tbuckley/cabot-search huggingface dataset:
Amiodarone and its desethyl metabolite: tissue distribution and morphologic changes during long-term therapy.
Authors: P C Adams, D W Holt, G C Storey, A R Morley, J Callaghan, R W Campbell
Journal: Circulation (1985)

The pharmacokinetic characteristics of amiodarone suggest extensive tissue deposition. We confirmed this by measuring tissue concentrations of the drug and of its major metabolite, desethylamiodarone, in human tissues. These were obtained at autopsy (n = 9), surgery (n = 7), or biopsy (n = 2) from 18 patients who had been treated with amiodarone for varying periods of time. High concentrations of amiodarone were found in fat (316 mg/kg wet weight in autopsy specimens, 344 mg/kg wet weight in biopsy specimens). Amiodarone and desethylamiodarone concentrations (mg/kg wet weight, autopsy samples) were also high in liver (391 and 2354), lung (198 and 952), adrenal gland (137 and 437), testis (89 and 470), and lymph node (83 and 316). We also found high concentrations of amiodarone (306 mg/kg wet weight) and desethylamiodarone (943 mg/kg wet weight) in abnormally pigmented ("blue") skin from patients with amiodarone-induced skin pigmentation. These values were 10-fold higher than those in unpigmented skin from the same patients. These high concentrations were associated with lysosomal inclusion bodies in dermal macrophages in the pigmented skin. The inclusion bodies were intrinsically electron dense and were shown to contain iodine by energy dispersive x-ray microanalysis. Lysosomal inclusion bodies shown by electron microscopy to be multilamellar were seen in other tissues. These tissues included terminal nerve fibers in pigmented skin, pulmonary macrophages, blood neutrophils, and hepatocytes and Kupffer cells. These characteristic ultrastructural findings occur in both genetic lipidoses and lipidoses induced by other drugs, e.g., perhexiline. We conclude that during therapy with amiodarone, widespread deposition of amiodarone and desethylamiodarone occurs. This leads to ultrastructural changes typical of a lipidosis. These changes are seen clearly in tissues associated with the unwanted effects of amiodarone, e.g., skin, liver and lung.
S60 Risk factors associated with mycobacterium tuberculosis (MTB) infection and progression to active TB disease in child contacts
Authors: N Karnani, S Sridhar, D Connell, A Lalvani
Journal: Thorax (2013)

<h3>Background</h3> Mathematical modelling has shown the most effective strategy to eliminate tuberculosis (TB) worldwide is to address the large burden of latent TB infection (LTBI). Identification of the risk factors which predispose individuals to acquire Mtb infection and those determining risk of progressing from infection to active disease will enable risk stratification for targeted TB interventions. <h3>Objective</h3> To identify host, socioeconomic and environmental risk factors for acquiring Mtb infection following exposure to TB and risk factors for progression from infection to active TB disease. <h3>Methods</h3> Risk factors associated with infection and progression were investigated in a primary analysis of a well-defined cohort of 965 Turkish household child contacts exposed to smear positive pulmonary TB patients. Risk factors for infection were assessed in study subjects with and without Mtb infection. Mtb infection was defined by interferon gamma-release assay (IGRA) results at two time points–baseline and 6 months–thus creating robust criteria to avoid misclassification of IGRA converters and IGRA reverters. Adjusted odd ratios were estimated using stepwise logistic regression including variables with p &lt; 0.2 on univariate regression. <h3>Results</h3> In the child cohort passive smoking was found to be an independent risk factor for Mtb infection (OR: 1.52, 95% CI: 1.09 –2.12). Higher household monthly income was an independent protective factor against Mtb infection (OR: 0.55, 95% CI: 0.38 –0.79). Increasing age was associated with a decreased risk of progressing from infection to disease (OR: 0.67, 95% CI: 0.51–0.87). Children exposed to more than 1 TB patient were 8 times more likely to progress to disease (OR: 8.66, 95% CI: 1.54–48.55). <h3>Conclusion</h3> Identification of an association between passive exposure to cigarette smoke and acquisition of Mtb infection in children adds new evidence for smoking cessation strategies to be incorporated into TB prevention programmes. To aid TB elimination we therefore advocate an enforcement of stricter tobacco control policies, particularly in regions with a high burden of TB.
Oral tolerance to food-induced systemic anaphylaxis mediated by the C-type lectin SIGNR1
Authors: Yufeng Zhou, Hirokazu Kawasaki, Shih Chang Hsu, Reiko T. Lee, Xu Yao, Beverly Plunkett, Jinrong Fu, Kuender Yang, Yuan C. Lee, Shau Ku Huang
Journal: Nature Medicine (2010)
Vascular endothelial growth factor production in peritoneal macrophages of cirrhotic patients: Regulation by cytokines and bacterial lipopolysaccharide
Authors: Manuel Pérez-Ruiz, Josefa Ros, Manuel Morales-Ruiz, Miguel Navasa, Jordi Colmenero, Luis Ruiz-del-Arbol, Pilar Cejudo, Joan Clària, Francisca Rivera, Vicente Arroyo, Juan Rodés, Wladimiro Jiménez
Journal: Hepatology (1999)

