tbuckley/cabot-search huggingface dataset:
Pseudolaric Acid B, a Novel Microtubule-Destabilizing Agent That Circumvents Multidrug Resistance Phenotype and Exhibits Antitumor Activity <i>In vivo</i>
Authors: Vincent K.W. Wong, Pauline Chiu, Stephen S.M. Chung, Larry M.C. Chow, Yun-Zhe Zhao, Burton B. Yang, Ben C.B. Ko
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Pseudolaric acid B (PAB) is the major bioactive constituent in the root bark of Pseudolarix kaempferi that has been used as an antifungal remedy in traditional Chinese medicine. Previous studies showed that PAB exhibited substantial cytotoxicity. The aims of this study were to elucidate the molecular target of PAB, to examine its mechanism of action, and to evaluate the efficacy of this compound in vivo. Experimental Design: The effect of PAB on cell growth inhibition toward a panel of cancer cell lines was assayed. Cell cycle analysis, Western blotting, immunocytochemistry, and apoptosis analysis were carried out to examine the mechanism of action. Tubulin polymerization assays were conducted to examine the interaction between PAB and tubulin. A P-glycoprotein–overexpressing cell line was used to evaluate the efficacy of PAB toward multidrug-resistant phenotypes. In vivo efficacy of PAB was evaluated by the murine xenograft model. Results: PAB induces cell cycle arrest at G2-M transition, leading to apoptosis. The drug disrupts cellular microtubule networks and inhibits the formation of mitotic spindles. Polymerization of purified bovine brain tubulin was dose-dependently inhibited by PAB. Furthermore, PAB circumvents the multidrug resistance mechanism, displaying notable potency also in P-glycoprotein–overexpressing cells. Finally, we showed that PAB is effective in inhibiting tumor growth in vivo. Conclusions: We identified the microtubules as the molecular target of PAB. Furthermore, we showed that PAB circumvents P-glycoprotein overexpression-induced drug resistance and is effective in inhibiting tumor growth in vivo. Our work will facilitate the future development of PAB as a cancer therapeutic.
The Foundations of Bioethics
Authors: James M. Humber
Journal: JAMA (1996)

The first edition of Engelhardt's bioethics text was published in 1986. It was an excellent and influential text of nearly 400 pages. The second edition is almost 50 pages longer with a smaller typeface; it, too, is an excellent book and promises to be as influential as its predecessor. Engelhardt's purposes in writing a second edition are threefold. First, he wants to update various discussions in the text. Second, he believes that some of the positions he staked out in the first edition were misunderstood and that this led to a number of criticisms of his earlier work. With this in mind, he wants to clarify his earlier views. Finally, he wants to improve upon his earlier work by offering a more complete justification for "a moral framework by which individuals who belong to diverse moral communities, who do not share a contentfull moral vision, can still regard themselves bound
<i>In vitro</i> and <i>In vivo</i> Radiosensitization of Glioblastoma Cells by the Poly (ADP-Ribose) Polymerase Inhibitor E7016
Authors: Andrea L. Russo, Hyuk-Chan Kwon, William E. Burgan, Donna Carter, Katie Beam, Xu Weizheng, Jie Zhang, Barbara S. Slusher, Arnab Chakravarti, Philip J. Tofilon, Kevin Camphausen
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Poly (ADP-ribose) polymerase (PARP) inhibitors are undergoing clinical evaluation for cancer therapy. Because PARP inhibition has been shown to enhance tumor cell sensitivity to radiation, we investigated the in vitro and in vivo effects of the novel PARP inhibitor E7016. Experimental Design: The effect of E7016 on the in vitro radiosensitivity of tumor cell lines was evaluated using clonogenic survival. DNA damage and repair were measured using γH2AX foci and neutral comet assay. Mitotic catastrophe was determined by immunostaining. Tumor growth delay was evaluated in mice for the effect of E7016 on in vivo (U251) tumor radiosensitivity. Results: Cell lines exposed to E7016 preirradiation yielded an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 from 1.4 to 1.7. To assess DNA double-strand breaks repair, γH2AX measured at 24 hours postirradiation had significantly more foci per cell in the E7016/irradiation group versus irradiation alone. Neutral comet assay further suggested unrepaired double-strand breaks with significantly greater DNA damage at 6 hours postirradiation in the combination group versus irradiation alone. Mitotic catastrophe staining revealed a significantly greater number of cells staining positive at 24 hours postirradiation in the combination group. In vivo, mice treated with E7016/irradiation/temozolomide had an additional growth delay of six days compared with the combination of temozolomide and irradiation. Conclusions: These results indicate that E7016 can enhance tumor cell radiosensitivity in vitro and in vivo through the inhibition of DNA repair. Moreover, enhanced growth delay with the addition of E7016 to temozolomide and radiotherapy in a glioma mouse model suggests a potential role for this drug in the treatment of glioblastoma multiforme.
Doctors not obliged to carry out treatment they think "futile"
Authors: T. Sheldon
Journal: BMJ (1999)

In a legal test case a Dutch court has ruled that contrary to the wishes of the next of kin a hospital is not obliged to return an 80 year old patient with cancer to intensive care if his condition deteriorates.

