tbuckley/cabot-search huggingface dataset:
Abstract 3169: APOBEC-mediated cytosine deamination is a prominent mutagenic mechanism in human papillomavirus-driven cancer
Authors: Stephen Henderson, Ankur Chakravarthy, Xiaoping Su, Chris Boshoff, Tim R. Fenton
Journal: Cancer Research (2014)

Abstract APOBEC3B cytosine deaminase activity has recently emerged as a significant mutagenic factor in human cancer. APOBEC activity is induced in virally infected cells and APOBEC signature mutations occur at high frequency in cervical cancers, over 99% of which are caused by high risk variants of Human Papillomavirus (HPV). We tested the hypothesis that APOBEC-mediated mutagenesis plays a particularly important role in HPV-associated cancer by analysing head and neck squamous cell carcinoma (HNSCC), a tumor type for which exome sequence data from The Cancer Genome Atlas project are available from both HPV+ and HPV- variants. We show that HPV+ tumors express more APOBEC3B and harbor a higher proportion of APOBEC signature mutations than HPV- tumors. The APOBEC mutational signature is absent from hepatitis virus-associated hepatocellular carcinoma, indicating it is not simply a consequence of the immune response to persistent viral infection. We also uncover a strong linear relationship between APOBEC signature mutations and APOBEC-independent mutations in both HNSCC and in breast cancer, such that in high APOBEC subsets (HPV+ HNSCC and HER2-amplified breast cancer), the proportion of mutations due to APOBEC activity is consistently increased, regardless of the overall mutational burden in the tumor. Finally, HPV+ HNSCC and cervical cancer show particularly strong enrichment for APOBEC signature mutations in known cancer genes, implicating APOBEC activity as a key driver of HPV-induced transformation. Citation Format: Stephen Henderson, Ankur Chakravarthy, Xiaoping Su, Chris Boshoff, Tim R. Fenton. APOBEC-mediated cytosine deamination is a prominent mutagenic mechanism in human papillomavirus-driven cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3169. doi:10.1158/1538-7445.AM2014-3169
PTU-163 Proximal Oesophageal Functional Mucosal Integrity during Distal Oesophageal Acidification in Patients with Nerd and FH
Authors: P Woodland, M Al-Zinaty, E Yazaki, J Jafari, D Sifrim
Journal: Gut (2013)

<h3>Introduction</h3> Although macroscopically normal, the oesophageal mucosa in patients with non-erosive reflux disease (NERD) displays epithelial dilated intercellular spaces (DIS). Such loss of barrier integrity is thought to be important in disease pathogenesis. Patients with NERD have DIS in both the distal and proximal oesophagus. Patients with functional heartburn (FH) do not have DIS. In healthy volunteers acid perfusion of the distal ooesophagus induces DIS not only in the exposed distal, but also the unexposed proximal oesophagus. It is unknown what impact distal acid perfusion has in the proximal oesophageal mucosa in symptomatic patients. Oesophageal impedance measurements can be an “in vivo” surrogate marker of functional mucosal integrity. We <b>aimed</b> to assess with impedance the proximal oesophageal mucosal integrity during distal acid perfusion in symptomatic patients with NERD (+ve DIS) and FH (-ve DIS). <h3>Methods</h3> We studied 22 patients (mean age 48, range 20–75) with typical reflux symptoms and negative endoscopy. 24-hour MII-pH monitoring identified 11 patients with NERD and 11 with FH. A pH-impedance catheter was inserted transnasally such that the proximal impedance segment was 15cm above the LOS. A 10 minute perfusion (10ml/min) of a neutral (pH7), then acidic (pH1) solution was performed in the distal oesophagus (10 cm from LOS) whilst simultaneously measuring proximal impedance. The absence of proximal fluid contamination was suggested by a lack of impedance drop during the neutral perfusion. Baseline impedance, and percentage change from baseline during the perfusion was calculated. <h3>Results</h3> Distal perfusion of neutral solution caused no fall in proximal impedance (mean impedance 107 ± 2.8% of baseline). Distal perfusion of acidic solution caused a significant reduction in proximal impedance (mean impedance 80.3 ± 5.3% of baseline, p &lt; 0.01). The drop of proximal impedance started at a mean of 175 seconds after commencement of acid perfusion. Proximal impedance did increase to a mean of 90% of baseline until 30 minutes after cessation of the acid perfusion. There was no significant difference in baseline proximal impedance (3165 ± 216Ω vs. 3116 ± 232Ω) or acid-induced change in proximal impedance (79.4 ± 8.1% vs. 81.2 ± 7.1% of baseline) between FH and NERD patients respectively. <h3>Conclusion</h3> In keeping with morphological studies of healthy volunteers, distal oesophageal acidification modifies mucosal functional integrity of the proximal, unexposed oesophagus. This appears to occur regardless of the presence of pre-existing proximal DIS, suggesting that mechanisms of functional mucosal integrity as measured by impedance are beyond DIS formation. <h3>Disclosure of Interest</h3> None Declared.
Twenty one years of legal abortion.
Authors: D. Munday, C. Francome, W. Savage
Journal: BMJ (1989)

