bluuebunny/crossref_metadata_2025 huggingface dataset:
Families with multiple problems: Some challenges in identifying and providing services to those experiencing adversities across the life course
Authors: Spratt Trevor
Published: September 2010

• Summary: A concern amongst policy-makers to identify high cost and low productivity populations has created a new interest in identifying those who experience adversities across the life course. This article outlines the development of conceptual understandings of families whose children experience multiple adversities and links this with later poor outcomes in adult life and examines some of the research challenges in establishing such linkages.

• Findings: It is argued that current thinking with regard to these issues reflects historical domains within which services to children and to adults are located. The challenge to domain thinking is both horizontal and vertical, policy being required to address the horizontal axis by co-ordinating planned approaches to multiple needs across services, and policy being necessary to address the vertical cleavage between children’s and adult services in ways which join up services across the life path; conceptually and practically acknowledging the links between child and adult experiences.

• Applications: Such policy developments will inevitably require social work to develop alternative paradigms for understanding the needs of children and adults and designing services to effectively meet these.
Disability compensation and responsibility
Authors: Cappelen Alexander W. , Norheim Ole Frithjof , Tungodden Bertil
Published: September 2010

It is a central political goal to secure disabled individuals the same opportunities as others to pursue their conception of a good life. This goal reflects an ambition to combine an egalitarian and a liberal moral intuition. In this article, we analyse how disabled individuals who take part in economic activity should be compensated in order to respect these two intuitions. The article asks how a system of disability compensation should be structured and what the level of such compensation should be. It also analyses how the answers to these questions depend on whether the disabled individuals are held responsible for their choice of work effort.
Why universal welfare rights are impossible and what it means
Authors: Frederick Danny
Published: September 2010

Cranston argued that scarcity makes universal welfare rights impossible. After showing that this argument cannot be avoided by denying scarcity, I consider four challenges to the argument which accept the possibility of conflicts between the duties implied by rights. The first denies the agglomeration principle; the second embraces conflicts of duties; the third affirms the violability of all rights-based duties; and the fourth denies that duties to compensate are overriding. I argue that all four challenges to the scarcity argument are unsuccessful. I then discuss Eddy’s recent challenge, which makes welfare rights context dependent, but I argue that this also fails because it makes rights unknowable. I conclude that the scarcity argument, restated in the light of the discussion, shows that universal welfare rights, as ordinarily understood, are impossible and I explain the philosophical and practical significance of this conclusion.
The effectiveness of the Talking Mats framework in helping people with dementia to express their views on well-being
Authors: Murphy Joan , Gray Cindy M. , van Achterberg Theo , Wyke Sally , Cox Sylvia
Published: September 2010

Deteriorating communication is one of the most distressing aspects of dementia and it becomes increasingly difficult to ensure that the person’s views are heard. This study involved 31 people at different stages of dementia who were each interviewed about their well-being using Talking Mats, a low-tech communication framework, and usual communication methods. The communication effectiveness of each method was compared. This study found that the Talking Mats framework was associated with better communication at all stages of dementia compared to usual communication methods. Better communication effectiveness was evident in the participants’ understanding, engagement, keeping on-track and ability to make their views understood. There was also less repetitive behaviour and less distractibility when using the Talking Mats framework. The findings suggest that the Talking Mats framework can play an important role in improving communication by providing an accessible, low cost tool which family and staff can use with people with dementia to help them express their views.
Patterns of Cognitive Decline, Conversion Rates, and Predictive Validity for 3 Models of MCI
Authors: Ritchie Lesley J. , Tuokko Holly
Published: September 2010

Our objective was to compare the predictive ability of different models of mild cognitive impairment (MCI) as a marker of incipient dementia in a longitudinal population-based Canadian sample. We examined the use of existing, well-documented MCI criteria using data from persons who underwent a clinical examination in the second wave of the Canadian Study of Health and Aging (CSHA). Demographic characteristics, average neuropsychological test performance, and sample frequencies and conversion rates were calculated for each classification. Receiver operating characteristic (ROC) analyses were employed to assess the predictive power of each cognitive classification. The highest sample frequencies and conversion rates were associated with case definitions of multiple-domain MCI. The only diagnostic criteria to significantly predict dementia 5 years later was the cognitive impairment no dementia (CIND)-2 case definition. More restrictive MCI case definitions fail to address the varying temporal increases in decline across different cognitive domains in the progression from normal cognitive functioning and dementia.
Distrust and Simultaneous Activation of Multiple Categories
Authors: Friesen Justin , Sinclair Lisa
Published: September 2010

Two studies examined the effects of distrust on social categorization. In Study 1, undergraduate participants completed a distrust or neutral prime, watched a video of a Black or White doctor, and then completed a lexical decision task containing words related to the categories of Black people and doctors. Distrustful participants who viewed a Black doctor activated the Black and doctor categories. No other participants showed category activation. Study 2 added a trust prime condition and a no video control condition. Only distrustful participants who viewed a Black doctor activated the Black and doctor categories. Thus, when perceivers are distrustful they may reserve judgment about which individual categories apply to an out-group member and instead simultaneously activate multiple categories.
Sequential treatment of CD34+ cells from patients with primary myelofibrosis with chromatin-modifying agents eliminate JAK2V617F-positive NOD/SCID marrow repopulating cells
Authors: Wang Xiaoli , Zhang Wei , Tripodi Joseph , Lu Min , Xu Mingjiang , Najfeld Vesna , Li Yan , Hoffman Ronald
Published: September 2010

