bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoxic induction of vascular endothelial growth factor regulates murine hematopoietic stem cell function in the low-oxygenic niche
Authors: Rehn Matilda , Olsson André , Reckzeh Kristian , Diffner Eva , Carmeliet Peter , Landberg Göran , Cammenga Jörg
Published: June 2011

Hypoxia is emerging as an important characteristic of the hematopoietic stem cell (HSC) niche, but the molecular mechanisms contributing to quiescence, self-renewal, and survival remain elusive. Vascular endothelial growth factor A (VEGFA) is a key regulator of angiogenesis and hematopoiesis. Its expression is commonly regulated by hypoxia-inducible factors (HIF) that are functionally induced in low-oxygen conditions and that activate transcription by binding to hypoxia-response elements (HRE). Vegfa is indispensable for HSC survival, mediated by a cell-intrinsic, autocrine mechanism. We hypothesized that a hypoxic HSC microenvironment is required for maintenance or up-regulation of Vegfa expression in HSCs and therefore crucial for HSC survival. We have tested this hypothesis in the mouse model Vegfaδ/δ, where the HRE in the Vegfa promoter is mutated, preventing HIF binding. Vegfa expression was reduced in highly purified HSCs from Vegfaδ/δ mice, showing that HSCs reside in hypoxic areas. Loss of hypoxia-regulated Vegfa expression increases the numbers of phenotypically defined hematopoietic stem and progenitor cells. However, HSC function was clearly impaired when assessed in competitive transplantation assays. Our data provide further evidence that HSCs reside in a hypoxic microenvironment and demonstrate a novel way in which the hypoxic niche affects HSC fate, via the hypoxia-VEGFA axis.
Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia
Authors: Badoux Xavier C. , Keating Michael J. , Wang Xuemei , O'Brien Susan M. , Ferrajoli Alessandra , Faderl Stefan , Burger Jan , Koller Charles , Lerner Susan , Kantarjian Hagop , Wierda William G.
Published: June 2011

Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes.
How I treat Gaucher disease
Authors: Zimran Ari
Published: June 2011

This review presents a cohesive approach to treating patients with Gaucher disease. The spectrum of the clinical presentation of the disease is broad, yet heretofore there was only one disease-specific treatment. In the past 2 years, a global shortage of this product has resulted in reassessment of the “one enzyme–one disease–one therapy” mantra. It has also showcased the multiple levels that engage the patient, the treating physician, and the third-party insurer in providing adequate treatment to all symptomatic patients. The key points summarizing the way I manage my patients include accurate enzymatic diagnosis with mutation analysis (for some prognostication and better carrier detection in the family), a detailed follow-up every 6-12 months (with an option to see consultants and attention to comorbidities), and initiation of enzyme replacement therapy according to symptoms or deterioration in clinically significant features or both. I do not treat patients with very mild disease, but I consider presymptomatic therapy for patients at risk, including young women with poor obstetric history. I prefer the minimal-effective dose rather than the maximally tolerated dose, and when the difference between high-dose and lower-dose regimens is (merely statistically significant but) clinically meaningless, minimizing the burden on society by advocating less-expensive treatments is ethically justified.
Mutations in GATA2 are associated with the autosomal dominant and sporadic monocytopenia and mycobacterial infection (MonoMAC) syndrome
Authors: Hsu Amy P. , Sampaio Elizabeth P. , Khan Javed , Calvo Katherine R. , Lemieux Jacob E. , Patel Smita Y. , Frucht David M. , Vinh Donald C. , Auth Roger D. , Freeman Alexandra F. , Olivier Kenneth N. , Uzel Gulbu , Zerbe Christa S. , Spalding Christine , Pittaluga Stefania , Raffeld Mark , Kuhns Douglas B. , Ding Li , Paulson Michelle L. , Marciano Beatriz E. , Gea-Banacloche Juan C. , Orange Jordan S. , Cuellar-Rodriguez Jennifer , Hickstein Dennis D. , Holland Steven M.
Published: June 2011

The syndrome of monocytopenia, B-cell and NK-cell lymphopenia, and mycobacterial, fungal, and viral infections is associated with myelodysplasia, cytogenetic abnormalities, pulmonary alveolar proteinosis, and myeloid leukemias. Both autosomal dominant and sporadic cases occur. We identified 12 distinct mutations in GATA2 affecting 20 patients and relatives with this syndrome, including recurrent missense mutations affecting the zinc finger-2 domain (R398W and T354M), suggesting dominant interference of gene function. Four discrete insertion/deletion mutations leading to frame shifts and premature termination implicate haploinsufficiency as a possible mechanism of action as well. These mutations were found in hematopoietic and somatic tissues, and several were identified in families, indicating germline transmission. Thus, GATA2 joins RUNX1 and CEBPA not only as a familial leukemia gene but also as a cause of a complex congenital immunodeficiency that evolves over decades and combines predisposition to infection and myeloid malignancy.
A minor role of CD4+ T lymphocytes in the control of a primary infection of cattle with Mycoplasma mycoides subsp. mycoides
Authors: Sacchini Flavio , Naessens Jan , Awino Elias , Heller Martin , Hlinak Andreas , Haider Wolfram , Sterner-Kock Anja , Jores Joerg
Published: June 2011

