bluuebunny/crossref_metadata_2025 huggingface dataset:
Disability pensioning: The gender divide can be explained by occupation, income, mental distress and health
Authors: Claussen Bjørgulf , Dalgard Odd Steffen
Published: June 2009

Background: We aimed to test the hypothesis that gender divide in disability pensioning is attributable to differences in health, mental distress, occupation, and income. Methods: In a health survey between 2000 and 2001, a total of 11,072 (48.7%) of all Oslo inhabitants aged 40, 45, 59, and 60 years participated. Survey data were linked to data from the National Insurance Administration and Statistics Norway for 10,421 of the participants, and 9,195 of those were eligible to receive disability pension at the end of 2000. Occupation, general health, and mental distress were self-reported, while income was obtained from official statistics. Results: Approximately 5% of the eligible sample received a disability pension during the four years following the health survey. The age-adjusted odds of receiving disability pension for women was greater (odds ratio = 1.41) than for men. Self-reported health significantly contributed to the risk of receiving a pension, and seemed to reduce the imbalance in disability rates between the genders, as did adjusting for level of mental distress. Further adjustment for occupation and working conditions reduced the gender divide to an insignificant level, and the inclusion of income level (income three years prior to pensioning) completely eliminated any gender difference in risk of receiving a pension. Conclusions: Gender differences in disability pensioning in Oslo are attributable to women’s poorer self-reported health, greater levels of mental distress, lower wages, and more unfavourable working conditions such as job strain and less control over work.
Job satisfaction among hospital doctors in Norway and Germany. A comparative study on national samples
Authors: Rosta Judith , Nylenna Magne , Aasland Olaf G.
Published: June 2009

Aims: To compare German and Norwegian hospital doctors on 10 different aspects of job satisfaction and general life satisfaction. Methods: The study population consisted of a representative sample of 1,448 German and 484 Norwegian hospital doctors aged 33—65 years (n = 1,932), selected from nationwide postal surveys in 2006. The questionnaires contained items on subjective life satisfaction and the validated 10-item Job Satisfaction Scale. Each item was scored on a seven-point Likert scale from 1 (very dissatisfied) to 7 (very satisfied). A mean sum score was calculated, ranging from 1 to 7. Regression analyses and generalized-linear-model-estimated means controlled for age and gender with 95% confidence intervals were used for comparison. Results: Norwegian hospital doctors had significantly higher life satisfaction (mean 5.31 vs. 5.15) and job satisfaction (mean 5.09 vs. 4.55) than their German colleagues. Item by item, doctors in Norway were significantly more content with seven aspects of their work: ``Freedom to choose your own methods of working'' (mean 5.00 vs. 4.72), ``opportunities to use your skills'' (mean 5.49 vs. 5.01), ``physical working conditions'' (mean 4.62 vs. 4.08), ``recognition you get for good achievements'' (mean 4.83 vs. 4.26), ``overall job situation'' (mean 5.57 vs. 4.64), ``work hours'' (mean 4.39 vs. 3.39), ``rate of pay'' (mean 4.70 vs. 3.70). General life satisfaction and age, but not gender, were positively associated with job satisfaction in both countries. Conclusions: Norwegian hospital doctors enjoy a higher level of life and job satisfaction than German hospital doctors. The most likely reasons for this are more acceptable work hours, salary and control over clinical work in Norway.
Cold Agglutinins in HIV-Seropositive Participants and Diagnosis of Respiratory Disease Due to Mycoplasma pneumoniae
Authors: Esaki Muthu Shankar  , Vignesh Ramachandran , Balakrishnan Pachamuthu , Velu Vijayakumar , Ponmalar Esakimuthu , Murugavel Kailapuri G. , Saravanan Shanmugam , Nandagopal Panneerselvam , Hayath Kownhar , Solomon Suniti , Vengatesan Appasamy , Usha Anand Rao
Published: June 2009

Objectives. Cold agglutinin (CA) titers are one among the first pathological indicators for diagnosing Mycoplasma pneumoniae disease. We prospectively studied the prevalence of CAs in 300 HIV-positive and 75 HIV-negative individuals with respiratory disease in Chennai, India. Methods. The cold agglutination test was used and retrospectively compared with the results of a particle agglutination test. Results. While CAs were positive in 51 HIV cases, particle agglutination test detected anti-M pneumoniae antibodies from 43 cases with HIV disease (P = .001). The seroprevalence of CAs was 2.6% (n = 2) among HIV-negative participants. The mean CD4 count in CApositive and -negative HIV cases was 107.4 + 121.2 and 259.2 + 247.2 cells/µL (P = .001), respectively. Conclusion. Our report suggests a basis for the existence of CAs in HIV-positive cases. Definitive diagnosis may be done only when CA detection is used in conjunction with a specific test.
Immune Reconstitution Visceral Leishmaniasis Presented as Hemophagocytic Syndrome in a Patient With AIDS From a Nonendemic Area: A Case Report
Authors: Patel Ketan K. , Patel Atul K. , Sarda Parimal , Shah Bhavin A. , Ranjan Rajiv
Published: June 2009

