bluuebunny/crossref_metadata_2025 huggingface dataset:
American Society of Clinical Oncology/National Comprehensive Cancer Network Quality Measures
Authors: Desch Christopher E. , McNiff Kristen K. , Schneider Eric C. , Schrag Deborah , McClure Joan , Lepisto Eva , Donaldson Molla S. , Kahn Katherine L. , Weeks Jane C. , Ko Clifford Y. , Stewart Andrew K. , Edge Stephen B.
Published: July 2008

Purpose

The National Cancer Policy Board recommended the creation of quality measures and a national reporting system in 1999. Representatives from the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) collaborated to create metrics suitable for national performance measurement.

Methods

Content and methodology experts nominated by ASCO and NCCN met to select and refine metrics for breast, colon, and rectal cancer based on National Initiative for Cancer Care Quality and NCCN measures and NCCN and ASCO guidelines. Measures were selected based on their impact on disease free and overall survival, the degree to which opportunities for improvement exist, and the feasibility of data collection.

Results

Three breast cancer measures and four colorectal cancer measures were chosen. Measures for breast cancer included adjuvant hormone therapy for hormone receptor–positive tumors, chemotherapy for hormone receptor–negative cancer, and radiation after lumpectomy. Colorectal measures included adjuvant radiation and chemotherapy for rectal cancer, and adjuvant chemotherapy for colon cancer. All but one were recommended as accountability measures and one for quality improvement (removal and examination of 12 or more lymph nodes in colon cancer). Specifications were developed for each measure using tumor registries as the data source.

Conclusion

ASCO/NCCN measures can be implemented by health systems, provider groups or payors for improvement or accountability using local tumor registries to furnish data on staging and treatment.
Geriatric Oncology: Past, Present, Future
Authors: Rao Arati V. , Hurria Arti , Kimmick Gretchen , Pinheiro Sandro , Seo Pearl H.
Published: July 2008

Efforts to integrate geriatric oncology principles in the training of all medical oncologists are underway.
Development and use of an anisotropic damage model for the high-temperature life assessment of a P91 weldment
Authors: Peravali S , Hyde T H , Cliffe K A , Leen S B
Published: July 2008

This paper describes the development of a finite element (FE) continuum damage mechanics methodology to deal with anisotropic creep and anisotropic damage for a P91 weld metal. The method employs a second-order damage tensor, together with a novel rupture stress approach to define the evolution of this tensor. The method takes advantage of the transverse isotropic nature of the weld metal, to achieve a reduction in the number of material constants required from test data (and hence tests) to define the damage evolution. Hill's anisotropy potential theory is employed to model the secondary creep. An FE implementation of the model is applied to the creep life assessment of an internally pressurized axisymmetric P91 pipe weldment. The study also considered the effect of various material mismatch ratios in the various zones of the weldment. Here material mismatch is considered to be a combination of the difference in uniaxial minimum strain rates and in the uniaxial rupture times.
Design analysis of ductile failure in dovetail connections
Authors: Naruse T , Mackenzie D
Published: July 2008

The static plastic collapse of ductile dovetail structures is investigated by three analysis methods: slip-line field (SLF) theory based on a sheet drawing model, finite element limit analysis, and linear elastic finite element analysis with adapted pressure vessel design stress linearization and categorization methods. A range of angles and heights are considered in the investigation. Three experimental test cases are also presented. The limit analysis results are found to give the best comparison with the limited experimental results, indicating similar collapse loads and modes of ductile collapse. The SLF solution is found to give conservative but useful failure loads for small dovetail angles but, at angles greater than 30°, the solution is not generally conservative. The pressure vessel design by the analysis stress categorization procedure was adapted for dovetail analysis and was found to give reasonably conservative collapse loads in most cases. However, the procedure requires the designer to consider a number of different stress classification lines to ensure that a conservative collapse load is identified. It is concluded that the finite element limit analysis approach provides the best and most direct route to calculating the allowable load for the joint and is the preferred method when appropriate finite element analysis facilities are available.
Finite element simulation of welding and residual stresses in a P91 steel pipe incorporating solid-state phase transformation and post-weld heat treatment
Authors: Yaghi A H , Hyde T H , Becker A A , Sun W
Published: July 2008

The finite element (FE) method has been applied to simulate residual axial and hoop stresses generated in the weld region and heat-affected zone of an axisymmetric 50-bead circumferentially butt-welded P91 steel pipe, with an outer diameter of 145 mm and wall thickness of 50 mm. The FE simulation consists of a thermal analysis and a sequentially coupled structural analysis. Solid-state phase transformation (SSPT), which is characteristic of P91 steel during welding thermal cycles, has been modelled in the FE analysis by allowing for volumetric changes in steel and associated changes in yield stress due to austenitic and martensitic transformations. Phase transformation plasticity has also been taken into account. The effects of post-weld heat treatment (PWHT) have been investigated, including those of heat treatment holding time. Residual axial and hoop stresses have been depicted through the pipe wall thickness as well as along the outer surface of the pipe. The results indicate the importance of including SSPT in the simulation of residual stresses during the welding of P91 steel as well as the significance of PWHT on stress relaxation.
An edge dislocation in a semi-infinite elastic wedge
Authors: Karuppanan S , Hills D A
Published: July 2008

