tbuckley/cabot-search huggingface dataset:
Physicians for Social Responsibility
Authors: J. Marrow
Journal: BMJ (1980)

doses of chlorpromazine intravenously had an initial reduction in high pressure that was followed by a severe pressure drop and a fatal outcome.We feel like Dr Young and colleagues that the hypotensive effect of phenothiazines, to which group chlorpromazine belongs, is not well known among physicians, and we once again would caution against too high initial doses of these drugs when used in emergency treatment of severe hypertension.
Antitumor Activity of Gemcitabine and Oxaliplatin Is Augmented by Thymoquinone in Pancreatic Cancer
Authors: Sanjeev Banerjee, Ahmed O. Kaseb, Zhiwei Wang, Deujan Kong, Mussop Mohammad, Subhash Padhye, Fazlul H. Sarkar, Ramzi M. Mohammad
Journal: Cancer Research (2009)

Abstract Previous studies have shown biological activity of thymoquinone, an active compound extracted from Nigella sativa, in pancreatic cancer cells; however, preclinical animal studies are lacking. Here, we report, for the first time, the chemosensitizing effect of thymoquinone to conventional chemotherapeutic agents both in vitro and in vivo using an orthotopic model of pancreatic cancer. In vitro studies revealed that preexposure of cells with thymoquinone (25 μmol/L) for 48 h followed by gemcitabine or oxaliplatin resulted in 60% to 80% growth inhibition compared with 15% to 25% when gemcitabine or oxaliplatin was used alone. Moreover, we found that thymoquinone could potentiate the killing of pancreatic cancer cells induced by chemotherapeutic agents by down-regulation of nuclear factor-κB (NF-κB), Bcl-2 family, and NF-κB-dependent antiapoptotic genes (X-linked inhibitors of apoptosis, survivin, and cyclooxygenase-2). As shown previously by our laboratory, NF-κB gets activated on exposure of pancreatic cancer cells to conventional chemotherapeutic agents; interestingly, thymoquinone was able to down-regulate NF-κB in vitro, resulting in chemosensitization. In addition to in vitro results, here we show for the first time, that thymoquinone in combination with gemcitabine and/or oxaliplatin is much more effective as an antitumor agent compared with either agent alone. Most importantly, our data also showed that a specific target, such as NF-κB, was inactivated in animal tumors pretreated with thymoquinone followed by gemcitabine and/or oxaliplatin. These results provide strong in vivo molecular evidence in support of our hypothesis that thymoquinone could abrogate gemcitabine- or oxaliplatin-induced activation of NF-κB, resulting in the chemosensitization of pancreatic tumors to conventional therapeutics. [Cancer Res 2009;69(13):5575–83]
The Pathophysiology of Bartter Syndrome
Authors: Neil A. Kurtzman
Journal: JAMA (1975)

BARTTER and associates,<sup>1</sup>in 1962, described two patients who had hyperplasia and hypertrophy of the juxtaglomerular apparatus, hyperaldosteronism, hypokalemic metabolic alkalosis, and normal blood pressure. Since that time, many cases have been reported with these findings, and the entity has come to be called Bartter syndrome. The observation that these patients showed marked resistance to the pressor effects of infused exogenous angiotensin caused Bartter and his colleagues to hypothesize that the syndrome was the result of a primary inability of the vasculature of arterial circulation to respond to the pressor effects of angiotensin. This, they reasoned, resulted in a slack circulation sensed by the kidney as a contraction of the effective arterial volume; the kidney in turn increased the production of renin, with consequent increase in circulating levels of angiotensin II. But the latter had no effect on the state of arterial contraction, since the arterial vessels were unable
Flash-lag: Prediction or emergent property of directional selectivity mechanisms?
Authors: Julia Berzhanskaya
Journal: Behavioral and Brain Sciences (2008)

