tbuckley/cabot-search huggingface dataset:
In Search of a Good Death: Observations of Patients, Families, and Providers
Authors: Karen E. Steinhauser, Elizabeth C. Clipp, Maya McNeilly, Nicholas A. Christakis, Lauren M. McIntyre, James A. Tulsky
Journal: Annals of Internal Medicine (2000)

Despite a recent increase in the attention given to improving end-of-life care, our understanding of what constitutes a good death is surprisingly lacking. The purpose of this study was to gather descriptions of the components of a good death from patients, families, and providers through focus group discussions and in-depth interviews. Seventy-five participants—including physicians, nurses, social workers, chaplains, hospice volunteers, patients, and recently bereaved family members—were recruited from a university medical center, a Veterans Affairs medical center, and a community hospice. Participants identified six major components of a good death: pain and symptom management, clear decision making, preparation for death, completion, contributing to others, and affirmation of the whole person. The six themes are process-oriented attributes of a good death, and each has biomedical, psychological, social, and spiritual components. Physicians' discussions of a good death differed greatly from those of other groups. Physicians offered the most biomedical perspective, and patients, families, and other health care professionals defined a broad range of attributes integral to the quality of dying. Although there is no “right” way to die, these six themes may be used as a framework for understanding what participants tend to value at the end of life. Biomedical care is critical, but it is only a point of departure toward total end-of-life care. For patients and families, psychosocial and spiritual issues are as important as physiologic concerns.
Dose dependent increased mortality risk in COPD patients treated with oral glucocorticoids
Authors: A.M.W.J. Schols, G. Wesseling, A.D.M. Kester, G. de Vries, R. Mostert, J. Slangen, E.F.M. Wouters
Journal: European Respiratory Journal (2001)

Systemic corticosteroids are often administered in COPD patients. The relationship between systemic glucocorticoids and mortality in patients with moderate to severe chronic obstructive pulmonary disease (COPD) was retrospectively analysed. Baseline characteristics of the patients, in stable clinical condition, were collected on admission to a pulmonary rehabilitation centre. Overall mortality was asessed at the end of follow-up. The Cox proportional hazards model was used to quantify the relationship between glucocorticoid use, distinguishing administration route (oral/inhalation) and oral dose, and overall mortality, adjusted for the influence of age, sex, smoking, lung function, resting arterial blood gases and body mass index. On multivariate analysis, oral glucocorticoid use at a (prednisone equivalent) dose of 10 mg x day(-1) without inhaled glucocorticoids, was associated with an increased risk (RR=2.34, 95% confidence interval (CI) 1.24-4.44) while 15 mg x day(-1) carried a relative risk of 4.03, CI = 1.99-8.15). A significant interaction was observed between inhaled and oral glucocorticoid use. Combined with inhaled glucocorticoids, the relative risk of oral glucocorticoid use appeared to be significantly smaller. It is concluded that in severe chronic obstructive pulmonary disease, maintenance treatment with oral glucocorticoids is associated with increased mortality in a dose-dependent manner. Since the present study design cannot exclude the possibility of bias by indication, further prospective studies are indicated using a broader patient characterization.
Linking MLL and the HGF-MET signaling pathway in liver cancer
Authors: Jens U. Marquardt, Snorri S. Thorgeirsson
Journal: Journal of Clinical Investigation (2013)

Mixed-lineage leukemia (MLL; also known as myeloid/lymphoid), the human homolog of trithorax in Drosophila, is a transcriptional coactivator that plays an essential role during early development and hematopoiesis. Furthermore, MLL is critically involved in the epigenetic regulation of cell cycle, senescence, DNA damage, and stem cell self-renewal. Chromosomal aberrations of MLL in acute leukemias are well documented, but the role of this gene in solid malignancies remains unclear. In this issue of the JCI, Takeda et al. describe a novel epigenetic link between MLL and the HGF-MET signaling pathway conferring invasive and metastatic properties to hepatocellular carcinoma cells.
Electrotonic interaction during canine ventricular repolarization.
Authors: H Toyoshima, M J Burgess
Journal: Circulation Research (1978)

