tbuckley/cabot-search huggingface dataset:
The Prognostic Value of <i>TP53</i> Mutations in Chronic Lymphocytic Leukemia Is Independent of Del17p13: Implications for Overall Survival and Chemorefractoriness
Authors: Davide Rossi, Michaela Cerri, Clara Deambrogi, Elisa Sozzi, Stefania Cresta, Silvia Rasi, Lorenzo De Paoli, Valeria Spina, Valter Gattei, Daniela Capello, Francesco Forconi, Francesco Lauria, Gianluca Gaidano
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Del17p13 predicts poor outcome and chemorefractoriness in chronic lymphocytic leukemia (CLL). Conversely, it is unknown whether TP53 mutations carry any prognostic value independent of del17p13. We tested the independent prognostic value of TP53 mutations in CLL. Experimental Design: The study was based on a consecutive series of 308 CLL. DNA sequencing of TP53 exons 2 to 10 and del17p13 interphase fluorescence in situ hybridization were done at CLL diagnosis. Study end points were survival and chemorefractoriness. Results: At diagnosis, TP53 mutations (n = 32) occurred in 31 of 308 (10.0%) patients. Of all CLL showing TP53 disruption by either mutation and/or deletion (n = 44), 10 cases (22.7%) showed TP53 mutations in the absence of del17p13. Multivariate analysis selected TP53 mutations (hazard ratio, 3.20; P = 0.002) as an independent predictor of overall survival after adjustment for del17p13. Also, multivariate analysis selected TP53 mutations (hazard ratio, 3.97; P &amp;lt; 0.001) as an independent predictor of chemorefractoriness after adjustment for del17p13. Compared with cases without TP53 alterations, CLL harboring any type of TP53 disruption (mutation only, del17p13 only, or both mutation and del17p13) uniformly displayed a high prevalence of unfavorable prognosticators and poor outcome. Analysis of sequential CLL samples showed the acquisition of new or additional TP53 alterations at the time of chemorefractoriness. Conclusions: These data show that (a) TP53 mutations are an independent predictor of short survival and chemorefractoriness, and (b) that CLL presenting with TP53 mutations without del17p13 fare as poorly as CLL carrying del17p13. Because CLL harboring TP53 mutations without del17p13 are currently not recognized by conventional diagnostic strategies, these results may be relevant for a comprehensive prognostic characterization of CLL.
Chemistry and Therapy of Collagen Diseases
Authors: A. St. J. Dixon
Journal: Annals of the Rheumatic Diseases (1963)

Kugelmass, is "charged with the nisus elan of chemical wisdom, supreme in choice of international authors, optimal in standards of chemical scholarship, provocative in imagination for experimental research, comprehensive in discussion of scientific medicine, and authoritative in chemical perspective of human disorders".Of course, nobody expects a preface to be taken seriously, but any reader who is obsessive enough to look at this preface and who might get the idea that he is about to be sold the elixir of life, can be reassured that the book is no more than (and no less than) a sequence of brief, useful, and well-balanced reviews, along orthodox lines, under the chapter headings Biochemistry of Connective Tissue, Biochemistry of Rheumatoid Arthritis, Systemic Lupus, Periarteritis Nodosa, Dermatomyositis, and Diffuse Scleroderma.Students and others seeking up-to-date introduction to these subjects will find these chapters helpful, although less comprehensive than accounts of similar topics in standard texts.The last
Characteristics and outcomes of doctors in a substance dependence monitoring programme in Canada: prospective descriptive study
Authors: J. M Brewster, I M. Kaufmann, S. Hutchison, C. MacWilliam
Journal: BMJ (2008)

