tbuckley/cabot-search huggingface dataset:
Human alveolar epithelial cells induce nitric oxide synthase‐2 expression in alveolar macrophages
Authors: D.V. Pechkovsky, G. Zissel, C. Stamme, T. Goldmann, H. Ari Jaffe, M. Einhaus, C. Taube, H. Magnussen, M. Schlaak, J. Müller­Quernheim
Journal: European Respiratory Journal (2002)

It was hypothesized that cell-to-cell interaction between human alveolar macrophages (AM) and alveolar epithelium, might be an important factor leading to nitric oxide synthase-2 (NOS2) messenger ribonucleic acid (mRNA) and protein expression by constituent cells of the alveolar wall and/or AM. NOS2 mRNA and the protein expression patterns of human AM and alveolar epithelial cells type II (AEC-II) isolated from normal parts of lung resections of patients with pulmonary malignancies were determined. In addition, NOS2 mRNA expression in human AM co-cultured with autologous AEC-II in the presence of pro-inflammatory cytokines interleukin (IL)-1beta, tumour necrosis factor (TNF)-alpha, interferon (IFN)-gamma or lipopolysaccharide (LPS) was investigated. The effect of human surfactant protein-A (SP-A) on IFN-gamma-mediated NOS2 mRNA expression in human AM was also studied. Neither NOS2 mRNA nor protein could be detected in freshly isolated, unstimulated or cytokine-stimulated AEC-II. In contrast, freshly isolated AM from bronchoalveolar lavage or lung tissue samples expressed immunoreactivity for NOS2 protein, but no NOS2 mRNA could be detected by reverse transcriptase polymerase chain reaction. All stimuli tested failed to induce NOS2 mRNA expression in human AM in vitro. Only AM-AEC-II co-culture in the presence of IFN-gamma led to NOS2 mRNA and protein expression. In situ hybridization of NOS2 mRNA on lung tissue explants and immunohistochemical staining of cytospin preparations of AM-AEC-II co-cultures demonstrated that NOS2 is expressed in AM but not in AEC-II. This co-culture effect could not be reproduced by substitution of AEC-II with SP-A. These data give evidence of a regulatory network controlling human nitric oxide synthase-2 expression in the lower respiratory tract.
Extended Follow-up of Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia
Authors: Ching-Hon Pui, Cheng Cheng, Wing Leung, Shesh N Rai, Gaston K Rivera, John T Sandlund, Raul C Ribeiro, Mary V Relling, Larry E Kun, William E Evans, Melissa M Hudson
Journal: New England Journal of Medicine (2003)

Children who survive acute lymphoblastic leukemia are at risk for leukemia-related or treatment-related complications, which can adversely affect survival and socioeconomic status. We determined the long-term survival and the rates of health insurance coverage, marriage, and employment among patients who had attained at least 10 years of event-free survival.
Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness
Authors: Martina Kovarova, Christopher A. Wassif, Sandra Odom, Katherine Liao, Forbes D. Porter, Juan Rivera
Journal: The Journal of Experimental Medicine (2006)

Mutation of the 3β-hydroxysterol Δ7-reductase gene (Dhcr7−/−) results in Smith-Lemli-Opitz syndrome (SLOS). Patients, and genetically altered mice, are unable to produce cholesterol and accumulate 7-dehydrocholesterol (DHC) in serum and tissue. This causes multiple growth and developmental abnormalities as well as immune system anomalies including allergy. Because cholesterol is a key component of liquid-ordered membranes (lipid rafts) and these domains have been implicated in regulating mast cell activation, we examined whether mast cell responsiveness is altered in this model. Mast cells derived from Dhcr7−/− mice (DHCR KO) showed constitutive cytokine production and hyper-degranulation after stimulation of the high affinity IgE receptor (FcεRI). DHCR KO mast cells, but not wild-type mast cells, accumulated DHC in lipid rafts. DHC partially disrupted lipid raft stability and displaced Lyn kinase protein and activity from lipid rafts. This led to down-regulation of some Lyn-dependent signaling events but increased Fyn kinase activity and Akt phosphorylation. The Lyn-dependent phosphorylation of Csk-binding protein, which negatively regulates Fyn activity, was decreased. This phenotype reproduces some of the characteristics of Lyn-null mast cells, which also demonstrate hyper-degranulation. These findings provide the first evidence of lipid raft dysfunction in SLOS and may explain the observed association of allergy with SLOS.
Effect of age on immune function in terms of chemically induced cancers
Authors: Michael Bennett
Journal: Environmental Health Perspectives (1979)