Visceral Leishmaniasis (VL) is endemic in the Ganges and Brahmaputra plains of India. Leishmaniasis/HIV coinfection is on the rise in India and may pose a real diagnostic and therapeutic challenge. HIV-related immunosuppression increases the risk of reactivating leishmaniasis by 100 to 1000 times and it also increases the risk of drug resistant leishmaniasis. Immune reconstitution VL is not very well reported in literature. Hemophagocytosis is known to occur with various infectious agents like viruses, bacteria, and parasites, but is rare to occur with leishmaniasis. Here the authors describe a case of VL presenting as immune reconstitution disease and hemophagocytosis in an HIV infected patient coming from a nonendemic area.
Service Quality in the Hotel Industry
Authors: Ching Yick Tse Eliza , Ho Suk-Ching
Published: June 2009

An analysis of 168 critical incidents of service success or failure for seventeen hotels in Hong Kong found that the most common critical incident involved a hotel employee responding to a guest request. That stands in contrast to an earlier study conducted in Western hotels that identified service recovery as the most common critical incident. The analysis is based on interviews with fifty-six front-desk employees in a diverse group of Hong Kong hotels. When it came to service recovery, hotels in Hong Kong were inclined to apply compensatory responses, while earlier studies found that Western hotels favored corrective responses, even when customers preferred compensation. The comparison of Western studies with those of Hong Kong highlight cultural differences with regard to service. One particular difference was employees’ assessment of the source of customer dissatisfaction. Whereas respondents in Western studies seemed to cite external causes, the delivery system, or the customers themselves for customer dissatisfaction, the respondents in the Hong Kong study uniformly blamed themselves.
Loyalty Programs
Authors: Dekay Frederick , Toh Rex S. , Raven Peter
Published: June 2009

Compared to hotel frequent-guest programs, airline frequent-flyer programs have gained not only more membership but greater penetration of key groups of travelers, notably, business travelers and high-income, high-frequency travelers. Based on a survey of 287 guests at nine hotels in Seattle, Washington, airline loyalty programs have gained considerably greater awareness among travelers than have hotel programs. One-third of the leisure travelers in this survey reported that they were not aware of hotel loyalty programs (even though they were staying in a hotel). The study found that travelers who join both hotel and airline loyalty programs are also the most frequent travelers. By far, the proportion of travelers who join airline frequent-flyer programs exceeds that of those who have joined hotel frequent-guest programs. Perhaps most critically for hotel programs, the surveyed guests would prefer to receive airline miles for their hotel stay than to receive hotel points.
Thiopurine methyltransferase genetics is not a major risk factor for secondary malignant neoplasms after treatment of childhood acute lymphoblastic leukemia on Berlin-Frankfurt-Münster protocols
Authors: Stanulla Martin , Schaeffeler Elke , Möricke Anja , Coulthard Sally A. , Cario Gunnar , Schrauder André , Kaatsch Peter , Dördelmann Michael , Welte Karl , Zimmermann Martin , Reiter Alfred , Eichelbaum Michel , Riehm Hansjörg , Schrappe Martin , Schwab Matthias
Published: June 2009

Thiopurine methyltransferase (TPMT)is involved in the metabolism of thiopurines such as 6-mercaptopurine and 6-thioguanine. TPMT activity is significantly altered by genetics, and heterozygous and even more homozygous variant people reveal substiantially decreased TPMT activity. Treatment for childhood acute lymphoblastic leukemia (ALL) regularly includes the use of thiopurine drugs. Importantly, childhood ALL patients with low TPMT activity have been considered to be at increased risk of developing therapy-associated acute myeloid leukemia and brain tumors. In the present study, we genotyped 105 of 129 patients who developed a secondary malignant neoplasm after ALL treatment on 7 consecutive German Berlin-Frankfurt-Münster trials for all functionally relevant TPMT variants. Frequencies of TPMT variants were similarly distributed in secondary malignant neoplasm patients and the overall ALL patient population of 814 patients. Thus, TPMT does not play a major role in the etiology of secondary malignant neoplasm after treatment for childhood ALL, according to Berlin-Frankfurt-Münster strategies.
Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation
Authors: Matsuno Naofumi , Wake Atsushi , Uchida Naoyuki , Ishiwata Kazuya , Araoka Hideki , Takagi Shinsuke , Tsuji Masanori , Yamamoto Hisashi , Kato Daisuke , Matsuhashi Yoshiko , Seo Sachiko , Masuoka Kazuhiro , Miyakoshi Shigesaburo , Makino Shigeyoshi , Yoneyama Akiko , Kanda Yoshinobu , Taniguchi Shuichi
Published: June 2009

Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34+ cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.
Role of tissue factor in a mouse model of thrombotic microangiopathy induced by antiphospholipid antibodies
Authors: Seshan Surya V. , Franzke Claus-Werner , Redecha Patricia , Monestier Marc , Mackman Nigel , Girardi Guillermina
Published: June 2009

Using different mouse monoclonal and human antiphospholipid (aPL) antibodies, we developed a new animal model of renal injury that shares many features with thrombotic microangiopathy (TMA). We found that more than 1 mechanism/signaling pathway is involved in glomerular injury induced by aPL antibodies in this model. Both complement-dependent and complement-independent pathways were identified that lead to glomerular endothelial cell damage and renal function impairment. We also found that C5a-C5aR interaction is a crucial step for the activation of the coagulation cascade and glomerular injury induced by complement-activating antibodies. In addition, our studies demonstrated complement-independent mechanisms in which reactivity with β2 glycoprotein I (β2GPI) plays an important role in aPL-induced glomerular damage and renal failure. Independently of the mechanism responsible for aPL-induced TMA, mice that express low levels of tissue factor (TF) were protected from glomerular injury. That genetic reduction of TF prevents renal injury induced by different aPL antibodies indicates that TF is a common mediator of glomerular damage and a possible target for selective pharmacologic intervention. Treatment with pravastatin, which down-regulates glomerular TF synthesis, prevents aPL-induced TMA in this mouse model, thus emphasizing that targeting TF might be a good therapeutic intervention in patients with TMA.
KW-2449, a novel multikinase inhibitor, suppresses the growth of leukemia cells with FLT3 mutations or T315I-mutated BCR/ABL translocation
Authors: Shiotsu Yukimasa , Kiyoi Hitoshi , Ishikawa Yuichi , Tanizaki Ryohei , Shimizu Makiko , Umehara Hiroshi , Ishii Kenichi , Mori Yumiko , Ozeki Kazutaka , Minami Yosuke , Abe Akihiro , Maeda Hiroshi , Akiyama Tadakazu , Kanda Yutaka , Sato Yuko , Akinaga Shiro , Naoe Tomoki
Published: June 2009

