tbuckley/cabot-search huggingface dataset:
Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.
Authors: G Saeter, T A Alvegård, I Elomaa, A E Stenwig, T Holmström, O P Solheim
Journal: Journal of Clinical Oncology (1991)

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.
Reduced Hepatic Synthesis of Calcidiol in Uremia
Authors: Josée Michaud, Judith Naud, Denis Ouimet, Christian Demers, Jean-Luc Petit, Francois A. Leblond, Alain Bonnardeaux, Marielle Gascon-Barré, Vincent Pichette
Journal: Journal of the American Society of Nephrology (2010)

Calcidiol insufficiency is highly prevalent in chronic kidney disease (CKD), but the reasons for this are incompletely understood. CKD associates with a decrease in liver cytochrome P450 (CYP450) enzymes, and specific CYP450 isoforms mediate vitamin D(3) C-25-hydroxylation, which forms calcidiol. Abnormal levels of parathyroid hormone (PTH), which also modulates liver CYP450, could also contribute to the decrease in liver CYP450 associated with CKD. Here, we evaluated the effects of PTH and uremia on liver CYP450 isoforms involved in calcidiol synthesis in rats. Uremic rats had 52% lower concentrations of serum calcidiol than control rats (P < 0.002). Compared with controls, uremic rats produced 71% less calcidiol and 48% less calcitriol after the administration of vitamin D(3) or 1alpha-hydroxyvitamin D(3), respectively, suggesting impaired C-25-hydroxylation of vitamin D(3). Furthermore, uremia associated with a reduction of liver CYP2C11, 2J3, 3A2, and 27A1. Parathyroidectomy prevented the uremia-associated decreases in calcidiol and liver CYP450 isoforms. In conclusion, these data suggest that uremia decreases calcidiol synthesis secondary to a PTH-mediated reduction in liver CYP450 isoforms.
Growth hormone, prolactin, and corticosteroid responses to insulin hypoglycaemia in alcoholics
Authors: R J Chalmers, E H Bennie, R H Johnson, G Masterton
Journal: BMJ (1978)

Plasma growth hormone (GH), prolactin, and corticosteroid responses to insulin-induced hypoglycaemia were studied in 24 men with progressive alcoholism who had been abstinent for two to seven days. Ten normal healthy subjects (five men, five women) served as controls for comparing GH and prolactin responses, while cortisol responses were studied in a further six male controls. Blood samples were taken at intervals after an injection of soluble insulin (0·1 U/kg body weight). All patients developed adequate hypoglycaemia (blood glucose &lt;2·2 mmol/l (&lt;39·6 mg/100 ml)) and nine had impaired GH responses (peak concentration &lt;10 mU/1). Prolactin concentrations fell or remained unchanged in nine patients, eight of whom also had impaired GH responses. In seven patients corticosteroid concentrations decreased from basal concentrations, and six of these patients had impaired GH responses. All three hormone responses were impaired in several patients, and significant correlations were found between the GH and prolactin responses at 45 and 60 minutes. GH response was not correlated with age, duration of drinking, duration of alcoholism, or admitted alcohol intake. GH responses were significantly lower in patients who had the most severe withdrawal symptoms. Our observations of impaired stress responses in some recently abstinent alcoholics may have important implications for the management of alcohol withdrawal syndrome.
Direct Vascular Effects of Furosemide in Humans
Authors: Peter Pickkers, Tom P. J. Dormans, Frans G. M. Russel, Alun D. Hughes, Theo Thien, Nicolaas Schaper, Paul Smits
Journal: Circulation (1997)

