tbuckley/cabot-search huggingface dataset:
Temporal Trails of Natural Selection in Human Mitogenomes
Authors: S. Subramanian
Journal: Molecular Biology and Evolution (2009)

Mildly deleterious mutations initially contribute to the diversity of a population, but later they are selected against at high frequency and are eliminated eventually. Using over 1,500 complete human mitochondrial genomes along with those of Neanderthal and Chimpanzee, I provide empirical evidence for this prediction by tracing the footprints of natural selection over time. The results show a highly significant inverse relationship between the ratio of nonsynonymous-to-synonymous divergence (dN/dS) and the age of human haplogroups. Furthermore, this study suggests that slightly deleterious mutations constitute up to 80% of the mitochondrial amino acid replacement mutations detected in human populations and that over the last 500,000 years these mutations have been gradually removed.
Calcified pulmonary chondromas in Carney's triad
Authors: Helmy Haja Mydin, Keith M Kerr, Owen Dempsey
Journal: Thorax (2013)

A 20-year-old woman presented with haematemesis. Endoscopy identified gastric ulceration. Chest imaging (figures 1 and 2) and subsequent surgical biopsy confirmed pulmonary chondromas (figures 3 and 4). These benign cartilaginous tumours, typically found in young women, can form part of ‘Carney's triad’ …
Syndecan-4: a novel regulator of collagen synthesis and deposition in the pressure-overloaded myocardium
Authors: Andriy Yabluchanskiy, Yonggang Ma, Merry L. Lindsey
Journal: Cardiovascular Research (2015)

This editorial refers to 'Syndecan-4 is a key determinant of collagen cross-linking and passive myocardial stiffness in the pressure-overloaded heart' by K.M. Herum et al., pp.217-226.Approximately one in 10 deaths in developed countries is attributed to heart failure, and the prevalence of heart failure (HF) is expected to increase 50% by 2030. 1 Diastolic dysfunction is central to HF development and is defined as increased stiffness of the left ventricle (LV) resulting in abnormal relaxation, decreased compliance, and impaired filling.On the molecular level, myocardial stiffness can develop as a result of altered sarcomere structure and function and extracellular matrix (ECM) reorganization. 2,3erum et al. 4 investigated the impact of syndecan-4 deletion on myocardial stiffness and LV remodelling in a mouse model of pressure overload induced by aortic banding.Syndecan-4 null mice showed reduced concentric hypertrophic remodelling after banding, resulting in significantly lower passive tension.Passive tension was not affected by altered cardiomyocyte function, as there was no change in the ratio of compliant to stiff titin isoforms.Rather, the passive tension changes were attributed to ECM changes.Previously, this same group has shown that syndecan-4 deletion attenuates collagen deposition 24 h after aortic banding through the calcineurin/nuclear factor of activated T-cells (NFAT) signalling, but that by day 7 the effect was lost. 5This finding suggested that in chronic pressure overload, syndecan-4 properties shift from ECM induction and deposition to ECM cross-linking and reorganization.Indeed, calcineurin stimulation of cardiac fibroblasts induced osteopontin, which is known to enhance lysyl oxidase (LOX) expression and activity. 6Further, osteopontin production in cardiac fibroblasts was inhibited after treatment with an NFAT inhibitor.Syndecan-4 directly promotes LOX expression during all stages of LV remodelling stimulated by aortic banding, as this effect is attenuated in the absence of syndecan-4.Interestingly, the extracellular domain of syndecan-4 was also shown to interact with collagen fibrils and to promote collagen cross-linking by LOX.A mechanistic diagram depicting syndecan-4 regulation of myocardial stiffness is shown in Figure 1.Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed by multiple cell types, including macrophages, fibroblasts, smooth muscle cells, and cardiomyocytes. 7,8Syndecan-4 interacts
Cystic fibrosis: terminology and diagnostic algorithms
Authors: K De Boeck
Journal: Thorax (2005)

