Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy ...neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We infer the properties of massive star populations using the far-ultraviolet stellar continua of 61 star-forming galaxies: 42 at low redshift observed with the Hubble Space Telescope and 19 at z ~ 2 ...from the MegaSaura sample. We fit each stellar continuum with a linear combination of up to 50 single-age and single-metallicity starburst99 models. From these fits, we derive light-weighted ages and metallicities, which agree with stellar wind and photospheric spectral features, and infer the spectral shapes and strengths of the ionizing continua. Inferred light-weighted stellar metallicities span 0.05–1.5 Z(sub ⊙) and are similar to the measured nebular metallicities. We quantify the ionizing continua using the ratio of the ionizing flux at 900 Å to the non-ionizing flux at 1500 Å and demonstrate the evolution of this ratio with stellar age and metallicity using theoretical single-burst models. These single-burst models only match the inferred ionizing continua of half of the sample, while the other half are described by a mixture of stellar ages. Mixed-age populations produce stronger and harder ionizing spectra than continuous star formation histories, but, contrary to previous studies that assume constant star formation, have similar stellar and nebular metallicities. Stellar population age and metallicity affect the far-UV continua in different and distinguishable ways; assuming a constant star formation history diminishes the diagnostic power. Finally, we provide simple prescriptions to determine the ionizing photon production efficiency (ξ(sub ion)) from the stellar population properties. The ξ(sub ion) inferred from the observed star-forming galaxies has a range of log(ξ(sub ion)) = 24.4–25.7 Hz erg(exp −1) that depends on the stellar population age, metallicity, star formation history, and contributions from binary star evolution. These stellar population properties must be observationally determined to accurately determine the number of ionizing photons generated by massive stars.
Lung cancer risks at which individuals should be screened with computed tomography (CT) for lung cancer are undecided. This study's objectives are to identify a risk threshold for selecting ...individuals for screening, to compare its efficiency with the U.S. Preventive Services Task Force (USPSTF) criteria for identifying screenees, and to determine whether never-smokers should be screened. Lung cancer risks are compared between smokers aged 55-64 and ≥ 65-80 y.
Applying the PLCO(m2012) model, a model based on 6-y lung cancer incidence, we identified the risk threshold above which National Lung Screening Trial (NLST, n = 53,452) CT arm lung cancer mortality rates were consistently lower than rates in the chest X-ray (CXR) arm. We evaluated the USPSTF and PLCO(m2012) risk criteria in intervention arm (CXR) smokers (n = 37,327) of the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO). The numbers of smokers selected for screening, and the sensitivities, specificities, and positive predictive values (PPVs) for identifying lung cancers were assessed. A modified model (PLCOall2014) evaluated risks in never-smokers. At PLCO(m2012) risk ≥ 0.0151, the 65th percentile of risk, the NLST CT arm mortality rates are consistently below the CXR arm's rates. The number needed to screen to prevent one lung cancer death in the 65th to 100th percentile risk group is 255 (95% CI 143 to 1,184), and in the 30th to <65th percentile risk group is 963 (95% CI 291 to -754); the number needed to screen could not be estimated in the <30th percentile risk group because of absence of lung cancer deaths. When applied to PLCO intervention arm smokers, compared to the USPSTF criteria, the PLCO(m2012) risk ≥ 0.0151 threshold selected 8.8% fewer individuals for screening (p<0.001) but identified 12.4% more lung cancers (sensitivity 80.1% 95% CI 76.8%-83.0% versus 71.2% 95% CI 67.6%-74.6%, p<0.001), had fewer false-positives (specificity 66.2% 95% CI 65.7%-66.7% versus 62.7% 95% CI 62.2%-63.1%, p<0.001), and had higher PPV (4.2% 95% CI 3.9%-4.6% versus 3.4% 95% CI 3.1%-3.7%, p<0.001). In total, 26% of individuals selected for screening based on USPSTF criteria had risks below the threshold PLCO(m2012) risk ≥ 0.0151. Of PLCO former smokers with quit time >15 y, 8.5% had PLCO(m2012) risk ≥ 0.0151. None of 65,711 PLCO never-smokers had PLCO(m2012) risk ≥ 0.0151. Risks and lung cancers were significantly greater in PLCO smokers aged ≥ 65-80 y than in those aged 55-64 y. This study omitted cost-effectiveness analysis.
