tbuckley/cabot-search huggingface dataset:
Qualitative and quantitative differences in the pathways of extrathyroidal triiodothyronine generation between euthyroid and hypothyroid rats.
Authors: J E Silva, M B Gordon, F R Crantz, J L Leonard, P R Larsen
Journal: Journal of Clinical Investigation (1984)

Propylthiouracil (PTU) in maximally inhibitory doses for liver and kidney iodothyronine 5'-deiodinase activity (5'D-I), reduces extrathyroidal T4 to T3 conversion by only 60-70% in euthyroid rats. A second pathway of T4 to T3 conversion (5'D-II) has been found in pituitary, central nervous system, and brown adipose tissue. 5'D-II is insensitive to PTU and increases in hypothyroidism, whereas 5'D-I decreases in hypothyroid rats. Thyroxine (T4) and triiodothyronine (T3) kinetics were assessed in euthyroid and thyroidectomized rats by noncompartmental analysis after injecting [125I]T4 and [131I]T3. Neither the volume of distribution nor the rate of fractional removal of plasma T4 was affected by the thyroid status, but the fractional removal rate of T3 was approximately 50% reduced in hypothyroid rats (P less than 0.001). Fractional T4 to T3 conversion was 22% in euthyroid and 26% in hypothyroid rats. In euthyroid rats, sufficient PTU to inhibit liver and kidney 5'D-I greater than 90% reduced serum [125I]T3 after [125I]T4 (results given as percent dose per milliliter X 10(-3) +/- SEM): 4 h, control 16 +/- 2 vs. PTU 4 +/- 1, P less than 0.005, and 22 h, control 6.4 +/- 0.4 vs. PTU 3.6 +/- 0.7, P less than 0.025. In thyroidectomized rats, the same dose of PTU also inhibited 5'D-I in liver and kidney, but had no effect on the generation of serum [125I]T3 from [125I]T4. Similarly, after 1 microgram T4/100 g bw was given to thyroidectomized rats, serum T3 (radioimmunoassay) increased by 0.30 +/- 0.6 ng/ml in controls and 0.31 +/- 0.09 ng/ml in PTU-treated rats. However, when the dose of T4 was increased to 2-10 micrograms/100 g bw, PTU pretreatment significantly reduced the increment in serum T3. T3 clearance was not affected by PTU in hypothyroid rats. The 5'D-II in brain, pituitary, and brown adipose tissue was reduced to less than or equal to 60% of control by 30 micrograms/100 g bw reverse T3 (rT3), an effect that lasted for at least 3 h after rT3 had been cleared. In rT3-pretreated thyroidectomized rats, the generation of [125I]T3 from tracer [125I]T4 was reduced in the serum: 6 +/- 1 vs. 12 +/- 1 X 10(-3)% dose/ml, P less than 0.01, during this 3-h period. We conclude that virtually all the T3 produced from low doses of exogenous T4 given to hypothyroid rats is generated via a PTU-insensitive pathway, presumably catalyzed by the 5'D-II. This is a consequence of the enhanced activity of this low Km enzyme together with the concomitant decrease in the hepatic and renal 5'D-I characteristic of the hypothyroid state. The results indicate that in some circumstances, 5D-II activity may contribute to the extracellular, as well as intracellular, T3 pool.
Risk of aspirin-associated major upper-gastrointestinal bleeding with enteric-coated or buffered product
Authors: Judith P Kelly, David W Kaufman, Jan M Jurgelon, Jane Sheehan, Raymond S Koff, Samuel Shapiro
Journal: The Lancet (1996)