The state of stress is deduced for an edge dislocation present in a semi-infinite wedge. Particular attention is paid to the case when both the dislocation and the observation point lie on a projection line from one of the free surfaces, permitting the solution to be used as a strain nucleus when solving for local slip and separation conditions at the edge of a complete frictional contact. The solution has obvious further application to edge cracks between bonded components.
Finite element analysis of wear and its effect on squeal generation
Authors: Abu Bakar A R , Ouyang H , James S , Li L
Published: July 2008

In the past, wear at the pad interface of disc brakes has rarely been accounted for in studies of brake squeal using the finite element method, and its effect on disc brake squeal has been investigated largely through experimental methods. In the present paper, wear taking place at this interface over time is simulated using a modified wear rate formula. The surface topographies of two new and unworn pairs of brake pads are measured. The same brake pads are tested under braking applications of three time durations. For each braking application, the static contact pressure distribution is measured using pressure-indicating film. The results are used to compare with the simulated results predicted by the three-dimensional finite element model of a real disc brake.

The paper also investigates squeal generation due to the above braking applications using complex eigenvalue analysis that is available in a commercial software package. It is found that the predicted unstable frequency is very close to the observed squeal frequency and that they take place in the same braking duration.
Brake squeal control with shunted piezoceramics — efficient modelling and experiments
Authors: Neubauer M , Oleskiewicz R
Published: July 2008

Due to increased interest in comfort features, considerable effort has been spent on the modification of brake prototypes in order to suppress brake squeal. Recently, piezoelectric transducers have been investigated as an innovative way of controlling the vibrations of a brake. This paper presents an efficient mechanical model for the description of a brake with embedded transducers. Different control strategies are discussed and compared. Measurements on a brake test rig validate the obtained results.
Understanding and improving the convective cooling of brake discs with radial vanes
Authors: Galindo-Lopez C H , Tirovic M
Published: July 2008

Detailed computational fluid dynamics (CFD) analyses of airflow and convective heat dissipation from a standard disc with radial vanes gave vital information regarding its weak points. Heat transfer from vanes is found to be particularly non-uniform, offering the largest scope for increasing local and average values of the coefficient of convective heat dissipation. A relatively simple modification — installation of an additional small vane (per channel, between the existing vanes) — demonstrated the ability to increase convective cooling from the ventilation channels. The radial position of these additional vanes was altered from disc ID towards OD, and best results were obtained with the vanes placed at the channel outlets (OD). An improvement in the total convective cooling (product of the average convective heat transfer coefficient and the entire disc wetted area) of nearly 14 per cent was achieved. In spite of better cooling, the new design has lower mass (air) flow when compared with the baseline design. The results are also presented in the form of Nusselt numbers, enabling their wider use. Conducted validation provided strong confidence in the accuracy of the results when searching for new solutions.
A computational fluid dynamic analysis on the effect of front row pin geometry on the aerothermodynamic properties of a pin-vented brake disc
Authors: Palmer E , Mishra R , Fieldhouse J
Published: July 2008

Increasing demand from the consumer for higher levels of refinement from their passenger vehicles has put considerable pressure on the automotive industry to produce ever quieter cars. In order to prevent the occurrence of many forms of brake noise, especially judder and drone, excessive heating of the brake disc must be avoided, while minimizing temperature variations across the rotor. In order for this to be achieved the brake rotor must be designed such that it ensures sufficient uniform heat dissipation and thermal capacity. In high-demand braking applications, vented discs consisting of two rubbing surfaces separated by straight radial vanes are normally employed, as they utilize a greater surface area to dissipate heat. Within this paper the effects of changing the geometry of the first row of pins on aerothermo-dynamic properties of a pin-vented brake rotor are investigated using computational fluid dynamics (CFD). The validated CFD model shows that decreasing the thickness of the first row of pins by 10 per cent improves the mass flowrate through the rotor by 14 per cent and the heat transfer rate by 6 per cent. The results obtained can be used for the design of brake discs which are efficient with respect to heat dissipation.
Comparison and evaluation of brake yaw motion controllers with an antilock brake system
Authors: Song Jeonghoon , Che Woo Seong
Published: July 2008

Two brake yaw motion controllers (BYMC1 and BYMC2) designed to enhance the lateral stability and controllability of cars on slippery roads were evaluated. The motion controllers control the inner rear wheel slip of a vehicle engaged in turning manoeuvres or running on a split-μ road. Their performance was compared with that of a vehicle equipped with an antilock brake system under various road and driving conditions. The results show that the motion controllers reduce the vehicle slip angle and tyre slip angle under all conditions. They also reduce the yaw rate and the lateral acceleration on a split-μ road, and decrease the response variation during lane-change manoeuvres. BYMC1 and BYMC2 extended the limits of adhesion between tyre and road, and increased lateral stability and controllability.
Results from an exploratory study to identify the factors that contribute to success for UK medical device small- and medium-sized enterprises
Authors: Hourd P C , Williams D J
Published: July 2008

