tbuckley/cabot-search huggingface dataset:
Sympathetic stimulation-evoked overflow of norepinephrine and neuropeptide Y from the heart.
Authors: M R Warner, P D Senanayake, C M Ferrario, M N Levy
Journal: Circulation Research (1991)

Neuropeptide Y (NPY) and norepinephrine are released together on sympathetic activation. To compare the time courses of NPY and norepinephrine washout from cardiac tissues, we measured the overflow of NPY-like immunoreactivity (NPY-LI) and norepinephrine in coronary sinus blood before, during, and after 3-minute trains of ansae subclaviae stimulation in 13 anesthetized dogs. We also measured vagally induced cardiac cycle length responses before and after ansae stimulation. Ansae stimulation increased NPY-LI and norepinephrine overflow from the heart in a frequency-dependent manner (p less than 0.02). After stimulation of the ansae at 5 and 10 Hz, the peak norepinephrine overflows decayed by 90% within 2 minutes, but the NPY-LI overflows required 17 +/- 11 and 35 +/- 21 minutes, respectively, to decay by 90%. Cardiac vagal effects were inhibited after 5- and 10-Hz ansae stimulations, and the peak inhibitions decayed by 90% after 19 +/- 7 and 39 +/- 16 minutes, respectively. The 90% decay times of the NPY-LI overflows were longer (p less than 0.003) than those of the norepinephrine overflows but did not differ significantly (p greater than 0.4) from the 90% decay times of the inhibition of vagal effects. We characterized NPY-LI in coronary sinus and arterial plasma by reversed-phase high-performance liquid chromatography. Before ansae stimulation, the main peak of NPY-LI in the plasma had a retention time similar to that of the oxidized human NPY-(1-36) standard. During ansae stimulation, however, there was a substantial increase in the peak of NPY-LI that eluted in a position similar to that of the monoxidized human NPY-(1-36) standard. These data support the hypothesis that neurally released NPY mediates the sympathetically evoked inhibition of vagal effects and indicate that the time course of removal of NPY from the heart differs substantially from that of norepinephrine. Moreover, under basal conditions, most NPY in the circulation is present in the oxidized form or as a fragment of the 36-amino-acid peptide. In contrast, cardiac sympathetic stimulation evokes the overflow of monoxidized NPY-(1-36) into the coronary sinus plasma.
Mammalian Evolution May not Be Strictly Bifurcating
Authors: B. M. Hallstrom, A. Janke
Journal: Molecular Biology and Evolution (2010)

The massive amount of genomic sequence data that is now available for analyzing evolutionary relationships among 31 placental mammals reduces the stochastic error in phylogenetic analyses to virtually zero. One would expect that this would make it possible to finally resolve controversial branches in the placental mammalian tree. We analyzed a 2,863,797 nucleotide-long alignment (3,364 genes) from 31 placental mammals for reconstructing their evolution. Most placental mammalian relationships were resolved, and a consensus of their evolution is emerging. However, certain branches remain difficult or virtually impossible to resolve. These branches are characterized by short divergence times in the order of 1-4 million years. Computer simulations based on parameters from the real data show that as little as about 12,500 amino acid sites could be sufficient to confidently resolve short branches as old as about 90 million years ago (Ma). Thus, the amount of sequence data should no longer be a limiting factor in resolving the relationships among placental mammals. The timing of the early radiation of placental mammals coincides with a period of climate warming some 100-80 Ma and with continental fragmentation. These global processes may have triggered the rapid diversification of placental mammals. However, the rapid radiations of certain mammalian groups complicate phylogenetic analyses, possibly due to incomplete lineage sorting and introgression. These speciation-related processes led to a mosaic genome and conflicting phylogenetic signals. Split network methods are ideal for visualizing these problematic branches and can therefore depict data conflict and possibly the true evolutionary history better than strictly bifurcating trees. Given the timing of tectonics, of placental mammalian divergences, and the fossil record, a Laurasian rather than Gondwanan origin of placental mammals seems the most parsimonious explanation.
Tumor Eradication by Wild-type p53-specific Cytotoxic T Lymphocytes
Authors: Michel P.M. Vierboom, Hans W. Nijman, Rienk Offringa, Ellen I.H. van der Voort, Thorbald van Hall, Lambert van den Broek, Gert Jan Fleuren, Peter Kenemans, W. Martin Kast, Cornelis J.M. Melief
Journal: The Journal of Experimental Medicine (1997)

