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EMBARGOED FOR RELEASE: 11 A.M. (ET), MONDAY, JANUARY 11, 2016

 Media Advisory: To contact study corresponding author Morgan E. Grams, M.D., call Lauren Nelson at 410-955-8725 or email Laurennelson@jhmi.edu. To contact editorial corresponding author Adam Jacob Schoenfeld, M.D., call Scott Maier at 415-476-3595 or email scott.maier@ucsf.edu.

 To place an electronic embedded link in your story: Links are live at the embargo time: http://archinte.jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2015.7193; http://archinte.jamanetwork.com/article.aspx?doi=10.1001/jamainternmed.2015.7927

 JAMA Internal Medicine

 Proton pump inhibitors (PPIs), which are commonly used drugs to reduce acid in the stomach, appear to be associated with an increased risk of chronic kidney disease but more research is needed to determine whether PPI use causes kidney damage, according to an article published online by JAMA Internal Medicine.

 PPIs are one of the most commonly prescribe medications in the United States and an estimated 25 percent to 70 percent of these prescriptions may have no appropriate indication for use. Other observational studies have linked PPIs to serious adverse health outcomes. However, the authors note that no population-based studies, to their knowledge, have looked at the association between PPI use and the risk of chronic kidney disease (CKD).

 Morgan E. Grams, M.D., Ph.D., of Johns Hopkins University, Baltimore, and coauthors quantified the association between PPI use and incident CKD in the general population using data on self-reported PPI use in the Atherosclerosis Risk in Communities (ARIC) study (10,482 participants followed up for a median of nearly 14 years) or an outpatient PPI prescription in the Geisinger Health System in Pennsylvania (248,751 participants followed up for a median of six years). The results were replicated at Geisinger.

 At baseline, PPI users in both groups were more likely to have a higher body mass index and take antihypertensive, aspirin or statin medications.

 In the ARIC group, there were 56 incident CKD events among 322 baseline PPI users (14.2 per 1,000-person years) and 1,382 events among 10,160 baseline nonusers (10.7 per 1,000 person-years). PPI use was associated with risk of incident CKD in unadjusted and adjusted analyses. The 10-year estimated absolute risk of CKD among the 322 baseline PPI users was 11.8 percent while the expected risk had they not used PPIs was 8.5 percent, according to the results.

 In the replication group at Geisinger, there were 1,921 incident CKD events among 16,900 baseline PPI users (20.1 per 1,000 person-years) and 28,226 events among 231,851 baseline nonusers (18.3 per 1,000 person-years). PPI use was associated with risk of incident CKD in analyses. The 10-year absolute risk of CKD among the 16,900 baseline PPI users was 15.6 percent and the expected risk had they not used PPIs was 13.9 percent, results indicate.

 The authors note several study limitations, including that participants who are prescribed PPIs may be at higher risk of CKD for reasons unrelated to their PPI use.

 “We note that our study is observational and does not provide evidence of causality. However, a causal relationship between PPI use and CKD could have a considerable public health effect given the widespread extent of use. More than 15 million Americans used prescription PPIs in 2013, costing more than $10 billion. Study findings suggest that up to 70 percent of these prescriptions are without indication and that 25 percent of long-term PPI users could discontinue therapy without developing symptoms. Indeed, there are already calls for the reduction of unnecessary use of PPIs,” the study concludes.

 (JAMA Intern Med. Published online January 11, 2016. doi:10.1001/jamainternmed.2015.7193. Available pre-embargo to the media at http://media.jamanetwork.com.)

 Editor’s Note: The study includes funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures.

 Editorial: Adverse Effects Associated with Proton Pump Inhibitors

 Adam Jacob Schoenfeld, M.D., and Deborah Grady, M.D., M.P.H., of the University of California, San Francisco, wrote a related editorial summarizing recent data on the adverse effects of PPI use.

 “A large number of patients are taking PPIs for no clear reason – often remote symptoms of dyspepsia or “heartburn” that have since resolved. In these patients, PPIs should be stopped to determine if symptomatic treatment is needed,” they conclude.

 (JAMA Intern Med. Published online January 11, 2016. doi:10.1001/jamainternmed.2015.7927. Available pre-embargo to the media at http://media.jamanetwork.com.)

 Editor’s Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures.

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 For more information, contact JAMA Network Media Relations at 312-464-JAMA (5262) or email mediarelations@jamanetwork.org. ||||| Popular Heartburn Pills Can Be Hard To Stop, And May Be Risky

 Enlarge this image Katherine Streeter for NPR Katherine Streeter for NPR

 When Marcella Lafayette started having really bad heartburn, she went to her doctor to see if there was anything that might help.

 "I was experiencing a lot of chest pain, back pain caused from heartburn," says Lafayette, 62, of Portland, Ore.

 Her doctor diagnosed her with gastroesophageal reflux disease, or GERD, and prescribed a drug called a proton pump inhibitor, or PPI. The drug worked, but Lafayette soon started having other problems, such as muscle weakness and severe leg cramping.

 Lafayette discovered she was suffering from a magnesium deficiency, a side effect of the drug. She also learned that PPIs can cause not just deficiencies of nutrients but other side effects, such as an increased risk for infections.

 So Lafayette decided to try to stop using her PPI. But whenever she did, her heartburn returned. And the symptoms were much worse.

 "I can't seem to get off the drug, because when I do, I experience severe stomach pain. I can't eat anything without experiencing stomach pain," Lafayette says. "It just feels like you've got a knife in your gut. It's just really painful."

 Lafayette is not alone. Many people have trouble discontinuing PPIs because the amount of acid in their digestive system surges when they stop taking the drug.

 Experiences like Lafayette's, and rising evidence that the drugs may be associated with a variety of increased risks, are making doctors increasingly worried about their wide use.

 "The teaching for many years was that these drugs were quite safe," says John Clarke, a gastroenterologist at Johns Hopkins Hospital in Baltimore. "But there is data that's emerging that suggests PPIs may not be as safe as we think they are."

 An estimated 15 million Americans use PPIs, which are sold by prescription and over the counter under a variety of brand names, including Nexium, Prilosec and Prevacid.

 They work by blocking production of stomach acid. And that could be the root of the problem, according to Clarke. Stomach acid helps digest food and also has a "barrier function against different pathogens which are ingested," he says.

 So when there's less stomach acid, it leaves people vulnerable to nutritional deficiencies and infections, including food poisoning like salmonella, a serious, sometimes life-threatening digestive system infection called Clostridium difficile, and perhaps pneumonia.

 Stomach acid also helps digest food. So if you don't have any of that acid, it can make it hard to get the vitamins, minerals and other nutrients you need from your food — including nutrients that keep bones strong and prevent fractures.

 In addition, one recent study suggested people who take PPIs may be at greater risk of heart disease; another suggested the drugs could increase the risk for chronic kidney disease.

 Updated Feb. 15, 11 a.m. ET: The latest concern is that PPIs might increase the risk for dementia. Britta Haenisch and colleagues at the German Center for Neurodegenerative Diseases in Bonn studied 73,679 people ages 75 and older. The researchers found regular PPI users had at least a 44 percent increased risk of dementia compared with those not using the drugs.

 The researchers caution that the risk could only be considered an "association," until more research could be conducted to produce more conclusive evidence. But the findings indicate "the avoidance of PPI medication may contribute to the prevention of dementia."

 How PPIs might increase the risk for dementia is unclear. But other researchers recently reported that, in the brains of mice, PPIs seem to increase levels of a damaging protein that accumulates in the brains of dementia patients, known as beta-amyloid.

 In an editorial accompanying the study in the journal JAMA Neurology, Lewis Kuller of the University of Pittsburgh wrote that the findings "provided an important and interesting challenge to evaluate the possible association," which is a "very important issue given" how commonly the drugs are used by the elderly, who are already at increased risk for dementia.

 Our original post continues: As this evidence has emerged, Clarke says, "I think it's imperative that people who take these drugs really make sure that they are looking at the risks versus benefit and people don't use these drugs lightly."

 Many people take PPIs when they don't really need them, Clarke says. They could get rid of their heartburn by making lifestyle changes, such as losing weight and cutting back on alcohol, caffeine and spicy and fatty foods. And many people stay on them a lot longer than they need them, he says. PPIs are usually supposed to be taken for two to eight weeks, although doctors may recommend more.

 The companies that make PPIs say they're safe for most people if they use them the way they're supposed to. And doctors say many people really need to take a PPI for severe heartburn.

 "Proton pump inhibitors do have some very positive benefits to patients," says Kenneth DeVault, a gastroenterologist at the Mayo Clinic who is president of the American College of Gastroenterology. "They relieve symptoms better than any other medication that has ever been developed."

 The most important "positive effect of proton pump inhibitors is restoration of a quality of life," DeVault says. "This is probably the big one."

 PPIs may also reduce the risk for esophageal cancer for some people, he says.

 DeVault says if someone really needs a PPI, they should take one. But they should try everything else first, keep an eye out for any side effects, and talk to their doctor about how long they should stay on it. ||||| A key event in the pathogenesis of Alzheimer’s disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.

 Competing interests: Albert Pujol and Mireia Coma are employed by Anaxomics Biotech. However, there are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

 Funding: The present work has been supported by the Spanish Ministerio de Ciencia e Innovación (PSE-010000-2009-1; BIO2010-22073) and by the own fund of each institute, and the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

 Copyright: © 2013 Badiola et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

 In this study, we explore the effects of lansoprazole, and other PPIs, on β-amyloid production in a well-established cellular model of amyloid pathology, with special attention to the effect over the different Aβ species. We assess the in vivo relevance of our findings in wild-type (wt) and AD triple transgenic (3xTg-AD) mice and we ultimately speculate about the potential mechanisms underlying the observed alterations.

