tbuckley/cabot-search huggingface dataset:
On the Use of Belladonna in Certain Cases of Hernia
Authors: W. S. Batten
Journal: BMJ (1882)

sented elsewhere, if the full quantity have been dispensed, the order or prescription would be null and void.If this should be impossible, I would suggest that only one druggist, in a population of ten thousand, should be licensed to sell poisons of this description ; and that his premises and books should be regularly inspected by a Government in- spector, like the brewers and beer-shops; that his term of licence should be two or three years, when another druggist in the town should have his turn.This plan should be so arranged as not to interfere with the dispensing of physician's prescriptions.Another subject, bearing somewhat on the above, demands our attention; and that is, the prevention of the use of arsenic in the manu- facture of our wall-papers, dress-fabrics, etc.The common idea is, that the only papers which contain this poison are certain green shades;
First Clinical Experience with α-Emitting Radium-223 in the Treatment of Skeletal Metastases
Authors: Sten Nilsson, Roy H. Larsen, Sophie D. Fosså, Lise Balteskard, Kari W. Borch, Jan-Erik Westlin, Gro Salberg, Øyvind S. Bruland
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The main goals were to study the safety and tolerability of the α-emitter radium-223 (223Ra) in breast and prostate cancer patients with skeletal metastases. In addition, pain palliation was evaluated. Experimental Design: Fifteen prostate and 10 breast cancer patients enrolled in a phase I trial received a single i.v. injection of 223Ra. Five patients were included at each of the dosages: 46, 93, 163, 213, or 250 kBq/kg and followed for 8 weeks. Palliative response was evaluated according to the pain scale of the European Organization for Research and Treatment of Cancer QLQ C30 questionnaire at baseline and at 1, 4, and 8 weeks after injection. Results: Weekly blood sampling during follow-up revealed mild and reversible myelosuppression with nadir 2 to 4 weeks after the injection. Importantly, for thrombocytes only grade 1 toxicity was reported. Grade 3 neutropenia and leucopenia occurred in two and three patients, respectively. Mild, transient diarrhea was observed in 10 of the 25 patients. Nausea and vomiting was more frequently observed in the highest dosage group. Serum alkaline phosphatase decreased with nadir averages of 29.5% in females and 52.1% in males. Pain relief was reported by 52%, 60%, and 56% of the patients after 7 days, 4, and 8 weeks, respectively. 223Ra cleared rapidly from blood and was below 1% of initial level at 24 hours. Gamma camera images indicated, in accordance with pretreatment 99mTc-MDP scans, accumulation of 223Ra in skeletal lesions. Elimination was mainly intestinal. Median survival exceeded 20 months. Conclusions: 223Ra was well tolerated at therapeutically relevant dosages. Phase II studies have therefore been initiated.
β-alanine suppresses malignant breast epithelial cell aggressiveness through alterations in metabolism and cellular acidity in vitro
Authors: Roger A Vaughan, Nicholas P Gannon, Randi Garcia-Smith, Yamhilette Licon-Munoz, Miguel A Barberena, Marco Bisoffi, Kristina A Trujillo
Journal: Molecular Cancer (2014)

Deregulated energetics is a property of most cancer cells. This phenomenon, known as the Warburg Effect or aerobic glycolysis, is characterized by increased glucose uptake, lactate export and extracellular acidification, even in the presence of oxygen. β-alanine is a non-essential amino acid that has previously been shown to be metabolized into carnosine, which functions as an intracellular buffer. Because of this buffering capacity, we investigated the effects of β-alanine on the metabolic cancerous phenotype. Non-malignant MCF-10a and malignant MCF-7 breast epithelial cells were treated with β-alanine at 100 mM for 24 hours. Aerobic glycolysis was quantified by measuring extracellular acidification rate (ECAR) and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR). mRNA of metabolism-related genes was quantified by qRT-PCR with corresponding protein expression quantified by immunoblotting, or by flow cytometry which was verified by confocal microscopy. Mitochondrial content was quantified using a mitochondria-specific dye and measured by flow cytometry. Cells treated with β-alanine displayed significantly suppressed basal and peak ECAR (aerobic glycolysis), with simultaneous increase in glucose transporter 1 (GLUT1). Additionally, cells treated with β-alanine exhibited significantly reduced basal and peak OCR (oxidative metabolism), which was accompanied by reduction in mitochondrial content with subsequent suppression of genes which promote mitochondrial biosynthesis. Suppression of glycolytic and oxidative metabolism by β-alanine resulted in the reduction of total metabolic rate, although cell viability was not affected. Because β-alanine treatment reduces extracellular acidity, a constituent of the invasive microenvironment that promotes progression, we investigated the effect of β-alanine on breast cell viability and migration. β-alanine was shown to reduce both cell migration and proliferation without acting in a cytotoxic fashion. Moreover, β-alanine significantly increased malignant cell sensitivity to doxorubicin, suggesting a potential role as a co-therapeutic agent. Taken together, our results suggest that β-alanine may elicit several anti-tumor effects. Our observations support the need for further investigation into the mechanism(s) of action and specificity of β-alanine as a co-therapeutic agent in the treatment of breast tumors.
Antihistamine effects on actual driving performance in a standard test: a summary of Dutch experience, 1989‐94
Authors: J. F. O'Hanlon, J. G. Ramaekers
Journal: Allergy (1995)

