bluuebunny/crossref_metadata_2025 huggingface dataset:
Choice of management strategy for colorectal cancer based on a diagnostic immunohistochemical test for defective mismatch repair
Authors: Cawkwell L , Gray S , Murgatroyd H , Sutherland F , Haine L , Longfellow M , O’Loughlin S , Cross D , Kronborg O , Fenger C , Mapstone N , Dixon M , Quirke P
Published: June 2010

BACKGROUND

Despite intensive research into the molecular abnormalities associated with colorectal cancer (CRC), no diagnostic tests have emerged which usefully complement standard histopathological assessments.

AIMS

To assess the feasibility of using immunohistochemistry to detect replication error (RER) positive CRCs and determine the incidence of RER positivity within distinct patient subgroups.

METHODS

502 CRCs were analysed for RER positivity (at least two markers affected) and/or expression of hMSH2 and hMLH1.

RESULTS

There were 15/30 (50%) patients with metachronous CRCs, 16/51 (31%) with synchronous CRCs, 14/45 (31%) with a proximal colon carcinoma, and 4/23 (17%) who developed a CRC under the age of 50 showed RER positivity. However, 0/54 patients who developed a solitary carcinoma of the rectum/left colon over the age of 50 showed RER positivity. Immunohistochemical analysis revealed that 66/66 (100%) RER positive carcinomas were associated with complete lack of expression of either hMSH2 or hMLH1. This correlation was confirmed using a further 101 proximal colon carcinomas. Patients with a mismatch repair defective carcinoma showed improved survival but a 5.54 times relative risk of developing a metachronous CRC. A prospective immunohistochemical study revealed 13/117 (11%) patients had a mismatch repair defective carcinoma. A fivefold excess of hMLH1 defective cases was noted.

CONCLUSIONS

All RER positive carcinomas were identified by the immunohistochemical test. This is the first simple laboratory test which can be performed routinely on all CRCs. It will provide a method for selecting patients who should be investigated for HNPCC, offered long term follow up, and who may not respond to standard chemotherapy regimens.
Hepatic manifestations of familial patent ductus venosus in adults
Authors: Jacob S , Farr G , De Vun D , Takiff H , Mason A
Published: June 2010

BACKGROUND

The ductus venosus connects the umbilical vein to the inferior vena cava during fetal life and subsequently closes rapidly after birth. It is known as patent ductus venosus when it remains patent in adulthood.

PATIENTS

A 43 year old man with a history of panhypopituitarism presented with recurrent bouts of pedal oedema associated with fatigue, hypoalbuminaemia, and elevated prothrombin time. An ultrasound examination of his abdomen with Doppler revealed notable attenuation of the main portal vein with diminished intrahepatic branches; a computed tomography scan with angiography revealed a large collateral vein within the liver consistent with a patent ductus venosus. Sequential liver biopsies showed a considerable reduction in the calibre and number of the portal veins. His younger brother, who was diagnosed with alcohol related cirrhosis, suffered from intermittent bouts of encephalopathy and was found to have the same vascular lesion. A third brother was found to have a patent ductus venosus as well as two large hepatic masses consistent with focal nodular hyperplasia.

CONCLUSION

The syndrome of familial patent ductus venosus has only previously been described in three infant brothers who presented with hepatic encephalopathy and fatty degeneration of the liver. This report documents three brothers with a patent ductus venosus presenting in adulthood with different manifestations of liver disease. The presence of the same vascular anomaly in three brothers is highly suggestive of a recessive genetic trait with an anatomical manifestation of patent ductus venosus.
The effects of short term lipid infusion on plasma and hepatic bile lipids in humans
Authors: Pakula R , Konikoff F M , Moser A M , Greif F , Tietz A , Gilat T , Rubin M
Published: June 2010

BACKGROUND

Patients on parenteral nutrition have an increased incidence of gall bladder sludge and gallstone disease, thought to be related to bile stasis. Intravenous lipid emulsions, especially those containing medium chain triglycerides, have also been shown to have a lithogenic effect on the composition of bile in the gall bladder.

AIMS

To determine whether lipid infusion influences hepatic bile composition in patients with an indwelling T tube following cholecystectomy and choledochotomy.

METHODS

In eight patients undergoing the above surgical procedure, the time at which effects of the interrupted enterohepatic circulation were minimal was determined. Twenty two cholesterol gallstone patients with bile fistula were then randomised to receive an infusion of a lipid emulsion containing either long chain triglycerides or a mixture of long and medium chain triglycerides.

RESULTS

Lipid infusion resulted in a significant increase in plasma levels of triglycerides and phospholipids. Both lipid emulsions caused an increase in hepatic biliary cholesterol level and cholesterol saturation index, but this effect was more pronounced with medium chain triglycerides. The fatty acid composition of biliary phospholipids showed a significant enrichment of linoleic acid by both lipid infusions.

CONCLUSIONS

Infusion of triglycerides causes lithogenic changes in hepatic bile composition in humans, the lithogenic effect of infusion of medium chain triglycerides being more pronounced than that of long chain triglycerides. This effect, coupled with gall bladder stasis, may be responsible for the increased risk of biliary sludge and gallstone formation in patients on long term lipid infusion.
Firearms regulation and declining rates of male suicide in Quebec
Authors: Gagné Mathieu , Robitaille Yvonne , Hamel Denis , St-Laurent Danielle
Published: June 2010

Objectives

To examine whether significant changes in method-specific male suicide rates occurred in the province of Quebec after stronger firearms regulations were introduced in Canada in 1991; to ascertain whether more stringent firearms regulations influence firearms and total suicide trends among men and to determine whether different results are obtained according to the statistical methods used.

