tbuckley/cabot-search huggingface dataset:
Proinflammatory Effects of Bacterial Recombinant Human C-Reactive Protein Are Caused by Contamination With Bacterial Products, Not by C-Reactive Protein Itself
Authors: Mark B. Pepys, Philip N. Hawkins, Melvyn C. Kahan, Glenys A. Tennent, J. Ruth Gallimore, David Graham, Caroline A. Sabin, Arturo Zychlinsky, Juana de Diego
Journal: Circulation Research (2005)

Intravenous administration to human volunteers of a commercial preparation of recombinant human C-reactive protein (CRP) produced in Escherichia coli was recently reported in this journal to induce an acute phase response of serum amyloid A protein (SAA) and of CRP itself, and to activate the coagulation system. The authors concluded that CRP is probably a mediator of atherothrombotic disease. Here we confirm that this recombinant CRP preparation was proinflammatory both for mouse macrophages in vitro and for mice in vivo, but show that pure natural human CRP had no such activity. Furthermore mice transgenic for human CRP, and expressing it throughout their lives, maintained normal concentrations of their most sensitive endogenous acute phase reactants, SAA and serum amyloid P component (SAP). The patterns of in vitro cytokine induction and of in vivo acute phase stimulation by the recombinant CRP preparation were consistent with contamination by bacterial products, and there was 46.6 EU of apparent endotoxin activity per mg of CRP in the bacterial product, compared with 0.9 EU per mg of our isolated natural human CRP preparation. The absence of any proinflammatory activity in natural CRP for macrophages or healthy mice strongly suggests that the in vivo effects of the recombinant preparation observed in humans were attributable to proinflammatory bacterial products and not human CRP.
Plasma Levels of Heat Shock Protein 90 Alpha Associated with Lung Cancer Development and Treatment Responses
Authors: Yuankai Shi, Xiaoqing Liu, Jiatao Lou, Xiaohong Han, Lijian Zhang, Qingtao Wang, Baolan Li, Mei Dong, Yinghong Zhang
Journal: Clinical Cancer Research (2014)

Altered expression of heat shock protein 90 alpha (Hsp90α) was associated with tumor development, progression, and metastasis. This study explored plasma levels of Hsp90α protein in patients with lung cancer and other controls to assess its diagnostic value and monitor treatment responses for patients with lung cancer.A total of 2,247 individuals were recruited and assigned into two cohorts as static and dynamic groups. ELISA analysis and confirmation of plasma Hsp90α protein levels for association with tumor stages and treatment responses, respectively, were performed.The average plasma levels of Hsp90α protein in patients with lung cancer were significantly higher than in healthy controls (P < 0.0001). Plasma levels of Hsp90α protein in patients with advanced lung cancer (stage III-IV) were higher than in patients with early-stage lung cancer (stage I-II; P < 0.001). Using a cutoff value of 56.33 ng/mL to separate lung cancer from other controls, the sensitivity and specificity reached 72.18% (95% CI, 0.695-0.749) and 78.70% (95% CI, 0.761-0.813), respectively. To confirm the different levels in the second cohort, plasma levels of Hsp90α protein showed a statistically significant difference between preoperative and postoperative patients in surgical patient groups (P < 0.007). There was also a statistically significant difference between the disease progressive group and stable disease group, with regard to partial response after chemotherapy (P < 0.0001).This study demonstrated that plasma Hsp90α protein levels are useful as a diagnostic biomarker in lung cancer and predict the responses of patients with lung cancer to chemotherapy.
Classification systems for reinjuries: a continuing challenge
Authors: Ian Shrier, Russell J Steele
Journal: British Journal of Sports Medicine (2013)

Finch and Cook1 recently requested feedback on their proposed classification for reinjuries. We applaud them for identifying key challenging areas, and summarising standard statistical approaches to time-to-event data.2–5 Developed within a Bayesian framework, their approach can be applied equally well within a frequentist framework. However, we do not believe their claims that the proposed new classification solves the current analytical challenges. Although we cannot offer solutions at the present time, we do believe the previous classification systems6 ,7 mentioned by Finch and Cook should remain the focus of analytical strategies at this time.

Previous reinjury classifications focused on the previous injury's healing state. If not healed, subsequent injuries are exacerbations. If healed, subsequent injuries are classified according to anatomic location. The proposed classification simply splits each of the previous classification categories6 ,7 into two groups: ‘related to index injury’ and ‘not related to index injury’. The same relationships could be modelled using the previous classifications by simply adding a dichotomous variable (yes/no) called ‘Relation to Index Injury’ in the categorisation scheme. Is including such a variable beneficial?

