tbuckley/cabot-search huggingface dataset:
Combination of a Normal D-Dimer Concentration and a Non-High Pretest Clinical Probability Score Is a Safe Strategy to Exclude Deep Venous Thrombosis
Authors: R.E.G. Schutgens, P. Ackermark, F.J.L.M. Haas, H.K. Nieuwenhuis, H.G. Peltenburg, A.H. Pijlman, M. Pruijm, R. Oltmans, J.C. Kelder, D.H. Biesma
Journal: Circulation (2003)

Serial ultrasonography is reliable for the diagnosis of deep venous thrombosis in symptomatic patients, but the low prevalence of thrombosis in this group renders the approach costly and inconvenient to patients. We studied the clinical validity of the combination of a pretest clinical probability score and a D-dimer test in the initial evaluation of patients suspected of deep venous thrombosis.Patients with a normal D-dimer concentration (<500 fibrin equivalent units [FEU] microg/L) and a non-high probability score (<3) had no further testing. Patients with a normal D-dimer concentration and a high probability score (> or =3) underwent one ultrasonogram. Serial ultrasonography was performed in patients with an abnormal D-dimer concentration. Patients were followed for 3 months. A total of 812 patients were evaluable for efficacy. Only 1 of 176 patients (0.6%; 95% CI, 0.02% to 3.1%) with a normal D-dimer concentration and a non-high probability score developed thrombosis during follow-up. A normal D-dimer concentration and a high probability score were found in 39 patients; 3 of them (7.7%; 95% CI, 1.6% to 20.9%) had thrombosis at presentation, and one (2.8%; 95% CI, 0.07% to 14. 5%) developed pulmonary embolism during follow-up. In 306 of 597 patients (51.3%) with an abnormal D-dimer concentration, thrombosis was detected by serial ultrasonography. Six patients (2.1%; 95% CI, 0.8% to 4. 4%) developed thrombosis during follow-up. No deaths due to thromboembolism occurred during follow-up. The total need for ultrasonography was reduced by 29%.The combination of a non-high pretest clinical probability score and a normal D-dimer concentration is a safe strategy to rule out deep venous thrombosis and to withhold anticoagulation.
Clinical Outcomes and Genome-Wide Association for a Brain Methylation Site in an Antidepressant Pharmacogenetics Study in Mexican Americans
Authors: Ma-Li Wong, Chuanhui Dong, Deborah L. Flores, Monika Ehrhart-Bornstein, Stefan Bornstein, Mauricio Arcos-Burgos, Julio Licinio
Journal: American Journal of Psychiatry (2014)

The authors compared the effectiveness of fluoxetine and desipramine treatment in a prospective double-blind pharmacogenetics study in first-generation Mexican Americans and examined the role of whole-exome functional gene variations in the patients' antidepressant response.A total of 232 Mexican Americans who met DSM-IV criteria for major depressive disorder were randomly assigned to receive 8 weeks of double-blind treatment with desipramine (50-200 mg/day) or fluoxetine (10-40 mg/day) after a 1-week placebo lead-in period. Outcome measures included the Hamilton Depression Rating Scale (HAM-D), the Hamilton Anxiety Rating Scale, and the Beck Depression Inventory. At week 8, whole-exome genotyping data were obtained for 36 participants who remitted and 29 who did not respond to treatment.Compared with desipramine treatment, fluoxetine treatment was associated with a greater reduction in HAM-D score, higher response and remission rates, shorter time to response and remission, and lower incidences of anticholinergic and cardiovascular side effects. Pharmacogenetics analysis showed that exm-rs1321744 achieved exome-wide significance for treatment remission. This variant is located in a brain methylated DNA immunoprecipitation sequencing site, which suggests that it may be involved in epigenetic regulation of neuronal gene expression. This and two other common gene variants provided a highly accurate cross-validated predictive model for treatment remission of major depression (receiver operating characteristic integral=0.95).Compared with desipramine, fluoxetine treatment showed a more rapid reduction of HAM-D score and a lower incidence of side effects in a population comprising primarily first-generation Mexican Americans with major depression. This study's pharmacogenetics approach strongly implicates the role of functional variants in antidepressant treatment response.
Risk of cancer in <i>MSH6</i> mutation carriers: an international collaboration
Authors: M. A. Jenkins, L. Baglietto, J. G. Dowty, H. F. Vasen, A. de la Chapelle, H. L. Hampel, M. G. Dunlop, S. N. Thibodeau, N. M. Lindor
Journal: Journal of Clinical Oncology (2008)

