Comparing Safety and Efficacy of First-line Irinotecan/fluoropyrimidine Combinations in Elderly Versus Nonelderly Patients with Metastatic Colorectal Cancer: Findings from the Bolus, Infusional, or Capecitabine with Camptostar-celecoxib Study

Cancer. Jun, 2009  |  Pubmed ID: 19382200

Irinotecan-based chemotherapy regimens are 1 option for treatment of metastatic colorectal cancer (mCRC). The authors report the safety and efficacy of such regimens in elderly patients using a large phase III trial (bolus, infusional, or capecitabine with camptostar-celecoxib [BICC-C]) cohort.

Evaluation of [64Cu]Cu-DOTA and [64Cu]Cu-CB-TE2A Chelates for Targeted Positron Emission Tomography with an Alphavbeta6-specific Peptide

Molecular Imaging. Mar-Apr, 2009  |  Pubmed ID: 19397856

Significant upregulation of the integrin alpha(v)beta(6) has been described as a prognostic indicator in several cancers, making it an attractive target for tumor imaging. This study compares variants of a PEGylated alpha(v)beta(6)-targeting peptide, bearing either an [(18)F]fluorobenzoyl prosthetic group ([(18)F]FBA-PEG-A20FMDV2) or different [(64)Cu]copper chelators (DOTA-PEG-A20FMDV2, CB-TE2A-PEG-A20FMDV2). The compounds were evaluated in vitro by enzyme-linked immunosorbent assay (against the integrin alpha(v)beta(6) and the closely related integrin alpha(v)beta(3)) and by cell labeling (alpha(v)beta(6)-positive DX3purobeta6/alpha(v)beta(6)-negative DX3puro) and in vivo using micro-positron emission tomography in a mouse model bearing paired DX3purobeta6/Dx3puro xenografts. In vitro, all three compounds showed excellent alpha(v)beta(6)-specific binding (50% inhibitory concentration [IC(50)](alpha(v)beta(6)) = 3 to 6 nmol/L; IC(50)(alpha(v)beta(3)) > 10 micromol/L). In vivo, they displayed comparable, preferential uptake for the alpha(v)beta(6)-expressing xenograft over the alpha(v)beta(6)-negative control (> 4:1 ratio at 4 hours postinjection). Whereas [(64)Cu]Cu-DOTA-PEG-A20FMDV2 resulted in increased levels of radioactivity in the liver, [(64)Cu]Cu-CB-TE2A-PEG-A20FMDV2 did not. Significantly, both (64)Cu-labeled tracers showed unexpectedly high and persistent levels of radioactivity in the kidneys (> 40% injected dose/g at 4 and 12 hours postinjection). The findings underscore the potential influence of the prosthetic group on targeted in vivo imaging of clinically relevant markers such as alpha(v)beta(6). Despite identical targeting peptide moiety and largely equal in vitro behavior, both (64)Cu-labeled tracers displayed inferior pharmacokinetics, making them in their present form less suitable candidates than the (18)F-labeled tracer for in vivo imaging of alpha(v)beta(6).

Galpha(i1) and Galpha(i3) Are Required for Epidermal Growth Factor-mediated Activation of the Akt-mTORC1 Pathway

Science Signaling. 2009  |  Pubmed ID: 19401591

The precise mechanism whereby epidermal growth factor (EGF) activates the serine-threonine kinase Akt and the mammalian target of rapamycin (mTOR) complex 1 (mTORC1) remains elusive. Here, we report that the alpha subunits of the heterotrimeric guanine nucleotide-binding proteins (G proteins) Galpha(i1) and Galpha(i3) are critical for this activation process. Both Galpha(i1) and Galpha(i3) formed complexes with growth factor receptor binding 2 (Grb2)-associated binding protein 1 (Gab1) and the EGF receptor (EGFR) and were required for the phosphorylation of Gab1 and its subsequent interaction with the p85 subunit of phosphatidylinositol 3-kinase in response to EGF. Loss of Galpha(i1) and Galpha(i3) severely impaired the activation of Akt and of p70 S6 kinase and 4E-BP1, downstream targets of mTORC1, in response to EGF, heparin-binding EGF-like growth factor, and transforming growth factor alpha, but not insulin, insulin-like growth factor, or platelet-derived growth factor. In addition, ablation of Galpha(i1) and Galpha(i3) largely inhibited EGF-induced cell growth, migration, and survival and the accumulation of cyclin D1. Overall, this study suggests that Galpha(i1) and Galpha(i3) lie downstream of EGFR, but upstream of Gab1-mediated activation of Akt and mTORC1, thus revealing a role for Galpha(i) proteins in mediating EGFR signaling.

Too Much Information

Gastrointestinal Cancer Research : GCR. Mar, 2009  |  Pubmed ID: 19461905

Biomarkers of Sepsis

Critical Care Medicine. Jul, 2009  |  Pubmed ID: 19487943

A complex network of biological mediators underlies the clinical syndrome of sepsis. The nonspecific physiologic criteria of sepsis syndrome or the systemic inflammatory response syndrome do not adequately identify patients who might benefit from either conventional anti-infective therapies or from novel therapies that target specific mediators of sepsis. Validated biomarkers of sepsis may improve diagnosis and therapeutic decision making for these high-risk patients.

The Effect of Gene Drive on Containment of Transgenic Mosquitoes

Journal of Theoretical Biology. May, 2009  |  Pubmed ID: 19490857

Mosquito-borne diseases such as malaria and dengue fever continue to be a major health problem through much of the world. Several new potential approaches to disease control utilize gene drive to spread anti-pathogen genes into the mosquito population. Prior to a release, these projects will require trials in outdoor cages from which transgenic mosquitoes may escape, albeit in small numbers. Most genes introduced in small numbers are very likely to be lost from the environment; however, gene drive mechanisms enhance the invasiveness of introduced genes. Consequently, introduced transgenes may be more likely to persist than ordinary genes following an accidental release. Here, we develop stochastic models to analyze the loss probabilities for several gene drive mechanisms, including homing endonuclease genes, transposable elements, Medea elements, the intracellular bacterium Wolbachia, engineered underdominance genes, and meiotic drive. We find that Medea and Wolbachia present the best compromise between invasiveness and containment for the six gene drive systems currently being considered for the control of mosquito-borne disease.

3D Collagen Orientation Study of the Human Cornea Using X-ray Diffraction and Femtosecond Laser Technology

Investigative Ophthalmology & Visual Science. Nov, 2009  |  Pubmed ID: 19516010

To study the distribution and predominant orientations of fibrillar collagen at different depths throughout the entire thickness of the human cornea. This information will form the basis of a full three-dimensional reconstruction of the preferred orientations of corneal lamellae.

Targeted in Vivo Imaging of Integrin Alphavbeta6 with an Improved Radiotracer and Its Relevance in a Pancreatic Tumor Model

Cancer Research. Jul, 2009  |  Pubmed ID: 19549907

The cell surface receptor alpha(v)beta(6) is epithelial specific, and its expression is tightly regulated; it is low or undetectable in adult tissues but has been shown to be increased in many different cancers, including pancreatic, cervical, lung, and colon cancers. Studies have described alpha(v)beta(6) as a prognostic biomarker linked to poor survival. We have recently shown the feasibility of imaging alpha(v)beta(6) in vivo by positron emission tomography (PET) using the peptide [(18)F]FBA-A20FMDV2. Here, we describe improved alpha(v)beta(6) imaging agents and test their efficacy in a mouse model with endogenous alpha(v)beta(6) expression. The modified compounds maintained high affinity for alpha(v)beta(6) and >1,000-fold selectivity over related integrins (by ELISA) and showed significantly improved alpha(v)beta(6)-dependent binding in cell-based assays (>60% binding versus <10% for [(18)F]FBA-A20FMDV2). In vivo studies using either a melanoma cell line (transduced alpha(v)beta(6) expression) or the BxPC-3 human pancreatic carcinoma cell line (endogenous alpha(v)beta(6) expression) revealed that the modified compounds showed significantly improved tumor retention. This, along with good clearance of nonspecifically bound activity, particularly for the new radiotracer [(18)F]FBA-PEG(28)-A20FMDV2, resulted in improved PET imaging. Tumor/pancreas and tumor/blood biodistribution ratios of >23:1 and >47:1, respectively, were achieved at 4 hours. Significantly, [(18)F]FBA-PEG(28)-A20FMDV2 was superior to 2-[(18)F]fluoro-2-deoxy-d-glucose ([(18)F]FDG) in imaging the BxPC-3 tumors. Pancreatic ductal adenocarcinoma is highly metastatic and current preoperative evaluation of resectability using noninvasive imaging has limited success, with most patients having metastases at time of surgery. The fact that these tumors express alpha(v)beta(6) suggests that this probe has significant potential for the in vivo detection of this malignancy, thus having important implications for patient care and therapy.

Development and Validation of a Risk Score for Post-infectious Irritable Bowel Syndrome

The American Journal of Gastroenterology. Sep, 2009  |  Pubmed ID: 19568228

Acute gastroenteritis (GE) is an important risk factor for the development of irritable bowel syndrome (IBS). We used observational data from the Walkerton Health Study (WHS) to develop and validate a risk score for post-infectious (PI) IBS.

The 'Consent to Research' Paradigm in Critical Care: Challenges and Potential Solutions

Intensive Care Medicine. Oct, 2009  |  Pubmed ID: 19582396

Estradiol and Progesterone-induced Slowing of Gonadotropin-releasing Hormone Pulse Frequency is Not Reversed by Subsequent Administration of Mifepristone

Endocrine. Oct, 2009  |  Pubmed ID: 19609733

Subsequent to suppression of LH (GnRH) pulse frequency by progesterone (P) and estradiol (E(2)), LH pulse frequency remains slow for 7 days after P withdrawal if mid-luteal E(2) concentrations are maintained. This may reflect an ability of E(2) to potentiate the suppressive effects of low P levels. We explored this notion in a similar experimental paradigm by administering a P-receptor antagonist (mifepristone) after P withdrawal while continuing E(2). Studies were performed in seven ovulatory, non-obese women. Transdermal E(2) (0.2 mg/day) and oral micronized P (100 mg every 8 h) were started within 24 h of the LH surge and continued for 10 days. Subjects then underwent a 13-h blood sampling protocol for determination of LH pulse characteristics and various hormone concentrations. Oral P was then discontinued, and oral mifepristone (50, 100, or 200 mg daily) and transdermal E(2) (0.2 mg/day) were administered for 7 days, after which the above sampling protocol was repeated. Results with all mifepristone doses were similar and therefore pooled. Mean LH, LH amplitude, and mean FSH markedly decreased after 7 days of mifepristone, but LH pulse frequency did not change (3.3 +/- 1.5 vs. 2.4 +/- 1.5 pulses/13 h). Prolactin and androstenedione increased between the first and second admissions, with no changes in E(2), cortisol, testosterone, or DHEAS. In conclusion, blockade of P action by mifepristone does not reverse a suppressed LH pulse frequency within 7 days when E(2) concentrations are maintained, suggesting that P withdrawal alone may not explain the luteal-follicular increase of GnRH pulse frequency.

SAP97 and CASK Mediate Sorting of NMDA Receptors Through a Previously Unknown Secretory Pathway

Nature Neuroscience. Aug, 2009  |  Pubmed ID: 19620977

Synaptic plasticity is dependent on the differential sorting, delivery and retention of neurotransmitter receptors, but the mechanisms underlying these processes are poorly understood. We found that differential sorting of glutamate receptor subtypes began in the endoplasmic reticulum of rat hippocampal neurons. As AMPA receptors (AMPARs) were trafficked to the plasma membrane via the conventional somatic Golgi network, NMDA receptors (NMDARs) were diverted from the somatic endoplasmic reticulum into a specialized endoplasmic reticulum subcompartment that bypasses somatic Golgi, merging instead with dendritic Golgi outposts. This endoplasmic reticulum subcompartment was composed of highly mobile vesicles containing the NMDAR subunits NR1 and NR2B, the microtubule-dependent motor protein KIF17, and the postsynaptic adaptor proteins CASK and SAP97. Our data demonstrate that the retention and trafficking of NMDARs in this endoplasmic reticulum subcompartment requires both CASK and SAP97. These findings indicate that NMDARs are sorted away from AMPARs via a non-conventional secretory pathway that utilizes dendritic Golgi outposts.

Heading in the Right Direction

Gastrointestinal Cancer Research : GCR. May, 2009  |  Pubmed ID: 19626151

Post-infectious Irritable Bowel Syndrome

World Journal of Gastroenterology : WJG. Aug, 2009  |  Pubmed ID: 19653335

Post-infectious irritable bowel syndrome (PI-IBS) is a common disorder wherein symptoms of IBS begin after an episode of acute gastroenteritis. Published studies have reported incidence of PI-IBS to range between 5% and 32%. The mechanisms underlying the development of PI-IBS are not fully understood, but are believed to include persistent sub-clinical inflammation, changes in intestinal permeability and alteration of gut flora. Individual studies have suggested that risk factors for PI-IBS include patients' demographics, psychological disorders and the severity of enteric illness. However, PI-IBS remains a diagnosis of exclusion with no specific disease markers and, to date, no definitive therapy exists. The prognosis of PI-IBS appears favorable with spontaneous and gradual resolution of symptoms in most patients.

Tandem Mass Spectrometry of Human Tryptic Blood Peptides Calculated by a Statistical Algorithm and Captured by a Relational Database with Exploration by a General Statistical Analysis System

Journal of Proteomics. Nov, 2009  |  Pubmed ID: 19703602

A goodness of fit test may be used to assign tandem mass spectra of peptides to amino acid sequences and to directly calculate the expected probability of mis-identification. The product of the peptide expectation values directly yields the probability that the parent protein has been mis-identified. A relational database could capture the mass spectral data, the best fit results, and permit subsequent calculations by a general statistical analysis system. The many files of the Hupo blood protein data correlated by X!TANDEM against the proteins of ENSEMBL were collected into a relational database. A redundant set of 247,077 proteins and peptides were correlated by X!TANDEM, and that was collapsed to a set of 34,956 peptides from 13,379 distinct proteins. About 6875 distinct proteins were only represented by a single distinct peptide, 2866 proteins showed 2 distinct peptides, and 3454 proteins showed at least three distinct peptides by X!TANDEM. More than 99% of the peptides were associated with proteins that had cumulative expectation values, i.e. probability of false positive identification, of one in one hundred or less. The distribution of peptides per protein from X!TANDEM was significantly different than those expected from random assignment of peptides.

Regulation of Lhb and Egr1 Gene Expression by GNRH Pulses in Rat Pituitaries is Both C-Jun N-terminal Kinase (JNK)- and Extracellular Signal-regulated Kinase (ERK)-dependent

Biology of Reproduction. Dec, 2009  |  Pubmed ID: 19710510

Pulsatile GNRH regulates the gonadotropin subunit genes in a differential manner, with faster frequencies favoring Lhb gene expression and slower frequencies favoring Fshb. Early growth response 1 (EGR1) is critical for Lhb gene transcription. We examined GNRH regulation of EGR1 and its two corepressors, Ngfi-A-binding proteins 1 and 2 (NAB1 and NAB2), both in vivo and in cultured rat pituitary cells. In rats, fast GNRH pulses (every 30 min) stably induced Egr1 primary transcript (PT) and mRNA 2-fold (P < 0.05) for 1-24 h. In contrast, slow GNRH pulses (every 240 min) increased Egr1 PT at 24 h (6-fold; P < 0.05) but increased Egr1 mRNA 4- to 5-fold between 4 and 24 h. Both GNRH pulse frequencies increased EGR1 protein 3- to 4-fold. In cultured rat pituitary cells, GNRH pulses (every 60 min) increased Egr1 (PT, 2.5- to 3-fold; mRNA, 1.5- to 2-fold; P < 0.05). GNRH pulses had little effect on Nab1/2 PT/mRNAs either in vivo or in vitro. We also examined specific intracellular signaling cascades activated by GNRH. Inhibitors of mitogen-activated protein kinase 8/9 (MAPK8/9 [also known as JNK]; SP600125) and MAP Kinase Kinase 1 (MAP2K1 [also known as MEK1]; PD98059) either blunted or totally suppressed the GNRH induction of Lhb PT and Egr1 PT/mRNA, whereas the MAPK14 (also known as p38) inhibitor SB203580 did not. In summary, pulsatile GNRH stimulates Egr1 gene expression and protein in vivo but not in a frequency-dependent manner. Additionally, GNRH-induced Egr1 gene expression is mediated by MAPK8/9 and MAPK1/3, and both are critical for Lhb gene transcription.

ISGIO: Setting the Standard of Care for the Future

Gastrointestinal Cancer Research : GCR. Jul, 2009  |  Pubmed ID: 19742138

Safety of Chronic Low-dose Capecitabine As Maintenance Therapy in Gastrointestinal Cancers

Gastrointestinal Cancer Research : GCR. Jul, 2009  |  Pubmed ID: 19742139

Maintenance chemotherapy is not routinely used in gastrointestinal (GI) cancers. Capecitabine is an oral formulation that is enzymatically converted to 5-fluorouracil preferentially in tumor tissue. We hypothesize that capecitabine could be used as a long-term maintenance therapy to improve outcomes in patients with high-risk GI cancers following standard chemotherapy regimens.

Effect of Epithelial Retention and Removal on Riboflavin Absorption in Porcine Corneas

Journal of Refractive Surgery (Thorofare, N.J. : 1995). Sep, 2009  |  Pubmed ID: 19772262

To compare stromal riboflavin absorption after 20% alcohol application and partial or complete epithelial removal by analyzing light transmission properties of porcine corneas after riboflavin/ultraviolet A (UVA) corneal collagen cross-linking.

Evaluation and Stages of Surgical Innovations

Lancet. Sep, 2009  |  Pubmed ID: 19782874

Surgical innovation is an important part of surgical practice. Its assessment is complex because of idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical innovations can derive from evidence-based principles rather than trial and error. A regulatory framework is also desirable to protect patients against the potential harms of any novel procedure. In this first of three Series papers on surgical innovation and evaluation, we propose a five-stage paradigm to describe the development of innovative surgical procedures.

Challenges in Evaluating Surgical Innovation

Lancet. Sep, 2009  |  Pubmed ID: 19782875

Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures-for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential.

No Surgical Innovation Without Evaluation: the IDEAL Recommendations

Lancet. Sep, 2009  |  Pubmed ID: 19782876

Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies.

Anti-inflammatory Effects of Intravenously Administered Lidocaine Hydrochloride on Ischemia-injured Jejunum in Horses

American Journal of Veterinary Research. Oct, 2009  |  Pubmed ID: 19795941

To investigate effects of lidocaine hydrochloride administered IV on mucosal inflammation in ischemia-injured jejunum of horses treated with flunixin meglumine.

High-throughput in Vivo Screening of Targeted Molecular Imaging Agents

Proceedings of the National Academy of Sciences of the United States of America. Oct, 2009  |  Pubmed ID: 19815497

The rapid development and translation of targeted molecular imaging agents from bench to bedside is currently a slow process, with a clear bottleneck between the discovery of new compounds and the development of an appropriate molecular imaging agent. The ability to identify promising new molecular imaging agents, as well as failures, much earlier in the development process using high-throughput screening techniques could save significant time and money. This work combines the advantages of combinatorial chemistry, site-specific solid-phase radiolabeling, and in vivo imaging for the rapid screening of molecular imaging agents. A one-bead-one-compound library was prepared and evaluated in vitro, leading to the identification of 42 promising lead peptides. Over 11 consecutive days, these peptides, along with a control peptide, were successfully radiolabeled with 4-[(18)F]fluorobenzoic acid and evaluated in vivo using microPET. Four peptides were radiolabeled per day, followed by simultaneous injection of each individual peptide into 2 animals. As a result, 4 promising new molecular imaging agents were identified that otherwise would not have been selected based solely on in vitro data. This study is the first example of the practical application of a high-throughput screening approach using microPET imaging of [(18)F]-labeled peptides for the rapid in vivo identification of potential new molecular imaging agents.

Adherence to Guidelines for Surveillance Colonoscopy in Patients with Ulcerative Colitis at a Canadian Quaternary Care Hospital

Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. Sep, 2009  |  Pubmed ID: 19816624

Patients with ulcerative colitis (UC) are at high risk of colonic dysplasia. Therefore, surveillance colonoscopy to detect early dysplasia has been endorsed by many professional organizations.

Myocardial Infarction, Peptic Ulcer and Acetylsalicylic Acid: of Good and Evil

Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. Sep, 2009  |  Pubmed ID: 19816625

Is Levoleucovorin an Alternative to Racemic Leucovorin? A Literature Review

Clinical Colorectal Cancer. Oct, 2009  |  Pubmed ID: 19822510

Our purpose is to perform a comprehensive literature review of the use of levoleucovorin in gastrointestinal malignancies and to assess whether levoleucovorin is a reasonable alternative to racemic leucovorin.

Critically Ill Patients with 2009 Influenza A(H1N1) Infection in Canada

JAMA : the Journal of the American Medical Association. Nov, 2009  |  Pubmed ID: 19822627

Between March and July 2009, the largest number of confirmed cases of 2009 influenza A(H1N1) infection occurred in North America.

