Novel small molecule therapeutics in rheumatoid arthritis.

A new wave of emerging therapies for the treatment of autoimmune and inflammatory diseases is under development. These therapies interrupt intracellular signalling through kinase inhibition. By interrupting one or more kinases it is possible to modulate the function of cellular structures such as surface receptors, signalling proteins and transcription of nuclear proteins and thus influence the behaviour of the cell types targeted.

Pegloticase and the patient with treatment-failure gout.

Gout is an inflammatory arthritis characterized by sudden, painful inflammation. Gout can affect any joint in an asymmetric distribution. Gouty attacks may be isolated or can be followed by years of recurrent flares.

Health-related quality of life in chronic myeloid leukemia.

The increased survival associated with treatments for CML emphasize the importance of understanding the HRQOL of newly diagnosed and previously treated CML patients with all phases of disease. Functional Assessment of Cancer Therapy-Leukemia results from a phase 3 and a phase 2 trial are reported for over 900 1st, 2nd, 3rd line CP, AP, and BP patients. Physical Well-being and Leukemia symptoms were worse for patients in later lines of therapy.

Functional mobility limitations and falls in assisted living residents with dementia: physical performance assessment and quantitative gait analysis.

Background And Purpose: The prevalence of functional mobility limitations and falls is higher in people with dementia compared with cognitively healthy older adults, and both are associated with gait and motor impairments. The aims of this study were to examine concurrent validity of physical performance assessments and spatiotemporal gait measures in older adults with advanced dementia and to prospectively examine their relationship to functional mobility limitations and falls over a 4-month period.

Methods: Thirty-one older adults living in dementia-specific assisted living residences participated.

Factors influencing dynamic prioritization during dual-task walking in healthy young adults.

Appropriate prioritization during dual-task walking is necessary to achieve task goals and maintain walking stability. We examined the effects of increased walking task difficulty on dual-task walking prioritization in healthy young adults. Walking under simple usual-base conditions was similar between equal-focus and cognitive-focus instructions, but these differed from walking-focus instructions, consistent with cognitive task prioritization.

Dissemination bottleneck in a murine model of inhalational anthrax.

Inhalational anthrax is caused by the sporulating bacterium Bacillus anthracis. A current model for progression in mammalian hosts includes inhalation of bacterial spores, phagocytosis of spores in the nasal mucosa-associated lymphoid tissue (NALT) and lungs by macrophages and dendritic cells, trafficking of phagocytes to draining lymph nodes, germination of spores and multiplication of vegetative bacteria in the NALT and lymph nodes, and dissemination of bacteria via the bloodstream to multiple organs. In previous studies, the kinetics of infection varied greatly among mice, leading us to hypothesize the existence of a bottleneck past which very few spores (perhaps only one) progress to allow the infection to proceed.

Hypoxia Moderates γ(1)34.5-Deleted Herpes Simplex Virus Oncolytic Activity in Human Glioma Xenoline Primary Cultures.

Hypoxia plays a critical role in the tumor microenvironment of high-grade gliomas by promoting the glioma stem cell (GSC)-like phenotype, which displays resistance to standard therapies. We tested three glioblastoma multiforme xenograft lines (xenolines) against γ(1)34.5-deleted recombinant oncolytic herpes simplex virus (oHSV) C101 under 1% (hypoxia) and 20.

Regulation of adipocyte 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by CCAAT/enhancer-binding protein (C/EBP) β isoforms, LIP and LAP.

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyses intracellular regeneration of active glucocorticoids, notably in liver and adipose tissue. 11β-HSD1 is increased selectively in adipose tissue in human obesity, a change implicated in the pathogenesis of metabolic syndrome. With high fat (HF)-feeding, adipose tissue 11β-HSD1 is down-regulated in mice, plausibly to counteract metabolic disease.

CD133 marks a myogenically primitive subpopulation in rhabdomyosarcoma cell lines that are relatively chemoresistant but sensitive to mutant HSV.

Background: Rhabdomyosarcoma (RMS) is characterized by features of skeletal muscle and is comprised of two major histological subtypes, embryonal (E-RMS), and alveolar (A-RMS). Subsets of each RMS subtype demonstrate resistance to multimodal therapy leading to treatment failure. Cancer stem cells or cancer-initiating cells (CIC) represent a theorized population of cells that give rise to tumors and are responsible for treatment resistance.

Introducing GRADE across the NICE clinical guideline program.

Objectives: Grading of Recommendations Assessment, Development and Evaluation (GRADE) is a system for rating the confidence in estimates of effect and grading guideline recommendations. It promotes evaluation of the quality of the evidence for each outcome and an assessment of balance between desirable and undesirable outcomes leading to a judgment about the strength of the recommendation. In 2007, the National Institute for Health and Clinical Excellence began introducing GRADE across its clinical guideline program to enable separation of judgments about the evidence quality from judgments about the strength of the recommendation.

Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure.

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.

Effect of airway smooth muscle tone on airway distensibility measured by the forced oscillation technique in adults with asthma.

Airway distensibility appears to be unaffected by airway smooth muscle (ASM) tone, despite the influence of ASM tone on the airway diameter-pressure relationship. This discrepancy may be because the greatest effect of ASM tone on airway diameter-pressure behavior occurs at low transpulmonary pressures, i.e.

Nonhuman primate model of pertussis.

