tbuckley/cabot-search huggingface dataset:
Endothelin in chronic heart failure: current position and future prospects
Authors: M. P. Love, J. J.V. McMurray
Journal: Cardiovascular Research (1996)

Though much has still to be learned about the various actions of endothelin-1 in human physiology, current evidence suggests an important role for the peptide in the pathophysiology of CHF. The development of novel and more effective therapeutic strategies for CHF is an important priority in cardiovascular medicine, and anti-endohelin drugs appear to offer promise in this regard. The impact of ACE inhibitors has been such that for a new treatment modality to be of real value in CHF, it will need to offer haemodynamic benefit over and above that already obtained with an ACE inhibitor; anti-endothelin drugs seem to have this potential [57,98]. Ongoing studies with agents which inhibit either the generation or actions of endothelin-1 will clarify its role in the pathophysiology of CHF and determine whether anti-endothelin drugs represent a further therapeutic advance in the treatment of this disease.
Psychiatric Complications with Chloroquine and Quinacrine
Authors: DON A. ROCKWELL
Journal: American Journal of Psychiatry (1968)

Quinacrine and chloroquine are being used increasingly in the United States in the treatment of malaria and as an anti-inflammatory agent. In the two cases reported here, quinacrine was administered within the normal therapeutic range and toxic psychoses resulted. Chloroquine produces similar conditions. The author predicts an increase in the complications of suicide, malingering, and toxic psychoses associated with the increasing use of the two drugs.
Repeat exposure to incremental doses of acetaminophen provides protection against acetaminophen-induced lethality in mice: An explanation for high acetaminophen dosage in humans without hepatic injury
Authors: Rass M. Shayiq, Dean W. Roberts, Kenneth Rothstein, John E. Snawder, Wayne Benson, Xiang Ma, Martin Black
Journal: Hepatology (1999)

In studies designed to simulate a clinical observation in which an individual became tolerant to normally lethal doses of acetaminophen (APAP), mice were pretreated with increasing doses of APAP for 8 days and challenged on day 9 with normally supralethal doses of APAP. These animals developed minimal hepatotoxicity after a challenge dose with a fourfold increase in LD 50 to 1,350 mg/kg. The pretreatment regimen resulted in hepatic changes including: centrilobular localization of 3–(cysteine– S –yl)APAP protein adducts, selective down–regulation of cytochrome P4502E1 (CYP2E1) and CYP1A2 that produced the toxic metabolite, N –acetyl– p –benzoquinone imine, higher levels of reduced glutathione (GSH), centrilobular inflammation, and a fourfold increase in hepatocellular proliferation. The protection against the lethal APAP doses afforded by pretreatment is secondary to these changes and to the associated regional shift in the bioactivation of the APAP challenge dose from centrilobular to periportal regions where CYP2E1 is not found, protective GSH is more abundant, and where cell–proliferative responses are better able to sustain repair. This shift in APAP bioactivation results in less–intense covalent binding that is more diffuse and spread uniformly throughout the hepatic lobe, most likely contributing to protection by delaying the early onset of liver injury that has been generally associated with centrilobular localization of the adducts. Intervention of APAP pretreatment-induced cell division in mice with colchicine left them resistant to a 500–mg/kg (normally lethal) dose of APAP, but unable to survive a 1,000–mg/kg APAP challenge dose. The data demonstrate multiple mechanistic components to the protection afforded by APAP pretreatment. Whereas metabolic and physiological changes not dependent on cell proliferation are adequate to protect against 500 mg/kg APAP, these changes plus a potentiated cell–proliferative response are necessary for protection against the supralethal 1,000–mg/kg APAP dose. Furthermore, the data document an uncoupling of the traditional association between covalent binding and toxicity, and suggest that the assessment of toxicity following repeated or chronic APAP exposure must consider altered drug interactions and parameters besides those historically used to assess acute APAP overdose. (Hepatology 1999;29:451–463.)
Abstract 2981: Regulation of Snail by DDX3 and ATM in response to DNA damage
Authors: Mianen Sun, Tong Zhou, Yancey Gillespie, Bo Xu, Richard Jope
Journal: Cancer Research (2010)

