tbuckley/cabot-search huggingface dataset:
Primary Care in a New Era: Disillusion and Dissolution?
Authors: Lewis G. Sandy, Steven A. Schroeder
Journal: Annals of Internal Medicine (2003)

The current dilemmas in primary care stem from 1) the unintended consequences of forces thought to promote primary care and 2) the "disruptive technologies of care" that attack the very function and concept of primary care itself. This paper suggests that these forces, in combination with "tiering" in the health insurance market, could lead to the dissolution of primary care as a single concept, to be replaced by alignment of clinicians by economic niche. Evidence already exists in the marketplace for both tiering of health insurance benefits and corresponding practice changes within primary care. In the future, primary care for the top tier will cater to the affluent as "full-service brokers" and will be delivered by a wide variety of clinicians. The middle tier will continue to grapple with tensions created by patient demand and bureaucratic systems but will remain most closely aligned to primary care as a concept. The lower tier will become increasingly concerned with community health and social justice. Each primary care specialty will adapt in a unique way to a tiered world, with general internal medicine facing the most challenges. Given this forecast for the future, those concerned about primary care should focus less on workforce issues and more on macro health care financing and organization issues (such as Medicare reform); appropriate training models; and the development of a conception of primary care that emphasizes values and ethos, not just function.
A difference in the composition of bronchial mucus between smokers and non-smokers.
Authors: N Kollerstrom, P W Lord, W F Whimster
Journal: Thorax (1977)

The ratio of the amount of sulphated to sialic acid mucin (Su/Si) in the mucous glands of the human tracheobronchial tree has been investigated in seven smokers and seven non-smokers. The two mucins were studied in histological sections stained by the high iron diamine/Alcian blue pH 2-5 sequence and assessed by a point-counting method. Su/Si was greater in the smokers than in the non-smokers, who were almost completely distinguished by this ratio. A decrease in the ratio with each generation of branching from the trachea down the inferior lingular bronchial segmental pathway was seen in both the smoking and non-smoking groups. Analysis of the logarithm of Su/Si showed the smoking group means to be 2-3 times that of the non-smokers at each generation, and over both groups the average decrease down successive generations was given by a factor of 0-9.
Race and Ethnicity and Breast Cancer Outcomes in an Underinsured Population
Authors: Ian K. Komenaka, Maria Elena Martinez, Robert E. Pennington, Chiu-Hsieh Hsu, Susan E. Clare, Patricia A. Thompson, Colleen Murphy, Noelia M. Zork, Robert J. Goulet
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundThe disparity in breast cancer mortality between African American women and non-Hispanic white women has been the subject of increased scrutiny. Few studies have addressed these differences in the setting of equal access to health care. We compared the breast cancer outcomes of underinsured African American and non-Hispanic white patients who were treated at a single institution.
Phase I Trial of Tipifarnib in Patients With Recurrent Malignant Glioma Taking Enzyme-Inducing Antiepileptic Drugs: A North American Brain Tumor Consortium Study
Authors: Timothy F. Cloughesy, John Kuhn, H. Ian Robins, Lauren Abrey, Patrick Wen, Karen Fink, Frank S. Lieberman, Minesh Mehta, Susan Chang, Alfred Yung, Lisa DeAngelis, David Schiff, Larry Junck, Morris Groves, Steve Paquette, John Wright, Kathleen Lamborn, Said M. Sebti, Michael Prados
Journal: Journal of Clinical Oncology (2005)

