Arabinogalactan-folic acid-drug conjugate for targeted delivery and target-activated release of anticancer drugs to folate receptor-overexpressing cells.

Folic acid (FA) is a high affinity ligand (K(d) = 0.1-1 nM) of folate receptors (FRs) responsible for cellular uptake of folates via receptor-mediated endocytosis. FRs are frequently overexpressed in malignant epithelial cells including ovary, brain, kidney, breast, colon, and lung.

Prenylation-deficient G protein gamma subunits disrupt GPCR signaling in the zebrafish.

Prenylation of G protein gamma (gamma) subunits is necessary for the membrane localization of heterotrimeric G proteins and for functional heterotrimeric G protein coupled receptor (GPCR) signaling. To evaluate GPCR signaling pathways during development, we injected zebrafish embryos with mRNAs encoding Ggamma subunits mutated so that they can no longer be prenylated. Low-level expression of these prenylation-deficient Ggamma subunits driven either ubiquitously or specifically in the primordial germ cells (PGCs) disrupts GPCR signaling and manifests as a PGC migration defect.

Development of an electronic medical record-based clinical decision support tool to improve HIV symptom management.

Common symptoms associated with HIV disease and its management are often underrecognized and undertreated. A clinical decision support tool for symptom management was developed within the Veterans Health Administration electronic medical record (EMR), aiming at increasing provider awareness of and response to common HIV symptoms. Its feasibility was studied in March to May 2007 by implementing it within a weekly HIV clinic, comparing a 4-week intervention period with a 4-week control period.

Comparing narrative and multiple-choice formats in online communication skill assessment.

Objectives: We compared multiple-choice and open-ended responses collected from a web-based tool designated 'Case for Change', which had been developed for assessing and teaching medical students in the skills involved in integrating sexual risk assessment and behaviour change discussions into patient-centred primary care visits.

Methods: A total of 111 Year 3 students completed the web-based tool. A series of videos from one patient encounter illustrated how a clinician uses patient-centred communication and health behaviour change skills while caring for a patient presenting with a urinary tract infection.

Raltegravir with unboosted atazanavir 300 mg twice daily in antiretroviral treatment-experienced participants.

Raltegravir (RAL) is an HIV integrase inhibitor characterized by potent antiretroviral activity, few adverse effects, and lack of cross-resistance to other antiretroviral (ARV) agents. RAL is emerging as a component of effective alternative ARV therapy for those who experience therapeutic failure or intolerance to reverse transcriptase inhibitors (NRTI and NNRTI) and ritonavir (RTV)-boosted protease inhibitor (PI) containing regimens. The combination of RAL with atazanavir (ATV) without a concomitant NRTI-based backbone or the inclusion of RTV may provide an alternative strategy for those unable to tolerate these latter ARV agents.

Ecosystem services and economic theory: integration for policy-relevant research.

It has become essential in policy and decision-making circles to think about the economic benefits (in addition to moral and scientific motivations) humans derive from well-functioning ecosystems. The concept of ecosystem services has been developed to address this link between ecosystems and human welfare. Since policy decisions are often evaluated through cost-benefit assessments, an economic analysis can help make ecosystem service research operational.

In vivo imaging of zebrafish digestive organ function using multiple quenched fluorescent reporters.

Optical clarity of larvae makes the zebrafish ideal for real-time analyses of vertebrate organ function through the use of fluorescent reporters of enzymatic activities. A key function of digestive organs is to couple the generation of enzymes with mechanical processes that enable nutrient availability and absorption. However, it has been extremely difficult, and in many cases not possible, to directly observe digestive processes in a live vertebrate.

A "block and rescue" pharmacogenetic approach to dissecting a biochemical pathway controlling germ cell migration.

Specific small molecule inhibitors of the de novo cholesterol synthesis pathway (statins) and the protein prenylation pathway were used to study their effect on germ cell migration. Hydroxymethylglutaryl-Coenzyme A reductase (HMGCoAR) catalyzes the rate-limiting step in the mevalonate pathway that produces isoprenoids and cholesterol. Pharmacological HMGCoAR inhibition by statins alters zebrafish development and germ cell migration.

A web based resource characterizing the zebrafish developmental profile of over 16,000 transcripts.

Using a spotted 65-mer oligonucleotide microarray, we have characterized the developmental expression profile from mid-gastrulation (75% epiboly) to 5 days post-fertilization (dpf) for >16,000 unique transcripts in the zebrafish genome. Microarray profiling data sets are often immense, and one challenge is validating the results and prioritizing genes for further study. The purpose of the current study was to address such issues, as well as to generate a publicly available resource for investigators to examine the developmental expression profile of any of the over 16,000 zebrafish genes on the array.

p53 activation by knockdown technologies.

Morpholino phosphorodiamidate antisense oligonucleotides (MOs) and short interfering RNAs (siRNAs) are commonly used platforms to study gene function by sequence-specific knockdown. Both technologies, however, can elicit undesirable off-target effects. We have used several model genes to study these effects in detail in the zebrafish, Danio rerio.

Genome-wide reverse genetics framework to identify novel functions of the vertebrate secretome.

Background: Understanding the functional role(s) of the more than 20,000 proteins of the vertebrate genome is a major next step in the post-genome era. The approximately 4,000 co-translationally translocated (CTT) proteins - representing the vertebrate secretome - are important for such vertebrate-critical processes as organogenesis. However, the role(s) for most of these genes is currently unknown.

