tbuckley/cabot-search huggingface dataset:
Mechanisms of Atrial Fibrillation Termination by Pure Sodium Channel Blockade in an Ionically-Realistic Mathematical Model
Authors: James Kneller*, Jérôme Kalifa*, Renqiang Zou, Alexey V. Zaitsev, Mark Warren, Omer Berenfeld, Edward J. Vigmond, L. Joshua Leon, Stanley Nattel, José Jalife
Journal: Circulation Research (2005)

The mechanisms by which Na+-channel blocking antiarrhythmic drugs terminate atrial fibrillation (AF) remain unclear. Classical "leading-circle" theory suggests that Na+-channel blockade should, if anything, promote re-entry. We used an ionically-based mathematical model of vagotonic AF to evaluate the effects of applying pure Na+-current (I(Na)) inhibition during sustained arrhythmia. Under control conditions, AF was maintained by 1 or 2 dominant spiral waves, with fibrillatory propagation at critical levels of action potential duration (APD) dispersion. I(Na) inhibition terminated AF increasingly with increasing block, terminating all AF at 65% block. During 1:1 conduction, I(Na) inhibition reduced APD (by 13% at 4 Hz and 60% block), conduction velocity (by 37%), and re-entry wavelength (by 24%). During AF, I(Na) inhibition increased the size of primary rotors and reduced re-entry rate (eg, dominant frequency decreased by 33% at 60% I(Na) inhibition) while decreasing generation of secondary wavelets by wavebreak. Three mechanisms contributed to I(Na) block-induced AF termination in the model: (1) enlargement of the center of rotation beyond the capacity of the computational substrate; (2) decreased anchoring to functional obstacles, increasing meander and extinction at boundaries; and (3) reduction in the number of secondary wavelets that could provide new primary rotors. Optical mapping in isolated sheep hearts confirmed that tetrodotoxin dose-dependently terminates AF while producing effects qualitatively like those of I(Na) inhibition in the mathematical model. We conclude that pure INa inhibition terminates AF, producing activation changes consistent with previous clinical and experimental observations. These results provide insights into previously enigmatic mechanisms of class I antiarrhythmic drug-induced AF termination. The full text of this article is available online at http://circres.ahajournals.org
H63D is an haemochromatosis associated allele
Authors: V F FAIRBANKS, D J BRANDHAGEN, S N THIBODEAU, K SNOW, P C WOLLAN
Journal: Gut (1998)

Editor,—The UK Haemochromatosis Consortium's report ( Gut 1997; 41 :841–4) questions the importance of the H63D allele in hereditary haemochromatosis (HHC). In their commentary, Goldwurm and Powell ( Gut 1997; 41 :855–6) also doubt the relevance of H63D. However, there is compelling evidence that the H63D allele is associated with HHC.1-12 To evaluate the association of H63D with haemochromatosis, one must first recognise that H63D and C282Y are independent mutations of the HFE gene. Because the C282Y mutation is so common and is highly penetrant, homozygous C282Y predominates among cases of haemochromatosis, and H63D is not observed in C282Y homozygotes. If one excludes from analysis the C282Y homozygotes, then the strong association of H63D with HHC becomes apparent. For five large series from North America1-5 that have been analysed in this manner, we found a highly significant (p=0.000001) twofold "enrichment" of HHC cases with H63D, compared with random control cases. For studies reported from Europe,6-10 we also found a highly significant "enrichment", in which groups with HHC have roughly twice the frequency of H63D compared with control groups: Borot et al , p=0.003; Jouanolle et al , p=0.00004; Carella et al , p= 0.073; Martinez et al , p=0.000002; and Gottschalk et al , p=0.02. When all the data reported from Europe and from North America are combined, including those of the Consortium, the association of H63D with HHC is quite significant (p < 0.000001). The strong association of H63D with haemochromatosis might depend on the fact that patients who are compound heterozygotes—that is, C282Y/H63D, are at risk of developing clinically significant iron overload. Therefore, one may question whether H63D itself is associated with haemochromatosis. We have tested this possibility by re-analysing all the published data (combining data from 10 studies, including those of the UK Haemochromatosis … Dr Robson (email:krobson{at}hammer.imm.ox.ac.uk).
mTOR inhibition improves immune function in the elderly
Authors: Joan B. Mannick, Giuseppe Del Giudice, Maria Lattanzi, Nicholas M. Valiante, Jens Praestgaard, Baisong Huang, Michael A. Lonetto, Holden T. Maecker, John Kovarik, Simon Carson, David J. Glass, Lloyd B. Klickstein
Journal: Science Translational Medicine (2014)