<b>Objective</b> To describe the characteristics at enrolment and outcomes of doctors in a substance dependence monitoring programme in Canada. <b>Design</b> Prospective descriptive study. <b>Setting</b> Provincial physician health programme, Canada. <b>Participants</b> All 100 doctors consecutively admitted to a substance dependence monitoring programme and followed until completion of monitoring or on leaving the programme. <b>Main outcome measure</b> Relapse during long term monitoring for five years. <b>Results</b> Ninety per cent of the doctors enrolled on the programme were men, 66% were married or living with a partner, 44% had had previous treatment for substance dependence, and 36% had had previous psychiatric treatment. Smokers were over-represented compared with the general population of US doctors (38% <i>v</i> 5%). During the monitoring period 71% of participants had no known relapse. An additional 14% went on to complete the programme, after some form of relapse. In total, 85% of the doctors successfully completed the programme. <b>Conclusion</b> In this cohort of doctors enrolled on the Ontario Physician Health Program for substance dependence, most were men who were dependent on alcohol or opioids. Smokers were over-represented compared with the general population of US doctors. Eighty five per cent successfully completed the programme.
Lead Poisoning Due to Adulterated Marijuana
Authors: Franziska Busse, Leyla Omidi, Alexander Leichtle, Michael Windgassen, Eyleen Kluge, Michael Stumvoll
Journal: New England Journal of Medicine (2008)

Recently, 29 patients were admitted to four different hospitals in the greater Leipzig area with classic signs and symptoms of lead intoxication. Despite great efforts, the source of lead could not be identified. The patients eventually conceded that they were regular users of marijuana.
Arachidonic acid as a bioactive molecule
Authors: Alan R. Brash
Journal: Journal of Clinical Investigation (2001)

Arachidonic acid is a slippery molecule that owes its mobility to its four cis double bonds. These are the source of its flexibility, keeping the pure fatty acid liquid, even at subzero temperatures, and helping to give mammalian cell membranes their correct fluidity at physiological temperatures. The double bonds are also the key to the propensity of arachidonic acid to react with molecular oxygen. This can happen nonenzymatically, contributing to oxidative stress, or through the actions of three types of oxygenase: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450. While the products of these enzymes and of the nonenzymatic transformations have well-substantiated bioactivities, unchanged arachidonic acid itself has biological activity. This will be a main focus this review. Before dealing with bioactivity, I will consider the solubility properties of the molecule, which are crucial to understanding the availability within the cell of endogenous and exogenous arachidonic acid. I then discuss two controversial issues, arachidonic acid transport into cells and the accessibility of added arachidonic acid to endogenous cellular compartments, and finally turn to selected biological actions of this lipid. The enzymes of arachidonic acid release have been well covered in specialized reviews and are introduced here only in passing.
UNDETECTED SYPHILIS AND RHEUMATIC INFECTION IN CHILDHOOD
Authors: A. D. Fordyce
Journal: BMJ (1930)

IN tlle course of wrork with rheumiiatic children I have recently been forced to consideration along new lines.Havinig hiad referi'ed to me a child with acute rheumatismii and cai'ditis, it ultim:iately became evidenit that the rheniln- atic infectioni was superimposed upon a congenital syphlilitic tainit.Shortly afterwards a similar case was encoulntered, and I investigated a small series of cases with the object of obtainiing informationi oni the relationship between con- genital syphilis and rheumL-atism.I obtained results which in tlheii' suggestiveness were to me strikiii-and unexpected.The following are the details, in short, of nine children dealt witlh in my rheumatic clinics, and wlho, I hold, w-ere congenital syphilitics, and the striking featur e in the cases is the fr-equent absence of clinical signs pointing to the presence of a syphilitic infection.I am impressed witlh tlle suggestion that ani imiiportant subgr oulp of rlheumatic children can be (lefined-ilailiely, thos-e in wlhomii the rheuiin- atic inifection is superimIposed upon conigelnital syplhilitic infectioni, amid more particularly untreate(l and undetecte(d syphlilis-anid that progiiOSis ill suchl cases mlaly be seriously influenced.
Intrarenal dopamine deficiency leads to hypertension and decreased longevity in mice
Authors: Ming-Zhi Zhang, Bing Yao, Suwan Wang, Xiaofeng Fan, Guanqing Wu, Haichun Yang, Huiyong Yin, Shilin Yang, Raymond C. Harris
Journal: Journal of Clinical Investigation (2011)