KW-2449, a multikinase inhibitor of FLT3, ABL, ABL-T315I, and Aurora kinase, is under investigation to treat leukemia patients. In this study, we examined its possible modes of action for antileukemic effects on FLT3-activated, FLT3 wild-type, or imatinib-resistant leukemia cells. KW-2449 showed the potent growth inhibitory effects on leukemia cells with FLT3 mutations by inhibition of the FLT3 kinase, resulting in the down-regulation of phosphorylated-FLT3/STAT5, G1 arrest, and apoptosis. Oral administration of KW-2449 showed dose-dependent and significant tumor growth inhibition in FLT3-mutated xenograft model with minimum bone marrow suppression. In FLT3 wild-type human leukemia, it induced the reduction of phosphorylated histone H3, G2/M arrest, and apoptosis. In imatinib-resistant leukemia, KW-2449 contributed to release of the resistance by the simultaneous down-regulation of BCR/ABL and Aurora kinases. Furthermore, the antiproliferative activity of KW-2449 was confirmed in primary samples from AML and imatinib-resistant patients. The inhibitory activity of KW-2449 is not affected by the presence of human plasma protein, such as α1-acid glycoprotein. These results indicate KW-2449 has potent growth inhibitory activity against various types of leukemia by several mechanisms of action. Our studies indicate KW-2449 has significant activity and warrants clinical study in leukemia patients with FLT3 mutations as well as imatinib-resistant mutations.
MicroRNA: mIR-ly regulators of DNMT?
Authors: Griffiths Elizabeth A. , Gore Steven D.
Published: June 2009

In this issue of Blood, Garzon and colleagues present evidence for a functional role of miR 29b in controlling DNMT levels in leukemia. Their work may provide insight into the mechanism of action of the azanucleotides and could potentially offer the first pharmacologically active miRNA.
NKT cells in p53 deficiency
Authors: Dhodapkar Madhav V. , Neparidze Natalia
Published: June 2009

In this issue of Blood, Swann and colleagues show that type I NKT cells mediate protection against tumor development in p53-deficient mice.
Escaping the niche
Authors: Handin Robert
Published: June 2009

In this issue of Blood, Zou and colleagues unravel a long-standing mystery—how megakaryocyte precursors make the transition from the collagen-rich osteoblastic bone marrow niche to the collagen-poor vascular niche while expressing 2 receptors that interact with collagen—GpVI and the α2β1 integrin.
Is a little GVHD a good thing?
Authors: Fry Terry J.
Published: June 2009

In this issue of Blood, Clave and colleagues explore the impact of acute GVHD on thymic recovery following hematopoietic stem cell transplantation and begin to address the mechanism by which alloreactivity may impair thymic function in humans.
Dissecting VHL-associated pathologies
Authors: Metzen Eric , Brockmeier Ulf
Published: June 2009

In this issue of Blood, van Rooijen and colleagues demonstrate that zebrafish carrying a mutation in the von Hippel Lindau gene (VHL) develop Chuvash polycythemia, a hereditary human disease characterized by the dysregulation of hypoxia-inducible proteins including erythropoietin.
The evolution of YidC/Oxa/Alb3 family in the three domains of life: a phylogenomic analysis
Authors: Zhang Yu-Juan , Tian Hai-Feng , Wen Jian-Fan
Published: June 2009

Background

YidC/Oxa/Alb3 family includes a group of conserved translocases that are essential for protein insertion into inner membranes of bacteria and mitochondria, and thylakoid membranes of chloroplasts. Because mitochondria and chloroplasts are of bacterial origin, Oxa and Alb3, like many other mitochondrial/chloroplastic proteins, are hypothetically derived from the pre-existing protein (YidC) of bacterial endosymbionts. Here, we test this hypothesis and investigate the evolutionary history of the whole YidC/Oxa/Alb3 family in the three domains of life.

Results

Our comprehensive analyses of the phylogenetic distribution and phylogeny of the YidC/Oxa/Alb3 family lead to the following findings: 1) In archaea, YidC homologs are only sporadically distributed in Euryarchaeota; 2) Most bacteria contain only one YidC gene copy; some species in a few taxa (Bacillus, Lactobacillales, Actinobacteria and Clostridia) have two gene copies; 3) Eukaryotic Oxa and Alb3 have two separate prokaryotic origins, but they might not arise directly from the YidC of proteobacteria and cyanobacteria through the endosymbiosis origins of mitochondrium and chloroplast, respectively; 4) An ancient duplication occurred on both Oxa and Alb3 immediately after their origins, and thus most eukaryotes generally bear two Oxa and two Alb3. However, secondary loss, duplication or acquisition of new domain also occurred on the two genes in some lineages, especially in protists, resulting in a rich diversity or adaptive differentiation of the two translocases in these lineages.