Alphav Beta3 Integrin Limits the Contribution of Neuropilin-1 to Vascular Endothelial Growth Factor-induced Angiogenesis

The Journal of Biological Chemistry. Dec, 2009  |  Pubmed ID: 19837659

Both vascular endothelial growth factor receptors (VEGFR) and integrins are major regulators of VEGF-induced angiogenesis. Previous work has shown that beta3 integrin can regulate negatively VEGFR2 expression. Here we show that beta3 integrin can regulate negatively VEGF-mediated angiogenesis by limiting the interaction of the co-receptor NRP1 (neuropilin-1) with VEGFR2. In the presence of alphav beta3 integrin, NRP1 contributed minimally to VEGF-induced angiogenic processes in vivo, ex vivo, and in vitro. Conversely, when beta3 integrin expression is absent or low or its function is blocked with RGD-mimetic inhibitors, VEGF-mediated responses became NRP1-dependent. Indeed, combined inhibition of beta3 integrin and NRP1 decreased VEGF-mediated angiogenic responses further than individual inhibition of these receptors. We also show that alphav beta3 integrin can associate with NRP1 in a VEGF-dependent fashion. Our data suggest that beta3 integrin may, in part, negatively regulate VEGF signaling by sequestering NRP1 and preventing it from interacting with VEGFR2.

Storage and Transpiration Have Negligible Effects on Delta13C of Stem CO2 Efflux in Large Conifer Trees

Tree Physiology. Dec, 2009  |  Pubmed ID: 19840994

Stem respiration rates are often quantified by measuring the CO(2) efflux from stems into chambers. It has been suggested that these measurements underestimate respiration because some of the respired CO(2) can be either retained or transported upwards in the transpiration stream. If the stem CO(2) efflux does not represent all respired CO(2), then the interpretation of its isotopic signal may be compromised as well. The C-isotope composition of the respired CO(2) and the measured efflux could differ due to (i) the release of CO(2) produced elsewhere into the stem and transported upwards in xylem water (soil CO(2) or root respired CO(2)); (ii) the retention or release of CO(2) storage pools within the tree stem and (iii) the removal of CO(2) by the transpiration stream. We investigated the effects of these processes in large conifer trees using two manipulative experiments: a labelling experiment and a crown removal experiment. The labelling experiment used an extreme enrichment of dissolved CO(2) in soil water to assess the C uptake by the roots. In this experiment, we found no contamination of the stem CO(2) pool despite clear evidence that the water itself had been taken up. The crown removal experiment tested for vertical CO(2) flux in xylem water by eliminating transpiration. Here, we found no change in the delta(13)C of stem CO(2) efflux (delta(EA); P > 0.05). We concluded that for these large conifers, sap-flow influenced neither delta(13)C of stem efflux nor that of the stem CO(2) pool. By parameterizing Henry's Law for conditions inside the stem, we estimated the transport flux to represent 1-3% of the stem CO(2) efflux to the atmosphere. Finally, assuming a 2 per thousand difference between delta(13)C of root and stem respiration, we estimated that potential contamination of delta(EA) by root respired CO(2) would be < 0.1 per thousand. Thus, neither the release of soil or root CO(2), nor storage in the stem, nor vertical transport of CO(2) in the xylem sap had any detectable influence on delta(13)C of the CO(2) measured in stem efflux.

Coupling Tree-ring Delta13C and Delta15N to Test the Effect of Fertilization on Mature Douglas-fir (Pseudotsuga Menziesii Var. Glauca) Stands Across the Interior Northwest, USA

Tree Physiology. Dec, 2009  |  Pubmed ID: 19855101

Nitrogen (N) fertilization causes long-term increases in biomass production in many N-limited forests around the world, but the mechanistic basis underlying the increase is often unclear. One possibility, especially in summer-dry climates, is that N fertilization increases the efficiency with which a finite water supply is consumed to support photosynthesis. This increase is achieved by a reduction in the canopy-integrated concentration of internal CO(2) and thus discrimination against (13)C. We used stable isotopes of carbon (delta(13)C) in tree rings to experimentally test the physiological impact of N fertilization on mature Douglas-fir (Pseudotsuga menziesii Franco var. glauca) stands across the geographic extent of the Intermountain West, USA. The concentration and the stable isotopes of N (delta(15)N) in tree rings were also used to assess the presence and activity of fertilizer N. We hypothesized that N fertilization would (i) increase delta(15)N and N concentration of stemwood relative to non-fertilized stands and (ii) increase stemwood delta(13)C as photosynthetic gas exchange responded to the additional N. This experiment included two rates of urea addition, 178 kg ha(-1) (low) and 357 kg ha(-1) (high), which were applied twice over a 6-year interval bracketed by the 18 years of wood production measured in this study. Foliar N concentrations measured the year after each fertilization treatment suggest that the fertilizer N had been assimilated by the trees (P < 0.001). The N fertilization significantly enriched stemwood delta(15)N by 1.3 per thousand at the low fertilization rate and by 2.4 per thousand at the high rate (P < 0.001) despite variation in soil N between sites. However, we found no significant effect of the N fertilizer on delta(13)C of the annual rings (P = 0.76). These data lead us to suggest that alternative mechanisms underlie the growth response to fertilizer, i.e., increase in canopy area and shifts in biomass allocation.

Principles of Source Control in the Management of Sepsis

Critical Care Clinics. Oct, 2009  |  Pubmed ID: 19892251

The term "source control" encompasses all those physical measures used to control a focus of invasive infection and to restore the optimal function of the affected area. Source-control measures can be categorized into 3 broad modalities: drainage controls the liquid component of an infection by converting a closed space infection to a controlled sinus or fistula; debridement is the physical removal of solid necrotic tissue (removal of an infected device can be considered a form of debridement); definitive measures seek to restore optimal function to the involved area. This article discusses specific approaches to source control in the abdomen, chest, and skin and soft tissues.

Analysis of Low-concentration Gas Samples with Continuous-flow Isotope Ratio Mass Spectrometry: Eliminating Sources of Contamination to Achieve High Precision

Rapid Communications in Mass Spectrometry : RCM. Dec, 2009  |  Pubmed ID: 19902416

Developments in continuous-flow isotope ratio mass spectrometry have made possible the rapid analysis of delta13C in CO2 of small-volume gas samples with precisions of < or = 0.1 per thousand. Prior research has validated the integrity of septum-capped vials for collection and short-term storage of gas samples. However, there has been little investigation into the sources of contamination during the preparation and analysis of low-concentration gas samples. In this study we determined (1) sources of contamination on a Gasbench II, (2) developed an analytical procedure to reduce contamination, and (3) identified an efficient, precise method for introducing sample gas into vials. We investigated three vial-filling procedures: (1) automated flush-fill (AFF), (2) vacuum back-fill (VBF), and (3) hand-fill (HF). Treatments were evaluated based on the time required for preparation, observed contamination, and multi-vial precision. The worst-case observed contamination was 4.5% of sample volume. Our empirical estimate showed that this level of contamination results in an error of 1.7 per thousand for samples with near-ambient CO2 concentrations and isotopic values that followed a high-concentration carbonate reference with an isotope ratio of -47 per thousand (IAEA-CO-9). This carry-over contamination on the Gasbench can be reduced by placing a helium-filled vial between the standard and the succeeding sample or by ignoring the first two of five sample peaks generated by each analysis. High-precision (SD < or = 0.1 per thousand) results with no detectable room-air contamination were observed for AFF and VBF treatments. In contrast, the precision of HF treatments was lower (SD > or = 0.2 per thousand). VBF was optimal for the preparation of gas samples, as it yielded faster throughput at similar precision to AFF.

Evaluation of Hypertension As a Marker of Bevacizumab Efficacy

Journal of Gastrointestinal Cancer. 2009  |  Pubmed ID: 19921473

Predictive factors for efficacy of vascular endothelial growth factor pathway-targeted therapies have not been identified or confirmed. Hypertension has been observed as a side effect to anti-vascular endothelial growth factor therapy. The goal of our study was to retrospectively assess if hypertension induced during treatment with bevacizumab was associated with clinical outcome in metastatic colorectal cancer patients treated with bevacizumab.

International Study of the Prevalence and Outcomes of Infection in Intensive Care Units

JAMA : the Journal of the American Medical Association. Dec, 2009  |  Pubmed ID: 19952319

Infection is a major cause of morbidity and mortality in intensive care units (ICUs) worldwide. However, relatively little information is available about the global epidemiology of such infections.

Comparison of Flat-panel Digital to Conventional Film-screen Radiography in Detection of Experimentally Created Lesions of the Equine Third Metacarpal Bone

Veterinary Radiology & Ultrasound : the Official Journal of the American College of Veterinary Radiology and the International Veterinary Radiology Association. Nov-Dec, 2009  |  Pubmed ID: 19999339

Radiographic diagnosis of equine bone disease using digital radiography is prevalent in veterinary practice. However, the diagnostic quality of digital vs. conventional radiography has not been compared systematically. We hypothesized that digital radiography would be superior to film-screen radiography for detection of subtle lesions of the equine third metacarpal bone. Twenty-four third metacarpal bones were collected from horses euthanized for reasons other than orthopedic disease. Bones were dissected free of soft tissue and computed tomography was performed to ensure that no osseous abnormalities were present. Subtle osseous lesions were produced in the dorsal cortex of the third metacarpal bones, and the bones were radiographed in a soft tissue phantom using indirect digital and conventional radiography at standard exposures. Digital radiographs were printed onto film. Three Diplomates of the American College of Veterinary Radiology evaluated the radiographs for the presence or absence of a lesion. Receiver operator characteristic curves were constructed, and the area under these curves were compared to assess the ability of the digital and film-screen radiographic systems to detect lesions. The area under the ROC curves for film-screen and digital radiography were 0.87 and 0.90, respectively (P = 0.59). We concluded that the digital radiographic system was comparable to the film-screen system for detection of subtle lesions of the equine third metacarpal bone.

An Exploratory Study of the Characteristics of an Admired Leader

U.S. Army Medical Department Journal. Oct-Dec, 2009  |  Pubmed ID: 20073356

Vascular Endothelial Growth Factor Plus Epidermal Growth Factor Receptor Dual Targeted Therapy in Metastatic Colorectal Cancer: Synergy or Antagonism?

Journal of Oncology. 2009  |  Pubmed ID: 20016807

There has been an intensive effort to develop novel therapies for the treatment of metastatic colorectal cancer (mCRC). The anti-epidermal growth factor receptor (EGFR) antibodies panitumumab and cetuximab and the anti-vascular endothelial growth factor (VEGF) antibody bevacizumab have demonstrated clinical efficacy and acceptable toxicity in the treatment of mCRC as single agents or in combination with chemotherapy. Recent clinical trials have explored the efficacy and safety of treatment regimens incorporating chemotherapy in combination with bevacizumab and either panitumumab or cetuximab in patients with mCRC. Results from the BOND-2 trial, which investigated cetuximab, bevacizumab, and chemotherapy in mCRC, provided support for this therapeutic approach. Two large randomized phase 3 trials were initiated to evaluate firstline treatment of mCRC. The Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study investigated the efficacy and safety of oxaliplatin- or irinotecan-based chemotherapy and bevacizumab with or without panitumumab; CAIRO2 assessed the efficacy and safety of capecitabine/oxaliplatin and bevacizumab with or without cetuximab. In both trials, the combination of bevacizumab, an EGFR-specific antibody, and chemotherapy in first-line treatment of mCRC was associated with increased toxicity and no improvement in patient outcome. These results suggest that these specific combinations should not be used in first-line mCRC outside investigational studies.

CAGS and ACS Evidence Based Reviews in Surgery. 31. The Use of Intensive Insulin Therapy and Pentastarch Resuscitation in Patients with Severe Sepsis

Canadian Journal of Surgery. Journal Canadien De Chirurgie. Dec, 2009  |  Pubmed ID: 20011189

Accomplishments in 2008 in the Adjuvant Treatment of Colon Cancer

Gastrointestinal Cancer Research : GCR. Sep, 2009  |  Pubmed ID: 20011560

Overview of the Disease IncidencePrognosisCurrent General Therapy Standards StagingLymph Node ExcisionStage III DiseaseStage II DiseaseMolecular MarkersAccomplishments During the Year Therapy Cytotoxic ChemotherapyChemotherapy Plus Targeted TherapySpecial PopulationsBasic Science-BiomarkersMethodologyWhat Needs to Be Done Application of the AccomplishmentsControversies and DisagreementsFuture Directions Comments on ResearchObstacles to Progress.

Assessing the Educational Needs of Canadian Gastroenterologists and Gastroenterology Nurses: Challenges to Optimal Care in Crohn's Disease

Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. Dec, 2009  |  Pubmed ID: 20011732

A national needs assessment of Canadian gastroenterologists and gastroenterology nurses was undertaken to determine the perceived and unperceived educational and performance barriers to caring for patients with Crohn's disease (CD).

Serum 25-hydroxyvitamin D is Independently Associated with High-density Lipoprotein Cholesterol and the Metabolic Syndrome in Men and Women

Journal of Clinical Lipidology. Aug, 2009  |  Pubmed ID: 21291826

Low vitamin D status has been associated with markers of cardiovascular disease risk.

A Comprehensive Catalogue of Somatic Mutations from a Human Cancer Genome

Nature. Jan, 2010  |  Pubmed ID: 20016485

All cancers carry somatic mutations. A subset of these somatic alterations, termed driver mutations, confer selective growth advantage and are implicated in cancer development, whereas the remainder are passengers. Here we have sequenced the genomes of a malignant melanoma and a lymphoblastoid cell line from the same person, providing the first comprehensive catalogue of somatic mutations from an individual cancer. The catalogue provides remarkable insights into the forces that have shaped this cancer genome. The dominant mutational signature reflects DNA damage due to ultraviolet light exposure, a known risk factor for malignant melanoma, whereas the uneven distribution of mutations across the genome, with a lower prevalence in gene footprints, indicates that DNA repair has been preferentially deployed towards transcribed regions. The results illustrate the power of a cancer genome sequence to reveal traces of the DNA damage, repair, mutation and selection processes that were operative years before the cancer became symptomatic.

A Small-cell Lung Cancer Genome with Complex Signatures of Tobacco Exposure

Nature. Jan, 2010  |  Pubmed ID: 20016488

Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

The Incidence of Norovirus-associated Gastroenteritis Outbreaks in Victoria, Australia (2002-2007) and Their Relationship with Rainfall

International Journal of Environmental Research and Public Health. Jul, 2010  |  Pubmed ID: 20717541

The relationship between the incidence of norovirus-associated gastroenteritis outbreaks (NAGOs) in Victoria, Australia for the period 2002-2007 and rainfall was examined. Statistical analysis involving the correlation between time series indicated that there was a statistically significant (p < 0.05) correlation between monthly NAGO incidence and average monthly rainfall. There was a lag of an average of about three months between peak average rainfall and a NAGO epidemic. The findings thus indicate rainfall can influence NAGO incidence. In an era where there is concern about the potential effects of global warming on weather patterns, it should be borne in mind that future changes in NAGO incidence may reflect altered world weather patterns.

Safety of Capecitabine: a Review

Expert Opinion on Drug Safety. Sep, 2010  |  Pubmed ID: 20722491

Fluoropyrimidines, in particular 5-fluorouracil (5-FU), have been the mainstay of treatment for several solid tumors, including colorectal, breast and head and neck cancers, for > 40 years.

Preexisting Immunity and Low Expression in Primates Highlight Translational Challenges for Liver-directed AAV8-mediated Gene Therapy

Molecular Therapy : the Journal of the American Society of Gene Therapy. Nov, 2010  |  Pubmed ID: 20736932

Liver-directed gene therapy with adeno-associated virus (AAV) vectors effectively treats mouse models of lysosomal storage diseases (LSDs). We asked whether these results were likely to translate to patients. To understand to what extent preexisting anti-AAV8 antibodies could impede AAV8-mediated liver transduction in primates, commonly preexposed to AAV, we quantified the effects of preexisting antibodies on liver transduction and subsequent transgene expression in mouse and nonhuman primate (NHP) models. Using the highest viral dose previously reported in a clinical trial, passive transfer of NHP sera containing relatively low anti-AAV8 titers into mice blocked liver transduction, which could be partially overcome by increasing vector dose tenfold. Based on this and a survey of anti-AAV8 titers in 112 humans, we predict that high-dose systemic gene therapy would successfully transduce liver in >50% of human patients. However, although high-dose AAV8 administration to mice and monkeys with equivalent anti-AAV8 titers led to comparable liver vector copy numbers, the resulting transgene expression in primates was ~1.5-logs lower than mice. This suggests vector fate differs in these species and that strategies focused solely on overcoming preexisting vector-specific antibodies may be insufficient to achieve clinically meaningful expression levels of LSD genes using a liver-directed gene therapy approach in patients.

Demographic Characteristics of Horses Donated to the North Carolina State University Equine Health Center, 1996-2008

Journal of the American Veterinary Medical Association. Jun, 2010  |  Pubmed ID: 20550449

To determine demographic characteristics of horses donated to the North Carolina State University Equine Health Center (EHC) between 1996 and 2008.

Inhibition of Glycogen Biosynthesis Via MTORC1 Suppression As an Adjunct Therapy for Pompe Disease

Molecular Genetics and Metabolism. Aug, 2010  |  Pubmed ID: 20554235

Pompe disease, also known as glycogen storage disease (GSD) type II, is caused by deficiency of lysosomal acid alpha-glucosidase (GAA). The resulting glycogen accumulation causes a spectrum of disease severity ranging from a rapidly progressive course that is typically fatal by 1-2years of age to a more slowly progressive course that causes significant morbidity and early mortality in children and adults. Recombinant human GAA (rhGAA) improves clinical outcomes with variable results. Adjunct therapy that increases the effectiveness of rhGAA may benefit some Pompe patients. Co-administration of the mTORC1 inhibitor rapamycin with rhGAA in a GAA knockout mouse reduced muscle glycogen content more than rhGAA or rapamycin alone. These results suggest mTORC1 inhibition may benefit GSDs that involve glycogen accumulation in muscle.

A Role for P11 in the Antidepressant Action of Brain-derived Neurotrophic Factor

Biological Psychiatry. Sep, 2010  |  Pubmed ID: 20591415

The protein p11 (also called S100A10) is downregulated in human and rodent depressive-like states. Considerable experimental evidence also implicates p11 in the mechanism of action of antidepressant drugs and electroconvulsive seizures, in part due to its interaction with specific serotonin receptors. Brain-derived neurotrophic factor (BDNF) has been linked to the therapeutic activity of antidepressants in rodent models and humans. In the current study, we investigated whether BDNF regulates p11 in vitro and in vivo.

Regulation of Apoptosis and Priming of Neutrophil Oxidative Burst by Diisopropyl Fluorophosphate

Journal of Inflammation (London, England). 2010  |  Pubmed ID: 20609247

Diisopropyl fluorophosphate (DFP) is a serine protease inhibitor that is widely used as an inhibitor of endogenous proteases in in vitro neutrophil studies. Its effects on neutrophil function are unclear. We sought to determine the biological effects of DFP on human neutrophil apoptosis and oxidative burst.

High-resolution in Vivo Imaging of Breast Cancer by Targeting the Pro-invasive Integrin Alphavbeta6

The Journal of Pathology. Sep, 2010  |  Pubmed ID: 20629113

The integrin alphavbeta6 is expressed only on epithelia and then usually only during processes of tissue remodelling including cancer, where its high expression correlates with reduced survival. Thus, alphavbeta6 represents an important target for imaging and therapy of cancer and new molecular-specific targeting agents are required. We have developed A20FMDV2, a peptide derived from the VP1 coat protein of foot-and-mouth-disease virus that binds specifically and stably to alphavbeta6. Using a newly generated pair of isogenic human cell lines that differ only in alphavbeta6 expression, it was shown, using biodistribution and SPECT imaging, that indium-111-labelled A20FMDV2 locates specifically to alphavbeta6-expressing tissues in vivo, achieving at least seven-times higher retention in alphavbeta6-positive than in alphavbeta6-negative tumours. In further studies with MCF10.DCIS.COM and MCF10A.CA1a breast carcinoma cell lines, which express alphavbeta6 endogenously, the radiopeptide achieved similar levels of tumour retention and permitted excellent discriminatory imaging of tumours. Thus, A20FMDV2 can be used for molecular-specific targeting of alphavbeta6 for imaging in vivo the often more aggressive, alphavbeta6-positive cancers. In the future, A20FMDV2 could serve also to deliver therapy to these same cancers.

Dissecting the Transcriptional Networks Underlying Breast Cancer: NR4A1 Reduces the Migration of Normal and Breast Cancer Cell Lines

Breast Cancer Research : BCR. 2010  |  Pubmed ID: 20642837

Breast cancer currently accounts for more than one-quarter of all female cancers and, despite the great progress in treatment observed in the past few years, the need for identification of new gene targets that can be used for diagnosis, prognosis and therapy is evident. A previous study identified the transcription factor NR4A1 as a gene upregulated in primary breast cancer compared with normal tissue by microarray analysis and sequencing technologies. The purpose of the study was to identify the role of NR4A1 in normal mammary epithelial and breast cancer cell biology.

In Vitro Lens Capsule Model for Investigation of Posterior Capsule Opacification

Journal of Cataract and Refractive Surgery. Aug, 2010  |  Pubmed ID: 20656145

A modified dissection technique of donor eyes for investigating posterior capsule opacification (PCO) that preserves normal capsule and zonule architecture is described. The intact crystalline lens-zonule-ciliary body complex is dissected from the globe in one piece and pinned with 8 entomological pins through the ciliary body to a soft silicone ring with an internal diameter of 12.7 mm. The specimen is iridectomized and cataract extraction performed; the specimen is then placed in culture. The capsule is supported by the native zonules and suspended freely within culture medium. The entire capsular bag is visible, allowing observation of lens epithelial cell (LEC) growth. In 15 eyes of 13 donors, the mean time to LEC confluence was 10.4 days +/- 1.4 [SD]. This technique builds on previous capsular bag models, providing a more physiological model for observation of PCO in vitro. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

The Cartagena Protocol and Genetically Modified Mosquitoes

Nature Biotechnology. Sep, 2010  |  Pubmed ID: 20829820

Two-dimensional Heteronuclear Saturation Transfer Difference NMR Reveals Detailed Integrin αvβ6 Protein-peptide Interactions

Chemical Communications (Cambridge, England). Oct, 2010  |  Pubmed ID: 20838674

We report the first example of peptide-protein heteronuclear two-dimensional (2D) saturation transfer difference nuclear magnetic resonance (STD NMR). This method, resulting in dramatically reduced overlap, was applied to the interaction of the integrin αvβ6 with a known peptide ligand and highlights novel contact points between the substrate and target protein.

