tbuckley/cabot-search huggingface dataset:
Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels.
Authors: C B Treasure, J L Klein, J A Vita, S V Manoukian, G H Renwick, A P Selwyn, P Ganz, R W Alexander
Journal: Circulation (1993)

BACKGROUND Patients with hypertension and myocardial hypertrophy may have signs and symptoms of myocardial ischemia in the absence of obstructive coronary disease. Prior investigations have demonstrated impaired coronary flow reserve and have led to speculation that microvascular dysfunction might contribute to ischemia in these patients. Experimental studies have shown that the endothelium, an important regulator of microvascular tone, can be damaged by hypertension and is dysfunctional in cardiomyopathy. We hypothesized that endothelium-dependent vasodilation is impaired in the coronary microvasculature of patients with hypertension and ventricular hypertrophy. METHODS AND RESULTS We studied coronary microvascular responses in 10 patients with left ventricular hypertrophy secondary to essential hypertension (HTN) (mean arterial pressure at catheterization, 151/94 mm Hg; mean posterior wall thickness, 1.4 +/- 0.1 cm) and nine normal control subjects with no history of hypertension (mean arterial pressure at catheterization, 128/75 mm Hg; mean posterior wall thickness, 1.0 +/- 0.02 cm) using the intracoronary Doppler catheter and quantitative angiography to assess changes in coronary blood flow (CBF). All patients had normal left ventricular systolic function. To assess microvascular endothelial function, we infused the endothelium-dependent vasodilator acetylcholine (10(-8)-10(-6) M) and the endothelium-independent vasodilator adenosine (10(-6)-10(-4) M) into the left anterior descending coronary artery. In response to acetylcholine, CBF increased only 32 +/- 25% in HTN patients, whereas CBF increased 192 +/- 39% in normal control subjects (p = 0.003). CBF increased 465 +/- 93% in HTN patients and 439 +/- 41% in normal control subjects in response to adenosine (p = NS). The proportion of coronary flow reserve attributable to endothelium-dependent dilation (obtained from peak acetylcholine/peak adenosine flow response) was 48 +/- 9% in normal control subjects but only 7 +/- 8% in HTN patients (p = 0.008). CONCLUSIONS Endothelium-dependent vasodilation is markedly impaired in the coronary microvessels of patients with hypertension and ventricular hypertrophy. Loss of this vasodilator mechanism may contribute to disordered coronary flow regulation and the ischemic manifestations of hypertensive heart disease.
A Microperfusion Study of Phsophate Reabsorption by the Rat Proximal Renal Tubule EFFECT OF PARATHYROID HORMONE
Authors: Norman Bank, Hagop S. Aynedjian, Stephen W. Weinstein
Journal: Journal of Clinical Investigation (1974)

To study the mechanism of phsophate reabsorption by the proximal tubule and the effect of parathyroid hormone (PTH), microperfusion experiments were carried out in rats. Segments of proximal tubule isolated by oil blocks were perfused in vivo with one of three solutions, each containing 152 meq/liter Na(+) and 2 mmol/liter phosphate, but otherwise differing in composition. The pH of solution 1 was 6.05-6.63, indicating that 60-85% of the phosphate was in the form of H(2)PO(4) (-). The pH of solution 2 was 7.56-7.85, and 85-92% of the phosphate was in the form of HPO(4) (=). Solution 3 contained HCO(3) (-) and glucose and had a pH of 7.50-7.65. When the proximal tubules were perfused with solution 1, the (32)P concentration in the collected perfusate was found to be consistently lower than in the initial perfusion solution. In sharp contrast, when the tubules were perfused with solutions 2 or 3, (32)P concentration usually rose above that in the initial solution. Water (and persumably Na(+)) reabsorption, as measured with [(3)H]inulin, was the same with the acid and alkaline solutions. Administration of partially purified PTH clearly prevented the fall in phosphate concentration with the acid solution, but had a less discernible effect on phosphate reabsorption with the two alkaline solutions. Measurements of pH within the perfused segments with antimony microelectrodes demonstrated that PTH enhanced alkalinization of the acid perfusion solution. The findings are consistent with the view that H(2)PO(4) (-) is reabsorbed preferentially over HPO(4) (=). This can be attributed to either an active transport mechanism for H(2)PO(4) (-) or selective membrane permeability to this anion. PTH appears to either inhibit an active transport process for H(2)PO(4) (-), or to interfere with passive diffusion of phosphate by alkalinizing the tubular lumen.
Demographic Changes in the United States
Authors: C. Anello, C. S. Lao
Journal: JAMA (1978)