Abstract Epithelial-mesenchymal transition (EMT) is the initial step for cancer invasion and metastasis. The hallmark of EMT is the loss of expression of E-cadherin, a cell-cell adhesion protein, allowing cancer cells to gain mobility leaving the site of primary tumor to invade adjacent tissues. Snail, as a transcription repressor, binds to the E-boxes of E-cadherin and then inhibits E-cadherin expression. Thus, Snail is essential to trigger EMT during tumor progression and it has been implicated in the acquisition of invasive growth phenotype of tumors. There is a strong correlation of Snail over-expression with tumor invasion and metastasis. However, how Snail expression is regulated is not fully known. Here we report that Snail is regulated by DDX3, a DEAD box protein family member which contributes to cancer progression. Knock-down of DDX3 by shRNA reduces the basal level of Snail, and this is associated with reduced cell proliferation and migration. Snail protein and mRNA levels are increased in the presence of the HDAC inhibitors sodium butyrate or trichostatin A, and the increases are attenuated in cells with DDX3 knocked down. Treatment of cells with a DNA damaging agent camptothecin also enhances Snail protein levels in a DDX3 dependent manner. Therefore we conclude that DDX3 is required for the basal level and the increase in Snail induced by HDAC inhibitors or camptothecin, indicating that this action of DDX3 may contribute to its promotion of the progression of some cancers. This conclusion is supported by our clinical investigations that analysis of 31 glioblastoma patient samples has revealed a strong correlation between the levels of DDX3 and Snail. Snail is a phosphor-protein, and kinases responsible for phosphorylation include Pak1 and GSK3-β. We also find Pak-1 and GSK-3 independent Snail phosphorylation in response to DNA damage. Further we find that inhibition of the activity of the ATM kinase, a critical element in DNA damage responses, eliminated DNA damage-induced Snail stabilization. Taken together, these observations have highlighted a comprehensive signaling network regulating Snail in response to DNA damage and indicated a critical role of optimal DNA damage responses in tumor invasion and metastasis. 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 2981.
The National Practitioner Data Bank: bane or benefit?
Authors: B. S. Goffen
Journal: JAMA (1992)

To the Editor.  —The Special Communication on the National Practitioner Data Bank (NPDB) 1 reflects remarkable variability in the reporting of adverse actions involving practitioners' licensure, privileging, and malpractice by the 53 localities providing the raw data accepted for inclusion. For example, the authors speculate on, but provide no good explanation for, the difference by a factor of 10 between the adverse action rates for New York State and Mississippi. Similarly, the clinical privilege action rate varies by a factor of five between Illinois (0.7) and Washington (3.2), Colorado (3.6), or Arizona (3.6).  Considering the lack of uniformity in the laws regulating medical practice in the reporting localities, the variability noted should be expected. At the same time, without evaluating individually each action to eliminate those that fall outside the norm for the United States, the value of the project is compromised.  The following examples of physician censure by the
ULTRA-VIOLET LIGHT AND VACCINE VIRUS
Authors: Thomas M. Rivers, Henry Stevens, Frederick L. Gates
Journal: The Journal of Experimental Medicine (1928)

Rabbit skin treated for a few minutes with ultra-violet light and then inoculated at once with vaccine virus is less susceptible to the action of the virus than is untreated skin. If 24, 48, or 72 hours elapse between the time of irradiation and inoculation, the treated skin appears to be more susceptible than is untreated skin. Skin repeatedly exposed to ultra-violet light is less susceptible to the action of vaccine virus than is non-irradiated skin.
Sensitization to allergens of house‐dust mite in adults with atopic dermatitis in a cold temperate region
Authors: L Holm, S Öhman, M Van Hage‐hamsten, A Scheynius
Journal: Allergy (1999)

