bluuebunny/crossref_metadata_2025 huggingface dataset:
Simulation, analysis and validation of residual stresses on LY2 aluminium alloy by laser shock processing with elliptical spot
Authors: Lu J. Z. , Luo K. Y. , Yu S. S. , Feng A. X. , Yang C. J.
Published: March 2010

The effects of laser shock processing on the residual stresses of the LY2 aluminium alloy samples with elliptical spot (long axis length, 12 mm; short axis length, 3 mm) were experimentally investigated, and the effects of the overlapping rate on the residual stresses were simulated using the Abaqus software. The simulated residual stresses were basically in agreement with the measured data, and the relationship between the magnitude and uniformity of residual stress and the overlapping rate was also addressed. Results show that the largest stress magnitudes are located on the top surface of the sample, and the greatest uniformity is achieved by the overlapping of elliptical laser spots. The overlapping rate is critical for the uniformity of the residual stress across the surface. Within a certain impact number range of one to four times, increasing the shocked number can increase the magnitude of residual stress near the surface but not effectively increase the plastically affected depth.
Effect of austenitising temperature on microstructure and mechanical properties of 30Si2CrNi4MoNb ultrahigh strength steel
Authors: Xia Z. X. , Zhang C. , Yang Z. Y.
Published: March 2010

The microstructure and mechanical properties of 30Si2CrNi4MoNb ultrahigh strength steel were investigated after austenitising over a range of temperature between 1133 and 1483 K. The experimental results show that the isotropy of impact toughness and mechanical properties were greatly improved due to the disappearance of undissolved aligned second phase when the austenitising temperature was over 1233 K. When the austenitising temperature was over 1383 K, martensite lath and packet abnormally grew up due to dissolution of spheroidal Nb rich carbonitrides; both the platelet size and morphology of martensite were changed, which has an effect on the mechanical properties of the samples. It was noticed that the finer self-tempered carbides, which strengthened martensitic matrix, appeared after austenitising temperature over 1283 K. The strength profiles show a marked plateau for the samples austenitised from 1283 to 1433 K; however, the strength was deteriorated due to coarsening of these self-tempered carbides at 1483 K. It was confirmed that calcium treatment can help improve the isotropy of mechanical properties by modifying sulphide inclusion morphology.
Comparison of textures determined by X-ray and electron backscatter diffraction in aluminium alloy AA 6111 sheets with different levels of cube texture
Authors: Jin H.
Published: March 2010

The crystallographic textures in five AA 6111 aluminium alloy sheets, having an increasing cube ({001}<100>) texture component, were determined by X-ray diffraction and electron backscatter diffraction (EBSD) techniques. It has been demonstrated that the two techniques yield very similar results in regard to pole figures, but they may give different volume fractions of texture components. The difference is limited when the specimen is weakly textured, but it increases with increasing dominant texture component. The EBSD technique gives a sharper dominant texture component than the X-ray technique. This could be attributed to the fact that the two methods apply different mathematics in data analyses. The different levels of systematic error and instrumental broadening may also be critical.
Shear test parameters for brittle fracture of flip chip solder joint
Authors: Ha S.-S. , Kim J.-W. , Ha S.-O. , Jung S.-B.
Published: March 2010

Compared to conventional Sn-Pb solder, ternary Pb free solder alloys are particular susceptible to brittle fracture through the formation of intermetallic compound layers. However, the conventional shear test of the solder ball joint has been reported to be inappropriate for confirming the susceptibility to brittle fracture of ball grid array solder joints. In this study, we investigated the effects of two shear test parameters, the shear height and shear speed to determine the optimum shear conditions for the brittle fracture of flip chip solder joints. The solder composition and process used in this study were Sn-3·0Ag-0·5Cu and low cost bumping with electroless nickel immersion gold followed by solder paste screen printing. Increasing shear height, at a fixed shear speed, decreased the shear force, whereas increasing the shear speed, at a fixed shear height, increased the shear force. The experimental and computational simulation results indicated that a low shear height and high shear speed improve the bonding force and are generally more appropriate for the brittle fracture of flip chip solder joints. The failure mechanisms were discussed in terms of the von Mises stresses and equivalent plastic strain distributions.
“Microenvironmental contaminations” induced by fluorescent lipophilic dyes used for noninvasive in vitro and in vivo cell tracking
Authors: Lassailly Francois , Griessinger Emmanuel , Bonnet Dominique
Published: March 2010