Abstract 3D FORMOTION, a unified cortical model of motion integration and segmentation, explains how brain mechanisms of form and motion processing interact to generate coherent percepts of object motion from spatially distributed and ambiguous visual information. The same cortical circuits reproduce motion-induced distortion of position maps, including both flash-lag and flash-drag effects.
Reproducibility of a Semiquantitative Measurement of Circulating DNA in Plasma From Neoplastic Patients
Authors: Milo Frattini, Debora Balestra, Paolo Verderio, Gianfrancesco Gallino, Ermanno Leo, Gabriella Sozzi, Marco A. Pierotti, Maria Grazia Daidone
Journal: Journal of Clinical Oncology (2005)
409 PROSPECTIVE RISK ASSESSMENT FOR HEPATOCELLULAR CARCINOMA DEVELOPMENT IN CHRONIC HEPATITIS C PATIENTS BY TRANSIENT ELASTOGRAPHY
Authors: R. Masuzaki, R. Tateishi, H. Yoshida, E. Goto, T. Sato, T. Ohki, J. Imamura, T. Goto, H. Ikeda, S. Shiina, T. Kawabe, M. Omata
Journal: Journal of Hepatology (2009)
Abstract 3500: Nucleolytic processing of Topoisomerase 2 covalent complexes
Authors: John L. Nitiss, Karim Bahmed, Margarita Mishina, Jeffrey Berk, Karin C. Nitiss
Journal: Cancer Research (2010)

Abstract The generation of elevated levels of enzyme: DNA covalent complexes is the key event in cell killing by many drugs targeting DNA topoisomerases. These agents, termed topoisomerase poisons generate protein linked DNA strand that block transcription and replication, leading to cell death. A critical step in the repair of topoisomerase mediated DNA damage is the removal of protein that is covalently attached to DNA. Several specialized repair enzymes, including Tdp1 (tyrosyl DNA phosphodiesterase I) and TTRAP (TRAF and TNF receptor-associated protein) can hydrolyze phosphotyrosyl: DNA linkages. We previously reported that yeast Tdp1 could hydrolyze 5′ as well as 3′ phosphotyrosyl linkages. Human Tdp1 can also hydrolyze 5′ phosphotyrosyl linkages, although the efficiency of the reaction with the human enzyme is much less than that seen with the yeast enzyme. Interestingly, the human enzyme processes adducts bearing a seven amino acid peptide linked to an oligonucleotide with greater efficiency than a 5′ biotin linked oligonucleotide, suggesting that the nature of the adduct at DNA ends influences Tdp1 reaction kinetics. We also used substrates derived from Top2 trapped covalent complexes to assess the ability of other DNA repair enzymes to remove peptides covalently bound to DNA. We found that the heterodimeric nuclease Slx1/Slx4 is able to remove Top2 peptides that are covalently bound to DNA. This result is consistent with our genetic data from yeast that a mutation in the subunit that includes the nuclease (Slx1) is hypersensitive to Top2 poisons, but not sensitive to other DNA damaging agents. Our results indicate that there are multiple pathways for repairing Top2 covalent complexes and suggest that the Slx1/Slx4 dependent pathway may be particularly relevant to repairing topoisomerase mediated damage at replication forks. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3500.
Muzzling scientific debate will lead to false convictions, warns expert witness
Authors: C. Dyer
Journal: BMJ (2011)

Expert witnesses who challenge mainstream opinion face possible investigation for professional misconduct, with “profound professional and personal consequences,” a leading expert on shaken baby cases says.

Waney Squier, a consultant neuropathologist at John Radcliffe Hospital, Oxford, reveals in the January issue of Clinical Risk (2011;17:3-5, doi:10.1258/cr.2010.100002) that police filed a complaint with the General Medical Council about her and a fellow expert witness, Marta Cohen, after a High Court judge accused them of having “developed a scientific prejudice.”

