Patients with advanced post-thrombotic syndrome (PTS) and chronic iliac vein obstruction suffer major physical limitations and impairment of health-related quality of life. Currently there is a lack ...of evidence-based treatment options for these patients. Early studies suggest that imaging-guided, catheter-based endovascular therapy can eliminate iliac vein obstruction and saphenous venous valvular reflux, resulting in reduced PTS severity; however, these observations have not been rigorously validated. A multidisciplinary expert panel meeting was convened to plan a multicenter randomized controlled clinical trial to evaluate endovascular therapy for the treatment of advanced PTS. This article summarizes the findings of the panel, and is expected to assist in developing a National Institutes of Health-sponsored clinical trial and other studies to improve the care of patients with advanced PTS.
Magnesium supplementation is often suggested for restless legs syndrome (RLS) or period limb movement disorder (PLMD) based on anecdotal evidence that it relieves symptoms and because it is also ...commonly recommended for leg cramps. We aimed to review all articles reporting the effects of magnesium supplementation on changes in RLS and/or PLMD.
We conducted a systematic search looking for all relevant articles and then two reviewers read all article titles and abstracts to identify relevant studies. Eligible studies were scored for their quality as interventional trials.
We found 855 abstracts and 16 of these could not be definitively excluded for not addressing all aspects of our research question. Seven full-text articles were unlocatable and one was ineligible which left eight studies with relevant data. One was a randomised placebo-controlled trial, three were case series and four were case studies. The RCT did not find a significant treatment effect of magnesium but may have been underpowered. After quality appraisal and synthesis of the evidence we were unable to make a conclusion as to the effectiveness of magnesium for RLS/PLMD.
It is not clear whether magnesium helps relieve RLS or PLMD or in which patient groups any benefit might be seen.
•Iodinated contrast media modify absorbed doses to blood vessels from X-ray exposures.•Dose enhancement is greatest within the blood and first micrometre of vessel wall.•Dose enhancement is minimal ...beyond around 50 μm outside the vessel lumen.•Macroscopic organ doses may overestimate impact in terms of cancer risk.•Macroscopic organ doses may underestimate risk of cardiovascular disease.
Studies suggest iodinated contrast media (ICM) may increase organ dose and blood cell DNA damage for a given X-ray exposure. The impact of ICM on dose/damage to extravascular cells and cancer risks is unclear.
We used Monte Carlo modelling to investigate the microscopic distribution of absorbed dose outside the lumen of arteries, capillaries and interstitial fluids containing blood and various concentrations of iodine. Models were irradiated with four X-ray spectra representing clinical procedures.
For the artery model, The average dose enhancement factors (DEF) to blood were 1.70, 2.38, 7.38, and 12.34 for mass concentrations of iodine in blood (ρiI) of 5, 10, 50 and 100 mg/ml, respectively, compared to 0 mg/ml. Average DEFs were reduced to 1.26, 1.51, 3.48 and 5.56, respectively, in the first micrometre of the vessel wall, falling to 1.01, 1.02, 1.06 and 1.09 at 40–50 μm from the lumen edge. For the capillary models, DEF for extravascular tissues was on average 48% lower than DEF for the whole model, including capillaries. A similar situation was observed for the interstitial model, with DEF to the cell nucleus being 35% lower than DEF for the whole model.
While ICM may modify the absorbed doses from diagnostic X-ray examinations, the effect is smaller than suggested by assays of circulating blood cells or blood dose enhancement. Conversely, the potentially large increase in dose to the endothelium of blood vessels means that macroscopic organ doses may underestimate the risk of radiation induced cardiovascular disease for ICM-enhanced exposures.
Background: Production of polychlorinated biphenyls (PCBs) ended in the United States in the 1970s, but PCBs persist in the environment and are detectable in the blood of approximately 80% of ...Americans over age 50. PCBs decrease dopamine levels in rats and monkeys. Loss of dopamine is the hallmark of Parkinson disease, a neurodegenerative disease. There are no epidemiologic studies of PCBs and neurodegenerative disease. Methods: We conducted a retrospective mortality study of 17,321 PCB-exposed workers to determine whether mortality from Parkinson disease, dementia, and amyotrophic lateral sclerosis was elevated compared with the U.S. population. All workers had a least 90 days employment in 1 of 3 electrical capacitor plants using PCBs from the 1940s to the 1970s. PCB serum levels from a sample of these workers in the 1970s were approximately 10 times the level of community controls. Results: We found no overall excess of Parkinson disease, amyotrophic lateral sclerosis, or dementia in the PCB-exposed cohort (standardized mortality ratios SMRs-1.40, 1.11, and 1.26, respectively, and number of deaths-14, 10, and 28 respectively). However, sex-specific analyses revealed that women had an excess of amyotrophic lateral sclerosis (SMR-2.26; 95% confidence interval CI = 1.08-4.15; 10 deaths). Furthermore, among highly exposed women (defined by a job-exposure matrix), we found an excess of Parkinson disease (SMR-2.95; 95% CI = 1.08-6.42; 6 deaths) and dementia (SMR-2.04; 95% CI = 1.12-3.43; 14 deaths). Conclusions: Our data are limited due to small numbers and reliance on mortality rather than incidence data, but are suggestive of an effect of PCBs on neurodegenerative disease for women. The literature does not offer an explanation for why women would be more affected than men by PCB exposure for these outcomes.