Determining how normal and leukemic stem cells behave in vivo, in a dynamic and noninvasive way, remains a major challenge. Most optical tracking technologies rely on the use of fluorescent or bioluminescent reporter genes, which need to be stably expressed in the cells of interest. Because gene transfer in primary leukemia samples represents a major risk to impair their capability to engraft in a xenogenic context, we evaluated the possibility to use gene transfer–free labeling technologies. The lipophilic dye 3,3,3′,3′ tetramethylindotricarbocyanine iodide (DiR) was selected among 4 near-infrared (NIR) staining technologies. Unfortunately we report here a massive transfer of the dye occurring toward the neighbor cells both in vivo and in vitro. We further demonstrate that all lipophilic dyes tested in this study (1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine perchlorate [DiI], DiD, DiR, and PKH26) can give rise to microenvironmental contamination, including when used in suboptimal concentration, after extensive washing procedures and in the absence of phagocytosis or marked cell death. This was observed from all cell types tested. Eventually, we show that this microenvironmental contamination is mediated by both direct cell-cell contacts and diffusible microparticles. We conclude that tracking of labeled cells using non–genetically encoded markers should always be accompanied by drastic cross validation using multimodality approaches.
C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S–independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies
Authors: Buil Alfonso , Trégouët David-Alexandre , Souto Juan Carlos , Saut Noémie , Germain Marine , Rotival Maxime , Tiret Laurence , Cambien Françcois , Lathrop Mark , Zeller Tanja , Alessi Marie-Christine , Rodriguez de Cordoba Santiago , Münzel Thomas , Wild Philipp , Fontcuberta Jordi , Gagnon France , Emmerich Joseph , Almasy Laura , Blankenberg Stefan , Soria José-Manuel , Morange Pierre-Emmanuel
Published: March 2010

Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, α7β1, α6β1, and α7β0, we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with α7β0 levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased α7β0 plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.
Mitochondrial haplogroup U is associated with a reduced risk to develop exfoliation glaucoma in the German population
Authors: Wolf Christiane , Gramer Eugen , Müller-Myhsok Bertram , Pasutto Francesca , Wissinger Bernd , Weisschuh Nicole
Published: March 2010

Background

Various lines of evidence demonstrate the involvement of mitochondrial dysfunction in the pathogenesis of glaucoma. Therefore, mitochondrial DNA is a promising candidate for genetic susceptibility studies on glaucoma. To test the hypothesis that mitochondrial haplogroups influence the risk to develop glaucoma, we genotyped 12 single-nucleotide polymorphisms that define the European mitochondrial DNA haplogroups in healthy controls and two German patient cohorts with either exfoliation glaucoma or the normal tension subgroup of primary open angle glaucoma.

Results

Mitochondrial haplogroup U was significantly under-represented in patients with exfoliation glaucoma (8.3% compared with 18.9% in controls; p = 0.004).

Conclusions

People with haplogroup U have a lower risk to develop exfoliation glaucoma. Our results substantiate the suggestion that mitochondrial alterations have an impact on the etiology of glaucoma.
Recombinational landscape of porcine X chromosome and individual variation in female meiotic recombination associated with haplotypes of Chinese pigs
Authors: Ma Junwu , Iannuccelli Nathalie , Duan Yanyu , Huang Weibing , Guo Beili , Riquet Juliette , Huang Lusheng , Milan Denis
Published: March 2010

Background

Variations in recombination fraction (θ) among chromosomal regions, individuals and families have been observed and have an important impact on quantitative trait loci (QTL) mapping studies. Such variations on porcine chromosome X (SSC-X) and on other mammalian chromosome X are rarely explored. The emerging assembly of pig sequence provides exact physical location of many markers, facilitating the study of a fine-scale recombination landscape of the pig genome by comparing a clone-based physical map to a genetic map. Using large offspring of F1 females from two large-scale resource populations (Large White ♂ × Chinese Meishan ♀, and White Duroc ♂ × Chinese Erhualian ♀), we were able to evaluate the heterogeneity in θ for a specific interval among individual F1 females.

Results

Alignments between the cytogenetic map, radiation hybrid (RH) map, genetic maps and clone map of SSC-X with the physical map of human chromosome X (HSA-X) are presented. The most likely order of 60 markers on SSC-X is inferred. The average recombination rate across SSC-X is of ~1.27 cM/Mb. However, almost no recombination occurred in a large region of ~31 Mb extending from the centromere to Xq21, whereas in the surrounding regions and in the Xq telomeric region a recombination rate of 2.8-3.3 cM/Mb was observed, more than twice the chromosome-wide average rate. Significant differences in θ among F1 females within each population were observed for several chromosomal intervals. The largest variation was observed in both populations in the interval UMNP71-SW1943, or more precisely in the subinterval UMNP891-UMNP93. The individual variation in θ over this subinterval was found associated with F1 females' maternal haplotypes (Chinese pig haplotypes) and independent of paternal haplotype (European pig haplotypes). The θ between UMNP891 and UMNP93 for haplotype 1122 and 4311 differed by more than fourteen-fold (10.3% vs. 0.7%).