The USPSTF criteria for CT screening include some low-risk individuals and exclude some high-risk individuals. Use of the PLCO(m2012) risk ≥ 0.0151 criterion can improve screening efficiency. Currently, never-smokers should not be screened. Smokers aged ≥ 65-80 y are a high-risk group who may benefit from screening. Please see later in the article for the Editors' Summary.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Converging evidence from genetic, pathological and experimental studies have increasingly suggested an important role for autophagy impairment in Parkinson's Disease (PD). Genetic studies have ...identified mutations in genes encoding for components of the autophagy-lysosomal pathway (ALP), including glucosidase beta acid 1 (GBA1), that are associated with increased risk for developing PD. Observations in PD brain tissue suggest an aberrant regulation of autophagy associated with the aggregation of α-synuclein (α-syn). As autophagy is one of the main systems involved in the proteolytic degradation of α-syn, pharmacological enhancement of autophagy may be an attractive strategy to combat α-syn aggregation in PD. Here, we review the potential of autophagy enhancement as disease-modifying therapy in PD based on preclinical evidence. In particular, we provide an overview of the molecular regulation of autophagy and targets for pharmacological modulation within the ALP. In experimental models, beneficial effects on multiple pathological processes involved in PD, including α-syn aggregation, cell death, oxidative stress and mitochondrial dysfunction, have been demonstrated using the autophagy enhancers rapamycin and lithium. However, selectivity of these agents is limited, while upstream ALP signaling proteins are involved in many other pathways than autophagy. Broad stimulation of autophagy may therefore cause a wide spectrum of dose-dependent side-effects, suggesting that its clinical applicability is limited. However, recently developed agents selectively targeting core ALP components, including Transcription Factor EB (TFEB), lysosomes, GCase as well as chaperone-mediated autophagy regulators, exert more specific effects on molecular pathogenetic processes causing PD. To conclude, the targeted manipulation of downstream ALP components, rather than broad autophagy stimulation, may be an attractive strategy for the development of novel pharmacological therapies in PD. Further characterization of dysfunctional autophagy in different stages and molecular subtypes of PD in combination with the clinical translation of downstream autophagy regulation offers exciting new avenues for future drug development.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Survival after nontraumatic out-of-hospital (OOH) cardiac arrest in Tucson, Arizona, has been flat at 6% (121/2177) for the decade 1992 to 2001. We hypothesized that interruptions of chest ...compressions occur commonly and for substantial periods during treatment of OOH cardiac arrest and could be contributing to the lack of improvement in resuscitation outcome.
Sixty-one adult OOH cardiac arrest patients treated by automated external defibrillator (AED)-equipped Tucson Fire Department first responders from November 2001 through November 2002 were retrospectively reviewed. Reviews were performed according to the code arrest record and verified with the AED printout. Validation of the methodology for determining the performance of chest compressions was done post hoc. The median time from "9-1-1" call receipt to arrival at the patient's side was 6 minutes, 27 seconds (interquartile range IQR, 25% to 75%, 5 minutes, 24 seconds, to 7 minutes, 34 seconds). An additional 54 seconds (IQR, 38 to 74 seconds) was noted between arrival and the first defibrillation attempt. Initial defibrillation shocks never restored a perfusing rhythm (0/21). Chest compressions were performed only 43% of the time during the resuscitation effort. Although attempting to follow the 2000 guidelines for cardiopulmonary resuscitation, chest compressions were delayed or interrupted repeatedly throughout the resuscitation effort. Survival to hospital discharge was 7%, not different from that of our historical control (4/61 versus 121/2177; P=0.74).
Frequent interruption of chest compressions results in no circulatory support during more than half of resuscitation efforts. Such interruptions could be a major contributing factor to the continued poor outcome seen with OOH cardiac arrest.