Neonatal, fetal, and very old animals are particularly sensitive to chemical carcinogenesis. Reasons for this increased sensitivity could be due to increased susceptibility of “target” organs or cells, peculiar hormonal levels at these age groups, relatively deficient immune functions, or combinations of these and/or other factors. During the late fetal and first three weeks of neonatal life, the immune system is rapidly maturing, is relatively incompetent, and its diverse components are developing at different rates. For example, thymus-dependent (T) alloreactive cells capable of proliferating in mixed lymphocyte reactions (T helper cells) develop by 7 days of age, but precursors of T killer cells are not competent until approximately 14 days of age. Bursa equivalent-dependent (B) cells capable of generating antibody responses are present in fetal liver but are extremely sensitive to tolerance induction until 10-14 days of age when IgD cell surface receptors are detectable. Marrow-dependent (M) cells responsible for regulation of suppressor cells and for natural cytotoxicity to transformed tumor cells do not mature until 3 weeks of age. In very old animals, the thymus is atrophic and cell-mediated immunity is moderately suppressed. Natural cytotoxicity against tumor cells is less than normal but antibody formation (B cell function) is adequate. Gonadotrophic hormones of the pituitary or placenta are high during pregnancy, the early neonatal period, after the menopause, and in a large fraction of men over 60 years of age. These and other hormones are immunosuppressive and could theoretically facilitate carcinogenesis. The particular immune cell type, if any, responsible for resistance to chemically induced tumors has not been determined. One can only state that susceptibility to chemical carcinogenesis is associated with a relative dysfunction of the immune system and that age is an important factor.
The danger signal plus DNA damage two-hit hypothesis for chronic inflammation in COPD
Authors: Kazutetsu Aoshiba, Takao Tsuji, Kazuhiro Yamaguchi, Masayuki Itoh, Hiroyuki Nakamura
Journal: European Respiratory Journal (2013)

Inflammation in chronic obstructive pulmonary disease (COPD) is thought to originate from the activation of innate immunity by a danger signal (first hit), although this mechanism does not readily explain why the inflammation becomes chronic. Here, we propose a two-hit hypothesis explaining why inflammation becomes chronic in patients with COPD. A more severe degree of inflammation exists in the lungs of patients who develop COPD than in the lungs of healthy smokers, and the large amounts of reactive oxygen species and reactive nitrogen species released from inflammatory cells are likely to induce DNA double-strand breaks (second hit) in the airways and pulmonary alveolar cells, causing apoptosis and cell senescence. The DNA damage response and senescence-associated secretory phenotype (SASP) are also likely to be activated, resulting in the production of pro-inflammatory cytokines. These pro-inflammatory cytokines further stimulate inflammatory cell infiltration, intensifying cell senescence and SASP through a positive-feedback mechanism. This vicious cycle, characterised by mutually reinforcing inflammation and DNA damage, may cause the inflammation in COPD patients to become chronic. Our hypothesis helps explain why COPD tends to occur in the elderly, why the inflammation worsens progressively, why inflammation continues even after smoking cessation, and why COPD is associated with lung cancer.
An official systematic review of the European Respiratory Society/American Thoracic Society: measurement properties of field walking tests in chronic respiratory disease
Authors: Sally J. Singh, Milo A. Puhan, Vasileios Andrianopoulos, Nidia A. Hernandes, Katy E. Mitchell, Catherine J. Hill, Annemarie L. Lee, Carlos Augusto Camillo, Thierry Troosters, Martijn A. Spruit, Brian W. Carlin, Jack Wanger, Véronique Pepin, Didier Saey, Fabio Pitta, David A. Kaminsky, Meredith C. McCormack, Neil MacIntyre, Bruce H. Culver, Frank C. Sciurba, Susan M. Revill, Veronica Delafosse, Anne E. Holland
Journal: European Respiratory Journal (2014)