Study design

Descriptive analyses of time trends in method-specific suicide rates for men from 1981 to 2006 using Joinpoint regression models and pre–post firearms regulation analyses.

Setting

Quebec (Canada).

Patients or Subjects

Men who have commited suicide aged 15–34, 35–64 and 65 years and over, based on the Quebec mortality database, 1981–2006.

Interventions

A national firearms control initiative enacted in 1991.

Results

The Joinpoint regression models suggest that firearm suicide rates declined towards the end of the 1990s. Since 1996, the pace of decline was twice as great in men aged 15–34 years (annual percentage change (APC) −11.1%) compared with men aged 35–64 years (APC −5.6%). Total suicide rates also declined among men aged 15–34 and 35–64 years during this period. Pre–post firearms regulation Poisson regression analyses failed to detect the specific point in time when significant changes in the trend occurred.

Conclusions

Male firearm suicide rates declined following the introduction of restrictive firearms regulations in Canada. Whether this represents a causal relationship requires further study.
Is length of stay in hospital a stable proxy for injury severity?
Authors: Cryer C , Gulliver P , Langley J D , Davie G
Published: June 2010

Research question

Is length of stay (LoS) in hospital a stable proxy for severity of injury when monitoring time trends in serious injury incidence?

Objective

To investigate whether LoS metrics (mean, median and proportion exceeding several LoS thresholds) have changed over time for injury diagnoses with known severity.

Design

Time series investigation.

Subjects and setting

New Zealand population admitted to hospital for injury and discharged during the period 1989 to 1998.

Main outcome measures

Interpolated median and geometric mean lengths of stay, as well as the proportion of cases that have an LoS greater than or equal to 3, 4, 7 and 14 days in hospital.

Methods

ICD-9-CM diagnoses that are approximately homogeneous in regard to severity of injury (ICD-HS diagnoses) were identified. Trends were investigated in the LoS statistics for: injury and non-injury diagnoses combined; all injury diagnoses; major body sites of injury; severity strata; and ICD-HS diagnoses.

Results

Almost without exception, there was a decline in the LoS statistics over time for all diagnoses, all injury diagnoses, each body site of injury investigated, severity strata, and the ICD-HS diagnoses.

Conclusions

Reductions in median and geometric mean LoS over time, as well as reductions in the proportion exceeding selected LoS thresholds, were due to factors other than reductions in the incidence of serious injury; for example, changes in service delivery over time. An LoS threshold shouldnotbe used as a proxy for severity of injury if the goal is to monitor time trends in injury incidence.
Young Egyptians' perceptions, attitudes and knowledge of injuries
Authors: Day Hannah R , El-Setouhy Maged , El-Shinawi Mohamed , Assem Amr , Ismail Mona , Salem Marwa , Smith Gordon S , Hirshon Jon Mark
Published: June 2010

The objective of this study was to qualitatively evaluate young Egyptians' perceptions, attitudes, knowledge and behaviour towards injuries before implementation of an extensive questionnaire about injuries among Egyptian youth. In 2008, five focus groups of three to nine participants each were conducted in Cairo, Egypt in Arabic to evaluate young Egyptians' attitudes towards injuries, injury prevention, and their understanding of ‘accidents’ and fatalism. Participants were 14–26 years of age and were from medium to high socioeconomic status. Focus group participants noted that the concept ofhadthah(‘accident’) signified an event determined by destiny, whereasesabah(‘injury’) was the result of human actions. The results of these focus groups indicate that young, educated Egyptians are interested in injury prevention programmes despite low confidence in the preventability of injuries.
Oral squamous cell carcinoma: status of tight junction claudins in the different histopathological patterns and relationship with clinical parameters. A tissue-microarray-based study of 136 cases
Authors: Lourenço Silvia V , Coutinho-Camillo Cláudia M , Buim Marcilei E C , Pereira Cláudia M , Carvalho André L , Kowalski Luiz P , Soares Fernando A
Published: June 2010

Aims

Claudins are integral transmembrane proteins of the tight junctions, critical for maintaining cell adhesion and polarity. Alterations in the expression of individual claudins have been detected in carcinomas and appear to correlate with tumour progression.

Methods

In this study, a panel of anti-claudin antibodies (anti-claudins 1, 2, 3, 4, 5 and 7) was employed to map claudin expression in 136 cases of oral squamous cell carcinoma (OSCC) organised in a tissue microarray.

Results

Claudins were expressed in a reticular pattern up to the prickle layer in normal mucosal epithelium. In OSCC, claudins were strongly present in well-differentiated tumours, they presented mild and low expression in moderately differentiated OSCC, and were negative in poorly differentiated OSCC; the absences of claudin 1 (p=0.002) and claudin 4 (p<0.001) were associated with moderately/poorly differentiated tumours. Strong expression of claudin 4 was associated with decreased perineural infiltration (p=0.024). Claudins 5 and 7 were mostly negative or weakly expressed in all cases studied. Expression of claudin 7 was associated with the early clinical stages of the disease, whereas loss of claudin 7 tended to be more frequent in advanced stages of OSCC (p=0.054). Absence of claudin 7 was also associated with absent vascular infiltration (p=0.045) and with presence of recurrence (p=0.052).