This paper reports the results from an exploratory study that sets out to identify and compare the strategic approaches and patterns of business practice employed by 14 UK small- and medium-sized enterprises to achieve success in the medical device sector of the health-care industry. An interview-based survey was used to construct individual case studies of the medical device technology (MDT) companies. A cross-case analysis was performed to search for patterns and themes that cut across these individual cases. Exploratory results revealed the heterogeneity of MDT companies and the distinctive features of the MDT innovation process that emphasize the importance of a strategic approach for achieving milestones in the product development and exploitation process and for creating value for the company and its stakeholders. Recognizing the heterogeneity of MDT companies, these exploratory findings call for further investigation to understand better the influence of components of the MDT innovation process on the commercialization life cycle and value trajectory. This is required to assist start-up or spin-out MDT companies in the UK and worldwide to navigate the critical transitions that determine access to financial and consumer markets and enhance the potential to build a successful business. This will be important not only for bioscience-based companies but also for engineering-based companies aiming to convert their activities into medical devices and the health- and social-care market.
An objective tool for assessing the outcome of total knee replacement surgery
Authors: Jones L , Holt C A
Published: July 2008

The need for an objective tool to assess the outcome of total knee replacement (TKR) surgery is widely recognized. This study investigates the potential of an objective diagnostic tool for assessing the outcome of TKR surgery based on motion analysis techniques. The diagnostic tool has two main elements: collection of data using motion analysis, and the assessment of knee function using a classifier that is based around the Dempster—Shafer theory of evidence. The tool was used to analyse the knee function of nine TKR subjects pre-operatively and at three stages post-operatively. Using important measurable characteristics of the knee, the tool was able to establish the level of benefit achieved by surgery and to enable a comparison of subjects. No subject recovered normal knee function following TKR surgery. This has important implications for knee implant designs.
A new soft-tissue indentation model for estimating circular indenter ‘force—displacement’ characteristics
Authors: Al-ja'afreh T , Zweiri Y , Seneviratne L , Althoefer K
Published: July 2008

Models that predict soft-tissue indentation forces have many important applications including estimation of interaction forces, palpation simulation, disease diagnosis, and robotic assistance. In many medical applications such as rehabilitation, clinical palpation, and manipulation of organs, characterizing soft-tissue properties mainly depends on the accurate estimation of indentation forces. A new indentation model for estimating circular indenter ‘force—displacement’ characteristics is presented in this paper. The proposed model is motivated by a ‘force—displacement’ soil—tool model and is computationally efficient. The main feature of the proposed model is that it can be used to predict the force variations for a variety of tools without the need for retuning the model parameters for each tool. A six-degree-of-freedom robot manipulator with force and position sensors is used to validate the indentation model. Measured force versus tool displacement data for lamb liver and kidney, for a variety of tool diameters, are presented and compared with the forces predicted by the model, showing good agreement (RMS error <8 per cent).
Retrograde bridging nail in periprosthetic femoral fracture treatment which allows direct weight bearing
Authors: Zuurmond R G , Pilot P , Verburg A D , van Os J J , Verdonschot N
Published: July 2008

The bridging nail is a retrograde intramedullary femoral nail designed to stabilize periprosthetic femoral fractures. It offers a minimal invasive surgical approach in combination with early mobilization. The goal of this study was to evaluate the osteosynthesis under full weight-bearing conditions. Three groups of five composite fibreglass femora were prepared with a cemented hip stem. Group 1 underwent cyclic axial loading with 1500 N during 150 000 cycles. After completion, linear loading to failure was conducted. Groups 2 and 3 were submitted to linear increased torsional loading with and without an axial load respectively. Failure was defined as rotational movement of the connection (slippage). In the axial cyclic loading configuration, one specimen failed after 122 000 cycles. Four specimens passed 150 000 cycles and failed after linearly increasing the axial loading of 1940–2600 N (mean, 2408 N ± 313 standard deviation (SD)). Slippage was first detected at a torque varying between 2.5 and 8.2 N m (mean, 5.1 N m ± 2.1 SD) in group 2 and between 10.0 and 15.4 N m (mean, 13.0 N m ± 2.3 SD) in group 3. In conclusion the bridging nail offers a stable connection with the stem of a hip arthroplasty which can resist high repetitive loads, representative of direct full axial weight bearing. The biomechanical results support the clinical experience of a stable osteosynthesis enabling early post-operative mobilization.
Femoral stem wear in cemented total hip replacement
Authors: Zhang H-Y , Blunt L , Jiang X-Q , Brown L , Barrans S , Zhao Y
Published: July 2008

The great success of cemented total hip replacement to treat patients with end-stage osteoarthritis and osteonecrosis has been well documented. However, its long-term survivorship has been compromised by progressive development of aseptic loosening, and few hip prostheses could survive beyond 25 years. Aseptic loosening is mainly attributed to bone resorption which is activated by an in-vivo macrophage response to particulate debris generated by wear of the hip prosthesis. Theoretically, wear can occur not only at the articulating head—cup interface but also at other load-bearing surfaces, such as the stem—cement interface. Recently, great progress has been made in reducing wear at the head—cup interface through the introduction of new materials and improved manufacture; consequently femoral stem wear is considered to be playing an increasingly significant role in the overall wear of cemented total hip replacement. In this review article, the clinical incidences of femoral stem wear are comprehensively introduced, and its significance is highlighted as a source of generation of wear debris and corrosion products. Additionally, the relationship between femoral stem surface finish and femoral stem wear is discussed and the primary attempts to reproduce femoral stem wear through in-vitro wear testing are summarized. Furthermore, the initiation and propagation processes of femoral stem wear are also proposed and a better understanding of the issue is considered to be essential to reduce femoral stem wear and to improve the functionality of cemented total hip replacement.
The possible role of arterial radial vibration in heart rate and blood pressure matching
Authors: Hsiu H , Chao P-T , Hsu W-C , Jan M-Y , Wang Y-Y L , Wang W-K
Published: July 2008

