tbuckley/cabot-search huggingface dataset:
Reactive airways dysfunction syndrome due to chlorine: sequential bronchial biopsies and functional assessment
Authors: C Lemiere, JL Malo, M Boutet
Journal: European Respiratory Journal (1997)

Very little information is available on the acute histopathological bronchial alterations caused by reactive airways dysfunction syndrome (RADS). We had the opportunity to carry out sequential bronchial biopsies in a subject with RADS due to chlorine (60 h, 15 days, 2 and 5 months after the acute exposure), and also to assess spirometry and bronchial responsiveness to methacholine. A 36 year old worker in a water-filtration plant (nonsmoker) abruptly inhaled high concentrations of chlorine on September 12, 1994. He experienced immediate nasal and throat burning, retrosternal burning and wheezing, and these symptoms persisted during and after the workshift. Two days later, he complained of retrosternal burning, dyspnoea and wheezing. Inspiratory wheezing was documented. His forced expiratory volume in one second (FEV1) was 66% of predicted and the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20) was slightly abnormal (2.5 mg.mL-1). On the following day, the patient underwent bronchial biopsies, which showed almost complete replacement of the epithelium by a fibrinohaemorhagic exsudate. The subject was prescribed inhaled steroids. Fifteen days after the accident, the PC20 was improved to 6 mg.mL-1. Bronchial biopsies showed considerable epithelial desquamation with an inflammatory exudate and swelling of the subepithelial space. Five weeks after the accident, the PC20 was normal (57 mg.mL-1). Inhaled steroids were stopped. Two months after the accident, the PC20 deteriorated to 4 mg.mL-1. Biopsies then showed regeneration of the epithelium by basal cells and there was still a pronounced inflammatory infiltrate. Inhaled steroids were restarted. Three and five months later, the PC20 was normal (24 mg.mL-1). Bronchial biopsies showed a greatly improved epithelium and reduction of the inflammatory infiltrate. This case report shows that reactive airways dysfunction syndrome can cause acute, marked, though partially reversible, histological abnormalities. Inhaled steroids may modulate changes in bronchial responsiveness in this condition.
Signal Transduction Pathways of Tumor Necrosis Factor–mediated Lung Injury Induced by Ozone in Mice
Authors: Hye-Youn Cho, Daniel L. Morgan, Alison K. Bauer, Steven R. Kleeberger
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Increasing evidence suggests that tumor necrosis factor (TNF)-alpha plays a key role in pulmonary injury caused by environmental ozone (O(3)) in animal models and human subjects. We previously determined that mice genetically deficient in TNF response are protected from lung inflammation and epithelial injury after O(3) exposure.The present study was designed to determine the molecular mechanisms of TNF receptor (TNF-R)-mediated lung injury induced by O(3).TNF-R knockout (Tnfr(-/-)) and wild-type (Tnfr(+/+)) mice were exposed to 0.3 ppm O(3) or air (for 6, 24, or 48 h), and lung RNA and proteins were prepared. Mice deficient in p50 nuclear factor (NF)-kappaB (Nfkb1(-/-)) or c-Jun-NH(2) terminal kinase 1 (Jnk1(-/-)) and wild-type controls (Nfkb1(+/+), Jnk1(+/+)) were exposed to O(3) (48 h), and the role of NF-kappaB and mitogen-activated protein kinase (MAPK) as downstream effectors of lung injury was analyzed by bronchoalveolar lavage analyses.O(3)-induced early activation of TNF-R adaptor complex formation was attenuated in Tnfr(-/-) mice compared with Tnfr(+/+) mice. O(3) significantly activated lung NF-kappaB in Tnfr(+/+) mice before the development of lung injury. Basal and O(3)-induced NF-kappaB activity was suppressed in Tnfr(-/-) mice. Compared with Tnfr(+/+) mice, MAPKs and activator protein (AP)-1 were lower in Tnfr(-/-) mice basally and after O(3). Furthermore, inflammatory cytokines, including macrophage inflammatory protein-2, were differentially expressed in Tnfr(-/-) and Tnfr(+/+) mice after O(3). O(3)-induced lung injury was significantly reduced in Nfkb1(-/-) and Jnk1(-/-) mice relative to respective control animals.Results suggest that NF-kappaB and MAPK/AP-1 signaling pathways are essential in TNF-R-mediated pulmonary toxicity induced by O(3).
Renal cytochrome P450 ω-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride
Authors: A.O. Oyekan, T. Youseff, D. Fulton, J. Quilley, J.C. McGiff
Journal: Journal of Clinical Investigation (1999)

Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of omega-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [(14)C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 microM), an NO donor, inhibited renal microsomal conversion of [(14)C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 microM), the cell-permeable analogue of cGMP, did not affect conversion of [(14)C]AA. Inhibition of NOS with N(omega)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [(14)C]AA to HETE and greatly increased the expression of omega-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygenase activity, both in the cortex and the medulla. In contrast, cortical omega-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [(14)C]AA to HETEs without affecting epoxygenase activity. Thus, inhibition of NOS increased omega-hydroxylase activity, CYP4A expression, and renal efflux of 20-HETE, whereas 2% NaCl stimulated epoxygenase activity.
Hepatocyte Nuclear Factor-4α Promotes Gut Neoplasia in Mice and Protects against the Production of Reactive Oxygen Species
Authors: Mathieu Darsigny, Jean-Philippe Babeu, Ernest G. Seidman, Fernand-Pierre Gendron, Emile Levy, Julie Carrier, Nathalie Perreault, François Boudreau
Journal: Cancer Research (2010)

Hepatocyte nuclear factor-4α (Hnf4α) is a transcription factor that controls epithelial cell polarity and morphogenesis. Hnf4α conditional deletion during postnatal development has minor effects on intestinal epithelium integrity but promotes activation of the Wnt/β-catenin pathway without causing tumorigenesis. Here, we show that Hnf4α does not act as a tumor-suppressor gene but is crucial in promoting gut tumorigenesis in mice. Polyp multiplicity in ApcMin mice lacking Hnf4α is suppressed compared with littermate ApcMin controls. Analysis of microarray gene expression profiles from mice lacking Hnf4α in the intestinal epithelium identifies novel functions of this transcription factor in targeting oxidoreductase-related genes involved in the regulation of reactive oxygen species (ROS) levels. This role is supported with the demonstration that HNF4α is functionally involved in the protection against spontaneous and 5-fluorouracil chemotherapy-induced production of ROS in colorectal cancer cell lines. Analysis of a colorectal cancer patient cohort establishes that HNF4α is significantly upregulated compared with adjacent normal epithelial resections. Several genes involved in ROS neutralization are also induced in correlation with HNF4A expression. Altogether, the findings point to the nuclear receptor HNF4α as a potential therapeutic target to eradicate aberrant epithelial cell resistance to ROS production during intestinal tumorigenesis.
Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs
Authors: Christine Katlama, Steven G Deeks, Brigitte Autran, Javier Martinez-Picado, Jan van Lunzen, Christine Rouzioux, Michael Miller, Stefano Vella, Joern E Schmitz, Jeffrey Ahlers, Douglas D Richman, Rafick P Sekaly
Journal: The Lancet (2013)
Effect of chronic potassium loading on potassium secretion by the pars recta or descending limb of the juxtamedullary nephron in the rat.
Authors: C A Battilana, D C Dobyan, F B Lacy, J Bhattacharya, P A Johnston, R L Jamison
Journal: Journal of Clinical Investigation (1978)

Recently we demonstrated potassium secretion by the pars recta or by the descending limb of the juxtamedullary nephron. The purpose of this present investigation is to study the effect of a chronic high-potassium intake on this phenomenon. Fractional reabsorption of water and sodium by the juxtamedullary proximal nephron was decreased when compared to that in normal hydropenic rats. There was a striking increase in the fraction of filtered potassium at the end of the juxtamedullary descending limb from 94+/11% to 180+/18%, which was principally a result of enhanced potassium secretion. When the concentration of potassium in the collecting tubule fluid of potassium-loaded rats was reduced after the administration of amiloride, a sharp fall was observed in the amount of potassium which reached the end of the descending limb (64+/8%). A direct correlation was observed between the fraction of filtered potassium at the descending limb and the potassium concentration in the final urine (P less than 0.001). The findings suggest that potassium, like urea, normally undergoes medullary recycling, which is enhanced by chronic potassium loading.
Towards elimination of tuberculosis in a low income country: the experience of Cuba, 1962-97
Authors: A. Marrero
Journal: Thorax (2000)

