tbuckley/cabot-search huggingface dataset:
Unexplained sporadic and recurrent miscarrage in the new millennium: a critical analysis of immune mechanisms and treatments
Authors: D. A. Clark
Journal: Human Reproduction Update (2001)

There have been important advances in basic science investigation of mechanisms underlying spontaneous miscarriages which lend support to empirical treatments such as intravenous immunoglobulin G and allogeneic leukocyte immunotherapy. The results from clinical trials of these and other proposed treatments have been problematic. There is only one published meta-analysis of sufficient power and appropriate stratification to qualify as Level 1 evidence, and that deals only with leukocyte immunotherapy. Here we critically review current trials and their flaws, update the meta-analysis, and comment on potential new approaches. Inadequate sample size, better definition of heterogeneity, and proper stratification to minimize the effects of heterogeneity remain as problems. Verification that the experimental or test treatment was active in producing the expected alteration in immunophysiology in the recipient is lacking in most trials; use of stored rather than fresh allogeneic leukocytes appears problematic. Hidden biases that affect trial significance emerge with critical analysis, and the focus on apparent 'high quality' of design in published reports may be misleading. We conclude that there seem to be enough patients to conduct clinical trials of sufficient size to achieve adequate power to test therapies showing promise in pilot studies, but at present, the only Level 1 evidence concerns leukocyte immunotherapy which appears to increase the chance of a live birth if given to appropriate patients.
Breast Cancer Resistance Protein in Drug Resistance of Primitive CD34+38− Cells in Acute Myeloid Leukemia
Authors: Marc H.G.P. Raaijmakers, Elke P.L.M. de Grouw, Leonie H.H. Heuver, Bert A. van der Reijden, Joop H. Jansen, Rik J. Scheper, George L. Scheffer, Theo J.M. de Witte, Reinier A.P. Raymakers
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Acute myeloid leukemia (AML) is considered a stem cell disease. Incomplete chemotherapeutic eradication of leukemic CD34+38− stem cells is likely to result in disease relapse. The purpose of this study was to investigate the role of the breast cancer resistance protein (BCRP/ATP-binding cassette, subfamily G, member 2) in drug resistance of leukemic stem cells and the effect of its modulation on stem cell eradication in AML. Experimental Design: BCRP expression (measured flow-cytometrically using the BXP21 monoclonal antibody) and the effect of its modulation (using the novel fumitremorgin C analogue KO143) on intracellular mitoxantrone accumulation and in vitro chemosensitivity were assessed in leukemic CD34+38− cells. Results: BCRP was preferentially expressed in leukemic CD34+38− cells and blockage of BCRP-mediated drug extrusion by the novel fumitremorgin C analogue KO143 resulted in increased intracellular mitoxantrone accumulation in these cells in the majority of patients. This increase, however, was much lower than in the mitoxantrone-resistant breast cancer cell line MCF7-MR and significant drug extrusion occurred in the presence of BCRP blockage due to the presence of additional drug transport mechanisms, among which ABCB1 and multiple drug resistance protein. In line with these findings, selective blockage of BCRP by KO143 did not enhance in vitro chemosensitivity of leukemic CD34+38− cells. Conclusions: These results show that drug extrusion from leukemic stem cells is mediated by the promiscuous action of BCRP and additional transporters. Broad-spectrum inhibition, rather than modulation of single mechanisms, is therefore likely to be required to circumvent drug resistance and eradicate leukemic stem cells in AML.
Nutrition and Mutagenesis
Authors: Lynnette R. Ferguson, Martin Philpott
Journal: Annual Review of Nutrition (2008)

