tbuckley/cabot-search huggingface dataset:
Estimation of the Spontaneous Mutation Rate in Heliconius melpomene
Authors: Peter D. Keightley, Ana Pinharanda, Rob W. Ness, Fraser Simpson, Kanchon K. Dasmahapatra, James Mallet, John W. Davey, Chris D. Jiggins
Journal: Molecular Biology and Evolution (2014)

We estimated the spontaneous mutation rate in Heliconius melpomene by genome sequencing of a pair of parents and 30 of their offspring, based on the ratio of number of de novo heterozygotes to the number of callable site-individuals. We detected nine new mutations, each one affecting a single site in a single offspring. This yields an estimated mutation rate of 2.9 × 10−9 (95% confidence interval, 1.3 × 10−9–5.5 × 10−9), which is similar to recent estimates in Drosophila melanogaster, the only other insect species in which the mutation rate has been directly estimated. We infer that recent effective population size of H. melpomene is about 2 million, a substantially lower value than its census size, suggesting a role for natural selection reducing diversity. We estimate that H. melpomene diverged from its Müllerian comimic H. erato about 6 Ma, a somewhat later date than estimates based on a local molecular clock.
A SUBCLASS OF HUMAN γA-GLOBULINS (γA2) WHICH LACKS THE DISULFIDE BONDS LINKING HEAVY AND LIGHT CHAINS
Authors: Howard M. Grey, Carlos A. Abel, William J. Yount, Henry G. Kunkel
Journal: The Journal of Experimental Medicine (1968)

The gammaA2-subgroup of gammaA-globulins, previously delineated by antigenic studies, was found to differ strikingly from other immunoglobulins in the manner in which the polypeptide chains are bound together. The heavy and light chains were not linked to each other by disulfide bonds. Instead the light chains were disulfide linked to one another, and were present in the gammaA2-molecule as disulfide bridged L-L dimers. Antisera specific for gammaA2-proteins indicated the occurrence of two different antigenic types in all normal sera as well as saliva and colostrum. Both of these showed the unique interchain disulfide linkage. Quantitative analyses indicated higher levels of gammaA2-proteins in external secretions.
Recovery of neutrophil apoptosis by ectoine: a new strategy against lung inflammation
Authors: Ulrich Sydlik, Henrike Peuschel, Adnana Paunel-Görgülü, Stefanie Keymel, Ursula Krämer, Alexander Weissenberg, Matthias Kroker, Samira Seghrouchni, Christian Heiss, Joachim Windolf, Andreas Bilstein, Malte Kelm, Jean Krutmann, Klaus Unfried
Journal: European Respiratory Journal (2012)

The life span of neutrophilic granulocytes has a determining impact on the intensity and duration of neutrophil driven lung inflammation. Based on the compatible solute ectoine, we aimed to prevent anti-apoptotic reactions in neutrophils triggered by the inflammatory microenvironment in the lung. Neutrophils from chronic obstructive pulmonary disease patients and control individuals were exposed to inflammatory mediators and xenobiotics in the presence or absence of ectoine. The in vivo relevance of this approach was tested in xenobiotic-induced lung inflammation in rats. The reduction of apoptosis rates of ex vivo -exposed neutrophils from all study groups was significantly restored in the presence of ectoine. However, natural apoptosis rates not altered by inflammatory stimuli were not changed by ectoine. Mechanistic analyses demonstrated the preventive effect of ectoine on the induction of anti-apoptotic signalling. Neutrophilic lung inflammation induced by single or multiple expositions of animals to environmental particles was reduced after the therapeutic intervention with ectoine. Analyses of neutrophils from bronchoalveolar lavage indicate that the in vivo effect is due to the restoration of neutrophil apoptosis. Ectoine, a compound of the highly compliant group of compatible solutes, demonstrates a reproducible and robust effect on the resolution of lung inflammation.
Senescence and the Renal Vasculature in Normal Man
Authors: NORMAN K. HOLLENBERG, DOUGLASS F. ADAMS, HAROLD S. SOLOMON, ABDUR RASHID, HERBERT L. ABRAMS, JOHN P. MERRILL
Journal: Circulation Research (1974)