A judge in Utrecht ruled that doctors were not obliged tocarry out treatment that they regarded as “medically futile.” The decision about what treatment to give was a medical one for …
Effects of anti-C5a antibodies on the adult respiratory distress syndrome in septic primates.
Authors: J H Stevens, P O'Hanley, J M Shapiro, F G Mihm, P S Satoh, J A Collins, T A Raffin
Journal: Journal of Clinical Investigation (1986)

In vitro and in vivo studies have suggested that human complement component C5a plays a key role in neutrophil injury in the adult respiratory distress syndrome (ARDS). First, using leukocyte aggregometry, we demonstrated that the addition of a recently developed rabbit anti-human polyclonal antibody to C5a des arg to endotoxin-activated plasma prevented leukocyte aggregation in vitro. We then administered the anti-C5a des arg antibody to septic primates (Macaca fascicularis). Three groups of primates, control, septic, and anti-C5a antibody treated septic, were studied (n = 4 in each group). A 30-min infusion of Escherichia coli (1 X 10(10)/kg) resulted in severe sepsis and ARDS. Primates were killed 4 h after completion of the E. coli infusion. Septic animals not treated with anti-C5a antibody had 75% mortality (3/4), decreased oxygenation, severe pulmonary edema, and profound hypotension. Septic primates treated with anti-C5a antibodies did not die and did not develop decreased oxygenation (P less than 0.05) or increased extravascular lung water (P less than 0.05). They also had a marked recovery in their mean arterial blood pressure (P less than 0.05). This study demonstrates that treatment with rabbit anti-human C5a des arg antibodies attenuates ARDS and some of the systemic manifestations of sepsis in nonhuman primates.
Closed Irrigation-Suction of Spine Infections
Authors: Edward O. Leventen
Journal: JAMA (1966)

A relatively simple technique is adapted for closed suction-irrigation with antibiotic and detergent as treatment of chronic osteomyelitis of the spine. The antibiotic used is one known to be effective against the infecting organism. The irrigation is continued until two consecutive negative cultures of suction fluid are obtained. This is usually a week to ten days. Of four successfully treated patients, one had been draining continuously for six years and the others for about six months.
CYTOGENETICS OF B-CELL LINEAGE ACUTE LYMPHOCYTIC LEUKAEMIAS OF CHILDHOOD
Authors: JohnF. Jackson, Jeanette Pullen, DorothyL. Williams, Paul Bowman, Maryann Roper, AndrewJ. Carroll, Larry Vogler, WilliamM. Crist, KennethA. Starling, Jan Van Eys
Journal: The Lancet (1982)
Curable Renal Hypertension— Renin, Marker or Cause?
Authors: John H. Laragh
Journal: JAMA (1971)

The identification of patients who might have curable hypertension secondary to unilateral renal disease has been aided by the application of differential renal function tests as first introduced by Howard.<sup>1</sup>However, despite numerous modifications,<sup>2</sup>these tests have proved to have limitations both in their application and in predicting operative curability. An example of this latter problem appears in a recent issue ofThe Journalin a paper by Fair and Stamey.<sup>3</sup>This group of investigators, who have pioneered in the application of such tests, now demonstrate that despite prior conclusions to the contrary,<sup>4</sup>hypertension in patients with unilateral, but segmental, renal ischemia can represent a true "Goldblatt effect," and cure can be accomplished even though hemodynamic and excretory function may be nearly normal in the affected kidney. The other side of this coin is presented in another paper by Palmer<sup>5</sup>in the same issue of
Validation of four prognostic scores in patients with cancer admitted to Brazilian intensive care units: results from a prospective multicenter study
Authors: Márcio Soares, Ulisses V. A. Silva, José M. M. Teles, Eliézer Silva, Pedro Caruso, Suzana M. A. Lobo, Felipe Dal Pizzol, Luciano P. Azevedo, Frederico B. de Carvalho, Jorge I. F. Salluh
Journal: Intensive Care Medicine (2010)
Law and the general practitioner: appearing in court.
Authors: B Knight
Journal: BMJ (1981)

