tbuckley/cabot-search huggingface dataset:
Community-acquired pneumonia (CAP) caused by mycoplasma pneumoniae or chlamydophila pneumoniae in children: Are there reliable signs/symptoms for clinical diagnostics?
Authors: Tereshchenko Sergey, Gorbacheva Nina
Journal: European Respiratory Journal (2013)

According existing guidelines macrolide antibiotics as first-line therapy should be used in children older than 5 years with CAP “if either Mycoplasma or Chlamydia pneumonia is suspected”, but reliable signs/symptoms for this choice are not known.   AIM:  To determine which clinical signs/symptoms may be useful for clinical diagnostics of non-severe CAP caused by  Mycoplasma pneumoniae  or  Chlamydophila pneumonia  in children.   METHODS:  We compared 36 clinical signs/symptoms in two groups of children aged 4-16 years with non-severe CAP: with (12 children) or without (19 children) presence of specific IgM antibodies to  M. pneumoniae  (5) or  Ch. pneumonia  (7) in serum. Enzyme immunoassay techniques were used for IgM detection. The signs involved disease history, clinical symptoms, chest radiographic findings and laboratory examination data. For each sign/symptom we calculated Sensitivity (Se), Specificity (Sp), Positive (PPV) and Negative (NPV) Predictive Values.   RESULTS:  Only two from 36 signs/symptoms have suboptimal diagnostic relevance for distinction between groups: gradual disease onset (p=0.005, Se=54.5, Sp=94.7, PPV=85.7, NPV=78.3) and presence of nonspecific rash (p=0.027, Se=62.5, Sp=82.4, PPV=62.5, NPV=82.4). Both signs were registered more often in the group with detection of specific IgM antibodies to intracellular causative agents .    CONCLUSION:  There are few reliable signs/symptoms for clinical diagnostics CAP caused by intracellular causative agents in children. All from 36 analyzed signs/symptoms have inefficient sensitivity with maximal specificity for “gradual disease onset” and “presence of nonspecific rash”.
Systemic Lupus Erythematosus
Authors: Masoud El-Magadmi, Helena Bodill, Yasmeen Ahmad, Paul N. Durrington, Michael Mackness, Michael Walker, Robert M. Bernstein, Ian N. Bruce
Journal: Circulation (2004)

Systemic lupus erythematosus (SLE) patients have a significantly increased risk of coronary heart disease (CHD) that is not fully explained by classic risk factors. Endothelial dysfunction is an early stage in the process of atherogenesis. Our aim was to determine whether endothelial dysfunction occurs in SLE and whether it is associated with the occurrence of classic Framingham risk factors.We studied 62 women with SLE (1997 revised criteria) and 38 healthy women. Demographic and risk factor data were collected. In patients, disease activity and treatment-related parameters were also assessed. Endothelial function was assessed by flow-mediated dilation (FMD) in the brachial artery in response to reactive hyperemia. Carotid intima-media thickness (IMT) and the presence of carotid plaques were also assessed in SLE patients. FMD was impaired in SLE patients (median, 3.6%; range, -6.3% to 13.7%; versus median, 6.9%; range, -6.6% to 17.8%, P<0.01). Using multiple regression analysis that included all subjects in which we retained all the classic CHD risk factors, we found that systolic blood pressure (P=0.019) and SLE (P=0.017) were significantly associated with impaired FMD. Within SLE patients, IMT showed a negative correlation with percent FMD (r=-0.37, P<0.01). In stepwise multiple regression of SLE patients only that also included SLE factors and IMT, IMT alone was independently associated with FMD (P=0.037).Patients with SLE have endothelial dysfunction that remained significant even after adjustment for other classic CHD risk factors. Within SLE patients, endothelial dysfunction correlates negatively with IMT, another marker of early atherosclerosis. Understanding the mechanism(s) of endothelial dysfunction in SLE may suggest novel strategies for CHD prevention in this context.
Influence of Cheyne-Stokes Respiration on Cardiovascular Oscillations in Heart Failure
Authors: Richard S. T. Leung, John S. Floras, Geraldo Lorenzi-Filho, Fiona Rankin, Peter Picton, T. Douglas Bradley
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

