TIR-containing adaptors in Toll-like receptor signalling.

While the Toll-like receptors (TLRs) are responsible for the recognition and response to pathogen ligands, increasing evidence suggests that the family of five cytosolic Toll/IL-1 receptor (TIR) adaptor proteins also play a crucial role in the specificity of the response. Genetic studies in mice, and increasingly in human polymorphic populations, have given us a greater understanding the role these adaptors play in orchestrating and coordinating the multifaceted immune response to multiple exogenous threats. Importantly, with growing evidence of the critical role TLRs play in responses to host danger signals and autoimmune disease, a more comprehensive understanding and appreciation of the role these adaptors play in disease progression may provide future targets for therapeutic intervention in human disease.

Does caring for your spouse harm one's health? Evidence from a United States nationally-representative sample of older adults.

The purpose of this article is to investigate the relationship between spousal care-giving and declines in functioning and self-rated health among older care-givers. The authors used data from the 2000 and 2002 waves of the United States Health and Retirement Study, a biennial longitudinal survey of a nationally representative cohort of adults aged 50 or more years. Two outcomes were examined, declines in functioning and declines in self-rated health.

Imaging and analytical methods as applied to the evaluation of vasculature and hypoxia in human brain tumors.

Tissue hypoxia results from the interaction of cellular respiration, vascular oxygen carrying capacity, and vessel distribution. We studied the relationship between tumor vasculature and regions of low pO(2) using quantitative analysis of binding of the 2-nitroimidazole EF5 given to patients intravenously (21 mg/kg) approximately 24 h preceding surgery. We describe new computer algorithms for determining EF5 binding as a function of radial distance from individual blood vessels and converting this value to tissue pO(2).

The in vitro and in ovo responses of chickens to TLR9 subfamily ligands.

Although Toll-like receptors (TLRs) have been well characterised in mammals, less work has been carried out in non-mammalian species, such as chickens. In this study the response of chicken cells to the TLR9 subfamily of ligands was characterised in vitro and in ovo. It was found that even though chickens appear to have only one functional receptor to represent the TLR9 subfamily, stimulation of chicken splenocytes with TLR7 and TLR9 ligands induced proinflammatory cytokine production and cell proliferation, similar to that observed when the homologous mammalian receptors are stimulated.

Operation of graphene transistors at gigahertz frequencies.

Top-gated graphene transistors operating at high frequencies (gigahertz) have been fabricated and their characteristics analyzed. The measured intrinsic current gain shows an ideal 1/f frequency dependence, indicating a FET-like behavior for graphene transistors. The cutoff frequency f(T) is found to be proportional to the dc transconductance g(m) of the device, consistent with the relation f(T) = g(m)/(2piC(G)).

Nomenclature and databases for the surgical treatment of congenital cardiac disease--an updated primer and an analysis of opportunities for improvement.

This review discusses the historical aspects, current state of the art, and potential future advances in the areas of nomenclature and databases for the analysis of outcomes of treatments for patients with congenitally malformed hearts. We will consider the current state of analysis of outcomes, lay out some principles which might make it possible to achieve life-long monitoring and follow-up using our databases, and describe the next steps those involved in the care of these patients need to take in order to achieve these objectives. In order to perform meaningful multi-institutional analyses, we suggest that any database must incorporate the following six essential elements: use of a common language and nomenclature, use of an established uniform core dataset for collection of information, incorporation of a mechanism of evaluating case complexity, availability of a mechanism to assure and verify the completeness and accuracy of the data collected, collaboration between medical and surgical subspecialties, and standardised protocols for life-long follow-up.

Program at home: a Veterans Affairs Healthcare Program to deliver hospital care in the home.

The Portland Veterans Affairs Medical Center (PVAMC) participated in a research-based National Demonstration and Evaluation Study of Hospital at Home Care for Elderly Patients. PVAMC continued hospital at home care in a modified form based on the results of that research phase and feedback from patients, families, and staff. The modified clinical program (referred to as Program @ Home) provided care for the same diagnoses (exacerbation of congestive heart failure, exacerbation of chronic obstructive pulmonary disease, community-acquired pneumonia, cellulitis) but differed from the research-based demonstration project in that it accepted patients of all ages, accepted early-discharge patients from the hospital, and provided a less-intensive physician and nursing model.

CE: Continuing Education article. Patient management in chronic kidney disease stages 4 to 5.

This is the second article in a two part Continuing Education (CE) series on managing patients with Chronic Kidney Disease (CKD). The first CE article addressed the management of patients during CKD stages 1 to 3. This article will focus on the management of patients during CKD stages 4 to 5.

Stratification of complexity: the Risk Adjustment for Congenital Heart Surgery-1 method and the Aristotle Complexity Score--past, present, and future.

Meaningful evaluation of quality of care must account for variations in the population of patients receiving treatment, or "case-mix". In adult cardiac surgery, empirical clinical data, initially from tens of thousands, and more recently hundreds of thousands of operations, have been used to develop risk-models, to increase the accuracy with which the outcome of a given procedure on a given patient can be predicted, and to compare outcomes on non-identical patient groups between centres, surgeons and eras. In the adult cardiac database of The Society of Thoracic Surgeons, algorithms for risk-adjustment are based on over 1.

Databases for assessing the outcomes of the treatment of patients with congenital and paediatric cardiac disease--the perspective of cardiology.