The xenon washout technique and the renal blood flow response to vasoactive agents or alterations in sodium intake were used to characterize the effect of aging on the renal vasculature in 207 normal human subjects ranging in age from 17 to 76 years. A highly significant, progressive reduction in the mean blood flow, the rapid-component flow rate, and the percent of flow into the rapid-flow (cortical) compartment accompanied advancing age. Because 133 Xe measures flow per unit tissue mass, the results indicated a larger reduction in flow than in mass--the anticipated finding if flow reduction is primary in the genesis of atrophy. Age also reduced the vasodilation consequent to administration of acetylcholine or a sodium load; this finding is consistent with a fixed lesion of the vessels. Responses to angiotensin were not modified by age. Thus, offsetting factors of increased ratio of wall to lumen thickness and smooth muscle atrophy are precisely matched. The findings in this study agree with earlier hypotheses based on morphology that suggest a primary vascular process in the development of age-related renal changes.
Mounting Evidence for Prediagnostic Use of Statins in Reducing Risk of Lethal Prostate Cancer
Authors: Lorelei A. Mucci, Meir J. Stampfer
Journal: Journal of Clinical Oncology (2013)

during follow-up, reporting a relative risk of 0.39 (95% CI, 0.19 to 0.77) among men who were statin users compared with nonusers. The emphasis on lethal prostate cancer in that study was important, given the considerable biologic heterogeneity in metastatic potential of prostate cancer over a man’s life and also because the etiology of lethal prostate cancer clearly differs from that of indolent disease. 3,4 A large fraction of men harbor latent prostate cancer,andwiththehighprevalenceofprostate-specificantigen(PSA) screening in Western populations, most of the diagnosed prostate cancers are indolent in the sense that they never would have otherwise come to clinical attention. Much of the apparent inconsistency among studies on statins and prostate cancer disappears when one distinguishes associations with risk of advanced-stage—or preferably lethal—prostate cancer from overall incidence. A meta-analysis of 27 observational studies publishedin2012reportedapooledrelativeriskof0.93(95%CI,0.87 to 0.99) for total incident prostate cancer and a more pronounced inverse association for advanced disease, with a relative risk of 0.80 (95% CI, 0.70 to 0.90) on the basis of seven studies. 5 One challenge in the interpretation of thefindings is a lack of consistency in the definition of advanced prostate cancer, with investigators using various definitions and often classifying T3a or T2 as advanced. From the perspectiveofetiologyandprevention,weproposethatlethalprostate cancer is the optimal disease end point for epidemiologic investigations. Given the long natural history of prostate cancer, such studies require long-term and complete follow-up of large cohorts of men. Since the publication of the 2012 meta-analysis, five additional epidemiologic studies have reported on associations between statin use and lethal prostate cancer, all suggesting inverse associations. UsingSEERdatainWashingtonstate,Geybelsetal 6 reportedarelative risk of 0.19 (95% CI, 0.06 to 0.56) on the basis of 39 lethal cases in a case-only analysis; thesefindings are notably in contrast with the null resultsforstatinsandPSAprogressioninthesamestudy.Thisisakey issue in prostate cancer research, given that PSA recurrence is an imperfect classifier of the lethal potential of a cancer. In a Danish population registry-based study, statin users had significantly lower rates of prostate cancer mortality, with a relative risk of 0.81 (95% CI, 0.75 to 0.88). 7 However, these results were adjusted only for age and nototherriskfactorsforlethalprostatecancer.Inastudyshowingthat postdiagnostic use of metformin was associated with substantially reducedprostatecancermortalityindiabetics,Margeletal 8 alsonoted
Extracardiac pressure and ventricular haemodynamics
Authors: J. S JANICKI, K. T WEBER, J. LOSCALZO, S. SHROFF
Journal: Cardiovascular Research (1987)

