Feasibility of Photofrin II as a radiosensitizing agent in solid tumors - Preliminary results

Background: Photofrin II has been demonstrated to serve as a specific and selective radiosensitizing agent in in vitro and in vivo tumor models. We aimed to investigate the feasibility of a clinical application of Photofrin II. Material and Methods: 12 patients were included in the study (7 unresectable solid tumors of the pelvic region, 3 malignant gliomas, 1 recurrent oropharyngeal cancer, 1 recurrent adenocarcinoma of the sphenoid sinus). The dose of ionizing irradiation was 30-50.4 Gy; a boost irradiation of 14 Gy was added for the pelvic region. All patients were intravenously injected with 1 mg/kg Photofrin II 24 h prior to the commencement of radiotherapy. Magnetic resonance imaging (MRI) controls and in some cases positron emission tomography (PET) were performed in short intervals. The mean follow-up was 12.9 months. Results: No major adverse events were noted. Minor adverse events consisted of mild diarrhea, nausea and skin reactions. A complete remission was observed in 4/12 patients. A reduction in local tumor volume of > 45% was achieved in 4/12 patients. Stable disease was observed in 4/12 patients. 1 patient showed local disease progression after 5 months. Conclusion: The early follow-up results are encouraging regarding the feasibility of the application of Photofrin II as a radiosensitizing agent

Increasing confidence and changing behaviors in primary care providers engaged in genetic counselling.

BackgroundScreening and counseling for genetic conditions is an increasingly important part of primary care practice, particularly given the paucity of genetic counselors in the United States. However, primary care physicians (PCPs) often have an inadequate understanding of evidence-based screening; communication approaches that encourage shared decision-making; ethical, legal, and social implication (ELSI) issues related to screening for genetic mutations; and the basics of clinical genetics. This study explored whether an interactive, web-based genetics curriculum directed at PCPs in non-academic primary care settings was superior at changing practice knowledge, attitudes, and behaviors when compared to a traditional educational approach, particularly when discussing common genetic conditions.MethodsOne hundred twenty one PCPs in California and Pennsylvania physician practices were randomized to either an Intervention Group (IG) or Control Group (CG). IG physicians completed a 6 h interactive web-based curriculum covering communication skills, basics of genetic testing, risk assessment, ELSI issues and practice behaviors. CG physicians were provided with a traditional approach to Continuing Medical Education (CME) (clinical review articles) offering equivalent information.ResultsPCPs in the Intervention Group showed greater increases in knowledge compared to the Control Group. Intervention PCPs were also more satisfied with the educational materials, and more confident in their genetics knowledge and skills compared to those receiving traditional CME materials. Intervention PCPs felt that the web-based curriculum covered medical management, genetics, and ELSI issues significantly better than did the Control Group, and in comparison with traditional curricula. The Intervention Group felt the online tools offered several advantages, and engaged in better shared decision making with standardized patients, however, there was no difference in behavior change between groups with regard to increases in ELSI discussions between PCPs and patients.ConclusionWhile our intervention was deemed more enjoyable, demonstrated significant factual learning and retention, and increased shared decision making practices, there were few differences in behavior changes around ELSI discussions. Unfortunately, barriers to implementing behavior change in clinical genetics is not unique to our intervention. Perhaps the missing element is that busy physicians need systems-level support to engage in meaningful discussions around genetics issues. The next step in promoting active engagement between doctors and patients may be to put into place the tools needed for PCPs to easily access the materials they need at the point-of-care to engage in joint discussions around clinical genetics

Increased spatiotemporal resolution reveals highly dynamic dense tubular matrices in the peripheral ER

