tbuckley/cabot-search huggingface dataset:
Exercise regulation of intestinal tight junction proteins
Authors: Micah Zuhl, Suzanne Schneider, Katherine Lanphere, Carole Conn, Karol Dokladny, Pope Moseley
Journal: British Journal of Sports Medicine (2012)

Gastrointestinal distress, such as diarrhoea, cramping, vomiting, nausea and gastric pain are common among athletes during training and competition. The mechanisms that cause these symptoms are not fully understood. The stress of heat and oxidative damage during exercise causes disruption to intestinal epithelial cell tight junction proteins resulting in increased permeability to luminal endotoxins. The endotoxin moves into the blood stream leading to a systemic immune response. Tight junction integrity is altered by the phosphoylation state of the proteins occludin and claudins, and may be regulated by the type of exercise performed. Prolonged exercise and high-intensity exercise lead to an increase in key phosphorylation enzymes that ultimately cause tight junction dysfunction, but the mechanisms are different. The purpose of this review is to (1) explain the function and physiology of tight junction regulation, (2) discuss the effects of prolonged and high-intensity exercise on tight junction permeability leading to gastrointestinal distress and (3) review agents that may increase or decrease tight junction integrity during exercise.
Asthma in African cities
Authors: P CULLINAN
Journal: Thorax (1998)

Does African city life provoke asthma? In this issue of Thorax Ng’ang’a and colleagues present the findings from a meticulous cross sectional survey of 10 year old schoolchildren in Kenya.1 One quarter of 573 children living in the capital, Nairobi, developed a 10% fall in baseline forced expiratory volume in one second (FEV1) after exercise—approximately twice the prevalence among a similar number of children living in “rural” locations. The difference was more pronounced in boys but when both sexes were combined it disappeared after statistical adjustment for a variety of “host” and “environmental” characteristics. In both rural and urban children the prevalences of exercise provoked bronchial reactivity were considerably higher than in earlier studies in Africa; these are helpfully summarised by the authors of the present survey.

Bronchial hyperresponsiveness measured using an exercise stimulus is not, of course, necessarily synonymous with “asthma”. Although a reasonable specificity (and somewhat lower sensitivity) in children has been demonstrated against conventional indices of asthma,2it is worth remembering that these comparisons have been made in communities with very different disease patterns and cultural experiences from rural or newly urban Africa. Atmospheric conditions too, particularly air humidity and temperature,3 are important determinants of test results and, where geographical differences are being claimed, it is comforting to know that the measurements were made under similar ambient conditions. On the assumption, however, that the test has equivalent validity in rural and urban Kenyan children, these results indicate a doubling of asthma risk among the latter and, in part, circumvent the seemingly intractable linguistic and conceptual problems …
Pathogenesis of Polyarteritis Nodosa in Hypertensive Rats
Authors: GEORGE J. RACE, ERNST PESCHEL
Journal: Circulation Research (1954)

The pathogenesis of the vascular lesions of polyarteritis nodosa found in young rats with experimental renal hypertension is described. The panarteritic lesion was a product of the combination of renal injury and feeding sodium chloride. It began with a fibrinoid necrosis of the intima and media which was followed by an extensive inflammatory reaction with subsequent fibrosis of all layers of the vessel wall.
Treatment of Donor Bone Marrow with Monoclonal Anti-T-Cell Antibody and Complement for the Prevention of Graft-Versus-Host Disease
Authors: R. T. Mitsuyasu, Richard E Champlin, R. P. Gale, W. G. Ho, C. Lenarsky, D. Winston, M. Selch, R. Elashoff, J. V. Giorgi, J. Wells
Journal: Annals of Internal Medicine (1986)

The effects of ex-vivo depletion of T lymphocytes from donor bone marrow using a monoclonal anti-T-cell antibody (CT-2) and complement on the outcome of allogeneic bone marrow transplantation was evaluated in a prospective, randomized, double-blind study of 40 patients with leukemia. Patients receiving T-cell-depleted bone marrow had a lower incidence of acute graft-versus-host disease than control patients (3 of 20 compared with 13 of 20; p = 0.004), and mortality due to acute graft-versus-host disease was reduced. Five patients in the T-cell-depletion group developed graft failure; all control patients had sustained engraftment (p < 0.05). Clinically apparent relapse of leukemia occurred in 7 patients from the T-cell-depletion group and in 2 controls (p, not significant). Cytogenetic evidence of residual leukemia was also detected in the 5 patients with graft failure without overt relapse. Infections and overall survival were similar in the two groups. The effects of T-cell depletion on engraftment and recurrence of leukemia require further evaluation.
Fine particle mass from the Diskus inhaler and Turbuhaler inhaler in children with asthma
Authors: H Bisgaard, B Klug, B S Sumby, P K Burnell
Journal: European Respiratory Journal (1998)