Background: An IgE‐mediated contact reaction to airborne allergens has been suggested as one important pathogenetic mechanism in atopic dermatitis (AD). The house‐dust mite (HDM) might be a common allergen involved. In Scandinavia, sensitization to HDM has been rare, probably because of the cold, dry climate. However, recent studies indicate high levels of domestic mites and HDM allergen in 15–20% of homes in central and northern Sweden. Methods: To evaluate the importance of the HDM in patients with AD in the Stockholm region, we screened 81 adult Stockholm residents with AD, for the prevalence and degree of sensitization to the HDM, according to specific IgE (RAST), skin prick test (SPT), and atopy patch test (APT). We also assessed the HDM exposure in their homes and correlated the results with clinical history, severity of the dermatitis, and type of residence during childhood and today. Results: The sensitization rate to HDM was high (56% according to RAST, 24% according to SPT, and 47% according to APT), and 20% of the patients were exposed to HDM allergens in their beds. Mite exposure seemed to aggravate the dermatitis in highly sensitized patients. Conclusions: The results indicate that we have to take the HDM into account when discussing aggravating factors in adult patients with AD in the Stockholm region.
Australia may alter compensation scheme
Authors: C Zinn
Journal: BMJ (1994)

Medical mistakes by Australian doctors are costing taxpayers more than $A500m (pounds sterling 243m) a year, but compensation is being paid to only a couple of thousand patients, said a government report last week. In one of his last actions as federal health minister Senator Graham Richardson has proposed an overhaul of the medical compensation system after releasing the 400 page report from the Government Professional Indemnity Review. Its author, Ms Fiona Tito, found that up to 146 000 patients a year suffered from medical mistakes but that only 2000 received compensation. Medical mistakes - …
Abstract 4327: Development of pancreatic cancer specific targeting agents as imaging agents
Authors: Yoshiko Maeda, Wenwu Xiao, Ruiwu Liu, Shiro Uriyama, Anirban Maitra, Kit Lam, Pappanaicken R. Kumaresan
Journal: Cancer Research (2010)

Abstract In the “one bead one compound” combinatorial library method, millions of In the “one bead one compound” combinatorial library method, millions of random peptides can be generated rapidly, such that each bead displays only one peptide entity. When live cancer cells are co-cultured with these peptide-bead libraries, beads with cell adhesion peptides will be covered entirely by the cells. Low passage human pancreatic cancer (PDAC cells;XPA1, XPA3) and immortalized normal pancreas cells were used for this study. Positive peptide-beads were then isolated for sequence analysis. Using this high throughput screening approach, we evaluated four different peptide libraries and identified several peptides that bind to pancreatic cancer cells. To test their binding specificity, these peptides were labeled with fluorophor or biotinylated, and used as reagents for in vivo imaging. Athymic nude mice were used to induce pancreatic xenografts and very low uptake in liver. One of the cyclic peptide (PCa-pep6) targets pancreatic xenografts selectively. Based on the antibody blocking assay, PCa-pep6 binds to alpha-2 and alpha-6 integrins which are over expressed in pancreatic cancer. Therefore it may potentially be used as lead compounds for the development of high affinity and high specificity therapeutic and imaging agents for pancreatic cancers. This work is supported by grant RO3-CA129786 Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. 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 4327.
William Harford Rutherford
Authors: John Rutherford, Jonathan Marrow
Journal: BMJ (2008)

William Rutherford, whose death is announced, worked as a medical missionary for many years in India. He returned to work in accident and emergency medicine in Belfast. He was personally involved in the care of many of the victims of the Troubles in that city and also worked at a personal level for better relations between communities. He made a major contribution to the development of accident and emergency medicine throughout the United Kingdom, and internationally. He took a lead in pressing the UK government to introduce legislation to make the wearing of seat belts compulsory, and his study of rates of injury before and after the change in the law provided strong evidence in support of the measure.

William Rutherford, the son of a Presbyterian minister, was born in Warrenpoint, County Down, at the foot of the Mourne mountains, and brought up around the time of the partition of Ireland. At the age of 6 he moved with his family to Dun Laoghaire, on the coast near Dublin, but William went to boarding school at Campbell College in Belfast. His father thought learning some Greek would be useful if he chose to become a minister, but William disliked the teacher who taught Greek, and asked to learn physics and chemistry instead. When asked why he wished to change he made the excuse it was because he wanted to do medicine.