Inhibition of the mammalian target of rapamycin (mTOR) pathway extends life span in all species studied to date, and in mice delays the onset of age-related diseases and comorbidities. However, it is unknown if mTOR inhibition affects aging or its consequences in humans. To begin to assess the effects of mTOR inhibition on human aging-related conditions, we evaluated whether the mTOR inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination. RAD001 enhanced the response to the influenza vaccine by about 20% at doses that were relatively well tolerated. RAD001 also reduced the percentage of CD4 and CD8 T lymphocytes expressing the programmed death-1 (PD-1) receptor, which inhibits T cell signaling and is more highly expressed with age. These results raise the possibility that mTOR inhibition may have beneficial effects on immunosenescence in the elderly.
Rarity of hypertension in adult patients with atopic dermatitis
Authors: M. Uehara, H. Sugiura, K. Tanaka
Journal: British Journal of Dermatology (2002)

Patients with atopic dermatitis show a tendency for vasoconstriction of the small vessels in the skin. As peripheral vasoconstriction contributes to the cause of hypertension, it is natural to suppose that blood pressures might be on the high side in adult patients with atopic dermatitis. In the literature, however, there was little information on the subject.To study the incidence of hypertension in adult patients with atopic dermatitis.Blood pressure was measured in 521 adult patients with active atopic dermatitis (235 males; 286 females) aged 30-59 years, and 87 adults with "healed" atopic dermatitis (26 males; 61 females) aged 34-52 years. The blood pressures were classified as definite hypertension, borderline hypertension or normal blood pressure.In those patients aged 30-39 years with active atopic dermatitis, the incidence of definite hypertension in the male patients and the female patients was 1.1% and 1.6%, respectively. The incidence remained almost at a plateau for the 30-39-year-old age group through to the 50-59-year-old age group, in both the male and female patients. There was no difference in the incidence of definite hypertension between patients with severe dermatitis and patients with mild dermatitis. Adult patients with "healed" atopic dermatitis also showed a low incidence of definite hypertension.These findings indicate that hypertension is rare in adult patients with atopic dermatitis. It is most probable that the rarity of hypertension is a primary feature of the disease.
Coexpression of type 2 immune targets in sputum-derived epithelial and dendritic cells from asthmatic subjects
Authors: Bertram Bleck, Angeliki Kazeros, Keren Bakal, Lymaris Garcia-Medina, Alexandra Adams, Mengling Liu, Richard A. Lee, Doris B. Tse, Amanda Chiu, Gabriele Grunig, John P. Egan, Joan Reibman
Journal: Journal of Allergy and Clinical Immunology (2015)
Hypoxia Predicts Aggressive Growth and Spontaneous Metastasis Formation from Orthotopically Grown Primary Xenografts of Human Pancreatic Cancer
Authors: Qing Chang, Igor Jurisica, Trevor Do, David W. Hedley
Journal: Cancer Research (2011)