The …
Successful adoptive transfer and in vivo expansion of human haploidentical NK cells in patients with cancer
Authors: Jeffrey S. Miller, Yvette Soignier, Angela Panoskaltsis-Mortari, Sarah A. McNearney, Gong H. Yun, Susan K. Fautsch, David McKenna, Chap Le, Todd E. Defor, Linda J. Burns, Paul J. Orchard, Bruce R. Blazar, John E. Wagner, Arne Slungaard, Daniel J. Weisdorf, Ian J. Okazaki, Philip B. McGlave
Journal: Blood (2005)
Targeting RET Receptor Tyrosine Kinase Activation in Cancer
Authors: John E. Phay, Manisha H. Shah
Journal: Clinical Cancer Research (2010)

After ligand binding induces dimerization, the RET receptor tyrosine kinase activates multiple signal transduction pathways. Constitutively activating mutations and chromosomal rearrangements are the primary oncogenic event in a significant number of medullary thyroid cancers (MTC) and papillary thyroid cancers (PTC), respectively. When specific germline mutations in RET are identified early, prophylactic thyroidectomy can be timed to remove at-risk tissue in patients with multiple endocrine neoplasia 2 (MEN2) syndromes who would otherwise develop MTC. Conventional therapy for progressive metastatic MTC is limited. Small-molecule tyrosine kinase inhibitors can target multiple kinases at nanomolar concentrations, including RET, and have shown efficacy against a variety of malignancies. Initial clinical evidence suggests that several of these inhibitors, including sorafenib, vandetanib, motesanib, sunitinib, and XL-184, may have some benefit in treating progressive MTC. Although initial success seen in these trials seems to be modest, it represents a major breakthrough in the treatment of patients with widespread metastatic MTC.
A Cellular Mechanism Contributing to Postvagal Tachycardia Studied in Isolated Pacemaker Cells From Cat Right Atrium
Authors: Yong Gao Wang, Stephen L. Lipsius
Journal: Circulation Research (1996)

Vagal nerve-induced inhibition of the heartbeat is followed by a postvagal increase in heart rate above control levels, postvagal tachycardia. In the present study, we used a perforated-patch/whole-cell recording method to determine the role of L-type Ca2+ current (ICa,L) and the hyperpolarization-activated inward current (I(f)) in the positive chronotropic response elicited by withdrawal of acetylcholine (ACh). Experiments were performed on sinoatrial node (SAN) and latent atrial pacemaker (LAP) cells isolated from cat right atrium. Withdrawal of a 2-minute exposure to 1 mumol/L ACh elicited a rebound stimulation of ICa,L in both SAN (33 +/- 4%) and LAP (50 +/- 6%) cells above control. Similarly, withdrawal of ACh (1 mumol/L) elicited a rebound stimulation of I(f) in both SAN (21 +/- 4%) and LAP (20 +/- 6%) cells. During the rebound stimulation of ICa,L, peak amplitude was increased throughout the voltage range, and the voltage dependence of activation was shifted to more negative voltages. Action potential recordings from both SAN and LAP cells showed that following ACh-induced inhibition, withdrawal of ACh elicited a concomitant rebound increase in action potential amplitude ( + 21 +/- 2% and + 21 +/- 3%, respectively) and decrease in pacemaker cycle length (30 +/- 5% and 44 +/- 5%, respectively) compared with control. H-89 (2 mumol/L), an inhibitor of cAMP-dependent protein kinase A, abolished the rebound increase of ICa,L, I(f), action potential amplitude, and decrease in pacemaker cycle length elicited by withdrawal of ACh. In the presence of 2 mmol/L cesium, a blocker of I(f), the rebound decrease in pacemaker cycle length elicited by withdrawal of ACh was unchanged. We conclude that in SAN and LAP cells, withdrawal of ACh elicits a positive chronotropic response primarily through a cAMP-mediated rebound stimulation of ICa,L. These findings are the first demonstration of an intrinsic cellular mechanism that may contribute directly to the nonadrenergic component of postvagal tachycardia.
Pharmacological basis of the therapeutic effect of (−)deprenyl in age‐related neurological diseases
Authors: Jozsef Knoll
Journal: Medicinal Research Reviews (1992)