To investigate the relative influence of pericardial and intrathoracic pressures on left and right ventricular diastolic and systolic pressures two experimental groups were studied: group 1-10 open chest dogs with a controlled pericardial effusion; and group 2 - five closed chest dogs with a controlled pneumothorax at constant transpulmonary pressure and lung volume. In both groups right and left ventricular diastolic pressures were linear functions of external pressure with respective slopes of 0.71 and 0.39 for group 1 and 0.80 and 0.78 for group 2. The left ventricular slope of 0.39 indicates that left ventricular volume decreased more with increments in pericardial pressure since a slope of approximately 1.00 would be expected if the filling volume was invariant. Accordingly, the fall in left ventricular systolic pressure that occurred in both groups was two to three times greater in group 1. Right ventricular systolic pressure fell in group 1 whereas it increased in group 2. It is concluded that there are no major differences between the influence of either type of external pressure on right ventricular filing. In contrast, the left ventricle, and in particular the filling pressure gradient between the pulmonary circulation and the left ventricle, is more sensitive to pericardial pressure.
Quantifying the Effect of Changes in the Hemodialysis Prescription on Effective Solute Removal with a Mathematical Model
Authors: WILLIAM R. CLARK, JOHN K. LEYPOLDT, LEE W. HENDERSON, BRUCE A. MUELLER, MERI KAY SCOTT, EDWARD F. VONESH
Journal: Journal of the American Society of Nephrology (1999)

Abstract. One potential benefit of chronic hemodialysis (HD) regimens of longer duration or greater frequency than typical three-times-weekly schedules is enhanced solute removal over a relatively wide molecular weight spectrum of uremic toxins. This study assesses the effect of variations in HD frequency ( F : per week), duration ( T : min per treatment), and blood/dialysate flow rates ( Q B / Q D : ml/min) on steady-state concentration profiles of five surrogates: urea (U), creatinine (Cr), vancomycin (V), inulin (I), and β 2 -microglobulin (β2M). The regimens assessed for an anephric 70-kg patient were: A (standard): F = 3, T = 240, Q B = 350, Q D = 600; B (daily/short-time): F = 7, T = 100, Q B = 350, Q D = 600; C/D/E (low-flow/long-time): F = 3/5/7, T = 480, Q B = 300, Q D = 100. HD was simulated with a variable-volume double-pool model, which was solved by numerical integration (Runge-Kutta method). Endogenous generation rates ( G ) for U, Cr, and β2M were 6.25, 1.0, and 0.17 mg/min, respectively; constant infusion rates for V and I of 0.2 and 0.3 mg/min, respectively, were used to simulate middle molecule (MM) G values. Intercompartment clearances of 600, 275, 125, 90, and 40 ml/min were used for U, Cr, V, I, and β2M, respectively, For each solute/regimen combination, the equivalent renal clearance (EKR: ml/min) was calculated as a dimensionless value normalized to the regimen A EKR, which was 13.4, 10.8, 6.6, 3.7, and 4.8 ml/min for U, Cr, V, I, and β2M, respectively. For regimens B, C, D, and E, respectively, these normalized EKR values were U: 1.04, 0.96, 1.58, and 2.22; Cr: 1.03, 1.08, 1.80, and 2.55; V: 1.06, 1.32, 2.21, and 3.12; I: 1.05, 1.54, 2.57, and 3.62; β2M: 1.00, 1.27, 1.73, and 2.19. The extent of post-HD rebound (%) was highest for regimens A and B, ranging from 16% (urea) to 50% (inulin), and lowest for regimen E, ranging from 6% (urea) to 28% (β2M). The following conclusions can be made: ( 1 ) Relative to a standard three-times-weekly HD regimen of approximately the same total (weekly) treatment duration, a daily/short-time regimen results in modest (3 to 6%) increases in effective small solute and MM removal. ( 2 ) Relative to a standard three-times-weekly HD regimen, a three-times-weekly low-flow/long-time regimen results in comparable effective small solute removal and progressive increases in MM and β2M removal. A daily low-flow/long-time regimen substantially increases the effective removal of all solutes.
The response of adenomyosis to endometrial ablation/resection
Authors: V McCausland
Journal: Human Reproduction Update (1998)

Operative hysteroscopy is a relatively new technique that has significantly improved the diagnosis and therapy of abnormal uterine bleeding. At first, the success of operative hysteroscopy in controlling this bleeding seemed extremely high but, with long-term follow-up, a significant failure rate became evident requiring a repeat hysteroscopic procedure or a hysterectomy. Deep adenomyosis is a major cause of these failures. This paper describes three operative ablation techniques and relates many of their failures to deep adenomyosis. The definition and pathophysiology of adenomyosis are also explored. The possibility of delaying the diagnosis of endometrial cancer under an ablation scan is discussed. Ultimately the depth of adenomyosis seems to correlate with the outcome of endometrial ablation or resection. Patients without or with only minimal endometrial penetration of <2.5 mm (superficial adenomyosis) have good results from the ablation. Patients with deep endometrial penetration of >2.5 mm (deep adenomyosis) usually have persistent problems and should be offered hysterectomy over repeat ablation. Magnetic resonance imaging or ultrasound may be an appropriate pre-operative screening tool to determine the depth of adenomyosis.
A 17mer Peptide Interferes With Acidification-Induced Uncoupling of Connexin43
Authors: Guillermo Calero, Martha Kanemitsu, Steven M. Taffet, Alan F. Lau, Mario Delmar
Journal: Circulation Research (1998)

