tbuckley/cabot-search huggingface dataset:
Association of Apolipoprotein E Genotypes With Lipid Levels and Coronary Risk
Authors: Anna M. Bennet, Emanuele Di Angelantonio, Zheng Ye, Frances Wensley, Anette Dahlin, Anders Ahlbom, Bernard Keavney, Rory Collins, Björn Wiman, Ulf de Faire, John Danesh
Journal: JAMA (2007)

Previous reviews of associations of apolipoprotein E (apoE) genotype and coronary disease have been dominated by smaller studies that are liable to biases.To reassess associations of apoE genotypes with circulating lipid levels and with coronary risk.We conducted an updated meta-analysis including both published and previously unreported studies, using MEDLINE, EMBASE, BIOSIS, Science Citation Index, and the Chinese National Knowledge Infrastructure Database published between January 1970 and January 2007, reference lists of articles retrieved, and a registry of relevant studies.Eighty-two studies of lipid levels (86,067 healthy participants) and 121 studies of coronary outcomes (37,850 cases and 82,727 controls) were identified, with prespecified principal focus on studies with at least 1000 healthy participants for lipids and those with at least 500 coronary outcomes.Information on genotype frequencies, lipid levels, coronary outcomes, and laboratory and population characteristics were recorded independently by 2 investigators and/or supplied by study investigators.In the most extreme comparison, people with the epsilon2/epsilon2 genotype had 1.14 mmol/L (95% confidence interval [CI], 0.87-1.40 mmol/L [44.0 mg/dL; 95% CI; 33.6-51.1 mg/dL]) or about 31% (95% CI, 23%-38%) lower mean low-density lipoprotein cholesterol (LDL-C) values than those with the epsilon4/epsilon4 genotype. There were approximately linear relationships of apoE genotypes (when ordered epsilon2/epsilon2, epsilon2/epsilon3, epsilon2/epsilon4, epsilon3/epsilon3, epsilon3/epsilon4, epsilon4/epsilon4) with LDL-C and with coronary risk. The relationship with high-density lipoprotein cholesterol was inverse and shallow and that with triglycerides was nonlinear and largely confined to the epsilon2/epsilon2 genotype. Compared with epsilon3/epsilon3, the odds ratio for coronary disease was 0.80 (95% CI, 0.70-0.90) in epsilon2 carriers and was 1.06 (95% CI, 0.99-1.13) in epsilon4 carriers.There are approximately linear relationships of apoE genotypes with both LDL-C levels and coronary risk. Compared with individuals with the epsilon3/epsilon3 genotype, epsilon2 carriers have a 20% lower risk of coronary heart disease and epsilon4 carriers have a slightly higher risk.
Neutrophils and the blood–brain barrier dysfunction after trauma
Authors: Martin Scholz, Jindrich Cinatl, Michael Schädel‐Höpfner, Joachim Windolf
Journal: Medicinal Research Reviews (2006)

Abstract Despite the fact that neutrophils are essential for the protection from invading pathogens, hyperactive neutrophils may elicit detrimental cerebral damage after severe trauma. The neutrophil interactions with the neurovascular unit entail endothelial dysfunction involving endothelial leakage, formation of edema, coagulation abnormalities, disturbed hemodynamics, tissue infiltration etc. These elements of the “whole body inflammation,” designated systemic inflammatory response syndrome (SIRS) in conjunction with intracerebral proinflammatory activities, are important triggers of post‐traumatic cerebral damage and mortality according to the “second hit” concept. From the immunologic point of view, the brain is an immune privileged site, known to resist autodestructive inflammatory activity much more efficiently than other organs because of the highly efficient diverse functions of the blood–brain barrier (BBB). However, both the underlying strategy of the BBB to maintain cerebral protecting functions against the post‐traumatic neutrophil‐mediated “second hit” and how activated neutrophils may overcome the BBB are currently unknown. Therefore, this review summarizes the current understanding of the “second hit,” the BBB physiology, and its role in the maintenance of cerebral immune privilege, and discusses recent findings that may explain the pathophysiologic neutrophil–BBB interactions occurring after severe trauma, thus offering novel therapeutic options to protect from post‐traumatic brain damage. © 2006 Wiley Periodicals, Inc. Med Res Rev, 27, No. 3, 401–416, 2007
Putting normativity in its proper place
Authors: Tania Lombrozo, Kevin Uttich
Journal: Behavioral and Brain Sciences (2010)

