Using GlimmerM to Find Genes in Eukaryotic Genomes

Current Protocols in Bioinformatics / Editoral Board, Andreas D. Baxevanis ... [et Al.]. Nov, 2002  |  Pubmed ID: 18792941

GlimmerM is a eukaryotic gene finder that has been used in the annotation of the genomes of Plasmodium falciparum (the malaria parasite), the model plant Arabidopsis thaliana, Oryza sativa (rice), the parasite Theileria parva, and the fungus Aspergillus fumigatus. A unique feature of the system compared to other eukaryotic gene finders is a module that allows users to provide their own data and train GlimmerM for any organism.

Using MUMmer to Identify Similar Regions in Large Sequence Sets

Current Protocols in Bioinformatics / Editoral Board, Andreas D. Baxevanis ... [et Al.]. Feb, 2003  |  Pubmed ID: 18428693

The MUMmer sequence alignment package is a suite of computer programs designed to detect regions of homology in long biological sequences. Version 2.1 makes several improvements to the package, including: increased speed and reduced memory requirements; the ability to handle both protein and DNA sequences; the ability to handle multiple sequence fragments; and new algorithms for clustering together basic matches. The system is particularly efficient at comparing highly similar sequences, such as alternative versions of fragment assemblies or closely related strains of the same bacterium.

Lymphoblastic Leukemia/lymphoma in Mice Overexpressing the Mer (MerTK) Receptor Tyrosine Kinase

Oncogene. Oct, 2006  |  Pubmed ID: 16652142

Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (Mer(Tg)) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the Mer(Tg) mice. At 12-24 months of age, greater than 55% of the Mer(Tg) mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in Mer(Tg) mice. Additionally, a significant survival advantage was noted in Mer(Tg) lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.

Ectopic Expression of the Proto-oncogene Mer in Pediatric T-cell Acute Lymphoblastic Leukemia

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. May, 2006  |  Pubmed ID: 16675557

The Mer receptor tyrosine kinase, cloned from a B-lymphoblastoid library, is the mammalian orthologue of the chicken retroviral oncogene v-eyk and sends antiapoptotic and transforming signals when activated. To determine if Mer expression is ectopic in T-cell acute lymphoblastic leukemia (ALL) and potentially important in leukemogenesis, we analyzed Mer expression in normal human thymocytes and lymphocytes and in pediatric ALL patient samples.

Serious Infections and Mortality in Association with Therapies for Crohn's Disease: TREAT Registry

Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association. May, 2006  |  Pubmed ID: 16678077

Long-term safety data for infliximab and other therapies in Crohn's disease (CD) are needed.

Left Ventricular False Aneurysm Following Percutaneus Balloon Aortic Valvuloplasty: Magnetic Resonance Imaging As Diagnostic Tool

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Jul, 2006  |  Pubmed ID: 16730187

A Three-dimensional Ring Annuloplasty for the Treatment of Tricuspid Regurgitation

The Annals of Thoracic Surgery. Jun, 2006  |  Pubmed ID: 16731167

Significant functional tricuspid regurgitation should be corrected in patients undergoing surgery for left-sided valvular diseases. Several clinical studies have shown the superiority of the remodeling annuloplasty over other repair techniques. Herein we report our early experience with a new three-dimensional remodeling prosthetic ring (Edwards MC3 annuloplasty system [Edwards LifeSciences, Irvine, CA]).

Automatic Image Segmentation with Linear Clustering for Quantification of Neointimal Formation After Surgical Vein Grafting

Analytical and Quantitative Cytology and Histology / the International Academy of Cytology [and] American Society of Cytology. Dec, 2006  |  Pubmed ID: 17220144

To identify extracellular matrix deposition on combined Masson elastin stains from cross-sectional, fixed vein grafts.

C-reactive Protein Levels in Patients with Aggressive Periodontitis

Journal of Periodontology. Jun, 2006  |  Pubmed ID: 16734565

Sera from patients with periodontal infections contain elevated levels of C-reactive protein (CRP) compared to periodontally healthy individuals. Most studies to date have included patients with chronic periodontitis, and few investigators have studied CRP levels in subjects with aggressive periodontitis (AgP). The purpose of this study was to determine the relative levels of serum CRP in AgP patients and periodontally healthy subjects and to examine patients' characteristics that might account for intergroup differences.

It is Time to End the Patenting of Software

Bioinformatics (Oxford, England). Jun, 2006  |  Pubmed ID: 16766564

Outcomes and Predictors of Success of a Radiofrequency- or Cryothermy-simplified Left-sided Maze Procedure in Patients Undergoing Mitral Valve Surgery

The Journal of Heart Valve Disease. May, 2006  |  Pubmed ID: 16784073

Restoration of sinus rhythm with a maze procedure after concomitant mitral valve (MV) surgery has been shown to reduce the rate of stroke and improve cardiac function and quality of life compared to MV surgery alone. Unlike the classical Cox-Maze III operation, a simplified left-sided maze procedure can be performed without any significant increase in operative complexity.

Nonexpansive Immediate Breast Reconstruction Using Human Acellular Tissue Matrix Graft (AlloDerm)

Annals of Plastic Surgery. Jul, 2006  |  Pubmed ID: 16799299

Immediate breast reconstruction has become a standard of care following mastectomy for cancer, largely due to improved esthetic and psychologic outcomes achieved with this technique. However, the current historical standards--transverse rectus abdominis myocutaneous flap reconstruction and expander--implant surgery-still have limitations as regards patient morbidity, short-term body-image improvements, and even cost. To address these shortcomings, we employ a novel concept of human tissue replacement to enhance breast shape and provide total coverage, enabling immediate mound reconstruction without the need for breast expansion prior to permanent implant placement. AlloDerm (human acellular tissue matrix) is a human-derived graft tissue with extensive experience in various settings of skin and soft tissue replacement surgery. This report describes the success using acellular tissue matrix to provide total coverage over the prosthesis in immediate reconstruction, with limited muscle dissection. In this population, 49 patients (76 breasts) successfully underwent the acellular tissue matrix-based immediate reconstruction, resulting in durable breast reconstruction with good symmetry. These findings may predict that acellular tissue matrix-supplemented immediate breast reconstruction will become a new technique for the immediate reconstruction of the postmastectomy breast.

Increased Neointimal Formation After Surgical Vein Grafting in a Murine Model of Type 2 Diabetes

Circulation. Jul, 2006  |  Pubmed ID: 16820590

Diabetes is an independent risk factor for the development of neointimal hyperplasia and subsequent vein graft failure after coronary or peripheral artery bypass grafting. We evaluate a new mouse model of surgical vein grafting to investigate the mechanisms of neointimal formation in the setting of type 2 diabetes.

Mitral Valve Repair with Carpentier-McCarthy-Adams IMR ETlogix Annuloplasty Ring for Ischemic Mitral Regurgitation: Early Echocardiographic Results from a Multi-center Study

Circulation. Jul, 2006  |  Pubmed ID: 16820643

Ischemic mitral regurgitation (IMR) is associated with asymmetric changes in annular and ventricular geometry. Surgical repair with standard symmetric annuloplasty rings results in a high incidence of residual or recurrent mitral regurgitation (MR). The Carpentier-McCarthy-Adams (CMA) IMR ETlogix annuloplasty ring is the first remodeling ring specifically designed to treat asymmetric leaflet tethering and annular dilatation. We used quantitative 2-dimensional echo to examine early results of mitral valve (MV) repair with the CMA IMR ETlogix annuloplasty ring in patients with IMR.

Excellent Outcomes of Cardiac Surgery in Patients Infected with HIV in the Current Era

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Aug, 2006  |  Pubmed ID: 16838245

Over the past decade, significant advances have been made in the medical treatment of patients with human immunodeficiency virus type 1 infection, leading to a steady increase in referrals for cardiac surgery. We report the outcome of cardiac surgery recently performed in patients with documented human immunodeficiency virus type 1 infection.

Nano- and Microparticles As Adjuvants in Vaccine Design: Success and Failure is Related to Host Natural Antibodies

Vaccine. Oct, 2006  |  Pubmed ID: 16842893

Bovine serum albumin (BSA) and the surface A-layer protein (AP) of an atypical strain of fish bacterial pathogen Aeromonas salmonicida were covalently linked with polymeric nano- and microparticles, and antigenicity of the resulted conjugates was compared in mice and goldfish. Distinct albeit different levels of natural BSA and AP antibodies were present in both animal species. Significant stimulation of the anti-AP antibody response in mice strikingly contrasted to unresponsiveness or even suppression in fish. The results negatively correlate with the levels of respective natural antibodies in the host and are discussed in context of problems related to fish vaccination. The work reinforces the instructive role of natural antibodies in adaptive immune response.

Sixty-four-slice Computed Tomographic Coronary Angiography in Pseudoaneurysm of the Ascending Aorta: a Useful Modality to Supplement the Diagnosis

The Journal of Thoracic and Cardiovascular Surgery. Aug, 2006  |  Pubmed ID: 16872935

JIGSAW, GeneZilla, and GlimmerHMM: Puzzling out the Features of Human Genes in the ENCODE Regions

Genome Biology. 2006  |  Pubmed ID: 16925843

Predicting complete protein-coding genes in human DNA remains a significant challenge. Though a number of promising approaches have been investigated, an ideal suite of tools has yet to emerge that can provide near perfect levels of sensitivity and specificity at the level of whole genes. As an incremental step in this direction, it is hoped that controlled gene finding experiments in the ENCODE regions will provide a more accurate view of the relative benefits of different strategies for modeling and predicting gene structures.

Macronuclear Genome Sequence of the Ciliate Tetrahymena Thermophila, a Model Eukaryote

PLoS Biology. Sep, 2006  |  Pubmed ID: 16933976

The ciliate Tetrahymena thermophila is a model organism for molecular and cellular biology. Like other ciliates, this species has separate germline and soma functions that are embodied by distinct nuclei within a single cell. The germline-like micronucleus (MIC) has its genome held in reserve for sexual reproduction. The soma-like macronucleus (MAC), which possesses a genome processed from that of the MIC, is the center of gene expression and does not directly contribute DNA to sexual progeny. We report here the shotgun sequencing, assembly, and analysis of the MAC genome of T. thermophila, which is approximately 104 Mb in length and composed of approximately 225 chromosomes. Overall, the gene set is robust, with more than 27,000 predicted protein-coding genes, 15,000 of which have strong matches to genes in other organisms. The functional diversity encoded by these genes is substantial and reflects the complexity of processes required for a free-living, predatory, single-celled organism. This is highlighted by the abundance of lineage-specific duplications of genes with predicted roles in sensing and responding to environmental conditions (e.g., kinases), using diverse resources (e.g., proteases and transporters), and generating structural complexity (e.g., kinesins and dyneins). In contrast to the other lineages of alveolates (apicomplexans and dinoflagellates), no compelling evidence could be found for plastid-derived genes in the genome. UGA, the only T. thermophila stop codon, is used in some genes to encode selenocysteine, thus making this organism the first known with the potential to translate all 64 codons in nuclear genes into amino acids. We present genomic evidence supporting the hypothesis that the excision of DNA from the MIC to generate the MAC specifically targets foreign DNA as a form of genome self-defense. The combination of the genome sequence, the functional diversity encoded therein, and the presence of some pathways missing from other model organisms makes T. thermophila an ideal model for functional genomic studies to address biological, biomedical, and biotechnological questions of fundamental importance.

A Phylogenetic Generalized Hidden Markov Model for Predicting Alternatively Spliced Exons

Algorithms for Molecular Biology : AMB. 2006  |  Pubmed ID: 16934144

An important challenge in eukaryotic gene prediction is accurate identification of alternatively spliced exons. Functional transcripts can go undetected in gene expression studies when alternative splicing only occurs under specific biological conditions. Non-expression based computational methods support identification of rarely expressed transcripts.

Trastuzumab (Herceptin) in Patients with HER-2-overexpressing Metastatic or Locally Advanced Transitional Cell Carcinoma of the Bladder: Report on 7 Patients

European Journal of Cancer (Oxford, England : 1990). Oct, 2006  |  Pubmed ID: 16934972

Celecoxib for the Prevention of Sporadic Colorectal Adenomas

The New England Journal of Medicine. Aug, 2006  |  Pubmed ID: 16943400

Studies showing that drugs that inhibit cyclooxygenase-2 (COX-2) reduce the number of colorectal adenomas in animals and patients with familial adenomatous polyposis suggest that COX-2 inhibitors may also prevent sporadic colorectal neoplasia.

From Machine and Tape to Structure and Function: Formulation of a Reflexively Computing System

Artificial Life. 2006  |  Pubmed ID: 16953782

The relationship between structure and function is explored via a system of labeled directed graph structures upon which a single elementary read/write rule is applied locally. Boundaries between static (information-carrying) and active (information-processing) objects, imposed by mandate of the rules or physics in earlier models, emerge instead as a result of a structure-function dynamic that is reflexive: objects may operate directly on their own structure. A representation of an arbitrary Turing machine is reproduced in terms of structural constraints by means of a simple mapping from tape squares and machine states to a uniform medium of nodes and links, establishing computation universality. Exploiting flexibility of the formulation, examples of other unconventional "self-computing" structures are demonstrated. A straightforward representation of a kinematic machine system based on the model devised by Laing is also reproduced in detail. Implications of the findings are discussed in terms of their relation to other formal models of computation and construction. It is argued that reflexivity of the structure-function relationship is a critical informational dynamic in biochemical systems, overlooked in previous models but well captured by the proposed formulation.

How Fast Does an Atrial Myxoma Grow?

The Annals of Thoracic Surgery. Oct, 2006  |  Pubmed ID: 16996968

We describe the case of a 58-year-old man who underwent coronary artery bypass grafting with an unremarkable transesophageal echocardiogram. Three years later he underwent a routine transthoracic echocardiogram that was normal. Eleven months later he presented with dyspnea and right-sided heart failure. Transthoracic echocardiogram showed a large mass located in the right atrium in which the base was inserted by the junction of the inferior vena cava and coronary sinus. Pathology showed a myxoma that measured 15 x 3 cm implying a growth rate of 1.36 x 0.3 cm/month.

A Second Look at the Palmes' Diffusive Sampler

Journal of the Air & Waste Management Association (1995). Oct, 2006  |  Pubmed ID: 17063865

The Palmes' tube, the first diffusive sampler incorporating a fixed path length, has received wide usage for the sampling of a large number of gaseous pollutants. But despite numerous previous studies, questions remain regarding the accuracy of these inexpensive, simple-to-construct, open-ended samplers. Here the mass transfer resistance in a Palmes' diffusive sampler was measured using the loss of cyclohexane from a Palmes' tube containing liquid cyclohexane at its base. The average loss rates, at factorial combinations of five air incidence angles evenly spaced from 270 degrees to 90 degrees, and five air speeds from 0.5 m/sec to 2.5 m/sec ranged from 46% to 121% higher than rates calculated from the physical dimensions of the sampler, proving the need to calibrate these samplers rather than relying on a theoretical calculation. The mass transfer resistance was nearly constant when the airflow was perpendicular to the sampler and sufficiently high to avoid stagnation, a finding that may explain the widespread acceptance of the results obtained using this sampler.

Surgical Management of Functional Tricuspid Regurgitation with a New Remodeling Annuloplasty Ring

The Mount Sinai Journal of Medicine, New York. Oct, 2006  |  Pubmed ID: 17117314

Moderate-to-severe functional tricuspid regurgitation (TR) should be corrected in patients undergoing surgery for left-sided valvular diseases, to improve long-term outcomes. Several techniques of surgical repair (suture annuloplasty or prosthetic annuloplasty) to correct this condition have been described. Multiple clinical studies have shown the superiority of prosthetic remodeling annuloplasty over the other surgical approaches. Despite this, suture-based annuloplasty remains the most commonly used technique for tricuspid valve repair. A new 3-dimensional remodeling prosthesis has been developed to address the issue of residual TR. We report our early experience with this new 3-dimensional prosthetic remodeling ring, the Edwards MC 3 system.

Structure-based Identification of Small Molecule Binding Sites Using a Free Energy Model

Journal of Chemical Information and Modeling. Nov-Dec, 2006  |  Pubmed ID: 17125203

We separately have shown that the maximal druglike affinity of a given binding site on a protein can be calculated on the basis of the binding-site structure alone by using a desolvation-based free energy model along with the notion that druglike ligands fall into certain physiochemical property ranges. Here, we present an approach where we reformulate the calculated druggability affinity as an additive free energy to facilitate the searching of whole protein surfaces for druglike binding sites. The highest-scoring patches in many cases represent known ligand-binding sites for druggable targets, but not for difficult targets. This approach differs from other approaches in that it does not simply identify pockets with the greatest volume but instead identifies pockets that are likely to be amenable to druglike small-molecule binding. Combining the method with a functional residue prediction method called SCA (statistical coupling analysis) results in the prediction of potentially druggable allosteric binding sites on p38alpha kinase.

Large Annuloplasty Rings Facilitate Mitral Valve Repair in Barlow's Disease

The Annals of Thoracic Surgery. Dec, 2006  |  Pubmed ID: 17126117

Excess leaflet tissue in Barlow's disease predisposes patients to left ventricular outflow tract obstruction and residual mitral regurgitation after mitral valve repair as a result of systolic anterior motion of the anterior mitral leaflet. In addition to conventional repair techniques such as sliding plasty and leaflet shortening, our approach in Barlow's disease has included the use of large remodeling annuloplasty rings (up to size 40 mm). We report our experience with the use of large rings in Barlow's disease.

Depression in Temporal Lobe Epilepsy Surgery Patients: an FDG-PET Study

Epilepsia. Dec, 2006  |  Pubmed ID: 17201712

Depression is common in temporal lobe epilepsy (TLE) and after temporal lobectomy, and its etiology is obscure. In nonepileptic depression (including depression associated with other neurologic disorders), a consistent PET imaging finding is frontal lobe hypometabolism. Many TLE patients have hypometabolism involving frontal regions. Thus in data available from routine clinical assessments in an epilepsy surgery unit, we tested the hypothesis that the pattern of hypometabolism, particularly in the frontal lobe, may be associated with the depression seen in patients with TLE and TLE surgery.

Multimodal Characterization of a Large Right Atrial Mass After Surgical Repair of an Atrial Septal Defect

The Mount Sinai Journal of Medicine, New York. Dec, 2006  |  Pubmed ID: 17285207

A 43-year-old woman with exertional dyspnea and a history of surgically repaired atrial septal defect was referred for a transthoracic echocardiogram, which demonstrated a large, mobile mass in her right atrium. The mass was further characterized with contrast transesophageal echocardiography (TEE) and delayed enhancement MRI, which together suggested a thrombus, attached to the eustachian valve and prolapsing through the tricuspid valve. The mass was resected and the diagnosis confirmed on histopathologic examination. This case illustrates the utility of a multimodal approach in characterizing cardiac masses.

A Mechanical Spike Accompanies the Action Potential in Mammalian Nerve Terminals

Biophysical Journal. May, 2007  |  Pubmed ID: 17307820

Large and rapid changes in light scattering accompany secretion from nerve terminals of the mammalian neurohypophysis (posterior pituitary). In the mouse, these intrinsic optical signals are intimately related to the arrival of the action potential E-wave and the release of arginine vasopressin and oxytocin (S-wave). Here we have used a high bandwidth atomic force microscope to demonstrate that these light-scattering signals are associated with changes in terminal volume that are detected as nanometer-scale movements of a cantilever positioned on top of the neurohypophysis. The most rapid mechanical response ("spike"), having a duration shorter than the action potential but comparable to that of the E-wave, represents a transient increase in terminal volume due to water movement associated with Na(+)-influx. The slower mechanical event ("dip"), on the other hand, depends upon Ca(2+)-entry as well as on intraterminal Ca(2+)-transients and, analogously to the S-wave, seems to monitor events associated with secretion.

Rapid, Accurate, Computational Discovery of Rho-independent Transcription Terminators Illuminates Their Relationship to DNA Uptake

Genome Biology. 2007  |  Pubmed ID: 17313685

In many prokaryotes, transcription of DNA to RNA is terminated by a thymine-rich stretch of DNA following a hairpin loop. Detecting such Rho-independent transcription terminators can shed light on the organization of bacterial genomes and can improve genome annotation. Previous computational methods to predict Rho-independent terminators have been slow or limited in the organisms they consider.