(-)Deprenyl (Selegiline, Jumex, Eldepryl, Movergan), a close structural relative to phenylethylamine (PEA), is a drug of a unique pharmacological spectrum. (a) It is highly potent and selective irreversible inhibitor of B-type monoamine oxidase (MAO), a predominantly glial enzyme in the brain, the activity of which significantly increases with age. (-)Deprenyl was the first selective inhibitor of MAO-B described in literature, became the worldwide research tool used for blocking selectively B-type MAO, and is still the only MAO-B inhibitor in clinical use. (b) (-)Deprenyl interferes with the uptake of catecholamines and indirectly acting sympathomimetics because it is handled by the catecholaminergic neuron similarly to the physiological substances transported through the axonal end-organ and vesicular membrane. The unique behavior of (-)deprenyl is that, in striking contrast to PEA and its relatives, it does not push the transmitter from the storage places, i.e., it is not a releaser. The net result is that (-)deprenyl inhibits the releasing effect of tyramine and is presently the only safe MAO inhibitor which can be administered without dietary restrictions. (c) Maintenance on (-)deprenyl enhances selectively superoxide dismutase (SOD) and catalase activity in the striatum. This effect is unrelated to the MAO and uptake inhibitory effects of the drug. (d) Maintenance on (-)deprenyl facilitates the activity of the nigrostriatal dopaminergic neurons with remarkable selectivity. This effect is also unrelated to either the MAO or the uptake inhibitory effects of the drug. All in all, (-)deprenyl maintains the activity of the nigrostriatal dopaminergic machinery on a higher activity level and slows down its age-related decline. Male rats maintained on (-)deprenyl lost their capacity to ejaculate later, retained their learning ability longer, and lived longer than their saline-treated peers. Parkinsonians on levodopa plus (-)deprenyl (10 mg daily) lived significantly longer than those on levodopa alone. (-)Deprenyl is the first drug which retards the progress of Parkinson's disease. Freshly diagnosed parkinsonians maintained on (-)deprenyl did not require levodopa until significantly later than their placebo-treated peers. Maintenance on (-)deprenyl significantly improved the performance of patients with Alzheimer's disease. It is concluded that in Parkinson's disease and Alzheimer's disease patients need to be treated daily with 10 mg (-)deprenyl from diagnosis until death, irrespective of other medication.(ABSTRACT TRUNCATED AT 400 WORDS)
MPs reject government's preferred candidate to chair Monitor
Authors: A. O'Dowd
Journal: BMJ (2013)

MPs on the parliamentary select committee that scrutinises health and social care have decided to reject the government’s preferred candidate to chair Monitor, the body that regulates healthcare in England.

The highly unusual step is the result of disagreement between MPs of different political backgrounds on the committee and of a vote that led to the decision not to endorse the candidate.

The government’s preferred candidate for the post, Dominic Dodd, appeared before MPs on the Health Committee on 15 October as part of a pre-appointment hearing.1 During the evidence session Dodd, who is currently chairman of the Royal Free London NHS Foundation Trust, was forced to defend his previous role working for a management consultancy that advises private health companies on how to exploit opportunities in the NHS.

The committee is always asked to hold a pre-appointment evidence session to assess the …
Medical students' risk of infection with bloodborne viruses at home and abroad: questionnaire survey
Authors: C. F Gamester, A. J Tilzey, J. E Banatvala
Journal: BMJ (1999)

To determine risks of exposure to and prevention of bloodborne virus infections among medical students during their elective period.Questionnaire study of students returning from their electives in 1997-8.Urban teaching hospital.220 final year medical students.148 students (67%) returned questionnaires; all had been vaccinated against hepatitis B. 65 respondents (44%) had visited areas of relatively high endemicity for HIV, although 27 (42%) of these, all of whom had visited areas other than sub-Saharan Africa, were unaware of this. All but one had discussed their elective with advisers. Four students experienced percutaneous or mucosal exposure to potentially infectious body fluids, three in areas with a high prevalence of HIV infection. 44 respondents (30%) had experienced at least one such exposure during their clinical training; 75% of these exposures were unreported. 34% (13/38) students who visited areas known to have a high prevalence of HIV infection took with them a starter pack of zidovudine for post-exposure prophylaxis; 53% (20) took latex gloves and 63% (24) a medi-kit. None of the 27 students who were unaware that the areas they visited had a relatively high prevalence of HIV infection took zidovudine; only 15% (4) took gloves and 30% (8) a medi-kit.Medical schools should produce, regularly update, and implement guidelines regarding protection from bloodborne viruses during clinical studies, including electives. Education and training in infection control should start at the earliest opportunity.
Low level laser: does it influence wound healing in venous leg ulcers? A randomized, placebo-controlled, double-blind study
Authors: D. Kopera, R. Kokol, C. Berger, J. Haas
Journal: British Journal of Dermatology (2005)