Abstract Knobe considers two explanations for the influence of moral considerations on “non-moral” cognitive systems: the “person as moralist” position, and the “person as [biased] scientist” position. We suggest that this dichotomy conflates questions at computational and algorithmic levels, and suggest that distinguishing the issues at these levels reveals a third, viable option, which we call the “rational scientist” position.
Apolipoprotein E ε4 Allele and Whole Brain Atrophy in Late-Onset Alzheimer's Disease
Authors: Minoru Yasuda, Etsuro Mori, Hajime Kitagaki, Hikari Yamashita, Nobutsugu Hirono, Kenichi Shimada, Kiyoshi Maeda, Chikako Tanaka
Journal: American Journal of Psychiatry (1998)

Diffuse brain atrophy is one of the gross pathological features of Alzheimer's disease and is a result of degenerative changes. The epsilon 4 allele of apolipoprotein E (APOE) is a risk factor or susceptibility gene in late-onset sporadic Alzheimer's disease and may influence the pathological changes associated with the disease. The aim of this study was to examine the relationship between the APOE epsilon 4 allele and whole brain atrophy.Whole brain volume was quantified by using high-resolution magnetic resonance imaging and the computerized brain segmentation technique in 178 patients with late-onset sporadic Alzheimer's disease who carried no APOE epsilon 4 alleles (N = 62), one epsilon 4 allele (N = 93), or two (N = 23) and had comparable clinical severity of dementia.An apparent positive correlation was found between normalized whole brain volume (relative to total intracranial volume) and number of APOE epsilon 4 alleles; i.e., patients carrying two APOE epsilon 4 alleles had the least brain atrophy. This association between the APOE epsilon 4 allele and brain volume was similar in women and men and was independent of age, level of education, duration of illness since symptom onset, and severity of dementia.The results indicate that cognitive dysfunction progresses before severe brain atrophy develops in patients carrying the APOE epsilon 4 allele and suggest that an APOE epsilon 4-allele-related mechanism that affects neuronal function before a decrement in brain matter is involved in the development of dementia.
Plant, Synthetic, and Endogenous Cannabinoids in Medicine
Authors: Vincenzo Di Marzo, Luciano De Petrocellis
Journal: Annual Review of Medicine (2005)

Although used for more than 4000 years for recreational and medicinal purposes, Cannabis and its best-known pharmacologically active constituents, the cannabinoids, became a protagonist in medical research only recently. This revival of interest is explained by the finding in the 1990s of the mechanism of action of the main psychotropic cannabinoid, Delta9-tetrahydrocannabinol (THC), which acts through specific membrane receptors, the cannabinoid receptors. The molecular characterization of these receptors allowed the development of synthetic molecules with cannabinoid and noncannabinoid structure and with higher selectivity, metabolic stability, and efficacy than THC, as well as the development of antagonists that have already found pharmaceutical application. The finding of endogenous agonists at these receptors, the endocannabinoids, opened new therapeutic possibilities through the modulation of the activity of cannabinoid receptors by targeting the biochemical mechanisms controlling endocannabinoid tissue levels.
Relationship of Fasting and Hourly Blood Glucose Levels to HbA1c Values
Authors: Satish Garg, Lois Jovanovic
Journal: Diabetes Care (2006)

