tbuckley/cabot-search huggingface dataset:
The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer
Authors: Danuta S. Kalinowski, Des R. Richardson
Journal: Pharmacological Reviews (2005)

The evolution of iron chelators from a range of primordial siderophores and aromatic heterocyclic ligands has lead to the formation of a new generation of potent and efficient iron chelators. For example, various siderophore analogs and synthetic ligands, including ICL670A [4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid], 4′-hydroxydesazadesferrithiocin, and Triapine, have been developed from predecessors and illustrate potent iron-mobilizing or antineoplastic activities. This review focuses on the evolution of iron chelators from initial lead compounds through to the development of novel chelating agents, many of which show great potential to be clinically applied in the treatment of iron overload disease and cancer.
eNOS allelic variants at the same locus associate with HAPE and adaptation
Authors: A Ahsan
Journal: Thorax (2004)

High altitude pulmonary oedema (HAPE) is a severe form of altitude illness that may develop in individuals on rapid ascent to altitudes above 2500 m.1 The disease is characterised by hypoxia induced pulmonary vasoconstriction caused by endothelial dysfunction and intravascular fluid retention.2,3 While some families and individuals are at risk, those with a long ancestry at high altitude have a lower risk. Moreover, individuals who have had HAPE are at a greater risk of repeat events. Such data support a strong genetic component to HAPE susceptibility, perhaps associated with a founder effect. It is likely that long term exposure to high altitude provides a natural positive adaptive pressure to alleles that prevent the illness. We hypothesise that allelic variants at the same locus in a gene are involved in adaptation and HAPE.

We therefore investigated the Glu298Asp and 4b/4a polymorphisms of the endothelial nitric oxide synthase gene ( eNOS ) and −344T/C, intron-2 conversion and Lys173Arg polymorphisms of the aldosterone synthase gene ( CYP11B2 ) in 59 patients with HAPE who developed the disease at 3400 m, …
Hormone Replacement Therapy and Its Relationship to Lipid and Glucose Metabolism in Diabetic and Nondiabetic Postmenopausal Women
Authors: Carlos J. Crespo, Ellen Smit, Anastacia Snelling, Christopher T. Sempos, Ross E. Andersen
Journal: Diabetes Care (2002)

Among postmenopausal women, those with diabetes experience more cardiovascular diseases than those without diabetes. We examine the relationship of hormone replacement therapy (HRT) with indicators of lipid and glucose metabolism using a national sample of diabetic and nondiabetic postmenopausal women.We used data from the Third National Health and Nutrition Examination Survey, conducted from 1988 to 1994. A total of 2,786 postmenopausal women aged 40-74 years participated in an oral glucose tolerance test, had blood drawn for lipid assessment, and responded to HRT questions.Our results show that postmenopausal women with diabetes had increased dyslipidemia compared with nondiabetic women. Among diabetic women, current users of HRT had significant different lipid and glucose control levels than never users of HRT for the following variables: total cholesterol (225 vs. 241 mg/dl), non-HDL (169 vs. 188 mg/dl), apoA (171 vs. 147 mg/dl), fibrinogen (306 vs. 342 mg/dl), glucose (112 vs. 154 mg/dl), insulin (16.81 vs. 22.6 uU/ml), and GHb (6.03 vs. 7.13 mg/dl).Diabetic and nondiabetic postmenopausal women currently taking HRT had better lipoprotein profile than never or previous users of HRT. Diabetic women currently taking HRT had better glycemic control than never or previous users of HRT.
Genome Scans for Detecting Footprints of Local Adaptation Using a Bayesian Factor Model
Authors: Nicolas Duforet-Frebourg, Eric Bazin, Michael G.B. Blum
Journal: Molecular Biology and Evolution (2014)

