tbuckley/cabot-search huggingface dataset:
K858, a Novel Inhibitor of Mitotic Kinesin Eg5 and Antitumor Agent, Induces Cell Death in Cancer Cells
Authors: Ryuichiro Nakai, Shin-ichi Iida, Takeshi Takahashi, Tetsuya Tsujita, Seiho Okamoto, Chie Takada, Kazuhito Akasaka, Shunji Ichikawa, Hiroyuki Ishida, Hideaki Kusaka, Shiro Akinaga, Chikara Murakata, Shinobu Honda, Masayuki Nitta, Hideyuki Saya, Yoshinori Yamashita
Journal: Cancer Research (2009)

Abstract The aim of this study was to investigate the mechanism of inhibition of Eg5 (kinesin spindle protein), a mitotic kinesin that plays an essential role in establishing mitotic spindle bipolarity, by the novel small molecule inhibitor K858. K858 was selected in a phenotype-based forward chemical genetics screen as an antimitotic agent, and subsequently characterized as an inhibitor of Eg5. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. In contrast, treatment of nontransformed cells with K858 resulted in mitotic slippage without cell death, and cell cycle arrest in G1 phase in a tetraploid state. In contrast to paclitaxel, K858 did not induce the formation of micronuclei in either cancer or nontransformed cells, suggesting that K858 has minimal effects on abnormalities in the number and structure of chromosomes. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues. Importantly, K858, unlike antimicrotubule agents, had no effect on microtubule polymerization in cell-free and cell-based assays, and was not neurotoxic in a motor coordination test in mice. Taken together, the Eg5 inhibitor K858 represents an important compound for further investigation as a novel anticancer therapeutic. [Cancer Res 2009;69(9):3901–9]
Telemetry and Coronary Heart Disease
Authors: Daniel J. Bleifer
Journal: JAMA (1975)

<h3>To the Editor.—</h3> The editorial entitled "Telemetry—Best Detective in Tracing CHD" (229:1475, 1974) refers to the application of Holter monitoring in the detection of coronary heart disease. It would appear that the use of the term "telemetry" is confusing, in that the Holter system consists of a continuous electrocardiogram recorded on a small portable tape recorder through a direct heart wire attachment to the chest leads. There is no radio transmission of the signal to a radio receiver, such as occurs with usual telemetry equipment. This is a great advantage to the Holter system since the distance limitations of telemetry equipment and the vagaries of telemetry reception are avoided. We are certainly in full agreement with the medical content of the editorial.
Unrecognized Pulmonary Venous Desaturation Early After Norwood Palliation Confounds Q̇p:Q̇s Assessment and Compromises Oxygen Delivery
Authors: Roozbeh Taeed, Steven M. Schwartz, Jeffrey M. Pearl, Jenni L. Raake, Robert H. Beekman, Peter B. Manning, David P. Nelson
Journal: Circulation (2001)

Background —Hemodynamic stability after Norwood palliation often requires manipulation of pulmonary vascular resistance to alter the pulmonary-to-systemic blood flow ratio (Q̇p:Q̇s). Q̇p:Q̇s is often estimated from arterial saturation (Sa o 2 ), a practice based on 2 untested assumptions: constant systemic arteriovenous O 2 difference and normal pulmonary venous saturation. Methods and Results —In 12 patients early (≤3 days) after Norwood palliation, simultaneous arterial, superior vena caval (Ssvc o 2 ), and pulmonary venous (Spv o 2 ) oximetry was used to test whether Sa o 2 accurately predicts Q̇p:Q̇s. Stepwise multiple regression assessed the contributions of Sa o 2 , Ssvc o 2 , and Spv o 2 to Q̇p:Q̇s determination. Sa o 2 correlated weakly with Q̇p:Q̇s ( R 2 =0.08, P &lt;0.05). Inclusion of Ssvc o 2 and Spv o 2 improved Q̇p:Q̇s prediction accuracy. Pulmonary venous desaturation (Spv o 2 &lt;95%) was observed frequently (30%), especially at Fi o 2 ≤0.21, but normalized with higher Fi o 2 or PEEP in all patients. In 6 patients, Fi o 2 was increased incrementally from 0.17 to 0.50 to determine whether this was an effective means to manipulate Q̇p:Q̇s. Q̇p:Q̇s failed to change predictably with increased Fi o 2 . In 5 of 6 patients, however, higher Spv o 2 and Sa o 2 enhanced systemic oxygen delivery, as demonstrated by improvement in oxygen extraction. Conclusions —Sa o 2 correlated poorly with Q̇p:Q̇s because of variability in Ssvc o 2 and Spv o 2 . A novel observation was that pulmonary venous desaturation occurred frequently early after Norwood palliation but normalized with higher Fi o 2 or PEEP. Because unrecognized pulmonary venous desaturation confounds Q̇p:Q̇s assessment and compromises Sa o 2 and oxygen delivery, judicious use of inspired oxygen and PEEP may be beneficial in selected patients early after Norwood palliation.
Transverse Myelitis after Vaccination
Authors: N. C. Shyamalan, S. S. Singh, D. B. Bisht
Journal: BMJ (1964)