Hypoxia in solid tumors is associated with treatment resistance and increased metastatic potential. Although hypoxia has been reported in pancreatic cancer patients, there is little direct evidence that this contributes to their overall poor prognosis. To address this, we examined the associations between hypoxia and biological aggression in a series of patient-derived xenografts grown orthotopically. Early passage xenografts were established from 16 patients undergoing surgery for pancreatic cancer and maintained in the pancreas of immune-deprived mice. Hypoxic cells were labeled using the 2-nitroimidazole probe EF5 and stained for immunofluorescence microscopy of tissue sections or as cell suspensions for flow cytometry. Bromodeoxyuridine (BrdUrd) uptake, microvessel density, cleaved caspase-3, and the differentiation markers E-cadherin, cytokeratin 19, and vimentin were analyzed in relation to hypoxia. Orthotopic implants closely resembled the histology of the original surgical samples. The 16 primary xenografts showed a wide range in their growth rates and metastatic potential, reminiscent of the spectrum of behavior seen in the clinic. EF5 labeling, tumor growth rates, and metastatic patterns were highly consistent within replicates, indicating a significant transmissible (genetic or epigenetic) component. Hypoxia was highly correlated with rapid tumor growth, increased BrdUrd uptake, and with spontaneous metastasis formation. mRNA expression analysis showed increased expression of genes involved in cell survival and proliferation in the hypoxic models. The results suggest that hypoxia is a major adverse prognostic factor in pancreatic cancer patients and support the introduction of techniques to measure hypoxia directly in patients and the development of treatment protocols to target hypoxia.
2014 AHA/ACC Guideline for the Management of Patients With Non–ST-Elevation Acute Coronary Syndromes
Authors: Ezra A. Amsterdam, Nanette K. Wenger, Ralph G. Brindis, Donald E. Casey, Theodore G. Ganiats, David R. Holmes, Allan S. Jaffe, Hani Jneid, Rosemary F. Kelly, Michael C. Kontos, Glenn N. Levine, Philip R. Liebson, Debabrata Mukherjee, Eric D. Peterson, Marc S. Sabatine, Richard W. Smalling, Susan J. Zieman
Journal: Journal of the American College of Cardiology (2014)
Thyroid function tests---time for a reassessment
Authors: D. S. O'Reilly
Journal: BMJ (2000)

In 1999, 890 000 measurements of thyroid stimulating hormone were performed by Scottish hospital laboratories—approximately one test for every six of Scotland's 5.1 million people.1 This number does not include tests performed in the non-NHS laboratories or as part of the screening programme for congenital hypothyroidism. Although laboratory statistics are not collected nationally in England and Wales, the market in the United Kingdom (population 59 million) for thyroid stimulating hormone diagnostic tests is currently estimated at 9-10 million each year.

A remarkable downgrading of the clinical aspects of hypothyroidism and hyperthyroidism has paralleled the inexorable increase in the number of thyroid function tests performed over the past 20 years. This has led to chaos in the diagnosis of hypothyroidism. It has been stated that a diagnosis of clinical hypothyroidism can be made on the basis of biochemical measurements alone and that signs and symptoms are unnecessary.2 Other authors protest, and maintain that biochemical tests can be misleading and that the diagnosis can be made on clinical grounds alone.3 In hyperthyroidism, a suppressed thyroid stimulating hormone concentration is currently the cornerstone of biochemical diagnosis. No numerical value has been assigned to the serum concentration of thyroid stimulating hormone below which suppression is considered to occur. This value varies from centre to centre depending on the sensitivity of the local assay. Thus, to many non-specialists the diagnosis of hyperthyroidism is also confusing.

#### Summary points

There are no data on the relative importance of biochemical thyroid function tests and clinical symptoms and signs in assessing thyroid dysfunction.

Secretion of thyroid stimulating hormone is influenced by many factors other than the negative feedback inhibition by thyroxine or triiodothyronine.

Changes in thyroid stimulating hormone, thyroxine, and triiodothyronine concentrations during systemic illness are poorly understood.