There is great heterogeneity in the clinical manifestations of cystic fibrosis (CF). Some patients may have all the classical manifestations of CF from infancy and have a relatively poor prognosis, while others have much milder or even atypical disease manifestations and still carry mutations on each of the CFTR genes. It is important to distinguish between these categories of patients. The European Diagnostic Working Group proposes the following terminology. Patients are diagnosed with classic or typical CF if they have one or more phenotypic characteristics and a sweat chloride concentration of >60 mmol/l. The vast majority of CF patients fall into this category. Usually one established mutation causing CF can be identified on each CFTR gene. Patients with classic CF can have exocrine pancreatic insufficiency or pancreatic sufficiency. The disease can have a severe course with rapid progression of symptoms or a milder course with very little deterioration over time. Patients with non-classic or atypical CF have a CF phenotype in at least one organ system and a normal (<30 mmol/l) or borderline (30-60 mmol/l) sweat chloride level. In these patients confirmation of the diagnosis of CF requires detection of one disease causing mutation on each CFTR gene or direct quantification of CFTR dysfunction by nasal potential difference measurement. Non-classic CF includes patients with multiorgan or single organ involvement. Most of these patients have exocrine pancreatic sufficiency and milder lung disease. Algorithms for a structured diagnostic process are proposed.
Frequent mutations in the GATA-1 gene in the transient myeloproliferative disorder of Down syndrome
Authors: Gang Xu, Masumi Nagano, Rika Kanezaki, Tsutomu Toki, Yasuhide Hayashi, Takeshi Taketani, Tomohiko Taki, Tetsuo Mitui, Kenichi Koike, Koji Kato, Masue Imaizumi, Isao Sekine, Yasuhiko Ikeda, Ryoji Hanada, Masahiro Sako, Kazuko Kudo, Seiji Kojima, Osamu Ohneda, Masayuki Yamamoto, Etsuro Ito
Journal: Blood (2003)
British Thoracic Society guideline on pulmonary rehabilitation in adults: accredited by NICE
Authors: Charlotte E Bolton, Elaine F Bevan-Smith, John D Blakey, Patrick Crowe, Sarah L Elkin, Rachel Garrod, Neil J Greening, Karen Heslop, James H Hull, William D-C Man, Michael D Morgan, David Proud, C Michael Roberts, Louise Sewell, Sally J Singh, Paul P Walker, Sandy Walmsley
Journal: Thorax (2013)

### The role of pulmonary rehabilitation

### Referral and assessment of patients for pulmonary rehabilitation

#### Specific situations at assessment

##### Smoking
Immunity to a pulmonary Cryptococcus neoformans infection requires both CD4+ and CD8+ T cells.
Authors: G B Huffnagle, J L Yates, M F Lipscomb
Journal: The Journal of Experimental Medicine (1991)

The role of CD4+ and CD8+ T cells in mediating pulmonary clearance of a cryptococcal infection was investigated. Intratracheal inoculation of BALB/c and C.B-17 mice with a moderately virulent strain of Cryptococcus neoformans (52D) resulted in a pulmonary infection, which was cleared by a T cell-dependent mechanism. During this clearance, there was a significant influx of both CD4+ and CD8+ T cells into the lungs. Depletion of CD4+ T cells by injections of CD4-specific monoclonal antibody (mAb) prevented pulmonary clearance and also resulted in significant colonization of the brain and spleen of infected mice. CD4 depletion did not prevent the influx of CD8+ T cells into the lungs. Surprisingly, depletion of CD8+ T cells by mAb also ablated pulmonary clearance. CD8-depleted mice also had a small but significant increase in brain and spleen colony-forming unit compared to control mice by the end of the study. CD4+ T cell pulmonary influx was independent of the presence of CD8+ T cells. The lungs of T cell-depleted mice were examined histologically. CD4+ and CD8+ T cells each mediated a degree of inflammatory influx seen in the lungs of infected mice and raised the possibility that CD4+ and CD8+ T cells may synergize to generate the inflammatory response in the lungs. Numerous phagocytized but intact cryptococci were seen in the inflammatory foci of CD8-depleted mice but not in control or CD4-depleted mice. We propose that CD4+ T cells may recruit and activate effector phagocytes while CD8+ T cells predominantly function to lyse cryptococcus-laden unactivated phagocytes similar to the function of CD8+ T cells during listeria and mycobacteria infections.
Endogenous Cardiotonic Steroids: Physiology, Pharmacology, and Novel Therapeutic Targets
Authors: Alexei Y. Bagrov, Joseph I. Shapiro, Olga V. Fedorova
Journal: Pharmacological Reviews (2009)

