tbuckley/cabot-search huggingface dataset:
Enhancement of neutrophil function by the bronchial epithelium stimulated by epidermal growth factor
Authors: M Uddin, G Seumois, L C Lau, P Rytila, D E Davies, R Djukanovic
Journal: European Respiratory Journal (2007)

The bronchial epithelium is an important physical barrier that regulates physiological processes including leukocyte trafficking. The aim of the present study was to elucidate the mechanisms whereby the bronchial epithelium, stimulated by epidermal growth factor (EGF) as part of a response to acute or chronic injury, could activate and chemoattract human neutrophils. Subconfluent human bronchial epithelial (16HBE) cells were stimulated with EGF to mimic the in vivo events after injury. The effect of the resulting EGF-conditioned media (CM) was compared with that of basal-CM with respect to neutrophil activation and chemotaxis. Such findings were then confirmed using primary bronchial epithelial cells (PBECs) from healthy volunteers. EGF-CM from 16HBE cells caused increased expression of CD11b/CD66b and CD62L loss on neutrophils when compared with basal-CM. EGF-CM contained significant neutrophil chemotactic activity involving granulocyte-macrophage colony-stimulating factor and interleukin-8 that was potentiated by leukotriene B(4). This was dependent on neutrophil phosphatidylinositol-3-kinase activation and Akt phosphorylation, with partial regulation by phospholipase D, but not mammalian target of rapamycin. Consistent with these observations, EGF-CM derived from PBECs displayed increased chemotactic activity. The present results suggest that the enhanced chemotactic activity of the epidermal growth factor-conditioned epithelium can enhance neutrophil-mediated immunity during acute injury, while during continued injury and repair, as in chronic asthma, this could contribute to persistent neutrophilic inflammation.
Spina bifida and anencephaly: fewer patients, more problems.
Authors: I Leck
Journal: BMJ (1983)

Pregnancy in patients with prosthetic heart valves Patients who have had palliative or corrective cardiac surgery for congenital or acquired heart disease are being seen increasingly often as candidates for antenatal cardiac care.Cardiac surgery is usually not curative and each such patient requires individual assessment.The chances of success depend on their haemodynamic state, the effects of pregnancy on this and on fetal development, the likelihood of thromboembolic or infective complications, the possible effects on the child of on 23 July 2023 by guest.
The role of ethnicity and diagnosis in rates of adolescent psychiatric admission and compulsory detention: a longitudinal case-note study
Authors: Richard Corrigall, Dinesh Bhugra
Journal: Journal of the Royal Society of Medicine (2013)

To explore whether ethnic variations in psychiatric admission and detention reported for adults also apply to adolescents and to establish the influence of diagnosis.A longitudinal, case-note study over a 10-year period.An adolescent inpatient psychiatric unit in London.All adolescents admitted to the unit.Rates of admission and detention under the Mental Health Act, according to catchment area population.Young Black people were nearly six times more likely than the White group to be admitted with psychosis but showed no increase in admission for non-psychotic conditions. Young people in the Other group were over three times more likely to be admitted with psychosis but showed only a modest increase in admission with non-psychotic conditions. Young Asians were over twice as likely to be admitted with psychosis but were only one-third as likely to be admitted with non-psychotic conditions. Young people with psychosis in the Black and Other groups were around three times more likely to have been detained, but there were no significant differences for non-psychotic conditions.Significant ethnic variation was found in the rates of admission and detention for adolescents. However, diagnosis was also an important consideration and must be taken into account when examining for evidence of ethnic bias in the use of mental health services by young people. Further investigation is required to establish whether adolescent care pathways are providing a safe and appropriate level of inpatient care for all ethnic groups.
Assessment of the accuracy of segmental perfusion under an occluding balloon for measuring the intrajejunal secretion of albumin and immunoglobulin A.
Authors: J C Rambaud, F Duprey, O Nouel, J Hostein, B Delpech, J J Bernier
Journal: Gut (1981)

The suitability was investigated of the segmental perfusion technique under an occluding balloon (which prevents the contamination of the test segment by upper digestive secretions and pancreatic proteolytic enzymes) for measuring immunoglobulin A (IgA) and serum albumin outputs into the jejunal lumen. The influence of the perfusion rate and of the transintestinal water movements in the 40 cm long test segment was studied in 11 healthy subjects. IgA and serum albumin outputs did not differ significantly when the same isotonic solution was perfused at rates of 5 or 10 ml/min, nor when water absorption was stimulated by the presence of glucose. A possible artefact linked to intestinal wall distension by the occluding balloon was evaluated in eight subjects with complete exocrine pancreas insufficiency. IgA and serum albumin outputs obtained under the occluding balloon were compared with those found with the triple non-occlusive method. Care was taken to achieve a similar flow rate and solute composition of the fluid entering the test segments with both techniques in each subject. Under these conditions, IgA and serum albumin outputs measured with both methods did not differ significantly. These findings validate the use of the segmental perfusion technique under an occluding balloon to measure IgA and serum albumin outputs into the human small intestine.
<i>Pten</i>-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction
Authors: Natasha L. Curry, Mari Mino-Kenudson, Trudy G. Oliver, Ömer H. Yilmaz, Vedat O. Yilmaz, Jade Y. Moon, Tyler Jacks, David M. Sabatini, Nada Y. Kalaany
Journal: Cancer Discovery (2013)