Because primary myelofibrosis (PMF) originates at the level of the pluripotent hematopoietic stem cell (HSC), we examined the effects of various therapeutic agents on the in vitro and in vivo behavior of PMF CD34+ cells. Treatment of PMF CD34+ cells with chromatin-modifying agents (CMAs) but not hydroxyurea, Janus kinase 2 (JAK2) inhibitors, or low doses of interferon-α led to the generation of greater numbers of CD34+ chemokine (C-X-C motif) receptor (CXCR)4+ cells, which were capable of migrating in response to chemokine (C-X-C motif) ligand (CXCL)12 and resulted in a reduction in the proportion of hematopoietic progenitor cells (HPCs) that were JAK2V617F+. Furthermore, sequential treatment of PMF CD34+ cells but not normal CD34+ cells with decitabine (5-aza-2′-deoxycytidine [5azaD]), followed by suberoylanilide hydroxamic acid (SAHA; 5azaD/SAHA), or trichostatin A (5azaD/TSA) resulted in a higher degree of apoptosis. Two to 6 months after the transplantation of CMAs treated JAK2V617F+ PMF CD34+ cells into nonobese diabetic/severe combined immunodeficient (SCID)/IL-2Rγnull mice, the percentage of JAK2V617F/JAK2total in human CD45+ marrow cells was dramatically reduced. These findings suggest that both PMF HPCs, short-term and long-term SCID repopulating cells (SRCs), are JAK2V617F+ and that JAK2V617F+ HPCs and SRCs can be eliminated by sequential treatment with CMAs. Sequential treatment with CMAs, therefore, represents a possible effective means of treating PMF at the level of the malignant SRC.
Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia
Authors: Chen Jing , Petrus Mike , Bryant Bonita R. , Phuc Nguyen Vinh , Goldman Carolyn K. , Bamford Richard , Morris John C. , Janik John E. , Waldmann Thomas A.
Published: September 2010

Adult T-cell leukemia (ATL), a heterogeneous disease, can be divided into smoldering, chronic, lymphoma, and acute types clinically. In addition to different clinical manifestations, different stages of ATL have different molecular signatures. Here, we demonstrated that smoldering/chronic ATL peripheral blood mononuclear cells spontaneously proliferated ex vivo in a cytokine (interleukin -12 [IL-12]/IL-9/IL-15)–dependent manner, while acute-type ATL peripheral blood mononuclear cells did not proliferate or proliferated independent of cytokines. Smoldering/chronic ATL cells produced IL-2 and IL-9 in 6-day ex vivo cultures. Interestingly, the addition of an anti–IL-2R-α monoclonal antibody profoundly inhibited IL-9 expression, suggesting optimal expression of IL-9 was dependent on IL-2 signaling in these patients. To determine whether there would be autonomous proliferation of ATL leukemic cells, we purified leukemic cells from patients with smoldering/chronic ATL. Purified leukemic cells cultured alone produced IL-2/IL-9, and the downstream Janus kinase/signal transducer and activator of transcription pathway was activated. However, the leukemic cells did not proliferate independently, but required coculture with autologous monocytes to induce proliferation. Moreover, interaction between leukemic cells and monocytes was contact dependent, and major histocompatibility complex class II expression may have contributed to this interaction. In conclusion, our data provide evidence that there is autocrine/paracrine cytokine stimulation of leukemic cell proliferation in patients with smoldering/chronic ATL that could be targeted for treatment.
Does microgranular variant morphology of acute promyelocytic leukemia independently predict a less favorable outcome compared with classical M3 APL? A joint study of the North American Intergroup and the PETHEMA Group
Authors: Tallman Martin S. , Kim Haesook T. , Montesinos Pau , Appelbaum Frederick R. , de la Serna Javier , Bennett John M. , Deben Guillermo , Bloomfield Clara D. , Gonzalez Jose , Feusner James H. , Gonzalez Marcos , Gallagher Robert , Miguel Jose D. Gonzalez-San , Larson Richard A. , Milone Gustavo , Paietta Elisabeth , Rayon Chelo , Rowe Jacob M. , Rivas Concha , Schiffer Charles A. , Vellenga Edo , Shepherd Lois , Slack James L. , Wiernik Peter H. , Willman Cheryl L. , Sanz Miguel A.
Published: September 2010

Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid–based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.
Clinical and genetic features of therapy-related myeloid neoplasms after chemotherapy for acute promyelocytic leukemia
Authors: Imagawa Jun , Harada Yuka , Shimomura Takeshi , Tanaka Hideo , Okikawa Yoshiko , Hyodo Hideo , Kimura Akiro , Harada Hironori
Published: September 2010