Background In humans, hemodynamic changes observed within minutes after systemic administration of furosemide are often referred to as direct vasoactivity. However, these immediate changes do not per se imply a direct vascular effect. We examined the genuine direct vascular effects of furosemide on the human forearm vascular bed and dorsal hand vein. Methods and Results Forearm blood flow in response to infusion of increasing dosages of furosemide into the brachial artery was recorded by venous occlusion plethysmography. Local plasma concentrations of furosemide reached a maximum of 234±40 μg/mL during the highest infused dose but did not significantly affect the ratio of flow in the infused/noninfused arms. Venous distensibility of a dorsal hand vein was measured with a linear variable differential transformer. During precontraction with norepinephrine, five increasing dosages of furosemide (1 to 100 μg/min) were administered locally. Additional experiments using local administration of indomethacin or N G -monomethyl- l -arginine (L-NMMA) were carried out to determine whether effects were dependent on local prostaglandin or nitric oxide synthesis, respectively. Also, the effects of systemic administration of furosemide were examined. Local administration of furosemide led to a dose-dependent venorelaxation of 18±6% at the first to 72±16% at the last dose. Indomethacin almost completely abolished furosemide-induced venorelaxation, whereas L-NMMA had no effect. Systemic administration of furosemide resulted in a time-dependent increase of hand vein distensibility, reaching 45±11% after 8 minutes. Conclusions Furosemide does not exert any direct arterial vasoactivity in the human forearm, even at supratherapeutic concentrations. In contrast, at concentrations estimated to be in the therapeutic range, we observed a dose-dependent direct venodilator effect on the dorsal hand vein that appears to be mediated by local vascular prostaglandin synthesis.
Role of Intracellular Glutathione in Cell Sensitivity to the Apoptosis Induced by Tumor Necrosis Factor α–Related Apoptosis-Inducing Ligand/Anticancer Drug Combinations
Authors: Olivier Meurette, Luz Lefeuvre-Orfila, Amélie Rebillard, Dominique Lagadic-Gossmann, Marie-Thérèse Dimanche-Boitrel
Journal: Clinical Cancer Research (2005)

Abstract Purpose: We have recently shown that combination of tumor necrosis factor α–related apoptosis-inducing ligand (TRAIL) with anticancer drugs induced an apoptotic cell death pathway involving both caspases and mitochondria. The present work further explores the role of intracellular reduced glutathione (GSH) level in cell sensitivity to this cell death pathway. Experimental Design: Intracellular GSH level was measured by high-performance liquid chromatography. Cell death was detected by immunofluorescence after Hoechst 33342/propidium iodide staining. Reactive oxygen species production was evaluated by flow cytometry after dihydroethidium probe labeling. Western blot analysis was done to study stress-activated protein kinase/c-jun NH2-terminal kinase (SAPK/JNK) phosphorylation. The Student's t test was used to determine significance of the results. Three to six experiments were done. Results: GSH depletion enhanced apoptosis induced by TRAIL/cisplatin (CDDP) or TRAIL/5-fluorouracil (5-FU) combinations in both human HT29 colon carcinoma and HepG2 hepatocarcinoma cells, whereas it enhanced cytotoxicity induced only by TRAIL/CDDP in human primary hepatocytes. Our results further suggested that GSH depletion enhanced SAPK/JNK phosphorylation upon TRAIL/5-FU exposure and likely reduced the detoxification mechanisms of CDDP in HT29 cells. Resistance of Bcl-2–expressing HT29 and HepG2 cells to combined treatment was not overcome by GSH depletion, thus indicating that Bcl-2–mediated antiapoptotic effect occurs independently of intracellular GSH level. Conclusion: GSH depletion could be useful to increase the therapeutic efficacy of cancer treatment by TRAIL/anticancer drug combinations. Furthermore, TRAIL/5-FU combination might be a potential anticancer treatment of human tumors, being ineffective on human primary hepatocytes and thus could be of interest in clinical cancer treatment. Nevertheless, Bcl-2 expression remains an important resistance factor.
The Pulmonary Vessels in Incipient Left Ventricular Decompensation
Authors: MORRIS SIMON
Journal: Circulation (1961)

Dilatation of the pulmonary vessels of the upper zones and constriction of the vessels of the lower zones characterizes left ventricular decompensation. These changes may precede the onset of clinical symptoms providing a useful warning sign of impending danger. A hypothesis is suggested to account for the non-uniform vessel pattern. An exception is noted in patients with severe emphysema or bronchitis in whom generalized dilatation may occur.
Management of acute bursitis: outcome study of a structured approach
Authors: Ian M Stell
Journal: Journal of the Royal Society of Medicine (1999)