Conclusions

Claudin expression patterns showed a strong correlation with histological type of OSCC; claudin expression was decreased in areas of invasion, and negative in poorly differentiated tumours. This pattern may be related to evolution and prognosis of these tumours, especially in the case of claudin 7, which seems to be associated with a poor prognosis in OSCC.
E-cadherin immunoexpression patterns in the characterisation of gastric carcinoma histotypes
Authors: Almeida P R , Ferreira V A , Santos C C , Rocha-Filho F D , Feitosa R R , Falcão E A A , Cavada B K , Ribeiro R A
Published: June 2010

Aims

E-cadherin, the main epithelial intercellular adhesion molecule, is abnormally expressed in many cancer types, including gastric carcinoma, which is the second leading cause of cancer death worldwide. The aim of this study was to contribute to the characterisation of gastric carcinoma histotypes based on a new approach to E-cadherin immunoexpression.

Methods

97 gastric tumour samples obtained from the files of the Hospital of Cancer/Cancer Institute of Ceará, Brazil, were histologically analysed and classified as intestinal (n=40), diffuse (n=34), mixed (n=16) or unclassified (n=7) carcinomas. Immunohistochemistry was performed on the tissue microarray sections. Scores were applied according to the system of Jawhari: 0, no staining; 1, cytoplasmic staining; 2, cytoplasmic and membranous staining in the same case; 3, normal membranous immunoexpression; abnormal patterns: scores 0, 1 and 2; normal pattern: score 3. Jawhari scores were then evaluated utilising another approach: the absence of membranous expression scores (0 and 1) versus the presence of membranous expression (scores 2 and 3).

Results

A significant association between membranous expression of E-cadherin and the intestinal histotype (36/40 (90%), and 28/41 (68%) for other histotypes) was found, while diffuse carcinomas were related to the absence of membranous expression. A very strong and peculiar relationship was observed between cytoplasm-exclusive E-cadherin expression (score 1) and the diffuse component of mixed tumours (11/16 (69%)).

Conclusions

E-cadherin immunoexpression patterns help us to characterise gastric carcinoma histotypes. The presence or absence of membranous staining is the most valuable criterion in evaluating E-cadherin expression. Mixed tumours show a characteristic E-cadherin cytoplasmic expression in gastric carcinomas.
Using Digital Storytelling for Creative and Innovative e-Learning
Authors: Sharda Nalin
Published: June 2010

This article discusses how creativity and innovation can be enhanced with e-learning systems based on digital storytelling. A story creation model called movement-oriented design (MOD) is introduced for systematically developing effective digital stories, in conjunction with story creation principles articulated by Robert McKee, a Hollywood guru of script writing.
An Interview with Jack E. Kosakowski of JA Worldwide
Authors: Gualtieri Lisa , Kosakowski Jack E.
Published: June 2010

Jack E. Kosakowski is the executive vice president and chief operating officer of JA Worldwide, a nonprofit organization dedicated to educating young people about work readiness, entrepreneurship and financial literacy. He is also president of Junior Achievement USA. Kosakowski was appointed by President George W. Bush to serve a two-year term on the President's Advisory Council on Financial Literacy in January 2008. He also serves on the Board of Directors of the Achievement Foundation, and is a member of the United States Commission for UNESCO. eLearn Magazine spoke with him about JA Worldwide's online initiatives, such as simulation- and game-based training.
Better Design Doesn't Take Longer!
Authors: Quinn Clark
Published: June 2010

Too many people subscribe to the idea that better design takes too long. This, if true, would be a significant barrier to more quality, and an explanation for the undesirable amount of bad e-learning out there. However, Clark Quinn says he doesnt buy it.
Creating Online Professional Learning Communities
Authors: Gruenbaum Elizabeth A.
Published: June 2010

When authors refer to a Professional Learning Community (PLC) within a school, they commonly mean a community of stakeholders that are all working together focused on the best interest of the students, where results are measured by an increase in student achievement. These stakeholders are anyone with an interest in that particular school from within the school communityschool leaders or administrators, teachers, staff, parents, and community members. Collaboration is a key factor in a PLC. Imagine everyone working together for the best interest of the students and focused on a culture of assessment-driven continuous improvement, and you have a PLC.
Character animation in two-player adversarial games
Authors: Wampler Kevin , Andersen Erik , Herbst Evan , Lee Yongjoon , Popović Zoran
Published: June 2010

The incorporation of randomness is critical for the believability and effectiveness of controllers for characters in competitive games. We present a fully automatic method for generating intelligent real-time controllers for characters in such a game. Our approach uses game theory to deal with the ramifications of the characters acting simultaneously, and generates controllers which employ both long-term planning and an intelligent use of randomness. Our results exhibit nuanced strategies based on unpredictability, such as feints and misdirection moves, which take into account and exploit the possible strategies of an adversary. The controllers are generated by examining the interaction between the rules of the game and the motions generated from a parametric motion graph. This involves solving a large-scale planning problem, so we also describe a new technique for scaling this process to higher dimensions.
Inconsistent formation and nonfunction of insulin-positive cells from pancreatic endoderm derived from human embryonic stem cells in athymic nude rats
Authors: Matveyenko Aleksey V. , Georgia Senta , Bhushan Anil , Butler Peter C.
Published: June 2010