He did go on to study medicine at Trinity College, Dublin (TCD), starting in 1939. Like many young men at this time, he had some heart-searching about the rightness of continuing studies in wartime but he was persuaded to press on. William’s older sister studied medicine in Dublin at the same time. They had to cope with their father’s death from cancer while they were students, with changes in …
Risk of severe liver disease in nonalcoholic fatty liver disease: Role of insulin resistance
Authors: Anna Ludovica Fracanzani, Luca Valenti, Silvia Fargion
Journal: Hepatology (2008)

We thank Dr Manco and coworkers for their comments to our manuscript.1 They confirm in a pediatric population a high prevalence of hepatic fibrosis in subjects with biopsy confirmed nonalcoholic fatty liver disease (NAFLD) and aminotransferase (ALT) levels within normal limits, and an association between the degree of insulin resistance and the severity of liver damage.2 The similarity in findings in Italian children and adults with NAFLD reinforces the message of our manuscript. A key aspect is that, even in children with a short-lived history of steatosis, insulin resistance is strongly associated with fibrosis independently of ALT values. This suggests that insulin resistance may precede liver damage and be directly involved in the fibrogenic process. These data allow us to speculate that genetic factors regulating different steps of the insulin signaling pathway (modulating not only glucose and lipoprotein metabolism, but also hepatocellular survival to apoptotic stimuli,3, 4 and / or alterations in adipocytokines levels may be crucial in determining the severity of NAFLD. However, no definite data are yet available to support this hypothesis. Large collaborative studies enlisting both pediatric and adult patients of different ethnic groups will be required to clarify this issue, and may prove useful in the quest for the identification of reliable markers able to discriminate patients with uncomplicated steatosis from those with progressive nonalcoholic steatohepatitis (NASH) since the early stages of the disease. In conclusion, the data underscore that NAFLD has to be considered a potentially progressive disease even in the presence of normal ALT levels. In particular, evidence of alterations in glucose metabolism parameters should prompt a careful follow up of patients independently of their age to prevent major complications. Anna Ludovica Fracanzani*, Luca Valenti*, Silvia Fargion*, * Dipartimento Medicina Interna, Centro Malattie Metaboliche del Fegato, Fondazione IRCCS Ospedale Maggiore Policlinico, Università di Milano, Italia.
309 Quantitative tests (QLFTS) detect impaired hepatic function in a high proportion of chronic hepatitis C patients with fibrosis or compensated cirrhosis and may predict risk of cirrhosis, splenomegally, and varices
Authors: G EVERSON, M KUGELMAS, J DESANTOS, S LAURISKI, M SHIFFMAN, R STERLING, H CHARLOTTE, T MORGAN, J HOEFS, N MILNE
Journal: Hepatology (2003)
Flow cytometric analysis of changes in cytoskeletal proteins during platelet destruction and activation using a monoclonal antibody against platelet myosin
Authors: Kazuyuki Yamaguchi, Shosaku Nomura, Hirofumi Kido, Toshihiro Kawakatsu, Tsutomu Fukuroi, Masahiro Suzuki, Kenjiro Hamamoto, Mutsumasa Yanabu, Terutoshi Kokawa, Kojiro Yasunaga
Journal: American Journal of Hematology (1993)

Abstract We developed a new monoclonal antibody directed against platelet myosin (NNKY6‐19). Using this antibody, we analyzed platelet cytoskeletal changes related to stimulation with thrombin and to long‐term storage. Immunoelectron microscopy showed increased binding of NNKY6‐19 to pseudopods and the open canalicular system during treatment with thrombin (0.1 U/ml) and during storage for 7 days. Flow cytometry also showed increased binding to platelets by NNKY6‐19 and an antiactin monoclonal antibody during storage. The binding of NNKY6‐19 showed an increase greater than that with the antiactin antibody after storage of platelets for 7 days and after thrombin treatment. These findings indicated that the increased binding of NNKY6‐19 had some relationship to changes in intracellular myosin and platelet morphology. Thus use of NNKY6‐19 allowed analysis of subtle changes related to platelet activation, which differed from those detected by antibodies against platelet glycoproteins or by the antiactin antibody. This antibody appears to provide a simple method for studying changes in platelet cytoskeletal and surface proteins. © 1993 Wiley‐Liss, Inc.
Effect of Helicobacter pylori infection on colloidal bismuth subcitrate concentration in gastric mucus.
Authors: D J Munoz, C Tasman-Jones, J Pybus
Journal: Gut (1992)