Endogenous cardiotonic steroids (CTS), also called digitalis-like factors, have been postulated to play important roles in health and disease for nearly half a century. Recent discoveries, which include the specific identification of endogenous cardenolide (endogenous ouabain) and bufadienolide (marinobufagenin) CTS in humans along with the delineation of an alternative mechanism by which CTS can signal through the Na<sup>+</sup>/K<sup>+</sup>-ATPase, have increased the interest in this field substantially. Although CTS were first considered important in the regulation of renal sodium transport and arterial pressure, more recent work implicates these hormones in the regulation of cell growth, differentiation, apoptosis, and fibrosis, the modulation of immunity and of carbohydrate metabolism, and the control of various central nervous functions and even behavior. This review focuses on the physiological interactions between CTS and other regulatory systems that may be important in the pathophysiology of essential hypertension, preeclampsia, end-stage renal disease, congestive heart failure, and diabetes mellitus. Based on our increasing understanding of the regulation of CTS as well as the molecular mechanisms of these hormone increases, we also discuss potential therapeutic strategies.
Diet and asthma in Dutch school children (ISAAC-2)
Authors: C Tabak, A H Wijga, G de Meer, N A H Janssen, B Brunekreef, H A Smit
Journal: Thorax (2005)

<b>Background:</b> The rise in the prevalence of asthma in western societies may be related to changed dietary habits. Epidemiological studies in children have shown inverse associations of asthma related outcomes with intake of fruits, vegetables, dairy and whole grain products, and fish. In contrast to most previous studies, we used both questionnaire and clinical data to define asthma. <b>Methods:</b> Intake of the abovementioned foods was studied in relation to asthma in 598 Dutch children aged 8–13 years. Dietary intake was estimated using a parent completed semi-quantitative food frequency questionnaire. Current wheeze and current asthma were defined based on questionnaire data. More complex end points were defined using information on bronchial hyperresponsiveness (BHR) and atopic sensitisation as well. Linear associations were studied using logistic regression analysis and odds ratios presented for the highest versus the lowest tertile of intake. In the final models, adjustments were made for maternal educational level, foreign descent, and total energy intake. <b>Results:</b> The intake of whole grain products and of fish was inversely associated with asthma. Adjusted odds ratios for the independent associations with whole grains and fish were 0.46 (95% CI 0.19 to 1.10) and 0.34 (95% CI 0.13 to 0.85) for current asthma and 0.28 (95% CI 0.08 to 0.99) and 0.12 (95% CI 0.02 to 0.66) for atopic asthma with BHR. Similar results were observed for current wheeze and atopic wheeze with BHR. Intake of (citrus) fruits, vegetables, and dairy products showed no clear associations with asthma end points. <b>Conclusions:</b> Our findings suggest that a high intake of whole grain products and fish may have a protective effect against asthma in children.
Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth
Authors: Christopher W. Gregory, Young E. Whang, Wesley McCall, Xiaoyin Fei, Yuanbo Liu, Liliana A. Ponguta, Frank S. French, Elizabeth M. Wilson, H. Shelton Earp
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The androgen receptor (AR) is a ligand-dependent transcription factor that mediates gene expression and growth of normal and malignant prostate cells. In prostate tumors that recur after androgen withdrawal, the AR is highly expressed and transcriptionally active in the absence of testicular androgens. In these “androgen-independent” tumors, alternative means of AR activation have been invoked, including regulation by growth factors and their receptors in prostate cancer recurrence. Experimental Design and Results: In this report, we show that HER receptor tyrosine kinases 1 through 4 are expressed in the CWR-R1 recurrent prostate cancer cell line; their stimulation by epidermal growth factor (EGF) and heregulin activates downstream signaling, including mitogen-activated protein kinase and phosphatidylinositol-3 kinase and Akt pathways. We show that heregulin activates HER2 and HER3 and increases androgen-dependent AR transactivation of reporter genes in CWR-R1 cells. Tyrosine phosphorylation of HER2 and HER3, AR transactivation, and cell proliferation induced by heregulin were more potently inhibited by the EGFR/HER2 dual tyrosine kinase inhibitor GW572016 (lapatinib) than the EGFR-specific inhibitor ZD1839 (gefitinib). Basal proliferation in the absence of growth factors was also inhibited by GW572016 to a greater extent than ZD1839, suggesting that low level HER2/HER3 activation perhaps by an autocrine pathway contributes to the proliferation signal. Conclusions: These data indicate that heregulin signaling through HER2 and HER3 increases AR transactivation and alters growth in a recurrent prostate cancer cell line. Therefore, inhibition of low-level HER2 signaling may be a potential novel therapeutic strategy in prostate cancer.
Characterization of the cardiomyopathy in infants of diabetic mothers.
Authors: H P Gutgesell, M E Speer, H S Rosenberg
Journal: Circulation (1980)

