tbuckley/cabot-search huggingface dataset:
THE physiology of jaundice: Molecular and functional characterization of the Crigler-Najjar syndromes
Authors: Carl L. Berg
Journal: Hepatology (1995)

Crigler-Najjar (CN) disease is classified into two subtypes, type I and II. The molecular basis for the difference between these types is not well understood. Several mutations in the bilirubin UDP-glucuronosyltransferase (B-UGT) gene of six CN type I and two CN type II patients were identified. Recombinant cDNAs containing these mutations were expressed in COS cells. B-UGT activity was measured using HPLC and the amount of expressed protein was quantitated using a sandwich ELISA. This enabled us to determine the specific activities of the expressed enzymes. All type I patients examined had mutations in the B-UGT1 gene that lead to completely inactive enzymes. The mutations in the B-UGT1 gene of patients with CN type II only partially inactivated the enzyme. At saturating concentrations of bilirubin (75 μM) CN type II patient A had 4.4 ± 2% residual activity and CN type II patient B had 38 ± 2% residual activity. Kinetic constants for the glucuronidation of bilirubin were determined. The affinities for bilirubin of B-UGT1 expressed in COS cells and B-UGT from human liver microsomes were similar with K m of 5.1 ± 0.9 μM and 7.9 ± 5.3 μM, respectively. B-UGT1 from patient B had a tenfold decreased affinity for bilirubin, K m = 56 ± 23 μM. At physiological concentrations of bilirubin both type II patients will have a strongly reduced conjugation capacity, whereas type I patients have no B-UGT activity. We conclude that CN type I is caused by a complete absence of functional B-UGT and that in CN type II B-UGT activity is reduced. ( J. Clin. Invest. 1994. 94:2385-2391.) Key words: hereditary diseases · site directed mutagenesis · enzyme-linked immunosorbent assay · enzyme kinetics · enzyme activity. (Reproduced from The Journal of Clinical Investigation, 1994, vol. 94, pp. 2385-2391 by copyright permission of The Society for Clinical Investigation.
Effects of prostaglandin E1 and 15-methyl-prostaglandin E1 on the cardiovascular responses to bilateral carotid arterial occlusion
Authors: J. NAKANO, R. B. MCCLOY
Journal: Cardiovascular Research (1974)

Journal Article Effects of prostaglandin E1 and 15-methyl-prostaglandin E1 on the cardiovascular responses to bilateral carotid arterial occlusion Get access JIRO NAKANO, JIRO NAKANO From the Departments of Pharmacology and Medicine, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar ROBERT B. MCCLOY, JR ROBERT B. MCCLOY, JR 2 From the Departments of Pharmacology and Medicine, University of Oklahoma College of Medicine, Oklahoma City, Oklahoma, USA 2Trainee of the US Public Health Service Psychosomatic Medicine Training Program (HL 05351). Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 8, Issue 6, November 1974, Pages 750–757, https://doi.org/10.1093/cvr/8.6.750 Published: 01 November 1974
The Evolution of Multimeric Protein Assemblages
Authors: M. Lynch
Journal: Molecular Biology and Evolution (2011)

Although the mechanisms by which complex cellular features evolve constitute one of the great unsolved problems of evolutionary biology, it is clear that the emergence of new protein–protein interactions, often accompanied by the diversification of duplicate genes, is involved. Using information on the levels of protein multimerization in major phylogenetic groups as a guide to the patterns that must be explained and relying on results from population-genetic theory to define the relative plausibility of alternative evolutionary pathways, a framework for understanding the evolution of dimers is developed. The resultant theory demonstrates that the likelihoods of alternative pathways for the emergence of protein complexes depend strongly on the effective population size. Nonetheless, it is equally clear that further advancements in this area will require comparative studies on the fitness consequences of alternative monomeric and dimeric proteins.
Write for money.
Authors: M O'Donnell
Journal: BMJ (1987)

