1–70 months). High expression of Ang‐1 was significantly correlated with positive nodal stage (P = 0.041). Patients with more advanced recurrent stage of the tumors (P = 0.0036) and high expression of Ang‐2 (P = 0.045) showed lower actuarial 3‐year disease‐free survival. However, Cox's regression analysis revealed that only recurrent tumor (rT) stage was an independent prognostic factor for survival (P = 0.019, 95% CI = 1.473–82.017, relative risk = 10.992).

Conclusions

Recurrent OCSCC with high Ang‐1 or Ang‐2 expression in the tumor bed exhibits aggressive tumor behavior. However, the salvage outcome depends on the rT stage. J. Surg. Oncol. 2008;97:273–277. © 2007 Wiley‐Liss, Inc.
Concurrent administration of zoledronic acid and irradiation leads to improved bone density, biomechanical strength, and microarchitecture in a mouse model of tumor‐induced osteolysis
Authors: Arrington Sarah A. , Damron Timothy A. , Mann Kenneth A. , Allen Matthew J.
Published: December 2007

Background and Objectives

Bone metastases are typically treated with bisphosphonates as adjuncts to radiation therapy. The goal of this study was to determine whether radiotherapy combined with a bisphosphonate could restore bone density, microarchitecture, and biomechanical strength of a tumor‐burdened bone to normal.

Materials and Methods

Breast cancer cells were injected into the right femur of 30 female nude mice. Mice were divided into three treatment groups (0 Gy, 20 Gy, and 20 Gy + ZA). Left limbs served as non‐operated normal bones. Tumor‐bearing femora were irradiated 3 weeks later. ZA (100 µg/kg SC) was administered once weekly for 6 weeks. Mice were euthanized at 9 weeks or earlier if severe lameness or pathology occurred.

Results

Mice treated with 20 Gy/ZA exhibited higher bone density, bone volume, fractional trabecular bone volume, and biomechanical strength compared to mice treated with 20 Gy only (P < 0.05). Statistical analysis revealed that mice treated with 20 Gy/ZA were not significantly different from normal bones with respect to bone density and strength. Micro‐CT reconstructions showed improved microarchitecture in the 20 Gy/ZA group compared to 20 Gy.

Conclusions

Treatment of an osteolytic bone with radiation therapy plus zoledronic acid restores normal bone qualities with respect to bone density, microarchitecture, and biomechanical strength. J. Surg. Oncol. 2008;97:284–290. © 2007 Wiley‐Liss, Inc.
Poorly differentiated colorectal adenocarcinomas show higher rates of microsatellite instability and promoter methylation of p16 and hMLH1: A study matched for T classification and tumor location
Authors: Kazama Yoshihiro , Watanabe Toshiaki , Kanazawa Takamitsu , Tanaka Junichiro , Tanaka Toshiaki , Nagawa Hirokazu
Published: December 2007

Background

Extensive genetic and epigenetic analysis of poorly differentiated colorectal adenocarcinomas (Por) has been difficult, as the number of cases is too small.

Methods

We investigated genetic and epigenetic alterations of 53 cases of Por and 53 cases of well‐differentiated colorectal adenocarcinomas (WD) to clarify their differences. The cases of WD were matched with the cases of Por for T classification and tumor location, which influence genetic and epigenetic alterations. We evaluated microsatellite instability (MSI) status and loss of heterozygosity (LOH) of four loci (2p, 5q, 17p, 18q), and defined “MSI tumors” as those that showed MSI‐H, and “chromosomal instability (CIN) tumors” as those that showed LOH but not MSI‐H. Further, we evaluated the methylation status of the hMLH1 and p16 promoter region.

Results

MSI tumors were significantly more frequent in Por (22.6%) than in WD (3.8%; P = 0.0041). CIN tumors were significantly less frequent in Por (64.2%) than in WD (83.0%; P = 0.046). Further, methylation of the p16 and hMLH1 promoter region was significantly more frequent in Por than in WD (P = 0.037, P = 0.047, respectively).

Conclusions

Our results indicate that Por tumorigenesis strongly correlates with MSI and methylation of the p16 and hMLH1 promoter region. J. Surg. Oncol. 2008;97:278–283. © 2007 Wiley‐Liss, Inc.
Laser Trimming of Micro Mirror Devices
Authors: Hänel Jens , Keiper Bernd , Bleul Karsten , Kaufmann Christian , Bonitz Jens
Published: December 2007

Laser trimming of Micro Mirror Devices promises an increasing yield in microsystem technology. Therefore the 3D‐Micromac AG and the Center for Microtechnologies (ZfM) have developed a module for measuring and tuning silicon micro actuators as well as microstructures. By using an ultra short pulsed laser with an UV‐wavelength the cutting of previously etched mass trimming elements and beam stiffness trimming elements has been implemented. These elements for modifying the resonant frequency of the micro mirror device are cut off by removing of silicon connector bars. The resonant frequency was influenced successfully by using this laser trimming tool in a clean room environment at wafer level and the subsequent bonding process of the wafer was demonstrated.
Femtosecond Laser Technology in Use: Safety Aspects
Authors: Krüger Jörg , Spielmann Christian
Published: December 2007

