142 research outputs found
Novel Escape Mutants Suggest an Extensive TRIM5α Binding Site Spanning the Entire Outer Surface of the Murine Leukemia Virus Capsid Protein
After entry into target cells, retroviruses encounter the host restriction
factors such as Fv1 and TRIM5α. While it is clear that these factors target
retrovirus capsid proteins (CA), recognition remains poorly defined in the
absence of structural information. To better understand the binding interaction
between TRIM5α and CA, we selected a panel of novel N-tropic murine
leukaemia virus (N-MLV) escape mutants by a serial passage of replication
competent N-MLV in rhesus macaque TRIM5α (rhTRIM5α)-positive cells using
a small percentage of unrestricted cells to allow multiple rounds of virus
replication. The newly identified mutations, many of which involve changes in
charge, are distributed over the outer ‘top’ surface of N-MLV CA,
including the N-terminal β-hairpin, and map up to 29 Ao apart.
Biological characterisation with a number of restriction factors revealed that
only one of the new mutations affects restriction by human TRIM5α,
indicating significant differences in the binding interaction between N-MLV and
the two TRIM5αs, whereas three of the mutations result in dual sensitivity
to Fv1n and Fv1b. Structural studies of two mutants show
that no major changes in the overall CA conformation are associated with escape
from restriction. We conclude that interactions involving much, if not all, of
the surface of CA are vital for TRIM5α binding
A systematic review and meta-synthesis of the impact of low back pain on people's lives
Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives.
Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach.
Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly.
Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U
A model of impairment and functional limitation in rheumatoid arthritis
BACKGROUND: We have previously proposed a theoretical model for studying physical disability and other outcomes in rheumatoid arthritis (RA). The purpose of this paper is to test a model of impairment and functional limitation in (RA), using empirical data from a sample of RA patients. We based the model on the disablement process framework. METHODS: We posited two distinct types of impairment in RA: 1) Joint inflammation, measured by the tender, painful and swollen joint counts; and 2) Joint deformity, measured by the deformed joint count. We hypothesized direct paths from the two impairments to functional limitation, measured by the shirt-button speed, grip strength and walking velocity. We used structural equation modeling to test the hypothetical relationships, using empirical data from a sample of RA patients recruited from six rheumatology clinics. RESULTS: The RA sample was comprised of 779 RA patients. In the structural equation model, the joint inflammation impairment displayed a strong significant path toward the measured variables of joint pain, tenderness and swelling (standardized regression coefficients 0.758, 0.872 and 0.512, P ≤ 0.001 for each). The joint deformity impairment likewise displayed significant paths toward the measured upper limb, lower limb, and other deformed joint counts (standardized regression coefficients 0.849, 0.785, 0.308, P ≤ 0.001 for each). Both the joint inflammation and joint deformity impairments displayed strong direct paths toward functional limitation (standardized regression coefficients of -0.576 and -0.564, respectively, P ≤ 0.001 for each), and explained 65% of its variance. Model fit to data was fair to good, as evidenced by a comparative fit index of 0.975, and the root mean square error of approximation = 0.058. CONCLUSION: This evidence supports the occurrence of two distinct impairments in RA, joint inflammation and joint deformity, that together, contribute strongly to functional limitations in this disease. These findings may have implications for investigators aiming to measure outcome in RA
Chronic non-specific low back pain - sub-groups or a single mechanism?
Copyright 2008 Wand and O'Connell; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain is a substantial health problem and has subsequently attracted a
considerable amount of research. Clinical trials evaluating the efficacy of a variety of interventions
for chronic non-specific low back pain indicate limited effectiveness for most commonly applied
interventions and approaches.
Discussion: Many clinicians challenge the results of clinical trials as they feel that this lack of
effectiveness is at odds with their clinical experience of managing patients with back pain. A
common explanation for this discrepancy is the perceived heterogeneity of patients with chronic
non-specific low back pain. It is felt that the effects of treatment may be diluted by the application
of a single intervention to a complex, heterogeneous group with diverse treatment needs. This
argument presupposes that current treatment is effective when applied to the correct patient.
An alternative perspective is that the clinical trials are correct and current treatments have limited
efficacy. Preoccupation with sub-grouping may stifle engagement with this view and it is important
that the sub-grouping paradigm is closely examined. This paper argues that there are numerous
problems with the sub-grouping approach and that it may not be an important reason for the
disappointing results of clinical trials. We propose instead that current treatment may be ineffective
because it has been misdirected. Recent evidence that demonstrates changes within the brain in
chronic low back pain sufferers raises the possibility that persistent back pain may be a problem of
cortical reorganisation and degeneration. This perspective offers interesting insights into the
chronic low back pain experience and suggests alternative models of intervention.