Motivation: This study tests if the ‘oscillating spring’ analogy for the radial vibration of the arterial wall can help to describe the relationship between the heart rate (HR), the blood pressure (BP), and properties of the arterial wall when different types of stimulation are applied on the cardiovascular system. It may help to suggest a possible role for arterial radial vibration in the association between the arterial stiffening and hypertension. Methods: Either mechanical stimulation was applied (0.5-mmHg pressure variation) to Wistar rats by at near-HR frequency (group A) or administered Propranolol (2mg/kg i.p.; group B), and measured HR and BP simultaneously. Results: In both groups, HR and BP were noted to change in the same direction ( r2 = 0.72 and 0.62, respectively; p both < 0.05 by F-test). ANCOVA was performed on these two regression lines, and it was found that there was no significant difference between them ( p>0.3). Conclusion: In both groups, changes in haemodynamic parameters can be explained by the ‘oscillating spring’ analogy for the radial vibration of the arterial wall. This illustrates that, when facing various stimulations, it may be an important regulatory mechanism for the heart and the arteries to restore their frequency-matching condition in order to improve the arterial transmission efficiency. Paying more attention to the radial movement of the wall may therefore help to suggest a novel explanation of the mechanism that underlies the bi-directional relation between hypertension and arterial stiffening.
A comparison of the measured and predicted flowfield in a patient-specific model of an abdominal aortic aneurysm
Authors: O'Rourke M J , McCullough J P
Published: July 2008

Numerical simulation is increasingly being used to predict the flowfield within patient-specific geometries of abdominal aortic aneurysms under physiologically realistic flow conditions. This paper reports on a comparison between the flowfield measured in vitro within a patient-specific model of a mature abdominal aortic aneurysm and that predicted using computational fluid dynamics (CFD). Visualization and traverses of axial velocity were obtained at a number of locations in the aneurysm region under both steady and physiologically realistic pulsatile flow conditions. Comparisons between the measured and predicted flowfield show good agreement throughout the aneurysm. Although turbulence was observed distal in the aneurysm during late diastole, best agreement was achieved using a simple laminar flow model.
Dynamic simulation of a displacement-controlled total knee replacement wear tester
Authors: Lanovaz J L , Ellis R E
Published: July 2008

This paper presents a dynamic finite element method (FEM) model of a commercial displacement-controlled total knee replacement (TKR) wear tester. The first goal of the study was to validate the model, which included both the wear tester and the TKR components. Convergence simulations and experimental testing were performed. These included a novel experimental determination of the coefficient of friction and an evaluation of predicted joint contact areas by comparing simulation results with experimental data collected using pressure-sensitive film. The second goal of this study was to develop a procedure for implementing force-based testing protocols on a displacement-controlled TKR wear tester. A standard force-based cyclic wear-testing protocol was simulated using the FEM model and resulting displacement waveforms were extracted. These were used as control inputs to the physical wear tester and an experimental wear test was performed. Reaction loads on the tibial components were measured and compared with the simulated results. The model was capable of accurately predicting the tibial loads throughout the test cycle, verifying the model's contact mechanics. The study demonstrated the use of computational modelling to convert a force-based testing protocol into displacement-based control parameters for use in a displacement-controlled mechanical testing system.
A new bioreactor for the controlled application of complex mechanical stimuli for cartilage tissue engineering
Authors: Laganà K , Moretti M , Dubini G , Raimondi M T
Published: July 2008

Mechanical stimuli have been shown to enhance chondrogenesis on both animal and human chondrocytes cultured in vitro. Different mechanical stimuli act simultaneously in vivo in cartilage tissue and their effects have been extensively studied in vitro, although often in a separated manner. A new bioreactor is described where different mechanical stimuli, i.e. shear stress and hydrostatic pressure, can be combined in different ways to study the mechanobiology of tissue engineered cartilage. Shear stress is imposed on cells by forcing the culture medium through the scaffolds, whereas a high hydrostatic pressure up to 15 MPa is generated by pressurizing the culture medium. Fluid-dynamic experimental tests have been performed and successful validation of the bioreactor has been carried out by dynamic culture of tissue-engineered cartilage constructs. The bioreactor system allows the investigation of the combined effects of different mechanical stimuli on the development of engineered cartilage, as well as other possible three-dimensional tissue-engineered constructs.
Cost Allocation for Joint Replenishment Models
Authors: Zhang Jiawei
Published: July 2008

