Absorptive transport of amino acids by the rat colon.

The capacity of the colon to absorb microbially produced amino acids (AAs) and the underlying mechanisms of AA transport are incompletely defined. We measured the profile of 16 fecal AAs along the rat ceco-colonic axis and compared unidirectional absorptive AA fluxes across mucosal tissues isolated from the rat jejunum, cecum, and proximal colon using an Ussing chamber approach, in conjunction with 1H-NMR and ultra-performance liquid chromatography-mass spectrometry chemical analyses. Passage of stool from cecum to midcolon was associated with segment-specific changes in fecal AA composition and a decrease in total AA content. Simultaneous measurement of up to 16 AA fluxes under native luminal conditions, with correction for endogenous AA release, demonstrated absorptive transfer of AAs across the cecum and proximal colon at rates comparable (30-80%) to those across the jejunum, with significant Na+-dependent and H+-stimulated components. Expression profiling of 30 major AA transporter genes by quantitative PCR revealed comparatively high levels of transcripts for 20 AA transporters in the cecum and/or colon, with the levels of 12 exceeding those in the small intestine. Our results suggest a more detailed model of major apical and basolateral AA transporters in rat colonocytes and provide evidence for a previously unappreciated transfer of AAs across the colonic epithelium that could link the prodigious metabolic capacities of the luminal microbiota, the colonocytes, and the body tissues.NEW & NOTEWORTHY This study provides evidence for a previously unappreciated transfer of microbially generated amino acids across the colonic epithelium under physiological conditions that could link the prodigious metabolic capacities of the luminal microbiota, the colonocytes, and the body tissues. The segment-specific expression of at least 20 amino acid transporter genes along the colon provides a detailed mechanistic basis for uniport, heteroexchange, Na+-cotransport, and H+-cotransport components of colonic amino acid absorption

Safety, pharmacokinetics, and pharmacodynamics of escalating repeat doses of GSK249320 in patients with stroke.

Background and purposeRestorative therapies have the potential to improve function and reduce disability after stroke with a wide therapeutic window. The current study evaluated GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule myelin-associated glycoprotein and also protects oligodendrocytes.MethodsPatients with mild-moderate stroke were randomized to intravenous GSK249320 (1, 5, or 15 mg/kg per infusion, in escalating cohorts of 8-9 subjects) versus placebo (n=17). Infusion 1 was 24 to 72 hours after stroke; infusion 2 was 9 ± 1 days later. The primary objective evaluated safety and tolerability, and the secondary objectives evaluated immunogenicity, pharmacokinetics, biomarkers, neurophysiology, and motor function.ResultsBaseline (n=42) characteristics were similar across treatment groups. No safety concerns were found based on adverse events, examination, vital signs, ECG, nerve conduction tests, brain imaging, motor function testing, and laboratory studies. Two of the 25 subjects dosed with GSK249320 developed transient antidrug antibodies after infusion 1. The pharmacokinetics profile was as expected for an IgG1 type monoclonal antibody. Serum levels of the biomarker S100β did not differ between groups. Global outcome measures were similar across groups. Modality-specific end points could be consistently measured in the first few days after stroke, and one of these, gait velocity, demonstrated a trend toward improvement with GSK249320 compared with placebo.ConclusionsGSK249320 was generally well tolerated. No major safety issues were identified in this first study of a monoclonal antibody to modulate the neurobiology of brain repair after stroke. Future studies might explore the efficacy of GSK249320 as a restorative therapy for stroke. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique Identifier: NCT00833989

A Description of the Development, Capabilities, and Operational Status of the Test SLATE Data Acquisition System at the National Transonic Facility

The paper will present a brief background of the previous data acquisition system at the National Transonic Facility (NTF) and the reasoning and goals behind the upgrade to the current Test SLATE (Test Software Laboratory and Automated Testing Environments) data acquisition system. The components, performance characteristics, and layout of the Test SLATE system within the NTF control room will be discussed. The development, testing, and integration of Test SLATE within NTF operations will be detailed. The operational capabilities of the system will be outlined including: test setup, instrumentation calibration, automatic test sequencer setup, data recording, communication between data and facility control systems, real time display monitoring, and data reduction. The current operational status of the Test SLATE system and its performance during recent NTF testing will be highlighted including high-speed, frame-by-frame data acquisition with conditional sampling post-processing applied. The paper concludes with current development work on the system including the capability for real-time conditional sampling during data acquisition and further efficiency enhancements to the wind tunnel testing process

Off-Label Use of Transmucosal Ketamine as a Rapidacting Antidepressant: A Retrospective Chart Review