To determine the maximum-tolerated dose (MTD), toxicities, and clinical effect of tipifarnib, a farnesyltransferase (FTase) inhibitor, in patients with recurrent malignant glioma taking enzyme-inducing antiepileptic drugs (EIAEDs). This study compares the pharmacokinetics and pharmacodynamics of tipifarnib at MTD in patients on and off EIAEDs.Recurrent malignant glioma patients were treated with tipifarnib using an interpatient dose-escalation scheme. Pharmacokinetics and pharmacodynamics were assessed.Twenty-three assessable patients taking EIAEDs received tipifarnib in escalating doses from 300 to 700 mg bid for 21 of 28 days. The dose-limiting toxicity was rash, and the MTD was 600 mg bid. There were significant differences in pharmacokinetic parameters at 300 mg bid between patients on and not on EIAEDs. When patients on EIAEDs and not on EIAEDs were treated at MTD (600 and 300 mg bid, respectively), the area under the plasma concentration-time curve (AUC)(0-12 hours) was approximately two-fold lower in patients on EIAEDs. Farnesyltransferase inhibition was noted at all tipifarnib dose levels, as measured in peripheral-blood mononuclear cells (PBMC).Toxicities and pharmacokinetics differ significantly when comparing patients on or off EIAEDs. EIAEDs significantly decreased the maximum concentration, AUC(0-12 hours), and predose trough concentrations of tipifarnib. Even in the presence of EIAEDs, the levels of tipifarnib were still sufficient to potently inhibit FTase activity in patient PBMCs. The relevance of these important findings to clinical activity will be determined in ongoing studies with larger numbers of patients.
Screening research papers by reading abstracts: Idea seems reasonable
Authors: S S Musheer Hussain
Journal: BMJ (2004)

Governance of academic medicine should be with public trusteesEditor-Many of the problems arising in academic medicine are due to the divergence of academic goals and the values of society.Academic institutions are not currently governed in a way that fosters a strong and healthy alliance with government and the population at large, and there is a failure to support satisfactorily the public interest against vested and other competing interests. 1e suggest that a good first step is to turn over the governance of academic medicine to public trustees with protected authority.Public trustees must ensure that the three familiar goals of research, teaching, and patient care are supplemented by the unsung fourth goal of community service.Moreover, trustees have the right to insist that most of the research and teaching programmes in academic medicine be placed in the context of the health needs of the entire population.It is also time to reform the governance of medical schools.We suggest that it fosters tunnel vision for the dean when the executive committee of the medical school is composed primarily of department chairpeople whose main responsibility is the welfare of individual departments, not the mission of the school as a whole.We advocate instead an executive committee comprising senior faculty and public representatives, while excluding department heads.If academic medicine exists to promote the public interest, is it not time to grant patients and the public at large a controlling interest in setting priorities and overseeing operations?
The effects of astemizole, cetirizine and loratadine on the time course of weal and flare reactions to histamine, codeine and antigen
Authors: FRANCES HUMPHREYS, J.A.A. HUNTER
Journal: British Journal of Dermatology (1991)

Journal Article The effects of astemizole, cetirizine and loratadine on the time course of weal and flare reactions to histamine, codeine and antigen Get access FRANCES HUMPHREYS, FRANCES HUMPHREYS University Department of Dermatelogy, The Royal Infirmary, Edinburgh, U.K. Dr F. Humphreys, Department of Dermatology. The Lauriston Building, The Royal Infirmary, Edinburg, EH8, 9YW, U.K. Search for other works by this author on: Oxford Academic Google Scholar J.A.A. HUNTER J.A.A. HUNTER University Department of Dermatelogy, The Royal Infirmary, Edinburgh, U.K. Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 125, Issue 4, 1 October 1991, Pages 364–367, https://doi.org/10.1111/j.1365-2133.1991.tb14173.x Published: 01 October 1991
Dystrophin Is Not a Specific Component of the Cardiac Costamere
Authors: Shirley Stevenson, Stephen Rothery, Michael J. Cullen, Nicholas J. Severs
Journal: Circulation Research (1997)

Dystrophin is a key component of the subsarcolemmal skeleton of muscle cells, and lack of dystrophin is the direct cause of Duchenne muscular dystrophy. In skeletal muscle, dystrophin is reported to be localized specifically at costameres, transversely oriented riblike subsarcolemmal plaques that mechanically couple the contractile apparatus to the extracellular matrix. Costameres are characteristically rich in vinculin and are prominent in cardiac as well as skeletal muscle. To define the precise spatial relationship between dystrophin in relation to the costamere in cardiac muscle, we applied high-resolution single- and double-immunolabeling techniques, under a range of preparative conditions, with visualization of vinculin (as a costamere marker) and dystrophin by confocal microscopy and by the freeze-fracture cytochemical technique, fracture label. Immunoconfocal visualization revealed dystrophin as a continuous uniform layer at the cytoplasmic surface of the peripheral plasma membrane of the rat cardiac myocyte at both costameric and noncostameric regions. The pattern of labeling was reproducible with three different antibodies and was independent of time and antibody concentration. Platinum/carbon replicas and thin sections of fracture-label specimens permitted high-resolution visualization of the distribution of dystrophin in plan views of the freeze-fractured plasma membrane and in relation to the sarcomeric banding patterns of the underlying myofibrils. These results confirmed no preferential association of dystrophin with costameres or with any region of the sarcomeres of underlying myofibrils in rat cardiac tissue. We conclude that in contrast to skeletal muscle, dystrophin in cardiac muscle is not exclusively a component of the costamere.
Inhibition of ER stress–associated IRE-1/XBP-1 pathway reduces leukemic cell survival
Authors: Chih-Hang Anthony Tang, Sujeewa Ranatunga, Crystina L. Kriss, Christopher L. Cubitt, Jianguo Tao, Javier A. Pinilla-Ibarz, Juan R. Del Valle, Chih-Chi Andrew Hu
Journal: Journal of Clinical Investigation (2014)