In patients with septic bursitis the indications for admission and surgical intervention remain unclear, and practice has varied widely. The effectiveness of a conservative outpatient based approach was assessed by an outcome study in a prospective case series. Consecutive patients attending an emergency department with acute swelling of the olecranon or prepatellar bursa were managed according to a structured approach, subjective and objective outcomes being assessed after two to three days, and subsequently as required until clinical discharge. Long-term outcomes were assessed by telephone follow-up for up to eighteen months. 47 patients were included in the study: 22 had septic bursitis, 15 of the olecranon bursa and 7 of the prepatellar bursa. The mean visual analogue pain scores of those with septic bursitis improved from 4.8 at presentation to 1.7 at first follow-up for olecranon bursitis, and from 3.8 to 2.7 for prepatellar bursitis. Symptoms improved more slowly for patients with non-septic bursitis. No patients were admitted initially, but 2 were admitted (two days each) after the first follow-up appointment. One patient had incision and drainage on the third attendance, and 3 patients developed discharging sinuses, which all healed spontaneously. All patients made a good long-term symptomatic recovery and all could lean on the elbow or kneel by the end of the follow-up period. The management protocol, with specific criteria for admission and surgical intervention, thus produced good results with little need for operation or admission.
Proximity of <i>TPR</i> and <i>NTRK1</i> Rearranging Loci in Human Thyrocytes
Authors: Emanuela Roccato, Paola Bressan, Guido Sabatella, Cristiano Rumio, Laura Vizzotto, Marco A. Pierotti, Angela Greco
Journal: Cancer Research (2005)

Abstract Chromosomal rearrangements are frequently associated with cancer; the mechanisms underlying their cell-type specificity are poorly understood. Papillary thyroid carcinomas are marked by a high frequency of chromosome rearrangements involving the RET and NTRK1 tyrosine kinase receptor genes and producing RET and TRK oncogenes. An explanation for the propensity of thyrocytes to undergo gene rearrangements has been recently proposed by Nikiforova and colleagues, who showed that the recombination between RET and H4 is favored by the loci proximity in interphase nuclei. We investigated whether the spatial proximity is a contributing factor also in the generation of the thyroid-specific TRK oncogenes. The distance between NTRK1 and its oncogenic partner TPR was determined by two-color fluorescence in situ hybridization and two-dimensional microscopy. A three-dimensional reconstruction of the data was also done. We show that the two loci in thyrocytes nuclei display a distance reduced with respect to peripheral blood lymphocytes, thus supporting the notion that spatial proximity of translocation-prone gene loci may favor gene rearrangements.
Indicator-Dilution Measurement of Cardiac Output with Dissolved Hydrogen
Authors: FRANCIS J. KLOCKE, DAVID G. GREENE, ROBERT C. KOBERSTEIN
Journal: Circulation Research (1968)

Dissolved H 2 has been used as an indicator for measuring cardiac output by the techniques of constant-rate injection and sudden, single injection indicator dilution. Because of its low solubility, H 2 is eliminated essentially quantitatively in the lungs and recirculates negligibly. The constant-rate injection technique involves the gas chromatographic measurement of pulmonary (or systemic) arterial H 2 concentration during an infusion of dissolved H 2 into a vena cava (or the left atrium). Measurements in anesthetized dogs agreed well with simultaneous measurements by dye dilution, direct Fick, and direct volumetric techniques. Measurements could be repeated several times a minute, and using a linearly responding platinum electrode, intravascular H 2 concentrations could be recorded continuously. In the sudden, single injection technique, dissolved H 2 was injected into a vena cava (or the left atrium) while monitoring pulmonary (or systemic) arterial H 2 concentration with a chromatographically calibrated platinum electrode. Measurements again agreed with simultaneous measurements by dye dilution, constant-rate injection of H 2 , and the direct volumetric technique. Hydrogen curves could be repeated rapidly and integrated instantaneously. Hydrogen appears to be a useful indicator for rapidly repeated determinations of cardiac output and for measurements of output in situations in which recirculation of conventional indicators limits their usefulness.
The Case of the Bare Lymphocyte Syndrome — Tracking Down Faulty Transcription Factors
Authors: Robert S. Schwartz
Journal: New England Journal of Medicine (1997)