The study aimed to investigate dose consistency and particle distribution from the dry powder inhalers Diskus and Turbuhaler. Full profiles of inhalation pressure versus time were recorded in 18 4 yr old and 18 8 yr old asthmatic children through Diskus and Turbuhaler inhalers. These data were used in an inhalation profile simulator to assess drug delivery from both a Diskus inhaler and a Turbuhaler inhaler, and in particular to assess the proportion of drug emitted in the coarse (&gt;4.7 microm) and fine (&lt;4.7 microm) particle size range from each type of inhaler. The inhalation profile more accurately represents the changes in flow rate over time through the device than the constant flow rate usually applied with an impactor alone. The aerosol cloud was released before the peak inspiratory effort had been achieved and accordingly the early part and not the peak of the inspiratory performance is a determinant of the quality of the aerosol. The mean (SD) amount of drug in large particles (&gt;4.7 microm), fine particles (&lt;4.7 microm) and very fine particles (&lt;2.1 microm) in percentage of label claim from the Fluticasone Diskus was 72 (5), 15 (2) and 2 (1) from the 4 yr old children and 71 (3), 18 (2) and 2 (1) from the 8 yr old children, respectively. Similar particle fractions from the Budesonide Turbuhaler were 35 (9), 21 (10) and 7 (5) from 4 yr old children and 30 (7), 32 (9) and 12 (6) from 8 yr old children. In conclusion, the Diskus inhaler provides an improved dose consistency through the varying age groups and inspiratory flow performances when compared to the Turbuhaler in terms of the proportion of the dose emitted at each particle size. This improvement is at the expense of a low fine particle mass and a high proportion of coarse particles from the Diskus as compared with the Turbuhaler.
Development of sex differences in physical aggression: The maternal link to epigenetic mechanisms
Authors: Richard E. Tremblay, Sylvana M. Côté
Journal: Behavioral and Brain Sciences (2009)

Abstract As Archer argues, recent developmental data on human physical aggression support the sexual selection hypothesis. However, sex differences are largely due to males on a chronic trajectory of aggression. Maternal characteristics of these males suggest that, in societies with low levels of physical violence, females with a history of behavior problems largely contribute to maintenance of physical aggression sex differences.
Guidelines of care for the management of atopic dermatitis
Authors: Lawrence F. Eichenfield, Wynnis L. Tom, Sarah L. Chamlin, Steven R. Feldman, Jon M. Hanifin, Eric L. Simpson, Timothy G. Berger, James N. Bergman, David E. Cohen, Kevin D. Cooper, Kelly M. Cordoro, Dawn M. Davis, Alfons Krol, David J. Margolis, Amy S. Paller, Kathryn Schwarzenberger, Robert A. Silverman, Hywel C. Williams, Craig A. Elmets, Julie Block, Christopher G. Harrod, Wendy Smith Begolka, Robert Sidbury
Journal: Journal of the American Academy of Dermatology (2013)
Non-cirrhotic portal hypertension with hypoxaemia.
Authors: C Babbs, T W Warnes, N Y Haboubi
Journal: Gut (1988)

Hypoxaemia and digital clubbing are rare but well recognised associations of hepatic cirrhosis with portal hypertension. We report the first European patient with idiopathic non-cirrhotic portal hypertension complicated by these features. Pulmonary physiological studies show the hypoxaemia to be the result of anatomical and physiological intrapulmonary shunting.
P72 Relationship between quadriceps rectus femoris anatomical cross-sectional area, physiological cross-sectional area and pennation angle in healthy subjects
Authors: B. Connolly, A. Lunt, J. Moxham, N. Hart
Journal: Thorax (2011)