In recent years, femtosecond lasers matured from sensitive research setups to turnkey systems for an increasing number of applications. Now that running an ultra‐short pulse laser system needs no longer a specialized scientist, safety issues become more crucial. Ultrashort laser pulses have extremely high peak powers and even scattered radiation may possess severe risks to the unprotected eye. Accordingly, special protection schemes are necessary for these unique laser systems.
Human herpesvirus 6 infection in adult living related liver transplant recipients
Authors: Ohashi Masahiro , Sugata Ken , Ihira Masaru , Asano Yoshizo , Egawa Hiroto , Takada Yasutsugu , Uemoto Shinji , Yoshikawa Tetsushi
Published: December 2007

To analyze human herpesvirus 6 (HHV-6) infection in adult living related liver transplantation, we performed a virological analysis, including viral isolation, serological assay, and real-time polymerase chain reaction, of serially collected blood samples from 67 recipients. In addition, cytokine levels were measured to determine their role in viral reactivation. HHV-6 was isolated from only 4 recipients (6.0%), and viral DNA was detected in 15 (22.4%) of the 67 recipients. A significant increase in HHV-6 immunoglobulin G antibody titers was observed in 19 (28.4%) of the 67 recipients. Finally, 26 recipients (38.8%) had HHV-6 reactivation 2-6 weeks after transplantation. HHV-6 associated clinical features were analyzed in the 17 recipients presenting with either viremia or DNAemia. Two recipients with viremia and 3 recipients with DNAemia had unexplained fever at the time of viral infection. An increase in aminotransferase levels was observed in 2 recipients with viremia and 3 recipients with DNAemia. Recipients with liver cirrhosis caused by hepatitis B virus or hepatitis C virus infection as the underlying disease were more likely to have HHV-6 infection (P = 0.025). Mortality at the last follow-up in recipients with HHV-6 reactivation was significantly higher than in those without viral reactivation (P = 0.0118). Plasma interleukin-6 levels were significantly higher in the recipients with HHV-6 viremia than in the recipients without viremia at 4 weeks post-transplant (P = 0.0411). Moreover, tumor necrosis factor α levels were also higher in recipients with HHV-6 viremia (P < 0.0001) or reactivation (P = 0.0011) than in recipients without viremia or reactivation 4 weeks post-transplant. Liver Transpl, 2007. © 2007 AASLD.
Association between donor-recipient serum sodium differences and orthotopic liver transplant graft function
Authors: Cywinski Jacek B. , Mascha Edward , Miller Charles , Eghtesad Bijan , Nakagawa Shunichi , Vincent Joseph P. , Pesa Nick , Na Jie , Fung John J. , Parker Brian M.
Published: December 2007

Previous studies have shown that donor hypernatremia and possibly recipient hyponatremia negatively impact graft function after orthotopic liver transplant (OLT). The purpose of this retrospective investigation was to determine whether measured differences in serum sodium values between cadaveric donors and OLT recipients (ΔNa+) influence immediate postoperative allograft function and short-term patient outcomes. Two hundred and fifty patients that underwent OLT from January 2001 to December 2005 were included in this study. The ΔNa+ for each donor recipient pair was correlated with standard postoperative liver function tests as well as recipient length of intensive care unit stay (LOICUS), length of hospital stay (LOHS) and recipient survival. The relationship between donor hypernatremia (serum sodium ≥ 155 mEq/mL), recipient hyponatremia (serum sodium level ≤ 130 mEq/mL), and postoperative outcomes were analyzed as well. Adjustments were made for baseline potential confounders, including model for end-stage liver disease (MELD) score, preservation solution used (HTK vs. UW), recipient and donor demographics and cold ischemia time (CIT). ΔNa+ as well as donor hypernatremia and recipient hyponatremia were not found to be associated with immediate postoperative allograft function, intraoperative blood product usage, LOICUS, LOHS or short-term patient survival. However, both the preoperative MELD score and HTK preservation solution used were significantly associated with several patient outcomes. A higher MELD score was associated with both increased red blood cell (RBC) (P < 0.001) and fresh frozen plasma (FFP) usage (P = 0.002), elevated postoperative total bilirubin levels (P < 0.001), increased LOHS (P = 0.04), and a higher 30-day post transplant mortality (P = 0.02). The use of HTK preservation solution was associated with higher mean postoperative aspartate aminotransferase levels (P = 0.02) and decreased mean RBC (P < 0.001) and FFP usage (P = 0.009) compared to UW preservation solution use. Liver Transpl 14:59–65, 2008. © 2007 AASLD.
Preserving renal function in liver transplant recipients with rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitors
Authors: Bajjoka Iman , Hsaiky Lama , Brown Kimberly , Abouljoud Marwan
Published: December 2007