Vascular endothelial growth factor (VEGF) is an angiogenic peptide with vascular permeability and relaxing properties. This study assessed whether peritoneal macrophages of cirrhotic patients can be up–regulated to produce VEGF under proper stimulatory conditions. Macrophages were isolated from ascites. VEGF protein secretion and mRNA expression were measured in basal conditions and after stimulation with lipopolysaccharide (LPS), tumor necrosis factor α (TNF–α), and interleukin–1 (IL–1). These substances induced a time– and dose–dependent increase in both VEGF production and transcript expression. Assays with actinomycin D showed that VEGF mRNA induction is secondary to both higher VEGF gene transcription and mRNA stability. Ascites and plasma concentration of VEGF was also measured in cirrhotic patients with (n = 15) and without (n = 10) spontaneous bacterial peritonitis (SBP). Plasma values did not differ between both groups of patients. However, ascites VEGF levels were higher in SBP patients than in noninfected cirrhotic patients (710 ± 183 vs. 94 ± 15 pg/mL; P &lt; .025). These results indicate that cytokines and LPS markedly increase VEGF protein secretion and mRNA expression in macrophages of cirrhotic patients, and suggest that this substance could be an important mediator of the pronounced arterial vasodilation frequently occurring in SBP patients
Diagnosis of lung cancer: FOB before CT or CT before FOB?
Authors: M F MUERS
Journal: Thorax (2000)

Thirty years ago Staphylococcus aureus and not Pseudomonas aeruginosa was considered to be the most important lung pathogen in cystic fibrosis. 1 Those who believed that P aeruginosa was a pathogen in cystic fibrosis thought that various virulence factors such as exotoxin A, exoenzyme S, elastase, alkaline protease, phospholipase C, lipopolysaccharide and phenazine pigments were responsible for the lung tissue damage by drawing parallels with acute P aeruginosa infections in patients with burns or leukaemia. 2Only acute exacerbations, frequently caused by a virus, 3 were therefore treated with antibiotics, although invasive disseminating P aeruginosa infection on July 16, 2023 by guest.
Distinct Costimulatory Molecules Are Required for the Induction of Effector and Memory Cytotoxic T Lymphocytes
Authors: Yang Liu, Roland H. Wenger, Min Zhao, Peter J. Nielsen
Journal: The Journal of Experimental Medicine (1997)

A successful T cell immune response has two major products: effector T cells which directly or indirectly remove the antigens, and memory T cells, which allow a faster and more efficient recall response when challenged by related antigens. An important issue is whether costimulatory molecules on the antigen-presenting cells are involved in determining whether T cells will differentiate into effector or memory cells after antigenic stimulation. To address this issue, we have produced mice with targeted mutations of either the heat-stable antigen (HSA), or both HSA and CD28. We show that CD28/B7 and HSA provide two alternative costimulatory pathways for induction of immunological memory to influenza virus. Furthermore, our results revealed that B7 is essential for the generation of effector T cells from either naive or memory T cells, while HSA is not necessary for the generation of effector T cells. Our results demonstrate that the induction of memory T cells and effector T cells can utilize distinct costimulatory molecules. These results have important implications on lineage relationship between effector and memory T cells.
Loss of Rab25 promotes the development of intestinal neoplasia in mice and is associated with human colorectal adenocarcinomas
Authors: Ki Taek Nam, Hyuk-Joon Lee, J. Joshua Smith, Lynne A. Lapierre, Vidya P. Kamath, Xi Chen, Bruce J. Aronow, Timothy J. Yeatman, Sheela G. Bhartur, Benjamin C. Calhoun, Brian Condie, Nancy R. Manley, R. Daniel Beauchamp, Robert J. Coffey, James R. Goldenring
Journal: Journal of Clinical Investigation (2010)