H1N1: Communication Patterns Among Emergency Department Staff During the H1N1 Outbreak, April 2009

Prehospital and Disaster Medicine. Jul-Aug, 2010  |  Pubmed ID: 20845313

The H1N1 influenza virus has been described by the World Health Organization (WHO) and the media as a disease that could rival the 1918 Spanish Influenza epidemic in deaths. During the spring of 2009, emergency departments across the world saw a spike in the number of influenza cases and by June 2009, the WHO had declared H1N1 a pandemic. In order to prevent emergency department staff from becoming ill and to provide up-to-date medical care to patients, information had to be disseminated quickly to emergency department staff.

Statistical Analysis Plan of PROWESS SHOCK Study

Intensive Care Medicine. Nov, 2010  |  Pubmed ID: 20689934

Multi-modality Therapy for Metastatic Colorectal Cancer-ready for Prime Time?

The American Surgeon. Jul, 2010  |  Pubmed ID: 20698392

Norovirus GII.4 Variant 2006b Caused Epidemics of Acute Gastroenteritis in Australia During 2007 and 2008

Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology. Dec, 2010  |  Pubmed ID: 20888289

Over the last decade, four epidemics of norovirus-associated gastroenteritis have been reported in Australia. These epidemics were characterized by numerous outbreaks in institutional settings such as hospitals and nursing homes, as well as increases in requests for NoV testing in diagnostic centers. During 2007 and 2008, widespread outbreaks of acute gastroenteritis were once again seen across Australia, peaking during the winter months.

Betel-derived Alkaloid Up-regulates Keratinocyte Alphavbeta6 Integrin Expression and Promotes Oral Submucous Fibrosis

The Journal of Pathology. Sep, 2010  |  Pubmed ID: 20976685

Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7-13%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As αvβ6 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. αvβ6 was markedly up-regulated in OSF, with high expression detected in 22 of 41 cases (p < 0.001). We investigated the functional role of αvβ6 using oral keratinocyte-derived cells genetically modified to express high αvβ6 (VB6), and also NTERT-immortalized oral keratinocytes, which express low αvβ6 (OKF6/TERT-1). VB6 cells showed significant αvβ6-dependent activation of TGF-β1, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up-regulation of genes associated with tissue fibrosis. These experimental in vitro findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF-β1-dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up-regulated keratinocyte αvβ6 expression. This was modulated through the M(4) muscarinic acetylcholine receptor and was suppressed by the M(4) antagonist, tropicamide. Arecoline-dependent αvβ6 up-regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF-related oral cancers examined had moderate/high αvβ6 expression. These data suggest that the pathogenesis of OSF may be epithelial-driven and involve arecoline-dependent up-regulation of αvβ6 integrin. Copyright © 2010 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mass Spectrometry of Peptides and Proteins from Human Blood

Mass Spectrometry Reviews. Nov, 2010  |  Pubmed ID: 21046662

It is difficult to convey the accelerating rate and growing importance of mass spectrometry applications to human blood proteins and peptides. Mass spectrometry can rapidly detect and identify the ionizable peptides from the proteins in a simple mixture and reveal many of their post-translational modifications. However, blood is a complex mixture that may contain many proteins first expressed in cells and tissues. The complete analysis of blood proteins is a daunting task that will rely on a wide range of disciplines from physics, chemistry, biochemistry, genetics, electromagnetic instrumentation, mathematics and computation. Therefore the comprehensive discovery and analysis of blood proteins will rank among the great technical challenges and require the cumulative sum of many of mankind's scientific achievements together. A variety of methods have been used to fractionate, analyze and identify proteins from blood, each yielding a small piece of the whole and throwing the great size of the task into sharp relief. The approaches attempted to date clearly indicate that enumerating the proteins and peptides of blood can be accomplished. There is no doubt that the mass spectrometry of blood will be crucial to the discovery and analysis of proteins, enzyme activities, and post-translational processes that underlay the mechanisms of disease. At present both discovery and quantification of proteins from blood are commonly reaching sensitivities of ∼1 ng/mL. © 2010 Wiley Periodicals, Inc. Mass Spec Rev.

Role of Probiotics in Management of Diverticular Disease

Journal of Gastroenterology and Hepatology. Dec, 2010  |  Pubmed ID: 21091992

Patients with diverticular disease may experience a variety of chronic symptoms, including abdominal discomfort, bloating, and altered bowel habit. They are also at risk of complications, including hemorrhage, diverticulitis, abscess, and fistula formation. The potential role of abnormal colonic microflora in the pathogenesis of diverticular inflammation has led to investigation of novel therapies such as probiotics. Probiotics are microorganisms that may be of net benefit to humans when consumed. The rationale and safety of their use in diverticular disease is discussed and current literature is reviewed.

CAGS and ACS Evidence Based Reviews in Surgery. 35: Efficacy and Safety of Low-dose Hydrocortisone Therapy in the Treatment of Septic Shock

Canadian Journal of Surgery. Journal Canadien De Chirurgie. Dec, 2010  |  Pubmed ID: 21092435

To evaluate the efficacy and safety of low-dose hydrocortisone therapy in patients with septic shock.

Substrate Reduction Augments the Efficacy of Enzyme Therapy in a Mouse Model of Fabry Disease

PloS One. 2010  |  Pubmed ID: 21124789

Fabry disease is an X-linked glycosphingolipid storage disorder caused by a deficiency in the activity of the lysosomal hydrolase α-galactosidase A (α-gal). This deficiency results in accumulation of the glycosphingolipid globotriaosylceramide (GL-3) in lysosomes. Endothelial cell storage of GL-3 frequently leads to kidney dysfunction, cardiac and cerebrovascular disease. The current treatment for Fabry disease is through infusions of recombinant α-gal (enzyme-replacement therapy; ERT). Although ERT can markedly reduce the lysosomal burden of GL-3 in endothelial cells, variability is seen in the clearance from several other cell types. This suggests that alternative and adjuvant therapies may be desirable. Use of glucosylceramide synthase inhibitors to abate the biosynthesis of glycosphingolipids (substrate reduction therapy, SRT) has been shown to be effective at reducing substrate levels in the related glycosphingolipidosis, Gaucher disease. Here, we show that such an inhibitor (eliglustat tartrate, Genz-112638) was effective at lowering GL-3 accumulation in a mouse model of Fabry disease. Relative efficacy of SRT and ERT at reducing GL-3 levels in Fabry mouse tissues differed with SRT being more effective in the kidney, and ERT more efficacious in the heart and liver. Combination therapy with ERT and SRT provided the most complete clearance of GL-3 from all the tissues. Furthermore, treatment normalized urine volume and uromodulin levels and significantly delayed the loss of a nociceptive response. The differential efficacies of SRT and ERT in the different tissues indicate that the combination approach is both additive and complementary suggesting the possibility of an improved therapeutic paradigm in the management of Fabry disease.

Principles of Source Control in the Early Management of Sepsis

Current Infectious Disease Reports. Sep, 2010  |  Pubmed ID: 21308516

Source control refers to the spectrum of physical measures that are undertaken to control a focus of infection, and to facilitate restoration of optimal anatomy and physiology. These measures are classified as drainage-the evacuation of infected liquid through the creation of a controlled sinus or fistula, debridement-the physical removal of necrotic infected tissue, device removal, and the definitive measures that comprise the process of reconstruction and rehabilitation. Effective and timely source control is critical to the successful management of life-threatening infection. This article reviews the principles of diagnosis and source-control management, and their application to common infections that result in severe sepsis and septic shock.

Critical Illness is an Iatrogenic Disorder

Critical Care Medicine. Oct, 2010  |  Pubmed ID: 21164401

Iatrogenic illnesses are those that arise as a result of the process of medical care and are potentially preventable by improvements to patient care. The term is commonly used to denote medical error; however, for the critically ill patient the term has a much more fundamental meaning. Critical illness is inherently iatrogenic: it only develops in those patients who have been resuscitated from an otherwise life-threatening disorder, and its subsequent evolution is shaped by the beneficial and adverse consequences of therapeutic and supportive interventions. The construct of organ dysfunction describes both the nature of this support and its inadvertent consequences. This review explores evolving evidence on the iatrogenic nature of critical illness and the implications of an iatrogenic model of disease on the taxonomy, management, and prevention of the complex processes that threaten to limit the survival of the critically ill patient.

Stromal Features Are Predictive of Disease Mortality in Oral Cancer Patients

The Journal of Pathology. Nov, 2010  |  Pubmed ID: 21207486

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6-dependent TGF-β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

From the Bedside Back to the Bench: the Role of Preclinical Studies in Understanding Clinical Therapies

Critical Care Medicine. Jan, 2010  |  Pubmed ID: 20023488

Clinical Research Ethics for Critically Ill Patients: a Pandemic Proposal

Critical Care Medicine. Apr, 2010  |  Pubmed ID: 20029349

Pandemic H1N1 influenza is projected to be unprecedented in its scope, causing acute critical illness among thousands of young otherwise healthy adults, who will need advanced life support. Rigorous, relevant, timely, and ethical clinical and health services research is crucial to improve their care and outcomes. Studies designed and conducted during a pandemic should be held to the same high methodologic and implementation standards as during other times. However, unique challenges arise with the need to conduct investigations as efficiently as possible, focused on the optimal outcome for the individual patient, while balancing the need for maximal societal benefit. We believe that clinical critical care research during a pandemic must be approached differently from research undertaken under nonemergent circumstances. We propose recommendations to clinical investigators and research ethics committees regarding clinical and health services research on pandemic-related critical illness. We also propose strategies such as expedited and centralized research ethics committee reviews and alternate consent models.

Precipitation and Selective Extraction of Human Serum Endogenous Peptides with Analysis by Quadrupole Time-of-flight Mass Spectrometry Reveals Posttranslational Modifications and Low-abundance Peptides

Analytical and Bioanalytical Chemistry. Feb, 2010  |  Pubmed ID: 20033139

The endogenous peptides of human serum may have regulatory functions, have been associated with physiological states, and their modifications may reveal some mechanisms of disease. In order to correlate levels of specific peptides with disease alongside internal standards, the polypeptides must first be reliably extracted and identified. Endogenous blood peptides can be effectively enriched by precipitation of the serum with organic solvents followed by selective extraction of peptides using aqueous solutions modified with organic solvents. Polypeptides on filter paper were assayed with Coomasie brilliant blue binding. The polypeptides were resolved by detergent tricine polyacrylamide electrophoresis and visualized by diamine silver staining. Peptides in the extracts were collected by C18 and analyzed by matrix-assisted laser desorption/ionization and liquid chromatography-electrospray ionization-tandem mass spectrometry (MS/MS) quadrupole time-of-flight MS/MS. Peptides were resolved as multiple isotopic peaks in MS mode with mass deviation of 0.1 Da or less and similar accuracy for fragments. The sensitivity of MS and MS/MS analysis was estimated to be in the picomolar range or less. The peptide composition of the extracts was dependent on solvent formulation. Multiple peptides from apolipoproteins, complement proteins, coagulation factors, and many others were identified by X!Tandem with high mass accuracy of peptide ions and fragments from collision-induced dissociation. Many previously unreported posttranslational modifications of peptides including phosphorylations, oxidations, glycosylations, and others were detected with high mass accuracy and may be of clinical importance. About 4,630 redundant peptides were identified with 99% confidence separately, and together some 1,251 distinct proteins were identified with 99% confidence or greater using the Paragon algorithm.

The Surviving Sepsis Campaign: Results of an International Guideline-based Performance Improvement Program Targeting Severe Sepsis

Critical Care Medicine. Feb, 2010  |  Pubmed ID: 20035219

The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations.

Increased Sequestration of Matrix Metalloproteinases in Ageing Human Bruch's Membrane: Implications for ECM Turnover

Investigative Ophthalmology & Visual Science. May, 2010  |  Pubmed ID: 20042661

The ageing of Bruch's membrane is associated with progressive reduction in the degradation of the capacity for ECM turnover mediated by the matrix metalloproteinase (MMP) system. In this study, the free and bound pools of all gelatinase species were quantified to aid in assessing the likelihood of reduced availability of pro-MMPs for activation in ageing Bruch's membrane.

Genetic Risk Factors for Post-infectious Irritable Bowel Syndrome Following a Waterborne Outbreak of Gastroenteritis

Gastroenterology. Apr, 2010  |  Pubmed ID: 20044998

Acute gastroenteritis is the strongest risk factor for irritable bowel syndrome (IBS). In May 2000, >2300 residents of Walkerton, Ontario, developed gastroenteritis from microbial contamination of the municipal water supply; a longitudinal study found that >36.2% of these developed IBS. We used this cohort to study genetic susceptibility to post-infectious (PI)-IBS.

The Surviving Sepsis Campaign: Results of an International Guideline-based Performance Improvement Program Targeting Severe Sepsis

Intensive Care Medicine. Feb, 2010  |  Pubmed ID: 20069275

The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes.

Eight Year Prognosis of Postinfectious Irritable Bowel Syndrome Following Waterborne Bacterial Dysentery

Gut. May, 2010  |  Pubmed ID: 20427395

Although postinfectious irritable bowel syndrome (PI-IBS) is a well-recognised complication of acute gastroenteritis, its prognosis remains poorly defined. The natural history of PI-IBS was assessed among participants in the Walkerton Health Study (WHS), which has followed the long-term effects of a large outbreak of acute gastroenteritis related to municipal water contamination in May 2000.

Pilot Study of New Focus-shift Accommodating Intraocular Lens

Journal of Cataract and Refractive Surgery. May, 2010  |  Pubmed ID: 20457367

To determine the visual and accommodative performance of the OPAL-A focus-shift accommodating intraocular lens (IOL).

Anterior Chamber Depth Measurements in Eyes with an Accommodating Intraocular Lens: Agreement Between Partial Coherence Interferometry and Optical Coherence Tomography

Journal of Cataract and Refractive Surgery. May, 2010  |  Pubmed ID: 20457371

To determine agreement between partial coherence interferometry (PCI) and anterior segment optical coherence tomography (AS-OCT) measurements of anterior chamber depth (ACD) and axial intraocular lens (IOL) movement in eyes with an accommodating IOL.

Perspectives of People in Mali Toward Genetically-modified Mosquitoes for Malaria Control

Malaria Journal. 2010  |  Pubmed ID: 20470410

Genetically-modified (GM) mosquitoes have been proposed as part of an integrated vector control strategy for malaria control. Public acceptance is essential prior to field trials, particularly since mosquitoes are a vector of human disease and genetically modified organisms (GMOs) face strong scepticism in developed and developing nations. Despite this, in sub-Saharan Africa, where the GM mosquito effort is primarily directed, very little data is available on perspectives to GMOs. Here, results are presented of a qualitative survey of public attitudes to GM mosquitoes for malaria control in rural and urban areas of Mali, West Africa between the months of October 2008 and June 2009.

Endotoxin in the Pathogenesis of Sepsis

Contributions to Nephrology. 2010  |  Pubmed ID: 20519894

The word 'sepsis' is a descriptive term that denotes the clinical syndrome resulting from the activation of an innate host response to infection. Sepsis is a useful concept that underlines the fact that the morbidity of serious infection arises through the response of the host, rather than through intrinsic cytopathic effects of the microorganism. However, it has proven inadequate as a means to delineate a population of patients who might benefit from therapies that modulate this response. The syndrome is variable in its clinical expression, and not specific for infection as a cause. Emerging insights into the biology of the innate host immune response reveal that the cellular response can be evoked by a variety of stimuli - including both microbial products and host-derived molecules that are normally intracellular - that signal danger to the host. The disconnect between concept and disease that has hampered the conduct of clinical trials is nicely exemplified in the host response to endotoxin. Endotoxemia occurs in many patients with sepsis, but also in many clinical settings that are noninfectious in nature. Moreover, the biologic behavior of endotoxin resembles that of a hormone more than that of a toxin, suggesting that low level endotoxemia may, under some circumstances, be beneficial. Future studies of antiendotoxin strategies in acute illness are more likely to succeed if they recruit patients with endotoxemia, and titrate therapy to an optimal level.

IgG₄-related Sclerosing Disease: a Novel Mimic of Inflammatory Bowel Disease

Digestive Diseases and Sciences. Nov, 2010  |  Pubmed ID: 20521111

High levels of IgG₄-positive plasma cells are commonly seen in autoimmune pancreatitis. It has recently become evident that autoimmune pancreatitis is one component of a larger multi-system disease. IgG₄-positive plasma cells have been identified in many extrapancreatic tissues, including the colon, biliary tract, liver, and lungs, and thus the term "IgG₄-related sclerosing disease" has been proposed. Awareness of IgG₄-related sclerosing disease is important, as it has been shown to mimic other conditions like malignancy. This review discusses IgG₄-related colitis and its potential for mimicking inflammatory bowel disease.

The Surviving Sepsis Campaign: a History and a Perspective

Surgical Infections. Jun, 2010  |  Pubmed ID: 20524900

The Surviving Sepsis Campaign (SSC) was launched in 2002 as a collaborative initiative of the European Society of Intensive Care Medicine (ESICM), the International Sepsis Forum (ISF), and the Society of Critical Care Medicine (SCCM). Its objective was, through the development and promulgation of evidence-based guidelines that facilitated the application of knowledge derived from clinical trials to bedside practice, to effect a 25% reduction in the relative risk of death from severe sepsis and septic shock.

Phase I Dose Finding Studies of Obatoclax (GX15-070), a Small Molecule Pan-BCL-2 Family Antagonist, in Patients with Advanced Solid Tumors or Lymphoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Aug, 2010  |  Pubmed ID: 20538761

Two phase I, single-agent studies were conducted to determine the dose and regimen of obatoclax, an antagonist of all BCL-2 antiapoptotic proteins, for evaluation in phase II trials. The two studies, GX001 and GX005, evaluated the safety and tolerability of weekly 1-hour and 3-hour infusions of obatoclax, respectively.

Pancreatic Cancer Organotypic Cultures

Journal of Biotechnology. Jul, 2010  |  Pubmed ID: 20083148

Pancreatic cancer, the fourth most common cause of cancer-related death, is a devastating disease with poor prognosis. Over the last four decades, no effective new treatments have been developed for this cancer. As a result, its prognosis has remained unchanged. Appropriate cancer models, representing all aspects of pancreatic cancer, will enhance our understanding of its biology. In this review we discuss the evolution and merit of organotypic culture models. These co-culture in vitro systems of cancer and stromal cells grown within, or on top of, reconstituted extracellular matrix gels model pancreatic cancer more realistically than 2D systems. Different methodologies are discussed which enable interrogation of various hypotheses examining the tumour-stroma cross-talk. Thus this validated organotypic culture model provides a system, which can be easily manipulated and used to test (novel) treatment options targeting the cancer, the stromal compartment or both, in a physiologically relevant environment. The big challenge for future research is to expand this model further so that its mimicry of the human tumour is more robust. This will increase our understanding of the biology of this aggressive tumour; ultimately resulting in improved therapies and, therefore, a better prognosis.

Molecular Changes Associated with Altered Patterns of Norovirus Outbreak Epidemics in Victoria, Australia, in 2006 to 2007

Journal of Clinical Microbiology. Mar, 2010  |  Pubmed ID: 20089762

Noroviruses (NoVs) are now considered the most common cause of outbreaks of nonbacterial gastroenteritis, but the factors which control the incidence of NoVs are poorly understood. In 2006, the pattern of NoV outbreak epidemics in Victoria, Australia, changed compared to the pattern for 2002 to 2005 and 2007. This study examined molecular correlates of the changed NoV periodicity. For the period of 2002 to 2007, 8,507 fecal specimens from 1,495 gastroenteritis outbreaks were tested for NoV by reverse transcription-PCR, and 1,018 NoV outbreaks were identified. Nucleotide sequence analysis was used to define genotypes and GII.4 variants. For 2002 to 2007, GII.4 was the predominant genotype. For the period of 2002 to 2005 and 2007, a single NoV outbreak epidemic occurred in warmer months of each year, but in 2006 two epidemics occurred in 1 year, one in colder months and one in warmer months of the year. For 2002 to 2007, four major GII.4 variants, "2002 Oxford/Farmington Hills," "2004 Hunter," "2006a," and "2006b," were identified. Each NoV outbreak epidemic was linked principally to one of these four variants, and there was a time link, a delay of 2 to 6 months, between the first detection of a GII.4 variant and the first outbreak epidemic in which it was the principal variant. The unusual 2006 pattern of outbreak epidemics can then be correlated with the appearance of two GII.4 variants within a short space of time, resulting in two outbreak epidemics in a short space of time, i.e., in the 1 year. This study provides a potentially greater ability to predict the characteristics of NoV epidemics.

Rectal 5-aminosalicylic Acid for Induction of Remission in Ulcerative Colitis

Cochrane Database of Systematic Reviews (Online). 2010  |  Pubmed ID: 20091560

5-Aminosalicylates (5-ASA) are considered a first-line therapy for inducing and maintaining remission of mild to moderately active ulcerative colitis (UC). When inflammation in UC is limited to the distal colon, 5-ASA can also be administered rectally as a suppository, enema or foam.