Conclusion

YidC is distributed in bacteria and some Euryarchaeota. Although mitochondrial Oxa and chloroplastic Alb3 are derived from the prokaryotic YidC, their origin might be not related to the endosymbiosis events of the two organelles. In some eukaryotic lineages, especially in protists, Oxa and Alb3 have diverse evolutionary histories. Finally, a model for the evolutionary history of the entire YidC/Oxa/Alb3 family in the three domains of life is proposed.
Assessment of adaptive evolution between wheat and rice as deduced from full-length common wheat cDNA sequence data and expression patterns
Authors: Kawaura Kanako , Mochida Keiichi , Enju Akiko , Totoki Yasushi , Toyoda Atsushi , Sakaki Yoshiyuki , Kai Chikatoshi , Kawai Jun , Hayashizaki Yoshihide , Seki Motoaki , Shinozaki Kazuo , Ogihara Yasunari
Published: June 2009

Background

Wheat is an allopolyploid plant that harbors a huge, complex genome. Therefore, accumulation of expressed sequence tags (ESTs) for wheat is becoming particularly important for functional genomics and molecular breeding. We prepared a comprehensive collection of ESTs from the various tissues that develop during the wheat life cycle and from tissues subjected to stress. We also examined their expression profiles in silico. As full-length cDNAs are indispensable to certify the collected ESTs and annotate the genes in the wheat genome, we performed a systematic survey and sequencing of the full-length cDNA clones. This sequence information is a valuable genetic resource for functional genomics and will enable carrying out comparative genomics in cereals.

Results

As part of the functional genomics and development of genomic wheat resources, we have generated a collection of full-length cDNAs from common wheat. By grouping the ESTs of recombinant clones randomly selected from the full-length cDNA library, we were able to sequence 6,162 independent clones with high accuracy. About 10% of the clones were wheat-unique genes, without any counterparts within the DNA database. Wheat clones that showed high homology to those of rice were selected in order to investigate their expression patterns in various tissues throughout the wheat life cycle and in response to abiotic-stress treatments. To assess the variability of genes that have evolved differently in wheat and rice, we calculated the substitution rate (Ka/Ks) of the counterparts in wheat and rice. Genes that were preferentially expressed in certain tissues or treatments had higher Ka/Ks values than those in other tissues and treatments, which suggests that the genes with the higher variability expressed in these tissues is under adaptive selection.

Conclusion

We have generated a high-quality full-length cDNA resource for common wheat, which is essential for continuation of the ongoing curation and annotation of the wheat genome. The data for each clone's expression in various tissues and stress treatments and its variability in wheat and rice as a result of their diversification are valuable tools for functional genomics in wheat and for comparative genomics in cereals.
Induction of protective and therapeutic anti-pancreatic cancer immunity using a reconstructed MUC1 DNA vaccine
Authors: Rong Yefei , Jin Dayong , Wu Wenchuan , Lou Wenhui , Wang Danshong , Kuang Tiantao , Ni Xiaoling , Qin Xinyu
Published: June 2009

Background

Pancreatic cancer is a common, highly lethal disease with a rising incidence. MUC1 is a tumor-associated antigen that is over-expressed in pancreatic adenocarcinoma. Active immunotherapy that targets MUC1 could have great treatment value. Here we investigated the preventive and therapeutic effect of a MUC1 DNA vaccine on the pancreatic cancer.

Methods

MUC1-various tandem repeat units(VNTR) DNA vaccine was produced by cloning one repeat of VNTR and inserting the cloned gene into the pcDNA3.1. In the preventive group, female C57BL/6 mice were immunized with the vaccine, pcDNA3.1 or PBS; and challenged with panc02-MUC1 or panc02 cell. In the therapeutic group the mice were challenged with panc02-MUC1 or panc02 cell, and then immunized with the vaccine, pcDNA3.1 or PBS. The tumor size and the survival time of the animals were compared between these groups.

Results

The DNA vaccine pcDNA3.1-VNTR could raise cytotoxic T lymphocyte (CTL) activity specific for MUC1. In the preventive experiment, the mice survival time was significantly longer in the vaccine group than in the control groups (P < 0.05). In the therapeutic experiment, the DNA vaccine prolonged the survival time of the panc02-MUC1-bearing mice (P < 0.05). In both the preventive and therapeutic experiments, the tumor size was significantly less in the vaccine group than in the control groups (P < 0.05). This pcDNA3.1-VNTR vaccine, however, could not prevent the mice attacked by panc02 cells and had no therapeutic effect on the mice attacked by panc02 cells.

Conclusion

The MUC1 DNA vaccine pcDNA3.1-VNTR could induce a significant MUC1-specific CTL response; and had both prophylactic and therapeutic effect on panc02-MUC1 tumors. This vaccine might be used as a new adjuvant strategy against pancreatic cancer.
Triple negative breast carcinoma is a prognostic factor in Taiwanese women
Authors: Lin Che , Chien Su-Yu , Chen Li-Sheng , Kuo Shou-Jen , Chang Tsai-Wang , Chen Dar-Ren
Published: June 2009

Background

Currently, there is a debate as to whether triple negative breast carcinoma (TNBC) has a worse prognosis than non-TNBC. Our aim was to determine whether TNBC is a prognostic factor for survival.