<h3>To the Editor.—</h3> In March 1976, Cruz-Coke<sup>1</sup>reported on a pattern of "genetic changes" in Chile. Of particular importance were the findings that the introduction of birth control measures has resulted in lowerbirth rates, lower parity, lower perinatal mortality, lower antenatal mortality, a fall in the sex ratio in stillbirths, and an increased sex ratio at birth. Cruz-Coke also found the incidence of anencephaly increased. He attributed this increase to low parity and low sex-ratio in stillbirths. Although no mass birth control campaign was initiated by the US government, oral contraceptive use and family planning have come into general use in the past 15 years. We have used data from the National Center for Health Statistics and constructed a Table of demographic changes in the United States from 1960 to 1974. The US data support the Chilean data in the findings related to parity, birth rates, and sex
Abstract 2920: Estrogen, tamoxifen, and Akt modulate expression of putative housekeeping genes in breast cancer cells
Authors: Khyati Niral Shah, Jesika S. Faridi
Journal: Cancer Research (2011)

Abstract For quantitative reverse transcription-polymerase chain reaction (RT-qPCR), accurate data normalization requires the use of a stable reference gene. In estrogen-dependent cells, the identification of an appropriate housekeeping gene that is unaltered regardless of experimental conditions has been difficult. Additionally since cross-talk between the estrogen receptor and Akt pathways has been reported, the goal of this study was to identify the most stable reference gene for RT-qPCR (from a panel of nine putative housekeeping genes) that remains unaltered despite estrogen or tamoxifen treatment or stable overexpression of active Akt. Gene expression of nine candidate genes (GAPDH, ACTB, RPL13A, PGK1, TFRC, PPIA, HPRT1, B2M, and GUSB) was determined in parental and Akt overexpressing MCF-7 breast cancer cells treated with estrogen, tamoxifen, or vehicle, and gene stability was analyzed using two different statistical models. We observed that GAPDH, HPRT1, PGK1, and B2M were highly estrogen-regulated in parental MCF-7 cells. We also observed that seven out of the nine candidate genes were significantly altered in at least one of the Akt overexpressing MCF-7 cells. Based on our results, we suggest RPL13A as the most suitable internal reference gene that is both stable and remains unaltered in MCF-7 cells regardless of estrogen or tamoxifen treatment or Akt overexpression. In addition, our work emphasizes the importance of a preliminary study to validate each reference gene that will used for RT-qPCR. 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 2920. doi:10.1158/1538-7445.AM2011-2920
Textbooks for Pleasure
Authors: Henry Miller
Journal: JAMA (1965)

The present title I borrow from that of<i>Proverbs for Pleasure</i>, which although not itself a textbook is a fascinating compilation of the world's most cogent proverbial sayings, assembled in 1954 by H. Pullar-Strecker, a psychiatrist who came to England from Germany in the thirties. This book is a sheer delight: it is a matter of taste whether the reader prefers "Always take the fee while the tear is in the eye," "The higher the ape climbs the more he shows his bald behind," "The poor are cured by work, the rich by the doctor," or "When they came to shoe the Pasha's horses the beetle stretched out its leg." Comprising a distillation of the traditional wisdom of Arab, Jew, Scot, Muscovite, and Oriental, this is the perfect bedside book. It is the sober truth that the present writer has lost so many copies to his friends (and patients) that
Intracellular calcium concentration ([Ca12+]) in vascular smooth muscle cells (VSMC) of cirrhotic rats. Effect of angiotensin II (AII)
Authors: A. Castro, W. Jiménez, J. Llibre, J. Clària, J. Gaya, J. Ros, M. Asbert, V. Arroyo, F. Rivera, J. Rodés
Journal: Journal of Hepatology (1991)
Fibrillin immunoreactivity is associated with normal or fragmented elastic microfibrils at the dermal-epidermal junction in recessive dystrophic epidermolysis bullosa
Authors: J.A. MCGRATH, L.Y. SAKAI, R.A.J. EADY
Journal: British Journal of Dermatology (2006)

