tbuckley/cabot-search huggingface dataset:
P92 C reactive protein as a predictive indicator of treatment and disease progression in patients with sarcoidosis: a retrospective observational cohort study in the West of Ireland
Authors: M. J. McDonnell, I. Saleem, R. Rutherford, A. O'Regan, J. J. Gilmartin
Journal: Thorax (2011)

<h3>Introduction</h3> C reactive protein (CRP) is an acute-phase protein synthesised in response to tissue damage or inflammation. Previous studies evaluating the role of CRP in sarcoidosis have focussed on disease monitoring. Adequate markers to determine predictors of progression in sarcoidosis are currently lacking. <h3>Objectives</h3> The aim of this retrospective observational study is to evaluate the utility and practical application of baseline serum CRP in predicting treatment indication and disease severity in a well-defined sarcoidosis population over a 26-year follow-up period. <h3>Methods</h3> We reviewed the clinical, biochemical, radiological and physiological findings in all confirmed sarcoidosis patients attending a regional referral centre between 1983 and 2009. Disease progression was defined in two ways: decline in lung function as per Hunninghake criteria (&gt;15% reduction in baseline FEV<sub>1</sub> % and/or &gt;10% decline in baseline DLCO%); and radiological progression (defined as worsening stage of disease and/or development of bronchiectasis or cavitation). Indication for treatment was defined as need for corticosteroid treatment throughout duration of follow-up. Correlation coefficients and multiple logistic regression (MLR) analysis were performed to determine independent baseline variables relating to outcome. Results are expressed as OR, 95%-CIs and p-values. <h3>Results</h3> 328/409 (80.2%) of sarcoidosis patients were suitable for inclusion, 46.6% of whom had an abnormally elevated CRP at presentation. MLR analysis of presenting characteristics with baseline CRP showed strong associations with Löfgren9s syndrome (p=0.002) and FVC % (p=0.009), consistent with previously published data. In terms of predicting outcomes, CRP was found to be an independent predictor of both radiological progression and physiological deterioration (p=0.026 and 0.048 respectively). Other independent indices for radiological progression were smoking status, Löfgren9s syndrome and Scadding CXR stage at presentation (p=0.035, 0.002 and &lt;0.001 respectively). DLCO % was shown to be a further independent predictor of physiological decline (p=0.015). <h3>Conclusion</h3> This is one of the largest clinical studies investigating the predictive influence of CRP in sarcoidosis. The data suggests a role for CRP as a predictive indicator of physiological deterioration and radiological progression. Therefore, a subset of chronic sarcoidosis patients with high baseline CRP at presentation may benefit from closer monitoring and extra attention to parameters of physiological and radiological decline.
A tyrosine703serine polymorphism of CD109 defines the Gov platelet alloantigens
Authors: Andre C. Schuh, Nick A. Watkins, Quang Nguyen, Nicholas J. Harmer, Martin Lin, Joseph Y. A. Prosper, Kate Campbell, D. Robert Sutherland, Paul Metcalfe, Wendy Horsfall, Willem H. Ouwehand
Journal: Blood (2002)
The Beta-Carotene and Retinol Efficacy Trial: Incidence of Lung Cancer and Cardiovascular Disease Mortality During 6-Year Follow-up After Stopping -Carotene and Retinol Supplements
Authors: G. E. Goodman, M. D. Thornquist, J. Balmes, M. R. Cullen, F. L. Meyskens, G. S. Omenn, B. Valanis, J. H. Williams
Journal: JNCI Journal of the National Cancer Institute (2004)