Transformation of epithelial cells is associated with loss of cell polarity, which includes alterations in cell morphology as well as changes in the complement of plasma membrane proteins. Rab proteins regulate polarized trafficking to the cell membrane and therefore represent potential regulators of this neoplastic transition. Here we have demonstrated a tumor suppressor function for Rab25 in intestinal neoplasia in both mice and humans. Human colorectal adenocarcinomas exhibited reductions in Rab25 expression independent of stage, with lower Rab25 expression levels correlating with substantially shorter patient survival. In wild-type mice, Rab25 was strongly expressed in cells luminal to the proliferating cells of intestinal crypts. While Rab25-deficient mice did not exhibit gross pathology, ApcMin/+ mice crossed onto a Rab25-deficient background showed a 4-fold increase in intestinal polyps and a 2-fold increase in colonic tumors compared with parental ApcMin/+ mice. Rab25-deficient mice had decreased β1 integrin staining in the lateral membranes of villus cells, and this pattern was accentuated in Rab25-deficient mice crossed onto the ApcMin/+ background. Additionally, Smad3+/– mice crossed onto a Rab25-deficient background demonstrated a marked increase in colonic tumor formation. Taken together, these results suggest that Rab25 may function as a tumor suppressor in intestinal epithelial cells through regulation of protein trafficking to the cell surface.
Differential Effects of Angiotensin II Versus Endothelin-1 Inhibitions in Hypertrophic Left Ventricular Myocardium During Transition to Heart Failure
Authors: Yoshitaka Iwanaga, Yasuki Kihara, Koichi Inagaki, Yoko Onozawa, Takeshi Yoneda, Kazuaki Kataoka, Shigetake Sasayama
Journal: Circulation (2001)

Background In view of their mutual crosstalk, the roles of angiotensin II (Ang II) and endothelin-1 (ET-1) in the myocardium are assumed to be synergistic and supplemental. Methods and Results In the phase of compensated left ventricular (LV) hypertrophy of Dahl salt-sensitive rats, Ang II peptide and the ACE mRNA in the LV were increased by 1.6- and 3.8-fold, respectively. In contrast, ET-1 peptide and the preproET-1 mRNA remained unchanged. In subsequent congestive heart failure (CHF), Ang II and ACE mRNA did not show further increases. But ET-1 and the mRNA were increased de novo by 5.3- and 4.1-fold, respectively. In ascending aorta-banded rats, the local activations of Ang II and ET-1 also showed a differential time course between LV hypertrophy and CHF. Long-term treatments of Dahl salt-sensitive rats with temocapril (an ACE inhibitor) and with bosentan (a mixed ET receptor blocker) equally improved long-term survival. Temocapril reduced the LV/body weight ratio and ameliorated LV fractional shortening. Conversely, although bosentan equally improved fractional shortening, it did not reduce the increase in LV mass. Combined treatment with these 2 drugs further ameliorated the animal’s survival without additional decreases in systolic pressure. Conclusions The pathophysiological roles in the myocardium during the transition to CHF differ qualitatively between Ang II and ET-1. Thus, long-term therapy with a combination of ACE inhibition and ET antagonism may provide a new approach for heart failure in humans.
Clinical and pathological spectrum of coeliac disease.
Authors: M N Marsh
Journal: Gut (1993)

The authors examined a cognitive function mediated by the cerebellum, classical eyeblink conditioning, and its relationship to cerebellar volume in healthy controls (n = 59) and temporal lobe epilepsy subjects (n = 77). Controls demonstrated better conditioning, larger cerebellar volumes, and an association between conditioning and cerebellar volume that was not observed in epilepsy patients. These findings provide support for the hypothesis that cerebellar atrophy in epilepsy affects procedural memory.
Inhibition of prolyl 4-hydroxylase, beta polypeptide (P4HB) attenuates temozolomide resistance in malignant glioma via the endoplasmic reticulum stress response (ERSR) pathways
Authors: Stella Sun, Derek Lee, Amy S.W. Ho, Jenny K.S. Pu, X.Q. Zhang, Nikki P. Lee, Philip J.R. Day, W.M. Lui, C.F. Fung, Gilberto K.K. Leung
Journal: Neuro-Oncology (2013)