<h3>Introduction</h3> Although quadriceps rectus femoris anatomical cross-sectional area (RF<sub>ACSA</sub>) has been shown to correlate with both volitional and non-volitional measures of quadriceps strength, this only incorporates the cross-sectional muscle mass and disregards the contribution of fibre orientation to the force generating capacity of the muscle. We therefore hypothesised that quadriceps rectus femoris physiological cross-sectional area (RF<sub>PCSA</sub>), which incorporates both RF<sub>ACSA</sub> and rectus femoris pennation angle (RF<sub>PA</sub>) would demonstrate a stronger relationship with, and be more representative of, quadriceps strength. <h3>Method</h3> 21 healthy adults were recruited, 9 of whom were males, median (IQR) age 31 (25–37) years. RF<sub>ACSA</sub> and RF<sub>PA</sub> were determined using real-time B-mode ultrasonography using an 8MHz 5.6 cm linear transducer (PLM805, Toshiba Medical Systems Ltd, Crawley, UK) at a point three-fifths distance from the anterior superior iliac spine to the superior patellar border. Values for RF<sub>PCSA</sub> were calculated from RF<sub>ACSA</sub> and RF<sub>PA</sub>. QMVC was assessed using the technique of isometric maximum voluntary contraction and twitch tension (TwQ) following magnetic stimulation of the femoral nerve. <h3>Results</h3> Males had significantly greater QMVC (55.2±7.1 kg vs 36.3±7.5 kg; p&lt;0.0001), TwQ (12.6±3.6 kg vs 7.4±2.5 kg; p=0.0002), RF<sub>ACSA</sub> (8.9±1.7 cm<sup>2</sup> vs 5.9±1.3 cm<sup>2</sup>; p=0.0001) and RF<sub>PCSA</sub> (8.8±1.7 cm<sup>2</sup> vs 5.8±1.2 cm<sup>2</sup>; p=0.0001). There was no gender difference evident for RF<sub>PA</sub> (10.3 (9.7–10.7)° vs 10.8 (9.8–12.1)°; p=0.4) and percent muscle activation during QMVC (83.9±9.3% vs 86.9±9.8%; p=0.5). Identical correlations between RF<sub>ACSA</sub> and RF<sub>PCSA</sub> and both QMVC and TwQ were observed (r=0.7, p=0.001). There were no significant correlations evident between RF<sub>PA</sub> and anthropomorphic measures of age, height, weight, body-mass index, fat-free mass or thigh length. <h3>Conclusion</h3> The pennation angle of the rectus femoris muscle was observed to be independent of anthropomorphic variables. Furthermore, and contrary to our original hypothesis, RF<sub>PCSA</sub> did not demonstrate a stronger relationship with quadriceps strength than RF<sub>ACSA</sub>. This is an important finding for the clinician as the additional step of measuring the pennation angle of the muscle adds a complexity to this simple bedside test that would reduce its widespread clinical applicability.
Neoadjuvant Treatment With Trastuzumab in HER2-Positive Breast Cancer: Results From the GeparQuattro Study
Authors: Michael Untch, Mahdi Rezai, Sibylle Loibl, Peter A. Fasching, Jens Huober, Hans Tesch, Ingo Bauerfeind, Jörn Hilfrich, Holger Eidtmann, Bernd Gerber, Claus Hanusch, Thorsten Kühn, Andreas du Bois, Jens-Uwe Blohmer, Christoph Thomssen, Serban Dan Costa, Christian Jackisch, Manfred Kaufmann, Keyur Mehta, Gunter von Minckwitz
Journal: Journal of Clinical Oncology (2010)

PURPOSE Trastuzumab, a humanized antibody against the human epidermal growth factor receptor type 2 (HER2), has shown high efficacy in breast cancer. We prospectively investigated its efficacy given simultaneously with anthracycline-taxane-based neoadjuvant chemotherapy. PATIENTS AND METHODS Patients with operable or locally advanced, HER2-positive tumors were treated preoperatively with four cycles of epirubicin/cyclophosphamide followed by four cycles of docetaxel with or without capecitabine (EC-T[X]) and trastuzumab 6 mg/kg (with a loading dose of 8 mg/kg) every 3 weeks during all chemotherapy cycles. Patients with HER2-negative tumors treated in the same study with the same chemotherapy but without trastuzumab were used as a reference group. Results Of 1,509 participants, 445 had HER2-positive tumors treated with trastuzumab and chemotherapy. Pathologic complete response (pCR; defined as no invasive or in situ residual tumors in the breast) rate was 31.7%, which was 16% higher than that in the reference group (15.7%). HER2-positive patients without response to the first four cycles of EC showed an unexpectedly high pCR rate of 16.6% (3.3% in the reference group). Breast conservation rate was 63.1% and comparable to that of the reference group (64.7%). EC-T(X) plus trastuzumab was associated with more febrile neutropenia and conjunctivitis, but with a comparable short-term cardiac toxicity profile as the reference group. CONCLUSION This trial confirms that combining trastuzumab with anthracycline-taxane-based neoadjuvant chemotherapy results in a high pCR rate without clinically relevant early toxicity. Combination of chemotherapy with trastuzumab should be considered when neoadjuvant treatment is given to patients with HER2-positive breast cancer.
A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck
Authors: A.R. Abdul Razak, D. Soulières, S.A. Laurie, S.J. Hotte, S. Singh, E. Winquist, S. Chia, C. Le Tourneau, P.- F. Nguyen-Tan, E.X. Chen, K.K. Chan, T. Wang, N. Giri, C. Mormont, S. Quinn, L.L. Siu
Journal: Annals of Oncology (2012)
BIM Expression in Treatment-Naïve Cancers Predicts Responsiveness to Kinase Inhibitors
Authors: Anthony C. Faber, Ryan B. Corcoran, Hiromichi Ebi, Lecia V. Sequist, Belinda A. Waltman, Euiheon Chung, Joao Incio, Subba R. Digumarthy, Sarah F. Pollack, Youngchul Song, Alona Muzikansky, Eugene Lifshits, Sylvie Roberge, Erik J. Coffman, Cyril H. Benes, Henry L. Gómez, José Baselga, Carlos L. Arteaga, Miguel N. Rivera, Dora Dias-Santagata, Rakesh K. Jain, Jeffrey A. Engelman
Journal: Cancer Discovery (2011)

Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is a wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pretreatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR-mutant, HER2-amplified, and PIK3CA-mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR-mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment-naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms.
100O Results of A Randomized Phase 2 Study of Pd 0332991, A Cyclin-Dependent Kinase (Cdk) 4/6 Inhibitor, In Combination with Letrozole vs Letrozole Alone For First-Line Treatment of ER + /Her2- Advanced Breast Cancer (Bc)
Authors: R.S. Finn, J.P. Crown, K. Boer, I. Lang, R.J. Parikh, A. Breazna, S.N. Ho, S.T. Kim, S. Randolph, D.J. Slamon
Journal: Annals of Oncology (2012)
Interactions between Vitamin D Deficiency and Phosphorus Depletion in the Rat
Authors: Nachman Brautbar, Marlin W. Walling, Jack W. Coburn, John O. Steppe
Journal: Journal of Clinical Investigation (1979)

To evaluate the role of vitamin D in the physiologic response to phosphorus depletion (P depleton) and the response to vitamin D administration in P depletion, we studied vitamin D-deficient (−D) rats, fed either a normal or low phosphorus diet and then injected intraperitoneally on alternate days with replacement vitamin D3, 1.25 μg qod (D3); 1.25-dihydroxy-vitamin D3[1,25(OH)2D3] in physiologic, 54 ng qod (LD), and pharmacologic doses, 400 ng qod (HD); or vehicle alone (−D). The following results were obtained: (a) With P depletion, urinary excretion of inorganic phosphorus (Pi) fell to almost undetectable levels in −D rats, and two physiologic features of P depletion a calcemic effect and hypercalciuria, ensued. (b) With administration of vitamin D3 or 1,25(OH)2D3 in either doses to P-depleted rats, the renal retention of Pi was unaltered despite a significant elevation of serum Pi. (c) The calcemic response to P depletion was accentuated by vitamin D sterols, and the hypercalciuria of P depletion was reduced by 1,25(OH)2D3, HD > LD > D3. (d) In −D animals receiving normal Pi (+P), D3, and 1,25(OH)2D3, both LD and HD produced a significant calcemic and phosphatemic effect. (e) Urinary Pi excretion in +P animals was reduced slightly by vitamin D3 whereas 1,25(OH)2D3, both LD and HD, lowered urinary Pi markedly despite an increased serum Pi. (f) The serial values of serum Ca and Pi and urinary Ca in PD rats and the sequential values for urinary and serum Pi in +P rats indicated more rapid effects of 1,25(OH)2D3, both HD and LD, compared with D3. We conclude that: (a) The renal adaptation and physiologic response to PD does not require the presence of vitamin D. (b) 1,25(OH)2D3 may directly enhance the renal tubular reabsorption of Pi even as serum Pi rises. (c) A hypocalciuric action of 1,25(OH)2D3 in rats on low phosphorus diet could be direct or occur as a consequence of an increase in serum Pi produced by 1,25(OH)2D3. The different sequential renal response to D3 compared with 1,25-(OH)2D3 raises the possibility that other natural forms of vitamin D3 [i.e., 25(OH)D3, 24,25(OH)2D3, etc.] which may be present in vitamin D-fed rats but not those given only 1,25(OH)2D3, could modify the actions of 1,25(OH)2D3.
Neural Stem Cell Engraftment and Myelination in the Human Brain
Authors: Nalin Gupta, Roland G. Henry, Jonathan Strober, Sang-Mo Kang, Daniel A. Lim, Monica Bucci, Eduardo Caverzasi, Laura Gaetano, Maria Luisa Mandelli, Tamara Ryan, Rachel Perry, Jody Farrell, Rita J. Jeremy, Mary Ulman, Stephen L. Huhn, A. James Barkovich, David H. Rowitch
Journal: Science Translational Medicine (2012)