Minimus: a Fast, Lightweight Genome Assembler

BMC Bioinformatics. 2007  |  Pubmed ID: 17324286

Genome assemblers have grown very large and complex in response to the need for algorithms to handle the challenges of large whole-genome sequencing projects. Many of the most common uses of assemblers, however, are best served by a simpler type of assembler that requires fewer software components, uses less memory, and is far easier to install and run.

Hawkeye: an Interactive Visual Analytics Tool for Genome Assemblies

Genome Biology. 2007  |  Pubmed ID: 17349036

Genome sequencing remains an inexact science, and genome sequences can contain significant errors if they are not carefully examined. Hawkeye is our new visual analytics tool for genome assemblies, designed to aid in identifying and correcting assembly errors. Users can analyze all levels of an assembly along with summary statistics and assembly metrics, and are guided by a ranking component towards likely mis-assemblies. Hawkeye is freely available and released as part of the open source AMOS project http://amos.sourceforge.net/hawkeye.

Early and Late Outcome of Cardiac Surgery in Patients with Liver Cirrhosis

Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Jul, 2007  |  Pubmed ID: 17427174

Liver cirrhosis is a major risk factor in general surgery. Few studies have reported on the outcome of cardiac surgery in these patients. Herein we report our recent experience in this high-risk patient population according to the Child-Turcotte-Pugh classification and Model for End-Stage Liver Disease (MELD) score. Between January 1998 and December 2004, 27 patients (mean age 58 +/- 10 yr, 20 male) with cirrhosis who underwent cardiac surgery were identified. Patients were in Child-Turcotte-Pugh class A (n = 10), B (n = 11), and C (n = 6) and mean MELD score was 14.2 +/- 4.2. Operative mortality was 26% (n = 7). Stratified mortality according to Child-Turcotte-Pugh class was 11%, 18%, and 67% for class A, B, and C, respectively. No mortality occurred in patients who had revascularization without the use of cardiopulmonary bypass (n = 5). The 1-yr survival was 80%, 45%, and 16% for Child-Turcotte-Pugh class A, B, and C, respectively (P = 0.02). Major postoperative complications occurred in 22%, 56%, and 100% for Child-Turcotte-Pugh class A, B, and C, respectively. Child-Turcotte-Pugh classification was a better predictor of hospital mortality (P = 0.02) compared to MELD score (P = 0.065). In conclusion, our results suggest that cardiac surgery can be performed safely in patients with Child-Turcotte-Pugh class A and selected patients with class B. Operative mortality remains high in class C patients. Careful patient selection is critical in order to improve surgical outcome in patients with cirrhosis.

The Effect and Safety of Short-term Creatine Supplementation on Performance of Push-ups

Military Medicine. Mar, 2007  |  Pubmed ID: 17436778

The effects of short-term oral creatine (Cr) supplementation on exercise performance and on blood pressure and renal function were assessed. Thirty-five healthy, active duty, U.S. Army volunteers (20 men and 15 women; age, 22-36 years) at Fort Sam Houston, Texas, supplemented their diet for 7 days with 20 g/day of either Cr or taurine (as placebo). There was no significant difference in 2-minute push-up counts between the Cr and taurine groups from before to after supplementation (p = 0.437; power = 0.98). The Cr group demonstrated a significant increase in serum creatinine levels (p < 0.001), compared with the taurine group, and this increase could be misinterpreted as impairment of renal function. No adverse changes in blood pressure, body composition, weight, or serum Cr phosphokinase levels were observed. We conclude that short-term Cr supplementation appears to be safe but does not enhance push-up performance.

Survival Without Common Toxicity Criteria Grade 3/4 Toxicity for Pemetrexed Compared with Docetaxel in Previously Treated Patients with Advanced Non-small Cell Lung Cancer (NSCLC): a Risk-benefit Analysis

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. May, 2007  |  Pubmed ID: 17473654

In a recent large phase III study, previously treated patients with advanced non-small cell lung cancer who received pemetrexed demonstrated a survival time similar to patients who received docetaxel (median, 8.3 months with pemetrexed versus 7.9 months with docetaxel), with a more favorable toxicity profile, and significantly fewer Common Toxicity Criteria grade 3/4 toxicities. This is a retrospective risk-benefit analysis of survival without grade 3/4 toxicity, defined as the time to the first occurrence of Common Toxicity Criteria grade 3 or 4 toxicity or death, in the prospective phase III study comparing pemetrexed with docetaxel.

An Antibiotic-inducible Cell Wall-associated Protein That Protects Bacillus Subtilis from Autolysis

Journal of Bacteriology. Jul, 2007  |  Pubmed ID: 17483219

In Bacillus subtilis, antibiotics that impair cell wall synthesis induce a characteristic stress response including the sigma(W) and sigma(M) regulons and the previously uncharacterized yoeB gene. Here we demonstrate that YoeB is a cell wall-associated protein with weak sequence similarity to a noncatalytic domain of class B penicillin-binding proteins. A yoeB-null mutant exhibits an increased rate of autolysis in response to cell wall-targeting antibiotics or nutrient depletion. This phenotype does not appear to be correlated with gross alterations in peptidoglycan structure or levels of autolysins. Promoter dissection experiments define a minimal region necessary for antibiotic-mediated induction of yoeB, and this region is highly conserved preceding yoeB homologs in close relatives of B. subtilis. These results support a model in which induction of YoeB in response to cell envelope stress decreases the activity of autolysins and thereby reduces the rate of antibiotic-dependent cell death.

Genome Sequence of Aedes Aegypti, a Major Arbovirus Vector

Science (New York, N.Y.). Jun, 2007  |  Pubmed ID: 17510324

We present a draft sequence of the genome of Aedes aegypti, the primary vector for yellow fever and dengue fever, which at approximately 1376 million base pairs is about 5 times the size of the genome of the malaria vector Anopheles gambiae. Nearly 50% of the Ae. aegypti genome consists of transposable elements. These contribute to a factor of approximately 4 to 6 increase in average gene length and in sizes of intergenic regions relative to An. gambiae and Drosophila melanogaster. Nonetheless, chromosomal synteny is generally maintained among all three insects, although conservation of orthologous gene order is higher (by a factor of approximately 2) between the mosquito species than between either of them and the fruit fly. An increase in genes encoding odorant binding, cytochrome P450, and cuticle domains relative to An. gambiae suggests that members of these protein families underpin some of the biological differences between the two mosquito species.

Comprehensive DNA Signature Discovery and Validation

PLoS Computational Biology. May, 2007  |  Pubmed ID: 17511514

DNA signatures are nucleotide sequences that can be used to detect the presence of an organism and to distinguish that organism from all other species. Here we describe Insignia, a new, comprehensive system for the rapid identification of signatures in the genomes of bacteria and viruses. With the availability of hundreds of complete bacterial and viral genome sequences, it is now possible to use computational methods to identify signature sequences in all of these species, and to use these signatures as the basis for diagnostic assays to detect and genotype microbes in both environmental and clinical samples. The success of such assays critically depends on the methods used to identify signatures that properly differentiate between the target genomes and the sample background. We have used Insignia to compute accurate signatures for most bacterial genomes and made them available through our Web site. A sample of these signatures has been successfully tested on a set of 46 Vibrio cholerae strains, and the results indicate that the signatures are highly sensitive for detection as well as specific for discrimination between these strains and their near relatives. Our approach, whereby the entire genomic complement of organisms are compared to identify probe targets, is a promising method for diagnostic assay development, and it provides assay designers with the flexibility to choose probes from the most relevant genes or genomic regions. The Insignia system is freely accessible via a Web interface and has been released as open source software at: http://insignia.cbcb.umd.edu.

A Computational Survey of Candidate Exonic Splicing Enhancer Motifs in the Model Plant Arabidopsis Thaliana

BMC Bioinformatics. 2007  |  Pubmed ID: 17517127

Algorithmic approaches to splice site prediction have relied mainly on the consensus patterns found at the boundaries between protein coding and non-coding regions. However exonic splicing enhancers have been shown to enhance the utilization of nearby splice sites.

Alternating Electric Fields Arrest Cell Proliferation in Animal Tumor Models and Human Brain Tumors

Proceedings of the National Academy of Sciences of the United States of America. Jun, 2007  |  Pubmed ID: 17551011

We have recently shown that low intensity, intermediate frequency, electric fields inhibit by an anti-microtubule mechanism of action, cancerous cell growth in vitro. Using implanted electrodes, these fields were also shown to inhibit the growth of dermal tumors in mice. The present study extends these findings to additional cell lines [human breast carcinoma; MDA-MB-231, and human non-small-cell lung carcinoma (H1299)] and to animal tumor models (intradermal B16F1 melanoma and intracranial F-98 glioma) using external insulated electrodes. These findings led to the initiation of a pilot clinical trial of the effects of TTFields in 10 patients with recurrent glioblastoma (GBM). Median time to disease progression in these patients was 26.1 weeks and median overall survival was 62.2 weeks. These time to disease progression and OS values are more than double the reported medians of historical control patients. No device-related serious adverse events were seen after >70 months of cumulative treatment in all of the patients. The only device-related side effect seen was a mild to moderate contact dermatitis beneath the field delivering electrodes. We conclude that TTFields are a safe and effective new treatment modality which effectively slows down tumor growth in vitro, in vivo and, as demonstrated here, in human cancer patients.

Genome Analysis Linking Recent European and African Influenza (H5N1) Viruses

Emerging Infectious Diseases. May, 2007  |  Pubmed ID: 17553249

To better understand the ecology and epidemiology of the highly pathogenic avian influenza virus in its transcontinental spread, we sequenced and analyzed the complete genomes of 36 recent influenza A (H5N1) viruses collected from birds in Europe, northern Africa, and southeastern Asia. These sequences, among the first complete genomes of influenza (H5N1) viruses outside Asia, clearly depict the lineages now infecting wild and domestic birds in Europe and Africa and show the relationships among these isolates and other strains affecting both birds and humans. The isolates fall into 3 distinct lineages, 1 of which contains all known non-Asian isolates. This new Euro-African lineage, which was the cause of several recent (2006) fatal human infections in Egypt and Iraq, has been introduced at least 3 times into the European-African region and has split into 3 distinct, independently evolving sublineages. One isolate provides evidence that 2 of these sublineages have recently reassorted.

An Open-label, Noncomparative Phase II Trial to Evaluate the Efficacy and Safety of Docetaxel in Combination with Gefitinib in Patients with Hormone-refractory Metastatic Prostate Cancer

Onkologie. Jul, 2007  |  Pubmed ID: 17596743

Prostate cancer is the most common type of cancer in men, however, therapeutic options are limited. 50-90% of hormone-refractory prostate cancer cells show an overexpression of epidermal growth factor receptor (EGFR), which may contribute to uncontrolled proliferation and resistance to chemotherapy. In vitro, gefitinib, an orally administered tyrosine kinase inhibitor, has shown a significant increase in antitumor activity when combined with chemotherapy.

COX-2 Inhibitors and Cardiovascular Risk

Sub-cellular Biochemistry. 2007  |  Pubmed ID: 17612050

The development of drugs that selectively inhibit cyclooxygenase-2 (COX-2) demonstrates translational research from bench to bedside based on underlying knowledge of micro-cellular structure and function. However, theoretical concerns about potentially prothrombotic effects of selective COX-2 inhibitors coupled with observations of increased cardiovascular risk have produced significant consternation and lead to the withdrawal of two of these agents from the market. A number of questions remain unanswered. It appears clear that both selective and non-selective COX inhibitors are associated with increases in blood pressure. In addition, blood pressure is often increased after starting nonsteroidal therapy, and we know that even small increases in blood pressure in subjects with pre-existing vascular disease are associated with substantial increases in the risk of cardiovascular morbidity. Given this line of reasoning, one might hypothesize that the observed increases in the risk of cardiovascular events associated with COX-inhibitors are largely due to increases in blood pressure in populations of subjects who are already at high risk. But can we generalize that the adverse cardiovascular effects observed for rofecoxib and valdecoxib are sufficient to indict the entire class of COX-2 inhibitors, or is this not a class effect, but dependent upon the degree of COX-2 selectivity? In either case, it seems prudent to recommend that subjects who are at higher risk for a cardiovascular event and receiving a COX-inhibitor should also be treated with low dose ASA with close follow up of blood pressure and efficacious use of anti-hypertensive medications. Finally, modest dietary salt restriction may help lessen the effects of COX-inhibitors on blood pressure.

The Acceleration of Amygdala Kindling Epileptogenesis by Chronic Low-dose Corticosterone Involves Both Mineralocorticoid and Glucocorticoid Receptors

Psychoneuroendocrinology. Aug, 2007  |  Pubmed ID: 17614213

We have previously demonstrated that low-dose corticosterone (CS) administration, used as a model of the effect of chronic stress, accelerates epileptogenesis in the electrical amygdala kindling rat model of temporal lobe epilepsy (TLE). This current study examined the relative contributions to this effect of mineralocorticoid (MR) and glucocorticoid (GR) subtypes of glucocorticoid receptors. Female non-epileptic wistar rats 10-13 weeks of age were implanted with a bipolar electrode into the left amygdala. Five treatment groups were subjected to rapid amygdala kindling: water-control (n=9), CS treated (6 mg/100 ml added to drinking water; n=9), CS+spironolactone (MR antagonist, 50 mg/kg sc; n=9), CS+mifepristone (GR antagonist, 25 mg/kg sc; n=9), and CS+both antagonists (n=7). Rats were injected with vehicle or the relevant antagonist twice daily for the entire kindling period. Experimental groups differed significantly in the number of stimulations required to reach the 'fully kindled state' (Racine, 1972) ANOVA, F(4,38)=2.73, p=0.04). Amygdala kindling was accelerated in the CS-treated group compared with water controls (mean stimulations for full kindling: 45.2 vs. 86.5, p<0.01). This acceleration was inhibited by both the MR and GR antagonist treatments (mean stimulations: 69.6 and 70.4, p=0.04 and 0.04 vs. CS group, respectively), with the kindling rates in these groups not significantly different from water-treated subjects (p=0.26 and 0.29, respectively). The kindling rates in the MR and GR antagonist treatment groups did not significantly differ from each other (p=0.93), nor from the combined treatment group (mean stimulations: 62.8, p=0.59 and 0.54, respectively). This study demonstrates that activation of both high-affinity (MR) and low-affinity (GR) glucocorticoid receptors are involved in mediating CS-induced acceleration of amygdala kindling epileptogenesis.

A Unified Model Explaining the Offsets of Overlapping and Near-overlapping Prokaryotic Genes

Molecular Biology and Evolution. Sep, 2007  |  Pubmed ID: 17642473

Overlapping genes are a common phenomenon. Among sequenced prokaryotes, more than 29% of all annotated genes overlap at least 1 of their 2 flanking genes. We present a unified model for the creation and repair of overlaps among adjacent genes where the 3' ends either overlap or nearly overlap. Our model, derived from a comprehensive analysis of complete prokaryotic genomes in GenBank, explains the nonuniform distribution of the lengths of such overlap regions far more simply than previously proposed models. Specifically, we explain the distribution of overlap lengths based on random extensions of genes to the next occurring downstream stop codon. Our model also provides an explanation for a newly observed (here) pattern in the distribution of the separation distances of closely spaced nonoverlapping genes. We provide evidence that the newly described biased distribution of separation distances is driven by the same phenomenon that creates the uneven distribution of overlap lengths. This suggests a dynamic picture of continual overlap creation and elimination.

Additional Sex Combs Affects Antennal Development by Means of Spatially Restricted Repression of Antp and Wg

Developmental Dynamics : an Official Publication of the American Association of Anatomists. Aug, 2007  |  Pubmed ID: 17654717

Additional sex combs (Asx) is thought to function in protein complexes of both the Trithorax and Polycomb groups, but very little is known about its developmental roles. Here, we present a detailed analysis of Asx's role in antennal development. We show that loss of Asx in the antennal disc causes a complex phenotype, which consists of distal antenna-to-leg transformations and outgrowth of ectopic leg-like appendages from the Dpp-expressing domain of the disc. Our analyses suggest that these phenotypes are caused mainly by segment-specific de-repression of Antp and expansion of wg expression. We thus conclude that Asx functions normally to repress Antp and to restrict wg expression in specific regions of the developing disc. We also show that, in the absence of Asx's function, Antp expression does not lead to efficient repression of the antennal-determining gene hth, suggesting that Asx is also required for the repression of hth by Antp.

Draft Genome of the Filarial Nematode Parasite Brugia Malayi

Science (New York, N.Y.). Sep, 2007  |  Pubmed ID: 17885136

Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the approximately 90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict approximately 11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during approximately 350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design.

A Phase I Study of Visilizumab, a Humanized Anti-CD3 Monoclonal Antibody, in Severe Steroid-refractory Ulcerative Colitis

Gastroenterology. Nov, 2007  |  Pubmed ID: 17920064

To evaluate the safety and biological activity of visilizumab (a humanized anti-CD3 monoclonal antibody) and to determine a maximum tolerated dose in patients with severe ulcerative colitis that had not responded to 5 days of treatment with intravenous corticosteroids.

Epidemiology of Stroke After Cardiac Surgery in the Current Era

The Journal of Thoracic and Cardiovascular Surgery. Nov, 2007  |  Pubmed ID: 17976438

Previous studies of the epidemiology of stroke in patients undergoing cardiac surgery have been based primarily on patients having coronary bypass surgery and therefore have limited applicability to the more heterogenous populations seen in the current era. We examine the epidemiology of stroke after cardiac surgery in a contemporary surgical population.

Evolution of Genes and Genomes on the Drosophila Phylogeny

Nature. Nov, 2007  |  Pubmed ID: 17994087

Comparative analysis of multiple genomes in a phylogenetic framework dramatically improves the precision and sensitivity of evolutionary inference, producing more robust results than single-genome analyses can provide. The genomes of 12 Drosophila species, ten of which are presented here for the first time (sechellia, simulans, yakuba, erecta, ananassae, persimilis, willistoni, mojavensis, virilis and grimshawi), illustrate how rates and patterns of sequence divergence across taxa can illuminate evolutionary processes on a genomic scale. These genome sequences augment the formidable genetic tools that have made Drosophila melanogaster a pre-eminent model for animal genetics, and will further catalyse fundamental research on mechanisms of development, cell biology, genetics, disease, neurobiology, behaviour, physiology and evolution. Despite remarkable similarities among these Drosophila species, we identified many putatively non-neutral changes in protein-coding genes, non-coding RNA genes, and cis-regulatory regions. These may prove to underlie differences in the ecology and behaviour of these diverse species.

Early Postnatal Stress Confers Enduring Vulnerability to Limbic Epileptogenesis

Epilepsia. Nov, 2007  |  Pubmed ID: 17999745

Early life stress has enduring behavioral and neuroendocrine effects, particularly in hippocampus and amygdala. This may be relevant to mesial temporal lobe epilepsy (MTLE) that arises from these structures. In rats, we tested the hypothesis that early postnatal stress, in the form of maternal separation (MS), creates vulnerability to limbic epileptogenesis in adult life.

An Open-label, Multicenter Study of Outpatient Capecitabine Monotherapy in 631 Patients with Pretreated Advanced Breast Cancer

Oncology. 2007  |  Pubmed ID: 18004077

Phase II/III trials have shown that capecitabine is an active, well-tolerated therapy for metastatic breast cancer (MBC). We report clinical findings from an expanded access program enabling patients ineligible for investigative trials to receive capecitabine before its approval and availability.

Structure-based Maximal Affinity Model Predicts Small-molecule Druggability

Nature Biotechnology. Jan, 2007  |  Pubmed ID: 17211405

Lead generation is a major hurdle in small-molecule drug discovery, with an estimated 60% of projects failing from lack of lead matter or difficulty in optimizing leads for drug-like properties. It would be valuable to identify these less-druggable targets before incurring substantial expenditure and effort. Here we show that a model-based approach using basic biophysical principles yields good prediction of druggability based solely on the crystal structure of the target binding site. We quantitatively estimate the maximal affinity achievable by a drug-like molecule, and we show that these calculated values correlate with drug discovery outcomes. We experimentally test two predictions using high-throughput screening of a diverse compound collection. The collective results highlight the utility of our approach as well as strategies for tackling difficult targets.