Inflammation-dependent Alpha 5 Beta 1 (very Late Antigen-5) Expression on Leukocytes Reveals a Functional Role for This Integrin in Acute Peritonitis

Journal of Leukocyte Biology. May, 2010  |  Pubmed ID: 20097849

The potential role of alpha 5 beta 1 (VLA-5) in leukocyte trafficking in zymosan-induced acute peritonitis was determined. In naïve mice, approximately 98% of Gr1(high) cells (PMN) in bone marrow and circulation were alpha 5 beta 1-negative; these profiles were modestly affected by peritoneal injection of zymosan. In contrast, approximately 30% of Gr1(high) cells recruited by zymosan (24 h) to the peritoneal cavity expressed alpha 5 beta 1. With respect to F4/80(+) cells, approximately 60% of bone marrow and peripheral blood populations expressed alpha 5 beta 1, with approximately 90% positivity in resident cells of noninflamed peritoneum. Analysis of alpha 5 beta 1 expression revealed inflammation-dependent increased expression on Gr1(high) and F4/80(+) cells in bone marrow, blood, and peritoneal cavity. Blockade of alpha 5 beta 1, by an anti-alpha 5 mAb, attenuated zymosan-induced 24 h recruitment of Gr1(high) and F4/80(+) cells. At least one underlying mechanism of this action was reduction of cell adhesion and transmigration across microvascular vessels, as revealed by intravital microscopy. Confocal analyses indicated that deposition of fibronectin, the principal ligand for alpha 5 beta 1, was up-regulated significantly on and around the inflamed mesenteric microvasculature. These data suggest that the effects of alpha 5-blockade may be a result of inhibition of alpha 5 beta 1-dependent leukocyte adhesion to and migration along the fibronectin matrix. This is the first report that identifies a functional role for alpha 5 beta 1 in leukocyte trafficking during acute inflammation.

Early Observational Research and Registries During the 2009-2010 Influenza A Pandemic

Critical Care Medicine. Apr, 2010  |  Pubmed ID: 20101176

As a critical care community, we have an obligation to provide not only clinical care but also the research that guides initial and subsequent clinical responses during a pandemic. There are many challenges to conducting such research. The first is speed of response. However, given the near inevitability of certain events, for example, viral respiratory illness such as the 2009 pandemic, geographically circumscribed natural disasters, or acts of terror, many study and trial designs should be preplanned and modified quickly when specific events occur. Template case report forms should be available for modification and web entry; centralized research ethics boards and funders should have the opportunity to preview and advise on such research beforehand; and national and international research groups should be prepared to work together on common studies and trials for common challenges. We describe the early international critical care research response to the influenza A 2009 (H1N1) pandemic, including specifics of observational study case report form, registry, and clinical trial design, cooperation of international critical care research organizations, and the early results of these collaborations.

Prevalence of Uninvestigated Dyspepsia 8 Years After a Large Waterborne Outbreak of Bacterial Dysentery: a Cohort Study

Gastroenterology. May, 2010  |  Pubmed ID: 20117111

Symptoms of dyspepsia may occur following an episode of acute gastroenteritis, but data are conflicting. We assessed prevalence of uninvestigated dyspepsia in a cohort of individuals, some of whom were exposed to bacterial dysentery in May 2000, as well as risk factors for dyspepsia in exposed individuals.

Inhibition of Transforming Growth Factor-beta1 and Its Effects on Human Corneal Fibroblasts by Mannose-6-phosphate Potential for Preventing Haze After Refractive Surgery

Journal of Cataract and Refractive Surgery. Jan, 2010  |  Pubmed ID: 20117715

To evaluate the action of mannose-6-phosphate (M6P) as an inhibitor of transforming growth factor-beta1 (TGF-beta1) and its effects on human corneal fibroblasts.

Molecular and Epidemiological Characteristics of Norovirus Associated with Community-based Sporadic Gastroenteritis Incidents and Norovirus Outbreaks in Victoria, Australia, 2002-2007

Intervirology. 2010  |  Pubmed ID: 20130414

The molecular and epidemiological features of community-based norovirus-associated sporadic gastroenteritis incidents (NASGIs) are poorly understood. This study examined these features and compared the findings with studies of community-based and institutional norovirus-associated gastroenteritis outbreaks (NAGOs).

Should My Patient with Inflammatory Bowel Disease on Immunosuppressive Therapy Be Vaccinated Against Influenza Virus?

Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. Feb, 2010  |  Pubmed ID: 20151071

Crohn's disease and ulcerative colitis are variants of inflammatory bowel disease (IBD) for which immunosuppressive therapy is often required. Immunosuppressed patients are at increased risk for infections, including vaccine-preventable diseases such as influenza. Although several guidelines recommend routine influenza immunization for such patients, recent literature suggests that this patient population may be inadequately immunized. Current research suggests that inactivated influenza vaccines are effective, well tolerated and can be administered safely in most IBD patients. Studies in other immunosuppressed populations have also demonstrated the safety of inactivated vaccines. The present article reviews the literature regarding the safety and efficacy of influenza vaccination in IBD patients receiving immunosuppressive therapy.

Effect of Intraocular Lens Asphericity on Vertical Coma Aberration

Journal of Cataract and Refractive Surgery. Feb, 2010  |  Pubmed ID: 20152600

To analyze the effect of asphericity of intraocular lenses (IOLs) on vertical coma aberration after implantation of spherical, spherically neutral, and aspheric IOLs.

Meta Sequence Analysis of Human Blood Peptides and Their Parent Proteins

Journal of Proteomics. Apr, 2010  |  Pubmed ID: 20170764

Sequence analysis of the blood peptides and their qualities will be key to understanding the mechanisms that contribute to error in LC-ESI-MS/MS. Analysis of peptides and their proteins at the level of sequences is much more direct and informative than the comparison of disparate accession numbers. A portable database of all blood peptide and protein sequences with descriptor fields and gene ontology terms might be useful for designing immunological or MRM assays from human blood. The results of twelve studies of human blood peptides and/or proteins identified by LC-MS/MS and correlated against a disparate array of genetic libraries were parsed and matched to proteins from the human ENSEMBL, SwissProt and RefSeq databases by SQL. The reported peptide and protein sequences were organized into an SQL database with full protein sequences and up to five unique peptides in order of prevalence along with the peptide count for each protein. Structured query language or BLAST was used to acquire descriptive information in current databases. Sampling error at the level of peptides is the largest source of disparity between groups. Chi Square analysis of peptide to protein distributions confirmed the significant agreement between groups on identified proteins.

Phase 1 Experience with an Anti-glycotope Monoclonal Antibody, RAV12, in Recurrent Adenocarcinoma

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research. Mar, 2010  |  Pubmed ID: 20179219

RAV12 is a high affinity, internalizing, chimeric IgG1 monoclonal antibody that binds RAAG12, a novel primate-restricted N-linked carbohydrate epitope present on multiple cell surface proteins. RAAG12 is highly expressed on many adenocarcinomas, particularly those of gastrointestinal origin. A phase 1 dose-escalation safety and pharmacokinetics trial was conducted in patients with metastatic or recurrent adenocarcinomas.

An Outbreak of Acute Bacterial Gastroenteritis is Associated with an Increased Incidence of Irritable Bowel Syndrome in Children

The American Journal of Gastroenterology. Apr, 2010  |  Pubmed ID: 20179687

Acute bacterial gastroenteritis is associated with subsequent post-infectious irritable bowel syndrome (PI-IBS) in adults. Less is known about this relationship in children. In May 2000, contamination of municipal water by Escherichia coli 0157:H7 and Campylobacter species caused a large outbreak of acute gastroenteritis in Walkerton, Ontario. We assessed this association among a cohort of children enrolled in the Walkerton Health Study (WHS).

Keratorefractive Effect of Microwave Keratoplasty on Human Corneas

Journal of Cataract and Refractive Surgery. Mar, 2010  |  Pubmed ID: 20202547

To determine the change in dioptric power on excised human corneoscleral buttons after microwave keratoplasty application and to determine the qualitative effect on the cornea using histology and scanning electron microscopy.

The Endogenous Peptides of Normal Human Serum Extracted from the Acetonitrile-insoluble Precipitate Using Modified Aqueous Buffer with Analysis by LC-ESI-Paul Ion Trap and Qq-TOF

Journal of Proteomics. Apr, 2010  |  Pubmed ID: 20211283

Many peptides of biological or medicinal importance may be derived from proteolytic actions and are found at low concentrations in human blood fluids. Endogenous polypeptides from human serum were precipitated in acetonitrile and the precipitate was then selectively extracted with water modified by organic solvents and collected over C18 resin. Extraction of serum with C18 alone, and the acetonitrile supernatant or ultrafiltration collected over C18, served as controls. The samples were analyzed by SDS-PAGE, or C18 high pressure liquid chromatography with electrospray ionization using a Paul ion trap and Qq-TOF. Spectra were correlated without specifying an enzyme using the X!TANDEM or the Paragon algorithms. Multiple endogenous peptides from plasminogen, coagulation factors, collagens, serum amyloid, receptors, zinc finger/bromo peptide proteins, ryanodine receptor, calmodulin binding activator, erythroid differentiation factor, testes cancer antigen, extracellular matrix protein, myeloid/lymphoid leukemia 2 and many low abundance proteins were correlated by X!TANDEM with protein expect values of approximately E-16 or less. Proteins with binding sites for nucleic acids, phosphoinositides, and other cellular locations were also observed using the Qq-TOF and Paragon algorithm. Proteins with low expectation scores and overlapping peptides sequences were observed. The existence of these proteins in serum has been confirmed by tryptic digestion and LC-ESI-MS/MS. The presence of plasminogen, serum amyloid and zinc finger RNA binding proteins were confirmed by Western blot. There was agreement on the detection of endogenous peptides from low abundance proteins associated with the biology of cancer from the examination of the blood peptides by ion trap and Qq-TOF, tryptic digests of blood proteins, and Western blot.

Evaluation of Pneumonia Severity and Acute Physiology Scores to Predict ICU Admission and Mortality in Patients Hospitalized for Influenza

PloS One. 2010  |  Pubmed ID: 20221431

The demand for inpatient medical services increases during influenza season. A scoring system capable of identifying influenza patients at low risk death or ICU admission could help clinicians make hospital admission decisions.

Risk Assessment in Stage II Colorectal Cancer

Oncology (Williston Park, N.Y.). Jan, 2010  |  Pubmed ID: 20225606

In the treatment of colon cancer today, the decision-making involved in the treatment of stage II disease is probably the most challenging aspect. The major question is whether or not these patients should receive postoperative adjuvant chemotherapy. Approximately 75% of stage II colon cancer is cured by surgery alone. For the remaining 25% of cases, there is great debate over whether adjuvant chemotherapy is sufficiently effective in enough patients to warrant the exposure to potentially toxic treatments. In the important QUASAR clinical trial, stage II patients were randomized to either fluorouracil (5-FU)-based therapy or observation. The results demonstrated an approximate 3% improvement in outcome for the 5-FU-treated patients. This leads to the assumption that treating all stage II patients with adjuvant chemotherapy is gross overtreatment, when essentially 97% of these patients will not benefit. Clearly the only way to approach this decision is through risk determination. In this article, I will describe the current state of defining high- and low-risk disease, which is mainly through histopathologic characteristics, as well as discuss emerging approaches such as molecular markers and genomic profiling.

Phylogeographic Analysis and Environmental Niche Modeling of the Plain-bellied Watersnake (Nerodia Erythrogaster) Reveals Low Levels of Genetic and Ecological Differentiation

Molecular Phylogenetics and Evolution. Jun, 2010  |  Pubmed ID: 20302955

Species that exhibit geographically defined phenotypic variation traditionally have been divided into subspecies. Subspecies based on phenotypic features may not comprise monophyletic groups due to selection, gene flow, and/or convergent evolution. In many taxonomic groups the number of species once designated as widespread is dwindling rapidly, and many workers reject the concept of subspecies altogether. We tested whether currently recognized subspecies in the plain-bellied watersnake Nerodia erythrogaster are concordant with relationships based on mitochondrial markers, and whether it represents a single widespread species. The range of this taxon spans multiple potential biogeographic barriers (especially the Mississippi and Apalachicola Rivers) that correspond with lineage breaks in many species, including other snakes. We sequenced three mitochondrial genes (NADH-II, Cyt-b, Cox-I) from 156 geo-referenced specimens and developed ecological niche models using Maxent and spatially explicit climate data to examine historical and ecological factors affecting variation in N. erythrogaster across its range. Overall, we found little support for the recognized subspecies as either independent evolutionary lineages or geographically circumscribed units and conclude that although some genetic and niche differentiation has occurred, most populations assigned to N. erythrogaster appear to represent a single, widespread species. However, additional sampling and application of nuclear markers are necessary to clarify the status of the easternmost populations.

Impact of Selective Decontamination of the Digestive Tract on Multiple Organ Dysfunction Syndrome: Systematic Review of Randomized Controlled Trials

Critical Care Medicine. May, 2010  |  Pubmed ID: 20308882

We examined the impact of selective decontamination of the digestive tract on multiple organ dysfunction syndrome.

Improved Management of Lysosomal Glucosylceramide Levels in a Mouse Model of Type 1 Gaucher Disease Using Enzyme and Substrate Reduction Therapy

Journal of Inherited Metabolic Disease. Jun, 2010  |  Pubmed ID: 20336375

Gaucher disease is caused by a deficiency of the lysosomal enzyme glucocerebrosidase (acid beta-glucosidase), with consequent cellular accumulation of glucosylceramide (GL-1). The disease is managed by intravenous administrations of recombinant glucocerebrosidase (imiglucerase), although symptomatic patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy (ERT) is not an option may also be treated by substrate reduction therapy (SRT) with miglustat. To determine whether the sequential use of both ERT and SRT may provide additional benefits, we compared the relative pharmacodynamic efficacies of separate and sequential therapies in a murine model of Gaucher disease (D409V/null). As expected, ERT with recombinant glucocerebrosidase was effective in reducing the burden of GL-1 storage in the liver, spleen, and lung of 3-month-old Gaucher mice. SRT using a novel inhibitor of glucosylceramide synthase (Genz-112638) was also effective, albeit to a lesser degree than ERT. Animals administered recombinant glucocerebrosidase and then Genz-112638 showed the lowest levels of GL-1 in all the visceral organs and a reduced number of Gaucher cells in the liver. This was likely because the additional deployment of SRT following enzyme therapy slowed the rate of reaccumulation of GL-1 in the affected organs. Hence, in patients whose disease has been stabilized by intravenously administered recombinant glucocerebrosidase, orally administered SRT with Genz-112638 could potentially be used as a convenient maintenance therapy. In patients naïve to treatment, ERT followed by SRT could potentially accelerate clearance of the offending substrate.

Neurotoxic Methamphetamine Regimens Produce Long-lasting Changes in Striatal G-proteins

Synapse (New York, N.Y.). Nov, 2010  |  Pubmed ID: 20336628

Animals repeatedly dosed with methamphetamine during a single day suffer damage to brain dopamine and serotonin terminals and show behavioral deficits. These methamphetamine regimens also produce long-term reductions in dopamine agonist-stimulated immediate-early gene responses both in striatum and several cortical areas, but the mechanism(s) underlying these long-lasting effects of methamphetamine remain uncertain. Six weeks after a neurotoxic regimen of methamphetamine (4 × 4 mg/kg) or saline, α subunit levels of striatal G-proteins that couple dopamine receptors to second messenger systems were measured. Because the damage to striatal monoamine terminals produced by methamphetamine is regionally heterogeneous, we used radioimmunocytochemistry, which combines quantification with regional resolution. We found significant increases in G(iα) and G(olfα) expression in the ventral striatum (but not in the dorsolateral striatum or nucleus accumbens) of methamphetamine-pretreated rats, a regional pattern similar to that reported for methamphetamine effects on dopamine terminal markers. By contrast, G(qα) expression was unaffected in all striatal subregions. The central roles of G(i) and G(olf) in modulating the activity of a series of interlinked intracellular signaling pathways suggest that methamphetamine-induced changes in G(i) and G(olf) can have lasting effects on striatal neuronal function.

Hyperandrogenemia in Obese Peripubertal Girls: Correlates and Potential Etiological Determinants

Obesity (Silver Spring, Md.). Nov, 2010  |  Pubmed ID: 20339367

Obesity in peripubertal girls is associated with hyperandrogenemia (HA), which can represent a forerunner of polycystic ovary syndrome (PCOS). However, not all obese girls demonstrate HA, and determinants of HA in obese girls remain unclear. We hypothesized that insulin and luteinizing hormone (LH) are independent predictors of free testosterone (T) concentration in obese girls. To assess this further, fasting morning blood samples were collected from 92 obese (BMI-for-age percentile ≥95) girls in various stages of puberty. A multivariate regression model was then constructed using free T (dependent variable), LH, insulin, pubertal group (early, mid-, or late puberty), BMI z-score, and age. Free testosterone (T) concentrations were highly variable among obese girls in each pubertal group. The regression model accounted for roughly half of the variability of free T in obese girls (adjusted R(2) = 0.53, P < 0.001). LH was found to have the greatest independent ability to predict free T, followed by insulin, then age and BMI z-score. Pubertal group was not an independent predictor of free T. We conclude that morning LH and fasting insulin are significant predictors of free T in obese girls, even after adjusting for potential confounders (age, pubertal group, adiposity). We suggest that abnormal LH secretion and hyperinsulinemia can promote HA in some peripubertal girls with obesity.

Fighting a Smarter War on Cancer

Oncology (Williston Park, N.Y.). Feb, 2010  |  Pubmed ID: 20361472

Patient Outcomes After Anti TNF-alpha Drugs for Crohn's Disease

Expert Review of Pharmacoeconomics & Outcomes Research. Apr, 2010  |  Pubmed ID: 20384563

Crohn's disease (CD) is a chronic inflammatory bowel disease with a relatively high prevalence rate in North America. More than 50% of CD patients require surgery at some stage of their disease. Anti-TNF-alpha drugs are increasingly being used in patients with CD who have had an inadequate response to conventional therapy. Treatment with anti-TNF-alpha agents aims at improving symptom control and reducing the need for hospitalization and surgery. This review examines the clinical effectiveness of three anti-TNF-alpha agents (infliximab, adalimumab and etanercept) in moderate and severe CD. The review further considers the evidence for the harms and benefits associated with switching from one anti-TNF-alpha agent to another and strategies to optimize the timing of therapy.

High Molecular-weight Gelatinase Species of Human Bruch's Membrane: Compositional Analyses and Age-related Changes

Investigative Ophthalmology & Visual Science. May, 2010  |  Pubmed ID: 20007823

The structural and functional demise of aging Bruch's membrane is associated with a reduction in the activity of the matrix metalloproteinase (MMP) degradation system. The gelatinase component of the MMP system consists of MMP2 and MMP9 and two high molecular-weight (HMW1, HMW2) species that are yet to be characterized and whose roles in the aging process are yet to be elucidated. The purpose of this study was to determine the age-related changes in levels of expression and subunit characterization of the HMW gelatinase species of Bruch's membrane.

A Sensitizing D-amphetamine Dose Regimen Induces Long-lasting Spinophilin and VGLUT1 Protein Upregulation in the Rat Diencephalon

Neuroscience Letters. Jan, 2010  |  Pubmed ID: 19932152

Numerous studies in this lab and others have reported psychostimulant-induced alterations in both synaptic protein expression and synaptic density in striatum and prefrontal cortex. Recently we have shown that chronic D-amphetamine (D-AMPH) administration in rats increased synaptic protein expression in striatum and limbic brain regions including hippocampus, amygdala, septum, and paraventricular nucleus of the thalamus (PVT). Potential synaptic changes in thalamic nuclei are interesting since the thalamus serves as a gateway to cerebral cortex and a nodal point for basal ganglia influences. Therefore we sought to examine drug-induced differences in synaptic protein expression throughout the diencephalon. Rats received an escalating (1-8 mg/kg) dosing regimen of D-AMPH for five weeks and were euthanized 28 days later. Radioimmunocytochemistry (RICC) revealed significant upregulation of both spinophilin and the vesicular glutamate transporter, VGLUT1, in PVT, mediodorsal (MD), and ventromedial (VM) thalamic nuclei as well as in lateral hypothalamus (LH) and habenula. Strong positive correlations were observed between VGLUT1 and spinophilin expression in PVT, medial habenula, MD, VM and LH of D-AMPH-treated rats. No significant D-AMPH effect was seen in sensorimotor cortices for either protein. Additionally, no significant differences in the general vesicular protein synaptophysin were observed for any brain region. These findings add to evidence suggesting that long-lasting stimulant-induced synaptic alterations are widespread but not ubiquitous. Moreover, they suggest that D-AMPH-induced synaptic changes may occur preferentially in excitatory synapses.

Revascularization for Coronary Artery Disease: Stents Versus Bypass Surgery

Annual Review of Medicine. 2010  |  Pubmed ID: 19824825

Coronary artery disease (CAD) is one manifestation of ischemic heart disease, which is the leading cause of mortality in the world. In addition to preventive medical therapy and lifestyle changes, consideration of revascularization of obstructed arteries to reduce ischemia, alleviate angina, and improve quality of life is a mainstay of current practice. However, the benefits of different methods of revascularization in particular patient populations are debated. Percutaneous coronary intervention (PCI), which involves placement of intracoronary stents in most patients, is a less invasive procedure than coronary artery bypass graft (CABG) surgery. Although it is generally accepted that patients with single-vessel obstructive CAD are best treated with PCI, patients with multivessel CAD have a higher ischemia burden, a greater risk for developing recurrent ischemic events, and a higher mortality. It is in this patient population where the debate over revascularization with stents versus surgery continues.

