tbuckley/cabot-search huggingface dataset:
Pharmacokinetics (PK) and efficacy of sunitinib in patients with metastatic renal cell carcinoma (mRCC)
Authors: B. E. Houk, M. Amantea, R. J. Motzer, M. D. Michaelson, B. I. Rini, D. J. George, B. G. Redman, G. R. Hudes, B. Poland, C. L. Bello
Journal: Journal of Clinical Oncology (2006)

4531 Background: Sunitinib malate (SU11248) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, PDGFR, KIT, FLT3, and RET. Clinical studies have demonstrated efficacy of sunitinib in patients with multiple tumor types including two phase II studies in mRCC, where second-line monotherapy with sunitinib showed a response rate of greater than 40% by RECIST, with an additional ≥25% of pts exhibiting prolonged stable disease. A population PK analysis was performed to assess the exposure-response relationship between PK and tumor volume changes, clinical response, and time to tumor progression (TTP) in these two mRCC studies. Methods: In these two studies, 169 patients with mRCC were treated with sunitinib 50 mg/day for 4 weeks, followed by a 2-week off period (Schedule 4/2). Response to treatment was assessed by measuring tumor volume. Clinical response was assessed using RECIST and TTP using logistic regression and Kaplan-Meier survival analysis. A previously described population PK model of sunitinib and its primary active metabolite SU12662 was updated using additional data from three trials, including the two RCC trials. Using the model and trough plasma concentrations, steady-state AUCs of sunitinib plus SU12662 were estimated for each mRCC patient and tested as a predictor of response. Results: PK profiles were evaluable for 149 patients in the two mRCC trials. Plasma clearance (CL) decreased by an average of 28% in mRCC patients relative to healthy volunteers. Covariates, such as gender, age, and ECOG score also affected CL, however all of these changes were less than the estimated inter-individual variability in CL of 43%. Improved clinical response and longer TTPs were associated with greater AUCs. Within 12 weeks of treatment, mean tumor volume decreased by 24–32% in each trial. Conclusions: Individual patient exposures to sunitinib and SU12662 can be predicted with sparse concentration measurements using population PK analysis, and an exposure-response relationship is evident in mRCC. Dose adjustment is not warranted based upon any evaluated covariate. Over the first 12 weeks of treatment at 50 mg daily on Schedule 4/2, increased exposure was associated with improved clinical response and decreased tumor volumes. [Table: see text]
Hyaluronic acid production in vitro by synovial lining cells from normal and rheumatoid joints.
Authors: I M Dahl, G Husby
Journal: Annals of the Rheumatic Diseases (1985)

Organ cultures and primary cell cultures were established from synovial tissue collected from patients with rheumatoid arthritis. Hyaluronic acid measured by the incorporation of [3H]glucosamine into the polysaccharide was found to be synthesised in the cultures immediately after transfer from in-vivo to in-vitro conditions. This was in contrast to the primary cultures established from cells isolated from normal joints. The latter cells did not synthesise any detectable hyaluronate. 90-100% of the cells in primary culture were found to be esterase positive, indicating their macrophage nature. The molecular weight of the hyaluronate produced by the pathological cells was low (approximately 50 000) compared with the molecular weight of hyaluronate found in joint fluid from normal or rheumatoid joints. Cell lines of fibroblasts established from rheumatoid joints and studied after four or seven passages also produced hyaluronate of low molecular weight. It is known that similar cell lines from normal joints produce a high molecular weight polymer.
The sap from Euphorbia peplus is effective against human nonmelanoma skin cancers
Authors: J.R. Ramsay, A. Suhrbier, J.H. Aylward, S. Ogbourne, S.-J. Cozzi, M.G. Poulsen, K.C. Baumann, P. Welburn, G.L. Redlich, P.G. Parsons
Journal: British Journal of Dermatology (2011)