Early renal dysfunction following liver transplantation is associated with increased morbidity and mortality. To evaluate the impact of delayed initiation of calcineurin inhibitor on renal function, we conducted a retrospective study comparing 118 liver transplant recipients who received rabbit anti-thymocyte globulin and delayed initiation of calcineurin inhibitor with 80 liver transplant recipients who received no antibody and early initiation of calcineurin inhibitor (control group). All patients received mycophenolate mofetil and steroids. Delayed calcineurin inhibitor initiation with anti-thymocyte globulin was associated with significant improvement in renal function throughout the first year post-transplant. At 12 months post-transplant, patients treated with this regimen experienced lower serum creatinine (1.4 ± 0.5 versus 1.7 ± 0.5 mg/dL, P < 0.001), a higher estimated glomerular filtration rate (57.4 ± 20.5 versus 43.7 ± 14.4 mL/min/1.73 m2, P < 0.001), and less dependence on dialysis (0.8% versus 13%, P < 0.001) in comparison with no antibody and early calcineurin inhibitor initiation. Patient survival and graft survival were similar between groups; however, there was a trend of a lower incidence of early biopsy-proven acute rejection with anti-thymocyte globulin. Overall infection and cytomegalovirus infection were significantly lower in anti-thymocyte globulin–treated patients, and there was no increased incidence of hepatitis C recurrence in comparison with controls. In conclusion, delayed initiation of calcineurin inhibitor with anti-thymocyte globulin in liver transplant recipients is safe and is associated with improvements in renal function and a lower incidence of early acute rejection in comparison with no antibody and early initiation of calcineurin inhibitor. Liver Transpl 14:66–72, 2008. © 2007 AASLD.
Caroli's disease and outcomes after liver transplantation
Authors: Millwala Farida , Segev Dorry L. , Thuluvath Paul J.
Published: December 2007

Caroli's disease is a rare autosomal recessive disorder characterized by intrahepatic cystic dilatation of the bile ducts that, when progressive, leads to intrahepatic stones, recurrent cholangitis, portal hypertension, cholangiocarcinoma, and liver failure. Liver transplantation is a promising curative option for advanced Caroli's disease. The aim of this study was to determine the outcomes of liver transplantation in unselected patients with Caroli's disease and recommend an evidence-based therapeutic algorithm for the management of Caroli's disease. Of the 78,124 patients transplanted in the United States between 1987 and 2006, 104 had Caroli's disease; 96 of these underwent liver alone, and 8 underwent combined liver/kidney transplantation. The patient survival and graft survival were analyzed by Kaplan-Meier survival analysis, and risk of death and risk of graft loss were analyzed by Cox proportional hazards regression. The overall 1-, 3-, and 5-year graft (79.9%, 72.4%, and 72.4%) and patient (86.3%, 78.4%, and 77%) survival rates were excellent for patients after liver transplantation. For combined liver/kidney transplantation (n = 8), the 1-year patient survival and graft survival were 100%. Proportional hazards analysis identified Asian ethnicity, elevated bilirubin, requirement of life support or hospitalization prior to transplantation, and a cold ischemia time greater than 12 hours as associated with increased risk of both graft loss and death. A history of prior transplant or prior abdominal surgery was also associated with increased risk of graft loss. In conclusion, liver transplantation is an excellent treatment option for patients with advanced Caroli's disease and should be considered in a timely fashion to prevent worsening complications including refractory cholangitis and cholangiocarcinoma. Liver Transpl 14:11–17, 2008. © 2007 AASLD.
Early invasive Listeria monocytogenes infection after orthotopic liver transplantation: Case report and review of the literature
Authors: Kruszyna Thomas , Walsh Mark , Peltekian Kevork , Molinari Michele
Published: December 2007

Infection with Listeria monocytogenes is rare, with a reported annual incidence of 4.4 cases per million individuals. It is caused by a gram-positive rod-shaped bacterium (Listeria monocytogenes) that can be found in soil, vegetation, water, sewage, and silage and in feces of humans and animals. It is a facultative intracellular pathogen with the ability to survive and multiply in phagocytic host cells, even in adverse environmental circumstances. Listeriosis has rarely been reported after orthotopic liver transplantation, and transplant physicians are often unfamiliar with the clinical presentation of this rare but virulent infection, which accounts for 20%-30% mortality in affected individuals. We present a case of invasive Listeria infection causing bacteremia and peritonitis in the early postoperative period after cadaveric liver transplantation in a previously asymptomatic patient. Liver Transpl 14:88–91, 2008. © 2007 AASLD.
Osteoblasts‐derived TGF‐β1 enhance motility and integrin upregulation through Akt, ERK, and NF‐κB‐dependent pathway in human breast cancer cells
Authors: Wei Ying‐Ying , Chen Ying‐Ju , Hsiao Yu‐Chun , Huang Yi‐Chia , Lai Tzu‐Hsu , Tang Chih‐Hsin
Published: December 2007