Reversal-specific Learning Impairments After a Binge Regimen of Methamphetamine in Rats: Possible Involvement of Striatal Dopamine

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jan, 2010  |  Pubmed ID: 19794407

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

Ten Reasons Why We Should NOT Use Severity Scores As Entry Criteria for Clinical Trials or in Our Treatment Decisions

Critical Care Medicine. Jan, 2010  |  Pubmed ID: 19730252

Severity scores such as Acute Physiology and Chronic Health Evaluation II have been advocated as entry criteria for clinical trials and in clinical decision-making. We present ten reasons why we believe this approach is not appropriate and may even be detrimental.

Cardiac Arrest with Residual Blindness After Overdose of Tessalon® (benzonatate) Perles

The Journal of Emergency Medicine. Aug, 2011  |  Pubmed ID: 19892505

The extent to which benzonatate (Tessalon®), a structurally similar agent to other local anesthetics including tetracaine and procaine, poses a risk to the public is not fully appreciated as it is still one of the most widely prescribed antitussives available.

Live or Let Die: Epithelial Flap Vitality and Keratocyte Proliferation Following LASEK and Epi-LASIK in Human Donor and Porcine Eyes

Journal of Refractive Surgery (Thorofare, N.J. : 1995). Feb, 2011  |  Pubmed ID: 20415285

To determine the relationship between epithelial flap vitality and stromal keratocyte proliferation following two epithelial refractive techniques: epi-LASIK and laser epithelial keratomileusis (LASEK).

Optical Coherence Tomography May Be Used to Predict Visual Acuity in Patients with Macular Edema

Investigative Ophthalmology & Visual Science. Apr, 2011  |  Pubmed ID: 20538987

To determine whether the volume of retinal tissue passing between the inner and outer retina in macular edema could be used as an indicator of visual acuity.

Relationship of Catheter-associated Urinary Tract Infection to Mortality and Length of Stay in Critically Ill Patients: a Systematic Review and Meta-analysis of Observational Studies

Critical Care Medicine. May, 2011  |  Pubmed ID: 21242789

To determine whether catheter-associated urinary tract infections are associated with increased morbidity and mortality in critically ill patients.

Exome Sequencing Identifies Frequent Mutation of the SWI/SNF Complex Gene PBRM1 in Renal Carcinoma

Nature. Jan, 2011  |  Pubmed ID: 21248752

The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell carcinoma (ccRCC), the commonest histological subtype. A recent large-scale screen of ∼3,500 genes by PCR-based exon re-sequencing identified several new cancer genes in ccRCC including UTX (also known as KDM6A), JARID1C (also known as KDM5C) and SETD2 (ref. 2). These genes encode enzymes that demethylate (UTX, JARID1C) or methylate (SETD2) key lysine residues of histone H3. Modification of the methylation state of these lysine residues of histone H3 regulates chromatin structure and is implicated in transcriptional control. However, together these mutations are present in fewer than 15% of ccRCC, suggesting the existence of additional, currently unidentified cancer genes. Here, we have sequenced the protein coding exome in a series of primary ccRCC and report the identification of the SWI/SNF chromatin remodelling complex gene PBRM1 (ref. 4) as a second major ccRCC cancer gene, with truncating mutations in 41% (92/227) of cases. These data further elucidate the somatic genetic architecture of ccRCC and emphasize the marked contribution of aberrant chromatin biology.

Minimum Velocity Necessary for Nonconventional Projectiles to Penetrate the Eye: an Experimental Study Using Pig Eyes

The American Journal of Forensic Medicine and Pathology. Jun, 2011  |  Pubmed ID: 21263287

To satisfy the Criminal Code of Canada's definition of a firearm, a barreled weapon must be capable of causing serious bodily injury or death to a person. Canadian courts have accepted the forensically established criteria of "penetration or rupture of an eye" as serious bodily injury. The minimal velocity of nonconventional ammunition required to penetrate the eye including airsoft projectiles has yet to be established. To establish minimal threshold requirements for eye penetration, empirical tests were conducted using a variety of airsoft projectiles. Using the data obtained from these tests, and previous research using "air gun" projectiles, an "energy density" parameter was calculated for the minimum penetration threshold of an eye. Airsoft guns capable of achieving velocities in excess of 99 m/s (325 ft/s) using conventional 6-mm airsoft ammunition will satisfy the forensically established criteria of "serious bodily injury." The energy density parameter for typical 6-mm plastic airsoft projectiles is 4.3 to 4.8 J/cm². This calculation also encompasses 4.5-mm steel BBs.

Evaluation of the Cyclooxygenase Selectivity of Robenacoxib and Its Effect on Recovery of Ischemia-injured Jejunal Mucosa in Horses

American Journal of Veterinary Research. Feb, 2011  |  Pubmed ID: 21281197

To determine the cyclooxygenase (COX) selectivity of robenacoxib and its effect on recovery of jejunal mucosa following ischemic injury in horses.

Stratigraphy of the Anthropocene

Philosophical Transactions. Series A, Mathematical, Physical, and Engineering Sciences. Mar, 2011  |  Pubmed ID: 21282159

The Anthropocene, an informal term used to signal the impact of collective human activity on biological, physical and chemical processes on the Earth system, is assessed using stratigraphic criteria. It is complex in time, space and process, and may be considered in terms of the scale, relative timing, duration and novelty of its various phenomena. The lithostratigraphic signal includes both direct components, such as urban constructions and man-made deposits, and indirect ones, such as sediment flux changes. Already widespread, these are producing a significant 'event layer', locally with considerable long-term preservation potential. Chemostratigraphic signals include new organic compounds, but are likely to be dominated by the effects of CO(2) release, particularly via acidification in the marine realm, and man-made radionuclides. The sequence stratigraphic signal is negligible to date, but may become geologically significant over centennial/millennial time scales. The rapidly growing biostratigraphic signal includes geologically novel aspects (the scale of globally transferred species) and geologically will have permanent effects.

Betel-derived Alkaloid Up-regulates Keratinocyte Alphavbeta6 Integrin Expression and Promotes Oral Submucous Fibrosis

The Journal of Pathology. Feb, 2011  |  Pubmed ID: 21171082

Oral submucous fibrosis (OSF) is a premalignant, fibrosing disorder of the mouth, pharynx, and oesophagus, with a malignant transformation rate of 7-13%. OSF is strongly associated with areca (betel) nut chewing and worldwide, over 5 million people are affected. As αvβ6 integrin is capable of promoting both tissue fibrosis and carcinoma invasion, we examined its expression in fibroepithelial hyperplasia and OSF. αvβ6 was markedly up-regulated in OSF, with high expression detected in 22 of 41 cases (p < 0.001). We investigated the functional role of αvβ6 using oral keratinocyte-derived cells genetically modified to express high αvβ6 (VB6), and also NTERT-immortalized oral keratinocytes, which express low αvβ6 (OKF6/TERT-1). VB6 cells showed significant αvβ6-dependent activation of TGF-β1, which induced transdifferentiation of oral fibroblasts into myofibroblasts and resulted in up-regulation of genes associated with tissue fibrosis. These experimental in vitro findings were confirmed using human clinical samples, where we showed that the stroma of OSF contained myofibroblasts and that TGF-β1-dependent Smad signalling was detectable both in keratinocytes and in myofibroblasts. We also found that arecoline, the major alkaloid of areca nuts, up-regulated keratinocyte αvβ6 expression. This was modulated through the M(4) muscarinic acetylcholine receptor and was suppressed by the M(4) antagonist, tropicamide. Arecoline-dependent αvβ6 up-regulation promoted keratinocyte migration and induced invasion, raising the possibility that this mechanism may support malignant transformation. Over 80% of OSF-related oral cancers examined had moderate/high αvβ6 expression. These data suggest that the pathogenesis of OSF may be epithelial-driven and involve arecoline-dependent up-regulation of αvβ6 integrin.

Management of Patients With Nonvariceal Upper Gastrointestinal Bleeding

Clinical Gastroenterology and Hepatology : the Official Clinical Practice Journal of the American Gastroenterological Association. Aug, 2011  |  Pubmed ID: 21820395

Unblinding Plan of PROWESS-SHOCK Trial

Intensive Care Medicine. Aug, 2011  |  Pubmed ID: 21691888

Acute Pain Management Curriculum for Emergency Medicine Residency Programs

Academic Emergency Medicine : Official Journal of the Society for Academic Emergency Medicine. Oct, 2011  |  Pubmed ID: 21692900

Pain is the most common reason people visit emergency departments (EDs); this implies that emergency physicians (EPs) should be experts in managing acute painful conditions. The current trend in the literature, however, demonstrates that EPs possess inadequate knowledge and lack formal training in acute pain management. The purpose of this article is to create a formal educational curriculum that would assist emergency medicine (EM) residents in proper assessment and treatment of acute pain, as well as in providing a solid theoretical and practical knowledge base for managing acute pain in the ED. The authors propose a series of lectures, case-oriented study groups, practical small group sessions, and class-specific didactics with the goal of enhancing the theoretical and practical knowledge of acute pain management in the ED.

The Dynamics of Norovirus Outbreak Epidemics: Recent Insights

International Journal of Environmental Research and Public Health. Apr, 2011  |  Pubmed ID: 21695033

Noroviruses are a major cause of gastroenteritis outbreaks worldwide. Norovirus outbreaks frequently occur as epidemics which appear to be related to both genetic and environmental factors. This review considers recent progress in understanding these factors. The norovirus genome undergoes continuous change and this appears to be important in the persistence of the virus in the community. Studies on the common GII.4 genotype have shown that some norovirus outbreak epidemics involving this genotype are correlated with specific changes in the genome. In contrast to the growing understanding of the role of genetic factors in norovirus outbreak epidemics, the role of environmental factors is less well understood. Topics reviewed here include long term excretion of norovirus in some individuals, long term survivability of norovirus in the environment, the role of meteorological factors in the control of norovirus outbreaks and the possible zoonotic transmission of the virus.

Systemic Administration of AAV8-α-galactosidase A Induces Humoral Tolerance in Nonhuman Primates Despite Low Hepatic Expression

Molecular Therapy : the Journal of the American Society of Gene Therapy. Nov, 2011  |  Pubmed ID: 21712814

In mice, liver-restricted expression of lysosomal enzymes from adeno-associated viral serotype 8 (AAV8) vectors results in reduced antibodies to the expressed proteins. To ask whether this result might translate to patients, nonhuman primates (NHPs) were injected systemically with AAV8 encoding α-galactosidase A (α-gal). As in mice, sustained expression in monkeys attenuated antibody responses to α-gal. However, this effect was not robust, and sustained α-gal levels were 1-2 logs lower than those achieved in male mice at the same vector dose. Because our mouse studies had shown that antibody levels were directly related to expression levels, several strategies were evaluated to increase expression in monkeys. Unlike mice, expression in monkeys did not respond to androgens. Local delivery to the liver, immune suppression, a self-complementary vector and pharmacologic approaches similarly failed to increase expression. While equivalent vector copies reached mouse and primate liver and there were no apparent differences in vector form, methylation or deamination, transgene expression was limited at the mRNA level in monkeys. These results suggest that compared to mice, transcription from an AAV8 vector in monkeys can be significantly reduced. They also suggest some current limits on achieving clinically useful antibody reduction and therapeutic benefit for lysosomal storage diseases using a systemic AAV8-based approach.

BTB-Kelch Proteins and Ubiquitination of Kainate Receptors

Advances in Experimental Medicine and Biology. 2011  |  Pubmed ID: 21713671

Kainate receptors (KAR) form a class of glutamate receptors that have been implicated in epilepsy, stroke, Alzheimer's and neuropathic pain.1 KAR subtypes are known to be segregated to specific locations within neurons and play significant roles in synaptic transmission and plasticity.2 Increasing evidence suggests a the role for ubiqutination in regulating the number of synaptic neurotransmitter receptors.3-5 The ubiquitin pathway consists of activation (E1), conjugation (E2) and ligation (E3). Cullins form the largest family of E3 ligase complexes. We have recently shown that the BTB/Kelch domain proteins, actinfilin and mayven, bind both Cul3 and specific KAR subtypes (GluR6 and GluR5-2b) to target these KARs for ubiquitination and degradation.5 In this chapter we will review how these interactions occur, what they mean for the stability of KARs and their associated proteins and how, in turn, they may affect synaptic functions in the central nervous system.

Endoscopic Transsphenoidal Surgery for Acromegaly: Remission Using Modern Criteria, Complications, and Predictors of Outcome

The Journal of Clinical Endocrinology and Metabolism. Sep, 2011  |  Pubmed ID: 21715544

Despite the growing application of endoscopic transsphenoidal surgery (ETSS), outcomes for GH adenomas are not clearly defined.

A Phase I Trial of Bexarotene in Combination with Docetaxel in Patients with Advanced Solid Tumors

Clinical Lung Cancer. Jul, 2011  |  Pubmed ID: 21726822

The purpose of this study was to identify dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of docetaxel with a fixed-dose of bexarotene.

Tissue and Serum MicroRNAs in the Kras(G12D) Transgenic Animal Model and in Patients with Pancreatic Cancer

PloS One. 2011  |  Pubmed ID: 21738581

microRNAs (miRs) modulate the expression levels of mRNAs and proteins and can thus contribute to cancer initiation and progression. In addition to their intracelluar function, miRs are released from cells and shed into the circulation. We postulated that circulating miRs could provide insight into pathways altered during cancer progression and may indicate responses to treatment. Here we focus on pancreatic cancer malignant progression. We report that changes in miR expression patterns during progression of normal tissues to invasive pancreatic adenocarcinoma in the p48-Cre/LSL-Kras(G12D) mouse model mirrors the miR changes observed in human pancreatic cancer tissues. miR-148a/b and miR-375 expression were found decreased whereas miR-10, miR-21, miR-100 and miR-155 were increased when comparing normal tissues, premalignant lesions and invasive carcinoma in the mouse model. Predicted target mRNAs FGFR1 (miR-10) and MLH1 (miR-155) were found downregulated. Quantitation of nine microRNAs in plasma samples from patients distinguished pancreatic cancers from other cancers as well as non-cancerous pancreatic disease. Finally, gemcitabine treatment of control animals and p48-Cre/LSL-Kras(G12D) animals with pancreatic cancer caused distinct and up to 60-fold changes in circulating miRs that indicate differential drug effects on normal and cancer tissues. These findings support the significance of detecting miRs in the circulation and suggests that circulating miRs could serve as indicators of drug response.

Iminosugar-based Inhibitors of Glucosylceramide Synthase Increase Brain Glycosphingolipids and Survival in a Mouse Model of Sandhoff Disease

PloS One. 2011  |  Pubmed ID: 21738789

The neuropathic glycosphingolipidoses are a subgroup of lysosomal storage disorders for which there are no effective therapies. A potential approach is substrate reduction therapy using inhibitors of glucosylceramide synthase (GCS) to decrease the synthesis of glucosylceramide and related glycosphingolipids that accumulate in the lysosomes. Genz-529468, a blood-brain barrier-permeant iminosugar-based GCS inhibitor, was used to evaluate this concept in a mouse model of Sandhoff disease, which accumulates the glycosphingolipid GM2 in the visceral organs and CNS. As expected, oral administration of the drug inhibited hepatic GM2 accumulation. Paradoxically, in the brain, treatment resulted in a slight increase in GM2 levels and a 20-fold increase in glucosylceramide levels. The increase in brain glucosylceramide levels might be due to concurrent inhibition of the non-lysosomal glucosylceramidase, Gba2. Similar results were observed with NB-DNJ, another iminosugar-based GCS inhibitor. Despite these unanticipated increases in glycosphingolipids in the CNS, treatment nevertheless delayed the loss of motor function and coordination and extended the lifespan of the Sandhoff mice. These results suggest that the CNS benefits observed in the Sandhoff mice might not necessarily be due to substrate reduction therapy but rather to off-target effects.

Transwell(®) Invasion Assays

Methods in Molecular Biology (Clifton, N.J.). 2011  |  Pubmed ID: 21748672

The need to identify inhibitors of cancer invasion has driven the development of quantitative in vitro invasion assays. The most common assays used are based on the original Boyden assay system. Today commercially available plastic inserts for multi-well plates, which possess a cell-permeable membrane, as typified by Transwell(®) Permeable Supports, permit accurate repeatable invasion assays. When placed in the well of a multi-well tissue culture plate these inserts create a two-chamber system separated by the cell-permeable membrane. To create an invasion assay the pores in the membrane are blocked with a gel composed of extracellular matrix that is meant to mimic the typical matrices that tumour cells encounter during the invasion process in vivo. By placing the cells on one side of the gel and a chemoattractant on the other side of the gel, invasion is determined by counting those cells that have traversed the cell-permeable membrane having invaded towards the higher concentration of chemoattractant. In this chapter, in addition to protocols for performing Transwell invasion assays, there is consideration of the limitations of current assay designs with regard to available matrices and the absence of tumour microenvironment cells.

A Phase 1 Study of a Vaccine Targeting Preferentially Expressed Antigen in Melanoma and Prostate-specific Membrane Antigen in Patients with Advanced Solid Tumors

Journal of Immunotherapy (Hagerstown, Md. : 1997). Sep, 2011  |  Pubmed ID: 21760528

Preferentially expressed antigen in melanoma (PRAME) and prostate-specific membrane antigen (PSMA) are tumor-associated antigens implicated in cellular differentiation, genetic stability, and angiogenesis. MKC1106-PP is an immunotherapeutic regimen cotargeting PRAME and PSMA, comprised of a recombinant plasmid (pPRA-PSM encoding fragments derived from both antigens) and 2 peptides (E-PRA and E-PSM derived from PRAME and PSMA, respectively). This multicenter study evaluated MKC1106-PP with a fixed plasmid dose and 2 different peptide doses, administered by intralymph node injection in a prime-boost sequence in human leukocyte antigen-A*0201 and tumor-antigen-positive patients with progressing metastatic solid tumors who had failed standard therapy. Immune monitoring was done by tetramer and enzymatic-linked immune spot analysis. The treatment was well tolerated, with no significant differences in safety, immune response, and clinical outcome relative to peptide doses. Fifteen of 24 evaluable patients showed an immune response, as defined by the expansion of PRAME-specific or PSMA-specific T cells in the blood. There were no partial or complete responses by the Response Evaluation Criteria in Solid Tumors. Seven patients showed stable disease (SD) for 6 months or longer, or prostate specific antigen decline: 4 of 10 with prostate carcinoma, 2 of 2 with renal clear cell carcinoma, and 1 of 10 with metastatic melanoma. In addition, there was an association between the induction and persistence of antigen-specific T cells in blood above baseline levels and disease control, defined as SD for 6 months or longer. These results support further development of MKC1106-PP in specific clinical indications.

The Global Sepsis Alliance: Building New Collaborations to Confront an Under-recognized Threat

Surgical Infections. Feb, 2011  |  Pubmed ID: 21309683

Principles of Source Control in the Management of Sepsis

Critical Care Nursing Clinics of North America. Mar, 2011  |  Pubmed ID: 21316570

This brief overview of the role of source control in sepsis emphasizes the underlying principles rather than the empiric evidence from well-performed clinical studies. The reasons for this are several. First there is a paucity of high-level published evidence, with few rigorous large clinical series, and even fewer clinical trials. Second, the decision-making process in the individual patient is complex, and often not amenable to study using the design of a randomized controlled trial, for decisions involve consideration not only of the underlying disease but of the stability of the patient, the presence of comorbidities, and the prior surgical history, all factors that can heavily influence the decision to choose one therapeutic option rather than another. The scope of the topic is large, and the space limited. Interested readers are referred to more detailed discussions such as that found in the background to the recommendations on source control in the guidelines of the Surviving Sepsis Campaign.(1) Source control is a core treatment modality in the management of the patient with severe sepsis or septic shock. Its optimal use assumes a comprehensive knowledge of biologic principles, the complexities of the septic response, and the range of surgical and nonsurgical options, and a combination of therapeutic aggressiveness and judicious caution in the clinician charged with making the decision. As every intensivist learns, appropriate source-control intervention can rapidly alter the course of sepsis to a more favorable direction, and suboptimal decision-making can change a difficult clinical challenge into a nightmare.

Incidence of Complications After Colonoscopy: Capturing an Elusive Beast

Gastrointestinal Endoscopy. Mar, 2011  |  Pubmed ID: 21353849

Multinational, Observational Study of Procalcitonin in ICU Patients with Pneumonia Requiring Mechanical Ventilation: a Multicenter Observational Study

Critical Care (London, England). 2011  |  Pubmed ID: 21385367

The intent of this study was to determine whether serum procalcitonin (PCT) levels are associated with prognosis, measured as organ dysfunctions and 28-day mortality, in patients with severe pneumonia.

A Canadian Critical Care Trials Group Project in Collaboration with the International Forum for Acute Care Trialists - Collaborative H1N1 Adjuvant Treatment Pilot Trial (CHAT): Study Protocol and Design of a Randomized Controlled Trial

Trials. 2011  |  Pubmed ID: 21388549

Swine origin influenza A/H1N1 infection (H1N1) emerged in early 2009 and rapidly spread to humans. For most infected individuals, symptoms were mild and self-limited; however, a small number developed a more severe clinical syndrome characterized by profound respiratory failure with hospital mortality ranging from 10 to 30%. While supportive care and neuraminidase inhibitors are the main treatment for influenza, data from observational and interventional studies suggest that the course of influenza can be favorably influenced by agents not classically considered as influenza treatments. Multiple observational studies have suggested that HMGCoA reductase inhibitors (statins) can exert a class effect in attenuating inflammation. The Collaborative H1N1 Adjuvant Treatment (CHAT) Pilot Trial sought to investigate the feasibility of conducting a trial during a global pandemic in critically ill patients with H1N1 with the goal of informing the design of a larger trial powered to determine impact of statins on important outcomes.