This systematic review examined the measurement properties of the 6-min walk test (6MWT), incremental shuttle walk test (ISWT) and endurance shuttle walk test (ESWT) in adults with chronic respiratory disease. Studies that report the evaluation or use of the 6MWT, ISWT or ESWT were included. We searched electronic databases for studies published between January 2000 and September 2013. The 6-min walking distance (6MWD) is a reliable measure (intra-class correlation coefficients ranged from 0.82 to 0.99 in seven studies). There is a learning effect, with greater distance walked on the second test (pooled mean improvement of 26 m in 13 studies). Reliability was similar for ISWT and ESWT, with a learning effect also evident for ISWT (pooled mean improvement of 20 m in six studies). The 6MWD correlates more strongly with peak work capacity (r=0.59–0.93) and physical activity (r=0.40–0.85) than with respiratory function (r=0.10–0.59). Methodological factors affecting 6MWD include track length, encouragement, supplemental oxygen and walking aids. Supplemental oxygen also affects ISWT and ESWT performance. Responsiveness was moderate to high for all tests, with greater responsiveness to interventions that included exercise training. The findings of this review demonstrate that the 6MWT, ISWT and ESWT are robust tests of functional exercise capacity in adults with chronic respiratory disease.
P16 Loss and Mitotic Activity Predict Poor Survival in Patients with Peritoneal Malignant Mesothelioma
Authors: Alain C. Borczuk, Robert N. Taub, Mary Hesdorffer, Hanina Hibshoosh, John A. Chabot, Mary L. Keohan, Ritchie Alsberry, Diane Alexis, Charles A. Powell
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Peritoneal malignant mesothelioma is an aggressive neoplasm for which intensive therapy improves survival in a subset of patients. We hypothesized that pathologic variables would stratify patients into favorable and unfavorable survival subgroups. Experimental Design: Fifty-four patients with peritoneal malignant mesothelioma were evaluated for trimodal therapy from 1995 to 2003. Two pathologists evaluated pathologic variables independently, and p16 status was analyzed by immunohistochemistry. Results: Patients not receiving trimodal therapy had a significantly increased risk of death [hazard ratio (HR), 9.6; 4.3-21.6; P &amp;lt; 0.0001]. Biphasic histology was also associated with increased risk of death (HR, 8.5; 3.4-21.8; P &amp;lt; 0.0001). In multivariate analysis adjusting for treatment modality and histologic type, high mitotic rate and p16 loss were associated with increased risk of death (HR, 3.074; 1.05-9.0; P &amp;lt; 0.04 and HR, 3.65; 1.3-10.2; P &amp;lt; 0.014, respectively). Conclusions: Biphasic histology, increased mitotic rate, and p16 loss were independently associated with poorer survival in peritoneal malignant mesothelioma. Among the trimodal treated patients, increased mitotic rate was associated with increased risk of death.
Hall of Mirrors
Authors: J. O'Sullivan
Journal: BMJ (2008)

In Hall of Mirrors a distinguished London physician, Sir Thomas Gilling, sues a professor of surgery for libel. The surgeon’s team has developed a computer aided diagnostic machine, and in a public letter he alleges that Gilling was negligent in declining to use it for a difficult case. The title refers to the fairground exhibit where people see themselves in distorting mirrors—a metaphor for how Gilling is presented by the opposing counsel in court. His own barrister presents him as “the perfection of clinical, scientific and administrative medicine.” To the other side, however, he is “a rigid, inflexible old man, …
Carotid Plaques Increase the Risk of Stroke and Subtypes of Cerebral Infarction in Asymptomatic Elderly
Authors: M. Hollander, M.L. Bots, A. Iglesias del Sol, P.J. Koudstaal, J.C.M. Witteman, D.E. Grobbee, A. Hofman, M.M.B. Breteler
Journal: Circulation (2002)