In addition to its role as an essential neurotransmitter, dopamine serves important physiologic functions in organs such as the kidney. Although the kidney synthesizes dopamine through the actions of aromatic amino acid decarboxylase (AADC) in the proximal tubule, previous studies have not discriminated between the roles of extrarenal and intrarenal dopamine in the overall regulation of renal function. To address this issue, we generated mice with selective deletion of AADC in the kidney proximal tubules (referred to herein as ptAadc-/- mice), which led to selective decreases in kidney and urinary dopamine. The ptAadc-/- mice exhibited increased expression of nephron sodium transporters, decreased natriuresis and diuresis in response to l-dihydroxyphenylalanine, and decreased medullary COX-2 expression and urinary prostaglandin E2 excretion and developed salt-sensitive hypertension. They had increased renin expression and altered renal Ang II receptor (AT) expression, with increased AT1b and decreased AT2 and Mas expression, associated with increased renal injury in response to Ang II. They also exhibited a substantially shorter life span compared with that of wild-type mice. These results demonstrate the importance of the intrarenal dopaminergic system in salt and water homeostasis and blood pressure control. Decreasing intrarenal dopamine subjects the kidney to unbuffered responses to Ang II and results in the development of hypertension and a dramatic decrease in longevity.
The Role of Dimethylarginine Dimethylaminohydrolase in Idiopathic Pulmonary Fibrosis
Authors: Soni Savai Pullamsetti, Rajkumar Savai, Rio Dumitrascu, Bhola Kumar Dahal, Jochen Wilhelm, Melanie Konigshoff, Dariusz Zakrzewicz, Hossein Ardeschir Ghofrani, Norbert Weissmann, Oliver Eickelberg, Andreas Guenther, James Leiper, Werner Seeger, Friedrich Grimminger, Ralph Theo Schermuly
Journal: Science Translational Medicine (2011)

Inhibition of dimethylarginine dimethylaminohydrolase enzyme in lung attenuates two hallmarks of pulmonary fibrosis, excess cells and excess collagen, thereby offering a therapeutic approach.
CD24 Expression Causes the Acquisition of Multiple Cellular Properties Associated with Tumor Growth and Metastasis
Authors: Petra Baumann, Natascha Cremers, Frans Kroese, Gertraud Orend, Ruth Chiquet-Ehrismann, Toshi Uede, Hideo Yagita, Jonathan P. Sleeman
Journal: Cancer Research (2005)

Abstract The glycosylphosphatidylinositol-anchored membrane protein CD24 functions as an adhesion molecule for P-selectin and L1 and plays a role in B-cell development and neurogenesis. Over the last few years, a large body of literature has also implicated CD24 expression in tumorigenesis and progression. Here, we show that ectopic CD24 expression can be sufficient to promote tumor metastasis in experimental animals. By developing a doxycycline-inducible system for the expression of CD24 in breast cancer cells, we have also analyzed the cellular properties that CD24 expression influences. We found that CD24 expression increased tumor cell proliferation. Furthermore, in addition to promoting binding to P-selectin, CD24 expression also indirectly stimulated cell adhesion to fibronectin, collagens I and IV, and laminin through the activation of α3β1 and α4β1 integrin activity. Moreover, CD24 expression supported rapid cell spreading and strongly induced cell motility and invasion. CD24-induced proliferation and motility were integrin independent. Together, these observations implicate CD24 in the regulation of multiple cell properties of direct relevance to tumor growth and metastasis.
Temporary Preservation of β-Cell Function by Diazoxide Treatment in Childhood Type 1 Diabetes
Authors: Eva Örtqvist, Elisabeth Björk, Måna Wallensteen, Johnny Ludvigsson, Jan Åman, Calle Johansson, Gun Forsander, Fredrik Lindgren, Lars Berglund, Mats Bengtsson, Christian Berne, Bengt Persson, F. Anders Karlsson
Journal: Diabetes Care (2004)