A central part of population genomics consists of finding genomic regions implicated in local adaptation. Population genomic analyses are based on genotyping numerous molecular markers and looking for outlier loci in terms of patterns of genetic differentiation. One of the most common approach for selection scan is based on statistics that measure population differentiation such as $F_{ST}$. However they are important caveats with approaches related to $F_{ST}$ because they require grouping individuals into populations and they additionally assume a particular model of population structure. Here we implement a more flexible individual-based approach based on Bayesian factor models. Factor models capture population structure with latent variables called factors, which can describe clustering of individuals into populations or isolation-by-distance patterns. Using hierarchical Bayesian modeling, we both infer population structure and identify outlier loci that are candidates for local adaptation. As outlier loci, the hierarchical factor model searches for loci that are atypically related to population structure as measured by the latent factors. In a model of population divergence, we show that the factor model can achieve a 2-fold or more reduction of false discovery rate compared to the software BayeScan or compared to a $F_{ST}$ approach. We analyze the data of the Human Genome Diversity Panel to provide an example of how factor models can be used to detect local adaptation with a large number of SNPs. The Bayesian factor model is implemented in the open-source PCAdapt software.
Metabolic fate of L-arginine in relation to microbiostatic capability of murine macrophages.
Authors: D L Granger, J B Hibbs, J R Perfect, D T Durack
Journal: Journal of Clinical Investigation (1990)

L-arginine is required for the fungistatic action of murine macrophages in vitro. To further investigate this requirement, L-arginine metabolism by macrophages was measured under conditions where fungistasis either succeeded or failed. Macrophage fungistasis correlated with metabolism of L-arginine to citrulline, nitrite, and nitrate. The metabolic rate was dependent on extracellular L-arginine concentration, reaching a maximum of 67 nmol nitrite/h per mg protein. It accounted for one-third of arginine consumed by fungistatic macrophages. Equimolar amounts of citrulline and total nitrite plus nitrate accumulated in medium. This was consistent with the hypothesis that one of the equivalent guanidino nitrogens of L-arginine was oxidized to both nitrite and nitrate leaving L-citrulline as the amino acid reaction product. The analogue, NG-mono-methyl-L-arginine, selectively inhibited nitrogen oxidation and it was shown previously that it inhibited fungistatic capability. Resident macrophages were not fungistatic and their nitrogen oxidation was low. Once macrophages began producing nitrite/nitrate, protein synthesis was not required during the next 8 h for either fungistasis or nitrogen oxidation. Two-thirds of L-arginine consumption was due to macrophage arginase yielding L-ornithine and urea, which accumulated in medium. This activity was dissociated from macrophage fungistasis. Nitrogen oxidation metabolism by macrophages is linked to a mechanism that inhibits proliferation of fungi. This may involve synthesis of an intermediate compound(s) that has antimicrobial properties.
On the Final Result of a Case in which the Shoulder and Elbow-Joints of the Right Arm were Excised for Gunshot Injury
Authors: W. Mac Cormac
Journal: BMJ (1880)

MEDICAL 7OVURNAL. '763 performed excision.This was soon followed by relief from suffering, restoration to a very great degree of the functions of the hand, improved health, and a capability of enjoying life.The successful result that I am able to record to-day, three years after the operation, is, I believe, ample justification for any little risk in- curred in its performance.
A disposable one-piece left ventriculo-aortic bypass cannula.
Authors: A J Gunning
Journal: Thorax (1972)

The orbitofrontal cortex (OFC) and amygdala are both necessary for decisions based on expected outcomes. Although behavioral and imaging data suggest that these brain regions are affected by advanced age, the extent to which aging alters appetitive processes coordinated by the OFC and the amygdala is unknown. In the current experiment, young and aged bonnet macaques were trained on OFC- and amygdala-dependent tasks that test the degree to which response selection is guided by reward value and can be adapted when expected outcomes change. To assess whether the structural integrity of these regions varies with levels of performance on reward devaluation and object reversal tasks, volumes of areas 11/13 and 14 of the OFC, central/medial (CM), and basolateral (BL) nuclei of the amygdala were determined from high-resolution anatomical MRIs. With age, there were significant reductions in OFC, but not CM and BL, volume. Moreover, the aged monkeys showed impairments in the ability to associate an object with a higher value reward, and to reverse a previously learned association. Interestingly, greater OFC volume of area 11/13, but not 14, was significantly correlated with an animal9s ability to anticipate the reward outcome associated with an object, and smaller BL volume was predictive of an animal9s tendency to choose a higher value reward, but volume of neither region correlated with reversal learning. Together, these data indicate that OFC volume has an impact on monkeys9 ability to guide choice behavior based on reward value but does not impact ability to reverse a previously learned association.
Tumor Necrosis Factor–Mediated E2F1 Suppression in Endothelial Cells
Authors: Raj Kishore, Corinne Luedemann, Evelyn Bord, David Goukassian, Douglas W. Losordo
Journal: Circulation Research (2003)