Thyroid function tests cannot be interpreted in patients with systemic …
Long-term Effect of Continuous Positive Airway Pressure in Hypertensive Patients with Sleep Apnea
Authors: Ferran Barbé, Joaquín Durán-Cantolla, Francisco Capote, Monica de la Peña, Eusebi Chiner, Juan F Masa, Mónica Gonzalez, Jose M Marín, Francisco Garcia-Rio, Josefa Diaz de Atauri, Joaquín Terán, Mercedes Mayos, Carmen Monasterio, Felix del Campo, Sivia Gomez, Manuel Sanchez de la Torre, Montse Martinez, José M Montserrat
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Continuous positive airway pressure (CPAP) is the current treatment for patients with symptomatic obstructive sleep apnea (OSA). Its use for all subjects with sleep-disordered breathing, regardless of daytime symptoms, is unclear.Objectives: This multicenter controlled trial assesses the effects of 1 year of CPAP treatment on blood pressure (BP) in nonsymptomatic, hypertensive patients with OSA.Methods: We evaluated 359 patients with OSA. Inclusion criteria consisted of an apnea–hypopnea index (AHI) greater than 19 hour−1, an Epworth Sleepiness Scale score less than 11, and one of the following: under antihypertensive treatment or systolic blood pressure greater than 140 or diastolic blood pressure greater than 90 mm Hg. Patients were randomized to CPAP (n = 178) or to conservative treatment (n = 181). BP was evaluated at baseline and at 3, 6, and 12 months of follow-up.Measurements and Main Results: Mean (SD) values were as follows: age, 56 ± 10 years; body mass index (BMI), 32 ± 5 kg · m−2; AHI, 45 ± 20 hour−1; and Epworth Sleepiness Scale score, 7 ± 3. After adjusting for follow-up time, baseline blood pressure values, AHI, time with arterial oxygen saturation less than 90%, and BMI, together with the change in BMI at follow-up, CPAP treatment decreased systolic blood pressure by 1.89 mm Hg (95% confidence interval: −3.90, 0.11 mm Hg; P = 0.0654), and diastolic blood pressure by 2.19 mm Hg (95% confidence interval: −3.46, −0.93 mm Hg; P = 0.0008). The most significant reduction in BP was in patients who used CPAP for more than 5.6 hours per night. CPAP compliance was related to AHI and the decrease in Epworth Sleepiness Scale score.Conclusions: In nonsleepy hypertensive patients with OSA, CPAP treatment for 1 year is associated with a small decrease in BP. This effect is evident only in patients who use CPAP for more than 5.6 hours per night.Clinical trial registered with www.clinicaltrials.gov (NCT00127348).
Maternal age and the risk of developing ankylosing spondylitis
Authors: K. RAZA, L G. KENNEDY, A. CALIN
Journal: Annals of the Rheumatic Diseases (1997)

We read with interest the article by Weinreich and colleagues.1 They showed that transgenic mice born to mothers aged 8 months or older had a significantly lower frequency of murine ankylosing enthesopathy than mice born to younger mothers. They speculated that an age related increase in maternal antibody levels resulted in increasing protection of offspring against a ubiquitous, potentially arthritogenic, micro-organism. In humans, as in the mouse model, environmental factors must influence the development of ankylosing spondylitis (AS). We sought evidence that the age of conception in women with AS influenced the risk of their offspring developing disease.

We collected data from …
Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews
Authors: F. Song, Y. K Loke, T. Walsh, A.-M. Glenny, A. J Eastwood, D. G Altman
Journal: BMJ (2009)

<b>Objective</b> To investigate basic assumptions and other methodological problems in the application of indirect comparison in systematic reviews of competing healthcare interventions. <b>Design</b> Survey of published systematic reviews. <b>Inclusion criteria</b> Systematic reviews published between 2000 and 2007 in which an indirect approach had been explicitly used. <b>Data extraction</b> Identified reviews were assessed for comprehensiveness of the literature search, method for indirect comparison, and whether assumptions about similarity and consistency were explicitly mentioned. <b>Results</b> The survey included 88 review reports. In 13 reviews, indirect comparison was informal. Results from different trials were naively compared without using a common control in six reviews. Adjusted indirect comparison was usually done using classic frequentist methods (n=49) or more complex methods (n=18). The key assumption of trial similarity was explicitly mentioned in only 40 of the 88 reviews. The consistency assumption was not explicit in most cases where direct and indirect evidence were compared or combined (18/30). Evidence from head to head comparison trials was not systematically searched for or not included in nine cases. <b>Conclusions</b> Identified methodological problems were an unclear understanding of underlying assumptions, inappropriate search and selection of relevant trials, use of inappropriate or flawed methods, lack of objective and validated methods to assess or improve trial similarity, and inadequate comparison or inappropriate combination of direct and indirect evidence. Adequate understanding of basic assumptions underlying indirect and mixed treatment comparison is crucial to resolve these methodological problems. <b>Appendix 1</b> PubMed search strategy <b>Appendix 2</b> Characteristics of identified reports <b>Appendix 3</b> Identified studies References of included studies
Inflammatory Markers and Diabetic Retinopathy in Type 1 Diabetes
Authors: Kenneth E. Izuora, H. Peter Chase, William E. Jackson, Joseph R. Coll, Iris M. Osberg, Peter A. Gottlieb, Marian J. Rewers, Satish K. Garg
Journal: Diabetes Care (2005)

Retinopathy affects ∼86% of people in the U.S. with type 1 diabetes (1). This percentage is higher than would be expected as a result of poor glycemic control, blood pressure elevations, and smoking. Another possible risk factor for microvascular disease in type 1 diabetes might be inflammation. Inflammation, as measured by C-reactive protein (CRP), has been shown to be increased in people with type 1 and type 2 diabetes who have macrovascular complications (2–5). A recent study in laboratory animals has suggested that inflammation may be important in the etiology of diabetic retinopathy (6). The purpose of this study was to determine if there was an association between inflammatory markers and diabetic retinopathy.