11006 Background: Inherited mutations in mismatch repair genes increase risk of cancer. The majority of studies have concentrated on MLH1 and MSH2. Germline mutations in the mismatch repair gene MSH6 account for about 13% of colorectal cancer caused by mismatch repair gene mutations, however the risk of cancer is uncertain due to the low numbers of carriers studied. Methods: We identified 113 families of MSH6 mutation carriers (probands) for the analysis from the Netherlands (n=41), USA (n=31), Scotland (n=21), Australia (n=15) and Canada (n=5). These were ascertained from family cancer clinics because of a family history of cancer (n=65) or from cancer registries independent of family history (n=48). MSH6 mutation status, sex, age, history of cancer, polypectomy, and hysterectomy were sought from 3,104 relatives of the probands. Hazard ratios (HR) of risk of cancer in carriers compared to the general population, and age-specific cumulative risks in carriers (penetrance) were estimated. We used a modified segregation analysis that incorporates both genotyped and ungenotyped relatives and conditioning on ascertainment to produce unbiased estimates. Results: Male and female mutation carriers had a 7-fold increased risk of colorectal cancer (HR 6.8; 95% confidence interval 4.7-9.7) compared to the population. Risk of endometrial cancer was increased more than 20-fold (HR 22.8; 95%CI 14.7-35.4). There was no evidence of increased risk in males for other Lynch-related cancers (gastric, small bowel, kidney, ureter, brain, or ovary) (HR 1.1; 95%CI 0.2-8.0), however females were at 5-fold increased risk (HR 5.2; 95%CI 2.7-10.0). In a North American population, these hazard ratios would result in the following cumulative risks to age 70: male colorectal cancer, 25% (95%CI 18%-34%); female colorectal cancer, 19% (95%CI 14%-26%); endometrial cancer, 39% (95%CI 27%-54%); male other Lynch cancers, 3% (0%-18%) and female other Lynch cancers, 11% (6%-20%). The risk to age 70 of any Lynch cancer was 26% in males and 49% in female carriers of deleterious mutations in MSH6. Conclusions: This international study suggests that risk of Lynch-related cancers in MSH6 mutation carriers appears to be lower than previously reported for MLH1 and MSH2 and twice as high in females compared to males. No significant financial relationships to disclose.
SARS: understanding the coronavirus: Apoptosis may explain lymphopenia of SARS
Authors: R. O'Donnell
Journal: BMJ (2003)

Editor—In their review of the severe acute respiratory syndrome (SARS) Wong et al emphasise lymphopenia as a hallmark feature.1 Panesar suggested that glucocorticoids or stimulation of the hypothalamic-pituitary-adrenal axis leads to lymphocyte margination and that patients without lymphopenia may have adrenal insufficiency.2

Apoptosis may also explain the lymphopenia of SARS. In severe paramyxovirus infections in humans such as measles, lymphopenia is commonly present and associated with more severe disease. One of us with Carrington recently reported that lymphopenia is also seen with another paramyxovirus infection: respiratory syncytial virus, which causes bronchiolitis in young children.3

Children with more severe bronchiolitis from respiratory syncytial virus infection have significantly lower absolute lymphocyte counts than those with mild disease. Bronchiolitis is ubiquitous and, in the developed world, the commonest reason a child under 1 year of age is admitted to hospital. Studies in mice show that not only is the lymphocyte immune response to virus essential in controlling the virus but it also causes disease.4 The fact the immune response is both saint and sinner is believed to be why the use of ribavirin has proved less effective in bronchiolitis than was first hoped.​hoped.




