tbuckley/cabot-search huggingface dataset:
531Platelet-derived deoxyribose-1-phosphate promotes endothelial cell motility and angiogenesis in vivo via redox stimulation
Authors: D Vara, C Wheeler-Jones, K Mace, H Mellor, G Pula
Journal: Cardiovascular Research (2014)

Redox regulation of angiogenesis is an important and emerging topic in vascular sciences; reactive oxygen species (ROS) modulate vascular endothelial cell (EC) proliferation and migration, but the molecular mechanism underlying this phenomenon remains largely unclear. We have shown micromolar concentrations of the pro-angiogenic metabolite deoxyribose-1-phosphate (dRP) detected by mass spectrometry (MS) and nuclear magnetic resonance (NMR) in the supernatants of collagen- and thrombin-stimulated platelets. The genetic silencing of dRP-generating enzymes uridine phosphorylase (UP) and thymidine phosphorylase (TP) in mouse platelets significantly reduced the levels of dRP in platelet supernatants and impaired the ability of protein-free platelet supernatants to enhance human umbilical vein endothelial cell (HUVEC) motility. Chick chorioallantoic membrane (CAM) vascularisation assays performed with protein-free supernatants suggested that the release of dRP by platelets stimulates angiogenesis in vivo. To understand the pro-angiogenic effect of dRP, we investigated further the molecular mechanism of action of dRP and whether this effect was observed in other nucleoside derivatives deoxyribose-5-phospate (dR5P), ribose-1-phosphate (R1P) and deoxyribose (dR). Using live cell real-time confocal imaging and fluorescence assays, HUVEC treatment with dRP significantly increased ROS generation. Similarly, dR5P and R1P also induced ROS accumulation in HUVECs, whereas dR did not. The protein expression of the redox stress marker heme oxygenase-1 (HO-1) and Integrin β3 were shown to be upregulated by dRP and its phosphorylated derivatives (except dR) by immunoblot experiments. Vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR2), interleukin 8 (IL-8), and stromal cell-derived factor 1α (SDF-1α) showed a similar effect. In parallel, only dRP and its phosphorylated derivatives increased HUVEC cell motility in scratch-healing assays and capillary tube formation using Matrigel™ assays. The causative link between integrin β3 upregulation and increased HUVEC motility/capillary tube formation was proved using integrin-specific inhibitory antibodies'. Furthermore the angiogenic potential of dRP was confirmed in vivo. In summary, dRP and its phosphorylated derivatives were shown to play a relevant role in the paracrine regulation of EC motility and pro-angiogenic activity by up-regulating integrin β3 in a ROS-dependent manner possibly signaling via VEGFR2. dRP is likely to play a role in the stimulation of postnatal angiogenesis and tissue regeneration.
Sirolimus Therapy for Angiomyolipoma in Tuberous Sclerosis and Sporadic Lymphangioleiomyomatosis: A Phase 2 Trial
Authors: D. Mark Davies, Petrus J. de Vries, Simon R. Johnson, Deborah L. McCartney, Jane A. Cox, Andreas L. Serra, Peter C. Watson, Christopher J. Howe, Tim Doyle, Kate Pointon, Justin J. Cross, Anne E. Tattersfield, J. Chris Kingswood, Julian R. Sampson
Journal: Clinical Cancer Research (2011)

