bluuebunny/crossref_metadata_2025 huggingface dataset:
Cost comparison of predictive genetic testing versus conventional clinical screening for familial adenomatous polyposis
Authors: Bapat B , Noorani H , Cohen Z , Berk T , Mitri A , Gallie B , Pritzker K , Gallinger S , Detsky A S
Published: June 2010

BACKGROUND

Mutations of theAPC gene cause familial adenomatous polyposis (FAP), a hereditary colorectal cancer predisposition syndrome.

AIMS

To conduct a cost comparison analysis of predictive genetic testing versus conventional clinical screening for individuals at risk of inheriting FAP, using the perspective of a third party payer.

METHODS

All direct health care costs for both screening strategies were measured according to time and motion, and the expected costs evaluated using a decision analysis model.

RESULTS

The baseline analysis predicted that screening a prototype FAP family would cost $4975/£3109 by molecular testing and $8031/£5019 by clinical screening strategy, when family members were monitored with the same frequency of clinical surveillance (every two to three years). Sensitivity analyses revealed that the genetic testing approach is cost saving for key variables including the kindred size, the age of screening onset, and the cost of mutation identification in a proband. However, if theAPC mutation carriers were monitored at an increased (annual) frequency, the cost of the genetic screening strategy increased to $7483/£4677 and was especially sensitive to variability in age of onset of screening, family size, and cost of genetic testing of at risk relatives.

CONCLUSIONS

In FAP kindreds, a predictive genetic testing strategy costs less than conventional clinical screening, provided that the frequency of surveillance is identical using either strategy. An additional significant benefit is the elimination of unnecessary colonic examinations for those family members found to be non-carriers.
Cardiac function and haemodynamics in alcoholic cirrhosis and effects of the transjugular intrahepatic portosystemic stent shunt
Authors: Huonker M , Schumacher Y O , Ochs A , Sorichter S , Keul J , Rössle M
Published: June 2010

BACKGROUND

A portosystemic stent shunt may impair cardiac function and haemodynamics.

AIMS

To investigate the effects of a transjugular intrahepatic portosystemic shunt (TIPS) on cardiac function and pulmonary and systemic circulation in patients with alcoholic cirrhosis.

PATIENTS/METHODS

17 patients with alcoholic cirrhosis and recent variceal bleeding were evaluated by echocardiography and catheterisation of the splanchnic and pulmonary circulation before and after TIPS. The period of catheter measurement was extended to nine hours in nine of the patients. The portal vein was investigated by Doppler ultrasound before and nine hours after TIPS.

RESULTS

Baseline echocardiography showed the left atrial diameter to be slightly increased and the left ventricular volume to be in the upper normal range. Nine hours after TIPS, the left atrial diameter and left ventricular end diastolic volume were increased (by 6% (p<0.01) and 7% (p<0.01) respectively); end systolic volume had not changed significantly. Invasive measurements showed a sharp increase in right atrial pressure (by 101%; p<0.01), mean pulmonary artery pressure (by 92%; p<0.01), pulmonary capillary wedge pressure (by 111%; p<0.01), and cardiac output (8.1 (1.6) to 11.9 (2.4) l/min; p<0.01). Systemic vascular resistance decreased (824 (242) to 600 (265) dyn·s·cm−5 p<0.01), and total pulmonary resistance increased (140 (58.5) to 188 (69.5) dyn·s·cm−5; p<0.05). Total pulmonary resistance (12%; NS), cardiac output (1.4 l/min; p<0.05), and portal vein blood flow (1.4 l/min; p<0.05) remained elevated for nine hours after TIPS in the subgroup. Portoatrial pressure gradient (43%; p<0.05), portohepatic vascular resistance (72%; p<0.05), and systemic vascular resistance (27%; p<0.01) were consistently reduced.

CONCLUSIONS

The increase in the left atrial diameter, the pulmonary capillary wedge pressure, and total pulmonary resistance observed after the TIPS procedure reflected diastolic dysfunction of the hyperdynamic left ventricle in patients with alcoholic cirrhosis. The haemodynamic effects of the portosystemic stent shunt itself on the splanchnic circulation seem to be mainly responsible for the further decrease in systemic vascular resistance. TIPS may unmask a coexisting preclinical cardiomyopathy in patients with alcoholic cirrhosis and portal hypertension.
Thrombopoietin concentrations are low in patients with cirrhosis and thrombocytopenia and are restored after orthotopic liver transplantation
Authors: Goulis J , Chau T N , Jordan S , Mehta A B , Watkinson A , Rolles K , Burroughs A K
Published: June 2010

BACKGROUND

Thrombocytopenia in cirrhotic patients may be due to deficient production of thrombopoietin.

AIMS

To determine the relation between thrombopoietin and thrombocytopenia in cirrhotic patients before and after orthotopic liver transplantation.

METHODS

Thrombopoietin concentrations and platelet counts were measured in 43 cirrhotic patients and 21 normal controls and serially for 14 days after transplantation in 23/43 patients.

RESULTS

27 of the 43 patients had thrombocytopenia (platelet count less than 120 × 109/l; group 1) whereas 16 patients had normal platelet count (group 2). Thrombopoietin concentrations were lower in group 1 than in group 2 (92.5 (20.3–286.3) v 226.6 (30.1–848.3) pg/ml, p=0.003) and normal controls (92.5 (20.3–286.3)v 158.3 (22.5–232.9) pg/ml, p=0.028). Post-transplantation thrombopoietin concentrations increased with a peak at day 5. The rise was significant in patients with low pretransplantation platelet count (89.1 (21.29–247.6) to 545.1 (66.2–2569) pg/ml; n=16, p=0.001) but not in those with normal platelet count (262.8 (30.1–848.3) to 315.1 (114–954.6) pg/ml; n=7, p=0.47). No correlation was found pretransplantation between spleen volume and platelet count (r=−0.11, p=0.6) or thrombopoietin concentrations (r=−0.04, p=0.8). However, pretransplantation thrombopoietin concentrations correlated with platelet count (r=0.47, p=0.0015), whereas an inverse correlation was found between peak thrombopoietin concentrations and nadir platelet count (r=−0.41 p=0.049) post-transplantation.