Elastic microfibrils containing fibrillin are a part of the fibroreticular network of normal epidermal basement membrane. In dystrophic epidermolysis bullosa (DEB) at least one other fibroreticular component, anchoring fibrils, which contain type VII collagen, is known to be abnormal. We therefore questioned whether elastic microfibrils and fibrillin expression might also be abnormal in DEB. By indirect immunofluorescence, and pre-embedding immunogold electron microscopy using a monoclonal antifibrillin antibody, we found no difference from control samples in either the quantity of the labelling or in the ultrastructural appearances of the immunolabelled fibrils in intact DEB skin. In areas of dermal-epidermal separation, however, we observed a number of thin, fragmented sublamina densa wisp-like structures, which still labelled for fibrillin despite lacking the typical ultrastructural features of normal elastic microfibril bundles. As a consequence of blistering in DEB, elastic microfibril bundles are disrupted, and fragmented microfibrils may still remain attached to the blister roofs. Many of these elastic microfibrils cannot be distinguished from rudimentary or altered anchoring fibrils on morphology alone, and might therefore account for misinterpretation of ultrastructural disorders of the dermal-epidermal junction. We postulate that, in intact skin, elastic microfibrils might contribute to dermal-epidermal adherence, in the absence of normal-functioning anchoring fibrils.
Scientists fertilise mouse eggs without sperm
Authors: D. Josefson
Journal: BMJ (2001)

Australian researchers have devised a method of fertilising eggs without sperm. Dr Orly Lacham-Kaplan's research unit at the Monash University's Institute of Reproduction and Development in Melbourne developed the procedure with the hopes that it could one day serve as a viable alternative to sperm donation for infertile men.

Theoretically, it may also be used to produce biological children for homosexual partners of either sex. The technique relies on somatic cell transfer and is …
Electrocardiographic Changes after Glucose Ingestion
Authors: LEON D. OSTRANDER, BELSON JACK WEINSTEIN
Journal: Circulation (1964)

In order to determine the effect of glucose ingestion on the electrocardiogram, 23 men with coronary heart disease and 30 without known heart disease had electrocardiograms in the fasting state and serial tracings at 30-minute intervals after the administration of 100 Gm. of oral glucose. In both groups the mean changes after glucose ingestion were slight ST-segment depression, a moderate decrease in T-wave amplitude, and a slight increase in heart rate, although individual variability was great. When the electrocardiograms were classified by a uniform coding system, new ST-segment or T-wave classifications were recorded for eight of 23 subjects with coronary heart disease and three of 30 men without known heart disease. Since ST-segment and T-wave changes regularly follow glucose ingestion and are sometimes of sufficient degree to suggest heart disease in apparently normal individuals, electrocardiograms recorded within several hours after glucose administration must be interpreted with caution. Because of the uncertain significance of postprandial ST-segment and T-wave changes, electrocardiograms after glucose ingestion do not appear to be a very useful method for the detection of occult heart disease. Glucose ingestion should be avoided before routine clinical tracings.
Zoledronic Acid for Treatment of Osteopenia and Osteoporosis in Women with Primary Breast Cancer (BC) Undergoing Adjuvant Aromatase Inhibitor (AI) Therapy.
Authors: S. Hines, J. Sloan, P. Atherton, E. Perez, S. Dakhil, D. Johnson, P. Reddy, R. Dalton, B. Mattar, C. Loprinzi
Journal: Cancer Research (2009)

Abstract Background: Postmenopausal women with significant osteopenia/osteoporosis are at increased risk of fracture, a risk that is exacerbated by the use of Aromatase Inhibitors (AIs). Bisphosphonates may be used for these patients because there is no known interaction with estrogen and/or progesterone receptors (ER, PR). This study evaluated the concurrent use of zoledronic acid in patients with significant osteopenia or osteoporosis who received initial adjuvant letrozole therapy for primary BC, to determine if further bone mineral density (BMD) loss could be prevented.Methods: Postmenopausal women with Stage I-IIIa, ER and/or PR + BC, no evidence of metastatic disease, and a BMD T-score &amp;lt; -2.0 were treated with daily letrozole 2.5 mg/d, vitamin D 400 international units/d, calcium 500 mg twice daily, and 4 mg I.V. zoledronic acid every 6 months (for 5 years). The BMD was measured at baseline and at one year. Kruskall-Wallis p-value methodology was used as the method of statistical analysis. Since this was a single-arm study, the analysis plan was primarily descriptive. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year.Results: 60 patients were enrolled; 46 completed 1 year of treatment. Mean patient age was 67 years, with 44% having taken prior tamoxifen. At 1 year (see figure 1), LS BMD increased 2.66% (p=0.01), femoral neck (FN) BMD increased 4.81% (p=0.01), and any measured endpoint (within the LS or FN) increased 4.55% (p=0.0052). 7% of patients experienced a fracture vs.13% with a pre-existing history of fracture before enrollment. No patients had disease recurrence during year 1. Toxicity was minimal with arthralgia as the most common complaint. There were no reports of osteonecrosis of the jaw.Conclusion: Zoledronic acid prevents additional bone loss in postmenopausal women with significant osteopenia or osteoporosis initiating letrozole. Treatment with zoledronic acid was associated with an improvement in BMD. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2103.
Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in <i>Braf-</i>Mutant Human Cutaneous Melanoma Cells
Authors: Y.N. Vashisht Gopal, Wanleng Deng, Scott E. Woodman, Kakajan Komurov, Prahlad Ram, Paul D. Smith, Michael A. Davies
Journal: Cancer Research (2010)