OBJECTIVE—In this study, we evaluated the safety and efficacy of 7-day transcutaneous, real-time, continuous glucose monitoring (CGM) in subjects with insulin-requiring diabetes. RESEARCH DESIGN AND METHODS—Eighty-six subjects were enrolled at five U.S. centers. Subjects wore a sensor inserted under the skin of the abdomen for 7 days during each of three consecutive periods. Data were blinded during period 1 and unblinded during periods 2 and 3. RESULTS—Of the 6,811 matched self-monitoring of blood glucose to sensor values prospectively analyzed, 97.2% fell in the Clarke error grid zones A and B, and median absolute relative difference was 11.4%. After unblinding, subjects reduced time spent at &amp;lt;55 mg/dl by 0.3 h/day, reduced time spent at &amp;gt;240 mg/dl by 1.5 h/day, and increased time in the target zone (81–140 mg/dl) by 1.4 h/day (P &amp;lt; 0.05 for all three comparisons). Improvements were seen in both types 1 and 2 diabetes and with use of both multiple daily injections and continuous subcutaneous insulin infusion. Modal day graphs were generated in six groups of subjects based on HbA1c (A1C) (≤6, 6–7, 7–8, 8–9, 9–10, and &amp;gt;10%). Mean glucose levels from midnight to 7:00 a.m. (fasting and dawn phenomenon periods) were only normal for subjects with A1C ≤6%. All other groups were hyperglycemic during this and all periods. Reductions in overall mean glucose were achieved for the four highest A1C groupings with unblinded device use. CONCLUSIONS—This is the first report of a real-time, transcutaneous glucose sensor that functioned for 7 days. The use of CGM in the unblinded phase resulted in improvements in target-range glycemia across all A1C values.
Treatment-Associated Leukemia Following Testicular Cancer
Authors: L. B. Travis
Journal: JNCI Journal of the National Cancer Institute (2000)

Men with testicular cancer are at an increased risk of leukemia, but the relationship to prior treatments is not well characterized. The purpose of our study was to describe the risk of leukemia following radiotherapy and chemotherapy for testicular cancer.Within a population-based cohort of 18 567 patients diagnosed with testicular cancer (from 1970 through 1993), a case-control study of leukemia was undertaken. Radiation dose to active bone marrow and type and cumulative amount of cytotoxic drugs were compared between 36 men who developed leukemia and 106 matched control patients without leukemia. Conditional logistic regression was used to estimate the relative risk of leukemia associated with specific treatments. All P values are two-sided.Radiotherapy (mean dose to active bone marrow, 12.6 Gy) without chemotherapy was associated with a threefold elevated risk of leukemia. Risk increased with increasing dose of radiation to active bone marrow (P for trend =.02), with patients receiving radiotherapy to the chest as well as to the abdominal/pelvic fields accounting for much of the risk at higher doses. Radiation dose to active bone marrow and the cumulative dose of cisplatin (P for trend =.001) were both predictive of excess leukemia risk in a model adjusted for all treatment variables. The estimated relative risk of leukemia at a cumulative dose of 650 mg cisplatin, which is commonly administered in current testicular cancer treatment regimens, was 3.2 (95% confidence interval = 1.5-8.4); larger doses (1000 mg) were linked with statistically significant sixfold increased risks.Past treatments for testicular cancer are associated with an increased risk of leukemia, with evidence for dose-response relationships for both radiotherapy and cisplatin-based chemotherapy. Statistically nonsignificant excesses are estimated for current radiotherapy regimens limited to the abdomen and pelvis: Among 10 000 patients given a treatment dose of 25 Gy and followed for 15 years, an excess of nine leukemias is predicted; cisplatin-based chemotherapy (dose, 650 mg) might result in 16 cases of leukemia. The survival advantage provided by current radiotherapy and chemotherapy regimens for testicular cancer far exceeds the small absolute risk of leukemia.
Sequential Intravesical Chemoimmunotherapy with Mitomycin C and Bacillus Calmette-Guérin and with Bacillus Calmette-Guérin Alone in Patients with Carcinoma in Situ of the Urinary Bladder: Results of an EORTC Genito-Urinary Group Randomized Phase 2 Trial (30993)
Authors: Willem Oosterlinck, Ziya Kirkali, Richard Sylvester, Fernando Calais da Silva, Christer Busch, Ferran Algaba, Sandra Collette, Aldo Bono
Journal: European Urology (2010)
Role of the MHC2TA gene in autoimmune diseases
Authors: Alfonso Martínez, Marta Sánchez-Lopez, Jezabel Varadé, Ana Mas, M Carmen Martín, Virginia de las Heras, Rafael Arroyo, Juan Luis Mendoza, Manuel Díaz-Rubio, Benjamín Fernández-Gutiérrez, Emilio G de la Concha, Elena Urcelay
Journal: Annals of the Rheumatic Diseases (2006)