Figure 1




SARS, respiratory syncytial virus disease, measles, and sepsis show parallels in the occurrence of lymphopenia. In sepsis and measles apoptosis is believed to be the mechanism of lymphopenia. In models of sepsis, for example, inhibitors of apoptosis ameliorate illness and prevent death.5 There may be important therapeutic implications for patients with SARS from these new research areas.
The Primary Benefits of Angiotensin-Converting Enzyme Inhibition on Cardiac Remodeling Occur During Sleep Time in Murine Pressure Overload Hypertrophy
Authors: Tami A. Martino, Nazneen Tata, Jeremy A. Simpson, Rachel Vanderlaan, Fayez Dawood, M. Golam Kabir, Neelam Khaper, Carlo Cifelli, Peter Podobed, Peter P. Liu, Mansoor Husain, Scott Heximer, Peter H. Backx, Michael J. Sole
Journal: Journal of the American College of Cardiology (2011)
HOMEOSTATIC CONTROL OF NEURAL ACTIVITY: From Phenomenology to Molecular Design
Authors: Graeme W. Davis
Journal: Annual Review of Neuroscience (2006)

Homeostasis is a specialized form of regulation that precisely maintains the function of a system at a set point level of activity. Recently, homeostatic signaling has been suggested to control neural activity through the modulation of synaptic efficacy and membrane excitability ( Davis &amp; Goodman 1998a , Turrigiano &amp; Nelson 2000 , Marder &amp; Prinz 2002 , Perez-Otano &amp; Ehlers 2005 ). In this way, homeostatic signaling is thought to constrain neural plasticity and contribute to the stability of neural function over time. Using a restrictive definition of homeostasis, this review first evaluates the phenomenological and molecular evidence for homeostatic signaling in the nervous system. Then, basic principles underlying the design and molecular implementation of homeostatic signaling are reviewed on the basis of work in other, simplified biological systems such as bacterial chemotaxis and the heat shock response. Data from these systems are then discussed in the context of homeostatic signaling in the nervous system.
Physiological effect of endobronchial radiotherapy in patients with major airway occlusion by carcinoma.
Authors: J M Goldman, A S Bulman, A J Rathmell, B M Carey, M F Muers, C A Joslin
Journal: Thorax (1993)

BACKGROUND: Endobronchial radiotherapy by a high dose rate remote after-loading technique (high dose rate brachytherapy) has become an established treatment for major airway occlusion by inoperable carcinoma of the bronchus. Only limited objective data on its effect on pulmonary physiology and on radiographic and bronchoscopic appearances are available. The aim of this study was to make a detailed assessment of patients before and after high dose rate brachytherapy to determine which investigations were useful and to generate data for comparing this with other methods of treatment. METHODS: Twenty patients with major airway obstruction by inoperable lung cancer underwent a detailed assessment before receiving endobronchial radiotherapy (15 Gy at 1 cm in a single fraction) and six weeks after treatment. This included chest radiography, computed tomography of the thorax, bronchoscopy including an obstruction index, five minute walking tests, isotope ventilation and perfusion lung scanning, and full lung function tests with maximum inspiratory and expiratory flow-volume loops. RESULTS: Nineteen patients (mean age 69 years) completed the study. Symptomatic improvement occurred in 17 patients. A collapsed lobe or lung, seen on the chest radiograph in 13, reexpanded in nine. Bronchoscopic appearances improved in 18, the mean obstruction index decreasing from 6.2 to 2.8. The isotope scans showed significant increases in the percentage of total lung ventilation (V) and perfusion (Q) measured over the abnormal lung (V 17.7% to 27.7%, Q 15.1 to 21.9%). Five minute walking distance (305 to 329 m), forced expiratory volume in one second (FEV1 1.45 to 1.61 l), forced vital capacity (FVC 2.17 to 2.48 l) and ratio of forced expiratory to forced inspiratory flow rate at 50% vital capacity (FEF50/FIF50 0.58 to 0.88) all increased significantly. CONCLUSIONS: Endobronchial radiotherapy led to subjective benefit in most cases in terms of symptoms and bronchoscopic and radiological appearances. There was objective improvement in spirometric indices and in exercise tolerance with increased pulmonary ventilation and perfusion and evidence of decreased intrathoracic airway obstruction.
Significance of iron status in hair loss in women
Authors: A.J. Chamberlain, R.P.R. Dawber
Journal: British Journal of Dermatology (2003)