Aspirin products are known to cause irritation and injury to the gastric mucosa. The belief that enteric-coated and buffered varieties are less likely to occasion major upper-gastrointestinal bleeding (UGIB) than plain aspirin was tested in data from a multicentre case-control study.550 incident cases of UGIB admitted to hospital with melaena or haematemesis and confirmed by endoscopy, and 1202 controls identified from population census lists, were interviewed about use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) during the 7 days before the onset of bleeding (cases) or interview (controls). Relative risks of UGIB for each type of aspirin used regularly (at least every other day) were calculated overall, and according to dose, by multiple logistic regression, with control for age, sex, marital status, date, education, cigarette smoking, alcohol use, and use of NSAIDs.The relative risks of UGIB for plain, enteric-coated, and buffered aspirin at average daily doses of 325 mg or less were 2.6, 2.7, and 3.1, respectively. At doses greater than 325 mg, the relative risk was 5.8 for plain and 7.0 for buffered aspirin; there were insufficient data to evaluate enteric-coated aspirin at this dose level. There were no important differences in risk attributable to the three aspirin forms according to bleeding site (gastric vs duodenal), or when users of NSAIDs were excluded.Use of low doses of enteric-coated or buffered aspirin carries a three-fold increase in the risk of major UGIB. The assumption that these formulations are less harmful than plain aspirin may be mistaken.
Simultaneous cutaneous and ungual alternariosis in a renal transplant recipient
Authors: C. Baykal, R. Kazancioğlu, N. Büyükbabani, A.V. Çelik, Y. Yeğenoğlu, S.M. Kayacan, D. S¸atana, M.S¸. Sever
Journal: British Journal of Dermatology (2000)
Identifying Optimal Biologic Doses of Everolimus (RAD001) in Patients With Cancer Based on the Modeling of Preclinical and Clinical Pharmacokinetic and Pharmacodynamic Data
Authors: Chiaki Tanaka, Terence O’Reilly, John M. Kovarik, Nicholas Shand, Katharine Hazell, Ian Judson, Eric Raymond, Sabine Zumstein-Mecker, Christine Stephan, Anne Boulay, Marc Hattenberger, George Thomas, Heidi A. Lane
Journal: Journal of Clinical Oncology (2008)

To use preclinical and clinical pharmacokinetic (PK)/pharmacodynamic (PD) modeling to predict optimal clinical regimens of everolimus, a novel oral mammalian target of rapamycin (mTOR) inhibitor, to carry forward to expanded phase I with tumor biopsy studies in cancer patients.Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor-bearing rats.Time- and dose-dependent S6K1 inhibition was demonstrated in human PBMCs. In the rat model, a relationship was shown between S6K1 inhibition in tumors or PBMCs and antitumor effect. This allowed development of a direct-link PK/PD model that predicted PBMC S6K1 inhibition-time profiles in patients. Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a greater effect than weekly administration at higher doses.A direct-link PK/PD model predicting the time course of S6K1 inhibition during weekly and daily everolimus administration allowed extrapolation from preclinical studies and first clinical results to select optimal doses and regimens of everolimus to explore in future clinical trials.
Inhaled PGE2 prevents aspirin-induced bronchoconstriction and urinary LTE4 excretion in aspirin-sensitive asthma.
Authors: P Sestini, L Armetti, G Gambaro, M G Pieroni, R M Refini, A Sala, A Vaghi, G C Folco, S Bianco, M Robuschi
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Bronchial overproduction of leukotrienes and inhibition of prostaglandin synthesis are involved in the pathogenesis of aspirin-induced asthma. We investigated whether inhaled prostaglandin E2 (PGE2) attenuates the response to bronchial challenge with lysine acetylsalicylate (LASA) and the associated increase in urinary leukotriene E4 (u-LTE4) in seven aspirin-sensitive subjects with asthma. Each subject performed two challenges with a single dose of LASA that caused a decrease in FEV1 of 20% or more in a preliminary test, immediately after inhaling 100 micrograms PGE2 in 4 ml saline or placebo, according to a randomized double-blind protocol. FEV1 was recorded at 30-min intervals for 4 h. u-LTE4 was measured by combined high-performance liquid chromatography enzyme immunoassay at 2-h intervals. After placebo, LASA caused an obstructive reaction in all patients, with a maximum decrease in FEV1 of 35 +/- 5% with respect to baseline. u-LTE4 rose from 911 +/- 261 picograms (pg)/mg creatinine at baseline to a maximum value of 2249 +/- 748 after challenge. Inhaled PGE2 provided almost complete protection in all patients. Baseline u-LTE4 was 883 +/- 243 pg/mg creatinine and did not change significantly during the test, reaching a maximum value of 864 +/- 290 (p < 0.05 versus placebo). These results confirm that PGE2 is highly effective in preventing aspirin-induced asthma and suggest that this effect is mediated by inhibition of sulfidopeptide leukotriene production.
Monocyte Chemoattractant Protein-1 is Upregulated in Rats With Volume-Overload Congestive Heart Failure
Authors: Thomas M. Behr, Xinkang Wang, Nambi Aiyar, Robert W. Coatney, Xiang Li, Paul Koster, Christiane E. Angermann, Eliot Ohlstein, Giora Z. Feuerstein, Joseph Winaver
Journal: Circulation (2000)