In this issue of the Journal, Villard and his colleagues in Geneva report a new kind of mutation in children with primary deficiency of major-histocompatibility-complex (MHC) class II molecules (also called the bare lymphocyte syndrome).1 Since there are fewer than 100 known cases of this disorder worldwide, it is unlikely that readers of the Journal will ever encounter the problem in clinical practice. Why, then, did we decide to publish Villard's paper? Because it is an elegant piece of medical detective work that illuminates an important principle about genetic diseases.A rarity is not necessarily uninteresting — an exhibition of . . .
Value of severity scales in predicting mortality from community-acquired pneumonia: systematic review and meta-analysis
Authors: Y. K. Loke, C. S. Kwok, A. Niruban, P. K. Myint
Journal: Thorax (2010)

<h3>Background</h3> Several scoring systems have been used to predict mortality in patients with community-acquired pneumonia. The properties of commonly used risk stratification scales were systematically reviewed. <h3>Methods</h3> MEDLINE and EMBASE (January 1999–October 2009) were searched for prospective studies that reported mortality at 4–8 weeks in patients with radiographically-confirmed community-acquired pneumonia. The search focused on the Pneumonia Severity Index (PSI) and the three main iterations of the CURB (confusion, urea nitrogen, respiratory rate, blood pressure) scale (CURB-65, CURB, CRB-65), and test performance was evaluated based on ‘higher risk’ categories as follows: PSI class IV/V, CURB-65 (score ≥3), CURB (score ≥2) and CRB-65 (score ≥2). Random effects meta-analysis was used to generate summary statistics of test performance and receiver operating characteristic curves were used for predicting mortality. <h3>Results</h3> 402 articles were screened and 23 studies involving 22 753 participants (average mortality 7.4%) were retrieved. The respective diagnostic odds ratios for mortality were 10.77 (PSI), 6.40 (CURB-65), 5.97 (CRB-65) and 5.75 (CURB). Overall, PSI had the highest sensitivity and lowest specificity for mortality, CRB-65 was the most specific (but least sensitive) test and CURB-65/CURB were between the two. Negative predictive values for mortality were similar among the tests, ranging from 0.94 (CRB-65) to 0.98 (PSI), whereas positive predictive values ranged from 0.14 (PSI) to 0.28 (CRB-65). <h3>Conclusions</h3> The current risk stratification scales (PSI, CURB-65, CRB-65 and CURB) have different strengths and weaknesses. All four scales had good negative predictive values for mortality in populations with a low prevalence of death but were less useful with regard to positive predictive values.
Chemokine C Receptor 7 Expression and Protection of Circulating CD8+ T Lymphocytes from Apoptosis
Authors: Jeong-Whun Kim, Robert L. Ferris, Theresa L. Whiteside
Journal: Clinical Cancer Research (2005)

Abstract Chemokine C receptor 7 (CCR7) expression is important for lymphocyte homing to tissues. We hypothesized that CCR7 also plays a role in CD8+ T-cell protection from apoptosis. Its expression was determined on circulating T cells in patients with cancer and related to that of molecules responsible for lymphocyte susceptibility/resistance to apoptosis. Peripheral blood mononuclear cells were obtained from 36 patients with squamous cell carcinoma of the head and neck and 16 normal controls. Multicolor flow cytometry was used to evaluate CCR7, Fas, Bax, and Bcl-2 expression in CD8+ T cells. Annexin V binding to CD8+CCR7+ and CD8+CCR7− T-cell subsets was compared. Fewer CD8+CCR7+ T cells bound Annexin V than CD8+CCR7− T cells in normal control and patients (P &amp;lt; 0.0001). CCR7 expression correlated with higher Bcl-2 but lower Bax and Fas expression levels in CD8+ T cells in both normal control and patients (P &amp;lt; 0.0001). In patients, the CD8+CCR7+ subset was reduced relative to normal control (P = 0.008) and replaced with an excess of apoptosis-sensitive CD8+CCR7− T cells. To study CCR7 signaling, CD8+ T cells were stimulated with CCR7 ligands, chemokine C ligands 19 or 21. Ligand binding to CCR7 resulted in phosphorylation of Akt and increased Bcl-2 expression in CD8+CCR7+ T cells, suggesting that CCR7 protects effector T cells from apoptosis through the phosphatidylinositol 3-kinase/Akt pathway. The absence of CCR7 expression on the majority of CD8+ T cells in the peripheral circulation of patients with squamous cell carcinoma of the head and neck contributes to apoptosis and a rapid turnover of these effector cells.
GSK3β N-terminus binding to p53 promotes its acetylation
Authors: Tae-Yeon Eom, Richard S Jope
Journal: Molecular Cancer (2009)