Contagious bovine pleuropneumonia (CBPP), caused by Mycoplasma mycoides subsp. mycoides, is an important livestock disease in Africa. The current control measures rely on a vaccine with limited efficacy and occasional severe side effects. Knowledge of the protective arms of immunity involved in this disease will be beneficial for the development of an improved vaccine. In previous studies on cattle infected with M. mycoides subsp. mycoides, a correlation was detected between the levels of mycoplasma-specific IFN-γ-secreting CD4+ T lymphocytes and reduced clinical signs. However, no cause and effect has been established, and the role of such cells and of protective responses acquired during a primary infection is not known.

We investigated the role of CD4+ T lymphocytes in CBPP by comparing disease patterns and post mortem findings between CD4+ T cell depleted and non-depleted cattle. The depletion was carried out using several injections of BoCD4 specific murine monoclonal antibody on day 6 after experimental endotracheal infection with the strain Afadé. All cattle were monitored clinically daily and sacrificed 28-30 days post-infection. Statistically significant but small differences were observed in the mortality rate between the depleted and non-depleted animals. However, no differences in clinical parameters (fever, signs of respiratory distress) and pathological lesions were observed, despite elimination of CD4+ T cells for more than a week. The slightly higher mortality in the depleted group suggests a minor role of CD4+ T cells in control of CBPP.
Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities
Authors: Fu Yao , Jarboe Laura R , Dickerson Julie A
Published: June 2011

Background

Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element.

Results

This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called G ene expression and T ranscription factor activity based R elevance N etwork (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by using our reconstructed network.

Conclusions

The GTRNetwork algorithm introduces the hidden layer TFA into classic relevance score-based gene regulatory network reconstruction processes. Integrating the TFA biological information with regulatory network reconstruction algorithms significantly improves both detection of new links and reduces that rate of false positives. The application of GTRNetwork on E. coli gene transcriptome data gives a set of potential regulatory links with promising biological significance for isobutanol stress and other conditions.
The Sphingosine-1-phospate receptor 1 mediates S1P action during cardiac development
Authors: Poulsen Ryan R , McClaskey Carolyn M , Rivkees Scott A , Wendler Christopher C
Published: June 2011

Background

Sphingosine-1-phosophate (S1P) is a biologically active sphingolipid metabolite that influences cellular events including differentiation, proliferation, and migration. S1P acts through five distinct cell surface receptors designated S1P1-5R, with S1P1R having the highest expression level in the developing heart. S1P1R is critical for vascular maturation, with its loss leading to embryonic death by E14.5; however, its function during early cardiac development is not well known. Our previous studies demonstrated that altered S1P levels adversely affects atrioventricular (AV) canal development in vitro, with reduced levels leading to cell death and elevated levels inhibiting cell migration and endothelial to mesenchymal cell transformation (EMT).

Results

We determined, by real-time PCR analysis, that S1P1R was expressed at least 10-fold higher than other S1P receptors in the developing heart. Immunohistochemical analysis revealed S1P1R protein expression in both endothelial and myocardial cells in the developing atrium and ventricle. Using AV canal cultures, we observed that treatment with either FTY720 (an S1P1,3,4,5R agonist) or KRP203 (an S1P1R-specific agonist) caused similar effects on AV canal cultures as S1P treatment, including induction of cell rounding, inhibition of cell migration, and inhibition of EMT. In vivo, morphological analysis of embryonic hearts at E10.5 revealed that S1P1R-/- hearts were malformed with reduced myocardial tissue. In addition to reduced myocardial tissue, E12.5 S1P1R-/- hearts had disrupted morphology of the heart wall and trabeculae, with thickened and disorganized outer compact layer and reduced fibronectin (FN) deposition compared to S1P1R+/+ littermates. The reduced myocardium was accompanied by a decrease in cell proliferation but not an increase in apoptosis.

Conclusions

These data indicate that S1P1R is the primary mediator of S1P action in AV canal cultures and that loss of S1P1R expression in vivo leads to malformed embryonic hearts, in part due to reduced fibronectin expression and reduced cell proliferation.
Characterization of single-nucleotide variation in Indian-origin rhesus macaques (Macaca mulatta)
Authors: Fawcett Gloria L , Raveendran Muthuswamy , Deiros David Rio , Chen David , Yu Fuli , Harris Ronald Alan , Ren Yanru , Muzny Donna M , Reid Jeffrey G , Wheeler David A , Worley Kimberly C , Shelton Steven E , Kalin Ned H , Milosavljevic Aleksandar , Gibbs Richard , Rogers Jeffrey
Published: June 2011

Background

Rhesus macaques are the most widely utilized nonhuman primate model in biomedical research. Previous efforts have validated fewer than 900 single nucleotide polymorphisms (SNPs) in this species, which limits opportunities for genetic studies related to health and disease. Extensive information about SNPs and other genetic variation in rhesus macaques would facilitate valuable genetic analyses, as well as provide markers for genome-wide linkage analysis and the genetic management of captive breeding colonies.