OBJECTIVE—We examined the effect of diazoxide, an ATP-sensitive K+ channel opener and inhibitor of insulin secretion, on β-cell function and remission in children at clinical onset of type 1 diabetes. RESEARCH DESIGN AND METHODS—A total of 56 subjects (21 girls and 35 boys, age 7–17 years) were randomized to 3 months of active treatment (diazoxide 5–7.5 mg/kg in divided doses) or placebo in addition to multiple daily insulin injections and were followed for 2 years. RESULTS—Diazoxide decreased circulating C-peptide concentrations by ∼50%. After cessation of the treatment, basal and meal-stimulated C-peptide concentrations increased to a maximum at 6 months, followed by a decline. Meal-stimulated C-peptide concentration was significantly higher at 12 months (0.43 ± 0.22 vs. 0.31 ± 0.26 nmol/l, P = 0.018) and tended to fall less from clinical onset to 24 months in the diazoxide- vs. placebo-treated patients (−0.05 ± 0.24 vs. −0.18 ± 0.26 nmol/l, P = 0.064). At 24 months, the meal-stimulated C-peptide concentrations were 0.24 ± 0.20 and 0.20 ± 0.17 nmol/l, respectively. Side effects of diazoxide were prevalent. CONCLUSIONS—This study demonstrates that partial inhibition of insulin secretion for 3 months at onset of childhood type 1 diabetes suspends the period of remission and temporarily preserves residual insulin production. Further evaluation of the full potential of β-cell rest will require compounds with less side effects as well as protocols optimized for sustained secretory arrest.
Endothelial cell colonization and angiogenic potential of combined nano- and micro-fibrous scaffolds for bone tissue engineering
Authors: Marina I. Santos, Kadriye Tuzlakoglu, Sabine Fuchs, Manuela E. Gomes, Kirsten Peters, Ronald E. Unger, Erhan Piskin, Rui L. Reis, C. James Kirkpatrick
Journal: Biomaterials (2008)
What to do when a competent ICU patient does not want to live anymore but is dependent on life-sustaining treatment? Experience from The Netherlands
Authors: Ben van der Hoven, Yorick J. de Groot, Wilhelmina J. Thijsse, Erwin J. O. Kompanje
Journal: Intensive Care Medicine (2010)

If patients on the intensive care unit (ICU) are awake and life-sustaining treatment is suspended because of the patients' request, because of recovering from the disease, or because independence from organ function supportive or replacement therapy outside the ICU can no longer be achieved, these patients can suffer before they inevitably die. In The Netherlands, two scenarios are possible for these patients: (1) deep palliative (terminal) sedation through ongoing administration of barbiturates or benzodiazepines before withdrawal of treatment, or (2) deliberate termination of life (euthanasia) before termination of treatment. In this article we describe two awake patients who asked for withdrawal of life-sustaining measures, but who were dependent on mechanical ventilation. We discuss the doctrine of double effect in relation to palliative sedation on the ICU. Administration of sedatives and analgesics before withdrawal of treatment is seen as normal palliative care. We conclude that the doctrine of the double effect is not applicable in this situation, and mentioning it criminalised the practice unnecessarily and wrongfully.
Searching historical herbal texts for potential new drugs
Authors: Eric J Buenz, Brent A Bauer, Holly E Johnson, Gaugau Tavana, Eric M Beekman, Kristi L Frank, Charles L Howe
Journal: BMJ (2006)

The medicinal uses of plants have been described in herbal texts for thousands of years. 1 This documentation is fortunate, as knowledge of traditional medicine is continually lost, and such knowledge is useful for the discovery of new drugs.Here we show that a treatment for dysentery, identified by "mining" a 400 year old Dutch text on herbal medicines, has antibacterial effects that are specific to the part of the plant described in the historical text. The searchWe used a novel semantic bioinformatics tool 2 to search the text of the Ambonese Herbal, which was written nearly 400 years ago by G E Rumphius, an employee of the Dutch East India Company.In this text he described the medicinal uses of plants on the island of Ambon in Indonesia.Our search identified the kernels of the atun tree (fig 1) as a potential source of an antibacterial or antimotility compound. 2 3About the atun tree he wrote, ". . .these same kernels . . .will halt all kinds of diarrhoea, but very suddenly, forcefully and powerfully, so that one should use them with care in dysentery cases, because that illness or affliction should not be halted too quickly: and some considered this medicament a great secret, and relied on it completely." 4e therefore organised an expedition to the Independent State of Samoa to collect botanical specimens, so that we could examine extracts of this plant for potential antibacterial properties.The leaves and fruit of the atun tree were collected (Atuna racemosa Raf, originally incorrectly identified as Parinari glaberrima Hassk), and voucher specimens were deposited in the National Tropical Botanical Gardens, Kalaheo, Hawaii, USA.
Concept of unbearable suffering in context of ungranted requests for euthanasia: qualitative interviews with patients and physicians
Authors: H R W Pasman, M L Rurup, D L Willems, B D Onwuteaka-Philipsen
Journal: BMJ (2009)