Renal angiomyolipomas are a frequent manifestation of tuberous sclerosis and sporadic lymphangioleiomyomatosis (LAM). These disorders are associated with mutations of TSC1 or TSC2 that lead to overactivation of mTOR complex 1 (mTORC1), suggesting an opportunity for targeted therapy by using mTORC1 inhibitors. This study investigated the efficacy and safety of the mTORC1 inhibitor sirolimus for treatment of renal angiomyolipomas in patients with these disorders.In this multicenter phase 2 nonrandomized open label trial, 16 patients with tuberous sclerosis or sporadic LAM and renal angiomyolipoma(s) were treated with oral sirolimus for up to 2 years. Steady-state blood levels were 3 to 10 ng/mL. The primary outcome was change in size of renal angiomyolipomas measured by MRI and assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes included safety, neurocognitive function, and pulmonary function.The response rate, by RECIST criteria, was 50%. Summated angiomyolipoma diameters were reduced in all 16 patients and by 30% or more in eight (all from the per protocol group of 10). Forty-one of 48 angiomyolipomas were smaller at the last measurement than at baseline. Most shrinkage occurred during the first year of treatment. There was little change in pulmonary function. Recall memory improved in seven of eight patients with tuberous sclerosis. Adverse events were consistent with the known toxicities of sirolimus.This study showed sustained regression of renal angiomyolipomas in patients with tuberous sclerosis or sporadic LAM receiving 2 years of sirolimus treatment. Possible effects on pulmonary function and neurocognition require further investigation.
Acute Renal Failure Following Cholecystography
Authors: John G. Setter
Journal: JAMA (1963)

Acute renal failure occurred in nine cases after cholecystography when a new orally administered contrast medium, bunamiodyl, was used. The patients were four men and five women; their ages ranged from 41 to 71 yr. Four had also received methylglucamine iodipamide intravenously. Oliguria was noted in most cases, and in all there was an acute elevation of serum urea nitrogen. In no case had there been any antecedent condition that would explain the acute renal failure. The severity of renal failure seemed to be related to the total amount of iodine administered, and the double dose technique was rarely successful. In tissue obtained at necropsy in the four patients who died and at biopsy in two others, diffuse tubular necrosis was present, and in the four autopsy specimens birefringent green-brown, calcium-containing crystals were noted.
Insulinoma unmasked by the Cambridge diet.
Authors: M Labib, V Marks, J Patten, P Barker, S Laurent, P Boulter
Journal: BMJ (1987)

towards treating end stage renal failure in more elderly people and those with underlying diseases such as diabetes, and the less skilled they will be in diagnosing chronic renal failure.These findings suggest that intraregional variation should be examined more closely, as the findings may have implications for the organisation of treatment for end stage renal failure in the National Health Service.We thank the strategic planning group, renal interest group, and clinical and scientific services directorate of North West Thames Regional Health Authority.We are also particularly grateful to Julie Kelly for her excellent secretarial help.
Endothelin 1 aggravates acute liver injury in perfused livers of rats after treatment withd -galactosamine
Authors: Masaru Iwai, Tadashige Yamauchi, Takashi Shimazu
Journal: Hepatology (1998)

The effects of endothelin 1 (ET-1) on hemodynamics and acute liver damage were studied using perfused livers of rats treated with d -galactosamine. In control liver perfused in situ with constant pressure, infusion of ET-1 into the portal vein at a concentration of 0.1 nmol/L decreased the flow rate without a significant leakage of lactate dehydrogenase (LDH) or aspartate transaminase (AST) into the effluent. In contrast, in similarly perfused liver 24 hours after treatment with d -galactosamine (800 mg/kg intraperitoneally), ET-1 caused rapid and remarkable increases in the leakage of LDH and AST from the liver accompanied by the reduction of perfusion flow to the extent similar to that observed in control livers. In addition, ET-1 decreased oxygen uptake and bile secretion in galactosamine-treated livers. The potentiating effects of ET-1 on enzyme leakage were also observed under constant flow conditions. Moreover, infusion of the thromboxane A 2 analogue at a concentration of 10 nmol/L decreased the flow rate markedly, yet the rapid increases in enzyme leakage were not observed. Infusion of ET-3 induced the responses of flow reduction and the potentiation of rapid enzyme leakage similar to those obtained with ET-1. Neither the endothelin A-receptor antagonist BQ485 nor the endothelin B-receptor antagonist BQ788 could inhibit the acute liver damage caused by ET-1; instead they exaggerated its effects. The combination of both antagonists together, however, almost completely suppressed the flow reduction and the potentiation of enzyme leakage caused by ET-1. These results indicate that ET-1 is capable of aggravating acute liver damage not merely through reduction of the flow rate but through direct action on liver cells. They also suggest that both the endothelin A and endothelin B receptors are involved in this action of ET-1.
Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity Against Multidrug-Resistant Gram-Negative Bacilli
Authors: George G. Zhanel, Phillip Chung, Heather Adam, Sheryl Zelenitsky, Andrew Denisuik, Frank Schweizer, Philippe R. S. Lagacé-Wiens, Ethan Rubinstein, Alfred S. Gin, Andrew Walkty, Daryl J. Hoban, Joseph P. Lynch, James A. Karlowsky
Journal: Drugs (2013)
Non-absorbable cystic duct ligatures and common bile duct calculi.
Authors: C E Newman, J D Hamer
Journal: BMJ (1975)

