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The air–sea exchange of heat and carbon in the Southern Ocean (SO) plays an important role in mediating the climate state. The dominant role the SO plays in storing anthropogenic heat and carbon is a direct consequence of the unique and complex ocean circulation that exists there. Previous generations of climate models have struggled to accurately represent key SO properties and processes that influence the large-scale ocean circulation. This has resulted in low confidence ascribed to twenty-first-century projections of the state of the SO from previous generations of models. This analysis provides a detailed assessment of the ability of models contributed to the sixth phase of the Coupled Model Intercomparison Project (CMIP6) to represent important observationally based SO properties. Additionally, a comprehensive overview of CMIP6 performance relative to CMIP3 and CMIP5 is presented. CMIP6 models show improved performance in the surface wind stress forcing, simulating stronger and less equatorward-biased wind fields, translating into an improved representation of the Ekman upwelling over the Drake Passage latitudes. An increased number of models simulate an Antarctic Circumpolar Current (ACC) transport within observational uncertainty relative to previous generations; however, several models exhibit extremely weak transports. Generally, the upper SO remains biased warm and fresh relative to observations, and Antarctic sea ice extent remains poorly represented. While generational improvement is found in many metrics, persistent systematic biases are highlighted that should be a priority during model development. These biases need to be considered when interpreting projected trends or biogeochemical properties in this region.

It is unknown how hypohydration influences fine motor performance training and motor learning. Here, 30 participants (aged 19–46 years) were randomly assigned to a hypohydration (HYPO) or control (CON) group (both n = 15). Moderate hypohydration (~ 2.4% loss in body mass) was produced in HYPO via active dehydration before a 46 min fluid restricted rest period was undertaken. The conclusion of rest coincided with when CON attended the facilities. Both groups undertook a discrete sequence production task consisting of 6 training blocks, and returned ~ 300 min later to complete a delayed retention and transfer test while euhydrated. Bilateral pre-frontal cortex (PFC) haemodynamics were assessed using functional near-infrared spectroscopy throughout training and delayed learning assessments. Response time improved across training (P < 0.01) and was similar between the groups (both P = 0.22). Analysis of training PFC haemodynamics revealed a significant group by block interaction for oxygenated (O2Hb; P < 0.01), but not deoxygenated haemoglobin (P = 0.77). In training block 1, bilateral O2Hb was higher in HYPO (P = 0.02), while bilateral O2Hb increased in CON between blocks 2–3 and 5–6 (both P ≤ 0.03). During the delayed retention and transfer test, no group differences or interactions were found in response time, response error, or PFC haemodynamics (all P ≥ 0.27). Moderate hypohydration does increase PFC activation during motor skill learning, however, this appears to be transient and of little consequence to training or delayed retention or transfer performance.

To summarize the ongoing Prevention of Alzheimer's Disease (AD) by Vitamin E and Selenium (PREADViSE) trial as an ancillary study to SELECT (a large prostate cancer prevention trial) and to present the blinded results of the first year as an exposure study. PREADViSE was designed as a double blind randomized controlled trial (RCT). SELECT terminated after median of 5.5 years of exposure to supplements due to a futility analysis. Both trials then converted into an exposure study. In the randomized component PREADViSE enrolled 7,547 men age 62 or older (60 if African American). Once the trial terminated 4,246 of these men volunteered for the exposure study. Demographics were similar for both groups with exposure volunteers having baseline mean age 67.3 ± 5.2 years, 15.3 ± 2.4 years of education, 9.8% African Americans, and 22.0% reporting a family history of dementia. In the RCT men were randomly assigned to either daily doses of 400 IU of vitamin E or placebo and 200 µg of selenium or placebo using a 2×2 factorial structure. In the RCT, participants completed the Memory Impairment Screen (MIS), and if they failed, underwent a longer screening (based on an expanded Consortium to Establish a Registry in AD [CERAD] battery). CERAD failure resulted in visits to their clinician for medical examination with records of these examinations forwarded to the PREADViSE center for further review. In the exposure study, men are contacted by telephone and complete the telephone version of the memory impairment screen (MIS-T) screen. If they fail the MIS-T, a Modified Telephone Interview of Cognitive Status (TICS-M) exam is given. A failed TICS-M exam also leads to a visit to their clinician for an in-depth examination and forwarding of records for a centralized consensus diagnosis by expert clinicians. A subgroup of the men who pass the MIS-T also take the TICS-M exam for validation purposes. While this ancillary trial was open to all 427 SELECT clinical sites, only 130 (30.0%) of the sites chose to participate in PREADViSE. Staff turnover at the sites presented challenges when training persons unfamiliar with cognitive testing procedures to conduct the memory screens. In the RCT few participants (1.6%) failed the MIS screen and among those who passed this screen a significant practice effect was encountered. In the exposure study 3,581 men were reached by phone in year 1, 15.7% could not be reached after 5 calls, and of those contacted 6.0% refused the screen even after consenting to the procedures at their clinical site. Most notable is that the failure rate for the MIS-T increased fourfold to 7.2%. Of the 257 men who took the TICS-M, 84.0% failed and were asked to contact their physicians for a more detailed memory assessment, and approximately half of these had some form of dementia or cognitive impairment. Several of these dementia cases are not AD. Partnering with SELECT led to an AD prevention trial conducted at a very reasonable cost by taking advantage of the experience and efficient clinical trial management found in a cancer cooperative group (Southwest Oncology Group or SWOG). Once unblinded, the RCT and exposure study data have the potential to yield new information on long term exposure to antioxidant supplements under controlled conditions.

