tbuckley/cabot-search huggingface dataset:
Lobular distribution of alcohol dehydrogenase in the rat liver
Authors: Masayoshi Yamauchi, James J. Potter, Esteban Mezey
Journal: Hepatology (1988)

The hepatic lobular localization of alcohol dehydrogenase was determined in male, female and castrated male rats. Alcohol dehydrogenase immunoreactive protein and activity were increased in female and castrated rats as compared to normal male rats. By immunohistochemistry, alcohol dehydrogenase protein was found localized principally in the perivenous area of the hepatic lobule in all of the animals. Alcohol dehydrogenase activity eluted from the male rat liver, during bidirectional digitonin perfusion, exhibited a pattern characteristic of cytosolic enzymes predominantly localized to the perivenous area. The elution of the enzyme was more rapid during cava-porta than porta-cava perfusion occurring in close association with the elution of glucokinase, an enzyme localized principally in the perivenous area. By contrast, elution of lactate dehydrogenase, which is located predominantly in the periportal area, preceded elution of alcohol dehydrogenase during porta-cava perfusion, but followed it during cava-porta perfusion. These differences were less apparent in the cava-porta than in the porta-cava direction. The predominant localization of alcohol dehydrogenase immunoreactive protein and activity to the perivenous area of hepatic lobule was not affected by sexual difference or increase in the enzyme following castration.
A Preliminary Evaluation of Magnesium Pemoline in Chronic Schizophrenic Patients
Authors: M. P. BISHOP, D. M. GALLANT, R. D. THOMPSON
Journal: American Journal of Psychiatry (1968)

Magnesium pemoline was investigated for its possible beneficial effects upon intellective and memory functioning and clinical psychiatric status of chronic schizophrenic patients. Sixteen patients received magnesium pemoline for eight weeks in dosages beginning at 12.5 mg. daily and increasing after two weeks to 25 mg. daily. Four patients received magnesium pemoline at these same dosages in addition to already effective antipsychotic medications. Eight subjects from the larger group received a second fourweek trial of magnesium pemoline; four of these patients received 100 mg. daily and the other four were given 12.5 mg. every other day. All study subjects were evaluated by means of repeated psychological and psychiatric procedures as well as by extensive laboratory examinations and special tests for cardiac and dermatologic effects. Results suggested that magnesium pemoline in dosages of 12.5 mg. to 25 mg. daily has no therapeutic efficacy in chronic schizophrenic patients. Possible antidepressant activity was suggested at a dosage of 12.5 mg. every other day, but this was based on data for only four subjects and requires replication in a larger and more appropriate patient group. Addition of magnesium pemoline to an already effective regimen of antipsychotic drugs produced no further significant benefit. The effect of magnesium pemoline upon intellective and memory functioning in chronic schizophrenic patients remains equivocal. Suggestion of possible slight enhancement of such function was seen with administration of 25 mg. daily, but even if this could be clearly corroborated the degree of change does not appear to be of real clinical significance in patients of this type. With the exception of a transient rise in pulse rate and suggestion of some insomnia, evaluations for toxicity and side reactions were consistently negative at all dosages. In summary, findings from these pilot investigations offer no support for further study of magnesium pemoline in chronic schizophrenic patients.
Relationship of large and small airway response with inhaled corticosteroids to asthma control
Authors: Arvind Manoharan, William Anderson, Brian Lipworth
Journal: European Respiratory Journal (2013)