Changes in Coping Style and Treatment Outcome Following Motor Vehicle Accident

Rehabilitation Psychology. Feb, 2011  |  Pubmed ID: 21401285

Motor vehicle accidents (MVAs) are highly prevalent and can result in a complex interplay of physical injury, disability, and emotional distress. It has been suggested that the manner in which individuals cope with pain experienced after injury may determine how much recovery of function can be achieved. Only a limited number of studies have examined this process in the context of a rehabilitation program, and to date few studies have examined both functional and quality of life outcomes in MVA recovery in a tertiary level program as a function of coping style.

Cost-utility of Laparoscopic Nissen Fundoplication Versus Proton Pump Inhibitors for Chronic and Controlled Gastroesophageal Reflux Disease: a 3-year Prospective Randomized Controlled Trial and Economic Evaluation

Value in Health : the Journal of the International Society for Pharmacoeconomics and Outcomes Research. Mar-Apr, 2011  |  Pubmed ID: 21402295

Very few randomized controlled trials (RCTs) have compared laparoscopic Nissen fundoplication (LNF) to proton pump inhibitors (PPI) medical management for patients with chronic gastroesophageal reflux disease (GERD). Larger RCTs have been relatively short in duration, and have reported mixed results regarding symptom control and effect on quality of life (QOL). Economic evaluations have reported conflicting results.

Glucocorticosteroid Therapy in Inflammatory Bowel Disease: Systematic Review and Meta-analysis

The American Journal of Gastroenterology. Apr, 2011  |  Pubmed ID: 21407179

The use of glucocorticosteroids to treat both Crohn's disease (CD) and ulcerative colitis (UC) is widespread, but no systematic review and meta-analysis has examined the issue of efficacy of these agents in its entirety.

Antibiotic Therapy in Inflammatory Bowel Disease: a Systematic Review and Meta-analysis

The American Journal of Gastroenterology. Apr, 2011  |  Pubmed ID: 21407187

The etiology of inflammatory bowel disease (IBD) is unknown but may relate to an unidentified bacterial pathogen or an immunological reaction to gut microbiota. Antibiotics have therefore been proposed as a therapy for Crohn's disease (CD) and ulcerative colitis (UC) to induce remission in active disease to prevent relapse. Current data are conflicting and we therefore conducted a systematic review of randomized controlled trials (RCTs) evaluating antibiotics in IBD. Only parallel group RCTs were considered eligible. Studies with adult patients receiving any dose of therapy for at least 7 days and up to 16 weeks for active disease, or at least 6 months of follow-up for preventing relapse in quiescent disease were analyzed. We included any antibiotics alone or in combination using predefined definitions of remission and relapse. Two reviewers independently assessed eligibility and extracted data. The primary outcome was remission or relapse using an intention-to-treat methodology. The data were summarized using relative risk (RR) and pooled using a random effects model. For active CD, there were 10 RCTs involving 1,160 patients. There was a statistically significant effect of antibiotics being superior to placebo (RR of active CD not in remission=0.85; 95% confidence interval (CI)=0.73-0.99, P=0.03). There was moderate heterogeneity between results (I(2)=48%) and a diverse number of antibiotics were tested (anti-tuberculosis therapy, macrolides, fluroquinolones, 5-nitroimidazoles, and rifaximin) either alone or in combination. Rifamycin derivatives either alone or in combination with other antibiotics appeared to have a significant effect at inducing remission in active CD. In perianal CD fistula there were three trials evaluating 123 patients using either ciprofloxacin or metronidazole. There was a statistically significant effect in reducing fistula drainage (RR=0.8; 95% CI=0.66-0.98) with no heterogeneity (I(2)=0%) and an number needed to treat 5 (95% CI=3-20). For quiescent CD, there were 3 RCTs involving 186 patients treated with different antibiotics combinations (all including antimycobacterials) vs. placebo. There was a statistically significant effect in favor of antibiotics vs. placebo (RR of relapse=0.62; 95% CI=0.46-0.84), with no heterogeneity (I(2)=0%). In active UC, there were 9 RCTs with 662 patients and there was a statistically significant benefit for antibiotics inducing remission (RR of UC not in remission=0.64; 95% CI=0.43-0.96). There was moderate heterogeneity (I(2)=69%) and antibiotics used were all different single or combination drugs. Antibiotic therapy may induce remission in active CD and UC, although the diverse number of antibiotics tested means the data are difficult to interpret. This systematic review is a mandate for further trials of antibiotic therapy in IBD.

Efficacy of 5-aminosalicylates in Ulcerative Colitis: Systematic Review and Meta-analysis

The American Journal of Gastroenterology. Apr, 2011  |  Pubmed ID: 21407188

The efficacy of 5-aminosalicylic acids (5-ASAs) in ulcerative colitis (UC) has been studied previously in meta-analyses. However, several randomized controlled trials (RCTs) have been published recently, and no previous meta-analysis has studied the effect of 5-ASA dosage used.

Efficacy of 5-aminosalicylates in Crohn's Disease: Systematic Review and Meta-analysis

The American Journal of Gastroenterology. Apr, 2011  |  Pubmed ID: 21407190

Crohn's disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. Evidence for treatment with 5-aminosalicylic acid (5-ASA) drugs is conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to examine this issue.

GnRH Pulse Frequency Differentially Regulates Steroidogenic Factor 1 (SF1), Dosage-sensitive Sex Reversal-AHC Critical Region on the X Chromosome Gene 1 (DAX1), and Serum Response Factor (SRF): Potential Mechanism for GnRH Pulse Frequency Regulation of LH Beta Transcription in the Rat

Endocrine. Jun, 2011  |  Pubmed ID: 21409515

The issue of how rapid frequency GnRH pulses selectively stimulate LH transcription is not fully understood. The rat LHβ promoter contains two GnRH-responsive regions: the proximal region has binding elements for SF1, and the distal site contains a CArG box, which binds SRF. This study determined whether GnRH stimulates pituitary SF1, DAX1 (an endogenous SF1 inhibitor), and SRF transcription in vivo, and whether regulation is frequency dependent. Male rats were pulsed with 25 ng GnRH i.v. every 30 min or every 240 min for 1-24 h, and primary transcripts (PTs) and mRNAs were measured by real time PCR. Fast frequency GnRH pulses (every 30 min) increased SF1 PT (threefold) within 1 h, and then declined after 6 h. SF1 mRNA also increased within 1 h and remained elevated through 24 h. Fast frequency GnRH also stimulated a transient increase in DAX1 PT (twofold after 1 h) and mRNA (1.7-fold after 6 h), while SRF mRNA rose briefly at 1 h. Slow frequency pulses did not affect gene expression of SF1, DAX1, or SRF. These findings support a mechanistic link between SF1 in the frequency regulation of LHβ transcription by pulsatile GnRH.

Inverse Medea As a Novel Gene Drive System for Local Population Replacement: a Theoretical Analysis

The Journal of Heredity. May-Jun, 2011  |  Pubmed ID: 21493596

One strategy to control mosquito-borne diseases, such as malaria and dengue fever, on a regional scale is to use gene drive systems to spread disease-refractory genes into wild mosquito populations. The development of a synthetic Medea element that has been shown to drive population replacement in laboratory Drosophila populations has provided encouragement for this strategy but has also been greeted with caution over the concern that transgenes may spread into countries without their consent. Here, we propose a novel gene drive system, inverse Medea, which is strong enough to bring about local population replacement but is unable to establish itself beyond an isolated release site. The system consists of 2 genetic components--a zygotic toxin and maternal antidote--which render heterozygous offspring of wild-type mothers unviable. Through population genetic analysis, we show that inverse Medea will only spread when it represents a majority of the alleles in a population. The element is best located on an autosome and will spread to fixation provided any associated fitness costs are dominant and to very high frequency otherwise. We suggest molecular tools that could be used to build the inverse Medea system and discuss its utility for a confined release of transgenic mosquitoes.

Disturbed Matrix Metalloproteinase Activity of Bruch's Membrane in Age-related Macular Degeneration

Investigative Ophthalmology & Visual Science. Jun, 2011  |  Pubmed ID: 21498613

To evaluate the potential role of the matrix metalloproteinase (MMP) system of Bruch's membrane in the pathology of age-related macular degeneration.

A Randomized Controlled Trial of Laparoscopic Nissen Fundoplication Versus Proton Pump Inhibitors for the Treatment of Patients with Chronic Gastroesophageal Reflux Disease (GERD): 3-year Outcomes

Surgical Endoscopy. Aug, 2011  |  Pubmed ID: 21512887

A randomized controlled trial (RCT) investigated patients with gastroesophageal reflux disease (GERD) who were stable and symptomatically controlled with long-term medical therapy to compare ongoing optimized medical therapy with laparoscopic Nissen fundoplication (LNF).

Antidepressant Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) Are Attenuated by Antiinflammatory Drugs in Mice and Humans

Proceedings of the National Academy of Sciences of the United States of America. May, 2011  |  Pubmed ID: 21518864

Antiinflammatory drugs achieve their therapeutic actions at least in part by regulation of cytokine formation. A "cytokine hypothesis" of depression is supported by the observation that depressed individuals have elevated plasma levels of certain cytokines compared with healthy controls. Here we investigated a possible interaction between antidepressant agents and antiinflammatory agents on antidepressant-induced behaviors and on p11, a biochemical marker of depressive-like states and antidepressant responses. We found that widely used antiinflammatory drugs antagonize both biochemical and behavioral responses to selective serotonin reuptake inhibitors (SSRIs). In contrast to the levels detected in serum, we found that frontal cortical levels of certain cytokines (e.g., TNFα and IFNγ) were increased by serotonergic antidepressants and that these effects were inhibited by antiinflammatory agents. The antagonistic effect of antiinflammatory agents on antidepressant-induced behaviors was confirmed by analysis of a dataset from a large-scale real-world human study, "sequenced treatment alternatives to relieve depression" (STAR*D), underscoring the clinical significance of our findings. Our data indicate that clinicians should carefully balance the therapeutic benefits of antiinflammatory agents versus the potentially negative consequences of antagonizing the therapeutic efficacy of antidepressant agents in patients suffering from depression.

Pre-B Cell Colony-enhancing Factor (PBEF/Nampt/visfatin) Primes Neutrophils for Augmented Respiratory Burst Activity Through Partial Assembly of the NADPH Oxidase

Journal of Immunology (Baltimore, Md. : 1950). Jun, 2011  |  Pubmed ID: 21518975

Pre-B cell colony-enhancing factor ([PBEF] also known as Nampt/visfatin) is a pleiotropic 52-kDa cytokine-like molecule whose activity has been implicated in multiple inflammatory disease states. PBEF promotes polymorphonuclear neutrophil (PMN) proinflammatory function by inhibiting constitutive PMN apoptosis. We investigated whether PBEF activates or primes for PMN respiratory burst. We found that although PBEF did not activate respiratory burst on its own, it primed for increased reactive oxygen species generation through the NADPH oxidase. PBEF promoted membrane translocation of cytosolic NADPH oxidase subunits p40 and p47, but not p67, induced p40 phosphorylation on Thr(154), and activated the small GTPase Rac. Priming, translocation, and phosphorylation were dependent on activation of p38 and ERK MAPKs, but not of PI3K. Priming by PBEF occurred independent of its NAD-generating capacity because neither nicotinamide mononucleotide or NAD could recapitulate the effects, and a specific inhibitor of PBEF, APO-866, could not inhibit priming. Taken together, these results demonstrate that PBEF can prime for PMN respiratory burst activity by promoting p40 and p47 translocation to the membrane, and this occurs in a MAPK-dependent fashion.

The Relationship Between Health Care and Nonhealth Care Norovirus Outbreak Settings and Norovirus Genotype in Victoria, Australia, 2002-2005

Journal of Microbiology, Immunology, and Infection = Wei Mian Yu Gan Ran Za Zhi. Aug, 2011  |  Pubmed ID: 21524956

There is evidence that norovirus genotype is an important factor in determining norovirus epidemiology, but detailed information is lacking. This report examined this question by studying whether the mix of norovirus genotypes associated with norovirus outbreaks in health care settings was different to that in nonhealth care settings.

The Age of Blood Evaluation (ABLE) Randomized Controlled Trial: Study Design

Transfusion Medicine Reviews. Jul, 2011  |  Pubmed ID: 21550205

Red blood cells (RBCs) are transfused to treat anemia and to maintain oxygen delivery to vital organs during critical illness. Laboratory and observational studies have raised the possibility that prolonged RBC storage may adversely affect clinical outcomes. Compared with RBCs stored less than 1 week, there are no clinical data demonstrating that RBCs stored longer remain as effective at carrying or releasing oxygen, and observational studies have risen to possibility that prolonged RBC storage might result in harm to vulnerable patients requiring blood transfusions. The "Age of Blood Evaluation" (ABLE) study (ISRCTN44878718) is a double-blind, multicenter, parallel randomized controlled clinical trial. It will test the hypothesis that the transfusion of prestorage leukoreduced RBCs stored for 7 days or less (fresh arm) as compared with standard-issue RBCs stored, on average, 15 to 20 days (control arm) will lead to lower 90-day all-cause mortality and reduced morbidity in critically ill adults. We include adults in intensive care units (ICUs) who (1) have had a request for a first RBC unit transfusion during the first 7 days of ICU admission and (2) have an anticipated requirement for ongoing invasive and noninvasive mechanical ventilation exceeding 48 hours. Enrolled patients are randomized at the time of transfusion to receive either standard-issue RBC units or RBCs stored 7 days or less issued by the local hospital transfusion service. The primary outcome is 90-day all-cause mortality. Secondary outcomes include ICU and hospital mortality, organ failure, and serious nosocomial infections. With 2510 patients, we will be able to detect a 5% absolute risk reduction (from 25% to 20%). The ABLE study is currently enrolling patients in 23 university-affiliated and community-hospital ICUs across Canada; sites in France and United Kingdom are expected to start recruitment in 2011. Regardless of the results, ABLE study will have significant implications on the duration of RBC storage. A negative trial will reassure clinicians and blood bankers regarding the effectiveness and safety of standard-issue RBCs. A positive trial will have significant implications with respect to inventory management of RBCs given to critically ill adults with a high risk of mortality and will also prompt research to better understand the RBC storage lesion in the hopes of minimizing its clinical consequences through the development of better storage methods.

Vertical and Seasonal Variation in the δ¹³C of Leaf-respired CO₂ in a Mixed Conifer Forest

Tree Physiology. Apr, 2011  |  Pubmed ID: 21551356

The C-isotopic composition (δ¹³C) of leaf respiration (δ(LR)) has previously been shown to vary among functional groups, plant organs and times of day. We here investigated vertical and seasonal variation in δ(LR) through deep (~35 m) forest canopies. We measured δ(LR), δ¹³C of leaf bulk organic matter (δ(LB)), specific leaf area, net photosynthesis (A) and dark respiration in shade, middle and sun foliage in four conifer species from May to August. We used Keeling plots to estimate δ(LR); we developed a novel technique for ensuring that the respiratory substrate was not changing over the course of the measurement. Variables δ(LR) and δ(LB) displayed a vertical pattern in Abies grandis, Pseudotsuga menziesii and Thuja plicata, but were independent of canopy position in Larix occidentalis. Vertical gradients in δ(LB) (3.6‰) and δ(LR) (2.8‰) were similar. The respiratory enrichment (δ(LR)-δ(LB)) was smaller in expanding (3‰) than mature (4-8‰) foliage. There was a linear relationship between the respiratory enrichment and A. Our data support the hypothesis that δ(LR) values are related to patterns of C allocation among metabolic pathways. We demonstrated that considerable variation in δ(LR) occurs vertically through the canopy (3‰ gradient) and seasonally (3-7‰). Understanding sources of variation in respiratory signals is fundamental to comprehending C dynamics and for global model applications.

Estimation of Canopy Average Mesophyll Conductance Using δ(13) C of Phloem Contents

Plant, Cell & Environment. Sep, 2011  |  Pubmed ID: 21554329

Conductance to CO(2) inside leaves, known as mesophyll conductance (g(m)), imposes large limitations on photosynthesis. Because g(m) is difficult to quantify, it is often neglected in calculations of (13)C photosynthetic discrimination. The 'soluble sugar method' estimates g(m) via differences between observed photosynthetic discrimination, calculated from the δ(13)C of soluble sugars, and discrimination when g(m) is infinite. We expand upon this approach and calculate a photosynthesis-weighted average for canopy mesophyll conductance ((c) g(m)) using δ(13)C of stem phloem contents. We measured gas exchange at three canopy positions and collected stem phloem contents in mature trees of three conifer species (Pseudotsuga menziesii, Thuja plicata and Larix occidentalis). We generated species-specific and seasonally variable estimates of (c)g(m) . We found that (c)g(m) was significantly different among species (0.41, 0.22 and 0.09 mol m(-2) s(-1) for Larix, Pseudotsuga and Thuja, respectively), but was similar throughout the season. Ignoring respiratory and photorespiratory fractionations ((c)Δ(ef)) resulted in ≈30% underestimation of (c)g(m) in Larix and Pseudotsuga, but was innocuous in Thuja. Substantial errors (~1-4‰) in photosynthetic discrimination calculations were introduced by neglecting (c)g(m) and (c)Δ(ef) . Our method is easy to apply and cost-effective, captures species variation and would have captured seasonal variation had it existed. The method provides an average canopy value, which makes it suitable for parameterization of canopy-scale models of photosynthesis, even in tall trees.

Striatal Dopamine D1 and D2 Receptors: Widespread Influences on Methamphetamine-induced Dopamine and Serotonin Neurotoxicity

Synapse (New York, N.Y.). Nov, 2011  |  Pubmed ID: 21584865

Methamphetamine (mAMPH) is an addictive psychostimulant drug that releases monoamines through nonexocytotic mechanisms. In animals, binge mAMPH dosing regimens deplete markers for monoamine nerve terminals, for example, dopamine and serotonin transporters (DAT and SERT), in striatum and cerebral cortex. Although the precise mechanism of mAMPH-induced damage to monoaminergic nerve terminals is uncertain, both dopamine D1 and D2 receptors are known to be important. Systemic administration of dopamine D1 or D2 receptor antagonists to rodents prevents mAMPH-induced damage to striatal dopamine nerve terminals. Because these studies employed systemic antagonist administration, the specific brain regions involved remain to be elucidated. The present study examined the contribution of dopamine D1 and D2 receptors in striatum to mAMPH-induced DAT and SERT neurotoxicities. In this experiment, either the dopamine D1 antagonist, SCH23390, or the dopamine D2 receptor antagonist, sulpiride, was intrastriatally infused during a binge mAMPH regimen. Striatal DAT and cortical, hippocampal, and amygdalar SERT were assessed as markers of mAMPH-induced neurotoxicity 1 week following binge mAMPH administration. Blockade of striatal dopamine D1 or D2 receptors during an otherwise neurotoxic binge mAMPH regimen produced widespread protection against mAMPH-induced striatal DAT loss and cortical, hippocampal, and amygdalar SERT loss. This study demonstrates that (1) dopamine D1 and D2 receptors in striatum, like nigral D1 receptors, are needed for mAMPH-induced striatal DAT reductions, (2) these same receptors are needed for mAMPH-induced SERT loss, and (3) these widespread influences of striatal dopamine receptor antagonists are likely attributable to circuits connecting basal ganglia to thalamus and cortex.

The Role of α9β1 Integrin in Modulating Epithelial Cell Behaviour

Journal of Oral Pathology & Medicine : Official Publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. Nov, 2011  |  Pubmed ID: 21615501

Integrins initiate signalling in response to the extracellular matrix (ECM), which is important in wound healing and cancer. Previous studies have shown that over-expression of the αvβ6 integrin in oral squamous cell carcinoma (OSCC) cells results in enhanced motility and expression of matrix-degrading proteases, and the aim of this study was to investigate whether this is also the case for the α9β1 integrin.

Proceedings from the Montebello Round Table Discussion. Second Annual Conference on Complexity and Variability Discusses Research That Brings Innovation to the Bedside

Journal of Critical Care. Jun, 2011  |  Pubmed ID: 21616298

Bowel Preparation with Split-dose Polyethylene Glycol Before Colonoscopy: a Meta-analysis of Randomized Controlled Trials

Gastrointestinal Endoscopy. Jun, 2011  |  Pubmed ID: 21628016

Polyethylene glycol (PEG) is a commonly used bowel preparation for colonoscopy. Unfortunately, the standard large-volume solution may reduce patient compliance. Split-dosing of PEG has been studied in various randomized, controlled trials (RCTs). However, results have been conflicting.

Whole-genome Sequencing Identifies Recurrent Mutations in Chronic Lymphocytic Leukaemia

Nature. Jul, 2011  |  Pubmed ID: 21642962

Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer.