Results

We used the available rhesus macaque draft genome sequence, new sequence data from unrelated individuals and existing published sequence data to create a genome-wide SNP resource for Indian-origin rhesus monkeys. The original reference animal and two additional Indian-origin individuals were resequenced to low coverage using SOLiD™ sequencing. We then used three strategies to validate SNPs: comparison of potential SNPs found in the same individual using two different sequencing chemistries, and comparison of potential SNPs in different individuals identified with either the same or different sequencing chemistries. Our approach validated approximately 3 million SNPs distributed across the genome. Preliminary analysis of SNP annotations suggests that a substantial number of these macaque SNPs may have functional effects. More than 700 non-synonymous SNPs were scored by Polyphen-2 as either possibly or probably damaging to protein function and these variants now constitute potential models for studying functional genetic variation relevant to human physiology and disease.

Conclusions

Resequencing of a small number of animals identified greater than 3 million SNPs. This provides a significant new information resource for rhesus macaques, an important research animal. The data also suggests that overall genetic variation is high in this species. We identified many potentially damaging non-synonymous coding SNPs, providing new opportunities to identify rhesus models for human disease.
Identification of CRISPR and riboswitch related RNAs among novel noncoding RNAs of the euryarchaeon Pyrococcus abyssi
Authors: Phok Kounthéa , Moisan Annick , Rinaldi Dana , Brucato Nicolas , Carpousis Agamemnon J , Gaspin Christine , Clouet-d'Orval Béatrice
Published: June 2011

Background

Noncoding RNA (ncRNA) has been recognized as an important regulator of gene expression networks in Bacteria and Eucaryota. Little is known about ncRNA in thermococcal archaea except for the eukaryotic-like C/D and H/ACA modification guide RNAs.

Results

Using a combination of in silico and experimental approaches, we identified and characterized novel P. abyssi ncRNAs transcribed from 12 intergenic regions, ten of which are conserved throughout the Thermococcales. Several of them accumulate in the late-exponential phase of growth. Analysis of the genomic context and sequence conservation amongst related thermococcal species revealed two novel P. abyssi ncRNA families. The CRISPR family is comprised of crRNAs expressed from two of the four P. abyssi CRISPR cassettes. The 5'UTR derived family includes four conserved ncRNAs, two of which have features similar to known bacterial riboswitches. Several of the novel ncRNAs have sequence similarities to orphan OrfB transposase elements. Based on RNA secondary structure predictions and experimental results, we show that three of the twelve ncRNAs include Kink-turn RNA motifs, arguing for a biological role of these ncRNAs in the cell. Furthermore, our results show that several of the ncRNAs are subjected to processing events by enzymes that remain to be identified and characterized.

Conclusions

This work proposes a revised annotation of CRISPR loci in P. abyssi and expands our knowledge of ncRNAs in the Thermococcales, thus providing a starting point for studies needed to elucidate their biological function.
A species independent universal bio-detection microarray for pathogen forensics and phylogenetic classification of unknown microorganisms
Authors: Shallom Shamira J , Weeks Jenni N , Galindo Cristi L , McIver Lauren , Sun Zhaohui , McCormick John , Adams L Garry , Garner Harold R
Published: June 2011

Background

The ability to differentiate a bioterrorist attack or an accidental release of a research pathogen from a naturally occurring pandemic or disease event is crucial to the safety and security of this nation by enabling an appropriate and rapid response. It is critical in samples from an infected patient, the environment, or a laboratory to quickly and accurately identify the precise pathogen including natural or engineered variants and to classify new pathogens in relation to those that are known. Current approaches for pathogen detection rely on prior genomic sequence information. Given the enormous spectrum of genetic possibilities, a field deployable, robust technology, such as a universal (any species) microarray has near-term potential to address these needs.

Results

A new and comprehensive sequence-independent array (Universal Bio-Signature Detection Array) was designed with approximately 373,000 probes. The main feature of this array is that the probes are computationally derived and sequence independent. There is one probe for each possible 9-mer sequence, thus 49(262,144) probes. Each genome hybridized on this array has a unique pattern of signal intensities corresponding to each of these probes. These signal intensities were used to generate an un-biased cluster analysis of signal intensity hybridization patterns that can easily distinguish species into accepted and known phylogenomic relationships. Within limits, the array is highly sensitive and is able to detect synthetically mixed pathogens. Examples of unique hybridization signal intensity patterns are presented for differentBrucellaspecies as well as relevant host species and other pathogens. These results demonstrate the utility of the UBDA array as a diagnostic tool in pathogen forensics.

