tbuckley/cabot-search huggingface dataset:
Randomized Cross-Over Evaluation of Body-Surface Area–Based Dosing Versus Flat-Fixed Dosing of Paclitaxel
Authors: Carolien H. Smorenburg, Alex Sparreboom, Marijke Bontenbal, Gerrit Stoter, Kees Nooter, Jaap Verweij
Journal: Journal of Clinical Oncology (2003)

Despite dose calculation using body-surface area (BSA), pharmacokinetics of most anticancer drugs show wide interindividual variability. In this study, we evaluated the role of BSA in paclitaxel disposition.Paclitaxel pharmacokinetics were prospectively studied in 12 patients that were treated in a randomized cross-over design with paclitaxel (3-hour infusion at a 3-week interval) at 175 mg/m2 in cycle 1 (A) and a flat-fixed dose of 300 mg in cycle 2 (B), or vice versa. Blood samples were collected up to 24 hours after dosing and analyzed for total and unbound paclitaxel.The area under the curves (AUC) of unbound paclitaxel were similar in both dosing groups, with mean values +/- SD (A v B) of 1.34 +/- 0.158 versus 1.30 +/- 0.329 microM x h, indicating that BSA-based dosing reduced the coefficient of variation by 53.3%. Unbound and total paclitaxel clearance was also significantly related to various body-size measures, including BSA (R > or = 0.617; P < or =.033), weight (R >or = 0.621; P < or =.031), and lean-body mass (r > or = 0.630; P < or = .028). We hypothesize that this is caused by the association of paclitaxel in the circulation with Cremophor EL, the distribution of which is linked to total blood volume, and thus to BSA.This study indicates that paclitaxel disposition is significantly related to BSA. This provides a pharmacokinetic rationale for BSA-based dosing of this drug.
Modulation of hepatitis B virus replication and hepatocyte differentiation by MicroRNA-1
Authors: Xiaoyong Zhang, Ejuan Zhang, Zhiyong Ma, Rongjuan Pei, Min Jiang, Joerg F. Schlaak, Michael Roggendorf, Mengji Lu
Journal: Hepatology (2011)

Abstract MicroRNAs (miRNAs) are highly conserved small noncoding RNAs participating in regulation of various cellular processes. Viruses have been shown to utilize cellular miRNAs to increase their replication in host cells. Until now, the role of miRNAs in hepatitis B virus (HBV) replication has remained largely unknown. In this study, a number of miRNA mimics were transfected into hepatoma cell lines with HBV replication. It was noted that microRNA-1 (miR-1) transfection resulted in a marked increase of HBV replication, accompanied with up-regulated HBV transcription, antigen expression, and progeny secretion. However, bioinformatics and luciferase reporter analysis suggested that miR-1 may not target the HBV genome directly but regulate the expression of host genes to enhance HBV replication. Further studies showed that miR-1 was able to enhance the HBV core promoter transcription activity by augmenting farnesoid X receptor α expression. In addition, miR-1 arrested the cell cycle at the G1 phase and inhibited cell proliferation by targeting histone deacetylase 4 and E2F transcription factor 5. Analysis of the cellular gene expression profile indicated that miR-1 transfected hepatoma cells developed a differentiated phenotype of hepatocytes. Conclusion: MiR-1 regulates the expression of several host genes to enhance HBV replication and reverse cancer cell phenotype, which is apparently beneficial for HBV replication. Our findings provide a novel perspective on the role of miRNAs in host-virus interactions in HBV infection. (Hepatology 2011;)
Sympathetic activation, ventricular repolarization and Ikrblockade: Implications for the antifibrillatory efficacy of potassium channel blocking agents
Authors: Emilio Vanoli, Silvia G. Priori, Hiroshi Nakagawa, Kenzo Hirao, Carlo Napolitano, Livia Diehl, Ralph Lazzara, Peter J. Schwartz
Journal: Journal of the American College of Cardiology (1995)
Health-related quality of life following sport-related concussion in interscholastic athletes
Authors: Tamara C Valovich McLeod, R Curtis Bay, Alison R Valier, Kenneth C Lam, John T Parsons
Journal: British Journal of Sports Medicine (2013)