Conclusions

This study reveals marked regional, individual and haplotype-specific differences in recombination rate on SSC-X. Lack of recombination in such a large region makes it impossible to narrow QTL interval using traditional fine-mapping approaches. The relationship between recombination variation and haplotype polymorphism is shown for the first time in pigs.
Documentation of preventive screening interventions by general practitioners: a retrospective chart audit
Authors: Ngwakongnwi Emmanuel , Hemmelgarn Brenda , Quan Hude
Published: March 2010

Background

Screening and early diagnosis has been shown to reduce the morbidity and mortality associated with certain conditions such as cervical cancer. The role of general practitioners in promoting primary prevention of diseases is particularly important given that they have frequent contact with a large proportion of the population. This study assessed the extent to which general practitioners documented recommended preventive screening interventions among eligible patients.

Methods

We used a retrospective chart audit to assess patient visits to primary care clinics in Calgary, Canada from 2002-2004. We included fee for service physicians who practiced ≥ 2 days per week at their current location and excluded those whose primary practice was at walk-in clinics, community health centers, hospitals or emergency rooms. We included charts of patients who during the study period were age 35 years or older and had at least 2 visits to a clinic. We randomly selected and reviewed charts (N = 600) from 12 primary care clinics and abstracted information on 6 conditions recommended for preventive screening. Opportunities for preventive screening were determined based on recommendations of the Canadian Task Force on Preventive Health Care, the American College of Physicians, and the Canadian Cancer Society. Our main outcome measures included cancer screening (mammography and pap smears), immunization (influenza and pneumococcal), and risk factor assessment (cholesterol measurement and smoking cessation consultation).

Results

Patient visits to GP clinics present opportunities for preventive screening. However, we found that documentation of interventions was low, ranging from 40.3% (cholesterol measurement) to 0.9% (pneumococcal vaccination) within 1 year, and from 67.4% to 1.8% within the prior 3 years.

Conclusions

Documentation of preventive screening interventions by general practitioners was relatively low compared to the number of patients eligible for preventive screening. Some physicians opt to screen for PSA and DRE which is not recommended by the Canadian Task Force on Preventive HealthCare.
Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases
Authors: Grimm Martin , Gasser Martin , Bueter Marco , Strehl Johanna , Wang Johann , Nichiporuk Ekaterina , Meyer Detlef , Germer Christoph T , Waaga-Gasser Ana M , Thalheimer Andreas
Published: March 2010

Background

The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth.

Methods

CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate.

Results

Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-β and TNF-α were increased during tumor growth whereas IFN-γ showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location.

Conclusions

This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer.
The diagnostic value of ultrasonography-derived edema of the temporal artery wall in giant cell arteritis: a second meta-analysis
Authors: Arida Aikaterini , Kyprianou Miltiades , Kanakis Meletios , Sfikakis Petros P
Published: March 2010

Background

Ultrasonography of temporal arteries is not commonly used in the approach of patients with suspected giant cell arteritis (GCA) in clinical practice. A meta-analysis of primary studies available through April 2004 concluded that ultrasonography could indeed be helpful in diagnosing GCA. We specifically re-examined the diagnostic value of the ultrasonography-derived halo sign, a dark hypoechoic circumferential thickening around the artery lumen, indicating vasculitic wall edema, in GCA.

Methods

Original, prospective studies in patients with suspected GCA that examined ultrasonography findings of temporal arteries using the ACR 1990 classification criteria for GCA as reference standard, published through 2009, were identified. Only eight studies involving 575 patients, 204 of whom received the final diagnosis of GCA, fulfilled technical quality criteria for ultrasound. Weighted sensitivity and specificity estimates of the halo sign were assessed, their possible heterogeneity was investigated and pooled diagnostic odds ratio was determined.

Results

Unilateral halo sign achieved an overall sensitivity of 68% (95% CI, 0.61-0.74) and specificity of 91% (95% CI, 0.88-0.94) for GCA. The values of inconsistency coefficient (I2) of both sensitivity and specificity of the halo sign, showed significant heterogeneity concerning the results between studies. Pooled diagnostic odds ratio, expressing how much greater the odds of having GCA are for patients with halo sign than for those without, was 34 (95% CI, 8.21-138.23). Diagnostic odds ratio was further increased to 65 (95% CI, 17.86-236.82) when bilateral halo signs were present (sensitivity/specificity of 43% and 100%, respectively). In both cases, it was found that DOR was constant across studies.