<b>Objectives:</b> Expression of major histocompatibility complex (MHC) class II genes is almost exclusively regulated by the class II transactivator. A promoter polymorphism (−168A/G, rs3087456) in the <i>MHC2TA</i> gene was associated with increased susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction in a northern European population. However, no evidence of association of this <i>MHC2TA</i> variant with the two autoimmune diseases could be subsequently detected in independent cohorts. <b>Aim:</b> To test the aforementioned single nucleotide polymorphism and another G→C change (nt1614 from coding sequence, rs4774) to analyse the haplotype pattern in this <i>MHC2TA</i> gene. <b>Methods:</b> A case–control study was performed with 350 patients with rheumatoid arthritis, 396 patients with multiple sclerosis, 663 patients with inflammatory bowel disease (IBD) and 519 healthy controls from Madrid. Genotyping was ascertained by using TaqMan assays-on-demand on a 7900HT analyser, following the manufacturer's suggestions (Applied Biosystems, Foster City, California, USA). Haplotypes were inferred with the expectation–maximisation algorithm implemented by the Arlequin software. <b>Results:</b> No independent association with these autoimmune diseases was found for either polymorphism in the Spanish cohorts tested. However, when haplotypes were compared between patients with rheumatoid arthritis and controls, a significant difference in their overall frequency distribution was observed, evidencing a protective haplotype (−168A/1614C, p = 0.006; odds ratio (OR) 0.7) and a risk haplotype (−168G/1614C, p = 0.019; OR 1.6). Patients with multiple sclerosis mirrored these results, but no effect on IBD was identified. <b>Conclusions:</b> The <i>MHC2TA</i> gene influences predisposition to rheumatoid arthritis and multiple sclerosis, but not to IBD. The −168G allele is not an aetiological variant in itself, but a genetic marker of susceptibility/protection haplotypes.
A DLBCL Patient Accompanied by ITP Treated with R-CHOP and Thrombopoietin Receptor Agonist
Authors: D. Kurita, Y. Hatta, Y. Kobayashi, Y. Hirabayashi, S. Kiso, H. Kodaira, H. Takahashi, K. Miura, M. Nakagawa, J. Takeuchi
Journal: Annals of Oncology (2013)
A Silk Sericin/Silicone Nerve Guidance Conduit Promotes Regeneration of a Transected Sciatic Nerve
Authors: Hongjian Xie, Wen Yang, Jianghai Chen, Jinxiang Zhang, Xiaochen Lu, Xiaobo Zhao, Kun Huang, Huili Li, Panpan Chang, Zheng Wang, Lin Wang
Journal: Advanced Healthcare Materials (2015)

