tbuckley/cabot-search huggingface dataset:
A simplified single stage total hepatectomy in the rat with maintenance of gastrointestinal absorptive function
Authors: Yasuo Yamaguchi, R. Randal Bollinger, Eliana Defaria, Barry Landis, Steven Quarfordt
Journal: Hepatology (1989)

A technique is described to remove the entire liver in a single stage with preservation of intestinal absorptive function. An inverted V-shape polyethylene cannula, either heparin bonded or silicon coated, was inserted into the portal vein and inferior vena cava to maintain venous return from the splanchnic and lower caval regions of the anhepatic rat. Blood glucose fell at a rate of 7 to 11 mg per hr per total plasma volume (4% body weight), usually resulting in hypoglycemia within the initial 2 hr. Euglycemia could be maintained in the first 3 hr after hepatectomy with hourly intravenous infusions of 2.5 to 5 mg per 100 gm body weight of glucose. Larger infusions of glucose (10 to 12.5 mg per hr per 100 gm body weight) were necessary for normal levels at later times. A 0.5 gm per 100 gm rat weight intestinal glucose bolus restored euglycemia for at least a 2-hr interval. Intestinal absorption of cholesterol and oleic acid was demonstrated in the anhepatic rat, although the latter was not so efficiently absorbed as in the control. The plasma cholesterol decreased with time in the anhepatic rat. Prompt increases were observed in plasma free fatty acid and glycerol concentrations after hepatectomy. Progressive increases in both direct and indirect plasma bilirubin levels were noted after hepatectomy. With appropriate maintenance of blood sugar, survival of 36 hr was observed. This procedure for single stage total hepatectomy in the rat can be performed in less than 30 min. The model is particularly useful for studies of the influence of the liver on postabsorptive metabolism.
Synthesis of Prostacyclin from Platelet-derived Endoperoxides by Cultured Human Endothelial Cells
Authors: Aaron J. Marcus, Babette B. Weksler, Eric A. Jaffe, M. Johan Broekman
Journal: Journal of Clinical Investigation (1980)

We have previously shown that aspirin-treated endothelial cells synthesize prostacyclin (PGI2) from the purified prostaglandin endoperoxide PGH2 (1978. J. Biol. Chem.253: 7138). To ascertain whether aspirin-treated endothelial cells produce PGI2 from endoperoxides released by stimulated platelets, [3H]arachidonic acid-prelabeled platelets were reacted in aggregometer cuvettes with the calcium ionophore A 23187, thrombin, or collagen in the presence of aspirin-treated endothelial cell suspensions. This procedure permitted thin-layer radiochromatographic quantitation of [3H]PGI2 as [3H]6-keto-PGF1α and [3H]thromboxane A2 (TXA2) as [3H]TXB2, as well as analysis of platelet aggregation responses in the same sample. In the presence of aspirin-treated endothelial cells, platelet aggregation in response to all three agents was inhibited. [3H]6-keto-PGF1α was recovered from the supernates of the combined cell suspensions after stimulation by all three agents. The order of PGI2 production initiated by the stimuli was ionophore > thrombin > collagen. The amounts of platelet [3H]TXB2 recovered were markedly reduced by the addition of aspirin-treated endothelial cells. In separate experiments, 6-keto-PGF1α and TXB2 were quantitated by radioimmunoassay; the results paralleled those obtained with the use of radiolabeling. The quantity of 6-keto-PGF1α measured by radioimmunoassay represented amounts of PGI2 sufficient to inhibit platelet aggregation. These results were obtained when 200,000 platelets/μl were combined with 3,000-6,000 aspirin-treated endothelial cells/μl. At higher platelet levels the proportion of 6-keto-PGF1α to TXB2 decreased and platelet aggregation occurred. Control studies indicated that aspirin-treated endothelial cells could not synthesize PGI2 from exogenous radioactive or endogenous arachidonate when stimulated with thrombin. Therefore the endothelial cell suspensions could only have used endoperoxides from stimulated platelets.
Absence of autoantigen Ku in mature human neutrophils and human promyelocytic leukemia line (HL-60) cells and lymphocytes undergoing apoptosis.
Authors: A K Ajmani, M Satoh, E Reap, P L Cohen, W H Reeves
Journal: The Journal of Experimental Medicine (1995)