reflexes, normal serum potassium, and a normal ECG.He experienced two further attacks of paralysis just after starting antithyroid treatment, and on each occasion weakness and hyporeflexia were demonstrated together with hypokalaemia (serum potassium 2-5 and 2 6 mmol/l).On each occasion he recovered completely 12 hours later with no treatment, the serum potassium reverting to normal, as did the ECG.Extensive investigations during and between the attacks showed normal results.Treatment with carbimazole and propranolol resulted in weight gain, and, apart from one mild abortive attack, no further episodes of paralysis occurred over the next seven months.
The Pathology of Bright's Disease
Authors: G. Johnson
Journal: BMJ (1872)

THE BRITISH MEDICAL JOUR7NAL.une 22, I872.may therefore become so slow in the particular part as to allow of the formation of a small coagulum of fibrin or a thrombosis; there would then be complete obstruction, and consequently the greatest possible pressure would be brought to bear on the arterial wall, and result very probably in rupture.In this way not only may cerebral apoplexy be accounted for, but pulmonary apoplexy and apoplexies in the kidneys and spleen, or hemorrhagic infarctions, occurring in cases where no en- docardiac or valvular mischief has existed.The same explanation may be offered with respect to cedema of the integument and dropsy, as is given for cedema of the lungs.A characteristic of the cedema in Bright's disease is that it changes its position, now attacking one organ, now another.How is this?And why does the morbidly altered blood cause contraction of the minute arteries; is it by direct contact with the vessel, or is this the result of the action of the blood on the ganglionic cells of the nervous system ?These are interesting questions still requiring explanation.
Proteolytic Enzymes and Altered Glycosylation Modulate Dystroglycan Function in Carcinoma Cells
Authors: Jarnail Singh, Yoko Itahana, Selena Knight-Krajewski, Motoi Kanagawa, Kevin P. Campbell, Mina J. Bissell, John Muschler
Journal: Cancer Research (2004)

Abstract Alterations in the basement membrane receptor dystroglycan (DG) are evident in muscular dystrophies and carcinoma cells and characterized by a selective loss or modification of the extracellular α-DG subunit. Defects in posttranslational modifications of DG have been identified in some muscular dystrophies, but the underlying modifications in carcinoma cells have not yet been defined. We reveal here multiple posttranslational modifications that modulate the composition and function of DG in normal epithelial cells and carcinoma cells. We show that α-DG is shed from the cell surface of normal and tumorigenic epithelial cells through a proteolytic mechanism that does not require direct cleavage of either α- or β-DG. Shedding is dependent on metalloprotease activity and the proprotein convertase furin. Surprisingly, furin is also found to directly process α-DG as a proprotein substrate, changing the existing model of DG composition. We also show that the glycosylation of α-DG is altered in invasive carcinoma cells, and this modification causes complete loss of laminin binding properties. Together, these data elucidate several novel events regulating the functional composition of DG and reveal defects that arise during cancer progression, providing direction for efforts to restore this link with the basement membrane in carcinoma cells.
Splanchnic and leg exchange of glucose, amino acids, and free fatty acids during exercise in diabetes mellitus.
Authors: J Wahren, L Hagenfeldt, P Felig
Journal: Journal of Clinical Investigation (1975)