Acute promyelocytic leukemia (APL) is a highly curable disease with excellent complete remission and long-term survival rates. However, the development of therapy-related myeloid neoplasms (t-MN) is being reported with increasing frequency in patients successfully treated for APL. We attempted to clarify the different clinical features and hematologic findings between t-MN and relapse cases, and to identify gene alterations involved in t-MN. We compared 10 relapse and 11 t-MN cases that developed in 108 patients during their first complete remission from APL. At APL diagnosis, t-MN patients had lower white blood cell counts than did relapse patients (P = .048). Overall survival starting from chemotherapy was significantly worse in t-MN patients than in relapse patients (P = .022). The t-MN cases were characterized as CD34+/HLA-DR+ and PML-RARA−, and 4 RUNX1/AML1 mutations were detected. T-MN is easily distinguished from APL relapse by evaluating these hematologic features, and it may originate from primitive myeloid cells by chemotherapy-induced RUNX1 mutations.
Preferential nuclear accumulation of JAK2V617F in CD34+ but not in granulocytic, megakaryocytic, or erythroid cells of patients with Philadelphia-negative myeloproliferative neoplasia
Authors: Rinaldi Ciro R. , Rinaldi Paola , Alagia Adele , Gemei Marica , Esposito Nicola , Formiggini Fabio , Martinelli Vincenzo , Senyuk Vitalyi , Nucifora Giuseppina , Pane Fabrizio
Published: September 2010

Recently, Dawson et al identified a previously unrecognized nuclear role of JAK2 in the phosphorylation of histone H3 in hematopoietic cell lines. We searched nuclear JAK2 in total bone marrow (BM) cells and in 4 sorted BM cell populations (CD34+, CD15+, CD41+, and CD71+) of 10 myeloproliferative neoplasia (MPN) patients with JAK2V617F mutation and 5 patients with wild-type JAK2 MPN. Confocal immunofluorescent images and Western blot analyses of nuclear and cytoplasmic fractions found nuclear JAK2 in CD34+ cells of 10 of 10 JAK2-mutated patients but not in patients with wild-type JAK2. JAK2 was predominantly in the cytoplasmic fraction of differentiated granulocytic, megakaryocytic, or erythroid cells obtained from all patients. JAK2V617F up-regulates LMO2 in K562 and in JAK2V617F-positive CD34+ cells. The selective JAK2 inhibitor AG490 normalizes the LMO2 levels in V617F-positive K562 and restores the cyto-plasmic localization of JAK2.
The effects of oligomerization on Saccharomyces cerevisiae Mcm4/6/7 function
Authors: Ma Xiaoli , Stead Brent E , Rezvanpour Atoosa , Davey Megan J
Published: September 2010

Background

Minichromosome maintenance proteins (Mcm) 2, 3, 4, 5, 6 and 7 are related by sequence and form a variety of complexes that unwind DNA, including Mcm4/6/7. A Mcm4/6/7 trimer forms one half of the Mcm2-7 hexameric ring and can be thought of as the catalytic core of Mcm2-7, the replicative helicase in eukaryotic cells. Oligomeric analysis of Mcm4/6/7 suggests that it forms a hexamer containing two Mcm4/6/7 trimers, however, under certain conditions trimeric Mcm4/6/7 has also been observed. The functional significance of the different Mcm4/6/7 oligomeric states has not been assessed. The results of such an assessment would have implications for studies of both Mcm4/6/7 and Mcm2-7.

Results

Here, we show that Saccharomyces cerevisiae Mcm4/6/7 reconstituted from individual subunits exists in an equilibrium of oligomeric forms in which smaller oligomers predominate in the absence of ATP. In addition, we found that ATP, which is required for Mcm4/6/7 activity, shifts the equilibrium towards larger oligomers, likely hexamers of Mcm4/6/7. ATPγS and to a lesser extent ADP also shift the equilibrium towards hexamers. Study of Mcm4/6/7 complexes containing mutations that interfere with the formation of inter-subunit ATP sites (arginine finger mutants) indicates that full activity of Mcm4/6/7 requires all of its ATP sites, which are formed in a hexamer and not a trimer. In keeping with this observation, Mcm4/6/7 binds DNA as a hexamer.

Conclusions

The minimal functional unit of Mcm4/6/7 is a hexamer. One of the roles of ATP binding by Mcm4/6/7 may be to stabilize formation of hexamers.
PeptideMine - A webserver for the design of peptides for protein-peptide binding studies derived from protein-protein interactomes
Authors: Shameer Khader , Madan Lalima L , Veeranna Shivamurthy , Gopal Balasubramanian , Sowdhamini Ramanathan
Published: September 2010

Background

Signal transduction events often involve transient, yet specific, interactions between structurally conserved protein domains and polypeptide sequences in target proteins. The identification and validation of these associating domains is crucial to understand signal transduction pathways that modulate different cellular or developmental processes. Bioinformatics strategies to extract and integrate information from diverse sources have been shown to facilitate the experimental design to understand complex biological events. These methods, primarily based on information from high-throughput experiments, have also led to the identification of new connections thus providing hypothetical models for cellular events. Such models, in turn, provide a framework for directing experimental efforts for validating the predicted molecular rationale for complex cellular processes. In this context, it is envisaged that the rational design of peptides for protein-peptide binding studies could substantially facilitate the experimental strategies to evaluate a predicted interaction. This rational design procedure involves the integration of protein-protein interaction data, gene ontology, physico-chemical calculations, domain-domain interaction data and information on functional sites or critical residues.