The review summarizes the major results of eight double‐blind, placebo‐controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of “sedating” and “nonsedating” antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine, loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular “weaving” (i.e., standard deviation of lateral position (SDLP)). Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4–5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1–2 × the currently recommended levels. One or possibly two of the newer drugs possessed both performance‐enhancing and ‐impairing properties, depending on dose, suggesting two mechanisms of action.
Incidence and Mortality of Acute Lung Injury and the Acute Respiratory Distress Syndrome in Three Australian States
Authors: ANDREW D. BERSTEN, CYRUS EDIBAM, TAMARA HUNT, JOHN MORAN, THE AUSTRALIAN AND NEW ZEALAND INTENSIVE CARE SOCIETY CLINIC GROUP
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

To determine the incidence and 28-d mortality rate for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) using the 1994 American–European Consensus Conference definitions, we prospectively screened every admission to all 21 adult intensive care units in the States of South Australia, Western Australia, and Tasmania (total population older than 15 yr of age estimated as 2,941,137), between October 1 and November 30, 1999. A total of 1,977 admissions were screened of which 168 developed ALI and 148 developed ARDS, which represents a first incidence of 34 and 28 cases per 100,000 per annum, respectively. The respective 28-d mortality rates were 32% and 34%. The most common predisposing factors for ALI were nonpulmonary sepsis (31%) and pneumonia (28%). Although the incidences of ALI and ARDS are higher and the mortality rates are lower than those reported from studies in other countries, multicenter international studies are required to exclude methodological differences as the cause for this finding.
The Integrase Cofactor LEDGF/p75 Associates with Iws1 and Spt6 for Postintegration Silencing of HIV-1 Gene Expression in Latently Infected Cells
Authors: Annabelle Gérard, Emmanuel Ségéral, Monica Naughtin, Ahmed Abdouni, Bénédicte Charmeteau, Rémi Cheynier, Jean-Christophe Rain, Stéphane Emiliani
Journal: Cell Host & Microbe (2015)
Monocanalicular nasolacrimal duct intubation11The following letters address an article that appeared in the February 1998 issue of the Journal: Monocanalicular intubation with Monoka tubes for the treatment of congenital nasolacrimal duct obstruction (Ophthalmology 1998;105:336–41)
Authors: Saaeha Rauz
Journal: Ophthalmology (1998)
Inhibition of PKCα/β With Ruboxistaurin Antagonizes Heart Failure in Pigs After Myocardial Infarction Injury
Authors: Dennis Ladage, Lisa Tilemann, Kiyotake Ishikawa, Robert N. Correll, Yoshiaki Kawase, Steven R. Houser, Jeffery D. Molkentin, Roger J. Hajjar
Journal: Circulation Research (2011)

Protein kinase Cα (PKCα) activity and protein level are induced during cardiac disease where it controls myocardial contractility and propensity to heart failure in mice and rats. For example, mice lacking the gene for PKCα have enhanced cardiac contractility and reduced susceptibility to heart failure after long-term pressure overload or after myocardial infarction injury. Pharmacological inhibition of PKCα/β with Ro-32-0432, Ro-31-8220 or ruboxistaurin (LY333531) similarly enhances cardiac function and antagonizes heart failure in multiple models of disease in both mice and rats.Large and small mammals differ in several key indexes of heart function and biochemistry, lending uncertainty as to how PKCα/β inhibition might affect or protect a large animal model of heart failure.We demonstrate that ruboxistaurin administration to a pig model of myocardial infarction-induced heart failure was protective. Twenty-kilogram pigs underwent left anterior descending artery occlusion resulting in myocardial infarctions and were then divided into vehicle or ruboxistaurin feed groups, after which they were monitored monthly for the next 3 months. Ruboxistaurin administered pigs showed significantly better recovery of myocardial contractility 3 months after infarction injury, greater ejection fraction, and greater cardiac output compared with vehicle-treated pigs.These results provide additional evidence in a large animal model of disease that PKCα/β inhibition (with ruboxistaurin) represents a tenable and novel therapeutic approach for treating human heart failure.
The WNK Kinase Network Regulating Sodium, Potassium, and Blood Pressure
Authors: Ewout J. Hoorn, Joshua H. Nelson, James A. McCormick, David H. Ellison
Journal: Journal of the American Society of Nephrology (2011)