CONCLUSIONS

Inadequate thrombopoietin production may contribute to cirrhotic thrombocytopenia. Thrombopoietin production is restored after liver transplantation leading to the resolution of thrombocytopenia.
Expression and activity of mitogen activated protein kinases in human colorectal carcinoma
Authors: Eggstein S , Franke M , Kutschka I , Manthey G , von Specht B U , Ruf G , Farthmann E H
Published: June 2010

BACKGROUND

Mitogen activated protein kinases (MAPKs) play a central role in the regulation of both cell growth and differentiation. They are involved in signal transduction of oncogenes and growth factors. The role of MAPK in colonic carcinoma is unknown.

AIMS

To establish whether the expression and activity of p42/44 MAPKs are altered in colorectal tumours as compared with normal mucosa.

METHODS

The expression and activity of p42/p44 MAPK were investigated in 22 colorectal carcinomas, four adenomas, and the corresponding normal colorectal mucosa by the use of western blotting, immunoprecipitation, and in vitro kinase assays.

RESULTS

After immunoprecipitation with an antibody specific for p42 MAPK, we found significant inactivation of p42 MAPK in colonic carcinomas as well as in adenomas, whereas most sample pairs showed only minor differences in p42 MAPK expression. Investigation of MAPK with an antibody capable of detecting both p42 and p44 MAPK showed a slight but significant decrease in p44 MAPK content in malignant tissues. With this antibody, only minor alterations in MAPK activity and no correlation with p42 MAPK activity were found.

CONCLUSIONS

Inactivation of p42 MAPK could be associated with colonic carcinogenesis.
High prevalence of NSAID enteropathy as shown by a simple faecal test
Authors: Tibble J A , Sigthorsson G , Foster R , Scott D , Fagerhol M K , Roseth A , Bjarnason I
Published: June 2010

BACKGROUND

The diagnosis of non-steroidal anti-inflammatory drug (NSAID) induced enteropathy is difficult, requiring enteroscopy or the use of four day faecal excretion of 111In labelled white cells.

AIMS

To assess faecal calprotectin (a non-degraded neutrophil cytosolic protein) as a method for diagnosing NSAID enteropathy.

METHODS

Single stool faecal calprotectin concentrations were compared with the four day faecal excretion of 111In labelled white cells in 47 patients taking NSAIDs. The prevalence and severity of NSAID enteropathy was assessed using this method in 312 patients (192 with rheumatoid arthritis, 65 with osteoarthritis, 55 with other conditions) taking 18 different NSAIDs.

RESULTS

The four day faecal excretion of 111In white cells correlated significantly with faecal calprotectin concentrations. In the group of 312 patients on NSAIDs faecal calprotectin concentrations were significantly higher than in controls, the prevalence of NSAID enteropathy being 44%. The prevalence and severity of NSAID enteropathy was independent of the particular type or dose of NSAID being taken or other patient variables.

CONCLUSIONS

Assay of faecal calprotectin provides a simple practical method for diagnosing NSAID enteropathy in man. Forty four per cent of patients receiving these drugs had NSAID induced enteropathy when assessed by this technique; 20% of these had comparable levels of inflammation to that previously reported in patients with inflammatory bowel disease.
Potentiation of cytokine induced iNOS expression in the human intestinal epithelial cell line, DLD-1, by cyclic AMP
Authors: Cavicchi M , Whittle B J R
Published: June 2010

BACKGROUND

Nitric oxide production by the inducible isoform of nitric oxide synthase (iNOS) is thought to play a role in the pathogenesis of inflammatory bowel disease along with other proinflammatory mediators.

AIMS

To examine the effects of cAMP, an intracellular mediator of several proinflammatory mediators, on iNOS expression in the human intestinal epithelial cell line, DLD-1.

METHODS

iNOS activity was assessed by measuring the NO stable oxidative product NO2−. iNOS protein expression and iNOS mRNA levels were determined by western blotting and northern blotting, respectively.

RESULTS

iNOS activity, protein, and mRNA were induced by a combination of interleukin 1β (0.5–5 ng/ml), interferon γ (20–200 u/ml), and tumour necrosis factor α (10–100 ng/ml). The cytokine induced NOS activity was potentiated by N6,2′-O-dibutyryladenosine 3′:5′-cyclic monophosphate and 8-bromoadenosine 3′:5′-cyclic monophosphate (0.1–1 mM), and the adenylate cyclase activator, forskolin (1–100 μM). This activity was inhibited by the selective iNOS inhibitor, 1400W (0.1–100 μM). These agents increased iNOS protein. The cAMP analogues potentiated iNOS at the transcriptional level as shown by effects of actinomycin D (5 μg/ml) and northern blot analyses; the nuclear factor (NF) κB inhibitor, pyrrolidine dithiocarbamate (10–200 μM), significantly reduced this potentiation. The cAMP potentiated iNOS activity was inhibited by the tyrosine kinase inhibitor, A25 (10–200 μM) and the Janus activated kinase 2 inhibitor, B42 (10–200 μM).