form.Juvenile diabetes mellitus with optic atrophy but without diabetes insipidus has been repeatedly reported in the past as a familial recessive syndrome.`'In most of these individuals profound perceptive hearing loss and in some an automatic bladder developed subsequently.Furthermore, the familial association of Friedreich's ataxia with diabetes mellitus of early onset has been recorded far too fre- quently to be fortuitous.Recent descriptions are to be found in the papers of N. S. Schlezinger and K. Goldstein6 and D. W. Ashby and P. S. Tweedy.7In the former, optic atrophy in addition was recorded in each of two affected sisters; in the latter, while optic atrophy was not a feature of their cases, the authors mentioned that Dr. H. A. Dewar had told them of two sisters with juvenile diabetes mellitus, ataxia, and optic atrophy.In general, optic atrophy is a wellknown complication of Friedreich's ataxia.C. H. Allstrom et al.8 reported a recessive syndrome consisting of retinal degeneration (including optic atrophy), obesity, diabetes mellitus of early onset, and perceptive deaf- ness, and this was mentioned in your annota- tion in 1959.'While these authors claimed that this syndrome was quite distinct from that attributed to
Gout and Achievement
Authors: Murray E. Jarvik
Journal: JAMA (1980)

<h3>To the Editor.—</h3> The letter from Norman Sher, MD (243:1711, 1980), might give some small mental comfort to gout sufferers. Unfortunately, the evidence that gout is associated with exceptional achievement is scanty and hardly acceptable at a scientific level. One might equally argue that since uric acid is a risk factor in coronary disease, it is responsible for the great achievement in sufferers from this disease. A large number of prominent people also have been shown to suffer from cancer of the lung, peptic ulcer, constipation, brain tumors, and athlete's foot. When enough anecdotes about a condition exist, one suspects that there might be a scintilla of truth underneath. To confirm the relationship between achievement and gout, one would have to take a large population at random—for instance, large population of a community—and independently determine achievement and the existence of gout or preferably uric acid levels. If there turned out to
Accidental Loss of Plastic Tube into Venous System
Authors: T. E. Udwadia, A. E. Edwards
Journal: BMJ (1963)

in muscle, while leaving the constrictor (alpha) actions unopposed.We would suggest on this limited experience the following pre-operative regime: phenoxybenzamine 1 mg./kg./day orally, plus pronethalol 300-400 mg./day (in three or four doses), for an adult, both drugs for three days before surgery.If, during operation, undue tachycardia or abnormal rhythms occur, intravenous pronethalol might be necessary -say, 25 mg.at first.We are grateful to the clinicians in charge of these cases for leave to refer to them here.
Robert Charles Fuller
Authors: W Brychan Morris
Journal: BMJ (2004)

Former consultant general surgeon London (b Acton, London, 1916; q St Mary's Hospital, London, 1939; FRCS), died from peripheral vascular disease and diabetes mellitus on 9 May 2004.​2004.




Figure 1




After house appointments he joined the Royal Air Force as a medical officer and served in the United Kingdom and later in India and South East Asia. He became involved in the land battles around Imphal which resulted in the defeat of the Japanese attempt to invade India. He took up surgery after war service and trained in Birmingham, Worcester, and London, particularly St Mark's, where he developed an interest in proctology. As well as consultant surgeon to Acton, Wembley, and Hammersmith hospitals, he was also visiting consultant surgeon to Wormwood Scrubs prison. He and his wife, Elaine, retired to the country in 1978.
Effect of sulphasalazine and its active metabolite, 5-amino-salicylic acid, on toxic oxygen metabolite production by neutrophils.
Authors: J G Williams, M B Hallett
Journal: Gut (1989)