Bone metastases are common complications of breast cancer. Integrins are the major adhesive molecules in mammalian cells. Here we found that osteoblast conditioned medium (OBCM) increased the migration and cell surface expression of β1 or β3 integrin in human breast cancer cells (MDA‐MB‐231 cells). β1 or β3 integrin monoclonal antibodies (mAbs) or small interference RNA (siRNA) against β1 or β3 integrin inhibited the OBCM‐induced increase in the migration of breast cancer cells. Transforming growth factor‐β1 (TGF‐β1) siRNA could remarkably blocked OBCM‐induced chemomigration and β1 and β3 integrin expression in breast cancer cells. Stimulation of cells with OBCM caused an increase in Akt and extracellular signal‐regulated kinase (ERK) phosphorylation in a time‐dependent manner. In addition, treatment of MDA‐MB‐231 cells with phosphatidylinositol 3‐kinase inhibitor (LY294002), ERK inhibitor (PD98059), NF‐κB inhibitor (PDTC), or IκB protease inhibitor (TPCK) inhibited OBCM‐induced cells migration and integrins expression. Treatment of MDA‐MB‐231 cells with OBCM induced IκB kinase α/β (IKK α/β) phosphorylation, IκBα phosphorylation, IκBα degradation, p65 Ser536 phosphorylation, and κB‐luciferase activity. The OBCM‐mediated increases in IKK α/β phosphorylation, p65 Ser536 phosphorylation, and κB‐luciferase activity were inhibited by LY294002 and PD98059. In addition, TGF‐β1 siRNA also reduced the OBCM‐induced ERK, Akt, IKKα/β, IκBα, and p65 phosphorylation. Taken together, these results suggest that the osteoblast‐derived TGF‐β1 acts through Akt and ERK, which in turn activates IKKα/β and NF‐κB, resulting in the activations of β1 and β3 integrins and contributing the migration of breast cancer cell. © 2007 Wiley‐Liss, Inc.
Short‐Term culture of in vitro produced bovine preimplantation embryos with insulin‐like growth factor‐i prevents heat shock‐induced apoptosis through activation of the Phosphatidylinositol 3‐Kinase/Akt pathway
Authors: Jousan F. Dean , Oliveira Lilian J. , Hansen Peter J.
Published: December 2007

Insulin‐like growth factor (IGF‐I) has been implicated as a thermoprotective molecule for the preimplantation bovine embryo. Here, it was shown that effects of heat shock (41°C for 15 hr) on induction of apoptosis and reduction in cell number in bovine embryos collected at Day 5 after fertilization were blocked by addition of 100 ng/ml IGF‐I at the initiation of heat shock. This action of IGF‐I to block heat shock‐induced apoptosis was eliminated if embryos were cultured with either a phosphatidylinositol 3‐kinase (PI3K) inhibitor (wortmannin) or an Akt inhibitor (1L‐6‐hydroxymethyl‐chiro‐inositol 2‐(R)‐2‐o‐methyl‐3‐o‐octadecylcarbonate). Immunofluorescence microscopy confirmed the expression of phosphorylated Akt for IGF‐I and control embryos. Immunoblotting using an antibody to Akt (phospho S473) indicated increased phosphorylation of Akt in IGF‐I‐treated embryos. In conclusion, short‐term treatment of embryos with IGF‐I can block induction of apoptosis caused by heat shock through signaling events requiring PI3K and Akt. Mol. Reprod. Dev. 75: 681–688, 2008. © 2007 Wiley‐Liss, Inc.
Confirmation of the role of N‐acetyltransferase 2 in teratogen‐induced cleft palate using transgenics and knockouts
Authors: Erickson Robert P. , Cao Wen , Acuña Diana K. , Strnatka Diana W. , Hunter Robert J. , Chau Binh T. , Wakefield Larissa V. , Sim Edith , McQueen Charlene A.
Published: December 2007

Previous work on Dilantin‐ and hydrocortisone‐induced cleft palate and cleft lip with or without cleft palate using congenics for the N‐acetyltransferase loci (Nat1 and Nat2 are closely linked) and recombinant inbred lines implicated the Nat1,2 region in susceptibility to teratogen‐induced orofacial clefting. Since Nat1 does not differ between the two strains, Nat2 appeared to be responsible. We have now tested this conclusion using transgenics and knockouts. Transgenics for human NAT1 (equivalent to mouse Nat2) and knockouts for Nat2 were tested for susceptibility to Dilantin, hydrocortisone, and 6‐aminonicotinamide‐induced orofacial clefting. We found that Nat2 greatly influences teratogen‐induced orofacial clefting on the A/J background but not on the C57BL/6J background. The magnitude and direction of the effects depended on which teratogen was used. The Nat2 knockout did not make C57BL/6J susceptible or A/J (already with very low activity) more susceptible but significantly decreased sporadic clefting in the A/J strain. We conclude that only the A/J strain, with several loci affecting orofacial clefting, is influenced by Nat2. Mol. Reprod. Dev. 75: 1071–1076, 2007. © 2007 Wiley‐Liss, Inc.
The cell cycle control protein cdc25C is present, and phosphorylated on serine 214 in the transition from germinal vesicle to metaphase II in human oocyte meiosis
Authors: Cunat S. , Anahory T. , Berthenet C. , Hedon B. , Franckhauser C. , Fernandez A. , Hamamah S. , Lamb N.J.C.
Published: December 2007