Background The sap from Euphorbia peplus, commonly known as petty spurge in the U.K. or radium weed in Australia, has been used as a traditional treatment for a number of cancers. Objective To determine the effectiveness of E. peplus sap in a phase I/II clinical study for the topical treatment of basal cell carcinomas (BCC), squamous cell carcinomas (SCC) and intraepidermal carcinomas (IEC). Methods Thirty‐six patients, who had refused, failed or were unsuitable for conventional treatment, were enrolled in a phase I/II clinical study. A total of 48 skin cancer lesions were treated topically with 100–300 μL of E. peplus sap once daily for 3 days. Results The complete clinical response rates at 1 month were 82% (n =28) for BCC, 94% (n =16) for IEC and 75% (n =4) for SCC. After a mean follow‐up of 15 months these rates were 57%, 75% and 50%, respectively. For superficial lesions < 16 mm, the response rates after follow‐up were 100% for IEC (n =10) and 78% for BCC (n =9). Conclusions The clinical responses for these relatively unfavourable lesions (43% had failed previous treatments, 35% were situated in the head and neck region and 30% were > 2 cm in diameter), are comparable with existing nonsurgical treatments. An active ingredient of E. peplus sap has been identified as ingenol mebutate (PEP005). This clinical study affirms community experience with E. peplus sap, and supports further clinical development of PEP005 for the treatment of BCC, SCC and IEC.
Neuroleptics and operant behavior: The anhedonia hypothesis
Authors: Roy A. Wise
Journal: Behavioral and Brain Sciences (1982)

Abstract Neuroleptic drugs disrupt the learning and performance of operant habits motivated by a variety of positive reinforcers, including food, water, brain stimulation, intravenous opiates, stimulants, and barbiturates. This disruption has been demonstrated in several kinds of experiments with doses that do not significantly limit normal response capacity. With continuous reinforcement neuroleptics gradually cause responding to cease, as in extinction or satiation. This pattern is not due to satiation, however, because it also occurs with nonsatiating reinforcement (such as saccharin or brain stimulation). Repeated tests with neuroleptics result in earlier and earlier response cessation reminiscent of the kind of decreased resistance to extinction caused by repeated tests without the expected reward. Indeed, withholding reward can have the same effect on responding under later neuroleptic treatment as prior experience with neuroleptics themselves; this suggests that there is a transfer of learning (really unlearning) from nonreward to neuroleptic conditions. These tests under continuous reinforcement schedules suggest that neuroleptics blunt the ability of reinforcers to sustain responding at doses which largely spare the ability of the animal to initiate responding. Animals trained under partial reinforcement, however, do not respond as well during neuroleptic testing as animals trained under continuous reinforcement. Thus, neuroleptics can also impair responding (though not response capacity ) that is normally sustained by environmental stimuli (and associated expectancies) in the absence of the primary reinforcer. Neuroleptics also blunt the euphoric impact of amphetamine in humans. These data suggest that the most subtle and interesting effect of neuroleptics is a selective attenuation of motivational arousal which is (a) critical for goal-directed behavior, (b) normally induced by reinforcers and associated environmental stimuli, and (c) normally accompanied by the subjective experience of pleasure. Because these drugs are used to treat schizophrenia and because they cause parkinsonian-like side effects, this action has implications for a better understanding of human pathology as well as normal motivational processes.
Role of Dendritic Cells in the Induction of Proliferative T Lymphocyte-Mediated Responses to Iodine Contrast Media
Authors: C ANTUNEZ, A BARBAUD, R GUEANTRODRIGUEZ, C MAYORGA, J CORNEJOGARCIA, M TORRES, J GUEANT, M BLANCA
Journal: Journal of Allergy and Clinical Immunology (2008)
Characteristics of traditional Chinese medicine use in children with asthma: a nationwide population-based study
Authors: T.-P. Huang, P.-H. Liu, A. S.-Y. Lien, S.-L. Yang, H.-H. Chang, H.-R. Yen
Journal: Allergy (2013)

Asthma is a chronic inflammatory airway disease accounting for severe morbidity and mortality in children. To determine the characteristics of traditional Chinese medicine (TCM) used to treat pediatric asthma, we conducted a nationwide population-based study by analyzing a cohort of one million randomly sampled patients from the beneficiaries of the National Health Insurance Program in Taiwan from 2002 to 2010. Children under 18 years of age with newly diagnosed asthma (ICD-9-CM code: 493, N = 45 833) were enrolled, and 57.95% (N = 26 585) of them had used TCM. The number of TCM users was significantly more than that of non-TCM users in school-age children. The most commonly prescribed TCM formula is Ding-chuan-tang, or Xing-ren (Semen Armeniacae Amarum) for the single herb. Our study is the first to reveal characteristics and prescription patterns of the use of TCM in children with asthma. Further research is needed to elucidate the efficacy and safety of these Chinese herbal products.
Genome-wide association study of recalcitrant atopic dermatitis in Korean children
Authors: Kyung Won Kim, Rachel A. Myers, Ji Hyun Lee, Catherine Igartua, Kyung Eun Lee, Yoon Hee Kim, Eun-Jin Kim, Dankyu Yoon, Joo-Shil Lee, Tomomitsu Hirota, Mayumi Tamari, Atsushi Takahashi, Michiaki Kubo, Je-Min Choi, Kyu-Earn Kim, Dan L. Nicolae, Carole Ober, Myung Hyun Sohn
Journal: Journal of Allergy and Clinical Immunology (2015)
THE UNIVERSAL SERVICE PETITION
Authors: E. Waggett
Journal: BMJ (1910)