<b>Objective</b> To obtain in-depth information about the views of patients and physicians on suffering in patients who requested euthanasia in whom the request was not granted or granted but not performed. <b>Design </b>In-depth interviews with a topic list. <b>Setting </b>Patients' homes and physicians' offices. <b>Participants </b>10 patients who explicitly requested euthanasia but whose request was not granted or performed and eight physicians of these patients; and eight physicians of patients who had requested euthanasia but had died before the request had been granted or performed or had died after the request was refused by the physician or after the patient had withdrawn his or her request. <b>Results </b>Not all patients who requested euthanasia thought their suffering was unbearable, although they had a lasting wish to die. Patients and physicians seemed to agree about this. In cases in which patients said they suffered unbearably there was less agreement about what constitutes unbearable suffering; patients put more emphasis on psychosocial suffering, such as dependence and deterioration, whereas physicians referred more often to physical suffering. In some cases the physician thought that the suffering was not unbearable because the patient's behaviour seemed incompatible with unbearable suffering—for instance, because the patient was still reading books. <b>Conclusions </b>Patients do not always think that their suffering is unbearable, even if they have a lasting wish to die. Physicians seem to have a narrower perspective on unbearable suffering than patients and than case law suggests. In an attempt to solve the problem of different perspectives, physicians should take into account the different aspects of suffering as described in the literature and a framework for assessing the suffering of patients who ask for euthanasia.
Loss of the glomerular contractile response to angiotensin in rats following myohemoglobinuric acute renal failure.
Authors: B M Wilkes, W J Caldicott, G Schulman, N K Hollenberg
Journal: Circulation Research (1981)

To examine the state of the glomerulus in rats protected from acute renal failure (ARF) by prior insult, we measured the contractile responses of isolated glomeruli to angiotensin II (AII) and dibutyryl cyclic AMP (DBcAMP). In healthy rats, both agents induced a dose-related fall in glomerular diameter (P less than 0.001). Saralasin, the angiotensin antagonist, blocked the glomerular response to AII totally and to DBcAMP partially. Two weeks following ARF induced with 50% glycerol (10 ml/kg, im), azotemia had reversed and the nephrotoxic effect of mercuric chloride (4.7 mg/kg, sc) was blunted, as anticipated. AII did not reduce glomerular size, but the response to DBcAMP was sustained at this time. To determine the specificity of the loss of the glomerular response to AII, we also assessed the effects of an AII infusion (1 microgram/kg/min) on blood pressure and renal blood flow. There was a substantial rise in blood pressure (control, 104 +/- 11.8 mm Hg; AI, 131.0 +/- 5.3 mm HG; P less than 0.001) and fall in renal blood flow (control, 2.45 ml/g per min; AII, 0.81 +/- 0.10 ml/g per min; P less than 0.025). Vascular responsiveness to AII was preserved at a time when glomeruli were totally unresponsive and rats were resistant to ARF. The loss of glomerular contractility may, in part, account for the protection from ARF seen in this model: if so, glomerular abnormalities may play a pathogenetic role.
Serum retinol-binding protein 4 correlates with obesity, insulin resistance, and dyslipidemia in HIV-infected subjects receiving highly active antiretroviral therapy
Authors: Sang Hoon Han, Bum Sik Chin, Han Sung Lee, Su Jin Jeong, Hee Kyoung Choi, Chang Oh Kim, Jun Yong Choi, Young Goo Song, Hyun Chul Lee, June Myung Kim
Journal: Metabolism (2009)
ON THE ROLE OF RIBONUCLEIC ACID IN ANIMAL VIRUS SYNTHESIS
Authors: Igor Tamm, Rostom Bablanian
Journal: The Journal of Experimental Medicine (1960)

Ribonuclease is a highly active inhibitor of vaccinia virus multiplication in vitro in the chorioallantoic membrane removed from embryonated chicken eggs. It is also a highly active inhibitor of pock formation by vaccinia and herpes simplex viruses on the chorioallantoic membrane in vivo. Marked inhibitory effects were obtained with 12.5 microg. of RNase. However, complete inhibition was not obtained with several hundred micrograms of the enzyme. RNase caused no inactivation of the infectivity of vaccinia virus particles but it had a marked inhibitory effect on multiplication of this virus when administered many hours after infection of host cells had occurred. RNase also failed to inactivate the infectivity of herpes simplex virus particles. The results obtained indicate that ribonucleic acid is necessary for the multiplication of two DNA-containing viruses; i.e., vaccinia and herpes simplex.