After balloon angioplasty, locally expressed tumor necrosis factor (TNF)-α disrupts endothelial cell (EC) proliferation and reendothelialization of the injured vessel. We have previously reported that TNF inhibits the EC cycle and downregulates the transcription factor E2F1. Ectopic expression of E2F1 at the site of injury improves reendothelialization of the injured vessel. In this study, we report that c-Jun N-terminal kinase (JNK) 1 and p38 mitogen-activated protein kinases (MAPKs) are differentially required for E2F1 expression and activity in ECs. Overexpression of constitutively active JNK1 mimicked TNF-mediated inhibitory events, whereas dominant-negative JNK1 prevented these effects. E2F cis elements in the promoter of E2F1 gene mediate suppressive actions of TNF, because removal of these sites rendered E2F1 promoter activity insensitive to TNF. JNK1 physically interacted with E2F1 and inactivated it via direct phosphorylation. Additionally, TNF inhibited Rb phosphorylation and dissociation from E2F1. Overexpression of constitutively active p38 MAPK facilitated Rb-E2F1 dissociation, whereas that of dominant-negative p38 MAPK did not. Taken together, these data suggest a differential requirement of JNK1 and p38 MAPK in TNF regulation of E2F1. Targeted inactivation of JNK1 at arterial injury sites may represent a potential therapeutic intervention for ameliorating TNF-mediated EC dysfunction.
A Galactolipid Possesses Novel Cancer Chemopreventive Effects by Suppressing Inflammatory Mediators and Mouse B16 Melanoma
Authors: Chia-Chung Hou, Yi-Ping Chen, Jyh-Horng Wu, Chi-Chang Huang, Sheng-Yang Wang, Ning-Sun Yang, Lie-Fen Shyur
Journal: Cancer Research (2007)

Crassocephalum rabens (Asteraceae) is a popular anti-inflammatory folk medicine and food supplement. We investigated the cancer chemopreventive bioactivity of C. rabens phytocompounds in vitro and in vivo using cell- and gene-based bioassays and a mouse B16 melanoma model. The bioactive glyceroglycolipid 1,2-di-O-alpha-linolenoyl-3-O-beta-galactopyranosyl-sn-glycerol (dLGG) that was identified from C. rabens was found in vitro and in vivo to be a potent nitric oxide (NO) scavenger. dLGG treatment inhibited both mRNA and protein expression of inducible NO synthase and cyclooxygenase-2 (COX-2) in murine macrophages and inhibited COX-2 gene transcription in 12-O-tetradecanoylphorbol-13-acetate (TPA)-treated B16 cells. In immunohistochemical studies, dLGG inhibited TPA-induced expression of COX-2 and nitration of proteins in mouse skin. dLGG could also significantly inhibit lipopolysaccharide-induced prostaglandin E(2) production in murine macrophages. Furthermore, dLGG prevented nuclear translocation of cytoplasmic nuclear factor-kappaB (NF-kappaB) by suppressing IkappaBalpha phosphorylation and degradation. Structure-activity relationship study by electrophoretic mobility shift assay indicated that the dilinolenoylglycerol moiety in dLGG is the essential structural feature preventing NF-kappaB.DNA complex formation. A dLGG-enriched extract from C. rabens (10 mg/kg) markedly suppressed B16 melanoma growth in C57BL/6J mice following i.p. administration, an effect comparable with that of cisplatin, a cancer chemotherapeutic drug. This study shows the detailed molecular mechanism(s) underlying the anti-inflammatory and tumor-suppressive effects of a natural galactolipid.
Descending Control of Itch Transmission by the Serotonergic System via 5-HT1A-Facilitated GRP-GRPR Signaling
Authors: Zhong-Qiu Zhao, Xian-Yu Liu, Joseph Jeffry, W.K. Ajith Karunarathne, Jin-Lian Li, Admire Munanairi, Xuan-Yi Zhou, Hui Li, Yan-Gang Sun, Li Wan, Zhen-Yu Wu, Seungil Kim, Fu-Quan Huo, Ping Mo, Devin M. Barry, Chun-Kui Zhang, Ji-Young Kim, N. Gautam, Kenneth J. Renner, Yun-Qing Li, Zhou-Feng Chen
Journal: Neuron (2014)
Diagnostic problems and hypothermia.
Authors: E L Lloyd
Journal: BMJ (1972)

