tbuckley/cabot-search huggingface dataset:
Intermittent hypoxia-activated cyclooxygenase pathway: role in atherosclerosis
Authors: Elodie Gautier-Veyret, Claire Arnaud, Magnus Bäck, Jean-Louis Pépin, Marcelo H. Petri, Jean-Philippe Baguet, Renaud Tamisier, Patrick Lévy, Françoise Stanke-Labesque
Journal: European Respiratory Journal (2012)

Intermittent hypoxia, the main stimulus of obstructive sleep apnoea (OSA), induces inflammation, leading to early atherosclerosis. Whether the cyclooxygenase (COX) pathway contributes to intermittent hypoxia-induced atherosclerosis remains to be determined. We studied the effects of 8-weeks of intermittent hypoxia exposure on COX-pathway gene expression and atherosclerosis, and the influence of COX-1 inhibition by SC-560 on atherosclerosis progression in aortas of apolipoprotein E -/- mice. Urinary 11-dehydrothromboxane B 2 (11-dTXB 2 ) was assessed in 50 OSA subjects free of cardiovascular risk factor matched for age and body mass index with 25 controls, and 56 OSA with cardiovascular risk factor. Intermittent hypoxia significantly increased atherosclerotic lesion sizes, mRNA levels of COX-1 and thromboxane synthase (TXBS). Lesion sizes correlated to COX-1 (r = 0.654, p = 0.0003) and TXBS (r = 0.693, p&lt;0.0001) mRNA levels. COX-1 inhibition reduced lesion progression in intermittent hypoxia mice only (p = 0.04). Urinary 11-dTXB 2 was similar in OSA subjects free of cardiovascular risk factor and controls, but was increased by 13% (p = 0.007) in OSA subjects with cardiovascular risk factor compared with those without. Although OSA itself was not associated with increased urinary 11-dTXB 2 concentration, the COX-1 pathway was activated in intermittent hypoxia-exposed mice and in OSA subjects presenting with cardiovascular risk factor, and may contribute to intermittent hypoxia-induced atherogenesis. COX-1 inhibition could be of clinical interest in the prevention of cardiovascular morbidity in OSA.
Prostate-cancer mortality in the USA and UK in 1975–2004: an ecological study
Authors: Simon M Collin, Richard M Martin, Chris Metcalfe, David Gunnell, Peter C Albertsen, David Neal, Freddie Hamdy, Peter Stephens, J Athene Lane, Rollo Moore, Jenny Donovan
Journal: The Lancet Oncology (2008)

There is no conclusive evidence that screening based on serum prostate-specific antigen (PSA) tests decreases prostate-cancer mortality. Since its introduction in the USA around 1990, uptake of PSA testing has been rapid in the USA, but much less common in the UK. Our aim was to study trends over time in prostate-cancer mortality and incidence in the USA and UK in 1975-2004, and compare these patterns with trends in screening and treatment.Joinpoint regression analysis of cancer-mortality statistics from Cancer Research UK (London, UK) and from the US National Cancer Institute Surveillance, Epidemiology and End Results (SEER) programme from 1975 to 2004 was used to estimate the annual percentage change in prostate-cancer mortality in both countries and the points in time when trends changed. The ratio of USA to UK age-adjusted prostate-cancer incidence was also assessed.Age-specific and age-adjusted prostate-cancer mortality peaked in the early 1990s at almost identical rates in both countries, but age-adjusted mortality in the USA subsequently declined after 1994 by -4.17% (95% CI -4.34 to -3.99) each year, four-times the rate of decline in the UK after 1992 (-1.14% [-1.44 to -0.84]). The mortality decline in the USA was greatest and most sustained in patients aged 75 years or older (-5.32% [-8.23 to -2.32]), whereas death rates had plateaued in this age group in the UK by 2000. The mean ratio of USA to UK age-adjusted prostate-cancer incidence rates in 1975-2003 was 2.5, with a pronounced peak around the time that PSA testing was introduced in the USA. Numbers needed to treat to prevent one death from prostate cancer were 33 000 in the 55-64-year age group.The striking decline in prostate-cancer mortality in the USA compared with the UK in 1994-2004 coincided with much higher uptake of PSA screening in the USA. Explanations for the different trends in mortality include the possibility of an early effect of initial screening rounds on men with more aggressive asymptomatic disease in the USA, different approaches to treatment in the two countries, and bias related to the misattribution of cause of death. Speculation over the role of screening will continue until evidence from randomised controlled trials is published.
A regulator of ubiquitin-proteasome activity, 2-hexyldecanol, suppresses melanin synthesis and the appearance of facial hyperpigmented spots
Authors: T. Hakozaki, T. Laughlin, S. Zhao, J. Wang, D. Deng, E. Jewell-Motz, L. Elstun
Journal: British Journal of Dermatology (2013)