Neural stem cell transplantation study suggests myelin formation in children with a severe hypomyelination disorder.
Up-Regulation of Egr1 by 1,25-Dihydroxyvitamin D3 Contributes to Increased Expression of p35 Activator of Cyclin-Dependent Kinase 5 and Consequent Onset of the Terminal Phase of HL60 Cell Differentiation
Authors: Fei Chen, Qing Wang, Xuening Wang, George P. Studzinski
Journal: Cancer Research (2004)

Abstract Advances in differentiation therapy of cancer are likely to depend on improved understanding of molecular events that underlie cell differentiation. We reported recently that cyclin-dependent kinase (Cdk)5 and p35Nck5a (p35) are expressed in human leukemia HL60 cells induced to differentiate to monocytes by an exposure to 1,25-dihydroxyvitamin D3 (1,25D3), form a complex, and this complex has kinase activity (F. Chen and G. P. Studzinski, Blood 2001;97:3763). This laboratory has also provided evidence that the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway is active in the early (24–48 h) stages of HL60 cell differentiation induced by 1,25D3 but declines in the later, terminal phase of this form of differentiation (X. Wang and G. P. Studzinski, J Cell Biochem 2001;80:471). We examine now the hypothesis that Egr1 protein contributes to the up-regulation of p35 gene transcription and, thus, activated Cdk5/p35 kinase phosphorylates and inactivates mitogen-activated protein/extracellular signal-regulated kinase kinase 1 (MEK1). Our data show that in 1,25D3-treated cells, p35 and Egr1 protein levels are elevated in a dose-dependent manner at the onset of the late stage of differentiation. We show also that 1,25D3 treatment of HL60 cells markedly increases the binding of Egr1 to an element in the p35 gene promoter, whereas transfection of an excess of this Egr1-binding oligonucleotide (“promoter decoy”) reduces p35 gene transcription and cell differentiation. Additionally, Cdk5/p35 phosphorylates MEK1 and inhibits its ability to phosphorylate its downstream target Erk2. These data suggest that in 1,25D3-treated HL60 cells, Egr1 up-regulates p35 gene transcription and that Cdk5/p35 kinase inactivates the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway by phosphorylation of MEK1, and this contributes to terminal differentiation of these cells.
Great expectations of modern RA treatment
Authors: S Irvine
Journal: Annals of the Rheumatic Diseases (2005)

Rheumatological professionals and their patients should have high expectations of treatment

In recent years the expectation of benefit of treatment of rheumatoid arthritis (RA) has evolved. Remission, as defined by the disease activity score (table 1), is now a goal for many clinicians. To achieve this it is standard practice to institute disease modifying antirheumatic drug (DMARD) treatment early in the disease course and to use combination DMARD treatment when single drugs prove ineffective. In addition, anti-tumour necrosis factor α (TNFα) treatment has an established role in severe RA. However, despite these advances remission is achieved in only a minority of patients. Few randomised controlled trials (RCTs) in RA report remission data, which in itself is testament to the infrequency of remission. Why are expectations of greater benefit not realised?

View this table:

 Table 1  
 Definitions of disease activity using DAS and DAS289–11



In RCTs of the commonly used DMARDs methotrexate (MTX), sulfasalazine (SSZ), and leflunomide (LEF) as monotherapy, remission rates of 12.7–25% have been reported, depending on the population studied.1–3 Although individual clinical responses to anti-TNFα monotherapy can be dramatic, remission rates in patients treated with anti-TNFα agents alone in RCTs have been disappointing, with 22.4% of patients with established disease achieving remission at 2 years.1

However, the combination of MTX and anti-TNFα treatment has provided more encouraging clinical results. At 2 years’ follow up in the TEMPO study the combination of etanercept and MTX resulted in remission in 42.4% of patients with established RA compared with 25% remission with MTX or etanercept monotherapy.1 Similar rates of remission were also seen in the combination arm (MTX, SSZ, hydroxychloroquine (HCQ), and low dose prednisolone) of the FIN-RACo early RA study at 2 years.2

Although there are no published data on remission rates with triple treatment (MTX, SSZ, and …