We consider the one-warehouse multiple retailer inventory model with a submodular joint setup cost function. The objective of this model is to determine an inventory replenishment policy that minimizes the long-run average system cost over an infinite time horizon. Although the optimal policy for this problem is still unknown, a class of easy-to-implement power-of-two policies are 98% effective. This paper focuses on how the cost, under an optimal power-of-two policy, should be allocated to the retailers. This question generates an interesting cooperative game. We prove that this cooperative game has a nonempty core. The key to our result is a strong duality theorem for the one-warehouse multiple retailer problem under power-of-two policies.
A potential role for tissue kallikrein-related peptidases in human cervico-vaginal physiology
Authors: Shaw Julie L.V. , Diamandis Eleftherios P.
Published: July 2008

Human tissue kallikrein-related peptidases (KLK) are a family of 15 genes located on chromosome 19q13.4 that encode secreted serine proteases with trypsin- and/or chymotrypsin-like activity. Relatively large levels of many KLKs are present in human cervico-vaginal fluid (CVF) and in the supernatant of cultured human vaginal epithelial cells. Many KLKs are also hormonally regulated in vaginal epithelial cells, particularly by glucocorticoids and estrogens. The physiological role of KLK in the vagina is currently unknown; however, analysis of the CVF proteome has revealed clues for potential KLK functions in this environment. Here, we detail potential roles for KLKs in cervico-vaginal physiology. First, we suggest that KLKs play a role in the vagina similar to their role in skin physiology: (1) in the desquamation of vaginal epithelial cells, similar to their activity in the desquamation of skin corneocytes; and (2) in their ability to activate antimicrobial proteins in CVF as they do in sweat. Consequently, we hypothesize that dysregulated KLK expression in the vagina could lead to the development of pathological conditions such as desquamative inflammatory vaginitis. Second, we propose that KLKs may play a role in premature rupture of membranes and pre-term birth through their cleavage of fetal membrane extracellular matrix proteins.
Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor
Authors: Westermann Dirk , Lettau Olga , Sobirey Meike , Riad Alexander , Bader Michael , Schultheiss Heinz-Peter , Tschöpe Carsten
Published: July 2008

Clinical use of the anthracycline doxorubicin (DOX) is limited by its cardiotoxic effects, which are attributed to the induction of apoptosis. To elucidate the possible role of the kinin B1 receptor (B1R) during the development of DOX cardiomyopathy, we studied B1R knockout mice (B1R-/-) by investigating cardiac inflammation and apoptosis after induction of DOX-induced cardiomyopathy. DOX control mice showed cardiac dysfunction measured by pressure-volume loops in vivo. This was associated with a reduced activation state of AKT, as well as an increased bax/bcl2 ratio in Western blots, indicating cardiac apoptosis. Furthermore, mRNA levels of the proinflammatory cytokine interleukin 6 were increased in the cardiac tissue. In DOX B1R-/- mice, cardiac dysfunction was improved compared to DOX control mice, which was associated with normalization of the bax/bcl-2 ratio and interleukin 6, as well as AKT activation state. These findings suggest that B1R is detrimental in DOX cardiomyopathy in that it mediates the inflammatory response and apoptosis. These insights might have useful implications for future studies utilizing B1R antagonists for treatment of human DOX cardiomyopathy.
An AKT activity threshold regulates androgen-dependent and androgen-independent PSA expression in prostate cancer cell lines
Authors: Paliouras Miltiadis , Diamandis Eleftherios P.
Published: July 2008

The androgen receptor (AR) plays an important role in early prostate cancer by activating transcription of a number of genes participating in cell proliferation and growth and cancer progression. However, as the cancer progresses, prostate cancer cells transform from an androgen-dependent to an androgen-independent state. Androgen-independent prostate cancer can manifest itself in several forms, including a percentage of cancers that show reduced levels of prostate-specific antigen (PSA) and can progress without the need for the ligand or active receptor. Therefore, our goal was to examine the role of intracellular signaling pathways in an androgen-independent prostate cancer in vitro model. Using the cell line PC3(AR)2, we stimulated cells with 5-α-dihydrotestosterone (DHT) and epidermal growth factor (EGF) and then analyzed PSA expression. We observed lower PSA expression when cells were jointly stimulated with DHT and EGF, and this was associated with an increase in AKT activity. We examined the role of AKT in AR activity and PSA expression by creating stable PC3(AR)2 cell lines transfected with a PI3K-Ras-effector loop mutant. These cell lines showed lower DHT-stimulated PSA expression that correlated to changes in the phosphorylated state of AR. Therefore, we propose an in vitro androgen-independent model in which a PI3K/AKT activity threshold and subsequent AR transactivation regulate PSA expression.
Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7
Authors: Debela Mekdes , Beaufort Nathalie , Magdolen Viktor , Schechter Norman M. , Craik Charles S. , Schmitt Manfred , Bode Wolfram , Goettig Peter
Published: July 2008