2‐Hexyldecanol has long been used in skin‐care products, but has not previously been reported as an active ingredient for skin benefits. To evaluate 2‐hexyldecanol in in vitro and ex vivo systems and, if found to be active, progress it to topical clinical testing to determine effects on pigmentation in skin. 2‐Hexyldecanol was tested in melanocyte cell culture systems (B16 mouse melanoma cells and normal human melanocytes) for its effect on proteolytic activity and melanin production, in the absence and presence of the proteasome‐specific inhibitor, MG132. It was further tested in a human skin explant model for its effect on melanin production. Lastly, topically applied 2‐hexyldecanol was evaluated for its effect on the appearance of facial pigmentation in an 8‐week, randomized, double‐blind, vehicle‐controlled, split‐face incomplete block design study in Chinese women. In submerged cell culture, 2‐hexyldecanol upregulated proteolytic activity and decreased melanin synthesis. These effects were antagonized by the proteasome‐specific inhibitor MG132. MG132, tested in the absence of 2‐hexyldecanol, increased melanin production. In a human skin explant model, topical 2‐hexyldecanol suppressed the production of melanin vs. a vehicle control. In a human clinical study in Chinese women (n =110 observations per test material), a 2‐hexyldecanol‐containing formulation significantly reduced the appearance of facial hyperpigmented spots vs. its control. These data indicate that regulation of proteasome activity is a viable target for control of melanin production, that 2‐hexyldecanol upregulates proteasomal activity in melanocytes, and that topical 2‐hexyldecanol reduces the appearance of hyperpigmentation.
Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer
Authors: Julie Brahmer, Karen L. Reckamp, Paul Baas, Lucio Crinò, Wilfried E.E. Eberhardt, Elena Poddubskaya, Scott Antonia, Adam Pluzanski, Everett E. Vokes, Esther Holgado, David Waterhouse, Neal Ready, Justin Gainor, Osvaldo Arén Frontera, Libor Havel, Martin Steins, Marina C. Garassino, Joachim G. Aerts, Manuel Domine, Luis Paz-Ares, Martin Reck, Christine Baudelet, Christopher T. Harbison, Brian Lestini, David R. Spigel
Journal: New England Journal of Medicine (2015)

Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population.We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival.The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group.Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).
Physiologic evaluation of factors controlling glucose tolerance in man: measurement of insulin sensitivity and beta-cell glucose sensitivity from the response to intravenous glucose.
Authors: R N Bergman, L S Phillips, C Cobelli
Journal: Journal of Clinical Investigation (1981)