This study describes the epidemiological trends of tuberculosis in Cuba and the performance of the tuberculosis control programme. The circumstances that caused an increase in the incidence of new cases of tuberculosis between 1991 and 1994 had been analysed and were corrected in 1995-7.A descriptive study of the incidence rates of new cases of tuberculosis notified from 1962 to 1997 was made, with special emphasis on the total change between 1965 and 1991 and the increase thereafter.The case notification rate of 14.7 per 100 000 in 1994 was almost three times the rate found in 1991 (4.8 per 100 000) and reversed the mean annual decrease of 5% observed since 1965. This increase was almost twofold in the rate of smear positive new cases (4.4 per 100 000 in 1991 and 8.3 in 1994). From 1971 onwards the programme had achieved a cure rate of 90% throughout the country with only 2% absconding by applying directly observed treatment. The main factors associated with the increasing trends were: (1) a probable underdetection of cases for the 1988-92 period that generated contagious sources in the community; (2) improved case finding from 1993 onwards and the introduction of an expanded case definition in 1994; (3) a considerable increase in the diagnostic delay from initial medical consultation to beginning of antituberculosis treatment (56.9 days in 1993); and (4) operational changes in the tuberculosis control programme due to the economic crisis in Cuba. In 1995, 1996 and 1997 it has been possible to reverse this trend, achieving rates of 14.1, 13.5, and 12.2 per 100 000, respectively (7. 6, 7.6, and 6.9 for smear positive cases) as a result of effective intervention correcting the problems identified. Reducing the diagnostic delay attributable to shortcomings in the health care system and the study of contacts were of particular importance for re-establishing the tuberculosis programme as a priority.Cuba represents a good example of how it is possible to fight against tuberculosis effectively, even in a low income country, by applying control strategies advocated by the World Health Organisation and the International Union Against Tuberculosis and Lung Disease and by giving adequate support to the programme through political commitment.
Hebbian and Homeostatic Plasticity Mechanisms in Regular Spiking and Intrinsic Bursting Cells of Cortical Layer 5
Authors: Stuart David Greenhill, Adam Ranson, Kevin Fox
Journal: Neuron (2015)