Results

Here we describe an integrated approach called "PeptideMine" for the identification of peptides based on specific functional patterns present in the sequence of an interacting protein. This approach based on sequence searches in the interacting sequence space has been developed into a webserver, which can be used for the identification and analysis of peptides, peptide homologues or functional patterns from the interacting sequence space of a protein. To further facilitate experimental validation, the PeptideMine webserver also provides a list of physico-chemical parameters corresponding to the peptide to determine the feasibility of using the peptide for in vitro biochemical or biophysical studies.

Conclusions

The strategy described here involves the integration of data and tools to identify potential interacting partners for a protein and design criteria for peptides based on desired biochemical properties. Alongside the search for interacting protein sequences using three different search programs, the server also provides the biochemical characteristics of candidate peptides to prune peptide sequences based on features that are most suited for a given experiment. The PeptideMine server is available at the URL: http://caps.ncbs.res.in/peptidemine
Therapeutic angiogenesis by transplantation of induced pluripotent stem cell-derived Flk-1 positive cells
Authors: Suzuki Hirohiko , Shibata Rei , Kito Tetsutaro , Ishii Masakazu , Li Ping , Yoshikai Toru , Nishio Naomi , Ito Sachiko , Numaguchi Yasushi , Yamashita Jun K , Murohara Toyoaki , Isobe Kenichi
Published: September 2010

Background

Induced pluripotent stem (iPS) cells are the novel stem cell population induced from somatic cells. It is anticipated that iPS will be used in the expanding field of regenerative medicine. Here, we investigated whether implantation of fetal liver kinase-1 positive (Flk-1+) cells derived from iPS cells could improve angiogenesis in a mouse hind limb model of ischemia.

Results

Flk-1+ cells were induced from iPS cells after four to five days of culture. Hind limb ischemia was surgically induced and sorted Flk-1+ cells were directly injected into ischemic hind limbs of athymic nude mice. Revascularization of the ischemic hind limb was accelerated in mice that were transplanted with Flk-1+ cells compared with control mice, which were transplanted with vehicle, as evaluated by laser Doppler blood flowmetry. Transplantation of Flk-1+ cells also increased expression of VEGF mRNA in ischemic tissue compared to controls.

Conclusions

Direct local implantation of iPS cell-derived Flk-1+ cells would salvage tissues from ischemia. These data indicate that iPS cells could be valuable in the therapeutic induction of angiogenesis.
Characterising B cell numbers and memory B cells in HIV infected and uninfected Malawian adults
Authors: Longwe Herbert , Gordon Stephen , Malamba Rose , French Neil
Published: September 2010

Background

Untreated human immunodeficiency virus (HIV) disease disrupts B cell populations causing reduced memory and reduced naïve resting B cells leading to increases in specific co-infections and impaired responses to vaccines. To what extent antiretroviral treatment reverses these changes in an African population is uncertain.

Methods

A cross-sectional study was performed. We recruited HIV-uninfected and HIV-infected Malawian adults both on and off antiretroviral therapy attending the Queen Elizabeth Central hospital in Malawi. Using flow cytometry, we enumerated B cells and characterized memory B cells and compared these measurements by the different recruitment groups.

Results

Overall 64 participants were recruited - 20 HIV uninfected (HIV-), 30 HIV infected ART naïve (HIV+N) and 14 HIV-infected ART treated (HIV+T). ART treatment had been taken for a median of 33 months (Range 12-60 months). Compared to HIV- the HIV+N adults had low absolute number of naïve resting B cells (111 vs. 180 cells/μl p = 0.008); reduced memory B cells (27 vs. 51 cells/μl p = 0.0008). The HIV+T adults had B-cell numbers similar to HIV- except for memory B cells that remained significantly lower (30 vs. 51 cells/μl p = 0.02). In the HIV+N group we did not find an association between CD4 count and B cell numbers.

Conclusions

HIV infected Malawian adults have abnormal B-cell numbers. Individuals treated with ART show a return to normal in B-cell numbers but a persistent deficit in the memory subset is noted. This has important implications for long term susceptibility to co-infections and should be evaluated further in a larger cohort study.
A six-generation Chinese family in haplogroup B4C1C exhibits high penetrance of 1555A > G-induced hearing Loss
Authors: Bai Yan , Wang Zhengmin , Dai Wenjia , Li Qingzhong , Chen Guoling , Cong Ning , Guan Minxin , Li Huawei
Published: September 2010

Background

The 1555A > G mutation is the most common cause of aminoglycoside-induced and non-syndromic deafness. However, the variable clinical phenotype and incomplete penetrance of A1555G-induced hearing loss complicate our understanding of this mutation. Environmental factors, nuclear genes, mitochondrial haplotypes/variants and a possible threshold effect have been reported to may be involved in its manifestation.

Methods

Here, we performed a clinical, molecular, genetic and phylogenic analysis in a six-generation Chinese family.