The tumor suppressor protein p53 is overexpressed in close to 50% of all human malignancies. The p53 protein is therefore an attractive target for immunotherapy. Cytotoxic T lymphocytes (CTLs) recognizing a murine wild-type p53 peptide, presented by the major histocompatibility complex class I molecule H-2Kb, were generated by immunizing p53 gene deficient (p53 −/−) C57BL/6 mice with syngeneic p53-overexpressing tumor cells. Adoptive transfer of these CTLs into tumor-bearing p53 +/+ nude mice caused complete and permanent tumor eradication. Importantly, this occurred in the absence of any demonstrable damage to normal tissue. When transferred into p53 +/+ immunocompetent C57BL/6 mice, the CTLs persisted for weeks in the absence of immunopathology and were capable of preventing tumor outgrowth. Wild-type p53-specific CTLs can apparently discriminate between p53-overexpressing tumor cells and normal tissue, indicating that widely expressed autologous molecules such as p53 can serve as a target for CTL-mediated immunotherapy of tumors.
Multiple Gastrointestinal Polyps in Patients Treated with BRAF Inhibitors
Authors: Ravi K. Amaravadi, Kathryn E. Hamilton, Xiaohong Ma, Shengfu Piao, Armando Del Portillo, Katherine L. Nathanson, Matteo S. Carlino, Georgina V. Long, Igor Puzanov, Xiaowei Xu, Jennifer J.D. Morrissette, Kenneth Y. Tsai, Keith T. Flaherty, Jeffrey A. Sosman, Grant R. Goodman, Grant A. McArthur, Anil K. Rustgi, David C. Metz, Lynn M. Schuchter, Paul B. Chapman, Antonia R. Sepulveda
Journal: Clinical Cancer Research (2015)

BRAF inhibitors (BRAFi) extend survival in BRAF-mutant melanoma but can promote the growth of Ras-mutant neoplasms. This study determined if gastrointestinal polyps found in BRAFi-treated patients harbored Ras mutations.Colonic and gastric polyps were identified and resected from BRAFi-treated melanoma patients. Next-generation sequencing (NGS) was performed on polyps. The ability of BRAFi to promote polyp formation was functionally characterized in Apc Min(+/-) mice. MAPK and β-catenin pathway activity was assessed by immunohistochemistry in mouse and human polyps.Fourteen patients treated with BRAFi underwent endoscopy to assess for polyps. Seven out of 7 patients >40 years of age and treated for >2 years were found to have colonic tubular adenomas with 4 out of the 7 patients having 5 or more polyps. One patient presented with bleeding from hyperplastic gastric polyps that recurred 6 months after BRAFi rechallenge. NGS performed on polyps found no mutations in MAPK pathway genes, but found APC mutations in all tubular adenomas. A significant increase in the number of polyps was observed in BRAFi-treated compared with control-treated Apc Min(+/-) mice (20.8 ± 9.2 vs 12.8 ± 0.1; P = 0.016). No polyps were observed in BRAFi-treated wild-type mice.BRAFi may increase the risk of developing hyperplastic gastric polyps and colonic adenomatous polyps. Due to the risk of gastrointestinal bleeding and the possibility of malignant transformation, further studies are needed to determine whether or not endoscopic surveillance should be recommended for patients treated with BRAFi.
Endoscopic injection therapy for bleeding peptic ulcer; a comparison of adrenaline alone with adrenaline plus ethanolamine oleate.
Authors: C P Choudari, K R Palmer
Journal: Gut (1994)

One hundred and seven consecutive patients presenting with significant peptic ulcer haemorrhage were randomised to endoscopic injection with 3-10 ml of 1:100,000 adrenaline (55 patients, group 1) or to a combination of adrenaline and 5% ethanolamine (52 patients, group 2). All had major stigmata of haemorrhage and endoscopic injection was undertaken by a single endoscopist. The groups were well matched with regard to risk factors. Rebleeding occurred in eight of the group 1 patients and seven in the group 2 patients; surgical operation rates, median blood transfusion requirements, and hospital stay were similar in both groups. The efficacy of either form of injection was similar whether patients presented with active bleeding or a non-bleeding visible vessel. No complications occurred. In patients presenting with significant peptic ulcer bleeding, the addition of a sclerosant confers no advantage over injection with adrenaline alone.
Metaphysics of money: A special case of emerging autonomy in evolving subsystems
Authors: Robert B. Glassman
Journal: Behavioral and Brain Sciences (2006)