 Lansoprazole is a proton pump inhibitor (PPI) drug widely used in the treatment of peptic ulcer disease and other conditions where inhibition of gastric secretion may be beneficial [26] , [27] . PPIs are generally well tolerated, and adverse effects are relatively infrequent [28] , [29] . Yet, chronic administration of PPIs is becoming increasingly common, and there is a growing concern about potential unexplored adverse effects from such long-term therapy [30] .

 Despite all the efforts put on AD research over the past years, there are no effective treatments to prevent, halt or cure the disease. Indeed, there are only four FDA-approved drugs for AD treatment, although they mainly provide a symptomatic improvement and are unable to stop the disease progression [22] . This prompted us to use the therapeutic performance mapping system (TPMS) [23] to explore potential novel indications of marketed drugs to modify the biology of AD. In brief, the TPMS is a top-down systems biology approach with potential applications in drug repositioning [24] . Starting from the clinical effects produced by different therapeutic compounds (both, positive and negative), we first split them into causative physiological motifs and identified the responsible molecular effectors, which were then mapped onto the disease-related cell network. We afterwards established different relationships between drug targets and effector proteins in the network that are used for training a classifier, with capacity for predicting and scoring novel potential indications on AD of totally unrelated drugs. The complete results of this study will be published elsewhere [25] . Interestingly, the TPMS analysis suggested that lansoprazole could act as a strong potential modulator of the processes involved in amyloid-β pathology.

 More recently, an alternative hypothesis has been growing and gaining support, based on the idea that the toxic component is within the soluble fraction. There is data showing that soluble forms of Aβ correlate more closely with dementia severity than fibrillar Aβ [9] , [10] , [11] , [12] and that Aβ oligomers alter dendritic spine density and affect hippocampal synaptic plasticity in vivo [13] , [14] , [15] , [16] , [17] . Furthermore, it has been demonstrated that brain oligomeric Aβ, but not total amyloid plaque burden, correlates with neuronal loss and astrocyte inflammatory response in APP/Tau transgenic mouse model [18] . In this context, several studies show the presence of Aβ oligomers in CSF of AD patients, while not in healthy individuals, and also the direct correlation of oligomers with cognitive impairment [19] , [20] , [21] .

 Several studies support the hypothesis that classic fibrillar amyloid plaques are deleterious to the brain, showing that the subpopulation of dense-core Aβ plaques in particular, the so-called neuritic plaques, are intimately associated with local dendritic spine loss, changes in neurites, and gliosis in AD and mouse models [5] , [6] . However, the total number of amyloid plaques do not correlate well with the severity of illness [7] or with loss of neurons [8] , arguing against a direct causal effect of plaques on cognition or neuronal cell death in AD.

 Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder worldwide. Many molecular lesions have been detected in AD, but one of the major pathological hallmarks is the extracellular deposition of amyloid-β (Aβ) peptides in the brain [1] , that results in oxidative and inflammatory damage, which in turn leads to energy failure and synaptic dysfunction [2] . Formation of Aβ species is caused by the sequential cleavage of amyloid precursor protein (APP) by two proteases, β-secretase, also called β-site APP-cleaving enzyme 1 (BACE1), and γ-secretase. Aβ40 is the major secreted form while Aβ42 has been suggested to be the main pathological species in AD pathogenesis [3] , although other truncated Aβ peptides might also contribute substantially to toxicity and amyloidogenesis [4] .

 We determined lysate protein concentration using the Bio-Rad D C protein assay (Bio-Rad Laboratories). We loaded 20–40 µg of each cell lysate and electrophoresed in 10% Tris-glycine gels for Western blot analysis. For Aβ species detection, supernatants we run in 11% urea gels. For the immunoblotting we incubated overnight at 4°C with the following primary antibodies: rabbit polyclonal anti-C-terminal APP (Sigma-Aldrich), rabbit polyclonal anti-BACE (catalytic domain, Abcam), rabbit polyclonal anti-sAPPβ (IBL), 6E10 (against Aβ 1–16, Covance) or mouse monoclonal anti-actin (Sigma-Aldrich) antibodies. Afterwards, we incubated with either an HRP-conjugated secondary antibody plus enhanced chemiluminescence substrate (Millipore), or with an infrared fluorescent-labelled secondary antibody (IRDye, Rockland Immunochemicals, Gilbertsville, PA) for 1 h at room temperature.

 We thawed 3xTg-AD mouse brains on ice in 3× (w/v) 2% SDS with a protease inhibitor cocktail (Complete® EDTA-free, Roche) and then we homogenized them. Next, we centrifuged homogenates at 100.000 g for 1 h at 4°C. Finally, we collected the supernatants and we stored samples at −80°C as SDS-soluble Aβ fractions.

 We thawed non-transgenic mouse brains on ice in 3× (w/v) 0.2% of diethylamine (DEA) and 50 mM of NaCl buffer with a protease inhibitor cocktail (Complete® EDTA-free, Roche), and then we homogenized them. We subsequently centrifuged homogenates at 100.000 g for 1 h at 4°C. Finally, we collected the supernatants, and neutralized them by addition of 1∶10 volume of 0.5 M Tris-HCl pH 6.8. We stored samples at −80°C as DEA-soluble Aβ fractions.

 We treated both female 3xTg-AD mice (Charles River) and non-transgenic mice (B6129SF1/J) at 7 month of age for 5 consecutive days with an intraperitoneal injection of lansoprazole. We diluted and administered lansoprazole in 10% DMSO and 18% of encapsin (2-hydroxipropil beta-cyclodextrine), at 20 mg/kg or 100 mg/kg, respectively. At the end point, we sacrificed mice 5 h after the last treatment and we froze each hemisphere in liquid nitrogen and stored them at −80°C.

 All animals were housed in an animal facility that is fully compliant with the European policy on the use of Laboratory Animals. Experimental protocols were approved by the Parc Científic of Barcelona Committee and meet the European and Spanish guidelines of animal experimentation.

 We used W0-2antibody and Protein-G Sepharose beads to immunoprecipitate human Aβ from conditioned media. We washed Sepharose beads twice in PBS and twice in 100 mM ammonium acetate. We then eluted Aβ twice with 300 µl of 50% acetic acid and vacuum-dried. Finally, we resuspended the samples in 10 µl of 33% acetonitrile containing 0.1% tri-fluoric acetic acid and ultrasonicated. Afterwards we analyzed Aβ species by MALDI-MS on sinapinic acid matrix with an UltraflexII TOF/TOF (BrukerDaltonics).

 We quantified human Aβ42 and Aβ40 levels by human β-amyloid (1–42) and (1–40) ELISA kits (Wako Pure Chemical Industries), respectively. We loaded 100 µL of conditioned media on every assay. For 3xTg-AD mouse brain extracts we previously diluted them 1/40 in standard buffer and then we loaded following manufacturer’s protocol. We measured rodent Aβ40 and Aβ42 levels with ELISA kits (IBL International) according to manufacturer’s protocol.

 For Aβ production analysis, we seeded PS70 cells in 12-well plates at a density of 150,000 cells per well and we subsequently treated for 24 h with lansoprazole, omeprazole, pantoprazole or esomeprazole (Sigma-Aldrich) at different concentrations. We used the γ–secretase inhibitor DAPT (N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester, Sigma-Aldrich) at 2 µM as a positive control. Lastly, we collected and stored cell culture supernatants at −80°C until further use.

 Results and Discussion

 Lansoprazole and Other PPIs Increase Aβ Levels in AD-like Cellular Models To investigate the potential effect of lansoprazole on Aβ production, we treated PS70 Chinese hamster ovary (CHO) cells stably expressing both wild-type human APP and presenilin 1 (PS1) with increasing concentrations of lansoprazole for 24 h. We first used the MTT reduction assay as a proxy to determine whether the tested concentrations caused cell toxicity, which was not the case below 50 µM (data not shown), in agreement with previous studies [32]. We subsequently measured the Aβ40 and Aβ42 levels in conditioned media of cultures by specific ELISA immunoassays. We observed that Aβ40 levels in the conditioned media increased after treatments above 10 µM (Figure 1A), up to 2-fold increase in the amount of Aβ40 with respect to the vehicle-treated cultured cells. Furthermore, we observed a dose-dependent increase in Aβ42 between 5 µM and 50 µM (Figure 1A), with more than 200% Aβ42 increase at 25 µM and over 300% when treated with 50 µM. As expected, cells treated with the γ–secretase inhibitor N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) showed negligible levels of Aβ. These results indicate that lansoprazole treatment increase Aβ production at commonly used concentrations [32], [33], [34], [35], [36], which in turn are comparable to other Aβ inducers such as the calcium ionophore A23187, which increases the production of Aβ approximately 3-fold [37], or caffeine (at millimolar concentrations), that increases Aβ levels until 4-fold [38]. In addition, we have observed an Aβ42 increase of over 250% compared to vehicle in cell cultures treated at 50 µM lansoprazole, while fenofibrate, a potent Aβ42 raising Aβ38 lowering compound, generates an increase of 125% at the same concentration [39]. Overall, these findings provide further evidence about the accuracy of the TPMS to predict pharmacological alterations in Aβ metabolism. PPT PowerPoint slide

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 larger image TIFF original image Download: Figure 1. Lansoprazole and similar PPIs increase Aβ levels at 5 µM–50 µM range in AD-like cells. A, Treatment of PS70 cells with lansoprazole at different concentrations (250 nM–50 µM) for 24 h increased Aβ40 and Aβ42 levels, as measured by ELISA immunoassays (n = 6± SD) p<0.05 (+), p<0.01 (*). B, Similar treatment with omeprazole, pantoprazole and esomeprazole at different concentrations (5 µM–50 µM) also increased Aβ40 and Aβ42 levels (n = 4± SD) p<0.05 (+), p<0.01 (*). https://doi.org/10.1371/journal.pone.0058837.g001 To check whether these results could also be extrapolated to other PPIs, we examined the effect of compounds of the same drug class on Aβ production. Omeprazole is one of the most widely prescribed drugs worldwide, which is administered as a racemic mixture of its two enantiomers, S-omeprazole (esomeprazole) and R-omeprazole. Similarly, pantoprazole is also broadly used because of its relatively long duration of action compared with other PPIs, and its lower propensity to become activated in slightly acidic body compartments [40]. Since the chemical structures and pharmacological targets of the four PPIs are very similar, our TPMS computational analyses also predicted an effect of these compounds on the Aβ metabolism. Thus, we decided to investigate the effect of omeprazole, pantoprazole and esomeprazole within 5 µM and 50 µM range, based on our previous results. Although the increase in Aβ40 was non-homogeneous for the 3 drugs, they did show a dose-dependent increase in Aβ42 levels (Fig. 1B), achieving up to 175% increase. Hence, these results suggest that the modulation of Aβ production is a shared feature among the PPI drug class.

 Lansoprazole Might Modulate the γ-secretase Complex To gain a deeper insight in the relative formation of Aβ species induced by lansoprazole, we conducted an Aβ-immunoprecipitation coupled with mass spectrometry analysis of high dose lansoprazole-conditioned media. Different Aβ species are generated because γ–secretase has multiple APP cleavage sites. The main produced species is Aβ40 and, to a lower extent, Aβ38 and Aβ42. Intriguingly, small molecule drugs called γ–secretase modulators (GSM) are able to shift the γ–secretase cleavage site, being classified as straight GSMs when they lower Aβ42 and rise Aβ38 [41], or as inverse GSMs (iGSM) when they do the opposite [39], [42], [43]. Interestingly, our MALDI-MS analysis revealed a considerably altered Aβ peptide pattern in cells treated with lansoprazole at 50 µM. The relative levels of Aβ42 increased whereas the relative levels of Aβ38 decreased (Figure 2A). Intriguingly, there was also an increase in Aβ37. As expected, the γ-secretase inhibitor DAPT completely abrogated Aβ production, showing no Aβ peaks. We further confirmed the Aβ42 increase and Aβ38 decrease by Western blot (Figure 2B). Therefore, attending to the results obtained with lansoprazole in the Aβ species production shift, one possible explanation would be that lansoprazole might act as an inverse GSM. PPT PowerPoint slide

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 larger image TIFF original image Download: Figure 2. Lansoprazole changes the production levels of several Aβ species. A, MALDI-MS analysis of Aβ-immunoprecipitated species from conditioned PS70 supernatants. Cells treated with lansoprazole at 50 µM for 24 h showed a significant increase on Aβ42 compared to vehicle spectrum. DAPT treated cells were used as a negative control, showing none Aβ species as expected. B, Western blot analysis of the different Aβ species present in treated PS70 supernatants. A decrease on Aβ38 and increase on Aβ42 was detected in conditioned media of treated cells with lansoprazole at 50 µM for 24 h. Short and long exposures are shown for better visualization. C, Aβ40/42 levels in conditioned media from treated PS70 cells were measured by ELISA immunoassays (n = 3± SD) p<0.01 (*). Cells treated with both lansoprazole at 50 µM and R-flurbiprofen at 200 µM for 24 h displayed reduced Aβ42 levels when compared to lansoprazole-only treated cells, indicating the lansoprazole is capable to counteract the R-flurbiprofen Aβ42 lowering effect. D, Western blot analysis of APP and BACE1 protein levels in total lysates, showing no differences between treated and non-treated cells. A representative experiment is shown (n = 3 independent experiments). E, Western blot analysis of sAPPβ and sAPPα protein levels in conditioned media. The immunoblot shows an increase in sAPPβ in conditioned media from cells treated with lansoprazole. A representative experiment is shown (n = 3 independent experiments). https://doi.org/10.1371/journal.pone.0058837.g002 To further investigate this hypothesis, we wanted to test if lansoprazole was able to counterbalancing the Aβ42-lowering capability of R-flurbiprofen, a well characterized non-steroidal anti-inflammatory drug (NSAID) that acts as straight GSM [44], [45]. NSAIDs are widespread used due to the prevalence of diseases in the aging population and to their crucial role as effective antipyretic analgesics in a wide spectrum of conditions and diseases ranging from a common cold to rheumatoid arthritis [46]. However, they are known to disrupt the mucosal resistance to gastric acid through several mechanisms including suppression of prostaglandin production and are thus associated with adverse events such as gastric or duodenal ulcers. For that reason, the co-administration with PPIs is strongly recommended in certain circumstances [47], [48]. Notably, albeit we can find straight and inverse GSM modulators within NSAIDs, the former have been considered as very interesting therapeutic agents in AD, since they can lower Aβ42 without perturbing the cyclooxygenase (COX) activity, the principal pharmacological target of NSAIDs [41], [49]. As expected, cells treated with R-flurbiprofen showed decreased Aβ42 levels while cells treated with lansoprazole increased Aβ42 levels (Figure 2C). Interestingly, when the two drugs were combined, lansoprazole blocked the Aβ42 decrease induced by R-flurbiprofen. Therefore, these results suggest that concomitant administration of PPIs with NSAIDs may neutralize the Aβ42 lowering effect provided by NSAIDs, at least in cell culture. Taken together, these findings suggest that lansoprazole increase Aβ42 production similarly to other described iGSMs. Nevertheless, alternative mechanisms related to APP dimerization processes could also play a role in the observed changes of Aβ42 levels [50].

 Lansoprazole Might Increase BACE1 and Meprin β Protease Activities The putative iGSM activity of lansoprazole could explain the increase of Aβ42 coupled to a decrease of Aβ38, but it cannot account for the rise of Aβ40. Hence, we wanted to investigate other possible effects of lansoprazole on Aβ production. The APP can be processed by two different pathways: the non-amyloidogenic pathway, involving α-secretase and γ-secretase activities, and the amyloidogenic pathway, requiring BACE1 and γ-secretase [2]. If the first cleavage is performed by α-secretase, soluble APPα (sAPPα) and APP C83 C-terminal fragments are generated, and the consecutive cleavage by γ-secretase produces the p3 peptides, which are non-amylodogenic. On other hand, when APP is first cleaved by BACE1, soluble APPβ (sAPPβ) and APP C99 fragments are otherwise generated, and γ-secretase cleavage ultimately generates Aβ peptides and the amyloid precursor protein intracellular domain (AICD) fragments. To explore how lansoprazole was able to increase Aβ37 and Aβ40 levels, we first tested whether it increased APP or BACE1 protein levels, since higher amounts of Aβ substrate or processing enzyme would certainly explain the increase in Aβ production [1], [51]. However, we did not observe any significant change in the protein expression levels of either protein (Figure 2D). We then interrogated if lansoprazole could enhance BACE1 activity instead, and measured the generation of sAPPβ, a BACE1 cleavage product. Interestingly, we observed that lansoprazole promoted sAPPβ production, suggesting an increase of BACE1 activity. In contrast, sAPPα remained unaffected by lansoprazole treatment (Figure 2E). In addition, the mass spectra also revealed a slight increase of the Aβ2-37, Aβ2-40 and Aβ2-42 species (Fig. 2A), which could be accounted for the meprin β metalloprotease, recently identified as an APP cleaving enzyme at the p2 position [52]. Variations in the media pH induced by lansoprazole could thus boost this protease activity, generating Aβ2-x peptides. Overall, these findings suggest that lansoprazole may not only modulate γ-secretase, but also seems to increase BACE1 activity, boosting the Aβ species production that would be eventually reflected in Aβ40 and Aβ37 increased levels. Nevertheless, since the PPIs are known to be irreversible inhibitors of H+/K+ ATPase, lansoprazole-induced variations in the media pH may also affect the activity of other proteases, such as meprin β, and ultimately affecting Aβ production, particularly Aβ2-x species.

 Acute Treatment with Lansoprazole Increases Aβ Levels in Both wt and AD Mouse Models Our results would not go beyond a cellular curiosity if lansoprazole could not cross the blood brain barrier. However, it has been reported that it can indeed cross it and exert its effects in brain tissue [53]. Thus, to determine whether lansoprazole is capable of altering Aβ production in the brain, we conducted short-term intraperitoneal administration in wt and AD triple-transgenic (3xTg-AD) mouse models, like in previous studies [39] (Figure 3). 3xTg-AD mice overexpress human tau and APP in a mutant PS1 knock-in background, and present both plaque and tangle pathologies in an age-related manner [54]. Even though, acute treatments do not enable an evaluation of histopathological or cognitive alteration, since changes in Aβ plaque burden or cognitive impairment usually occur after a long and sustained treatment of at least 2–3 months. Yet, 8-month age transgenic mice typically contain few Aβ plaques but they have significant amounts of intracellular and soluble Aβ [54], being a suitable age to test changes in soluble Aβ. PPT PowerPoint slide

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 larger image TIFF original image Download: Figure 3. Lansoprazole raises Aβ40 production in mice. A, Non-transgenic mice were treated 5 consecutive days with 100 kg/mg of lansoprazole (n = 10). Soluble Aβ40 and Aβ42 from brain extracts were measured by ELISA (n = 10± SD) p<0.05 (+). Lansoprazole increased Aβ40 levels in non-transgenic mice. B, 3xTg-ADwere treated 5 consecutive days with 100 kg/mg of lansoprazole (n = 6). Soluble Aβ40 and Aβ42 from brain extracts were measured by ELISA (n = 6± SD) p<0.05 (+), p<0.01 (*). Lansoprazole increased soluble Aβ40 levels in 3xTg-AD mice in a dose-dependent manner. https://doi.org/10.1371/journal.pone.0058837.g003 We used administration doses of 20 mg/kg/day and 100 mg/kg/day. When compared to the equivalent doses in human [55], the administered concentrations are far below the LC50 (5000 mg/Kg) and comparable to the doses prescribed to treat certain pathologies, such as the Zollinger-Ellison syndrome, 180 mg/day [56]. We found that, indeed, acute treatment with 100 mg/kg/day intraperitoneally administered lansoprazole increased soluble Aβ40 levels in healthy, non-transgenic mice (Figure 3A). Levels of soluble Aβ42 were also slightly increased, although they did not reach statistical significance. In the case of 3xTg-AD mice, short-term treatment with 20 mg/kg/day or 100 mg/kg/day of lansoprazole dramatically raised soluble Aβ40 levels in a dose-dependent manner (Figure 3B). Interestingly, Aβ40 production was higher than in non-transgenic mice, attaining almost to the 250% rise at 100 mg/kg/day. Similarly to the non-transgenic mice, we also observed a moderate increase in soluble Aβ42 levels, although they were not statistically significant either. In order to contextualize the relevance of the effects shown in mice at doses used in this study, it is worth to mention that a recent patent proposes a daily dose up to 400 mg of lansoprazole to inhibit tumor growth in humans [33]. Using the body surface area (BSA) normalization method [55], the conversion of the 20 mg/Kg and 100 mg/Kg mouse doses into equivalent human doses results in around 100 mg/day and 486 mg/day, respectively. Interestingly, we found an increase of Aβ levels in 3xTg-AD mice treated with 20 mg/Kg/day of lansoprazole, providing evidence of a clear effect at human prescribed equivalent doses. The differences observed in the Aβ40/Aβ42 levels between cellular and mouse models could be partially explained by the Aβ quantization, since we only measured extracellular Aβ in cells, while we measured both extracellular and intracellular Aβ species in brain homogenates. Despite these differences, our findings demonstrate that lansoprazole is able to augment Aβ production both in vitro and in vivo models, with an exacerbated effect in AD models. ||||| WASHINGTON, Feb. 15 (UPI) -- The number of potential side effects from the use of proton-pump inhibiting drugs to control heartburn continues to grow, with new research in Germany linking them to the development of dementia.

 A new study links the widely used PPIs -- which include Nexium, Prevacid and Prilosec -- to an increased risk for cognitive decline, though researchers caution the study has limitations, and does not show a definite cause.

 PPIs have recently been linked to kidney disease, heart disease, and deficiencies of B12 and other vitamins. While patients have reported side effects of the drugs, not taking them often results in stomach pains and worse heartburn as the drug leaves their systems.

 "It does not tell us anything that should change medical practice right now," Keith Fargo, director of scientific programs and outreach for the Alzheimer's Association, told CBS News. "I don't think there's going to be an uprising among doctors telling patients not to take their PPIs. This doesn't rise anywhere near the level of evidence you would need for that."

 For the study, published in JAMA Neurology, researchers analyzed patient data collected from 2004 to 2011 by the German health insurer Allgemeine Ortskrankenkassen for 73,679 of its customers.

 The patients, who were 75 years or older and did not have dementia, on PPI drugs showed a 44 percent increased risk of dementia compared with those who did not use them. Researchers said in the study the data is supported by recent studies with mice that found rodents on PPIs had increased levels of amyloid plaques in their brains, the buildup of which contributed to dementia.

 Researchers and doctors note that these studies have not accounted for lifestyle or diet, both of which affect the risk for dementia, or other diseases for which PPIs may increase risk.

 "The teaching for many years was that these drugs were quite safe," John Clarke, a gastroenterologist at Johns Hopkins Hospital, told NPR. "But there is data that's emerging that suggests PPIs may not be as safe as we think they are." ||||| Importance Medications that influence the risk of dementia in the elderly can be relevant for dementia prevention. Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases but have also been shown to be potentially involved in cognitive decline.

 Objective To examine the association between the use of PPIs and the risk of incident dementia in the elderly.

 Design, Setting, and Participants We conducted a prospective cohort study using observational data from 2004 to 2011, derived from the largest German statutory health insurer, Allgemeine Ortskrankenkassen (AOK). Data on inpatient and outpatient diagnoses (coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and drug prescriptions (categorized according to the Anatomical Therapeutic Chemical Classification System) were available on a quarterly basis. Data analysis was performed from August to November 2015.

 Exposures Prescription of omeprazole, pantoprazole, lansoprazole, esomeprazole, or rabeprazole.

 Main Outcomes and Measures The main outcome was a diagnosis of incident dementia coded by the German modification of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. The association between PPI use and dementia was analyzed using time-dependent Cox regression. The model was adjusted for potential confounding factors, including age, sex, comorbidities, and polypharmacy.

 Results A total of 73 679 participants 75 years of age or older and free of dementia at baseline were analyzed. The patients receiving regular PPI medication (n = 2950; mean [SD] age, 83.8 [5.4] years; 77.9% female) had a significantly increased risk of incident dementia compared with the patients not receiving PPI medication (n = 70 729; mean [SD] age, 83.0 [5.6] years; 73.6% female) (hazard ratio, 1.44 [95% CI, 1.36-1.52]; P < .001).

 Conclusions and Relevance The avoidance of PPI medication may prevent the development of dementia. This finding is supported by recent pharmacoepidemiological analyses on primary data and is in line with mouse models in which the use of PPIs increased the levels of β-amyloid in the brains of mice. Randomized, prospective clinical trials are needed to examine this connection in more detail. ||||| A popular class of heartburn medications might raise a senior's risk of dementia, a new study suggests.

 Called proton pump inhibitors (PPIs), this group of drugs includes Prilosec, Nexium and Prevacid. They work by lowering the amount of acid produced by the stomach.

 But German researchers found that people 75 or older who regularly take the medications had a 44 percent increased risk of dementia, compared with seniors not using the drugs. The study only found an association, however, and not a cause-and-effect link.

 "To evaluate cause-and-effect relationships between long-term PPI use and possible effects on cognition in the elderly, randomized, prospective clinical trials are needed," said corresponding author Britta Haenisch, from the German Center for Neurodegenerative Diseases in Bonn.

 In the meantime, "Clinicians should follow guidelines for PPI prescription, to avoid overprescribing PPIs and inappropriate use," Haenisch said.

 The report was published Feb. 15 in the journal JAMA Neurology.

 The results are surprising enough that at least one leading expert on aging, Dr. Malaz Boustani, plans to share the findings with older patients who are using PPIs.

 Boustani said earlier studies have linked another type of antacid, H2 blockers, with an increased risk of dementia. Up to now, he's recommended that patients use PPIs to treat acid reflux and steer clear of H2 blockers like Tagamet, Pepcid and Zantac.

 "I'm going to disclose the finding to my patients and then let them decide whether they will take the risk or not," said Boustani, a professor of medicine with the Indiana University Center for Aging Research and a spokesman for the American Federation for Aging Research. "On Monday I have clinic, and if I have patients taking a PPI or an H2 blocker I will tell them exactly what I'm telling you, and then they can decide."

 More than 15 million Americans used prescription PPIs in 2013, at a total cost of more than $10 billion, according to a report by the IMS Institute for Healthcare Informatics. Several popular PPIs -- Prilosec, Prevacid and Zegerid -- also are available over-the counter, further boosting their use.

 Concern has been increasing that Americans might be overusing PPIs to treat minor cases of heartburn or acid reflux.

 As many as 70 percent of PPI prescriptions in the United States have been inappropriately handed out by doctors, and 25 percent of long-term users could stop taking the medication without suffering increased heartburn or acid reflux, according to a study published in January in the journal JAMA Internal Medicine.

 Overuse of PPIs could have drastic effects on health, that study found. For example, the medications have been linked to a 20 percent to 50 percent higher risk of chronic kidney disease.

 And now the German researchers report there also is some evidence that PPI use might affect a person's ability to reason.

 PPIs appear to effect levels of amyloid beta and tau, which are proteins associated with Alzheimer's disease, the German authors said. PPI use can also lead to vitamin B12 deficiency, which has been associated with cognitive decline.

 To test the possible association between PPIs and dementia, the German researchers collected data from a large German health insurance firm on almost 74,000 seniors aged 75 or older. The data ran from 2004 to 2011, and included diagnoses and drug prescriptions.

 About 2,950 patients regularly used PPIs, which for this study was defined as at least one PPI prescription in each quarter of an 18-month interval.

 Regular users of PPIs had a 44 percent increased risk of dementia compared with those not receiving PPI medications.

 However, the study doesn't make clear whether PPIs are also available over the counter in Germany, as they are in the United States, said Dr. Arun Swaminath, director of the inflammatory bowel disease program at Lenox Hill Hospital in New York City.

 If over-the-counter PPIs are available, then more people might have been taking them and the dementia risk described in this paper could be overestimated, Swaminath said.

 "However, I think the point here is that for some patients, weaning off PPIs is reasonable and they should make this decision with their doctors," he said.

 People who want to ease off PPIs can take a number of steps to reduce excess acid or prevent acid reflux, Boustani said. They can eat smaller meals, lay off chocolate and caffeine, and stay upright for a few hours following each meal.

 Boustani added that his group has received federal funding to design clinical trials in which people would be weaned off PPIs, to see how it affects their ability to remember and think.

 Dr. Gisele Wolf-Klein, director of geriatric education at North Shore-LIJ Health System in New Hyde Park, N.Y., added that even the researchers aren't sure why PPIs would affect the aging brain.

 "We don't know what is causing the brain to deteriorate. Until we know this, there's no reason for people who are taking PPIs to be too concerned about that and stop taking those agents if they are needed," Wolf-Klein said.

 Another expert agreed.

 While the study is intriguing, it's not enough for doctors to warn patients off PPI use, said Keith Fargo, director of scientific programs and outreach for the Alzheimer's Association.

 "It does not tell us anything that should change medical practice right now," Fargo said. "I don't think there's going to be an uprising among doctors telling patients not to take their PPIs. This doesn't rise anywhere near the level of evidence you would need for that."

 One of the paper's main flaws is that researchers could not control for diet and body weight as risk factors, Fargo said.

 "Both of those things, we know, are risk factors for developing cognitive decline and dementia in later life, and both of those are reasons why a person might need to take a proton pump inhibitor," Fargo explained. |||||

– Certain heartburn drugs have already been linked to heath woes including heart disease and kidney disease. Now a study in JAMA Neurology says those drugs—proton-pump inhibitors like Prilosec, Prevacid, and Nexium—may also boost the chance of dementia, UPI reports. Analyzing a German health insurer's data on nearly 74,000 customers aged 75 and up from 2004 to 2011, researchers found a 44% higher dementia risk among "PPI" users. The finding also coincides with research showing that mice on PPIs had higher amyloid plaque levels in their brains, which has been linked to dementia. So what to do, when roughly 15 million Americans use prescription PPIs and other patients take over-the-counter versions? For now, nothing. More clinical trials are needed to analyze the possible PPI-dementia link, senior study author Britta Haenisch tells CBS News. For one thing, the JAMA Neurology study didn't account for lifestyle and diet, which can influence dementia risk. But, she adds, "clinicians should follow guidelines for PPI prescription, to avoid overprescribing PPIs and inappropriate use." Up to 70% of PPI prescriptions may be needless reactions to minor cases of acid reflux or heartburn, per a recent study. Big picture: PPIs are being seen in a whole new light. "The teaching for many years was that these drugs were quite safe," a gastroenterologist tells NPR. "But there is data that's emerging that suggests PPIs may not be as safe as we think they are." (Turns out vegetable oils may cause dementia when heated.)


Rapper Andre Johnson made headlines this past April when he cut off his own penis and jumped off the second story of a North Hollywood building.

 He survived, and on Sunday, he spoke to E! News exclusively about why he cut off his penis, noting that this is the first time he's spoken truthfully about the incident.

 "Yes, I was using drugs that night, but I was in complete control," said the rapper, who also goes by the name of Christ Bearer. "I cut it off because that was the root of all my problems. My solution to the problem was the realization that sex is for mortals, and I am a god...Those kinds of activities got me into trouble, and I came here to be a god." ||||| John Chapple for New York Daily News Andre Johnson, who performs under the stage name Christ Bearer with the Wu-Tang affiliated group Northstar, chopped off his own penis in April.

 The Wu-Tang Clan-affiliated rapper who cut off his own penis in a drug-fueled delirium last April is rebutting reports that surgeons re-attached his private part.

 "Doctors didn't reattach it, but I definitely have some penis left," Northstar rapper Christ Bearer, whose real name is Andre Johnson, told the Daily News Monday.

 "I always say a penis is a penis. And the sensation is still there. I definitely still get extremely aroused if I see a beautiful woman," he continued. "That being said, I definitely believe sex is for mortals, and I am god. So this is a blessing, not a curse."

 Johnson, 41, said he wasn't trying to commit suicide when he cut himself and jumped off the second-story balcony of his condo in North Hollywood on April 16.

 John Chapple for New York Daily News Johnson says wasn't trying to commit suicide when he cut himself and jumped off the second-story balcony of his condo in North Hollywood on April 16.

 "By no means was I trying to kill myself. I was under the influence of PCP. It's a drug that I had stopped doing for years, but I just got back from Ohio and got back into that lifestyle for a few days. It definitely was not wise," he told The News.

 Johnson said he had been studying some literature about monks and vasectomies and was extremely high when he took the knife to his genitals and jumped.

 "I was lucky I was only on the second floor. If I was any higher, it would have been a tragedy. The height didn't make any difference to me. I wasn't aware of the height," he said. "I was so happy to wake up in the hospital."

 John Chapple for New York Daily News July 14, 2014. Van Nuys, California. Andre Johnson - who performs under the stage name Christ Bearer with the Wu-Tang affiliated group Northstar. Johnson (40) chopped off his own penis inside a North Hollywood apartment about 1am on April 16 He then jumped off a second story balcony. Photo Copyright John Chapple / www.JohnChapple.com Enlarge John Chapple for New York Daily News July 14, 2014. Van Nuys, California. Andre Johnson - who performs under the stage name Christ Bearer with the Wu-Tang affiliated group Northstar. Johnson (40) chopped off his own penis inside a North Hollywood apartment about 1am on April 16 He then jumped off a second story balcony. Photo Copyright John Chapple / www.JohnChapple.com Enlarge The rapper says he still has 'some penis left,' adding that it's a 'blessing,' because 'sex is for mortals, and I am god.'

 Johnson said he welcomed a new daughter named Kennedy into the world just two weeks after his bizarre breakdown and hospitalization at Cedars Sinai Medical Center in Los Angeles.

 He also has two older daughters, Lana, 2, and Lauren, 8.

 "I'm very optimistic about the future," he told The News. "I just had a daughter, and I plan to be part of her life for a long time."

 Facebook Christ Bearer said he had been studying some literature about monks and vasectomies and was extremely high when he took the knife to his genitals and jumped.

 He said he's still writing music and hopes to sign with an agent soon to start doing some stand-up comedy.

 Wu Tang Clan leader RZA produced Northstar's well-received 2004 debut album and featured the Long Beach group on the Wu Tang Killa Bees albums.

 "I'm excited about getting back. I'm looking forward to what will occur," Johnson told The New Monday.

 "The future belongs to those who believe in the beauty of their dreams," he said. "My message is about peace and harmony and love, everybody getting along."

 ndillon@nydailynews.com |||||

Write a summary.

– Andre Johnson, the Wu-Tang Clan-affiliated rapper who severed his own penis in April before jumping off a building, has explained his actions ... sort of. "I cut it off because that was the root of all my problems," the 41-year-old rapper, who also uses the name Christ Bearer, tells E!. "My solution to the problem was the realization that sex is for mortals, and I am a god. ... Those kinds of activities got me into trouble, and I came here to be a god." He also spoke to the New York Daily News, noting that he had been reading about monks and vasectomies at the time. Oh, and probably coincidentally, he admits he was on drugs, too. "But I was in complete control," he insists, and "I didn't want to kill myself." He also notes, contrary to some media reports, that doctors couldn't re-attach the member. "But, it still gets hard, the little bit that I got. I still got some penis that works," he says. "I definitely still get extremely aroused if I see a beautiful woman." But, despite his previous remarks, he adds, "I wasn't having that much sex up to that point anyways. My days of reproducing are over. But now I'm a reborn man." As for why he jumped, "That was just my response to the demons. They were doing their best to get to me, but being alive solidified my thoughts," he says. "I'm alive, penis or no penis." He's speaking out for the first time since the incident because "the truth must be told," he says. What's next for him? "I love comedy," he says. "I'm going to do stand up along with making music."


Article:
This was the year everyone went gaga for Lady Gaga.

 The shape-shifting pop star takes home Billboard's top artist of the year honors, just a year after she earned top new artist applause. The last time an act made a move from "new" to "top" faster was in 2006, when Chris Brown snared both titles concurrently. Before that, the last woman to graduate nearly as fast was Whitney Houston, who was our top new artist of 1985 and then became the top artist the following year.

 See all of Billboard's 2010 Year-End Charts

 Billboard's year-end music recaps are based on chart performance during the chart year that began with last year's Dec. 5 issue and ended with the Nov. 27, 2010, issue. The year-end Top Artists list ranks the best-performing acts of the year derived from activity on two charts: the Billboard 200 albums tally and the Billboard Hot 100 singles list.

 Since we created the top overall artist category with our year-end recaps in 1981, only seven women have taken home the trophy, including Gaga. Taylor Swift nabbed it in 2009, preceded by LeAnn Rimes (1997), Alanis Morissette (1996), Mariah Carey (1991), Whitney Houston (1986) and Madonna (1985).

 Gaga takes the artist of the year honor thanks in part to the chart performance of her first two albums, "The Fame" and "The Fame Monster" (both on Streamline/KonLive/Cherrytree/Interscope), which rank at Nos. 4 and 13, respectively, on the year-end Top Billboard 200 Albums tally. Four singles from those albums appear on the Hot 100 Songs roundup, led by "Bad Romance" at No. 8.

 Swift is 2010's No. 2 artist of the year -- not too shabby for the Big Machine singer who was our top artist last year. With her one-two punch in 2009 and 2010, it marks the first time an act has been one of the top two artists in successive years since Destiny's Child was the top artist in 2000 and 2001. Narrowing the accolade among only soloists, Garth Brooks was the last to do so, when he was the No. 1 act in 1992 and 1993. The last woman? Mariah Carey, who was No. 1 in 1991 and No. 2 in 1992.

 Over on our year-end Billboard 200 albums tally, four of the top 10 slots are occupied by just two artists: Taylor Swift and Justin Bieber. Swift's "Fearless" (2009) is at No. 7 while the just-released "Speak Now" is at No. 9. The Bieb's "My World 2.0" is No. 5 while his 2009 "My World" (EP) is at No. 8. For each, it marks the first time on act has held down two of the top 10 year-end Billboard 200 albums since 1992. That was when Brooks finished the year with "Ropin' the Wind" at No. 1 and "No Fences" at No. 6.

 "Speak Now" charted for only three weeks during the 2010 chart year, making its No. 9 placing a stunning achievement. Ranking on the year-end tally is determined by a title's weekly charting sales. So, "Speak Now" made up for its short chart life in the chart year with massive sales: It moved 1.6 million units in those three weeks, according to Nielsen SoundScan.

 Elsewhere, neither Gaga nor Swift charted on the Top R&B/Hip-Hop Albums tally, marking the first time neither of the top two artists of the year have done so since 1997, when Rimes and Spice Girls came in at Nos. 1 and 2, respectively, on that chart.

 So, last year Gaga was our new artist and then became the top artist this year. Could Ke$ha, who snags the throne on 2010's Top New Artists list, win the big prize in 2011? This year the Kemosabe/RCA singer celebrates not just her new artist win but also her crowning of the Hot 100 Songs roundup, where her debut charting single "TiK ToK" is tops. The track spent nine weeks at No. 1 on the weekly Hot 100 list.

 The last time an act's first charting single became the top song of the year was only two years ago, when Flo Rida reigned with "Low." However, since Billboard began producing year-end recaps in 1946, no woman -- until Ke$ha -- had managed the feat.

 Two steps behind Ke$ha on the new artist tally is Susan Boyle, who earns her ranking mostly on the strength of her two hit albums, "I Dreamed a Dream" and "The Gift." The former spent six weeks atop the Billboard 200 and finishes 2010 as the No. 1 Top Billboard 200 album.

 At No. 2 on the year-end Billboard 200 albums list is Eminem's "Recovery." All of the rapper's albums -- save for his debut, "The Slim Shady LP" -- have finished among the year-end top 10 Billboard 200 albums. He's ranked in the top two twice before: in 2005 with "Encore" (No. 2) and in 2002 with "The Eminem Show" (No. 1).

 Eminem also ends 2010 as the No. 3 artist of the year, and with Gaga and Swift at Nos. 1 and 2, he's our top male artist.

 Country trio Lady Antebellum is the highest-ranking group on the top artist recap, coming in at No. 4. It's the first time a country act is the biggest group of the year.

 Since Billboard began compiling year-end combined pop artist categories in 1977 (for males, females and duo/groups, respectively) no country act had ever finished the year as the top overall duo/group.

 Lady A also takes home the No. 2 honor on the Hot 100 Songs recap with its Capitol Nashville single "Need You Now," which spent two weeks at No. 2 on the weekly tally, but lingered for 42 weeks within the top 40 during the eligibility period. A country single last reached such heights on the year-end Hot 100 tally in 2000, when Faith Hill's "Breathe" was the top Hot 100 song. ||||| Billboard Honors Lady Gaga and Ke$ha With Year's Top Awards

 Email This Gaga ooh la la is right!

 The meat-wearing songstress has been honored with Billboard's Artist of the Year award for 2010, a prize nabbed by paparazzi darling

 Despite being ousted from the top spot by Gaga, the 'Speak Now' singer hasn't been left out of the 2010 lineup completely. Swift comes in at number two this year, and is the only solo artist to spend two successive years in the top two spots since Garth Brooks in the early 1990s. Gaga ooh la la is right! Lady Gaga is taking home Billboard 's top honor for 2010.The meat-wearing songstress has been honored with Billboard's Artist of the Year award for 2010, a prize nabbed by paparazzi darling Taylor Swift in 2009. This is not the first time Gaga has received recognition from Billboard -- just last year, the 'Alejandro' singer took home the coveted Top New Artist Award.Despite being ousted from the top spot by Gaga, the 'Speak Now' singer hasn't been left out of the 2010 lineup completely. Swift comes in at number two this year, and is the only solo artist to spend two successive years in the top two spots since Garth Brooks in the early 1990s.

 Of course, with Gaga vacating the Top New Artist throne, there's room for a new entrant. Cue 'Cannibal' Ke$ha, whose Jack Daniels-doused oral hygiene and songwriting styles have won the hearts of a nation.Boosting her into the honor is her 2010 hit 'Tik Tok,' which spent nine weeks atop the Hot 100 list. Impressively, 'Tik Tok' was Ke$ha's first single to make it on to Billboard's charts.The recipients of Billboard's highest group honor are country crooners Lady Antebellum, whose hit 'Need You Now' spent a whopping 42 weeks of the eligibility period on the Billboard top 40. |||||Summary:

– Lady Gaga was Billboard’s top new artist last year, and this year she’s moved on to snag the top artist-of-the-year honors. That’s the fastest any woman has moved from one category to the other since Whitney Houston managed the feat in 1985-86. (Chris Brown managed to snag both titles simultaneously, in 2006.) The ranking is determined based on chart performance. So who’s this year’s top new artist? Ke$ha. For more on the rankings and to see what happened to last year’s top artist, Taylor Swift, click here.


Write a summary based on this article:

Tweet with a location

 You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| Tweet with a location

 You can add location information to your Tweets, such as your city or precise location, from the web and via third-party applications. You always have the option to delete your Tweet location history. Learn more ||||| Playboy Twins Move Back Into The Mansion

 Seems like Hef‘s broken heart is recovering rather quickly!

 Just days after his fiance Crystal Harris dumped him and moved out of the mansion, it seems that a couple of Hef’s favorite ladies have already moved in to take her place.

 Playboy twins, and Hef’s exes, Karissa and Kristina Shannon have moved back IN to the mansion a year and a half after moving out.

 In fact, it seems that Karissa has broken up with Sam Jones III so that she and her twin sis could go back to Hef.

 Hmm, well, that didn’t take too long. Guess Hef needs all the support he can get to mend that broken heart.

 [Image via WENN.] ||||| Hugh Hefner The Best Way to Get Over a Girl ...

 Hugh Hefner -- The Best Way to Get Over a Girl ... |||||

– Crystal Harris and Hugh Hefner didn't tie the knot yesterday, and they didn't mope, either. Hef took to Twitter to share his chin-up attitude: "This was going to be my wedding day, but life is full of surprises," the 85-year-old wrote. "After all is said & done, staying single is probably for the best." Single, however, is not code for "alone." Perez Hilton reports that exes Karissa and Kristina Shannon (yep, twins) have already moved back into the mansion, which they left a year and a half ago. And TMZ reports that Hef has been cozying up to Miss January 2011. And how did the runaway bride spend her day? Hanging poolside in Las Vegas in a teeny bikini and high heels with a group of friends, one of which was Heidi Montag. But do we detect a hint of sadness in Hugh's voice? A series of tweets posted in rapid succession this afternoon sound a little down. An example: "The Sunday night Mansion movie is Elle Fanning, Amanda Michalka & Kyle Chandler in JJ Abrams' Super 8. Life goes on."


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 OREM — In a case that offers a new definition of expensive tastes, police arrested a woman after they say she swallowed a ring to keep it from being found.

 A man was looking at a ring worth thousands of dollars at the Zales store at University Mall, 575 E. University Parkway, Friday evening, according to a statement by Orem police Lt. Craig Martinez. The man left the store and entered a white Pontiac G6 with a woman at the wheel.

 Police responded around 7:36 p.m. and found that an employee had been chasing, but did not capture, the man. The Pontiac was last seen headed west on University Parkway, with sticky notes covering the car's license plate, Martinez said.

 About a half-hour later, a Utah Valley University officer stopped a car matching the suspect's vehicle description at Ventana Student Housing, 1386 S. 400 West, according to police. Inside they found Bryan Ford, 30, at the wheel, and passenger Christina Schlegel, 25.

 A Zales employee identified Ford as the man who stole the ring, Martinez said. After following leads with no success, investigators discovered that Schlegel swallowed the ring so police would not find it when they pulled over the car.

 An X-ray taken at a local hospital revealed the ring in Schlegel's stomach, according to police.

 Police booked Schlegel and Ford into the Utah County Jail on investigation of theft.

 Email: wevans@deseretnews.com

 Twitter: whitevs7 |||||
What is a one-paragraph summary of the above article?

– They might have gotten away with it, if it wasn't for those pesky X-rays: Police in Orem, Utah, who pulled over a man suspected of stealing a ring worth thousands of dollars last Friday eventually discovered it in his passenger's belly, reports the Deseret News. Bryan Ford, 30, and Christina Schlegel, 25, were taken to a police station and sent cops seeking the ring on "several wild goose chases" before an X-ray revealed that Schlegel had swallowed it when the pair were first pulled over, according to Tucson News Now. Both have been charged with felony theft.


Article:
Alan Dershowitz may not want to jump aboard Donald Trump's legal team, but apparently, he has no qualms with advising Harvey Weinstein's legal team.

 On Thursday, Weinstein continued his bid in Delaware Bankruptcy Court to obtain personal and business records kept by The Weinstein Co. The movie mogul is currently facing investigation by law enforcement authorities over allegations of sexual misconduct. For months, he's been in court and in arbitration without success in an effort to obtain old emails. He believes the material will allow him to "exonerate himself."

 In new court papers, Weinstein's attorneys repeat their claims that due process rights are being violated. Plus, it's argued that Weinstein should get the benefit of discovery to see if any property for sale belongs to him.

 What's substantively new here is a declaration from Dershowitz, a Harvard Law professor who is a frequent legal commentator on CNN and Fox News. The former O.J. Simpson defense attorney has been especially vocal of late on the investigation into Russian collusion in the election and sat down to dinner with Trump recently. He was reportedly asked to join the president's team. That didn't happen, but he's interested in Weinstein too.

 "I have been retained to consult with Benjamin Brafman, Esquire who is representing Harvey Weinstein," he states in a declaration. "I have agreed to consult on the specific issue of Mr. Brafman’s access to his client’s personal and business emails. On information and belief, it is my professional opinion that Mr. Brafman has the right to see and review these emails in order to prepare his constitutionally-mandated role as counsel to Mr. Weinstein. Mr. Brafman has the right to defend his client in the courts of law, in negotiations with prosecutors, in resolving civil claims in negotiation with civil lawyers and in the court of public opinion. On information and belief these emails contain information which is exculpatory of Mr. Brafman’s client and places the allegations against him in a truthful context."

 Although Dershowitz says he is only a consultant, he also tells the judge he is prepared to offer a memorandum in support of Weinstein's bid for documents. ||||| Having never met a camera he didn’t like nor a high-profile case that he couldn’t contribute to, it should be no surprise that Alan Dershowitz has joined the cast of characters in The Weinstein Company bankruptcy case.

 Perhaps hoping to see another reversal of fortune, disgraced producer Harvey Weinstein has brought the cable new regular onboard as a consultant in the proceeding in U.S. Court in Delaware.

 “If Mr. Weinstein were ever to be charged with a crime, he would of course have a constitutional right to all of his emails and other exculpatory materials, under Brady, Giglio and their progeny,” the Harvard Law professor said in a declaration submitted today with other material by Weinstein’s lawyers (read it here).

 As he has in other cases, the much accused and investigated Weinstein is trying to grab ahold of his TWC correspondence and files as the company he co-founded goes through a death spiral of sorts. Following an expose by the New York Times in early October, Weinstein has been accused by dozens and dozens of women of sexual harassment and assault. He is presently being investigated by the NYPD, UK police and has seen the LAPD and the Beverley Hills Police submit findings to the LA County D.A. Earlier this week, Ashley Judd sued Weinstein on claims that he tried to torpedo her career because she wouldn’t submit to his sexual advances.

 In that context and the straining bankruptcy, contrarian and once O.J. lawyer Dershowitz has leaped in – even as TWC said last month that Weinstein’s document request has zero to do with the bankruptcy. A POV that Dershowitz rejects.

 “I believe that his lawyer also has a constitutional right to these materials while there are ongoing criminal investigations in order to present prosecutors with exculpatory information that could persuade them not to bring charges,” Dershowitz adds in his declaration Thursday. “Moreover, basic fairness dictates that Mr. Brafman be given exculpatory information now rather than later, since such information could prevent false charges from being filed,” he adds. “The exculpatory emails have no legitimate commercial value to the bankrupt company. Their only value – and it is not commercial – is to Mr. Brafman and his client in their efforts to achieve justice.”

 “If helpful to the Court, at the appropriate time I will prepare a memorandum of law providing legal support for the claims made above,” Dershowitz declares, already casting a bigger role for himself, unsurprisingly.

 And the circus goes on. |||||Summary:

– A former member of OJ Simpson's defense team is now assisting Harvey Weinstein. Alan Dershowitz—a Harvard Law School professor and frequent guest on cable news—is serving as a consultant to Weinstein's effort to obtain emails from The Weinstein Company that he sent and received before he was fired in October. Weinstein, facing dozens of accusations of sexual assault and harassment, apparently believes the emails will exonerate him, the Hollywood Reporter notes. He has been fighting for months to get the emails, and Dershowitz filed a declaration supporting the effort in Delaware Bankruptcy Court on Thursday. Weinstein's lawyer has "a constitutional right to these materials while there are ongoing criminal investigations in order to present prosecutors with exculpatory information that could persuade them not to bring charges," Dershowitz said in the filing, per Deadline. He also stated that if Weinstein —who's being investigated by authorities in two countries—is charged with a crime, "he would of course have a constitutional right to all of his emails and other exculpatory materials." (Ashley Judd is suing the disgraced producer for allegedly "torpedoing" her career after she rejected his advances.)


Write an article based on this summary:

– It has been a bad month to be a train commuter: Canada, France, Spain, and now ... Switzerland, where two commuter trains collided head-on today, injuring 44, four seriously, reports CNN. Local TV says one person is yet to be recovered from the wreckage, the AP reports. The crash happened between the cities of Moudon and Payerne. "We don't know why this crash happened," says a Swiss Federal Railways spokesman, per CNN. "There is currently no train service between these two cities until midnight tonight at least."

(CNN) -- Two commuter trains collided head-on Monday evening in western Switzerland, injuring dozens, officials said.

 One locomotive's driver was missing after the crash, police said, and search crews were trying to pry open the train's crushed cab.

 At least 40 people were injured, including five seriously, Swiss Federal Railways spokesman Reto Schaerli told CNN.

 The collision happened in the village of Granges-pr├Ęs-Marnand, about 8 km (5 miles) south of Payerne, around 6:45 p.m.

 Rescue teams at the scene included paramedics, firefighters, police and an air rescue helicopter, police said.

 Authorities are investigating what caused the crash.

 "At the moment, we don't have any ... information how this collision happened," Schaerli said.

 The trains were on a route between Payerne and Lausanne, a city on the shores of Lake Geneva, Schaerli said.

 The crash will interrupt train service between Payerne and Moudon -- a city near the line's halfway point -- until at least midnight, Schaerli said.

 CNN's Stefan Simons contributed to this report. ||||| Swiss television, citing local police, reports that 44 people have been injured, four of them seriously, in a head-on train collision in the west of the country.

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 Police inspect the site where two passenger trains collided head-on in Granges-pres-Marnand, western Switzerland, Monday, July 29, 2013. Numerous people have been injured. (AP Photo/Keystone, Laurent... (Associated Press)

 A police officer inspects the site where two passenger trains collided head-on in Granges-pres-Marnand, western Switzerland, Monday, July 29, 2013. Numerous people have been injured. (AP Photo/Keystone,... (Associated Press)

 Public TV station SRF quotes Vaud canton (state) police spokesman Pierre-Olivier Gaudard as saying one person has yet to be recovered from the wreckage.

 The crash happened late Monday on a regional line about 50 kilometers (31 miles) southwest of the capital, Bern.

 Pictures on the website of local daily 24 Heures showed the two regional trains locked together but still on the tracks.

 Earlier this month, 79 people were killed in a high-speed derailment in Spain. |||||


Summarize this article:

BOSTON (AP) — Lawyers for Boston Marathon bomber Dzhokhar Tsarnaev (joh-HAHR' tsahr-NEYE'-ehv) say his trial should have been held outside the city because jurors couldn't avoid widespread outrage over the deadly attack and he deserves a new trial elsewhere.

 A filing by the lawyers on Monday explains their push for a new trial for Tsarnaev, who was sentenced to death.

 The filing says even on social media jurors would have seen friends and relatives posting about the 2013 bombing.

 The lawyers argue a recent Supreme Court ruling about the vagueness of the definition of a "crime of violence" throws many convictions into question. The legal term "crime of violence" was applied to Tsarnaev's actions.

 Tsarnaev was convicted of 30 federal charges in the bombing, which killed three people died and injured more than 260. He apologized at his sentencing. ||||| Attorneys for Boston Marathon bomber Dzhokhar Tsarnaev appealed his conviction and death sentence on Monday, arguing that publicity made it impossible for him to get a fair trial in the city and that capital punishment is unconstitutional.

 In court papers, defense lawyer William Fick cited a recent dissent by U.S. Supreme Court Justice Stephen Breyer in which he said that he believes the death penalty "now likely constitutes a legally prohibited 'cruel and unusual punishment.'"

 However, the majority opinion in that very same case opened with the declaration that "capital punishment is constitutional."

 Tsarnaev was sentenced to death in June for helping his older brother carry out the April 15, 2013, blasts that killed three people and injured and maimed more than 200 others.

 The appeal claims that "continuous and unrelenting publicity" about the bombings, the defendant and his family, and wrenching survivor stories prevented him from getting an impartial hearing. It notes that Boston announced a new holiday marking the bombings while jurors were deliberating Tsarnaev's guilt.

 As users of social media, the jurors would have found it impossible to avoid coverage, the appeal argues.

 "Put simply, prejudicial media coverage, events, and environment saturated greater Boston, including the social networks of actual trial jurors, and made it an improper venue for the trial of this case," the court papers say.

 The defense repeatedly asked for a change of venue before the trial began, but the requests were rejected by the judge. ||||| Despite the dramatic news from court, the Boston Marathon bomber’s fate will take years to reach its conclusion: only three of 340 prisoners sentenced to federal death row have been executed in the last 50 years

 Dzhokhar Tsarnaev has become the 62nd inmate on federal death row after he was sentenced to death on Friday for his part in the Boston Marathon bombings.

 He will now join the rarified group of men and women (two are female) awaiting execution on federal death row; at 21 he will be the youngest.

 Boston Marathon bomber Dzhokhar Tsarnaev sentenced to death Read more

 But despite the dramatic news from the Boston courtroom on Friday, Tsarnaev’s fate will take years to reach its conclusion. Many of his new federal death row peers have been sitting waiting for the appeals process to work its way out for more than 20 years.

 Though the Justice Department could attempt to fast-track executions in the name of public interest, death penalty experts expect the very quickest timeframe from Friday’s sentence to Tsarnaev actually being put on a gurney and injected with lethal chemicals would be at least 10 years. The prisoner’s team of legal defenders, led by Judy Clarke, have already indicated two strong lines of likely appeal: that on prejudicial grounds the trial should never have been held in Boston where the bombings happened; and that the defense was given insufficient time to mount a full argument in mitigation that might have convinced the jury to spare Tsarnaev from the federal death chamber in Terre Haute, Indiana.

 Most capital cases in the US are handled by individual death penalty states, mainly in the deep south, while the involvement of the federal government in America’s most controversial judicial practice has become increasingly unusual in modern times.

 Although a total number of 340 prisoners have been executed by the US government since 1790, in the past 50 years only three have died: Timothy McVeigh in June 2001 for the Oklahoma City bombing; Juan Raul Garza, also in 2001, for a triple drug murder; and convicted rapist and murderer Louis Jones two years later.

 One of the paradoxes about federal death row is that being the responsibility of the US government, it might be assumed to have a national logic in terms of the types of crimes and regions of the country in which it is deployed. But in fact capital punishment has been even more maverick in its application federally than by individual states.

 Almost half of Tsarnaev’s new federal death row peers were put there by just three states: Texas, which has put 11 prisoners there; Missouri, nine; and Virginia, seven. A further 13 states have one inmate each.

 Very few of those individuals fall into the same category as the Boston Marathon bomber, whose involvement in extreme acts of public violence or domestic terrorism brought a genuinely nationwide spotlight on them. Most of the 62 inmates were put there for reasons that seem almost tangential – maybe a murder was conducted on federal land, or the gun used in a shooting was carried across state lines. |||||

– Not a huge surprise: Lawyers for Boston marathon bomber Dzhokhar Tsarnaev today appealed his death-penalty conviction, arguing that "continuous and unrelenting publicity" biased jurors and made a fair trial in Boston impossible, NBC News reports. "Put simply, prejudicial media coverage, events, and environment saturated greater Boston, including the social networks of actual trial jurors, and made it an improper venue for the trial of this case," say the papers. The lawyers want another trial at a new location, the AP reports. Earlier this year, the Guardian reminded us that Tsarnaev's appeals will likely delay his punishment for "at least a decade." The April 15, 2013, bomb strike in Boston left three dead and more than 200 maimed or injured.


Jesse James' Alleged Mistresses -- #3 Surfaces

 Jesse James' Alleged Mistresses -- #3 Surfaces

 She claims to be' third mistress -- but says her relationship with Jesse was much more of a flash in the pan than the other two.-- a Los Angeles photographer -- claims Jesse hired her in 2008 to do styling work for aphoto shoot. She says the two emailed and texted each other for a year, but claims they only had sex four times before she cut it off.Daguerre has 195 text messages between her and Jesse (the cell phone numbers sync up) ... many of them extremely graphic. Among the milder, Jesse says, "I'll be your monkey."Throughout the exchanges, Jesse repeatedly asks Daguerre to send pictures and set up rendezvous. In one exchange, Daguerre complained that Jesse wasn't letting loose. He explains, "I'm texting you in secret."We could not reach James' rep for comment. ||||| Melissa Smith -- a stripper who claims she had a wild two-year fling with Jesse James during his marriage to Sandra Bullock -- had two serious brushes with the law in the past year ... and even served jail time.

 Sources tell TMZ Smith was busted last May for beating up a cop and resisting arrest.

 Smith pled guilty and served 20 days in a California jail.

 And just two days ago -- the same day she sold her Jesse James story to a tabloid -- Smith plead "not guilty" to a DUI charge.

 Smith was arrested for that DUI last month and blew a .18 -- in technical terms, she was sloshed.

  ||||| Jesse James' Other Other Woman: One More Busty, Tattooed Gal

 Email This If there's anything Jesse James likes as much as motorcycles, it's shapely, tattooed women. In the new issue of Star magazine, heavily-inked stripper Melissa Smith reveals she carried on a two-year affair with James -- beginning a year after he wed Sandra Bullock. See Photos.

 James contacted Smith via Myspace in 2006 after seeing photos of her at a West Coast Choppers event. He then invited her to his California office. The meet-and-greet turned into a romp, according to Smith. "We ended up having sex on his couch, and he didn't use a condom."

 Star says the rendezvous was "just the first of many," reporting that James and Smith met every two months. The magazine calls James a "serial cheater," a title his porn star ex-wife Janine Lindemulder recently If there's anything Jesse James likes as much as motorcycles, it's shapely, tattooed women. In the new issue of, heavily-inked stripper Melissa Smith reveals she carried on a two-year affair with James -- beginning a year after he wed Sandra Bullock.James contacted Smith via Myspace in 2006 after seeing photos of her at a West Coast Choppers event. He then invited her to his California office. The meet-and-greet turned into a romp, according to Smith. "We ended up having sex on his couch, and he didn't use a condom."Star says the rendezvous was "just the first of many," reporting that James and Smith met every two months. The magazine calls James a "serial cheater," a title his porn star ex-wife Janine Lindemulder recently corroborated in In Touch magazine.

 One encounter occurred after Smith had breast enhancement surgery. "[Jesse] said, 'We'll have to take those girls for a test drive.' He was in awe of my boob job," Smith says, adding James did not wear a wedding ring during these hook-ups and Sandra's name "never came up -- and there wasn't even one photograph of her in his office."Star's piece includes photos of Smith wearing a jean jacket reading "Jesse's Girl" -- a gift from James, she says.Smith believes James lost interest in her when Bombshell McGee entered the scene. "His attention was on the next woman," Smith says, adding that Bullock should divorce James. "Once a cheater, always a cheater." |||||

Write a summary.

– Move over, Tiger Woods, a new mistress count has been established: It’s for Jesse James, and he’s already up to No. 3. First to follow Michelle “Bombshell” McGee was Melissa Smith, another heavily tattooed stripper who claims a two-year affair. Classy: They met on MySpace. Classier: “We ended up having sex on his couch, and he didn't use a condom,” she tells Star. Classiest: She’s been arrested twice, reports TMZ. For more on her, click here. Alleged mistress No. 3 is Brigitte Daguerre, a California photographer who says she only slept with James four times. She saved 195 text messages the two sent each other, including one from James that says, “I’ll be your monkey,” TMZ reports. Apparently James’ cheating—with as many as 11 women during his marriage to Sandra Bullock—was an open secret that everyone (except a blinded-by-love Bullock, apparently) from his ex-wife to his employees knew about, according to the New York Post, which rounds up several recent tabloid articles.


Here is a news article: The seed for Wide00014 was:

 - Slash pages from every domain on the web:

 -- a ranking of all URLs that have more than one incoming inter-domain link (rank was determined by number of incoming links using Wide00012 inter domain links)

 -- up to a maximum of 100 most highly ranked URLs per domain

 - Top ranked pages (up to a max of 100) from every linked-to domain using the Wide00012 inter-domain navigational link graph ||||| On Wednesday Night’s Countdown on Current, Keith Olbermann named Florida Representative Brad Drake as one of his “Worst Persons In The World” for sponsoring legislation to replace lethal injection as a execution method with electrocution or by firing squad. Drake had said if it was up to him, he would “throw them off the Sunshine Skyway Bridge and be done with it.” Olbermann responded, “You first, asshole!”

 Olbermann finished his segment by saying “There it is, America 2011, laws written by sociopaths like Brad Drake inspired by bloodthirsty goobers he met at the Waffle House!”

 Olbermann’s obscenity aired uncensored. The lefty political commentator may have been making a legitimate point that Drake was foolish to base capital punishment laws on conversations he’s had at breakfast fast-food chains, but gratuitously hurling invective at the politician debases our political discourse and makes his entire network look bad.

 MSNBC suspended Mark Halperin for calling President Obama a dick. It seems unlikely Al Gore will punish his flagship star at all for his use of profanity on the air, but viewers of his channel deserve better.

 Watch the segment below via Current:

 Have a tip we should know? tips@mediaite.com ||||| Saying it's time to stop letting convicted killers "get off that easy," a Florida state lawmaker wants to use firing squads or the electric chair for those on death row.

 Rep. Brad Drake filed a bill this week that would end the use of lethal injection in Florida executions. Instead, those with a death sentence would choose between electrocution or a firing squad.

 Drake, a Republican, said the idea came to him after having a conversation with a constituent at a Waffle House over the legal battles associated with the Sept. 28 execution of Manuel Valle.

 Valle's lawyers tried to stop the execution by arguing that a new lethal drug cocktail would cause him pain and therefore constitute cruel and unusual punishment. Courts, however, rejected that argument and let the execution go forward.

 But Drake said the person at the restaurant questioned why death row inmates should even be allowed to die by lethal injection. Drake said he agreed and decided to sponsor the bill that would mandate a switch. The GOP-controlled Florida Legislature will consider the bill during the 2012 session that starts in January.

 He said government is spending too much time listening to advocacy groups and instead should put in place a death sentence that forces convicted murderers to contemplate their fates.

 Lethal injection just allows a person to die in their sleep while a firing squad or electrocution would force death row inmates to think about their punishment "every morning," Drake said.

 "I think if you ask a hundred people, not even talking to criminals, how would you like to die, if you were drowned, if you were shot, and if you say you were put to sleep, 90 percent of some of the people would say I want to be put to sleep," Drake said. "Let's put our pants back on the right way."

 Florida first began using the electric chair in 1924. Before then, most executions were carried out by hanging.

 But the state switched to lethal injection in 2000. Then-Gov. Jeb Bush and the Republican-controlled Legislature pushed through the change after several botched electrocutions raised concerns that the state's death penalty would be declared unconstitutional. The U.S. Supreme Court had agreed at the time to hear a challenge to the use of the electric chair.

 Since the state made the switch, a total of 26 people have died by lethal injection, including Valle and serial killers Danny Rolling and Aileen Wuornos.

 Howard Simon, executive director of the American Civil Liberties Union of Florida, said Drake's legislation would just cause embarrassment for Florida if it were adopted.

 "Just when you thought that public policy in Florida couldn't get worse, along comes a state rep who develops proposed legislation from what he overhears at the Waffle House," Simon said. "Given all that former members of the Florida Supreme Court and the American Bar Association have said about Florida's broken death penalty system, including the nation's highest number of exonerations, this would be embarrassing _ if our legislature were capable of embarrassment."

 But Drake said that those who caused suffering and grief for families should get their day of reckoning.

 "I just don't think they should be able to get off that easy," he said. |||||
A summary of this is?

– Lethal injection is just such a pleasant way to die. At least according to Florida state Rep. Brad Drake, who wants to put an end to the execution method in the state. He argues that Death Row killers shouldn't be allowed to "get off that easy"; the electric chair would be more appropriate he says—as would a firing squad. Drake this week filed a bill that would put an end to lethal injection and give convicts facing death the choice of the latter two, reports the AP. "I think if you ask a hundred people, not even talking to criminals, how would you like to die, if you were drowned, if you were shot, and if you say you were put to sleep, 90% of some of the people would say I want to be put to sleep," says the Republican, who apparently equates lethal injection with taking a permanent nap. "Let's put our pants back on the right way," Drake urges, adding that his proposed switch would force death row inmates to think about their punishment "every morning." And they'd be getting off easy, because, as reported by the Florida Current, if it were up to Drake, "we would just throw them off the Sunshine Skyway bridge and be done with it." Mediaite notes that Keith Olbermann is not a fan of the idea. (Click for another odd political push in Florida.)