In patients with congestive heart failure, Cheyne-Stokes respiration is accompanied by oscillations in blood pressure and heart rate at a very low frequency. It is not known whether these cardiovascular oscillations are primarily related to oscillations in ventilation or oxyhemoglobin saturation. We hypothesized that abolition of the ventilatory oscillations of Cheyne-Stokes respiration by CO2 inhalation would eliminate accompanying oscillations in blood pressure and heart rate but that elimination of hypoxic dips by supplemental O2 would not. We studied 10 subjects with heart failure and Cheyne-Stokes respiration during sleep using frequency spectral analysis. During Cheyne-Stokes respiration, heart rate and blood pressure oscillated in association with respiratory oscillations at very low frequency. Inhalation of CO2 abolished Cheyne-Stokes respiration and associated oscillations in both blood pressure and heart rate. In contrast, inhalation of O2 sufficient to eliminate hypoxic dips had no significant effect on Cheyne-Stokes respiration, blood pressure (n = 6), or heart rate (n = 5). We conclude that ventilatory oscillations during Cheyne-Stokes respiration rather than oscillations in oxygenation per se powerfully induce heart rate and blood pressure oscillations. Cheyne-Stokes respiration is therefore one of the mechanisms that contributes to the very low-frequency oscillations in heart rate and blood pressure observed in patients with heart failure.
A Human Type 5 Adenovirus–Based Tuberculosis Vaccine Induces Robust T Cell Responses in Humans Despite Preexisting Anti-Adenovirus Immunity
Authors: Fiona Smaill, Mangalakumari Jeyanathan, Marek Smieja, Maria Fe Medina, Niroshan Thanthrige-Don, Anna Zganiacz, Cindy Yin, Armando Heriazon, Daniela Damjanovic, Laura Puri, Jemila Hamid, Feng Xie, Ronan Foley, Jonathan Bramson, Jack Gauldie, Zhou Xing
Journal: Science Translational Medicine (2013)

An adenovirus-based TB vaccine elicits T cell immunogenicity despite preexisting anti-AdHu5 immunity in people.
Selection Maintains MHC Diversity through a Natural Population Bottleneck
Authors: M. K. Oliver, S. B. Piertney
Journal: Molecular Biology and Evolution (2012)

A perceived consequence of a population bottleneck is the erosion of genetic diversity and concomitant reduction in individual fitness and evolutionary potential. Although reduced genetic variation associated with demographic perturbation has been amply demonstrated for neutral molecular markers, the effective management of genetic resources in natural populations is hindered by a lack of understanding of how adaptive genetic variation will respond to population fluctuations, given these are affected by selection as well as drift. Here, we demonstrate that selection counters drift to maintain polymorphism at a major histocompatibility complex (MHC) locus through a population bottleneck in an inbred island population of water voles. Before and after the bottleneck, MHC allele frequencies were close to balancing selection equilibrium but became skewed by drift when the population size was critically low. MHC heterozygosity generally conformed to Hardy-Weinberg expectations except in one generation during the population recovery where there was a significant excess of heterozygous genotypes, which simulations ascribed to strong differential MHC-dependent survival. Low allelic diversity and highly skewed frequency distributions at microsatellite loci indicated potent genetic drift due to a strong founder affect and/or previous population bottlenecks. This study is a real-time examination of the predictions of fundamental evolutionary theory in low genetic diversity situations. The findings highlight that conservation efforts to maintain the genetic health and evolutionary potential of natural populations should consider the genetic basis for fitness-related traits, and how such adaptive genetic diversity will vary in response to both the demographic fluctuations and the effects of selection.
Distinct Heritable Patterns of Angiographic Coronary Artery Disease in Families With Myocardial Infarction
Authors: Marcus Fischer, Ulrich Broeckel, Stephan Holmer, Andrea Baessler, Christian Hengstenberg, Bjoern Mayer, Jeanette Erdmann, Gernot Klein, Guenter Riegger, Howard J. Jacob, Heribert Schunkert
Journal: Circulation (2005)