The relationship between renal salt handling and hypertension is intertwined historically. The discovery of WNK kinases (With No lysine = K) now offers new insight to this relationship because WNKs are a crucial molecular pathway connecting hormones such as angiotensin II and aldosterone to renal sodium and potassium transport. To fulfill this task, the WNKs also interact with other important kinases, including serum and glucocorticoid-regulated kinase 1, STE20/SPS1-related, proline alanine-rich kinase, and oxidative stress responsive protein type 1. Collectively, this kinase network regulates the activity of the major sodium and potassium transporters in the distal nephron, including thiazide-sensitive Na-Cl cotransporters and ROMK channels. Here we show how the WNKs modulate ion transport through two distinct regulatory pathways, trafficking and phosphorylation, and discuss the physiologic and clinical relevance of the WNKs in the kidney. This ranges from rare mutations in WNKs causing familial hyperkalemic hypertension to acquired forms of hypertension caused by salt sensitivity or diabetes mellitus. Although many questions remain unanswered, the WNKs hold promise for unraveling the link between salt and hypertension, potentially leading to more effective interventions to prevent cardiorenal damage.
Web-Based Cognitive Behavioral Therapy Intervention for the Prevention of Suicidal Ideation in Medical Interns
Authors: Constance Guille, Zhuo Zhao, John Krystal, Breck Nichols, Kathleen Brady, Srijan Sen
Journal: JAMA Psychiatry (2015)