the red end of the spectrum at 655 my, the part in which differences due to varying melanin content are not obscured by varia- tions in the other components of skin pig- mentation, and it is well established that upon the amount of melanin present in the skin depends the penetration of ultraviolet radiation through it.It would be worth examining the skin colour of the subjects on whom Dr. Ford and his colleagues report and, indeed extending their study to other more deeply pigmented groups in Britain such as immigrants from the West Indies and Africa.Apart from the public health interest here it might prove possible to quantify the evolutionary sig- nificance of skin colour differences.
Response to steroids in<i>de novo</i>autoimmune hepatitis after liver transplantation
Authors: Magdalena Salcedo, Javier Vaquero, Rafael Bañares, Margarita Rodríguez-Mahou, Emilio Alvarez, Jose Luis Vicario, Alicia Hernández-Albújar, José Luis R. Tíscar, Diego Rincón, Sonia Alonso, Alejandro De Diego, Gerardo Clemente
Journal: Hepatology (2002)

Graft dysfunction associated with autoimmune phenomena has been recently described in liver transplant recipients without previous autoimmune disease. However, the natural history, diagnostic criteria, and definitive therapeutic approach of de novo autoimmune hepatitis ( de novo AIH) are poorly understood. We report 12 cases of de novo AIH 27.9 ± 24.5 months after liver transplantation: the outcome of 7 patients treated with steroids is compared with a group of 5 nontreated patients. Nontreated patients lost the graft after 5.8 ± 2.6 months from de novo AIH onset. All treated patients were alive after 48.4 ± 14 (29-65) months from de novo AIH onset, and none of them lost the graft. However, 5 patients relapsed in relation to steroid tapering. All patients presented an atypical antiliver/kidney cytosolic autoantibody, associated to classical autoantibodies in 10 cases. Histological study showed several degrees of lobular necrosis and inflammatory infiltrate. HLA antigen frequencies and matching were compared with 2 control groups (16 orthotopic liver transplantation [LTX] patients without de novo AIH and 929 healthy blood donors); de novo AIH patients showed a higher prevalence of HLA-DR3 (54.5% vs. 25.9%, P = .04) than healthy controls, which was not observed in LTX patients without de novo AIH. In conclusion, this new disease should be included in the differential diagnosis of unexplained graft dysfunction. In addition, treatment with steroids results in a dramatically improved outcome. However, maintenance therapy is usually required.
Symptomatic Effects of Exposure to Diluted Air Sampled from a Swine Confinement Atmosphere on Healthy Human Subjects
Authors: Susan S. Schiffman, Clare E. Studwell, Lawrence R. Landerman, Katherine Berman, John S. Sundy
Journal: Environmental Health Perspectives (2005)