Draft Genome Sequence of the Sexually Transmitted Pathogen Trichomonas Vaginalis

Science (New York, N.Y.). Jan, 2007  |  Pubmed ID: 17218520

We describe the genome sequence of the protist Trichomonas vaginalis, a sexually transmitted human pathogen. Repeats and transposable elements comprise about two-thirds of the approximately 160-megabase genome, reflecting a recent massive expansion of genetic material. This expansion, in conjunction with the shaping of metabolic pathways that likely transpired through lateral gene transfer from bacteria, and amplification of specific gene families implicated in pathogenesis and phagocytosis of host proteins may exemplify adaptations of the parasite during its transition to a urogenital environment. The genome sequence predicts previously unknown functions for the hydrogenosome, which support a common evolutionary origin of this unusual organelle with mitochondria.

Identifying Bacterial Genes and Endosymbiont DNA with Glimmer

Bioinformatics (Oxford, England). Mar, 2007  |  Pubmed ID: 17237039

The Glimmer gene-finding software has been successfully used for finding genes in bacteria, archaea and viruses representing hundreds of species. We describe several major changes to the Glimmer system, including improved methods for identifying both coding regions and start codons. We also describe a new module of Glimmer that can distinguish host and endosymbiont DNA. This module was developed in response to the discovery that eukaryotic genome sequencing projects sometimes inadvertently capture the DNA of intracellular bacteria living in the host.

Genome Re-annotation: a Wiki Solution?

Genome Biology. 2007  |  Pubmed ID: 17274839

The annotation of most genomes becomes outdated over time, owing in part to our ever-improving knowledge of genomes and in part to improvements in bioinformatics software. Unfortunately, annotation is rarely if ever updated and resources to support routine reannotation are scarce. Wiki software, which would allow many scientists to edit each genome's annotation, offers one possible solution.

Computed Tomography Angiography is an Excellent Tool for the Diagnosis of Congenital Coronary Artery Anomalies: a Report of 2 Cases

The Heart Surgery Forum. 2007  |  Pubmed ID: 17284399

Congenital coronary artery anomalies are sporadically discovered in patients undergoing coronary angiography and in autopsy series. Although most anomalies are clinically insignificant, some may become causes of cardiovascular morbidities and mortality. Diagnosis is commonly made with conventional coronary artery angiography. The current development of modern cardiac computed tomography allows less invasive imaging of the coronary arteries and might provide additional anatomical and morphological information. Herein, we report our experience with computed tomography coronary angiography, describing 2 clinical cases of patients with symptomatic congenital coronary artery anomalies requiring cardiac surgery.

A Graph-based Reflexive Artificial Chemistry

Bio Systems. Jan, 2007  |  Pubmed ID: 16733079

The conceptual divide between formal systems of computation and abstract models of chemistry is considered. As an attempt to concretely bridge this divide, a formalism is proposed that describes a constructive artificial chemistry on a space of directed graph structures. The idea for the formalism originates in computer science theory, with the traditional abstraction of a physical machine, the finite-state machine (FSM). In the FSM, the machine (state-transition graph) and input string (series of binary digits) are fundamentally distinct objects, separated by nature of the underlying formalism. This distinction is dissolved in the proposed system, resulting in a construction process that is reflexive: graphs interact with their own topological structure to generate a product. It is argued that this property of reflexivity is a key element missing from earlier model chemistries. Examples demonstrate the continuous emergence complex self-similar topologies, novel reaction pathways, and seemingly open-ended diversity. Implications of these findings are discussed.

The Neurologist, Psychogenic Nonepileptic Seizures, and Borderline Personality Disorder

Epilepsy & Behavior : E&B. Dec, 2007  |  Pubmed ID: 18054130

Patients with psychogenic nonepileptic seizures (PNES) are common in tertiary epilepsy centers, emergency departments, and neurological practices. Psychiatric discussion of patients with PNES has emphasized the role of trauma and dissociation. Personality disorder has been considered, but its extensive implications for neurological management have not been fully appreciated. We propose that the most difficult aspects of management stem not from the convulsive episodes, but from the personality disorder that frequently accompanies them. Although it is not the neurologist's role to treat personality disorder, the conduct of the physician-patient relationship can have potent consequences for good or ill on the outcome. We present a brief guide to current concepts of personality disorder; discuss the literature concerning its association with PNES, and offer practical guidelines for the conduct of the neurologist-patient relationship. This perspective offers resolutions to longstanding controversies, including how to communicate the diagnosis, discontinuing medication, and ongoing neurological contact.

Pegylated Liposomal Doxorubicin (caelyx) in Metastatic Breast Cancer: a Community-based Observation Study

Oncology. 2007  |  Pubmed ID: 18087175

Pegylated liposomal doxorubicin (PLD) has improved therapy options significantly, as it causes less myelosuppression, nausea, vomiting, and alopecia than conventional doxorubicin, while maintaining efficacy. The goal of this survey was to determine whether the use of PLD in a community-based patient group is comparable regarding chemotherapeutic doses and side effects to preselected study patients.

Is RAS Blockade Routinely Indicated in Hypertensive Kidney Transplant Patients?

Current Hypertension Reports. Nov, 2007  |  Pubmed ID: 18177591

There is a high incidence of hypertension after kidney transplantation, which has been associated with the development of left ventricular hypertrophy, an increased risk for acute rejection, lower graft survival, and increased mortality. The pathogenesis of post-transplant hypertension is multifactorial, and therefore optimum therapy for it is not clearly defined. Historically, use of renin-angiotensin system (RAS) blockade in post-transplant hypertension has been limited given concerns of inducing worsening allograft function. Recent data demonstrated that subjects with post-transplant hypertension can be treated effectively with RAS blockers, and that these agents may offer significant additional benefits beyond blood pressure control. Review of the literature suggests that RAS blockers should be considered as useful agents for treatment of post-transplant hypertension not due to transplant renal artery stenosis.

A Multicenter Retrospective Experience of Infliximab in Crohn's Disease Patients: Infusion Reaction Rates and Treatment Persistency

Gastroenterology & Hepatology. May, 2007  |  Pubmed ID: 21960854

Background: Infusion reactions have been associated with infliximab therapy, but no study has assessed how physicians treat and manage this common adverse event. Goals: To determine how gastroenterologists manage infusion reactions, identify prophylactic pretreatment protocols, and determine infliximab treatment persistence in the presence of infusion reactions. Method: This retrospective multicenter chart review analyzed data from adults younger than 90 years at the time of their first infliximab infusion from 9 academic or community-based gastroenterology practices. Infusion reaction rates were compared using a Chi-square test with Yates' correction. Kaplan-Meier methods assessed infliximab treatment persistency. Results: Among 6,468 infusions with known infusion reaction status administered to 447 patients, 3.5% (226/6,468) of infusions resulted in an infusion reaction, and less than 0.1% (2/6,468) were associated with a serious infusion reaction. Among all patients, 19.7% (88/447) experienced at least 1 infusion reaction, whereas 0.4% (2/447) experienced a serious infusion reaction. Patients receiving concomitant immunosuppressives had fewer infusion reactions compared to patients not receiving them (57/322 patients, 17.7% vs 31/125 patients, 24.8%; P=.118). The cumulative proportion of patients continuing infliximab therapy at 2, 4, and 5 years was 73%, 58%, and 54%, respectively. Conclusions: The incidence of serious infusion reactions was low. In the overall experience observed in this clinical practice retrospective cohort, no conclusions can be drawn regarding the effectiveness of specific infusion reaction prophylactic measures. In spite of infusion reactions, the long-term infliximab treatment persistence rate was high.

Automated Eukaryotic Gene Structure Annotation Using EVidenceModeler and the Program to Assemble Spliced Alignments

Genome Biology. 2008  |  Pubmed ID: 18190707

EVidenceModeler (EVM) is presented as an automated eukaryotic gene structure annotation tool that reports eukaryotic gene structures as a weighted consensus of all available evidence. EVM, when combined with the Program to Assemble Spliced Alignments (PASA), yields a comprehensive, configurable annotation system that predicts protein-coding genes and alternatively spliced isoforms. Our experiments on both rice and human genome sequences demonstrate that EVM produces automated gene structure annotation approaching the quality of manual curation.

Bioinformatics Challenges of New Sequencing Technology

Trends in Genetics : TIG. Mar, 2008  |  Pubmed ID: 18262676

New DNA sequencing technologies can sequence up to one billion bases in a single day at low cost, putting large-scale sequencing within the reach of many scientists. Many researchers are forging ahead with projects to sequence a range of species using the new technologies. However, these new technologies produce read lengths as short as 35-40 nucleotides, posing challenges for genome assembly and annotation. Here we review the challenges and describe some of the bioinformatics systems that are being proposed to solve them. We specifically address issues arising from using these technologies in assembly projects, both de novo and for resequencing purposes, as well as efforts to improve genome annotation in the fragmented assemblies produced by short read lengths.

Analysis of Carica Papaya Telomeres and Telomere-Associated Proteins: Insights into the Evolution of Telomere Maintenance in Brassicales

Tropical Plant Biology. Dec, 2008  |  Pubmed ID: 20664721

Telomeres are terminal regions of linear eukaryotic chromosomes that are critical for genome stability and continued cell proliferation. The draft assembly of the papaya genome provides an opportunity to analyze and compare the evolution of telomeric DNA sequence composition and telomere maintenance machinery in this and other organisms of the Brassicales Order, which includes Arabidopsis. Here we investigate telomere size and sequence variation at papaya chromosome ends. As with most other plant species, papaya telomeres consist of TTTAGGG repeats. However, in contrast to members of the closely related Brassicaceae family, telomeres in papaya are ~10-fold longer. Sequence analysis reveals that many centromereproximal telomere repeats in papaya harbor nucleotide substitutions and insertions of Gs and Ts. In contrast, we found very few N-to-C substitutions, and even fewer instances of nucleotide deletion, suggesting that a six-nucleotide telomere repeat is not well tolerated. The papaya genome encodes single-copy sequence homologues of several genes involved in telomere maintenance and chromosome end protection, including the Telomerase Reverse Transcriptase (TERT) and Protection Of Telomeres (POT1). Notably, unlike Arabidopsis, which encodes six Telomere Repeat binding Factor-like (TRFL) proteins that bind double-stranded telomere DNA, papaya appears to encode only two such proteins. Thus, the more streamlined genome of papaya will provide an excellent resource for comparative and functional analysis of telomeres in plants.

Lung Cancer Symptom Scale Outcomes in Relation to Standard Efficacy Measures: an Analysis of the Phase III Study of Pemetrexed Versus Docetaxel in Advanced Non-small Cell Lung Cancer

Journal of Thoracic Oncology : Official Publication of the International Association for the Study of Lung Cancer. Jan, 2008  |  Pubmed ID: 18166838

Patients with advanced non-small cell lung cancer (NSCLC) require care that emphasizes symptom palliation in addition to extending survival. The low response rates and minimal survival gains observed in second-line studies underscore the need to assess treatment efficacy with symptomatic end points.

Two-photon Excitation of Potentiometric Probes Enables Optical Recording of Action Potentials from Mammalian Nerve Terminals in Situ

Journal of Neurophysiology. Mar, 2008  |  Pubmed ID: 18171710

We report the first optical recordings of action potentials, in single trials, from one or a few (approximately 1-2 microm) mammalian nerve terminals in an intact in vitro preparation, the mouse neurohypophysis. The measurements used two-photon excitation along the "blue" edge of the two-photon absorption spectrum of di-3-ANEPPDHQ (a fluorescent voltage-sensitive naphthyl styryl-pyridinium dye), and epifluorescence detection, a configuration that is critical for noninvasive recording of electrical activity from intact brains. Single-trial recordings of action potentials exhibited signal-to-noise ratios of approximately 5:1 and fractional fluorescence changes of up to approximately 10%. This method, by virtue of its optical sectioning capability, deep tissue penetration, and efficient epifluorescence detection, offers clear advantages over linear, as well as other nonlinear optical techniques used to monitor voltage changes in localized neuronal regions, and provides an alternative to invasive electrode arrays for studying neuronal systems in vivo.

Human K10 Epithelial Keratin is the Most Abundant Protein in Airborne Dust of Both Occupied and Unoccupied School Rooms

Journal of Environmental Monitoring : JEM. Jan, 2008  |  Pubmed ID: 18175017

Previously it was demonstrated that the levels of large particles (>2 micron) and associated bacterial cell envelope markers increase greatly on occupation in schools; it was hypothesized that the source of both was shed human skin. In the current work to test this hypothesis, room air cleaners were used to collect airborne dust (>50-100 mg) from occupied and unoccupied school rooms which was then subjected to proteomic analysis. Proteins were extracted from the dust and separated using two dimensional gel electrophoresis (2D GE). In situ digestion of protein spots with trypsin released peptides, which were subsequently analyzed by matrix assisted laser desorption/deionization, time-of-flight mass spectrometry (MALDI-TOF-MS) and tandem mass spectrometry (MALDI-TOF-MS-MS). In Coomassie blue stained gels, a single spot generally dominated the 2D gels; this protein was identified by tandem mass spectrometry as K10 epithelial keratin. The results experimentally confirm previous anecdotal reports that human skin is readily shed into air and suggest that increased levels of microbial markers and large particles observed in occupied rooms are also derived from skin.

Evaluation of a High Visibility Enforcement Project Focused on Passenger Vehicles Interacting with Commercial Vehicles

Journal of Safety Research. 2008  |  Pubmed ID: 19010119

In 2004, Washington State applied NHTSA's High Visibility Enforcement model used in the Click It or Ticket seat belt campaign in an attempt to reduce unsafe driving behaviors around commercial motor vehicles (CMVs). The program was called Ticketing Aggressive Cars and Trucks (TACT). This paper details the methods used to evaluate the program's effectiveness and the results of the evaluation.

Acquisition and Evolution of Plant Pathogenesis-associated Gene Clusters and Candidate Determinants of Tissue-specificity in Xanthomonas

PloS One. 2008  |  Pubmed ID: 19043590

Xanthomonas is a large genus of plant-associated and plant-pathogenic bacteria. Collectively, members cause diseases on over 392 plant species. Individually, they exhibit marked host- and tissue-specificity. The determinants of this specificity are unknown.

Experimental Traumatic Brain Injury Induces a Pervasive Hyperanxious Phenotype in Rats

Journal of Neurotrauma. Nov, 2008  |  Pubmed ID: 19061380

Mood disturbances, including depression and anxiety disorders, are common and disabling long-term sequelae of traumatic brain injury (TBI). These psychiatric conditions have generally been considered psychosocial consequences of the trauma, but neurobiological alterations and causes have also been implicated. Using a rat model of TBI (lateral fluid-percussion injury), this longitudinal study seeks to assess anxiety and depression-like behaviors following experimental TBI. Male Wistar rats (n = 20) received a severe (approximately 3.5 atmosphere) pressure pulse directed to the right sensorimotor cortex, or sham surgery (n = 15). At 1, 3, and 6 months following injury, all rats underwent four assessments of anxiety and depression-like behaviors: exposure to an open field, elevated plus maze test, the forced swim test, and the sucrose preference test. Injured animals displayed increased anxiety-like behaviors throughout the study, as evidenced by reduced time spent (p = 0.014) and reduced entries (p < 0.001) into the center area of the open field, and reduced proportion of time in the open arms of the plus maze (p = 0.015), compared to sham-injured controls. These striking changes were particularly evident 1 and 3 months after injury. No differences were observed in depression-like behaviors in the forced swim test (a measure of behavioral despair) and the sucrose preference test (a measure of anhedonia). This report provides the first evidence of persistent anxiety-like disturbances in an experimental model of TBI. This finding indicates that the common occurrence of these symptoms in human sufferers is likely to have, at least in part, a neurobiological basis. Studies in this model could provide insight into the mechanisms underlying affective disturbance in brain-injured patients.

B-type Natriuretic Peptide (BNP) in Patients Undergoing Mitral Valve Surgery

Journal of Cardiac Surgery. Nov-Dec, 2008  |  Pubmed ID: 18793229

Plasma B-type natriuretic peptide (BNP) level may be increased in patients with valvular disease. Recent studies have suggested that in patients undergoing aortic valve replacement, an increased preoperative BNP is associated with a worse operative outcome. Little is known about the perioperative value of BNP in patients undergoing mitral valve (MV) surgery. We measured the preoperative and postoperative BNP levels in this population and analyzed the impact of the increased BNP level on surgical outcome.

Gene-boosted Assembly of a Novel Bacterial Genome from Very Short Reads

PLoS Computational Biology. 2008  |  Pubmed ID: 18818729

Recent improvements in technology have made DNA sequencing dramatically faster and more efficient than ever before. The new technologies produce highly accurate sequences, but one drawback is that the most efficient technology produces the shortest read lengths. Short-read sequencing has been applied successfully to resequence the human genome and those of other species but not to whole-genome sequencing of novel organisms. Here we describe the sequencing and assembly of a novel clinical isolate of Pseudomonas aeruginosa, strain PAb1, using very short read technology. From 8,627,900 reads, each 33 nucleotides in length, we assembled the genome into one scaffold of 76 ordered contiguous sequences containing 6,290,005 nucleotides, including one contig spanning 512,638 nucleotides, plus an additional 436 unordered contigs containing 416,897 nucleotides. Our method includes a novel gene-boosting algorithm that uses amino acid sequences from predicted proteins to build a better assembly. This study demonstrates the feasibility of very short read sequencing for the sequencing of bacterial genomes, particularly those for which a related species has been sequenced previously, and expands the potential application of this new technology to most known prokaryotic species.

Phenotypic and Transcriptomic Characterization of Bacillus Subtilis Mutants with Grossly Altered Membrane Composition

Journal of Bacteriology. Dec, 2008  |  Pubmed ID: 18820022

The Bacillus subtilis membrane contains diacylglycerol-based lipids with at least five distinct headgroups that together help to define the physical and chemical properties of the lipid bilayer. Here, we describe the phenotypic characterization of mutant strains lacking one or more of the following lipids: glycolipids (ugtP mutants), phosphatidylethanolamine (pssA and psd mutants), lysylphosphatidylglycerol (mprF), and cardiolipin (ywnE and ywjE). Alterations of membrane lipid headgroup composition are generally well-tolerated by the cell, and even severe alterations lead to only modest effects on growth proficiency. Mutants with decreased levels of positively charged lipids display an increased sensitivity to cationic antimicrobial compounds, and cells lacking glycolipids are more sensitive to the peptide antibiotic sublancin and are defective in swarming motility. A quadruple mutant strain (ugtP pssA mprF ywnE), with a membrane comprised predominantly of phosphatidylglycerol, is viable and grows at near-wild-type rates, although it forms long, coiled filaments. Transcriptome comparisons identified numerous regulons with altered expression in cells of the ugtP mutant, the pssA mprF ywnE triple mutant, and the ugtP pssA mprF ywnE quadruple mutant. These effects included a general decrease in expression of the SigD and FapR regulons and increased expression of cell envelope stress responses mediated by sigma(M) and the YvrGHb two-component system.

Comparative Genomics of the Neglected Human Malaria Parasite Plasmodium Vivax

Nature. Oct, 2008  |  Pubmed ID: 18843361

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

Re-assembly of the Genome of Francisella Tularensis Subsp. Holarctica OSU18

PloS One. 2008  |  Pubmed ID: 18927608

Francisella tularensis is a highly infectious human intracellular pathogen that is the causative agent of tularemia. It occurs in several major subtypes, including the live vaccine strain holarctica (type B). F. tularensis is classified as category A biodefense agent in part because a relatively small number of organisms can cause severe illness. Three complete genomes of subspecies holarctica have been sequenced and deposited in public archives, of which OSU18 was the first and the only strain for which a scientific publication has appeared. We re-assembled the OSU18 strain using both de novo and comparative assembly techniques, and found that the published sequence has two large inversion mis-assemblies. We generated a corrected assembly of the entire genome along with detailed information on the placement of individual reads within the assembly. This assembly will provide a more accurate basis for future comparative studies of this pathogen.