Objective To determine the impact of concussion on general, fatigue-specific, and headache-specific Health-related quality of life (HRQOL). Design Repeated measures. Setting High school athletic facilities. Patients Two hundred and fifty-nine adolescent athletes who sustained a concussion diagnosed by their athletic trainer (218 males, 41 females, age=15.9±1.2 years, grade=10.0±1.1). Interventions Participants completed the paediatric Quality of Life Inventory (PedsQL), PedsQL Multidimensional Fatigue Scale (MFS), and Headache Impact Test (HIT-6) during a preseason baseline (BL) and on days 3 (D3), 10 (D10) and 30 (D30) post-concussion. Main Outcome Measures Dependent variables included: 4 PedsQL subscale scores (physical (PF), emotional (EF), social (SOF), school (SCF) functioning), 3 MFS subscale scores (general (GF), sleep (SLF), cognitive (CF) fatigue), and the HIT-6 total score. Higher scores on the HIT-6 and lower scores on the PedsQL and MFS indicate lower HRQOL. Analyses were conducted using generalised estimating equations with follow-up Bonferroni corrections. Results All omnibus tests were significant (p&lt;0.001). Athletes reported significantly lower HRQOL on D3 than BL for PF (D3=77.8, 95% CI 75.1 to 80.4; BL=92.9, 95% CI 91.4 to 94.4), SCF (D3=78.6, 95% CI 76.3 to 80.8; BL=83.9, 95% CI 81.8 to 86.0), CF(D3=73.2, 95% CI 70.3 to 76.1; BL=82.6, 95% CI 79.9 to 85.1), GF (D3=74.9, 95% CI 72.0 to 77.9; BL=85.1, 95% CI 82.8 to 87.4) and HIT-6 (D3=51.5, 95% CI 50.3 to 52.6; BL=45.4, 95% CI 44.5 to 46.4). All D10 and D30 subscale scores were significantly higher than BL. Conclusions Concussed athletes demonstrated lower general, fatigue-specific, and headache-specific HRQOL in the immediate days post-injury. These findings corroborate reports of the symptoms experienced acutely post-concussion and align with a time when athletes are often restricted from participating in physical and cognitive activities. The effects of concussion on HRQOL appear short-lived, with recovery by 10 days post-injury. Acknowledgements This study was funded by a grant from the National Operating Committee for Standards on Athletic Equipment (NOCSAE). Competing interests None.
Paclitaxel Disposition in Plasma and Central Nervous Systems of Humans and Rats With Brain Tumors
Authors: M. J. Glantz, H. Choy, C. M. Kearns, P. C. Mills, L. U. Wahlberg, E. G. Zuhowski, P. Calabresi, M. J. Egorin
Journal: JNCI Journal of the National Cancer Institute (1995)

Background: Paclitaxel (Taxol) has been shown to sensitize some malignant cells to the effects of radiation. A number of clinical protocols, combining paclitaxel with radiation therapy, have been designed to exploit this phenomenon. The radiation-potentiating effect of paclitaxel is likely dependent on the ability of the drug to penetrate the tissue being radiated. Paclitaxel is known to have limited access to the central nervous system (CNS) of rats and mice, but its ability to penetrate malignant tissue in the CNS is inadequately documented. Purpose: Our purpose was to examine the concentrations of paclitaxel in the cerebrospinal fluid (CSF) of patients with CNS malignancies and in normal and malignant tissues from the brains of Fischer rats bearing the C6 rat glioma and then to compare those paclitaxel concentrations with concomitant paclitaxel concentrations in the plasma of those same patients and animals. Methods: Four patients were treated with 3-hour infusions of paclitaxel at doses between 90 and 200 mg/m2. Plasma and CSF were sampled at 0.33, 1.5, 3.25, 5, 6, and 24 hours after initiation of the paclitaxel infusion. Four Fischer rats had 20 000 C6 glioma cells stereotactically implanted into their right frontal lobes; 28 days later, they were given 3-hour infusions of paclitaxel at 10 mg/kg. Plasma was sampled during the paclitaxel infusion. At the completion of the infusion, rats were killed, and portions of their normal and malignant CNS tissues were removed for histologic assessment. Concentrations of paclitaxel in plasma, CSF, and brain tissue were determined with high-pressure liquid chromatography. Results: Plasma pharmacokinetics of paclitaxel in patients with brain tumors were comparable to those previously described in patients with other malignancies. Paclitaxel could be measured in CSF of all patients, but concentrations were very low. Peak paclitaxel concentrations in CSF ranged between 5 and 83 nM and occurred between 3.25 and 5 hours after initiation of the paclitaxel infusion. Peak paclitaxel concentrations in CSF were between 0.12% and 8.3% of those present in concomitant plasma samples. Paclitaxel was not detectable in the normal or malignant CNS tissue of any rat, despite the fact that plasma concentrations of paclitaxel at the time of tissue acquisition ranged from 0.62 to 153 μM. Conclusions: Paclitaxel has only limited access to the CSF of patients with CNS malignancies and to normal and malignant CNS tissues of rats bearing brain tumors. Implications: The utility of combining paclitaxel with radiation therapy to treat CNS malignancies should be considered in light of the documented limited access of paclitaxel to the CNS. [J Natl Cancer Inst 87:1077–1081, 1995]
The Surgeon and the HIV-Infected Patient-Reply
Authors: Lawrence O. Gostin
Journal: JAMA (1990)