Introduction and background : Inhaled corticosteroids (ICS) are first line controller therapy in persistent asthma. While FEV 1  and FEF 25-75  are often used to assess large and small airways response respectively, there are few studies using impulse oscillometry (IOS) looking at similar outcomes.   Aims and objectives:  A post hoc analysis of a previous study was used to compare large and small airway outcomes to low dose ICS and to investigate their relationships to asthma control using the Asthma Control Questionnaire (ACQ-5).   Methods:  The study was a randomised cross-over trial in 21 mild-to-moderate persistent asthmatics: mean age, 36.7 years, FEV 1  88.5%; R5 118%. Patients were stepped off their usual ICS over 2 weeks, with a further 2-week ICS free washout period prior to randomisation. Spirometry, IOS and ACQ-5 were measured at baseline and after 2 weeks of inhaled HFA fluticasone propionate 50 µg bid (FP100). We correlated IOS and spirometry parameters to ACQ-5 at baseline and after two weeks of treatment with FP100.   Results:  Both large (FEV 1 ,R5) and small airway (FEF 25-75 ,R5-R20) outcomes significantly correlated with ACQ-5 at baseline and after 2 weeks of treatment with FP100.   Conclusions:  Large and small airways response to low dose ICS correlated to a similar degree with asthma control using either spirometry or IOS.
<i>p27Kip1</i> Repression of ErbB2-Induced Mammary Tumor Growth in Transgenic Mice Involves Skp2 and Wnt/β-Catenin Signaling
Authors: James Hulit, Richard J. Lee, Zhiping Li, Chenguang Wang, Sanjay Katiyar, Jianguo Yang, Andrew A. Quong, Kongming Wu, Chris Albanese, Robert Russell, Dolores Di Vizio, Andrew Koff, Saiinder Thummala, Hui Zhang, Jennifer Harrell, Hong Sun, William J. Muller, Giorgio Inghirami, Michael P. Lisanti, Richard G. Pestell
Journal: Cancer Research (2006)

Abstract Expression of the cyclin-dependent kinase (Cdk) inhibitor (p27Kip1) is frequently reduced in human tumors, often correlating with poor prognosis. p27Kip1 functions as a haploinsufficient tumor suppressor; however, the mechanism by which one allele of p27Kip1 regulates oncogenic signaling in vivo is not well understood. We therefore investigated the mechanisms by which p27Kip1 inhibits mammary tumor onset. Using the common background strain of FVB, p27Kip1 heterozygosity (p27+/−) accelerated ErbB2-induced mammary tumorigenesis. We conducted microarray analyses of mammary tumors developing in mice with genetic haploinsufficiency for p27Kip1 expressing a mammary-targeted ErbB2 oncogene. Global gene expression profiling and Western blot analysis of ErbB2/p27+/− tumors showed that the loss of p27Kip1 induced genes promoting lymphangiogenesis, cellular proliferation, and collaborative oncogenic signaling (Wnt/β-catenin/Tcf, Cdc25a, Smad7, and Skp2). Skp2 expression was induced by ErbB2 and repressed by p27Kip1. Degradation of p27Kip1 involves an SCF-type E3 ubiquitin ligase, including Skp2. The Skp2 component of the SCFSKP2 complex that degrades p27Kip1 was increased in ErbB2 tumors correlating with earlier tumor onset. In both murine and human ErbB2-overexpressing breast cancers, p27Kip1 levels correlated inversely with Skp2. p27Kip1 haploinsufficiency activated Wnt/β-catenin/hedgehog signaling. Reintroduction of p27Kip1 inhibited β-catenin induction of Tcf-responsive genes (Siamosis, c-Myc, and Smad7). p27Kip1 is haploinsufficient for ErbB2 mammary tumor suppression in vivo and functions to repress collaborative oncogenic signals including Skp2 and Wnt/β-catenin signaling. (Cancer Res 2006; 66(17): 8529-41)
SPECT imaging of the stomach: comparison with barostat, and effects of sex, age, body mass index, and fundoplication
Authors: E P Bouras
Journal: Gut (2002)