Results

A clinical evaluation revealed that affected individuals without aminoglycoside exposure developed hearing loss extending gradually from 12000 Hz to 8000 Hz and then to 4000 Hz. Using pyrosequencing, we detected an identical homoplasmic 1555A > G mutation in all individuals except one. We did not find any correlation between the mutation load and the severity of hearing loss. T123N coexisted with the 1555A > G mutation in six affected subjects in our pedigree. Analysis of the complete mtDNA genome of this family revealed that this family belonged to haplotype B4C1C and exhibited high penetrance. Upon the inclusion of subjects that had been exposed to aminoglycosides, the penetrance of the hearing loss was 63.6%.; without exposure to aminoglycosides, it was 51.5%. This pedigree and another reported Chinese pedigree share the same haplotype (B4C1C) and lack functionally significant mitochondrial tRNA variants, but nevertheless they exhibit a different penetrance of hearing loss.

Conclusions

Our results imply that the factors responsible for the higher penetrance and variable expression of the deafness associated with the 1555A > G mutation in this pedigree may not be mtDNA haplotype/variants, but rather nuclear genes and/or aminoglycosides.
Variant rs9939609 in the FTO gene is associated with body mass index among Chinese children
Authors: Fang Hongyun , Li Yanping , Du Songming , Hu Xiaoqi , Zhang Qian , Liu Ailing , Ma Guansheng
Published: September 2010

Background

Fat-mass and obesity-associated (FTO) gene is a gene located in chromosome region 16q12.2. Genetic variants in FTO are associated with the obesity phenotype in European and Hispanic populations. However, this association still remains controversial in Asian population. We aimed to test the association of FTO genetic variants with obesity and obesity-related metabolic traits among children living in Beijing, China.

Methods

We genotyped FTO variants rs9939609 in 670 children (332 girls and 338 boys) aged 8-11 years living in Beijing, and analyzed its association with obesity and obesity-related metabolic traits. Overweight and obesity were defined by age- and sex-specific BMI reference for Chinese children. Obesity-related metabolic traits included fasting plasma glucose, lipid profiles, leptin, ghrelin, adiponectin and blood pressures.

Results

The frequency of rs9939609 A allele was 12.2%, which was 21.9% for the heterozygote and 1.2% for the homozygote of the A allele. The obesity prevalence among the carriers of AA/AT genotypes was significantly higher than that among those with TT genotype (36.4% vs. 22.6%, P = 0.004). Compared to the carrier of TT genotype, the likelihood of obesity was 1.79 (95% confidence interval (95% CI) 1.20-2.67, P = 0.004) for the carrier of AA/AT genotype, after adjustment of sex, age and puberty stages. The BMI Z-score of children with AA/AT genotype were significantly higher than that of their counterparts with the TT genotype (1.1 ± 0.1 vs. 0.8 ± 0.1, P = 0.02). The concentration of triglyceride was 1.03 ± 0.52 mmol/L among TT carrier and 1.13 ± 0.68 mmol/L among AA/AT carrier (P = 0.045). While, the concentrations of adiponectin were 18.0 ± 0.4 μg/ml among carriers of TT and 16.2 ± 0.7 μg/ml among subjects with AA/AT genotype (P = 0.03). The level of glucose marginally increased in the AA/AT genotype subjects (4.67 ± 0.40 mmol/L vs. 4.60 ± 0.35 mmol/L, P = 0.08). The evidence of association was reduced after adjustment for BMI (P = 0.38 for triglyceride, P = 0.20 for adiponectin and glucose). There was weak evidence of association between rs9939609 and other obesity-related metabolic traits including total cholesterol (3.92 ± 0.03 mmol/L vs. 4.02 ± 0.05 mmol/L, P = 0.10), insulin (2.69 ± 1.77 ng/ml vs. 3.12 ± 2.91 ng/ml, P = 0.14), and insulin resistance (HOMA-IR 0.56 ± 0.03 vs. 0.66 ± 0.05, P = 0.10).

Conclusions

Genetic variation in the FTO gene associates with obesity in Chinese children.
Novel association of severe neonatal encephalopathy and Hirschsprung disease in a male with a duplication at the Xq28 region
Authors: Fernández Raquel M , Núñez-Torres Rocío , González-Meneses Antonio , Antiñolo Guillermo , Borrego Salud
Published: September 2010

Background

Hirschsprung disease (HSCR) is a neurocristopathy characterized by the absence of parasympathetic intrinsic ganglion cells in the submucosal and myenteric plexuses along a variable portion of the intestinal tract. In approximately 18% of the cases HSCR also presents with multiple congenital anomalies including recognized syndromes.

Methods

A combination of MLPA and microarray data analysis have been undertaken to refine a duplication at the Xq28 region.

Results

In this study we present a new clinical association of severe neonatal encephalopathy (Lubs syndrome) and HSCR, in a male patient carrying a duplication at the Xq28 region which encompasses the MECP2 and L1CAM genes.

Conclusions

While the encephalopathy has been traditionally attributed to the MECP2 gene duplication in patients with Lubs syndrome, here we propose that the enteric phenotype in our patient might be due to the dosage variation of the L1CAM protein, together with additional molecular events not identified yet. This would be in agreement with the hypothesis previously forwarded that mutations in L1CAM may be involved in HSCR development in association with a predisposing genetic background.
17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells
Authors: Karkoulis Panagiotis K , Stravopodis Dimitrios J , Margaritis Lukas H , Voutsinas Gerassimos E
Published: September 2010

Background

17-Allylamino-17-demethoxygeldanamycin (17-AAG), a benzoquinone ansamycin antibiotic, specifically targets heat shock protein 90 (Hsp90) and interferes with its function as a molecular chaperone that maintains the structural and functional integrity of various protein clients involved in cellular signaling. In this study, we have investigated the effect of 17-AAG on the regulation of Hsp90-dependent signaling pathways directly implicated in cell cycle progression, survival and motility of human urinary bladder cancer cell lines.