Canine ventricular refractory periods were measured during test site drive, during drive of single ectopic sites, during fusion drive from two ectopic sites, and during fusion drive from an ectopic site and the test site. Refractory period duration was dependent on the driving modes employed. Refractory periods were 2.63 +/- 0.73%, 3.42 +/- 0.87%, 3.54 +/- 100%, and 4.68 +/- 1.36% (mean +/- SD) shorter during drive of single ectopic sites 2, 4, 6, and 40-60 mm, respectively, from the test site than during test site drive. During fusion drive from two ectopic sites, refractory periods were an average of 2.44 +/- 1.04 msec (mean +/- SD) less than during drive from a single ectopic site (P less than 0.005). When fusion of activation, induced by ectopic and test site drive, was located within 4 mm or less of the test site, refractory periods during fusion drive were also significantly shorter than during test site drive (P less than 0.05). Refractory periods were as much as 10 msec shorter when fusion occurred within 1 mm of the test site than their durations during test site drive. The differences in refractory periods measured during various driving modes were most likely due to electrotonic interactions during ventricular repolarization and are explicable on the basis of the intracellular distribution of potentials to be expected with each driving mode.
Quality of Life in Allergic Rhinitis and Asthma
Authors: BÉNÉDICTE LEYNAERT, CATHERINE NEUKIRCH, RENATA LIARD, JEAN BOUSQUET, FRANÇOISE NEUKIRCH
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Quality of life has been found to be impaired both in patients with asthma and in patients with allergic rhinitis, but the relative burden of these diseases has not been investigated. We analyzed answers to the SF-36 questionnaire from 850 subjects recruited in two French centers participating in the European Community Re-spiratory Health Survey, a population-based study of young adults. Both asthma and allergic rhinitis were associated with an impairment in quality of life. However, 78% of asthmatics also had allergic rhinitis. Subjects with allergic rhinitis but not asthma (n = 240) were more likely than subjects with neither asthma nor rhinitis (n = 349) to report problems with social activities, difficulties with daily activities as a result of emotional problems, and poorer mental well-being. Patients with both asthma and allergic rhinitis (n = 76) experienced more physical limitations than patients with allergic rhinitis alone, but no difference was found between these two groups for concepts related to social/mental health. As asthma was not found to further impair the quality of life in subjects with allergic rhinitis for concepts related to mental disability and well-being, and as subjects with asthma often also suffer from allergic rhinitis, further studies on quality of life in asthma should ensure that the impairment in quality of life attributed to asthma could not result from concomitant allergic rhinitis.
Simian virus 40 (SV40)-transgenic mice that develop tumors are specifically tolerant to SV40 T antigen.
Authors: S J Faas, S Pan, C A Pinkert, R L Brinster, B B Knowles
Journal: The Journal of Experimental Medicine (1987)

The ability to mount an immune response to simian virus 40 (SV40) T antigen was evaluated using mice from two distinct SV40 transgenic lines derived from injection of the same gene construct. Our studies demonstrate functional immune tolerance to SV40 T antigen in a SV40 transgenic line that consistently develops tumors of the choroid plexus by 7 mo of age. Antibodies to SV40 T antigen are undetectable in the serum of these animals; furthermore, mice from this line are unable to generate SV40-specific CTL after primary or secondary immunization with the virus, although they mount a normal CTL response to vaccinia virus when appropriately immunized. In contrast, we find that mice from a second transgenic line of low tumor incidence can mount a humoral response to SV40 T antigen, and upon immunization they generally respond with a vigorous cytotoxic T cell response to SV40 T antigen. These data suggest that specific immune tolerance to the product of an integrated viral oncogene may be induced, and is likely a reflection of the time in development at which the gene product first appears. Immune tolerance or responsiveness to the endogenous oncogene product may in turn play a role in the tumorigenic potential of such genes.
Principles of phenomics in endometriosis
Authors: P. Viganò, E. Somigliana, P. Panina, E. Rabellotti, P. Vercellini, M. Candiani
Journal: Human Reproduction Update (2012)