Glioblastoma multiforme (GBM), the most aggressive malignant primary brain tumor of the central nervous system, is characterized by a relentless disease recurrence despite continued advancement in surgery, radiotherapy, and chemotherapy. Resistance to temozolomide (TMZ), a standard chemotherapeutic agent for GBM, remains a major challenge. Understanding the mechanisms behind TMZ resistance can direct the development of novel strategies for the prevention, monitoring, and treatment of tumor relapse. Our research platform, based on the establishment of 2 pairs of TMZ-sensitive/resistant GBM cells (D54-S and D54-R; U87-S and U87-R), has successfully identified prolyl 4-hydroxylase, beta polypeptide (P4HB) over-expression to be associated with an increased IC50 of TMZ. Elevated P4HB expression was verified using in vivo xenografts developed from U87-R cells. Clinically, we found that P4HB was relatively up-regulated in the recurrent GBM specimens that were initially responsive to TMZ but later developed acquired resistance, when compared with treatment-naive tumors. Functionally, P4HB inhibition by RNAi knockdown and bacitracin inhibition could sensitize D54-R and U87-R cells to TMZ in vitro and in vivo, whereas over-expression of P4HB in vitro conferred resistance to TMZ in both D54-S and U87-S cells. Moreover, targeting P4HB blocked its protective function and sensitized glioma cells to TMZ through the PERK arm of the endoplasmic reticulum stress response. Our study identified a novel target together with its functional pathway in the development of TMZ resistance. P4HB inhibition may be used alone or in combination with TMZ for the treatment of TMZ-resistant GBM.
Serum Ferritin and Risk of the Metabolic Syndrome in U.S. Adults
Authors: Megan Jehn, Jeanne M. Clark, Eliseo Guallar
Journal: Diabetes Care (2004)

OBJECTIVE—We examined the relationship among iron stores, the metabolic syndrome, and insulin resistance. RESEARCH DESIGN AND METHODS—We conducted a cross-sectional study of 6,044 adults &amp;gt;20 years of age who participated in the Third National Health and Nutrition Examination Survey. Metabolic syndrome was defined as the presence of at least three of the following: elevated blood pressure, low HDL cholesterol, elevated serum triglycerides, elevated plasma glucose, and abdominal obesity. Insulin resistance was estimated using homeostasis model assessment (for insulin resistance), fasting insulin, and triglyceride–to–HDL cholesterol ratio. RESULTS—After excluding individuals with likely hemochromatosis, mean serum ferritin values in premenopausal women, postmenopausal women, and men were 33.6, 93.4, and 139.9 μg/l, respectively. Metabolic syndrome was more common in those with the highest compared with the lowest levels of serum ferritin in premenopausal women (14.9 vs. 6.4%, P = 0.002), postmenopausal women (47.5 vs. 28.2%, P &amp;lt; 0.001), and men (27.3 vs. 13.8%, P &amp;lt; 0.001). Insulin resistance also increased across quartiles of serum ferritin for men and postmenopausal women and persisted after adjustment for age, race/ethnicity, C-reactive protein, smoking, alcohol intake, and BMI. CONCLUSIONS—Elevated iron stores were positively associated with the prevalence of the metabolic syndrome and with insulin resistance.
Adaptive immunity suppresses formation and progression of diethylnitrosamine-induced liver cancer
Authors: Carlo Schneider, Andreas Teufel, Tetyana Yevsa, Frank Staib, Anja Hohmeyer, Gudrun Walenda, Henning W Zimmermann, Mihael Vucur, Sebastian Huss, Nikolaus Gassler, Hermann E Wasmuth, Sergio A Lira, Lars Zender, Tom Luedde, Christian Trautwein, Frank Tacke
Journal: Gut (2012)

<h3>Background</h3> Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer, but may also provoke antitumour immune responses whose significance and underlying mechanisms are incompletely understood. <h3>Objective</h3> To characterise immune responses in the diethylnitrosamine (DEN)-liver cancer mouse model. <h3>Design</h3> Tumour development and immune cell functions upon DEN treatment were compared between C57BL/6 wild-type (WT), chemokine scavenging receptor D6-deficient, B cell- (Igh6), CD4 T cell- (MHC-II) and T-/B cell-deficient (Rag1) mice. Relevance for human HCC was tested by comparing gene array results from 139 HCC tissues. <h3>Results</h3> The induction of premalignant lesions after 24 weeks and of HCC-like tumours after 42 weeks by DEN in mice was accompanied by significant leucocyte infiltration in the liver and upregulation of distinct intrahepatic chemokines (CCL2, CCL5, CXCL9). Macrophages and CD8 (cytotoxic) T cells were most prominently enriched in tumour-bearing livers, similar to samples from human HCC. Myeloid-derived suppressor cells (MDSC) increased in extrahepatic compartments of DEN-treated mice (bone marrow, spleen). The contribution of immune cell subsets for DEN-induced hepatocarcinogenesis was functionally dissected. In D6<sup>−/−</sup> mice, which lack the chemokine scavenging receptor D6, hepatic macrophage infiltration was significantly increased, but tumour formation and progression did not differ from that of WT mice. In contrast, progression of hepatic tumours (numbers, diameters, tumour load) was strikingly enhanced in T-/B cell-deficient Rag1<sup>−/−</sup> mice upon DEN treatment. When mice deficient for B cells (Igh6<sup>−/−</sup>, μMT) or major histocompatibility complex II were used, the data indicated that T cells prevent initial tumour formation, while B cells critically limit growth of established tumours. Accordingly, in tumour-bearing mice antibody production against liver-related model antigen was enhanced, indicating tumour-associated B cell activation. In agreement, T and B cell pathways were differentially regulated in gene array analyses from 139 human HCC tissues and significantly associated with patients9 survival. <h3>Conclusions</h3> Distinct axes of the adaptive immune system, which are also prognostic in human HCC, actively suppress DEN-induced hepatocarcinogenesis by controlling tumour formation and progression.
Mortality and causes of death in Crohn's disease. Review of 50 years' experience in Leiden University Hospital.
Authors: I T Weterman, I Biemond, A S Pena
Journal: Gut (1990)