Peripheral nerve gap defects lead to significant loss of sensory or motor function. Tissue engineering has become an important alternative to nerve repair. Sericin, a major component of silk, is a natural protein whose value in tissue engineering has just begun to be explored. Here, the first time use of sericin in vivo is reported as a long-term implant for peripheral nerve regeneration. A sericin nerve guidance conduit is designed and fabricated. This conduit is highly porous with mechanical strength matching peripheral nerve tissue. It supports Schwann cell proliferation and is capable of up-regulating the transcription of glial cell derived neurotrophic factor and nerve growth factor in Schwann cells. The sericin conduit wrapped with a silicone conduit (sericin/silicone double conduits) is used for bridging repair of a 5 mm gap in a rat sciatic nerve transection model. The sericin/silicone double conduits achieve functional recovery comparable to that of autologous nerve grafting as evidenced by drastically improved nerve function and morphology. Importantly, this improvement is mainly attributed to the sericin conduit as the silicone conduit alone only produces marginal functional recovery. This sericin/silicone-double-conduit strategy offers an efficient and valuable alternative to autologous nerve grafting for repairing damaged peripheral nerve.
Stiff-Man Syndrome and Clonazepam
Authors: Ulf Westblom
Journal: JAMA (1977)

<h3>To the Editor.—</h3> In 1956, Moersch and Woltman<sup>1</sup>first described the stiffman syndrome, a disease characterized by progressive fluctuating muscular rigidity and spasm. By now, more than 50 cases are known in the literature, two of which were reported inThe Journal(195:222, 1966). Gordon et al<sup>2</sup>made a thorough survey of the syndrome in 1967. Diazepam in high dosages, usually around 40 to 60 mg/day, has been the only known treatment, with considerable relief of symptoms in a majority of cases. Mertens and Ricker<sup>3</sup>have also found clinical improvement after administration of γ-amino-β-hydroxybutyric acid derivatives. I report a patient who had good clinical improvement after receiving the new benzodiazepine derivative, clonazepam. <h3>Report of a Case.—</h3> A 55-year-old diabetic woman was admitted to the hospital in April 1976 with the diagnosis of drug abuse. She had been found to consume up to 40 mg diazepam (Valium) daily.
Mechanisms of atrial flutter and atrial fibrillation: distinct entities or two sides of a coin?
Authors: A Waldo
Journal: Cardiovascular Research (2002)

Time for primary review 23 days. 

There has been a long recognized clinical interrelationship between atrial flutter and atrial fibrillation. Patients who primarily manifest atrial flutter commonly also experience atrial fibrillation and vice versa [1,2]. Both are very common as a temporary atrial tachyarrhythmia shortly after open heart surgery, and often in the same patient [3]. And some antiarrhythmic agents, notably class IC drugs, IA drugs and amiodarone, used to suppress atrial fibrillation not uncommonly ‘convert’ recurrences of atrial tachyarrhythmia to atrial flutter [4–6]. Are these clinical associations mere coincidences, or do they reflect an important underlying similar pathophysiology and even similar mechanism(s)? Data derived largely from a series of unconnected studies in animal models and patients seemingly point to a clear interrelationship between the two, suggesting, if not indicating, that they are two sides of a coin.

Classical atrial flutter, now called typical and reverse typical atrial flutter [7], is well recognized to be due to a macro-reentrant mechanism, in which the reentrant wave front travels up the inter-atrial septum and down the right atrial free wall or vice versa, respectively [1,7]. Critical to the development and maintenance of this reentrant circuit are the lateral boundaries, one being fixed (anatomic), the tricuspid valve annulus, and the other almost always being functional, a line of block between the venae cavae. We shall develop the theme that one of the fundamental features that determines whether an atrial tachyarrhythmia becomes sustained atrial flutter or atrial fibrillation is the development of the line of block between the venae cavae. We shall also develop the theme that another of the fundamental features that determine whether the atrial tachyarrhythmia becomes atrial flutter or atrial fibrillation often will be the atrial flutter cycle length, i.e. the cycle length of a stable … 