We are informed by another correspondent that in London it is firmly believed by many who ought to know better that women suffering from syphilis are smothered under mattresses at the Lock Hospital.Is this foolish belief inspired by moral indignation-which in old days used either to deny the shelter of hospitals to venereal cases, or cause the unfortunate sufferers to be treated in the most barbarous fashion ?Or is it a confusion of ideas arising from the old stories about the way in which cases of hydrophobia were dealt with ?COLONIAL PRACTITIONERS AND THE BRITISH REGISTER.SIR,-Will you allow me a short space to direct atten.tion to the question of medical registration in Great Britain.If I remember correctly, the fee that I paid for registration was 5 guineas.The advantages thus paid for were medical status and a power by law to recover debts for medical and surgical attendance.For a student fighting against odds to enter the medical profession the fee was certainly heavy.At all events, it should have ensured a protection of the name and registration for the period of the enrolled practitioner's lifetime.It did not so protect myself.It is over thirty years ago, while in practice in Lameth, that, after a serious illnees, I had to flee to save my life.I recovered, and for the above period have carried on the practice of my profession for eight or nine years in Victoria, and since that in Queensland, Australia.In both Colonies I was duly enrolled by the Medical Boards, as I supposed in virtue of and in conjunction with my London registration.In neither instance had I to pay for the same.On returning to London on a visit, I found that my name had been erased from the Register, also from Churchill's Medical Directory.On appealing, I am informed that a letter sent to me was unanswered, and so my name was struck off.That is according to the law of the Council.First of all, let me point out, that British practitioners pioneering new countries, may easily never receive letters; if sent, I never received this one.Secondly,
Comparative study of aminoglycoside nephrotoxicity in normal rats and rats with experimental cirrhosis
Authors: Jordi Camps, Xavier Sola, Antoni Rimola, Albert Parés, Antoni Rives, Juan M. Salmeron, Vicente Arroyo, Joan Rodés
Journal: Hepatology (1988)

