Medroxyprogesterone improves nocturnal breathing in postmenopausal women with chronic obstructive pulmonary disease

BACKGROUND: Progestins as respiratory stimulants in chronic obstructive pulmonary disease (COPD) have been investigated in males and during wakefulness. However, sleep and gender may influence therapeutic responses. We investigated the effects of a 2-week medroxyprogesterone acetate (MPA) therapy on sleep and nocturnal breathing in postmenopausal women. METHODS: A single-blind placebo-controlled trial was performed in 15 postmenopausal women with moderate to severe COPD. A 12-week trial included 2-week treatment periods with placebo and MPA (60 mg/d/14 days). All patients underwent a polysomnography with monitoring of SaO(2 )and transcutaneous PCO(2 )(tcCO(2)) at baseline, with placebo, with medroxyprogesterone acetate (MPA 60 mg/d/14 days), and three and six weeks after cessation of MPA. RESULTS: Thirteen patients completed the trial. At baseline, the average ± SD of SaO(2 )mean was 90.6 ± 3.2 % and the median of SaO(2 )nadir 84.8 % (interquartile range, IQR 6.1). MPA improved them by 1.7 ± 1.6 %-units (95 % confidence interval (CI) 0.56, 2.8) and by 3.9 %-units (IQR 4.9; 95% CI 0.24, 10.2), respectively. The average of tcCO(2 )median was 6.0 ± 0.9 kPa and decreased with MPA by 0.9 ± 0.5 kPa (95% CI -1.3, -0.54). MPA improved SaO(2 )nadir and tcCO(2 )median also during REM sleep. Three weeks after cessation of MPA, the SaO(2 )mean remained 1.4 ± 1.8 %-units higher than at baseline, the difference being not significant (95% CI -0.03, 2.8). SaO(2 )nadir was 2.7 %-units (IQR 4.9; 95% CI 0.06, 18.7) higher than at baseline. Increases in SaO(2 )mean and SaO(2 )nadir during sleep with MPA were inversely associated with baseline SaO(2 )mean (r = -0.70, p = 0.032) and baseline SaO(2 )nadir (r = -0.77, p = 0.008), respectively. Treatment response in SaO(2 )mean, SaO(2 )nadir and tcCO(2 )levels did not associate with pack-years smoked, age, BMI, spirometric results or sleep variables. CONCLUSION: MPA-induced respiratory improvement in postmenopausal women seems to be consistent and prolonged. The improvement was greater in patients with lower baseline SaO(2 )values. Long-term studies in females are warranted

Landscape Ecotoxicology of Coho Salmon Spawner Mortality in Urban Streams

In the Pacific Northwest of the United States, adult coho salmon (Oncorhynchus kisutch) returning from the ocean to spawn in urban basins of the Puget Sound region have been prematurely dying at high rates (up to 90% of the total runs) for more than a decade. The current weight of evidence indicates that coho deaths are caused by toxic chemical contaminants in land-based runoff to urban streams during the fall spawning season. Non-point source pollution in urban landscapes typically originates from discrete urban and residential land use activities. In the present study we conducted a series of spatial analyses to identify correlations between land use and land cover (roadways, impervious surfaces, forests, etc.) and the magnitude of coho mortality in six streams with different drainage basin characteristics. We found that spawner mortality was most closely and positively correlated with the relative proportion of local roads, impervious surfaces, and commercial property within a basin. These and other correlated variables were used to identify unmonitored basins in the greater Seattle metropolitan area where recurrent coho spawner die-offs may be likely. This predictive map indicates a substantial geographic area of vulnerability for the Puget Sound coho population segment, a species of concern under the U.S. Endangered Species Act. Our spatial risk representation has numerous applications for urban growth management, coho conservation, and basin restoration (e.g., avoiding the unintentional creation of ecological traps). Moreover, the approach and tools are transferable to areas supporting coho throughout western North America

Recurrent Die-Offs of Adult Coho Salmon Returning to Spawn in Puget Sound Lowland Urban Streams

Several Seattle-area streams in Puget Sound were the focus of habitat restoration projects in the 1990s. Post-project effectiveness monitoring surveys revealed anomalous behaviors among adult coho salmon returning to spawn in restored reaches. These included erratic surface swimming, gaping, fin splaying, and loss of orientation and equilibrium. Affected fish died within hours, and female carcasses generally showed high rates (>90%) of egg retention. Beginning in the fall of 2002, systematic spawner surveys were conducted to 1) assess the severity of the adult die-offs, 2) compare spawner mortality in urban vs. non-urban streams, and 3) identify water quality and spawner condition factors that might be associated with the recurrent fish kills. The forensic investigation focused on conventional water quality parameters (e.g., dissolved oxygen, temperature, ammonia), fish condition, pathogen exposure and disease status, and exposures to metals, polycyclic aromatic hydrocarbons, and current use pesticides. Daily surveys of a representative urban stream (Longfellow Creek) from 2002–2009 revealed premature spawner mortality rates that ranged from 60–100% of each fall run. The comparable rate in a non-urban stream was <1% (Fortson Creek, surveyed in 2002). Conventional water quality, pesticide exposure, disease, and spawner condition showed no relationship to the syndrome. Coho salmon did show evidence of exposure to metals and petroleum hydrocarbons, both of which commonly originate from motor vehicles in urban landscapes. The weight of evidence suggests that freshwater-transitional coho are particularly vulnerable to an as-yet unidentified toxic contaminant (or contaminant mixture) in urban runoff. Stormwater may therefore place important constraints on efforts to conserve and recover coho populations in urban and urbanizing watersheds throughout the western United States

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research

Identification of semicarbazones, thiosemicarbazones and triazine nitriles as inhibitors of Leishmania mexicana cysteine protease CPB

Cysteine proteases of the papain superfamily are present in nearly all eukaryotes. They play pivotal roles in the biology of parasites and inhibition of cysteine proteases is emerging as an important strategy to combat parasitic diseases such as sleeping sickness, Chagas' disease and leishmaniasis. Homology modeling of the mature Leishmania mexicana cysteine protease CPB2.8 suggested that it differs significantly from bovine cathepsin B and thus could be a good drug target. High throughput screening of a compound library against this enzyme and bovine cathepsin B in a counter assay identified four novel inhibitors, containing the warhead-types semicarbazone, thiosemicarbazone and triazine nitrile, that can be used as leads for antiparasite drug design. Covalent docking experiments confirmed the SARs of these lead compounds in an effort to understand the structural elements required for specific inhibition of CPB2.8. This study has provided starting points for the design of selective and highly potent inhibitors of L. mexicana cysteine protease CPB that may also have useful efficacy against other important cysteine proteases