The influence of exercise on leg and splanchnic exchange of substrates was examined in eight insulin-dependent diabetics 24 h after withdrawal of insulin and in eight healthy controls studied at rest and after 40 min of bicycle ergometer exercise at 55-60% of maximal capacity. In four of the diabetic subjects, basal arterial ketone acid levels were 3-4 mmol/ liter (ketotic diabetics) and in the remainder, below 1 mmol/liter (nonketotic diabetics). ,ree fatty acid (FFA) turnover and regional exchange were evaluated with 14-C- labeled oleic acid. Leg uptake of blood glucose rose 13-18 fold during exercise in both the diabetics and controls and accounted for a similar proportion of the total oxygen uptake by leg muscles (25-28%) in the two groups. In contrast, leg uptake of FFA corresponded to 39% of leg oxygen consumption in the diabetic group but only 27% in controls. Systemic turnover of oleic acid was similar in the two groups. Splanchnic glucose output increased during exercise 3-4 fold above resting levels in both groups. In the diabetics, splanchnic uptake of lactate, pyruvate, glycerol, and glycogenic amino acids rose more than twofold above resting levels and was fourfold greater than in exercising controls. Total precursor uptake could account for 30% of the splanchnic glucose output in the diabetic group. In contrast, in the controls, total splanchnic uptake of glucose precursors was no greater during exercise than in the resting state and could account for no more than 11% of splanchnic glucose output. The augmented precursor uptake during exercise in the diabetics was a consequence of increased splanchnic fractional extraction as well as increased peripheral production of gluconeogenic substrates. The arterial glucagon concentration was unchanged by exercise in both groups, but was higher in the diabetics. In the diabetic subjects with ketosis in the resting state, exercise elicited a rise in arterial glucose and FFA, an augmented splanchnic uptake of FFA, and a 2-3 fold increase in splanchnic output of 3-hydroxybutyrate. Uptake of 3-hydroxybutyrate by the exercising leg rose more rapidly than splanchnic production, resulting in a fall in arterial levels of 3-hydroxybutyrate. It is concluded that (a) glucose uptake by exercising muscle in hyperglycemic diabetics is no different from that of controls; (b) splanchnic glucose output rises during exercise to a similar extent in diabetics and controls, while uptake of gluconeogenic substrates is markedly higher in diabetics and accounts for a greater proportion of total splanchnic glucose output; (c) exercise in diabetic patients with mild ketosis is associated with a rise in blood glucose and FFA levels as well as augmented splanchnic production and peripheral uptake of ketone bodies.
Atrial Fibrillation Promotion With Long-Term Repetitive Obstructive Sleep Apnea in a Rat Model
Authors: Yu-ki Iwasaki, Takeshi Kato, Feng Xiong, Yan-Fen Shi, Patrice Naud, Ange Maguy, Kyoichi Mizuno, Jean-Claude Tardif, Philippe Comtois, Stanley Nattel
Journal: Journal of the American College of Cardiology (2014)
The Use of Cinefluorography in Acquired Heart Disease
Authors: JOSEPH JORGENS, ARTHUR LIEBER
Journal: Circulation (1961)

The additional important information obtained through cinefluorography warrants the use of this method in acquired heart disease. It is superior to all other methods for recording cardiac pulsations and calcifications. Its unique advantage for recording fat lines about the heart is extremely important. As the equipment improves, biplaned cinecardioangiography will be part of the armamentarium of all cardiac laboratories.
Human B cells promote T-cell plasticity to optimize antibody response by inducing coexpression of TH1/TFH signatures
Authors: Jelle de Wit, Tineke Jorritsma, Mateusz Makuch, Ester B.M. Remmerswaal, Hanny Klaasse Bos, Yuri Souwer, Jacques Neefjes, Ineke J.M. ten Berge, S. Marieke van Ham
Journal: Journal of Allergy and Clinical Immunology (2014)
MENINGISM AS DISTINGUISHED FROM MENINGITIS.FROM AN OTOLOGIC VIEWPOINT.
Authors: CHEVALIER JACKSON
Journal: JAMA (1907)