The Ku autoantigen is a heterodimer of 70- and 80-kD proteins recognized by autoantibodies from patients with systemic lupus erythematosus and related diseases that is the DNA-binding component of a DNA-dependent protein kinase. The catalytic activity of DNA-dependent protein kinase is carried by a 350-kD subunit (p350). In light of the recently described role of Ku in repairing double-strand DNA breaks, we investigated the regulation of Ku and p350 levels in neutrophils, a terminally differentiated cell type destined to undergo apoptosis. Since the appearance of double-strand DNA breaks is characteristic of apoptosis, we were interested in the possibility that Ku might oppose programmed cell death. Analysis of peripheral blood cells by flow cytometry using anti-Ku and anti-p350 monoclonal antibodies revealed that neutrophils were unstained, whereas resting (G0) lymphocytes were positive. The absence of Ku in mature neutrophils was confirmed by Western blotting and enzyme-linked immunosorbent assay for Ku antigen. In contrast, the human promyelocytic leukemia line, HL-60, which undergoes differentiation toward neutrophils after dimethylsulfoxide treatment, was positive for Ku and p350. In view of the short lifespan of neutrophils and the prolonged half-life of Ku and p350 (&amp;gt; 5 d), these data suggested that Ku was actively degraded during myeloid differentiation. Analysis of HL-60 cells by flow cytometry revealed that Ku staining was bimodal. Cells in G1/G0, S, or G2/M were all stained positively, whereas cells with a subdiploid DNA content characteristic of apoptosis were Ku negative. Similar results were obtained with phytohemagglutin-stimulated human lymphocytes. These data suggest that the Ku antigen is actively degraded in both myeloid cells destined to undergo apoptosis and apoptotic lymphocytes, raising the possibility that degradation of Ku may help to prevent the inappropriate repair of fragmented nuclear DNA during apoptosis.
Inhibition of Glutamate Cysteine Ligase Activity Sensitizes Human Breast Cancer Cells to the Toxicity of 2-Deoxy-<scp>d</scp>-Glucose
Authors: Kelly K. Andringa, Mitchell C. Coleman, Nukhet Aykin-Burns, Michael J. Hitchler, Susan A. Walsh, Frederick E. Domann, Douglas R. Spitz
Journal: Cancer Research (2006)

It has been hypothesized that cancer cells increase glucose metabolism to protect against metabolic fluxes of hydroperoxides via glutathione-dependent peroxidases. 2-Deoxy-D-glucose, inhibits glucose metabolism and has been shown to cause cytotoxicity in cancer cells that is partially mediated by disruptions in thiol metabolism. In the current study, human breast cancer cells were continuously treated (24 hours) with 2-deoxy-D-glucose, and total glutathione content as well as the expression of the first enzyme in the glutathione synthetic pathway [glutamate cysteine ligase (GCL)] were found to be induced 2.0-fold. Inhibiting GCL activity during 2-deoxy-D-glucose exposure using l-buthionine-[S,R]-sulfoximine (BSO) significantly enhanced the cytotoxic effects of 2-deoxy-D-glucose and caused increases in endpoints indicative of oxidative stress, including % oxidized glutathione and steady-state levels of pro-oxidants as assayed using an oxidation-sensitive fluorescent probe. These results show that treatment of human breast cancer cells with 2-deoxy-d-glucose causes metabolic oxidative stress that is accompanied by increases in steady-state levels of GCL mRNA, GCL activity, and glutathione content. Furthermore, inhibition of 2-deoxy-D-glucose-mediated induction of GCL activity with BSO increases endpoints indicative of oxidative stress and sensitizes cancer cells to 2-deoxy-D-glucose-induced cytotoxicity. These results support the hypothesis that drug combinations capable of inhibiting both glucose and hydroperoxide metabolism may provide an effective biochemical strategy for sensitizing human cancer cells to metabolic oxidative stress.
Comparison of clinical characteristics and performance of pneumonia severity score and CURB-65 among younger adults, elderly and very old subjects
Authors: J.-H. Chen, S.-S. Chang, J. J. Liu, R.-C. Chan, J.-Y. Wu, W.-C. Wang, S.-H. Lee, C.-C. Lee
Journal: Thorax (2010)