A general practitioner may be called upon to give evidence in a variety of courts for a variety of reasons, but the basic principles are the same. In this article we assume that the doctor's evidence is in relation to his professional activities and not to some non medical happening such as witnessing a road accident, where his standing in court will be the same as any other member of the public. In his professional capacity the general practitioner, unless a police surgeon, will seldom act as an expert witness. This is usually the role of the consultant pathologist or surgeon who appears in court to interpret and give opinions on postmortem findings or the prognosis of a disabled patient. Most of the legal pronouncements of family doctors will concern matters of medical fact arising out of their practice, though there is a somewhat indistinct zone between this aspect and an opinion upon those same facts, which then merges into the purview of the expert witness.
Phytohaemagglutinin and transfer factor in the leucocyte migration inhibition test in patients with sarcoidosis.
Authors: W L Morison
Journal: Thorax (1976)

A new system of phytohaemagglutinin stimulation in vitro using the leucocyte migration inhibition test has been applied to patients with active and inactive sarcoidosis and subjects with a persistently negative response to tuberculin. Patients with active sarcoidosis and the tuberculin-negative subjects have a depressed response to the mitogen. This response is improved by the addition of transfer factor to the cultures.
Hypoxic Cell Radiosensitizers
Authors: James A. Belli, Samuel Hellman
Journal: New England Journal of Medicine (1976)

Oxygen is an important radiation sensitizer of mammalian cells. The possibility that some human neoplasms contain foci of hypoxia within which tumor cells are relatively radiation resistant has concerned radiation oncologists for many years. The presence of hypoxic foci may be one of the reasons why some human tumors are difficult to control locally with radiation. Therefore, the radiation oncologist is anxious to develop methods that render hypoxic cells as radiosensitive as oxygenated cells; success in this direction promises to yield an increased probability of local tumor control after a course of radiation therapy.In one attempt to circumvent the . . .
Randomised controlled trials: "within subject" versus "between subject" designs
Authors: P. Sedgwick
Journal: BMJ (2014)

A study investigated the effectiveness of morphine in relieving the sensation of breathlessness in patients in whom the underlying cause was maximally treated. A randomised double blind placebo controlled crossover (“within subjects”) design was used. The intervention was four days of 20 mg sustained release oral morphine or corresponding placebo. No washout period was included. Laxatives were provided as needed. Participants were 48 patients who had not previously been treated with opioids. Most of the patients had chronic obstructive pulmonary disease (42; 88%).1 The main outcome measures were dyspnoea, as measured in the morning and evening on a 100 mm visual analogue scale, plus quality of sleep and side effects. Outcome measures were recorded at the end of each four day treatment period. Participants reported significantly different dyspnoea scores when treated with morphine: an improvement of 6.6 mm (95% confidence interval 1.6 to 11.6; P=0.011) in the morning and 9.5 mm (3.0 to 16.1; P=0.006) in the evening. Participants also reported significantly better sleep during the period when taking morphine (P=0.039). Significantly more participants reported distressing constipation while taking morphine (P=0.021) despite the use of laxatives. It was concluded that sustained release oral morphine at low dosage provides significant symptomatic improvement in refractory dyspnoea. Which of the following statements, if any, are true?
Off-Target Lapatinib Activity Sensitizes Colon Cancer Cells Through TRAIL Death Receptor Up-Regulation
Authors: Nathan G. Dolloff, Patrick A. Mayes, Lori S. Hart, David T. Dicker, Robin Humphreys, Wafik S. El-Deiry
Journal: Science Translational Medicine (2011)

The breast cancer drug lapatinib increases the sensitivity of colon cancer cells to apoptosis through a HER2- and EGFR-independent mechanism.
Weight loss interventions in asthma: <scp>EAACI</scp> Evidence‐Based Clinical Practice Guideline (Part I)
Authors: A. Moreira, M. Bonini, V. Garcia‐Larsen, S. Bonini, S. R. Del Giacco, I. Agache, J. Fonseca, N. G. Papadopoulos, K.‐H. Carlsen, L. Delgado, T. Haahtela
Journal: Allergy (2013)

