tbuckley/cabot-search huggingface dataset:
Positron emission tomography in the diagnostic work-up of screening-detected lung nodules
Authors: Giulia Veronesi, Laura L. Travaini, Patrick Maisonneuve, Cristiano Rampinelli, Raffaella Bertolotti, Lorenzo Spaggiari, Massimo Bellomi, Giovanni Paganelli
Journal: European Respiratory Journal (2014)

Low-dose computed tomography (CT) screening for lung cancer can reduce lung cancer mortality, but overdiagnosis, false positives and invasive procedures for benign nodules are worrying. We evaluated the utility of positron emission tomography (PET)-CT in characterising indeterminate screening-detected lung nodules. 383 nodules, examined by PET-CT over the first 6 years of the COSMOS (Continuous Observation of Smoking Subjects) study to diagnose primary lung cancer, were reviewed and compared with pathological findings (surgically-treated patients) or follow-up (negative CT for ⩾2 years, considered negative); 196 nodules were malignant. The sensitivity, specificity and accuracy of PET-CT for differentially diagnosing malignant nodules were, respectively, 64%, 89% and 76% overall, and 82%, 92% and 88% for baseline-detected nodules. Performance was lower for nodules found at repeat annual scans, with sensitivity ranging from 22% for nonsolid to 79% for solid nodules (p=0.0001). Sensitivity (87%) and specificity (73%) were high for nodules ⩾15 mm, better (sensitivity 98%) for solid nodules ⩾15 mm. PET-CT was highly sensitive for the differential diagnosis of indeterminate nodules detected at baseline, nodules ⩾15 mm and solid nodules. Sensitivity was low for sub-solid nodules and nodules discovered after baseline for which other methods, e.g. volume doubling time, should be used.
Serum Adiponectin Levels Are an Independent Predictor of the Extent of Coronary Artery Disease in Men
Authors: Maximilian von Eynatten, Jochen G. Schneider, Per M. Humpert, Joerg Kreuzer, Helmut Kuecherer, Hugo A. Katus, Peter P. Nawroth, Klaus A. Dugi
Journal: Journal of the American College of Cardiology (2006)
Combination of Insulin and Metformin in the Treatment of Type 2 Diabetes
Authors: Michiel G. Wulffelé, Adriaan Kooy, Philippe Lehert, Daniel Bets, Jeles C. Ogterop, Bob Borger van der Burg, Ab J.M. Donker, Coen D.A. Stehouwer
Journal: Diabetes Care (2002)

OBJECTIVE—To investigate the metabolic effects of metformin, as compared with placebo, in type 2 diabetic patients intensively treated with insulin. RESEARCH DESIGN AND METHODS—Metformin improves glycemic control in poorly controlled type 2 diabetic patients. Its effect in type 2 diabetic patients who are intensively treated with insulin has not been studied. A total of 390 patients whose type 2 diabetes was controlled with insulin therapy completed a randomized controlled double-blind trial with a planned interim analysis after 16 weeks of treatment.The subjects were selected from three outpatient clinics in regional hospitals and were randomly assigned to either the placebo or metformin group, in addition to insulin therapy. Intensive glucose monitoring with immediate insulin adjustments according to strict guidelines was conducted. Indexes of glycemic control, insulin requirements, body weight, blood pressure, plasma lipids, hypoglycemic events, and other adverse events were measured. RESULTS—Of the 390 subjects, 37 dropped out (12 in the placebo and 25 in the metformin group). Of those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with improved glycemic control (mean daily glucose at 16 weeks 7.8 vs. 8.8 mmol/l, P = 0.006; mean GHb 6.9 vs. 7.6%, P &amp;lt; 0.0001); reduced insulin requirements (63.8 vs. 71.3 IU, P &amp;lt; 0.0001); reduced weight gain (−0.4 vs. +1.2 kg, P &amp;lt; 0.01); and decreased plasma LDL cholesterol (−0.21 vs. −0.02 mmol/l, P &amp;lt; 0.01). Risk of hypoglycemia was similar in both groups. CONCLUSIONS—In type 2 diabetic patients who are intensively treated with insulin, the combination of insulin and metformin results in superior glycemic control compared with insulin therapy alone, while insulin requirements and weight gain are less.
Understanding the cardiac role of K2P channels: A new TASK for electrophysiologists
Authors: F CHARPENTIER
Journal: Cardiovascular Research (2007)