In the United States, approximately 1 physician dies by suicide every day. Training physicians are at particularly high risk, with suicidal ideation increasing more than 4-fold during the first 3 months of internship year. Despite this increase, to our knowledge, very few efforts have been made to prevent the escalation of suicidal thoughts among training physicians.To assess the effectiveness of a web-based cognitive behavioral therapy (wCBT) program delivered prior to the start of internship year in the prevention of suicidal ideation in medical interns.A randomized clinical trial conducted at 2 university hospitals with 199 interns from multiple specialties during academic years 2009-2010 or 2011-2012. The current study was conducted from May 2009 to June 2010 and May 2011 to June 2012, and data were analyzed using intent-to-treat principles, including last observation carried forward.Interns were randomly assigned to 2 study groups (wCBT and attention-control group [ACG]), and completed study activities lasting 30 minutes each week for 4 weeks prior to starting internship year. Participants assigned to wCBT completed online CBT modules and those assigned to ACG received emails with general information about depression, suicidal thinking, and local mental health professionals.The Patient Health Questionnaire-9 was used to assess suicidal ideation (ie, "thoughts that you would be better off dead or hurting yourself in some way") prior to the start of intern year and at 3-month intervals throughout the year.A total of 62.2% of interns (199 of 320) agreed to take part in the study; 100 were assigned to the wCBT group and 99 to the ACG. During at least 1 point over the course of internship year, 12% of interns (12 of 100) assigned to wCBT endorsed suicidal ideation compared with 21.2% of interns (21 of 99) assigned to ACG. After adjusting for covariates identified a priori that have previously shown to increase the risk for suicidal ideation, interns assigned to wCBT were less likely to endorse suicidal ideation during internship year (relative risk, 0.40; 95% CI, 0.17- 0.91; P = .03) compared with those assigned to ACG.This study demonstrates that a free, easily accessible, brief wCBT program is associated with reduced likelihood of suicidal ideation among medical interns. Prevention programs with these characteristics could be easily disseminated to medical training programs across the country.anzctr.org.au Identifier: ACTRN12610000628044.
Role of Oxidative Stress in Endothelial Dysfunction and Enhanced Responses to Angiotensin II of Afferent Arterioles from Rabbits Infused with Angiotensin II
Authors: Dan Wang, Yifan Chen, Tina Chabrashvili, Shakil Aslam, Lillian J. Borrego Conde, Jason G. Umans, Christopher S. Wilcox
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. The hypothesis that O 2 ·− enhances angiotensin II (AngII)-induced vasoconstriction and impairs acetylcholine-induced vasodilation of afferent arterioles (Aff) in AngII–induced hypertension was investigated. Rabbits ( n = 6 per group) received 12 to 14 d of 0.154 M NaCl (Sham), subpressor AngII (60 ng/kg per min; AngII 60) or slow pressor AngII (200 ng/kg per min; AngII 200). Individual Aff were perfused in vitro at 60 mmHg. AngII 200 increased mean arterial pressure (mean ± SD; 103 ± 9 versus 73 ± 6 mmHg; P &lt; 0.01), plasma lipid peroxides (2.6 ± 0.3 versus 2.0 ± 0.3 nM; P &lt; 0.05), renal cortical NADPH- and NADH-dependent O 2 ·− generation, and Aff mRNA for p22 phox 5-fold ( P &lt; 0.001) but decreased that for AT 1 -receptor 2.4-fold ( P &lt; 0.01). AngII 60 increased only NADH-dependent O 2 ·− generation by renal cortex. Aff from AngII 200 rabbits had diminished acetylcholine relaxations (+50 ± 4 versus +85 ± 6%; P &lt; 0.001), but these became similar in the presence of nitro-L-arginine (10 −4 M). Aff from AngII 60 and AngII 200 rabbits had unchanged norepinephrine contractions (10 −7 M) but significantly ( P &lt; 0.05) enhanced AngII contractions (10 −8 M: Sham −52 ± 5 versus AngII 60 to 77 ± 5 versus AngII 200 to 110 ± 10%). The superoxide dismutase mimetic tempol (10 −4 M) moderated the AngII responses of Aff from AngII 200 rabbits to levels of AngII 60 rabbits (−64 ± 7%). The AngII slow pressor response enhances renal cortical O 2 ·− and p22 phox expression. Increased O 2 ·− generation in Aff mediates an impaired nitric oxide synthase–dependent endothelium-derived relaxing factor response and paradoxically enhances contractions to AngII despite downregulation of the mRNA for AT 1 receptors. A subpressor dose of AngII enhances Aff responses to AngII independent of O 2 ·− . E-mail: wilcoxch@georgetown.edu
Kirsten ras Mutations in Patients With Colorectal Cancer: the Multicenter "RASCAL" Study
Authors: H. J. N. Andreyev, A. R. Norman, P. A. Clarke, D. Cunningham, J. R. Oates
Journal: JNCI Journal of the National Cancer Institute (1998)

Kirsten ras (Ki-ras) gene mutations occur early in the progression of colorectal adenoma to carcinoma. The aim of this collaborative study was to clarify the association between Ki-ras mutations, patient outcome, and tumor characteristics by use of data from colorectal cancer patients worldwide.Investigators who had published data on Ki-ras and colorectal cancer were invited to complete a questionnaire for each patient entered into a database. Two-sided statistical tests were used to analyze data.Patients (n = 2721) were recruited from 22 groups in 13 countries. Mutations of Ki-ras codon 12 (wild type = GGT = glycine) or codon 13 (wild type = GGC = glycine) were detected in 37.7% of the tumors; 80.8% (584 of 723) of all the specified mutations occurred in codon 12, and 78.1% (565 of 723) of all the specified mutations were at the second base of either codon. Mutations were not associated with sex, age, tumor site, or Dukes' stage. Mutation rates seen in patients with sporadic tumors were comparable to those observed in patients with a predisposing cause for their cancer. Poorly differentiated tumors were less frequently mutated (P = .002). Multivariate analysis suggested that the presence of a mutation increased risk of recurrence (P<.001) and death (P = .004). In particular, any mutation of guanine (G) to thymine (T) but not to adenine (A) or to cytosine (C) increased the risk of recurrence (P = .006) and death (P<.001). When individual, specific mutations were evaluated, only valine codon 12 was found to convey an independent, increased risk of recurrence (P = .007) and death (P = .004).Ki-ras mutations are associated with increased risk of relapse and death, but some mutations are more aggressive than others.
Using population admixture to help complete maps of the human genome
Authors: Giulio Genovese, Robert E Handsaker, Heng Li, Nicolas Altemose, Amelia M Lindgren, Kimberly Chambert, Bogdan Pasaniuc, Alkes L Price, David Reich, Cynthia C Morton, Martin R Pollak, James G Wilson, Steven A McCarroll
Journal: Nature Genetics (2013)
Essential Fatty Acids and Polyunsaturated Fatty Acids: Significance in Cutaneous Biology
Authors: Vincent A. Ziboh, Craig C. Miller
Journal: Annual Review of Nutrition (1990)