Abstract PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss. Significance: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway. Cancer Discov; 3(8); 908–21. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 826
Current Perspective on the Global and United States Cancer Burden Attributable to Lifestyle and Environmental Risk Factors
Authors: David Schottenfeld, Jennifer L. Beebe-Dimmer, Patricia A. Buffler, Gilbert S. Omenn
Journal: Annual Review of Public Health (2013)

Our objective is to provide a current perspective on the avoidable causes of global and US cancer incidence and mortality. Cancer registry–based incidence patterns, population behavioral risk-factor survey data, and systematic reviews of epidemiologic studies are the basis for estimates of relative risk, the prevalence of exposures to various lifestyle and environmental risk factors, and their impact expressed as population attributable fractions (PAFs). Of the total 59 million global deaths in 2008, 12–13% were attributed to cancer. The increasing burden of cancers in low- and middle-income countries (LMICs) is attributable in part to increasing urbanization, expansion of the adult population at risk, and increasing or persistent exposures to infectious agents, tobacco, and dietary deficiencies. Attributable fractions for lifestyle and environmental risk factors are summarized for the United States, the United Kingdom, and France. Assuming minimal overlap in the distribution of risk factors in the population and discounting the potential for interaction in their combined effects, we estimate that a maximum of 60% of cancer deaths in the United States may be attributed to eight risk factors: tobacco, alcohol, ionizing and solar radiations, occupations, infectious agents, obesity, and physical inactivity.
Influenza A Virus Inhibits Alveolar Fluid Clearance in BALB/c Mice
Authors: Kendra E. Wolk, Eduardo R. Lazarowski, Zachary P. Traylor, Erin N. Z. Yu, Nancy A. Jewell, Russell K. Durbin, Joan E. Durbin, Ian C. Davis
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Pulmonary infections can impair alveolar fluid clearance (AFC), contributing to formation of lung edema. Effects of influenza A virus (IAV) on AFC are unknown.To determine effects of IAV infection on AFC, and to identify intercellular signaling mechanisms underlying influenza-mediated inhibition of AFC.BALB/c mice were infected intranasally with influenza A/WSN/33 (10,000 or 2,500 focus-forming units per mouse). AFC was measured in anesthetized, ventilated mice by instilling 5% bovine serum albumin into the dependent lung.Infection with high-dose IAV resulted in a steady decline in arterial oxygen saturation and increased lung water content. AFC was significantly inhibited starting 1 hour after infection, and remained suppressed through Day 6. AFC inhibition at early time points (1-4 h after infection) did not require viral replication, whereas AFC inhibition later in infection was replication-dependent. Low-dose IAV infection impaired AFC for 10 days, but induced only mild hypoxemia. High-dose IAV infection increased bronchoalveolar lavage fluid ATP and UTP levels. Impaired AFC at Day 2 resulted primarily from reduced amiloride-sensitive AFC, mediated by increased activation of the pyrimidine-P2Y purinergic receptor axis. However, an additional component of AFC impairment was due to activation of A(1) adenosine receptors and stimulation of increased cystic fibrosis transmembrane regulator-mediated anion secretion. Finally, IAV-mediated inhibition of AFC at Day 2 could be reversed by addition of beta-adrenergic agonists to the AFC instillate.AFC inhibition may be an important feature of early IAV infection. Its blockade may reduce the severity of pulmonary edema and hypoxemia associated with influenza pneumonia.
Epithelial myosin light chain kinase-dependent barrier dysfunction mediates T cell activation-induced diarrhea in vivo
Authors: D. R. Clayburgh
Journal: Journal of Clinical Investigation (2005)