In Reply.—  Dr Shewell enunciates an understandable concern among physicians that the law requires them to treat patients infected with HIV but provides little employment protection if they seroconvert in the course of practicing medicine.  The probable enactment of the Americans With Disabilities Act (which would ban discrimination against handicapped people in the private as well as the public sector) only reinforces the point made in the AIDS Litigation Project that health care providers may not discriminate against patients infected with HIV. This means that providers may not test patients without their consent, arbitrarily refer infected patients to other providers, or refuse to treat them. The reason for these strict legal requirements is that HIV infection is a handicap under federal and state law. Persons cannot be discriminated against because of their disability, any more than they can because of their race or gender. The law, of course, does not
Progress against Rare and Not-So-Rare Cancers
Authors: Bruce A. Chabner, Michael A. Friedman
Journal: New England Journal of Medicine (1992)

THE use of chemotherapy has resulted in substantial progress in the treatment of certain uncommon cancers, such as childhood leukemia, testicular cancer, and the lymphomas, whereas the more common epithelial tumors of adults have in general proved far more resistant. Only as an adjuvant to surgery has chemotherapy improved the outlook for patients with breast, colon, or rectal cancer. This pattern of dramatic progress against the rarer tumors and more modest gains against common tumors in early stages continues. Two new agents, deoxycoformycin1 and 2-chlorodeoxyadenosine,2 are highly effective in patients with hairy-cell leukemia. Another antimetabolite, fludarabine, has clear clinical benefit . . .
Large hepatocellular cancers: hepatic resection or liver transplantation.
Authors: L H Blumgart, O Soreide, A Czerniak
Journal: BMJ (1985)

data shows that the prevalence of diabetes mellitus in patients with acute stroke admitted to the Royal Victoria Infirmary and Freeman Hospital, New- castle UpoIn Tyne, was 31I,O (24/78) as defined by a raised stable HbA,, (<7o5%, that is, above the 95'%) confidence limits).There were four patients within this group with previously diagnosed diabetes mellitus, resulting in an overall incidence of unrecognised diabetes mellitus of 26°/., (20/78).There is therefore a significant number of patients with acute stroke presenting with previously un- recognised diabetes mellitus (p<OO5).The group of patients presenting with a raised HbA,, value also, and not surprisingly, had a significantly higher blood glucose concentration than those with a normal HbA,, value.The report fails to emphasise the role of stress hyperglycaemia in predicting outcome, an important omission because our observed mortality rates suggest a higher mortality in those patients with stress hyperglycaemia (normal HbA1, but blood glucose <8 mmol/l (14-4 mg/100 ml)): 42 80% compared with 30% for diabetic patients recognised and unrecognised.We think therefore that undiagnosed diabetes mellitus is a more important factor in acute stroke than reported but that stress hyperglycaemia is more important in predicting early mortality.
Decisions from the House of Lords
Authors: C. Dyer
Journal: BMJ (1987)

Dyer predicts that a decision by the House of Lords authorizing the contraceptive sterilization of a severely retarded 17-year-old girl called Jeannette may bring to court many similar cases that previously would have been quietly decided by parents and physicians. The law lords rejected the Canadian Supreme Court's conclusion in a recent case, Re Eve, that sterilization of a mentally handicapped person for nontherapeutic purposes should never be authorized. Instead, the British decision found compelling reasons for the sterilization in Jeannette's developmental and behavioral characteristics and in the contraindications for other forms of contraception in her case. The lords chose not to commit themselves on whether the court would be able to act if she were no longer a minor.
Influence of calcium permeabilization and membrane‐attached hemoglobin on erythrocyte deformability
Authors: E. Friederichs, R. A. Farley, H. J. Meiselman
Journal: American Journal of Hematology (1992)

