Self-gravity as an explanation of the fractal structure of the interstellar medium

The gas clouds of the interstellar medium have a fractal structure, the origin of which has generally been thought to lie in turbulence. The energy of turbulence could come from galactic rotation at large-scale, then cascade down to be dissipated on small-scales by viscosity; it has been suggested that such turbulence helps to prevent massive molecular clouds from collapsing in response to their own gravity. Here we show that, on the contrary, self-gravity itself may be the dominant factor in making clouds fractal. We develop a field-theory approach to the structure of clouds, assuming them to be isothermal, and with only gravitational interactions; we find that the observed fractal dimension of the clouds arise naturally from this approach. Although this result does not imply that turbulence is not important, it does demonstrate that the fractal structure can be understood without it.Comment: Latex file, four pages and two colour figures in .cps files. To appear in Nature, 5 September 199

Access, accountability, and the proliferation of psychological therapy:On the introduction of the IAPT initiative and the transformation of mental healthcare

Psychological therapy today plays a key role in UK public mental health. In large part, this has been through the development of the (specifically English) Improving Access to Psychological Therapies (IAPT) programme. Through IAPT, millions of citizens have encountered interventions such as cognitive behaviour therapy, largely for the treatment of depression and anxiety. This article interrogates how this national response to problems of mental ill-health – and the problematization itself – was developed, accounted for, and sustained. By imbricating economic expertise with accounts of mental ill-health and mechanisms of treatment, IAPT has revivified psychological framings of pathology and therapy. However, it has done so in ways that are more familiar within biomedical contexts (e.g. through recourse to randomized controlled trial studies). Today, the initiative is a principal player in relation to which other services are increasingly developed. Indeed, in many respects IAPT has transformed from content to context within UK public mental health (in a process of what I term ‘contextification’). By documenting these developments, this paper contributes to re-centring questions about the place and role of psychology in contemporary healthcare. Doing so helps to complicate assumptions about the dominance of linear forms of (de)biomedicalization in health-systems

Examining intra-rater and inter-rater response agreement: A medical chart abstraction study of a community-based asthma care program

<p>Abstract</p> <p>Background</p> <p>To assess the intra- and inter-rater agreement of chart abstractors from multiple sites involved in the evaluation of an Asthma Care Program (ACP).</p> <p>Methods</p> <p>For intra-rater agreement, 110 charts randomly selected from 1,433 patients enrolled in the ACP across eight Ontario communities were re-abstracted by 10 abstractors. For inter-rater agreement, data abstractors reviewed a set of eight fictitious charts. Data abstraction involved information pertaining to six categories: physical assessment, asthma control, spirometry, asthma education, referral visits, and medication side effects. Percentage agreement and the kappa statistic (κ) were used to measure agreement. Sensitivity and specificity estimates were calculated comparing results from all raters against the gold standard.</p> <p>Results</p> <p>Intra-rater re-abstraction yielded an overall kappa of 0.81. Kappa values for the chart abstraction categories were: physical assessment (κ 0.84), asthma control (κ 0.83), spirometry (κ 0.84), asthma education (κ 0.72), referral visits (κ 0.59) and medication side effects (κ 0.51). Inter-rater abstraction of the fictitious charts produced an overall kappa of 0.75, sensitivity of 0.91 and specificity of 0.89. Abstractors demonstrated agreement for physical assessment (κ 0.88, sensitivity and specificity 0.95), asthma control (κ 0.68, sensitivity 0.89, specificity 0.85), referral visits (κ 0.77, sensitivity 0.88, specificity 0.95), and asthma education (κ 0.49, sensitivity 0.87, specificity 0.77).</p> <p>Conclusion</p> <p>Though collected by multiple abstractors, the results show high sensitivity and specificity and substantial to excellent inter- and intra-rater agreement, assuring confidence in the use of chart abstraction for evaluating the ACP.</p

Long-Term Functional Side-Effects of Stimulants and Sedatives in Drosophila melanogaster