Conclusion

Temporal artery edema demonstrated as halo sign should be always looked for in ultrasonography when GCA is suspected. Providing that currently accepted technical quality criteria are fulfilled, halo sign's sensitivity and specificity are comparable to those of autoantibodies used as diagnostic tests in rheumatology. Validation of revised GCA classification criteria which will include the halo sign may be warranted.
Decreased HIV diversity after allogeneic stem cell transplantation of an HIV-1 infected patient: a case report
Authors: Kamp Christel , Wolf Timo , Bravo Ignacio G , Kraus Benjamin , Krause Birgit , Neumann Britta , Winskowsky Gudrun , Thielen Alexander , Werner Albrecht , Schnierle Barbara S
Published: March 2010

The human immunodeficiency virus type 1 (HIV-1) coreceptor use and viral evolution were analyzed in blood samples from an HIV-1 infected patient undergoing allogeneic stem cell transplantation (SCT). Coreceptor use was predictedin silicofrom sequence data obtained from the third variable loop region of the viral envelope gene with two software tools. Viral diversity and evolution was evaluated on the same samples by Bayesian inference and maximum likelihood methods. In addition, phenotypic analysis was done by comparison of viral growth in peripheral blood mononuclear cells and in a CCR5 (R5)-deficient T-cell line which was controlled by a reporter assay confirming viral tropism.In silicocoreceptor predictions did not match experimental determinations that showed a consistent R5 tropism. Anti-HIV directed antibodies could be detected before and after the SCT. These preexisting antibodies did not prevent viral rebound after the interruption of antiretroviral therapy during the SCT. Eventually, transplantation and readministration of anti-retroviral drugs lead to sustained increase in CD4 counts and decreased viral load to undetectable levels. Unexpectedly, viral diversity decreased after successful SCT. Our data evidence that only R5-tropic virus was found in the patient before and after transplantation. Therefore, blocking CCR5 receptor during stem cell transplantation might have had beneficial effects and this might apply to more patients undergoing allogeneic stem cell transplantation. Furthermore, we revealed a scenario of HIV-1 dynamic different from the commonly described ones. Analysis of viral evolution shows the decrease of viral diversity even during episodes with bursts in viral load.
Hemizygosity for Atm and Brca1 influence the balance between cell transformation and apoptosis
Authors: Su Fengtao , Smilenov Lubomir B , Ludwig Thomas , Zhou Libin , Zhu Jiayun , Zhou Guangming , Hall Eric J
Published: March 2010

Background

In recent years data from both mouse models and human tumors suggest that loss of one allele of genes involved in DNA repair pathways may play a central role in genomic instability and carcinogenesis. Additionally several examples in mouse models confirmed that loss of one allele of two functionally related genes may have an additive effect on tumor development. To understand some of the mechanisms involved, we examined the role of monoallelic loss or Atm and Brca1 on cell transformation and apoptosis induced by radiation.

Methods

Cell transformation and apoptosis were measured in mouse embryo fibroblasts (MEF) and thymocytes respectively. Combinations of wild type and hemizygous genotypes for ATM and BRCA1 were tested in various comparisons.

Results

Haploinsufficiency of either ATM or BRCA1 resulted in an increase in the incidence of radiation-induced transformation of MEF and a corresponding decrease in the proportion of thymocytes dying an apoptotic death, compared with cells from wild-type animals. Combined haploinsufficiency for both genes resulted in an even larger effect on apoptosis.

Conclusions

Under stress, the efficiency and capacity for DNA repair mediated by the ATM/BRCA1 cell signalling network depends on the expression levels of both proteins.
A Novel microRNA and transcription factor mediated regulatory network in schizophrenia
Authors: Guo An-Yuan , Sun Jingchun , Jia Peilin , Zhao Zhongming
Published: March 2010

Background

Schizophrenia is a complex brain disorder with molecular mechanisms that have yet to be elucidated. Previous studies have suggested that changes in gene expression may play an important role in the etiology of schizophrenia, and that microRNAs (miRNAs) and transcription factors (TFs) are primary regulators of this gene expression. So far, several miRNA-TF mediated regulatory modules have been verified. We hypothesized that miRNAs and TFs might play combinatory regulatory roles for schizophrenia genes and, thus, explored miRNA-TF regulatory networks in schizophrenia.

Results

We identified 32 feed-forward loops (FFLs) among our compiled schizophrenia-related miRNAs, TFs and genes. Our evaluation revealed that these observed FFLs were significantly enriched in schizophrenia genes. By converging the FFLs and mutual feedback loops, we constructed a novel miRNA-TF regulatory network for schizophrenia. Our analysis revealed EGR3 and hsa-miR-195 were core regulators in this regulatory network. We next proposed a model highlighting EGR3 and miRNAs involved in signaling pathways and regulatory networks in the nervous system. Finally, we suggested several single nucleotide polymorphisms (SNPs) located on miRNAs, their target sites, and TFBSs, which may have an effect in schizophrenia gene regulation.