The quantitative contributions of pancreatic responsiveness and insulin sensitivity to glucose tolerance were measured using the "minimal modeling technique" in 18 lean and obese subjects (88-206% ideal body wt). The individual contributions of insulin secretion and action were measured by interpreting the dynamics of plasma glucose and insulin during the intravenous glucose tolerance test in terms of two mathematical models. One, the insulin kinetics model, yields parameters of first-phase (phi 1) and second-phase (phi 2) responsivity of the beta-cells to glucose. The other glucose kinetics model yields the insulin sensitivity parameters, SI. Lean and obese subjects were subdivided into good (KG greater than 1.5) and lower (KG less than 1.5) glucose tolerance groups. The etiology of lower glucose tolerance was entirely different in lean and obese subjects. Lean, lower tolerance was related to pancreatic insufficiency (phi 2 77% lower than in good tolerance controls [P less than 0.03]), but insulin sensitivity was normal (P greater than 0.5). In contrast, obese lower tolerance was entirely due to insulin resistance (SI diminished 60% [P less than 0.01]); pancreatic responsiveness was not different from lean, good tolerance controls (phi 1: P greater than 0.06; phi 2: P greater than 0.40). Subjects (regardless of weight) could be segregated into good and lower tolerance by the product of second-phase beta-cell responsivity and insulin sensitivity (phi 2 . SI). Thus, these two factors were primarily responsible for overall determination of glucose tolerance. The effect of phi 1 was to modulate the KG value within those groups whose overall tolerance was determined by phi 2 . SI. This phi 1 modulating influence was more pronounced among insulin sensitive (phi 1 vs. KG, r = 0.79) than insulin resistant (obese, low tolerance; phi 1 vs. KG, r = 0.91) subjects. This study demonstrates the feasibility of the minimal model technique to determine the etiology of impaired glucose tolerance.
Inflammasome recognition of influenza virus is essential for adaptive immune responses
Authors: Takeshi Ichinohe, Heung Kyu Lee, Yasunori Ogura, Richard Flavell, Akiko Iwasaki
Journal: The Journal of Experimental Medicine (2009)

Influenza virus infection is recognized by the innate immune system through Toll like receptor (TLR) 7 and retinoic acid inducible gene I. These two recognition pathways lead to the activation of type I interferons and resistance to infection. In addition, TLR signals are required for the CD4 T cell and IgG2a, but not cytotoxic T lymphocyte, responses to influenza virus infection. In contrast, the role of NOD-like receptors (NLRs) in viral recognition and induction of adaptive immunity to influenza virus is unknown. We demonstrate that respiratory infection with influenza virus results in the activation of NLR inflammasomes in the lung. Although NLRP3 was required for inflammasome activation in certain cell types, CD4 and CD8 T cell responses, as well as mucosal IgA secretion and systemic IgG responses, required ASC and caspase-1 but not NLRP3. Consequently, ASC, caspase-1, and IL-1R, but not NLRP3, were required for protective immunity against flu challenge. Furthermore, we show that caspase-1 inflammasome activation in the hematopoietic, but not stromal, compartment was required to induce protective antiviral immunity. These results demonstrate that in addition to the TLR pathways, ASC inflammasomes play a central role in adaptive immunity to influenza virus.
Clinical features of dementia with lewy bodies in 35 Chinese patients
Authors: Ding Han, Qiong Wang, Zhongbao Gao, Tong Chen, Zhenfu Wang
Journal: Translational Neurodegeneration (2014)