Cdc25C is a dual specificity phosphatase essential for dephosphorylation and activation of cyclin‐dependent kinase 1 (cdk1), a prerequisite step for mitosis in all eucaryotes. Cdc25C activation requires phosphorylation on at least six sites including serine 214 (S214) which is essential for metaphase/anaphase transit. Here, we have investigated S214 phosphorylation during human meiosis with the objectives of determining if this mitotic phosphatase cdc25C participates in final meiotic divisions in human oocytes. One hundred forty‐eight human oocytes from controlled ovarian stimulation protocols were stained for immunofluorescence: 33 germinal vesicle (GV), 37 metaphase stage I (MI), and 78 unfertilized metaphase stage II (MII). Results were stage dependent, identical, independent of infertility type, or stimulation protocol. During GV stages, phospho‐cdc25C is localized at the oocyte periphery. During early meiosis I (MI), phosphorylated cdc25C is no longer detected until onset of meiosis I. Here, phospho‐cdc25C localizes on interstitial microtubules and at the cell periphery corresponding to the point of polar body expulsion. As the first polar body reaches the periphery, phosphorylated cdc25C is localized at the junction corresponding to the mid body position. On polar body expulsion, the interior signal for phospho‐cdc25C is lost, but remains clearly visible in the extruded polar body. In atresic or damaged oocytes, the polar body no longer stains for phospho‐cdc25C. Human cdc25C is both present and phosphorylated during meiosis I and localizes in a fashion similar to that seen during human mitotic divisions implying that the involvement of cdc25C is conserved and functional in meiotic cells. Mol. Reprod. Dev. 75: 1176–1184, 2008. © 2007 Wiley‐Liss, Inc.
Bayesian enhanced decision making for deteriorating repairable systems with preventive maintenance
Authors: Huang Yeu‐Shiang , Hung Chi‐Chang , Fang Chih‐Chiang
Published: December 2007

Since a system and its components usually deteriorate with age, preventive maintenance (PM) is often performed to restore or keep the function of a system in a good state. Furthermore, PM is capable of improving the health condition of the system and thus prolongs its effective age. There has been a vast amount of research to find optimal PM policies for deteriorating repairable systems. However, such decisions involve numerous uncertainties and the analyses are typically difficult to perform because of the scarcity of data. It is therefore important to make use of all information in an efficient way. In this article, a Bayesian decision model is developed to determine the optimal number of PM actions for systems which are maintained according to a periodic PM policy. A non‐homogeneous Poisson process with a power law failure intensity is used to describe the deteriorating behavior of the repairable system. It is assumed that the status of the system after a PM is somewhere between as good as new for a perfect repair and as good as old for a minimal repair, and for failures between two preventive maintenances, the system undergoes minimal repairs. Finally, a numerical example is given and the results of the proposed approach are discussed after performing sensitivity analysis. © 2007 Wiley Periodicals, Inc. Naval Research Logistics, 2008
Simultaneous determination of production and maintenance schedules using in‐line equipment condition and yield information
Authors: Sloan Thomas
Published: December 2007

In many manufacturing environments, equipment condition has a significant impact on product quality, or yield. This paper presents a semi‐Markov decision process model of a single‐stage production system with multiple products and multiple maintenance actions. The model simultaneously determines maintenance and production schedules, accounting for the fact that equipment condition affects the yield of each product differently. It extends earlier work by allowing the expected time between decision epochs to vary by both action and machine state, by allowing multiple maintenance actions, and by treating the outcome of maintenance as less than certain. Sufficient conditions are developed that ensure the monotonicity of both the optimal production and maintenance actions. While the maintenance conditions closely resemble previously studied conditions for this type of problem, the production conditions represent a significant departure from earlier results. The simultaneous solution method is compared to an approach commonly used in industry, where the maintenance and production problems are treated independently. Solving more than one thousand test problems confirms that the combination of both features of the model—accounting for product differences and solving the problems simultaneously—has a significant impact on performance. © 2007 Wiley Periodicals, Inc. Naval Research Logistics, 2008
Pitfalls of using a single criterion for selecting experimental designs
Authors: Goel Tushar , Haftka Raphael T. , Shyy Wei , Watson Layne T.
Published: December 2007