Asthma and obesity are chronic multifactorial conditions that are associated with gene-environment interaction and immune function. Although the data are not fully consistent, it seems that obesity increases the risk of asthma and compromises asthma control.To investigate the impact that weight changes have on asthma.We carried out a systematic review of three large biomedical databases. Studies were scrutinized and critically appraised according to agreed exclusion and inclusion criteria. Quality assessment of eligible papers was conducted using the GRADE method. Meta-analyses of comparable studies were carried out.Thirty studies met the eligibility criteria of the review. Interventions were limited to dietary manipulation in three studies, one of which also used anti-obesity drugs, and bariatric surgery in four. All the other studies reported observational data. Becoming obese increased the odds for incident asthma by 1.82 (95% CI 1.47, 2.25) in adults and 1.98 (95% CI 0.71, 5.52) in children. Weight loss was associated with significant improvement in mean scores for symptoms, rescue medication score, and asthma exacerbations in the only randomized controlled trial. Similarly, evidence gathered from observational studies, with follow-up ranging between 8 weeks to 1 year, and from changes 1 year after bariatric surgery showed improvements in all asthma control-related outcomes. Changes in lung function were reported in one randomized controlled and eight observational studies of asthmatic subjects, with conflicting results. Either improvement after weight loss, decline with weight gain, or no effects at all were reported. Changes in airway inflammation and responsiveness were reported only by observational studies.Weight increases above the obesity threshold significantly increase the risk of asthma. The available studies show weak evidence of benefits from weight reduction on asthma outcomes.
GMC hears case against paediatrician in Sally Clark trial
Authors: Clare Dyer
Journal: BMJ (2005)

The retired consultant paediatrician Roy Meadow gave “misleading and flawed” evidence in the trial of Sally Clark, a mother accused of murdering her two baby sons, the General Medical Council heard this week.

Robert Seabrook QC, for the GMC, said Professor Meadow had breached his duties as a medical expert witness and “misused” statistics and research in his evidence to the jury at the 1999 trial of Mrs Clark, a solicitor, whose conviction was overturned on her second appeal in 2003. Professor Meadow, 72, denies serious professional misconduct.

Mr Seabrook QC …
448 RESPONSE-GUIDED THERAPY WITH BOCEPREVIR PLUS PEGINTERFERON ALFA-2B/RIBAVIRIN REDUCES DURATION IN NAIVE AND PEGINTERFERON ALFA-2B/RIBAVIRIN PREVIOUS-TREATMENT-FAILURE PATIENTS WITH HCV GENOTYPE 1
Authors: M.P. Manns, F. Poordad, B.R. Bacon, S. Bruno, R. Esteban, M. Silva, M. Buti, M. Burroughs, V. Sniukiene, N. Boparai, C.A. Brass, J.K. Albrecht, J.-P. Bronowicki
Journal: Journal of Hepatology (2011)
The Genesis and Importance of the Electrocardiogram in Coarctation of the Aorta
Authors: ROBERT F. ZIEGLER
Journal: Circulation (1954)

The electrocardiogram in uncomplicated coarctation of the aorta in infants reflects the pattern of the fetal circulation and serves as a useful prognostic guide. When the fetal ductus inserts proximally to the region of coarctation and closes at birth, right ventricular enlargement is present at birth but is retrogressive. Furthermore, in this situation collateral circulation has begun to develop before birth so that the left ventricle can compensate on assumption of the postnatal circulation, and the prognosis is good. When the insertion of the fetal ductus is distal to the coarctation, progressive, and frequently fatal, left ventricular enlargement and failure develop shortly after birth. Modifications of these electrocardiographic patterns in the production of right bundle branch block are also discussed and illustrated.
TCT-251 Impact of Plaque Composition Assessed by iMap™-intravascular Ultrasound on Elevation of High Sensitive Cardiac Troponin T After Percutaneous Coronary Intervention
Authors: Seiji Koga, Satoshi Ikeda, Tomoo Nakata, Takeo Yoshida, Masayoshi Takeno, Yuji Koide, Koji Maemura
Journal: Journal of the American College of Cardiology (2012)
Central venous to mixed venous blood oxygen and lactate gradients are associated with outcome in critically ill patients
Authors: Guillermo Gutierrez, Pablo Comignani, Luis Huespe, F. Javier Hurtado, Arnaldo Dubin, Vinayak Jha, Yanina Arzani, Silvio Lazzeri, Lombardo Sosa, Juan Riva, Wolf Kohn, Daniela Suarez, Gonzalo Lacuesta, Daniela Olmos, Carlos Mizdraji, Alejandra Ojeda
Journal: Intensive Care Medicine (2008)
The UK's NHS and pharma: need for more clinical pharmacologists
Authors: Jeffrey K Aronson, David B Barnett, Alasdair M Breckenridge, Robin E Ferner, Peter Jackson, Simon R Maxwell, Gordon T McInnes, Michael D Rawlins, James M Ritter, Philip Routledge, Tom J Walley, David J Webb, David Williams, Kent L Woods
Journal: The Lancet (2009)
Florid Polyarticular Gout Mimicking Septic Arthritis
Authors: Aravind S. Ravi Kumar, Chuong Bui, George Szwarc, Hugh Dixson
Journal: Clinical Nuclear Medicine (2004)

Crystal arthropathies such as gout often present as an acute inflammatory monoarthritis. There could be a low-grade fever but patients are not usually systemically unwell. Septic arthritis is included in the differential diagnosis of both typical and atypical presentations of gout and could coexist with gout. A 46-year-old Tongan man with alcoholic liver disease and cardiomyopathy presented with fevers up to 39°C and severe polyarticular joint pain affecting large and small joints causing marked restriction of movement. Urgent investigations were performed to establish the diagnosis.
490 The role of AKT in regulation of smooth muscle alpha-actin protein expression in injured liver
Authors: S LIU, D ROCKEY
Journal: Hepatology (2003)

In rats treated with dimethylnitrosamine (DMN), the sensitivity of [3H] thymidine incorporation to inhibition by hydroxyurea was determined in the liver and kidney. A 70% inhibition was produced in control animals with doses of hydroxyurea from 50 to 250 mg/kg body wt. Twelve hours after administration of DMN, hepatic thymidine incorporation was unaffected by 50 mg/kg hydroxyurea, progressive reduction in incorporation occurred as the dose of inhibitor was increased. A similar result was obtained in kidney only by dietary conditioning of rats to ensure a high renal metabolism of the DMN. In contrast, at 72 h after DMN treatment thymidine incorporation in both liver and kidney was rapidly inhibited by administration of 50 mg/kg hydroxyurea. The data, assessed together with various parameters of DMN-induced repair and replicative DNA synthesis, suggest the use of hydroxyurea as a means to study DNA repair in intact animals.
Doctors need better training to help war veterans
Authors: L. Eaton
Journal: BMJ (2010)

Doctors could be better trained to meet the mental health needs of troops returning from war zones, advises the Mental Health Foundation.

Veterans might be more willing to seek help if primary healthcare staff had a better understanding of the culture of the armed forces and the particular pressures they are under, says the report, The Mental Health of Veterans. It argues for veterans to take part in awareness training for health and social care professionals who come into regular contact with veterans.

Support services for war veterans remain patchy, says the report. It also highlights the …
More people should be tested for HIV to reduce late diagnosis and prevent deaths, say guidelines
Authors: S. Mayor
Journal: BMJ (2009)

One third of deaths related to HIV in the United Kingdom could be prevented if testing for the disease were more widespread and more socially acceptable, says a summary of guidelines published on 1 October ( Clinical Medicine 2009;9:471-6). The guidelines aim to facilitate earlier diagnosis of HIV by encouraging healthcare workers to carry out HIV tests on a wider range of people than is traditionally considered to be at high risk of infection.

The guidelines say that HIV tests should be offered to everyone who accesses sexual health services; antenatal and abortion services; drug dependency programmes; and healthcare services for people diagnosed as having tuberculosis, hepatitis B, hepatitis C, and lymphoma. Tests should also be routinely offered to anyone who presents with other clinical indicators for HIV infection or with an identified risk factor for HIV whenever they access healthcare services.

“Many people in the UK are infected with HIV but …
What do symptoms mean?
Authors: J. Ogden
Journal: BMJ (2003)

Symptoms should be explained in the broader perspective of the patient's cognition and mood 

Doctors often turn to psychology when trying to understand patients and their problems, especially when no underlying physical pathology can be found. They focus on depression and anxiety as causes of symptoms and propose therapies such as counselling and cognitive behaviour therapy as possible solutions. The symptom itself is rarely questioned. But is the symptom so unproblematic? Why does one person experience headaches and sore throats whereas another has migraines and tonsillitis? Why does retirement exacerbate symptoms but a busy job make them disappear? And why do some patients bring their headaches to the doctor whereas others manage their migraines at home? An understanding of how symptoms arise and how only some are given the status of a problem can create a broader psychological perspective in which to understand patients' health and illness.

In this issue Mercer et al and Nazareth et al describe “lacking interest in sex” as the problem reported most often.1 2 In their anxiety not to feed into the medicalisation …