Embryonic stem cell therapy has been proposed as a therapeutic strategy to restore β-cell mass and function in T1DM. Recently, a group from Novocell (now ViaCyte) reported successful development of glucose-responsive islet-like structures after implantation of pancreatic endoderm (PE) derived from human embryonic stem cells (hESC) into immune-deficient mice. Our objective was to determine whether implantation of hESC-derived pancreatic endoderm from Novocell into athymic nude rats results in development of viable glucose-responsive pancreatic endocrine tissue. Athymic nude rats were implanted with PE derived from hESC either via implantation into the epididymal fat pads or by subcutaneous implantation into TheraCyte encapsulation devices for 20 wk. Blood glucose, weight, and human insulin/C-peptide secretion were monitored by weekly blood draws. Graft β-cell function was assessed by a glucose tolerance test, and graft morphology was assessed by immunohistochemistry and immunofluorescence. At 20 wk postimplantation, epididymal fat-implanted PE progressed to develop islet-like structures in 50% of implants, with a mean β-cell fractional area of 0.8 ± 0.3%. Human C-peptide and insulin were detectable, but at very low levels (C-peptide = 50 ± 26 pmol/l and insulin = 15 ± 7 pmol/l); however, there was no increase in human C-peptide/insulin levels after glucose challenge. There was no development of viable pancreatic tissue or meaningful secretory function when human PE was implanted in the TheraCyte encapsulation devices. These data confirm that islet-like structures develop from hESC differentiated to PE by the protocol developed by NovoCell. However, the extent of endocrine cell formation and secretory function is not yet sufficient to be clinically relevant.
Desmosomal Molecules In and Out of Adhering Junctions: Normal and Diseased States of Epidermal, Cardiac and Mesenchymally Derived Cells
Authors: Pieperhoff Sebastian , Barth Mareike , Rickelt Steffen , Franke Werner W.
Published: June 2010

Current cell biology textbooks mention only two kinds of cell‐to‐cell adhering junctions coated with the cytoplasmic plaques: the desmosomes (maculae adhaerentes), anchoring intermediate‐sized filaments (IFs), and the actin microfilament‐anchoring adherens junctions (AJs), including both punctate (puncta adhaerentia) and elongate (fasciae adhaerentes) structures. In addition, however, a series of other junction types has been identified and characterized which contain desmosomal molecules but do not fit the definition of desmosomes. Of these special cell‐cell junctions containing desmosomal glycoproteins or proteins we review the composite junctions (areae compositae) connecting the cardiomyocytes of mature mammalian hearts and their importance in relation to human arrhythmogenic cardiomyopathies. We also emphasize the various plakophilin‐2‐positive plaques in AJs (coniunctiones adhaerentes) connecting proliferatively active mesenchymally‐derived cells, including interstitial cells of the heart and several soft tissue tumor cell types. Moreover, desmoplakin has also been recognized as a constituent of the plaques of the complexus adhaerentes connecting certain lymphatic endothelial cells. Finally, we emphasize the occurrence of the desmosomal transmembrane glycoprotein, desmoglein Dsg2, out of the context of any junction as dispersed cell surface molecules in certain types of melanoma cells and melanocytes. This broadening of our knowledge on the diversity of AJ structures indicates that it may still be too premature to close the textbook chapters on cell‐cell junctions.
Stillbirths in Rural Hospitals in The Gambia: A Cross‐Sectional Retrospective Study
Authors: Jammeh Abdou , Vangen Siri , Sundby Johanne
Published: June 2010

Objective. We determined the stillbirth rate and associated factors among women who delivered in rural hospitals in The Gambia. Method. A cross‐sectional retrospective case review of all deliveries between July and December 2008 was undertaken. Maternity records were reviewed and abstracted of the mother’s demographic characteristics, obstetric complications and foetal outcome. Main Outcome Measure: The stillbirth rate was calculated as deaths per 1000 births. Results. The hospital‐based stillbirth rate was high, 156 (95% CI 138–174) per 1000 births. Of the 1,519 deliveries, there were 237 stillbirths of which 137 (57.8%) were fresh. Severe obstetric complication, birth weight <2500 g, caesarean section delivery, and referral from a peripheral health facility were highly significantly associated with higher stillbirth rates, OR = 6.68 (95% CI 3.84–11.62), 4.47 (95% CI 3.04–6.59), 4.35 (95% CI 2.46–7.69), and 3.82 (95% CI 2.24–6.51), respectively. Half (50%) of the women with stillbirths had no antenatal care OR = 4. 46(95% CI 0.84–23.43). Conclusion. We observed an unacceptably high stillbirth rate in this study. As most of the stillbirths were fresh, improved intrapartum care supported by emergency transport services and skilled personnel could positively impact on perinatal outcomes in rural hospitals in The Gambia.
Gene Transfer into the Lung by Nanoparticle Dextran-Spermine/Plasmid DNA Complexes
Authors: Abdullah Syahril , Wendy-Yeo Wai Yeng , Hosseinkhani Hossein , Hosseinkhani Mohsen , Masrawa Ehab , Ramasamy Rajesh , Rosli Rozita , Rahman Sabariah A. , Domb Abraham J.
Published: June 2010