The Draft Genome of the Transgenic Tropical Fruit Tree Papaya (Carica Papaya Linnaeus)

Nature. Apr, 2008  |  Pubmed ID: 18432245

Papaya, a fruit crop cultivated in tropical and subtropical regions, is known for its nutritional benefits and medicinal applications. Here we report a 3x draft genome sequence of 'SunUp' papaya, the first commercial virus-resistant transgenic fruit tree to be sequenced. The papaya genome is three times the size of the Arabidopsis genome, but contains fewer genes, including significantly fewer disease-resistance gene analogues. Comparison of the five sequenced genomes suggests a minimal angiosperm gene set of 13,311. A lack of recent genome duplication, atypical of other angiosperm genomes sequenced so far, may account for the smaller papaya gene number in most functional groups. Nonetheless, striking amplifications in gene number within particular functional groups suggest roles in the evolution of tree-like habit, deposition and remobilization of starch reserves, attraction of seed dispersal agents, and adaptation to tropical daylengths. Transgenesis at three locations is closely associated with chloroplast insertions into the nuclear genome, and with topoisomerase I recognition sites. Papaya offers numerous advantages as a system for fruit-tree functional genomics, and this draft genome sequence provides the foundation for revealing the basis of Carica's distinguishing morpho-physiological, medicinal and nutritional properties.

Genome Sequence and Rapid Evolution of the Rice Pathogen Xanthomonas Oryzae Pv. Oryzae PXO99A

BMC Genomics. 2008  |  Pubmed ID: 18452608

Xanthomonas oryzae pv. oryzae causes bacterial blight of rice (Oryza sativa L.), a major disease that constrains production of this staple crop in many parts of the world. We report here on the complete genome sequence of strain PXO99A and its comparison to two previously sequenced strains, KACC10331 and MAFF311018, which are highly similar to one another.

The Effect of Calcium Intake and Physical Activity on Bone Quantitative Ultrasound Measurements in Children: a Pilot Study

Journal of Bone and Mineral Metabolism. 2008  |  Pubmed ID: 18470665

Environmental factors, such as nutritional status, physical activity, and drug therapy, can affect bone mineralization. Our objective was to evaluate the relationship between nutritional status, physical activity, and bone mineralization as assessed by multisite quantitative ultrasound technology in children. The study group comprised 67 children, aged 6-17 years (mean, 9.4), attending a primary care clinic. Data on calcium intake and physical activity were collected using a detailed questionnaire. Speed of sound measurements were performed at the distal 1/3 radius and the midshaft tibia using Sunlight Omnisense apparatus. The reported mean calcium intake was 1105 mg/day. There was a significant difference in Z-scores at the radius and tibia between the low-and high-calcium-intake groups (P = 0.004, P = 0.035, respectively). A similar difference was found between the low-and normal-physical-activity groups (P = 0.015, P = 0.036, respectively). In this pilot study, a positive association was found between calcium intake, physical activity, and bone status, as assessed by the quantitative ultrasound technique.

Chromosomal Binding Sites of the Homeotic Cofactor Homothorax

Molecular Genetics and Genomics : MGG. Jul, 2008  |  Pubmed ID: 18481089

The Meis family oncoproteins play a crucial role in leukemogenesis and are highly expressed in other types of cancer as well. The transforming potential of Meis proteins depends on their ability to activate gene expression and therefore, revealing the identity of their target genes is very important. The genome of the fruit fly Drosophila melanogaster contains a single Meis gene, homothorax (hth), which plays multiple roles in embryonic and adult development. Mutations in hth affect the development of numerous embryonic and adult tissues, suggesting that Hth regulates the transcription of a large number of genes. However, it is not known how many genes are regulated directly by Hth and what is the nature of these genes. To address this question, we examined the distribution of the in vivo binding sites of Hth on polytene chromosomes. We found that in the salivary glands (SG) of third instar larvae, Hth binds to approximately 150 chromosomal sites in a very reproducible pattern. More than hundred of these sites were mapped cytologically. Interestingly, Hth accumulates at high levels in some of the most prominent hormone-induced chromosomal puffs, pointing to a possible role of Hth in activation of ecdysone-induced targets. Interfering with the normal transcriptional activity of Hth in larval SGs leads to dramatic reduction in cell size and DNA content implicating Hth in the regulation of cell growth and endoreplication in larval SGs.

Neuropsychiatric Morbidity in Focal Epilepsy

The British Journal of Psychiatry : the Journal of Mental Science. Jun, 2008  |  Pubmed ID: 18515901

Previous work has identified elevated prevalence rates for psychiatric disorders in individuals with medically refractory focal epilepsy, particularly temporal lobe epilepsy. Many studies were undertaken before the advent of video electroencephalogram monitoring (VEM) and magnetic resonance imaging (MRI).

Subcutaneous Mastectomy and Immediate Reconstruction for Prevention of Breast Cancer for High-risk Patients

Breast Cancer (Tokyo, Japan). 2008  |  Pubmed ID: 18575951

Breast cancer is the most common malignant tumor among females in the USA, with one out of eight American females developing breast cancer in their lifetimes. The latest studies show that 212,920 new cases of invasive cancer developed in 2006, which is 2.5 times more common than the incidence of lung cancer, and that 40,970 females will die from this disease each year. Therefore, awareness of this cancer is an important health issue, with more women beginning to assess their risk of breast cancer, either informally or with instruments such as the GAIL model. The availability of genetic testing for BRCA-1 and BRCA-2 has revealed many women who are at significantly increased risk. Many aggressive surveillance programs have been developed using advanced MRI and ultrasound, and reductions in breast cancer risk of 50% or more have been proven using chemoprevention strategies with tamoxifen and raloxifene. However, many women are starting to seriously consider prophylactic mastectomy for near-total reduction of breast cancer risk. At our institution, we have developed a procedure for prophylactic subcutaneous mastectomy via an inframammary incision that spares the nipple and is combined with immediate silicone implant reconstruction with the assistance of Alloderm. In this article we will describe the procedure and some of the important issues surrounding its implementation from our experience.

A Pilot Study with Very Low-intensity, Intermediate-frequency Electric Fields in Patients with Locally Advanced And/or Metastatic Solid Tumors

Onkologie. Jul, 2008  |  Pubmed ID: 18596382

The transmission of electric fields using insulated electrodes has demonstrated that very low-intensity, properly tuned, intermediate-frequency electric fields, termed tumor-treating fields (TTFields), selectively stunts tumor cell growth and is accompanied by a decrease in tumor angiogenesis.

The Contents of the Syringe

Nature. Jul, 2008  |  Pubmed ID: 18615063

Surgical Treatment of Atrial Fibrillation Using Cryothermy in Patients Undergoing Mitral Valve Surgery

Interactive Cardiovascular and Thoracic Surgery. Dec, 2008  |  Pubmed ID: 18628344

Surgical treatment of atrial fibrillation (AF) using a variety of energy sources and a mixture of lesion sets has become an important adjunct in patients undergoing cardiac surgery. We retrospectively analyzed prospectively collected data of 141 patients with a history of AF (mean duration of AF 35+/-39 months; intermittent AF: n=72; 51%; permanent AF: 69 (49%)) who underwent a left-sided Cryomaze procedure in conjunction with mitral valve (MV) surgery between January 2003 and September 2006. Freedom from AF was 77% at discharge and 87% at a mean follow-up of 305+/-195 days with a decreasing rate of AF during the first 3-9 months from 13% to 9% and an increase beyond the first year (29% at 2 years). Predictors of failed Cryomaze in multivariate analysis were left atrial size >50 mm (OR=5.7), AF at surgery (OR=5.0) and cardiac reoperation (OR=3.4), whereas preoperative beta-blocker treatment was a predictor of success (OR=0.2). Our data suggest that a left-sided Cryomaze procedure effectively restores sinus rhythm in patients with AF undergoing MV surgery. The success rate should not be evaluated immediately postoperatively because there is a steady increase in the rate of patients with freedom from AF in the first year. It appears, however, that there is a higher rate of recurrence during later follow-up.

Surgical Left Atrial Appendage Occlusion: Evaluation of a Novel Device with Magnetic Resonance Imaging

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Oct, 2008  |  Pubmed ID: 18693117

Management of the left atrial appendage (LAA) is considered an important adjunct to ablation in cardiac surgical patients with atrial fibrillation (AF). However, current surgical techniques, both cut-and-sew and stapling, have been associated with incomplete LAA occlusion and complications. Using cardiac magnetic resonance imaging (MRI), we studied the safety and effectiveness of a new device for LAA occlusion in a primate model.

Renal Consequences of Prostaglandin Inhibition in Heart Failure

Heart Failure Clinics. Oct, 2008  |  Pubmed ID: 18760760

Prostaglandins are products of intracellular arachidonate metabolism via the cyclooxygenase pathways. In the kidney, prostaglandins are modulators of afferent arteriole autoregulation. In diminished effective intravascular volume, vasodilatory prostaglandins reduce afferent arteriolar resistance, helping to maintain overall glomerular filtration. In subjects who have a low perfusion state, as in congestive heart failure, arthrosclerosis, hepatorenal syndrome, and cirrhosis, impaired renal autoregulation occurs, predisposing to kidney injury. Adverse effects of prostaglandin inhibition include acute kidney injury, hyperkalemia, hypertension, and edema. Hypertension and edema can occur because prostaglandins play an important role in renal regulation of salt and water balance. This review summarizes the renal consequences of using prostaglandin inhibitors in subjects who have congestive heart failure.

Use of Lipoteichoic Acid-T for Pleurodesis in Malignant Pleural Effusion: a Phase I Toxicity and Dose-escalation Study

The Lancet Oncology. Oct, 2008  |  Pubmed ID: 18775668

Bacterial infection of the pleural space often causes adherence of the pleural membranes by fibrous tissue, probably mediated by inflammation initiated by bacterial cell-wall motifs, including lipoteichoic acid-T (LTA-T). We postulated that therapeutically administered LTA-T might produce a similar effect, achieving control of malignant pleural effusion (pleurodesis).

What Are Decision Trees?

Nature Biotechnology. Sep, 2008  |  Pubmed ID: 18779814

Decision trees have been applied to problems such as assigning protein function and predicting splice sites. How do these classifiers work, what types of problems can they solve and what are their advantages over alternatives?

Elevated Anxiety and Depressive-like Behavior in a Rat Model of Genetic Generalized Epilepsy Suggesting Common Causation

Experimental Neurology. Jan, 2008  |  Pubmed ID: 18022621

The explanation for the increased prevalence of neuropsychiatric disorders in epilepsy patients is uncertain, with both biological and psychosocial factors proposed. Increasing evidence supports the idea of shared neurobiological processes leading both to seizures and to behavioral, emotional and cognitive disturbance. This study addresses this using Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a model of human generalized epilepsy. We subjected GAERS (n=47) and Non-Epileptic Control rats (NEC; n=73) to behavioral measures of depression and anxiety at 7 and 13 weeks of age, ages prior to and after seizure onset. We employed the Sucrose-Preference Test (SPT), the Elevated Plus Maze (EPM), and the Open Field Arena (OFA). GAERS exhibited significantly greater levels of both depression- and anxiety-like behaviors on all measures, including reduced consumption of sucrose solution in the SPT; lower percentage of time in the open arms of the EPM; and reduced exploratory activity and less time spent in the inner area of the OFA. These differences were evident at both 7 and 13 weeks of age, before and after the onset of epilepsy. Increased anxiety- and depressive-like behaviors are observed in GAERS. These behavioral differences exist before the onset of seizures indicating that they are not secondary consequences of seizures, and suggest shared factors in the biological diathesis underlying the two kinds of disorder. Studying affective disturbance in animal models of epilepsy may illuminate the pathogenesis of affective disorder more generally, as well as modeling psychiatric comorbidities common in epilepsy patients.

Obsessive-compulsive Disorder with Mitochondrial Disease

Psychosomatics. Nov-Dec, 2008  |  Pubmed ID: 19122133

Mitochondrial diseases are among the most common genetic disorders, and they have been associated with several psychiatric syndromes.

Morphometric Abnormalities and Hyperanxiety in Genetically Epileptic Rats: a Model of Psychiatric Comorbidity?

NeuroImage. Apr, 2009  |  Pubmed ID: 19167503

Imaging studies of epilepsy patients with comorbid affective disturbance demonstrate morphometric changes in limbic brain regions implicated in psychiatric disease. Genetic Absence Epilepsy Rats from Strasbourg (GAERS), specifically bred for their epilepsy phenotype, also exhibit elevated anxiety-like behaviors suggesting a common causality. Here we examined whether relevant cerebral morphological alterations exist in this rat strain using volumetric measurements and large deformation high dimensional mapping (HDM-LD), a tool recently validated to produce accurate three-dimensional surface representations of the hippocampus.

Ultrafast and Memory-efficient Alignment of Short DNA Sequences to the Human Genome

Genome Biology. 2009  |  Pubmed ID: 19261174

Bowtie is an ultrafast, memory-efficient alignment program for aligning short DNA sequence reads to large genomes. For the human genome, Burrows-Wheeler indexing allows Bowtie to align more than 25 million reads per CPU hour with a memory footprint of approximately 1.3 gigabytes. Bowtie extends previous Burrows-Wheeler techniques with a novel quality-aware backtracking algorithm that permits mismatches. Multiple processor cores can be used simultaneously to achieve even greater alignment speeds. Bowtie is open source (http://bowtie.cbcb.umd.edu).

TopHat: Discovering Splice Junctions with RNA-Seq

Bioinformatics (Oxford, England). May, 2009  |  Pubmed ID: 19289445

A new protocol for sequencing the messenger RNA in a cell, known as RNA-Seq, generates millions of short sequence fragments in a single run. These fragments, or 'reads', can be used to measure levels of gene expression and to identify novel splice variants of genes. However, current software for aligning RNA-Seq data to a genome relies on known splice junctions and cannot identify novel ones. TopHat is an efficient read-mapping algorithm designed to align reads from an RNA-Seq experiment to a reference genome without relying on known splice sites.

Five-year Efficacy and Safety Analysis of the Adenoma Prevention with Celecoxib Trial

Cancer Prevention Research (Philadelphia, Pa.). Apr, 2009  |  Pubmed ID: 19336730

The Adenoma Prevention with Celecoxib Trial examined the efficacy and safety of the cyclooxygenase (Cox)-2 inhibitor, celecoxib, for sporadic colorectal adenoma prevention in patients at high risk for colorectal cancer. The trial randomized 2,035 subjects to receive either placebo, celecoxib 200 mg twice daily, or celecoxib 400 mg twice daily. The primary study safety and efficacy analyses involved 3 years of treatment. The results showed significant antitumor effect but also indicated increased cardiovascular adverse events in patients treated with celecoxib compared with placebo. A total of 933 patients participated in an extension of the Adenoma Prevention with Celecoxib Trial, with a planned total treatment and surveillance duration of 5 years. Study medication was stopped early, resulting in a median treatment duration of 3.1 years for those with a year 5 colonoscopy. Patients treated on the placebo arm had a cumulative adenoma incidence of 68.4% over 5 years of observation. This figure was 59.0% (P < 0.0001) for those receiving low-dose celecoxib, and 60.1% (P < 0.0001) for those receiving high-dose celecoxib. The cumulative incidence of advanced adenomas over 5 years was 21.3% of those taking placebo, 12.5% (P < 0.0001) of those taking low dose celecoxib and 15.8% (P < 0.0001) of those taking high-dose celecoxib. Investigator reported treatment emergent adverse events were similar across all treatment groups for categories including renal and hypertensive events and gastrointestinal ulceration and hemorrhage events. For a category composed of cardiovascular and thrombotic events, the risk relative to placebo was 1.6 (95% confidence interval, 1.0, 2.5) for those using 200 mg twice daily celecoxib and 1.9 (95% confidence interval, 1.2, 3.1) for those using 400 mg twice daily celecoxib. Secondary analysis showed an interaction between a baseline history of atherosclerotic heart disease and study drug use with respect to cardiovascular and thrombotic adverse events (P = 0.004). These results confirm the inhibitory effect of celecoxib on colorectal adenoma formation, and provide additional safety data indicating an elevated risk for cardiovascular and thrombotic adverse events, particularly for patients with preexisting atherosclerotic heart disease.

A Whole-genome Assembly of the Domestic Cow, Bos Taurus

Genome Biology. 2009  |  Pubmed ID: 19393038

The genome of the domestic cow, Bos taurus, was sequenced using a mixture of hierarchical and whole-genome shotgun sequencing methods.

Anxiolytic Effects of Rapid Amygdala Kindling, and the Influence of Early Life Experience in Rats

Behavioural Brain Research. Oct, 2009  |  Pubmed ID: 19397932

The incidence of psychiatric disturbances is elevated in temporal lobe epilepsy (TLE) patients. Early life stressful events are believed to have a major impact on mental health later in life, and increasing evidence suggests that such stresses may also promote a vulnerability to TLE. This study investigated whether subjecting rats to early life stress exacerbated mood and cognitive disturbances associated with the development of epilepsy. On postnatal days 2-14, rat pups were separated from their dams for either 180 min/day (handling and maternal separation--HMS180, modelling early life stress) or 15 min/day (control handling and maternal separation--HMS15). At 7 weeks, rats were implanted with a bipolar electrode into the left amygdala. Following recovery, one group of rats from each litter underwent rapid amygdala kindling (RAK) epileptogenesis, while another underwent sham kindling. One week following this, rats were subjected to behavioural tests assessing anxiety and cognition. HMS180-exposed rats kindled faster than HMS15 rats (p<0.0001). RAK induced a potent anxiolytic effect as evidenced by increased % time spent in the open arms of the elevated plus maze, compared with sham kindled rats (p<0.0001). This anxiolytic effect was also observed in the open field task, as evidenced by increased time spent in the inner area (p=0.010). Neither RAK nor maternal separation had any effect on cognitive function in the Morris water maze. We conclude that maternal separation stress accelerates limbic epileptogenesis in adult rats, and that RAK induces potent anxiolytic effects that are not influenced by such early life stressful events.

Insignia: a DNA Signature Search Web Server for Diagnostic Assay Development

Nucleic Acids Research. Jul, 2009  |  Pubmed ID: 19417071

Insignia is a web application for the rapid identification of unique DNA signatures. DNA signatures are distinct nucleotide sequences that can be used to detect the presence of certain organisms and to distinguish those organisms from all other species. These signatures can be used as the basis for diagnostic assays to detect and genotype microbes in both environmental and clinical samples. Insignia identifies an exhaustive set of accurate DNA signatures for any set of target genomes, and screens these signatures against a comprehensive background that includes all sequenced bacteria and viruses, the human genome, and many other animals and plants. Identified signatures may be browsed by genomic location or proximal genes, filtered by composition, viewed in a genome browser or directly downloaded. Integrated PCR primer design is also provided for each signature. The Insignia website (http://insignia.cbcb.umd.edu) is free and open to all users and there is no login requirement. In addition, the source code for the computational pipeline is freely available.

How to Map Billions of Short Reads Onto Genomes

Nature Biotechnology. May, 2009  |  Pubmed ID: 19430453

Mapping the vast quantities of short sequence fragments produced by next-generation sequencing platforms is a challenge. What programs are available and how do they work?

Response to "The Guideline 'consultation Psychiatry' of the Netherlands Psychiatric Association"

Journal of Psychosomatic Research. Jun, 2009  |  Pubmed ID: 19446713

Psychiatric Comorbidity and Impact on Health Service Utilization in a Community Sample of Patients with Epilepsy

Epilepsia. Aug, 2009  |  Pubmed ID: 19490049

We aimed to determine the level of psychological distress in community-treated patients with epilepsy and to determine if this distress is associated with increased health service use. The Australian National prescription database was used to recruit patients with epilepsy onto the Tasmanian Epilepsy Register (TER). Psychological distress was measured using the K10 in the TER patients and compared to the Tasmanian population using the National Health Survey 2004-5. Of the 1,180 on the TER, 43 withdrew, 36 died, and 262 were excluded. Of 839 patients, 652 completed the K10 (78%). High-very high levels of psychological distress were observed in patients with epilepsy compared with the general population [odds ratio (OR) 2.14, 95% confidence interval (CI) 1.79-2.56]. Patients with high-very high psychological distress had increased attendance at general practitioners (p < 0.001), specialists (p = 0.02), and emergency departments (p = 0.004). Psychological distress is increased in community-treated patients with epilepsy compared to the general population, and is associated with increased health service use.