The effects of the 1967 Abortion Act, legislation which extends to women living in England, Wales, and Scotland, are reviewed. The Act was not backed by any specific allocation of money for facilities or staff within the National Health Service and the service provided has varied from district to district. Yet, the number of abortions increased rapidly in the late 1960s and early 1970s. This process had slowed down by 1974, when the number of abortions dropped for the 1st time. The introduction of free contraception seems to have had an important effect; the number of abortions declined by nearly 9000 from 1973-76, and the abortion rate fell from 11.4 to 10.5/1000 women aged 15-44. The number increased in 1977 and 1978, possibly because of adverse publicity about the side effects of oral contraception (OC). The rate of abortion in Scotland, although lower than the rate in England and Wales, has risen steadily since 1969. An important effect of the 1967 Act has been to reduce the number of deaths due to illegal abortions. In the 1st decade of legal abortion, the proportion of all maternal deaths that were due to abortion dropped from 25% to 7%. The number of recorded deaths due to abortion declined from 160 during 1961-63 to 9 during 1982-84. There were 7 deaths after legal abortions during 1982-84 and 4 during 1985-87. 21 years after the passage of the Act half of all women having legal abortions pay for them. The regional differences in the provision of abortion services have persisted since 1968. The proportion of abortions performed in the 1st trimester increased from 66% in 1969 to 86% in 1987, yet the proportions of early abortions in Britain still compare poorly with other countries. In the US, women have been able to request abortion in the 1st trimester since 1974; by 1977 this led to 91% of abortions being performed in this period. Regional differences in the surgical methods persist, and there may be considerable delays between a woman asking for an abortion and the procedure being performed. A Marplan poll conducted in 1988 reported that 80% of those surveyed thought that women should have the right to choose an abortion in the 1st few months of pregnancy; 15% disagreed, and 5% did not know or did not respond. The number of women coming to Britain for abortions peaked in 1973, when 56,000 came. The rate of abortion per 1000 women in England and Wales is 14.8, a moderate figure when compared to other nations -- rates range from 5.6 in the Netherlands to 181 in the USSR.
Cause of Cuban Outbreak Neuropathologic Puzzle
Authors: Paul Cotton
Journal: JAMA (1993)

VITAMINS being distributed to all 11 million Cubans may explain the waning of an outbreak of peripheral and optic neuropathy reported to affect nearly 47 000 people. See also p 511. Scientists are withholding final judgment on the etiology until more results are in. However, data so far seem to be ruling out a possible viral cause. After 5 weeks of laboratory investigation, virologists at the National Institutes of Health (NIH), Bethesda, Md, were not ready to give up, but still had not been able to grow any virus with samples brought back from Cuba. And cases were clearly not spread by contact, with no outbreaks in institutions like schools or army barracks. Instead, evidence is suggesting that a lack of animal protein, and therefore B-group vitamins, in the diet has set the stage for serious damage from high but otherwise tolerable levels of cyanide in tobacco and foods like
GPs threaten to leave NHS as stress levels rocket
Authors: Z. Kmietowicz
Journal: BMJ (2001)

Family doctors in the United Kingdom are considering leaving the NHS because of intolerable working conditions.

The BMA's General Practitioners Committee voted last week to ballot all its 36 000 members on whether they would resign if a new contract cannot be agreed with the government in the next 12 months. The results are due at the beginning of June, just days before the date expected for the general election, 7 June.