Several authors have suggested that the risk of developing aminoglycoside nephrotoxicity is greater in cirrhotic patients than in the noncirrhotic population. However, this has not been confirmed by other investigators. To compare the intensity and characteristics of aminoglycoside nephrotoxicity in cirrhotic and normal rats, 31 rats with carbon tetrachloride-induced cirrhosis with ascites and 35 control rats were treated with gentamicin. Each group of rats was divided into two subgroups in order to receive 10 or 40 mg per kg per day of gentamicin, and different subsets of animals were killed on Days 4, 8 and 12 of treatment for renal histological examination and determination of renal tissue gentamicin concentration. Urine volume, osmolality, sodium excretion and N-acetyl-β-D-glucosaminidase activity were measured daily throughout the study. Creatinine clearance and trough plasma concentration of gentamicin were determined in each animal immediately before killing. There were no significant differences between cirrhotic and control rats in relation to the magnitude of changes in urine volume, osmolality, sodium excretion and N-acetyl-β-D-glucosaminidase activity and creatinine clearance during gentamicin administration. The values of a histopathological score semiquantitatively assessing the renal morphological changes observed by light microscopy were not significantly different in cirrhotic and control rats. In addition, similar trough plasma and renal cortical tissue concentrations of gentamicin were observed in both groups of animals. These results suggest that, in this experimental model, cirrhosis does not increase the risk for aminoglycoside nephrotoxicity.
Severe Mechanical Dysfunction in Pharyngeal Muscle from Adult <i>mdx</i> Mice
Authors: PIERRE ATTAL, FRANCINE LAMBERT, SYLVAIN MARCHAND-ADAM, SERGE BOBIN, JEAN-CLAUDE POURNY, DENIS CHEMLA, YVES LECARPENTIER, CATHERINE COIRAULT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The mdx mouse is a widely used animal model of human muscular dystrophy. Although diaphragm muscle exhibits severe muscle weakness throughout the life of the animal, the limb muscle function of mdx mice spontaneously recovers by 6 mo of age. Pharyngeal dilator muscles such as sternohyoid (SH) contribute to upper airway patency during breathing. We hypothesized that SH muscle function was impaired in 6-mo-old mdx mice. Mechanical properties and myosin heavy chain (MHC) composition were investigated in isolated SH from 6-mo-old control (C, n = 10) and mdx (n = 10) mice. As compared with C, peak tetanic tension (Pmax) and maximum shortening velocity were 50% and 16% lower in mdx mice (p < 0.001 and p < 0.05, respectively). Peak mechanical power was lower in mdx than in C (19.0 ± 3.2 versus 57.4 ± 5.1 mW g− 1, p < 0.001). Both C and mdx SH were composed exclusively of fast myosin isoforms. As compared with C, mdx SH presented a higher proportion of IIX-MHC and a reduction in IIB-MHC (each p < 0.001). In conclusion, our results demonstrated severe SH muscle dysfunction in 6-mo-old mdx mice, that is, at a time when limb muscle function has recovered. Thus, SH muscle of the mdx mouse may be an excellent muscle for studying Duchenne muscular dystrophy.
Cutaneous viral infection as a presentation of intestinal lymphangiectasia
Authors: I.N. ROSS, I. CHESNER, R.A. THOMPSON, R.G. PARKER, P. ASQUITH
Journal: British Journal of Dermatology (1982)

Journal Article Cutaneous viral infection as a presentation of intestinal lymphangiectasia Get access I.N. ROSS, I.N. ROSS The Alistair Frazer and John Squire Metabolic and Clinical Research Unit, and the Regional Immunology Laboratory, East Birmingham Hospital, Bordesiey Green East, Birmingham 89 5ST Dr I.N.Ross, Department of Medicine, Clinical Sciences Building, Hope Hospital, Eccles Old Road, Salford M6 8HD. Search for other works by this author on: Oxford Academic Google Scholar I. CHESNER, I. CHESNER The Alistair Frazer and John Squire Metabolic and Clinical Research Unit, and the Regional Immunology Laboratory, East Birmingham Hospital, Bordesiey Green East, Birmingham 89 5ST Search for other works by this author on: Oxford Academic Google Scholar R.A. THOMPSON, R.A. THOMPSON The Alistair Frazer and John Squire Metabolic and Clinical Research Unit, and the Regional Immunology Laboratory, East Birmingham Hospital, Bordesiey Green East, Birmingham 89 5ST Search for other works by this author on: Oxford Academic Google Scholar R.G. PARKER, R.G. PARKER The Alistair Frazer and John Squire Metabolic and Clinical Research Unit, and the Regional Immunology Laboratory, East Birmingham Hospital, Bordesiey Green East, Birmingham 89 5ST Search for other works by this author on: Oxford Academic Google Scholar P. ASQUITH P. ASQUITH The Alistair Frazer and John Squire Metabolic and Clinical Research Unit, and the Regional Immunology Laboratory, East Birmingham Hospital, Bordesiey Green East, Birmingham 89 5ST Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 107, Issue 3, 1 September 1982, Pages 357–364, https://doi.org/10.1111/j.1365-2133.1982.tb00367.x Published: 01 September 1982 Article history Accepted: 03 December 1981 Published: 01 September 1982
Regulation of alveolar macrophage transforming growth factor-beta secretion by corticosteroids in bleomycin-induced pulmonary inflammation in the rat.
Authors: N Khalil, C Whitman, L Zuo, D Danielpour, A Greenberg
Journal: Journal of Clinical Investigation (1993)