Background: The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the effect of daily β-carotene (30 mg) and retinyl palmitate (25 000 IU) on the incidence of lung cancer, other cancers, and death in 18 314 participants who were at high risk for lung cancer because of a history of smoking or asbestos exposure. CARET was stopped ahead of schedule in January 1996 because participants who were randomly assigned to receive the active intervention were found to have a 28% increase in incidence of lung cancer, a 17% increase in incidence of death and a higher rate of cardiovascular disease mortality compared with participants in the placebo group. Methods: After the intervention ended, CARET participants returned the study vitamins to their study center and provided a final blood sample. They continue to be followed annually by telephone and mail self-report. Self-reported cancer endpoints were confirmed by review of pathology reports, and death endpoints were confirmed by review of death certificates. All statistical tests were two-sided. Results: With follow-up through December 31, 2001, the post-intervention relative risks of lung cancer and all-cause mortality for the active intervention group compared with the placebo group were 1.12 (95% confidence interval [CI] = 0.97 to 1.31) and 1.08 (95% CI = 0.99 to 1.17), respectively. Smoothed relative risk curves for lung cancer incidence and all-cause mortality indicated that relative risks remained above 1.0 throughout the post-intervention follow-up. By contrast, the relative risk of cardiovascular disease mortality decreased rapidly to 1.0 after the intervention was stopped. During the post-intervention phase, females had larger relative risks of lung cancer mortality (1.33 versus 1.14; P = .36), cardiovascular disease mortality (1.44 versus 0.93; P = .03), and all-cause mortality (1.37 versus 0.98; P = .001) than males. Conclusions: The previously reported adverse effects of β-carotene and retinyl palmitate on lung cancer incidence and all-cause mortality in cigarette smokers and individuals with occupational exposure to asbestos persisted after drug administration was stopped although they are no longer statistically significant. Planned subgroup analyses suggest that the excess risks of lung cancer were restricted primarily to females, and cardiovascular disease mortality primarily to females and to former smokers.
Uropod elongation is a common final step in leukocyte extravasation through inflamed vessels
Authors: Young-Min Hyun, Ronen Sumagin, Pranita P. Sarangi, Elena Lomakina, Michael G. Overstreet, Christina M. Baker, Deborah J. Fowell, Richard E. Waugh, Ingrid H. Sarelius, Minsoo Kim
Journal: The Journal of Experimental Medicine (2012)

The efficient trafficking of immune cells into peripheral nonlymphoid tissues is key to enact their protective functions. Despite considerable advances in our understanding of cell migration in secondary lymphoid organs, real-time leukocyte recruitment into inflamed tissues is not well characterized. The conventional multistep paradigm of leukocyte extravasation depends on CD18 integrin–mediated events such as rapid arrest and crawling on the surface of the endothelium and transmigration through the endothelial layer. Using enhanced three-dimensional detection of fluorescent CD18 fusion proteins in a newly developed knockin mouse, we report that extravasating leukocytes (neutrophils, monocytes, and T cells) show delayed uropod detachment and become extremely elongated before complete transmigration across the endothelium. Additionally, these cells deposit CD18+ microparticles at the subendothelial layer before retracting the stretched uropod. Experiments with knockout mice and blocking antibodies reveal that the uropod elongation and microparticle formation are the result of LFA-1–mediated adhesion and VLA-3–mediated cell migration through the vascular basement membrane. These findings suggest that uropod elongation is a final step in the leukocyte extravasation cascade, which may be important for precise regulation of leukocyte recruitment into inflamed tissues.
A novel gain-of-function KCNJ2 mutation associated with short-QT syndrome impairs inward rectification of Kir2.1 currents
Authors: T. Hattori, T. Makiyama, M. Akao, E. Ehara, S. Ohno, M. Iguchi, Y. Nishio, K. Sasaki, H. Itoh, M. Yokode, T. Kita, M. Horie, T. Kimura
Journal: Cardiovascular Research (2011)

Short-QT syndrome (SQTS) is a recently recognized disorder associated with atrial fibrillation (AF) and sudden death due to ventricular arrhythmias. Mutations in several ion channel genes have been linked to SQTS; however, the mechanism remains unclear. This study describes a novel heterozygous gain-of-function mutation in the inward rectifier potassium channel gene, KCNJ2, identified in SQTS. We studied an 8-year-old girl with a markedly short-QT interval (QT = 172 ms, QTc = 194 ms) who suffered from paroxysmal AF. Mutational analysis identified a novel heterozygous KCNJ2 mutation, M301K. Functional assays displayed no Kir2.1 currents when M301K channels were expressed alone. However, co-expression of wild-type (WT) with M301K resulted in larger outward currents than the WT at more than −30 mV. These results suggest a gain-of-function type modulation due to decreased inward rectification. Furthermore, we analysed the functional significance of the amino acid charge at M301 (neutral) by changing the residue. As with M301K, in M301R (positive), the homozygous channels were non-functional, whereas the heterozygous channels demonstrated decreased inward rectification. Meanwhile, the currents recorded in M301A (neutral) showed normal inward rectification under both homo- and heterozygous conditions. Heterozygous overexpression of WT and M301K in neonatal rat ventricular myocytes exhibited markedly shorter action potential durations than the WT alone. In this study, we identified a novel KCNJ2 gain-of-function mutation, M301K, associated with SQTS. Functional assays revealed no functional currents in the homozygous channels, whereas impaired inward rectification demonstrated under the heterozygous condition resulted in larger outward currents, which is a novel mechanism predisposing SQTS.
Relationship Between Electroneurographic Changes and Serum Ubiquitin Levels in Patients With Type 2 Diabetes
Authors: Ersin Akarsu, Ibrahim Pirim, Ilyas Çapoğlu, Orhan Deniz, Güngör Akçay, Necdet Ünüvar
Journal: Diabetes Care (2001)

The aim of the present study was to investigate any relationship between serum ubiquitin levels and electroneurographic changes in peripheral nerves for patients with type 2 diabetes.The study involved 34 patients (19 men, 15 women; mean age 46 +/- 13 years) with type 2 diabetes. Serum ubiquitin values were measured by sandwich enzyme-linked immunosorbent assay Measurement of nerve conduction velocity (NCV) was performed on three motor (median, tibial, and peroneal) and three sensory (median, ulnar, and sural) nerves. The value of motor compound muscle action potential (CMAP) was obtained from the sum of median, tibial, and peroneal motor nerve amplitudes, and sensory compound nerve action potential (CNAP) was computed as the sum of median and ulnar sensory nerve amplitudes.Patients with diabetes were divided into three groups: group 1 (n = 8) had normal electroneurography results, group 2 (n = 8) had slowed NCV, and group 3 (n = 18) had low values of motor CMAP and/or sensory CNAP as well as slowed NCV. Mean ubiquitin level in group 3 (20.4 +/- 2.9 ng/dl) was significantly higher than that in group 1 (11.2 +/- 1.1 ng/dl, t = 11.5, P < 0.0001) and group 2 (13.2 +/- 2.7 ng/dl, t = 5.9, P < 0.0001). Serum ubiquitin levels were inversely correlated with motor CMAP (r = -0.68) and sensory CNAP (r = -0.61) values.The results of this study indicate that there could be a relationship between the diminished amplitudes of axons of the peripheral nerve and the increase in serum ubiquitin levels in patients with type 2 diabetes. Further studies are required to confirm this relationship.
Notice of Concern
Authors: Darrell R. Abernethy
Journal: Pharmacological Reviews (2006)

It has come to our attention that the review by Suh and Checler [Suh Y-H and Checler F (2002) Amyloid precursor protein, presenilins, and α-synuclein: molecular pathogenesis and pharmacological applications to Alzheimer's disease. Pharmacol Rev 54: [469][1]–525] contains several paragraphs that
Avascular Necrosis of the Femoral Head with Combination Therapy
Authors: DONALD L. SWEET
Journal: Annals of Internal Medicine (1976)

Four patients with malignant lymphoma who were treated with multiple courses of combination chemotherapy, consisting of cyclophosphamide, Oncovin®, procarbazine, and prednisone (COPP), developed avascular necrosis of the femoral head(s). Disorders usually associated with the development of avascular necrosis were absent. The total prednisone dose received by each patient was small. Avascular necrosis of the femoral head should be considered in the differential diagnosis of bone pain in patients receiving multiple courses of combination chemotherapy.
A Few Short Notes on Tropical Butterflies
Authors: I. McClure
Journal: BMJ (2003)

John Murray Viking, £14.99, pp 274 ISBN 0 670 91347 2 Rating: ![Graphic][1]</img>![Graphic][2]</img>![Graphic][3]</img> For anyone still looking for holiday reading and wanting to escape all things medical, this debut collection of short stories may, at first glance, not appeal. Most of them focus on a doctor as the main character, while others have medicine or medics as a brooding background presence. It is no surprise, perhaps, that all of the stories are written by a doctor. If none of these factors puts you off, you may be interested to know that this book is full of dramatic moments, insights, and images that grip, enlighten, and linger in the memory. The stories' medical subject matter reminds us of the privileged access that doctors have into the lives of others. Their achievement also makes me wonder whether being a doctor lends itself, in some unique … [1]: /embed/inline-graphic-1.gif [2]: /embed/inline-graphic-2.gif [3]: /embed/inline-graphic-3.gif
K-<i>ras</i> Mutations in DNA Extracted From the Plasma of Patients With Pancreatic Carcinoma: Diagnostic Utility and Prognostic Significance
Authors: Antoni Castells, Pere Puig, Josefina Móra, Jaume Boadas, Loreto Boix, Eulàlia Urgell, Manel Solé, Gabriel Capellà, Fèlix Lluís, Laureano Fernández-Cruz, Salvador Navarro, Antoni Farré
Journal: Journal of Clinical Oncology (1999)

PURPOSE: Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed. PATIENTS AND METHODS: Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome. RESULTS: The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P &lt; .005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23). CONCLUSION: Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.
Folate, Homocysteine, and Arsenic Metabolism in Arsenic-Exposed Individuals in Bangladesh
Authors: Mary V. Gamble, Xinhua Liu, Habibul Ahsan, J. Richard Pilsner, Vesna Ilievski, Vesna Slavkovich, Faruque Parvez, Diane Levy, Pam Factor-Litvak, Joseph H. Graziano
Journal: Environmental Health Perspectives (2005)

Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = −0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = −0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = −0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = −0.45 for males, p < 0.0001; −0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high.
An ACP-Independent Fatty Acid Synthesis Pathway in Archaea: Implications for the Origin of Phospholipids
Authors: Jonathan Lombard, Purificación López-García, David Moreira
Journal: Molecular Biology and Evolution (2012)

Fatty acids (FAs) are major building blocks of membrane phospholipids in bacteria and eukaryotes. Their presumed absence in archaea led to propose a late origin in bacteria and eukaryotes and that the last common ancestor of living organisms (the cenancestor) was devoid of both FA and phospholipid membranes. However, small FA amounts and homologs of bacterial FA biosynthesis enzymes are found in archaea. We have investigated the origin of these archaeal enzymes using phylogenomic analyses of all enzymes of the main bacterial FA biosynthesis pathway. Our results suggest that modern archaea and their last common ancestor possessed a complete pathway except for the acyl carrier protein (ACP) processing machinery, which evolved in the bacterial lineage. This has not only implications for archaeal physiology but also opens the possibility for the presence of ACP-independent FA synthesis in the cenancestor, which may have been endowed with FA-phospholipid membranes.
Oncologic Phase 0 Trials Incorporating Clinical Pharmacodynamics: from Concept to Patient
Authors: James H. Doroshow, Ralph E. Parchment
Journal: Clinical Cancer Research (2008)

Abstract The U.S. Food and Drug Administration recently issued an Exploratory Investigational New Drug (IND) guidance that provides a platform for the evaluation of targeted anticancer agents in small, early-phase human clinical trials that can be used to establish the feasibility of proof-of-principle target modulation assays, as well as the preliminary pharmacokinetics and molecular imaging potential of new anticancer molecules. The exploratory IND allows for reduced requirements for manufacturing and toxicologic assessment. Early clinical trials done in this fashion have no therapeutic intent. In this series of articles in CCR Focus, the development of this new IND mechanism, its effect on clinical trial design and clinical pharmacodynamics, the ethical implications of nontherapeutic clinical investigations, and the perspective of the pharmaceutical industry on this approach are examined.
Actual Causes of Death in the United States, 2000
Authors: Ali H. Mokdad, James S. Marks, Donna F. Stroup, Julie L. Gerberding
Journal: JAMA (2004)

ContextModifiable behavioral risk factors are leading causes of mortality in the United States. Quantifying these will provide insight into the effects of recent trends and the implications of missed prevention opportunities.ObjectivesTo identify and quantify the leading causes of mortality in the United States.DesignComprehensive MEDLINE search of English-language articles that identified epidemiological, clinical, and laboratory studies linking risk behaviors and mortality. The search was initially restricted to articles published during or after 1990, but we later included relevant articles published in 1980 to December 31, 2002. Prevalence and relative risk were identified during the literature search. We used 2000 mortality data reported to the Centers for Disease Control and Prevention to identify the causes and number of deaths. The estimates of cause of death were computed by multiplying estimates of the cause-attributable fraction of preventable deaths with the total mortality data.Main Outcome MeasuresActual causes of death.ResultsThe leading causes of death in 2000 were tobacco (435 000 deaths; 18.1% of total US deaths), poor diet and physical inactivity (400 000 deaths; 16.6%), and alcohol consumption (85 000 deaths; 3.5%). Other actual causes of death were microbial agents (75 000), toxic agents (55 000), motor vehicle crashes (43 000), incidents involving firearms (29 000), sexual behaviors (20 000), and illicit use of drugs (17 000).ConclusionsThese analyses show that smoking remains the leading cause of mortality. However, poor diet and physical inactivity may soon overtake tobacco as the leading cause of death. These findings, along with escalating health care costs and aging population, argue persuasively that the need to establish a more preventive orientation in the US health care and public health systems has become more urgent.