There is “something more” to money, as this incisive review shows. The target article's shortcoming is its overextension of the “drug” metaphor as a blend of features that do not fit the rationalistic economics and behavioral psychologies summarized as tool theories, but this may be resolved by viewing money as a particular case of the more general evolutionary phenomenon of emergent subsystem autonomy.
Heme Oxygenase-1–Derived Carbon Monoxide Contributes to the Suppression of Acute Hypertensive Responses In Vivo
Authors: Roberto Motterlini, Armando Gonzales, Roberta Foresti, James E. Clark, Colin J. Green, Robert M. Winslow
Journal: Circulation Research (1998)

Abstract —The enzyme heme oxygenase, which exists in inducible (HO-1) and constitutive (HO-2) isoforms, catalyzes the degradation of heme to biliverdin and CO in mammalian tissues. CO has been implicated in the control of vascular tone in a manner similar to that for NO. In the present study, we investigated the contribution of the heme oxygenase/CO pathway to the modulation of acute hypertensive responses in vivo induced by (1) ααHb, a chemically modified hemoglobin known to scavenge NO, and (2) N G -nitro- l -arginine methyl ester (L-NAME), a competitive NOS inhibitor. Experiments were carried out in conscious rats in which femoral arteries and veins were surgically catheterized 1 or 5 days before treatment with the vasoconstrictor agents. Intravenous infusion of ααHb (8% solution) or L-NAME (30 mmol/kg) produced an acute and significant increase in mean arterial pressure ( P &lt;0.05) in rats at 5 days after catheter implantation. In contrast, no change in blood pressure was observed when ααHb or L-NAME was infused 1 day after the surgical intervention. The suppression of the hypertensive response observed at 1 day after surgery correlated with a significant ( P &lt;0.05) HO-1 expression in aorta, heart, and liver as well as increased aortic CO production and cGMP levels. At 1 day after surgery, pretreatment of animals with the heme oxygenase inhibitor zinc protoporphyrin IX (50 μmol/kg IP) markedly decreased aortic CO and cGMP levels and completely restored the vasoconstrictor effects of both ααHb and L-NAME. These results provide evidence for a crucial role of the heme oxygenase/CO pathway in the regulation of blood pressure under stress conditions in vivo.
Prevention of type 1 diabetes in mice by tolerogenic vaccination with a strong agonist insulin mimetope
Authors: Carolin Daniel, Benno Weigmann, Roderick Bronson, Harald von Boehmer
Journal: The Journal of Experimental Medicine (2011)

Type 1 diabetes (T1D) results from the destruction of insulin-secreting pancreatic β cells by autoreactive T cells. Insulin is an essential target of the autoimmune attack. Insulin epitopes recognized by diabetogenic T cell clones bind poorly to the class II I-Ag7 molecules of nonobese diabetic (NOD) mice, which results in weak agonistic activity of the peptide MHC complex. Here, we describe a strongly agonistic insulin mimetope that effectively converts naive T cells into Foxp3+ regulatory T cells in vivo, thereby completely preventing T1D in NOD mice. In contrast, natural insulin epitopes are ineffective. Subimmunogenic vaccination with strongly agonistic insulin mimetopes might represent a novel strategy to prevent T1D in humans at risk for the disease.
Letter: Clomiphene in investigation of ovulatory failure.
Authors: P Bye
Journal: BMJ (1975)

protracted and symptoms are relieved within half an hour of receiving glucose.2On the other hand, in a study of normal children (5 to 15 years of age) as little as 2 5 mg of glibenclamide produced a marked decrease in blood sugar with lower than normal blood sugar values persisting for more than six hours (six hours being the total investigation time).3In our patient there appeared to be a prolonged hypoglycaemic effect lasting 48-72 hours.Moreover, we can only conclude that the hypoglycaemia has caused per- manent cerebral damage with epilepsy.Mental retardation cannot be excluded.-Weare, etc.,
Generation and Evolution of Atubular Glomeruli in the Progression of Renal Disorders
Authors: Robert L. Chevalier, Michael S. Forbes
Journal: Journal of the American Society of Nephrology (2008)