<b>Background:</b> Impaired gastric accommodation may lead to dyspeptic symptoms. A non-invasive method using single photon emission computed tomography (SPECT) has been developed to measure gastric volumes. <b>Aims and methods:</b> Our aims were: to assess the accuracy of SPECT with three dimensional image analysis to measure balloon volumes in vitro; to compare gastric barostat balloon volumes measured post-meal and post-distension with total gastric volumes measured simultaneously with SPECT; to present normal gastric volume data for healthy adults; and to compare SPECT data in health with symptomatic post-fundoplication patients. <b>Results:</b> In vitro balloon volumes measured by SPECT were highly accurate (<i>R</i><sup>2</sup>=0.99). When measured simultaneously by gastric barostat and SPECT, postprandial/fasting volume ratios (2.2 (0.12) (mean (SEM)) <i>v</i> 2.3 (0.15), respectively; p=0.6) and post-distension volume ratios (1.4 (0.1) <i>v</i>1.3 (0.1); p=0.2) were highly comparable. In females, postprandial gastric volumes (675 (14) <i>v</i> 744 (20) ml for males; p=0.004) and changes in gastric volumes (464 (14) ml <i>v</i> 521 (20) ml for males; p=0.01) measured by SPECT were significantly lower than in males. No effects of age or body mass index were noted. The postprandial/fasting gastric volume ratio by SPECT was lower in post-fundoplication patients (2.7 (0.2)) than in healthy controls (3.4 (0.1); p=0.003). <b>Conclusions:</b> SPECT provides a non-invasive estimate of the effect of a meal on total gastric volume that is comparable to changes in balloon volume observed with the gastric barostat. The SPECT technique is promising for investigation of gastric volumes in health and disease and the effects of pharmacological agents.
Molecular Targeting and Treatment of Composite EGFR and EGFRvIII-Positive Gliomas Using Boronated Monoclonal Antibodies
Authors: Weilian Yang, Gong Wu, Rolf F. Barth, Michele R. Swindall, Achintya K. Bandyopadhyaya, Werner Tjarks, Kevin Tordoff, Melvin Moeschberger, Thomas J. Sferra, Peter J. Binns, Kent J. Riley, Michael J. Ciesielski, Robert A. Fenstermaker, Carol J. Wikstrand
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The purpose of the present study was to evaluate the anti–epidermal growth factor receptor (EGFR) monoclonal antibody (mAb), cetuximab, (IMC-C225) and the anti-EGFRvIII mAb, L8A4, used in combination as delivery agents for boron neutron capture therapy (BNCT) of a rat glioma composed of a mixture of cells expressing either wild-type (F98EGFR) or mutant receptors(F98npEGFRvIII). Experimental Design: A heavily boronated polyamidoamine dendrimer (BD) was linked by heterobifunctional reagents to produce the boronated mAbs, BD-C225 and BD-L8A4. For in vivo biodistribution and therapy studies, a mixture of tumor cells were implanted intracerebrally into Fischer rats. Biodistribution studies were carried out by administering 125I-labeled bioconjugates via convection-enhanced delivery (CED), and for therapy studies, nonradiolabeled bioconjugates were used for BNCT. This was carried out 14 days after tumor implantation and 24 h after CED at the Massachusetts Institute of Technology nuclear reactor. Results: Following CED of a mixture of 125I-BD-C225 and 125I-BD-L8A4 to rats bearing composite tumors, 61.4% of the injected dose per gram (ID/g) was localized in the tumor compared with 30.8% ID/g for 125I-BD-L8A4 and 34.7% ID/g for 125I-BD-C225 alone. The corresponding calculated tumor boron values were 24.4 μg/g for rats that received both mAbs, and 12.3 and 13.8 μg/g, respectively, for BD-L8A4 or BD-C225 alone. The mean survival time of animals bearing composite tumors, which received both mAbs, was 55 days (P &amp;lt; 0.0001) compared with 36 days for BD-L8A4 and 38 days for BD-C225 alone, which were not significantly different from irradiated controls. Conclusions: Both EGFRvIII and wild-type EGFR tumor cell populations must be targeted using a combination of BD-cetuximab and BD-L8A4. Although in vitro C225 recognized both receptors, in vivo it was incapable of delivering the requisite amount of 10B for BNCT of EGFRvIII-expressing gliomas.
Lenalidomide‐based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients
Authors: Chindu Govindaraj, Mutsa Madondo, Ying Ying Kong, Peter Tan, Andrew Wei, Magdalena Plebanski
Journal: American Journal of Hematology (2014)

A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro‐inflammatory cytokine present at high levels within patients, can induce TNF receptor‐2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune‐surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL‐2 and IFNγ production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome. Am. J. Hematol. 89:795–802, 2014. © 2014 Wiley Periodicals, Inc.
Durable Response in Multiple Myeloma Patients Treated with Induction and Post-Transplantation Therapy with Novel Drugs
Authors: S. Ito, M. Asahi, T. Shimoyama, Y. Suzuki, R. Sasaki, Y. Fujishima, T. Mine, T. Oyake, K. Murai, Y. Ishida
Journal: Annals of Oncology (2013)
Comparison of Sympathetic Nerve Activity in Normotensive and Hypertensive Subjects
Authors: B. GUNNAR WALLIN, WOLFRAM DELIUS, KARL-ERIK HAGBARTH
Journal: Circulation Research (1973)