Conclusions

This study provides many insights on the regulatory mechanisms of genes involved in schizophrenia. It represents the first investigation of a miRNA-TF regulatory network for a complex disease, as demonstrated in schizophrenia.
Continuous hypocenter and source mechanism inversion via a Green's function-based matching pursuit algorithm
Authors: Rodriguez Ismael Vera , Sacchi Mauricio D. , Gu Yu Jeffrey
Published: March 2010

The hydraulic fracturing of rock formations bearing oil and gas is a process that aims to improve well productivity. The breaking of rocks releases seismic energy that is recorded by stations usually located in nearby wells. By processing these recordings, the hypocenters of induced microseismic events are retrieved and interpreted to estimate the fractured volume. Several techniques have been developed to determine hypocenters; the most common are based in the inversion of P- and S-wave time picks from multiple stations (Pujol, 2004). There are also procedures that involve, for example, the back propagation in time of the recorded wavefields (Gajewski and Tessmer, 2005). Besides the hypocenter location of microseismic events, there is additional information embedded in the seismic recordings: the source mechanism, which is expressed via the seismic moment tensor (SMT). Not as common as the estimation of the hypocenter location, the SMT of induced microseismic events is also estimated from monitoring records (e.g., Nolen-Hoeksema and Ruff, 2001; Jechumtalova and Eisner, 2008). The SMT provides an additional source of information for understanding the fracturing process. A quasi real-time system for simultaneous event location and SMT inversion can reduce the processing and interpretation turnaround times. More notably, such a system could facilitate a realistic integration of microseismic geophysical data to significant decisions that are made during engineering operations such as fracturing.
Experiences and Attitudes of Patients With Terminal Cancer and Their Family Caregivers Toward the Disclosure of Terminal Illness
Authors: Yun Young Ho , Kwon Yong Chol , Lee Myung Kyung , Lee Woo Jin , Jung Kyung Hae , Do Young Rok , Kim Samyong , Heo Dae Seog , Choi Jong Soo , Park Sang Yoon
Published: March 2010

Purpose

We investigated the experiences of cancer patients and their family caregivers who became aware that the cancer was terminal, how they became aware, and how they felt about disclosure of the information.

Patients and Methods

In this cohort study, we administered questionnaires to 619 consecutive patients determined by physicians to be terminally ill and to their family caregivers.

Results

A total of 481 patients and 381 family caregivers completed the questionnaire. A majority of patients (58.0%) and caregivers (83.4%) were aware of the patient's terminal status. Approximately 28% of patients and 23% of caregivers reported that they guessed it from the patient's worsening condition. The patient group was more likely than the caregiver group (78.6% v 69.6%) to prefer that patients be informed of their terminal status. Patients informed of their terminal diagnosis had a significantly better quality of life and fewer symptoms and had a lower rate of emotional distress than patients who guessed it from their worsening condition. Younger patients and patients who paid the treatment costs themselves were significantly more likely to want to be told when their illness was terminal. If the patient paid the treatment cost and was employed at the time of the cancer diagnosis, the family caregivers were more likely to prefer disclosure of terminal illness.

Conclusion

Most patients with terminal cancer and their family caregivers preferred disclosure, and patients who knew of their terminal diagnosis had a lower rate of emotional distress and a higher health-related quality of life.
Benefits of the Intermittent Use of 6-Mercaptopurine and Methotrexate in Maintenance Treatment for Low-Risk Acute Lymphoblastic Leukemia in Children: Randomized Trial From the Brazilian Childhood Cooperative Group—Protocol ALL-99
Authors: Brandalise Silvia R. , Pinheiro Vitória R. , Aguiar Simone S. , Matsuda Eduardo I. , Otubo Rosemary , Yunes José A. , Pereira Waldir V. , Carvalho Eny G. , Cristofani Lilian M. , Souza Marcelo S. , Lee Maria L. , Dobbin Jane A. , Pombo-de-Oliveira Maria S. , Lopes Luiz F. , Melnikoff Katharina N.T. , Brunetto Algemir L. , Tone Luiz G. , Scrideli Carlos A. , Morais Vera L.L. , Viana Marcos B.
Published: March 2010

Purpose

To describe event-free survival (EFS) and toxicities in children with low-risk acute lymphoblastic leukemia (ALL) assigned to receive either continuous 6-mercaptopurine (6-MP) and weekly methotrexate (MTX) or intermittent 6-MP with intermediate-dose MTX, as maintenance treatment.

Patients and Methods

Between October 1, 2000, and December 31, 2007, 635 patients with low-risk ALL were enrolled onto Brazilian Childhood Cooperative Group for ALL Treatment (GBTLI) ALL-99 protocol. Eligible children (n = 544) were randomly allocated to receive either continuous 6-MP/MTX (group 1, n = 272) or intermittent 6-MP (100 mg/m2/d for 10 days, with 11 days resting) and MTX (200 mg/m2 every 3 weeks; group 2, n = 272).