Two-pore-domain K + channels (K 2P channels) form a newly identified class of 15 K + channels that possess four transmembrane-spanning domains and two pore domains.Studies in heterologous systems suggest that functional K 2P channels are dimers with an overall topology close to that of inward rectifier channels.Heterologous expression of these channels gives rise to instantaneous, non-inactivating K + currents that display little or no voltage dependence, suggesting that they might contribute to background or leak currents.These channels are sensitive to a large spectrum of physical and chemical factors such as membrane stretch, temperature, oxygen tension, pH, fatty acids, phospholipids, and anesthetics [1].Many of them are ubiquitously expressed, suggesting that they likely subserve a variety of important physiological and pathophysiological functions.Such a hypothesis is supported by studies regarding the central nervous system.For instance, TREK-1 seems to protect neuronal cells against excessive excitability and is a target for anesthetics [2], whereas TASK-1 contributes to the standingoutward K + current (IK SO ) of cerebellar granule neurons [3].Cardiomyocytes also express several K 2P channels, the main ones being TREK-1 (or K 2P 2.1, encoded by KCNK2 gene) and TASK-1 (or K 2P 3.1, encoded by KCNK3), but the contribution of these channels to the cardiac electrical activity has been
Objectively Measured Sedentary Time, Physical Activity, and Metabolic Risk
Authors: Genevieve N. Healy, Katrien Wijndaele, David W. Dunstan, Jonathan E. Shaw, Jo Salmon, Paul Z. Zimmet, Neville Owen
Journal: Diabetes Care (2008)

We examined the associations of objectively measured sedentary time and physical activity with continuous indexes of metabolic risk in Australian adults without known diabetes.An accelerometer was used to derive the percentage of monitoring time spent sedentary and in light-intensity and moderate-to-vigorous-intensity activity, as well as mean activity intensity, in 169 Australian Diabetes, Obesity and Lifestyle Study (AusDiab) participants (mean age 53.4 years). Associations with waist circumference, triglycerides, HDL cholesterol, resting blood pressure, fasting plasma glucose, and a clustered metabolic risk score were examined.Independent of time spent in moderate-to-vigorous-intensity activity, there were significant associations of sedentary time, light-intensity time, and mean activity intensity with waist circumference and clustered metabolic risk. Independent of waist circumference, moderate-to-vigorous-intensity activity time was significantly beneficially associated with triglycerides.These findings highlight the importance of decreasing sedentary time, as well as increasing time spent in physical activity, for metabolic health.
A PET Study of Dopamine D<sub>2</sub>and Serotonin 5-HT<sub>2</sub>Receptor Occupancy in Patients With Schizophrenia Treated With Therapeutic Doses of Ziprasidone
Authors: David Mamo, Shitij Kapur, C. M. Shammi, George Papatheodorou, Steve Mann, François Therrien, Gary Remington
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 receptors compared with dopamine D2 receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study. METHOD: The authors conducted a PET study to evaluate D2 occupancy (using [11C]raclopride) and 5-HT2 occupancy (using [18F]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12–16 hours after the last dose. RESULTS: The mean 5-HT2 receptor occupancy was significantly higher than the mean D2 receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 receptor occupancy was almost four times lower than that for D2 receptor occupancy. CONCLUSIONS: These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT2 than D2 receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D2 receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.
Effects of chronic hypoxia and altered hemodynamics on endothelial nitric oxide synthase expression in the adult rat lung.
Authors: T D Le Cras, R C Tyler, M P Horan, K G Morris, R M Tuder, I F McMurtry, R A Johns, S H Abman
Journal: Journal of Clinical Investigation (1998)

Mechanisms that regulate endothelial nitric oxide synthase (eNOS) expression in normal and hypoxic pulmonary circulation are poorly understood. Lung eNOS expression is increased after chronic hypoxic pulmonary hypertension in rats, but whether this increase is due to altered hemodynamics or to hypoxia is unknown. Therefore, to determine the effect of blood flow changes on eNOS expression in the normal pulmonary circulation, and to determine whether the increase in eNOS expression after chronic hypoxia is caused by hemodynamic changes or low oxygen tension, we compared eNOS expression in the left and right lungs of normoxic and chronically hypoxic rats with surgical stenosis of the left pulmonary artery (LPA). LPA stenosis in normoxic rats reduced blood flow to the left lung from 9.8+/-0.9 to 0.8+/-0.4 ml/100 mg/min (sham surgery controls vs. LPA stenosis, P < 0.05), but there was not a significant increase in right lung blood flow. When compared with the right lung, eNOS protein and mRNA content in the left lung was decreased by 32+/-7 and 54+/-13%, respectively (P < 0.05), and right lung eNOS protein content was unchanged. After 3 wk of hypoxia, LPA stenosis reduced blood flow to the left lung from 5.8+/-0.6 to 1.5+/-0.4 ml/100 mg/min, and increased blood flow to the right lung from 5.8+/-0.5 to 10.0+/-1.4 ml/ 100 mg/min (sham surgery controls vs. LPA stenosis, P < 0.05). Despite reduced flow and pressure to the left lung and increased flow and pressure to the right lung, left and right lung eNOS protein and mRNA contents were not different. There were also no differences in lung eNOS protein levels when compared with chronically hypoxic sham surgery controls (P > 0.05). We conclude that reduction of pulmonary blood flow decreases eNOS mRNA and protein expression in normoxic adult rat lungs, and that hypoxia increases eNOS expression independently of changes in hemodynamics. These findings demonstrate that hemodynamic forces maintain eNOS content in the normoxic pulmonary circulation of the adult rat, and suggest that chronic hypoxia increases eNOS expression independently of changes in hemodynamics.
S79 Potential diagnostic significance of neutrophil proteases in ventilator-associated pneumonia
Authors: A. Conway Morris, K. Kefala, T. S. Wilkinson, K. Dhaliwal, I. F. Laurenson, T. Walsh, D. F. McAuley, C. O'Kane, A. J. Simpson
Journal: Thorax (2010)