A novel cationic polymer, dextran-spermine (D-SPM), has been found to mediate gene expression in a wide variety of cell lines andin vivothrough systemic delivery. Here, we extended the observations by determining the optimal conditions for gene expression of D-SPM/plasmid DNA (D-SPM/pDNA) in cell lines and in the lungs of BALB/c mice via instillation delivery.In vitrostudies showed that D-SPM could partially protect pDNA from degradation by nuclease and exhibited optimal gene transfer efficiency at D-SPM to pDNA weight-mixing ratio of 12. In the lungs of mice, the levels of gene expression generated by D-SPM/pDNA are highly dependent on the weight-mixing ratio of D-SPM to pDNA, amount of pDNA in the complex, and the assay time postdelivery. Readministration of the complex at day 1 following the first dosing showed no significant effect on the retention and duration of gene expression. The study also showed that there was a clear trend of increasing size of the complexes as the amount of pDNA was increased, where the sizes of the D-SPM/pDNA complexes were within the nanometer range.
Targeted Immunotherapy with Rituximab Leads to a Transient Alteration of the IgG Autoantibody Profile in Pemphigus Vulgaris
Authors: Müller Ralf , Hunzelmann Nicolas , Baur Vera , Siebenhaar Guido , Wenzel Elke , Eming Rüdiger , Niedermeier Andrea , Musette Philippe , Joly Pascal , Hertl Michael
Published: June 2010

In pemphigus vulgaris (PV), IgG autoantibodies against the ectodomain of desmoglein 3 (Dsg3) have been shown to be directly responsible for the loss of keratinocyteadhesion. The aim of the present study was to study the effect of the B cell depleting anti‐CD20 monoclonal antibody, rituximab, on the profile of pathogenic IgG against distinct regions of the Dsg3 ectodomain in 22 PV patients who were followed up clinically and serologically by Dsg3 ELISA over 12‐24 months. Prior to rituximab, all the 22 PV patients showed IgG against Dsg3 (Dsc3EC1‐5). Specifically, 14/22 showed IgG reactivity against the Dsg3EC1 subdomain, 5/22 patients against Dsg3EC2, 7/22 against Dsg3EC3, 11/22 against Dsg3EC4, and 2/22 against Dsg3EC5. Within 6 months after rituximab, all the patients showed significant clinical improvement and reduced IgG against Dsg3 (5/22) and the various subdomains, that is, Dsg3EC1 (7/22), Dsg3EC2 (3/22), Dsg3EC3 (2/22), sg3EC4 (2/22), and Dsg3EC5 (0/22). During the entire observation period, 6/22 PV patients experienced a clinical relapse which was associated with the reappearance of IgG against previously recognized Dsg3 subdomains, particularly against the Dsg3EC1. Thus, in PV, rituximab only temporarily depletes pathogenic B cell responses against distinct subdomains of Dsg3 which reappear upon clinical relapse.
Emergence of Prediction by Reinforcement Learning Using a Recurrent Neural Network
Authors: Goto Kenta , Shibata Katsunari
Published: June 2010

To develop a robot that behaves flexibly in the real world, it is essential that it learns various necessary functions autonomously without receiving significant information from a human in advance. Among such functions, this paper focuses on learning “prediction” that is attracting attention recently from the viewpoint of autonomous learning. The authors point out that it is important to acquire through learning not only the way of predicting future information, but also the purposive extraction of prediction target from sensor signals. It is suggested that through reinforcement learning using a recurrent neural network, both emerge purposively and simultaneously without testing individually whether or not each piece of information is predictable. In a task where an agent gets a reward when it catches a moving object that can possibly become invisible, it was observed that the agent learned to detect the necessary factors of the object velocity before it disappeared, to relay the information among some hidden neurons, and finally to catch the object at an appropriate position and timing, considering the effects of bounces off a wall after the object became invisible.
Reactions of N,N′-bis(2-hydroxyethyl)oxalamide with Ethylene Carbonate and Use of the Obtained Products as Components of Polyurethanes Foams
Authors: Zarzyka-Niemiec Iwona
Published: June 2010

-bis(2-hydroxyethyl)oxalamide (BHEOA) was subject to hydroxyalkylation with ethylene carbonate (EC). By means of instrumental methods (IR, -NMR, MALDI ToF, GC, and GC-MS), an influence of the reaction conditions on structure and compositions of the obtained products was investigated. The hydroxyalkyl and hydroxyalkoxy derivatives of oxalamide (OA) were obtained by reaction of BHEOA with 2–10-molar excess of ethylene carbonate (EC, 1,3-dioxolane-2-one). The products have a good thermal stability and possess suitable physical properties as substrates for foamed polyurethanes. The obtained products were used in manufacturing the rigid polyurethane foams which possess enhanced thermal stability and good mechanical properties.
Effect of Trends on Detrended Fluctuation Analysis of Precipitation Series
Authors: Yue Jianhai , Zhao Xiaojun , Shang Pengjian
Published: June 2010

We use detrended fluctuation analysis (DFA) method to detect the long‐range correlation and scaling properties of daily precipitation series of Beijing from 1973 to 2004 before and after adding diverse trends to the original series. The correlation and scaling properties of the original series are difficult to analyze due to existing crossovers. The effects of the coefficient and the power of the added trends on the scaling exponents and crossovers of the series are tested. A crossover is found to be independent of the added trends, which arises from the intrinsic periodic trend of the precipitation series. However, another crossover caused by the multifractal vanishes with the increasing power of added trends.
Inference about the Tail ofa Distribution: Improvementon the Hill Estimator
Authors: Nuyts Jean
Published: June 2010

The Hill estimator is often used to infer the power behavior in tails of
experimental distribution functions. This estimator is known to produce bad results in certain situations which have lead to the so‐called Hill horror plots. In this brief note, we propose an improved estimator which is simple and coherent and often provides an efficient remedy in the bad situations, especially when the distribution is decreasing slowly, when the data is restricted by external cuts to lie within a finite domain, or even when the distribution is increasing.
Loss of Function of the Tumor Suppressor DKC1 Perturbs p27 Translation Control and Contributes to Pituitary Tumorigenesis
Authors: Bellodi Cristian , Krasnykh Olya , Haynes Nikesha , Theodoropoulou Marily , Peng Guang , Montanaro Lorenzo , Ruggero Davide
Published: June 2010