CONCLUSIONS

Increased intracellular cAMP is a potent stimulus of iNOS expression in combination with cytokines in DLD-1 cells, acting at the transcriptional level and involving NF-κB and the JAK-STAT pathways. Thus, proinflammatory mediators that increase cAMP levels may augment iNOS expression and NO production.
Alcoholic cirrhosis is a good indication for liver transplantation, even for cases of recidivism
Authors: Pageaux G-P , Michel J , Coste V , Perney P , Possoz P , Perrigault P-F , Navarro F , Fabre J-M , Domergue J , Blanc P , Larrey D
Published: June 2010

BACKGROUND/AIMS

Alcoholic cirrhosis remains a controversial indication for liver transplantation, mainly because of ethical considerations related to the shortage of donor livers. The aim of this study was to review experience to date, focusing on survival rates and complications, and the effect of alcohol relapse on outcome and alterations in marital and socioprofessional status.

METHODS

The results for 53 patients transplanted for alcoholic cirrhosis between 1989 and 1994 were compared with those for 48 patients transplanted for non-alcoholic liver disease. The following variables were analysed: survival, rejection, infection, cancer, retransplantation, employment and marital status, alcoholic recurrence. The same variables were compared between alcohol relapsers and non-relapsers.

RESULTS

Recovery of employment was the only significantly different variable between alcoholic (30%) and non-alcoholic patients (60%). Two factors influenced survival in the absence of alcohol recidivism: age and abstinence before transplantation. For all other variables, there were no differences between alcoholic and non-alcoholic patients, and, within the alcoholic group, between relapsers and non-relapsers. The recidivism rate was 32%.

CONCLUSION

The data indicate that liver transplantation is justified for alcoholic cirrhosis, even in cases of recidivism, which did no affect survival and compliance with the immunosuppressive regimen. These good results should help in educating the general population about alcoholic disease.
Longitudinal variation in hepatitis C virus (HCV) viraemia and early course of HCV infection after liver transplantation for HCV cirrhosis: the role of different immunosuppressive regimens
Authors: Papatheodoridis G V , Barton S G R G , Andrew D , Clewley G , Davies S , Dhillon A P , Dusheiko G , Davidson B , Rolles K , Burroughs A K
Published: June 2010

BACKGROUND

The role of the type of immunosuppression in the natural history of post-transplant hepatitis C virus (HCV) infection is unclear.

AIMS

To evaluate the fluctuation of HCV viraemia and the early course of infection, and their relation to the type of immunosuppression in HCV transplant patients.

METHODS

In 47 HCV transplant patients, serum HCV RNA levels were determined pretransplant and at one and two weeks, and three and 12 months after transplant. Initial immunosuppression was triple (cyclosporin, azathioprine, prednisolone) in 31, double (cyclosporin, prednisolone) in five, and single (cyclosporin or tacrolimus) in 11 patients. Prednisolone was withdrawn at a median of six months.

RESULTS

At three months, HCV RNA levels were higher in patients with single than with triple or double initial therapy. At 12 months, HCV RNA levels correlated only with duration of prednisolone treatment and were relatively higher in patients with triple compared with single initial immunosuppression. A higher necroinflammatory activity at 12 months post-transplant was found in patients with post-transplant acute hepatitis compared with those without. Extent of fibrosis at 12 months was associated with the 12 month HCV RNA level and occurrence of post-transplant acute hepatitis.

CONCLUSIONS

HCV RNA levels at three months after transplant are higher in patients treated with single initial immunosuppressive therapy, but at 12 months are higher in patients with longer duration of steroid treatment. HCV viraemia at 12 months seems to be particularly important, as its levels are strongly correlated with the severity of fibrosis.
Superior mesenteric vein stenosis complicating Crohn’s disease
Authors: Hodgson R S , Jackson J E , Taylor-Robinson S D , Walters J R F
Published: June 2010

BACKGROUND

Superior mesenteric vein stenosis as a consequence of mesenteric fibrosis, causing the development of small bowel varices, is an unrecognised association of Crohn’s disease.

CASE REPORTS

Two cases of gastrointestinal bleeding occurring in patients with Crohn’s disease, and a third case, presenting with pain and diarrhoea, are described. In all three patients, visceral angiography showed superior mesenteric vein stenosis with dilatation of draining collateral veins in the small bowel. Overt gastrointestinal bleeding or iron deficiency anaemia resulting from mucosal ulceration is common in Crohn’s disease, but acute or chronic bleeding from small bowel varices as a result of superior mesenteric vein stenosis due to fibrosis has not previously been reported.
KRASmutation and microsatellite instability in endometrial adenocarcinomas showing MELF-type myometrial invasion
Authors: Stewart C J R , Amanuel B , Grieu F , Carrello A , Iacopetta B
Published: June 2010

Background

Some uterine endometrioid adenocarcinomas exhibit a distinctive morphological phenotype characterised by the formation of microcystic, elongated and fragmented (MELF) glands. Immunohistochemical studies have suggested that MELF-type changes represent an epithelial–mesenchymal transition which has been associated withKRASactivation in various tumours.

Aims

To investigate the molecular characteristics of endometrial tumours showing MELF, with particular reference to the frequencies ofKRASandBRAFmutations and of microsatellite instability (MSI).

Methods

MSI, andKRASandBRAFmutation status, were assessed in 33 low-grade endometrial adenocarcinomas showing MELF features and the results compared with 33 control cases exhibiting a ‘conventional’ pattern of myometrial invasion. Standard histological parameters were also reviewed.

Results

Tumours with a MELF pattern of myometrial invasion showed more frequent vascular invasion and focal mucinous differentiation.KRASmutations were more frequent in MELF positive than MELF negative tumours (45% vs 30%), but this difference was not statistically significant.BRAFmutations were not identified in any of the cases. MSI was identified in 20% of cases overall but did not correlate with the MELF phenotype.