<h3>DEFINITION.</h3> Meningism is a morbid state characterized by a meningitic syndrome without intracranial inflammation. Obviously the word pseudomeningitis, or false meningitis, can not be applied, as there can be no such thing as a false inflammation. The term "meningeal irritation" is defective, inaccurate, and anyway, can be applied only to a limited class of cases. The name meningism has been applied by the French neurologists to several morbid conditions associated with a meningitic syndrome. None of these writers treat the subject from an otologic viewpoint. Dupré writes: In the course of some infections or intoxications, or certain morbid states less well defined (dentition, helminthiasis, etc.), of which the indirect influence is called reflex, there may appear, most often in young and hysteric subjects, a syndrome more or less closely simulating the picture of meningitis. The forms, acute or chronic, cerebral or spinal, of meningism, are of nice diagnosis, and of
Signpost your hospital.
Authors: J H Baron
Journal: BMJ (1987)

Those who work in institutions know where they are and where they are going; they are rarely conscious of the notices and signposts. Doctors should, but alas do not, have more awareness of the problem of patients and visitors, all of whom, quite apart from their specific diagnostic fears, are frightened of the health care system in general and of hospitals in particular. Patients and visitors have to make their way to a hospital and can be helped by a map being included in the literature sent out before admission. They need signs to tell them that they have arrived. They need to reach a particular part of the hospital and to know when they have achieved this objective. Each sign must be precisely located; of suitable size, material, and colour; and made up of legible and beautiful letters that suit the building.l Anyone concerned with signposting a hospital must obtain a copy of the Department of Health and Social Security's Signs,2 which provides full details of the Health Signs system and language. This article offers a personal user's guide for those who care about the visual environment of their hospital, whether old3 or new,4 and want to try to make their hospital both more efficient and more attractive.
Tamiflu: "a nice little earner"
Authors: A. Jack
Journal: BMJ (2014)

Is the story of oseltamivir, and similar antiviral drugs, a classic one of big pharma greed? Andrew Jack finds a more nuanced reality

Viewed with hindsight, the story of flu antiviral drugs seems to be a classic story of “big pharma” greed. On the back of media hype and unfulfilled fears, a new medicine backed by only modest clinical data became a “blockbuster” generating billions of dollars for its producer. The reality is more nuanced, and the tale could easily instead have been a commercial and public health nightmare.

There is no doubt that Roche, the Swiss based pharmaceutical group, and its shareholders, have done very well from oseltamivir (Tamiflu). The drug became one of the most widely recognised medicines in the world as concern grew about a new flu pandemic in the middle of the previous decade.

As one City financial analyst puts it: “Tamiflu was a nice little earner. It reflected opportunistic action by a multinational corporation, which was able to be a little bit sharper in its marketing practices than you could now, given the debates over the disclosure of clinical data and how effective the drug was.”

Yet other related antiviral drugs in the same class of neuraminidase inhibitors failed to take off; oseltamivir itself was nearly a flop; public health pressures capped its pricing; and policy makers and the drug company itself struggled with scant clinical information on efficacy. Its success was linked to the unprecedented purchase of such a large volume of drugs to prepare for a future pandemic threat from a still poorly understood infectious disease.

Since its launch in 1999, oseltamivir has generated cumulative sales in excess of $18bn (£11bn; €13bn) for Roche. Half of the total expenditure was by governments and companies around the world for stockpiles for pandemic preparations. The …
Palliation of Large-Bowel Obstruction Due to Recurrent Rectosigmoid Tumor Using Self-Expandable Endoprostheses
Authors: C. Feretis, P. Benakis, C. Dimopoulos, K. Georgopoulos, A. Manouras, N. Apostolidis
Journal: Endoscopy (1996)

When large-bowel obstruction supervenes in patients with rectal tumor recurrence and extensive nonresectable disease, a proximal diverting colostomy may be indicated. In this study, nonsurgical palliation of the obstruction was attempted by inserting self-expandable endoprostheses to bridge the stenotic lesion. The endoprostheses were positioned in two patients with large-bowel obstruction due to recurrent stenotic tumor, and extensive disease excluding palliative resection. Self-expandable endoprostheses with inner diameters of 18 mm and 22 mm were successfully inserted under endoscopic and radiographic control. Proper expansion of the endoprostheses was achieved in both patients, resulting in immediate decompression of the bowel and lasting relief of the obstruction.