A microneurographic technique was used to record multiunit sympathetic activity in skin and muscle nerves of 24 healthy subjects and 21 hypertensive subjects. In both groups, the sympathetic activity recorded during rest appeared in bursts following one of two highly different temporal patterns--one characteristic for muscle nerves and the other characteristic for skin nerves. Muscle nerve sympathetic activity probably consisting of vasoconstrictor impulses, occurred in bursts that followed the pulse rhythm and waxed and waned in inverse relation to spontaneous blood pressure fluctuations. Transient random elevations of blood pressure above a certain level caused total suppression of the sympathetic bursts. This inhibitory blood pressure level was higher in hypertensive subjects than it was in normotensive subjects, suggesting an elevated baroreflex working range in hypertension. No other important differences in muscle nerve sympathetic activity were noted between the two groups. Skin nerve sympathetic activity, probably consisting of both vasoconstrictor and sudomotor impulses, had a similar temporal pattern in normotensive and hypertensive subjects at rest: bursts of variable duration occurred randomly or were loosely related to the respiratory rhythm. In both groups of subjects, the strength of this activity increased in response to arousal stimuli, mental stress, and body cooling. These findings emphasize the necessity of having highly standardized experimental conditions in future studies aimed at a quantitative comparison of the absolute strength of sympathetic activity in normotensive and hypertensive subjects.
Uncovering Residual Effects of Chronic Sleep Loss on Human Performance
Authors: Daniel A. Cohen, Wei Wang, James K. Wyatt, Richard E. Kronauer, Derk-Jan Dijk, Charles A. Czeisler, Elizabeth B. Klerman
Journal: Science Translational Medicine (2010)

The cumulative effects of chronic sleep loss may be overcome at certain times of day, but the residual effects of sleep deprivation profoundly degrade performance and may thereby compromise safety.
Comment: genetic test available for sports performance
Authors: J Savulescu, B Foddy
Journal: British Journal of Sports Medicine (2005)

Genetic testing for sports performance introduces ethical problems for parents

For the first time, we can now obtain a cheap and non-invasive genetic test, which tells us not if we have a disease or whether we are related to our parents, but what kind of sports we are likely to be good at.

For AUD$110, the Australian company Genetic Technologies will test a cheek swab for the R577X variant of the ACTN3 gene. This gene normally produces the protein α-actinin-3, which helps to produce the fast twitch muscles used in sprint and power sports. The R577X variant is a common version of this gene which produces less of this protein. People with this variant therefore will grow less fast twitch muscle tissue in their body.

The test does not identify whether a person is good or bad at sport or …
P257 Sustained Aspirin effects on platelets function over 24 hours in patients with untreated Obstructive Sleep Apnoea Syndrome (OSAS)
Authors: M Wilczynska, KE Lewis, PR Williams, M Lawrence, K Hawkins, S Stanford, PA Evans
Journal: Thorax (2013)

<h3>Introduction</h3> Prevalence of OSAS in people with cardiovascular disease is much higher than in the general population. Many OSAS patients are prescribed Aspirin for secondary prevention of cardiovascular events but the effects of morning Aspirin might be attenuated by night of recurrent apnoeas and intermittent hypoxia. Therefore evening dosing might be more appropriate. <h3>Aim</h3> To assess platelets function in the afternoon and immediately post-sleep in untreated OSAS subjects who are on long term once daily 75mg Aspirin (am). <h3>Methods</h3> 11 subjects with newly diagnosed and untreated severe OSAS prescribed Aspirin by their physicians: 10 males, (mean + SD) BMI 40.8 ± 7.2 kg/m<sup>2</sup>, age 60.8 ± 10.02 years, 4% Desaturation rate (4% DR) 58.4 ± 40.8 events/hour. Platelet aggregation was induced <i>in vitro</i> by collagen (COL), adenosine-diphoshate (ADP), and arachidonic acid (ASPI). Platelet activation was measured by multiple electrode platelet aggregometry (Multiplate™). Blood samples were collected at 4pm then 7:30am the following morning, prior to the Aspirin dose. <h3>Results</h3> Platelet aggregation in response to ASPI was reduced in the presence of Aspirin as expected and the effects were the same in the afternoon (38.6 ± 44.4 units) versus morning (39.2 ± 36.2 units). There was no difference between afternoon and morning platelet function (p &gt; 0.05 for all measures of platelet aggregation using three agonists) (Figure 1). <h3>Conclusions</h3> 75 mg of once daily (morning) Aspirin was sufficient to block <i><i>in vitro</i></i> platelet aggregation in untreated severe OSAS over a 24 hour period and was not influenced by recurrent apnoeas occurring just prior to blood sampling.
Heterogeneity of DNA deletion in gamma delta beta-thalassemia.
Authors: S H Orkin, S C Goff, D G Nathan
Journal: Journal of Clinical Investigation (1981)