Activation of the ER stress response is associated with malignant progression of B cell chronic lymphocytic leukemia (CLL). We developed a murine CLL model that lacks the ER stress–associated transcription factor XBP-1 in B cells and found that XBP-1 deficiency decelerates malignant progression of CLL-associated disease. XBP-1 deficiency resulted in acquisition of phenotypes that are disadvantageous for leukemic cell survival, including compromised BCR signaling capability and increased surface expression of sphingosine-1-phosphate receptor 1 (S1P1). Because XBP-1 expression requires the RNase activity of the ER transmembrane receptor IRE-1, we developed a potent IRE-1 RNase inhibitor through chemical synthesis and modified the structure to facilitate entry into cells to target the IRE-1/XBP-1 pathway. Treatment of CLL cells with this inhibitor (B-I09) mimicked XBP-1 deficiency, including upregulation of IRE-1 expression and compromised BCR signaling. Moreover, B-I09 treatment did not affect the transport of secretory and integral membrane-bound proteins. Administration of B-I09 to CLL tumor–bearing mice suppressed leukemic progression by inducing apoptosis and did not cause systemic toxicity. Additionally, B-I09 and ibrutinib, an FDA-approved BTK inhibitor, synergized to induce apoptosis in B cell leukemia, lymphoma, and multiple myeloma. These data indicate that targeting XBP-1 has potential as a treatment strategy, not only for multiple myeloma, but also for mature B cell leukemia and lymphoma.
Predose and Postdose Forced Expiratory Flow Between 25% and 75% (FEF25-75%) in Adolescents and Adults With Asthma Treated With Twice-Daily Budesonide/Formoterol Pressurized Metered-Dose Inhaler (BUD/FM pMDI) or BUD pMDI for 1 Year
Authors: J. Zangrilli, J. McElhattan, C.D. O'Brien, J. Baker
Journal: Journal of Allergy and Clinical Immunology (2009)
Twitch potentiation following voluntary diaphragmatic contraction.
Authors: M J Mador, U J Magalang, T J Kufel
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The purpose of this study was to determine whether twitch potentiation (a transient augmentation of twitch tension following vigorous muscular contraction) occurs in the human diaphragm in vivo. Six healthy subjects were studied. To determine whether twitch potentiation occurs, the subjects attempted to maximally activate their diaphragm by performing the combined Mueller-expulsive maneuver with visual feedback (Pdi max maneuver). Twitches were obtained before, at 10 s after the transdiaphragmatic pressure (Pdi) maneuver, and at intervals over the ensuing 10 min. We also determined whether twitch potentiation would occur following submaximal voluntary diaphragmatic contractions (33 and 66% of Pdi max). In addition, we examined whether repeated voluntary contractions would result in greater twitch potentiation compared with that observed after a single voluntary contraction. Twitch potentiation was observed in every subject. The number of maximal voluntary contractions (MVC) (one, two, or four) had no significant effect on the degree of twitch potentiation. The increase in twitch amplitude (expressed as a percentage of the control value) averaged 63 +/- 35% (SD)(pooled data from one, two, and four contraction trials). Twitch potentiation decayed in a monoexponential fashion (r = 0.99) with a time constant of 125 s (95% Cl = 100 to 160 s). Twitch potentiation was also observed after submaximal voluntary diaphragmatic contractions. Again, the number of voluntary contractions (one or four) had no significant effect on the degree of twitch potentiation. After submaximal diaphragmatic contractions of 66% of Pdi max, the degree of twitch potentiation was not significantly different, 61 +/- 36% (pooled data from one and four contraction trials) from that observed following the maximal voluntary contraction maneuvers.(ABSTRACT TRUNCATED AT 250 WORDS)
<i>PHD2</i>Mutation and Congenital Erythrocytosis with Paraganglioma
Authors: Charline Ladroue, Romain Carcenac, Michel Leporrier, Sophie Gad, Claire Le Hello, Françoise Galateau-Salle, Jean Feunteun, Jacques Pouysségur, Stéphane Richard, Betty Gardie
Journal: New England Journal of Medicine (2008)