Dr Squier writes, “According to a public lecture, given by a representative of the police, the impetus for this complaint was …
The Influence of Acute Stress on the Response of Rabbits to Intravenous Endotoxin
Authors: JAMES M. ANDERSON, JOEL G. BRUNSON
Journal: Circulation Research (1959)

Immature rabbits were subjected to an acute stress period in a modified Noble-Collip drum, alone and in conjunction with an intravenous injection of E. coli endotoxin. The lethal effects and incidence and severity of the morphologic changes were appreciably greater in the animals given endotoxin in association with stress than in those subjected to rotation alone. The similarity of these lesions to those produced by two properly spaced injections of endotoxin is discussed. The results of the study support the hypothesis that adrenal gland hormones participate in the effects produced by endotoxin.
Analysis Of Drug Hypersensitivity Reactions In A Large Serie Of Children
Authors: Maria Angeles Zambonino, Candelaria Muñoz, Jose Luis Corzo, Gloria Requena, Adriana Ariza, Cristobalina Mayorga, Antonio Urda, Miguel Blanca, Maria J. Torres
Journal: Journal of Allergy and Clinical Immunology (2014)

RATIONALE: Drug allergy is a major problem encountered among general practitioners and allergists.Patients are frequently overdiagnosed as drug allergy without proper confirmatory tests.The aim of this study was to assess the prevalence, clinical presentation and outcomes of children that underwent evaluation for drug allergy.METHODS: Medical records of children suspected drug allergy who underwent evaluation for drug allergy from 2007 to 2013 were reviewed.Children were confirmed allergic by positive skin test and/or drug provocation test (DPT).RESULTS: Sixty children were evaluated for drug allergy.The most common suspected drug was antibiotics (72.3%), followed by acetaminophen (7.7%) and NSAIDs (3%).In the group of antibiotics, B-lactam antibiotic was the most common.The onset of symptom was highly variable (median 4.5 hours; 0.08-168) in which non-immediate onset was the majority.Skin and mucocutaneous reactions were the most common presentation (85.9%) particularly urticaria (50.7%) and maculopapular rash (28.2%).Only 26.6 percent of children were confirmed allergic to offending drugs (20% by skin test and 6.6% by DPT).Twenty three percent of them had positive DPT despite negative skin test.DPT reactions did not correlated with presenting symptoms of drug allergy.There were no differences in age, onset nor primary symptom of drug allergy between confirmed allergy and non-allergic group.History of atopy, autoimmune disease and malignancy were not associated with DPT outcomes.Conclusions : Drug allergy is commonly reported but only a minority of children have true allergy.There were no precise clinical predictors for drug allergy.Thus, DPT remains the gold standard for diagnosis.
John Rock, developer of contraceptive pill, dies
Authors: Terra Ziporyn
Journal: JAMA (1985)

John Rock, MD, the first scientist to perform in vitro fertilization of a human ovum in a test tube and one of the developers of the oral contraceptive, has died of a heart attack at the age of 94 years. He was a devout Roman Catholic, married in 1925 to Anna Thorndike by William Cardinal O'Connell of Boston. Rock subsequently became the father of four daughters and a son, and grandfather of 19. In the early 1920s, Rock began practicing obstetrics and gynecology in Boston and in 1924 he started the Fertility and Endocrine Clinic—one of the nation's first—at the Free Hospital for Women in Brookline, Mass. In 1944, he and Mirian F. Menkin, MD, conducted the first fertilization of a human ovum outside the body. Rock was best known for his work with Gregory Pincus, MD, and M. C. Chang, MD, in producing and clinically testing the oral contraceptive,
PROCEEDINGS OF THE FORTY-FIRST ANNUAL MEETING OF THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION HELD IN ATLANTIC CITY, N. J., MAY 2, 1949
Authors: Wesley W. Spink
Journal: Journal of Clinical Investigation (1949)