Chemokines are potent proinflammatory and immune modulators. Increased expression of chemokines, eg, monocyte chemoattractant protein-1 (MCP-1), has recently been described in clinical and experimental heart failure. The present report is aimed at exploring the expression, localization, and binding site regulation of MCP-1, a member of the C-C chemokine family, in a rat model of volume-overload congestive heart failure (CHF).An aortocaval fistula was surgically created between the abdominal aorta and inferior vena cava. Rats with CHF were further subdivided into compensated and decompensated subgroups. Northern blot analysis and real-time quantitative polymerase chain reaction demonstrated upregulation of MCP-1 mRNA expression correlating with the severity of CHF (288+/-22, 502+/-62, and 826+/-138 copies/ng total RNA for sham, compensated, and decompensated animals, respectively; n=5, P:<0.05). MCP-1 protein was localized by immunohistochemistry in cardiomyocytes, vascular endothelium and smooth muscle cells, infiltrating leukocytes, and interstitial fibroblasts, and its intensity increased with severity of CHF. In addition, rats with CHF displayed a significant decrease of (125)I-labeled MCP-1 binding sites to myocardium-derived membranes (384.3+/-57.0, 181.3+/-8.8, and 123.3+/-14.1 fmol/mg protein for sham, compensated, and decompensated animals, respectively).Volume-overload CHF in rats is associated with alterations in the expression, immunohistochemical localization, and receptor binding of the MCP-1 chemokine in the myocardium. These changes were more pronounced in rats with decompensated CHF. The data suggest that activation of the MCP-1 system may contribute to the progressive cardiac decompensation and development of CHF in rats with aortocaval fistula.
Dose-Dependent Increases in Circulating TGF-α and Other EGFR Ligands Act As Pharmacodynamic Markers for Optimal Biological Dosing of Cetuximab and Are Tumor Independent
Authors: Anthony J. Mutsaers, Giulio Francia, Shan Man, Christina R. Lee, John M.L. Ebos, Yan Wu, Larry Witte, Scott Berry, Malcolm Moore, Robert S. Kerbel
Journal: Clinical Cancer Research (2009)

The objective of this study was to characterize treatment-induced circulating ligand changes during therapy with epidermal growth factor receptor (EGFR) inhibitors and evaluate their potential as surrogate indicators of the optimal biological dose.Conditioned medium from human tumor cell lines, ascites fluid from tumor xenografts, and plasma samples from normal mice, as well as colorectal cancer patients, were assessed for ligand elevations using ELISA, following treatment with cetuximab (Erbitux), an anti-mouse EGFR neutralizing antibody, or a small-molecule EGFR tyrosine kinase inhibitor.A rapid elevation in human transforming growth factor alpha (TGF-alpha) was observed in all cell lines after treatment with cetuximab, but not with small-molecule inhibitors. The elevation showed a dose-response effect and plateau that corresponded to the maximal decrease in A431 proliferation in vitro and HT29 tumor growth in vivo. The TGF-alpha increase was exacerbated by ongoing ligand production and cleavage from the plasma membrane but did not involve transcriptional up-regulation of TGF-alpha or the matrix metalloproteinase tumor necrosis factor-alpha-converting enzyme/ADAM17. Elevations in plasma TGF-alpha, amphiregulin, and epiregulin were also detected in normal mice treated with an anti-mouse EGFR monoclonal antibody, illustrating a host tissue-dependent component of this effect in vivo. Finally, circulating TGF-alpha increased in the plasma of six patients with EGFR-negative colorectal tumors during cetuximab treatment.Treatment-induced increases in circulating ligands, particularly TGF-alpha, should be serially assessed in clinical trials of anti-EGFR therapeutic antibodies as potential biomarkers to aid in determination of the optimal biological dose.
Abrogation of MLL–AF10 and CALM–AF10-mediated transformation through genetic inactivation or pharmacological inhibition of the H3K79 methyltransferase Dot1l
Authors: L Chen, A J Deshpande, D Banka, K M Bernt, S Dias, C Buske, E J Olhava, S R Daigle, V M Richon, R M Pollock, S A Armstrong
Journal: Leukemia (2012)
The History of Scurvy and Vitamin C
Authors: S Shortt
Journal: Annals of Internal Medicine (1989)

and suggestive step.It seems difficult to dispute that a significant change did indeed occur in the early 19th century in the approach to the treatment of the insane, a change that in the English-speaking world began at and spread from the York Retreat.Similarly, after reading Digby's balanced account it seems naive to portray moral treatment as an entirely benign process in con- trast to the brutality of previous forms of treatment.Moral treat- ment too contained elements of coercion, force and manipulation, though present in a far more subtle guise.In short, this carefully writ- ten, meticulously researched and intelligently argued book is a major contribution to our under- standing of the origins of Anglo-American institutional psychiatry.
Development links psychological causes to evolutionary explanations
Authors: Mark Fedyk, Tamar Kushnir
Journal: Behavioral and Brain Sciences (2014)