Conclusions

Mutations inKRASandBRAFgenes are not directly implicated in the development of a MELF pattern of invasion in endometrial carcinoma. However, RAS-associated signalling pathways could be activated through other genetic or epigenetic mechanisms. The characterisation of such alterations may become increasingly important as novel therapies are developed that target mediators involved in tumour invasion.
FISH assay development for the detection ofp16/CDKN2Adeletion in malignant pleural mesothelioma
Authors: Chung Catherine T-S , Santos Gilda Da Cunha , Hwang David M , Ludkovski Olga , Pintilie Melania , Squire Jeremy A , Tsao Ming-Sound
Published: June 2010

Aims

To develop a fluorescence in-situ hybridisation (FISH) assay for detectingp16/CDKN2Adeletion on paraffin tissue sections for use as an ancillary test to distinguish reactive from malignant mesothelial proliferations.

Method

Dual-colour FISH forp16/CDKN2Aand chromosome 9 (CEP-9) was performed on 11 benign mesothelial proliferations and 54 malignant pleural mesothelioma (MPM) cases to establish cut-off values forp16/CDKN2Adeletion. A third MYC probe was used to verify cases showing homozygous deletion. Eight equivocal biopsies were used for assay testing.

Results

Cut-off values forp16/CDKN2Adeletion were calculated based on FISH signalling patterns obtained from the benign controls (mean percent nuclei plus three standard deviations). Hemizygous deletion was defined as >44% of nuclei showing the hemizygous (onep16/CDKN2A, two CEP-9 signals) or >15% of nuclei showing the monosomy (onep16/CDKN2A, one CEP-9 signal) deletion patterns. None of the benign cases showed a homozygous deletion pattern (nop16/CDKN2A, at least one CEP-9 signal). In the malignant cases, the percentage of nuclei showing homozygous deletion ranged from 1% to 87%. Therefore, the cut-off value for homozygous deletion was defined as >10%.P16/CDKN2Adeletion was detected in 61% (33/54) of MPM cases. Among the equivocal biopsies, four showed homozygous and one showed hemizygousp16/CDKN2Adeletion. Age over 60 years, asbestos exposure andp16/CDKN2Adeletion were associated with a worse prognosis.

Conclusion

Distinction between benign and malignant mesothelial proliferations can be diagnostically challenging. FISH forp16/CDKN2Adeletion is a useful test for confirming the diagnosis of MPM.
Positive screening and carrier results for the England-wide universal newborn sickle cell screening programme by ethnicity and area for 2005–07
Authors: Streetly Allison , Latinovic Radoslav , Henthorn Joan
Published: June 2010

Aims

The overall aim of the new national newborn programme is to identify infants at risk of sickle cell disease to allow early detection and to minimise deaths and complications.

Methods

Universal screening for sickle cell disease was introduced in England between September 2003 and July 2006. The 13 newborn laboratories each screen between 25 000 and 110 000 babies a year using the existing dried bloodspot cards. The specified conditions to be screened for include sickle cell anaemia (Hb SS), Hb SC disease, Hb S/βthalassaemia, Hb S/DPunjaband Hb S/OArab. Data are reported on screening results by ethnic group and geographical area.

Results

The prevalence of screen positive results across England is 1:2000. There is a 25-fold variation by geographical area. African babies make up 61% of all screen positive results despite representing only 4% of total births. Combined carrier rates vary widely by ethnicity, from 1.85 per 1000 (1:540) in ‘White British’ to 145 per 1000 (1:7) in ‘African’ babies. Refusal rates for screening show variation by ethnicity.

Conclusions

These results provide useful information both about the frequency of these conditions and the carrier state and their geographic and ethnic distribution across England. This can be used to refine counselling information and are also useful to target and plan services and public information.
Types and modularity for implicit invocation with implicit announcement
Authors: Steimann Friedrich , Pawlitzki Thomas , Apel Sven , Kästner Christian
Published: June 2010

Through implicit invocation, procedures are called without explicitly referencing them. Implicit announcement adds to this implicitness by not only keeping implicit which procedures are called, but also where or when—under implicit invocation with implicit announcement, the call site contains no signs of that, or what it calls. Recently, aspect-oriented programming has popularized implicit invocation with implicit announcement as a possibility to separate concerns that lead to interwoven code if conventional programming techniques are used. However, as has been noted elsewhere, as currently implemented it establishes strong implicit dependencies between components, hampering independent software development and evolution. To address this problem, we present a type-based modularization of implicit invocation with implicit announcement that is inspired by how interfaces and exceptions are realized in Java. By extending an existing compiler and by rewriting several programs to make use of our proposed language constructs, we found that the imposed declaration clutter tends to be moderate; in particular, we found that, for general applications of implicit invocation with implicit announcement, fears that programs utilizing our form of modularization become unreasonably verbose are unjustified.
A taxonomy of visualization strategies for cultural heritage applications
Authors: Foni Alessandro E. , Papagiannakis George , Magnenat-Thalmann Nadia
Published: June 2010

In this article we present a general classification of the different approaches that might be employed to constitute a visual representation of a cultural heritage item, including the ones featuring the use of traditional tools as the ones exhibiting the inclusion of modern 2D and 3D digital technologies. In order to establish a coherent taxonomy, specific elements characterizing such approaches will be discussed and employed to assist the definition of a general conceptual framework that will enable the classification of the possible design choices according to their specific characteristics. Finally, a selection of modeling and simulation techniques which are specifically related to the creation process underlying the virtual representation of heritage items by means of modern visualization technologies will be explored alongside the main areas of preferences linked to the major actors active in the cultural heritage field.
PEVIAR
Authors: Müller Florian , Fornaro Peter , Rosenthaler Lukas , Gschwind Rudolf
Published: June 2010