For surrogate construction, a good experimental design (ED) is essential to simultaneously reduce the effect of noise and bias errors. However, most EDs cater to a single criterion and may lead to small gains in that criterion at the expense of large deteriorations in other criteria. We use multiple criteria to assess the performance of different popular EDs. We demonstrate that these EDs offer different trade‐offs, and that use of a single criterion is indeed risky. In addition, we show that popular EDs, such as Latin hypercube sampling (LHS) and D‐optimal designs, often leave large regions of the design space unsampled even for moderate dimensions. We discuss a few possible strategies to combine multiple criteria and illustrate them with examples. We show that complementary criteria (e.g. bias handling criterion for variance‐based designs and vice versa) can be combined to improve the performance of EDs. We demonstrate improvements in the trade‐offs between noise and bias error by combining a model‐based criterion, like the D‐optimality criterion, and a geometry‐based criterion, like LHS. Next, we demonstrate that selecting an ED from three candidate EDs using a suitable error‐based criterion helped eliminate potentially poor designs. Finally, we show benefits from combining the multiple criteria‐based strategies, that is, generation of multiple EDs using the D‐optimality and LHS criteria, and selecting one design using a pointwise bias error criterion. The encouraging results from the examples indicate that it may be worthwhile studying these strategies more rigorously and in more detail. Copyright © 2007 John Wiley & Sons, Ltd.
Reproducing kernel enhanced local radial basis collocation method
Authors: Chen J. S. , Hu W. , Hu H. Y.
Published: December 2007

Standard radial basis functions (RBFs) offer exponential convergence, however, the method is suffered from the large condition numbers due to their ‘nonlocal’ approximation. The nonlocality of RBFs also limits their applications to small‐scale problems. The reproducing kernel functions, on the other hand, provide polynomial reproducibility in a ‘local’ approximation, and the corresponding discrete systems exhibit relatively small condition numbers. Nonetheless, reproducing kernel functions produce only algebraic convergence. This work intends to combine the advantages of RBFs and reproducing kernel functions to yield a local approximation that is better conditioned than that of the RBFs, while at the same time offers a higher rate of convergence than that of reproducing kernel functions. Further, the locality in the proposed approximation allows its application to large‐scale problems. Error analysis of the proposed method is also provided. Numerical examples are given to demonstrate the improved conditioning and accuracy of the proposed method. Copyright © 2007 John Wiley & Sons, Ltd.
Derivatives of complex eigenvectors with distinct and repeated eigenvalues
Authors: Xu Zhonghai , Wu Baisheng
Published: December 2007

In this paper, we investigate the computation of the first‐order derivatives of complex eigenvectors for general non‐defective eigensystems. A new normalization condition is proposed, with which we can compute unique first‐order derivatives of arbitrary differentiable eigenvectors of systems with distinct and repeated eigenvalues. We also present an efficient algorithm to compute the particular solutions to the governing equations of the first‐order derivatives of eigenvectors. Finally, numerical examples are included to demonstrate the validity of the proposed method. Copyright © 2007 John Wiley & Sons, Ltd.
English‐language acculturation predicts academic performance in nursing students who speak English as a second language
Authors: Salamonson Yenna , Everett Bronwyn , Koch Jane , Andrew Sharon , Davidson Patricia M.
Published: December 2007

Students who speak English as a second language (ESL) face considerable challenges in English language universities, but little is known about the relationship between English‐language acculturation and academic performance. A prospective, correlational design was used to validate the English Language Acculturation Scale (ELAS), a measure of the linguistic aspect of acculturation, and to determine the relationship between English‐language acculturation and academic achievement among 273 first‐year nursing students. Exploratory factor analyses demonstrated that the ELAS was a valid and reliable measure (α = .89). When ELAS scores were examined in relation to students' grades, students with the lowest ELAS scores also had the lowest mean subject grades, highlighting the need to place greater emphasis on identifying English‐language acculturation among ESL students. © 2007 Wiley Periodicals, Inc. Res Nurs Health 31:86–94, 2008
Physiological and psychological symptoms of grief in widows
Authors: Kowalski Susan D. , Bondmass Mary D.
Published: December 2007

In this cross‐sectional descriptive survey of 173 widows, we describe their grief symptoms using an open‐ended questionnaire and the Revised Grief Experience Inventory. Self‐reported physical symptoms included pain, gastro‐intestinal problems, medical/surgical conditions, sleep disturbances, and neurological/circulatory issues. Psychological symptoms were reported as depression, anxiety, and loneliness. The mean total grief score was 71.4 ± 30.2 (possible range 22–132). Physical symptoms were significantly correlated with the total mean grief score, and subscales of physical distress, depression, existential tension, and guilt. When the subjects were grouped by years since loss, (range 1–5 years), there was no significant decrease found in overall grief scores, suggesting symptoms of grief experienced by widows may continue up to at least 5 years. © 2007 Wiley Periodicals, Inc. Res Nurs Health 31:23–30, 2008
The role of TLR activation in inflammation
Authors: Sabroe I , Parker LC , Dower SK , Whyte MKB
Published: December 2007

The Toll‐like receptor family was originally identified in Drosophila, where it provides important developmental and immunological signalling. In mammals, the developmental signal appears to have been lost, but the immunological defence role of these receptors has been expanded to provide broad recognition of bacterial, fungal, viral and parasitic pathogens. There is increasing evidence that these receptors go beyond the recognition of microbial molecules to sense host tissue damage. Recognition of host molecules and commensal microbes is also involved in the restoration of normal tissue architecture after injury and in maintenance of epithelial health. Recent developments in the TLR field highlight the importance of these molecules to human health and disease and demonstrate that their targeting, to boost immunity or inhibit inflammation, is both feasible and also potentially challenging. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Control of apoptosis in autoimmunity
Authors: Maniati E , Potter P , Rogers NJ , Morley BJ
Published: December 2007