Abstract Our conscious abilities are learned in environments that have evolved to support them. This insight provides an alternative way of framing Huang &amp; Bargh's (H&amp;B's) provocative hypothesis. To understand the conflict between unconscious goals and consciousness, we can study the emergence of conscious thought and control in childhood. These developmental processes are also central to the best available current evolutionary theories.
Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene
Authors: Ana O. Hoff, Philip Catala-Lehnen, Pamela M. Thomas, Matthias Priemel, Johannes M. Rueger, Igor Nasonkin, Allan Bradley, Mark R. Hughes, Nelson Ordonez, Gilbert J. Cote, Michael Amling, Robert F. Gagel
Journal: Journal of Clinical Investigation (2002)

Calcitonin (CT) is a known inhibitor of bone resorption. Calcitonin gene–related peptide-α (CGRPα), produced by alternative RNA processing of the CT/CGRP gene, has no clearly defined role in bone. To better understand the physiologic role of the CT/CGRP gene we created a mouse in which the coding sequences for both CT and CGRPα were deleted by homologous recombination. The CT/CGRP–/– knockout (KO) mice procreated normally, there were no identifiable developmental defects at birth, and they had normal baseline calcium-related chemistry values. However, KO animals were more responsive to exogenous human parathyroid hormone as evidenced by a greater increase of the serum calcium concentration and urine deoxypyridinoline crosslinks, an effect reversed by CT and mediated by a greater increase in bone resorption than in controls. Surprisingly, KO mice have significantly greater trabecular bone volume and a 1.5- to 2-fold increase in bone formation at 1 and 3 months of age. This effect appears to be mediated by increased bone formation. In addition, KO mice maintain bone mass following ovariectomy, whereas wild-type mice lose approximately one-third of their bone mass over 2 months. These findings argue for dual roles for CT/CGRP gene products: prevention of bone resorption in hypercalcemic states and a regulatory role in bone formation.
The guinea pig I region. I. A structural and genetic analysis
Authors: BD Schwartz, AM Kask, WE Paul, AF Geczy, EM Shevach
Journal: The Journal of Experimental Medicine (1977)

The Ia antigens of the guinea pig have been shown to play a central role in the regulation of the immune response. We have previously partially characterized the chemical structure of these antigens. In this communication, we further characterize the structure of the five Ia antigens already described, as well as two new Ia antigens. Evidence is presented which shows that these seven Ia antigens can be organized into three distinct groups, each with a characteristic structure. The Ia.2 determinant of strain 2 and the Ia.3 and Ia.5 determinants of strain 13 animals are found on molecules composed of a 25,000 dalton chain and a 33,000 dalton chain in noncovalent association, or else are individually expressed on nonlinked 33,000 and 25,000 dalton molecules. The Ia.4 and Ia.5 determinants of strain 2 and the Ia.7 determinant of strain 13 are borne on 58,000 dalton molecules in which two chains are linked by disulfide bonds. The Ia.1 and Ia.6 determinants of strain 13 are found on a molecule of 26,000-27,000 daltons. Ia.6 of strain 2 has yet to be definitively assigned. Furthermore, in strain 13 animals the Ia.3 and Ia.5 determinants are borne on the same molecule, as are the Ia.1 and Ia.6 determinants. In strain 2 animals, the Ia.4 and Ia.5 determinants are found on the same molecule. On the basis of chemical structure, we have divided the guinea pig I region into three subregions. The accompanying paper presents evidence of associations between particular Ia genes and Ir genes.
Complete Spontaneous Regression of Primary Diffuse Large B-Cell Lymphoma of the Breast
Authors: Tsuguo Iwatani, Hidetaka Kawabata, Daishu Miura, Yasunori Ota, Kenichi Ohashi
Journal: Journal of Clinical Oncology (2010)