The prevalence in human cancers of mutations in p53 exemplifies its crucial role as a tumor suppressor transcription factor. Previous studies have shown that the constitutively active serine/threonine kinase glycogen synthase kinase-3beta (GSK3 beta) associates with the C-terminal basic domain of p53 and regulates its actions. In this study we identified the GSK3 beta N-terminal amino acids 78-92 as necessary for its association with p53. Inhibitors of GSK3 impaired the acetylation of p53 at Lys373 and Lys382 near the GSK3 beta binding region in p53, indicating that GSK3 beta facilitates p53 acetylation. We also found that acetylation of p53 reduced its association with GSK3 beta, as well as with GSK3alpha. These results indicate that the N-terminal region of GSK3 beta binds p53, this association promotes the acetylation of p53, and subsequently acetylated p53 dissociates from GSK3.
Demonstration of dual atrioventricular nodal pathways utilizing a ventricular extrastimulus in patients with atrioventricular nodal re-entrant paroxysmal supraventricular tachycardia.
Authors: D Wu, P Denes, C Wyndham, F Amat-y-Leon, R C Dhingra, K M Rosen
Journal: Circulation (1975)

In patients with atrioventricular (A-V) nodal re-entrant paroxysmal supraventricular tachycardia (PSVT), atrial extrastimulus technique frequently reveals discontinuous A1-A2, H1-H2 curves suggestive of dual A-V nodal pathways. To further test the hypothesis that these curves in fact reflect dual A-V nodal pathways, a ventricular extrastimulus (VS) was coupled either to A2 at a fixed A1-A2 interval which reliably produced an A-V nodal re-entrant atrial echo (E) with a constant A2-E interval in two patients, or to QRS complex (V) during sustained PSVT with a constant E-E interval in one patient. Three response zones were defined: at longer A2-VS or V-VS coupling interval, VS manifested no effect on the timing of E (Zone 1). At closer A2-VS or V-VS coupling interval, VS conducted to the atrium, shortening the apparent A2-E or E-E interval (Zone 2). At shortest A2-VS or V-VS coupling interval, VS was blocked retrogradely, and no E was induced (Zone 3). The ability of VS to preempt control of the atria (Zone 2 response) strongly suggests the presence of dual A-V nodal pathways in these PSVT patients. If only a single pathway were present, VS would of necessity collide with the antegrade impulse and could not reach the atria. The Zone 3 response occurs because of retrograde refractoriness of the fast pathway. Failure of the echo during Zone 3 probably reflects concealed conduction to the fast pathway, or possibly interference in the slow pathway.
Clinical Stress Testing in the Pediatric Age Group
Authors: Stephen M. Paridon, Bruce S. Alpert, Steven R. Boas, Marco E. Cabrera, Laura L. Caldarera, Stephen R. Daniels, Thomas R. Kimball, Timothy K. Knilans, Patricia A. Nixon, Jonathan Rhodes, Angela T. Yetman
Journal: Circulation (2006)

This statement is an updated report of the American Heart Association's previous publications on exercise in children. In this statement, exercise laboratory requirements for environment, equipment, staffing, and procedures are presented. Indications and contraindications to stress testing are discussed, as are types of testing protocols and the use of pharmacological stress protocols. Current stress laboratory practices are reviewed on the basis of a survey of pediatric cardiology training programs.