A transient form of hypertrophic cardiomyopathy has been previously described in infants of diabetic mothers (IDMs). The purpose of this study was to determine the incidence, natural history and pathologic features of this cardiomyopathy in symptomatic and asymptomatic IDMs. We studied 47 IDMs for evidence of cardiomyopathy. Among 24 symptomatic IDMs, five had marked septal hypertrophy with echocardiographic features suggesting left ventricular outflow obstruction and five had hypertrophy of the right ventricular free wall. With the exception of mild septal hypertrophy, these abnormalities resolved during the first 6 months of life, and echocardiograms in the first-degree family members were normal. Of 23 asymptomatic IDMs, three had septal hypertrophy and two had right ventricular free wall hypertrophy; none of the asymptomatic IDMs had evidence of outflow obstruction. One symptomatic IDM died, and autopsy revealed a hypertrophic septum that distorted both ventricular cavities. Microscopic examination revealed hypertrophic fibers and occasional areas of cellular disarray in the septum. Despite the clinical and pathologic similarities of the cardiomyopathy in IDMs to the hypertropic cardiomyopathies in older children and adults, its transient and nonfamilial nature suggest that it is a separate disease. We speculate that it is a manifestation of the generalized organomegaly in IDMs.
Radial glia cells are candidate stem cells of ependymoma
Authors: Michael D. Taylor, Helen Poppleton, Christine Fuller, Xiaoping Su, Yongxing Liu, Patricia Jensen, Susan Magdaleno, James Dalton, Christopher Calabrese, Julian Board, Tobey MacDonald, Jim Rutka, Abhijit Guha, Amar Gajjar, Tom Curran, Richard J. Gilbertson
Journal: Cancer Cell (2005)
Antimicrobial peptides in innate intestinal host defence
Authors: R N CUNLIFFE
Journal: Gut (2000)

Precursors of alpha-defensin peptides require activation for bactericidal activity.In mouse small intestine, matrilysin colocalized with alpha-defensins (cryptdins) in Paneth cell granules, and in vitro it cleaved the pro segment from cryptdin precursors.Matrilysin-deficient (MAT-/-) mice lacked mature cryptdins and accumulated precursor molecules.Intestinal peptide preparations from MAT-/-mice had decreased antimicrobial activity.Orally administered bacteria survived in greater numbers and were more virulent in MAT-/mice than in MAT+/+ mice.Thus, matrilysin functions in intestinal mucosal defense by regulating the activity of defensins, which may be a common role for this metalloproteinase in its numerous epithelial sites of expression.
Angiographic findings after minimally invasive coronary bypass operation: an angiographic study
Authors: M. Mastoor, R. Mehran, J.R. Laird, J.J. Popma, A.J. Lansky, A. Pfister, P. Corso, A.O. Pichard, L.F. Satler, M.K. Hong, K.M. Kent, M.B. Leon
Journal: Journal of the American College of Cardiology (1998)
612 THE EXTRA DOMAIN A FROM FIBRONECTIN (EDA) IMPROVES IMMUNOGENICITY OF NS3 PROTEIN IN A SEMLIKI FOREST VIRUS (SFV)-BASED VACCINE AGAINST HEPATITIS C
Authors: C. Mansilla, E. Casales, N. Casares, M. Martinez, P. Sarobe, F. Borras-Cuesta, J. Prieto, C. Smerdou, J.J. Lasarte
Journal: Journal of Hepatology (2008)
Rhinoviruses: markers of, or causative for, recurrent wheeze and asthma?
Authors: E. Kieninger, N. Regamey
Journal: European Respiratory Journal (2012)