Background— Coronary artery disease (CAD) and myocardial infarction (MI) are significantly determined by genetic background. Whether distinct angiographic features of CAD are affected by inherited factors has never been investigated. Thus, we analyzed comprehensively the extent to which various aspects of CAD, including disease severity, distribution of lesions, presence of coronary calcification, morphology of stenoses, and anatomic characteristics, are under genetic control. Methods and Results— We retrospectively studied the coronary angiograms of 882 siblings with CAD from 401 families. These families were ascertained through index patients defined by MI before the age of 60 years and at least 1 sibling with MI or coronary revascularization procedures. Heritability calculations were performed with variance-component analysis. Additionally, recurrence risks to siblings were analyzed. Traditional cardiovascular risk factors and age at the first coronary event displayed significant heritable components. After adjustment for age and sex, significant heritabilities were identified for proximal stenoses, in particular, left main CAD ( h 2 =0.49±0.12; P =0.01), coronary calcification ( h 2 =0.51±0.17; P =0.001), and ectatic coronary lesions ( h 2 =0.52±0.07; P =0.001). In contrast, no heritability was found for distal disease ( h 2 =0.05±0.19; NS), the pattern of coronary arterial blood supply, or the number of diseased vessels. Calculation of recurrence risks in siblings largely confirmed the heritability estimates. Conclusions— Distinct morphological characteristics associated with CAD show different degrees of heritability. Notably, the most hazardous localizations, like left main or proximal disease, display a high heritability. In contrast, some features of coronary morphology, such as distal disease, do not appear to be markedly influenced by heritable factors.
THE EFFECT OF AMINOMETHYLPTEROYLGLUTAMIC ACID ON THE DEVELOPMENT OF SKIN HYPERSENSITIVITY AND ON ANTIBODY FORMATION IN GUINEA PIGS
Authors: Robert M. Friedman, Charles E. Buckler, Samuel Baron
Journal: The Journal of Experimental Medicine (1961)

1. In guinea pigs, aminomethylpteroylglutamic acid (methotrexate) is capable of blocking the development of delayed skin hypersensitivity, the primary antibody response, and the specific febrile response to ovalbumin and diphtheria toxoid. The primary antibody response is more easily inhibited than is the development of delayed skin hypersensitivity. 2. The effect of methotrexate on immunologic responses depended upon the dose of methotrexate employed and the strength of the antigenic stimulus.
Molecular Mechanism for Hypertensive Renal Disease
Authors: Kuixing Zhang, Saiful A. Mir, C. Makena Hightower, Jose Pablo Miramontes-Gonzalez, Adam X. Maihofer, Yuqing Chen, Sushil K. Mahata, Caroline M. Nievergelt, Nicholas J. Schork, Barry I. Freedman, Sucheta M. Vaingankar, Daniel T. O'Connor
Journal: Journal of the American Society of Nephrology (2014)

Chromogranin A (CHGA) is coreleased with catecholamines from secretory vesicles in adrenal medulla and sympathetic axons. Genetic variation in the CHGA 3′-region has been associated with autonomic control of circulation, hypertension, and hypertensive nephropathy, and the CHGA 3′-untranslated region (3′-UTR) variant C+87T (rs7610) displayed peak associations with these traits in humans. Here, we explored the molecular mechanisms underlying these associations. C+87T occurred in a microRNA-107 (miR-107) motif (match: T&gt;C), and CHGA mRNA expression varied inversely with miR-107 abundance. In cells transfected with chimeric luciferase/ CHGA 3′-UTR reporters encoding either the T allele or the C allele, changes in miR-107 expression levels had much greater effects on expression of the T allele. Cotransfection experiments with hsa-miR-107 oligonucleotides and eukaryotic CHGA plasmids produced similar results. Notably, an in vitro CHGA transcription/translation experiment revealed that changes in hsa-miR-107 expression altered expression of the T allele variant only. Mice with targeted ablation of Chga exhibited greater eGFR. Using BAC transgenesis, we created a mouse model with a humanized CHGA locus (T/T genotype at C+87T), in which treatment with a hsa-miR-107 inhibitor yielded prolonged falls in SBP/DBP compared with wild-type mice. We conclude that the CHGA 3′-UTR C+87T disrupts an miR-107 motif, with differential effects on CHGA expression, and that a cis : trans (mRNA:miR) interaction regulates the association of CHGA with BP and hypertensive nephropathy. These results indicate new strategies for probing autonomic circulatory control and ultimately, susceptibility to hypertensive renal sequelae.
Long-Term Analysis of the IFM 99 Trials for Myeloma: Cytogenetic Abnormalities [t(4;14), del(17p), 1q gains] Play a Major Role in Defining Long-Term Survival
Authors: Hervé Avet-Loiseau, Michel Attal, Loic Campion, Denis Caillot, Cyrille Hulin, Gerald Marit, Anne-Marie Stoppa, Laurent Voillat, Marc Wetterwald, Brigitte Pegourie, Eric Voog, Mourad Tiab, Anne Banos, Jerome Jaubert, Didier Bouscary, Margaret Macro, Brigitte Kolb, Catherine Traulle, Claire Mathiot, Florence Magrangeas, Stephane Minvielle, Thierry Facon, Philippe Moreau
Journal: Journal of Clinical Oncology (2012)