The mass walk out is a protest against excessive workload and bureaucracy imposed by …
Jejunal immunoglobulin and antigliadin antibody secretion in adult coeliac disease.
Authors: J F Colombel, F Mascart-Lemone, J Nemeth, J P Vaerman, C Dive, J C Rambaud
Journal: Gut (1990)

We compared the local intestinal immunoglobulin (Ig) secretion in six adult patients with coeliac disease and nine control subjects by perfusion of a small bowel segment under an occluding balloon and analysis of the perfusion fluid for the content of Ig and secretory component. The results were compared to the number of Ig-containing plasma cells in the test segment. There was, respectively, a two-fold and a fivefold increase in jejunal secretion rates of IgA (both monomeric and polymeric) and IgM in patients with coeliac disease compared with control subjects. The high IgA and IgM secretion rates parallel the increase of Ig-containing plasma cells in the lamina propria. In contrast, the IgG plasma cell density increase was barely significant in patients with coeliac disease and did not result in a high IgG secretion rate. The jejunal secretion rate of secretory component was significantly increased in patients with coeliac disease and no free dimeric IgA was present in the jejunal fluid. Antigliadin-IgA was detected in the serum and jejunal fluid of the six patients with coeliac disease. Antigliadin-IgA, however, was almost entirely polymeric IgA linked to secretory component in jejunal fluid, whereas 61% was dimeric IgA not linked to secretory component in serum. This result, combined with a raised secretory component secretion rate with no evidence of secretory component saturation, suggests that serum and intestinal antigliadin IgA might be of different origins in coeliac disease.
Recipient HLA-DR3, tumour necrosis factor-α promoter allele-2 (tumour necrosis factor-2) and cytomegalovirus infection are inter-related risk factors for chronic rejection of liver grafts
Authors: Paul C Evans, Sheila Smith, Gideon Hirschfield, Eirini Rigopoulou, Timothy G Wreghitt, Derek G.D Wight, Craig J Taylor, Graeme J.M Alexander
Journal: Journal of Hepatology (2001)
Mechanism of ischemic mitral regurgitation with ventricular remodeling after-myocardial infarction: demonstration of leaflet tethering by three-dimensional echocardiography
Authors: Y. Otsuji, M.D. Handschumacher, N. Liel-Cohen, H. Tanabe, J.L. Guerrero, L.A. Nicholls, G.J. Vlahakes, R.A. Levine
Journal: Journal of the American College of Cardiology (1998)
Comparison of estimates of cardiac output by indicator dilution and freon 22 uptake during gas mixing in dogs
Authors: H. A Jones, S Lakshminarayan, J M Becket, J M B Hughes
Journal: Cardiovascular Research (1991)

Study objective — The aim was to measure cardiac output while rebreathing tidal volumes, by correction of soluble gas uptake for gaseous mixing. Design — Simultaneous measurements of cardiac output by indocyanin green and freon 22 uptake during rebreathing were made. Mixing for a hypothetical gas of identical gaseous diffusivity to freon 22 was calculated by interpolation between concentrations of two insoluble gases, helium and sulphur hexafluoride. Mixing efficiency was estimated by the number of breaths for helium to become 99% equilibrated with lung gas (n99-He). Experimental material — Five anaesthetised dogs rebreathed at intervals with 300 ml of test gas. Measurements and main results — 63 comparisons of cardiac output using indocyanin green and freon 22 uptake (over breaths 7-13 using the mean mixed volume of distribution), gave a mean (95% confidence interval) underestimation of 0.345 (0.093-0.597) litre·min−1 (14%). Exclusion of 12 points in which n99-He was greater than 15 resulted in a mean underestimation of 0.052(−0.163·0.267) litre·min−1(2%). Without correction for gaseous mixing, freon 22 uptake for these data overestimated blood flow by a mean of 1.31 litre·min−1 (overestimation = 2.7 over breaths 5-11). Use of the equilibrium volume of distribution resulted in an overestimation of blood flow relative to green dye of 1.2 litre·min−1 (breaths 5-11) and 0.76 litre·min−1 (breaths 7-13). Conclusions — Estimates of cardiac output by soluble gas uptake are optimal when correction is made for mixing of gas of identical diffusivity. The mean mixed gas volume gives the best correlation with the reference method, implying a selective distribution of blood flow to the better ventilated areas.
A Mechanical 'Hypothalamus' for Ovulation Induction Therapy
Authors: Victoria M. Sopelak
Journal: JAMA (1984)