Aortic Valve Vegetation Without Endocarditis

The Annals of Thoracic Surgery. Jul, 2009  |  Pubmed ID: 19559240

We present a 30-year-old man with an acute middle cerebral artery territory infarction. A transesophageal echocardiogram showed a large, highly mobile mass attached to the patient's aortic valve. We discuss the differential diagnosis of a cardiac mass that includes infection, tumor, and thrombus. A complete workup showed no evidence of systemic infection but did reveal the presence of antiphospholipid antibodies. The patient also had a history of a right lower extremity deep venous thrombosis. Anticoagulation therapy was started, and follow-up showed complete resolution of the aortic valve lesion. This case highlights that when a valvular vegetation is encountered in a clinical setting that does not suggest infectious endocarditis, the diagnosis of antiphospholipid antibody syndrome should be considered. This case and our review of the literature suggest that vegetations in antiphospholipid antibody syndrome, no matter how large and ominous in appearance, can be treated successfully with anticoagulation and vigilant observation.

The Genome of the Blood Fluke Schistosoma Mansoni

Nature. Jul, 2009  |  Pubmed ID: 19606141

Schistosoma mansoni is responsible for the neglected tropical disease schistosomiasis that affects 210 million people in 76 countries. Here we present analysis of the 363 megabase nuclear genome of the blood fluke. It encodes at least 11,809 genes, with an unusual intron size distribution, and new families of micro-exon genes that undergo frequent alternative splicing. As the first sequenced flatworm, and a representative of the Lophotrochozoa, it offers insights into early events in the evolution of the animals, including the development of a body pattern with bilateral symmetry, and the development of tissues into organs. Our analysis has been informed by the need to find new drug targets. The deficits in lipid metabolism that make schistosomes dependent on the host are revealed, and the identification of membrane receptors, ion channels and more than 300 proteases provide new insights into the biology of the life cycle and new targets. Bioinformatics approaches have identified metabolic chokepoints, and a chemogenomic screen has pinpointed schistosome proteins for which existing drugs may be active. The information generated provides an invaluable resource for the research community to develop much needed new control tools for the treatment and eradication of this important and neglected disease.

Open Access: the Sooner the Better

Science (New York, N.Y.). Jul, 2009  |  Pubmed ID: 19608896

2009 Swine-origin Influenza A (H1N1) Resembles Previous Influenza Isolates

PloS One. 2009  |  Pubmed ID: 19636415

In April 2009, novel swine-origin influenza viruses (S-OIV) were identified in patients from Mexico and the United States. The viruses were genetically characterized as a novel influenza A (H1N1) strain originating in swine, and within a very short time the S-OIV strain spread across the globe via human-to-human contact.

The Effects of Overfeeding on the Neuronal Response to Visual Food Cues in Thin and Reduced-obese Individuals

PloS One. 2009  |  Pubmed ID: 19636426

The regulation of energy intake is a complex process involving the integration of homeostatic signals and both internal and external sensory inputs. The objective of this study was to examine the effects of short-term overfeeding on the neuronal response to food-related visual stimuli in individuals prone and resistant to weight gain.

Phymm and PhymmBL: Metagenomic Phylogenetic Classification with Interpolated Markov Models

Nature Methods. Sep, 2009  |  Pubmed ID: 19648916

Metagenomics projects collect DNA from uncharacterized environments that may contain thousands of species per sample. One main challenge facing metagenomic analysis is phylogenetic classification of raw sequence reads into groups representing the same or similar taxa, a prerequisite for genome assembly and for analyzing the biological diversity of a sample. New sequencing technologies have made metagenomics easier, by making sequencing faster, and more difficult, by producing shorter reads than previous technologies. Classifying sequences from reads as short as 100 base pairs has until now been relatively inaccurate, requiring researchers to use older, long-read technologies. We present Phymm, a classifier for metagenomic data, that has been trained on 539 complete, curated genomes and can accurately classify reads as short as 100 base pairs, a substantial improvement over previous composition-based classification methods. We also describe how combining Phymm with sequence alignment algorithms improves accuracy.

Impact of Preoperative Nesiritide on Renal Function After Mitral Valve Surgery

The Heart Surgery Forum. Aug, 2009  |  Pubmed ID: 19683992

Nesiritide, a recombinant B-type natriuretic peptide used for the intravenous treatment of acute decompensated congestive heart failure. Concerns have been raised about the long-term use of nesiritide, but data is scarce regarding its use in acute congestive heart failure and during cardiac surgery. We conducted a retrospective data review to address the safety of nesiritide for pretreatment of patients undergoing mitral valve surgery.

NMDA Receptor Hypofunction Leads to Generalized and Persistent Aberrant Gamma Oscillations Independent of Hyperlocomotion and the State of Consciousness

PloS One. 2009  |  Pubmed ID: 19707548

The psychotomimetics ketamine and MK-801, non-competitive NMDA receptor (NMDAr) antagonists, induce cognitive impairment and aggravate schizophrenia symptoms. In conscious rats, they produce an abnormal behavior associated with a peculiar brain state characterized by increased synchronization in ongoing gamma (30-80 Hz) oscillations in the frontoparietal (sensorimotor) electrocorticogram (ECoG). This study investigated whether NMDAr antagonists-induced aberrant gamma oscillations are correlated with locomotion and dependent on hyperlocomotion-related sensorimotor processing. This also implied to explore the contribution of intracortical and subcortical networks in the generation of these pathophysiological ECoG gamma oscillations.

"When Aneurysm Ain't Aneurysm": Sinus of Valsalva Aneurysm Mimicked by Healed Abscess Cavity Under the Aortic Valve

The Thoracic and Cardiovascular Surgeon. Sep, 2009  |  Pubmed ID: 19707982

In a 70-year-old patient with severe aortic valve stenosis, preoperative standard imaging (transthoracic echocardiography and angiography) detected an unclear subannular cavity structure. Initially interpreted as an aneurysm of Valsalva, the structure was identified intraoperatively as a huge chronic abscess cavity and exclusion was carried out by pericardial patch plasty. This case draws attention to the importance of a differential diagnosis of an abscess due to infective endocarditis in cases of unclear subannular structures rashly diagnosed as aneurysm of Valsalva.

Searching for SNPs with Cloud Computing

Genome Biology. 2009  |  Pubmed ID: 19930550

As DNA sequencing outpaces improvements in computer speed, there is a critical need to accelerate tasks like alignment and SNP calling. Crossbow is a cloud-computing software tool that combines the aligner Bowtie and the SNP caller SOAPsnp. Executing in parallel using Hadoop, Crossbow analyzes data comprising 38-fold coverage of the human genome in three hours using a 320-CPU cluster rented from a cloud computing service for about $85. Crossbow is available from http://bowtie-bio.sourceforge.net/crossbow/.

OperonDB: a Comprehensive Database of Predicted Operons in Microbial Genomes

Nucleic Acids Research. Jan, 2009  |  Pubmed ID: 18948284

The fast pace of bacterial genome sequencing and the resulting dependence on highly automated annotation methods has driven the development of many genome-wide analysis tools. OperonDB, first released in 2001, is a database containing the results of a computational algorithm for locating operon structures in microbial genomes. OperonDB has grown from 34 genomes in its initial release to more than 500 genomes today. In addition to increasing the size of the database, we have re-designed our operon finding algorithm and improved its accuracy. The new database is updated regularly as additional genomes become available in public archives. OperonDB can be accessed at: http://operondb.cbcb.umd.edu.

The Complete Genome Sequence of Bacillus Anthracis Ames "Ancestor"

Journal of Bacteriology. Jan, 2009  |  Pubmed ID: 18952800

The pathogenic bacterium Bacillus anthracis has become the subject of intense study as a result of its use in a bioterrorism attack in the United States in September and October 2001. Previous studies suggested that B. anthracis Ames Ancestor, the original Ames fully virulent plasmid-containing isolate, was the ideal reference. This study describes the complete genome sequence of that original isolate, derived from a sample kept in cold storage since 1981.

Genome Sequence of the Wolbachia Endosymbiont of Culex Quinquefasciatus JHB

Journal of Bacteriology. Mar, 2009  |  Pubmed ID: 19114486

Wolbachia species are endosymbionts of a wide range of invertebrates, including mosquitoes, fruit flies, and nematodes. The wPip strains can cause cytoplasmic incompatibility in some strains of the Culex mosquito. Here we describe the genome sequence of a Wolbachia strain that was discovered in the whole-genome sequencing data for the mosquito Culex quinquefasciatus strain JHB.

Efficient Oligonucleotide Probe Selection for Pan-genomic Tiling Arrays

BMC Bioinformatics. 2009  |  Pubmed ID: 19758451

Array comparative genomic hybridization is a fast and cost-effective method for detecting, genotyping, and comparing the genomic sequence of unknown bacterial isolates. This method, as with all microarray applications, requires adequate coverage of probes targeting the regions of interest. An unbiased tiling of probes across the entire length of the genome is the most flexible design approach. However, such a whole-genome tiling requires that the genome sequence is known in advance. For the accurate analysis of uncharacterized bacteria, an array must query a fully representative set of sequences from the species' pan-genome. Prior microarrays have included only a single strain per array or the conserved sequences of gene families. These arrays omit potentially important genes and sequence variants from the pan-genome.

Risks of Complications by Attending Physicians After Performing Nighttime Procedures

JAMA : the Journal of the American Medical Association. Oct, 2009  |  Pubmed ID: 19826026

Few data exist on the relationships between experienced physicians' work hours and sleep, and patient safety.

Early Life Stress As an Influence on Limbic Epilepsy: an Hypothesis Whose Time Has Come?

Frontiers in Behavioral Neuroscience. 2009  |  Pubmed ID: 19838325

The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative - or complementary - perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research.

Severe Cardiomyopathy Following Treatment with the Tumour Necrosis Factor-alpha Inhibitor Adalimumab for Crohn's Disease

European Journal of Heart Failure. Nov, 2009  |  Pubmed ID: 19875411

Adalimumab belongs to the group of tumour necrosis factor-alpha inhibitors and has been approved for the treatment Crohn's Disease since 2007. Herein we report a severe adverse reaction to adalimumab in a 25-year-old female patient. One week after the initial-dose of adalimumab (160 mg), which was initiated due to an acute exacerbation of Crohn's disease, the patient developed a fulminant cardiomyopathy. In severe cardiogenic shock, the patient required an extracorporeal membrane-oxygenation system for 8 days until cardiac recovery.

The Effects of Video Modeling on Staff Implementation of a Problem-solving Intervention with Adults with Developmental Disabilities

Journal of Applied Behavior Analysis. 2009  |  Pubmed ID: 20514193

We investigated the effects of video modeling on the percentage of correctly implemented problem-solving steps by staff in a group home for adults with developmental disabilities, using a nonconcurrent multiple baseline design across participants. The treatment consisted of staff watching a video model demonstrating the correct implementation of a problem-solving intervention (i.e., teaching clients to identify problems, possible solutions, and consequences to each solution, and to choose the best solution). The percentage of correctly implemented problem-solving steps increased for all participants, and the effect was maintained over time, generalized to novel problems, and generalized from role play with a researcher to actual clients.

Survival After Acute and Complete Occlusion of Left Main Stem

Asian Cardiovascular & Thoracic Annals. Jun, 2010  |  Pubmed ID: 20519308

Long-lasting Intrinsic Optical Changes Observed in the Neurointermediate Lobe of the Mouse Pituitary Reflect Volume Changes in Cells of the Pars Intermedia

Neuroendocrinology. 2010  |  Pubmed ID: 20551618

Background/Aims: Complex intrinsic optical changes (light scattering) are readily observed in the neurointermediate lobe of the mouse pituitary gland following electrical stimulation of the infundibular stalk. Our laboratory has previously identified three distinct phases within the light scattering signal: two rapid responses to action potential stimulation and a long duration recovery. The rapid light scattering signals, restricted to the neurohypophysial portion (posterior pituitary) of the neurointermediate lobe, consist of an E-wave and an S-wave that reflect excitation and secretion, respectively. The E-wave has the approximate shape of the action potential and includes voltage- and current-related components and is independent of Ca(2+) entry. The S-wave is related to Ca(2+) entry and exocytosis. The slow recovery phase of the light scattering signal, which we designated the R-wave, is less well characterized. Methods: Using high temporal resolution light scattering measurements, we monitored intrinsic optical changes in the neurointermediate lobe of the mouse pituitary gland. Pharmacological interventions during the measurements were employed. Results: The data presented here provide optical and pharmacological evidence suggesting that the R-wave, which comprises signals from the posterior pituitary as well as from the pars intermedia, mirrors volume changes in pars intermedia cells following a train of stimuli applied to the infundibular stalk. These volume changes were blocked by the GABA-receptor antagonists bicuculline and picrotoxin, and were mimicked by direct application of GABA in the absence of electrical stimulation. Conclusions: These results emphasize the importance of central GABAergic projections into the neurointermediate lobe, and the potential role of GABA in effecting hormone release from the pars intermedia.

Real Life Cardio-thoracic Surgery Training in Europe: Facing the Facts

Interactive Cardiovascular and Thoracic Surgery. Sep, 2010  |  Pubmed ID: 20554650

The objective of this study was to determine the current status of training in cardio-thoracic surgery in Europe and the residents' perception of the effects of the full implementation of the European Working Time Directive (EWTD) on training. We conducted a web-based survey of trainees registered with the European Association of Cardio-Thoracic Surgery and 79 respondents form the basis for this analysis. A majority of trainees (69.6%) are aware of the implications of the EWTD and 58.7% believe it will have an impact on their training. Most residents (98.7%) work well over the time limitations stated in the Directive and 96.2% are of the opinion that a 48-hour week would be insufficient to meet their learning needs. A large proportion (60.5%) of European trainees are dissatisfied with their training and report low-levels of regular assessment of their progress (37.8%) and of training facilities (27.4%). Only 23.3% of European trainers appear to attend training courses. Striking differences exist among European countries with regards to standards of training. These findings are alarming. Training in cardio-thoracic surgery across the European Union requires urgent attention to unify and improve the standards of training and compensate the potential negative impact of the EWTD.

Cloud Computing and the DNA Data Race

Nature Biotechnology. Jul, 2010  |  Pubmed ID: 20622843

Left Atrial Appendage Clip Occlusion: Early Clinical Results

The Journal of Thoracic and Cardiovascular Surgery. May, 2010  |  Pubmed ID: 19880144

Atrial fibrillation puts patients at significant risk for embolic stroke originating from the left atrial appendage. Few means are available for safe, effective, and durable left atrial appendage occlusion. A new clip device was evaluated with regard to safety and effectiveness for epicardial left atrial appendage occlusion.

Genome Sequence of the Dioxin-mineralizing Bacterium Sphingomonas Wittichii RW1

Journal of Bacteriology. Nov, 2010  |  Pubmed ID: 20833805

Pollutants such as polychlorinated biphenyls and dioxins pose a serious threat to human and environmental health. Natural attenuation of these compounds by microorganisms provides one promising avenue for their removal from contaminated areas. Over the past 2 decades, studies of the bacterium Sphingomonas wittichii RW1 have provided a wealth of knowledge about how bacteria metabolize chlorinated aromatic hydrocarbons. Here we describe the finished genome sequence of S. wittichii RW1 and major findings from its annotation.

Neuropsychiatric Symptomatology Predicts Seizure Recurrence in Newly Treated Patients

Neurology. Sep, 2010  |  Pubmed ID: 20837970

To test the hypothesis that neuropsychiatric symptomatology is predictive of the success of seizure control in patients newly treated with antiepileptic drugs (AEDs), and that this predictive value adds to that provided by other clinical, imaging, and genomic factors in a multivariate model.

Multi-platform Next-generation Sequencing of the Domestic Turkey (Meleagris Gallopavo): Genome Assembly and Analysis

PLoS Biology. 2010  |  Pubmed ID: 20838655

A synergistic combination of two next-generation sequencing platforms with a detailed comparative BAC physical contig map provided a cost-effective assembly of the genome sequence of the domestic turkey (Meleagris gallopavo). Heterozygosity of the sequenced source genome allowed discovery of more than 600,000 high quality single nucleotide variants. Despite this heterozygosity, the current genome assembly (∼1.1 Gb) includes 917 Mb of sequence assigned to specific turkey chromosomes. Annotation identified nearly 16,000 genes, with 15,093 recognized as protein coding and 611 as non-coding RNA genes. Comparative analysis of the turkey, chicken, and zebra finch genomes, and comparing avian to mammalian species, supports the characteristic stability of avian genomes and identifies genes unique to the avian lineage. Clear differences are seen in number and variety of genes of the avian immune system where expansions and novel genes are less frequent than examples of gene loss. The turkey genome sequence provides resources to further understand the evolution of vertebrate genomes and genetic variation underlying economically important quantitative traits in poultry. This integrated approach may be a model for providing both gene and chromosome level assemblies of other species with agricultural, ecological, and evolutionary interest.

Probing the Pan-genome of Listeria Monocytogenes: New Insights into Intraspecific Niche Expansion and Genomic Diversification

BMC Genomics. 2010  |  Pubmed ID: 20846431

Bacterial pathogens often show significant intraspecific variations in ecological fitness, host preference and pathogenic potential to cause infectious disease. The species of Listeria monocytogenes, a facultative intracellular pathogen and the causative agent of human listeriosis, consists of at least three distinct genetic lineages. Two of these lineages predominantly cause human sporadic and epidemic infections, whereas the third lineage has never been implicated in human disease outbreaks despite its overall conservation of many known virulence factors.

Do-it-yourself Genetic Testing

Genome Biology. 2010  |  Pubmed ID: 20932271

We developed a computational screen that tests an individual's genome for mutations in the BRCA genes, despite the fact that both are currently protected by patents.

Clustering Metagenomic Sequences with Interpolated Markov Models

BMC Bioinformatics. 2010  |  Pubmed ID: 21044341

Sequencing of environmental DNA (often called metagenomics) has shown tremendous potential to uncover the vast number of unknown microbes that cannot be cultured and sequenced by traditional methods. Because the output from metagenomic sequencing is a large set of reads of unknown origin, clustering reads together that were sequenced from the same species is a crucial analysis step. Many effective approaches to this task rely on sequenced genomes in public databases, but these genomes are a highly biased sample that is not necessarily representative of environments interesting to many metagenomics projects.

Quake: Quality-aware Detection and Correction of Sequencing Errors

Genome Biology. 2010  |  Pubmed ID: 21114842

We introduce Quake, a program to detect and correct errors in DNA sequencing reads. Using a maximum likelihood approach incorporating quality values and nucleotide specific miscall rates, Quake achieves the highest accuracy on realistically simulated reads. We further demonstrate substantial improvements in de novo assembly and SNP detection after using Quake. Quake can be used for any size project, including more than one billion human reads, and is freely available as open source software from http://www.cbcb.umd.edu/software/quake.

The Proprioceptive and Contractile Systems in Drosophila Are Both Patterned by the EGR Family Transcription Factor Stripe

Developmental Biology. Jan, 2010  |  Pubmed ID: 19944090

Coordinated locomotion of Drosophila larvae depends on accurate patterning and stable attachment to the cuticle of both muscles and proprioceptors (chordotonal organs). Unlike muscle spindles in mammals, the fly chordotonal organs are not embedded in the body-wall muscles. Yet, the contractile system (muscles and tendons) and the chordotonal organs constitute two parts of a single functional unit that controls locomotion, and thus must be patterned in full coordination. It is not known how such coordination is achieved. Here we show that the positioning and differentiation of the migrating chordotonal organs are instructed by Stripe, the same transcription factor that promotes tendon cell specification and differentiation and is required for normal patterning of the contractile system. Our data demonstrate that although chordotonal organs are patterned in a Stripe-dependent mechanism similarly to muscles, this mechanism is independent of Stripe activity in tendon cells. Thus, the two parts of the locomotive system use similar but independent patterning mechanisms that converge to form a functional unit. Stripe plays at least a dual role in chordotonal development. It is required within the ligament cells for terminal differentiation and proper migration, without which no induction of ligament attachment cells takes place. Stripe's activity is then necessary within the recruited cells for their differentiation as attachment cells. Similarly to the biphasic differentiation program of tendons, terminal differentiation of chordotonal attachment cells is associated with sequential activation of the two Stripe isoforms-Stripe B and Stripe A.