Mutations in DKC1, encoding for dyskerin, a pseudouridine synthase that modifies rRNA and regulates telomerase activity, are associated with ribosomal dysfunction and increased cancer susceptibility in the human syndrome, X-linked dyskeratosis congenita (X-DC). In a mouse model for X-DC, impairments in DKC1 function affected the translation of specific mRNAs harboring internal ribosomal entry site (IRES) elements, including the tumor suppressor, p27. However, how this translational deregulation contributes to tumor initiation and progression remains poorly understood. Here, we report that impairment in p27 IRES-mediated translation due to decreased levels of DKC1 activity markedly increases spontaneous pituitary tumorigenesis in p27 heterozygous mice. Using a new bioluminescent mouse model, we monitored p27 translation in vivo and show that p27 IRES-mediated translation is reduced in the pituitary of DKC1 hypomorphic mice (DKC1m). Furthermore, we show that DKC1 has a critical role in regulating the assembly of the 48S translational preinitiation complex mediated by the p27 IRES element. An analysis of human tumors identified a novel mutation of DKC1 (DKC1S485G) in a human pituitary adenoma. We show that this specific amino acid substitution significantly alters DKC1 stability/pseudouridylation activity, and this correlates with reductions in p27 protein levels. Furthermore, DKC1S485G mutation does not alter telomerase RNA levels. Altogether, these findings show that genetic alterations in DKC1 could contribute to tumorigenesis associated with somatic cancers and establish a critical role for DKC1 in tumor suppression, at least in part, through translational control of p27. Cancer Res; 70(14); 6026–35. ©2010 AACR.
Targeting Epidermal Growth Factor Receptor–Associated Signaling Pathways in Non–Small Cell Lung Cancer Cells: Implication in Radiation Response
Authors: Choi Eun Jung , Ryu Yun Kyeong , Kim So Yeon , Wu Hong Gyun , Kim Jae Sung , Kim Il Han , Kim In Ah
Published: June 2010

Several studies have shown solid evidence for the potential value of targeting epidermal growth factor receptor (EGFR) signaling to enhance the antitumor activity of radiation. However, therapeutic resistance has emerged as an important clinical issue. Here, we investigated whether strategies for targeting EGFR-associated downstream signaling would radiosensitize a panel of non–small cell lung cancer cell lines. Inhibition of K-RAS using RNA interference attenuated downstream signaling and increased radiosensitivity of A549 and H460 cells, whereas inhibition of EGFR did not. A549 cells harboring a K-RAS mutation at codon V12 were radiosensitized by small interfering RNA (siRNA) targeting this codon. H460 cells having mutation at codon V61 was radiosensitized by siRNA targeting of this mutation. K-RAS siRNA did not radiosensitize H1299 cells possessing wild-type K-RAS. Inhibition of the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin pathway led to significant radiosensitization of the two cell lines, whereas selective inhibition of extracellular signal-regulated kinase signaling did not. Inhibitors targeting the PI3K-AKT-mTOR pathway also abrogated G2 arrest following irradiation and induced γH2AX foci formation. A dual inhibitor of class I PI3K and mammalian target of rapamycin effectively increased the radiosensitivity of A549 and H460 cells. Inhibition of PI3K-AKT signaling was associated with the downregulation of DNA-PKs. Although apoptosis was the primary mode of cell death when cells were pretreated with LY294002 or AKT inhibitor VIII, cells pretreated with rapamycin or PI-103 showed mixed modes of cell death, including apoptosis and autophagy. Our results suggest possible mechanisms for counteracting EGFR prosurvival signaling implicated in radioresistance and offer an alternative strategy for overcoming resistance to EGFR inhibitors used in combination with irradiation. Mol Cancer Res; 8(7); 1027–36. ©2010 AACR.
Functional Characterization of a Cancer Causing Mutation in Human Replication Protein A
Authors: Hass Cathy S. , Gakhar Lokesh , Wold Marc S.
Published: June 2010

Replication protein A (RPA) is the primary ssDNA-binding protein in eukaryotes. RPA is essential for DNA replication, repair, and recombination. Mutation of a conserved leucine residue to proline in the high-affinity DNA binding site of RPA (residue L221 in human RPA) has been shown to have defects in DNA repair and a high rate of chromosomal rearrangements in yeast. The homologous mutation in mice was found to be lethal when homozygous and to cause high rates of cancer when heterozygous. To understand the molecular defect causing these phenotypes, we created the homologous mutation in the human RPA1 gene (L221P) and analyzed its properties in cells and in vitro. RPA1(L221P) does not support cell cycle progression when it is the only form of RPA1 in HeLa cells. This phenotype is caused by defects in DNA replication and repair. No phenotype is observed when cells contain both wild-type and L221P forms of RPA1, indicating that L221P is not dominant. Recombinant L221P polypeptide forms a stable complex with the other subunits of RPA, indicating that the mutation does not destabilize the protein; however, the resulting complex has dramatically reduced ssDNA binding activity and cannot support SV40 DNA replication in vitro. These findings indicate that in mammals, the L221P mutation causes a defect in ssDNA binding and a nonfunctional protein complex. This suggests that haploinsufficiency of RPA causes an increase in the levels of DNA damage and in the incidence of cancer. Mol Cancer Res; 8(7); 1017–26. ©2010 AACR.
Symptomatic Intracranial Atherosclerotic Stenoses: Prevalence and Prognosis in Patients with Acute Cerebral Ischemia
Authors: Weber R. , Kraywinkel K. , Diener H.-C. , Weimar C.
Published: June 2010