but these increases in efficiency threaten financial crises.2122Attempts to explain variation in admission rates in the context of RAWP have so far concentrated on measures of social deprivation.But that variation is more likely to be due, as RAWP believed, to access to supply.Questions that do not seem to be asked are whether high admission rates are justified in terms of their outcomes and whetherincreases in admission rates are indeed genuine increases in efficiency.Although difficult, research into these questions is likely to be more soundly based than attempts to estimate the need for health services arising from social deprivation by using data on use and attempting to control for supply.We hope that the final report of the RAWP review recognises that research into the impact of variations in a populations' use of services in terms of outcomes is fundamental to future policies for the fair and efficient allocation of resources.
Vaccine-induced myeloid cell population dampens protective immunity to SIV
Authors: Yongjun Sui, Alison Hogg, Yichuan Wang, Blake Frey, Huifeng Yu, Zheng Xia, David Venzon, Katherine McKinnon, Jeremy Smedley, Mercy Gathuka, Dennis Klinman, Brandon F. Keele, Sol Langermann, Linda Liu, Genoveffa Franchini, Jay A. Berzofsky
Journal: Journal of Clinical Investigation (2014)

Vaccines are largely evaluated for their ability to promote adaptive immunity, with little focus on the induction of negative immune regulators. Adjuvants facilitate and enhance vaccine-induced immune responses and have been explored for mediating protection against HIV. Using a regimen of peptide priming followed by a modified vaccinia Ankara (MVA) boost in a nonhuman primate model, we found that an SIV vaccine incorporating molecular adjuvants mediated partial protection against rectal SIVmac251 challenges. Animals treated with vaccine and multiple adjuvants exhibited a reduced viral load (VL) compared with those treated with vaccine only. Surprisingly, animals treated with adjuvant alone had reduced VLs that were comparable to or better than those of the vaccine-treated group. VL reduction was greatest in animals with the MHC class I allele Mamu-A*01 that were treated with adjuvant only and was largely dependent on CD8+ T cells. Early VLs correlated with Ki67+CCR5+CD4+ T cell frequency, while set-point VL was associated with expansion of a myeloid cell population that was phenotypically similar to myeloid-derived suppressor cells (MDSCs) and that suppressed T cell responses in vitro. MDSC expansion occurred in animals receiving vaccine and was not observed in the adjuvant-only group. Collectively, these results indicate that vaccine-induced MDSCs inhibit protective cellular immunity and suggest that preventing MDSC induction may be critical for effective AIDS vaccination.
Disproportionate Decrease in α- Compared With β-Adrenergic Sensitivity in the Dorsal Hand Vein in Pregnancy Favors Vasodilation
Authors: Ruth Landau, Victor Dishy, Alastair J.J. Wood, C. Michael Stein, Richard M. Smiley
Journal: Circulation (2002)

Background— Altered vascular responses to adrenergic agonists during pregnancy are thought to play an important role in the regulation of blood pressure and placental blood flow. Because α 1 -adrenergic and β 2 -adrenergic sensitivity act in opposing directions to determine vascular tone, we simultaneously evaluated α-adrenergic–mediated vasoconstriction and β-adrenergic–mediated vasodilation in dorsal hand veins during and after pregnancy. Methods and Results— Twenty healthy pregnant women were studied at 32 to 37 weeks of gestation and again 12 weeks after delivery. Vascular response to phenylephrine (PE) and isoproterenol (ISO) was measured in a dorsal hand vein using the linear variable differential transformer technique. The dose of PE resulting in 50% constriction (CD 50 ) was determined. The response to ISO was measured after the PE preconstriction. Pregnant and postpartum values, expressed as geometric mean (95% CI), were compared by paired t test. α-Adrenergic sensitivity during pregnancy (CD 50 2.7 μg/min [95% CI, 1.5 to 5.0]) was markedly decreased, ≈7-fold, compared with postpartum (0.4 μg/min [95% CI, 0.3 to 0.7] [ P &lt;0.01]). β-Adrenergic vasodilation was also attenuated during pregnancy. The ED 50 of ISO (dose of ISO resulting in 50% of the maximal response, E max ) was greater during pregnancy (20 ng/min [95% CI, 11 to 35]) than postpartum (8 ng/min [95% CI, 5 to 12]) ( P &lt;0.05). ISO E max was also significantly less during pregnancy (81% [95% CI, 65 to 97] compared with postpartum (105% [95% CI, 97 to 113]) ( P &lt;01.01). Conclusions— Normal pregnancy is characterized by decreased venous sensitivity to both α 1 -adrenoceptor–mediated vasoconstriction and β 2 -adrenoceptor–mediated vasodilation. The greater decrease in α 1 compared with β 2 response may contribute to the vasodilated state characteristic of human pregnancy.
PISCES: A Horoscope for First-Line Targeted Therapy of Metastatic Renal Cell Carcinoma
Authors: Maxine Sun, Alessandro Larcher, Jonas Schiffmann, Pierre I. Karakiewicz
Journal: Journal of Clinical Oncology (2014)

