A pilot, prospective evaluation of a novel alternative for maintenance therapy of breast cancer-associated lymphedema [ISRCTN76522412]

BACKGROUND: Prospective investigations of complete decongestive lymphatic physiotherapy (CDPT), including manual lymphatic drainage (MLD), have validated the efficacy of these interventions for the initial reduction of edema and long-term maintenance of limb volume in lymphedema. However, CDPT demands substantial time and effort from patients to maintain these benefits; the treatments are not always well-accepted, and patients may suffer from a deterioration in quality-of-life or a time-dependent loss of initial treatment benefits. A new device designed for home use by the patient, the Flexitouch™, has been developed to mechanically simulate MLD. We have undertaken a prospective, randomized, crossover study of the efficacy of the Flexitouch™, when compared to massage, in the self-administered maintenance therapy of lymphedema. METHODS: A prospective, randomized, crossover study of maintenance therapy was performed in 10 patients with unilateral breast cancer-associated lymphedema of the arm. Each observation phase included self-administered treatment with the Flexitouch™ or massage, 1 hour daily for 14 days, respectively, followed by crossover to the alternate treatment phase. Each treatment phase was preceded by a 1 week treatment washout, with use of garment only. The sequence of treatment was randomly assigned. The potential impact of treatment modality on quality of life was assessed with serial administration of the SF-36. RESULTS: Statistical analysis disclosed that the order of treatment had no outcome influence, permitting 10 comparisons within each treatment group. Post-treatment arm volume reduced significantly after the Flexitouch™, but not after self-administered massage. The patients' mean weight decreased significantly with Flexitouch™ use, but not with massage. The Flexitouch™ device was apparently well-tolerated and accepted by patients. Serial SF-36 administration showed no deterioration in physical or psychosocial scores compared to baseline measurements; there were no statistical differences in scores when the two treatment modalities were compared. CONCLUSION: This short-term prospective evaluation of the Flexitouch™ suggests that the device may provide better maintenance edema control than self-adiminstered massage in breast cancer-associated lymphedema. The apparent ease of use and reliability of response to the device suggest that further broad-scale testing is warranted

Soil pH effects on the interactions between dissolved zinc, non-nano- and nano-ZnO with soil bacterial communities

Zinc oxide nanoparticles (ZnO NPs) are used in an array of products and processes, ranging from personal care products to antifouling paints, textiles, food additives, antibacterial agents and environmental remediation processes. Soils are an environment likely to be exposed to manmade nanoparticles due to the practice of applying sewage sludge as a fertiliser or as an organic soil improver. However, understanding on the interactions between soil properties, nanoparticles and the organisms that live within soil is lacking, especially with regards to soil bacterial communities. We studied the effects of nanoparticulate, non-nanoparticulate and ionic zinc (in the form of zinc chloride) on the composition of bacterial communities in soil with a modified pH range (from pH 4.5 to pH 7.2). We observed strong pH dependent effects on the interaction between bacterial communities and all forms of zinc, with the largest changes in bacterial community composition occurring in soils with low and medium pH levels (pH 4.8 and 5.9). The high pH soil (pH 7.2) was less susceptible to the effects of zinc exposure. At the highest doses of zinc (2500 mg/kg dw soil) both nano and non-nano particulate zinc applications elicited a similar response in the soil bacterial community, and this differed significantly to the ionic zinc salt treatment. The results highlight the importance of considering soil pH in nanotoxicology studies, although further work is needed to determine the exact mechanisms controlling the toxicity and fate and interactions of nanoparticles with soil microbial communities

Mre11-Rad50 Promotes Rapid Repair of DNA Damage in the Polyploid Archaeon Haloferax volcanii by Restraining Homologous Recombination