Apoptosis and the subsequent removal of apoptotic cells underpin a healthy immune system. They are crucial for both the maintenance of self‐tolerance and the contraction of clonally expanded lymphocytes at the conclusion of immune responses. Aberrant apoptosis and the disposal of apoptotic cells is implicated in the development of both systemic and organ‐specific autoimmune disease and is a major contributing factor in disease susceptibility. Dissection of the molecular mechanisms involved in dysregulated apoptosis may reveal pathways which can be targeted for more effective therapeutic intervention. This review highlights the molecular events underlying programmed cell death and apoptotic cell uptake, and summarizes recent studies that link impaired apoptotic death to autoimmunity. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Nod‐like proteins in inflammation and disease
Authors: Carneiro LAM , Magalhaes JG , Tattoli I , Philpott DJ , Travassos LH
Published: December 2007

The field of innate immunity has undergone an enormous upheaval during the last decade. The discovery of different groups of proteins, called pattern recognition molecules (PRMs), which detect microbial components, so‐called pathogen‐associated molecular patterns (PAMPs) and trigger protective responses, had a huge impact on the understanding of innate immune responses. Among the PRMs, the intracellular Nod‐like receptors (NLRs) have recently been identified as key mediators of inflammatory and immune responses. The NLR family is divided into subfamilies on the basis of their different signal transduction domains, and recent studies have highlighted the role of certain NLRs, including Nod1, Nod2, Nalp3, Ipaf and Naip5, in the detection of intracellular microbes and possibly ‘danger signals’. In this review, we summarize the current knowledge on the function of these proteins in immunity and inflammation, with a focus on their participation in different disease pathologies. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
IL‐10 and the resolution of infections
Authors: Filippi CM , von Herrath MG
Published: December 2007

Chronic viral infections pose serious health concerns, as secondary complications such as immunodeficiencies and cancers are common. Treating such infections with conventional vaccine approaches has proved to be difficult. Studies in animals and humans suggest that vaccine failure is probably due to exhaustion of antiviral T cell responses, which occurs in a number of chronic infections. Attempts to elucidate the causes of impairment of antiviral immunity have pointed to a role for the immunomodulatory cytokine IL‐10 in the ability of viruses to establish persistence. Induction of IL‐10 production by the host during chronic infection appears to be one of the viral means to alter the class of the antiviral immune response and induce generalized immune suppression. Recent work by us and others suggests that it is possible to resuscitate antiviral immunity by interfering with the IL‐10 signalling pathway. Targeting IL‐10 thus constitutes a promising alternative to conventional vaccine strategies which have not proved to be successful in treating chronic infections. In addition, sterile cure may be achieved with minimal side‐effects by combining agents that alter the IL‐10 signalling pathway with other compounds, such as antiviral drugs or interferon, but also agents neutralizing other crucial elements of T cell exhaustion, such as PD‐1. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Stress proteins in CNS inflammation
Authors: van Noort JM
Published: December 2007

Stress proteins or heat shock proteins (HSPs) are ubiquitous cellular components that have long been known to act as molecular chaperones. By assisting proper folding and transport of proteins, and by assisting in the degradation of aberrant proteins, they play key roles in cellular metabolism. The frequent accumulation of insoluble protein aggregates during chronic neurodegenerative disorders suggests failure of HSP functions to be a common denominator among such diseases. Recent developments have clarified that functions of HSPs extend well beyond their role in protein folding and degradation alone. Stress‐inducible HSPs also regulate apoptosis, antigen presentation, inflammatory signalling pathways and, intriguingly, also serve as extracellular mediators of inflammation. Several receptors have been identified for extracellular HSPs, which control inflammatory pathways similar to those activated by cytokines and chemokines. In this review, both the traditional and the exciting novel functions of HSPs are discussed, with a focus on their relevance for neurodegeneration and neuroinflammation. Recent advances in this field suggest that HSPs represent attractive novel targets as well as therapeutic entities for CNS disorders. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The immunology of sepsis
Authors: Sriskandan S , Altmann DM
Published: December 2007

Sepsis, the systemic inflammatory response to infection, is considered the major cause of death among critically ill patients in the developed world. While there is a general view that this reflects contributions from both the pathogen and the host with respect to an inappropriate inflammatory response, there is a lack of agreement as to the key immune mechanisms. This has been reflected in the diverse range of immunotherapies tested in clinical trials, often with rather marginal effects. The case has been made for a pathogenic role of excessive immunity, the so‐called ‘cytokine storm’, and for a role of too little immunity through immune paralysis. Apoptosis is implicated as a key mechanism in both this immune paralysis and the multi‐organ failure that is a feature of severe sepsis. A number of polymorphisms have been implicated in susceptibility to sepsis, including cytokine genes, HLA class II and caspase‐12. In this review we focus in particular on the role of group A streptococci in severe sepsis. Here the effect of bacterial superantigens appears to be a correlate of inflammatory activation, although the precise evolutionary role of the superantigens remains unclear. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Immune activation and inflammation in HIV‐1 infection: causes and consequences
Authors: Appay V , Sauce D
Published: December 2007