This review includes a brief discussion, from the perspective of the pediatric cardiologist, of the rationale for creation and maintenance of multi-institutional databases of outcomes of the treatment of patients with congenital and paediatric cardiac disease, together with a history of the evolution of such databases, and a description of the current state of the art. A number of projects designed to have broad-based impact are currently in the design phase, or have already been implemented. Not surprisingly, most of the efforts thus far have focused on catheterization procedures and interventions, although some work examining other aspects of paediatric cardiology practice is also beginning.

High throughput ADME screening: practical considerations, impact on the portfolio and enabler of in silico ADME models.

Evaluation and optimization of drug metabolism and pharmacokinetic data plays an important role in drug discovery and development and several reliable in vitro ADME models are available. Recently higher throughput in vitro ADME screening facilities have been established in order to be able to evaluate an appreciable fraction of synthesized compounds. The ADME screening process can be dissected in five distinct steps: (1) plate management of compounds in need of in vitro ADME data, (2) optimization of the MS/MS method for the compounds, (3) in vitro ADME experiments and sample clean up, (4) collection and reduction of the raw LC-MS/MS data and (5) archival of the processed ADME data.

Measurement of technical performance in surgery for congenital heart disease: the stage I Norwood procedure.

Objective: No method of measuring technical performance exists for the stage I Norwood procedure. Hospital mortality is usually used as a surrogate for technical performance, but evidence is lacking to support this concept. A technical score was designed by expert consensus.

CE: Continuing Education article. Patient management in CKD stages 1 TO 3.

This is the first article in a two-part Continuing Education (CE) series on the management of patients with Chronic Kidney Disease (CKD). CKD is now recognised as a global public health concern. It has been classified into five stages to assist healthcare professionals to care for patients presenting with this chronic illness.

Clopidogrel in a pediatric population: prescribing practice and outcomes from a single center.

Background: This study aimed to provide descriptive information about off-label treatment practice with clopidogrel in a pediatric population.

Methods: Patients less than 18 years of age prescribed clopidogrel between March 2002 and August 2005 were retrospectively identified at Children's Hospital, Boston. Data from the time of first documented clopidogrel use to the most recent follow-up assessment were collected.

Optimization of a series of multi-isoform PI3 kinase inhibitors.

Optimization of the cellular and pharmacological activity of a novel series of PI3 kinase inhibitors targeting multiple isoforms is described.

Lymphatic obstruction and protein-losing enteropathy in patients with congenital heart disease.

Objective: Protein-losing enteropathy (PLE) is a known complication of surgical procedures for congenital heart disease. The pathogenesis and pathophysiology of PLE remain poorly understood. However, lymphatic insufficiency appears central to the disease process.

A risk adjusted method for comparing adverse outcomes among practitioners in pediatric and congenital cardiac catheterization.

Objective: We sought to develop a method to adjust for case mix diversity and allow comparison of adverse outcome rates among practitioners in pediatric and congenital cardiac catheterization.

Patients And Methods: A single institutional database that captured demographic and procedural data was used to identify patient and procedural characteristics associated with adverse events (AE) and any high severity event classified as preventable or possibly preventable (P/PP). Diagnostic and procedural risk groups were created and indicators of hemodynamic vulnerability were defined.

Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-dihydro-2H-benzo[1,4]oxazines.

The SAR and pharmacokinetic profiles of a series of multi-isoform PI3K inhibitors based on a 3,4-dihydro-2H-benzo[1,4]oxazine scaffold are disclosed.

Determinants of right ventricular outflow tract conduit longevity: a multinational analysis.

Objective: The need for conduit replacement in the growing child remains a major problem after right ventricular outflow tract reconstruction. We compared two diverse surgical centers with considerable practice variation in Europe and the United States to identify modifiable risk factors that can increase conduit longevity.

Design: Retrospective analysis of 194 patients (56 Europe, 138 United States) who underwent primary right ventricular to pulmonary artery conduit placement between January 1987 and March 2003.

Diagnostic errors in pediatric echocardiography: development of taxonomy and identification of risk factors.

Background: Despite increased interest in complications within pediatric cardiology, the domain of imaging-related diagnostic errors has received little attention. We developed a new taxonomy for diagnostic errors within pediatric echocardiography that categorizes errors by severity, preventability, and primary contributor. Our objectives were to examine its findings when applied to diagnostic error cases and to identify risk factors for preventable or possibly preventable diagnostic errors.

IRAK-4 inhibitors. Part III: a series of imidazo[1,2-a]pyridines.

Following the identification of a potent IRAK inhibitor through routine project cross screening, a novel class of IRAK-4 inhibitor was established. The SAR of imidazo[1,2-a]pyridino-pyridines and benzimidazolo-pyridines was explored.

IRAK-4 inhibitors. Part II: a structure-based assessment of imidazo[1,2-a]pyridine binding.

A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR.

IRAK-4 inhibitors. Part 1: a series of amides.

The synthesis and profile of a series of amides are described. Some of these compounds were potent IRAK-4 inhibitors and two examples were evaluated in vivo.

Chronic kidney disease anaemia. 2: Overview of guidance.

This is part 2 of a two-part unit on managing anaemia of chronic kidney disease (CKD). Part 1 outlined its prevalence, causes, signs and symptoms, and screening for it. Part 2 presents key points from published guidance and a summary of treatment options, and discusses nurses' role in managing people who have anaemia in CKD.

Adverse event rates in congenital cardiac catheterization: a new understanding of risks.

We sought to characterize the frequency, severity, and attributability of adverse events (AE) in congenital cardiac catheterization and identify patient and procedural characteristics associated with AE. Risk for any AE was associated with age < 1 year (odds ratio [OR] 2.3), interventional cases (OR 2.