The Natural Product N-Palmitoyl-l-leucine Selectively Inhibits Late Assembly of Human Spliceosomes.

The spliceosome is a dynamic complex of five structural RNAs and dozens of proteins, which assemble together to remove introns from nascent eukaryotic gene transcripts in a process called splicing. Small molecules that target different components of the spliceosome represent valuable research tools to investigate this complicated macromolecular machine. However, the current collection of spliceosome inhibitors is very limited.

Tumors that mimic asbestos-related mesothelioma: time to consider a genetics-based tumor registry?

The diagnosis of mesothelioma is not always straightforward, despite known immunohistochemical markers and other diagnostic techniques. One reason for the difficulty is that extrapleural tumors resembling mesothelioma may have several possible etiologies, especially in cases with no meaningful history of amphibole asbestos exposure. When the diagnosis of mesothelioma is based on histologic features alone, primary mesotheliomas may resemble various primary or metastatic cancers that have directly invaded the serosal membranes.

Silver(I)-promoted conversion of thioamides to amidines: divergent synthesis of a key series of vancomycin aglycon residue 4 amidines that clarify binding behavior to model ligands.

Development of a general Ag(I)-promoted reaction for the conversion of thioamides to amidines is disclosed. This reaction was employed to prepare a key series of vancomycin aglycon residue 4 substituted amidines that were used to clarify their interaction with model ligands of peptidoglycan precursors and explore their resulting impact on antimicrobial properties.

Redesign of glycopeptide antibiotics: back to the future.

The glycopeptide antibiotics are the most important class of drugs used in the treatment of resistant bacterial infections including those caused by methicillin-resistant Staphylococcus aureus (MRSA). After more than 50 years of clinical use, the emergence of glycopeptide-resistant Gram-positive pathogens such as vancomycin-resistant enterococci (VRE) and vancomycin-resistant Staphylococcus aureus (VRSA) presents a serious global challenge to public health at a time few new antibiotics are being developed. This has led to renewed interest in the search for additional effective treatments including the development of new derivatives of the glycopeptide antibiotics.

Total synthesis of [Ψ[C(═S)NH]Tpg4]vancomycin aglycon, [Ψ[C(═NH)NH]Tpg4]vancomycin aglycon, and related key compounds: reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding.

The total synthesis of [Ψ[C(═S)NH]Tpg(4)]vancomycin aglycon (8) and its unique AgOAc-promoted single-step conversion to [Ψ[C(═NH)NH]Tpg(4)]vancomycin aglycon (7), conducted on a fully deprotected substrate, are disclosed. The synthetic approach not only permits access to 7, but it also allows late-stage access to related residue 4 derivatives, alternative access to [Ψ[CH(2)NH]Tpg(4)]vancomycin aglycon (6) from a common late-stage intermediate, and provides authentic residue 4 thioamide and amidine derivatives of the vancomycin aglycon that will facilitate ongoing efforts on their semisynthetic preparation. In addition to early stage residue 4 thioamide introduction, allowing differentiation of one of seven amide bonds central to the vancomycin core structure, the approach relied on two aromatic nucleophilic substitution reactions for formation of the 16-membered diaryl ethers in the CD/DE ring systems, an effective macrolactamization for closure of the 12-membered biaryl AB ring system, and the defined order of CD, AB, and DE ring closures.

A redesigned vancomycin engineered for dual D-Ala-D-ala And D-Ala-D-Lac binding exhibits potent antimicrobial activity against vancomycin-resistant bacteria.

The emergence of bacteria resistant to vancomycin, often the antibiotic of last resort, poses a major health problem. Vancomycin-resistant bacteria sense a glycopeptide antibiotic challenge and remodel their cell wall precursor peptidoglycan terminus from d-Ala-d-Ala to d-Ala-d-Lac, reducing the binding of vancomycin to its target 1000-fold and accounting for the loss in antimicrobial activity. Here, we report [Ψ[C(═NH)NH]Tpg(4)]vancomycin aglycon designed to exhibit the dual binding to d-Ala-d-Ala and d-Ala-d-Lac needed to reinstate activity against vancomycin-resistant bacteria.

Interventions to reduce the vasovagal reaction rate in young whole blood donors.

Background: There have been multiple reports concerning the predictors of fainting reactions in blood donors, but few attempts to reduce the rates of fainting reactions with concomitant rigorous attempts to monitor the success of the interventions.