The endoplasmic reticulum (ER) is an expansive, membrane-enclosed organelle that plays crucial roles in numerous cellular functions. We used emerging superresolution imaging technologies to clarify the morphology and dynamics of the peripheral ER, which contacts and modulates most other intracellular organelles. Peripheral components of the ER have classically been described as comprising both tubules and flat sheets. We show that this system consists almost exclusively of tubules at varying densities, including structures that we term ER matrices. Conventional optical imaging technologies had led to misidentification of these structures as sheets because of the dense clustering of tubular junctions and a previously uncharacterized rapid form of ER motion. The existence of ER matrices explains previous confounding evidence that had indicated the occurrence of ER "sheet" proliferation after overexpression of tubular junction-forming proteins

Particulate air pollution and survival in a COPD cohort

<p>Abstract</p> <p>Background</p> <p>Several studies have shown cross-sectional associations between long term exposure to particulate air pollution and survival in general population or convenience cohorts. Less is known about susceptibility, or year to year changes in exposure. We investigated whether particles were associated with survival in a cohort of persons with COPD in 34 US cities, eliminating the usual cross-sectional exposure and treating PM₁₀as a within city time varying exposure.</p> <p>Methods</p> <p>Using hospital discharge data, we constructed a cohort of persons discharged alive with chronic obstructive pulmonary disease using Medicare data between 1985 and 1999. 12-month averages of PM₁₀were merged to the individual annual follow up in each city. We applied Cox's proportional hazard regression model in each city, with adjustment for individual risk factors.</p> <p>Results</p> <p>We found significant associations in the survival analyses for single year and multiple lag exposures, with a hazard ratio for mortality for an increase of 10 μg/m³PM₁₀over the previous 4 years of 1.22 (95% CI: 1.17–1.27).</p> <p>Conclusion</p> <p>Persons discharged alive for COPD have substantial mortality risks associated with exposure to particles. The risk is evident for exposure in the previous year, and higher in a 4 year distributed lag model. These risks are significantly greater than seen in time series analyses.</p

Surface and Temporal Biosignatures

Recent discoveries of potentially habitable exoplanets have ignited the prospect of spectroscopic investigations of exoplanet surfaces and atmospheres for signs of life. This chapter provides an overview of potential surface and temporal exoplanet biosignatures, reviewing Earth analogues and proposed applications based on observations and models. The vegetation red-edge (VRE) remains the most well-studied surface biosignature. Extensions of the VRE, spectral "edges" produced in part by photosynthetic or nonphotosynthetic pigments, may likewise present potential evidence of life. Polarization signatures have the capacity to discriminate between biotic and abiotic "edge" features in the face of false positives from band-gap generating material. Temporal biosignatures -- modulations in measurable quantities such as gas abundances (e.g., CO2), surface features, or emission of light (e.g., fluorescence, bioluminescence) that can be directly linked to the actions of a biosphere -- are in general less well studied than surface or gaseous biosignatures. However, remote observations of Earth's biosphere nonetheless provide proofs of concept for these techniques and are reviewed here. Surface and temporal biosignatures provide complementary information to gaseous biosignatures, and while likely more challenging to observe, would contribute information inaccessible from study of the time-averaged atmospheric composition alone.Comment: 26 pages, 9 figures, review to appear in Handbook of Exoplanets. Fixed figure conversion error

Mechanical properties of β-HMX

Background: For a full understanding of the mechanical properties of a material, it is essential to understand the defect structures and associated properties and microhardness indentation is a technique that can aid this understanding. Results: The Vickers hardness on (010), {011} and {110} faces lay in the range of 304-363 MPa. The Knoop Hardnesses on the same faces lay in the range 314-482 MPa. From etching of three indented surfaces, the preferred slip planes have been identified as (001) and (101). For a dislocation glide, the most likely configuration for dislocation movement on the (001) planes is (001) [100] (|b| = 0.65 nm) and for the (101) plane as (101) 101~(|b| = 1.084 nm) although (101) [010] (|b| = 1.105 nm) is possible. Tensile testing showed that at a stress value of 2.3 MPa primary twinning occurred and grew with increasing stress. When the stress was relaxed, the twins decreased in size, but did not disappear. The twinning shear strain was calculated to be 0.353 for the (101) twin plane. Conclusions: HMX is considered to be brittle, compared to other secondary explosives. Comparing HMX with a range of organic solids, the values for hardness numbers are similar to those of other brittle systems. Under the conditions developed beneath a pyramidal indenter, dislocation slip plays a major part in accommodating the local deformation stresses. © 2015 Gallagher et al.; licensee Springer