Thorough research on HIV is progressively enabling us to understand the intricate mechanisms that link HIV‐1 infection to the onset of immunodeficiency. The infection and depletion of CD4+ T cells represent the most fundamental events in HIV‐1 infection. However, in recent years, the role played by chronic immune activation and inflammation in HIV pathogenesis has become increasingly apparent: quite paradoxically, immune activation levels are directly associated with HIV‐1 disease progression. In addition, HIV‐1‐infected patients present intriguing similarities with individuals of old age: their immune systems are characterized by a loss of regenerative capacity and an accumulation of ageing T cells. In this review, we discuss the potential reasons for the establishment of sustained immune activation and inflammation from the early stages of HIV‐1 infection, as well as the long‐term consequences of this process on the host immune system and health. A simplified model of HIV pathogenesis is proposed, which links together the three major facets of HIV‐1 infection: the massive depletion of CD4+ T cells, the paradoxical immune activation and the exhaustion of regenerative capacity. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Cellular and molecular mechanisms of fibrosis
Authors: Wynn TA
Published: December 2007

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Although current treatments for fibrotic diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis typically target the inflammatory response, there is accumulating evidence that the mechanisms driving fibrogenesis are distinct from those regulating inflammation. In fact, some studies have suggested that ongoing inflammation is needed to reverse established and progressive fibrosis. The key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen‐producing cell. Myofibroblasts are generated from a variety of sources including resident mesenchymal cells, epithelial and endothelial cells in processes termed epithelial/endothelial‐mesenchymal (EMT/EndMT) transition, as well as from circulating fibroblast‐like cells called fibrocytes that are derived from bone‐marrow stem cells. Myofibroblasts are activated by a variety of mechanisms, including paracrine signals derived from lymphocytes and macrophages, autocrine factors secreted by myofibroblasts, and pathogen‐associated molecular patterns (PAMPS) produced by pathogenic organisms that interact with pattern recognition receptors (i.e. TLRs) on fibroblasts. Cytokines (IL‐13, IL‐21, TGF‐β1), chemokines (MCP‐1, MIP‐1β), angiogenic factors (VEGF), growth factors (PDGF), peroxisome proliferator‐activated receptors (PPARs), acute phase proteins (SAP), caspases, and components of the renin–angiotensin–aldosterone system (ANG II) have been identified as important regulators of fibrosis and are being investigated as potential targets of antifibrotic drugs. This review explores our current understanding of the cellular and molecular mechanisms of fibrogenesis. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Macrophage activation by endogenous danger signals
Authors: Zhang X , Mosser DM
Published: December 2007

Macrophages are cells that function as a first line of defence against invading microorganisms. One of the hallmarks of macrophages is their ability to become activated in response to exogenous ‘danger signals’. Most microbes have molecular patterns (PAMPS) that are recognized by macrophages and trigger this activation response. There are many aspects of the activation response to PAMPS that are recapitulated when macrophages encounter endogenous danger signals. In response to damaged or stressed self, macrophages undergo physiological changes that include the initiation of signal transduction cascades from germline‐encoded receptors, resulting in the elaboration of chemokines, cytokines and toxic mediators. This response to endogenous mediators can enhance inflammation, and thereby contribute to autoimmune pathologies. Often the overall inflammatory response is the result of cooperative activation signals from both exogenous and endogenous signals. Macrophage activation plays a critical role, not only in the initiation of the inflammatory response but also in the resolution of this response. The clearance of granulocytes and the elaboration of anti‐inflammatory mediators by macrophages contribute to the dissolution of the inflammatory response. Thus, macrophages are a key player in the initiation, propagation and resolution of inflammation. This review summarizes our understanding of the role of macrophages in inflammation. We pay particular attention to the endogenous danger signals that macrophages may encounter and the responses that these signals induce. The molecular mechanisms responsible for these responses and the diseases that result from inappropriately controlled macrophage activation are also examined. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Innate and adaptive mechanisms to control of pathological intestinal inflammation
Authors: Kelsall BL
Published: December 2007

The intestine is the home of a tremendous number of commensal organisms that have a primary role in host metabolism. As a consquence, the gut mucosa has evolved multiple layers of protection. This review highlights both innate and adaptive mechanisms that prevent bacterial invasion and abnormal intestinal inflamamation, how a failure of these mechanisms may be involved in the pathogenesis of inflammatory bowel diseases, and discusses new findings implicating dendritic cells as central to the induction of active mucosal tolerance to commensal bacteria. Copyright © 2007 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.