Purpose In multiple myeloma, many prognostic parameters have been proposed. However, all of these predict shorter survival. To identify patients with a longer life expectancy, we updated the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials. Patients and Methods A series of 520 patients was analyzed. Median follow-up was 90.5 months. To perform a comprehensive analysis of the major prognostic factors, we reanalyzed all patients for 1q gains [in addition to updating del(13), t(4;14), and del(17p) analyses]. Results It was possible to identify a subgroup of patients (representing 20% of total patients) with an 8-year survival of 75%. These patients were defined by the absence of t(4;14), del(17p), and 1q gain and β 2 -microglobulin less than 5.5 mg/L. Conclusion We propose that all patients with newly diagnosed multiple myeloma be evaluated for these three chromosomal changes, not only to define high-risk patients but also to identify those with a longer life expectancy.
RNA Interference–Mediated Choline Kinase Suppression in Breast Cancer Cells Induces Differentiation and Reduces Proliferation
Authors: Kristine Glunde, Venu Raman, Noriko Mori, Zaver M. Bhujwalla
Journal: Cancer Research (2005)

Abstract Choline kinase is overexpressed in breast cancer cells and activated by oncogenes and mitogenic signals, making it a potential target for cancer therapy. Here, we have examined, for the first time, the effects of RNA interference (RNAi)–mediated down-regulation of choline kinase in nonmalignant and malignant human breast epithelial cell lines using magnetic resonance spectroscopy (MRS) as well as molecular analyses of proliferation and differentiation markers. RNAi knockdown of choline kinase reduced proliferation, as detected by proliferating cell nuclear antigen and Ki-67 expression, and promoted differentiation, as detected by cytosolic lipid droplet formation and expression of galectin-3. The functional importance of RNAi-mediated choline kinase down-regulation on choline phospholipid metabolism was confirmed by the significant reduction of phosphocholine detected by MRS. These results strongly support the targeting of choline kinase in breast cancer cells with RNAi and show the potential ability of noninvasive MRS to detect and evaluate future treatments incorporating such strategies.
A 13-Gene Signature Prognostic of HPV-Negative OSCC: Discovery and External Validation
Authors: Pawadee Lohavanichbutr, Eduardo Méndez, F. Christopher Holsinger, Tessa C. Rue, Yuzheng Zhang, John Houck, Melissa P. Upton, Neal Futran, Stephen M. Schwartz, Pei Wang, Chu Chen
Journal: Clinical Cancer Research (2013)

Abstract Purpose: To identify a prognostic gene signature for patients with human papilloma virus (HPV)–negative oral squamous cell carcinomas (OSCC). Experimental Design: Two gene expression datasets were used: a training dataset from the Fred Hutchinson Cancer Research Center (FHCRC, Seattle, WA; n = 97) and a validation dataset from the MD Anderson Cancer Center (MDACC, Houston, TX; n = 71). We applied L1/L2-penalized Cox regression models to the FHCRC data on the 131-gene signature previously identified to be prognostic in patients with OSCCs to identify a prognostic model specific for patients with high-risk HPV-negative OSCCs. The models were tested with the MDACC dataset using a receiver operating characteristic (ROC) analysis. Results: A 13-gene model was identified as the best predictor of HPV-negative OSCC-specific survival in the training dataset. The risk score for each patient in the validation dataset was calculated from this model and dichotomized at the median. The estimated 2-year mortality (±SE) of patients with high-risk scores was 47.1% (±9.24%) compared with 6.35% (±4.42) for patients with low-risk scores. ROC analyses showed that the areas under the curve for the age, gender, and treatment modality-adjusted models with risk score [0.78; 95% confidence interval (CI), 0.74–0.86] and risk score plus tumor stage (0.79; 95% CI, 0.75–0.87) were substantially higher than for the model with tumor stage (0.54; 95% CI, 0.48–0.62). Conclusions: We identified and validated a 13-gene signature that is considerably better than tumor stage in predicting survival of patients with HPV-negative OSCCs. Further evaluation of this gene signature as a prognostic marker in other populations of patients with HPV-negative OSCC is warranted. Clin Cancer Res; 19(5); 1197–203. ©2012 AACR.
Cyclic nucleotide phosphodiesterases and their role in immunomodulatory responses: Advances in the development of specific phosphodiesterase inhibitors
Authors: Ana Castro, Maria Jose Jerez, Carmen Gil, Ana Martinez
Journal: Medicinal Research Reviews (2004)