The Southern Ocean (SO) is vital to Earth’s climate system due to its dominant role in exchanging carbon and heat between the ocean and atmosphere and transforming water masses. Evaluating the ability of fully coupled climate models to accurately simulate SO circulation and properties is crucial for building confidence in model projections and advancing model fidelity. By analyzing multiple biases collectively across large model ensembles, physical mechanisms governing the diverse mean-state SO circulation found across models can be identified. This analysis 1) assesses the ability of a large ensemble of models contributed to phase 5 of the Coupled Model Intercomparison Project (CMIP5) to simulate observationally based metrics associated with an accurate representation of the Antarctic Circumpolar Current (ACC), and 2) presents a framework by which the quality of the simulation can be categorized and mechanisms governing the resulting circulation can be deduced. Different combinations of biases in critical metrics including the magnitude and position of the zonally averaged westerly wind stress maximum, wind-driven surface divergence, surface buoyancy fluxes, and properties and transport of North Atlantic Deep Water entering the SO produce distinct mean-state ACC transports. Relative to CMIP3, the quality of the CMIP5 SO simulations has improved. Eight of the thirty-one models simulate an ACC within observational uncertainty (2σ) for approximately the right reasons; that is, the models achieve accuracy in the surface wind stress forcing and the representation of the difference in the meridional density across the current. Improved observations allow for a better assessment of the SO circulation and its properties.

Observationally based metrics derived from the Rapid Climate Change (RAPID) array are used to assess the large-scale ocean circulation in the subtropical North Atlantic simulated in a suite of fully coupled climate models that contributed to phase 5 of the Coupled Model Intercomparison Project (CMIP5). The modeled circulation at 26.5°N is decomposed into four components similar to those RAPID observes to estimate the Atlantic meridional overturning circulation (AMOC): the northward-flowing western boundary current (WBC), the southward transport in the upper midocean, the near-surface Ekman transport, and the southward deep ocean transport. The decadal-mean AMOC and the transports associated with its flow are captured well by CMIP5 models at the start of the twenty-first century. By the end of the century, under representative concentration pathway 8.5 (RCP8.5), averaged across models, the northward transport of waters in the upper WBC is projected to weaken by 7.6 Sv (1 Sv ≡ 10⁶ m³ s−1; −21%). This reduced northward flow is a combined result of a reduction in the subtropical gyre return flow in the upper ocean (−2.9 Sv; −12%) and a weakened net southward transport in the deep ocean (−4.4 Sv; −28%) corresponding to the weakened AMOC. No consistent long-term changes of the Ekman transport are found across models. The reduced southward transport in the upper ocean is associated with a reduction in wind stress curl (WSC) across the North Atlantic subtropical gyre, largely through Sverdrup balance. This reduced WSC and the resulting decrease in the horizontal gyre transport is a robust feature found across the CMIP5 models under increased CO2 forcing.

The response of an ocean general circulation model to the onset of deep-water formation in the North Atlantic Ocean is explored. The processes of baroclinic adjustment to the new deep water mass and the adection of the new deep water mass are compared in both space and time.

Prostate cancer is the commonest non-skin malignancy in the United States and has a substantial mortality rate despite the use of PSA-based screening. Furthermore, therapy for prostate cancer by surgery, radiotherapy or hormonal manipulation carries a significant risk of treatment-related morbidity. Recent analysis of secondary endpoints of several large-scale randomized prospective clinical trials for other malignancies has suggested that selenium or vitamin E may result in a decreased incidence and mortality from prostate cancer. In vitro and preclinical studies of these antioxidants support this hypothesis. This review outlines the rationale and design of SELECT, the Selenium and Vitamin E Cancer Prevention Trial, designed to test the hypothesis that selenium or vitamin E alone or in combination can reduce the clinical incidence of prostate cancer in a population-based cohort of men at risk. SELECT is a phase III, randomized, double-blinded, prospective, 2x2 factorial clinical trial which will randomize 32,400 healthy men with normal DRE and serum PSA to one of four study arms: selenium alone, vitamin E alone, selenium+vitamin E, or placebo. Study agents will be taken orally for a minimum of 7 and maximum of 12 y with assessments of general health, incident prostate cancer and toxicity performed at 12 month intervals. Under the assumptions described, the detectable risk reduction is 25% for an effective single agent relative to placebo, with an additional 25% reduction for the combination relative to an effective single agent. The estimated power for the comparison of a single agent vs placebo is 96% and the power for the comparison of an effective single agent vs combination is 89%. Secondary endpoints will include prostate cancer-free survival, all-cause mortality, and the incidence and mortality of other cancers and diseases potentially impacted by the chronic use of selenium and vitamin E. Other trial objectives will include periodic quality of life assessments, assessment of serum micronutrient levels and prostate cancer risk, and studies of the evaluation of biological and genetic markers with the risk of prostate cancer. Prostate Cancer and Prostatic Diseases (2000) 3, 145-151