Conclusions

This pathogen detection system is fast, accurate and can be applied to any species. Hybridization patterns are unique to a specific genome and these can be used to decipher the identity of a mixed pathogen sample and can separate hosts and pathogens into their respective phylogenomic relationships. This technology can also differentiate between different species and classify genomes into their known clades. The development of this technology will result in the creation of an integrated biomarker-specific bio-signature, multiple select agent specific detection system.
Magnetic resonance imaging for lung cancer detection: Experience in a population of more than 10,000 healthy individuals
Authors: Wu Nai-Yuan , Cheng Hui-Cheng , Ko James S , Cheng Yu-Chen , Lin Po-Wei , Lin Wei-Chan , Chang Cheng-Yen , Liou Der-Ming
Published: June 2011

Background

Recent refinements of lung MRI techniques have reduced the examination time and improved diagnostic sensitivity and specificity. We conducted a study to assess the feasibility of MRI for the detection of primary lung cancer in asymptomatic individuals.

Methods

A retrospective chart review was performed on images of lung parenchyma, which were extracted from whole-body MRI examinations between October 2000 and December 2007. 11,766 consecutive healthy individuals (mean age, 50.4 years; 56.8% male) were scanned using one of two 1.5-T scanners (Sonata and Sonata Maestro, Siemens Medical Solutions, Erlangen, Germany). The standard protocol included a quick whole-lung survey with T2-weighted 2-dimensional half Fourier acquisition single shot turbo spin echo (HASTE) and 3-dimensional volumetric interpolated breath-hold examination (VIBE). Total examination time was less than 10 minutes, and scanning time was only 5 minutes. Prompt referrals and follow-ups were arranged in cases of suspicious lung nodules.

Results

A total of 559 individuals (4.8%) had suspicious lung nodules. A total of 49 primary lung cancers were diagnosed in 46 individuals: 41 prevalence cancers and 8 incidence cancers. The overall detection rate of primary lung cancers was 0.4%. For smokers aged 51 to 70 years, the detection rate was 1.4%. TNM stage I disease accounted for 37 (75.5%). The mean size of detected lung cancers was 1.98 cm (median, 1.5 cm; range, 0.5-8.2 cm). The most histological types were adenocarcinoma in 38 (77.6%).

Conclusion

Rapid zero-dose MRI can be used for lung cancer detection in a healthy population.
Limited importance of the dominant-negative effect of TP53missense mutations
Authors: Stoczynska-Fidelus Ewelina , Szybka Malgorzata , Piaskowski Sylwester , Bienkowski Michal , Hulas-Bigoszewska Krystyna , Banaszczyk Mateusz , Zawlik Izabela , Jesionek-Kupnicka Dorota , Kordek Radzislaw , Liberski Pawel P , Rieske Piotr
Published: June 2011

Background

Heterozygosity of TP53 missense mutations is related to the phenomenon of the dominant-negative effect (DNE). To estimate the importance of the DNE of TP53 mutations, we analysed the percentage of cancer cases showing a single heterozygous mutation of TP53 and searched for a cell line with a single heterozygous mutation of this gene. This approach was based on the knowledge that genes with evident DNE, such as EGFR and IDH1, represent nearly 100% of single heterozygous mutations in tumour specimens and cell lines.

Methods

Genetic analyses (LOH and sequencing) performed for early and late passages of several cell lines originally described as showing single heterozygous TP53 mutations (H-318, G-16, PF-382, MOLT-13, ST-486 and LS-123). Statistical analysis of IARC TP53 and SANGER databases. Genetic analyses of N-RAS, FBXW7, PTEN and STR markers to test cross-contamination and cell line identity. Cell cloning, fluorescence-activated cell sorting and SSCP performed for the PF-382 cell line.

Results

A database study revealed TP53 single heterozygous mutations in 35% of in vivo (surgical and biopsy) samples and only 10% of cultured cells (in vitro), although those numbers appeared to be overestimated. We deem that published in vivo TP53 mutation analyses are not as rigorous as studies in vitro, and we did not find any cell line showing a stable, single heterozygous mutation. G16, PF-382 and MOLT-13 cells harboured single heterozygous mutations temporarily. ST-486, H-318 and LS-123 cell lines were misclassified. Specific mutations, such as R175H, R273H, R273L or R273P, which are reported in the literature to exert a DNE, showed the lowest percentage of single heterozygous mutations in vitro (about 5%).