Pertussis is a highly contagious, acute respiratory illness caused by the bacterial pathogen Bordetella pertussis. Despite nearly universal vaccine coverage, pertussis rates in the United States have been rising steadily over the last 20 years. Our failure to comprehend and counteract this important public health concern is due in large part to gaps in our knowledge of the disease and the mechanisms of vaccine-mediated protection.

Automated detection of the phase III slope during inert gas washout testing.

We describe a method to determine the phase III slope for the purpose of calculating indexes of ventilation heterogeneity, S(acin) and S(cond), from the multiple breath nitrogen washout test (MBNW). Our automated method applies a recursive, segmented linear regression technique to each breath of the MBNW test and determines the best point of transition, or breakpoint, between each phase of the washout. A sample set of 50 MBNW tests (controls, asthma, and COPD) was used to establish the conditions in which the phase III slope obtained from the automated technique best matched that obtained by two manual interpreters.

A review of dual-task walking deficits in people with Parkinson's disease: motor and cognitive contributions, mechanisms, and clinical implications.

Gait impairments in Parkinson's disease (PD) are exacerbated under dual-task conditions requiring the simultaneous performance of cognitive or motor tasks. Dual-task walking deficits impact functional mobility, which often requires walking while performing concurrent tasks such as talking or carrying an object. The consequences of gait impairments in PD are significant and include increased disability, increased fall risk, and reduced quality of life.

Health-related quality of life of bosutinib (SKI-606) in imatinib-resistant or imatinib-intolerant chronic phase chronic myeloid leukemia.

Understanding the impact of second-line tyrosine kinase inhibitor therapy on the health-related quality of life (HRQOL) of imatinib (IM)-resistant and IM-intolerant chronic phase chronic myeloid leukemia (CP CML) patients is important given the increased survival that comes with therapy. As part of a bosutinib single-arm phase 2 trial, 200 IM-resistant and 88 IM-intolerant CP CML patients' HRQOL was assessed prior to and throughout treatment with the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu). Little HRQOL impairment was demonstrated at baseline.

Use of sensitive devices to assess the effect of medication on attentional demands of precision and power grips in individuals with Parkinson disease.

Deficits in fine motor control are a common early symptom in people with Parkinson disease (PD) and may serve as an ideal marker for the response to therapeutic interventions and progression of the disease. The long-term goal of this research is to develop sensitive clinical markers that can be used to accurately assess disease progression and the response to therapeutic interventions. The purpose of this preliminary study was to examine the effects of medication on the attentional demands of precision (Pre) and power (Pow) grips in individuals with PD.

Associations between physical performance and executive function in older adults with mild cognitive impairment: gait speed and the timed "up & go" test.

Background: Older adults with amnestic mild cognitive impairment (aMCI) are at higher risk for developing Alzheimer disease. Physical performance decline on gait and mobility tasks in conjunction with executive dysfunction has implications for accelerated functional decline, disability, and institutionalization in sedentary older adults with aMCI.

Objectives: The purpose of this study was to examine whether performance on 2 tests commonly used by physical therapists (usual gait speed and Timed "Up & Go" Test [TUG]) are associated with performance on 2 neuropsychological tests of executive function (Trail Making Test, part B [TMT-B], and Stroop-Interference, calculated from the Stroop Word Color Test) in sedentary older adults with aMCI.

Queuosine deficiency in eukaryotes compromises tyrosine production through increased tetrahydrobiopterin oxidation.

Queuosine is a modified pyrrolopyrimidine nucleoside found in the anticodon loop of transfer RNA acceptors for the amino acids tyrosine, asparagine, aspartic acid, and histidine. Because it is exclusively synthesized by bacteria, higher eukaryotes must salvage queuosine or its nucleobase queuine from food and the gut microflora. Previously, animals made deficient in queuine died within 18 days of withdrawing tyrosine, a nonessential amino acid, from the diet (Marks, T.

A hypofractionated radiotherapy regimen (0-7-21) for advanced gynaecological cancer patients.

Aims: To evaluate the efficacy of a palliative three fraction radiation regimen delivered on days 0, 7 and 21 (0-7-21 regimen) for advanced stage gynaecological cancer patients.

Materials And Methods: Fifty-one patients with advanced gynaecological cancer who were treated with the 0-7-21 regimen between 1998 and 2008 were identified. The median follow-up period was 1.

Emerging indirect and long-term road salt effects on ecosystems.

Widespread use of salts as deicing agents on roads has been perceived as a significant source of environmental and economic damage. Early studies focused on near-road and short-term effects where concentrations can exceed several grams per liter. Evidence is accumulating that the use of salts has significant effects over broader areas, longer time frames, and is affecting a range of ecological processes.

Modeling and therapy of human liver diseases using induced pluripotent stem cells: how far have we come?

. Modeling inherited metabolic disorders of the liver using human induced pluripotent stem cells. J Clin Invest.

The impact on sleep of a multidisciplinary cognitive behavioural pain management programme: a pilot study.

Background: Reduced sleep quality is a common complaint among patients with chronic pain, with 50-80% of patients reporting sleep disturbance. Improvements in pain and quality of life measures have been achieved using a multidisciplinary cognitive behavioural therapy pain management programme (CBT-PMP) that aims to recondition attitudes to pain, and improve patients' self-management of their condition. Despite its high prevalence in patients with chronic pain, there is very limited objective evidence for the effect of this intervention on sleep quality.