<h3>Background</h3> Age-related alterations in the clinical characteristics and performance of severity scoring systems for community-acquired pneumonia (CAP) are unknown. <h3>Methods</h3> Consecutive patients with CAP presenting to the emergency department were prospectively studied. Patients were classified as younger adults (age 18–64 years), elderly (age 65–84 years) and very old subjects (age ≥85 years). Clinical characteristics, complications, outcomes and validity of the pneumonia severity index (PSI) and CURB-65 categories were compared across these three age categories. <h3>Results</h3> Analysis involved 348 (35.3%) younger adult patients, 438 (44.3%) elderly patients and 201 (20.0%) very old patients. Compared with younger adults, elderly and very old patients had a higher burden of comorbidities and a higher incidence of CAP-related complications. The 30-day mortality rate was 5.2% in younger adults, 7.1% in elderly patients and 9.5% in very old patients. The area under the ROC curve (AUCs) for PSI were 0.87 (95% CI 0.77 to 0.97), 0.85 (95% CI 0.803 to 0.897) and 0.69 (95% CI 0.597 to 0.787) and the AUCs for CURB-65 were 0.80 (95% CI 0.67 to 0.93), 0.73 (95% CI 0.65 to 0.82) and 0.60 (95% CI 0.47 to 0.73) in the younger adult, elderly and very old patients, respectively. A modified PSI or CURB-65 excluding the age variable increased the AUC in most age categories. There was no significant effect of age on 30-day mortality after adjusting for other PSI or CURB-65 variables. <h3>Conclusion</h3> Elderly patients with CAP have more atypical clinical manifestations and worse outcomes. The underperformance of the PSI in elderly patients may be due to the inappropriate weight given to the age variable. A modification of the cut-off point for PSI or CURB-65 to define severe pneumonia may improve the score performance in elderly patients.
Human subtelomeric duplicon structure and organization
Authors: Anthony Ambrosini, Sheila Paul, Sufen Hu, Harold Riethman
Journal: Genome biology (2007)

Human subtelomeric segmental duplications ('subtelomeric repeats') comprise about 25% of the most distal 500 kb and 80% of the most distal 100 kb in human DNA. A systematic analysis of the duplication substructure of human subtelomeric regions was done in order to develop a detailed understanding of subtelomeric sequence organization and a nucleotide sequence-level characterization of subtelomeric duplicon families. The extent of nucleotide sequence divergence within subtelomeric duplicon families varies considerably, as does the organization of duplicon blocks at subtelomere alleles. Subtelomeric internal (TTAGGG)n-like tracts occur at duplicon boundaries, suggesting their involvement in the generation of the complex sequence organization. Most duplicons have copies at both subtelomere and non-subtelomere locations, but a class of duplicon blocks is identified that are subtelomere-specific. In addition, a group of six subterminal duplicon families are identified that, together with six single-copy telomere-adjacent segments, include all of the (TTAGGG)n-adjacent sequence identified so far in the human genome. Identification of a class of duplicon blocks that is subtelomere-specific will facilitate high-resolution analysis of subtelomere repeat copy number variation as well as studies involving somatic subtelomere rearrangements. The significant levels of nucleotide sequence divergence within many duplicon families as well as the differential organization of duplicon blocks on subtelomere alleles may provide opportunities for allele-specific subtelomere marker development; this is especially true for subterminal regions, where divergence and organizational differences are the greatest. These subterminal sequence families comprise the immediate cis-elements for (TTAGGG)n tracts, and are prime candidates for subtelomeric sequences regulating telomere-specific (TTAGGG)n tract length in humans.
Phase I Dose Escalation Study of Telatinib, a Tyrosine Kinase Inhibitor of Vascular Endothelial Growth Factor Receptor 2 and 3, Platelet-Derived Growth Factor Receptor β, and c-Kit, in Patients With Advanced or Metastatic Solid Tumors
Authors: Ferry A.L.M. Eskens, Neeltje Steeghs, Jaap Verweij, Johan L. Bloem, Olaf Christensen, Leni van Doorn, Jan Ouwerkerk, Maja J.A. de Jonge, Johan W.R. Nortier, Joern Kraetzschmar, Prabhu Rajagopalan, Hans Gelderblom
Journal: Journal of Clinical Oncology (2009)