Prolyl hydroxylase domain (PHD) proteins play a major role in regulating the hypoxia-inducible factor (HIF) that induces expression of genes involved in angiogenesis, erythropoiesis, and cell metabolism, proliferation, and survival. Germ-line mutations in the prolyl hydroxylase domain 2 gene (PHD2) have been reported in patients with familial erythrocytosis but not in association with tumors. We describe a patient with erythrocytosis and recurrent paraganglioma who carries a newly discovered PHD2 mutation. This mutation affects PHD2 function and stabilizes HIF-alpha proteins. In addition, we demonstrate loss of heterozygosity of PHD2 in the tumor, suggesting that PHD2 could be a tumor-suppressor gene.
Administrators recommend dissolving Mid Staffordshire trust
Authors: A. O'Dowd
Journal: BMJ (2013)

The body tasked with deciding on the best future for the troubled Mid Staffordshire NHS Foundation Trust is recommending that it be dissolved and its services split between neighbouring trusts.

The joint trust special administrators published a draft report1 on the future of hospital services from Mid Staffordshire on 31 July as well as their public consultation document2 on the proposals. The consultation runs from 6 August to 1 October and includes eight public meetings.

Proposals have to be approved by NHS regulator Monitor and signed off by the health secretary after consultation responses are collected.

The administrators said that the quality and safety of services for patients in the local area was central to their proposals, which include 14 main recommendations.

A report by independent assessors published in January concluded that the …
Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies
Authors: D Sugiyama, K Nishimura, K Tamaki, G Tsuji, T Nakazawa, A Morinobu, S Kumagai
Journal: Annals of the Rheumatic Diseases (2009)

Objectives: To assess whether smoking is a risk factor for developing rheumatoid arthritis (RA). Design: Meta-analysis. Method: Data sources were observational studies that examined the association between smoking history and the risk of developing RA identified through Medline and EMBASE (from 1966 to December 2006), relevant books and a reference search. Two authors independently extracted the following: authors’ names, publication year, sample size, participant characteristics, odds ratios (OR) or relative risks, adjustment factors, study design and area where the study was conducted. Data syntheses were based upon random effects model. Summarised syntheses effects were expressed by OR. Results: Sixteen studies were selected from among 433 articles. For men, summary OR for ever, current and past smokers were 1.89 (95% CI 1.56 to 2.28), 1.87 (1.49 to 2.34) and 1.76 (1.33 to 2.31), respectively. For rheumatoid factor-positive (RF+) RA, summary OR for ever, current and past smokers were 3.02 (2.35 to 3.88), 3.91 (2.78 to 5.50) and 2.46 (1.74 to 3.47), respectively. Summary OR for 20 or more pack-years of smoking was 2.31 (1.55 to 3.41). For women, summary OR for ever, current and past smokers were 1.27 (1.12 to 1.44), 1.31 (1.12 to 1.54) and 1.22 (1.06 to 1.40), respectively. For RF+ RA, summary OR for ever, current and past smokers were 1.34 (0.99 to 1.80), 1.29 (0.94 to 1.77) and 1.21 (0.83 to 1.77). Summary OR for 20 or more pack-years of smoking was 1.75 (1.52 to 2.02). Conclusion: Smoking is a risk factor for RA, especially RF+ RA men and heavy smokers.
Effects of high altitude and cold air exposure on airway inflammation in patients with asthma
Authors: Sven F Seys, Marc Daenen, Ellen Dilissen, Ruud Van Thienen, Dominique M A Bullens, Peter Hespel, Lieven J Dupont
Journal: Thorax (2013)