By restriction endonuclease mapping, gene cloning, and DNA sequencing we have determined the region of DNA that is deleted in a family with gamma delta beta-thalassemia. The deletion removes the linked epsilon, gamma-, and delta-globin structural genes and terminates within the coding portion of the beta-globin gene. Since the extent of DNA deletion in this family differs from that reported in another family, we conclude that gamma delta beta-thalassemia is heterogeneous at the molecular level.
Inpp5f Is a Polyphosphoinositide Phosphatase That Regulates Cardiac Hypertrophic Responsiveness
Authors: Wenting Zhu, Chinmay M. Trivedi, Diane Zhou, Lijun Yuan, Min Min Lu, Jonathan A. Epstein
Journal: Circulation Research (2009)

Cardiac hypertrophy occurs in response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress. The phosphatidylinositol 3-kinase (PI3K)/Akt pathway has previously been strongly associated with hypertrophic signaling in the heart, and with the control of cell size in multiple contexts. This pathway is tightly regulated by many factors, including a host of kinases and phosphatases that function at multiple steps in the signaling cascade. For example, the PTEN (phosphatase and tensin homolog) tumor suppressor protein is a phosphoinositide 3-phosphatase that, by metabolizing phosphatidylinositol 3,4,5-trisphosphate (PtdIns[3,4,5]P(3), PIP3), acts in direct antagonism to growth factor-stimulated PI3K. Inhibition of PTEN leads to cardiomyocyte hypertrophy. Another polyphoinositide phosphatase, inositol polyphosphate-5-phosphatase F (Inpp5f) has recently been implicated in regulation of cardiac hypertrophy. Like PTEN, this phosphatase can degrade PtdIns(3,4,5)P(3) and thus modulates the PI3K/Akt pathway.To characterize the role of Inpp5f in regulating cardiac hypertrophy.We generated homozygous Inpp5f knockout mice and cardiac specific Inpp5f overexpression transgenic mice. We evaluated their hearts for biochemical, structural and functional changes. Inpp5f knockout mice have augmented hypertrophy and reactivation of the fetal gene program in response to stress when compared to wild-type littermates. Furthermore, cardiac overexpression of Inpp5f in transgenic mice reduces hypertrophic responsiveness.Our results suggest that Inpp5f is a functionally important endogenous modulator of cardiac myocyte size and of the cardiac response to stress.
The effect of immunosuppressive agents on the induction of nuclear factors that bind to sites on the interleukin 2 promoter.
Authors: A Granelli-Piperno, P Nolan, K Inaba, R M Steinman
Journal: The Journal of Experimental Medicine (1990)

Cyclosporin A (CSA), FK506, and glucocorticosteroids all inhibit the production of lymphokines by decreasing lymphokine gene expression. Previous experiments have defined six different sites that may contribute to the transcriptional control of the interleukin 2 (IL-2) promoter, and for each, active nuclear binding factors are induced upon mitogenic stimulation. While dexamethasone markedly blocks the increase in IL-2 mRNA in stimulated human blood T cells, we found that the drug does not block the appearance of factors that bind to the transcriptional control sites termed AP-1, AP-3, NF-kB, OCT-1, B site, and NF-AT. In contrast, both CSA and FK506 have similar effects: the drugs cause modest decreases in AP-3 and NF-kB, and markedly decreases in the activity of AP-1 and NF-AT. Therefore, CSA and FK506, while chemically different, seem to act upon a similar pathway that leads to IL-2 gene expression, whereas glucocorticoids do not affect this pathway.