Layer 5 contains the major projection neurons of the neocortex and is composed of two major cell types: regular spiking (RS) cells, which have cortico-cortical projections, and intrinsic bursting cells (IB), which have subcortical projections. Little is known about the plasticity processes and specifically the molecular mechanisms by which these two cell classes develop and maintain their unique integrative properties. In this study, we find that RS and IB cells show fundementally different experience-dependent plasticity processes and integrate Hebbian and homeostatic components of plasticity differently. Both RS and IB cells showed TNFα-dependent homeostatic plasticity in response to sensory deprivation, but IB cells were capable of a much faster synaptic depression and homeostatic rebound than RS cells. Only IB cells showed input-specific potentiation that depended on CaMKII autophosphorylation. Our findings demonstrate that plasticity mechanisms are not uniform within the neocortex, even within a cortical layer, but are specialized within subcircuits.
Improved Tumor Targeting and Decreased Normal Tissue Accumulation through Extracorporeal Affinity Adsorption in a Two-Step Pretargeting Strategy
Authors: Linda Mårtensson, Rune Nilsson, Tomas Ohlsson, Hans-Olov Sjögren, Sven-Erik Strand, Jan Tennvall
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Evaluation of the possibilities of reducing the accumulation of radiolabeled streptavidin in radiosensitive organs by extracorporeal affinity adsorption (ECAT). Experimental Design: Rats were injected with biotinylated antibody and subjected to removal of the antibodies from the circulation by ECAT 24 h after injection (avidin column). Animals were then injected with 111In-1,4,7,10-tetra-azacylododecane N,N′,N″,N‴-tetraacetic acid (DOTA)-streptavidin. In a third step, animals were subjected to a second ECAT 8 h after injection to remove the DOTA-streptavidin from the circulation (biotin column). Biodistribution and tumor targeting of DOTA-streptavidin 24 h after injection was determined. Results: Elimination of biotinylated antibody by ECAT before injection of DOTA-streptavidin increased the tumor targeting by 50%. In addition, the levels of DOTA-streptavidin in liver and lymph nodes were reduced by 60%, which implied a 4.3- and 3.8-fold increase of tumor-to-liver and tumor-to-lymph node ratios, respectively. By doing a second ECAT to remove DOTA-streptavidin from the circulation, accumulation in normal tissues was reduced. However, this latter ECAT also reduced tumor accumulation by 25% (mostly corresponding to radioactivity in the circulation). Conclusions: ECAT was efficient as a means of removing biotinylated antibodies and would probably also be efficient for the clearance of streptavidin-conjugated antibodies. Conversely, the use of ECAT for removal of radiolabeled streptavidin seems not to offer any advantage.
Influence of Genes, Nevi, and Sun Sensitivity on Melanoma Risk in a Family Sample Unselected by Family History and in Melanoma-Prone Families
Authors: V. Chaudru, A. Chompret, B. Bressac-de Paillerets, A. Spatz, M.-F. Avril, F. Demenais
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: Few family studies have investigated the effects of genetic, environmental, and host factors on melanoma risk, and most have been restricted to high-risk families. We assessed the role of these factors on melanoma risk in two types of families: families ascertained through melanoma probands but unselected by family history and melanoma-prone families. Methods: Data on pigmentary traits, nevus phenotypes, exposure to sun, and reactions to sunlight were collected from 295 families unselected by family history and 53 melanoma-prone families. We modeled melanoma risk using a logistic regressive model incorporating the effect of a melanoma-predisposing gene, familial dependence, and potential risk factors (e.g., pigmentary traits, nevus phenotypes, history of sun exposure, skin reactions to sunlight). Maximum-likelihood estimates of the parameters of the regressive model were used to compute odds ratios associated with each risk factor and age-specific melanoma risk depending on the genotype at the melanoma-predisposing gene and the effects of risk factors. All statistical tests were two-sided. Results: In the families unselected by family history, there was statistically significant evidence (P<.001) for a dominant gene, with melanoma risk reaching 0.49 and 0.67 by age 80 years in male and female gene carriers, respectively. Melanoma risk was statistically significantly influenced by total nevi (odds ratio of hazard function [OR] = 5.81, 95% confidence interval [CI] = 3.47 to 8.99), sun exposure (OR = 5.37, 95% CI = 4.44 to 6.36), and sunburn interacting with the gene (OR = 26.31, 95% CI = 7.56 to 99.22 in gene carriers and OR = 1.67, 95% CI = 1.36 to 2.03 in noncarriers). Twenty of the 53 melanoma-prone families had cosegregating mutations in CDKN2A, a gene known to be associated with melanoma. In these 53 families, three risk factors in addition to CDKN2A mutations increased melanoma risk: dysplastic nevi (OR = 2.32, 95% CI = 2.08 to 2.58), total nevi (OR = 1.99, 95% CI = 1.61 to 2.20) and sunburn (OR = 5.16, 95% CI = 4.82 to 5.52). Conclusions: Together, a melanoma-predisposing gene (identified as being CDKN2A in melanoma-prone families), number of nevi and/or dysplastic nevi, and sun-related covariates influence melanoma risk in both families unselected by family history and melanoma-prone families.
Antibodies to type II and XI collagens: evidence for the formation of antigen specific as well as cross reacting antibodies in patients with rheumatoid arthritis.
Authors: K Morgan, C Buckee, I Collins, S Ayad, R B Clague, P J Holt
Journal: Annals of the Rheumatic Diseases (1988)