Results

The 5-year overall survival (OS) and EFS were 92.5% ± 1.5% SE and 83.6% ± 2.1% SE, respectively. According to maintenance regimen, the OS was 91.4% ± 2.2% SE (group 1) and 93.6% ± 2.1% SE (group 2; P = .28) and EFS 80.9% ± 3.2% SE (group 1) and 86.5% ± 2.8% SE (group 2; P = .089). Remarkably, the intermittent regimen led to significantly higher EFS among boys (85.7% v 74.9% SE; P = .027), while no difference was seen for girls (87.0% v 88.8% SE; P = .78). Toxic episodes were recorded in 226 and 237 children, respectively. Grade 3 to 4 toxic events for groups 1 and 2 were, respectively, 273 and 166 for hepatic dysfunction (P = .002), and 772 and 636 for hematologic episodes (P = .005). Deaths on maintenance were: seven (group 1) and one (group 2).

Conclusion

The intermittent use of 6-MP and MTX in maintenance is a less toxic regimen, with a trend toward better long-term EFS. Boys treated with the intermittent schedule had significantly better EFS.
Relapse and Late Mortality in 5-Year Survivors of Myeloablative Allogeneic Hematopoietic Cell Transplantation for Chronic Myeloid Leukemia in First Chronic Phase
Authors: Goldman John M. , Majhail Navneet S. , Klein John P. , Wang Zhiwei , Sobocinski Kathleen A. , Arora Mukta , Horowitz Mary M. , Rizzo J. Douglas
Published: March 2010

Purpose

Allogeneic hematopoietic cell transplantation (HCT) is curative therapy for chronic myeloid leukemia (CML), but its long-term outcomes are not well described. We studied the long-term outcomes of CML patients in first chronic phase who receive an allogeneic HCT.

Patients and Methods

Our study included 2,444 patients who received myeloablative HCT for CML in first chronic phase between 1978 and 1998 and survived in continuous complete remission for at least 5 years (median follow-up, 11 years; range, 5 to 25 years). Donor sources were human leukocyte antigen–matched siblings in 1,692 patients, unrelated donors in 639 patients, and other related donors in 113 patients.

Results

Overall survival rates at 15 years were 88% (95% CI, 86% to 90%) for sibling HCT and 87% (95% CI, 83% to 90%) for unrelated donor HCT. Corresponding cumulative incidences of relapse were 8% (95% CI, 7% to 10%) and 2% (95% CI, 1% to 4%), respectively. The latest relapse was reported 18 years post-HCT. In multivariable analyses, history of chronic graft-versus-host disease increased risks of late overall mortality and nonrelapse mortality but reduced risks of relapse. In comparison with age-, race-, and sex-adjusted normal populations, the mortality of HCT recipients was significantly higher until 14 years post-HCT; thereafter, mortality rates were similar to those of the general population (relative mortality ratio at 15 years, 2.3; 95% CI, 0 to 4.9).

Conclusion

Recipients of allogeneic HCT for CML in first chronic phase who remain in remission for at least 5 years have favorable subsequent long-term survival, and their mortality rates eventually approach those of the general population.
Planar cell polarity defects and defective Vangl2 trafficking in mutants for the COPII gene Sec24b
Authors: Wansleeben Carolien , Feitsma Harma , Montcouquiol Mireille , Kroon Carla , Cuppen Edwin , Meijlink Frits
Published: March 2010

Among the cellular properties that are essential for the organization of tissues during animal development, the importance of cell polarity in the plane of epithelial sheets has become increasingly clear in the past decades. Planar cell polarity (PCP) signaling in vertebrates has indispensable roles in many aspects of their development, in particular, controlling alignment of various types of epithelial cells. Disrupted PCP has been linked to developmental defects in animals and to human pathology. Neural tube closure defects (NTD) and disorganization of the mechanosensory cells of the organ of Corti are commonly known consequences of disturbed PCP signaling in mammals. We report here a typical PCP phenotype in a mouse mutant for the Sec24b gene, including the severe NTD craniorachischisis, abnormal arrangement of outflow tract vessels and disturbed development of the cochlea. In addition, we observed genetic interaction between Sec24b and the known PCP gene, scribble. Sec24b is a component of the COPII coat protein complex that is part of the endoplasmic reticulum (ER)-derived transport vesicles. Sec24 isoforms are thought to be directly involved in cargo selection, and we present evidence that Sec24b deficiency specifically affects transport of the PCP core protein Vangl2, based on experiments in embryos and in cultured primary cells.
Consistent left-right asymmetry cannot be established by late organizers inXenopusunless the late organizer is a conjoined twin
Authors: Vandenberg Laura N. , Levin Michael
Published: March 2010