Sir, We read with interest Sinclair's recent study1 concluding that there is no clear association between chronic diffuse telogen hair loss in women and low iron stores. At a recent international meeting attended by many of the world authorities on hair disorders (European Hair Research Society, Brussels, 27–30 June 2002) we hosted an open debate on the topic of diffuse hair loss in women, particularly concentrating on the role of iron.2 Sinclair's findings are in support of our clinical experience and interpretation of the literature—that the significance of iron deficiency in hair loss is dubious, despite textbook references to the contrary.3, 4 In our opinion, there are several limitations with respect to the literature concerning this possible association and these include: (i) variation in the biochemical definition of iron deficiency by gender and between laboratories; (ii) difficulty in isolating iron status from other variables that affect hair growth; (iii) lack of confirmation of iron deficiency as a relevant cause of hair loss by replacement therapy with meaningful follow‐up over time; and (iv) lack of consensus regarding the ideal means of measuring hair growth and response to therapy.5 Indeed, the first limitation has been the subject of hot debate just recently.6, 7 It must also be pointed out that some of the more emphatic papers suggesting a significance for iron status in hair loss have really only examined small numbers of women.8 While one may argue that Sinclair's period of follow‐up is too short to detect meaningful regrowth (which he acknowledges), one would certainly expect a reduction in shedding in those women in whom iron status was relevant (and this was not observed in his study). For the reasons stated above, in our hair clinic we too are reluctant to attribute chronic and diffuse hair loss in women to iron deficiency too readily when, in reality, this is usually more likely to be due to androgenetic alopecia or chronic telogen effluvium. It is equally curious to us why young women and even girls with iron deficiency due to menorrhagia rarely present to dermatologists with hair loss!
Early Life Arsenic Exposure and Acute and Long-term Responses to Influenza A Infection in Mice
Authors: Kathryn A. Ramsey, Rachel E. Foong, Peter D. Sly, Alexander N. Larcombe, Graeme R. Zosky
Journal: Environmental Health Perspectives (2013)

Arsenic is a significant global environmental health problem. Exposure to arsenic in early life has been shown to increase the rate of respiratory infections during infancy, reduce childhood lung function, and increase the rates of bronchiectasis in early adulthood.We aimed to determine if early life exposure to arsenic exacerbates the response to early life influenza infection in mice.C57BL/6 mice were exposed to arsenic in utero and throughout postnatal life. At 1 week of age, a subgroup of mice were infected with influenza A. We then assessed the acute and long-term effects of arsenic exposure on viral clearance, inflammation, lung structure, and lung function.Early life arsenic exposure reduced the clearance of and exacerbated the inflammatory response to influenza A, and resulted in acute and long-term changes in lung mechanics and airway structure.Increased susceptibility to respiratory infections combined with exaggerated inflammatory responses throughout early life may contribute to the development of bronchiectasis in arsenic-exposed populations.
Dyspnoea severity and pneumonia as predictors of in-hospital mortality and early readmission in acute exacerbations of COPD
Authors: J Steer, E M Norman, O A Afolabi, G J Gibson, S C Bourke
Journal: Thorax (2011)

<h3>Background</h3> Rates of mortality and readmission are high in patients hospitalised with acute exacerbations of chronic obstructive pulmonary disease (AECOPD). In this population, the prognostic value of the Medical Research Council Dyspnoea Scale (MRCD) is uncertain, and an extended MRCD (eMRCD) scale has been proposed to improve its utility. Coexistent pneumonia is common and, although the CURB-65 prediction tool is used, its discriminatory value has not been reported. <h3>Methods</h3> Clinical and demographic data were collected on consecutive patients hospitalised with AECOPD. The relationship of stable-state dyspnoea severity to in-hospital mortality and 28-day readmission was assessed. The discriminatory value of CURB-65, MRCD and eMRCD, in the prediction of in-hospital mortality, was assessed and compared. <h3>Results</h3> 920 patients were recruited. 10.4% died in-hospital and 19.1% of the 824 survivors were readmitted within 28 days of discharge. During their stable state prior to admission, 34.2% of patients were too breathless to leave the house. Mortality was significantly higher in pneumonic than in non-pneumonic exacerbations (20.1% vs 5.8%, p&lt;0.001). eMRCD was a significantly better discriminator than either CURB-65 or the traditional MRCD scale for predicting in-hospital mortality, and was a stronger prognostic tool than CURB-65 in the subgroup of patients with pneumonic AECOPD. <h3>Conclusions</h3> The severity of dyspnoea in the stable state predicts important clinical outcomes in patients hospitalised with AECOPD. The eMRCD scale identifies a subgroup of patients at a particularly high risk of in-hospital mortality and is a better predictor of mortality risk than CURB-65 in exacerbations complicated by pneumonia.
Novel Internal Regions of Fluorescent Proteins Undergo Divergent Evolutionary Patterns
Authors: D. F. Gruber, R. DeSalle, E. K. Lienau, D. Tchernov, V. A. Pieribone, H.-T. Kao
Journal: Molecular Biology and Evolution (2009)