The possibility that the mode of action of sulphasalazine and its active metabolite 5-amino-salicylic acid (5ASA) involves modification of toxic oxygen metabolite production by neutrophils has been investigated by measuring the effect of these drugs on luminol-dependent chemiluminescence, superoxide release and oxygen consumption by stimulated neutrophils in vitro. 5ASA, and to a lesser extent sulphasalazine, had profound inhibitory effects on the luminol dependent chemiluminescent response of neutrophils stimulated with formyl-methionyl-leucyl-phenylalanine (1 microM) + cytochalasin B (5 micrograms/ml). A concentration of 50 microM 5ASA or sulphasalazine produced 93.8 (2.3)% and 65.7 (3.7)% inhibition of control responses respectively. The concentration of 5ASA and sulphasalazine producing 50% inhibition of chemiluminescence were 3.6 (1.8) microM and 16.5 (6) microM respectively. Both drugs had little effect on the chemiluminescent response of neutrophils stimulated with phorbol myristate acetate (1 microgram/ml), producing only 11.4 (3.9)% and 34 (7)% inhibition respectively, at a concentration of 50 microM. Superoxide release from fMLP + CB stimulated neutrophils was also inhibited slightly by 5ASA (50 microM) by 35.6% and by sulphasalazine (50 microM) by 7.9%. Similarly, there was little inhibition in the rate of oxygen consumption by fMLP + CB stimulated neutrophils by either 5ASA or sulphasalazine at concentrations which produced near total abolition of luminol dependent chemiluminescence. These results show that sulphasalazine and 5ASA inhibit the reaction of toxic metabolites produced by stimulated neutrophils with luminol, without inhibition of the oxidase system producing these metabolites. The site of action of these drugs on neutrophils in vitro is thus extracellular, by scavenging a released metabolite, probably hypochlorite. This has important implications for their mode of action in vivo in inflammatory bowel disease.
Pyramidal Neurons Derived from Human Pluripotent Stem Cells Integrate Efficiently into Mouse Brain Circuits In Vivo
Authors: Ira Espuny-Camacho, Kimmo A. Michelsen, David Gall, Daniele Linaro, Anja Hasche, Jérôme Bonnefont, Camilia Bali, David Orduz, Angéline Bilheu, Adèle Herpoel, Nelle Lambert, Nicolas Gaspard, Sophie Péron, Serge N. Schiffmann, Michele Giugliano, Afsaneh Gaillard, Pierre Vanderhaeghen
Journal: Neuron (2013)
Nonremoval of Dentures During Anesthesia
Authors: Edward A. Talmage
Journal: JAMA (1974)

To the Editor.—  In answer to Dr. David Vernon Thomas's plea for others to present their experiences in nonremoval of dentures during surgical anesthesia, I can only say Amen.  I have been following the same plan as Dr. Thomas during approximately the last 14 years, and I, too, have seen many benefits from leaving dentures in place. In fact, we have seen a number of patients who could not maintain the patency of their upper airway without their dentures in situ. It would be surely a mistake to remove the dentures from such a patient, and then render him unable to clear his airway by a depressant drug.  Whether or not dentures should be removed during anesthesia and surgery should depend on a careful individual analysis of each situation, and there are very few indications for their removal other than actual oral surgery itself. My experience, like Dr. Thomas's, has
Long-term survival (up to 21 years) after coronary artery bypass surgery: importance of previous surgery for peripheral vascular disease
Authors: D. Blanchard, C. Cron, D. Bruère, A. Maudière, B. Mankikian, L. Turmel-Rodrigues, O. Bar, F. Baud, J.-P. Cron
Journal: Journal of the American College of Cardiology (1998)
Abstract LB-229: Arsenic trioxide, ascorbic acid and disulfiram (AAA) arrests pancreatic cancer development in a transgenic mouse model with p16 knockout and activated Kras
Authors: Richard D. Dinnen, Wanglong Qiu, Gloria H. Su, Robert L. Fine
Journal: Cancer Research (2011)