In the normal menstrual cycle, the functional integrity of the hypothalamic-pituitary-ovarian axis requires the pulsatile secretion of gonadotropin-releasing hormone (GnRH) from the hypothalamus. This hypothalamic hormone, also known as luteinizing hormone-releasing hormone, stimulates pituitary gonadotropin (luteinizing hormone and follicle-stimulating hormone) secretion, promoting ovarian follicular maturation, ovulation, and corpus luteum function.<sup>1,2</sup>When the hypothalamus fails to provide an appropriate GnRH stimulation of the pituitary gland, anovulatory infertility often occurs. Recent advances in neuroendocrine physiology demonstrate that pulsatile GnRH replacement therapy can restore ovulation and fertility. Infertility specialists are learning how to provide pulsatile GnRH therapy for the treatment of hypothalamic hypogonadism in both men and women.<sup>3-5</sup>Recent evidence also suggests that higher-dose pulsatile GnRH treatment may be used to achieve multiple follicular growth for in vitro fertilization therapy, when the collection of several mature oocytes is desired.<sup>6</sup>
Interaction between chemokines and oxidative stress: possible pathogenic role in acute coronary syndromes
Authors: Pål Aukrust, Rolf K. Berge, Thor Ueland, Ellinor Aaser, Jan Kristian Damås, Lisbeth Wikeby, Anne Brunsvig, Fredrik Müller, Kolbjørn Forfang, Stig S. Frøland, Lars Gullestad
Journal: Journal of the American College of Cardiology (2001)
Renal and Electrolyte Disorders
Authors: Leonard B. Berman
Journal: JAMA (1981)

This compact book faithfully reflects its editor's keen interest in the union of physiology and clinical medicine. The text is equally divided between fluid and electrolyte matters and renal diseases. The first half begins with an excellent description of water balance and disturbances of serum sodium. Particular and informative attention is paid to mixed acid-base disturbances and to the interpretation of high and low anion gaps. A tightly written chapter on magnesium is a welcome contribution. A few minor criticisms can be made. Some of the branching designs in the figures are a bit wearying to the eye, and the occurrence of blurred type in those figures is distracting. The second half of the book contains excellent chapters on proteinuria and glomerular diseases by Glassock and others. Dr Glassock revives a long-forgotten suggestion that glomerular disease must be described on four levels, ie, etiology, pathogenesis, morphology, and clinical syndromes. This,
Raised sympathetic activity and blood ammonia could increase sensitivity to infections in patients with cirrhosis and refractory ascites who are using beta-blockers
Authors: Georgios N. Kalambokis, Epameinondas V. Tsianos
Journal: Hepatology (2011)

We read with interest the study by Sersté et al. who found a negative impact of beta-blockers on survival in patients with cirrhosis and refractory ascites.1 Interestingly, 79.5% of patients with a specified cause of death died of sepsis, suggesting an association between chronic use of beta-blockers and development of bacterial infections, yet the authors did not provide an explanation. We suggest that raised blood norepinephrine (NE) and ammonia levels could contribute to increased vulnerability to bacterial infections in patients with refractory ascites who are taking beta-blockers. Circulating NE levels can be increased in cirrhosis due to reduced effective blood volume, impaired liver metabolism, portosystemic shunts, and propranolol treatment.2, 3 Patients with refractory ascites are commonly characterized by markedly increased plasma NE levels.2 High NE levels have been shown to suppress neutrophil chemotaxis4 and phagocytosis5 as well as to inhibit macrophage proliferation and promote their apoptosis.6 In the study of Sersté et al., beta-blocker–treated patients had worse liver function and systemic hemodynamics, which together with the presence of collaterals and propranolol treatment could result in higher NE concentration compared to the nontreatment group. Blood ammonia can also impair neutrophil phagocytosing function in cirrhosis7 and increases significantly with the grade of liver disease severity and esophageal varices,8 and after propranolol administration.9 Consequently, blood ammonia levels could be higher in the group treated with beta-blockers, which matches with the higher incidence of encephalopathy in these patients. We conclude that data regarding blood NE and ammonia concentration would be useful for the interpretation of the observations of Sersté et al. Georgios N. Kalambokis M.D.*, Epameinondas V. Tsianos M.D., Ph.D.*, * First Division of Internal Medicine and Hepato-Gastroenterology Unit, Medical School of Ioannina, Ioannina, Greece.
Economic growth alone will not alleviate poor nutrition in developing countries, concludes study
Authors: S. Bagcchi
Journal: BMJ (2014)