TO THE EDITOR: Escudier et al recently published a report of the PISCES (Patient Preference Study of Pazopanib Versus Sunitinib in Advanced or Metastatic Kidney Cancer) trial, which assessed treatment preferences for pazopanib versus sunitinib in newly diagnosed patients with metastatic clear cell renal cell carcinoma. We wish to congratulate the authors for the novelty of the study design. However, we are unsure whether the tested concept of a 10-week course of one targeted therapy followed by a 2-week washout and another 10-week period of a second targeted therapy (or vice versa) is of value, especially when treatment selection is made in a real-life clinical setting, where patients continue to receive therapy until disease progression or intolerable toxicity. The duration of therapy usually spans months or even years. Only occasionally is it administered for weeks (as in the study), for reasons such as early failure or unmanageable toxicity. The tolerability of targeted agents usually improves with time, and with dose and/or schedule adjustments. Moreover, the benefits of therapy, perceived toxicity, and patient acceptance of the targeted agent are also strongly affected by objective response rates. Under most circumstances, the efficacy is first assessed 12 weeks after the start of therapy. The relationship between efficacy, toxicity, tolerability, and the patient, as well as physician acceptance of this relationship, then determine whether treatment is pursued or abandoned. All of these processes are not realistically captured within the study design. Hence, the disconnect between the study design and the real-life clinical setting represents an important flaw. The study design also raises a concern with respect to short exposure time to two consecutive agents that are not administered with curative, but rather questionable, intent. Such exposure has unknown consequences and may induce resistance or other untoward effects when real-life treatment is needed to prevent life-threatening disease progression. The study design is actually reminiscent of studies where quality of life represents the main end point. There are settings in which such study design is appropriate, valid, and ethically acceptable, such as in patients with overactive bladder or benign prostate hyperplasia, where symptom relief represents the focal point of treatment and where drugs can be replaced or stopped without danger or consequence to patient survival. Conversely, we are concerned about the validity and appropriateness of the design of the study by Escudier et al in the context of a life-threatening disease, such as metastatic clear cell renal cell carcinoma, where short-term sequential use of two key agents is made without knowledge of its effect on further patient cancer control outcomes.
Multiple myeloma on the Fylde coast.
Authors: N G Flanagan, D S Harry, T Kozlowski, T Sorahan
Journal: BMJ (1984)

<b>Objective: </b> To examine mental health at the end of life among patients with ALS in three countries: Israel, Germany, and the United States. <b>Methods: </b> Patients met criteria for definite or probable ALS and had forced vital capacity (FVC) &lt;60% of predicted. Patients completed nonsomatic items from the Beck Depression Inventory and visual analogue scale ratings. <b>Results: </b> The three sites contributed a total of 92 patients; 60 died during follow-up. Patients at the three sites did not differ significantly in sociodemographic features or ALS Functional Rating Scale–Revised summary disability score; sites differed in use of nasal ventilation but not percutaneous esophageal gastrostomy (PEG) tube placement. In analyses that adjusted for disability and use of nasal ventilation, patients at the three sites differed in reports of pessimism and suffering; American patients reported the least distress and Israeli patients the most. In analyses limited to people who died, similar patterns emerged, with wish to live greatest in Americans and least among Israelis. These models adjusted for disability and days until death. <b>Conclusions: </b> Cultural factors may affect mental health at the end of life in patients with ALS.
Staphylococcal Infections: Mechanisms of Biofilm Maturation and Detachment as Critical Determinants of Pathogenicity
Authors: Michael Otto
Journal: Annual Review of Medicine (2012)