Conclusion

We suggest that the currently reported percentage of TP53 single heterozygous mutations in tumour samples and cancer cell lines is overestimated. Thus, the magnitude of the DNE of TP53 mutations is questionable. This scepticism is supported by database investigations showing that retention of the wild-type allele occurs with the same frequency as either nonsense or missense TP53 mutations.
c-Myc activates BRCA1 gene expression through distal promoter elements in breast cancer cells
Authors: Chen Yinghua , Xu Jinhua , Borowicz Stanley , Collins Cindy , Huo Dezheng , Olopade Olufunmilayo I
Published: June 2011

Background

The BRCA1 gene plays an important role in the maintenance of genomic stability. BRCA1 inactivation contributes to breast cancer tumorigenesis. An increasing number of transcription factors have been shown to regulate BRCA1 expression. c-Myc can act as a transcriptional activator, regulating up to 15% of all genes in the human genome and results from a high throughput screen suggest that BRCA1 is one of its targets. In this report, we used cultured breast cancer cells to examine the mechanisms of transcriptional activation of BRCA1 by c-Myc.

Methods

c-Myc was depleted using c-Myc-specific siRNAs in cultured breast cancer cells. BRCA1 mRNA expression and BRCA1 protein expression were determined by quantitative RT-PCR and western blot, respectively and BRCA1 promoter activities were examined under these conditions. DNA sequence analysis was conducted to search for high similarity to E boxes in the BRCA1 promoter region. The association of c-Myc with the BRCA1 promoter in vivo was tested by a chromatin immunoprecipitation assay. We investigated the function of the c-Myc binding site in the BRCA1 promoter region by a promoter assay with nucleotide substitutions in the putative E boxes. BRCA1-dependent DNA repair activities were measured by a GFP-reporter assay.

Results

Depletion of c-Myc was found to be correlated with reduced expression levels of BRCA1 mRNA and BRCA1 protein. Depletion of c-Myc decreased BRCA1 promoter activity, while ectopically expressed c-Myc increased BRCA1 promoter activity. In the distal BRCA1 promoter, DNA sequence analysis revealed two tandem clusters with high similarity, and each cluster contained a possible c-Myc binding site. c-Myc bound to these regions in vivo. Nucleotide substitutions in the c-Myc binding sites in these regions abrogated c-Myc-dependent promoter activation. Furthermore, breast cancer cells with reduced BRCA1 expression due to depletion of c-Myc exhibited impaired DNA repair activity.

Conclusions

The distal BRCA1 promoter region is associated with c-Myc and contributes to BRCA1 gene activation.
Biological Monitoring of Blood Naphthalene Levels as a Marker of Occupational Exposure to PAHs among Auto-Mechanics and Spray Painters in Rawalpindi
Authors: Kamal Atif , Qayyum Mazhar , Cheema Iqbal U , Rashid Audil
Published: June 2011

Background

Routine exposure to chemical contaminants in workplace is a cause for concern over potential health risks to workers. In Pakistan, reports on occupational exposure and related health risks are almost non-existent, which reflects the scarce availability of survey data and criteria for determining whether an unsafe exposure has occurred. The current study was designed to evaluate blood naphthalene (NAPH) levels as an indicator of exposure to polycyclic aromatic hydrocarbons (PAHs) among automobile workshop mechanics (MCs) and car-spray painters (PNs). We further determined the relationship between blood NAPH levels and personal behavioural, job related parameters and various environmental factors that may further be associated with elevated risks of occupational exposures to PAHs.

Methods

Sixty blood samples (n = 20 for each group i.e. MC, PN and control group) were collected to compare their blood NAPH levels among exposed (MCs and PNs) and un-exposed (control) groups. Samples were analyzed using high pressure liquid chromatography (HPLC). Data regarding demographic aspects of the subjects and their socioeconomic features were collected using a questionnaire. Subjects were also asked to report environmental hygiene conditions of their occupational environment.

Results

We identified automobile work areas as potential sites for PAHs exposure, which was reflected by higher blood NAPH levels among MCs. Blood NAPH levels ranged from 53.7 to 1980.6 μgL-1 and 54.1 to 892.9 μgL-1 among MCs and PNs respectively. Comparison within each group showed that smoking enhanced exposure risks several fold and both active and passive smoking were among personal parameters that were significantly correlated with log-transformed blood NAPH levels. For exposed groups, work hours and work experience were job related parameters that showed strong associations with the increase in blood NAPH levels. Poor workplace hygiene and ventilation were recognized as most significant predictors related to differences among workplaces that may enhance the extent of exposure to chemical contaminants.