Meig1 Deficiency Causes a Severe Defect in Mouse Spermatogenesis

Developmental Biology. Feb, 2010  |  Pubmed ID: 20004656

Meig1 is a mouse gene, abundantly expressed in the testis. It encodes two alternative transcripts that are expressed differentially in the somatic and germinal compartments of the testis. These transcripts share the same coding region but differ in their 5' un-translated regions, due to alternative promoters. Here we show that MEIG1 is a highly conserved short metazoan protein with a conserved core of 81 residues. It is present from chordates to radial symmetry animals, with an intriguing absence in insects and nematodes. It is also present in two earlier diverging protist lineages. To elucidate the role of MEIG1 during gamete production we established a knockout mouse line by eliminating the common coding region. Our results identified Meig1 as a critical spermatogenic gene, whose absence results in complete male infertility. Seminiferous tubules in Meig1-null males contained all early stages of spermatogenesis, up to elongating spermatids, but mature elongated spermatids were absent. Accordingly, the caudal epididymis was apparently missing spermatozoa, and the very few spermatozoa-like cells that were obtained were immotile and exhibited a wide range of severe morphological abnormalities. These results point at late spermiogenesis as the differentiative stage at which MEIG1's function is crucial. Nevertheless, delayed kinetics of earlier meiotic stages together with increased apoptosis of meiotic spermatocytes and haploid round spermadids in Meig1 knockout males, suggest involvement of MEIG1 in meiotic stages as well.

Medication Errors Recovered by Emergency Department Pharmacists

Annals of Emergency Medicine. Jun, 2010  |  Pubmed ID: 20005011

We assess the impact of emergency department (ED) pharmacists on reducing potentially harmful medication errors.

Despite Modern Off-pump Coronary Artery Bypass Grafting Women Fare Worse Than Men

Interactive Cardiovascular and Thoracic Surgery. May, 2010  |  Pubmed ID: 20051452

Female gender is an established risk factor for worse outcomes after cardiac surgery. Avoiding cardiopulmonary bypass (CPB) for coronary bypass grafting has an unknown effect on gender differences. Herein, we evaluate if gender has an impact on outcomes after modern off-pump coronary artery bypass grafting (OPCAB). From 2002 to 2007, we analyzed 983 patients (male: n=807/female: n=176) who underwent OPCAB with symptomatic multi-vessel disease at our institution. The link between gender and outcome was assessed by multivariate analysis and logistic regression. A composite endpoint was constructed from: 30-day-mortality, renal failure, prolonged intensive care unit (ICU) stay, neurological complications, use of intra-aortic balloon pump (IABP) and conversion to CPB. Mortality was 3.2% in women vs.1.8% in men (P=0.15) and the EuroSCORE was significantly correlated to gender (6.8 vs. 5.2; P<0.001), even after correction (P=0.036). Significant more occurrence of the composite endpoint was noted in women (39.8% vs. 29.0%; P=0.007) whereas for men the risk was much lower [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.46-0.92; P=0.015]. For both genders the logistic regression revealed a risk increase of 15% per one-point-increase of EuroSCORE (corrected) (OR 1.15; 95% CI: 1.10-1.19; P<0.0001). Women had more frequently a prolonged stay at ICU (P=0.006) and had a higher stroke rate (2.3% vs. 1.2%; P=0.29). Complete revascularization was achieved similarly (95% vs. 94%; P=0.93). OPCAB offers low mortality and excellent clinical outcome. Women are more likely to experience postoperative complications. Even if partially neutralized by avoiding CPB, gender differences remain present with modern OPCAB strategies.

Peptidoglycan Metabolism is Controlled by the WalRK (YycFG) and PhoPR Two-component Systems in Phosphate Limited Bacillus Subtilis Cells

Molecular Microbiology. Jan, 2010  |  Pubmed ID: 20059685

Summary In Bacillus subtilis, the WalRK (YycFG) two-component system controls peptidoglycan metabolism in exponentially growing cells while PhoPR controls the response to phosphate limitation. Here we examine the roles of WalRK and PhoPR in peptidoglycan metabolism in phosphate-limited cells. We show that B. subtilis cells remain viable in a phosphate-limited state for an extended period and resume growth rapidly upon phosphate addition, even in the absence of a PhoPR-mediated response. Peptidoglycan synthesis occurs in phosphate-limited wild-type cells at approximately 25% the rate of exponentially growing cells, and at approximately 18% the rate of exponentially growing cells in the absence of PhoPR. In phosphate-limited cells, the WalRK regulon genes yocH, cwlO(yvcE), lytE and ydjM are expressed in a manner that is dependent on the WalR recognition sequence and deleting these genes individually reduces the rate of peptidoglycan synthesis. We show that ydjM expression can be activated by PhoP approximately P in vitro and that PhoP occupies its promoter in phosphate-limited cells. However iseA(yoeB) expression cannot be repressed by PhoP approximately P in vitro, but can be repressed by nonphosphorylated WalR in vitro. Therefore we conclude that peptidoglycan metabolism is controlled both by WalRK and PhoPR in phosphate limited Bacillus subtilis cells.

Sex-based Differences in the Behavioral and Neuronal Responses to Food

Physiology & Behavior. Mar, 2010  |  Pubmed ID: 20096712

Sex-based differences in food intake related behaviors have been observed previously. The objective of this study was to examine sex-based differences in the behavioral and neuronal responses to food. 22 women and 21 men were studied. After 6 days of controlled eucaloric feeding, ad libitum energy intake (EI) was measured for 3 days. Appetite ratings using visual analog scales were obtained before and after each meal. Functional magnetic resonance imaging was performed in the overnight fasted state on the last day of eucaloric feeding while subjects were presented visual stimuli of food and neutral non-food objects. While hunger and prospective consumption were not different between sexes, women had higher post-meal satiety ratings and dietary restraint than men. Images of hedonic foods resulted in significantly greater activation of lateral and dorsolateral prefrontal cortex (DLPFC) and parietal cortex in women as compared to men. No brain regions were more activated in men as compared to women. Men increased their EI during the ad libitum diet phase. While measures of appetite or feeding behaviors did not correlate with either neuronal activation or subsequent EI, DLPFC activation in response to hedonic foods was negatively correlated with EI. In summary, greater prefrontal neuronal responses to food cues in women may suggest increased cognitive processing related to executive function, such as planning, guidance or evaluation of behavior. Finally, increased DLPFC activation, perhaps relating to inhibitory cognitive control in response to food cues may be a better predictor of food intake than behavioral measures.

Mind the Gaps

Nature Methods. Feb, 2010  |  Pubmed ID: 20111034

A Genetic Epilepsy Rat Model Displays Endophenotypes of Psychosis

Neurobiology of Disease. Jul, 2010  |  Pubmed ID: 20153428

The incidence of psychosis is increased in people with epilepsy, including idiopathic generalized epilepsies. To study the biological basis for this co-morbidity, we compared GAERS, a genetic rat model of absence epilepsy, to non-epileptic control rats (NEC). Mature, 14-week old GAERS showed enhanced amphetamine-induced locomotor hyperactivity - a feature also present in young (6-week old) GAERS prior to epilepsy onset. Prepulse inhibition and its disruption by psychotropic drugs did not differ between strains, although GAERS displayed elevated startle responses at both epileptic and pre-epileptic ages. The frontoparietal cortex of GAERS displayed a twofold increase in the power of gamma (30-80 Hz) oscillations, a proposed neurophysiological correlate of psychosis. Radioligand binding autoradiography demonstrated reduced densities of dopamine transporters in the caudate nucleus and nucleus accumbens core and of dopamine D2 receptors in the caudate nucleus. GAERS provide an opportunity to study the neurodevelopmental, genetic and therapeutic aspects of psychiatric comorbidities associated with epilepsy.

Detection and Correction of False Segmental Duplications Caused by Genome Mis-assembly

Genome Biology. 2010  |  Pubmed ID: 20219098

Diploid genomes with divergent chromosomes present special problems for assembly software as two copies of especially polymorphic regions may be mistakenly constructed, creating the appearance of a recent segmental duplication. We developed a method for identifying such false duplications and applied it to four vertebrate genomes. For each genome, we corrected mis-assemblies, improved estimates of the amount of duplicated sequence, and recovered polymorphisms between the sequenced chromosomes.

Classification of Alcohol Abuse by Plasma Protein Biomarkers

Biological Psychiatry. Aug, 2010  |  Pubmed ID: 20299005

Biochemical diagnostics of ethanol intake would improve alcohol abuse treatment and have applications in clinical trial and public safety settings. Self-reporting of alcohol use has clinical utility but lacks the desired reliability. Previously, proposed single-analyte biochemical tests of alcohol intake suffer from low sensitivity and specificity or examine only acute drinking and have therefore seen limited clinical use.

Routine Off-pump Coronary Artery Bypass Grafting is Safe and Feasible in High-risk Patients with Left Main Disease

The Annals of Thoracic Surgery. Apr, 2010  |  Pubmed ID: 20338319

Coronary artery bypass graft surgery (CABG) remains the method of choice for patients with left main disease (LMD). The precise role of off-pump coronary artery bypass graft surgery (OPCABG) remains unclear in this setting. We report the safety and feasibility of a routine OPCABG approach to patients with LMD.

MALDI-TOF Mass Spectrometry Speciation of Staphylococci and Their Discrimination from Micrococci Isolated from Indoor Air of Schoolrooms

Journal of Environmental Monitoring : JEM. Apr, 2010  |  Pubmed ID: 20383373

The focus of our work is the identification of medically relevant staphylococci from the environment; these organisms are among the major opportunistic pathogens associated with human disease. Andersen sampling was performed in schoolrooms during the school year. Eleven of thirty six isolates (all Gram-positive tetrads) were identified as staphylococci and 23 were characterized as micrococci. MALDI-TOF MS profiling was used as the first stage in the classification followed by standard biochemical tests including API Staph profiling. The staphylococcal isolates were each speciated; coagulase positive (Staphylococcus aureus [3 strains]) and coagulase negative: Staphylococcus warneri (4 isolates), Staphylococcus hominis (2), Staphylococcus saprophyticus (1) and Staphylococcus cohnii (1). S. aureus is most commonly found in the human nares but is frequently isolated from skin. The other staphylococcal species are among those most commonly isolated from human skin. Micrococci were much more frequently isolated from indoor air than reported by others for clinical samples. It is suggested that, without discrimination from micrococci, misidentification of staphylococci would be common on air sampling.

Inhibition of Mer and Axl Receptor Tyrosine Kinases in Astrocytoma Cells Leads to Increased Apoptosis and Improved Chemosensitivity

Molecular Cancer Therapeutics. May, 2010  |  Pubmed ID: 20423999

Astrocytomas account for the majority of malignant brain tumors diagnosed in both adult and pediatric patients. The therapies available to treat these neoplasms are limited, and the prognosis associated with high-grade lesions is extremely poor. Mer (MerTK) and Axl receptor tyrosine kinases (RTK) are expressed at abnormally high levels in a variety of malignancies, and these receptors are known to activate strong antiapoptotic signaling pathways that promote oncogenesis. In this study, we found that Mer and Axl mRNA transcript and protein expression were elevated in astrocytic patient samples and cell lines. shRNA-mediated knockdown of Mer and Axl RTK expression led to an increase in apoptosis in astrocytoma cells. Apoptotic signaling pathways including Akt and extracellular signal-regulated kinase 1/2, which have been shown to be activated in resistant astrocytomas, were downregulated with Mer and Axl inhibition whereas poly(ADP-ribose) polymerase cleavage was increased. Furthermore, Mer and Axl shRNA knockdown led to a profound decrease of astrocytoma cell proliferation in soft agar and a significant increase in chemosensitivity in response to temozolomide, carboplatin, and vincristine treatment. Our results suggest Mer and Axl RTK inhibition as a novel method to improve apoptotic response and chemosensitivity in astrocytoma and provide support for these oncogenes as attractive biological targets for astrocytoma drug development.

Transcript Assembly and Quantification by RNA-Seq Reveals Unannotated Transcripts and Isoform Switching During Cell Differentiation

Nature Biotechnology. May, 2010  |  Pubmed ID: 20436464

High-throughput mRNA sequencing (RNA-Seq) promises simultaneous transcript discovery and abundance estimation. However, this would require algorithms that are not restricted by prior gene annotations and that account for alternative transcription and splicing. Here we introduce such algorithms in an open-source software program called Cufflinks. To test Cufflinks, we sequenced and analyzed >430 million paired 75-bp RNA-Seq reads from a mouse myoblast cell line over a differentiation time series. We detected 13,692 known transcripts and 3,724 previously unannotated ones, 62% of which are supported by independent expression data or by homologous genes in other species. Over the time series, 330 genes showed complete switches in the dominant transcription start site (TSS) or splice isoform, and we observed more subtle shifts in 1,304 other genes. These results suggest that Cufflinks can illuminate the substantial regulatory flexibility and complexity in even this well-studied model of muscle development and that it can improve transcriptome-based genome annotation.

Between a Chicken and a Grape: Estimating the Number of Human Genes

Genome Biology. 2010  |  Pubmed ID: 20441615

Many people expected the question 'How many genes in the human genome?' to be resolved with the publication of the genome sequence in 2001, but estimates continue to fluctuate.

Peptidoglycan Metabolism is Controlled by the WalRK (YycFG) and PhoPR Two-component Systems in Phosphate-limited Bacillus Subtilis Cells

Molecular Microbiology. Feb, 2010  |  Pubmed ID: 20487291

In Bacillus subtilis, the WalRK (YycFG) two-component system controls peptidoglycan metabolism in exponentially growing cells while PhoPR controls the response to phosphate limitation. Here we examine the roles of WalRK and PhoPR in peptidoglycan metabolism in phosphate-limited cells. We show that B. subtilis cells remain viable in a phosphate-limited state for an extended period and resume growth rapidly upon phosphate addition, even in the absence of a PhoPR-mediated response. Peptidoglycan synthesis occurs in phosphate-limited wild-type cells at approximately 27% the rate of exponentially growing cells, and at approximately 18% the rate of exponentially growing cells in the absence of PhoPR. In phosphate-limited cells, the WalRK regulon genes yocH, cwlO(yvcE), lytE and ydjM are expressed in a manner that is dependent on the WalR recognition sequence and deleting these genes individually reduces the rate of peptidoglycan synthesis. We show that ydjM expression can be activated by PhoP approximately P in vitro and that PhoP occupies its promoter in phosphate-limited cells. However, iseA(yoeB) expression cannot be repressed by PhoP approximately P in vitro, but can be repressed by non-phosphorylated WalR in vitro. Therefore, we conclude that peptidoglycan metabolism is controlled by both WalRK and PhoPR in phosphate-limited B. subtilis cells.

Assembly of Large Genomes Using Second-generation Sequencing

Genome Research. Sep, 2010  |  Pubmed ID: 20508146

Second-generation sequencing technology can now be used to sequence an entire human genome in a matter of days and at low cost. Sequence read lengths, initially very short, have rapidly increased since the technology first appeared, and we now are seeing a growing number of efforts to sequence large genomes de novo from these short reads. In this Perspective, we describe the issues associated with short-read assembly, the different types of data produced by second-gen sequencers, and the latest assembly algorithms designed for these data. We also review the genomes that have been assembled recently from short reads and make recommendations for sequencing strategies that will yield a high-quality assembly.

Prospective Randomized Open-label Multicenter Phase I/II Dose Escalation Trial of Visilizumab (HuM291) in Severe Steroid-refractory Ulcerative Colitis

Inflammatory Bowel Diseases. Apr, 2010  |  Pubmed ID: 19714757

Visilizumab is a humanized IgG(2) monoclonal anti-CD3 antibody. We evaluated its safety and dose response in severe intravenous steroid-refractory ulcerative colitis (UC).

Recent Advances in RNA Sequence Analysis

F1000 Biology Reports. 2010  |  Pubmed ID: 21173855

The latest high-throughput DNA sequencing technology can now be applied on a large scale to capture the complete set of mRNA transcripts in a cell, using a technique called RNA-seq. Although RNA-seq is only 2 years old, it has rapidly swept through the field of genomics, and it is now being used to analyze the transcriptomes of organisms ranging from bacteria to primates. The depth of sequencing allows researchers to quantify the level of expression of genes, to discover alternative isoforms in eukaryotic species, and even to characterize the operon structure of bacterial genomes.

The Genome of Woodland Strawberry (Fragaria Vesca)

Nature Genetics. Feb, 2011  |  Pubmed ID: 21186353

The woodland strawberry, Fragaria vesca (2n = 2x = 14), is a versatile experimental plant system. This diminutive herbaceous perennial has a small genome (240 Mb), is amenable to genetic transformation and shares substantial sequence identity with the cultivated strawberry (Fragaria × ananassa) and other economically important rosaceous plants. Here we report the draft F. vesca genome, which was sequenced to ×39 coverage using second-generation technology, assembled de novo and then anchored to the genetic linkage map into seven pseudochromosomes. This diploid strawberry sequence lacks the large genome duplications seen in other rosids. Gene prediction modeling identified 34,809 genes, with most being supported by transcriptome mapping. Genes critical to valuable horticultural traits including flavor, nutritional value and flowering time were identified. Macrosyntenic relationships between Fragaria and Prunus predict a hypothetical ancestral Rosaceae genome that had nine chromosomes. New phylogenetic analysis of 154 protein-coding genes suggests that assignment of Populus to Malvidae, rather than Fabidae, is warranted.

[Renaissance of Surgery for Coronary Artery Disease]

Praxis. Jan, 2011  |  Pubmed ID: 21210357

Coronary bypass surgery is now a standard therapy for the treatment of coronary heart disease. Developed in the 1960s, the coronary artery bypass operation was the most performed operation at all in the 1980s. There was and still is rapidly advancing. The recovery of coronary surgery was held back in the 1970s with the introduction of heart catheterisation. To date, the number of interventional revascularizations has increased, while the number of bypass operations has reached a plateau. 30 resp. 40 years after the introduction of the two techniques it is still controversial which is the method of choice. According to the latest guidelines there is strong evidence that coronary artery surgery for patients with complex coronary artery disease is the gold standard: A Renaissance of bypass surgery.

Spatial Regulation of Cell Adhesion in the Drosophila Wing is Mediated by Delilah, a Potent Activator of βPS Integrin Expression

Developmental Biology. Mar, 2011  |  Pubmed ID: 21215259

In spite of our conceptual view of how differential gene expression is used to define different cell identities, we still do not understand how different cell identities are translated into actual cell properties. The example discussed here is that of the fly wing, which is composed of two main cell types: vein and intervein cells. These two cell types differ in many features, including their adhesive properties. One of the major differences is that intervein cells express integrins, which are required for the attachment of the two wing layers to each other, whereas vein cells are devoid of integrin expression. The major signaling pathways that divide the wing to vein and intervein domains have been characterized. However, the genetic programs that execute these two alternative differentiation programs are still very roughly drawn. Here we identify the bHLH protein Delilah (Dei) as a mediator between signaling pathways that specify intervein cell-fate and one of the most significant realizators of this fate, βPS integrin. Dei's expression is restricted to intervein territories where it acts as a potent activator of βPS integrin expression. In the absence of normal Dei activity the level of βPS integrin is reduced, leading to a failure of adhesion between the dorsal and ventral wing layers and a consequent formation of wing blisters. The effect of Dei on βPS expression is not restricted to the wing, suggesting that Dei functions as a general genetic switch, which is turned on wherever a sticky cell-identity is determined and integrin-based adhesion is required.