To determine the safety and efficacy of cryopreserved packed red blood cell (CPRBC) transfusion in trauma patients.
Liquid packed red blood cells (LPRBCs) have an abbreviated shelf-life and worsening ...storage lesion with age. CPRBCs are frozen 2 to 6 days after donation, stored up to 10 years, and are available for 14 days after thawing and washing. CPRBCs can be utilized in diverse settings, but the effect on clinical outcomes is unknown.
We performed a prospective, randomized, double-blind study at 5 level 1 trauma centers. Stable trauma patients requiring transfusion were randomized to young LPRBCs (≤14 storage days), old LPRBCs (>14 storage days), or CPRBCs. Tissue oxygenation (StO2), biochemical and inflammatory mediators were measured, and clinical outcomes were determined.
Two hundred fifty-six patients with well-matched injury severity and demographics (P > 0.2) were randomized (84 young, 86 old, and 86 CPRBCs). Pretransfusion and final hematocrits were similar (P > 0.68). Patients in all groups received the same number of units postrandomization (2 1-4; P > 0.05). There was no difference in the change in tissue oxygenation between groups. CPRBCs contained less α2-macrogobulin, haptoglobin, C-reactive protein, and serum amyloid P (P < 0.001). Organ failure, infection rate, and mortality did not differ between groups (P > 0.2).
Transfusion of CPRBCs is as safe and effective as transfusion of young and old LPRBCs and provides a mechanism to deliver PRBCs in a wide variety of settings.
BACKGROUND AND AIMS: Previous measurements of conifer alkaloids have revealed significant variation attributable to many sources, environmental and genetic. The present study takes a complementary ...and intensive, common garden approach to examine genetic variation in Pinus ponderosa var. ponderosa alkaloid production. Additionally, this study investigates the potential trade-off between seedling growth and alkaloid production, and associations between topographic/climatic variables and alkaloid production. METHODS: Piperidine alkaloids were quantified in foliage of 501 nursery seedlings grown from seed sources in west-central Washington, Oregon and California, roughly covering the western half of the native range of ponderosa pine. A nested mixed model was used to test differences among broad-scale regions and among families within regions. Alkaloid concentrations were regressed on seedling growth measurements to test metabolite allocation theory. Likewise, climate characteristics at the seed sources were also considered as explanatory variables. KEY RESULTS: Quantitative variation from seedling to seedling was high, and regional variation exceeded variation among families. Regions along the western margin of the species range exhibited the highest alkaloid concentrations, while those further east had relatively low alkaloid levels. Qualitative variation in alkaloid profiles was low. All measures of seedling growth related negatively to alkaloid concentrations on a natural log scale; however, coefficients of determination were low. At best, annual height increment explained 19·4 % of the variation in ln(total alkaloids). Among the climate variables, temperature range showed a negative, linear association that explained 41·8 % of the variation. CONCLUSIONS: Given the wide geographic scope of the seed sources and the uniformity of resources in the seedlings' environment, observed differences in alkaloid concentrations are evidence for genetic regulation of alkaloid secondary metabolism in ponderosa pine. The theoretical trade-off with seedling growth appeared to be real, however slight. The climate variables provided little evidence for adaptive alkaloid variation, especially within regions.
Understanding the human immune response to
gametocytes and its association with gametocytemia is essential for understanding the transmission of malaria as well as progressing transmission blocking ...vaccine candidates.
In a multi-national clinical efficacy trial of artemisinin therapies (13 sites of varying transmission over South-East Asia and Africa), we measured Immunoglobulin G (IgG) responses to recombinant
gametocyte antigens expressed on the gametocyte plasma membrane and leading transmission blocking vaccine candidates
s230 (
s230c and
s230D1M) and
s48/45 at enrolment in 1,114 participants with clinical falciparum malaria. Mixed effects linear and logistic regression were used to determine the association between gametocyte measures (gametocytemia and gametocyte density) and antibody outcomes at enrolment.