Conclusions

It appeared that chemical exposure at the workplace may be influenced by multiple environmental factors, but poor workplace hygiene and duration of exposure (long work hours) were the most important factors. Smoking and negligence of workers regarding self protection were among some of the important personal behaviours than can be addressed with better training. There is also a need to improve workplaces hygiene and to rationalize work hours to minimize health risks. Since smoking was an important confounding factor that supplemented most of the actual occupational exposure, a study based on non-smoker subjects is needed to separate out the effects of smoking and other confounding factors that may obscure measurements of actual extent of occupational exposure.
Patient safety education for undergraduate medical students: a systematic review
Authors: Nie Yanli , Li Lin , Duan Yurong , Chen Peixian , Barraclough Bruce H , Zhang Mingming , Li Jing
Published: June 2011

Background

To reduce harm caused by health care is a global priority. Medical students should be able to recognize unsafe conditions, systematically report errors and near misses, investigate and improve such systems with a thorough understanding of human fallibility, and disclose errors to patients. Incorporating the knowledge of how to do this into the medical student curriculum is an urgent necessity. This paper aims to systematically review the literature about patient safety education for undergraduate medical students in terms of its content, teaching strategies, faculty availability and resources provided so as to identify evidence on how to promote patient safety in the curriculum for medical schools. This paper includes a perspective from the faculty of a medical school, a major hospital and an Evidence Based Medicine Centre in Sichuan Province, China.

Methods

We searched MEDLINE, ERIC, Academic Source Premier(ASP), EMBASE and three Chinese Databases (Chinese Biomedical Literature Database, CBM; China National Knowledge Infrastructure, CNKI; Wangfang Data) from 1980 to Dec. 2009. The pre-specified form of inclusion and exclusion criteria were developed for literature screening. The quality of included studies was assessed using Darcy Reed and Gemma Flores-Mateo criteria. Two reviewers selected the studies, undertook quality assessment, and data extraction independently. Differing opinions were resolved by consensus or with help from the third person.

Results

This was a descriptive study of a total of seven studies that met the selection criteria. There were no relevant Chinese studies to be included. Only one study included patient safety education in the medical curriculum and the remaining studies integrated patient safety into clinical rotations or medical clerkships. Seven studies were of a pre and post study design, of which there was only one controlled study. There was considerable variation in relation to contents, teaching strategies, faculty knowledge and background in patient safety, other resources and outcome evaluation in these reports. The outcomes from including patient safety in the curriculum as measured by medical students' knowledge, skills, and attitudes varied between the studies.

Conclusions

There are only a few relevant published studies on the inclusion of patient safety education into the undergraduate curriculum in medical schools either as a selective course, a lecture program, or by being integrated into the existing curriculum even in developed countries with advanced health and education systems. The integration of patient safety education into the existing curriculum in medical schools internationally, provides significant challenges.
Differential effects of dietary canola and soybean oil intake on oxidative stress in stroke-prone spontaneously hypertensive rats
Authors: Papazzo Annateresa , Conlan Xavier A , Lexis Louise , Lewandowski Paul A
Published: June 2011

Background

Canola oil shortens the life span of stroke-prone spontaneously hypertensive (SHRSP) rats compared with rats fed soybean oil when given as the sole dietary lipid source. One possible mechanism leading to the damage and deterioration of organs due to canola oil ingestion is oxidative stress. This study investigated the effect of canola oil intake on oxidative stress in this animal model.

Method

Male SHRSP rats, were fed a defatted control diet containing 10% wt/wt soybean oil or a defatted treatment diet containing 10% wt/wt canola oil, and given water containing 1% NaCl. Blood pressure was measured weekly. Blood was collected prior to beginning the diets and at the end of completion of the study for analysis of red blood cell (RBC) antioxidant enzymes, RBC and plasma malondialdehyde (MDA), plasma 8-isoprostane and plasma lipids.

Results

Canola oil ingestion significantly decreased the life span of SHRSP rats compared with soybean oil, 85.8 ± 1.1 and 98.3 ± 3.4 days, respectively. Systolic blood pressure increased over time with a significant difference between the diets at the 6th week of feeding. Canola oil ingestion significantly reduced RBC superoxide dismutase, glutathione peroxidase and catalase activities, total cholesterol and low-density lipoprotein cholesterol compared with soybean oil. There were no significant differences in RBC MDA concentration between canola oil fed and soybean oil fed rats. In contrast, plasma MDA and 8-isoprostane concentration was significantly lower in the canola oil group compared to the soybean oil group.

Conclusion

In conclusion, canola oil ingestion shortens the life span of SHRSP rats and leads to changes in oxidative status, despite an improvement in the plasma lipids.
Angiographically borderline left main coronary artery lesions: correlation of transthoracic doppler echocardiography and intravascular ultrasound: a pilot study
Authors: Ruzsa Zoltán , Pálinkás Attila , Forster Tamás , Ungi Imre , Varga Albert
Published: June 2011

Background

the clinical decision making could be difficult in patients with borderline lesions (visually assessed stenosis severity of 30 to 50%) of the left main coronary artery (LM). The aim of the study was to evaluate the relationship between transthoracic Doppler (TTDE) peak diastolic flow velocity (PDV) and intravascular ultrasound (IVUS) measurements in the assessment of angiographically borderline LM lesions.

Methods

27 patients (mean age 64 ± 8 years, 21 males) with borderline LM stenosis referred for IVUS examination were included in the study. We performed standard IVUS with minimal lumen area (MLA) and plaque burden (PB) measurement and routine quantitative coronary angiography (QCA) with diameter stenosis (%DS) and area stenosis (%AS) assessment in all. During TTDE, resting PDV was measured in the LM.