Abstract The present study was designed to evaluate the influence of intracellular calcium [Ca] 1 regulated membrane attached hemoglobin (Hb m ) on the deformability of human RBC and ghosts. [Ca] 1 of RBC was elevated via the Ionophore A23187 (10 μM); the deformability of RBC and resealed ghosts was determined via measuring RBC and ghost transit times through 5 μm diameter pores with the Cell Transit Analyzer (CTA). Salient results included: (1) significantly increased RBC levels of Hb m following ionophore treatment; (2) elevated Hb m with increasing lysing medium calcium concentration (0–5 mM); (3) decreased deformability of both intact RBC and ghosts with increasing Hb m and significant (P &lt; 0.02 or better) linear relationships between Hb m and RBC or ghost transit times; and (4) an increased sensitivity to ionophore treatment/membrane attached hemoglobin for the higher percentiles of the CTA transit time distribution (i.e., for more rigid subpopulations). Our results thus indicate that calcium‐induced interaction of hemoglobin with the RBC membrane produces cellular rheological changes; in addition, they demonstrate the usefulness of the CTA system in measuring both average RBC rheologic behavior and the distribution of cellular rheologic properties within an erythrocyte population. © 1992 Wiley‐Liss, Inc.
Coping with AIDS
Authors: D S Weinberg, H W Murray
Journal: New England Journal of Medicine (1987)

First reported in 1981, the acquired immunodeficiency syndrome (AIDS) has moved with remarkable rapidity from a previously unrecognized disorder to the subject of headline news.1 The number of cases has increased relentlessly and has surpassed 40,000 nationwide. The absence of any clearly effective, nontoxic therapy or preventive vaccine has led to broad and increasing public concern.At the outset, AIDS was considered primarily a disease of white homosexual or bisexual men. However, with time, AIDS has become increasingly frequent among intravenous drug abusers, particularly those who are black or Hispanic, among newborns of women positive for the human immunodeficiency virus . . .
Patricia Ann Burgess
Authors: S. Munro
Journal: BMJ (2003)

Associate specialist in community paediatrics Royal Cornwall Hospitals Trust (b Cobridge, Staffordshire, 1949; q Cardiff 1973; DCH, MFCH), d 30 August 2003.​2003.




Figure 1




Pat was a paediatric senior house officer in Cardiff and Stoke-on-Trent and a paediatric registrar in Stoke-on-Trent and Liverpool. She moved to Cornwall to take up the post of clinical medical officer for the west Cornwall area in 1981 and became an associate specialist in April 1995. She worked in the west Cornwall area for 22 years and had an interest in developmental disorders and learning disability. Pat's hobbies extended from lace making, and bead and needlework to tap dancing. Her calm approach masked her endearing sense of mischief and enthusiasm for new interests.
Does Hepato-splanchnic V˙<scp>o</scp> <sub>2</sub>/D<scp>o</scp> <sub>2</sub> Dependency Exist in Critically Ill Septic Patients?
Authors: DANIEL DE BACKER, JACQUES CRETEUR, OALEED NOORDALLY, NADIA SMAIL, BÉATRICE GULBIS, JEAN-LOUIS VINCENT
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Since the gradient between the mixed venous and hepatic vein oxygen saturation (DSO2) is often increased in septic patients, we suspected these patients may have an imbalance between oxygen supply and demand in the hepato-splanchnic area. In 42 septic patients, hepato-splanchnic blood flow was determined by the indocyanine green clearance method with hepatic vein catheterization. The relationships between hepato-splanchnic oxygen delivery (DO2spla) and consumption (VO2spla) were analyzed during an increase in blood flow induced by a dobutamine infusion at doses up to 10 microg/kg x min. In 14 patients, positive end-expiratory pressure (PEEP) was also increased up to 20 cm H2O. The patients were separated according to their DSO2 (Group I: DSO2 < 10%, n = 13; and Group II: DSO2 > 10%, n = 29). Although DO2spla increased similarly in both groups, VO2spla only increased in Group II (from 45+/-22 to 59+/-39 ml/min x M2, p < 0.01). The slope of the VO2spla/DO2spla relationship was higher in Group II than in Group I (31.2+/-16.7 versus 10.4+/-5.1%, p < 0.001) and was similar during dobutamine and PEEP (21.9+/-14.2 versus 21.9+/-14.0%, p = NS). In conclusion, VO2spla increased only in septic patients with an increased DSO2 indicating splanchnic dysoxia. The similar slope observed with dobutamine and PEEP suggests that a thermogenic effect was unlikely.
New contract for government funded research workers
Authors: L. Zander, N. Mays
Journal: BMJ (1989)