Antigen specific and cross reacting antibodies to native and denatured types II and XI collagen were detected in the sera of rats immunised with either of these antigens. The antibodies from rats immunised with type XI collagen initially showed the strongest binding to the alpha 2(XI) chain of type XI collagen but later binding to the alpha 3(XI) chain was seen. Sera from patients with rheumatoid arthritis had antibodies that bound to both type II and XI collagens. Immunoblotting studies showed that most patients had antibodies which bound to the alpha 1(II) chain of type II collagen and to the alpha 3(XI) chain of type XI collagen. Some patients also had antibodies which bound to the alpha 1(XI) and to the alpha 2(XI) chains of type XI collagen. Thus antibodies to unique as well as to common epitopes on each of the two types of collagen molecule occur in some patients with rheumatoid arthritis.
A novel vascular pattern promotes metastasis of hepatocellular carcinoma in an epithelial–mesenchymal transition–independent manner
Authors: Jian‐Hong Fang, Hui‐Chao Zhou, Chong Zhang, Li‐Ru Shang, Lei Zhang, Jing Xu, Limin Zheng, Yunfei Yuan, Rong‐Ping Guo, Wei‐Hua Jia, Jing‐Ping Yun, Min‐Shan Chen, Yaojun Zhang, Shi‐Mei Zhuang
Journal: Hepatology (2015)

Early metastasis is responsible for frequent relapse and high mortality of hepatocellular carcinoma (HCC), but its underlying mechanisms remain unclear. Epithelial-mesenchymal transition (EMT) has been considered a key event in metastasis. Based on histological examination of serial HCC sections and three-dimensional reconstruction, we found a novel and prevalent vascular pattern, vessels that encapsulated tumor clusters (VETC) and formed cobweb-like networks. The presence of VETC (VETC(+) ) predicted higher metastasis and recurrence rates of HCC. Using clinical samples and mouse xenograft models, we further showed that VETC was composed of functional vessels with blood perfusion and induced by tumor cells at the early stage of HCC. Subsequent investigations revealed that HCC cell-derived angiopoietin-2 was a prerequisite for VETC formation and that the VETC pattern was a critical factor promoting HCC metastasis as knockdown of angiopoietin-2 abolished this vascular pattern and consequently attenuated in vivo tumor metastasis. Interestingly, abrogation of EMT by knockdown of Snail or Slug significantly diminished in vivo metastasis of VETC(-) xenografts but did not affect that of VETC(+) ones, although silencing of Snail or Slug substantially reduced the in vitro migration of both VETC(+) and VETC(-) HCC cells. In contrast to human VETC(-) cases, EMT signatures were rarely observed in VETC(+) cases with metastatic potential. Further analysis revealed that VETC provided an efficient metastasis mode by facilitating the release of whole tumor clusters into the bloodstream.Our findings identify a novel metastasis mechanism that relies on vascular pattern but is independent of EMT, which may provide new targets for antimetastasis therapy and offer a basis for selecting patients who may benefit from certain molecularly targeted drugs.
Human immunodeficiency virus and liver disease forum 2012
Authors: Kenneth E. Sherman, David Thomas, Raymond T. Chung
Journal: Hepatology (2013)

In the United States, more than 1.1 million individuals are infected with the human immunodeficiency virus (HIV). These patients exhibit a high frequency of coinfections with other hepatotropic viruses and ongoing fibrosis, leading to cirrhosis and liver-related mortality. Etiologies of liver disease include viral hepatitis coinfections, drug-related hepatotoxicity, fatty liver disease, and direct and indirect effects from HIV infection, including increased bacterial translocation, immune activation, and presence of soluble proteins, that modulate the hepatic cytokine environment. New treatments for hepatitis C virus (HCV) using direct-acting agents appear viable, though issues related to intrinsic toxicities and drug-drug interactions remain. Recent research suggests that acute HCV infection, unrecognized hepatitis D infection, and hepatitis E may all represent emergent areas of concern. Antiretroviral agents, including those used in recent years, may represent risk factors for hepatic injury and portal hypertension. Key issues in the future include systematic implementation of liver disease management and new treatment in HIV-infected populations with concomitant injection drug use, alcohol use, and low socioeconomic status.