Background: In Caucasian patients with acute stroke or transient ischemic attack (TIA) due to symptomatic intracranial atherosclerotic stenoses (ICAS), only limited data on the recurrent stroke rate and its associated risk factors have been reported. In view of the increasing options for endovascular interventions, we sought to investigate the prevalence, risk for recurrent stroke and mortality in these patients. Methods: A total of 304 consecutive patients with acute ischemic stroke or TIA due to 50–99% ICAS were prospectively documented in 19 German stroke centers. In 201 patients (68.1% of the survivors), a central biannual telephone follow-up could assess recurrent stroke and mortality up to a median of 2 years after the index event. Results: An ischemic cerebrovascular event attributable to symptomatic ICAS was found in 2.24% of the consecutively admitted patients. The overall cumulative recurrent stroke rate after admission was 17.9% (95% CI = 13.4–23.5) for the first year and 23.3% (95% CI = 17.8–29.8) over 3 years. After correction for age and sex, only previous stroke (HR = 2.11, 95% CI = 1.14–3.91) and diabetes (HR = 2.41, 95% CI = 1.33–4.37) were significantly associated with recurrent stroke. Conclusion: Although the prevalence of this etiology seems very low in patients admitted to German stroke centers, we found a high risk of recurrent stroke in patients with symptomatic ICAS. Whether endovascular interventions can reduce this high risk needs to be determined in a randomized trial.
Norepinephrine and Serotonin Transporter Genes: Impact on Treatment Response in Depression
Authors: Baffa Anna , Hohoff Christa , Baune Bernhard T. , Müller-Tidow Carsten , Tidow Nicola , Freitag Christine , Zwanzger Peter , Deckert Jürgen , Arolt Volker , Domschke Katharina
Published: June 2010

Background/Aims: The norepinephrine transporter (NET) and serotonin transporter (5-HTT) genes constitute promising candidate genes in major depression. Seven polymorphisms in the promoter, intronic and exonic region of the NET gene, as well as serotonin-transporter-linked promoter region (5-HTTLPR) and 5-HTT rs25531 polymorphisms were analyzed with respect to antidepressant treatment response with particular attention to gender effects and subtypes of melancholic or anxious depression. Methods: 252 unrelated Caucasian patients (f = 142; m = 110) with major depression were genotyped for NET and 5-HTT polymorphisms. Genotype effects on Hamilton Depression Rating Scale score changes over 6 weeks of antidepressant treatment were analyzed using analysis of covariance with repeated measures. Results: There was no effect of any of the 7 investigated NET, or the two 5-HTT polymorphisms, on the overall treatment response. An additional –/CT insertion/deletion (ins/del) polymorphism (rs58532686), however, was significantly associated with melancholic depression, with a better response in 12 patients carrying the deletion. Stratification for anxious versus nonanxious depression revealed a significantly detrimental effect of the less active 5-HTTLPR S allele (p = 0.007) and 5-HTTLPR/5-HTT rs25531 haplotypes on treatment response in patients with anxious depression. Conclusion: The present findings do not support a major impact of the NET and 5-HTT genes on antidepressant treatment response in major depression per se. However, there might be an impact of a –/CT ins/del polymorphism in the enhancer domain of the NET gene on treatment response in melancholic depression, which remains to be functionally investigated in future studies. The observed significant influence of the 5-HTT gene variation on antidepressant treatment in anxious depression points to anxious depression as a potential diagnostic entity of its own, requiring specific diagnostic and therapeutic attention.
In vitro effects of human neutrophil cathepsin G on thrombin generation: Both acceleration and decreased potential
Authors: Lecompte Thomas , Tournier Agnès , Morlon Lise , Marchand-Arvier Monique , Vigneron Claude , Perrin Julien
Published: June 2010

Cathepsin G (Cath G), a serine-protease found in neutrophils, has been reported to have effects that could either facilitate or impede coagulation. Thrombin generation (CAT method) was chosen to study its overall effect on the process, at a plasma concentration (240 nM) observed after neutrophil activation. Coagulation was triggered by tissue factor in the presence of platelets or phospholipid vesicles. To help identify potential targets of Cath G, plasma depleted of clotting factors or of inhibitors was used. Cath G induced a puzzling combination of two diverging effects of varying intensities depending on the phospholipid surface provided: accelerating the process under the three conditions (shortened clotting time by up to 30%), and impeding the process during the same thrombin generation time-course since thrombin peak and ETP (total thrombin potential) were decreased, up to 45% and 12%, respectively, suggestive of deficient prothrombinase. This is consistent with Cath G working on at least two targets in the coagulation cascade. Our data indicate that coagulation acceleration can be attributed neither to platelet activation and nor to activation of a clotting factor. When TFPI (tissue factor pathway inhibitor) was absent, no effect on lag time was observed and the anticoagulant activity of TFPI was decreased in the presence of Cath G. Consistent with the literature and the hypothesis of deficient prothrombinase, experiments using Russel’s Viper Venom indicate that the anticoagulant effect can be attributed to a deleterious effect on factor V. The clinical relevance of these findings deserves to be studied.
Oral direct factor Xa inhibition with edoxaban for thromboprophylaxis after elective total hip replacement
Authors: Cohen Alexander , Eriksson Bengt , Puskas David , Shi Minggao , Bocanegra Tomas , Weitz Jeffrey , Raskob Gary
Published: June 2010