Effect of Calcium Supplementation on Blood Lead Levels in Pregnancy: A Randomized Placebo-Controlled Trial

Background: Prenatal lead exposure is associated with deficits in fetal growth and neurodevelopment. Calcium supplementation may attenuate fetal exposure by inhibiting mobilization of maternal bone lead and/or intestinal absorption of ingested lead. Objective: Our goal was to evaluate the effect of 1,200 mg dietary calcium supplementation on maternal blood lead levels during pregnancy. Methods: In a double-blind, randomized, placebo-controlled trial conducted from 2001 through 2003 in Mexico City, we randomly assigned 670 women in their first trimester of pregnancy to ingest calcium (n = 334) or placebo (n = 336). We followed subjects through pregnancy and evaluated the effect of supplementation on maternal blood lead, using an intent-to-treat analysis by a mixed-effects regression model with random intercept, in 557 participants (83%) who completed follow-up. We then conducted as-treated analyses using similar models stratified by treatment compliance. Results: Adjusting for baseline lead level, age, trimester of pregnancy, and dietary energy and calcium intake, calcium was associated with an average 11% reduction (0.4 μg/dL) in blood lead level relative to placebo (p = 0.004). This reduction was more evident in the second trimester (−14%, p lesss than 0.001) than in the third (−8%, p = 0.107) and was strongest in women who were most compliant (those who consumed ≥ 75% calcium pills; −24%, p less than 0.001), had baseline blood lead greater than 5 μg/dL (−17%, p less than 0.01), or reported use of lead-glazed ceramics and high bone lead (−31%, p less than 0.01). Conclusion: Calcium supplementation was associated with modest reductions in blood lead when administered during pregnancy and may constitute an important secondary prevention effort to reduce circulating maternal lead and, consequently, fetal exposure

Acute and Chronic Effects of Particles on Hospital Admissions in New-England

Background: Many studies have reported significant associations between exposure to $PM_{2.5}$ and hospital admissions, but all have focused on the effects of short-term exposure. In addition all these studies have relied on a limited number of $PM_{2.5}$ monitors in their study regions, which introduces exposure error, and excludes rural and suburban populations from locations in which monitors are not available, reducing generalizability and potentially creating selection bias. Methods Using our novel prediction models for exposure combining land use regression with physical measurements (satellite aerosol optical depth) we investigated both the long and short term effects of $PM_{2.5}$ exposures on hospital admissions across New-England for all residents aged 65 and older. We performed separate Poisson regression analysis for each admission type: all respiratory, cardiovascular disease (CVD), stroke and diabetes. Daily admission counts in each zip code were regressed against long and short-term $PM_{2.5}$ exposure, temperature, socio-economic data and a spline of time to control for seasonal trends in baseline risk. Results: We observed associations between both short-term and long-term exposure to $PM_{2.5}$ and hospitalization for all of the outcomes examined. In example, for respiratory diseases, for every10-µg/m$^3$ increase in short-term $PM_{2.5}$ exposure there is a 0.70 percent increase in admissions (CI = 0.35 to 0.52) while concurrently for every10-µg/m$^3$ increase in long-term $PM_{2.5}$ exposure there is a 4.22 percent increase in admissions (CI = 1.06 to 4.75). Conclusions: As with mortality studies, chronic exposure to particles is associated with substantially larger increases in hospital admissions than acute exposure and both can be detected simultaneously using our exposure models

Vitamin D supplementation and breast cancer prevention : a systematic review and meta-analysis of randomized clinical trials

In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L