Background — Few studies have quantified the relation between carotid plaques and stroke in asymptomatic patients, and limited data exist on the importance of location of plaques or the association with subtypes of cerebral infarction. We investigated the relationship between carotid plaques, measured at different locations, and risk of stroke and subtypes of cerebral infarction in a population-based study. Methods and Results — The study was based on the Rotterdam Study and included 4217 neurologically asymptomatic subjects aged 55 years or older. Presence of carotid plaques at 6 locations in the carotid arteries was assessed at baseline. Severity was categorized according to the number of affected sites. After a mean follow-up of 5.2 years, 160 strokes had occurred. Data were analyzed using Cox proportional hazards regression. Plaques increased the risk of stroke and cerebral infarction ≈1.5-fold, irrespective of plaque location. Severe carotid plaques increased the risk of nonlacunar infarction in anterior (RR 3.2 [95% CI, 1.1 to 9.7]) but not in posterior circulation (RR 0.6 [95% CI, 0.1 to 4.9]). A &gt;10-fold increased risk of lacunar infarction was found in subjects with severe plaques (RR 10.8 [95% CI, 1.7 to 69.7]). No clear difference in risk estimates was seen between ipsilateral and contralateral infarction. Conclusions — Carotid plaques increase the risk of stroke and cerebral infarction, irrespective of their location. Plaques increase the risk of infarctions in the anterior but not in the posterior circulation. It is likely that carotid plaques in neurologically asymptomatic subjects are both markers of generalized atherosclerosis and sources of thromboemboli.
Managing HBV in patients with impaired immunity
Authors: K. Wursthorn, H. Wedemeyer, M. P. Manns
Journal: Gut (2010)

Chronic hepatitis B is one of the most common infectious diseases worldwide. In patients with an impaired immune system the prevalence of HBsAg is even higher and the course of hepatitis B infection is often aggravated. In HIV/HBV co-infected patients, liver related morbidity and mortality can be reduced by implementing highly active antiretroviral treatment (HAART) that contains substances active against HBV. Reactivation of HBV during chemotherapy may occur in HBsAg positive patients but can even occur in serologically recovered anti-HBc positive, HBsAg negative patients resulting in high mortality from liver disease. HBsAg positive patients irrespective of HBV DNA levels should receive preemptive treatment with HBV polymerase inhibitors which should be continued for 12 months after cessation of chemo- and or immunosuppressive therapy. The combination prophylaxis of passive immunisations with hepatitis B immunoglobulins (HBIG) and nucleos(t)ide analogues (NUC) is able to reduce HBV recurrence rates after transplantation to 0–10%. This review will summarise the current knowledge on pathogenesis, frequency and treatment options of HBV reactivations in patients with impaired immunity.
Highlights of the Year in JACC 2008
Authors: Anthony N. DeMaria, Ori Ben-Yehuda, Jeroen J. Bax, Gregory K. Feld, Barry H. Greenberg, Wilbur Y.W. Lew, João A.C. Lima, Alan S. Maisel, Sanjiv M. Narayan, David J. Sahn, Sotirios Tsimikas
Journal: Journal of the American College of Cardiology (2009)
Comprehensive study of the biliary bile acid composition of patients with cystic fibrosis and associated liver disease before and after UDCA administration
Authors: Michiko Nakagawa, Carla Colombo, Kenneth D.R. Setchell
Journal: Hepatology (1990)

The biliary bile acid composition was determined for patients with cystic fibrosis and associated liver disease before and after the administration of ursodeoxycholic acid (10 to 15 mg/kg body wt/day). Bile acids were analyzed by fast atom bombardment ionization-mass spectrometry, high performance liquid chromatography and gas chromatography-mass spectrometry after individual bile acids were separated according to their mode of conjugation using the lipophilic anion exchanger, diethylaminohydroxypropyl Sephadex LH-20. More than 50 individual bile acids were identified in the bile of cystic fibrosis patients and these acids were predominantly secreted as glycine and taurine conjugates. Small proportions (less than 8% of the total) of unconjugated and sulfate conjugates were present. Of interest was the identification of two side-chain-elongated (C25) bile acids, homocholic and homochenodeoxycholic acids. After ursodeoxycholic acid was administered, duodenal bile became enriched with the conjugated species of ursodeoxycholic acid (accounting for 11.9% to 32.5% of the total biliary bile acids), but to a lesser extent than reported previously for patients with other liver diseases or gallstones who received comparable doses of ursodeoxycholic acid, and this presumably occurs because of bile acid malabsorption that is a feature of cystic fibrosis. The mean glycine/taurine ratio increased from 2.4 before ursodeoxycholic acid administration to 5 after ursodeoxycholic acid administration even though these patients also received taurine. Despite the relatively low enrichment of the bile by ursodeoxycholic acid, biochemical indices of liver function all improved in these patients after ursodeoxycholic acid administration.
INFLUENZA VIRUS AND ITS MUCOPROTEIN SUBSTRATE IN THE CHORIOALLANTOIC MEMBRANE OF THE CHICK EMBRYO
Authors: R. Walter Schlesinger, H. Valerie Karr
Journal: The Journal of Experimental Medicine (1956)