Sternal Plate Closure: Indications, Surgical Procedure and Follow-up

The Thoracic and Cardiovascular Surgeon. Feb, 2011  |  Pubmed ID: 21243569

Titanium plate osteosynthesis (Synthes) is an alternative option for sternal closure. The indications and time point of application are still debated. This study investigated the application and feasibility of this technique after median sternotomy.

An 8-year Experience of Direct-to-implant Immediate Breast Reconstruction Using Human Acellular Dermal Matrix (AlloDerm)

Plastic and Reconstructive Surgery. Feb, 2011  |  Pubmed ID: 21285756

The advent of skin- and nipple-sparing mastectomy in conjunction with the use of human acellular dermal matrix to provide lower pole coverage has made direct-to-implant immediate breast reconstruction following mastectomy feasible. The purpose of this study was to evaluate long-term complications associated with this technique.

A Qualitative Study of Canada's Experience with the Implementation of Electronic Health Information Technology

CMAJ : Canadian Medical Association Journal = Journal De L'Association Medicale Canadienne. Mar, 2011  |  Pubmed ID: 21343262

In 2001, Canada Health Infoway unveiled a plan to implement a national system of interoperable electronic health records. This government-funded corporation introduced a novel model for interprovincial/territorial collaboration to establish core aspects of a national framework. Despite this $1.6 billion initiative, Canada continues to lag behind other Western countries in adopting electronic health records. We conducted a study to identify the success of different aspects of the Canadian plan and ways to improve the adoption of electronic health records.

Bacillus Anthracis Comparative Genome Analysis in Support of the Amerithrax Investigation

Proceedings of the National Academy of Sciences of the United States of America. Mar, 2011  |  Pubmed ID: 21383169

Before the anthrax letter attacks of 2001, the developing field of microbial forensics relied on microbial genotyping schemes based on a small portion of a genome sequence. Amerithrax, the investigation into the anthrax letter attacks, applied high-resolution whole-genome sequencing and comparative genomics to identify key genetic features of the letters' Bacillus anthracis Ames strain. During systematic microbiological analysis of the spore material from the letters, we identified a number of morphological variants based on phenotypic characteristics and the ability to sporulate. The genomes of these morphological variants were sequenced and compared with that of the B. anthracis Ames ancestor, the progenitor of all B. anthracis Ames strains. Through comparative genomics, we identified four distinct loci with verifiable genetic mutations. Three of the four mutations could be directly linked to sporulation pathways in B. anthracis and more specifically to the regulation of the phosphorylation state of Spo0F, a key regulatory protein in the initiation of the sporulation cascade, thus linking phenotype to genotype. None of these variant genotypes were identified in single-colony environmental B. anthracis Ames isolates associated with the investigation. These genotypes were identified only in B. anthracis morphotypes isolated from the letters, indicating that the variants were not prevalent in the environment, not even the environments associated with the investigation. This study demonstrates the forensic value of systematic microbiological analysis combined with whole-genome sequencing and comparative genomics.

Closure of the NCBI SRA and Implications for the Long-term Future of Genomics Data Storage

Genome Biology. 2011  |  Pubmed ID: 21418618

Deriving Realistic Source Boundary Conditions for a CFD Simulation of Concentrations in Workroom Air

The Annals of Occupational Hygiene. May, 2011  |  Pubmed ID: 21422277

Computational fluid dynamics (CFD) is used increasingly to simulate the distribution of airborne contaminants in enclosed spaces for exposure assessment and control, but the importance of realistic boundary conditions is often not fully appreciated. In a workroom for manufacturing capacitors, full-shift samples for isoamyl acetate (IAA) were collected for 3 days at 16 locations, and velocities were measured at supply grills and at various points near the source. Then, velocity and concentration fields were simulated by 3-dimensional steady-state CFD using 295K tetrahedral cells, the k-ε turbulence model, standard wall function, and convergence criteria of 10(-6) for all scalars. Here, we demonstrate the need to represent boundary conditions accurately, especially emission characteristics at the contaminant source, and to obtain good agreement between observations and CFD results. Emission rates for each day were determined from six concentrations measured in the near field and one upwind using an IAA mass balance. The emission was initially represented as undiluted IAA vapor, but the concentrations estimated using CFD differed greatly from the measured concentrations. A second set of simulations was performed using the same IAA emission rates but a more realistic representation of the source. This yielded good agreement with measured values. Paying particular attention to the region with highest worker exposure potential-within 1.3 m of the source center-the air speed and IAA concentrations estimated by CFD were not significantly different from the measured values (P = 0.92 and P = 0.67, respectively). Thus, careful consideration of source boundary conditions greatly improved agreement with the measured values.

PhymmBL Expanded: Confidence Scores, Custom Databases, Parallelization and More

Nature Methods. May, 2011  |  Pubmed ID: 21527926

Care Transitions As Opportunities for Clinicians to Use Data Exchange Services: How Often Do They Occur?

Journal of the American Medical Informatics Association : JAMIA. Nov-Dec, 2011  |  Pubmed ID: 21531703

The electronic exchange of health information among healthcare providers has the potential to produce enormous clinical benefits and financial savings, although realizing that potential will be challenging. The American Recovery and Reinvestment Act of 2009 will reward providers for 'meaningful use' of electronic health records, including participation in clinical data exchange, but the best ways to do so remain uncertain.

Off-pump Surgery for the Poor Ventricle?

Heart and Vessels. May, 2011  |  Pubmed ID: 21584751

Severely decreased ejection-fraction is an established risk-factor for worse outcome after cardiac surgery. We compare outcomes of off-pump coronary artery bypass grafting (OPCAB) and on-pump CABG (ONCABG) in patients with severely compromised EF. From 2004 to 2009, 478 patients with a decreased EF ≤35% underwent myocardial-revascularization. Patients received either OPCAB (n = 256) or ONCABG (n = 222). Propensity score (PS), including 50 preoperative risk-factors, was used to balance characteristics between groups. PS adjusted logistic regression analysis was performed to assess mortality and major adverse cardiac and cerebrovascular events (MACCE). A composite endpoint for major non-cardiac complications such as respiratory failure, renal failure, rethoracotomy was applied. Complete revascularization (CR) was assumed when the number of distal anastomoses was larger than that of diseased vessels. There was no difference for mortality (2.3 vs. 4.1%; PS-adjusted odds ratio (PS-OR) = 1.05; p = 0.93) and MACCE (13.7 vs. 17.6%; PS-OR = 1.22; p = 0.50) including myocardial-infarction (1.4 vs. 4.9%; PS-OR = 0.39; p = 0.26), low cardiac output (2.3 vs. 4.7%; PS-OR = 0.75; p = 0.72) and stroke (2.3 vs. 2.7%; PS-OR = 0.69; p = 0.66). OPCAB patients presented with a trend to less frequent occurrence of the non-cardiac composite (12.1 vs. 22.1%; PS-OR = 0.54; p = 0.059) including renal dysfunction (PAOR = 0.77; 95% CI 0.31-1.9; p = 0.57), bleeding (PAOR = 0.42; 95% CI 0.14-1.20; p = 0.10) and respiratory failure (PAOR = 0.39; 95% CI 0.05-3.29; p = 0.39). The rate of complete revascularization was similar (92.2 vs. 92.8%; PS-OR = 0.75; p = 0.50). OPCAB in patients with severely decreased EF is safe and feasible. It may even benefit these patients in regard to non-cardiac complications and does not come at cost of less complete revascularization.

Complete Columbian Mammoth Mitogenome Suggests Interbreeding with Woolly Mammoths

Genome Biology. 2011  |  Pubmed ID: 21627792

Late Pleistocene North America hosted at least two divergent and ecologically distinct species of mammoth: the periglacial woolly mammoth (Mammuthus primigenius) and the subglacial Columbian mammoth (Mammuthus columbi). To date, mammoth genetic research has been entirely restricted to woolly mammoths, rendering their genetic evolution difficult to contextualize within broader Pleistocene paleoecology and biogeography. Here, we take an interspecific approach to clarifying mammoth phylogeny by targeting Columbian mammoth remains for mitogenomic sequencing.

Cell Envelope Gene Expression in Phosphate-limited Bacillus Subtilis Cells

Microbiology (Reading, England). Sep, 2011  |  Pubmed ID: 21636651

The high phosphate content of Bacillus subtilis cell walls dictates that cell wall metabolism is an important feature of the PhoPR-mediated phosphate limitation response. Here we report the expression profiles of cell-envelope-associated and PhoPR regulon genes, determined by live cell array and transcriptome analysis, in exponentially growing and phosphate-limited B. subtilis cells. Control by the WalRK two-component system confers a unique expression profile and high level of promoter activity on the genes of its regulon with yocH and cwlO expression differing both qualitatively and quantitatively from all other autolysin-encoding genes examined. The activity of the PhoPR two-component system is restricted to the phosphate-limited state, being rapidly induced in response to the cognate stimulus, and can be sustained for an extended phosphate limitation period. Constituent promoters of the PhoPR regulon show heterogeneous induction profiles and very high promoter activities. Phosphate-limited cells also show elevated expression of the actin-like protein MreBH and reduced expression of the WapA cell wall protein and WprA cell wall protease indicating that cell wall metabolism in this state is distinct from that of exponentially growing and stationary-phase cells. The PhoPR response is very rapidly deactivated upon removal of the phosphate limitation stimulus with concomitant increased expression of cell wall metabolic genes. Moreover expression of genes encoding enzymes involved in sulphur metabolism is significantly altered in the phosphate-limited state with distinct perturbations being observed in wild-type 168 and AH024 (ΔphoPR) cells.

Service Use in Consultation-liaison Psychiatry: Guidelines for Baseline Staffing

Australasian Psychiatry : Bulletin of Royal Australian and New Zealand College of Psychiatrists. Jun, 2011  |  Pubmed ID: 21682625

The aim of this study was to determine how referrals and clinical activity in consultation-liaison psychiatry (C-L) vary according to unit type and size, length of stay and psychiatric diagnosis, and to use these data to inform recommendations for the minimum levels of staffing required to conduct consultations in a general hospital.

Aortic No-touch Technique Makes the Difference in Off-pump Coronary Artery Bypass Grafting

The Journal of Thoracic and Cardiovascular Surgery. Dec, 2011  |  Pubmed ID: 21683376

Both off-pump surgery (OPCAB) and aortic no-touch technique reduce stroke after coronary artery bypass grafting (CABG). We evaluate the impact of partial aortic clamping (PC) versus a no-touch technique using either the HEARTSTRING system (HS) or total arterial revascularization (TAR) on the incidence of stroke.

Errors Associated with Outpatient Computerized Prescribing Systems

Journal of the American Medical Informatics Association : JAMIA. Nov-Dec, 2011  |  Pubmed ID: 21715428

To report the frequency, types, and causes of errors associated with outpatient computer-generated prescriptions, and to develop a framework to classify these errors to determine which strategies have greatest potential for preventing them.

Improving Pan-genome Annotation Using Whole Genome Multiple Alignment

BMC Bioinformatics. 2011  |  Pubmed ID: 21718539

Rapid annotation and comparisons of genomes from multiple isolates (pan-genomes) is becoming commonplace due to advances in sequencing technology. Genome annotations can contain inconsistencies and errors that hinder comparative analysis even within a single species. Tools are needed to compare and improve annotation quality across sets of closely related genomes.

Detection of Lineage-specific Evolutionary Changes Among Primate Species

BMC Bioinformatics. 2011  |  Pubmed ID: 21726447

Comparison of the human genome with other primates offers the opportunity to detect evolutionary events that created the diverse phenotypes among the primate species. Because the primate genomes are highly similar to one another, methods developed for analysis of more divergent species do not always detect signs of evolutionary selection.

Genome Assembly Has a Major Impact on Gene Content: a Comparison of Annotation in Two Bos Taurus Assemblies

PloS One. 2011  |  Pubmed ID: 21731731

Gene and SNP annotation are among the first and most important steps in analyzing a genome. As the number of sequenced genomes continues to grow, a key question is: how does the quality of the assembled sequence affect the annotations? We compared the gene and SNP annotations for two different Bos taurus genome assemblies built from the same data but with significant improvements in the later assembly. The same annotation software was used for annotating both sequences. While some annotation differences are expected even between high-quality assemblies such as these, we found that a staggering 40% of the genes (>9,500) varied significantly between assemblies, due in part to the availability of new gene evidence but primarily to genome mis-assembly events and local sequence variations. For instance, although the later assembly is generally superior, 660 protein coding genes in the earlier assembly are entirely missing from the later genome's annotation, and approximately 3,600 (15%) of the genes have complex structural differences between the two assemblies. In addition, 12-20% of the predicted proteins in both assemblies have relatively large sequence differences when compared to their RefSeq models, and 6-15% of bovine dbSNP records are unrecoverable in the two assemblies. Our findings highlight the consequences of genome assembly quality on gene and SNP annotation and argue for continued improvements in any draft genome sequence. We also found that tracking a gene between different assemblies of the same genome is surprisingly difficult, due to the numerous changes, both small and large, that occur in some genes. As a side benefit, our analyses helped us identify many specific loci for improvement in the Bos taurus genome assembly.

Acute Administration of Typical and Atypical Antipsychotics Reduces EEG Gamma Power, but Only the Preclinical Compound LY379268 Reduces the Ketamine-induced Rise in Gamma Power

The International Journal of Neuropsychopharmacology / Official Scientific Journal of the Collegium Internationale Neuropsychopharmacologicum (CINP). Jun, 2011  |  Pubmed ID: 21733235

A single non-anaesthetic dose of ketamine, a non-competitive NMDA receptor (NMDAR) antagonist with hallucinogenic properties, induces cognitive impairment and psychosis, and aggravates schizophrenia symptoms in patients. In conscious rats an equivalent dose of ketamine induces key features of animal models of acute psychosis, including hyperlocomotor activity, deficits in prepulse inhibition and gating of auditory evoked potentials, and concomitantly increases the power of ongoing spontaneously occurring gamma (30-80 Hz) oscillations in the neocortex. This study investigated whether NMDAR antagonist-induced aberrant gamma oscillations could be modulated by acute treatment with typical and atypical antipsychotic drugs. Extradural electrodes were surgically implanted into the skull of adult male Wistar rats. After recovery, rats were subcutaneously administered either clozapine (1-5 mg/kg, n=7), haloperidol (0.05-0.25 mg/kg; n=8), LY379268 (a preclinical agonist at mGluR2/3 receptors: 0.3-3 mg/kg; n=5) or the appropriate vehicles, and 30 min later received ketamine (5 mg/kg s.c.). Quantitative measures of EEG gamma power and locomotor activity were assessed throughout the experiment. All three drugs significantly reduced the power of baseline EEG gamma oscillations by 30-50%, an effect most prominent after LY379268, and all inhibited ketamine-induced hyperlocomotor activity. However, only pretreatment with LY379268 attenuated trough-to-peak ketamine-induced gamma hyperactivity. These results demonstrate that typical and atypical antipsychotic drugs acutely reduce cortical gamma oscillations, an effect that may be related to their clinical efficacy.

Improved Diagnostic and Prognostic Performance of a New High-sensitive Troponin T Assay in Patients with Acute Coronary Syndrome

American Heart Journal. Jul, 2011  |  Pubmed ID: 21742093

In the present study, we aimed to analyze the diagnostic and prognostic potential of a newly developed high-sensitive troponin T assay and compared these results with those of a contemporary troponin T assay in 2 distinct patient cohorts, one including patients with evident ACS and the other one including patients with general chest pain.

Lessons from the Canadian National Health Information Technology Plan for the United States: Opinions of Key Canadian Experts

Journal of the American Medical Informatics Association : JAMIA. Jul, 2011  |  Pubmed ID: 21764888

Objective To summarize the Canadian health information technology (HIT) policy experience and impart lessons learned to the US as it determines its policy in this area. Design Qualitative analysis of interviews with identified key stakeholders followed by an electronic survey. Measurements We conducted semi-structured interviews with 29 key Canadian HIT policy and opinion leaders and used a grounded theory approach to analyze the results. The informant sample was chosen to provide views from different stakeholder groups including national representatives and regional representatives from three Canadian provinces. Results Canadian informants believed that much of the current US direction is positive, especially regarding incentives and meaningful use, but that there are key opportunities for the US to emphasize direct engagement with providers, define a clear business case for them, sponsor large scale evaluations to assess HIT impact in a broad array of settings, determine standards but also enable access to resources needed for mid-course corrections of standards when issues are identified, and, finally, leverage implementation of digital imaging systems. Limitations Not all stakeholder groups were included, such as providers or patients. In addition, as in all qualitative research, a selection bias could be present due to the relatively small sample size. Conclusions Based on Canadian experience with HIT policy, stakeholders identified as lessons for the US the need to increase direct engagement with providers and the importance of defining the business case for HIT, which can be achieved through large scale evaluations, and of recognizing and leveraging successes as they emerge.

Two New Complete Genome Sequences Offer Insight into Host and Tissue Specificity of Plant Pathogenic Xanthomonas Spp

Journal of Bacteriology. Oct, 2011  |  Pubmed ID: 21784931

Xanthomonas is a large genus of bacteria that collectively cause disease on more than 300 plant species. The broad host range of the genus contrasts with stringent host and tissue specificity for individual species and pathovars. Whole-genome sequences of Xanthomonas campestris pv. raphani strain 756C and X. oryzae pv. oryzicola strain BLS256, pathogens that infect the mesophyll tissue of the leading models for plant biology, Arabidopsis thaliana and rice, respectively, were determined and provided insight into the genetic determinants of host and tissue specificity. Comparisons were made with genomes of closely related strains that infect the vascular tissue of the same hosts and across a larger collection of complete Xanthomonas genomes. The results suggest a model in which complex sets of adaptations at the level of gene content account for host specificity and subtler adaptations at the level of amino acid or noncoding regulatory nucleotide sequence determine tissue specificity.

TopHat-Fusion: an Algorithm for Discovery of Novel Fusion Transcripts

Genome Biology. 2011  |  Pubmed ID: 21835007

TopHat-Fusion is an algorithm designed to discover transcripts representing fusion gene products, which result from the breakage and re-joining of two different chromosomes, or from rearrangements within a chromosome. TopHat-Fusion is an enhanced version of TopHat, an efficient program that aligns RNA-seq reads without relying on existing annotation. Because it is independent of gene annotation, TopHat-Fusion can discover fusion products deriving from known genes, unknown genes and unannotated splice variants of known genes. Using RNA-seq data from breast and prostate cancer cell lines, we detected both previously reported and novel fusions with solid supporting evidence. TopHat-Fusion is available at http://tophat-fusion.sourceforge.net/.

A Systematic Review: Plyometric Training Programs for Young Children

Journal of Strength and Conditioning Research / National Strength & Conditioning Association. Sep, 2011  |  Pubmed ID: 21849911

The purpose of this systematic review was to evaluate the efficacy and safety of plyometric training for improving motor performance in young children; to determine if this type of training could be used to improve the strength, running speed, agility, and jumping ability of children with low motor competence; and to examine the extent and quality of the current research literature. Primary research articles were selected if they (a) described the outcomes of a plyometric exercise intervention; (b) included measures of strength, balance, running speed, jumping ability, or agility; (c) included prepubertal children 5-14 years of age; and (d) used a randomized control trial or quasiexperimental design. Seven articles met the inclusion criteria for the final review. The 7 studies were judged to be of low quality (values of 4-6). Plyometric training had a large effect on improving the ability to run and jump. Preliminary evidence suggests plyometric training also had a large effect on increasing kicking distance, balance, and agility. The current evidence suggests that a twice a week program for 8-10 weeks beginning at 50-60 jumps a session and increasing exercise load weekly results in the largest changes in running and jumping performance. An alternative program for children who do not have the capability or tolerance for a twice a week program would be a low-intensity program for a longer duration. The research suggests that plyometric training is safe for children when parents provide consent, children agree to participate, and safety guidelines are built into the intervention.