Biofilm-associated infections are a significant cause of morbidity and death. Staphylococci, above all Staphylococcus aureus and S. epidermidis, are the most frequent causes of biofilm-associated infections on indwelling medical devices. Although the mechanistic basis for the agglomeration of staphylococcal cells in biofilms has been investigated in great detail, we lack understanding of the forces and molecular determinants behind the structuring of biofilms and the detachment of cellular clusters from biofilms. These processes are of key importance for the formation of vital biofilms in vivo with the capacity of bacterial dissemination to secondary sites of infection. Recent studies showed that the phenol-soluble modulins, surfactant peptides secreted by staphylococci in a quorum-sensing controlled fashion, structure biofilms in vitro and in vivo and lead to biofilm detachment with the in vivo consequence of bacterial dissemination. These findings substantiate that quorum sensing and surfactants have widespread importance for biofilm maturation processes in bacteria and establish a novel theory of the molecular determinants driving dissemination of biofilm-associated infection.
Assessment and management of psoriasis: summary of NICE guidance
Authors: E. Samarasekera, L. Sawyer, J. Parnham, C. H. Smith
Journal: BMJ (2012)

Psoriasis is a common inflammatory skin condition affecting about 1.3–2.2% of the UK population1 and may be associated with psoriatic arthritis.2 People with psoriasis, especially those with severe disease, are also at increased risk of cardiovascular disease,3 diabetes,4 and depression.5 Psoriasis may result in functional, psychological, and social morbidity, even in people with minimal involvement (less than the equivalent of three palm areas). However, doctors, including dermatologists, often fail to appreciate the extent of this disability,6 and many people with psoriasis are dissatisfied with their treatment.6 Yet, highly effective and cost effective treatments are available, and improving outcomes therefore requires better assessment and management of psoriasis, including its impact on a patient's wellbeing, by healthcare professionals. This article summarises the most recent recommendations from the National Institute for Health and Clinical Excellence (NICE) on the management of psoriasis.7 NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Principles of care [Based on the experience and opinion of the Guideline Development Group (GDG)] ### Assessment of disease severity and impact, and when to refer for specialist care [Based on the experience and opinion of the GDG]
Magnetic Resonance–Guided Focused Ultrasound for Patients With Painful Bone Metastases: Phase III Trial Results
Authors: Mark D. Hurwitz, Pejman Ghanouni, Sergey V. Kanaev, Dmitri Iozeffi, David Gianfelice, Fiona Mary Fennessy, Abraham Kuten, Joshua E. Meyer, Suzanne D. LeBlang, Ann Roberts, Junsung Choi, James M. Larner, Alessandro Napoli, Vladimir G. Turkevich, Yael Inbar, Clare Mary C. Tempany, Raphael M. Pfeffer
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundPain due to bone metastases is a common cause of cancer-related morbidity, with few options available for patients refractory to medical therapies and who do not respond to radiation therapy. This study assessed the safety and efficacy of magnetic resonance-guided focused ultrasound surgery (MRgFUS), a noninvasive method of thermal tissue ablation for palliation of pain due to bone metastases.
Cross‐reactivity between quinolones
Authors: I. Dávila, M. L. Diez, S. Quirce, J. Fraj, B. De La Hoz, M. Lazaro
Journal: Allergy (1993)