Abstract The majority of melanomas show constitutive activation of the RAS-RAF-MAP/ERK kinase (MEK)-mitogen-activated protein kinase (MAPK) pathway. AZD6244 is a selective MEK1/2 inhibitor that markedly reduces tumor P-MAPK levels, but it produces few clinical responses in melanoma patients. An improved understanding of the determinants of resistance to AZD6244 may lead to improved patient selection and effective combinatorial approaches. The effects of AZD6244 on cell growth and survival were tested in a total of 14 Braf-mutant and 3 wild-type human cutaneous melanoma cell lines. Quantitative assessment of phospho-protein levels in the Braf-mutant cell lines by reverse phase protein array (RPPA) analysis showed no significant association between P-MEK or P-MAPK levels and AZD6244 sensitivity, but activation-specific markers in the phosphoinositide 3-kinase (PI3K)-AKT pathway correlated with resistance. We also identified resistant cell lines without basal activation of the PI3K-AKT pathway. RPPA characterization of the time-dependent changes in signaling pathways revealed that AZD6244 produced durable and potent inhibition of P-MAPK in sensitive and resistant Braf-mutant cell lines, but several resistant lines showed AZD6244-induced activation of AKT. In contrast, sensitive cell lines showed AZD6244 treatment–induced upregulation of PTEN protein and mRNA expression. Inhibition of AKT, TORC1/2, or insulin-like growth factor I receptor blocked AZD6244-induced activation of AKT and resulted in synergistic cell killing with AZD6244. These findings identify basal and treatment-induced regulation of the PI3K-AKT pathway as a critical regulator of AZD6244 sensitivity in Braf-mutant cutaneous melanoma cells and the novel regulation of PTEN expression by AZD6244 in sensitive cells, and suggest new combinatorial approaches for patients. Cancer Res; 70(21); 8736–47. ©2010 AACR.
Novel Mechanism of Action for Hydralazine
Authors: Helen J. Knowles, Ya-Min Tian, David R. Mole, Adrian L. Harris
Journal: Circulation Research (2004)

The vasodilator hydralazine, used clinically in cardiovascular therapy, relaxes arterial smooth muscle by inhibiting accumulation of intracellular free Ca 2+ via an unidentified primary target. Collagen prolyl hydroxylase is a known target of hydralazine. We therefore investigated whether inhibition of other members of this enzyme family, namely the hypoxia-inducible factor (HIF)-regulating O 2 -dependent prolyl hydroxylase domain (PHD) enzymes, could represent a novel mechanism of action. Hydralazine induced rapid and transient expression of HIF-1α and downstream targets of HIF (endothelin-1, adrenomedullin, haem oxygenase 1, and vascular endothelial growth factor [VEGF]) in endothelial and smooth muscle cells and induced endothelial cell-specific proliferation. Hydralazine dose-dependently inhibited PHD activity and induced nonhydroxylated HIF-1α, evidence for HIF stabilization specifically by inhibition of PHD enzyme activity. In vivo, hydralazine induced HIF-1α and VEGF protein in tissue extracts and elevated plasma VEGF levels. In sponge angiogenesis assays, hydralazine increased stromal cell infiltration and blood vessel density versus control animals. Thus, hydralazine activates the HIF pathway through inhibition of PHD activity and initiates a pro-angiogenic phenotype. This represents a novel mechanism of action for hydralazine and presents HIF as a potential target for treatment of ischemic disease.
Short to long term mortality of patients hospitalised with heart failure in the Czech Republic—a report from the EuroHeart Failure Survey
Authors: Hana Rosolova, Jakub Cech, Jaroslav Simon, Jindrich Spinar, Ruzena Jandova, Jiri Widimský sen, Lubomir Holubec, Ondrej Topolcan
Journal: European Journal of Heart Failure (2005)
The legacy of Edward Jenner
Authors: M. M Levine
Journal: BMJ (1996)