Polyploidy is frequent in nature and is a hallmark of cancer cells, but little is known about the strategy of DNA repair in polyploid organisms. We have studied DNA repair in the polyploid archaeon Haloferax volcanii, which contains up to 20 genome copies. We have focused on the role of Mre11 and Rad50 proteins, which are found in all domains of life and which form a complex that binds to and coordinates the repair of DNA double-strand breaks (DSBs). Surprisingly, mre11 rad50 mutants are more resistant to DNA damage than the wild-type. However, wild-type cells recover faster from DNA damage, and pulsed-field gel electrophoresis shows that DNA double-strand breaks are repaired more slowly in mre11 rad50 mutants. Using a plasmid repair assay, we show that wild-type and mre11 rad50 cells use different strategies of DSB repair. In the wild-type, Mre11-Rad50 appears to prevent the repair of DSBs by homologous recombination (HR), allowing microhomology-mediated end-joining to act as the primary repair pathway. However, genetic analysis of recombination-defective radA mutants suggests that DNA repair in wild-type cells ultimately requires HR, therefore Mre11-Rad50 merely delays this mode of repair. In polyploid organisms, DSB repair by HR is potentially hazardous, since each DNA end will have multiple partners. We show that in the polyploid archaeon H. volcanii the repair of DSBs by HR is restrained by Mre11-Rad50. The unrestrained use of HR in mre11 rad50 mutants enhances cell survival but leads to slow recovery from DNA damage, presumably due to difficulties in the resolution of DNA repair intermediates. Our results suggest that recombination might be similarly repressed in other polyploid organisms and at repetitive sequences in haploid and diploid species

O-Antigen Delays Lipopolysaccharide Recognition and Impairs Antibacterial Host Defense in Murine Intestinal Epithelial Cells

Although Toll-like receptor (TLR) 4 signals from the cell surface of myeloid cells, it is restricted to an intracellular compartment and requires ligand internalization in intestinal epithelial cells (IECs). Yet, the functional consequence of cell-type specific receptor localization and uptake-dependent lipopolysaccharide (LPS) recognition is unknown. Here, we demonstrate a strikingly delayed activation of IECs but not macrophages by wildtype Salmonella enterica subsp. enterica sv. (S.) Typhimurium as compared to isogenic O-antigen deficient mutants. Delayed epithelial activation is associated with impaired LPS internalization and retarded TLR4-mediated immune recognition. The O-antigen-mediated evasion from early epithelial innate immune activation significantly enhances intraepithelial bacterial survival in vitro and in vivo following oral challenge. These data identify O-antigen expression as an innate immune evasion mechanism during apical intestinal epithelial invasion and illustrate the importance of early innate immune recognition for efficient host defense against invading Salmonella

Assessment of nerve involvement in the lumbar spine: agreement between magnetic resonance imaging, physical examination and pain drawing findings

<p>Abstract</p> <p>Background</p> <p>Detection of nerve involvement originating in the spine is a primary concern in the assessment of spine symptoms. Magnetic resonance imaging (MRI) has become the diagnostic method of choice for this detection. However, the agreement between MRI and other diagnostic methods for detecting nerve involvement has not been fully evaluated. The aim of this diagnostic study was to evaluate the agreement between nerve involvement visible in MRI and findings of nerve involvement detected in a structured physical examination and a simplified pain drawing.</p> <p>Methods</p> <p>Sixty-one consecutive patients referred for MRI of the lumbar spine were - without knowledge of MRI findings - assessed for nerve involvement with a simplified pain drawing and a structured physical examination. Agreement between findings was calculated as overall agreement, the p value for McNemar's exact test, specificity, sensitivity, and positive and negative predictive values.</p> <p>Results</p> <p>MRI-visible nerve involvement was significantly less common than, and showed weak agreement with, physical examination and pain drawing findings of nerve involvement in corresponding body segments. In spine segment L4-5, where most findings of nerve involvement were detected, the mean sensitivity of MRI-visible nerve involvement to a positive neurological test in the physical examination ranged from 16-37%. The mean specificity of MRI-visible nerve involvement in the same segment ranged from 61-77%. Positive and negative predictive values of MRI-visible nerve involvement in segment L4-5 ranged from 22-78% and 28-56% respectively.</p> <p>Conclusion</p> <p>In patients with long-standing nerve root symptoms referred for lumbar MRI, MRI-visible nerve involvement significantly underestimates the presence of nerve involvement detected by a physical examination and a pain drawing. A structured physical examination and a simplified pain drawing may reveal that many patients with "MRI-invisible" lumbar symptoms need treatment aimed at nerve involvement. Factors other than present MRI-visible nerve involvement may be responsible for findings of nerve involvement in the physical examination and the pain drawing.</p

Does physical activity change predict functional recovery in low back pain? Protocol for a prospective cohort study