Abstract —Structure/function analysis shows that the carboxyl terminal (CT) domain of connexin43 (Cx43) is essential for the chemical regulation of cell-cell communication. Of particular interest is the region between amino acids 260 and 300. Structural preservation of this region is essential for acidification-induced uncoupling (ie, pH gating). In this study, we report data showing that a 17mer peptide of the same sequence as amino acids 271 to 287 of Cx43 (CSSPTAPLSPMSPPGYK) can prevent pH gating of Cx43-expressing oocytes. Experiments were carried out in pairs of Xenopus oocytes previously injected with connexin38 antisense and expressing wild-type Cx43. Junctional conductance was measured electrophysiologically. pH i was determined from the light emission of the proton-sensitive dye dextran-seminaphtho- rhodafluor. Intracellular acidification was induced by superfusion with a bicarbonate-buffered solution gassed with a progressively increasing concentration of CO 2 . Injection of water alone into both oocytes of a Cx43-expressing pair or injection of a peptide from region 321 to 337 of Cx43 did not modify pH sensitivity. However, injection of a polypeptide corresponding to amino acids 241 to 382 of Cx43 interfered with the ability of gap junctions to close on acidification. Similar results were obtained when a 17mer peptide (region 271 to 287) was injected into both oocytes of the pair. Normal Cx43 pH gating was observed if (1) the amino acid sequence of the 17mer peptide was scrambled or (2) the N and the C ends of the 17mer peptide were not included in the sequence. This is the first demonstration of a molecule that can interfere with the chemical regulation of connexin channels in a cell pair. The data may lead to the development of small molecules that can be used in Cx43-expressing multicellular preparations to study the role of gap junction regulation in normal as well as diseased states.
Prostate Cancer SubtyPINg BiomarKers and Outcome: Is Clarity EmERGing?
Authors: Steven C. Smith, Scott A. Tomlins
Journal: Clinical Cancer Research (2014)

Molecular prostate cancer subtypes have been proposed on the basis of mutually exclusive SPINK1 and ERG overexpression, with conflicting reports on their prognostic ability. Flavin and colleagues report that SPINK1 is neither prognostic nor absolutely mutually exclusive with ERG, raising important questions about prostate cancer molecular subtyping and prognostic biomarker evaluation.
A meta-analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk
Authors: I. Tramacere, C. Pelucchi, V. Bagnardi, M. Rota, L. Scotti, F. Islami, G. Corrao, P. Boffetta, C. La Vecchia, E. Negri
Journal: Annals of Oncology (2011)
Peripheral blood neutrophil morphology reflects bone marrow dysplasia in myelodysplastic syndromes
Authors: S. Widell, E. Hellström‐Lindberg, Y. Kock, M. Lindberg, Å. Öst, R. Hast
Journal: American Journal of Hematology (1995)

Abstract Dysplastic features of cells in peripheral blood and bone marrow were studied in 51 patients with myelodysplastic syndromes (MDS) to evaluate the significance of the degree of neutrophil granulation (G‐score) and the percentage of pelgeroid polymorphs (ppp) in the peripheral blood, as indices of dysplastic changes in the bone marrow. There was a good correlation between peripheral blood and bone marrow findings, both for G‐score figures (r = 0.92, P &lt; 0.01) and ppp (r = 0.82, P &lt; 0.01). Significantly lower G‐score figures were found among patients with an increased percentage of bone marrow blasts ( P &lt; 0.05), while high ppp correlated with the presence of ring sideroblasts, the degree of bone marrow fibrosis, and findings of complex chromosomal abnormalities. Patients with a high degree of bone marrow dysplasia had significantly lower G‐score ( P &lt; 0.01) and significantly higher ppp ( P &lt; 0.05) figures, than those with less pronounced myelodysplasia. In addition, extreme hypogranulation (G‐score &lt;150) or very high ppp (≥20%) was generally a sign of bi‐ and tri‐lineage dysplasia in the bone marrow. The results thus show that quantitative estimation of peripheral blood polymorph dysplasia by G‐score figures and ppp seems to reflect the total degree of bone marrow dysplasia in MDS and may serve as a complement to bone marrow evaluation when the diagnosis of MDS is difficult. © 1995 Wiley‐Liss, Inc.
Informed Consent in Emergency Research
Authors: J. Douglas Leith
Journal: JAMA (1989)