Diet-related mutagenesis plays an etiologic role in chronic diseases, including cardiovascular disease and cancer. Many dietary mutagens are DNA reactive, leading to distinct spectra of base-pair substitution mutations and structural chromosome changes. Examples include aflatoxin B1, ochratoxin A, ptaquiloside, various pyrrolizidine alkaloids, heterocyclic amines including 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, and polycyclic aromatic hydrocarbons such as benzo[a]pyrene. However, endogenously or exogenously formed reactive species, inhibitors of topoisomerase II enzymes (e.g., flavonoids), of DNA repair (e.g., caffeine), or of the mitotic spindle (possibly acrylamide), also cause mutations, including structural chromosome changes and copy number variants. Genomic instability also results from inadequate nutrient intake (e.g., folate and selenium). Antimutagens include vitamin C, carotenoids, chlorophyllin, dietary fibers, and plant polyphenols acting through various mechanisms. Polymorphisms in genes for nutrient uptake, metabolism, and excretion will affect dietary intake in determining individual risk of disease development. Human studies utilizing nutrigenomic/nutrigenetic technologies will be essential to quantifying and overcoming diet-related mutagenesis.
From bench to bedside: current and future applications of molecular profiling in renal cell carcinoma
Authors: Androu Arsanious, Georg A Bjarnason, George M Yousef
Journal: Molecular Cancer (2009)

Abstract Among the adult population, renal cell carcinoma (RCC) constitutes the most prevalent form of kidney neoplasm. Unfortunately, RCC is relatively asymptomatic and there are no tumor markers available for diagnostic, prognostic or predictive purposes. Molecular profiling, the global analysis of gene and protein expression profiles, is an emerging promising tool for new biomarker identification in RCC. In this review, we summarize the existing knowledge on RCC regarding clinical presentation, treatment options, and tumor marker status. We present a general overview of the more commonly used approaches for molecular profiling at the genomic, transcriptomic and proteomic levels. We also highlight the emerging role of molecular profiling as not only revolutionizing the process of new tumor marker discovery, but also for providing a better understanding of the pathogenesis of RCC that will pave the way towards new targeted therapy discovery. Furthermore, we discuss the spectrum of clinical applications of molecular profiling in RCC in the current literature. Finally, we highlight some of the potential challenging that faces the era of molecular profiling and its transition into clinical practice, and provide an insight about the future perspectives of molecular profiling in RCC.
Criticisms of Swedish mammography trials were wrong
Authors: L. Tabar, S. W Duffy
Journal: BMJ (1999)

Synapse formation in the mammalian CNS is thought to involve specific target recognition processes between presynaptic and postsynaptic neurons leading to the establishment of defined neuronal circuits. To study the role of target neuron-specific factors in synaptogenesis, we used cocultures of presynaptic explants and dissociated target neurons from rat neocortex, which enabled us to selectively vary the postsynaptic target neurons. Cocultures containing target neurons that were obtained early during development [embryonic day 16 (E16)] were compared to cocultures containing target neurons that were obtained at a later embryonic stage (E19). Postsynaptic currents (PSCs) were evoked in target neurons by maximal extracellular stimulation in the presynaptic explant. The mean amplitudes of AMPA and NMDA receptor-mediated PSCs were sixfold reduced in E16 target neurons, whereas the mean amplitudes of GABA<sub>A</sub>receptor-mediated PSCs did not differ between E16 and E19 target neurons. This reduction was in part caused by an apparently twofold reduction in mean quantal amplitude, as shown by recording AMPA receptor-mediated miniature PSCs. In addition, a reduced number of glutamatergic release sites in E16 target neurons was revealed by synapsin I immunostaining of dendritic presynaptic terminals. No differences in mean release probability were observed between E16 and E19 target neurons. Thus, the formation of glutamatergic transmitter release sites was strongly influenced by target neuron-specific factors. The formation of functional GABAergic synapses, however, was independent of the type of target neurons, suggesting specific retrograde signaling during the establishment of glutamatergic synapses.
Biphasic effects of doxorubicin on the calcium release channel from sarcoplasmic reticulum of cardiac muscle.
Authors: K Ondrias, L Borgatta, D H Kim, B E Ehrlich
Journal: Circulation Research (1990)