The Bacillus Subtilis GntR Family Repressor YtrA Responds to Cell Wall Antibiotics

Journal of Bacteriology. Oct, 2011  |  Pubmed ID: 21856850

The transglycosylation step of cell wall synthesis is a prime antibiotic target because it is essential and specific to bacteria. Two antibiotics, ramoplanin and moenomycin, target this step by binding to the substrate lipid II and the transglycosylase enzyme, respectively. Here, we compare the ramoplanin and moenomycin stimulons in the Gram-positive model organism Bacillus subtilis. Ramoplanin strongly induces the LiaRS two-component regulatory system, while moenomycin almost exclusively induces genes that are part of the regulon of the extracytoplasmic function (ECF) σ factor σ(M). Ramoplanin additionally induces the ytrABCDEF and ywoBCD operons, which are not part of a previously characterized antibiotic-responsive regulon. Cluster analysis reveals that these two operons are selectively induced by a subset of cell wall antibiotics that inhibit lipid II function or recycling. Repression of both operons requires YtrA, which recognizes an inverted repeat in front of its own operon and in front of ywoB. These results suggest that YtrA is an additional regulator of cell envelope stress responses.

FLASH: Fast Length Adjustment of Short Reads to Improve Genome Assemblies

Bioinformatics (Oxford, England). Nov, 2011  |  Pubmed ID: 21903629

Next-generation sequencing technologies generate very large numbers of short reads. Even with very deep genome coverage, short read lengths cause problems in de novo assemblies. The use of paired-end libraries with a fragment size shorter than twice the read length provides an opportunity to generate much longer reads by overlapping and merging read pairs before assembling a genome.

Management of Hypertension in the Transplant Patient

Journal of the American Society of Hypertension : JASH. Sep-Oct, 2011  |  Pubmed ID: 21925458

In Patients Hospitalised with Acute Heart Failure, Nesiritide, Compared with Placebo, is Not Associated with Improvements in Dyspnoea or 30-day Rehospitalisation or Mortality

Evidence-based Medicine. Sep, 2011  |  Pubmed ID: 21949253

Uncovering the Blind Spot of Patient Satisfaction: an International Survey

BMJ Quality & Safety. Nov, 2011  |  Pubmed ID: 21949436

To achieve a high level of patient satisfaction, providers need to identify and address patients' expectations. However, providers' beliefs and attitudes regarding expectations, as well as how to manage them, are not well understood.

Early Life Stress Enhancement of Limbic Epileptogenesis in Adult Rats: Mechanistic Insights

PloS One. 2011  |  Pubmed ID: 21957442

Exposure to early postnatal stress is known to hasten the progression of kindling epileptogenesis in adult rats. Despite the significance of this for understanding mesial temporal lobe epilepsy (MTLE) and its associated psychopathology, research findings regarding underlying mechanisms are sparse. Of several possibilities, one important candidate mechanism is early life 'programming' of the hypothalamic-pituitary-adrenal (HPA) axis by postnatal stress. Elevated corticosterone (CORT) in turn has consequences for neurogenesis and cell death relevant to epileptogenesis. Here we tested the hypotheses that MS would augment seizure-related corticosterone (CORT) release and enhance neuroplastic changes in the hippocampus.

Mugsy: Fast Multiple Alignment of Closely Related Whole Genomes

Bioinformatics (Oxford, England). Feb, 2011  |  Pubmed ID: 21148543

The relative ease and low cost of current generation sequencing technologies has led to a dramatic increase in the number of sequenced genomes for species across the tree of life. This increasing volume of data requires tools that can quickly compare multiple whole-genome sequences, millions of base pairs in length, to aid in the study of populations, pan-genomes, and genome evolution.

Electrophysiological Insights into the Enduring Effects of Early Life Stress on the Brain

Psychopharmacology. Mar, 2011  |  Pubmed ID: 21165736

Increasing evidence links exposure to stress early in life to long-term alterations in brain function, which in turn have been linked to a range of psychiatric and neurological disorders in humans. Electrophysiological approaches to studying these causal pathways have been relatively underexploited. Effects of early life stress on neuronal electrophysiological properties offer a set of potential mechanisms for these susceptibilities, notably in the case of epilepsy. Thus, we review experimental evidence for altered cellular and circuit electrophysiology resulting from exposure to early life stress. Much of this work focuses on limbic long-term potentiation, but other studies address alterations in electrophysiological properties of ion channels, neurotransmitter systems, and the autonomic nervous system. We discuss mechanisms which may mediate these effects, including influences of early life stress on key components of brain synaptic transmission, particularly glutamate, GABA and 5-HT receptors, and influences on neuroplasticity (primarily neurogenesis and synaptic density) and on neuronal network activity. The existing literature, although small, provides strong evidence that early life stress induces enduring, often robust effects on a range of electrophysiological properties, suggesting further study of enduring effects of early life stress employing electrophysiological methods and concepts will be productive in illuminating disease pathophysiology.

Is Off-pump Superior to Conventional Coronary Artery Bypass Grafting in Diabetic Patients with Multivessel Disease?

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Jul, 2011  |  Pubmed ID: 21167727

Diabetic patients often present with diffuse coronary disease than nondiabetic patients posing a greater surgical challenge during off-pump revascularization. In this study, the safety, feasibility, and completeness of revascularization for this subset of patients was assessed.

Off-pump Surgery is Not a Contraindication for Patients with a Severely Decreased Ejection Fraction

The Heart Surgery Forum. Oct, 2011  |  Pubmed ID: 21997652

A severely impaired left ventricular ejection fraction (EF) (30%) increases the risk of surgical myocardial revascularization. We evaluated the safety and feasibility of off-pump coronary artery bypass (OPCAB) surgery in patients with a severely decreased EF.

Hawkeye and AMOS: Visualizing and Assessing the Quality of Genome Assemblies

Briefings in Bioinformatics. Dec, 2011  |  Pubmed ID: 22199379

Since its launch in 2004, the open-source AMOS project has released several innovative DNA sequence analysis applications including: Hawkeye, a visual analytics tool for inspecting the structure of genome assemblies; the Assembly Forensics and FRCurve pipelines for systematically evaluating the quality of a genome assembly; and AMOScmp, the first comparative genome assembler. These applications have been used to assemble and analyze dozens of genomes ranging in complexity from simple microbial species through mammalian genomes. Recent efforts have been focused on enhancing support for new data characteristics brought on by second- and now third-generation sequencing. This review describes the major components of AMOS in light of these challenges, with an emphasis on methods for assessing assembly quality and the visual analytics capabilities of Hawkeye. These interactive graphical aspects are essential for navigating and understanding the complexities of a genome assembly, from the overall genome structure down to individual bases. Hawkeye and AMOS are available open source at http://amos.sourceforge.net.

COMBREX: a Project to Accelerate the Functional Annotation of Prokaryotic Genomes

Nucleic Acids Research. Jan, 2011  |  Pubmed ID: 21097892

COMBREX (http://combrex.bu.edu) is a project to increase the speed of the functional annotation of new bacterial and archaeal genomes. It consists of a database of functional predictions produced by computational biologists and a mechanism for experimental biochemists to bid for the validation of those predictions. Small grants are available to support successful bids.

How Good Patient Blood Management Leads to Excellent Outcomes in Jehovah's Witness Patients Undergoing Cardiac Surgery

Interactive Cardiovascular and Thoracic Surgery. Feb, 2011  |  Pubmed ID: 20829389

The refusal of blood products makes open-heart surgery in Jehovah's witnesses (JW) an ethical challenge. We demonstrate how patient blood management strategies lead to excellent surgical outcomes.

Total Arterial Off-pump Surgery Provides Excellent Outcomes and Does Not Compromise Complete Revascularization

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Jan, 2012  |  Pubmed ID: 22241007

OBJECTIVESThe combination of aortic 'no-touch' off-pump surgery (OPCAB) and total arterial revascularization (TAR) can reduce peri-procedural morbidity and yields excellent long-term outcomes albeit at a reported risk of incomplete revascularization. The feasibility of OPCAB-TAR with specific regards to the complete revascularization (CR) in patients with multi-vessel disease was evaluated.METHODSFrom 2003 to 2010, 712 patients underwent TAR including 526 patients who had OPCAB-TAR and 186 patients who received on-pump TAR [(ONCAB grafting (ONCABG)-TAR)]. Of these, 52% (n = 272; OPCAB) vs. 83% (n = 155; ONCABG) had triple-vessel disease (TVD). To balance patient characteristics, a non-parsimonious, propensity score (PS) model was applied. Endpoints evaluated were mortality, stroke, major adverse cardiac and cerebrovascular events (MACCE). To evaluate CR, an 'Index of CR' (ICOR) was calculated, defined as the number of distal anastomoses divided by the number of the diseased coronary vessels. CR was assumed when the following requirements were fulfilled: the number of distal anastomoses was equal to or higher than that of diseased vessels (ICOR ≥ 1), and all affected coronary territories (left anterior descending, circumflex artery and/or right coronary artery) were grafted.RESULTSMortality was comparable between groups, whereas OPCAB patients suffered from significantly decreased rates of MACCE [3.0 vs. 7.0%; propensity-adjusted odd ratio (PAOR) = 0.24; confidence interval (CI) 95% 0.08-0.66; P = 0.006] including a clear trend towards reduced stroke and myocardial infarction. In the subgroup with TVD, OPCAB patients presented with significantly reduced rates for MACCE (1.8 vs. 5.8%; PAOR = 0.07; CI 95% 0.01-0.65; P = 0.02), including a significantly lower rate for stroke. For all-comers, the number of diseased vessels was lower after OPCAB (2.36 ± 0.73 vs. 2.87 ± 0.39; P < 0.001) and consequently, these patients received an overall lower number of distal anastomoses (2.42 ± 1.15 vs. 3.06 ± 0.98; P < 0.001). Although the ICOR was slightly lower (1.04 ± 0.37 vs. 1.07 ± 0.37; P = 0.02), CR was achieved more frequently in OPCAB patients (82.1 vs. 73.1%; P = 0.01). In the subgroup with TVD, the number of distal anastomoses (2.99 ± 1.14 vs. 3.10 ± 0.98; P = 0.19) and the ICOR (1.00 ± 0.38 vs. 1.03 ± 0.33; P = 0.19) was comparable between groups. The frequency of CR was slightly higher (75 vs. 67.7%; P = 0.11), and the proportion of complete in situ grafting was significantly higher after OPCAB (37.1 vs. 23.9%; P = 0.005).CONCLUSIONSAortic 'no-touch' OPCAB-TAR leads to a significant reduction of MACCE. It does not compromise CR in patients with TVD and thus can be safely applied to these patients.

Clinical Outcomes Associated with Screening and Referral for Depression in an Acute Cardiac Ward

Journal of Clinical Nursing. Jan, 2012  |  Pubmed ID: 22268823

Aim.  The aim of this paper is to describe the implementation of a depression screening and referral tool in two cardiac wards of a major metropolitan public hospital. The tool consisted of two sections: (1) screening for depression risk (Cardiac Depression Scale-5) and (2) consequential referral actions. Background.  Prior research has shown that depression in patients with heart disease is associated with significantly impaired quality of life, decreased medication adherence, increased morbidity and increased use of healthcare services. Design.  A prospective in-patient study design. Method.  A consecutive sample of 202 patients admitted to either the cardiac medical (n = 145) or surgical (n = 57) wards of a major Melbourne metropolitan hospital were recruited into the study over an 18-week period. Results.  Just over half (54%) of the patients were identified as 'at risk' of depression. Of these, 19% were assessed as moderate risk and 35% high risk. Of those patients, 91% had the risk score documented in their medical history, 90% had engaged in discussions with clinicians regarding their risk score, 85% had their risk score communicated formally to the medical team and 25% were formally referred for appropriate follow-up - significantly more than prior to implementation of the screening and referral tool. Conclusions.  By providing a formalised mechanism for detecting depression, documented screening and referral rates improved for those with comorbid depression and heart disease affording an opportunity for early intervention. These findings support a move towards integrated approaches to screening of depression to become standard practice in the acute cardiac setting. Relevance to clinical practice.  Such mechanisms also have the potential to initiate the development of new models of care that acknowledge the complexity of comorbid depression and heart disease and provide pathways from speciality to primary care which integrate the physical and psychosocial domains inclusive of screening, referral, systematic monitoring and streamlined behavioural and physical care.

Negative Microbiological Results Are Not Mandatory in Deep Sternal Wound Infections Before Wound Closure

European Journal of Cardio-thoracic Surgery : Official Journal of the European Association for Cardio-thoracic Surgery. Jan, 2012  |  Pubmed ID: 22290924

OBJECTIVESTo define the outcome of treatment for deep sternal wound infections (DSWIs) using direct wound closure (DC) or vacuum-assisted therapy (VAT) based on negative vs. positive microbiological results.METHODSBetween 1999 and 2008, 7746 patients underwent median sternotomy for cardiac surgery at our institution. Patients were screened for DSWI and out of the cohort 159 were identified (2%). These patients were treated, either using DC or VAT with delayed wound closure. Outcomes were retrospectively analysed to determine the effect of negative cultures at the time of closure.RESULTSThe indication for sternotomy was CABG 51%, isolated valve 18%, CABG/valve 18% and other related cardiovascular procedures 14%. Sixty-five percent of the wound infections was diagnosed during rehabilitation period. One hundred and five (66%) patients were treated with VAT vs. 54 (34%) patients with direct closure. Coagulase negative staphylococci were found in 48% of bacterial cultures. In 75% of the patients, the microbiological results were positive at time of wound closure (69.2% VAT vs. 87.0% direct closure, P = 0.014). Out of 159 patients, 5.0% were with positive microbiological results at the time of closure readmitted vs. 5.1% with negative microbiological results (P = 1.0). Patients with VAT stayed significantly longer in the hospital (mean 21 ± 16 vs. 13 ± 12, P = 0.002).CONCLUSIONSNegative microbiological results are not mandatory before wound closure, as the rate of readmissions for recurrence of infection showed no difference between groups. Our results also suggest that shortening of VAT despite positive microbiological results may be feasible.

Gene Prediction with Glimmer for Metagenomic Sequences Augmented by Classification and Clustering

Nucleic Acids Research. Jan, 2012  |  Pubmed ID: 22102569

Environmental shotgun sequencing (or metagenomics) is widely used to survey the communities of microbial organisms that live in many diverse ecosystems, such as the human body. Finding the protein-coding genes within the sequences is an important step for assessing the functional capacity of a metagenome. In this work, we developed a metagenomics gene prediction system Glimmer-MG that achieves significantly greater accuracy than previous systems via novel approaches to a number of important prediction subtasks. First, we introduce the use of phylogenetic classifications of the sequences to model parameterization. We also cluster the sequences, grouping together those that likely originated from the same organism. Analogous to iterative schemes that are useful for whole genomes, we retrain our models within each cluster on the initial gene predictions before making final predictions. Finally, we model both insertion/deletion and substitution sequencing errors using a different approach than previous software, allowing Glimmer-MG to change coding frame or pass through stop codons by predicting an error. In a comparison among multiple gene finding methods, Glimmer-MG makes the most sensitive and precise predictions on simulated and real metagenomes for all read lengths and error rates tested.

Repetitive DNA and Next-generation Sequencing: Computational Challenges and Solutions

Nature Reviews. Genetics. Jan, 2012  |  Pubmed ID: 22124482

Repetitive DNA sequences are abundant in a broad range of species, from bacteria to mammals, and they cover nearly half of the human genome. Repeats have always presented technical challenges for sequence alignment and assembly programs. Next-generation sequencing projects, with their short read lengths and high data volumes, have made these challenges more difficult. From a computational perspective, repeats create ambiguities in alignment and assembly, which, in turn, can produce biases and errors when interpreting results. Simply ignoring repeats is not an option, as this creates problems of its own and may mean that important biological phenomena are missed. We discuss the computational problems surrounding repeats and describe strategies used by current bioinformatics systems to solve them.

GAGE: A Critical Evaluation of Genome Assemblies and Assembly Algorithms

Genome Research. Jan, 2012  |  Pubmed ID: 22147368

New sequencing technology has dramatically altered the landscape of whole-genome sequencing, allowing scientists to initiate numerous projects to decode the genomes of previously unsequenced organisms. The lowest-cost technology can generate deep coverage of most species, including mammals, in just a few days. The sequence data generated by one of these projects consist of millions or billions of short DNA sequences (reads) that range from 50 to 150 nt in length. These sequences must then be assembled de novo before most genome analyses can begin. Unfortunately, genome assembly remains a very difficult problem, made more difficult by shorter reads and unreliable long-range linking information. In this study, we evaluated several of the leading de novo assembly algorithms on four different short-read data sets, all generated by Illumina sequencers. Our results describe the relative performance of the different assemblers as well as other significant differences in assembly difficulty that appear to be inherent in the genomes themselves. Three overarching conclusions are apparent: first, that data quality, rather than the assembler itself, has a dramatic effect on the quality of an assembled genome; second, that the degree of contiguity of an assembly varies enormously among different assemblers and different genomes; and third, that the correctness of an assembly also varies widely and is not well correlated with statistics on contiguity. To enable others to replicate our results, all of our data and methods are freely available, as are all assemblers used in this study.

The Effects of Exercise on the Neuronal Response to Food Cues

Physiology & Behavior. Feb, 2012  |  Pubmed ID: 22155218

Increased physical activity is associated with successful long-term weight loss maintenance due to mechanisms likely more complex than simply increased energy expenditure. The impact of physical activity on the central regulation of food intake may be an important mechanism of this effect. The objective of this study was to examine the effects of exercise training and acute exercise on the neuronal response to food cues as well as eating behaviors. fMRI was performed in the fasted state at baseline and again after a 6month progressive exercise intervention (supervised, 5days/wk) both with and without an acute exercise bout in 12 overweight/obese (5 women, 7 men; BMI 33±4kg/m(2)) healthy adults. fMRI data were acquired while subjects were presented with visual stimuli of foods of high hedonic value as compared to neutral control objects. Questionnaires on eating behaviors, ratings of appeal and desire for foods, and ratings of appetite (hunger, satiety, prospective intake) using visual analog scales were also performed at baseline and again after the 6-month exercise intervention. While only a trend was observed for a reduction in body weight (102±5 to 99±6kg, p=0.09), a significant reduction in fat mass was observed (36.4±2.8 to 33.7±3.2kg, p=0.04), although as expected changes in fat mass were variable (-10.0 to +3.7kg). Chronic exercise was associated with a reduction in the neuronal response to food, primarily in the posterior attention network and insula. A significant positive correlation between the change in fat/body mass and the change in insula response to food cues with chronic exercise was observed. An acute exercise bout attenuated the effects of chronic exercise. The exercise intervention, however, did not impact any of the measures of appetitive behavior. In summary, despite no effects on behavioral measures of appetite, chronic exercise training was associated with attenuation in the response to visual food cues in brain regions known to be important in food intake regulation. The insula, in particular, appears to play an important role in the potential exercise-induced weight loss and weight loss maintenance.

MiR-365 Regulates Lung Cancer and Developmental Gene Thyroid Transcription Factor 1

Cell Cycle (Georgetown, Tex.). Jan, 2012  |  Pubmed ID: 22185756

Thyroid transcription factor 1 (TTF-1 or NKX2-1) is an essential fetal lung developmental factor, which can be recurrently activated by gene amplification in adult lung cancer. We have discovered the first microRNA (i.e., miR-365) that directly regulates TTF-1 by interacting with its 3'-untranslated region. By gene expression profiling, we identified other putative targets of miR-365 and miR-365*. In line with the microRNA/target relationship, the expression patterns of miR-365 and TTF-1 were in an inverse relationship in human lung cancer. Exploration of human lung cancer genomics data uncovered that TTF-1 gene amplification was significantly associated with DNA copy number loss at one of the two genomic loci encoding the precursor RNA of mature miR-365 (i.e., mir-365-1). This implies the existence of genetic selection pressure to lose the repressive miR-365 that would otherwise suppress amplified TTF-1. We detected a signaling loop between transforming growth factor beta (TGFb) and miR-365 and this loop reinforced suppression of TTF-1 via miR-365. Mir-365 also targeted an epithelial mesenchymal transition (EMT)-promoting gene HMGA2. In summary, these data connect the lung transcriptional program to the microRNA network.