How embryos consistently orient asymmetries of the left-right (LR) axis is an intriguing question, as no macroscopic environmental cues reliably distinguish left from right. Especially unclear are the events coordinating LR patterning with the establishment of the dorsoventral (DV) axes and midline determination in early embryos. In frog embryos, consistent physiological and molecular asymmetries manifest by the second cell cleavage; however, models based on extracellular fluid flow at the node predict correct de novo asymmetry orientation during neurulation. We addressed these issues in Xenopus embryos by manipulating the timing and location of dorsal organizer induction: the primary dorsal organizer was ablated by UV irradiation, and a new organizer was induced at various locations, either early, by mechanical rotation, or late, by injection of lithium chloride (at 32 cells) or of the transcription factor XSiamois (which functions after mid-blastula transition). These embryos were then analyzed for the position of three asymmetric organs. Whereas organizers rescued before cleavage properly oriented the LR axis 90% of the time, organizers induced in any position at any time after the 32-cell stage exhibited randomized laterality. Late organizers were unable to correctly orient the LR axis even when placed back in their endogenous location. Strikingly, conjoined twins produced by late induction of ectopic organizers did have normal asymmetry. These data reveal that although correct LR orientation must occur no later than early cleavage stages in singleton embryos, a novel instructive influence from an early organizer can impose normal asymmetry upon late organizers in the same cell field.
Smed-SmB, a member of the LSm protein superfamily, is essential for chromatoid body organization and planarian stem cell proliferation
Authors: Fernandéz-Taboada Enrique , Moritz Sören , Zeuschner Dagmar , Stehling Martin , Schöler Hans R. , Saló Emili , Gentile Luca
Published: March 2010

Planarians are an ideal model system to study in vivo the dynamics of adult pluripotent stem cells. However, our knowledge of the factors necessary for regulating the ‘stemness’ of the neoblasts, the adult stem cells of planarians, is sparse. Here, we report on the characterization of the first planarian member of the LSm protein superfamily, Smed-SmB, which is expressed in stem cells and neurons in Schmidtea mediterranea. LSm proteins are highly conserved key players of the splicing machinery. Our study shows that Smed-SmB protein, which is localized in the nucleus and the chromatoid body of stem cells, is required to safeguard the proliferative ability of the neoblasts. The chromatoid body, a cytoplasmatic ribonucleoprotein complex, is an essential regulator of the RNA metabolism required for the maintenance of metazoan germ cells. However, planarian neoblasts and neurons also rely on its functions. Remarkably, Smed-SmB dsRNA-mediated knockdown results in a rapid loss of organization of the chromatoid body, an impairment of the ability to post-transcriptionally process the transcripts of Smed-CycB, and a severe proliferative failure of the neoblasts. This chain of events leads to a quick depletion of the neoblast pool, resulting in a lethal phenotype for both regenerating and intact animals. In summary, our results suggest that Smed-SmB is an essential component of the chromatoid body, crucial to ensure a proper RNA metabolism and essential for stem cell proliferation.
β-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1
Authors: Huh Sung-Ho , Ornitz David M.
Published: March 2010

DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt—β-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of β-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt—β-catenin signaling caused an increased incidence and severity of DGS-like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt—β-catenin signaling as a crucial upstream regulator of a Tbx1—Fgf8 signaling pathway and suggest that factors that affect Wnt—β-catenin signaling could modify the incidence and severity of DGS.
no tail integrates two modes of mesoderm induction
Authors: Harvey Steven A. , Tümpel Stefan , Dubrulle Julien , Schier Alexander F. , Smith James C.
Published: March 2010

During early zebrafish development the nodal signalling pathway patterns the embryo into three germ layers, in part by inducing the expression of no tail (ntl), which is essential for correct mesoderm formation. When nodal signalling is inhibited ntl fails to be expressed in the dorsal margin, but ventral ntl expression is unaffected. These observations indicate that ntl transcription is under both nodal-dependent and nodal-independent regulation. Consistent with these observations and with a role for ntl in mesoderm formation, some somites form within the tail region of embryos lacking nodal signalling. In an effort to understand how ntl is regulated and thus how mesoderm forms, we have mapped the elements responsible for nodal-dependent and nodal-independent expression of ntl in the margin of the embryo. Our work demonstrates that expression of ntl in the margin is the consequence of two separate enhancers, which act to mediate different mechanisms of mesoderm formation. One of these enhancers responds to nodal signalling, and the other to Wnt and BMP signalling. We demonstrate that the nodal-independent regulation of ntl is essential for tail formation. Misexpression of Wnt and BMP ligands can induce the formation of an ectopic tail, which contains somites, in embryos devoid of nodal signalling, and this tail formation is dependent on ntl function. Similarly, nodal-independent tail somite formation requires ntl. At later stages in development ntl is required for notochord formation, and our analysis has also led to the identification of the enhancer required for ntl expression in the developing notochord.
Wnt signaling and its downstream target N-myc regulate basal progenitors in the developing neocortex
Authors: Kuwahara Atsushi , Hirabayashi Yusuke , Knoepfler Paul S. , Taketo Makoto M. , Sakai Juro , Kodama Tatsuhiko , Gotoh Yukiko
Published: March 2010