Journal Article Low level laser: does it influence wound healing in venous leg ulcers? A randomized, placebo‐controlled, double‐blind study Get access D. Kopera, D. Kopera Departments of Dermatology and Venereology and *Gynaecology and Obstetrics, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, Austria E‐mail: daisy.kopera@meduni‐graz.at Search for other works by this author on: Oxford Academic Google Scholar R. Kokol, R. Kokol Departments of Dermatology and Venereology and *Gynaecology and Obstetrics, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, Austria E‐mail: daisy.kopera@meduni‐graz.at Search for other works by this author on: Oxford Academic Google Scholar C. Berger, C. Berger Departments of Dermatology and Venereology and *Gynaecology and Obstetrics, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, Austria E‐mail: daisy.kopera@meduni‐graz.at Search for other works by this author on: Oxford Academic Google Scholar J. Haas J. Haas Departments of Dermatology and Venereology and *Gynaecology and Obstetrics, Medical University of Graz, Auenbruggerplatz 8, A‐8036 Graz, Austria E‐mail: daisy.kopera@meduni‐graz.at Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 152, Issue 6, 1 June 2005, Pages 1368–1370, https://doi.org/10.1111/j.1365-2133.2005.06586.x Published: 01 June 2005
Effect of Muraglitazar on Death and Major Adverse Cardiovascular Events in Patients With Type 2 Diabetes Mellitus
Authors: Steven E. Nissen
Journal: JAMA (2005)

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors that modulate gene expression. Therapeutic agents targeting 2 distinct families of PPARs (alpha and gamma) have been introduced in the United States. The first dual-PPAR agonist, muraglitazar, was reviewed by a US Food and Drug Administration (FDA) advisory committee on September 9, 2005, resulting in a vote of 8:1 recommending approval for its use in controlling blood glucose levels in patients with type 2 diabetes.To evaluate the incidence of death, myocardial infarction (MI), stroke, congestive heart failure (CHF), and transient ischemic attack (TIA) in diabetic patients treated with muraglitazar compared with controls.The source material for this analysis consisted of documents about phase 2 and 3 clinical trials released under public disclosure laws for the FDA advisory committee meeting. All reviewed trials were prospective, randomized, double-blind, multicenter studies enrolling patients with type 2 diabetes and hemoglobin A(1c) levels between 7% and 10%. Patients (N = 3725) were randomized to receive differing doses of muraglitazar, pioglitazone, or placebo as monotherapy or in combination with metformin or glyburide in trials ranging from 24 to 104 weeks.The primary outcome was the incidence of death, nonfatal MI, or nonfatal stroke. A more comprehensive composite outcome included these events plus the incidence of CHF and TIA.In the muraglitazar-treated patients, death, MI, or stroke occurred in 35 of 2374 (1.47%) patients compared with 9 of 1351 (0.67%) patients in the combined placebo and pioglitazone treatment groups (controls) (relative risk [RR], 2.23; 95% confidence interval [CI], 1.07-4.66; P = .03). For the more comprehensive outcome measure that included TIA and CHF, the incidence was 50 of 2374 (2.11%) for muraglitazar compared with 11 of 1351 (0.81%) for controls (RR, 2.62; 95% CI, 1.36-5.05; P = .004). Relative risks for each of the individual components of the composite end point exceeded 2.1 but were not statistically significant. Incidence of adjudicated CHF was 13 of 2374 (0.55%) muraglitazar-treated patients and 1 of 1351 controls (0.07%) (RR, 7.43; 95% CI, 0.97-56.8; P = .053).Compared with placebo or pioglitazone, muraglitazar was associated with an excess incidence of the composite end point of death, major adverse cardiovascular events (MI, stroke, TIA), and CHF. This agent should not be approved to treat diabetes based on laboratory end points until safety is documented in a dedicated cardiovascular events trial.
Protein Kinase C Signaling Transduces Endorphin-Primed Cardiogenesis in GTR1 Embryonic Stem Cells
Authors: Carlo Ventura, Elisabetta Zinellu, Emiliana Maninchedda, Marina Fadda, Margherita Maioli
Journal: Circulation Research (2003)