Methods

We identified 1,048 Taiwanese breast carcinoma patients, of whom 167 (15.9%) had TNBC. Data used for analysis were derived from our cancer registry database for women with breast cancer who were diagnosed between 2002 January and 2006 December.

Results

In the Kaplan-Meier analysis, tumor subgroup (TNBC vs. non-TNBC) was a prognosis factor related to 5-year overall survival. In the univariate analysis, tumor subgroup (TNBC vs. non-TNBC) was a significant factor related to 5-year overall survival, in addition to age, tumor size, lymph node, metastasis, grade, stage, estrogen receptor status, progesterone receptor status, and HER2 overexpression status. In the multivariate analysis, tumor subgroup was not a significant factor related to 5-year disease-free survival (DFS). In node-positive patients, tumor subgroup was a significant factor related to 5-year overall survival, in addition to age, tumor size, metastasis, and grade. In node-negative patients, tumor subgroup was not a significant factor related to 5-year disease-free survival and 5-year overall survival.

Conclusion

Our results indicated that TNBC patients in Taiwan have worse 5-year overall survival than non-TNBC patients. Notably, in node-positive patients, TNBC played a prognostic role in 5-year overall survival.
CpG methylation profiling in VHL related and VHL unrelated renal cell carcinoma
Authors: McRonald Fiona E , Morris Mark R , Gentle Dean , Winchester Laura , Baban Dilair , Ragoussis Jiannis , Clarke Noel W , Brown Michael D , Kishida Takeshi , Yao Masahiro , Latif Farida , Maher Eamonn R
Published: June 2009

Background

Renal cell carcinoma (RCC) is histopathologically heterogeneous with clear cell and papillary the most common subtypes. The most frequent molecular abnormality in clear cell RCC is VHL inactivation but promoter methylation of tumour suppressor genes is common in both subtypes of RCC. To investigate whether RCC CpG methylation status was influenced by histopathology and VHL status we performed high-throughput epigenetic profiling using the Illumina Goldengate Methylation Array in 62 RCC (29 RCC from von Hippel-Lindau (VHL) disease patients, 20 sporadic clear cell RCC with wild type VHL and 13 sporadic papillary RCC).

Results

43 genes were methylated in >20% of primary RCC (range 20–45%) and most (37/43) of these had not been reported previously to be methylated in RCC. The distribution of the number of methylated CpGs in individual tumours differed from the expected Poisson distribution (p < 0.00001; log-likelihood G test) suggesting that a subset of RCC displayed a CpG Island Methylator Phenotype. Comparison of RCC subtypes revealed that, on average, tumour specific CpG methylation was most prevalent in papillary RCC and least in VHL RCC. Many of the genes preferentially methylated in pRCC were linked to TGFβ or ERK/Akt signalling.

Conclusion

These findings demonstrate differing patterns of tumour-specific CpG methylation in VHL and non VHL clear cell RCC and papillary RCC, and identify multiple novel potential CpG methylation biomarkers for RCC.
Molecular analysis of the apoptotic effects of BPA in acute myeloid leukemia cells
Authors: Bontempo Paola , Mita Luigi , Doto Antonella , Miceli Marco , Nebbioso Angela , Lepore Ilaria , Franci GianLuigi , Menafra Roberta , Carafa Vincenzo , Conte Mariarosaria , De Bellis Floriana , Manzo Fabio , Di Cerbo Vincenzo , Benedetti Rosaria , D'Amato Loredana , Marino Maria , Bolli Alessandro , Del Pozzo Giovanna , Diano Nadia , Portaccio Marianna , Mita Gustavo D , Vietri Maria Teresa , Cioffi Michele , Nola Ernesto , Dell'Aversana Carmela , Sica Vincenzo , Molinari Anna Maria , Altucci Lucia
Published: June 2009

Background:

BPA (bisphenol A or 2,2-bis(4-hydroxy-phenol)propane) is present in the manufacture of polycarbonate plastic and epoxy resins, which can be used in impact-resistant safety equipment and baby bottles, as protective coatings inside metal food containers, and as composites and sealants in dentistry. Recently, attention has focused on the estrogen-like and carcinogenic adverse effects of BPA. Thus, it is necessary to investigate the cytotoxicity and apoptosis-inducing activity of this compound.

Methods:

Cell cycle, apoptosis and differentiation analyses; western blots.

Results:

BPA is able to induce cell cycle arrest and apoptosis in three different acute myeloid leukemias. Although some granulocytic differentiation concomitantly occurred in NB4 cells upon BPA treatment, the major action was the induction of apoptosis. BPA mediated apoptosis was caspase dependent and occurred by activation of extrinsic and intrinsic cell death pathways modulating both FAS and TRAIL and by inducing BAD phosphorylation in NB4 cells. Finally, also non genomic actions such as the early decrease of both ERK and AKT phosphorylation were induced by BPA thus indicating that a complex intersection of regulations occur for the apoptotic action of BPA.

Conclusion:

BPA is able to induce apoptosis in leukemia cells via caspase activation and involvement of both intrinsic and extrinsic pathways of apoptosis.
SELDI-TOF MS profiling of serum for detection of nasopharyngeal carcinoma
Authors: Huang Yuan-Jiao , Xuan Chao , Zhang Bei-Bei , Liao Ming , Deng Kai-Feng , He Min , Zhao Jin-Min
Published: June 2009

Background

No satisfactory biomarkers are currently available to screen for nasopharyngeal carcinoma (NPC). We have developed and evaluated surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) for detection and analysis of multiple proteins for distinguishing individuals with NPC from control individuals.