A healthy 69-year-old woman presented with a 4-week history of an elastic hard lump in the upper aspect of her left breast.Physical examination demonstrated a 4-cm, elastic, hard mass located in the midportion above the nipple of her left breast.Axillary lymphadenopathy was not found.There was no significant past medical history, and she was not taking any medication.Family history was negative for malignant disease.Mammography of the left breast showed a dense mass with an ill-defined border.Ultrasonography revealed a hypoechoic lesion, measuring 47 ϫ 46 ϫ 20 mm with an irregular margin.These diagnostic imaging findings suggested a malignant tumor.Further examination was by magnetic resonance imaging (MRI), and core needle biopsy (CNB) was performed to determine the histopathologic diagnosis.MRI (gadolinium-enhanced fatsuppressed T1-weighted imaging) showed high-contrast rim enhancement of the lesion and rapid washout on the time-intensity curve (Fig 1A).Histopathologic evaluation of the CNB specimen showed cellular proliferation of atypical cells (Fig 2A) and diffuse growth of large lymphoid cells with frequent mitotic figures.The cells had scanty cytoplasm surrounding round and oval nuclei with a fine chromatin pattern (Fig 2B).Immunohistochemical examination was performed and was negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2).For immunophenotyping of T-and B-cell lineage, monoclonal antibodies were used (DAKO, Copenhagen, Denmark), including antibodies specific for CD3 (F7.2.38), CD5 (CD5/54/F6), CD10 (56C6), CD20 (L26), MUM-1 (MUM1p), bcl-2 (124), CD30 (BerH2), and CD56 (MOC-1).The lymphoma cells were positive for CD20 (Fig 2C), MUM-1, and bcl-2 and negative for CD3, CD5, and CD10.In situ hybridization for Epstein-Barr virus EBER protein was negative, and the MIB-1 (DAKO) labeling index was evaluated at 80% to 90% (Fig 2D).On the basis of the pathologic features, the tumor was classified as a diffuse large B-cell lymphoma (DLBCL).Bone marrow aspiration was performed and revealed a slightly hypocellular bone marrow with no evidence of lymphomatous infiltration.Positron emission tomography-computed tomography (PET-CT) revealed a large homogeneous mass measuring approximately 50 mm located in the left breast.No systemic lymphadenopathy was detected.The PET-CT findings indicated a stage IE tumor according to the Ann Arbor staging system.After CNB, the patient noticed that the tumor regressed rapidly and was nonpalpable within 11 days, without any specific treatment for DLBCL.We performed excisional biopsy for further pathologic assessment.This yielded a specimen measuring 70 ϫ 56 ϫ 12 mm, and we took thin sections of the whole specimen and examined them.
Small bowel cancer risk in Lynch syndrome
Authors: K. Schulmann, C. Engel, P. Propping, W. Schmiegel
Journal: Gut (2008)

<h3>Background</h3> Paraneoplastic neurological syndromes are usually associated with small cell lung cancer, gynaecological, lymphomas and renal cell carcinomas. A few studies report the association of neurological syndromes with squamous cell carcinoma of lung (SCC), the majority being sensory neuropathies. We describe a patient with a demyelinating motor polyneuropathy associated with a lung SCC. <h3>Case Report</h3> A 43-year-old male presented with limb weakness. On examination he was areflexic with predominantly proximal weakness of the lower limbs. Neurophysiology showed a demyelinating motor polyneuropathy. Cerebrospinal fluid examination and chest x-ray were normal. Antineuronal and antiganglioside antibody screens were negative. Repeated courses of intravenous immunoglobulins and plasmapheresis did not stop progression to complete paresis in all four limbs with preserved sensation and cranial nerve function. Whole body Positron Emission Tomography scanning showed avid mediastinal lymphadenopathy and SCC of lung was diagnosed at biopsy. Radiotherapy produced clearance of the malignancy which resulted in a dramatic recovery. He regained limb power such that he now walks short distances unaided and has functional use of the arms. <h3>Conclusion</h3> This is the first described case of antibody negative demyelinating peripheral motor neuropathy in association with SCC of lung. A thorough search for malignancy should be undertaken in demyelinating polyneuropathies.
Tracheo-oesophageal fistula and bilateral recurrent laryngeal nerve palsies after blunt chest trauma.
Authors: R D Stanbridge
Journal: Thorax (1982)

A tracheo-oesophageal fistula resulting from blunt chest trauma is rare, with only 40 cases reported since 1936.'-'This is a report of the successful treatment of such a fistula, which was combined with a bilateral recurrent laryngeal nerve palsy and is the first such case.It is further unusual in that both presentation and repair occurred within 24 hours of injury. Case reportA 23-year-old man fell out of his car and was hit by another passing car.He was unconscious from head injuries but was breathing satisfactorily.Surgical emphysema and bruising were present over his upper chest and neck.He vomited once and the vomit was bloodstained.A chest radiograph showed gross surgical emphysema, shallow bilateral pneumothoraces, and multi- ple right-sided rib fractures.Within an hour of admission his breathing became laboured.He was intubated and put on intermittent positive-pressure ventilation, and drainage tubes were inserted into each pleural cavity.Three hours later gross gastric dilatation was noted (fig 1); it was relieved by nasogastric suction.The arterial gases showed an A-a shunt of 20% with a Pao2 of 106 mmHg (14.1 kPa) and a Paco2 of 48.7 mmHg (6.5 kPa).