Microscopy detectable gametocytemia was observed in 11% (127/1,114) of participants at enrolment, and an additional 9% (95/1,114) over the follow-up period (up to day 42) (total 20% of participants 222/1,114). IgG levels in response to
s230c,
s48/45 and
s230D1M varied across study sites at enrolment (
), as did IgG seroprevalence for anti-
s230c and D1M IgG (
), but not for anti-
s48/45 IgG (
). In adjusted analyses, microscopy detectable gametocytemia at enrolment was associated with an increase in the odds of IgG seropositivity to the three gametocyte antigens (
s230c OR 95% CI,
: 1.70 1.10, 2.62,
;
s48/45: 1.45 0.85, 2.46,
;
s230D1M: 1.70 1.03, 2.80,
), as was higher gametocyte density at enrolment (per two-fold change in gametocyte density
s230c OR 95% CI,
: 1.09 1.02, 1.17,
;
s48/45: 1.05 0.98, 1.13,
;
s230D1M: 1.07 0.99, 1.14,
).
s230 and
s48/45 antibodies are naturally immunogenic targets associated with patent gametocytemia and increasing gametocyte density across multiple malaria endemic settings, including regions with emerging artemisinin-resistant
.
The conservation of biodiversity requires various forms of evidence to ensure effective outcomes. In this study, we provide an updated assessment of the state of evidence-based decision-making in ...Canada’s protected areas organizations by examining practitioner perceptions of: ( i) the value and use of various forms of evidence, ( ii) the availability of evidence to support decisions, and ( iii) the extent to which various institutional and behavioural barriers influence the use of evidence. Our results compare national surveys conducted in 2019 and 2013, revealing a significant and concerning decline in the use of all forms of evidence. We found significant declines in the use of peer-reviewed literature, local knowledge, and Indigenous knowledge. Our results correspondingly demonstrate a host of systemic barriers to the effective use of evidence, including a lack of trust, how to deal with uncertainty, and limited training. These challenges persist at a time when the quantity of information is greater than ever, and recognition of the value of Indigenous knowledge is relatively high (and increasing). Leadership is required to cultivate more relevant evidence, to embed scientists and Indigenous Knowledge-Holders in conservation organizations, to (re)establishing knowledge sharing forums, and to establish accountability and reporting measures to support efforts aimed at effectively achieving Canada’s biodiversity conservation goals.
The overall influence of gene interaction in human disease is unknown. In cystic fibrosis (CF) a single allele of the cystic fibrosis transmembrane conductance regulator (CFTR-incrementF508) accounts ...for most of the disease. In cell models, CFTR-incrementF508 exhibits defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-incrementF508. However it is not known whether genetic variation in such genes contributes to disease severity in patients. Nor is there an easy way to study how numerous gene interactions involving CFTR-incrementF would manifest phenotypically.
To gain insight into the function and evolutionary conservation of a gene interaction network that regulates biogenesis of a misfolded ABC-transporter, we employed yeast genetics to develop a "phenomic" model, in which the CFTR-incrementF508-equivalent residue of a yeast homolog is mutated (Yor1-incrementF670), and where the genome is scanned quantitatively for interaction. We first confirmed that Yor1-incrementF undergoes protein misfolding and has reduced half-life, analogous to CFTR-incrementF. Gene interaction was then assessed quantitatively by growth curves for all ~5000 double mutants, based on alteration in the dose response to growth inhibition by oligomycin, a toxin extruded from the cell at the plasma membrane by Yor1.
From a comparative genomic perspective, yeast gene interaction influencing Yor1-incrementF biogenesis was representative of human homologs previously found to modulate processing of CFTR-incrementF in mammalian cells. Additional evolutionarily conserved pathways were implicated by the study, and a incrementF-specific pro-biogenesis function of the recently discovered ER Membrane Complex (EMC) was evident from the yeast screen. This novel function was validated biochemically by siRNA of an EMC ortholog in a human cell line expressing CFTR-incrementF508. The precision and accuracy of quantitative high throughput cell array phenotyping (Q-HTCP), which captures tens of thousands of growth curves simultaneously, provided powerful resolution to measure gene interaction on a phenomic scale, based on discrete cell proliferation parameters.
We propose phenomic analysis of Yor1-incrementF as a model for investigating gene interaction networks that can modulate cystic fibrosis disease severity. Although the clinical relevance of the Yor1-incrementF gene interaction network for cystic fibrosis remains to be defined, the model appears to be informative with respect to human cell models of CFTR-incrementF. Moreover, the general strategy of yeast phenomics can be employed in a systematic manner to model gene interaction for other diseases relating to pathologies that result from protein misfolding or potentially any disease involving evolutionarily conserved genetic pathways.
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