of this Society, addressed the members on the subject, "The Science of Clinical Medicine: What it Ought to be and the Men to Uphold it."In his introductory re- marks he said, "The honor of the presidency of a society goes with the privilege of discussing some of the aims of that society."In discharging my responsibility as Presi- dent, forty years after Dr. Meltzer, I am tempted to review the accomplishments of this Society, but such would be idle boasting.I would like to call your atten- tion to the history of this Society by Dr. J. Harold Austin of Philadelphia which appears in the March, 1949 issue of the Journal of Clinical Investigation.It is well worth reading.Dr. Meltzer was deeply interested in the capable young individual who elected a career of clinical research.Since today, more than ever, young individuals are continuing to manifest an interest in clinical investi- gation, I would like to discuss with you some of the problems relating to their training.
Abstract PL6-1: Resistance to targeted therapies in a realistic mouse breast cancer model
Authors: Piet Borst, Sven Rottenberg, Jos Jonkers, Serge Zander, Marina Pajic, Janneke Jaspers
Journal: Clinical Cancer Research (2010)

Abstract The contribution of ABC-transporters to resistance in patients has remained controversial. We have tackled this problem in a mammary mouse tumor model. These Brca1−/−, p53−/− tumors arise “spontaneously” and closely resemble human breast cancer in BRCA1+/− carriers (Rottenberg, PNAS 2007;104:12117–22; 2008;105:17079–84). The tumors respond to chemotherapeutic agents used in human breast cancer, but eventually end up being resistant to most drugs. Resistance to doxorubicin in this tumor model is nearly always due to P-glycoprotein upregulation at the transcriptional level. A 5-fold increase in the low basal level of P-glycoprotein RNA in these tumors is sufficient for complete resistance. These levels of P-glycoprotein are not detectable with standard immunocytochemistry using the C219 Mab (Pajic, Cancer Res 2009;69:6396–404). Crossing in null alleles for Mdr1a/b made the tumors hypersensitive to doxorubicin, docetaxel, and to the PARP inhibitor olaparib. In about half of the mice treated with topotecan, resistance is associated with upregulation of Abcg2 (Bcrp). Tumors in Abcg2−/− mice take longer to become resistant (Zander, Cancer Res 2009 in press). Notwithstanding the complete remissions often obtained with some drugs, we are rarely able to eradicate the tumor. This is not due to the hypothetical unique properties of tumor stem cells. Supported by Dutch Cancer Foundation and EU Framework Program. Citation Information: Clin Cancer Res 2010;16(7 Suppl):PL6-1
Hyperosmolar Triggering of Histamine Release from Human Basophils
Authors: Steven R. Findlay, Ann M. Dvorak, Anne Kagey-Sobotka, Lawrence M. Lichtenstein
Journal: Journal of Clinical Investigation (1981)

Idiopathic reactions occurring during the infusion of hyperosmolar solutions, such as radiocontrast dyes, cause a significant number of deaths each year. These reactions are similar to those which follow mediator release during allergen-induced anaphylaxis. In attempting to explain these nonimmunologic reactions, we examined the direct effect of hyperosmolarity on normal human basophils with emphasis on release induced by mannitol.
Abstract 2768: IDH1057, A novel, synthetic, small molecule inhibitor of heat shock protein 90(Hsp90)
Authors: Jin-Sun Kwon, An-Na Moon, Joon-Tae Park, Soo-Jung Hong, Jin-Ah Jeong, Sung-Wook Kwon, Myong-Jae Lee, Hyeon-Soo Jang, Seung-Woo Yeon, Hong-Sub Lee, Jae-Hoon Kang
Journal: Cancer Research (2012)