Methods

A preliminary learning set and a classification tree of spectra derived from 24 patients with NPC and a group of 24 noncancer controls were used to develop a proteomic model that discriminated cancer from noncancer effectively. Then, the validity of the classification tree was challenged with a blind test set, which included another 20 patients with NPC and 12 noncancer controls.

Results

A panel of 3 biomarkers ranging m/z 3–20 k was selected to establish Decision Tree model by BPS with sensitivity of 91.66% and specificity of 95.83%. The ability to detect NPC patients was evaluated, a sensitivity of 95.0% and specificity of 83.33% were validated in blind testing set.

Conclusion

This high-flux proteomic classification system will provide a highly accurate and innovative approach for the detection/diagnosis of NPC.
Characterization of the tumor marker muc16 (ca125) expressed by murine ovarian tumor cell lines and identification of a panel of cross-reactive monoclonal antibodies
Authors: Goodell Cara AR , Belisle Jennifer A , Gubbels Jennifer AA , Migneault Martine , Rancourt Claudine , Connor Joseph , Kunnimalaiyaan Muthusamy , Kravitz Rachel , Tucker Ward , Zwick Michael , Patankar Manish S
Published: June 2009

Objectives

The ovarian tumor marker CA125 is expressed on human MUC16, a cell surface bound mucin that is also shed by proteolytic cleavage. Human MUC16 is overexpressed by ovarian cancer cells. MUC16 facilitates the binding of ovarian tumor cells to mesothelial cells lining the peritoneal cavity. Additionally, MUC16 also is a potent inhibitor of natural killer cell mediated anti-tumor cytotoxic responses. Extensive studies using human as well as murine ovarian tumor cell models are required to clearly define the function of MUC16 in the progression of ovarian tumors. The major objective of this study was to determine if the murine ovarian tumor cells, MOVCAR, express Muc16 and to characterize antibodies that recognize this mucin.

Methods

RT-PCR analysis was used for detecting the Muc16 message and size exclusion column chromatography for isolating Muc16 produced by MOVCAR cells. Soluble and cell-associated murine Muc16 were analyzed, respectively, by Western blotting and flow cytometry assays using a new panel of antibodies. The presence of N-linked oligosaccharides on murine Muc16 was determined by ConA chromatography.

Results

We demonstrate that murine Muc16 is expressed by mouse ovarian cancer cells as an ~250 kDa glycoprotein that carries both O-linked and N-linked oligosaccharides. In contrast to human MUC16, the murine ortholog is primarily released from the cells and cannot be detected on the cell surface. Since the released murine Muc16 is not detected by conventional anti-CA125 assays, we have for the first time identified a panel of anti-human MUC16 antibodies that also recognizes the murine counterpart.

Conclusion

The antibodies identified in this study can be used in future purification of murine Muc16 and exhaustive study of its properties. Furthermore, the initial identification and characterization of murine Muc16 is a vital preliminary step in the development of effective murine models of human ovarian cancer. These models will aid in the further elucidation of the role that human MUC16 plays in the etiology and progression of ovarian tumors.
Increasing arterial blood pressure with norepinephrine does not improve microcirculatory blood flow: a prospective study
Authors: Dubin Arnaldo , Pozo Mario O , Casabella Christian A , Pálizas Fernando , Murias Gastón , Moseinco Miriam C , Kanoore Edul Vanina S , Pálizas Fernando , Estenssoro Elisa , Ince Can
Published: June 2009

Introduction

Our goal was to assess the effects of titration of a norepinephrine infusion to increasing levels of mean arterial pressure (MAP) on sublingual microcirculation.

Methods

Twenty septic shock patients were prospectively studied in two teaching intensive care units. The patients were mechanically ventilated and required norepinephrine to maintain a mean arterial pressure (MAP) of 65 mmHg. We measured systemic hemodynamics, oxygen transport and consumption (DO2 and VO2), lactate, albumin-corrected anion gap, and gastric intramucosal-arterial PCO2 difference (ΔPCO2). Sublingual microcirculation was evaluated by sidestream darkfield (SDF) imaging. After basal measurements at a MAP of 65 mmHg, norepinephrine was titrated to reach a MAP of 75 mmHg, and then to 85 mmHg. Data were analyzed using repeated measurements ANOVA and Dunnett test. Linear trends between the different variables and increasing levels of MAP were calculated.

Results

Increasing doses of norepinephrine reached the target values of MAP. The cardiac index, pulmonary pressures, systemic vascular resistance, and left and right ventricular stroke work indexes increased as norepinephrine infusion was augmented. Heart rate, DO2 and VO2, lactate, albumin-corrected anion gap, and ΔPCO2 remained unchanged. There were no changes in sublingual capillary microvascular flow index (2.1 ± 0.7, 2.2 ± 0.7, 2.0 ± 0.8) and the percent of perfused capillaries (72 ± 26, 71 ± 27, 67 ± 32%) for MAP values of 65, 75, and 85 mmHg, respectively. There was, however, a trend to decreased capillary perfused density (18 ± 10,17 ± 10,14 ± 2 vessels/mm2, respectively, ANOVA P = 0.09, linear trend P = 0.045). In addition, the changes of perfused capillary density at increasing MAP were inversely correlated with the basal perfused capillary density (R2 = 0.95, P < 0.0001).