Endometriosis has been associated with specific morphometric characteristics and pigmentary traits. The purpose of this study was to systematically review prior publications dealing with this aspect in order to revisit phenotypic information in the context of phenomics principles. Comprehensive searches of Pubmed, Medline and Embase were conducted to identify studies, published from 1990 to 2011 in the English language literature, on the relationship between endometriosis and morphometric characteristics/pigmentary traits. We identified 11 studies on the association between endometriosis and body mass index (BMI) in the adult population and 5 studies on the same association during early life. While a modest inverse correlation was found between endometriosis and adult BMI, a stronger association was consistently demonstrated between endometriosis and early life body size, even after adjusting for confounding factors such as age, birthweight, age at menarche, parity and oral contraceptive use. Four papers have been published on the association between endometriosis and cutaneous naevi and five on the association between the disease and specific pigmentary traits. A skin phenotype characterized by the presence of naevi and freckles and by a high sensitivity to sun exposure is represented more frequently in women with endometriosis. Endometriosis appears to be associated with some phenotypic variations likely attributable to the strong effect of the environment on the expression and function of genes influencing the traits. Novel clues on endometriosis pathogenesis may derive from the analysis of the phenotypic traits associated with the disease.
Arterial stiffness and endothelial dysfunction in idiopathic pulmonary fibrosis (IPF)
Authors: Sergey Avdeev, Marina Makarova, Alexander Chuchalin
Journal: European Respiratory Journal (2011)

Background:  Fibrotic lung diseases are associated with an increased prevalence of coronary artery disease and cardiovascular complications [Kizer et al., 2004]. Arterial stiffness and endothelial dysfunction are widely accepted as markers of cardiovascular risk.   Objectives:  The aim of the present study was to assess aortic stiffness and endothelial dysfunction in patients with IPF and to determine the association of these markers with other clinical and functional parameters.   Methods:  We enrolled 25 IPF patients (age 57±8 yrs; FVC 80±18%; DL CO  38±15%) and 30 normal control subjects (age 52±5 yrs). Assessment of arterial stiffness was performed by use of digital photoplethysmography (Pulse Trace PCA 2, Micro Medical). Change in reflection index of the digital volume pulse in response to salbutamol (ΔRI SALB ) was used to assess endothelial function.   Results:  In IPF patients stiffness index (SI) was significantly higher than in normal control subjects: 9.8±3.1 vs 6.9±1.0 m/s (p 2   SALB  was significantly lower in IPF patients than in control subjects: 2.2±1.2% vs 15.8±9.3% (p=0.01). ΔRI SALB  was significantly associated with FEV 1  (r=-0.57, p 2  (r=-0.83, p   Conclusions:  Arterial stiffness and endothelial dysfunction are significantly impaired in IPF patients. Decreased FEV 1  was associated with endothelial dysfunction. Nocturnal hypoxemia and total cholesterol level have an association with both arterial stiffness and endothelial function.
CD8+ T-cell alveolitis in familial pulmonary alveolar microlithiasis
Authors: G. de Laurentiis, L. Vitiello, L. Racioppi, F. Perna, M. Galgani, G. Merola, P. Carratù, M. Maniscalco, S. Marsico, M. Sofia
Journal: European Respiratory Journal (2007)

Pulmonary alveolar microlithiasis (PAM) is a rare diffuse lung disease characterised by the accumulation of calcium phosphate microliths within the alveoli. The causative mechanism of PAM has only recently been discovered, and involves a gene mutation of sodium phosphate co-transporter, which is expressed by alveolar epithelial cells. This mutation may have variable consequences on the clinical phenotype. However, pulmonary cell immune phenotyping in familial PAM has not previously been assessed. In the present article, the analysis of bronchoalveolar lavage fluid of two siblings with PAM diagnosis revealed a pattern of lymphocytic alveolitis with accumulation of CD8+ T-cells. The clonal complexity of this lymphocyte’s population was assayed by spectratyping, which showed an oligoclonal accumulation of T-cells with a restricted variable beta T-cell receptor (TCR) gene usage. TCR analysis in peripheral blood lymphocytes revealed no abnormal patterns of T-lymphocytes. In the pulmonary alveolar microlithiasis familial cases reported, CD8-mediated maladaptive immune response may have taken place in the bronchoalveolar compartment. The relationship between this immune dysregulation and genetic background in pulmonary alveolar microlithiasis warrants further investigation.
Tuberculin skin test and IGRA test in the diagnosis and follow-up of bacteriologically confirmed pulmonary tuberculosis in HIV negative adults
Authors: Jiri Homolka, Ivana Hricikova, Emilia Kopecka, Martina Vasakova
Journal: European Respiratory Journal (2012)