Abstract Backgroud: The molecular chaperone Heat shock protein 90(Hsp90) governs the stabilization and activity of an array of over 100 ‘client proteins’, many of which are key signaling molecules involved in cell proliferation, survival, and transformation. A significant number of these client proteins are oncogenic in nature, including the protein kinases Her2, C-Raf, B-Raf, and AKT. We report here that IDH1057 is structurally distinct from a geldanamycin derivative, tanespimycin(17-AAG) as a novel and potent small molecule Hsp90 inhibitor that binds to the NH2-terminal ATP-binding pocket of Hsp90. Results: IDH1057 exhibited superior binding affinity for the ATPase domain of Hsp90(IDH1057, human Hsp90α FP IC50&amp;lt;150 nM) compared to 17-AAG(IC50 =456.3 nM) in vitro. IDH1057 also markedly inhibited proliferation in a broad panel of human tumor cell lines(IC50α100 nM) and depleted Her2 in SKBR3 breast cancer cells(IC50&amp;lt;50 nM). 10 NSCLC cell lines were relatively sensitive to IDH1057, irrespective of EGFR, Her2 or KRAS mutational status. IDH1057 was also highly effective against cell lines that displayed resistance to erlotinib. IDH1057 efficiently inhibited cell proliferation in 8 breast cancer cell lines including triple-negative breast cancer(TNBC) cell lines such as BT-20, Hs578T and MDA-MB-231. Exposure to IDH1057 led to a rapid and dramatic degradation of key signaling molecules in BT474 cells. Based on these results, we examined in vivo anti-tumor activity of IDH1057 in BT474 breast cancer xenografts. Following once daily oral dosing of IDH1057 at 200mg/kg on a weekly 5-day-on and 2-day-off schedule for 4 weeks, this compound showed statistically significant tumor growth inhibition(TGI=84.5%) and was well-tolerated with no observable body weight loss. A2780 ovarian cancer xenografts in mice treated orally with IDH1057 also resulted in potent tumor growth inhibition. More importantly, IDH1057 displayed favorable oral PK profiles in mice. Additionally, we performed in vitro ADME assays to characterize a new series of small molecule inhibitors. IDH1057 exhibited high metabolic stability in liver microsomes from human, mouse and beagle(≥60%). Five human CYP isoforms were not significantly inhibited by IDH1057 at 10uM. IDH1057 had moderate permeability in MDCK permeability assay(Papp=4.7x10−6 cm/sec). Conclusion: Our results indicate that IDH1057 is a novel and fully synthetic Hsp90 inhibitor with strong anti-tumor activity in vitro and in vivo. IDH1057 is a promising and orally active drug candidate for cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2768. doi:1538-7445.AM2012-2768
Canadian government is attacked for plan to legalise marijuana
Authors: D. Spurgeon
Journal: BMJ (2003)

Canada's federal government is under fire from US officials, the Canadian police, and even some of its own members of parliament for having introduced a bill decriminalising possession of small amounts of marijuana.

Under the Cannabis Reform Bill possession of less than 15 g of marijuana would still be illegal but would lead to fines of $C100 (£180; $290; €250) to $C400, depending on circumstances such as the age of possessors and whether they were driving a vehicle. Possession now carries a maximum penalty of six months in jail and a fine of …
RANDOMISED PLACEBO-CONTROLLED TRIAL OF HEPATITIS B SURFACE ANTIGEN VACCINE IN FRENCH HAEMODIALYSIS UNITS: I, MEDICAL STAFF
Authors: Jean Crosnier, Paul Jungers, Anne-Marie Couroucé, Agnès Laplanche, Ellen Benhamou, Francoise Degos, Bernard Lacour, Paul Prunet, Yvanne Cerisier, Pierre Guesry
Journal: The Lancet (1981)
Risk Factors for Central and Obstructive Sleep Apnea in 450 Men And Women with Congestive Heart Failure
Authors: DON D. SIN, FABIA FITZGERALD, JOHN D. PARKER, GARY NEWTON, JOHN S. FLORAS, T. DOUGLAS BRADLEY
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