As a preliminary to a study of the fate of mucoprotein substrate in tissues infected with influenza virus, some characteristics of soluble hemagglutination inhibitors (HI) extracted from chorioallantoic membranes (CAM) have been investigated. The inhibitory material was found to be heat-stable, precipitable with cold ethanol, and subject to progressive inactivation by active viruses or by receptor-destroying enzyme (RDE). Certain changes in the slope of titration curves obtained with precipitated and non-precipitated fractions upon alcohol fractionation suggested that the HI in heated CAM extracts was heterogeneous. Alcohol in low concentration precipitated preferentially the more efficient (longer?) HI leaving the "weak" component in the non-precipitated fraction. With higher concentrations of alcobol, "strong" HI were converted to "weak" ones, either by denaturation or as result of reduced solubility. These changes in slope of titration curves were reflected in significant discrepancies when densitometric titers (HI(50)) of fractions were compared with their titers in pattern tests. The action of active viruses on HI, on the other hand, did not induce qualitative changes in the composition of the inhibitory principle: Titration curves retained parallel slopes even when their position was markedly displaced from that of control curves. In its essential properties, the HI from the CAM appeared to be similar to inhibitors isolated from various other biological sources which have been identified as mucoprotein in nature. Standards for reproducibility of inhibitory titers obtained by the densitometric method of Hirst and Pickels have been presented. The relation of HI to the allantoic epithelium has been analyzed. It has been concluded that the HI is a normal constituent and secretion product of these cells. Under physiological conditions, i.e. in the intact egg, the HI contained in the mucoid outer layer of allantoic cells appears to be protected from enzymatic action from without, although adsorption of viral particles may be temporarily impeded. In deembryonated eggs, or in excised membranes, a reduction in total inhibitory substrate as a result of the action of RDE has been observed. It has been shown in experiments on adsorption of active or heat-inactivated virus on the allantoic membrane that prevention of adsorption by RDE may require the synergistic action of the active viral enzyme itself. It has been concluded that the maintenance or restoration of a normal supply of mucoprotein substrate is a function of the ability of allantoic cells to maintain homeostatic conditions under stress.
LKB1 Catalytically Deficient Mutants Enhance Cyclin D1 Expression
Authors: Kristine D. Scott, Suchita Nath-Sain, Meghan D. Agnew, Paola A. Marignani
Journal: Cancer Research (2007)

Abstract Mutations in the serine-threonine tumor-suppressor kinase LKB1 are responsible for Peutz-Jeghers syndrome, characterized by hamartomatous proliferation and an increased risk of developing cancer. Mutations in lkb1 have also been identified in sporadic cancers, suggesting a wider role for LKB1 in cancer that is not limited to hamartomatous polyposis syndromes. Here, we show that LKB1 catalytically deficient mutants, when introduced into DLD1p21−/−p53−/− colorectal cancer cells, allowed for progression of cells through to S phase of cell cycle and elicited the expression of Rb, cyclin E, and cyclin A2 whereas the introduction of LKB1 lead to G1 cell cycle arrest independent of p21WAF/CIP1 and/or p53 expression. Furthermore, we show that LKB1 catalytically deficient mutants activate the expression of cyclin D1 through recruitment to response elements within the promoter of the oncogene. In addition to compromising the tumor-suppressor function of LKB1, our findings highlight an emerging role for LKB1 catalytically deficient mutants, a gain of oncogenic properties. [Cancer Res 2007;67(12):5622–7]
The immune system in sport: getting the balance right
Authors: Richard O'kennedy
Journal: British Journal of Sports Medicine (2000)

The immune system consists of a vast number of cells, tissues, and messengers—for example, cytokines—that play a key role in the protection of the body against infection and in healing after injury. It is becoming increasingly evident that it is highly integrated with our neurological and endocrine systems, and research now seeks to understand and exploit these interactions.1 The need for an active immune system is self evident if an athlete is to continuously produce peak performances, but often intense exertion and treatment for inflammation lead to partially reduced immune capacity and consequently potential infection or disease. To circumvent such problems, it is of major importance to understand how to achieve the optimum balance of the immune system.

A review of the literature highlights the fact that sports immunology is …