Summary: The disappointing results of clinical research are commonly explained by the failure of
researchers to adequately attend to sub-grouping of the chronic non-specific low back pain
population. Alternatively, current approaches may be ineffective and clinicians and researchers may
need to radically rethink the nature of the problem and how it should best be managed
Proteasomal Degradation of TRIM5α during Retrovirus Restriction
The host protein TRIM5α inhibits retroviral infection at an early post-penetration stage by targeting the incoming viral capsid. While the detailed mechanism of restriction remains unclear, recent studies have implicated the activity of cellular proteasomes in the restriction of retroviral reverse transcription imposed by TRIM5α. Here, we show that TRIM5α is rapidly degraded upon encounter of a restriction-susceptible retroviral core. Inoculation of TRIM5α-expressing human 293T cells with a saturating level of HIV-1 particles resulted in accelerated degradation of the HIV-1-restrictive rhesus macaque TRIM5α protein but not the nonrestrictive human TRIM5α protein. Exposure of cells to HIV-1 also destabilized the owl monkey restriction factor TRIMCyp; this was prevented by addition of the inhibitor cyclosporin A and was not observed with an HIV-1 virus containing a mutation in the capsid protein that relieves restriction by TRIMCyp IVHIV. Likewise, human TRIM5α was rapidly degraded upon encounter of the restriction-sensitive N-tropic murine leukemia virus (N-MLV) but not the unrestricted B-MLV. Pretreatment of cells with proteasome inhibitors prevented the HIV-1-induced loss of both rhesus macaque TRIM5α and TRIMCyp proteins. We also detected degradation of endogenous TRIM5α in rhesus macaque cells following HIV-1 infection. We conclude that engagement of a restriction-sensitive retrovirus core results in TRIM5α degradation by a proteasome-dependent mechanism
Complex systems and the technology of variability analysis
Characteristic patterns of variation over time, namely rhythms, represent a defining feature of complex systems, one that is synonymous with life. Despite the intrinsic dynamic, interdependent and nonlinear relationships of their parts, complex biological systems exhibit robust systemic stability. Applied to critical care, it is the systemic properties of the host response to a physiological insult that manifest as health or illness and determine outcome in our patients. Variability analysis provides a novel technology with which to evaluate the overall properties of a complex system. This review highlights the means by which we scientifically measure variation, including analyses of overall variation (time domain analysis, frequency distribution, spectral power), frequency contribution (spectral analysis), scale invariant (fractal) behaviour (detrended fluctuation and power law analysis) and regularity (approximate and multiscale entropy). Each technique is presented with a definition, interpretation, clinical application, advantages, limitations and summary of its calculation. The ubiquitous association between altered variability and illness is highlighted, followed by an analysis of how variability analysis may significantly improve prognostication of severity of illness and guide therapeutic intervention in critically ill patients
Harpgophytum procumbens for osteoarthritis and low back pain: A systematic review
BACKGROUND: The objective of this review is to determine the effectiveness of Harpagophytum procumbens preparations in the treatment of various forms of musculoskeletal pain. METHODS: Several databases and other sources were searched to identify randomized controlled trials, quasi-randomized controlled trials, and controlled clinical trials testing Harpagophytum preparations in adults suffering from pain due to osteoarthritis or low back pain. RESULTS: Given the clinical heterogeneity and insufficient data for statistical pooling, trials were described in a narrative way, taking into consideration methodological quality scores. Twelve trials were included with six investigating osteoarthritis (two were identical trials), four low back pain, and three mixed-pain conditions. CONCLUSIONS: There is limited evidence for an ethanolic Harpagophytum extract containing less than <30 mg harpagoside per day in the treatment of knee and hip osteoarthritis. There is moderate evidence of effectiveness for (1) the use of a Harpagophytum powder at 60 mg harpagoside in the treatment of osteoarthritis of the spine, hip and knee; (2) the use of an aqueous Harpagophytum extract at a daily dose of 100 mg harpagoside in the treatment of acute exacerbations of chronic non-specific low back pain; and (3) the use of an aqueous extract of Harpagophytum procumbens at 60 mg harpagoside being non-inferior to 12.5 mg rofecoxib per day for chronic non-specific low-back pain (NSLBP) in the short term. Strong evidence exists for the use of an aqueous Harpagophytum extract at a daily dose equivalent of 50 mg harpagoside in the treatment of acute exacerbations of chronic NSLBP
Course and prognosis of recovery for chronic non-specific low back pain: design, therapy program and baseline data of a prospective cohort study
Background: There has been increasing focus on factors predicting the development of chronic musculoskeletal disorders. For patients already experiencing chronic non-specific low back pain it is also relevant to investigate which prognostic factors predict recovery. We present the design of a cohort study that aims to determine the course and prognostic factors for recovery in patients with chronic non-specific low back pain. Methods/Design. All participating patients were recruited (Jan 2003-Dec 2008) from the same rehabilitation centre and were evaluated by means of (postal) questionnaires and physical examinations at baseline, during the 2-month therapy program, and at 5 and 12 months after start of therapy. The therapy protocol at the rehabilitation centre used a bio-psychosocial approach to stimulate patients to adopt adequate (movement) behaviour aimed at physical and functional recovery. The program is part of regular care and consists of 16 sessions of 3 hours each, over an 8-week period (in total 48 hours), followed by a 3-month self-management program. The primary outcomes are low back pain intensity, disability, quality of life, patient's global perceived effect of recovery, and participation in work. Baseline characteristics include information on socio-demographics, low back pain, employment status, and additional clinical items status such as fatigue, duration of activities, and fear of kinesiophobia. Prognostic variables are determined for recovery at short-term (5 months) and long-term (12 months) follow-up after start of therapy. Discussion. In a routine clinical setting it is important to provide patients suffering from chronic non-specific low back pain with adequate information about the prognosis of their complaint
Back Complaints in the Elders (BACE); design of cohort studies in primary care: an international consortium
Background: Although back complaints are common among older people, limited information is available in the literature about the clinical course of back pain in older people and the identification of older persons at risk for the transition from acute back complaints to chronic back pain. The aim of this study is to assess the course of back complaints and identify prognostic factors for the transition from acute back complaints to chronic back complaints in older people who visit a primary health care physician. Methods/design. The design is a prospective cohort study with one-year follow-up. There will be no interference with usual care. Patients older than 55 years who consult a primary health care physician with a new episode of back complaints will be included in this study. Data will be collected using a questionnaire, physical examination and X-ray at baseline, and follow-up questionnaires afte
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