Necropsy gastric mucus infected with Helicobacter pylori has a reduced capacity to concentrate colloidal bismuth subcitrate when compared with non-infected mucus. Mucus mounted in a modified in vitro diffusion chamber was bathed with colloidal bismuth subcitrate solutions at different concentrations and pH levels. Bismuth was measured by atomic absorption spectrophotometry to assess intramucus colloidal bismuth subcitrate concentrations. Bismuth concentrations in non-infected mucus were higher than in Helicobacter pylori infected mucus at all experimental colloidal bismuth subcitrate concentrations and pH levels. Regardless of the infection status, the intramucus concentration of colloidal bismuth subcitrate was dependent upon the concentration of the bathing solution and independent of the pH and the mucus thickness. Colloidal bismuth subcitrate solubility in saline solution varied with pH, and was least soluble in the pH range 1.1 to 3.25 and more soluble above and below this pH range. This study suggests that Helicobacter pylori infection is associated with physicochemical changes in the gastric mucus with a reduction in its capacity to concentrate colloidal bismuth subcitrate. Such a reduction may compromise the attainment of optimum colloidal bismuth subcitrate concentrations necessary for its bactericidal activity.
THE SURGICAL TREATMENT OF HYPERINSULINISM
Authors: FRANK N. ALLAN
Journal: JAMA (1930)

Hyperinsulinism, in cases in which insulin has not been administered, is now recognized as an entity. It represents the antithesis of diabetes, just as hyperthyroidism is the reverse of myxedema. It is characterized by a constant tendency of the level of the blood sugar to fall. This necessitates the ingestion of food or sugar at frequent intervals to prevent the occurrence of hypoglycemic symptoms. The condition was first reported by Harris, 1 who introduced the term hyperinsulinism. He observed, in several cases, a subnormal concentration of blood sugar and certain symptoms resembling those seen in diabetic patients after overdosage with insulin. Further attention has been directed to the disorder by the observation, in a number of cases, of the severest symptoms of hypoglycemia, namely, mental confusion, coma and convulsions.  A definite pathologic basis for hyperinsulinism was demonstrated through the study of a case seen at the Mayo Clinic in 1926.
CXL-1020, A NOVEL HNO DONOR, DECREASES MYOCARDIAL LOADING AND ENHANCES LOAD-INDEPENDENT LUSITROPY AND INOTROPY VIA A ?-AR/ACE INDEPENDENT MECHANISM
Authors: Carlos L. Del Rio, Yukie Ueyama, Robert L. Hamlin, John Reardon, Reza Mazhari
Journal: Journal of the American College of Cardiology (2011)
Wrong-Way Traffic in the Gullet
Authors: Samuel Vaisrub
Journal: JAMA (1976)

The traditional rivalry between medicine and surgery in the therapy of gastrointestinal disorders—peptic ulcer, Crohn disease, ulcerative colitis—has not bypassed gastroesophageal reflux. As expected, competition focuses on the moderately severe cases. Patients with mild to moderate symptoms of postprandial or postural discomfort, who do well on medical treatment, pose no dilemmas, nor do the advanced cases with intractable esophagitis, bleeding, esophageal ulcer, or stricture, for whom surgery appears to be the inevitable answer. Quandaries arise only when patients with distressing symptoms of as yet uncomplicated reflux respond poorly to medical treatment. Should the physician persist with this treatment? And, if so, for how long? As a result of recently acquired insights into the nature of gastroesophageal reflux, surgery has much more to offer to the sufferer from this disorder than it did but a short while back. Manometric measurements have now conclusively demonstrated that an incompetent physiologic gastroesophageal sphincter (pressure