Abstract The activity of phosphodiesterases (PDEs) is associated with a wide variety of diseases and an intense effort toward the development of specific PDEs inhibitors has been generated for the last years. They are the enzymes responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate, and their complexity, as well as their different functional role, makes these enzymes a very attractive therapeutic target. This review is focused on the role of PDEs played on immunomodulatory processes and the advance on the development of specific inhibitors, covering PDEs mainly related to the regulation of autoimmune processes, PDE4 and PDE7. The review also highlights the novel structural classes of PDE4 and PDE7 inhibitors, and the therapeutic potential that combined PDE4/PDE7 inhibitors offer as immunomodulatory agents. © 2004 Wiley Periodicals, Inc. Med Res Rev
Colon cancer prevalence and estimation of differing care needs of colon cancer patients
Authors: G. Gatta, R. Capocaccia, F. Berrino, M.R. Ruzza, P. Contiero
Journal: Annals of Oncology (2004)

Background: Cancer prevalence—the proportion of people in a population with a diagnosis of cancer—includes groups with widely differing cancer care needs. We estimated the proportions of the prevalent colon cancer cases requiring initial care, terminal care and follow-up.Patients and methods: Prevalence by year since diagnosis was estimated from incidence and vital status data on 243 471 colon cancer cases collected by EUROPREVAL from 36 European population-based cancer registries. The proportions of cured and fatal cases were estimated by applying 'cure' survival models to the dataset. The proportion of recurrence-free cases was estimated by analysis of a representative sample of 278 colon cancer patients from the Lombardy Cancer Registry (LCR), northern Italy.Results: The proportions of total prevalence requiring initial care was estimated at 12% in the LCR and 10% in Italy and Europe. Recurrence-free patients formed 89% of the total prevalence in the LCR and 91% in Italy and Europe. Eleven per cent (LCR) and 9% (Italy, Europe) of the total prevalence had recurred and consisted of patients in the terminal phase of their illness.Conclusions: In 1992, 660 000 people were living with a diagnosis of colon cancer in Europe. We have estimated the proportions of this prevalence requiring particular types health care in the years following diagnosis, providing data useful for planning the allocation of health-care resources.
Prevention, Screening, and Surveillance Care for Breast Cancer Survivors Compared With Controls: Changes from 1998 to 2002
Authors: Claire F. Snyder, Kevin D. Frick, Melinda E. Kantsiper, Kimberly S. Peairs, Robert J. Herbert, Amanda L. Blackford, Antonio C. Wolff, Craig C. Earle
Journal: Journal of Clinical Oncology (2009)

To examine how care for breast cancer survivors compares with controls.Using the Surveillance, Epidemiology, and End Results-Medicare database, we examined five cohorts of stages 1 to 3 breast cancer survivors diagnosed from 1998 to 2002. For each survivor cohort (defined by diagnosis year), we calculated the number of visits to oncology specialists, primary care providers (PCPs), and other physicians and the percentage who received influenza vaccination, cholesterol screening, colorectal cancer screening, bone densitometry, and mammography during survivorship year 1 (days 366 to 730 postdiagnosis). We compared survivors' care to that of five cohorts of screening controls who were matched to survivors on age, ethnicity, sex, and region and who had a mammogram in the survivor's year of diagnosis and to that of five cohorts of comorbidity controls who were matched on age, ethnicity, sex, region, and comorbidity. We examined whether survivors' care was associated with the mix of physician specialties that were visited.A total of 23,731 survivors were matched with 23,731 screening controls and 23,396 comorbidity controls. There was no difference in trends over time in PCP visits between survivors and either control group. The survivors' rate of increase in other physician visits was greater than screening controls (P = .002) but was no different from comorbidity controls. Survivors were less likely to receive preventive care than screening controls but were more likely than comorbidity controls. Trends over time in survivors' care tended to be better than screening controls but were no different than comorbidity controls. Survivors who visited both a PCP and oncology specialist were most likely to receive recommended care.Involvement by both PCPs and oncology specialists can facilitate appropriate care for survivors.