Peptide-to-protein Distribution Versus a Competition for Significance to Estimate Error Rate in Blood Protein Identification

Analytical Biochemistry. Apr, 2011  |  Pubmed ID: 21138726

The simplest model-that authentic tandem mass spectrometry (MS/MS) spectra are no different from noise, random spectra, or false-positive results-may be directly examined by chi-square comparison of the peptide-to-protein distribution. The peptide-to-protein distribution of a set of 4151 redundant blood proteins identified by X!TANDEM indicated that there is a low probability that the authentic data were the same as noise, random spectra, or false-positive correlations (P<0.0001). In contrast, a competition for significance failed to distinguish approximately 90% of authentic blood proteins from those of noise, random spectra, or false-positive results (P<0.01) and apparently incurred a large type II error (false negative). The chi-square test of peptide-to-protein frequency distributions was found to be an efficient means to distinguish authentic data from false-positive results. Frequency-based statistics unambiguously demonstrated that proteins can be identified by liquid chromatography-electrospray ionization-MS/MS from human blood with acceptable confidence. Thus, the chi-square fit of the peptide-to-protein distribution could distinguish authentic data from random or false-positive data, but the score distribution method could not separate real results from false results.

Pulse Labeling of Dissolved (13) C-carbonate into Tree Xylem: Developing a New Method to Determine the Fate of Recently Fixed Photosynthate

Rapid Communications in Mass Spectrometry : RCM. Jan, 2011  |  Pubmed ID: 21154652

Stable carbon isotopes are often employed as tracers in plant and soil systems to study the fate and transformations of carbon as is it assimilated by the forest canopies and then translocated into the soil matrix and soil microorganisms. This experiment tested a new method of (13) C-labeling. We dissolved (13) C-carbonate into 12 mL of water and injected it into the xylem of a 6-cm diameter tree. The isotopic composition of foliage, stem CO(2) , and phloem contents were measured before the experiment and up to two weeks after the pulse label. Isotopic enrichments of 6.1‰ and 7.7‰ were observed in stem CO(2) and phloem contents, respectively. No enrichment in bulk foliage was observed. The pulse came through the phloem five days after the label was injected, consistent with expectations based on transport rates through the tree. The application of this xylem pulse-labeling method may provide new insights into labile carbon sequestration in trees, perhaps even in much larger trees. Furthermore, the method could be applied under experimental treatments that would elucidate the mechanisms controlling the fate and transformation of recently fixed photosynthate in forests.

Semele: a Killer-male, Rescue-female System for Suppression and Replacement of Insect Disease Vector Populations

Genetics. Feb, 2011  |  Pubmed ID: 21078687

Two strategies to control mosquito-borne diseases, such as malaria and dengue fever, are reducing mosquito population sizes or replacing populations with disease-refractory varieties. We propose a genetic system, Semele, which may be used for both. Semele consists of two components: a toxin expressed in transgenic males that either kills or renders infertile wild-type female recipients and an antidote expressed in females that protects them from the effects of the toxin. An all-male release results in population suppression because wild-type females that mate with transgenic males produce no offspring. A release that includes transgenic females results in gene drive since females carrying the allele are favored at high population frequencies. We use simple population genetic models to explore the utility of the Semele system. We find that Semele can spread under a wide range of conditions, all of which require a high introduction frequency. This feature is desirable since transgenic insects released accidentally are unlikely to persist, transgenic insects released intentionally can be spatially confined, and the element can be removed from a population through sustained release of wild-type insects. We examine potential barriers to Semele gene drive and suggest molecular tools that could be used to build the Semele system.

Chi-square Comparison of Tryptic Peptide-to-protein Distributions of Tandem Mass Spectrometry from Blood with Those of Random Expectation

Analytical Biochemistry. Feb, 2011  |  Pubmed ID: 20977879

Proteomics uses tandem mass spectrometers and correlation algorithms to match peptides and their fragment spectra to amino acid sequences. The replication of multiple liquid chromatography experiments with electrospray ionization of peptides and tandem mass spectrometry (LC-ESI-MS/MS) produces large sets of MS/MS spectra. There is a need to assess the quality of large sets of experimental results by statistical comparison with that of random expectation. Classical frequency-based statistics such as goodness-of-fit tests for peptide-to-protein distributions could be used to calculate the probability that an entire set of experimental results has arisen by random chance. The frequency distributions of authentic MS/MS spectra from human blood were compared with those of false positive MS/MS spectra generated by a computer, or instrument noise, using the chi-square test. Here the mechanics of the chi-square test to compare the results in toto from a set of LC-ESI-MS/MS experiments with those of random expectation is detailed. The chi-square analysis of authentic spectra demonstrates unambiguously that the analysis of blood proteins separated by partition chromatography prior to tryptic digestions has a low probability that the cumulative peptide-to-protein distribution is the same as that of random or noise false positive spectra.

Role of Dopamine D1 Receptors in the Activation of Nucleus Accumbens Extracellular Signal-regulated Kinase (ERK) by Cocaine-paired Contextual Cues

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology. Jan, 2011  |  Pubmed ID: 20944555

Exposure to drug-paired cues can trigger addicts to relapse into drug seeking. Although the molecular mechanisms underlying cue-elicited cocaine seeking are incompletely understood, the protein kinase extracellular signal-regulated kinase (ERK) is known to have an important role. Psychostimulants and their associated cues can activate ERK in medium spiny neurons of the nucleus accumbens core (AcbC). These medium spiny neurons can be classified according to their projections (to ventral pallidum and/or substantia nigra) and by their mRNA expression. The present experiments were designed to determine which distinct set of AcbC projection neurons expresses phosphorylated ERK (pERK) in response to cocaine-paired contextual cues. Combined use of the retrograde label Flurogold with immunohistochemical staining of pERK was used to show that the AcbC pERK accompanying preference for cocaine-paired contexts occurs in both the accumbens (Acb)-nigral and Acb-pallidal projections. The gene expression characteristics of the neurons expressing pERK in response to cocaine-paired cues was further investigated using combined in situ hybridization and immunocytochemistry to show that AcbC pERK+ cells correspond to D1, but not preproenkephalin, mRNA+ cells. Furthermore, intra-AcbC infusion of the D1-antagonist SCH23390 attenuated cue-induced AcbC pERK expression. In aggregate, these results indicate that (i) the D1-expressing AcbC neurons evidence long-term plasticity related to drug-cue memories and (ii) local dopamine D1 receptors are necessary for the expression of cocaine-paired cue-induced pERK in these AcbC neurons.

Use of the Double-pass Technique to Quantify Ocular Scatter in Patients with Uveitis: a Pilot Study

Ophthalmologica. Journal International D'ophtalmologie. International Journal of Ophthalmology. Zeitschrift Für Augenheilkunde. 2011  |  Pubmed ID: 20714184

to assess whether the double-pass technique can be employed to quantify the amount of light scattering in patients with uveitis.

Age-related Differences in the Elasticity of the Human Cornea

Investigative Ophthalmology & Visual Science. Jun, 2011  |  Pubmed ID: 20847118

The goal of this study was to determine age-related variation in the elasticity of the human cornea using nondestructive means.

Altered Inhibitory κBα Expression in LPS-stimulated Alveolar Macrophages Following Resuscitated Hemorrhagic Shock

Shock (Augusta, Ga.). Feb, 2011  |  Pubmed ID: 20661182

Patients resuscitated from hemorrhagic shock are at increased risk for the development of organ dysfunction, particularly acute respiratory distress syndrome. The "two-hit hypothesis" wherein shock/resuscitation (S/R) renders the immune system more responsive to subsequent inflammatory stimuli has been suggested as a major mechanism contributing to organ injury. Previous work has shown that S/R primes alveolar macrophages for increased nuclear factor κB (NF-κB) translocation in response to LPS, culminating in increased lung cytokine and chemokine production. Inhibitory κB (IκB) is known to be an important regulator of NF-κB activity. In this article, we investigated the effect of S/R on regulation of IκBα expression in response to LPS both in vitro and in vivo. Two discrete effects on IκB regulation were observed after S/R, which served to augment NF-κB activity. First, antecedent exposure of alveolar macrophages to S/R resulted in increased LPS-induced IκBα degradation through activation of upstream signaling, an effect that resulted in increased NF-κB translocation and cytokine-induced neutrophil chemoattractant gene expression. Second, cells recovered from rodents after S/R had reduced levels of IκB mRNA in response to LPS compared with sham/LPS treatment. This effect was primarily due to the ability of S/R to reverse the prolongation of IκB mRNA stability observed after LPS-alone treatment. Together, these effects on the important regulatory molecule IκB in the macrophage may contribute to the heightened inflammatory response observed after S/R.

A Neurotoxic Regimen of Methamphetamine Impairs Novelty Recognition As Measured by a Social Odor-based Task

Behavioural Brain Research. Jan, 2011  |  Pubmed ID: 20797410

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" regimen damages forebrain monoaminergic nerve terminals and produces subsequent cognitive deficits. Here we investigate performance on a social odor-based task, demonstrating enduring mAMPH-induced deficits in recognition memory. Three weeks after a neurotoxic mAMPH regimen, singly-housed male Long-Evans rats had four wooden beads placed in their home cage: three beads containing odors from their home cage (HC beads) and one bead from a cage of a rat not present in the colony room (N1 bead). Exploration times for each bead were recorded during three 1-min habituation trials separated by 1-min intertrial intervals. Twenty-four hours later, a 1-min memory test was conducted, in which animals were presented with two HC beads, one N1 bead, and one bead from another novel animal (N2). Saline- and mAMPH-treated rats showed similar, progressive decreases in exploration time for the N1 bead during the habituation trials, indicating equivalent short-term olfactory habituation to the novel odor. By contrast, during the subsequent memory test, saline-treated rats showed a strong preference for the N2 bead over the N1 bead while mAMPH-treated rats showed no preference. The use of the rats' primary sensory modality (olfaction) coupled with the social significance (from conspecifics) of the odors produces strong, long-lasting memories. Our results show that prior treatment with a neurotoxic regimen of mAMPH impairs long-term memory for the previously experienced odors. As compared with previously employed object recognition tasks, this test may be advantageous for investigating mAMPH-induced memory impairments in rodents.

Stromal Features Are Predictive of Disease Mortality in Oral Cancer Patients

The Journal of Pathology. Mar, 2011  |  Pubmed ID: 21294121

Worldwide, approximately 405 000 cases of oral cancer (OSCC) are diagnosed each year, with a rising incidence in many countries. Despite advances in surgery and radiotherapy, which remain the standard treatment options, the mortality rate has remained largely unchanged for decades, with a 5-year survival rate of around 50%. OSCC is a heterogeneous disease, staged currently using the TNM classification, supplemented with pathological information from the primary tumour and loco-regional lymph nodes. Although patients with advanced disease show reduced survival, there is no single pathological or molecular feature that identifies aggressive, early-stage tumours. We retrospectively analysed 282 OSCC patients for disease mortality, related to clinical, pathological, and molecular features based on our previous functional studies [EGFR, αvβ6 integrin, smooth muscle actin (SMA), p53, p16, EP4]. We found that the strongest independent risk factor of early OSCC death was a feature of stroma rather than tumour cells. After adjusting for all factors, high stromal SMA expression, indicating myofibroblast transdifferentiation, produced the highest hazard ratio (3.06, 95% CI 1.65-5.66) and likelihood ratio (3.6; detection rate: false positive rate) of any feature examined, and was strongly associated with mortality, regardless of disease stage. Functional assays showed that OSCC cells can modulate myofibroblast transdifferentiation through αvβ6-dependent TGF-β1 activation and that myofibroblasts promote OSCC invasion. Finally, we developed a prognostic model using Cox regression with backward elimination; only SMA expression, metastasis, cohesion, and age were significant. This model was independently validated on a patient subset (detection rate 70%; false positive rate 20%; ROC analysis 77%, p < 0.001). Our study highlights the limited prognostic value of TNM staging and suggests that an SMA-positive, myofibroblastic stroma is the strongest predictor of OSCC mortality. Whether used independently or as part of a prognostic model, SMA identifies a significant group of patients with aggressive tumours, regardless of disease stage.

Evaluation of the RIDA(®)QUICK Immunochromatographic Norovirus Detection Assay Using Specimens from Australian Gastroenteritis Incidents

Journal of Virological Methods. Apr, 2011  |  Pubmed ID: 21295607

A range of laboratory methods is now available for the detection of norovirus, a major cause of gastroenteritis. Recently, a commercial immunochromatographic assay for norovirus detection, the RIDA(®)QUICK assay, has become available, but there is still only limited information on its efficacy. This study examined the sensitivity and specificity of the RIDA(®)QUICK assay, using faecal material received for testing in a major diagnostic/reference laboratory in Australia. The sensitivity of the assay was found to be 83% and the specificity was 100%. No false positive norovirus results were found and the assay did not cross-react with common faecal viruses such as rotavirus, astrovirus, sapovirus and adenovirus. The assay was less reliable for genogroup I (GI) noroviruses than for genogroup II (GII) noroviruses. Genotypes detected by the assay included GII.1, GII.2, GII.3, GII.4, GII.6 and GII.7. The assay failed to detect any GI specimens in the test group. Genotypes not detected included GI.4 and GI.6. The assay was simple and quick to perform. It is valuable in a point-of-care situation or as a backup in a laboratory where a rapid initial norovirus result is required.

Effects of Prescription Omega-3-acid Ethyl Esters on Fasting Lipid Profile in Subjects with Primary Hypercholesterolemia

Journal of Cardiovascular Pharmacology. Apr, 2011  |  Pubmed ID: 21297494

This double-blind, randomized crossover study investigated the effects of 6 weeks of treatment with prescription omega-3-acid ethyl esters (POM3, 4 g/day) versus placebo (soy oil) on low-density lipoprotein cholesterol (LDL-C) and other aspects of the fasting lipid profile in 31 men and women with primary, isolated hypercholesterolemia (LDL-C 130-220 mg/dL and triglycerides less than 150 mg/dL while free of lipid-altering therapies). Mean ± standard error of the mean baseline concentrations of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein cholesterol, and triglycerides were 229 ± 3, 146 ± 3, 60 ± 2, 23 ± 2, and 113 ± 8 mg/dL, respectively. POM3 produced a modest increase from baseline in LDL-C (3.4%) versus the placebo response (-0.7%, P = 0.010). Significant changes (P < 0.05) for POM3 (placebo-corrected) were observed for very-low-density lipoprotein cholesterol (-18.8%), triglycerides (-18.7%), and HDL-C (3.3%). Nuclear magnetic resonance-determined very-low-density lipoprotein particle concentration and size and HDL particle concentration decreased significantly more with POM3 versus placebo, whereas LDL and HDL particle sizes increased significantly more with POM3 versus placebo. Total cholesterol, non-HDL-C, apolipoproteins A1 and B, and LDL particle concentration responses did not differ between treatments. These results did not confirm the hypothesis that POM3 treatment would lower LDL-C in primary, isolated hypercholesterolemia. Effects on other variables were consistent with prior results in mixed dyslipidemia.

The Toxin and Antidote Puzzle: New Ways to Control Insect Pest Populations Through Manipulating Inheritance

Bioengineered Bugs. Sep-Oct, 2011  |  Pubmed ID: 21876382

Insects carry out essential ecological functions, such as pollination, but also cause extensive damage to agricultural crops, and transmit human diseases such as malaria and dengue fever. Advances in insect transgenesis are making it increasingly feasible to engineer genes conferring desirable phenotypes, and gene drive systems are required to spread these genes into wild populations. Medea provides one solution, being able to spread into a population from very low initial frequencies through the action of a maternally-expressed toxin linked to a zygotically-expressed antidote. Several other toxin-antidote combinations are imaginable that distort the offspring ratio in favor of a desired transgene, or drive the population towards an all-male crash. We explore two such systems--Semele, which is capable of spreading a desired transgene into an isolated population in a confined manner; and Merea, which is capable of inducing a local population crash when located on the Z chromosome of a Lepidopteron pest.

Should Albumin Be Used in All Patients with Spontaneous Bacterial Peritonitis?

Canadian Journal of Gastroenterology = Journal Canadien De Gastroenterologie. Jul, 2011  |  Pubmed ID: 21876859

Patients with cirrhosis who develop spontaneous bacterial peritonitis (SBP) have been reported to experience a high incidence of renal impairment and mortality. Renal dysfunction is possibly related to altered systemic hemodynamics that leads to decreased effective arterial blood volume. Albumin, a plasma volume expander, has been investigated to determine whether it plays a role in patients with SBP. The current literature suggests that albumin can reduce renal impairment and mortality in high-risk SBP patients, defined as patients with a serum bilirubin level of greater than 68.4 μmol⁄L, a blood urea nitrogen level of greater than 10.7 mmol⁄L or a serum creatinine level greater than 88.4 μmol⁄L. The rationale for albumin and other volume expanders in SBP is discussed, accompanied by a review of the current literature.

The Fc Receptor-cytoskeleton Complex from Human Neutrophils

Journal of Proteomics. Dec, 2011  |  Pubmed ID: 21911091

The Fc receptor complex and its associated phagocytic cytoskeleton machinery were captured from the surface of live cells by IgG coated microbeads and identified by mass spectrometry. The random and independently sampled intensity values of peptides were similar in the control and IgG samples. After log transformation, the parent and fragment intensity values showed a normal distribution where ≥99.9% of the data was well above the background noise. Some proteins showed significant differences in intensity between the IgG and control samples by ANOVA followed by the Tukey-Kramer honestly significant difference test. However many proteins were specific to the IgG beads or the control beads. The set of detected cytoskeleton proteins, binding proteins and enzymes detected on the IgG beads were used to predict the network of actin-associated regulatory factors. Signaling factors/proteins such as PIK3, PLC, GTPases (such CDC42, Rho GAPs/GEFs), annexins and inositol triphosphate receptors were all identified as being specific to the activated receptor complex by mass spectrometry. In addition, the tyrosine kinase Fak was detected with the IgG coated beads. Hence, an activated receptor cytoskeleton complex and its associated regulatory proteins were captured from the surface of live human primary leukocytes.

Estimation of Estradiol in Mouse Serum Samples: Evaluation of Commercial Estradiol Immunoassays

Endocrinology. Nov, 2011  |  Pubmed ID: 21933867

The University of Virginia Center for Research in Reproduction Ligand Core performed an evaluation of nine commercial estradiol (E2) immunoassays for use with mouse serum. The evaluation had two components. 1) Recovery Studies: a mouse pool was spiked with E2 concentrations across the assay range, and percent recovery and parallelism to the assay standard curve were determined. 2) Correlation Studies: serum pools were collected from intact females, ovariectomized (OVX) and OVX-E2 treated mice and E2 assayed, then measured by gas chromatography/tandem mass spectrometry (GC/MSMS) for comparison to a gold standard method. Recovery results showed that E2 recovery from spiked mouse pools varied greatly (from <18% to >640%) among kits tested. However, three kits (DiaSorin Radioimmunoassay, Siemens Double Antibody RIA, and CalBiotech Enzyme Immunoassay) showed reasonable recoveries and parallelism. Data collected from the Correlation Study showed that values from intact, OVX and OVX-E2-treated mouse pools varied by several fold vs. GC/MSMS for most of the kits tested. The DiaSorin RIA and CalBiotech Enzyme Immunoassay Kits showed the best correlation to GC/MSMS. Unfortunately, while this evaluation was ongoing, the DiaSorin Kit was discontinued. In summary, the CalBiotech Kit was the only available assay tested that demonstrated good E2 parallelism to the assay standard curve and accuracy vs. a gold standard method (i.e. GC/MSMS). Also of note, the CalBiotech assay is sensitive and requires minimal sample volume. Therefore, based on these findings the CalBiotech E2 assay has been implemented for use in mouse serum samples within the Ligand Core.

Fluid Resuscitation with 5% Albumin Versus Normal Saline in Early Septic Shock: A Pilot Randomized, Controlled Trial

Journal of Critical Care. Dec, 2011  |  Pubmed ID: 22176806

PURPOSE: Randomized, controlled trials of fluid resuscitation in early septic shock face many logistic challenges. We describe the Fluid Resuscitation with 5% albumin versus Normal Saline in Early Septic Shock (PRECISE) pilot trial study design and report feasibility of patient recruitment. MATERIALS AND METHODS: Six Canadian academic centers enrolled adult patients with early suspected septic shock from the emergency department and intensive care unit department. Consent was deferred. Using concealed allocation, participants were randomized to either 5% albumin or 0.9% sodium chloride. Blinded fluid resuscitation started immediately and continued for 7 days in the intensive care unit. Target recruitment was established a priori at 2 patients per site per month. RESULTS: Fifty-one patients were enrolled; 50 patients received study fluid. We recruited a median of 2.5 patients (interquartile range [IQR], 1.5-3.0) per site per month into the trial. Median age and Acute Physiology and Chronic Health Evaluation II scores were 64.5 (IQR, 55.0-78.0) and 25.0 (IQR, 20.0-29.0), respectively. Most patients (n = 37 [74.0%]) were enrolled from the emergency department for a median of 1.6 hours (IQR, 0.8-3.5 hours) from their first hypotensive event and received a median of 2.4 L (IQR, 1.5-3.0 L) of resuscitation fluid before inclusion. Consent was deferred for 44 patients (89.8%). CONCLUSIONS: Patient recruitment into the PRECISE pilot trial met our prespecified feasibility targets, and the PRECISE team is planning the larger trial.