Abstract Previously, we found that four human pancreatic cancer (PC) cell lines underwent robust cell death associated with dramatic ATP decline and ROS accumulation when treated with clinically achievable concentrations of arsenic trioxide, ascorbic acid and disulfiram (AAA). Early apoptosis was shifted to aponecrosis, and dependent on the voltage-dependent anion channel (VDAC), since shRNA directed against VDAC-1 abrogated the ROS accumulation and blocked cell death. In this study, assessment of AAA was performed in Pdx1-Cre transgenic mice with a conditional p16 knockout (p16flox/flox), and oncogenic KrasG12D. The KrasG12D, p16flox/flox; LSL-KrasG12D; Pdx1-Cre mice develop the full spectrum of pancreatic intraepithelial neoplasia (mPanIN) lesions, pancreatic ductal adenocarcinoma, and hepatic and peritoneal metastases. Over 95% of human PC have p16 deficiency and Kras mutation. Eight week old mice were treated for 8 weeks, 3 times/week with AAA, sacrificed, and the development of PC assessed. Little or no toxicity of the mice to the AAA treatment was observed. Frank PC was zero in AAA-treated mice and 31% in controls. The mean number of PanIN-3 lesions/mouse declined from 14.1 in controls to 1.58 in AAA-treated mice (p=0.008). The mean number of PanIN-2 lesions declined from 5.18 in controls to 1.67 in AAA treated mice (p=0.06). The mean number of PanIN-1 lesions in control mice were 14.2 and in AAA-treated mice were 16.0, p=0.51 indicating no difference in PanIN-1 occurrence. Preliminary results from immunohistochemical staining of the PanIN lesions for VDAC, indicated that PanIN-1 lesions have low, and PanIN-2 and 3 lesions have high, VDAC expression. This result parallels the in vitro human cell line data showing VDAC expression is critical to AAA sensitivity, and suggests a similar mechanism of action in vivo as in vitro. Although collection of data is ongoing, this is the first treatment that has been shown to arrest PanIN and tumor development in any a genetically-engineered mouse model for PC. The data suggests AAA either arrests the development of pre-cancerous lesions after the PanIN-1 stage, or the PanIN-2 and PanIN-3 lesions are destroyed by AAA in a VDAC-dependent manner. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-229. doi:10.1158/1538-7445.AM2011-LB-229
Olive allergen‐specific IgE responses in patients with <i>Olea europaea</i> pollinosis
Authors: J. Quiralte, F. Florido, J. M. Arias de Saavedra, A. Gómez, B. Sáenz de San Pedro, E. González, R. Rodríguez
Journal: Allergy (2002)

Olive tree (Olea europaea) pollen is an important cause of pollinosis in the countries of the Mediterranean area.This work aimed to study the IgE-binding frequency of Ole e 1, Ole e 2, Ole e 3, Ole e 6 and Ole e 7 from O. europaea pollen in a large population of olive pollen-allergic patients.We studied: 119 consecutive patients with seasonal rhinitis and/or asthma and a positive skin prick test to O. europaea pollen extract; 10 atopic patients without history of pollinosis and a negative skin prick test to O. europaea; and 10 healthy controls. Allergens were purified from O. europaea pollen extract by reverse phase HPLC and characterized by N-terminal amino acid sequencing, MALDI analysis, and specific IgE immunodetection. Skin prick tests and ELISA titration against above mentioned purified olive pollen allergens were performed in all pollinic patients and controls.One-hundred and seven (90.7%) patients had a positive skin response to Ole e 1; 88 (74.6%) reacted to Ole e 2; 57 (47.9%) reacted to both Ole e 6 and Ole e 7; and 43 (37.8%) reacted to Ole e 3. The allergenic activity determined by ELISA to Ole e 1 was found in 84%; to Ole e 2 in 61.3%; to Ole e 3 in 31.9%; to Ole e 6 in 39.4%; and to Ole e 7 in 41.2% of patients. All patients had positive skin responses to at least one of the allergens tested, However, a combination of Ole e 1 and Ole e 2 together with a minor allergen Ole e 6 or Ole e 7, disclosed the same diagnostic value that was obtained with the use of crude olive pollen extract. The nonatopic and atopic control subjects did not react to any purified allergens on the skin prick test.These results indicate that Ole e 1 and Ole e 2 are major allergens in patients with O. europaea pollinosis in our population. A combination of a few olive pollen allergens can substitute the crude extract for in vivo as well as in vitro diagnostic purposes.
Antimicrobial Chemotherapeutic Agents: The Nature of Their Action and Selective Toxicity
Authors: David S. Feingold
Journal: New England Journal of Medicine (1963)

ANTIMICROBIAL agents encompass both synthetic compounds and natural products or antibiotics. The vast majority of antimicrobial drugs synthesized or isolated do not possess the requisite selectivity to be useful in the treatment of infectious diseases — that is, they affect the host organisms as well as the parasites. In this review discussion will be limited primarily to agents that have been found to show acceptable selective toxicity toward microorganisms and, hence, clinical usefulness. Attention will be focused on both the mechanism of action of these antimicrobial drugs and the nature of the selective toxicity that they exhibit.Sweeping advances toward . . .
Crystallization of prostaglandin-H synthase for X-ray structure analysis.
Authors: K Jahnke, G H Degen, M Buehner
Journal: Environmental Health Perspectives (1990)