Allergic and atopic disorders have increased over the past few decades and have been associated with neuropsychiatric conditions, such as autism spectrum disorder and asthmatic amyotrophy. Myelitis presenting with neuropathic pain can occur in patients with atopic disorder; however, the relationship between allergic inflammation and neuropathic pain, and the underlying mechanism, remains to be established. We studied whether allergic inflammation affects the spinal nociceptive system. We found that mice with asthma, atopic dermatitis, or atopic diathesis had widespread and significantly more activated microglia and astroglia in the spinal cord than those without atopy, and displayed tactile allodynia. Microarray analysis of isolated microglia revealed a dysregulated phenotype showing upregulation of M1 macrophage markers and downregulation of M2 markers in atopic mice. Among the cell surface protein genes, endothelin receptor type B (<i>EDNRB</i>) was most upregulated. Immunohistochemical analysis revealed that EDNRB expression was enhanced in microglia and astroglia, whereas endothelin-1, an EDNRB ligand, was increased in serum, lungs, and epidermis of atopic mice. No EDNRA expression was found in the spinal cord. Expression of FBJ murine osteosarcoma viral oncogene homolog B was significantly higher in the dorsal horn neurons of asthma mice than nonatopic mice. The EDNRB antagonist BQ788 abolished glial and neural activation and allodynia. We found increased serum endothelin-1 in atopic patients with myelitis and neuropathic pain, and activation of spinal microglia and astroglia with EDNRB upregulation in an autopsied case. These results suggest that allergic inflammation induces diffuse glial activation, influencing the nociceptive system via the EDNRB pathway. <b>SIGNIFICANCE STATEMENT</b> The prevalence of allergic disorders has markedly increased over the past few decades. Allergic disorders are associated with neuropsychiatric conditions; however, the relationship between allergic inflammation and CNS complications is unknown. A peculiar myelitis presenting with persistent neuropathic pain has been reported in patients with allergic disorders. We studied how atopy exerts substantial influence on the nociceptive system. We found that mice with allergic disorders had severe allodynia with activated astroglia and microglia, and showed marked upregulation of endothelin-1 (ET-1) receptor type B (EDNRB) in the spinal cord. A selective EDNRB antagonist prevented allodynia and glial activation. Our findings suggest a novel mechanism whereby atopy induces glial activation and neuropathic pain via an ET-1/EDNRB pathway.
Exhaled Nitric Oxide (FeNO) and T-Helper 2 Cell Biomarkers: Can They Predict Treatment Response To Dupilumab, An IL-4Rα Antibody, In An Eosinophilic Asthma Population?
Authors: Brian N. Swanson, Lin Wang, Jeffrey Ming, Jennifer D. Hamilton, Ariel Teper, Thomas Dicioccio, Yongtao Li, Neil Graham, Gianluca Pirozzi, Sally E. Wenzel
Journal: Journal of Allergy and Clinical Immunology (2014)
Pandemic flu: will there be a second wave?
Authors: F. Godlee
Journal: BMJ (2009)

Rates of swine flu are levelling off in the northern hemisphere as summer progresses. The question now is whether we’ll have a second wave this winter, and if so how bad it will be. Two evolutionary virologists writing in JAMA are cautiously reassuring ( JAMA 2009;302:679-80). Looking back over the 14 or so pandemics since 1510, they say that pandemic flu has never been able to infect the entire population at once, and although it tends to recur after a first wave, it eventually adopts the familiar seasonal flu pattern.

As for A/H1N1, they say its modest transmission efficiency and its arrival in the northern hemisphere’s early summer, as well as the degree of pre-existing population immunity from previous flu viruses and vaccines, …
Principles of bone remodeling; an account of post-natal growth and remodeling processes in long bones and the mandible.
Authors: James A. Yaeger
Journal: JAMA (1963)

In the review of literature which introduces this monograph, there is a quite thorough discussion of the gross and microscopic descriptions of bone growth and remodeling published during the 19th century. However, the bibliography becomes increasingly selective as recent decades are approached. The more recently described and clinically important relationships between bone remodeling and the chemical equilibrium between blood and bone are not discussed. The body of the monograph describes several types of mammalian cortical bone which are discernible with low power light microscopy. The development of these bone types is discussed, using long bones as examples. Although Enlow's descriptions are more profusely illustrated, I found these "principles of remodeling" as well explained in Lacroix's<i>The Organization of Bones</i>. Using these bone type-development relationships, the author presents a detailed description of the growth and remodeling of the Rhesus monkey mandible. This description demonstrates the value of the method in explaining