Results

interpretable Doppler signal could be obtained in 24 patients (88% feasibility); therefore these patients entered the final analysis. MLA was 7.1 ± 2.7 mm2. TTDE measured PDV correlated significantly with IVUS-derived MLA (r = -0.46, p < 0.05) and plaque burden (r = 0.51, p < 0.05). Using a velocity cut-off of 112 cm/sec TTDE showed a 92% sensitivity and 62% specificity to identify IVUS-significant (MLA < 6 mm2) LM stenosis.

Conclusion

In angiographically borderline LM disease, resting PDV from transthoracic echocardiography is increased in presence of increased plaque burden by IVUS. TTDE evaluation might be a useful adjunct to other invasive and non-invasive methods in the assessment of borderline LM lesions. Further, large scale studies are needed to establish the exact cut-off value of PDV for routine clinical application.
High prevalence of potential biases threatens the interpretation of trials in patients with chronic disease
Authors: Vollenweider Daniela , Boyd Cynthia M , Puhan Milo A
Published: June 2011

Background

The complexity of chronic diseases is a challenge for investigators conducting randomized trials. The causes for this include the often difficult control for confounding, the selection of outcomes from many potentially important outcomes, the risk of missing data with long follow-up and the detection of heterogeneity of treatment effects. Our aim was to assess such aspects of trial design and analysis for four prevalent chronic diseases.

Methods

We included 161 randomized trials on drug and non-drug treatments for chronic obstructive pulmonary disease, type 2 diabetes mellitus, stroke and heart failure, which were included in current Cochrane reviews. We assessed whether these trials defined a single outcome or several primary outcomes, statistically compared baseline characteristics to assess comparability of treatment groups, reported on between-group comparisons, and we also assessed how they handled missing data and whether appropriate methods for subgroups effects were used.

Results

We found that only 21% of all chronic disease trials had a single primary outcome, whereas 33% reported one or more primary outcomes. Two of the fifty-one trials that tested for statistical significance of baseline characteristics adjusted the comparison for a characteristic that was significantly different. Of the 161 trials, 10% reported a within-group comparison only; 17% (n = 28) of trials reported how missing data were handled (50% (n = 14) carried forward last values, 27% (n = 8) performed a complete case analysis, 13% (n = 4) used a fixed value imputation and 10% (n = 3) used more advanced methods); and 27% of trials performed a subgroup analysis but only 23% of them (n = 10) reported an interaction test. Drug trials, trials published after wide adoption of the CONSORT (CONsolidated Standards of Reporting Trials) statement (2001 or later) and trials in journals with higher impact factors were more likely to report on some of these aspects of trial design and analysis.

Conclusion

Our survey showed that an alarmingly large proportion of chronic disease trials do not define a primary outcome, do not use appropriate methods for subgroup analyses, or use naïve methods to handle missing data, if at all. As a consequence, biases are likely to be introduced in many trials on widely prescribed treatments for patients with chronic disease.
Epidemics of enterovirus infection in Chungnam Korea, 2008 and 2009
Authors: Baek KyoungAh , Yeo SangGu , Lee BaeckHee , Park KwiSung , Song JaeHyoung , Yu JeeSuk , Rheem InSoo , Kim JaeKyung , Hwang SeoYeon , Choi YoungJin , Cheon DooSung , Park JoonSoo
Published: June 2011

Previously, we explored the epidemic pattern and molecular characterization of enteroviruses isolated in Chungnam, Korea from 2005 to 2006. The present study extended these observations to 2008 and 2009. In this study, enteroviruses showed similar seasonal prevalent pattern from summer to fall and age distribution to previous investigation. The most prevalent month was July: 42.9% in 2008 and 31.9% in 2009. The highest rate of enterovirus-positive samples occurred in children < 1-year-old-age. Enterovirus-positive samples were subjected to sequence determination of the VP1 region, which resolved the isolated enteroviruses into 10 types in 2008 (coxsackievirus A4, A16, B1, B3, echovirus 6, 7, 9, 11, 16, and 30) and 8 types in 2009 (coxsackievirus A2, A4, A5, A16, B1, B5, echovirus 11, and enterovirus 71). The most prevalent enterovirus serotype in 2008 and 2009 was echovirus 30 and coxsackievirus B1, respectively, whereas echovirus 18 and echovirus 5 were the most prevalent types in 2005 and 2006, respectively. Comparison of coxsackievirus B1 and B5 of prevalent enterovirus type in Korea in 2009 with reference strains of each same serotype were conducted to genetic analysis by a phylogenetic tree. The sequences of coxsackievirus B1 strains segregated into four distinct clusters (A, B, C, and D) with some temporal and regional sub-clustering. Most of Korean coxsackievirus B1 strains in 2008 and 2009 were in cluster D, while only "Kor08-CVB1-001CN" was cluster C. The coxsackievirus B5 strains segregated in five distinct genetic groups (clusters A-E) were supported by high bootstrap values. The Korean strains isolated in 2001 belonged to cluster D, whereas Korean strains isolated in 2005 and 2009 belonged to cluster E. Comparison of the VP1 amino acid sequences of the Korean coxsackievirus B5 isolates with reference strains revealed amino acid sequence substitutions at nine amino acid sequences (532, 562, 570, 571, 576-578, 582, 583, and 585).
Characterization of the transcripts of human cytomegalovirus UL144
Authors: He Rong , Ma Yanping , Qi Ying , Wang Ning , Li Mali , Ji Yaohua , Sun Zhengrong , Jiang Shujuan , Ruan Qiang
Published: June 2011