An Inexpensive, Fast, and Reliable Method for Vacuum Extraction of Soil and Plant Water for Stable Isotope Analyses by Mass Spectrometry

Rapid Communications in Mass Spectrometry : RCM. Oct, 2011  |  Pubmed ID: 21953958

The stable isotopes of water (hydrogen and oxygen isotopes) are of utmost interest in ecology and the geosciences. In many cases water has to be extracted directly from a matrix such as soil or plant tissue before isotopes can be analyzed by mass spectrometry. Currently, the most widely used technique for water is cryogenic vacuum extraction. We present a simple and inexpensive modification of this method and document tests conducted with soils of various grain size and tree core replicates taken on four occasions during 2010. The accuracies for sandy soils are between 0.4‰ and 3‰ over a range of 21‰ and 165‰ for δ(18)O and δ(2)H, respectively. Spiking tests with water of known isotope composition were conducted with soil and tree core samples; they indicate reliable precision after an extraction time of 15 min for sandy soils. For clayey soils and tree cores, the deviations were up to 0.63‰ and 4.7‰ for δ(18)O and δ(2)H, respectively. This indicates either that the extraction time should be extended or that mechanisms different from Rayleigh fractionation play a role. The modified protocol allows a fast and reliable extraction of large numbers of water samples from soil and plant material in preparation for stable isotope analyses.

Development and Independent Validation of a Prognostic Assay for Stage II Colon Cancer Using Formalin-fixed Paraffin-embedded Tissue

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology. Dec, 2011  |  Pubmed ID: 22067406

Current prognostic factors are poor at identifying patients at risk of disease recurrence after surgery for stage II colon cancer. Here we describe a DNA microarray-based prognostic assay using clinically relevant formalin-fixed paraffin-embedded (FFPE) samples.

Increased Mortality Associated with Methicillin-resistant Staphylococcus Aureus (MRSA) Infection in the Intensive Care Unit: Results from the EPIC II Study

International Journal of Antimicrobial Agents. Oct, 2011  |  Pubmed ID: 21798720

Controversy continues regarding whether the presence of meticillin resistance increases mortality risk in Staphylococcus aureus infections. In this study, we assessed the role of meticillin resistance in survival of patients with S. aureus infection included in the EPIC II point-prevalence study of infection in critically ill patients performed on 8 May 2007. Demographic, physiological, bacteriological and therapeutic data were collected for 13796 adult patients in 1265 participating Intensive Care Units (ICUs) from 75 countries on the study day. ICU and hospital outcomes were recorded. Characteristics of patients with meticillin-sensitive S. aureus (MSSA) and meticillin-resistant S. aureus (MRSA) infections were compared. Co-morbidities, age, Simplified Acute Physiology Score (SAPS) II, site of infection, geographical region and MRSA/MSSA were entered into a multivariate model, and adjusted odds ratios (ORs) [95% confidence interval (CI)] for ICU and hospital mortality rates were calculated. On the study day, 7087 (51%) of the 13796 patients were classified as infected. There were 494 patients with MRSA infections and 505 patients with MSSA infections. There were no significant differences between the two groups in use of mechanical ventilation or haemofiltration/haemodialysis. Cancer and chronic renal failure were more prevalent in MRSA than in MSSA patients. ICU mortality rates were 29.1% and 20.5%, respectively (P<0.01) and corresponding hospital mortality rates were 36.4% and 27.0% (P<0.01). Multivariate analysis of hospital mortality for MRSA infection showed an adjusted OR of 1.46 (95% CI 1.03-2.06) (P=0.03). In ICU patients, MRSA infection is therefore independently associated with an almost 50% higher likelihood of hospital death compared with MSSA infection.

Stability of Serrated Gold Coil Markers in Prostate Localization

Journal of Applied Clinical Medical Physics / American College of Medical Physics. 2011  |  Pubmed ID: 21844856

We investigated the stability of serrated gold coils (Visicoil) implanted within the prostate glands of patients undergoing definitive external beam radiotherapy for prostate cancer. Radiopaque Visicoils of diameter 0.75 mm and median length 3 cm (range 2-4 cm) were implanted, one into each lobe of the prostate glands of 30 patients planned for external beam treatment. The coils were visualized on CT simulation and again after 25 fractions of treatment (5 WK). Data from 30 patients were studied, of whom 19 also received androgen ablation therapy. The average change in the distance between the two coils over five weeks of treatment was 0.8mm (± 0.6 mm), with a maximum of 2.5 mm in one patient. Average residual errors (standard deviations) for the positions of individual coil segments after five weeks of therapy were only 0.7 mm LAT, 0.6 mm AP, and 0.4 mm SI. The average change in distance between the coils over five weeks compared favorably with published data regarding marker seed stability. Overall, less than a 2 mm margin (i.e., 2 standard deviations) would adequately compensate for positioning uncertainty of the coils in more than 95% of cases.

Philanthropy, Advocacy and Colon Cancer

Clinical Colorectal Cancer. Dec, 2011  |  Pubmed ID: 22122894

Dopamine D1 Receptor Antagonism Impairs Extinction of Cocaine-cue Memories

Behavioural Brain Research. Jan, 2012  |  Pubmed ID: 21871500

Increasingly, research suggests a role for dopamine D1 receptors in the consolidation of extinction of both appetitive and aversive memories. However, a role for D1 receptors in extinction of memories involving drug reward has yet to be established. Here we show that post-retrieval, but not delayed, systemic administration of the D1 receptor antagonist SCH23390 results in prolonged extinction of cocaine conditioned place preference (CPP), suggesting a critical role for D1 receptors in the consolidation of extinction of cocaine-cue memories.

Confinement of Gene Drive Systems to Local Populations: a Comparative Analysis

Journal of Theoretical Biology. Feb, 2012  |  Pubmed ID: 22094363

Mosquito-borne diseases such as malaria and dengue fever pose a major health problem through much of the world. One approach to disease prevention involves the use of selfish genetic elements to drive disease-refractory genes into wild mosquito populations. Recently engineered synthetic drive systems have provided encouragement for this strategy; but at the same time have been greeted with caution over the concern that transgenes may spread into countries and communities without their consent. Consequently, there is also interest in gene drive systems that, while strong enough to bring about local population replacement, are unable to establish themselves beyond a partially isolated release site, at least during the testing phase. Here, we develop simple deterministic and stochastic models to compare the confinement properties of a variety of gene drive systems. Our results highlight several systems with desirable features for confinement-a high migration rate required to become established in neighboring populations, and low-frequency persistence in neighboring populations for moderate migration rates. Single-allele underdominance and single-locus engineered underdominance have the strongest confinement properties, but are difficult to engineer and require a high introduction frequency, respectively. Toxin-antidote systems such as Semele, Merea and two-locus engineered underdominance show promising confinement properties and require lower introduction frequencies. Killer-rescue is self-limiting in time, but is able to disperse to significant levels in neighboring populations. We discuss the significance of these results in the context of a phased release of transgenic mosquitoes, and the need for characterization of local ecology prior to a release.

Treatment of Hospitalized Adult Patients with Severe Ulcerative Colitis: Toronto Consensus Statements

The American Journal of Gastroenterology. Feb, 2012  |  Pubmed ID: 22108451

The objective of this study was to provide updated explicit and relevant consensus statements for clinicians to refer to when managing hospitalized adult patients with acute severe ulcerative colitis (UC).

Identification and Quantification of Peptides and Proteins Secreted from Prostate Epithelial Cells by Unbiased Liquid Chromatography Tandem Mass Spectrometry Using Goodness of Fit and Analysis of Variance

Journal of Proteomics. Feb, 2012  |  Pubmed ID: 22120120

The proteins secreted by prostate cancer cells (PC3(AR)6) were separated by strong anion exchange chromatography, digested with trypsin and analyzed by unbiased liquid chromatography tandem mass spectrometry with an ion trap. The spectra were matched to peptides within proteins using a goodness of fit algorithm that showed a low false positive rate. The parent ions for MS/MS were randomly and independently sampled from a log-normal population and therefore could be analyzed by ANOVA. Normal distribution analysis confirmed that the parent and fragment ion intensity distributions were sampled over 99.9% of their range that was above the background noise. Arranging the ion intensity data with the identified peptide and protein sequences in structured query language (SQL) permitted the quantification of ion intensity across treatments, proteins and peptides. The intensity of 101,905 fragment ions from 1421 peptide precursors of 583 peptides from 233 proteins separated over 11 sample treatments were computed together in one ANOVA model using the statistical analysis system (SAS) prior to Tukey-Kramer honestly significant difference (HSD) testing. Thus complex mixtures of proteins were identified and quantified with a high degree of confidence using an ion trap without isotopic labels, multivariate analysis or comparing chromatographic retention times.

Knowledge and Attitudes Regarding Expanded Genetic Carrier Screening Among Women's Healthcare Providers

Fertility and Sterility. Feb, 2012  |  Pubmed ID: 22137493

To determine women's healthcare providers' knowledge and attitudes regarding genetic disorders and expanded genetic screening.

Neuroendocrine Dysfunction in Polycystic Ovary Syndrome

Steroids. Mar, 2012  |  Pubmed ID: 22172593

Polycystic ovarian syndrome (PCOS) is a common disorder characterized by ovulatory dysfunction and hyperandrogenemia (HA). Neuroendocrine abnormalities including increased gonadotropin-releasing hormone (GnRH) pulse frequency, increased luteinizing hormone (LH) pulsatility, and relatively decreased follicle stimulating hormone contribute to its pathogenesis. HA reduces inhibition of GnRH pulse frequency by progesterone, causing rapid LH pulse secretion and increasing ovarian androgen production. The origins of persistently rapid GnRH secretion are unknown but appear to evolve during puberty. Obese girls are at risk for HA and develop increased LH pulse frequency with elevated mean LH by late puberty. However, even early pubertal girls with HA have increased LH pulsatility and enhanced daytime LH pulse secretion, indicating the abnormalities may begin early in puberty. Decreasing sensitivity to progesterone may regulate normal maturation of LH secretion, potentially related to normally increasing levels of testosterone during puberty. This change in sensitivity may become exaggerated in girls with HA. Many girls with HA-especially those with hyperinsulinemia-do not exhibit normal LH pulse sensitivity to progesterone inhibition. Thus, HA may adversely affect LH pulse regulation during pubertal maturation leading to persistent HA and the development of PCOS.

Should All Women with PCOS Be Treated for Insulin Resistance?

Fertility and Sterility. Jan, 2012  |  Pubmed ID: 22192137

PRO--A large majority of women with PCOS have insulin resistance, compensatory hyperinsulinemia with consequent reproductive and metabolic abnormalities. Metformin has been shown to be effective therapy and could be used more widely in obese adolescents with hyperandrogenemia, a forerunner of PCOS. CON--The severity of insulin resistance is highly variable in women with PCOS and may not be clinically relevant in milder phenotypes. Treatment should be directed at specific metabolic or reproductive problems and insulin sensitizing drugs are not always the optimum therapy.

The PRECISE RCT: Evolution of an Early Septic Shock Fluid Resuscitation Trial

Transfusion Medicine Reviews. Jan, 2012  |  Pubmed ID: 22222146

Severe sepsis and septic shock are the most common reasons for admission to an intensive care unit; and the risk of death is substantial, estimated at approximately 40%. Evidence suggests that early resuscitation strategies that include the use of resuscitation fluids, antibiotics, blood, and inotropes reduce death. Although fluid resuscitation is an immediate life-saving intervention, a fundamental question that remains unanswered is whether the type of resuscitation fluid impacts survival when it is initiated very early in the course of septic shock. A randomized controlled trial published in 2008 confirmed that hydroxyethyl starch fluids cause acute renal failure defined by the requirement for renal replacement therapy. In contrast, a subgroup analysis from a randomized controlled trial suggests that 4% albumin fluid may reduce death from severe sepsis; however, these findings require confirmation in a large randomized trial. Our team is planning a pragmatic early septic shock fluid resuscitation trial that will compare the effectiveness of 5% albumin vs normal saline on 90-day mortality (PRECISE). In this article, we summarize the scientific rationale and inherent challenges associated with the conduct of PRECISE, the background work and planning elements that have been undertaken, and the PRECISE RCT protocol with rationale and justifications provided for the chosen population, the interventions, and the outcome measures.

Canadian Cost-utility Analysis of Initiation and Maintenance Treatment with Anti-TNF-α Drugs for Refractory Crohn's Disease

Journal of Crohn's & Colitis. Feb, 2012  |  Pubmed ID: 22261531

Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract. Symptoms include but are not limited to abdominal pain, nausea, emesis, and diarrhea. Anti-TNF-α drugs are increasingly being used in patients with CD who have inadequate response to conventional therapy. However, these medications are quite expensive. The objective of this study is to evaluate the cost-utility of two anti-TNF-α drugs (infliximab, adalimumab) for refractory CD.

Fecal Transplant Via Retention Enema for Refractory or Recurrent Clostridium Difficile Infection

Archives of Internal Medicine. Jan, 2012  |  Pubmed ID: 22271132

Capture and Qualitative Analysis of the Activated Fc Receptor Complex from Live Cells

Current Protocols in Protein Science / Editorial Board, John E. Coligan ... [et Al.]. Feb, 2012  |  Pubmed ID: 22294325

This unit describes the isolation of activated Fc receptor complexes from RAW 264.7 macrophages using live-cell affinity receptor chromatography (LARC). The Fc receptor complex is activated and captured by IgG-coated microbeads on the surface of live macrophages. After the cells are disrupted, the receptor complexes are isolated by washing and sucrose gradient ultracentrifugation. Soluble proteins associated with the receptor complex are then eluted from the beads using a stepwise series of salt buffers and aqueous acetonitrile. The eluted proteins and the residual insoluble proteins on the beads can then be digested with trypsin and subjected to liquid chromatography, electrospray ionization, and tandem mass spectrometry (LC-ESI-MS/MS). Controls include IgG-coated beads incubated with crude cell lysates or growth medium and beads coated with oxidized LDL or bovine serum albumin. Using this method, proteins present in IgG-FcR complexes can be distinguished from those in control scavenger receptor complexes (oxLDL or BSA). Thus, LARC is capable of detecting specific members of IgG receptor supramolecular complexes.

Quantitative Statistical Analysis of Standard and Human Blood Proteins from Liquid Chromatography, Electrospray Ionization and Tandem Mass Spectrometry

Journal of Proteome Research. Feb, 2012  |  Pubmed ID: 22316523

It will be important to determine if the parent and fragment ion intensity results of liquid chromatography, electrospray ionization and tandem mass spectrometry (LC-ESI-MS/MS) experiments have been randomly and independently sampled from a normal population for the purpose of statistical analysis by general linear models and ANOVA. The tryptic parent peptide and fragment ion m/z and intensity data in the mascot generic files from LC-ESI-MS/MS of purified standard proteins, and human blood protein fractionated by partition chromatography, were parsed into a Structured Query Language (SQL) database and were matched with protein and peptide sequences provided by the X!TANDEM algorithm. The many parent and/or fragment ion intensity values were log transformed, tested for normality and analyzed using the generic Statistical Analysis System (SAS). Transformation of both parent and fragment intensity values by logarithmic functions yielded intensity distributions that closely approximate the log normal distribution. ANOVA models of the transformed parent and fragment intensity values showed significant effects of treatments, proteins, and peptides, as well as parent versus fragment ion types, with a low probability of false positive results. Transformed parent and fragment intensity values were compared over all sample treatments, proteins or peptides by the Tukey-Kramer Honestly Significant Difference (HSD) test. The approach provided a complete and quantitative statistical analysis of LC-ESI-MS/MS data from human blood.

S100P-Binding Protein, S100PBP, Mediates Adhesion Through Regulation of Cathepsin Z in Pancreatic Cancer Cells

The American Journal of Pathology. Feb, 2012  |  Pubmed ID: 22330678

Several S100 proteins are up-regulated in pancreatic ductal adenocarcinoma (PDAC), the most significant being S100P. We previously reported on S100PBP, a binding partner of S100P, that shows no homology to any described protein and whose functions are completely unknown. To determine S100PBP expression across human tissues and organs, IHC was performed using both multiorgan- and in-house-constructed pancreatic TMAs. To establish S100PBP functions, cell lines with either stably overexpressed or silenced S100PBP were generated and investigated using Affymetrix gene expression arrays and complementary functional assays. We show that S100PBP is differentially expressed in various healthy and tumor specimens, which is both cancer- and tissue-type dependent. In healthy pancreas, S100PBP is expressed in the nuclear/perinuclear region of both exocrine and endocrine compartments. In early precancerous lesions, S100PBP is translocated to the cytoplasm, whereas in PDAC and metastatic lesions, its expression is significantly diminished. The most pronounced phenotypic change after manipulation of S100PBP expression was seen in adhesion; this was significantly reduced after S100PBP up-regulation and increased after S100PBP silencing. Up-regulation or silencing of S100PBP also led to a concomitant change in the levels of the protease cathepsin Z, the silencing of which significantly reduced PDAC cell adhesion. We further demonstrate that the interaction of cathepsin Z with arginine-glycine-aspartic acid-binding integrins, specifically αvβ5, mediates the changes seen in adhesion of PDAC cells.

Phase I Trial of Ixabepilone Administered As Three Oral Doses Each Separated by 6 Hours Every 3 Weeks in Patients with Advanced Solid Tumors

Investigational New Drugs. Feb, 2012  |  Pubmed ID: 22331549

Background Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or βIII-tubulin. Materials and Methods This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. Results Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90-100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. Conclusions On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

Running Wheel Exercise Ameliorates Methamphetamine-induced Damage to Dopamine and Serotonin Terminals

Synapse (New York, N.Y.). Jan, 2012  |  Pubmed ID: 21953518

Repeated administration of methamphetamine (mAMPH) to rodents in a single-day "binge" produces long-lasting damage to dopaminergic and serotonergic terminals. Because previous research has demonstrated that physical activity can ameliorate nigrostriatal injury, this study investigated whether voluntary exercise in rats can alter the monoaminergic damage resulting from a neurotoxic mAMPH binge. Adult male rats were allowed constant access to running wheels or kept in nonwheel cages for three weeks, then given a binge dosing regimen of mAMPH or saline. The rats were returned to their original environments for three additional weeks post-mAMPH. [(125) I]RTI-55 binding and autoradiography was used to quantify dopamine transporters (DAT), and radioimmunocytochemistry was used to quantify striatal tyrosine hydroxylase (TH). Binge mAMPH treatment significantly reduced striatal DAT and TH in a regionally specific pattern; with greatest effects in ventral caudate-putamen (CP) and relative sparing of the nucleus accumbens septi (NAc). The effects of mAMPH on striatal DAT and TH were ameliorated in the running, compared to the sedentary, animals. Also, mAMPH was found to reduce [(125) I]RTI-55 binding to serotonin transporters (SERT) in frontoparietal cortex, and this too was significantly attenuated by exercise. Additional correlational analyses showed that the post-mAMPH running of individual animals predicted the amelioration of striatal DAT and TH as well as frontoparietal SERT. Overall, voluntary exercise significantly diminished mAMPH-induced forebrain monoaminergic damage. The significant correlations between post-mAMPH exercise and markers of monoaminergic terminal integrity provide novel evidence that voluntary exercise may exert beneficial effects on behavior in recovering mAMPH addicts.

Work Aversion and Associated Changes in Dopamine and Serotonin Transporter After Methamphetamine Exposure in Rats

Psychopharmacology. Jan, 2012  |  Pubmed ID: 21643674

Methamphetamine (mAMPH) administration in animals can lead to a variety of cognitive and behavioral deficits. We previously reported non-acute reversal learning impairments after a single-day administration of mAMPH, providing evidence of this drug's selective effects on inhibitory control. Effortful decision-making (i.e., how much effort to invest in rewards) is an aspect of cognition that has not yet been explored after mAMPH.

Readiness for Change Predicts Outcomes of Functional Rehabilitation Following Motor Vehicle Accident

Journal of Occupational Rehabilitation. Mar, 2012  |  Pubmed ID: 21792539

Introduction Previous research has found pre-treatment motivational readiness to engage in pain self-management to be associated with completion of a rehabilitation program. This preliminary study examined this relationship, as well as the ability of pre-treatment readiness to change to predict clinical decisions of post-treatment functional work capacity. Methods The sample consisted of 106 individuals involved in a tertiary functional rehabilitation program for motor vehicle accident (MVA) survivors. The Multidimensional Pain Inventory (MPI) and Pain Stages of Change Questionnaire (PSOCQ) were completed prior to treatment. Results Hierarchical logistic regression analyses revealed that PSOCQ profile scores (P = 0.008), including higher individual PSOCQ contemplation (OR = 5.30; P = 0.017) and action (OR = 5.16; P = 0.049) scores, significantly increased the likelihood of completing the functional rehabilitation program. Clinical decisions about functional work capacity were predicted by MPI profile scores (P = 0.001), and this model was significantly improved by the addition of PSOCQ scores (P = 0.037). Lower MPI interference (OR = 5.41; P = 0.002), and higher MPI affective distress (OR = 2.81; P = 0.010), MPI support (OR = 1.72; P = 0.027), and PSOCQ action (OR = 5.35; P = 0.038) scores were significant predictors of clinicians' decisions regarding functional work capacity in the final model that identified 88% of those judged capable of returning to work and 63% of those who were judged not capable of returning to work. Conclusions This preliminary study suggests that readiness to self-manage pain is an important predictor of both completion of functional rehabilitation program and clinicians' decisions regarding functional work capacity after an MVA. The latter outcome appears to be more complex, influenced both by motivational readiness to engage in pain self-management and cognitive-behavioral adaptation to pain.

Role of Androgen Receptor CAG Repeat Polymorphism Length in Hypothalamic Progesterone Sensitivity in Hyperandrogenic Adolescent Girls

Endocrine. Feb, 2012  |  Pubmed ID: 22081303

Transscleral Albumin Diffusion and Suprachoroidal Albumin Concentration in Uveal Effusion Syndrome

Retina (Philadelphia, Pa.). Jan, 2012  |  Pubmed ID: 21811210

To test the hypothesis that uveal effusion syndrome is caused by reduced transscleral albumin permeability.