In a model of pulmonary inflammation and fibrosis induced by the antineoplastic antibiotic, bleomycin, we previously demonstrated that TGF-beta was markedly elevated within 7 d of bleomycin administration. At the time of maximal TGF-beta production, TGF-beta 1 was localized by immunohistochemistry to be present almost exclusively in alveolar macrophages. In this study, we have demonstrated that alveolar macrophages stimulated by bleomycin-induced injury secrete large quantities of biologically active TGF-beta 1 when explanted into tissue culture. However, alveolar macrophages from normal saline-treated rats secrete small quantities of biologically inactive TGF-beta. In contrast, splenic macrophages secrete large quantities of inactive TGF-beta and are unaffected by the intratracheal bleomycin treatment. High doses of the corticosteroid methylprednisolone given intramuscularly before and concomitantly with bleomycin administration prevented the influx of alveolar macrophages into the lungs, diminishing both the number of macrophages present in the alveoli and the total lung content of TGF-beta. However, the rate of secretion of TGF-beta by alveolar macrophages recovered from the alveoli was unchanged after corticosteroid treatment. When activated alveolar macrophages were cultured in the presence of several concentrations of dexamethasone that completely suppressed IL-1 secretion, little effect on TGF-beta secretion was observed. The findings in this study demonstrate that during bleomycin-induced injury, alveolar macrophages not only secrete large quantities of active TGF-beta 1, but are a predominant source of the enhanced TGF-beta response seen in this model. Furthermore, the alveolar macrophage secretion of TGF-beta is not inhibited by the presence of high concentrations of corticosteroids.
Mature dendritic cells boost functionally superior CD8+ T-cell in humans without foreign helper epitopes
Authors: Madhav V. Dhodapkar, Joseph Krasovsky, Ralph M. Steinman, Nina Bhardwaj
Journal: Journal of Clinical Investigation (2000)

We have recently shown that a single injection of mature, antigen-pulsed, human dendritic cells (DCs) rapidly elicits CD4+ and CD8+ T-cell immunity in vivo. The DCs were pulsed with 2 foreign proteins, keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT), as well as an HLA A2.1-restricted influenza matrix peptide (MP). Responses to all 3 antigens peaked at 30–90 days after immunization and declined thereafter. To determine if the foreign helper proteins (TT and KLH) were essential for CD8+ T-cell responses to the viral peptide, we reinjected 3 of the HLA-2.1 subjects with mature DCs pulsed with MP alone. All 3 volunteers showed a rapid boost in MP-specific immunity, and freshly sampled blood from 1 contained cytolytic T cells. In all 3 subjects, CD8+ T-cell responses to booster DCs were faster and of greater magnitude than the responses to the first DC injection. Importantly, the T cells that proliferated after booster DC treatment secreted interferon-γ upon challenge with much lower doses of viral peptide than those elicited after the first injection, indicating a higher functional avidity for the ligand. These data begin to outline the kinetics of T-cell immunity in response to DCs and demonstrate that booster injections of mature DCs enhance both qualitative and quantitative aspects of CD8+ T-cell function in humans.
Risk of pancreatic cancer in patients with cystic fibrosis
Authors: P Maisonneuve, B C Marshall, A B Lowenfels
Journal: Gut (2007)

Furthermore, the association of coeliac disease and IBS symptoms is biologically plausible with many mechanisms being reported-for example, autonomic dysfunction, intussusception, exocrine pancreatic disease, small intestinal ulceration, and associated microscopic colitis.Our own group found an increased prevalence of coeliac disease in patients referred with surgical abdominal pain, notably in those with unexplained or non-specific abdominal pain. 9The association between IBS and coeliac disease appears to operate in both directions, as patients with coeliac disease (on a gluten-free diet) may describe IBS symptoms. 10Similarly, abdominal pain, diarrhoea, or constipation were associated with an increased risk of coeliac disease in a large multicentre study. 11All of these symptoms can overlap with IBS.From a clinical perspective, is investigating IBS patients for coeliac disease a valid approach?It is recognised that the majority of patients with coeliac disease have significant delays in diagnosis and once established on the gluten-free diet they derive symptomatic benefit.Case finding for coeliac disease in patients with IBS symptoms is both cost-effective and beneficial in terms of quality of life years gained, even at prevalence values of 1.1-2%. 12e accept that further multicentre studies in both primary and secondary care are required to resolve this debate.In such studies assessment of quality of life and symptom resolution (when individuals are established on a glutenfree diet) is imperative.Despite the existing evidence, investigating for coeliac disease in patients fulfilling the Rome II criteria is still not widely accepted (although recommended in UK guidelines).Why should this be?Is this a clash of ideological dogma when considering possible mechanisms for IBS?