Background: Small invertebrate animals, such as nematodes and fruit flies, are increasingly being used to test candidate drugs both for specific therapeutic purposes and for long-term health effects. Some of the protocols used in these experiments feature such experimental design features as lifelong virginity and very low densities. By contrast, the ability of both fruit flies and nematodes to resist stress is frequently correlated with their longevity and other functional measures, suggesting that low-stress assays are not necessarily the only useful protocol for testing the long-term effects of drugs. Methodology/Principal Findings: Here we report an alternative protocol for fruit fly drug-testing that maximizes reproductive opportunities and other types of interaction, with moderately high population densities. We validate this protocol using two types of experimental tests: 1. We show that this protocol detects previously well-established genetic differences between outbred fruit fly populations. 2. We show that this protocol is able to distinguish among the long-term effects of similar types of drugs within two broad categories, stimulants and tranquilizers. Conclusions: Large-scale fly drug testing can be conducted using mixed-sex high-density cage assays. We find that the commonly-used stimulants caffeine and theobromine differ dramatically in their chronic functional effects, theobromine being more benign. Likewise, we find that two generic pharmaceutical tranquilizers, lithium carbonate and valproic acid, differ dramatically in their chronic effects, lithium being more benign. However, these findings do not necessarily apply t

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydroxysteroid oxidoreductase and 3α(β)-hydroxysteroid oxidoreductases in tumorigenic (MCF-7, MDA-MB-231, T-47D) and nontumorigenic (MCF-10A) human breast cancer cells

BACKGROUND: Recent observations indicate that human tumorous breast tissue metabolizes progesterone differently than nontumorous breast tissue. Specifically, 5α-reduced metabolites (5α-pregnanes, shown to stimulate cell proliferation and detachment) are produced at a significantly higher rate in tumorous tissue, indicating increased 5α-reductase (5αR) activity. Conversely, the activities of 3α-hydroxysteroid oxidoreductase (3α-HSO) and 20α-HSO enzymes appeared to be higher in normal tissues. The elevated conversion to 5α-pregnanes occurred regardless of estrogen (ER) or progesterone (PR) receptor levels. To gain insight into these differences, the activities and expression of these progesterone converting enzymes were investigated in a nontumorigenic cell line, MCF-10A (ER- and PR-negative), and the three tumorigenic cell lines, MDA-MB-231 (ER- and PR-negative), MCF-7 and T-47D (ER- and PR-positive). METHODS: For the enzyme activity studies, either whole cells were incubated with [(14)C]progesterone for 2, 4, 8, and 24 hours, or the microsomal/cytosolic fraction was incubated for 15–60 minutes with [(3)H]progesterone, and the metabolites were identified and quantified. Semi-quantitative RT-PCR was employed to determine the relative levels of expression of 5αR type1 (SRD5A1), 5αR type 2 (SRD5A2), 20α-HSO (AKR1C1), 3α-HSO type 2 (AKR1C3), 3α-HSO type 3 (AKR1C2) and 3β-HSO (HSD3B1/HSD3B2) in the four cell lines using 18S rRNA as an internal control. RESULTS: The relative 5α-reductase activity, when considered as a ratio of 5α-pregnanes/4-pregnenes, was 4.21 (± 0.49) for MCF-7 cells, 6.24 (± 1.14) for MDA-MB-231 cells, 4.62 (± 0.43) for T-47D cells and 0.65 (± 0.07) for MCF-10A cells, constituting approximately 6.5-fold, 9.6-fold and 7.1 fold higher conversion to 5α-pregnanes in the tumorigenic cells, respectively, than in the nontumorigenic MCF-10A cells. Conversely, the 20α-HSO and 3α-HSO activities were significantly higher (p < 0.001) in MCF-10A cells than in the other three cell types. In the MCF-10A cells, 20α-HSO activity was 8-14-fold higher and the 3α-HSO activity was 2.5-5.4-fold higher than in the other three cell types. The values of 5αR:20α-HSO ratios were 16.9 – 32.6-fold greater and the 5αR:3α-HSO ratios were 5.2 – 10.5-fold greater in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. RT-PCR showed significantly higher expression of 5αR1 (p < 0.001), and lower expression of 20α-HSO (p < 0.001), 3α-HSO2 (p < 0.001), 3α-HSO3 (p < 0.001) in MCF-7, MDA-MB-231 and T-47D cells than in MCF-10A cells. CONCLUSION: The findings provide the first evidence that the 5αR activity (leading to the conversion of progesterone to the cancer promoting 5α-pregnanes) is significantly higher in the tumorigenic MCF-7, MDA-MB-231 and T-47D breast cell lines than in the nontumorigenic MCF-10A cell line. The higher 5αR activity coincides with significantly greater expression of 5αR1. On the other hand, the activities of 20α-HSO and 3α-HSO are higher in the MCF-10A cells than in MCF-7, MDA-MB-231 and T-47D cells; these differences in activity correlate with significantly higher expression of 20α-HSO, 3α-HSO2 and 3α-HSO3 in MCF-10A cells. Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for stimulating breast cancer by increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes

Impact of hormonal treatment duration in combination with radiotherapy for locally advanced prostate cancer: Meta-analysis of randomized trials

<p>Abstract</p> <p>Background</p> <p>Hormone therapy plus radiotherapy significantly decreases recurrences and mortality of patients affected by locally advanced prostate cancer. In order to determine if difference exists according to the hormonal treatment duration, a literature-based meta-analysis was performed.</p> <p>Methods</p> <p>Relative risks (RR) were derived through a random-effect model. Differences in primary (biochemical failure, BF; cancer-specific survival, CSS), and secondary outcomes (overall survival, OS; local or distant recurrence, LR/DM) were explored. Absolute differences (AD) and the number needed to treat (NNT) were calculated. Heterogeneity, a meta-regression for clinic-pathological predictors and a correlation test for surrogates were conducted.</p> <p>Results</p> <p>Five trials (3,424 patients) were included. Patient population ranged from 267 to 1,521 patients. The longer hormonal treatment significantly improves BF (with significant heterogeneity) with an absolute benefit of 10.1%, and a non significant trend in CSS. With regard to secondary end-points, the longer hormonal treatment significantly decrease both the LR and the DM with an absolute difference of 11.7% and 11.5%. Any significant difference in OS was observed. None of the three identified clinico-pathological predictors (median PSA, range 9.5-20.35, Gleason score 7-10, 27-55% patients/trial, and T3-4, 13-77% patients/trial), did significantly affect outcomes. At the meta-regression analysis a significant correlation between the overall treatment benefit in BF, CSS, OS, LR and DM, and the length of the treatment was found (p≤0.03).</p> <p>Conclusions</p> <p>Although with significant heterogeneity (reflecting different patient' risk stratifications), a longer hormonal treatment duration significantly decreases biochemical, local and distant recurrences, with a trend for longer cancer specific survival.</p

The Glyceraldehyde-3-Phosphate Dehydrogenase and the Small GTPase Rab 2 Are Crucial for Brucella Replication

The intracellular pathogen Brucella abortus survives and replicates inside host cells within an endoplasmic reticulum (ER)-derived replicative organelle named the “Brucella-containing vacuole” (BCV). Here, we developed a subcellular fractionation method to isolate BCVs and characterize for the first time the protein composition of its replicative niche. After identification of BCV membrane proteins by 2 dimensional (2D) gel electrophoresis and mass spectrometry, we focused on two eukaryotic proteins: the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and the small GTPase Rab 2 recruited to the vacuolar membrane of Brucella. These proteins were previously described to localize on vesicular and tubular clusters (VTC) and to regulate the VTC membrane traffic between the endoplasmic reticulum (ER) and the Golgi. Inhibition of either GAPDH or Rab 2 expression by small interfering RNA strongly inhibited B. abortus replication. Consistent with this result, inhibition of other partners of GAPDH and Rab 2, such as COPI and PKC ι, reduced B. abortus replication. Furthermore, blockage of Rab 2 GTPase in a GDP-locked form also inhibited B. abortus replication. Bacteria did not fuse with the ER and instead remained in lysosomal-associated membrane vacuoles. These results reveal an essential role for GAPDH and the small GTPase Rab 2 in B. abortus virulence within host cells