The prodynorphin gene and its product, dynorphin B, have been found to promote cardiogenesis in embryonic cells by inducing the expression of GATA-4 and Nkx-2.5, two transcription factor–encoding genes essential for cardiogenesis. The molecular mechanism(s) underlying endorphin-induced cardiogenesis remain unknown. In the present study, we found that GTR1 embryonic stem (ES) cells expressed cell surface κ opioid receptors, as well as protein kinase C (PKC)-α, -β 1 , -β 2 , -δ, -ε, and -ζ. Cardiac differentiation was associated with a marked increase in the B max value for a selective opioid receptor ligand and complex subcellular redistribution of selected PKC isozymes. PKC-α, -β 1 , -β 2 , -δ, and -ε all increased in the nucleus of ES-derived cardiac myocytes, compared with nuclei from undifferentiated cells. In both groups of cells, PKC-δ and -ε were mainly expressed at the nuclear level. The nuclear increase of PKC-α, -β 1 , and -β 2 was due to a translocation from the cytosolic compartment. In contrast, the increase of both PKC-δ and PKC-ε in the nucleus of ES-derived cardiomyocytes occurred independently of enzyme translocation, suggesting changes in isozyme turnover and/or gene expression during cardiogenesis. No change in PKC-ζ expression was observed during cardiac differentiation. Opioid receptor antagonists prevented the nuclear increase of PKC-α, PKC-β 1 , and PKC-β 2 and reduced cardiomyocyte yield but failed to affect the nuclear increase in PKC-δ and -ε. PKC inhibitors prevented the expression of cardiogenic genes and dynorphin B in ES cells and abolished their development into beating cardiomyocytes.
Pain Response in Depersonalization: A Functional Imaging Study Using Hypnosis in Healthy Subjects
Authors: Christian H. Röder, Matthias Michal, G. Overbeck, Vincent G. van de Ven, David E.J. Linden
Journal: Psychotherapy and Psychosomatics (2007)

&lt;i&gt;Background:&lt;/i&gt; Depersonalization (DP) is characterized by persistent or recurrent episodes of detachment from one’s self with reduced pain perception being a common feature. Alterations in the body schema similar to the cortico-limbic disconnection syndrome of pain asymbolia are suggested to be responsible for DP. In this study we used hypnosis to induce DP in healthy subjects and to examine neural patterns of pain perception in the state of DP by means of functional magnetic resonance imaging (fMRI). &lt;i&gt;Methods:&lt;/i&gt; Pain perception was investigated in 7 healthy subjects with high susceptibility to hypnosis in three different mental states: waking state (N-W), hypnotic relaxation (H-R) and hypnotic DP (H-DP). Pain was induced with electrical stimulation to the median nerve at the right wrist. fMRI measurements were performed during all states. &lt;i&gt;Results:&lt;/i&gt; Nociceptive stimuli led to an activation of the well described pain network including somatosensory and insular regions and the cerebellum. Activation was markedly reduced in the contralateral somatosensory cortex, parietal cortex (Brodmann area 40, BA40), prefrontal cortex (BA9), putamen and the ipsilateral amygdala during H-DP. Subjects also reported a significant decrease in pain intensity from N-W to H-DP. &lt;i&gt;Conclusion:&lt;/i&gt; Pain response during H-DP was reduced in sensory and affective pain-related areas, reflecting the diminished intensity of the perceived pain. Moreover, a network of cortical and subcortical areas that have been implicated in the perception of the own body was less responsive during DP, which might point to a specific neural mechanism underlying the ‘out-of-body’ experience. Although the small number of subjects does not allow a generalization of our findings, H-DP seems to be a promising tool for the investigation of psychological and biological mechanisms of self-inflicted injuries as well as the mind-body interplay within the realm of psychosomatic disorders.
Effects of drinking green tea
Authors: J A. Roberts
Journal: BMJ (1995)

general practice in the United Kingdom.Called, imaginatively, GP-UK, the list is run by collabo- ration between the Sowerby Unit for Primary Care Informatics at Newcastle University and the Primary Health Care Specialist Group of the British Computer Society.GP-UK deals with topics such as clinical research and medical informatics, with specific reference to British general practice.Within its first six months it has over 150 members.Views from outside the United Kingdom are also welcome, and, indeed, the list includes members from Europe, Australia, and the United States.To
Book: Sexually Transmitted Infections and AIDS in the Tropics
Authors: G. van Doornum
Journal: BMJ (1999)

Eds O P Arya, C A Hart CAboldI Puboldlishing, £60, pp 448 ISboldN 0 85199 262 5 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> A historical boldackground to the suboldjects of sexually transmitted diseases and the tropics has boldeen provided boldy D M Peers in a description of the campaigns to comboldat these diseases in colonial India during 1805-60: venereal diseases and the boldritish army of the 19th century were, for many contemporaries, almost synonymous. Aboldout 150 years later, the picture of the … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif