tbuckley/cabot-search huggingface dataset:
Ethnic- and Sex-free Formulae for Detection of Airway Obstruction
Authors: James E. Hansen, Xing-Guo Sun, Karlman Wasserman
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Spirometric detection of airway obstruction in adults requires separate predictive formulae for each ethnicity and sex for percentage of FEV(1)/FVC (%FEV(1)/FVC) and percentage of FEV(3)/FVC (%FEV(3)/FVC), the major measurements for defining airway obstruction.To eliminate the need for multiple formulae for black, Latin, and white men and women by developing single formulae with less variance than current formulae for %FEV(1)/FVC and %FEV(3)/FVC.Data from nearly 6,000 healthy never-smokers 20.0-79.9 yr of age in the Third National Health and Nutrition Examination Survey were reevaluated mathematically and graphically based on the preliminary hypothesis that predictive normal FEV(1)/FVC and FEV(3)/FVC ratios could be calculated from the age and FVC alone, without considering ethnicity, sex, or height. Current and new formulae were evaluated, first considering the population as consisting of 36 equally weighted subgroups (6 decades x 3 ethnicities x 2 sexes) and then weighting each individual equally.For each year of age, the slope of %FEV(1)/FVC versus FVC approximated -1.8%/l/yr; the slope of %FEV(3)/FVC versus FVC approximated -0.8%/l/yr. After trial and error iterations, the optimal formulae were %FEV(1)/FVC = 98.8 - 0.25 x years - 1.79 x FVC and %FEV(3)/FVC = 105.4 - 0.20 x years - 0.75 x FVC.These two new predicting formulae for %FEV(1)/FVC and %FEV(3)/FVC, which require only age and FVC as variables, approximate actual values closer than previously published separate formulae for each ethnicity and sex. With 95% confidence limits, they should allow better discrimination between normality and airway obstruction in adults of at least these three ethnicities.
Randomised study of effect of ibopamine on survival in patients with advanced severe heart failure
Authors: JR Hampton, DJ van Veldhuisen, FX Kleber, AJ Cowley, A Ardia, P Block, A Cortina, L Cserhalmi, F Follath, G Jensen, J Kayanakis, Kl Lie, G Mancia, AM Skene
Journal: The Lancet (1997)
Performance of Blood Glucose Meters in the Low-Glucose Range: Current Evaluations Indicate That It Is Not Sufficient From a Clinical Point of View
Authors: Lutz Heinemann, Eric Zijlstra, Stefan Pleus, Guido Freckmann
Journal: Diabetes Care (2015)

System accuracy requirements for blood glucose (BG) meters (BGMs) are defined in standards (1) or guidance documents (2). In 2013, International Organization for Standardization (ISO) 15197:2013 stated that BGMs are acceptably accurate if ≥95% of their measurement results are found within ±15 mg/dL (0.83 mmol/L) or ±15% (whichever is larger) of reference results (1). The 2014 U.S. Food and Drug Administration (FDA) draft guidance for over-the-counter BGMs requires ≥95% of results within ±15% and ≥99% of results within ±20% across the whole glycemic range (2). Thus, if a patient’s BG true concentration is 60 mg/dL (3.33 mmol/L), acceptably accurate results range from 45 to 75 mg/dL (2.50 to 4.16 mmol/L) according to the ISO limits and from 51 to 69 mg/dL (2.83 to 3.83 mmol/L) according to the FDA criteria. Two questions arise:

1.  Do current BGMs fulfill these criteria?

2.  If a BGM …
Pharmacogenetic analysis in metastatic colorectal cancer (mCRC) patients (pts) treated with second-line irinotecan (IR)+/− cetuximab (CB): The EPIC experience
Authors: D. Yang, A. Pohl, W. Zhang, G. Lurje, Y. Ning, A. El-Khoueiry, S. Khambata-Ford, C. Langer, S. Iqbal, H. Lenz
Journal: Journal of Clinical Oncology (2009)

4022 Background: EPIC, a multinational phase III clinical trial with IR + CB vs IR alone in mCRC pts in the second-line setting after failure of FOLFOX demonstrated a benefit for IR+CB in progression-free survival (PFS) and response rate (RR). We evaluated functional germline polymorphisms involved in the EGFR- (EGF, EGFR), angiogenesis- (VEGF, IL-8, CXCR-2) - and drug- metabolism related genes (UGT1A1, MTHFR) for their potential role as molecular predictors for clinical outcome in pts treated with CB/IR vs. IR alone. Methods: DNA was extracted from all available formalin-fixed paraffin-embedded tumor samples from the phase III EPIC trial (US sites only). Genotyping was performed using PCR-RFLP assays and 5’ -end [g-33P] ATP’ labeled PCR-protocols. Results: 186 pts were treated either with IR/CB (arm A, 84 pts) or IR (arm B, 102 pts) only. In arm A, 11/84 pts (13%) showed CR or PR, whereas 73/84 (87%) pts had SD or PD. For arm B, 6/102 pts (6%) showed CR or PR, whereas 96/102 pts (94%) had SD or PD. Median PFS in arm A was 3.0 months (95%CI: 2.4- 4.1 months) vs 2.7 months (95%CI: 2.2–2.9 months) in arm B; median overall survival (OS) was 9.3 months (95%CI: 7.1–12.1 months) in arm A vs. 12.3 months (95%CI: 10.4- 17.9 months) in arm B. K-ras mutation status was not significantly associated with PFS or response to CB/IR in the subgroup of 186 patients. We found an EGFR-CA- repeat in intron 1 in arm A to be associated with PFS (p=0.031, log-rank test). In arm B, we found a significant association with RR (p=0.0103, Fisher's exact test) for MTHFR1298. Furthermore, MTHFR 677 (p =0.0048, log-rank test) and MTHFR 1298 (p=0.038, log-rank test) were also found to be associated with OS in arm B. In multivariate analysis, EGFR-CA-repeat was significantly associated with PFS (adjusted p= 0.023). Furthermore, MTHFR 677 and MTHFR 1298 was associated with OS (adjusted p=0.028 and 0.026, respectively, Cox-proportional hazards models), independent from K-ras mutation status, race and number of disease sites. Conclusions: Our study demonstrates the potential predictive value of polymorphisms in the EGFR- and MTHFR- gene in mCRC pts treated with IR+ CB. Further validation in additional clinical trials is necessary. [Table: see text]
The SLC6A14 gene shows evidence of association with obesity
Authors: Elina Suviolahti, Laura J. Oksanen, Miina Öhman, Rita M. Cantor, Martin Ridderstråle, Tiinamaija Tuomi, Jaakko Kaprio, Aila Rissanen, Pertti Mustajoki, Pekka Jousilahti, Erkki Vartiainen, Kaisa Silander, Riika Kilpikari, Veikko Salomaa, Leif Groop, Kimmo Kontula, Leena Peltonen, Päivi Pajukanta
Journal: Journal of Clinical Investigation (2003)

In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polymorphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m2). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3′-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007–0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.
Kinetics of Acute Hepatitis B Virus Infection in Humans
Authors: Simon A. Whalley, John M. Murray, Dave Brown, George J.M. Webster, Vincent C. Emery, Geoffrey M. Dusheiko, Alan S. Perelson
Journal: The Journal of Experimental Medicine (2001)

Using patient data from a unique single source outbreak of hepatitis B virus (HBV) infection, we have characterized the kinetics of acute HBV infection by monitoring viral turnover in the serum during the late incubation and clinical phases of the disease in humans. HBV replicates rapidly with minimally estimated doubling times ranging between 2.2 and 5.8 d (mean 3.7 +/- 1.5 d). After a peak viral load in serum of nearly 10(10) HBV DNA copies/ml is attained, clearance of HBV DNA follows a two or three phase decay pattern with an initial rapid decline characterized by mean half-life (t(1/2)) of 3.7 +/- 1.2 d, similar to the t(1/2) observed in the noncytolytic clearance of covalently closed circular DNA for other hepadnaviruses. The final phase of virion clearance occurs at a variable rate (t(1/2) of 4.8 to 284 d) and may relate to the rate of loss of infected hepatocytes. Free virus has a mean t(1/2) of at most 1.2 +/- 0.6 d. We estimate a peak HBV production rate of at least 10(13) virions/day and a maximum production rate of an infected hepatocyte of 200-1,000 virions/day, on average. At this peak rate of virion production we estimate that every possible single and most double mutations would be created each day.
Increased synthesis of phospholipid during phagocytosis
Authors: Peter Elsbach
Journal: Journal of Clinical Investigation (1968)

Incorporation in vitro of (32)P-labeled lysolecithin (LPC) or lysophosphatidylethanolamine (LPE) into respectively lecithin (PC) and phosphatidylethanolamine (PE) of rabbit granulocytes and alveolar macrophages was compared in the absence and in the presence of ingestible particles. Maximal synthesis of PC by intact cells occurred at added LPC concentrations of less than 0.05 mmole/liter, i.e., at levels found in plasma. Accumulation of PC-(32)P proceeded linearly for at least 30 min and varied directly with cell concentration. While per cell granulocytes and macrophages converted comparable amounts of medium LPC to cellular PC, per milligram of protein, the granulocytes were approximately four times more active than the much larger macrophages. After 30 min newly synthesized PC-(32)P represented as much as 5% of total granulocyte PC. For macrophages this fraction did not exceed 1%. Addition of polystyrene or zymosan particles to the cell suspension resulted in up to 3-fold stimulation of incorporation of LPC-(32)P or LPE-(32)P into their respective diacyl derivatives. This stimulation did not occur when the cells were homogenized. Breakdown of LPC to water-soluble products during phagocytosis of polystyrene particles was the same as at rest. By use of doubly labeled LPC, the mechanism of PC synthesis by the two cell types has been identified as direct acylation of medium LPC, both at rest and during engulfment. Evidence presented in the case of granulocytes suggests that the increased translocation of medium LPC-(32)P during phagocytosis and its conversion to PC represents net synthesis. The findings indicate that LPC, a normal constituent of plasma, can serve as substrate in PC synthesis by phagocytic cells. This mechanism of PC synthesis can account for appreciable addition of membrane PC, especially by granulocytes. It is proposed that stimulation of this pathway provides building blocks for increased membrane formation during phagocytosis.
A1 Adenosine Receptors in Microglia Control Glioblastoma-Host Interaction
Authors: Michael Synowitz, Rainer Glass, Katrin Färber, Darko Markovic, Golo Kronenberg, Ken Herrmann, Juergen Schnermann, Christiane Nolte, Nico van Rooijen, Juergen Kiwit, Helmut Kettenmann
Journal: Cancer Research (2006)

Abstract We report that experimental glioblastoma grow more vigorously in A1 adenosine receptor (A1AR)–deficient mice associated with a strong accumulation of microglial cells at and around the tumors. A1ARs were prominently expressed in microglia associated with tumor cells as revealed with immunocytochemistry but low in microglia in the unaffected brain tissue. The A1AR could also be detected on microglia from human glioblastoma resections. To study functional interactions between tumor and host cells, we studied glioblastoma growth in organotypical brain slice cultures. A1AR agonists suppressed tumor growth. When, however, microglial cells were depleted from the slices, the agonists even stimulated tumor growth. Thus, adenosine attenuates glioblastoma growth acting via A1AR in microglia. (Cancer Res 2006; 66(17): 8550-7)
Icotinib versus gefitinib in previously treated advanced non-small-cell lung cancer (ICOGEN): a randomised, double-blind phase 3 non-inferiority trial
Authors: Yuankai Shi, Li Zhang, Xiaoqing Liu, Caicun Zhou, Li Zhang, Shucai Zhang, Dong Wang, Qiang Li, Shukui Qin, Chunhong Hu, Yiping Zhang, Jianhua Chen, Ying Cheng, Jifeng Feng, Helong Zhang, Yong Song, Yi-Long Wu, Nong Xu, Jianying Zhou, Rongcheng Luo, Chunxue Bai, Yening Jin, Wenchao Liu, Zhaohui Wei, Fenlai Tan, Yinxiang Wang, Lieming Ding, Hong Dai, Shunchang Jiao, Jie Wang, Li Liang, Weimin Zhang, Yan Sun
Journal: The Lancet Oncology (2013)
EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis
Authors: Haizhong Feng, Giselle Y. Lopez, Chung Kwon Kim, Angel Alvarez, Christopher G. Duncan, Ryo Nishikawa, Motoo Nagane, An-Jey A. Su, Philip E. Auron, Matthew L. Hedberg, Lin Wang, Jeffery J. Raizer, John A. Kessler, Andrew T. Parsa, Wei-Qiang Gao, Sung-Hak Kim, Mutsuko Minata, Ichiro Nakano, Jennifer R. Grandis, Roger E. McLendon, Darell D. Bigner, Hui-Kuan Lin, Frank B. Furnari, Webster K. Cavenee, Bo Hu, Hai Yan, Shi-Yuan Cheng
Journal: Journal of Clinical Investigation (2014)

Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.
Tumor-Derived Interleukin-4 Reduces Tumor Clearance and Deviates the Cytokine and Granzyme Profile of Tumor-Induced CD8+ T Cells
Authors: Stuart Olver, Penny Groves, Kathy Buttigieg, Edward S. Morris, Michelle L. Janas, Anne Kelso, Norbert Kienzle
Journal: Cancer Research (2006)

Abstract An interleukin (IL)-4-containing tumor environment is reported to be beneficial for immune clearance of tumor cells in vivo; however, the effect of IL-4 on the effector CD8+ T cells contributing to tumor clearance is not well defined. We have used the immunogenic HLA-CW3-expressing P815 (P.CW3) mastocytoma and investigated whether IL-4 expression by the tumor affects tumor clearance and, if so, whether it alters the tumor-induced Vβ10+ CD8+ T-cell response. P.CW3 were stably transfected with IL-4 or the empty control vector, and independent cell lines were injected i.p. into syngeneic DBA/2 mice. After apparent clearance of primary tumors over 12 to 15 days, secondary tumors arose that lacked surface expression and H-2-restricted antigen presentation of CW3 in part due to the loss of the HLA-CW3 expression cassette. Surprisingly, mice that received IL-4-producing tumor cells showed delayed primary tumor clearance and were significantly more prone to develop secondary tumors compared with mice receiving control tumor cells. Tumor clearance was dependent on CD8+ T cells. The IL-4-secreting P.CW3 tumor cells led to markedly higher mRNA expression of IL-4 and granzyme A and B but no differences in IFN-γ and IL-2 production, cell proliferation, or ex vivo CTL activity in primary Vβ10+ CD8+ T cells when compared with the control tumor cells. We concluded that tumor-derived IL-4 selectively changed the quality of the tumor-induced CD8+ T-cell response and resulted in unexpected negative effects on tumor clearance. These data bring into question the delivery of IL-4 to the tumor environment for improving tumor immunotherapy. (Cancer Res 2006; 66(1): 571-80)
Quality of life and sexual health in patients with genital psoriasis
Authors: K.A.P. Meeuwis, J.A. de Hullu, H.P. van de Nieuwenhof, A.W.M. Evers, L.F.A.G. Massuger, P.C.M. van de Kerkhof, M.M. van Rossum
Journal: British Journal of Dermatology (2011)

Knowledge about quality of life and sexual health in patients with genital psoriasis is limited.We studied quality of life and sexual function in a large group of patients with genital psoriasis by means of validated questionnaires. In addition, we evaluated whether sufficient attention is given by healthcare professionals to sexual problems in patients with psoriasis, as perceived by the patients.A self-administered questionnaire was sent to 1579 members of the Dutch Psoriasis Association. Sociodemographic patient characteristics, medical data and scores of several validated questionnaires regarding quality of life (Dermatology Life Quality Index) and sexual health (Sexual Quality of Life Questionnaire for use in Men, International Index of Erectile Function, Female Sexual Distress Scale and Female Sexual Function Index) were collected and analysed.This study (n = 487) shows that psoriasis has a detrimental effect on quality of life and sexual health. Patients with genital lesions reported even significantly worse quality of life than patients without genital lesions (mean ± SD quality of life scores 8·5 ± 6·5 vs. 5·5 ± 4·6, respectively, P < 0·0001). Sexual distress and dysfunction are particularly prominent in women (reported by 37·7% and 48·7% of the female patients, respectively). Sexual distress is especially high when genital skin is affected (mean ± SD sexual distress score in patients with genital lesions 16·1 ± 12·1 vs. 10·1 ± 9·7 in patients without genital lesions, P = 0·001). The attention given to possible sexual problems in the psoriasis population by healthcare professionals is perceived as insufficient by patients.In addition to quality of life, sexual health is diminished in a considerable number of patients with psoriasis and particularly women with genital lesions have on average high levels of sexual distress. We underscore the need for physicians to pay attention to the impact of psoriasis on psychosocial and sexual health when treating patients for this skin disease.
The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial
Authors: Jo Howard, Moira Malfroy, Charlotte Llewelyn, Louise Choo, Renate Hodge, Tony Johnson, Shilpi Purohit, David C Rees, Louise Tillyer, Isabeau Walker, Karin Fijnvandraat, Melanie Kirby-Allen, Eldon Spackman, Sally C Davies, Lorna M Williamson
Journal: The Lancet (2013)
Penicillamine in seronegative polyarthritis.
Authors: I A Jaffe
Journal: Annals of the Rheumatic Diseases (1977)

1961) who first described this reflux nor Cook et al. (1970) equate the late reflux directly with ineffective erythropoiesis.Pollycove and Mortimer (1961) felt that it was much too great to be entirely accounted for by ineffective erythropoiesis and suggested that it arose from the free non-haem iron which is reversibly bound to the cell membrane.In rheumatoid arthritis iron metabolism is known to be abnormal, and in particular, exogenous isotopically labelled iron is handled differently from endogenous iron (Bennett et al., 1974).This may affect the results obtained from ferrokinetic data.In order to clarify the role of ineffective erythropoiesis in the anaemia of rheumatoid arthritis we are planning a larger study of such patients, using two different methods of estimating ineffective erythropoiesis.
Regulation by Interleukin-10 and Interleukin-4 of Cyclooxygenase-2 Expression in Human Neutrophils
Authors: Hiroaki Niiro, Takeshi Otsuka, Kenji Izuhara, Kunihiro Yamaoka, Koichi Ohshima, Tadashi Tanabe, Shuntaro Hara, Yoshiaki Nemoto, Yosuke Tanaka, Hitoshi Nakashima, Yoshiyuki Niho
Journal: Blood (1997)
Inhibition of Respiration by Nitric Oxide Induces a Mycobacterium tuberculosis Dormancy Program
Authors: Martin I. Voskuil, Dirk Schnappinger, Kevin C. Visconti, Maria I. Harrell, Gregory M. Dolganov, David R. Sherman, Gary K. Schoolnik
Journal: The Journal of Experimental Medicine (2003)

An estimated two billion persons are latently infected with Mycobacterium tuberculosis. The host factors that initiate and maintain this latent state and the mechanisms by which M. tuberculosis survives within latent lesions are compelling but unanswered questions. One such host factor may be nitric oxide (NO), a product of activated macrophages that exhibits antimycobacterial properties. Evidence for the possible significance of NO comes from murine models of tuberculosis showing progressive infection in animals unable to produce the inducible isoform of NO synthase and in animals treated with a NO synthase inhibitor. Here, we show that O2 and low, nontoxic concentrations of NO competitively modulate the expression of a 48-gene regulon, which is expressed in vivo and prepares bacilli for survival during long periods of in vitro dormancy. NO was found to reversibly inhibit aerobic respiration and growth. A heme-containing enzyme, possibly the terminal oxidase in the respiratory pathway, likely senses and integrates NO and O2 levels and signals the regulon. These data lead to a model postulating that, within granulomas, inhibition of respiration by NO production and O2 limitation constrains M. tuberculosis replication rates in persons with latent tuberculosis.
What the pulmonary specialist should know about the new inhalation therapies
Authors: J.P. Mitchell
Journal: European Respiratory Journal (2012)

To the Editors:

In the recent report of the European Respiratory Society/International Society for Aerosols in Medicine Task Force [1], the authors correctly identify the need to prescribe spacers (sometimes termed valved holding chambers (VHCs) when an inhalation valve is present) to medication delivered from pressurised metered-dose inhalers (pMDIs). Although they mention that some pMDI products are licensed for use with a particular spacer, they have failed to point out that each pMDI–spacer combination should be treated as a unique system.

In 2008, the UK Medicines and Healthcare Products Regulatory Agency (MHRA) published a recommendation that for inhaled corticosteroids (ICSs), “Spacers should not be regarded as interchangeable: patients who use a spacer with their inhaler should use the spacer device named in the Summary of Product Characteristics” [2]. This guidance further stipulates “Patients whose asthma is well-controlled and who are using a spacer should always …
Homeobox Protein <i>Hop</i> Functions in the Adult Cardiac Conduction System
Authors: Fraz A. Ismat, Maozhen Zhang, Hyun Kook, Bin Huang, Rong Zhou, Victor A. Ferrari, Jonathan A. Epstein, Vickas V. Patel
Journal: Circulation Research (2005)

Hop is an unusual homeobox gene expressed in the embryonic and adult heart. Hop acts downstream of Nkx2-5 during development, and Nkx2-5 mutations are associated with cardiac conduction system (CCS) defects. Inactivation of Hop in the mouse is lethal in half of the expected null embryos. Here, we show that Hop is expressed strongly in the adult CCS. Hop-/- adult mice display conduction defects below the atrioventricular node (AVN) as determined by invasive electrophysiological testing. These defects are associated with decreased expression of connexin40. Our results suggest that Hop functions in the adult CCS and demonstrate conservation of molecular hierarchies between embryonic myocardium and the specialized conduction tissue of the mature heart.