Conclusions

Patients with septic shock showed severe sublingual microcirculatory alterations that failed to improve with the increases in MAP with norepinephrine. Nevertheless, there was a considerable interindividual variation. Our results suggest that the increase in MAP above 65 mmHg is not an adequate approach to improve microcirculatory perfusion and might be harmful in some patients.
Cell death serum biomarkers are early predictors for survival in severe septic patients with hepatic dysfunction
Authors: Hofer Stefan , Brenner Thorsten , Bopp Christian , Steppan Jochen , Lichtenstern Christoph , Weitz Jürgen , Bruckner Thomas , Martin Eike , Hoffmann Ursula , Weigand Markus A
Published: June 2009

Introduction

Severe sepsis, septic shock, and resulting organ failure represent the most common cause of death in intensive care medicine, with mortality ranging from 40% to 70%. It is still unclear whether necrosis or apoptosis plays the predominant role in severe sepsis. Determining the prevalent mode of cell death would be valuable, as new therapeutic agents (eg, antiapoptotic drugs such as caspase inhibitors) may improve unsatisfactory outcomes in patients with severe sepsis. Furthermore, the prognostic value of newly developed cell death serum biomarkers is of great interest.

Methods

In total, 147 patients (101 patients with severe sepsis, 28 postoperative patients after major abdominal surgery, 18 healthy volunteers) were enrolled. Baseline and clinical data were evaluated. Blood samples from patients with severe sepsis were collected at the time of sepsis diagnosis, and 48 and 120 hours later; samples from healthy volunteers were collected once, and from postoperative patients, once immediately after surgery. We measured caspase-cleaved and uncleaved cytokeratin-18 (CK-18, intermediate filament protein) as a marker of cell death, isolated CK-18 fragments as a marker of apoptosis, as well as IL-6, soluble vascular cell adhesion molecule, and soluble intercellular adhesion molecule.

Results

Age and sex of patients with severe sepsis and postoperative patients were comparable, whereas healthy volunteers were significantly younger. In healthy volunteers, the mode of cellular turnover was primarily apoptotic cell death. Postoperative patients showed comparable levels of apoptotic activity, but necrotic cell death was markedly increased, probably due to surgical tissue injury. In contrast, patients with severe sepsis, and especially non-survivors of the septic group showed increased levels of markers for both apoptotic and necrotic cell death. In severe septic patients with liver dysfunction, necrosis is increased relative to severe septic patients with intact hepatic function. For severe septic patients with liver dysfunction, a cut-off value for caspase-cleaved and uncleaved cytokeratin-18 could be calculated, in order to identify patients at high risk for death due to severe sepsis.

Conclusions

The measurement of caspase-cleaved and uncleaved cytokeratin-18 appears to be an early predictor for survival in severe septic patients with hepatic dysfunction. Furthermore, the loss of parenchymal cells due to necrosis may be the primary mode of cell death in these patients. This may limit possible therapeutic options.
Muscular dystrophy begins early in embryonic development deriving from stem cell loss and disrupted skeletal muscle formation
Authors: Merrick Deborah , Stadler Lukas Kurt Josef , Larner Dean , Smith Janet
Published: June 2009

Examination of embryonic myogenesis of two distinct, but functionally related, skeletal muscle dystrophy mutants (mdx and cav-3−/−) establishes for the first time that key elements of the pathology of Duchenne muscular dystrophy (DMD) and limb-girdle muscular dystrophy type 1C (LGMD-1c) originate in the disruption of the embryonic cardiac and skeletal muscle patterning processes. Disruption of myogenesis occurs earlier in mdx mutants, which lack a functional form of dystrophin, than in cav-3−/− mutants, which lack the Cav3 gene that encodes the protein caveolin-3; this finding is consistent with the milder phenotype of LGMD-1c, a condition caused by mutations in Cav3, and the earlier [embryonic day (E)9.5] expression of dystrophin. Myogenesis is severely disrupted in mdx embryos, which display developmental delays; myotube morphology and displacement defects; and aberrant stem cell behaviour. In addition, the caveolin-3 protein is elevated in mdx embryos. Both cav-3−/− and mdx mutants (from E15.5 and E11.5, respectively) exhibit hyperproliferation and apoptosis of Myf5-positive embryonic myoblasts; attrition of Pax7-positive myoblasts in situ; and depletion of total Pax7 protein in late gestation. Furthermore, both cav-3−/− and mdx mutants have cardiac defects. In cav-3−/− mutants, there is a more restricted phenotype comprising hypaxial muscle defects, an excess of malformed hypertrophic myotubes, a twofold increase in myonuclei, and reduced fast myosin heavy chain (FMyHC) content. Several mdx mutant embryo pathologies, including myotube hypotrophy, reduced myotube numbers and increased FMyHC, have reciprocity with cav-3−/− mutants. In double mutant (mdxcav-3+/−) embryos that are deficient in dystrophin (mdx) and heterozygous for caveolin-3 (cav-3+/−), whereby caveolin-3 is reduced to 50% of wild-type (WT) levels, these phenotypes are severely exacerbated: intercostal muscle fibre density is reduced by 71%, and Pax7-positive cells are depleted entirely from the lower limbs and severely attenuated elsewhere; these data suggest a compensatory rather than a contributory role for the elevated caveolin-3 levels that are found in mdx embryos. These data establish a key role for dystrophin in early muscle formation and demonstrate that caveolin-3 and dystrophin are essential for correct fibre-type specification and emergent stem cell function. These data plug a significant gap in the natural history of muscular dystrophy and will be invaluable in establishing an earlier diagnosis for DMD/LGMD and in designing earlier treatment protocols, leading to better clinical outcome for these patients.
Haploinsufficiency of the murine polycomb gene Suz12 results in diverse malformations of the brain and neural tube
Authors: Miró Xavier , Zhou Xunlei , Boretius Susann , Michaelis Thomas , Kubisch Christian , Alvarez-Bolado Gonzalo , Gruss Peter
Published: June 2009