Cross‐reactivity between quinolones in uncertain. Recently, we studied three patients who had developed suspected allergic reaction to a quinolone. For all of them we performed skin test, histamine release test, RAST, and oral provocation with the suspected quinolone and also with another quinolone of the opposite generation. Five atopic and five nonatopic subjects were used as controls. Neither skin test, histamine release test, nor RAST was useful in the diagnosis. By mean of oral controlled provocation, the reactions were reproduced, and all the patients also reacted to another quinolone. We conclude that cross‐reactivity between quinolone seems to be very important, and avoidance of any quinolone should be recommended to any patients who has suffered an allergic reaction to one of these drugs.
Development of EULAR recommendations for the reporting of clinical trial extension studies in rheumatology
Authors: Maya H Buch, Lucia Silva-Fernandez, Loreto Carmona, Daniel Aletaha, Robin Christensen, Bernard Combe, Paul Emery, Gianfranco Ferraccioli, Francis Guillemin, Tore K Kvien, Robert Landewe, Karel Pavelka, Kenneth Saag, Josef S Smolen, Deborah Symmons, Désirée van der Heijde, Joep Welling, George Wells, Rene Westhovens, Angela Zink, Maarten Boers
Journal: Annals of the Rheumatic Diseases (2014)

Objectives Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports. Methods We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A ‘0–10’ agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance. Results Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations. Conclusions This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes.
First-SIGNAL: First-Line Single-Agent Iressa Versus Gemcitabine and Cisplatin Trial in Never-Smokers With Adenocarcinoma of the Lung
Authors: Ji-Youn Han, Keunchil Park, Sang-We Kim, Dae Ho Lee, Hyae Young Kim, Heung Tae Kim, Myung Ju Ahn, Tak Yun, Jin Seok Ahn, Cheolwon Suh, Jung-Shin Lee, Sung Jin Yoon, Jong Hee Han, Jae Won Lee, Sook Jung Jo, Jin Soo Lee
Journal: Journal of Clinical Oncology (2012)

Gefitinib has shown high response rate and improved progression-free survival (PFS) in never-smokers with lung adenocarcinoma (NSLAs). We compared efficacy of gefitinib with gemcitabine and cisplatin (GP) chemotherapy in this group of patients as first-line therapy.In this randomized phase III trial, a total of 313 Korean never-smokers with stage IIIB or IV lung adenocarcinoma, Eastern Cooperative Oncology Group performance status 0 to 2, and adequate organ function were randomly assigned to receive either gefitinib (250 mg daily) or GP chemotherapy (gemcitabine 1,250 mg/m(2) on days 1 and 8; cisplatin 80 mg/m(2) on day 1 every 3 weeks, for up to nine courses). The primary objective was to demonstrate better overall survival (OS) for gefitinib compared with GP in chemotherapy-naive NSLAs.Three hundred nine patients were analyzed per protocol (gefitinib arm, n = 159; GP arm, n = 150). Gefitinib did not show better OS compared with GP (hazard ratio [HR], 0.932; 95% CI, 0.716 to 1.213; P = .604; median OS, 22.3 v 22.9 months, respectively). The 1-year PFS rates were 16.7% with gefitinib and 2.8% with GP (HR, 1.198; 95% CI, 0.944 to 1.520). Response rates were 55% with gefitinib and 46% with GP (P = .101). Myelosuppression, renal insufficiency, and fatigue were more common in the GP arm, but skin toxicities and liver dysfunction were more common in the gefitinib arm. Two patients (1.3%) in the gefitinib arm developed interstitial lung disease and died.Gefitinib failed to demonstrate superior OS compared with GP as first-line therapy for NSLAs.
Work-related respiratory disease in employees leaving an electronics factory.
Authors: W H Perks, P S Burge, M Rehahn, M Green
Journal: Thorax (1979)

Examination of the records of employees leaving an electronics factory over three-and-a-half years showed that a significantly greater proportion left the shop floor (where soldering took place) because of ill health than left the stores and office areas. This difference was largely due to work-related respiratory disease in those whose job was soldering. Shop floor workers leaving for health reasons also had increased sickness certification due to respiratory illness compared to stores and office workers. These findings suggest that work-related respiratory illness is a significant cause of morbidity and loss of employment in solderers working at the factory and that this has been a longstanding problem with its onset before the first recorded cases of occupational asthma caused by solder flux containing colophony.