Aerial emissions from a swine house at North Carolina State University's field laboratory were diluted to a level that could occur at varying distances downwind from a confined animal feeding operation (CAFO) both within and beyond the property line, and these emissions were delivered to an environmental exposure chamber. The study design consisted of two 1-hr sessions, one in which 48 healthy human adult volunteers were exposed to diluted swine air and another in which they were exposed to clean air (control). Objective measures of blood pressure, temperature, heart rate, respiratory rate, lung function, nasal inflammation, secretory immunity, mood, attention, and memory were correlated with objective measures of air quality. Ratings of perceived (self-reported) health symptoms were also obtained. The mean levels of airborne constituents in the swine air condition were hydrogen sulfide (24 ppb), ammonia (817 ppb), total suspended particulates (0.0241 mg/m3), endotoxin (7.40 endotoxin units/m3), and odor (57 times above odor threshold). No statistical differences on objective measures of physical symptoms, mood, or attention resulted from the 1-hr exposure to swine emissions in the environmental chamber when compared with clean air for healthy human volunteers. However, subjects were 4.1 (p = 0.001) times more likely to report headaches, 6.1 (p = 0.004) times more likely to report eye irritation, and 7.8 (p = 0.014) times more likely to report nausea in the swine air (experimental) condition than in the control condition. These results indicate that short-term exposure in an environmental chamber to malodorous emissions from a swine house at levels expected downwind can induce clinically important symptoms in healthy human volunteers.
Detrimental effects of adenosine signaling in sickle cell disease
Authors: Yujin Zhang, Yingbo Dai, Jiaming Wen, Weiru Zhang, Almut Grenz, Hong Sun, Lijian Tao, Guangxiu Lu, Danny C Alexander, Michael V Milburn, Louvenia Carter-Dawson, Dorothy E Lewis, Wenzheng Zhang, Holger K Eltzschig, Rodney E Kellems, Michael R Blackburn, Harinder S Juneja, Yang Xia
Journal: Nature Medicine (2010)
Relationship of Cellular Transmigration and Airway Response after Allergen Challenge
Authors: IKEADI MAURICE NDUKWU, EDWARD T. NAURECKAS, CHRISTOPHER MAXWELL, MICHAEL WALDMAN, ALAN R. LEFF
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We examined the relationship between eosinophil migration into the bronchoalveolar space and change in FEV(1) after endobronchial allergen challenge (EBAC) in atopic asthmatic (AA) and atopic nonasthmatic (ANA) subjects. The purpose of this study was to obtain continuous, intrasubject controlled assessment of the relationship between cell migration in control and allergen-challenged segments in the same individuals over 96 h. In AA subjects, the eosinophil (Eos) count in the bronchoalveolar lavage fluid (BALF) increased from a baseline of 7,896 +/- 3,865 to 416,476 +/- 231,012 Eos/ml by 72 h (p = 0.001) in the challenged segment post-EBAC. For ANA subjects, the postsegmental challenge count was 29,874 +/- 474 Eos/ml (p = 0.03 versus baseline and p < 0.05 AA peak versus ANA peak). In both groups, there was a comparable decrease in peripheral blood eosinophil count beginning 5 h after challenge, which resolved at 24 h. In AA subjects, 416,476 +/- 231,012 Eos/ml was obtained from the allergen-challenged segment and 23,522 +/- 8,298 Eos/ml was obtained from the sham-challenged segment (p < 0.001) at 72 h. In contrast, there was no difference in the Eos count obtained from the BALF between the antigen- and sham-challenged segments of ANA subjects. We also found that increased airway neutrophils were present in equal numbers in allergen-challenged and sham-challenged segments in both AA and ANA subjects. We conclude that augmented eosinophil migration after EBAC is a characteristic of atopic asthma and is not present in atopic subjects who do not have asthma. We find that BAL eosinophilia in ANA patients as well as neutrophilia in both ANA and AA subjects are nonspecific consequences of bronchoscopy. Finally, we find no relationship between specific airway eosinophil migration into the BALF and FEV(1) < 72 h after challenge; however, at 96 h, there is a substantial decrease in FEV(1) that accompanies BALF eosinophilia.
Genetic factors predicting response to interferon treatment for viral hepatitis C
Authors: P. Starkel
Journal: Gut (2007)

Since completion of the human genome and HapMap projects it is likely that an increasing number of studies dealing with genetic associations in specific diseases will be published in medical journals. Hepatitis C and especially its response to antiviral treatment does not constitute an exception to this rule. It has been known for quite a long time that viral factors such as genotype and viral load have a major influence on the outcome of antiviral treatment.1 Nevertheless, researchers have become increasingly aware that host genetic factors including ethnicity, human leucocyte antigens, cytokine production and differences in T cell immune responses can modulate the response to antiviral treatment and viral clearance.2 3 In this issue of Gut ( see page 10.1136/gut.2007.129478 ), Persico et al report on single nucleotide polymorphisms (SNPs) of suppressor of cytokine signalling 3 (SOCS3) being positively and negatively associated with response to antiviral therapy in hepatitis C virus (HCV) genotype-1-infected patients.4 Interestingly, these data were generated from peripheral mononuclear blood cells (PMBCs), a material that would be easily available for large-scale studies in the future. The concept of SOCS3 being involved in modulating antiviral response mechanisms is appealing to the scientific community. SOCS3 acts as a negative regulator of the cytokine-induced JAK–STAT (Janus kinase–signal transducer and activator of transcription) pathway. As a consequence of a classical negative feedback circuit, SOCS3 inhibits the cytokine receptor-associated JAK tyrosine kinase through either direct interaction with JAKs or indirect inhibition by binding to specific sites on the receptor.5 6 Inhibition of JAKs leads in turn to deficient STAT phosphorylation and dimerisation required for nuclear translocation of STATs and ultimately to blockage of transcriptional activity of STAT-responsive genes involved in regulation of immune responses and maintaining immunological homeostasis.6 Interferons (IFNs) are naturally occurring proteins that induce an antiviral state …