Polycomb proteins are epigenetic regulators of gene expression. Human central nervous system (CNS) malformations are congenital defects of the brain and spinal cord. One example of a human CNS malformation is Chiari malformation (CM), which presents as abnormal brainstem growth and cerebellar herniation, sometimes accompanied by spina bifida and cortical defects; it can occur in families. Clinically, CM ranges from an asymptomatic condition to one with incapacitating or lethal symptoms, including neural tube defects and hydrocephalus. However, no genes that are causally involved in any manifestation of CM or similar malformations have been identified. Here, we show that a pathway that involves Zac1 (also known as Plagl1 or Lot1) and controls neuronal proliferation is altered in mice that are heterozygous for the polycomb gene Suz12, resulting in a phenotype that overlaps with some clinical manifestations of the CM spectrum. Suz12 heterozygotes show cerebellar herniation and an enlarged brainstem, accompanied by occipital cortical alterations and spina bifida. Downward displacement of the cerebellum causes hydrocephalus in the most severely impaired cases. Although the involvement of polycomb genes in human disease is starting to be recognized, this is the first demonstration of their role in nervous system malformations. Our work strongly suggests that brain malformations such as CM can result from altered epigenetic regulation of genes involved in cell proliferation in the brain.
Factors associated with anaemia in HIV-infected individuals in southern India
Authors: Subbaraman R , Devaleenal B , Selvamuthu P , Yepthomi T , Solomon S S , Mayer K H , Kumarasamy N
Published: June 2009

Anaemia accelerates disease progression and increases mortality among HIV-infected individuals. Few studies have characterized this problem in developing countries. Haemoglobin values of adults presenting to an HIV tertiary care center in India between 1996 and 2007 were collected (n = 6996). Multivariate logistic regression analysis was performed to examine associations among anaemia, HIV progression and co-morbidities. Overall, anaemia prevalence was 41%. Twenty percent of patients with CD4 counts >500 cells/μL were anaemic, compared with 64% of those with CD4 counts P < 0.001). In multivariate analysis, CD4 count <100cells/μL (odds ratio [OR]:5.0, confidence interval [CI]:4.0–6.3), underweight body mass index (OR:4.8, CI:3.6–6.5), female gender (OR:3.1, CI:2.8–3.6) and tuberculosis (TB) (OR:1.6, CI:1.4–1.8) were significantly associated with anaemia. In this setting, management of anaemia should focus on antiretroviral therapy, nutritional supplementation and TB control. The high anaemia prevalence among patients meeting criteria for antiretroviral therapy highlights the need for increased access to non-zidovudine nucleoside reverse transcriptase inhibitors in developing countries.
Unawareness of HIV status in pregnancy, delay in testing and conflict between information on antenatal card and interview in Recife, Brazil
Authors: Ramos V de O X , Lacerda H R , Ximenes R A de A
Published: June 2009

Overall HIV test coverage among pregnant women in Brazil is 62%, but only 41% in northeastern Brazil. We aimed to identify risk factors for unawareness of HIV status among pregnant women and determine test coverage up to 14th week of pregnancy. We conducted a case-control study in a reference maternity hospital for high-risk pregnancy in Recife, where 485 puerperae were interviewed about their knowledge of results of HIV testing, biological, sociodemographic and healthcare data. Cases were those who were not aware of their HIV status and controls were those who were. Only 21.65% stated that they were unaware of their HIV status during pregnancy (78.35% coverage); however, test results were recorded on an antenatal card in only 48.35%. Only 22% received the result by the 14th week of pregnancy. Unawareness was associated with low schooling (odds ratio [OR] = 2.92; P = 0.006); living outside the state capital's metropolitan region (OR = 4.11; P = 0.001); test performed in the third trimester (OR = 11.6; P = 0.000); and lack of counselling (OR = 2.31; P = 0.022) in multivariate analysis. In conclusion, there has been a considerable delay in having an HIV test. Conflict of Information obtained by interview and that on the antenatal card raises questions about deficiencies in antenatal care or lack of comprehension about the HIV test.
Chlamydia trachomatis infection during pregnancy and the risk of preterm birth: a case-control study
Authors: Silveira M F , Ghanem K G , Erbelding E J , Burke A E , Johnson H L , Singh R H , Zenilman J M
Published: June 2009

Our goal was to define the risks of preterm birth associated with Chlamydia trachomatis (CT) and other sexually transmitted infections (STIs) among pregnant women. We accessed clinical records from July 2005 to February 2008. The study population included all pregnant women who gave birth to a singleton newborn of at least 20 weeks’ gestation, and who had antenatal care information. We estimated the impact of CT and other STI on the odds of preterm birth using logistic regression. Overall, 2127 women were included in this analysis. The prevalence of CT infection was 4.7%. CT diagnosis was not associated with preterm birth. In conclusion, this study did not find an association between CT and preterm birth. The lack of an association may be explained by early treatment. Future studies evaluating the timing of screening for STIs may help clarify whether pregnant women would benefit more from earlier screening.