Human kallikrein-related peptidases (KLKs) are (chymo)-trypsin-like serine proteinases that are expressed in a variety of tissues such as prostate, ovary, breast, testis, brain, and skin. Although their physiological functions have been only partly elucidated, many of the KLKs appear to be useful prognostic cancer markers, showing distinct correlations between their expression levels and different stages of cancer. Recent advances in the purification of ‘new type’ recombinant KLKs allowed solution of the crystal structures of KLK4, KLK5, KLK6, and KLK7. Along with these data, enzyme kinetic studies and extended substrate specificity profiling have led to an understanding of the non-prime-side substrate preferences of KLK4, 5, 6, and 7. The shape and polarity of the specificity pockets S1–S4 explain well their substrate preferences. KLK4, 5, and 6 exhibit trypsin-like specificity, with a strong preference for Arg at the P1 position of substrates. In contrast, KLK7 displays a unique chymotrypsin-like specificity for Tyr, which is also preferred at P2. All four KLKs show little specificity for P3 residues and have a tendency to accept hydrophobic residues at P4. Interestingly, for KLK4, 5, and 7 extended charged surface regions were observed that most likely serve as exosites for physiological substrates.
Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions
Authors: Eissa Azza , Diamandis Eleftherios P.
Published: July 2008

Human tissue kallikreins (KLKs) are the largest family of secreted serine protease endopeptidases encoded by 15 genes clustered on chromosome 19q13.4. Multiple KLK enzymes are co-localized in the upper stratum granulosum and stratum corneum of human epidermis, and in associated appendages such as hair follicle epithelia and sweat glands. Until recently, kallikrein proteolytic activity in the skin was exclusively attributed to KLK5 and KLK7. However, wider cutaneous roles of kallikreins became evident in recent years as the proposal of KLK proteolytic activation cascades emerged. We postulate that these proteolytic enzymes may serve as promiscuous mediators of different skin barrier functions, since they are capable of proteolysing different substrates that govern skin desquamation, antimicrobial defense, and lipid permeability. Growing evidence now attests to potential kallikrein involvement in skin inflammation, pigmentation, and tumor suppression via their ability to target proteinase-activated receptor signaling pathways. Current knowledge on kallikrein roles in skin physiology and pathobiology is described in this review.
Genetic deficiency in tissue kallikrein activity in mouse and man: effect on arteries, heart and kidney
Authors: Pizard Anne , Richer Christine , Bouby Nadine , Picard Nicolas , Meneton Pierre , Azizi Michel , Alhenc-Gelas François
Published: July 2008

Tissue kallikrein (KLK1) is a kinin-forming serine protease synthesized in many organs including arteries and kidney. Study of the physiological role of KLK1 has benefited from the availability of mouse and human genetic models of KLK1 deficiency, through engineering ofKLK1mouse mutants and discovery of a major polymorphism in the humanKLK1gene that induces a loss of enzyme activity. Studies in KLK1-deficient mice and human subjects partially deficient in KLK1 have documented its critical role in arterial function in both species. KLK1 is also involved in the control of ionic transport in the renal tubule, an action that may not be kinin-mediated. Studies of experimental diseases in KLK1-deficient mice have revealed cardio- and nephro-protective effects of KLK1 and kinins in acute cardiac ischemia, post-ischemic heart failure, and diabetes. Potential clinical and therapeutic developments are discussed.
Development of diabetic cardiomyopathy and the kallikrein-kinin system – new insights from B1 and B2 receptor signaling
Authors: Tschöpe Carsten , Westermann Dirk
Published: July 2008

Diabetic cardiomyopathy is a specific cardiomyopathy which develops in patients with diabetes mellitus in the absence of coronary atherosclerosis and hypertension. Despite the potential importance of this disease entity, the underlying mechanisms are only incompletely understood. Changes in calcium handling, disruption of the extracellular matrix regulation with accumulation of cardiac collagen, and furthermore cardiac inflammation may be an important mediator of this disease. This brief review focuses on the current aspects of the kallikrein-kinin system and its influence on the development of diabetic cardiomyopathy with particular regard to the kinin receptors B1 and B2, as their role in the development of this disease is still under discussion. Whether the role of the B1 receptor is similar to the well-described beneficial role of the B2 receptor or whether its function is opposed to the B2 receptor is controversial. Some recent findings suggest that the B1 receptor mediates cardiac inflammation and therefore may be detrimental for cardiac function in the setting of diabetic cardiomyopathy.
Immunofluorometric activity-based probe analysis of active KLK6 in biological fluids
Authors: Oikonomopoulou Katerina , Hansen Kristina K. , Baruch Amos , Hollenberg Morley D. , Diamandis Eleftherios P.
Published: July 2008

Immunoassay measurements of human kallikrein-related peptidases (KLKs) such as prostate-specific antigen (KLK3) are of great value as diagnostic indices of cancer. Despite extensive knowledge of the abundance of immunoreactive KLKs in normal and cancer-related settings, there is little information available about the proportion of immunoreactive KLK that represents active enzyme in such samples. Using KLK6 as a prototype enzyme, we have developed an assay using a serine proteinase-targeted activity-based probe coupled to antibody capture. By employing activity-based labeling, we were able to quantify the proportion of enzymatically active relative to total immunoreactive KLK6 in crude cerebrospinal fluid from routine analyses and ascites fluid from ovarian cancer patients, as well as in supernatants from cancer cell lines. Our approach allowed monitoring of pro-KLK6 conversion to its active enzyme species and demonstrated that up to 5% of immunoreactive KLK6 detected in clinical samples represents active enzyme. We suggest that this new activity-based probe assay will prove of value as a complement to routine KLK immunoassay measurements for validating KLKs as cancer biomarkers.
Kallikrein 6 is a mediator of K-RAS-dependent migration of colon carcinoma cells
Authors: Henkhaus Rebecca S. , Gerner Eugene W. , Ignatenko Natalia A.
Published: July 2008