Disruption of the intestinal epithelial barrier occurs in many intestinal diseases, but neither the mechanisms nor the contribution of barrier dysfunction to disease pathogenesis have been defined. We utilized a murine model of T cell-mediated acute diarrhea to investigate the role of the epithelial barrier in diarrheal disease. We show that epithelial barrier dysfunction is required for the development of diarrhea. This diarrhea is characterized by reversal of net water flux, from absorption to secretion; increased leak of serum protein into the intestinal lumen; and altered tight junction structure. Phosphorylation of epithelial myosin II regulatory light chain (MLC), which has been correlated with tight junction regulation in vitro, increased abruptly after T cell activation and coincided with the development of diarrhea. Genetic knockout of long myosin light chain kinase (MLCK) or treatment of wild-type mice with a highly specific peptide MLCK inhibitor prevented epithelial MLC phosphorylation, tight junction disruption, protein leak, and diarrhea following T cell activation. These data show that epithelial MLCK is essential for intestinal barrier dysfunction and that this barrier dysfunction is critical to pathogenesis of diarrheal disease. The data also indicate that inhibition of epithelial MLCK may be an effective non-immunosuppressive therapy for treatment of immune-mediated intestinal disease.
Correlations Between Apolipoprotein E ε4 Gene Dose and Whole Brain Atrophy Rates
Authors: Kewei Chen, Eric M. Reiman, Gene E. Alexander, Richard J. Caselli, Richard Gerkin, Daniel Bandy, Alisa Domb, David Osborne, Nick Fox, William R. Crum, Ann M. Saunders, John Hardy
Journal: American Journal of Psychiatry (2007)

Objective: The purpose of this study was to characterize the relationship between whole brain atrophy rates and three levels of genetic risk for Alzheimer's disease in cognitively normal persons. The authors previously found accelerated whole brain atrophy rates in patients with probable Alzheimer's disease by computing changes in brain volume from sequential magnetic resonance images (MRIs). Methods: The authors assessed 36 late-middle-aged persons from three genetic groups: those with two, one, and no copies of the apolipoprotein E (APOE) ε4 allele, a common Alzheimer's disease susceptibility gene. The participants had clinical ratings, neuropsychological tests, and volumetric T1-weighted MRIs during a baseline visit and again approximately 2 years later. Two different image-analysis techniques, brain boundary shift integration and iterative principal component analysis, were used to compute whole brain atrophy rates. Results: While there were no baseline, follow-up, or between-visit differences in the clinical ratings or neuropsychological test scores among the three subject groups, whole brain atrophy rates were significantly greater in the ε4 homozygote group than in noncarriers and were significantly correlated with ε4 gene dose (i.e., the number of ε4 alleles in a person's APOE genotype). Conclusion: Since APOE ε4 gene dose is associated with an increased risk of Alzheimer's disease and a younger median age at dementia onset, this study suggests an association between the risk of Alzheimer's disease and accelerated brain atrophy rates before the onset of cognitive impairment.
CHARACTERIZATION OF A NEW INTRA-<i>H-2</i> RECOMBINANT
Authors: Martin E. Dorf, Frank Lilly, Baruj Benacerraf
Journal: The Journal of Experimental Medicine (1974)

This report characterizes the intra-H-2 crossover in the D2.GD mouse strain. Recombination occurred within the I region between the immune response (Ir) gene controlling immune responsiveness to ragweed extract (RE). Ir-RE, and the Ir gene governing responsiveness to the random linear terpolymers of glutamic acid and lysine with either tyrosine or pheylalanine (Ir-GLT and Ir-GLϕ). The Ir-RE gene was tentatively located in the Ir-1A subregion and the Ir-GLT and Ir-GLϕ gene(s) tentatively placed in the Ir-1B subregion. The importance of this recombinant strain to further studies on the fine structure of the I region is discussed.
Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial
Authors: Merit E Cudkowicz, Leonard H van den Berg, Jeremy M Shefner, Hiroshi Mitsumoto, Jesus S Mora, Albert Ludolph, Orla Hardiman, Michael E Bozik, Evan W Ingersoll, Donald Archibald, Adam L Meyers, Yingwen Dong, Wildon R Farwell, Douglas A Kerr
Journal: The Lancet Neurology (2013)
Critical closure in the canine pulmonary vasculature.
Authors: R Graham, C Skoog, L Oppenheimer, J Rabson, H S Goldberg
Journal: Circulation Research (1982)

The vascular pressure-flow (P-Q) relationships in zone II (West et al.) were studied in isolated canine left lower lobes, in order to characterize the total resistance in the pulmonary vascular bed with respect to incremental or flow resistance and critical closure. At each of five levels of static lung inflation, the P-Q relationship was curvilinear at low flow and rectilinear at higher flows. The slope of the linear portion was not significantly different at alveolar pressures (PA) = 5, 7, or 9 cm H2O, but decreased significantly at PA = 11 and 15 cm H2O ((P less than 0.05), indicating an increase in flow resistance. The pulmonary artery pressure (Ppa) fell to the same value at zero flow regardless of inflation level [10.1 +/- 1.0 (SD) cm H2O at PA = 5 cm H2O to 10.9 +/- 2.7 (SD) at PA = 15 cm H2O]. The Ppa intercept (Ppai), extrapolated from the linear portion of the P-Q curve and representing the average closing pressure for the vascular bed, increased from 16.0 +/- 1.8 (SD) cm H2O at PA = 5.0 to 26.5 +/- 4.4 (SD) cm H2O at PA = 15 (P less than 0.05) in a direct one-to-one relationship with the increase in PA. Since this results in a constant transmural gradient at the alveolar vessel level, these vessels must be the major fraction which undergo critical closure. Operationally defined vascular compliance, determined from the slope of a simultaneously obtained pressure-volume (P-V) curve, decreased significantly from 1.51 +/- 0.62 (SD) ml/cm H2O at PA = 5.0 H2O to 0.87 +/- 0.27 ml/cm H2O at PA = 15 cm H2O (P less than 0.05).
In vitro steroid resistance correlates with outcome in severe alcoholic hepatitis
Authors: A. J. di Mambro, R. Parker, A. McCune, F. Gordon, C. M. Dayan, P. Collins
Journal: Hepatology (2011)