Introduction:  Tuberculosis (TB) remains a disease of serious concern worldwide. One third of world population is infected with  Mycobacterium tuberculosis complex  and eight to ten million persons develop the disease every year. The very important step to control TB is detecting TB infection by a sensitive test.   Objectives:  We prospectively evaluated the sensitivity of tuberculin skin test (TST) and IGRA test (Quantiferon-TB Gold) in HIV negative patients with bacteriologically confirmed pulmonary TB. In a subgroup of 40 TB patients we analyzed the results of IGRA test repeatedly (3 months, 6 months, 9 months and 15 months) after completion of AT therapy.   Results:  Starting January 1, 2008 to December 31, 2011 199 adult patients (mean age 46 yrs ± 18,3 yrs) were included in the study. All patients had positive cultivations for  Mycobacterium tuberculosis . TST was positive in 125 patients, negative in 65 patients and not done in 9 patients. The sensitivity of TST was 65,8%. IGRA test was positive in 119 patients, negative in 20 patients, indeterminate in 13 patients and not done in 47 patients. The sensitivity of IGRA test was 78,3%. In a subgroup of patients 75% were IGRA positive after 3 months, 65% after 6 months and 40% after 15 months after successful TB treatment.   Conclusion:  IGRA test showed better sensitivity compared to TST in HIV negative adults with pulmonary TB. The positivity of IGRA test can be observed for a long interval after the completion of AT regimen showing long lasting presence of sensitized T-cells in individuals successfully treated for pulmonary TB.
A New Subfamily of Major Intrinsic Proteins in Plants
Authors: Urban Johanson, Sofia Gustavsson
Journal: Molecular Biology and Evolution (2002)

The major intrinsic proteins (MIPs) form a large protein family of ancient origin and are found in bacteria, fungi, animals, and plants. MIPs act as channels in membranes to facilitate passive transport across the membrane. Some MIPs allow small polar molecules like glycerol or urea to pass through the membrane. However, the majority of MIPs are thought to be aquaporins (AQPs), i.e., they are specific for water transport. Plant MIPs can be subdivided into the plasma membrane intrinsic protein, tonoplast intrinsic protein, and NOD26-like intrinsic protein subfamilies. By database mining and phylogenetic analyses, we have identified a new subfamily in plants, the Small basic Intrinsic Proteins (SIPs). Comparisons of sequences from the new subfamily with conserved amino acid residues in other MIPs reveal characteristic features of SIPs. Possible functional consequences of these features are discussed in relation to the recently solved structures of AQP1 and GlpF. We suggest that substitutions at conserved and structurally important positions imply a different substrate specificity for the new subfamily.
ZINC IONIZATION IN CHRONIC URETHRITIS
Authors: P C. Fenwick
Journal: BMJ (1908)

<b>Background:</b> Too few patients with nonvalvular atrial fibrillation (NVAF) receive appropriate antithrombotic therapy. We tested the short-term (primary outcome) and long-term (secondary outcome) effect of a patient decision aid on the appropriateness of antithrombotic therapy among patients with NVAF. <b>Methods:</b> We conducted a cluster randomized trial with blinded outcome assessment involving 434 NVAF patients from 102 community-based primary care practices. Patients in the intervention group received a self-administered booklet and audiotape decision aid tailored to their personal stroke risk profile. Patients in the control group received usual care. The primary outcome measure was change in antithrombotic therapy at 3 months. Appropriateness of therapy was defined using the American College of Chest Physicians (ACCP) recommendations. <b>Results:</b> The mean patient age was 72 years, and the median duration of NVAF was 5 years. In the control group, there was a 3% decrease over 3 months in the number of patients receiving therapy appropriate to their risk of stroke (40% [85/215] at baseline v. 37% [79/215] at 3 months). In the intervention group, the number of patients receiving therapy appropriate to their stroke risk increased by 9% (32% [69/219] at baseline v. 41% [89/219] at 3 months). Although the proportion of patients whose therapy met the ACCP treatment recommendations did not differ between study arms at baseline (<i>p</i> = 0.11) or 3 months (<i>p</i> = 0.44), there was a 12% absolute improvement in the number of patients receiving appropriate care in the intervention group compared with the control group at 3 months (<i>p</i> = 0.03). The beneficial effect of the decision aid did not persist (<i>p</i> = 0.44 for differences between study arms after 12 months). <b>Interpretation:</b> There was short-term improvement in the appropriateness of antithrombotic care among patients with NVAF who were exposed to a decision aid, but the improvement did not persist.
Slip into Something More Functional: Selection Maintains Ancient Frameshifts in Homopolymeric Sequences
Authors: J. J. Wernegreen, S. N. Kauppinen, P. H. Degnan
Journal: Molecular Biology and Evolution (2009)