Kallikrein 6 (KLK6) is a trypsin-like serine peptidase whose relevance in various types of cancers is currently being explored. Previous studies have shown that KLK6 mRNA is upregulated in colon and gastric cancers; however, the regulatory mechanisms and phenotypic consequences of this upregulation are largely unknown. ActivatingK-RASmutations are common in colon cancer, occurring in approximately 50% of cases. We have recently reported the upregulation of KLK6 mRNA in Caco2 human colon cancer cells stably transfected with a mutantK-RASallele (K-RASG12V). In this study we examined the pattern of K-RAS-dependent KLK6 expression and secretion in colon cancer cells. Using pharmacological inhibitors of pathways downstream of K-RAS, we could show that the PI3K and p42/44 MAPK pathways play an important role in the induction of KLK6 in mutant K-RAS-expressing colon cancer cells. Increased KLK6 expression enhanced colon cancer cell migration through laminin and Matrigel. Inhibition of KLK6 using small interference RNA treatment or a specific KLK6 antibody in Caco2 cells stably expressing the mutant K-RAS and in SW480 cells carrying a mutation in theK-RASoncogene resulted in a reduction in invasiveness through cell culture inserts. These data support the oncogenic role of KLK6 in colorectal cancer.
Gene expression changes associated with the anti-angiogenic activity of kallikrein-related peptidase 3 (KLK3) on human umbilical vein endothelial cells
Authors: Mattsson Johanna M. , Laakkonen Pirjo , Kilpinen Sami , Stenman Ulf-Håkan , Koistinen Hannu
Published: July 2008

Kallikrein-related peptidase 3 (KLK3, also known as prostate-specific antigen, PSA) is a chymotrypsin-like kallikrein that has anti-angiogenic properties. We have previously shown in a human umbilical vein endothelial cell (HUVEC) model that the anti-angiogenic effect of KLK3 is related to its enzyme activity. However, the mechanism of this effect remains to be clarified. To this end, we used a DNA microarray to study KLK3-induced changes in gene expression associated with reduction of HUVEC tube formation. Among the 41 000 genes studied, 311 were differentially expressed between control and KLK3-treated cells. These changes were enriched in several pathways, including those associated with proteasome, ubiquitin-mediated proteolysis, focal adhesion and regulation of the actin cytoskeleton. Furthermore, the changes were opposite to those previously described to occur during tubulogenesis. In conclusion, our results show that KLK3 induces gene expression changes in HUVECs. Although these changes might be relevant for the mechanism by which KLK3 exerts its anti-angiogenic activity, it cannot be judged from the present results whether they reflect the primary mechanism mediating the effect of KLK3 or are secondary to morphogenic differentiation.
Comparative studies on the dissolution of ceramic UO2 pellets in nitric acid by microwave and conventional heating
Authors: Zhao Yunfeng , Chen Jing
Published: July 2008

The dissolution data of UO2 are important to develop the new process of uranium ore leaching and new head-end reprocessing of spent nuclear fuel. The dissolution experiments of UO2 pellets in 8 M nitric acid by microwave heating and conventional heating were carried out respectively in the present work. Compared with the conventional heating, the microwave heating can remarkably promote the dissolution process of UO2 pellets with a dissolution ratio increase of 26%–46%. The kinetics results show that the dissolution processes by microwave heating and conventional heating match well with the diffusion control model and the surface reaction control model, respectively.
Selenide retention onto pyrite under reducing conditions
Authors: Liu Xiaolan , Fattahi Massoud , Montavon Gilles , Grambow Bernd
Published: July 2008

Pyrite (FeS2) is a mineral phase often present as inclusions in temperate soils. Moreover, it turns out to be a sorption sink for certain radionuclides in deep geological disposals. The present study was thus initiated to determine the capacity of pyrite to immobilize selenide (Se(-II)). Due to the fact that pyrite surface oxidizes readily, potentials were applied in order to minimise its surface evolution, and ensure the reducing conditions necessary for stabilizing Se(-II). The sorption experiments were carried out in NaCl electrolyte and were amperometrically controlled. After only several minutes of reaction, at least 97% of Se(-II) initially present in solution was disappeared. The K
d values vary from 7–65 L/g and the isotherm curve shows site saturation at higher initial selenide concentrations and no pH-dependence. By means of several spectroscopic techniques, the reaction mechanism was investigated. The XRD and in situ XANES results indicate the presence of Se(0) on pyrite surface, which explain the rapid disappearance of Se observed in the sorption experiments. Moreover, XPS results obtained from Se-reacted pyrite particles reveal cleavage of S–S bonding which resulted in formation of S2− on pyrite surface. Thus, we conclude that Se(-II) can be immobilized by pyrite via surface redox reaction:

≡FeS2 + HSe− ⇔ ≡FeS + Se(0) + HS−.
Cross sections of proton induced nuclear reactions on natural cadmium leading to the formation of radionuclides of indium
Authors: Al-Saleh F. S.
Published: July 2008