Six hundred and seventy one patients (52.5% women) with Crohn9s disease seen at Leiden University Hospital between 1934 and 1984 were identified. Follow up was 98.2% complete. Sixty four (9.7%) of the 659 patients died. The cause of death was related to Crohn9s disease in 34 patients, probably related to the disease in four, and unrelated, from incidental causes, in 25. The cause of death could not be identified in one patient. There was a significant decrease of deaths related to the disease after 1973. Causes of death such as amyloidosis and malnutrition have disappeared and postoperative deaths have decreased. The standardised mortality ratio showed an excess mortality of 2.23 for all patients. It was higher for women (3.30) than for men (1.76). A comparison of two recent 10 year periods showed a significant decrease in standardised mortality ratio in men but not in women. Patients whose disease started before the age of 20 years had an excess mortality compared with older patients. This study supports the view that the prognosis of Crohn9s disease has improved in general but high quality medical and surgical management is important particularly for younger patients.
Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor
Authors: Matthew J Lyst, Robert Ekiert, Daniel H Ebert, Cara Merusi, Jakub Nowak, Jim Selfridge, Jacky Guy, Nathaniel R Kastan, Nathaniel D Robinson, Flavia de Lima Alves, Juri Rappsilber, Michael E Greenberg, Adrian Bird
Journal: Nature Neuroscience (2013)
Mutational Spectra of PTEN/MMAC1 Gene: a Tumor Suppressor With Lipid Phosphatase Activity
Authors: I. U. Ali, L. M. Schriml, M. Dean
Journal: JNCI Journal of the National Cancer Institute (1999)

PTEN/MMAC1 (phosphatase, tensin homologue/mutated in multiple advanced cancers) is a tumor suppressor protein that has sequence homology with dual-specificity phosphatases, which are capable of dephosphorylating both tyrosine phosphate and serine/threonine phosphate residues on proteins. The in vivo function of PTEN/MMAC1 appears to be dephosphorylation of phosphotidylinositol 3,4,5-triphosphate. The PTEN/MMAC1 gene is mutated in the germline of patients with rare autosomal dominant cancer syndromes and in subsets of specific cancers. Here we review the mutational spectra of the PTEN/MMAC1 gene in tumors from various tissues, especially endometrium, brain, prostate, and ovary, in which the gene is inactivated very frequently. Germline and somatic mutations in the PTEN/MMAC1 gene occur mostly in the protein coding region and involve the phosphatase domain and poly(A) 6 stretches. Compared with germline alterations found in the PTEN/MMAC1 gene, there is a substantially increased frequency of frameshift mutations in tumors. Glioblastomas and endometrial carcinomas appear to have distinct mutational spectra, probably reflecting differences in the underlying mechanisms of inactivation of the PTEN/MMAC1 gene in the two tissue types. Also, depending on the tissue type, the gene appears to be involved in the initiation or the progression of cancers. Further understanding of PTEN/MMAC1 gene mutations in different tumors and the physiologic consequences of these mutations is likely to open up new therapeutic opportunities for targeting this critical gene.
A STATISTICAL STUDY OF ONE THOUSAND PATIENTS
Authors: Frederick L. Hills
Journal: American Journal of Psychiatry (1901)

Of the different persons admitted 73.6 per cent of the men and 74.2 per Lent of the women were suffering from their first attack.21 per cent of the men had previously been under treatment, and 24.5 per cent of the women were formerly inmates of this or some other institution.These figures are nearly the same as those reported