Basal progenitors (also called non-surface dividing or intermediate progenitors) have been proposed to regulate the number of neurons during neocortical development through expanding cells committed to a neuronal fate, although the signals that govern this population have remained largely unknown. Here, we show that N-myc mediates the functions of Wnt signaling in promoting neuronal fate commitment and proliferation of neural precursor cells in vitro. Wnt signaling and N-myc also contribute to the production of basal progenitors in vivo. Expression of a stabilized form of β-catenin, a component of the Wnt signaling pathway, or of N-myc increased the numbers of neocortical basal progenitors, whereas conditional deletion of the N-myc gene reduced these and, as a likely consequence, the number of neocortical neurons. These results reveal that Wnt signaling via N-myc is crucial for the control of neuron number in the developing neocortex.
Multiple ulcers in primary syphilis with negative rapid plasma reagin and Venereal Disease Research Laboratory tests: an unusual presentation during the re-emergence of syphilis in Albania
Authors: Harxhi A , Kraja D , Shehu E , French P
Published: March 2010

Since 1995 infectious syphilis has re-emerged in Albania. As syphilis has become more common, more unusual presentations are being recognized. We present a case of an HIV-negative man with primary syphilis presenting with multiple penile ulcers and negative rapid plasma reagin and Venereal Disease Research Laboratory tests. The case illustrates the challenges of diagnosing early syphilis and the importance of not relying on non-treponemal tests.
A qualitative assessment of perspectives on the inclusion of adolescents in HIV vaccine trials in South Africa
Authors: Jaspan H B , Soka N F , Mathews C , Flisher A J , Mark D , Middelkoop K , Wood R , Bekker L-G
Published: March 2010

Adolescents are at high risk for HIV acquisition, and thus need to be included in HIV vaccine trials. In preparation for inclusion of adolescents in HIV vaccine trials in an urban community in Cape Town with a high antenatal HIV prevalence, the study assessed the attitudes towards the inclusion of adolescents in HIV vaccine trials. A total of 18 focus group discussions were conducted using a semistructured interview guide. The participants ( n = 200) were adolescents, young adults, parents and other key informants. Participants from all groups welcomed the inclusion of adolescents in HIV vaccine trials due to their high-risk status. There were, however, concerns about sexual disinhibition, fear of side-effects, fear of HIV testing and disclosure of HIV status, mistrust of nurses and clinics. The study highlighted a number of ethical and social issues that need to be addressed before the trials.
Mycoplasma genitalium symptoms, concordance and treatment in high-risk sexual dyads
Authors: Thurman A R , Musatovova O , Perdue S , Shain R N , Baseman J G , Baseman J B
Published: March 2010

The objective of this study was to determine the prevalence and concordance of Mycoplasma genitalium (MG) among Mexican American and African American women and their male sexual partners. Secondary objectives were to determine symptoms of MG infection and persistence of MG after antibiotic therapy. Heterosexual couples were tested for MG and interviewed separately regarding symptoms and behavioural/epidemiologic variables at baseline, six and 12 months. The overall prevalence of MG among women and men was 9.5% and 10.6%, respectively. Subjects were five times more likely to be infected with MG if their sexual partner was MG positive. Among men and women, MG prevalence and mean bacterial loads were similar after receiving single-dose azithromycin, doxycycline or no antibiotics. MG was associated with current urethral discharge in men. No clinical symptoms were specifically diagnostic of MG infection in women.
Disseminated mucocutaneous herpes simplex virus infection in an immunocompetent woman
Authors: Watanabe D , Kuhara T , Ishida N , Takeo T , Tamada Y , Matsumoto Y
Published: March 2010

Disseminated mucocutaneous herpes simplex virus (HSV) infection in an immunocompetent person is quite rare. A 19-year-old healthy Japanese woman presented with painful, umbilicated vesicles and pustules on her genital region, both nipples and on the forearm 10 days after the last sexual contact with her partner who had cold sore at that time. Tzanck test and biopsy confirmed the diagnosis of disseminated mucocutaneous HSV infection. She did not have any visceral HSV disease. Skin lesions improved after treatment with acyclovir and erythromycin for seven days. We propose that like herpes gladiatorum, HSV dissemination in this case was acquired by close body contact.
Syphilis: an important cause of infectious hepatitis
Authors: Rutland E , Harindra V K
Published: March 2010

The UK incidence of infectious syphilis has risen sharply over the last 10 years; however, its diagnosis can be overlooked in patients who fail to disclose risk factors for its acquisition. This patient presented with hepatitis as part of a multisystemic illness and was investigated extensively before being diagnosed with secondary syphilis. The delay to diagnosis and treatment resulted in irreversible disablement. Syphilis should be considered in the differential diagnosis of hepatitis of uncertain aetiology. In addition, due to the similar presentation and risk factors for acquisition, we suggest that syphilis serology should be performed concomitant to all HIV tests, particularly those from outside the genitourinary medicine clinic setting.