Patterns of responses on health-related quality of life questionnaires among patients with HIV/AIDS.

Background: Health-related quality of life (HRQoL) has become an important facet of HIV/AIDS research. Typically, the unit of analysis is either the total instrument score or subscale score. Developing a typology of responses across various HRQoL measures, however, may advance understating of patients' perspectives.

Faculty and student participation in online discussions of palliative care scenarios.

Background And Objectives: The use of online discussion is increasing in medical education curricula. Few studies have explored factors that affect patterns of participation in such an online learning environment. In this study, we examined how medical students interacted with one another in online discussions of end-of-life care during family medicine clerkships.

To PEG or not to PEG: a review of evidence for placing feeding tubes in advanced dementia and the decision-making process.

Percutaneous endoscopic gastrostomy (PEG) has evolved into a common low-risk procedure in current medical practice. Clinical evidence supporting the use of tube feedings in patients with advanced dementia is clearly lacking, yet PEG procedures continue to be performed in a large number of these cases. In fact, multiple studies have shown that feeding tubes seldom are effective in improving nutrition, maintaining skin integrity by increased protein intake, preventing aspiration pneumonia, minimizing suffering, improving functional status, or extending life.

Zebrafish fat-free is required for intestinal lipid absorption and Golgi apparatus structure.

The zebrafish fat-free (ffr) mutation was identified in a physiological screen for genes that regulate lipid metabolism. ffr mutant larvae are morphologically indistinguishable from wild-type sibling larvae, but their absorption of fluorescent lipids is severely impaired. Through positional cloning, we have identified a causative mutation in a highly conserved and ubiquitously expressed gene within the ffr locus.

Population meta-analysis of low plasma glucose thresholds in full-term normal newborns.

There is extreme variation in the definition of low plasma glucose levels in newborn infants in the first postnatal days, ranging from < 30 to < or = 60 mg/dL. The goal of the present study was to define low thresholds (< or = 5th percentile) of plasma glucose concentrations in full-term normal newborns during the first 72 hours of life. Population meta-analysis was performed on published studies of neonatal hypoglycemia ascertained by MedLine search.

Coordinate control of cell cycle regulatory genes in zebrafish development tested by cyclin D1 knockdown with morpholino phosphorodiamidates and hydroxyprolyl-phosphono peptide nucleic acids.

During early zebrafish (Danio rerio) development zygotic transcription does not begin until the mid-blastula transition (MBT) 3 h after fertilization. MBT demarcates transition from synchronous short cell cycles of S and M phases exclusively to full cycles encompassing G1 and G2 phases. Transcriptional profiling and RT-PCR analyses during these phases enabled us to determine that this shift corresponds to decreased transcript levels of S/M phase cell cycle control genes (e.

Free association reconsidered: the talking cure, the writing cure.

It has not been fully appreciated that psychoanalysis, in its origins, was both a talking and a writing cure. When Freud instructed his patients to say whatever came to mind, using words to verbalize that which was preconscious replaced the hypnotic technique as the "talking cure" and was the beginning of the psychoanalytic method. Freud used writing to an internal other in his self-analysis, and his free association writing has had an enormous influence on psychoanalysis.

D-glucuronyl C5-epimerase acts in dorso-ventral axis formation in zebrafish.

Background: Heparan sulfate (HS) is an ubiquitous component of the extracellular matrix that binds and modulates the activity of growth factors, cytokines and proteases. Animals with defective HS biosynthesis display major developmental abnormalities however the processes that are affected remain to be defined. D-glucuronyl-C5-epimerase (Glce) is a key HS chain modifying enzyme that catalyses the conversion of glucuronic acid into iduronic acid, a biosynthetic step that enhances HS biological activity.

Breaking the cycles of violence.

Violence begets violence and it is important to understand how cycles of violence are perpetuated if we are to find solutions to the global problems they present. A multi-disciplinary group of The International Work Group on Death, Dying and Bereavement has developed a model of the cyclical events that perpetuate violence at all levels including the family, community, nation, and world. This includes the Violent Act(s), the Perception of the Violent Act(s), the Immediate Response, Legitimising Authority, Destructive Codes, and Inflammatory/Polarising Strategies.

Diversity in secreted PLA2-IIA activity among inbred mouse strains that are resistant or susceptible to Apc Min/+ tumorigenesis.

The secreted phospholipase A2 type IIA (Pla2g2a) gene was previously identified as a modifier of intestinal adenoma multiplicity in Apc Min/+ mice. To determine if intestinal secreted phospholipase A2 (sPLA2) activity was also attenuated in susceptible strains, we developed a sensitive assay to directly quantitate sPLA2 activity in the murine intestinal tract utilizing a fluorescent BODIPY-labeled phospholipid substrate. Here, we report assay conditions that distinguish between secreted and cytosolic PLA2 enzyme activities in extracts of intestinal tissue.

Improving cancer pain management through a system wide commitment.

Despite the well documented need for better cancer pain management there is little evidence that conventional educational approaches have improved clinical practice. This article discusses strategies to improve cancer pain management, focusing particular attention to institutional approaches that contain quality assurance (QA) and quality improvement (QI) efforts. An innovative pain management project is described that includes an in-depth evaluation of system and provider strengths and weaknesses; a system-wide commitment to cancer pain management; patient/family, nurse, pharmacist, and physician collaborative teams; use of a Washington State law allowing pharmacist prescriptive authority of narcotics and other drugs within a prescribed treatment protocol; and QA and QI efforts to improve and document performance.