Functional nephrons can be lost through a process of glomerulotubular disconnection. Progressive development of atubular glomeruli seems to play a major role in a number of renal disorders, including glomerular diseases, ascribed to injury to the glomerulotubular junction as a result of proteinuria; however, formation of atubular glomeruli is even more common in tubulointerstitial disorders, such as obstructive nephropathy. Toxic nephropathy is also associated with the formation of atubular glomeruli, suggesting susceptibility of the glomerulotubular junction to toxic injury. Narrowing or other abnormalities of the glomerulotubular junction are described as precursors of glomerulotubular disconnection. Cystinosis represents a dramatic example of progressive injury to the glomerulotubular junction, with formation of the "swan-neck deformity" following degenerative tubular cell changes attributable to apoptosis. Significant numbers of atubular glomeruli have been reported in chronic pyelonephritis and renal allograft rejection; this suggests interstitial inflammation as a stimulus for the formation of atubular glomeruli. Because of difficulties in morphologic recognition, it is likely that glomerulotubular disconnection is an underappreciated mechanism in the progression of renal disease. A better understanding of the vulnerability of the glomerulotubular junction and its protection from injury should lead to better strategies for preserving renal function in many nephropathies.
Functional Diversification of Lepidopteran Opsins Following Gene Duplication
Authors: Adriana D. Briscoe
Journal: Molecular Biology and Evolution (2001)

A comparative approach was taken for identifying amino acid substitutions that may be under positive Darwinian selection and are correlated with spectral shifts among orthologous and paralogous lepidopteran long wavelength-sensitive (LW) opsins. Four novel LW opsin fragments were isolated, cloned, and sequenced from eye-specific cDNAs from two butterflies, Vanessa cardui (Nymphalidae) and Precis coenia (Nymphalidae), and two moths, Spodoptera exigua (Noctuidae) and Galleria mellonella (Pyralidae). These opsins were sampled because they encode visual pigments having a naturally occurring range of lambda(max) values (510-530 nm), which in combination with previously characterized lepidopteran opsins, provide a complete range of known spectral sensitivities (510-575 nm) among lepidopteran LW opsins. Two recent opsin gene duplication events were found within the papilionid but not within the nymphalid butterfly families through neighbor-joining, maximum parsimony, and maximum likelihood phylogenetic analyses of 13 lepidopteran opsin sequences. An elevated rate of evolution was detected in the red-shifted Papilio Rh3 branch following gene duplication, because of an increase in the amino acid substitution rate in the transmembrane domain of the protein, a region that forms the chromophore-binding pocket of the visual pigment. A maximum likelihood approach was used to estimate omega, the ratio of nonsynonymous to synonymous substitutions per site. Branch-specific tests of selection (free-ratio) identified one branch with omega = 2.1044, but the small number of substitutions involved was not significantly different from the expected number of changes under the neutral expectation of omega = 1. Ancestral sequences were reconstructed with a high degree of certainty from these data. Reconstructed ancestral sequences revealed several instances of convergence to the same amino acid between butterfly and vertebrate cone pigments, and between independent branches of the butterfly opsin tree that are correlated with spectral shifts.
Can manifesting heterozygotes have cystic fibrosis?
Authors: M. SUPER
Journal: Thorax (1999)

Scientific advances and the passage of time are causing us to review what constitutes a diagnosis of cystic fibrosis (CF). Over and above those with a typical presentation and laboratory findings, there have always been patients who fall in the grey area—“does she or doesn’t she have CF?” Since the discovery of the CFTR gene in 1989 and the ongoing discovery of mutations associated with CF (the mutation count now stands at over 800), genetic analysis has brought a new sophistication to the area but has not solved all the problems. A consensus conference on diagnostic criteria arranged by the North American Cystic Fibrosis Foundation has published the agreed criteria.1 In addition to those with typical features (sweat chloride levels above 60 mmol/l and the finding of two mutations of CFTR known to be associated with the disease), the consensus statement admits that approximately 2% have an atypical phenotype with chronic sinopulmonary disease, pancreatic sufficiency, and either borderline (40–60 mmol/l) or normal (<40 mmol/l) sweat chloride concentrations. The predominance of single features may still allow a diagnosis of CF if two CF mutations, or abnormal sweat electrolytes, or abnormal ion transport across the nasal epithelium are found.2 3 A truly borderline diagnostic situation may apply when congenital bilateral absence of the vas deferens (CBAVD) or another form …
Presence of a p53 Gene Deletion in Patients With Multiple Myeloma Predicts for Short Survival After Conventional-Dose Chemotherapy
Authors: Johannes Drach, Jutta Ackermann, Elke Fritz, Elisabeth Krömer, Rudolf Schuster, Heinz Gisslinger, Maria DeSantis, Niklas Zojer, Michael Fiegl, Sebastian Roka, Judith Schuster, Renate Heinz, Heinz Ludwig, Heinz Huber
Journal: Blood (1998)
THE GONOCOCCAL COMPLEMENT-FIXATION TEST
Authors: I. N. O. Price
Journal: BMJ (1931)