Even decades after the advent of computer technology, preserving information in digital archives remains a challenging task. Technological progress on all levels calls for migration as an essential component of any digital archive. Migration, however, is not only expensive, but also makes it difficult to ensure the authenticity of digital documents. The University of Basel's Imaging and Media Lab has developed PEVIAR (Permanent Visual Archive), an archiving solution addressing one of the fundamental challenges of digital archiving, migration, and introducing the notion of
digital originals
. Essentially, digital documents are inseparably bound to a migration-free medium, thereby overcoming the transient nature of today's state-of-the-art storage systems.
Dinus
Authors: Müller Kerstin , Fünfzig Christoph , Reusche Lars , Hansford Dianne , Farin Gerald , Hagen Hans
Published: June 2010

The Double Insertion, Nonuniform, Stationary subdivision surface (DINUS) generalizes both the nonuniform, bicubic spline surface and the Catmull-Clark subdivision surface. DINUS allows arbitrary knot intervals on the edges, allows incorporation of special features, and provides limit point as well as limit normal rules. It is the first subdivision scheme that gives the user all this flexibility and at the same time all essential limit information, which is important for applications in modeling and adaptive rendering. DINUS is also amenable to analysis techniques for stationary schemes. We implemented DINUS as an Autodesk Maya plugin to show several modeling and rendering examples.
Navajo Coal Combustion and Respiratory Health Near Shiprock, New Mexico
Authors: Bunnell Joseph E. , Garcia Linda V. , Furst Jill M. , Lerch Harry , Olea Ricardo A. , Suitt Stephen E. , Kolker Allan
Published: June 2010

Indoor air pollution has been identified as a major risk factor for acute and chronic respiratory diseases throughout the world. In the sovereign Navajo Nation, an American Indian reservation located in the Four Corners area of the USA, people burn coal in their homes for heat. To explore whether/how indoor coal combustion might contribute to poor respiratory health of residents, this study examined respiratory health data, identified household risk factors such as fuel and stove type and use, analyzed samples of locally used coal, and measured and characterized fine particulate airborne matter inside selected homes. In twenty-five percent of homes surveyed coal was burned in stoves not designed for that fuel, and indoor air quality was frequently found to be of a level to raise concerns. The average winter 24-hourPM2.5concentration in 20 homes was 36.0 μg/m3. This is the first time thatPM2.5has been quantified and characterized inside Navajo reservation residents' homes.
Optimal Fluxes, Reaction Replaceability, and Response to Enzymopathies in the Human Red Blood Cell
Authors: De Martino A. , Granata D. , Marinari E. , Martelli C. , Van Kerrebroeck V.
Published: June 2010

Characterizing the capabilities, key dependencies, and response to perturbations of genome-scale metabolic networks is a basic problem with important applications. A key question concerns the identification of the potentially most harmful reaction knockouts. The integration of combinatorial methods with sampling techniques to explore the space of viable flux states may provide crucial insights on this issue. We assess the replaceability of every metabolic conversion in the human red blood cell by enumerating the alternative paths from substrate to product, obtaining a complete map of he potential damage of single enzymopathies. Sampling the space of optimal steady state fluxes in the healthy and in the mutated cell reveals both correlations and complementarity between topologic and dynamical aspects.
Cytokines and Growth Factors Stimulate Hyaluronan Production: Role of Hyaluronan in Epithelial to Mesenchymal-Like Transition in Non-Small Cell Lung Cancer
Authors: Chow Geraldine , Tauler Jordi , Mulshine James L.
Published: June 2010

In this study, we investigated the role of hyaluronan (HA) in non-small cell lung cancer (NSCLC) since close association between HA level and malignancy has been reported. HA is an abundant extracellular matrix component and its synthesis is regulated by growth factors and cytokines that include epidermal growth factor (EGF) and interleukin-1β(IL-1β). We showed that treatment with recombinant EGF and IL-1β, alone or in combination with TGF-β, was able to stimulate HA production in lung adenocarcinoma cell line A549. TGF-β/IL-1βtreatment induced epithelial to mesenchymal-like phenotype transition (EMT), changing cell morphology and expression of vimentin and E-cadherin. We also overexpressed hyaluronan synthase-3 (HAS3) in epithelial lung adenocarcinoma cell line H358, resulting in induced HA expression, EMT phenotype, enhanced MMP9 and MMP2 activities and increased invasion. Furthermore, adding exogenous HA to A549 cells and inducing HA H358 cells resulted in increased resistance to epidermal growth factor receptor (EGFR) inhibitor, Iressa. Together, these results suggest that elevated HA production is able to induce EMT and increase resistance to Iressa in NSCLC. Therefore, regulation of HA level in NSCLC may be a new target for therapeutic intervention.
PECVD Silicon Nitride Passivation on Boron Emitter: The Analysis of Electrostatic Charge on the Interface Properties
Authors: Nursam Natalita M. , Ren Yongling , Weber Klaus J.
Published: June 2010