Background

The genome of human cytomegalovirus (HCMV) has been studied extensively, particularly in the UL/b' region. In this study, transcripts of one of the UL/b' genes, UL144, were identified in 3 HCMV isolates obtained from urine samples of congenitally infected infants.

Methods

Northern blot hybridization, cDNA library screening, and RACE-PCR were used.

Results

We identified at least 4 differentially regulated 3'-coterminal transcripts of UL144 in infected cells of 1,300, 1,600, 1,700, and 3,500 nucleotides (nt). The 1600 nt transcript was the major form of UL144 mRNA. The largest transcript initiated from the region within the UL141 open reading frame (ORF) and included UL141, UL142, UL143, UL144, and UL145 ORFs.

Conclusions

These findings reveal the complex nature of the transcription of the UL144 gene in clinical isolates.
Autosomal recessive primary microcephaly (MCPH): clinical manifestations, genetic heterogeneity and mutation continuum
Authors: Mahmood Saqib , Ahmad Wasim , Hassan Muhammad J
Published: June 2011

Autosomal Recessive Primary Microcephaly (MCPH) is a rare disorder of neurogenic mitosis characterized by reduced head circumference at birth with variable degree of mental retardation. In MCPH patients, brain size reduced to almost one-third of its original volume due to reduced number of generated cerebral cortical neurons during embryonic neurogensis. So far, seven genetic loci (MCPH1-7) for this condition have been mapped with seven corresponding genes (MCPH1,WDR62,CDK5RAP2,CEP152,ASPM,CENPJ, andSTIL) identified from different world populations. Contribution ofASPMandWDR62gene mutations in MCPH World wide is more than 50%. By and large, primary microcephaly patients are phenotypically indistinguishable, however, recent studies in patients with mutations inMCPH1, WDR62andASPMgenes showed a broader clinical and/or cellular phenotype. It has been proposed that mutations in MCPH genes can cause the disease phenotype by disturbing: 1) orientation of mitotic spindles, 2) chromosome condensation mechanism during embryonic neurogenesis, 3) DNA damage-response signaling, 4) transcriptional regulations and microtubule dynamics, 5) certain unknown centrosomal mechanisms that control the number of neurons generated by neural precursor cells. Recent discoveries of mammalian models for MCPH have open up horizons for researchers to add more knowledge regarding the etiology and pathophysiology of MCPH. High incidence of MCPH in Pakistani population reflects the most probable involvement of consanguinity. Genetic counseling and clinical management through carrier detection/prenatal diagnosis in MCPH families can help reducing the incidence of this autosomal recessive disorder.
Characterization the regulation of herpesvirus miRNAs from the view of human protein interaction network
Authors: Li Zhenpeng , Li Fei , Ni Ming , Li Peng , Bo Xiaochen , Wang Shengqi
Published: June 2011

Background

miRNAs are a class of non-coding RNA molecules that play crucial roles in the regulation of virus-host interactions. The ever-increasing data of known viral miRNAs and human protein interaction network (PIN) has made it possible to study the targeting characteristics of viral miRNAs in the context of these networks.

Results

We performed topological analysis to explore the targeting propensities of herpesvirus miRNAs from the view of human PIN and found that (1) herpesvirus miRNAs significantly target more hubs, moreover, compared with non-hubs (non-bottlenecks), hubs (bottlenecks) are targeted by much more virus miRNAs and virus types. (2) There are significant differences in the degree and betweenness centrality between common and specific targets, specifically we observed a significant positive correlation between virus types targeting these nodes and the proportion of hubs, and (3) K-core and ER analysis determined that common targets are closer to the global PIN center. Compared with random conditions, the giant connected component (GCC) and the density of the sub-network formed by common targets have significantly higher values, indicating the module characteristic of these targets.

Conclusions

Herpesvirus miRNAs preferentially target hubs and bottlenecks. There are significant differences between common and specific targets. Moreover, common targets are more intensely connected and occupy the central part of the network. These results will help unravel the complex mechanism of herpesvirus-host interactions and may provide insight into the development of novel anti-herpesvirus drugs.