L_EDICALpost-temporal bone of the whiting (Fig. 2).It is one of a string of bones attaching the pectoiral girdle to the back of the skull.From the shape of the bone one can see that the pain was caused by the bone presenting at the pyloric orifice with the two prongs in front, so that it was impossible for it to pass in this way.Taking some- thing into the stomach evidently had the effect of dis- lodging it for the time being.The bone presented a PTEROTIC \ PIOTIC SUPRA-_CCIFITAL.
Automated immunochemical quantitation of haemoglobin in faeces collected on cards for screening for colorectal cancer
Authors: C G Fraser, C M Mathew, K McKay, F A Carey, R J C Steele
Journal: Gut (2008)

<h3>Background:</h3> Simple card collection systems are becoming available for faecal immunochemical tests (FITs) as well as guaiac faecal occult blood tests (gFOBTs). FITs are now obtainable that allow quantitation of haemoglobin, so that the analytical detection limit can be set to give a positivity rate that is manageable in terms of the available colonoscopy. A combination of a card collection device and an automated FIT analytical system could be advantageous. <h3>Methods:</h3> The quantitation of haemoglobin in samples collected on cards with a new analytical system and the relationship between faecal haemoglobin concentration and pathology were investigated in a cohort of gFOBT-positive individuals. <h3>Results:</h3> All groups had large ranges of haemoglobin concentration and there was overlap between the groups. Median haemoglobin concentrations in participants with normal findings on colonoscopy (167), diverticular disease (43), hyperplastic polyps (41), low risk adenoma (63), higher risk adenoma (35) and cancer (27) were 13.5, 15.6, 16.8, 15.2, 65.6 and 168.9 ng/ml haemoglobin, respectively. Those with diverticular disease, hyperplastic polyps and low risk adenoma were not significantly different from the normal group (p&gt;0.2), but those with higher risk adenoma had significantly higher concentrations (p&lt;0.001), as did those with cancer (p&lt;0.001). Receiver operating characteristic analysis demonstrates that the cut-off concentration can be set to give appropriate clinical characteristics; optimum sensitivity and specificity are achieved at 26.7 ng/ml. <h3>Conclusions:</h3> The haemoglobin in faeces on simple FIT card collection devices can be immunoturbidimetrically analysed quantitatively, and the concentration relates to the presence or absence of significant neoplastic disease.
Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) Model for Breast Cancer Risk Prediction in Women With Atypical Hyperplasia
Authors: Judy C. Boughey, Lynn C. Hartmann, Stephanie S. Anderson, Amy C. Degnim, Robert A. Vierkant, Carol A. Reynolds, Marlene H. Frost, V. Shane Pankratz
Journal: Journal of Clinical Oncology (2010)

Accurate breast cancer risk assessment is vital to personalize screening and risk reduction strategies. Women with atypical hyperplasia have a four-fold higher risk of breast cancer. We evaluated the performance of the Tyrer-Cuzick model, which was designed to predict 10-year risk of breast cancer development, in a well-defined cohort of women with atypia.The Mayo Benign Breast Disease cohort includes 9,376 women who had a benign breast biopsy between 1967 and 1991. Among those, 331 women with atypia were identified by our study pathologists. Risk factor data for the Tyrer-Cuzick model were collated for each woman and used to predict individual risk of developing invasive breast cancer within 10 years.Over a median follow-up of 14.6 years, 64 (19%) of the 331 women developed invasive breast cancer. In the first 10 years after biopsy, 31 women developed invasive breast cancer whereas the Tyrer-Cuzick model predicted 58.9. The observed-to-predicted ratio was 0.53 (95% CI, 0.37 to 0.75). The concordance statistic was 0.540, revealing that the Tyrer-Cuzick model did not accurately distinguish, on an individual level, between women who developed invasive breast cancer and those who did not.The Tyrer-Cuzick model significantly overestimated risk of breast cancer for women with atypia, and individual risk estimates showed poor concordance between predicted risk and invasive breast cancer development. Thus, we cannot recommend the use of the Tyrer-Cuzick model to predict 10-year breast cancer risk in women with atypical hyperplasia.