The dependence of surface recombination of boron diffused and undiffused silicon surfaces passivated with a-Si:H on the net charge density is investigated in detail. The films are deposited by plasma-enhanced chemical vapour deposition using a 2.45 GHz microwave remote plasma system. The surface charge density on the samples is varied by depositing charge using a corona discharge chamber. Excess carrier lifetime, capacitance-voltage, and Kelvin probe measurements are combined to determine the surface recombination velocity and emitter saturation current density as a function of net charge density. Our results show that the application of negative charge causes a substantial reduction in the surface recombination of samples with boron diffused emitters, even for high boron surface concentrations of  . The significant difference observed in surface recombination between boron diffused and undiffused sample under accumulation implies that the presence of boron diffusion has results in some degradation of the Si-Si interface. Further, (111) oriented surfaces appear more sensitive to the boron surface concentration than (100) oriented surfaces.
Increased Expression of Ganglioside GM1 in Peripheral CD4+ T Cells Correlates Soluble Form of CD30 in Systemic Lupus Erythematosus Patients
Authors: Dong Lingli , Hu Shaoxian , Chen Fang , Lei Xiaomei , Tu Wei , Yu Yikai , Yang Liu , Sun Wei , Yamaguchi Takuro , Masaki Yasufumi , Umehara Hisanori
Published: June 2010

Gangliosides GM1 is a good marker of membrane microdomains (lipid rafts) with important function in cellular activation processes. In this study we found that GM1 expression on CD4+ T cells and memory T cells (CD45RO/CD4) were dramatic increased after stimulation with phytohaemagglutinin in vitro. Next, we examined the GM1 expression on peripheral blood CD4+ T cells and CD8+ T cells from 44 patients with SLE and 28 healthy controls by flow cytometry. GM1 expression was further analyzed with serum soluble CD30 (sCD30), IL-10, TNF-alpha and clinical parameters. The mean fluorescence intensity of GM1 on CD4+ T cells from patients with SLE was significantly higher than those from healthy controls, but not on CD8+ T cells. Increased expression of GM1 was more marked on CD4+/CD45RO+ memory T cells from active SLE patients. Patients with SLE showed significantly elevated serum sCD30 and IL-10, but not TNF-alpha levels. In addition, we found that enhanced GM1 expression on CD4+ T cells from patients with SLE positively correlated with high serum levels of sCD30 and IgG as well as disease activity (SLEDAI scores). Our data suggested the potential role of aberrant lipid raft/GM1 on CD4+ T cells and sCD30 in the pathogenesis of SLE.
Herpes Simplex Type 1 Encephalitis Restricted to the Brainstem in a Pediatric Patient
Authors: Arita Juliana Harumi , Lin Jaime , Peruchi Mirella Maccarini , Rodrigues Marcelo Masruha , Vilanova Luiz Celso Pereira
Published: June 2010

Herpes simplex encephalitis is a potentially fatal infection of central nervous system that typically involves frontal and temporal lobes. Occasionally, it presents an extratemporal involvement and in rarer cases, it is limited to the brainstem. We describe a case of an adolescent who presented with fever, sore throat, and vertigo. Clinical picture evolved to lethargy, tetraparesis, consciousness impairment, and respiratory failure. MRI showed lesions restricted to the brainstem. PCR of CSF was positive for herpes simplex type 1.
Molecular Characterization of the Onset and Progression of Colitis in Inoculated Interleukin-10 Gene-Deficient Mice: A Role for PPARα
Authors: Knoch Bianca , Barnett Matthew P. G. , Cooney Janine , McNabb Warren C. , Barraclough Diane , Laing William , Zhu Shuotun , Park Zaneta A. , MacLean Paul , Knowles Scott O. , Roy Nicole C.
Published: June 2010

The interleukin-10 gene-deficient (Il10-/-) mouse is a model of human inflammatory bowel disease andPparahas been identified as one of the key genes involved in regulation of colitis in the bacterially inoculatedIl10-/-model. The aims were to (1) characterize colitis onset and progression using a histopathological, transcriptomic, and proteomic approach and (2) investigate links between PPARαand IL10 using gene network analysis. Bacterial inoculation resulted in severe colitis inIl10-/-mice from 10 to 12 weeks of age. Innate and adaptive immune responses showed differences in gene expression relating to colitis severity. Actin cytoskeleton dynamics, innate immunity, and apoptosis-linked gene and protein expression data suggested a delayed remodeling process in 12-week-oldIl10-/-mice. Gene expression changes in 12-week-oldIl10-/-mice were related to PPARαsignaling likely to control colitis, but how PPARαactivation might regulate intestinal IL10 production remains to be determined.
Stochastic Navier‐Stokes Equations with Artificial Compressibility in Random Durations
Authors: Yin Hong
Published: June 2010

The existence and uniqueness of adapted solutions to the backward stochastic Navier‐Stokes equation with artificial compressibility in two‐dimensional bounded domains are shown by Minty‐Browder monotonicity argument, finite‐dimensional projections, and truncations. Continuity of the solutions with respect to terminal conditions is given, and the convergence of the system to an incompressible flow is also established.
Serum Persistent Organic Pollutants and Duration of Lactation among Mexican-American Women
Authors: Weldon Rosana H. , Webster Monique , Harley Kim G. , Bradman Asa , Fenster Laura , Davis Mark D. , Hubbard Alan , Barr Dana B. , Holland Nina , Eskenazi Brenda
Published: June 2010

Background. Research suggests that estrogenic endocrine-disrupting chemicals interfere with lactation.Objectives. (1) to determine if estrogenic persistent organic pollutants (POPs) are associated with shortened lactation duration; (2) to determine whether previous breastfeeding history biases associations.Methods and Results. We measured selected organochlorines and polychlorinated biphenyls (p,p′-DDE,p,p′-DDT,o,p′-DDT,β-hexachlorocyclohexane, hexachlorobenzene, and PCBs 44, 49, 52, 118, 138, 153, and 180) in serum from 366 low-income, Mexican-American pregnant women living in an agricultural region of California and assessed breastfeeding duration by questionnaires. We found no association between DDE, DDT, or estrogenic POPs with shortened lactation duration, but rather associations for two potentially estrogenic POPs with lengthened lactation duration arose (HR [95% CI]: 0.6 [0.4, 0.8] forp,p′-DDE & 0.8 [0.6, 1.0] for PCB 52). Associations between antiestrogenic POPs (PCBs 138 and 180) and shortened lactation duration were attributed to a lactation history bias.Conclusion. Estrogenic POPs were not associated with shortened lactation duration, but may be associated with longer lactation duration.
Runx Regulation of Sphingolipid Metabolism and Survival Signaling
Authors: Kilbey Anna , Terry Anne , Jenkins Alma , Borland Gillian , Zhang Qifeng , Wakelam Michael J.O. , Cameron Ewan R. , Neil James C.
Published: June 2010