so.In the presence of a septic or non-septic complication (for example, deep venous throm- bosis) the C reactive protein concentration either failed to fall exponentially as part of the normal response to trauma or rose again to a second peak.Hence an isolated raised C reactive protein measurement, say on the eighth postoperative day, could well be part of the normal response to trauma rather than an indication of a possible complication (for example, deep venous thrombosis).If these patients have serial postoperative measurements of C reactive protein then the normal response to trauma can be analysed, and should a second peak occur it can thus be interpreted as a sign of a possible complication.This fact, coupled with clinical suspicion of deep venous thrombosis, may help in selecting patients who will need a confirmatory phlebogram.
How DNA microarrays and expression profiling will affect clinical practice
Authors: S. H Friend
Journal: BMJ (1999)

In Plato's cave the participants are surrounded by shadows that allow them to see reality by careful examination. Similarly, we doctors at the end of the 20th century have found many indirect tests that allow us to follow what is happening in our patients' bodies and cells. We have learnt to cope with the fact that we cannot find drugs unless we pull proteins from those cells and develop inhibitors against them in the artificial context of a test tube. Imagine now a different world in which it would be possible simultaneously to follow many changes that were happening in cells. Imagine a doctor's office where you could take a blood sample from a patient and get an indication of where that patient's heart disease, kidney disease, and depression were plotted in a matrix, allowing us, as doctors, to see both the patient's relative state of health and any predisposition for other conditions or disorders. 

Some of the most exciting developments in the field of diagnostics and therapeutics are occurring in the adjacent fields …
Diaphanous-Related Formins Are Required for Invadopodia Formation and Invasion of Breast Tumor Cells
Authors: Floria Lizárraga, Renaud Poincloux, Maryse Romao, Guillaume Montagnac, Gaëlle Le Dez, Isabelle Bonne, Guillem Rigaill, Graça Raposo, Philippe Chavrier
Journal: Cancer Research (2009)

Abstract Proteolytic degradation of the extracellular matrix by metastatic tumor cells is initiated by the formation of invadopodia, i.e., actin-driven filopodia-like membrane protrusions endowed with matrix-degradative activity. A signaling cascade involving neural Wiskott-Aldrich syndrome protein and the Arp2/3 actin nucleating complex is involved in actin assembly at invadopodia. Yet, the mechanism of invadopodia formation is poorly understood. Based on their role as actin nucleators in cytoskeletal rearrangements, including filopodia formation, we examined the function of Diaphanous-related formins (DRF) in invadopodia formation and invasion by breast tumor cells. Using small interfering RNA silencing of protein expression in highly invasive MDA-MB-231 breast adenocarcinoma cells, we show that three members of the DRF family (DRF1–DRF3) are required for invadopodia formation and two-dimensional matrix proteolysis. We also report that invasion of a three-dimensional Matrigel matrix involves filopodia-like protrusions enriched for invadopodial proteins, including membrane type 1 matrix metalloproteinase, which depend on DRFs for their formation. These data identify DRFs as critical components of the invasive apparatus of tumor cells in two-dimensional and three-dimensional matrices and suggest that different types of actin nucleators cooperate during the formation of invadopodia. [Cancer Res 2009;69(7):2792–800]
National Health Care Reform An Aura of Inevitability Is Upon Us
Authors: George D. Lundberg
Journal: JAMA (1991)

"With malice toward none; with charity for all...." So spoke Abraham Lincoln in his second Inaugural Address, recognizing that he had no political consensus regarding either the constitutionality of states' seceding or the morality of slavery's being abolished. Nonetheless, he knew what was right and was able, through persuasive, often inspiring rhetoric, to conclude a bloody and divisive civil war and constitute the foundation for this great democracy. Yet, access to basic medical care for all of our inhabitants is still not a reality in this country. There are many reasons for this, not the least of which is long-standing, systematic, institutionalized racial discrimination. The major studies of health care maldistribution reinforce this statement with hard data, especially with regard to blacks and Hispanics.<sup>1,2</sup>It is not a coincidence that the United States of America and the Republic of South Africa—the only two developed, industrialized countries that do not
RANDOMISED CONTROLLED TRIAL OF ULTRASONOGRAPHIC SCREENING IN PREGNANCY
Authors: LeivS. Bakketeig, Geir Jacobsen, ChristianJ. Brodtkorb, BjarneC. Eriksen, SturlaH. Eik-Nes, MagnarK. Ulstein, Per Balstad, NilsPetter Jörgensen
Journal: The Lancet (1984)