Two hundred years after the pioneering clinical experiments of Edward Jenner, who inoculated humans with cowpox to prevent smallpox, we find ourselves at the threshold of a golden age of vaccinology. Much attention has recently been directed at the advances in modern biotechnology that are giving rise to exciting new vaccine candidates. Nevertheless, a long and arduous journey lies between being an innovative concept and becoming a licensed product that can serve as a public health tool. In fact, few concepts survive to become products. Less well appreciated are the advances in clinical vaccine testing that allow a vaccine to progress towards licensing; the epidemiological techniques devised to appraise its effectiveness after licensing, when the vaccine is used under real life conditions; and the tactics used to achieve high levels of vaccine coverage, particularly in less developed countries.

Biotechnology has opened entire new approaches to vaccine development, such as the rational and precise attenuation of bacteria and viruses to serve as live vaccines,1 the direct inoculation with plasmid DNA encoding protective antigens (“naked DNA” vaccines), and the microencapsulation of antigens to enhance immunogenicity and modulate the kinetics and type of immune response.2 Consequently, at various stages …
Low Dominance and High Intropunitiveness in Ulcerative Colitis and Irritable Bowel Syndrome
Authors: G. Arapakis, C.G. Lyketsos, K. Gerolymatos, S.C. Richardson, G.C. Lyketsos
Journal: Psychotherapy and Psychosomatics (1986)

Two experimental groups of patients with ulcerative colitis (UC) and irritable bowel syndrome (IBS) were compared for hostile personality characteristics and dysthymic states with physically ill patients. Both experimental groups were found to be less dominant, more intropunitive, more anxious and more depressed than the control group. IBS patients, however, were more dominant and less intropunitive than UC patients. Low dominance has been associated with psychosomatic illnesses, and high intropunitiveness with neurotic formation. Both UC and IBS patients have been found to be severely neurotic, a fact reflecting the concurrence of the psychosomatic and neurotic defences in these diseases. More IBS patients had premorbid psychiatric symptoms in comparison with controls and UC patients.
Mortality Study of the Significance of Extrasystoles in an Insured Population
Authors: MANUEL RODSTEIN, LEON WOLLOCH, RICHARD S. GUBNER
Journal: Circulation (1971)

The prognostic significance of extrasystoles was evaluated in 712 insured persons with this finding who were followed for an average period of 18 years. At the end of the study 356 persons were alive and 125 were dead. Two hundred and thirty-one persons had terminated their policies at a prior date by maturity or discontinuance and were not followed further. Although the lack of follow-up to 1968 of this latter group imposes limitations on the results and conclusions of the study, their exclusion resulted in no significant change in the mortality ratio of the remaining group of 481 persons followed to death or the anniversary of their policies in 1968. The observed mortality ratios showed no appreciable increase in a group of 604 individuals who were considered to have a normal life expectancy except for the presence of extrasystoles at the time of evaluation for insurance. Similar normal mortality ratios were observed in subgroups with simple and complex supraventricular and ventricular extrasystoles. There was no appreciable difference in mortality when those under 40 and those 40 years of age and over at the time of discovery of extrasystoles were compared. There was no significant difference in mortality between those who responded to exercise with an increase in the number of extrasystoles and those who had no change or a decrease immediately after exercise. An increase in the number of extrasystoles per minute was associated with an increase in mortality. There was a low incidence of sudden death among those with supraventricular extrasystoles. Ventricular extrasystoles, particularly those of complex types, were associated with a high incidence of death from myocardial infarction, often of a sudden nature, particularly in persons under the age of 56 years. There were too few cases of the individual types of complex ventricular extrasystoles to determine whether this was a characteristic of the group as a whole or of one or more of its constituent types. Ventricular extrasystoles in the presence of other cardiac abnormalities and/or elevation of the blood pressure were associated with an increase in mortality. The mortality experience in such persons was distinctly higher than in those with similar degrees of substandard expected mortality whose abnormalities were not of a cardiovascular nature.