<h3>Aims</h3> Eighteen patients with asthma were evaluated during preparation to climb to extreme altitude in order to study the effects of low fractional inspired oxygen (FiO<sub>2</sub>), prolonged exposure to cold air and high altitude on lung function, asthma control and airway inflammation. <h3>Methods</h3> Spirometry and airway inflammation (fractional exhaled nitric oxide (FeNO) and induced sputum) were studied under different test conditions: hypoxic (FiO<sub>2</sub>=11%) exercise test, 24-hour cold exposure (−5°C) and before, during and after an expedition that involved climbing the Aconcagua mountain (6965 m). <h3>Results</h3> Forced expiratory volume in 1 s (FEV<sub>1</sub>) and FeNO values were slightly lower (p&lt;0.04) after 1 h of normobaric hypoxia. FEV<sub>1</sub> decreased (p=0.009) after 24-hour cold exposure, accompanied by increased sputum neutrophilia (p&lt;0.01). During the expedition FEV<sub>1</sub> and forced vital capacity decreased (maximum FEV<sub>1</sub> decrease of 12.3% at 4300 m) and asthma symptoms slightly increased. After the expedition the Asthma Control Test score and prebronchodilator FEV<sub>1</sub> were reduced (p&lt;0.02), sputum neutrophil count was increased (p=0.04) and sputum myeloperoxidase levels, sputum interleukin 17 mRNA, serum and sputum vascular endothelial growth factor A levels were significantly higher compared with baseline. Patients with asthma with the lowest oxygen saturation during the hypoxic exercise test were more prone to develop acute mountain sickness. <h3>Conclusions</h3> Exposure to environmental conditions at high altitude (hypoxia, exercise, cold) was associated with a moderate loss of asthma control, increased airway obstruction and neutrophilic airway inflammation. The cold temperature is probably the most important contributing factor as 24-hour cold exposure by itself induced similar effects.
Genetic Polymorphism in Cytochrome <i>P</i>450 7A1 and Risk of Colorectal Cancer: The Fukuoka Colorectal Cancer Study
Authors: Tomoko Hagiwara, Suminori Kono, Guang Yin, Kengo Toyomura, Jun Nagano, Tetsuya Mizoue, Ryuichi Mibu, Masao Tanaka, Yoshihiro Kakeji, Yoshihiko Maehara, Takeshi Okamura, Kouji Ikejiri, Kitaroh Futami, Youichi Yasunami, Takafumi Maekawa, Kenji Takenaka, Hitoshi Ichimiya, Nobutoshi Imaizumi
Journal: Cancer Research (2005)

Abstract Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7α-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.
CONDITIONS INFLUENCING THE DISAPPEARANCE OF LIVING BACTERIA FROM THE BLOOD STREAM
Authors: Paul R. Cannon, F. L. Sullivan, E. F. Neckermann
Journal: The Journal of Experimental Medicine (1932)

1. The simultaneous intravenous injection into normal and actively immunized rabbits of equal quantities of living staphylococci or paratyphoid bacilli is followed by a distinctly accelerated rate of removal of the bacteria from the blood streams of the immune animals. 2. This altered reactivity is due essentially to specific active immunization. 3. The bacteria pass rapidly through the capillary bed of the lungs, extracellularly and dispersed for the most part, and become generalized through the blood stream. 4. The bacteria are quickly removed from the circulating blood in the immune animals and less rapidly in the normal ones, by various organs, particularly the liver and spleen, where they accumulate in enormous numbers, become adherent to the lining membrane of the sinusoids of the liver and apparently to the macrophages of the spleen and are phagocytosed by the macrophages and leucocytes in these organs. 5. Associated with this effect are morphological changes in the bacteria as shown by swelling, loss of staining power and evidences of increased cohesiveness and decreased viscosity, these changes being apparent as early as 2 minutes after their intravenous injection. 6. Inasmuch as these changes are not seen to a marked degree within the lungs or other organs, they are probably the result of a local antigen-antibody reaction of a bacteriotropic type in the two organs generally considered to be most actively concerned with the production of immune bodies. 7. By means of this accelerated bacteriotropic effect in the actively immunized animals, phagocytosis is facilitated and intracellular digestion of the bacteria is enhanced.