Mutational hotspots offer significant sources of genetic variability upon which selection can act. However, with a few notable exceptions, we know little about the dynamics and fitness consequences of mutations in these regions. Here, we explore evolutionary forces shaping homopolymeric tracts that are especially vulnerable to slippage errors during replication and transcription. Such tracts are typically eliminated by selection from most bacterial sequences, yet persist in genomes of endosymbionts with small effective population sizes (Ne) and biased base compositions. Focusing on Blochmannia, a bacterial endosymbiont of ants, we track the divergence of genes that contain frameshift mutations within long (9–11 bp) polyA or polyT tracts. Earlier experimental work documented that transcriptional slippage restores the reading frame in a fraction of messenger RNA molecules and thereby rescues the function of frameshifted genes. In this study, we demonstrate a surprising persistence of these frameshifts and associated tracts for millions of years. Across the genome of this ant mutualist, rates of indel mutation within homopolymeric tracts far exceed the synonymous mutation rate, indicating that long-term conservation of frameshifts within these tracts is inconsistent with neutrality. In addition, the homopolymeric tracts themselves are more conserved than expected by chance, given extensive neutral substitutions that occur elsewhere in the genes sampled. These data suggest an unexpected role for slippage-prone DNA tracts and highlight a new mechanism for their persistence. That is, when such tracts contain a frameshift, transcriptional slippage plays a critical role in rescuing gene function. In such cases, selection will purge nucleotide changes interrupting the slippery tract so that otherwise volatile sequences become frozen in evolutionary time. Although the advantage of the frameshift itself is less clear, it may offer a mechanism to lower effective gene expression by reducing but not eliminating transcripts that encode full-length proteins.
Small Molecule Disruption of Gβγ Signaling Inhibits the Progression of Heart Failure
Authors: Liam M. Casey, Andrew R. Pistner, Stephen L. Belmonte, Dmitriy Migdalovich, Olga Stolpnik, Frances E. Nwakanma, Gabriel Vorobiof, Olga Dunaevsky, Alessandra Matavel, Coeli M.B. Lopes, Alan V. Smrcka, Burns C. Blaxall
Journal: Circulation Research (2010)

Rationale: Excess signaling through cardiac Gβγ subunits is an important component of heart failure (HF) pathophysiology. They recruit elevated levels of cytosolic G protein–coupled receptor kinase (GRK)2 to agonist-stimulated β-adrenergic receptors (β-ARs) in HF, leading to chronic β-AR desensitization and downregulation; these events are all hallmarks of HF. Previous data suggested that inhibiting Gβγ signaling and its interaction with GRK2 could be of therapeutic value in HF. Objective: We sought to investigate small molecule Gβγ inhibition in HF. Methods and Results: We recently described novel small molecule Gβγ inhibitors that selectively block Gβγ-binding interactions, including M119 and its highly related analog, gallein. These compounds blocked interaction of Gβγ and GRK2 in vitro and in HL60 cells. Here, we show they reduced β-AR–mediated membrane recruitment of GRK2 in isolated adult mouse cardiomyocytes. Furthermore, M119 enhanced both adenylyl cyclase activity and cardiomyocyte contractility in response to β-AR agonist. To evaluate their cardiac-specific effects in vivo, we initially used an acute pharmacological HF model (30 mg/kg per day isoproterenol, 7 days). Concurrent daily injections prevented HF and partially normalized cardiac morphology and GRK2 expression in this acute HF model. To investigate possible efficacy in halting progression of preexisting HF, calsequestrin cardiac transgenic mice (CSQ) with extant HF received daily injections for 28 days. The compound alone halted HF progression and partially normalized heart size, morphology, and cardiac expression of HF marker genes (GRK2, atrial natriuretic factor, and β-myosin heavy chain). Conclusions: These data suggest a promising therapeutic role for small molecule inhibition of pathological Gβγ signaling in the treatment of HF.
Tetherin/BST-2 Is Essential for the Formation of the Intracellular Virus-Containing Compartment in HIV-Infected Macrophages
Authors: Hin Chu, Jaang-Jiun Wang, Mingli Qi, Jeong-Joong Yoon, Xuemin Chen, Xiaoyun Wen, Jason Hammonds, Lingmei Ding, Paul Spearman
Journal: Cell Host & Microbe (2012)