To define the mechanism of doxorubicin cardiotoxicity, the effects of doxorubicin and caffeine were examined on calcium release channels from cardiac sarcoplasmic reticulum. We found that calcium release from cardiac sarcoplasmic reticulum vesicles was induced by both compounds. When sarcoplasmic reticulum vesicles were incorporated into planar lipid bilayers, calcium-permeable channels were observed. Addition of caffeine (2.5-10 mM) increased channel open probability from less than 0.1% to 40%, and this effect persisted for a mean of 44 minutes. In contrast, doxorubicin (2.5-10 microM) had a biphasic effect; initially, doxorubicin activated the channel, whereas after a mean of 8 minutes, the channel became irreversibly inhibited. Although the degree of channel activation by doxorubicin was concentration dependent, the time needed to inactivate the channel was concentration independent. Pretreatment with dithiothreitol (0.2 mM) prevented doxorubicin-induced channel inactivation, and channel activity persisted for an average of 58 minutes. Dithiothreitol alone did not alter channel open probability. Our results support the hypotheses that 1) the integrity of sulfhydryl groups is important for some aspects of calcium release channel function and 2) activation and inactivation of the channel are separable processes. The biphasic effect of doxorubicin on channel function may also correspond to the clinically observed adverse effects of doxorubicin, a widely used chemotherapeutic agent that, after prolonged usage, causes a dilated cardiomyopathy.
RGS9 Modulates Dopamine Signaling in the Basal Ganglia
Authors: Zia Rahman, Johannes Schwarz, Stephen J Gold, Venetia Zachariou, Marc N Wein, Kwang-Ho Choi, Abraham Kovoor, Ching-Kang Chen, Ralph J DiLeone, Sigrid C Schwarz, Dana E Selley, Laura J Sim-Selley, Michel Barrot, Robert R Luedtke, David Self, Rachael L Neve, Henry A Lester, Melvin I Simon, Eric J Nestler
Journal: Neuron (2003)
PWE-001 The Impact of Colonic Resection for Neoplasia on Functional outcomes and Related Quality of Life: a Case-Controlled Study
Authors: A Brigic, S Sakuma, R Lovegrove, S K Clark, P Bassett, N J Mortensen, R H Kennedy
Journal: Gut (2013)

<h3>Introduction Aim</h3> Functional outcomes after elective colectomy (right, left or sigmoid) for neoplasia are poorly reported in the literature. This study evaluates bowel function and related quality of life in patients 2 – 4 years after hemicolectomy, comparing the results to healthy controls. <h3>Methods</h3> Eligible patients were identified from prospectively maintained colorectal databases at two teaching hospitals. Patients were recruited during regular follow up visits or by telephone interview. Patient relatives with an intact colon were recruited as controls. Study exclusion criteria were poor cognitive ability, inflammatory bowel disease, metastatic disease, previous pelvic radiation, prior colonic, stomach or small bowel resection, bypass surgery, vagotomy, an existing stoma and anal incontinence. The Memorial Sloan-Kettering Cancer Centre (MSKCC) questionnaire was used to assess bowel function and the EQ-5D questionnaire to assess quality of life (QOL). Parametric and non-parametric tests were used with log transformation and regression methods for skewed data. Association between EQ-5D and MSKCC scores was examined with Spearman’s rank correlation. <h3>Results</h3> A total of 85 patients (mean age 69 +/- 11.2 years) and 85 controls (mean age 58.2 +/- 13.4 years) were recruited in 12 months. Patients reported a significantly higher number of bowel movements per day than controls (2 versus 1, P &lt; 0.001). Initial analysis suggested that patients had a significantly lower total MSKCC score (group difference mean –3.1, CI –5.8 to –0.4, p = 0.02), indicating worse bowel function in the patient group. Following adjustment for age, sex and co-morbidities, differences in total score were no longer significant, but the patient group had a lower score for the frequency subscale and the ability to control flatus (p = 0.008 and p = &lt; 0.001). MSKCC frequency scores were worse after right-sided resections (p = 0.03). High scores for complete emptying and the differentiation between wind and solid had a positive correlation with better QOL (p = 0.007 and 0.02 respectively). There was a non-significant decrease in the overall QOL (EQ-5D p = 0.6, EQ-VAS p = 0.12) following hemicolectomy compared with controls. <h3>Conclusion</h3> Colonic resection has an adverse effect on bowel frequency with worse outcomes following right hemicolectomy. Good colonic function, as assessed by the MSKCC questionnaire, is associated with better QOL. <h3>Disclosure of Interest</h3> None Declared
Arterial endothelin-1 level in pulmonary emphysema and interstitial lung disease. Relation with pulmonary hypertension during exercise
Authors: T Yamakami, O Taguchi, EC Gabazza, M Yoshida, T Kobayashi, H Kobayashi, H Yasui, H Ibata, Y Adachi
Journal: European Respiratory Journal (1997)