Lung cancer screening guidelines recommend using individualized risk models to refer ever-smokers for screening. However, different models select different screening populations. The performance of ...each model in selecting ever-smokers for screening is unknown.
To compare the U.S. screening populations selected by 9 lung cancer risk models (the Bach model; the Spitz model; the Liverpool Lung Project LLP model; the LLP Incidence Risk Model LLPi; the Hoggart model; the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Model 2012 PLCOM2012; the Pittsburgh Predictor; the Lung Cancer Risk Assessment Tool LCRAT; and the Lung Cancer Death Risk Assessment Tool LCDRAT) and to examine their predictive performance in 2 cohorts.
Population-based prospective studies.
United States.
Models selected U.S. screening populations by using data from the National Health Interview Survey from 2010 to 2012. Model performance was evaluated using data from 337 388 ever-smokers in the National Institutes of Health-AARP Diet and Health Study and 72 338 ever-smokers in the CPS-II (Cancer Prevention Study II) Nutrition Survey cohort.
Model calibration (ratio of model-predicted to observed cases expected-observed ratio) and discrimination (area under the curve AUC).
At a 5-year risk threshold of 2.0%, the models chose U.S. screening populations ranging from 7.6 million to 26 million ever-smokers. These disagreements occurred because, in both validation cohorts, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) were well-calibrated (expected-observed ratio range, 0.92 to 1.12) and had higher AUCs (range, 0.75 to 0.79) than 5 models that generally overestimated risk (expected-observed ratio range, 0.83 to 3.69) and had lower AUCs (range, 0.62 to 0.75). The 4 best-performing models also had the highest sensitivity at a fixed specificity (and vice versa) and similar discrimination at a fixed risk threshold. These models showed better agreement on size of the screening population (7.6 million to 10.9 million) and achieved consensus on 73% of persons chosen.
No consensus on risk thresholds for screening.
The 9 lung cancer risk models chose widely differing U.S. screening populations. However, 4 models (the Bach model, PLCOM2012, LCRAT, and LCDRAT) most accurately predicted risk and performed best in selecting ever-smokers for screening.
Intramural Research Program of the National Institutes of Health/National Cancer Institute.
Summary Background Improvements in cancer survival have made the long-term risks from treatments more important, including the risk of developing a second cancer after radiotherapy. We aimed to ...estimate the proportion of second cancers attributable to radiotherapy in adults with data from the US Surveillance, Epidemiology and End Results (SEER) cancer registries. Methods We used nine of the SEER registries to systematically analyse 15 cancer sites that are routinely treated with radiotherapy (oral and pharynx, salivary gland, rectum, anus, larynx, lung, soft tissue, female breast, cervix, endometrial, prostate, testes, eye and orbit, brain and CNS, and thyroid). The cohort we studied was composed of patients aged 20 years or older who were diagnosed with a first primary invasive solid cancer reported in the SEER registries between Jan 1, 1973, and Dec 31, 2002. Relative risks (RRs) for second cancer in patients treated with radiotherapy versus patients not treated with radiotherapy were estimated with Poisson regression adjusted for age, stage, and other potential confounders. Findings 647 672 cancer patients who were 5-year survivors were followed up for a mean 12 years (SD 4·5, range 5–34); 60 271 (9%) developed a second solid cancer. For each of the first cancer sites the RR of developing a second cancer associated with radiotherapy exceeded 1, and varied from 1·08 (95% CI 0·79–1·46) after cancers of the eye and orbit to 1·43 (1·13–1·84) after cancer of the testes. In general, the RR was highest for organs that typically received greater than 5 Gy, decreased with increasing age at diagnosis, and increased with time since diagnosis. We estimated a total of 3266 (2862–3670) excess second solid cancers that could be related to radiotherapy, that is 8% (7–9) of the total in all radiotherapy patients (≥1 year survivors) and five excess cancers per 1000 patients treated with radiotherapy by 15 years after diagnosis. Interpretation A relatively small proportion of second cancers are related to radiotherapy in adults, suggesting that most are due to other factors, such as lifestyle or genetics. Funding US National Cancer Institute.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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