The objective of this review is to provide an overview of intermittent fasting regimens, summarize the evidence on the health benefits of intermittent fasting, and discuss physiological mechanisms by which intermittent fasting might lead to improved ...Read More
Economic Return of Clinical Trials Performed Under the Pediatric Exclusivity Program
Authors: Jennifer S. Li, Eric L. Eisenstein, Henry G. Grabowski, Elizabeth D. Reid, Barry Mangum, Kevin A. Schulman, John V. Goldsmith, M. Dianne Murphy, Robert M. Califf, Daniel K. Benjamin
Journal: JAMA (2007)

ContextIn 1997, Congress authorized the US Food and Drug Administration (FDA) to grant 6-month extensions of marketing rights through the Pediatric Exclusivity Program if industry sponsors complete FDA-requested pediatric trials.The program has been praised for creating incentives for studies in children and has been criticized as a "windfall" to the innovator drug industry.This critique has been a substantial
The molecular mechanisms of lymphocyte apoptosis disregulation at Th1- and Th2- cytokine disbalance
Authors: Elena Sazonova, Olga Chechina, Oksana Zhukova, Natalia Ruazanceva
Journal: European Respiratory Journal (2011)

Much of the literature elevates the Th1/Th2 balance concept to the level of paradigm. Although Th1 and Th2 cells are now virtually anointed with the responsibility for coordinating the immune system, critical investigators are finding discrepancies in the hypothesis (Dent, L.A. J Reprod Immunol 2002; 57: 255-272). By the other hand apoptosis is one of the fundamental mechanisms of immune reactions regulation. So the purpose of our research was to establish the molecular mechanisms of cytokine-mediated lymphocyte apoptosis disregulaion at polarization of the immune answer on Th1- or Th2-ways.

We assessed the concentration of IL-2, IL-4, IL-10, IL-12 and TNFα in supernatant fluid of mononuclear leukocytes of 44 people (21 man and 23 women from 18 to 50) with acute and chronic tick-borne encephalitis and 23 healthy donors by dint of enzyme-linked immunosorbent assay. Secondly we analyzed the level of spontaneous and IL-2-, IL-4- and TNFα-induced apoptosis, the quantity of complementary receptors by flow cytometry. In addition the assessment of Bax, Bad, Bcl-2, Bcl-xl, p53 and NF-kB level was done due to immunoblotting.

It was established that influence of cytokines on the apoptosis realization has dose-dependent character. Features of apoptosis realization revealed in experimentally created cytokine imbalance conditions by means of recombinant IL-2, IL-4 and TNFα due to change of a transcriptional factors level (p53, NF-kB) and pro-/antiapoptotic proteins correlation (Bax, Bad, Bcl-2, Bcl-xl). Molecular mechanisms of cytokine-mediated apoptosis disregulation can form a basis for development of immune cell modulation methodology at the immune answer polarization for Th1-or Th2-ways.
No entry for adenosine
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Constipation killsCellular constipation can be deadly, according to a study on page 1587.Wang and colleagues show that cells get clogged with aborted secretory cargo when they lack an enzyme that helps form vesicles.Deletion of this enzyme proved lethal in mice, halting brain, bone and vascular development.The enzyme in question is a protein tyrosine phosphatase (PTP) called MEG2.MEG2 binds lipids and resides on intracellular vesicle membranes, where it clips phosphate residues from the fusion protein NSF.Once dephosphorylated, NSF initiates homotypic fusion between immature secretory vesicles, a critical step in protein secretion.Knocking out MEG2, the team found, prevented T cells (isolated from chimeric mice) from secreting the autocrine growth factor interleukin-2, stunting T cell proliferation in response to stimulation.Electron micrographs of the deficient T cells revealed that the cells lacked mature secretory vesicles and were clogged with the dense remains of fusion-incompetent vesicles.Platelets that lacked MEG2 were also dysfunctional, failing to aggregate when exposed to the clotting factor thrombin.But the MEG2 defect spared neutrophils and macrophages, although these cells rely on the same cellular machinery for vesicle release.Cell type-specific PTPs might compensate for MEG2's absence in neutrophils and macrophages.Besides looking for these PTPs, the group is also investigating the mechanism behind the developmental defects in the MEG2-deficient mice, which they suspect result from an inability to produce growth factors that direct the migration and differentiation of progenitor cells.