Prostaglandin-H (PGH) synthase from ram seminal vesicles is a dimeric integral membrane protein of molecular weight 140 kDa. PGH synthase is a key enzyme in the biosynthesis of prostaglandins, has cyclooxygenase and peroxidase activities, and contains heme as a coenzyme. In the peroxidation step of its reaction. PGH synthase can use xenobiotics as co-substrates and can catalyze the metabolic activation of carcinogens such as diethylstilbestrol. To gain a detailed understanding of the inner workings of PGH synthase, we are investigating its three-dimensional structure by X-ray crystallography. A purification procedure was established that yields stable homogeneous PGH synthase that is at least 80% holoenzyme. The crucial aspect is the proper choice of type and concentration of detergent in all steps of the procedure. Single crystals can be obtained from concentrated solutions of PGH synthase in the presence of polyethylene glycol 4000 as a precipitant. Crystallization occurs during gas phase equilibration with a concentrated salt solution. The enzyme solution becomes turbid and forms a second liquid phase in which PGH synthase crystals grow up to 0.2 mm in length in the course of days. Manipulation of these crystals is very difficult due to the small volume of the growth phase. The crystals dissolved rapidly in all aqueous media into which they were transferred for mounting in X-ray capillaries. Therefore, we have not yet been able to demonstrate their true X-ray scattering power. A crystal provisionally dry mounted diffracted to about 8 A resolution.
ROCKY MOUNTAIN SPOTTED FEVER
Authors: JACK G. HUTTON
Journal: JAMA (1941)

Rocky Mountain spotted fever is an acute infectious disease caused by the virus-like organism Dermacentroxenus rickettsii, which is transmitted to human beings by an infected tick. The infection is characterized clinically by an acute onset with chills and fever, severe headache, restlessness, delirium and a characteristic hemorrhagic eruption of the skin. The histopathologic picture of the early stage of this cutaneous manifestation is a proliferation of the endothelial lining of the small blood vessels followed by necrosis of the endothelium and of the smooth muscle of the media. Later, typical manifestations of phlebitis, thrombosis and gangrene may be present. <h3>DISTRIBUTION AND CARRIERS</h3> Rocky Mountain spotted fever, recognized for half a century in the Rocky Mountain states, can no longer be considered as limited in distribution to the Rocky Mountain states area because the<i>Public Health Reports</i><sup>1</sup>show a total of 2,190 cases occurring in thirty-seven of the forty-eight states
558 COST-EFFECTIVENESS SIMULATION ANALYSIS OF TENOFOVIR DISOPROXIL FUMARATE (TENOFOVIR), LAMIVUDINE, ADEFOVIR DIPIVOXIL (ADEFOVIR) AND ENTECAVIR OF HBEAG NEGATIVE (-) PATIENTS WITH CHRONIC HEPATITIS-B (CHB) IN SPAIN
Authors: B. Deniz, M. Buti, M. Brosa, M.A. Casado, M. Rueda, F. Everhard, R. Esteban
Journal: Journal of Hepatology (2008)
Cardiovascular disease in the tropics. 3. Blood pressure and hypertension.
Authors: A G Shaper
Journal: BMJ (1972)

In most populations the mean blood pressure level in males and females rises progressively with increasing age.This gradual increase in blood pressure is not a benign process and there is an increasing morbidity and mortality as the pressure rises, even at levels which most clinicians would accept as normal.There is no clear dividing line in these populations between normal and abnormal, and most workers would agree that what we call es- sential hypertension represents the upper end of a frequency distribution curve.Nevertheless, there are communities in whom blood pressure does not rise with age and in whom the problem of essential hypertension and its complications appears to be virtually non-existent.I must emphasize that in the vast majority of tropical communities blood pressure patterns are similar to those seen in the economically advanced countries of the world.I am speaking of the exceptional minorities. Low-pressure CommunitiesThe list of these low-pressure communities is a long one, and includes New Guinea highlanders, Kalahari bushmen, Congo pygmies, Pacific islanders, South American Indians, Australian aborigines, and nomadic tribesmen in East Africa.What emerges from the many studies in these relatively small and isolated com- munities is that blood pressure need not necessarily rise with age.Are all these findings the artefacts of sampling or do they reflect the presence of factors such as chronic infection, para-