Background: Activity advice and prescription are commonly used in the management of low back pain (LBP). Although there is evidence for advising patients with LBP to remain active, facilitating both recovery and return to work, to date no research has assessed whether objective measurements of free living physical activity (PA) can predict outcome, recovery and course of LBP. Methods: An observational longitudinal study will investigate PA levels in a cohort of community-dwelling working age adults with acute and sub-acute LBP. Each participant's PA level, functional status, mood, fear avoidance behaviours, and levels of pain, psychological distress and occupational activity will be measured on three occasions during for 1 week periods at baseline, 3 months, and 1 year. Physical activity levels will be measured by self report, RT3 triaxial accelerometer, and activity recall questionnaires. The primary outcome measure of functional recovery will be the Roland Morris Disability Questionnaire (RMDQ). Free living PA levels and changes in functional status will be quantified in order to look at predictive relationships between levels and changes in free living PA and functional recovery in a LBP population. Discussion: This research will investigate levels and changes in activity levels of an acute LBP cohort and the predictive relationship to LBP recovery. The results will assess whether occupational, psychological and behavioural factors affect the relationship between free living PA and LBP recovery. Results from this research will help to determine the strength of evidence supporting international guidelines that recommend restoration of normal activity in managing LBP. Trial registration. [Clinical Trial Registration Number, ACTRN12609000282280]. © 2009 Hendrick et al; licensee BioMed Central Ltd

Accurate Prediction of Secreted Substrates and Identification of a Conserved Putative Secretion Signal for Type III Secretion Systems

The type III secretion system is an essential component for virulence in many Gram-negative bacteria. Though components of the secretion system apparatus are conserved, its substrates—effector proteins—are not. We have used a novel computational approach to confidently identify new secreted effectors by integrating protein sequence-based features, including evolutionary measures such as the pattern of homologs in a range of other organisms, G+C content, amino acid composition, and the N-terminal 30 residues of the protein sequence. The method was trained on known effectors from the plant pathogen Pseudomonas syringae and validated on a set of effectors from the animal pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) after eliminating effectors with detectable sequence similarity. We show that this approach can predict known secreted effectors with high specificity and sensitivity. Furthermore, by considering a large set of effectors from multiple organisms, we computationally identify a common putative secretion signal in the N-terminal 20 residues of secreted effectors. This signal can be used to discriminate 46 out of 68 total known effectors from both organisms, suggesting that it is a real, shared signal applicable to many type III secreted effectors. We use the method to make novel predictions of secreted effectors in S. Typhimurium, some of which have been experimentally validated. We also apply the method to predict secreted effectors in the genetically intractable human pathogen Chlamydia trachomatis, identifying the majority of known secreted proteins in addition to providing a number of novel predictions. This approach provides a new way to identify secreted effectors in a broad range of pathogenic bacteria for further experimental characterization and provides insight into the nature of the type III secretion signal

Extracting key information from historical data to quantify the transmission dynamics of smallpox

<p>Abstract</p> <p>Background</p> <p>Quantification of the transmission dynamics of smallpox is crucial for optimizing intervention strategies in the event of a bioterrorist attack. This article reviews basic methods and findings in mathematical and statistical studies of smallpox which estimate key transmission parameters from historical data.</p> <p>Main findings</p> <p>First, critically important aspects in extracting key information from historical data are briefly summarized. We mention different sources of heterogeneity and potential pitfalls in utilizing historical records. Second, we discuss how smallpox spreads in the absence of interventions and how the optimal timing of quarantine and isolation measures can be determined. Case studies demonstrate the following. (1) The upper confidence limit of the 99th percentile of the incubation period is 22.2 days, suggesting that quarantine should last 23 days. (2) The highest frequency (61.8%) of secondary transmissions occurs 3–5 days after onset of fever so that infected individuals should be isolated before the appearance of rash. (3) The U-shaped age-specific case fatality implies a vulnerability of infants and elderly among non-immune individuals. Estimates of the transmission potential are subsequently reviewed, followed by an assessment of vaccination effects and of the expected effectiveness of interventions.</p> <p>Conclusion</p> <p>Current debates on bio-terrorism preparedness indicate that public health decision making must account for the complex interplay and balance between vaccination strategies and other public health measures (e.g. case isolation and contact tracing) taking into account the frequency of adverse events to vaccination. In this review, we summarize what has already been clarified and point out needs to analyze previous smallpox outbreaks systematically.</p