Methods

We have used MTT-based assays, FACS analysis, Western blotting, semi-quantitative RT-PCR, immunocytochemistry and scratch-wound assay in RT4, RT112 and T24 human urinary bladder cancer cell lines.

Results

We have demonstrated that, upon 17-AAG treatment, bladder cancer cells are arrested in the G1 phase of the cell cycle and eventually undergo apoptotic cell death in a dose-dependent manner. Furthermore, 17-AAG administration was shown to induce a pronounced downregulation of multiple Hsp90 protein clients and other downstream effectors, such as IGF-IR, Akt, IKK-α, IKK-β, FOXO1, ERK1/2 and c-Met, resulting in sequestration-mediated inactivation of NF-κB, reduced cell proliferation and decline of cell motility.

Conclusions

In total, we have clearly evinced a dose-dependent and cell type-specific effect of 17-AAG on cell cycle progression, survival and motility of human bladder cancer cells, due to downregulation of multiple Hsp90 clients and subsequent disruption of signaling integrity.
Fibronectin 1 mRNA expression correlates with advanced disease in renal cancer
Authors: Waalkes Sandra , Atschekzei Faranaz , Kramer Mario W , Hennenlotter Jörg , Vetter Gesa , Becker Jan U , Stenzl Arnulf , Merseburger Axel S , Schrader Andres J , Kuczyk Markus A , Serth Jürgen
Published: September 2010

Background

Fibronectin 1 (FN1) is a glycoprotein involved in cellular adhesion and migration processes. The aim of this study was to elucidate the role of FN1 in development of renal cell cancer (RCC) and to determine a prognostic relevance for optimal clinical management.

Methods

212 renal tissue samples (109 RCC, 86 corresponding tissues from adjacent normal renal tissue and 17 oncocytomas) were collected from patients undergoing surgery for renal tumors and subjected to total RNA extraction. Detection of FN1 mRNA expression was performed using quantitative real time PCR, three endogenous controls, renal proximal tubular epithelial cells (RPTEC) as biological control and the ΔΔCt method for calculation of relative quantities.

Results

Mean tissue specific FN1 mRNA expression was found to be increased approximately seven fold comparing RCC and corresponding kidney control tissues (p < 0.001; ANOVA). Furthermore, tissue specific mean FN1 expression was increased approx. 11 fold in clear cell compared to papillary RCC (p = 9×10-5; Wilcoxon rank sum test). Patients with advanced disease had higher FN1 expression when compared to organ-confined disease (p < 0.001; Wilcoxon rank sum test). Applying subgroup analysis we found a significantly higher FN1 mRNA expression between organ-confined and advanced disease in the papillary and not in the clear cell RCC group (p = 0.02 vs. p = 0.2; Wilcoxon rank sum test). There was an increased expression in RCC compared to oncocytoma (p = 0.016; ANOVA).

Conclusions

To our knowledge, this is the first study to show that FN1 mRNA expression is higher in RCC compared to normal renal tissue. FN1 mRNA expression might serve as a marker for RCC aggressiveness, indicating early systemic progression particularly for patients with papillary RCC.
Educational inequalities in mortality and associated risk factors: German- versus French-speaking Switzerland
Authors: Faeh David , Bopp Matthias ,   Swiss National Cohort Study Group
Published: September 2010

Background

Between the French- and German-speaking areas of Switzerland, there are distinct differences in mortality, similar to those between Germany and France. Assessing corresponding inequalities may elucidate variations in mortality and risk factors, thereby uncovering public health potential. Our aim was to analyze educational inequalities in all-cause and cause-specific mortality in the two Swiss regions and to compare this with inequalities in behavioural risk factors and self-rated health.

Methods

The Swiss National Cohort, a longitudinal census-based record linkage study, provided mortality and survival time data (3.5 million individuals, 40-79 years, 261,314 deaths, 1990-2000). The Swiss Health Survey 1992/93 provided cross-sectional data on risk factors. Inequalities were calculated as percentage of change in mortality rate (survival time, hazard ratio) or risk factor prevalence (odds ratio) per year of additional education using multivariable Cox and logistic regression.

Results

Significant inequalities in mortality were found for all causes of death in men and for most causes in women. Inequalities were largest in men for causes related to smoking and alcohol use and in women for circulatory diseases. Gradients in all-cause mortality were more pronounced in younger and middle-aged men, especially in German-speaking Switzerland. Mortality inequalities tended to be larger in German-speaking Switzerland whereas inequalities in associated risk factors were generally more pronounced in French-speaking Switzerland.