Rhinovirus (RV) infections occur early and recurrently in life and impose a large burden of disease in infants and young children [1–3]. RVs are the most frequent pathogens detected during both upper and lower respiratory tract infections and are associated with a large spectrum of clinical outcomes in this age group [4, 5]. In the very young, they are one of the leading agents of bronchiolitis, second only to respiratory syncytial virus (RSV), and in children aged >12 months of age they are predominant pathogens associated with wheezing episodes [6–8]. In addition to their impact on short-term morbidity, RVs have been shown to represent an important pathogenic factor in the development of recurrent wheeze and asthma; a role which is yet not fully understood [9–12]. Several studies have been conducted over the past few years evaluating the influence of RV infections in early life on the development and incidence of wheezing and asthma [13–17]. They have clearly demonstrated that RV-associated wheezing is a risk factor for asthma development, and that approximately one third of infants with recurrent RV-induced wheezing illnesses go on to develop asthma. Unfortunately, most of these studies have been conducted in infants at high risk for atopy and asthma and not in unselected populations, or have included hospitalised children of a wide age range. These are significant limitations in the understanding of the respective influences of virus infections, atopy, age and maturity of the immune system …
NK-cell reconstitution after haploidentical hematopoietic stem-cell transplantations: immaturity of NK cells and inhibitory effect of NKG2A override GvL effect
Authors: Stephanie Nguyen, Nathalie Dhedin, Jean-Paul Vernant, Mathieu Kuentz, Ahmad Al Jijakli, Nathalie Rouas-Freiss, Edgardo D. Carosella, Ali Boudifa, Patrice Debré, Vincent Vieillard
Journal: Blood (2005)
Thrombolytic Therapy for the Treatment of Prosthetic Heart Valve Thrombosis in Pregnancy With Low-Dose, Slow Infusion of Tissue-Type Plasminogen Activator
Authors: Mehmet Özkan, Beytullah Çakal, Süleyman Karakoyun, Ozan Mustafa Gürsoy, Cihan Çevik, Macit Kalçık, Ali Emrah Oğuz, Sabahattin Gündüz, Mehmet Ali Astarcioglu, Ahmet Çağrı Aykan, Zübeyde Bayram, Murat Biteker, Evren Kaynak, Gökhan Kahveci, Nilüfer Ekşi Duran, Mustafa Yıldız
Journal: Circulation (2013)

Prosthetic valve thrombosis during pregnancy is life-threatening for mother and fetus, and the treatment of this complication is unclear. Cardiac surgery in pregnancy is associated with very high maternal and fetal mortality and morbidity. Thrombolytic therapy has rarely been used in these patients. The aim of this study is to evaluate the safety and efficacy of low-dose (25 mg), slow infusion (6 hours) of tissue-type plasminogen activator for the treatment of prosthetic valve thrombosis in pregnant women.Between 2004 and 2012, tissue-type plasminogen activator was administered to 24 consecutive women in 25 pregnancies with 28 prosthetic valve thrombosis episodes (obstructive, n=15; nonobstructive, n=13). Mean age of the patients was 29±6 years. Thrombolytic therapy sessions were performed under transesophageal echocardiography guidance. The mean dose of tissue-type plasminogen activator used was 48.7±29.5 mg (range, 25-100 mg). All episodes resulted in complete thrombus lysis after thrombolytic therapy. One patient had placental hemorrhage with preterm live birth at the 30th week, and 1 patient had minor bleeding.Low-dose, slow infusion of tissue-type plasminogen activator with repeated doses as needed is an effective therapy with an excellent thrombolytic success rate for the treatment of prosthetic valve thrombosis in pregnant women. This protocol also seems to be safer than cardiac surgery or any alternative medical strategies published to date. Thrombolytic therapy should be considered first-line therapy in pregnant patients with prosthetic valve thrombosis.
Real-Time Continuous Glucose Monitoring in Critically Ill Patients
Authors: Ulrike Holzinger, Joanna Warszawska, Reinhard Kitzberger, Marlene Wewalka, Wolfgang Miehsler, Harald Herkner, Christian Madl
Journal: Diabetes Care (2009)

OBJECTIVE To evaluate the impact of real-time continuous glucose monitoring (CGM) on glycemic control and risk of hypoglycemia in critically ill patients. RESEARCH DESIGN AND METHODS A total 124 patients receiving mechanical ventilation were randomly assigned to the real-time CGM group (n = 63; glucose values given every 5 min) or to the control group (n = 61; selective arterial glucose measurements according to an algorithm; simultaneously blinded CGM) for 72 h. Insulin infusion rates were guided according to the same algorithm in both groups. The primary end point was percentage of time at a glucose level &amp;lt;110 mg/dl. Secondary end points were mean glucose levels and rate of severe hypoglycemia (&amp;lt;40 mg/dl). RESULTS Percentage of time at a glucose level &amp;lt;110 mg/dl (59.0 ± 20 vs. 55.0 ± 18% in the control group, P = 0.245) and the mean glucose level (106 ± 18 vs. 111 ± 10 mg/dl in the control group, P = 0.076) could not be improved using real-time CGM. The rate of severe hypoglycemia was lower in the real-time CGM group (1.6 vs. 11.5% in the control group, P = 0.031). CGM reduced the absolute risk of severe hypoglycemia by 9.9% (95% CI 1.2–18.6) with a number needed to treat of 10.1 (95% CI 5.4–83.3). CONCLUSIONS In critically ill patients, real-time CGM reduces hypoglycemic events but does not improve glycemic control compared with intensive insulin therapy guided by an algorithm.