Steroids improve the outcome in alcoholic hepatitis (AH), but up to 40% of patients fail to respond adequately. Interleukin-2 (IL-2) exacerbates steroid resistance in vitro . We performed a prospective study to determine if intrinsic steroid sensitivity correlates with response to steroids in individuals with severe AH and if IL-2 receptor blockade can reverse this. Peripheral blood mononuclear cells (PBMCs) were isolated from 20 patients with AH and a Maddrey's score &gt;32. Patients were treated with oral prednisolone plus full supportive measures. Clinical resistance to oral steroid treatment was defined as a drop in serum bilirubin of &lt;25% within 7 days or death within 6 months. In vitro steroid resistance was measured in PBMC using the dexamethasone suppression of lymphocyte proliferation assay and repeated after the addition of the anti-IL-2 receptor (anti-CD25) monoclonal antibody, basiliximab. Suppression of lymphocyte proliferation &lt;60% was considered to indicate steroid resistance. In all, 82% (9/11) of in vitro steroid-resistant patients were dead at 6 months as compared to 21% (2/9) of steroid-sensitive patients ( P = 0.03). Similarly, 91% (10/11) of in vitro steroid-resistant patients failed to show a significant fall in bilirubin at day 7 as compared to 44% (4/9) of steroid-sensitive patients ( P &lt; 0.05). Basiliximab improved the maximal proliferation count in 91% (10/11) of in vitro steroid-resistant patients ( P = 0.003). Conclusion: Clinical outcome of steroid therapy in this patient cohort correlated with in vitro steroid resistance. IL-2 blockade improved in vitro steroid sensitivity. This suggests that intrinsic lack of steroid sensitivity may contribute to poor clinical response to steroids in severe AH. IL-2 receptor blockade represents a possible mechanism to overcome this. (HEPATOLOGY 2011;)
Prevalence of Prostate Cancer on Autopsy: Cross-Sectional Study on Unscreened Caucasian and Asian Men
Authors: Alexandre R. Zlotta, Shin Egawa, Dmitry Pushkar, Alexander Govorov, Takahiro Kimura, Masahito Kido, Hiroyuki Takahashi, Cynthia Kuk, Marta Kovylina, Najla Aldaoud, Neil Fleshner, Antonio Finelli, Laurence Klotz, Jenna Sykes, Gina Lockwood, Theodorus H. van der Kwast
Journal: JNCI Journal of the National Cancer Institute (2013)

Substantial geographical differences in prostate cancer (PCa) incidence and mortality exist, being lower among Asian (ASI) men compared with Caucasian (CAU) men. We prospectively compared PCa prevalence in CAU and ASI men from specific populations with low penetrance of prostate-specific antigen screening.Prostate glands were prospectively obtained during autopsy from men who died from causes other than PCa in Moscow, Russia (CAU), and Tokyo, Japan (ASI). Prostates were removed en-block and analyzed in toto. We compared across the 2 populations PCa prevalence, number and Gleason score (GS) of tumour foci, pathological stage, spatial location, and tumor volume using χ(2), Mann-Whitney-Wilcoxon tests, and multiple logistic regression. All statistical tests were two-sided.Three hundred twenty prostates were collected, 220 from CAU men and 100 from ASI mean. The mean age was 62.5 in CAU men and 68.5 years in ASI men (P < .001). PCa prevalences of 37.3% in CAU men and 35.0% in ASI men were observed (P = .70). Average tumor volume was 0.303cm(3). In men aged greater than 60 years, PCa was observed in more than 40% of prostates, reaching nearly 60% in men aged greater than 80 years. GS 7 or greater cancers accounted for 23.1% and 51.4% of all PCa in CAU and ASI men, respectively, (P = .003). When adjusted for age and prostate weight, ASI men still had a greater probability of having GS 7 or greater PCa (P = .03).PCa is found on autopsy in a similar proportion of Russian and Japanese men. More than 50% of cancers in ASI and nearly 25% of cancers in CAU men have a GS of 7 or greater. Our results suggest that the definition of clinically insignificant PCa might be worth re-examining.