Almost 3000 men who received a placebo in the Prostate Cancer Prevention Trial and who never had a prostate-specific antigen (PSA) level of more than 4.0 ng per milliliter during the seven years of the trial underwent a prostate biopsy at the end of the study. Biopsy revealed prostate cancer in 449 men (15 percent), 67 of whom had high-grade tumors. A PSA level of 4.0 ng per milliliter or less does not rule out the presence of prostate cancer, including high-grade tumors. When first described in 1979, prostate-specific antigen (PSA) was considered a useful marker for assessing treatment responses and follow-up among patients with prostate cancer. 1 After the publication of reports on several series in which the need for a biopsy of the prostate was based on the results of PSA tests, the potential of the PSA level as a screening tool was recognized. 2 , 3 Further experience led to the consensus that a PSA level of more than 4.0 ng per milliliter had predictive value for the diagnosis of prostate cancer. 4 Disease detection subsequently increased dramatically. 5 More recent data suggest that a . . .

The objectives of this study were to evaluate degradation of ergovaline in a tall fescue [ (Schreb.) Darbysh.] seed extract by rumen microbiota ex vivo and to identify specific bacteria capable of ergovaline degradation in vitro. Rumen cell suspensions were prepared by harvesting rumen fluid from fistulated wether goats ( = 3), straining, and differential centrifugation. Suspensions were dispensed into anaerobic tubes with added Trypticase with or without extract (∼10 μg kg ergovaline). Suspensions were incubated for 48 h at 39°C. Samples were collected at 0, 24, and 48 h for ergovaline analysis and enumeration of hyper-ammonia producing (HAB) and tryptophan-utilizing bacteria. Ergovaline values were analyzed by repeated measures using the mixed procedure of SAS. Enumeration data were log transformed for statistical analysis. When suspensions were incubated with extract, 11 to 15% of ergovaline disappearance was observed over 48 h ( = 0.02). After 24 h, suspensions with added extract had 10-fold less HAB than controls ( = 0.04), but treatments were similar by 48 h ( = 1.00). However, after 24 h and 48 h, suspensions with extract had 10-fold more tryptophan-utilizing bacteria ( < 0.01) that were later isolated and identified by their 16S RNA gene sequence as . The isolates and other known rumen pure cultures ( JB1, B159, HD4, B, F, MD1, SR) were evaluated for the ability to degrade ergovaline in vitro. Pure culture cell suspensions were incubated as described above and samples were taken at 0 and 48 h for ergovaline analysis. Data were analyzed using the ANOVA procedure of SAS. All HAB, including the isolates, tested degraded ergovaline (54 to 75%; < 0.05). B14 was also able to degrade ergovaline but to a lesser capacity (12%; < 0.05), but all other bacteria tested did not degrade ergovaline. The results of this study indicate which rumen bacteria may play an important role in ergovaline degradation and that microbiological strategies for controlling their activity could have ramifications for fescue toxicosis and other forms of ergotism in ruminants.

Background: Biopsies performed for elevated serum PSA often show inflammatory infiltrates. However, the influence of intraprostatic inflammation on serum PSA in men without biopsy indication and negative for prostate cancer has not been described in detail. Methods: We studied 224 men in the placebo arm of the Prostate Cancer Prevention Trial (PCPT) who underwent end-of-study biopsy per trial protocol, had PSA <4 ng ml −1 , normal digital rectal examination and a biopsy negative for cancer. We analyzed data from hematoxylin and eosin-stained slides containing a mean of three biopsy cores. Inflammation measures included the extent (percentage of tissue area with inflammation) and intensity (product of scores for extent and grade) of total, acute and chronic inflammation in the entire tissue area examined, and by tissue compartment. We calculated median measures of inflammation by prebiopsy serum PSA tertile (>0 to ≤0.8, >0.8 to ≤1.5 and >1.5 to <4.0 ng ml −1 ). We estimated the association between percentage of tissue area with inflammation and natural logarithm of PSA using linear regression adjusting for age at biopsy. Results: Median percentage of tissue area with inflammation increased from 2 to 5 to 9.5% across PSA tertiles ( P -trend <0.0001). For every 5% increase in tissue area with inflammation, log PSA increased by 0.061 ng ml −1 ( P =0.0002). Median extent and intensity scores increased across PSA tertiles in luminal and intraepithelial compartments for acute inflammation and in stromal and intraepithelial compartments for chronic inflammation (all P -trend ≤0.05). Conclusions: In men without clinical suspicion of prostate cancer, greater overall inflammation, luminal and intraepithelial acute inflammation and stromal and intraepithelial chronic inflammation were associated with higher serum PSA.