This study was undertaken to assess the arterial plasma levels of endothelin-1 (ET-1) and their relationship with pulmonary haemodynamic and gas exchange variables during exercise in patients with emphysema and interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. At rest, arterial ET-1 levels were higher in emphysema (1.86 +/- 0.35 pg.mL-1; p < 0.02) and ILD (1.75 +/- 0.25 pg.mL-1; p < 0.03) patients than in controls (1.35 +/- 0.18 pg.mL-1). Emphysema (2.08 +/- 0.26 versus 1.70 +/- 0.40 pg.mL-1) and ILD (1.98 +/- 0.21 versus 1.67 +/- 0.02 pg.mL-1) patients with pulmonary hypertension (PH) presented significantly (p < 0.05) higher arterial ET-1 levels than those without. At rest, arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (Ppa) in both ILD (r = 0.8, p = 0.01) and emphysema (r = 0.5, p = 0.03) patients. During exercise, the arterial ET-1 levels were significantly correlated with arterial oxygen (Pa,O2) (r = -0.6, p = 0.04), alveolar-arterial oxygen difference (r = 0.8, p = 0.01), and Ppa (r = 0.6, p = 0.04) in ILD patients, but not in those with emphysema. In brief, the results of this study suggest that arterial endothelin-1 is markedly increased in interstitial lung disease and emphysema patients, and that, it is related to the exercise-induced exacerbation of pulmonary hypertension in patients with interstitial lung disease, but not in those with emphysema.
Human cell exposure assays of Bacillus thuringiensis commercial insecticides: production of Bacillus cereus-like cytolytic effects from outgrowth of spores.
Authors: A F Tayabali, V L Seligy
Journal: Environmental Health Perspectives (2000)

Most contemporary bioinsecticides are derived from scaled-up cultures of Bacillus thuringiensis subspecies israelensis (Bti) and kurstaki (Btk), whose particulate fractions contain mostly B. thuringiensis spores (> 10(12)/L) and proteinaceous aggregates, including crystal-like parasporal inclusion bodies (PIB). Based on concerns over relatedness to B. cereus-group pathogens, we conducted extensive testing of B. thuringiensis (BT) products and their subfractions using seven human cell types. The Bti/Btk products generated nonspecific cytotoxicities involving loss in bioreduction, cell rounding, blebbing and detachment, degradation of immunodetectable proteins, and cytolysis. Their threshold dose (Dt approximately equal.5 times 10(-14)% BT product/target cell) equated to a single spore and a target cell half-life (tLD(50)) of approximately 16 hr. At Dts > 10(4), the tLD(50) rapidly shifted to < 4 hr; with antibiotic present, no component, including PIB-related [delta]-endotoxins, was cytolytic up to an equivalent of approximately 10(9 )Dt. The cytolytic agent(s) within the Bti/Btk-vegetative cell exoprotein (VCP) pool is an early spore outgrowth product identical to that of B. cereus and acting possibly by arresting protein synthesis. No cytolytic effects were seen with VCP from B. subtilis and Escherichia coli. These data, including recent epidemiologic work indicate that spore-containing BT products have an inherent capacity to lyse human cells in free and interactive forms and may also act as immune sensitizers. To critically impact at the whole body level, the exposure outcome would have to be an uncontrolled infection arising from intake of Btk/Bti spores. For humans, such a condition would be rare, arising possibly in equally rare exposure scenarios involving large doses of spores and individuals with weak or impaired microbe-clearance capacities and/or immune response systems.
Unplanned Extubations in the Adult Intensive Care Unit
Authors: THIERRY BOULAIN
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The predisposing factors and complications of unplanned extubation (UEX) in mechanically ventilated adult patients are not well recognized. We designed a prospective multicenter observational study to identify risk factors and describe the complications of UEX. We followed 426 ventilated patients over a 2-mo period. Clinical characteristics such as diagnosis on admission and reasons for ventilation were used to classify the patients. The presence or absence of potential risk factors was daily noted, including the types of ventilators, tracheal tubes, tube fixations, ventilatory support modes, route for intubation, and the use of intravenous sedation. Circumstances and complications of UEX were prospectively recorded. Forty-six (10.8%) patients experienced at least one episode of UEX. Ten UEX occurred during nursing procedures. At the moment of UEX, 61% of patients were agitated. The rates of mortality, laryngeal complications, nosocomial pneumonia after extubation, and the length of mechanical ventilation were similar in UEX and non-UEX patients. Patients were more often reintubated after UEX (28 of 46) than after planned extubation (28 of 284). All the non-reintubated UEX patients survived. One death occurred as a direct consequence of UEX. By use of multivariate analysis, we identified four factors contributing to UEX: chronic respiratory failure, endotracheal tube fixation with only thin adhesive tape, orotracheal intubation, and the lack of intravenous sedation. Considering these factors, we hypothesized that simple measures should be adopted to minimize the incidence of UEX and its related complications: more vigilance during procedures at patients' bedsides, adequate sedation of agitated patients, strong fixation of the tracheal tube, particular attention paid to orally intubated patients, and daily reassessment of the possibility of weaning from the ventilator.
NERVE ENDINGS IN NUTRITIONAL MUSCULAR DYSTROPHY IN GUINEA PIGS
Authors: W. M. Rogers, A. M. Pappenheimer, Marianne Goettsch
Journal: The Journal of Experimental Medicine (1931)