Abstract Objective To investigate the clinical features of dementia with Lewy bodies (DLB) in a Chinese population. Methods Computer-based online searches through China Biology Medicine disc and China National Knowledge Infrastructure were performed to collect case reports of DLB published between 1980 and 2012. Clinical characteristics were analyzed. Results A total of 18 studies comprising 35 patients (26 males and 9 females) were included. The mean age at onset was 67.2 ± 9.8 years. Onset was characterized by memory impairment and accounted for 58.8% of all cases, followed by parkinsonism (11.8%), visual hallucinations (8.8%), and compulsive personality disorder (2.9%). The other patients (17.6%) presented two of the three core features of DLB at onset. With disease progression, parkinsonism was reported in 100% of cases, followed by visual hallucinations (97.1%), psychiatric symptoms (85.7%), severe neuroleptic sensitivity (81.8%), fluctuating cognition (68.6%), repeated falls (40.0%), sleep disorders (22.9%), and transient loss of consciousness (17.1%). 26 patients who were subjected to Mini-Mental State Examination scored ≤ 24. 10 patients presented relative preservation of hippocampus and medial temporal lobe structures on CT/MRI scan. Occipital hypometabolism occurred in 2 of 3 patients who underwent SPECT/PET perfusion scan. 12 patients showed an increasing of slow frequency activity on EEG, prominently in frontal and temporal lobes. Conclusions DLB often strikes elderly individuals. Its clinical core features are dementia, fluctuating cognition, recurrent visual hallucinations and spontaneous features of parkinsonism. Neuropsychological, neuroimaging and EEG examinations may improve the diagnostic accuracy and discriminate DLB from other dementias.
Traffic-related air pollution is related to interrupter resistance in 4-year-old children
Authors: Esther Eenhuizen, Ulrike Gehring, Alet H. Wijga, Henriette A. Smit, Paul H. Fischer, Michael Brauer, Gerard H. Koppelman, Marjan Kerkhof, Johan C. de Jongste, Bert Brunekreef, Gerard Hoek
Journal: European Respiratory Journal (2012)

Outdoor air pollution has been associated with decrements in lung function and growth of lung function in school-age children. Lung function effects have not been examined in preschoolers, with the exception of one study on minute ventilation in newborns. Our goal was to assess the relationship between long- and short-term exposure to traffic-related air pollution and interrupter resistance in 4-year-old children. Lung function was measured using the interrupter resistance method in children participating in a Dutch birth cohort study. Long-term average air pollution concentrations of fine particulate matter, nitrogen dioxide and soot at the residential address at birth were assessed using land-use regression models. Daily average air pollution concentrations on the day of clinical examination were obtained from the Dutch National Air Quality Monitoring Network. Significant associations were found between long-term average air pollution concentrations and interrupter resistance. Interrupter resistance increased by 0.04 kPa·s·L −1 (95% CI 0.01–0.07) per interquartile range increase (3.3 μg·m −3 ) in fine particle concentration. Short-term exposure was not associated with interrupter resistance. Long-term exposure to traffic-related air pollution was associated with increased interrupter resistance in 4-year-old children, supporting previous birth cohort studies reporting effects of air pollution on subjectively reported respiratory symptoms in preschool children.
Cardiovascular Risks of Antiretroviral Therapies
Authors: Kristin Mondy, Pablo Tebas
Journal: Annual Review of Medicine (2007)

The use of highly active antiretroviral therapy (HAART) has resulted in sustained reductions in mortality from HIV infection. In recent years, HAART has also been associated with metabolic complications that may increase patients' cardiovascular disease risk. Recent studies have begun to support a more complex interaction between HAART, HIV infection itself, and other traditional social and immunologic factors that may predispose patients to premature cardiovascular disease. Substantial progress has been made in the development of newer antiretroviral therapies that have a better metabolic profile with respect to dyslipidemia, hyperglycemia, and lipodystrophy. Optimal selection of metabolically neutral antiretroviral therapies, together with aggressive management of other modifiable coronary risk factors, may improve cardiovascular disease risk in the long term.
Predictive and Explanatory Factors of Change in HbA1c in a 24-Week Observational Study of 66,726 People With Type 2 Diabetes Starting Insulin Analogs
Authors: Philip D. Home, Chunduo Shen, Mohammad I. Hasan, Zafar A. Latif, Jian-Wen Chen, Guillermo González Gálvez
Journal: Diabetes Care (2014)

OBJECTIVE Individualization of therapy choices requires the prediction of likely response. Predictor and explanatory factors of change in HbA1c were studied using data from a large observational study of starting insulin analog therapy (the A1chieve study). RESEARCH DESIGN AND METHODS Univariate analyses were performed for insulin-naive people and prior insulin users in the A1chieve study. Statistically significant factors were carried forward to baseline factor–only multivariate analyses (“predictor” analysis), and separately using all significant factors (“explanatory” analysis). Power was considered in terms of the variance explained. RESULTS Geographical region, baseline HbA1c level, lipid levels, and baseline insulin dose were the most powerful predictors of HbA1c change (mean change −2.1% [−23 mmol/mol]) observed in the univariate analysis (r2 &amp;gt; 0.010, P &amp;lt; 0.001). However, although the predictor and explanatory multivariate models explained 62–82% of the variance in HbA1c change, this was mainly associated with baseline HbA1c (r2 = 0.544–0.701) and region (r2 = 0.014–0.037). Other factors were statistically significant but had low predictive power (r2 &amp;lt; 0.010); in the explanatory analysis, this included end-of-study hypoglycemia (insulin-naive group), insulin dose, and health-related quality of life (r2 &amp;lt; 0.001–0.006, P ≤ 0.007). CONCLUSIONS Many factors can guide clinicians in predicting the response to starting therapy with insulin analogs, but many are interdependent and thus of poor utility. The factor explaining most of the variance in HbA1c change is baseline HbA1c level, with each increase of 1.0%-units (11 mmol/mol) providing a 0.7–0.8%-units (8–9 mmol/mol) greater fall. Other factors do not explain much of the remaining variance, even when including all end-of-trial measures.
More doctors are raising concerns with GMC about colleagues, MPs hear
Authors: A. O'Dowd
Journal: BMJ (2013)

The number of doctors who raise concerns about standards of care and colleagues’ practice is rising steadily, the doctors’ regulatory body has told MPs.

However, the rise has been happening for the past five years and does not seem to have been particularly boosted by Robert Francis QC’s report into poor standards of care at Mid Staffordshire NHS Foundation Trust, which criticised the failure of doctors there to speak up about the trust’s problems.1

The issue was raised during an evidence session of the parliamentary health select committee’s annual accountability hearing with the General Medical Council. MPs asked what the regulator was doing to help and encourage doctors to raise concerns about …
Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice
Authors: Christian E. Oberkofler, Perparim Limani, Jae-Hwi Jang, Andreas Rickenbacher, Kuno Lehmann, Dimitri A. Raptis, Udo Ungethuem, Yinghua Tian, Kamile Grabliauskaite, Rok Humar, Rolf Graf, Bostjan Humar, Pierre-Alain Clavien
Journal: Hepatology (2014)

Remote ischemic preconditioning (RIPC), the repetitive transient mechanical obstruction of vessels at a limb remote to the operative site, is a novel strategy to mitigate distant organ injury associated with surgery. In the clinic, RIPC has demonstrated efficacy in protecting various organs against ischemia reperfusion (IR), but a common mechanism underlying the systemic protection has not been identified. Here, we reasoned that protection may rely on adaptive physiological reponses toward local stress, as is incurred through RIPC. Standardized mouse models of partial hepatic IR and of RIPC to the femoral vascular bundle were applied. The roles of platelets, peripheral serotonin, and circulating vascular endothelial growth factor (Vegf) were studied in thrombocytopenic mice, Tph1− / − mice, and through neutralizing antibodies, respectively. Models of interleukin-10 (Il10) and matrix metalloproteinase 8 (Mmp8) deficiency were used to assess downstream effectors of organ protection. The protection against hepatic IR through RIPC was dependent on platelet-derived serotonin. Downstream of serotonin, systemic protection was spread through up-regulation of circulating Vegf. Both RIPC and serotonin-Vegf induced differential gene expression in target organs, with Il10 and Mmp8 displaying consistent up-regulation across all organs investigated. Concerted inhibition of both molecules abolished the protective effects of RIPC. RIPC was able to mitigate pancreatitis, indicating that it can protect beyond ischemic insults. Conclusions : We have identified a platelet-serotonin-Vegf-Il10/Mmp8 axis that mediates the protective effects of RIPC. The systemic action, the conservation of RIPC effects among mice and humans, and the protection beyond ischemic insults suggest that the platelet-dependent axis has evolved as a preemptive response to local stress, priming the body against impending harm. (Hepatology 2014;60:1409–1417)