To the Editor.—  The article on patient consent for in-ambulance thrombolytic therapy 1 describes the authors' ideas on a new way to get patient consent for clinical research. There is no research conducted on this idea: it is just unilaterally executed on a captive population, with no control subjects and no analysis of its effectiveness in overcoming the defects of the standard method. Since this apparently was supposed to be research into methods of gaining consent, it should not have been approved without a sound research design. 2   I agree that such ideas very much need to be tried, but it seems like a waste of scientific time (theirs and ours) to try such ideas without a randomized, controlled study comparing the proposed method with the standard, federally prescribed method. It seems premature to publish this nonresearch, consisting only of a description of the protocol without presenting any results or
Improving the experience of care for people using NHS services: summary of NICE guidance
Authors: N. O'Flynn, S. Staniszewska
Journal: BMJ (2012)

<h3>Objective</h3> Pulmonary hypertension (PH) is associated with increased mortality after surgical or transcatheter aortic valve replacement (TAVR) for aortic stenosis (AS), and when the pulmonary artery pressure is particularly elevated, there may be questions about the clinical benefit of TAVR. We aimed to identify clinical and haemodynamic factors associated with increased mortality after TAVR among those with moderate/severe PH. <h3>Methods</h3> Among patients with symptomatic AS at high or prohibitive surgical risk receiving TAVR in the Placement of Aortic Transcatheter Valves (PARTNER) I randomised trial or registry, 2180 patients with an invasive measurement of mean pulmonary artery pressure (mPAP) recorded were included, and moderate/severe PH was defined as an mPAP ≥35 mm Hg. <h3>Results</h3> Increasing severity of PH was associated with progressively worse 1-year all-cause mortality: none (n=785, 18.6%), mild (n=838, 22.7%) and moderate/severe (n=557, 25.0%) (p=0.01). The increased hazard of mortality associated with moderate/severe PH was observed in females, but not males (interaction p=0.03). In adjusted analyses, females with moderate/severe PH had an increased hazard of death at 1 year compared with females without PH (adjusted HR 2.14, 95% CI 1.44 to 3.18), whereas those with mild PH did not. Among males, there was no increased hazard of death associated with any severity of PH. In a multivariable Cox model of patients with moderate/severe PH, oxygen-dependent lung disease, inability to perform a 6 min walk, impaired renal function and lower aortic valve mean gradient were independently associated with increased 1-year mortality (p&lt;0.05 for all), whereas several haemodynamic indices were not. A risk score, including these factors, was able to identify patients with a 15% vs 59% 1-year mortality. <h3>Conclusions</h3> The relationship between moderate/severe PH and increased mortality after TAVR is altered by sex, and clinical factors appear to be more influential in stratifying risk than haemodynamic indices. These findings may have implications for the evaluation of and treatment decisions for patients referred for TAVR with significant PH. <h3>Trial registration</h3> NCT00530894.
The differential ability of human IgG1 and IgG4 to activate complement is determined by the COOH-terminal sequence of the CH2 domain.
Authors: M H Tao, S M Canfield, S L Morrison
Journal: The Journal of Experimental Medicine (1991)

Using domain switch chimeric antibodies, we confirm the important role of CH2 in complement activation. In addition, we demonstrate that the structures responsible for the differential ability of human IgG1 and IgG4 to activate complement are located at the COOH-terminal part (from residue 292 to 340) of the CH2 domain. The amino acids in CH2 that might be involved in complement interaction are discussed. While CH3 contributes to efficient complement activation, CH3 from IgG2 and CH3 IgG3 are equally effective.