The Runx genes (Runx1, 2, and 3) regulate cell fate in development and can operate as either oncogenes or tumor suppressors in cancer. The oncogenic potential of ectopic Runx expression has been shown in transgenic mice that develop lymphoma in potent synergy with overexpressed Myc, and in established fibroblasts that display altered morphology and increased tumorigenicity. Candidate oncogenic functions of overexpressed Runx genes include resistance to apoptosis in response to intrinsic and extrinsic stresses. In a search for gene targets responsible for this aspect of Runx phenotype, we have identified three key enzymes in sphingolipid metabolism (Sgpp1, Ugcg, and St3gal5/Siat9) as direct targets for Runx transcriptional regulation in a manner consistent with survival and apoptosis resistance. Consistent with these changes in gene expression, mass spectrometric analysis showed that ectopic Runx reduces intracellular long-chain ceramides in NIH3T3 fibroblasts and elevated extracellular sphingosine 1 phosphate. Runx expression also opposed the activation of c-Jun-NH2-kinase and p38MAPK, key mediators of ceramide-induced death, and suppressed the onset of apoptosis in response to exogenous tumor necrosis factor α. The survival advantage conferred by ectopic Runx could be partially recapitulated by exogenous sphingosine 1 phosphate and was accompanied by reduced phosphorylation of p38MAPK. These results reveal a novel link between transcription factor oncogenes and lipid signaling pathways involved in cancer cell survival and chemoresistance. Cancer Res; 70(14); 5860–9. ©2010 AACR.
Interleukin-27 Acts as Multifunctional Antitumor Agent in Multiple Myeloma
Authors: Cocco Claudia , Giuliani Nicola , Di Carlo Emma , Ognio Emanuela , Storti Paola , Abeltino Manuela , Sorrentino Carlo , Ponzoni Maurilio , Ribatti Domenico , Airoldi Irma
Published: June 2010

Purpose: Multiple myeloma (MM) derives from plasmablast/plasma cells that accumulate in the bone marrow. Different microenvironmental factors may promote metastatic dissemination especially to the skeleton, causing bone destruction. The balance between osteoclast and osteoblast activity represents a critical issue in bone remodeling. Thus, we investigated whether interluekin-27 (IL-27) may function as an antitumor agent by acting directly on MM cells and/or on osteoclasts/osteoblasts.

Experimental Design: The IL-27 direct antitumor activity on MM cells was investigated in terms of angiogenesis, proliferation, apoptosis, and chemotaxis. The IL-27 activity on osteoclast/osteoblast differentiation and function was also tested. In vivo studies were done using severe combined immunodeficient/nonobese diabetic mice injected with MM cell lines. Tumors from IL-27– and PBS-treated mice were analyzed by immunohistochemistry and PCR array.

Results: We showed that IL-27 (a) strongly inhibited tumor growth of primary MM cells and MM cell lines through inhibition of angiogenesis, (b) inhibited osteoclast differentiation and activity and induced osteoblast proliferation, and (c) damped in vivo tumorigenicity of human MM cell lines through inhibition of angiogenesis.

Conclusions: These findings show that IL-27 may represent a novel therapeutic agent capable of inhibiting directly MM cell growth as well as osteoclast differentiation and activity. Clin Cancer Res; 16(16); 4188–97. ©2010 AACR.
Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non–Small Cell Lung Cancer Cell Lines
Authors: Garon Edward B. , Finn Richard S. , Hosmer Wylie , Dering Judy , Ginther Charles , Adhami Shahriar , Kamranpour Naeimeh , Pitts Sharon , Desai Amrita , Elashoff David , French Tim , Smith Paul , Slamon Dennis J.
Published: June 2010

Selumetinib (AZD6244; ARRY-142886) is a tight-binding, uncompetitive inhibitor of mitogen-activated protein kinase kinases (MEK) 1 and 2 currently in clinical development. We evaluated the effects of selumetinib in 31 human breast cancer cell lines and 43 human non–small cell lung cancer (NSCLC) cell lines to identify characteristics correlating with in vitro sensitivity to MEK inhibition. IC50 <1 μmol/L (considered sensitive) was seen in 5 of 31 breast cancer cell lines and 15 of 43 NSCLC cell lines, with a correlation between sensitivity and raf mutations in breast cancer cell lines (P = 0.022) and ras mutations in NSCLC cell lines (P = 0.045). Evaluation of 27 of the NSCLC cell lines with Western blots showed no clear association between MEK and phosphoinositide 3-kinase pathway activation and sensitivity to MEK inhibition. Baseline gene expression profiles were generated for each cell line using Agilent gene expression arrays to identify additional predictive markers. Genes associated with differential sensitivity to selumetinib were seen in both histologies, including a small number of genes in which differential expression was common to both histologies. In total, these results suggest that clinical trials of selumetinib in breast cancer and NSCLC might select patients whose tumors harbor raf and ras mutations, respectively. Mol Cancer Ther; 9(7); 1985–94. ©2010 AACR.
A Novel Mechanism of Indole-3-Carbinol Effects on Breast Carcinogenesis Involves Induction of Cdc25A Degradation
Authors: Wu Yongsheng , Feng Xiaoling , Jin Yucui , Wu Zhaojia , Hankey William , Paisie Carolyn , Li Lei , Liu Fengjuan , Barsky Sanford H. , Zhang Weiwei , Ganju Ramesh , Zou Xianghong
Published: June 2010