In previous analyses of the occurrence of central (CSA) and obstructive sleep apnea (OSA) in patients with congestive heart failure (CHF), only men were studied and risk factors for these disorders were not well characterized. We therefore analyzed risk factors for CSA and OSA in 450 consecutive patients with CHF (382 male, 68 female) referred to our sleep laboratory. Risk factors for CSA were male gender (odds ratio [OR] 3.50; 95% confidence interval [CI], 1.39 to 8.84), atrial fibrillation (OR 4.13; 95% CI 1.53 to 11. 14), age > 60 yr (OR 2.37; 95% CI 1.35 to 4.15), and hypocapnia (PCO(2 )< 38 mm Hg during wakefulness) (OR 4.33; 95% CI 2.50 to 7. 52). Risk factors for OSA differed by gender: in men, only body mass index (BMI) was significantly associated with OSA (OR for a BMI > 35 kg/m(2), 6.10; 95% CI 2.86 to 13.00); whereas, in women, age was the only important risk factor (OR for age > 60 yr, 6.04; 95% CI 1.75 to 20.0). We conclude that historical information, supplemented by a few simple laboratory tests may enable physicians to risk stratify CHF patients for the presence of CSA or OSA, and the need for diagnostic polysomnography for such patients. Sin DD, Fitzgerald F, Parker JD, Newton G, Floras JS, Bradley TD. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure.
The Health Consequences of Smoking: The Changing Cigarette
Authors: Alan Blum
Journal: JAMA (1981)

The major point of this well-written 14th report of the Public Health Service on the health consequences of smoking is that there is no such thing as a safe—or even safer— cigarette, notwithstanding advertising claims to the contrary. In essence, it is not so much what is in a cigarette that causes the multifarious health problems—and there are more than 2,200 known compounds in the smoke—but the fact that cigarette smoking in any form can cause great harm. Switching from a high-tar to a low-tar brand is, in the words of a recent advertisement of Great Britain's Health Education Council, like jumping from the 36th floor instead of the 39th.  A key term is what the report calls compensatory smoking, ie, if a smoker compensates for reduced tar yield by increasing the number of cigarettes, the depth of inhalation, or the volume or frequency of puffs, a reduction in tar
Preoperative biochemical screening
Authors: R. Gabriel
Journal: BMJ (1988)

was plainly evident that enalapril had considerably improved the quality of life and possibly prolonged it in many seriously ill patients" but give no data to support this observation.Every method of assessing the benefit risk profile of a new chemical entity has its drawbacks, but we believe that the yellow card reports, prescription-event monitoring, and properly conducted postmarketing studies each contribute to our knowledge, albeit in different ways.In attempt- ing to compare different methods care must be exercised to ensure legitimacy of the conclusions.
Differential nephrotoxicity of low molecular weight proteins including Bence Jones proteins in the perfused rat nephron in vivo.
Authors: P W Sanders, G A Herrera, A Chen, B B Booker, J H Galla
Journal: Journal of Clinical Investigation (1988)

To investigate the pathogenetic mechanisms of tubule nephrotoxicity of low molecular weight proteins (LMWP), proximal tubules (PT) of rats were perfused in vivo with artificial tubule fluid (ATF) containing one of five LMWPs: three human Bence Jones proteins (BJP), beta-lactoglobulin (BLG), and rabbit myoglobin (MYG). Volume (JV), chloride (JCl) and glucose (JG) fluxes in these perfused PTs were compared with those determined using ATF alone. In separate experiments, perfused nephrons were examined with electron and immunoelectron microscopy. After exposure to BJP1 or BLG, JV, JCl, and JG were less (P less than 0.05) than corresponding control fluxes. Cell damage of these perfused PTs, along with cellular debris in the distal tubules, was prominent. The PT lysosomes often appeared atypical and contained crystals. In contrast, perfusion with BJP2, BJP3, or MYG did not alter JV, JCl, or JG. These findings were corroborated by the normal ultrastructure of these PTs despite immunohistochemical evidence of endocytosis of the BJPs. Isoelectric point, molecular form, and isotype were not factors associated with PT damage. In addition, proteins with pI less than 7.4 precipitated in the distal nephron, forming acellular casts. Thus, certain nephrotoxic LMWPs damaged the PT, while others precipitated in the distal tubule, obstructing the nephron. These two pathogenetic mechanisms may independently be responsible for tubulointerstitial nephropathy of LMWPs in humans.