Edoxaban is a new oral direct factor Xa inhibitor. The purpose of this study was to evaluate the efficacy and safety of different doses of edoxaban for the prevention of venous thromboembolism (VTE) in patients undergoing elective total hip replacement. A total of 903 patients were randomised to oral edoxaban 15, 30, 60 or 90 mg once daily or subcutaneous dalteparin once daily (initial dose 2,500 IU, subsequent doses 5,000 IU). Both drugs were begun 6–8 hours postoperatively and continued for 7–10 days, when bilateral venography was performed. The primary efficacy endpoint was the incidence of total VTE, which included proximal and/or distal deep-vein thrombosis (DVT) by venography or symptomatic, objectively confirmed DVT or pulmonary embolism during the treatment period. The primary safety outcome was the incidence of the composite of major and clinically relevant non-major bleeding. All venograms and bleeding events were reviewed by a central independent adjudication committee blinded as to treatment allocation. Of the 903 patients randomised, 776 were evaluable for the primary efficacy analysis. The incidences of VTE were 28.2%, 21.2%, 15.2%, and 10.6% in patients receiving edoxaban 15, 30, 60 and 90 mg, respectively, compared with 43.8% in the dalteparin group (p<0.005 ). There was a statistically significant (p<0.001) dose-response for efficacy across the edoxaban dose groups for total VTE and for major VTE. The incidence of clinically relevant bleeding was low and similar across the groups. Oral edoxaban once daily is effective for preventing VTE after total hip replacement.
The Prefrontal Cortex Modulates Category Selectivity in Human Extrastriate Cortex
Authors: Miller Brian T. , Vytlacil Jason , Fegen David , Pradhan Suraj , D'Esposito Mark
Published: June 2010

Different categories of visual objects evoke distinct stimulus-evoked sensory responses in extrastriate visual cortex. Although numerous lines of evidence support a distinct representational neural architecture, the mechanisms underlying the modulation of the category selectivity by top–down influences remains uncertain. In this study, we investigate the causal role of the PFC in the modulation of evoked activity to face and scene stimuli in the extrastriate cortex. We used two experimental approaches to disrupt prefrontal cortical function—repetitive TMS to PFC in healthy participants (Experiment 1) and focal PFC lesions in stroke patients (Experiment 2). After these perturbations to normal PFC function (pre- vs. post-TMS and lesion vs. intact hemisphere), stimulus-evoked activity in extrastriate cortex exhibited less distinct category selectivity to faces and scenes. These two experiments provide convergent evidence highlighting a direct role of PFC in the top–down modulation of bottom–up visual signals.
Regional Patterns of Sea Level Change Related to Interannual Variability and Multidecadal Trends in the Atlantic Meridional Overturning Circulation*
Authors: Lorbacher K. , Dengg J. , Böning C. W. , Biastoch A.
Published: June 2010

Some studies of ocean climate model experiments suggest that regional changes in dynamic sea level could provide a valuable indicator of trends in the strength of the Atlantic meridional overturning circulation (MOC). This paper describes the use of a sequence of global ocean–ice model experiments to show that the diagnosed patterns of sea surface height (SSH) anomalies associated with changes in the MOC in the North Atlantic (NA) depend critically on the time scales of interest. Model hindcast simulations for 1958–2004 reproduce the observed pattern of SSH variability with extrema occurring along the Gulf Stream (GS) and in the subpolar gyre (SPG), but they also show that the pattern is primarily related to the wind-driven variability of MOC and gyre circulation on interannual time scales; it is reflected also in the leading EOF of SSH variability over the NA Ocean, as described in previous studies. The pattern, however, is not useful as a “fingerprint” of longer-term changes in the MOC: as shown with a companion experiment, a multidecadal, gradual decline in the MOC [of 5 Sv (1 Sv ≡ 106 m3 s−1) over 5 decades] induces a much broader, basin-scale SSH rise over the mid-to-high-latitude NA, with amplitudes of 20 cm. The detectability of such a trend is low along the GS since low-frequency SSH changes are effectively masked here by strong variability on shorter time scales. More favorable signal-to-noise ratios are found in the SPG and the eastern NA, where a MOC trend of 0.1 Sv yr−1 would leave a significant imprint in SSH already after about 20 years.
Dust Aerosol Important for Snowball Earth Deglaciation
Authors: Abbot Dorian S. , Halevy Itay
Published: June 2010

Most previous global climate model simulations could only produce the termination of Snowball Earth episodes at CO2 partial pressures of several tenths of a bar, which is roughly an order of magnitude higher than recent estimates of CO2 levels during and shortly after Snowball events. These simulations have neglected the impact of dust aerosols on radiative transfer, which is an assumption of potentially grave importance. In this paper it is argued, using the Dust Entrainment and Deposition (DEAD) box model driven by GCM results, that atmospheric dust aerosol concentrations may have been one to two orders of magnitude higher during a Snowball Earth event than today. It is furthermore asserted on the basis of calculations using NCAR’s Single Column Atmospheric Model (SCAM)—a radiative–convective model with sophisticated aerosol, cloud, and radiative parameterizations—that when the surface albedo is high, such increases in dust aerosol loading can produce several times more surface warming than an increase in the partial pressure of CO2 from 10−4 to 10−1 bar. Therefore the conclusion is reached that including dust aerosols in simulations may reconcile the CO2 levels required for Snowball termination in climate models with observations.