This was a cross-sectional prospective study comprised of subjects with type 1 diabetes ( n = 154) matched by age and sex with nondiabetic control subjects in a 3:1 ratio. Eligible subjects (control subjects and type 1 diabetic patients) were between the ages of 14 and 42 years. Test subjects had type 1 diabetes for >5 years. Subjects were excluded if they had a blood pressure >140/90 mmHg, were tobacco users, were on medications known to affect CRP (ACE inhibitors, hydroxymethylglutaryl CoA reductase inhibitors, nonsteroidal anti-inflammatory agents, and aspirin), had other known concomitant illnesses, or were pregnant. Written informed consent was obtained …
P-glycoprotein expression in primary and metastatic malignant melanoma
Authors: D. SCHADENDORF, R. HERFORDT, B.M. CZARNETZKI
Journal: British Journal of Dermatology (2006)

Metastatic malignant melanoma is notoriously resistant to chemotherapeutic agents, but the exact mechanisms involved in this drug resistance arc unknown. One recently defined major mechanism of multidrug resistance involves the overexpression of P‐glycoprotein on cell membranes. In order to evaluate the significance of this putative drug efflux pump for chemoresistance of malignant melanoma, five different antibodies were employed to examine P‐glycoprotein expression on tissue from 33 primary malignant melanomas and 35 metastases, before and after chemotherapy, using immunohistological techniques. The expression of P‐glycoprotein was low on primary cutaneous melanomas (three of 33), and on metastases (one of 35). Normal tissue in and around the melanoma showed reactivity of endothelial cells, stromal cells and eccrine sweat glands with several antibodies tested. Chemotherapy with drugs commonly used in metastatic melanoma, including agents known to induce P‐glycoprotein expression in other tumours (vindesine, cisplatin) had no effect on P‐glycoprotein expression in human melanoma metastases. The high chemoresistance of human melanoma cells in vitro and in vivo is probably not mediated via P‐glycoprotein, and other possible mechanisms involved will have to be explored in future studies.
Apoptosis Induction by Retinoids in Eosinophilic Leukemia Cells: Implication of Retinoic Acid Receptor-α Signaling in All-<i>Trans</i>-Retinoic Acid Hypersensitivity
Authors: Carine Robert, Laurent Delva, Nicole Balitrand, Sarolta Nahajevszky, Tamàs Masszi, Christine Chomienne, Béla Papp
Journal: Cancer Research (2006)

Abstract Hypereosinophilic syndrome (HES) has recently been recognized as a clonal leukemic lesion, which is due to a specific oncogenic event that generates hyperactive platelet-derived growth factor receptor-α–derived tyrosine kinase fusion proteins. In the present work, the effect of retinoids on the leukemic hypereosinophilia-derived EoL-1 cell line and on primary HES-derived cells has been investigated. We show that all-trans-retinoic acid (ATRA) inhibits eosinophil colony formation of HES-derived bone marrow cells and is a powerful inducer of apoptosis of the EoL-1 cell line. Apoptosis was shown in the nanomolar concentration range by phosphatidylserine externalization, proapoptotic shift of the Bcl-2/Bak ratio, drop in mitochondrial membrane potential, activation of caspases, and cellular morphology. Unlike in other ATRA-sensitive myeloid leukemia models, apoptosis was rapid and was not preceded by terminal cell differentiation. Use of isoform-selective synthetic retinoids indicated that retinoic acid receptor-α–dependent signaling is sufficient to induce apoptosis of EoL-1 cells. Our work shows that the scope of ATRA-induced apoptosis of malignancies may be wider within the myeloid lineage than thought previously, that the EoL-1 cell line constitutes a new and unique model for the study of ATRA-induced cell death, and that ATRA may have potential for the management of clonal HES. (Cancer Res 2006; 66(12): 6336-44)