Over the past decade, fluorescent proteins (FPs) have become ubiquitous tools in biological research. Yet, little is known about the natural function or evolution of this superfamily of proteins that originate from marine organisms. Using molecular phylogenetic analyses of 102 naturally occurring cyan fluorescent proteins, green fluorescent proteins, red fluorescent proteins, as well as the nonfluorescent (purple-blue) protein sequences (including new FPs from Lizard Island, Australia) derived from organisms with known geographic origin, we show that FPs consist of two distinct and novel regions that have evolved under opposite and sharply divergent evolutionary pressures. A central region is highly conserved, and although it contains the residues that form the chromophore, its evolution does not track with fluorescent color and evolves independently from the rest of the protein. By contrast, the regions enclosing this central region are under strong positive selection pressure to vary its sequence and yet segregate well with fluorescence color emission. We did not find a significant correlation between geographic location of the organism from which the FP was isolated and molecular evolution of the protein. These results define for the first time two distinct regions based on evolution for this highly compact protein. The findings have implications for more sophisticated bioengineering of this molecule as well as studies directed toward understanding the natural function of FPs.
Why do people postpone parenthood? Reasons and social policy incentives
Authors: Melinda Mills, Ronald R. Rindfuss, Peter McDonald, Egbert te Velde
Journal: Human Reproduction Update (2011)

Never before have parents in most Western societies had their first children as late as in recent decades. What are the central reasons for postponement? What is known about the link between the delay of childbearing and social policy incentives to counter these trends? This review engages in a systematic analysis of existing evidence to extract the maximum amount of knowledge about the reasons for birth postponement and the effectiveness of social policy incentives.
Rapamycin-Sensitive Pathway Regulates Mitochondrial Membrane Potential, Autophagy, and Survival in Irradiated MCF-7 Cells
Authors: Shoshana Paglin, Na-Young Lee, Charles Nakar, Megan Fitzgerald, Jason Plotkin, Bethanne Deuel, Nadia Hackett, Melissa McMahill, Eleana Sphicas, Nina Lampen, Joachim Yahalom
Journal: Cancer Research (2005)

Radiation-induced inhibition of rapamycin-sensitive pathway and its effect on the cellular response to radiation were studied in the human breast cancer cell line MCF-7. Both radiation and rapamycin shared molecular targets and induced similar physiologic responses. Each of these treatments increased immunostaining of mammalian target of rapamycin (mTOR) in the nucleus, and radiation led to decreased phosphorylation of its autophosphorylation site Ser2481. In addition to dephosphorylation of established mTOR downstream effectors 4E-binding protein 1 and p70 ribosomal S6 kinase, both treatments decreased the level of eukaryotic initiation factor 4G. Experiments with the potentiometric dye, JC-1, revealed an oligomycin-dependent increase in mitochondrial membrane potential following radiation or rapamycin treatment, suggesting that both lead to reversal of F0F1ATPase activity. Both radiation and rapamycin induced sequestration of cytoplasmic material in autophagic vacuoles. In both cases, appearance of autophagic vacuoles involved the participation of microtubule-associated protein 1 light chain 3 (LC3). Transient cotransfection of green fluorescent protein-LC3 with either wild-type or dominant-negative mTOR further showed that inactivation of mTOR pathway is sufficient to induce autophagy in these cells. Finally, administration of rapamycin in combination with radiation led to enhanced mitochondria hyperpolarization, p53 phosphorylation, and increased cell death. Taken together, these experiments show that radiation-induced inhibition of rapamycin-sensitive pathway in MCF-7 cells causes changes in mitochondria metabolism, development of autophagy, and an overall decrease in cell survival.