The nutritional muscle dystrophy of guinea pigs and rabbits is primarily a degeneration of the muscle fibers and is not associated with visible alterations of the peripheral nerves or their motor terminals.
Confidential inquiries should be funded in clinical genetics
Authors: K. Challen
Journal: BMJ (2001)

EDITOR—The confidential inquiry into genetic counselling by non-geneticists (CEGEN) investigated free personal choice in consent for genetic screening, testing, or intervention in clinical records of non-directive genetic counselling. It audited 621 pregnancies affected by Down's syndrome in women over 34; 271 infants with neural tube defects; 46 infants with cystic fibrosis who had a full sibling with cystic fibrosis; 172 pregnancies affected by thalassaemia; and 212 people with multiple endocrine neoplasia type II. Adverse events were sought when cases lacked documentation of informed choice. …
A chronic pneumothorax and fitness to fly
Authors: G. P Currie, A.-M. Kennedy, E. Paterson, S. J Watt
Journal: Thorax (2007)

According to Boyle's law, as the pressure falls, the volume of gas rises in an inversely proportional manner. This means that during an aircraft flight, the volume of trapped air in gas filled body chambers will increase. As a consequence, it is fairly well established that individuals with an untreated pneumothorax should not participate in commercial flying due to the risk of it enlarging and the possible development of tension. However, whether this also applies to individuals who have a long-standing, clinically stable pneumothorax is uncertain. The following article describes two adult patients each with a chronic pneumothorax who asked whether they would be fit to fly in an aircraft. We outline their histories and subsequent evaluation which consisted of clinical assessment, computed tomographic imaging, a hypoxic challenge test and exposure to a hypoxic hypobaric environment in a decompression chamber.
Return to Work After a First Myocardial Infarction
Authors: G. Richard Smith
Journal: JAMA (1988)

The relationship between return to work within one year after a first myocardial infarction and selected sociodemographic, health, psychosocial, and vocational characteristics was assessed in 151 patients aged 24 to 70 years. Seventy-two percent of the sample returned to work. Education, physical activity associated with employment, severity of myocardial infarction, perception of health status, financial incentives, socioeconomic status, treatment hospital, rated social health status, locus of control, satisfaction with work, and early entry into the job force each proved to be significantly associated with return to work in independent univariate analyses. A stepwise multivariate regression analysis identified only the first four factors as important predictors of return to work. Further analyses show that given knowledge of the patients' educational level and the physical activity associated with employment, 71% of patients who returned to work were correctly classified. Return to work proved easier to predict than work disability. More knowledge is needed about the factors that are critical to a failure to resume employment after a myocardial infarction.
Liphagal, a new meroterpenoid from the Caribbean sponge Aka coralliphaga that shows potent and selective inhibition of P13 kinase alpha.
Authors: I. Hollander, F. Marion, D.E. Williams, R. Mallon, S. C. Kim, D. M. Roll, L. Feldberg, R.W.M. van Soest, R.J. Andersen
Journal: Clinical Cancer Research (2006)