Conclusions

With respect to inequalities in mortality and associated risk factors, we found characteristic differences between German- and French-speaking Switzerland, some of which followed gradients described in Europe. These differences only partially reflected inequalities in associated risk factors.
Urbanization, ethnicity and cardiovascular risk in a population in transition in Nakuru, Kenya: a population-based survey
Authors: Mathenge Wanjiku , Foster Allen , Kuper Hannah
Published: September 2010

Background

Cardiovascular disease (CVD) is the leading cause of death among older people in Africa. This study aimed to investigate the relationship of urbanization and ethnicity with CVD risk markers in Kenya.

Methods

A cross-sectional population-based survey was carried out in Nakuru Kenya in 2007-2008. 100 clusters of 50 people aged ≥50 years were selected by probability proportionate to size sampling. Households within clusters were selected through compact segment sampling. Participants were interviewed by nurses to collect socio-demographic and lifestyle information. Nurses measured blood pressure, height, weight and waist and hip circumference. A random finger-prick blood sample was taken to measure glucose and cholesterol levels.

Hypertension was defined as systolic blood pressure (SBP) ≥140 mm Hg, or diastolic blood pressure (DBP) ≥90 mm Hg or current use of antihypertensive medication; Diabetes as reported current medication or diet control for diabetes or random blood glucose level ≥11.1 mmol/L; High cholesterol as random blood cholesterol level ≥5.2 mmol/L; and Obesity as Body Mass Index (BMI)≥30 kg/m2.

Results

5010 eligible subjects were selected, of whom 4396 (88%) were examined. There was a high prevalence of hypertension (50.1%, 47.5-52.6%), obesity (13.0%, 11.7-14.5%), diabetes (6.6%, 5.6-7.7%) and high cholesterol (21.1%, 18.6-23.9). Hypertension, diabetes and obesity were more common in urban compared to rural groups and the elevated prevalence generally persisted after adjustment for socio-demographic, lifestyle, obesity and cardiovascular risk markers. There was also a higher prevalence of hypertension, obesity, diabetes and high cholesterol among Kikuyus compared to Kalenjins, even after multivariate adjustment. CVD risk markers were clustered both across the district and within individuals. Few people received treatment for hypertension (15%), while the majority of cases with diabetes received treatment (68%).

Conclusions

CVD risk markers are common in Kenya, particularly in urban areas. Exploring differences in CVD risk markers between ethnic groups may help to elucidate the epidemiology of these conditions.
Electrocardiographic changes with the onset of diabetes and the impact of aerobic exercise training in the Zucker Diabetic Fatty (ZDF) rat
Authors: VanHoose Lisa , Sawers Youssef , Loganathan Rajprasad , Vacek James L , Stehno-Bittel Lisa , Novikova Lesya , Al-Jarrah Muhammed , Smirnova Irina V
Published: September 2010

Background

Early markers of diabetic autonomic neuropathy (DAN) in an electrocardiogram (ECG) include elevated R wave amplitudes, widening of QTc intervals and decreased heart rate variability (HRV). The severity of DAN has a direct relationship with mortality risk. Aerobic exercise training is a common recommendation for the delay and possible reversal of cardiac dysfunction. Limited research exists on ECG measures for the evaluation of aerobic exercise training in Zucker Diabetic Fatty (ZDF) rat, a model of type 2 diabetes. The objective of this study was to assess whether aerobic exercise training may attenuate diabetes induced ECG changes.

Methods

Male ZDF (obese fa/fa) and control Zucker (lean fa/+) rats were assigned to 4 groups: sedentary control (SC), sedentary diabetic (SD), exercised control (EC) and exercised diabetic (ED). The exercised groups began 7 weeks of treadmill training after the development of diabetes in the ED group. Baseline (prior to the training) and termination measurements included body weight, heart weight, blood glucose and glycated hemoglobin levels and ECG parameters. One way repeated measures ANOVA (group) analyzed within and between subject differences and interactions. Pearson coefficients and descriptive statistics described variable relationships and animal characteristics.

Results

Diabetes caused crucial changes in R wave amplitudes (p < 0.001), heart rate variability (p < 0.01), QT intervals (p < 0.001) and QTc intervals (p < 0.001). R wave amplitude augmentation in SD rats from baseline to termination was ameliorated by exercise, resulting in R wave amplitude changes in ED animals similar to control rats. Aerobic exercise training neither attenuated QT or QTc interval prolongation nor restored decreases in HRV in diabetic rats.

Conclusion

This study revealed alterations in R wave amplitudes, HRV, QT and QTc intervals in ZDF rats. Of these changes, aerobic exercise training was able to correct R wave amplitude changes. In addition, exercise has beneficial effect in this diabetic rat model in regards to ECG correlates of left ventricular mass.
Salirasib inhibits the growth of hepatocarcinoma cell lines in vitro and tumor growth in vivo through ras and mTOR inhibition
Authors: Charette Nicolas , De Saeger Christine , Lannoy Valérie , Horsmans Yves , Leclercq Isabelle , Stärkel Peter
Published: September 2010

Background

Dysregulation of epidermal growth factor and insulin-like growth factor signaling play important roles in human hepatocellular carcinoma (HCC), leading to frequent activation of their downstream targets, the ras/raf/extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) pathways. Salirasib is an S-prenyl-cysteine analog that has been shown to block ras and/or mTOR activation in several non hepatic tumor cell lines. We investigated in vitro the effect of salirasib on cell growth as well as its mechanism of action in human hepatoma cell lines (HepG2, Huh7, and Hep3B) and its in vivo effect in a subcutaneous xenograft model with HepG2 cells.

Results

Salirasib induced a time and dose dependent growth inhibition in hepatocarcinoma cells through inhibition of proliferation and partially through induction of apoptosis. A 50 percent reduction in cell growth was obtained in all three cell lines at a dose of 150 μM when they were cultured with serum. By contrast, salirasib was more potent at reducing cell growth after stimulation with EGF or IGF2 under serum-free conditions, with an IC50 ranging from 60 μM to 85 μM. The drug-induced anti-proliferative effect was associated with downregulation of cyclin A and to a lesser extent of cyclin D1, and upregulation of p21 and p27. Apoptosis induction was related to a global pro-apoptotic balance with caspase 3 activation, cytochrome c release, death receptor upregulation, and a reduced mRNA expression of the apoptosis inhibitors cFLIP and survivin. These effects were associated with ras downregulation and mTOR inhibition, without reduction of ERK and Akt activation. In vivo, salirasib reduced tumour growth from day 5 onwards. After 12 days of treatment, mean tumor weight was diminished by 56 percent in the treated animals.

Conclusions

Our results show for the first time that salirasib inhibits the growth of human hepatoma cell lines through inhibition of proliferation and induction of apoptosis, which is associated with ras and mTOR inhibition. The therapeutic potential of salirasib in human HCC was further confirmed in a subcutaneous xenograft model.
Association between CETP Taq1B and LIPC -514C/T polymorphisms with the serum lipid levels in a group of Tehran's population: a cross sectional study
Authors: Kashani Farid Mohammad Ali , Azizi Fereidoun , Hedayati Mehdi , Daneshpour Maryam S , Shamshiri Ahmad Reza , Siassi Fereydoun
Published: September 2010

Background

Low level of high density lipoprotein cholesterol (HDL-C) has high prevalence in the Tehran Lipid and Glucose Study (TLGS) cohort. About 50% of the inter-individual variation in serum HDL-C levels is genetically determined. Polymorphisms in cholesteryl ester transfer protein (CETP) and hepatic lipase (LIPC) genes have been found to be associated with the metabolism and serum concentration of the HDL-C.

Objectives

To determine the association between Taq1B polymorphism in CETP gene and -514C/T polymorphism in LIPC gene with serum lipid levels and lipid peroxidation in a subgroup of the TLGS population.

Results

Serum HDL-C level had significant association with CETP Taq1B polymorphism and B2B2 subjects had the highest HDL-C levels compared to B2B1 and B1B1 genotypes (37.9 vs. 36.9 and 35.3 mg/dl, respectively; P = 0.01). However, carriers of "B1" allele, in comparison to the non carriers (B2B2), had significantly lower levels of TC (200.1 vs. 215.2 mg/dl; P = 0.005), HDL-C (35.8 vs. 37.9 mg/dl; P = 0.009) and malondialdehyde MDA (4.5 vs. 5.0 nmol/mL; P=0.031). Carriers of the "T" allele in -514C/T polymorphism in LIPC gene had higher means of HDL-C than non carriers (37.7 vs. 35.7 mg/dl, P = 0.04). No other association was found between -514C/T polymorphism and any other serum lipids or MDA level.

Conclusion

This study demonstrates the association between Taq1B and -514C/T polymorphisms in the CETP and LIPC genes with the serum HDL-C levels.
Impact of pericardial adhesions on diastolic function as assessed by vortex formation time, a parameter of transmitral flow efficiency
Authors: Jiamsripong Panupong , Alharthi Mohsen S , Calleja Anna M , McMahon Eileen M , Katayama Minako , Westerdale John , Milano Michele , Heys Jeffrey J , Mookadam Farouk , Belohlavek Marek
Published: September 2010

Background

Pericardial adhesions are a pathophysiological marker of constrictive pericarditis (CP), which impairs cardiac filling by limiting the total cardiac volume compliance and diastolic filling function. We studied diastolic transmitral flow efficiency as a new parameter of filling function in a pericardial adhesion animal model. We hypothesized that vortex formation time (VFT), an index of optimal efficient diastolic transmitral flow, is altered by patchy pericardial-epicardial adhesions.

Methods

In 8 open-chest pigs, the heart was exposed while preserving the pericardium. We experimentally simulated early pericardial constriction and patchy adhesions by instilling instant glue into the pericardial space and using pericardial-epicardial stitches. We studied left ventricular (LV) function and characterized intraventricular blood flow with conventional and Doppler echocardiography at baseline and following the experimental intervention.

Results

Significant decreases in end-diastolic volume, ejection fraction, stroke volume, and late diastolic filling velocity reflected the effects of the pericardial adhesions. The mean VFT value decreased from 3.61 ± 0.47 to 2.26 ± 0.45 (P = 0.0002). Hemodynamic variables indicated the inhibiting effect of pericardial adhesion on both contraction (decrease in systolic blood pressure and +dP/dt decreased) and relaxation (decrease in the magnitude of -dP/dt and prolongation of Tau) function.

Conclusion

Patchy pericardial adhesions not only negatively impact LV mechanical functioning but the decrease of VFT from normal to suboptimal value suggests impairment of transmitral flow efficiency.