Cross sections of proton induced nuclear reactions onnatCd, leading to the formation of110gIn,111In,113mIn, and116m1In for energies up to 14.7 MeV were measured using the stacked-foil irradiation technique and high resolution gamma-ray spectroscopy. Our experimental data were analyzed and the excitation functions for the studied radionuclides were compared with the previously reported data. Model codes ALICE-IPPE and EMPIRE-II were used for calculating the excitation functions theoretically. Integral yields of the radionuclides110gIn,111In,113mIn and116m1In were also calculated.
The Indirect Observation of the Decay of Mesotrons: Italian Experiments on Cosmic Radiation, 1937–1943
Authors: Monaldi Daniela
Published: July 2008

Following the discovery of mesotrons (intermediate-mass particles) in cosmic radiation in the 1930s, a group of physicists originating in Italy participated in a series of experiments designed to permit the observation of the spontaneous decay of elementary particles. The experimental results were classified as "indirect observations" of the microphysical process of decay, and the development of experimental methods was regarded as a progression toward increasing observational directness. This paper traces the activities of the cosmic-ray experimenters, viewing them as part of a stream in the international current of interest and research on the natural β radioactivity of the mesotrons. The paper pays particular attention to those aspects of experimental practice that the researchers associated with observational directness. I argue that the attribution of degrees of directness depended on the elimination of intrusive additional assumptions in the phenomenological models of the experiments. My study thus contributes to the analysis of experimental observation in microphysics.
Elective single embryo transfer
Authors: Kosmas Ioannis , Van der Elst Jossiane , Devroey Paul , Tournaye Herman
Published: July 2008

Elective single embryo transfer has been implemented in Belgium and Scandinavian countries to decrease the incidence of twin pregnancy and the associated complications.

The extra cost associated with achieving an equal number of pregnancies through elective single embryo transfer needs to be considered in the context of any additional neonatal care expenses associated with double embryo transfer.

Acceptable ongoing pregnancy and delivery rates have been obtained when comparing single with double embryo transfer.

Maternal age, previous attempts, day of embryo transfer and cost should be taken into account.

Learning objectives:

To understand the issues raised when helping a couple choose single or double embryo transfer.

Ethical issues:

Where does patient autonomy over treatment end and national regulation begin?

The management of obstetric complications and the long‐term sequelae of premature birth should be factored in when considering treatment costs.

Please cite this article as: Kosmas I, Van der Elst J, Devroey P, Tournaye H. Elective single embryo transfer. The Obstetrician & Gynaecologist 2008;10:163–169.
APOE-ε4 polymorphism and cognitive deficit among the elderly population of Fernando de Noronha
Authors: Garcia Anália Nusya , Silva Helker Albuquerque da , Silva Renan Carlos , Leal Eliane Maria Medeiros , Rodrigues Lorena , Silva Vanessa Cavalcante da , Dellalibera Edileine , Freitas Elizabete Malaquias , Ataíde Jr Luiz , Muniz Maria Tereza Cartaxo
Published: July 2008

BACKGROUND: Polymorphism of the gene for apolipoprotein E (APOE) is an important risk factor for the development of Alzheimer's disease. The ε4 allele of the APOE gene has been linked with a number of neuropsychiatric illnesses, and also with stress and depression among geriatric populations. OBJECTIVE: To identify APOE-ε4 polymorphism and correlate this with cognitive deficit among the elderly population of the island of Fernando de Noronha. METHOD: Neuropsychiatric tests (mini-mental state examination, verbal fluency test and clock drawing test) were applied to 52 elderly people without Alzheimer's disease. DNA was isolated from peripheral blood and genotyping of APOE was done by the PCR-RFLP method. RESULTS: 87% of the elderly population (mean age 69.6±7.0) had cognitive deficit. CONCLUSION: The observed frequency of the ε4 allele was 10%, but the correlation between the presence of ε4 and cognitive deficit in this population was not statistically significant.
Prospective and retrospective memory in mild Alzheimer's disease
Authors: Martins Sergilaine Pereira , Damasceno Benito Pereira
Published: July 2008

OBJECTIVE: To study prospective and retrospective memory in patients with mild Alzheimer's disease (AD). METHOD: Twenty mild AD and 20 matched normal control subjects were included. Diagnosis of AD was based on DSM-IV and NINCDS-ADRDA criteria, using CDR 1 and MMSE scores from 16 to 24 for mild AD. All subjects underwent retrospective (Rey Auditory Verbal Learning Test, RAVLT) and prospective memory tests (the appointment and belonging subtests of the Rivermead Behavioral Memory Test, RBMT; and two tests made to this study: the clock and the animals test), as well as MMSE, neuropsychological counterproofs, and Cornell Scale for Depression in Dementia. The data was analyzed with Wilcoxon test and Spearman correlation coefficient. RESULTS: AD patients performed worse than controls in prospective and retrospective memory tests, with poorer performance in retrospective memory. There was no correlation between prospective memory and attention, visual perception, executive function, or depression scores. CONCLUSION: Prospective and, in higher degree, retrospective memory are primarily and independently impaired in mild AD.