* Tel.: +1-216-844-7690; fax: +1-216-844-7196 alw2{at}po.cwru.edu
Hormone Replacement Therapy and Life Expectancy After Prophylactic Oophorectomy in Women With <i>BRCA1/2</i> Mutations: A Decision Analysis
Authors: Katrina Armstrong, J. Sanford Schwartz, Thomas Randall, Stephen C. Rubin, Barbara Weber
Journal: Journal of Clinical Oncology (2004)

Purpose The decision about prophylactic oophorectomy is difficult for many premenopausal women with BRCA1/2 mutations because of concerns and controversy about the use of hormone replacement therapy (HRT) after oophorectomy. Patients and Methods A Markov decision analytic model used the most current epidemiologic data to assess the expected outcomes of prophylactic oophorectomy with or without HRT (to age 50 years or for life) in cohorts of women with BRCA1/2 mutations. Sensitivity analyses were conducted to assess the impact of alternative assumptions about effects of HRT, effects of prophylactic oophorectomy, and risks of cancer associated with BRCA1/2 mutations. Results In our model, prophylactic oophorectomy lengthened life expectancy in women with BRCA1/2 mutations, irrespective of whether HRT was used after oophorectomy. This gain ranged from 3.34 to 4.65 years, depending on age at oophorectomy. Use of HRT after oophorectomy was associated with relatively small changes in life expectancy (+0.17 to −0.34 years) when HRT was stopped at age 50, but larger decrements in life expectancy if HRT was continued for life (−0.79 to −1.09 years). HRT was associated with a gain in life expectancy of between 0.39 and 0.79 years for mutation carriers undergoing both prophylactic mastectomy and oophorectomy. Conclusion On the basis of the results of this decision analysis, we recommend that women with BRCA1/2 mutations undergo prophylactic oophorectomy after completion of childbearing, decide about short-term HRT after oophorectomy based largely on quality-of-life issues rather than life expectancy, and, if using HRT, consider discontinuing treatment at the time of expected natural menopause, approximately age 50 years.
Protein Carbamylation Predicts Mortality in ESRD
Authors: Robert A. Koeth, Kamyar Kalantar-Zadeh, Zeneng Wang, Xiaoming Fu, W.H. Wilson Tang, Stanley L. Hazen
Journal: Journal of the American Society of Nephrology (2013)

Traditional risk factors fail to explain the increased risk for cardiovascular morbidity and mortality in ESRD. Cyanate, a reactive electrophilic species in equilibrium with urea, posttranslationally modifies proteins through a process called carbamylation, which promotes atherosclerosis. The plasma level of protein-bound homocitrulline (PBHCit), which results from carbamylation, predicts major adverse cardiac events in patients with normal renal function, but whether this relationship is similar in ESRD is unknown. We quantified serum PBHCit in a cohort of 347 patients undergoing maintenance hemodialysis with 5 years of follow-up. Kaplan-Meier analyses revealed a significant association between elevated PBHCit and death (log-rank P<0.01). After adjustment for patient characteristics, laboratory values, and comorbid conditions, the risk for death among patients with PBHCit values in the highest tertile was more than double the risk among patients with values in the middle tertile (adjusted hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.5–3.9) or the lowest tertile (adjusted HR, 2.3; 95% CI, 1.5–3.7). Including PBHCit significantly improved the multivariable model, with a net reclassification index of 14% (P<0.01). In summary, seurm PBHCit, a footprint of protein carbamylation, predicts increased cardiovascular risk in patients with ESRD, supporting a mechanistic link among uremia, inflammation, and atherosclerosis.
SHORT–TERM AND LONG–TERM OUTCOMES IN PATIENTS WITH CHRONIC OBSTRUCTS PULMONARY DISEASE UNDERGOING ISOLATED AORTIC VALVE REPLACEMENT FOR AORTIC STENOSIS
Authors: Salil Desai, Hersh Maniar, Toshinobu Kazui, Eric Novak, Ralph Damiano, Marc Moon, Jennifer Lawton, Alan Zajarias
Journal: Journal of the American College of Cardiology (2013)