Objective: This study evaluated the effectiveness and safety of subanesthetic doses of ketamine using an off-label, transmucosal administration route in patients with treatment-resistant depression. Methods: A retrospective chart review was conducted to identify patients who met the inclusion criteria for treatment-resistant major depressive disorder. Seventeen such patients who received subanesthetic doses of ketamine were included. Patient demographics, efficacy (drug refill, clinician notes), side effects, and concurrent medications were assessed. Results: Benefit from low-dose transmucosal ketamine was noted in 76% of subjects (average age 48 years, 88% female), with a dose duration lasting 7–14 days. No notable side effects were noted. The most common classes of concurrent medications to which ketamine was added were serotonin–norepinephrine reuptake inhibitors (59%), stimulants (47%), folate replacement (47%), and benzodiazepines (47%). Conclusion: Our results provide preliminary evidence of the effectiveness and safety of lowdose transmucosal ketamine in treatment-resistant patients. A controlled, prospective pilot study is warranted to validate these findings

Inhibition of lipid oxidation increases glucose metabolism and enhances 2-deoxy-2-[¹⁸F]fluoro-D-glucose uptake in prostate cancer mouse xenografts

Includes bibliographic references.PURPOSE: Prostate cancer (PCa) is the second most common cause of cancer-related death among men in the United States. Due to the lipid-driven metabolic phenotype of Pca, imaging with 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) is suboptimal, since tumors tend to have low avidity for glucose. PROCEDURES: We have used the fat oxidation inhibitor etomoxir (2-[6-(4-chlorophenoxy)-hexyl]oxirane-2-carboxylate) that targets carnitine-palmitoyl-transferase-1 (CPT-1) to increase glucose uptake in PCa cell lines. Small hairpin RNA specific for CPT1A was used to confirm the glycolytic switch induced by etomoxir in vitro. Systemic etomoxir treatment was used to enhance [¹⁸F]FDG-positron emission tomography ([¹⁸F]FDG-PET) imaging in PCa xenograft mouse models in 24 h. RESULTS: PCa cells significantly oxidize more of circulating fatty acids than benign cells via CPT-1 enzyme, and blocking this lipid oxidation resulted in activation of the Warburg effect and enhanced [¹⁸F]FDG signal in PCa mouse models. CONCLUSIONS: Inhibition of lipid oxidation plays a major role in elevating glucose metabolism of PCa cells, with potential for imaging enhancement that could also be extended to other cancers

The Grizzly, October 15, 1982

Students for Peace and Progress Get Started • Homecoming 1982 • Annual Parents Day a Success • Letters to the Editor • Opinion: Sorority Rushing Needs Revision • Lantern Format Undecided • Dance-a-Thon for Lupus • Japan: Big and Real • New Art at Myrin • Bear Booters Win Three • Now Hold it Just a Minute! • Grizzlies Win Third Straight • X-Country Wins • Penn Blasts Lady Bears 3-0https://digitalcommons.ursinus.edu/grizzlynews/1084/thumbnail.jp

Predicting functional gains in a stroke trial.

A number of therapies in development for patients with central nervous system injury aim to reduce disability by improving function of surviving brain elements rather than by salvaging tissue. The current study tested the hypothesis that, after adjusting for a number of clinical assessments, a measure of brain function at baseline would improve prediction of behavioral gains after treatment.Twenty-four patients with chronic stroke underwent baseline clinical and functional MRI assessments, received 6 weeks of rehabilitation therapy with or without investigational motor cortex stimulation, and then had repeat assessments. Thirteen baseline clinical/radiological measures were evaluated for ability to predict subsequent trial-related gains.Across all patients, bivariate analyses found that greater trial-related functional gains were predicted by (1) smaller infarct volume, (2) greater baseline clinical status, and (3) lower degree of activation in stroke-affected motor cortex on baseline functional MRI. When these 3 variables were further assessed using multivariate linear regression modeling, only lower motor cortex activation and greater clinical status at baseline remained significant predictors. Note that lower baseline motor cortex activation was also associated with larger increases in motor cortex activation after treatment.Lower motor cortex activity at baseline predicted greater behavioral gains after therapy, even after controlling for a number of clinical assessments. The boosts in cortical activity that paralleled behavioral gains suggest that in some patients, low baseline cortical activity represents underuse of surviving cortical resources. A measure of brain function might be important for optimal clinical decision-making in the context of a restorative intervention

Pneumonic Plague Cluster, Uganda, 2004

In a case cluster, pneumonic plague transmission was compatible with respiratory droplet rather than aerosol transmission

The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus

The frequency of antifungal resistance, particularly to the azole class of ergosterol biosynthetic inhibitors, is a growing global health problem. Survival rates for those infected with resistant isolates are exceptionally low. Beyond modification of the drug target, our understanding of the molecular basis of azole resistance in the fungal pathogen Aspergillus fumigatus is limited. We reasoned that clinically relevant antifungal resistance could derive from transcriptional rewiring, promoting drug resistance without concomitant reductions in pathogenicity. Here we report a genome-wide annotation of transcriptional regulators in A. fumigatus and construction of a library of 484 transcription factor null mutants. We identify 12 regulators that have a demonstrable role in itraconazole susceptibility and show that loss of the negative cofactor 2 complex leads to resistance, not only to the azoles but also the salvage therapeutics amphotericin B and terbinafine without significantly affecting pathogenicity