The natural compound indole-3-carbinol (I3C; found in vegetables of the genus Brassica) is a promising cancer prevention or therapy agent. The cell division cycle 25A (Cdc25A) phosphatase is overexpressed in a variety of human cancers and other diseases. In the present study, I3C induced degradation of Cdc25A, arrest of the G1 cell cycle, and inhibition of the growth of breast cancer cells. We also showed that the Ser124 site of Cdc25A, which is related to cyclin-dependent kinase 2, is required for I3C-induced degradation of Cdc25A in breast cancer cells, and that interruption of the ATM-Chk2 pathway suppressed I3C-induced destruction of Cdc25A. Our in vivo studies of different mutated forms of Cdc25A found that the mutation Cdc25AS124A (Ser124 to Ala124), which confers resistance to I3C-induced degradation of Cdc25A, attenuated I3C inhibition of breast tumorigenesis in a mouse xenograft model. The present in vitro and in vivo studies together show that I3C-induced activation of the ATM-Chk2 pathway and degradation of Cdc25A represent a novel molecular mechanism of I3C in arresting the G1 cell cycle and inhibiting the growth of breast cancer cells. The finding that I3C induces Cdc25A degradation underscores the potential use of this agent for preventing and treating cancers and other human diseases with Cdc25A overexpression. Cancer Prev Res; 3(7); 818–28. ©2010 AACR.
Pneumothorax in a Preterm Infant Monitored by Electrical Impedance Tomography: A Case Report
Authors: Miedema M. , Frerichs I. , de Jongh F.H.C. , van Veenendaal M.B. , van Kaam A.H.
Published: June 2010

Electrical impedance tomography (EIT) is a noninvasive bedside tool for monitoring regional changes in ventilation. We report, for the first time, the EIT images of a ventilated preterm infant with a unilateral pneumothorax, showing a loss of regional ventilation in the affected lung during both high-frequency oscillation and spontaneous ventilation.
Vitamin C Transporter Gene Polymorphisms, Dietary Vitamin C and Serum Ascorbic Acid
Authors: Cahill Leah E. , El-Sohemy Ahmed
Published: June 2010

Background/Aims: Vitamin C transporter proteins SVCT1 and SVCT2 are required for the absorption and transport of vitamin C in humans. This study aims to determine whether common SVCT genotypes modify the association between dietary vitamin C and serum ascorbic acid. Methods: Non-smoking men and women (n = 1,046) aged 20–29 were participants of the Toronto Nutrigenomics and Health Study. Overnight fasting blood samples were collected to determine serum ascorbic acid concentrations by HPLC and to genotype for two SVCT1 (rs4257763 and rs6596473) and two SVCT2 (rs6139591 and rs2681116) polymorphisms. Results: No diet-gene interactions were observed for the vitamin C transporter polymorphisms, however, the average (mean ± SE) serum ascorbic acid concentrations differed between rs4257763 genotypes (GG: 24.4 ± 1.3, GA: 26.8 ± 1.1, AA: 29.7 ± 1.4 µmol/l; p = 0.002). For this polymorphism, the correlation between dietary vitamin C and serum ascorbic acid was only significant in subjects with a G allele. The SVCT2 polymorphisms also appeared to modify the strength of the diet-serum correlation. Conclusions: Our findings demonstrate that genetic variation in SVCT1 can influence serum ascorbic acid concentrations and that SVCT1 and SVCT2 genotypes modify the strength of the correlation between dietary vitamin C and serum ascorbic acid.
Strenuous exercise promotes shear-induced thrombin generation by increasing the shedding of procoagulant microparticles from platelets
Authors: Chen Jan-Kan , Wang Jong-Shyan , Chen Yu-Wen
Published: June 2010

Vigorous exercise increases the risk of vascular thrombotic events. Shear stress enhances the shedding of procoagulant microparticles from platelets, and triggers thrombin generation (TG) in blood. This study explicates the manner in which strenuous exercise affects platelet- derived microparticles (PDMP) release and PDMP-mediated TG under various physio-pathological shear flows. Twenty-four sedentary healthy men performed a graded exercise test (up to VO2max) on a bicycle ergometer. At rest, immediately after and 2 hours after exercise, platelet-rich plasma (PRP) was exposed in a cone-and-plate viscometer to imitate static (0 dyne/cm2), physiological low (LS, 10 dyne/cm2) and pathological high (HS, 100 dyne/cm2) shear stresses ex vivo. The PDMP characteristics and dynamic TG were measured by two-colour flow cytometry and calibrated, automatic thrombinography, respectively. The results demonstrated that there is an increased level of total PDMP to- gether with elevated peak height and rate of TG in PRP in response to both LS and HS conditions. Furthermore, HS, but not LS, promoted the binding of FV/Va or FVIII and the exposure of phosphatidylserine (PS) on platelets. Application of HS after strenuous exercise increased the factor (F)V/Va-/FVIII-/tissue factor-rich and PS-exposing PDMP counts, enhanced the PDMP-promoted peak height and rate of TG, as well as increased the ability of FV/Va or FVIII to bind to PDMP or platelets. However, the enhancement of HS-induced procoagulant activity reversed to the pre-exercise status 2 hours following this exercise. Therefore, we conclude that strenuous exercise modestly contributes to the acceleration of shear-induced TG by increasing the release of procoagulant microparticles from platelets.