Telatinib (BAY 57-9352) is an orally available tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR) -2, VEGFR-3, platelet-derived growth factor receptor-beta, and c-Kit. This phase I dose escalation study was conducted to evaluate the safety and tolerability of telatinib, with additional pharmacokinetic, pharmacodynamic, and efficacy assessments.Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Doses of continuously administered telatinib were escalated from 20 mg once daily to 1,500 mg twice daily.Fifty-three patients were enrolled. Most frequently observed drug-related adverse events were nausea (26.4%; grade >or= 3, 0%) and hypertension (20.8%; grade 3, 11.3%; grade 4, 0%). Two dose-limiting toxicities were observed: one poorly controlled hypertension (600 mg twice daily), and one grade 2 weight loss, anorexia, and fatigue (1,500 mg twice daily). A formal maximum-tolerated dose was not reached. Telatinib was rapidly absorbed, with median time to peak concentration (t(max)) lower than 3 hours after dose. A nearly dose-proportional increase in exposure was observed with substantial variability. Telatinib half-life averaged 5.5 hours. Biomarker analyses showed dose-dependent increase in VEGF levels and decrease in plasma soluble VEGFR-2 levels, with a plateau at 900 mg twice daily. A decrease in tumor blood flow (K(trans) and IAUC(60)) was observed with dynamic contrast-enhanced magnetic resonance imaging. Best tumor response was stable disease, observed in 50.9% of patients.Telatinib was safe and well tolerated up to 1,500 mg twice daily. Based on pharmacodynamic and pharmacokinetic end points, telatinib 900 mg twice daily is the recommended dose for subsequent phase II studies.
On the Bactericidal Functions of the Liver and the Etiology of Progressive Hepatic Cirrhosis
Authors: J. G. Adami
Journal: BMJ (1898)

HEPATIC CIRRHOSIS.1 O,A 12151'common to all the blood vessels of the body.31Harvey, moreover, 'wasthefirsttointerpret correctlythephysiologyoftheheart.His great work on Animal Generation, of which he was so diffident, -and which was, as it were, dragged from him by his admiring friend, Sir George Ent, for the purpose of publication, would by itself have raised him to the first rank of biologists, al- 'though, as Willis remarks, to complete and perfect such a task as this was impossible, even for Harvey, with the means at his
Specificity of Tissue Transglutaminase Explains Cereal Toxicity in Celiac Disease
Authors: L. Willemijn Vader, Arnoud de Ru, Yvonne van der Wal, Yvonne M.C. Kooy, Willemien Benckhuijsen, M. Luisa Mearin, Jan Wouter Drijfhout, Peter van Veelen, Frits Koning
Journal: The Journal of Experimental Medicine (2002)

Celiac disease is caused by a selective lack of T cell tolerance for gluten. It is known that the enzyme tissue transglutaminase (tTG) is involved in the generation of T cell stimulatory gluten peptides through deamidation of glutamine, the most abundant amino acid in gluten. Only particular glutamine residues, however, are modified by tTG. Here we provide evidence that the spacing between glutamine and proline, the second most abundant amino acid in gluten, plays an essential role in the specificity of deamidation. On the basis of this, algorithms were designed and used to successfully predict novel T cell stimulatory peptides in gluten. Strikingly, these algorithms identified many similar peptides in the gluten-like hordeins from barley and secalins from rye but not in the avenins from oats. The avenins contain significantly lower percentages of proline residues, which offers a likely explanation for the lack of toxicity of oats. Thus, the unique amino acid composition of gluten and related proteins in barley and rye favors the generation of toxic T cell stimulatory gluten peptides by tTG. This provides a rationale for the observation that celiac disease patients are intolerant to these cereal proteins but not to other common food proteins.
THE INFLUENCE OF CHOLESTEROL ON EXPERIMENTAL TUBERCULOSIS
Authors: Richard E. Shope
Journal: The Journal of Experimental Medicine (1928)