Study Design And Methods: We used a retrospective observational cohort study design, comparing the likelihood of reaction from 213,031 allogeneic whole blood donations made by 17- to 22-year-old donors in two separate 12-month periods before and after the implementation of interventions to reduce reactions. The interventions were 1) a limit on the maximum percentage of estimated blood volume young donors could donate, 2) encouraging applied muscle tension during donation, and 3) providing approximately 500 mL of water before donation.

Delayed adverse reactions to blood donation.

Background: Blood donation is safe, but a small proportion of donors have delayed and/or off-site reactions that have the potential to lead to serious injury. This retrospective study sought to identify risk factors for delayed reactions (DRs).

Study Design And Methods: The records of 793,293 allogeneic whole blood and apheresis donations in 2007 were assessed for vasovagal reactions.

Using multiple data features improved the validity of osteoporosis case ascertainment from administrative databases.

Objectives: The aim was to construct and validate algorithms for osteoporosis case ascertainment from administrative databases and to estimate the population prevalence of osteoporosis for these algorithms.

Study Design And Setting: Artificial neural networks, classification trees, and logistic regression were applied to hospital, physician, and pharmacy data from Manitoba, Canada. Discriminative performance and calibration (i.

Development of a neurotoxic equivalence scheme of relative potency for assessing the risk of PCB mixtures.

PCBs produce adverse effects in humans and animals by several modes of action. The first mode of action is binding of coplanar or mono-ortho-PCBs to the aryl hydrocarbon (Ah) receptor leading to effects associated with the activation of this receptor. The remaining PCB congeners do not activate this receptor and have different modes of action underlying their toxic effects.

Evidence-based toxicology: a comprehensive framework for causation.

This paper identifies deficiencies in some current practices of causation and risk evaluation by toxicologists and formulates an evidence-based solution. The practice of toxicology focuses on adverse health events caused by physical or chemical agents. Some relations between agents and events are identified risks, meaning unwanted events known to occur at some frequency.

A model for non-communicable disease surveillance in Canada: the prairie pilot diabetes surveillance system.

The Prairie Pilot Diabetes Surveillance Project was organized to design and test a prototype population-based surveillance system, using administrative data, for a chronic disease exemplar - diabetes mellitus. The Canadian model of a public health surveillance system for chronic conditions described here specifies a process by which administrative and claims data arising from provincial health insurance programs are merged into an annual person-level summary file (APLSF), yielding one summary record for each person insured within each province. The APLSF is the basis for a variety of estimates, including incidence, prevalence, mortality, complication rates and health services utilization.

Development of an oral cancer slope factor for Aroclor 1268.

Rodent cancer bioassays indicate that substantial differences exist among PCB mixtures in terms of tumorigenic response, although no bioassay has been conducted with Aroclor 1268. The USEPA has used data from these studies to develop three sets of PCB cancer slope factors (CSFs) ranging from 0.07 to 2.

Geographic location of commercial plasma donation clinics in the United States, 1980-1995.

Objective: We examined the location of commercial plasma donation centers in the United States over the period 1980 to 1995 relative to the geographic distribution of risk behaviors associated with transfusion-transmissible infections.

Methods: The census tract locations of commercial source plasma clinics were described by measures of neighborhood social disadvantage and the prevalence of illicit drug use and active local drug economies.

Results: Depending on the measure of social environment used, commercial plasma clinics were 5 to 8 times more likely to be located in census tracts designated high-risk than would be expected by chance.

Incident cerebrovascular disease in rural and urban Alberta.

Study Objective: This study examines the pattern of incidence and health service utilisation of cerebrovascular disease cases in urban and rural areas within a publicly funded health care system.

Design: A population-based study covering a large geographic region, using population-wide administrative health data. Age- and sex-standardised incidence and mortality rates were calculated for rural and urban areas.

Regional comparisons of inpatient and outpatient patterns of cerebrovascular disease diagnosis in the province of Alberta.

The diagnosis of cerebrovascular disease (CBVD) from administrative data has been critically examined by epidemiologists in recent years. Much of the existing literature suggests that hospital discharge diagnoses based on ICD-9-CM codes are an unreliable source of information for determining a diagnosis of stroke, particularly when four- and five-digit codes are used. We examined how diagnoses for CBVD in hospital inpatient and outpatient facilities vary between rural and urban areas and among the 16 administrative health regions.

Evaluation of the carcinogenicity of 1,1-dichloroethylene (vinylidene chloride).

The U.S. Environmental Protection Agency has classified 1,1-dichloroethylene (vinylidene chloride; VDC) as a "C" carcinogen and has developed an inhalation unit risk value and an oral cancer slope factor for this chemical.