1. Cholesterol, administered intraperitoneally, in these experiments definitely prolonged the lives of tuberculous guinea pigs when the infection was of an acute type produced by inoculation with a small dose of very virulent human type organisms. 2. Intraperitoneally administered cholesterol did not definitely prolong the lives of tuberculous guinea pigs when the infection was of the chronic type produced by the injection of a small dose of human type tubercle bacilli of relatively low virulence, or when the infection was more acute owing to the injection of a large dose of organisms of low virulence. It had no beneficial effect on an acute type of infection produced by the bovine type organism. 3. Cholesteryl chloride, cholesteryl toluide, cholesteryl anilide, sodium cholesterol sulfate, and quinine cholesterylate did not significantly prolong the lives of tuberculous guinea pigs. 4. Sodium cholesterylate, in optimal dosage, definitely prolonged the lives of tuberculous guinea pigs. 5. There was a significant shortening in the duration of life of tuberculous guinea pigs subjected to the trauma of intraperitoneal injection and repeated handling as compared with tuberculous guinea pigs that were not handled or traumatized by intraperitoneal injections.
Effectiveness of a tuberculosis screening program in rheumatic patients treated with immunossuppressants
Authors: Joana Pimentel, Claudia Miguel, Mónica Grafino, Tiago Abreu, Margarida Felizardo, Ana Teixeira, José Vaz-Patto, Maria Conceição Gomes
Journal: European Respiratory Journal (2012)

Background: Immunosuppressants, including new biological therapies, enhance the risk of developing active tuberculosis (TB). An effective screening program is essential.  Aim: To investigate the impact of a TB screening program on the development of active TB in rheumatic patients treated with immunosuppressants.  Methods: Retrospective analysis of patients followed at Portuguese Institute of Rheumatology, screened for latent or active TB in the Pulmonology Diagnostic Center, since february 2005. The evaluation included clinical history, tuberculin skin test, chest x-ray, interferon gamma release assay and chest CT according to protocol. If any of these was positive, 9 months isoniazid (INH) and piridoxin was prescribed. If all were negative, patients remained under biannual monitoring.  Results: The study had 641 patients with 471 females and mean age 52±13 years. The average length of follow-up was 2,8±1,4 years. Main rheumatological diagnoses were rheumatoid arthritis (n=394), ankylosing spondylitis (n=104) and psoriatic arthritis (n=70). 173 were candidates to biological therapy and 468 were proposed or already treated with classic immunosuppressants. 532 patients were prescribed INH, of whom 14 refused and 10 suspended for intolerance (9 hepatotoxicity and 1 medullar aplasia). The remaining 109 were proposed only for clinical monitoring. No patient developed TB after the screening program.  Conclusion: In this population, 80% required chemoprophylaxis with INH and only 0,02% developed intolerance. The TB screening program used was effective, with no cases of TB reported, however these results did not allow calculating its impact in reducing the risk of TB.
Investigation of Second Genetic Hits at the <i>BMPR2</i> Locus as a Modulator of Disease Progression in Familial Pulmonary Arterial Hypertension
Authors: Rajiv D. Machado, Victoria James, Mark Southwood, Rachel E. Harrison, Carl Atkinson, Susan Stewart, Nicholas W. Morrell, Richard C. Trembath, Micheala A. Aldred
Journal: Circulation (2005)

Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression.To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients.Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.
Neanderthals did speak, but<i>FOXP2</i>doesn't prove it
Authors: Sverker Johansson
Journal: Behavioral and Brain Sciences (2014)

Abstract Ackermann et al. treat both genetic and paleoanthropological data too superficially to support their conclusions. The case of FOXP2 and Neanderthals is a prime example, which I will comment on in some detail; the issues are much more complex than they appear in Ackermann et al.