<h3>Introduction and Objectives</h3> The clinical diagnosis of ventilator-associated pneumonia (VAP) remains notoriously difficult, as several non-infective conditions mimic VAP. Microbiological confirmation of the diagnosis using conventional cultures typically takes 48–72 h. Identification of molecules measurable within a short time frame and closely associated with microbiologically confirmed VAP is therefore highly desirable. VAP is associated with significant influx of activated neutrophils into the alveolar space. We postulated that extracellular neutrophil proteases in bronchoalveolar lavage fluid (BALF) may reliably identify VAP in suspected cases. <h3>Methods</h3> Fifty-four intubated and mechanically ventilated patients in the intensive care unit developed clinically suspected VAP and were recruited. Bronchoalveolar lavage (BAL) was performed using a standardised protocol. An aliquot of BALF was sent to the diagnostic microbiology laboratory for quantitative culture, with confirmation of VAP defined as growth of a pathogen(s) at &gt;10<sup>4</sup> colony forming units/ml. Remaining BALF was centrifuged. The following neutrophil-specific proteases were assayed in cell-free BALF supernatant—matrix metalloproteinase (MMP)-8 and MMP-9 by Luminex assay, and human neutrophil elastase (HNE) by enzyme-linked immunosorbent assay. Urea was simultaneously measured in serum and BALF, and used to correct for the dilution of epithelial lining induced by BAL. Receiver operating characteristic (ROC) curves were constructed and optimal specificity and sensitivity for each marker calculated. <h3>Results</h3> Eleven patients (20%) had confirmed VAP. For HNE (cut off 670ng/ml) the ROC area under curve (AUC) was 0.87 (p&lt;0.0001), sensitivity 93%, specificity 79%. For MMP-8 (13 ng/ml), ROC AUC was 0.81 (p&lt;0.005), sensitivity 91%, specificity 63%. For MMP-9 (22 ng/ml), ROC AUC was 0.79 (p&lt;0.005), sensitivity 82%, specificity 63%. <h3>Conclusions</h3> Neutrophil proteases are strongly associated with confirmed infection in cases of suspected VAP. The values for HNE, in particular, compare extremely favourably with any previously published equivalent values. These data suggest that neutrophil protease concentrations in BALF deserve further attention as potentially diagnostic markers for VAP. They further suggest that neutrophil proteases, inappropriately released into the extracellular space, may contribute to the pathophysiology of VAP.
Assessing Glycemic Control in Maintenance Hemodialysis Patients With Type 2 Diabetes
Authors: Sara Kazempour-Ardebili, Varunika L. Lecamwasam, Thushara Dassanyake, Andrew H. Frankel, Frederick W.K. Tam, Anne Dornhorst, Gary Frost, Jeremy J.O. Turner
Journal: Diabetes Care (2009)

Optimizing glycemic control in diabetic patients undergoing maintenance hemodialysis requires accurate assessment. We hypothesize that 1) 48-h continuous glucose monitoring (CGM) provides additional, clinically relevant, information to that provided by the A1C measurement and 2) glycemic profiles differ significantly between day on and day off dialysis.With the use of GlucoDay S, 48-h CGM was performed in 19 type 2 diabetic subjects undergoing hemodialysis to capture consecutive 24-h periods on and off dialysis. Energy intake was calculated using food diaries. A1C was assayed by a high-performance liquid chromatography method.CGM data were available for 17 subjects (13 male) with a mean (range) age of 61.5 years (42-79 years) and diabetes duration of 18.8 years (4-30 years). The 24-h CGM area under the glucose curve and 24-h mean glucose values were significantly higher during the day off dialysis than on dialysis (5,932.1 +/- 2,673.6 vs. 4,694 +/- 1,988.0 mmol x 3 min(-1) x l(-1), P = 0.022, and 12.6 +/- 5.6 vs. 9.8 +/- 3.8 mmol/l, P = 0.013, respectively), independent of energy intake. Asymptomatic hypoglycemia occurred in 4 subjects, 3 within 24 h of dialysis, and the glucose nadir in 14 subjects occurred within 24 h of dialysis.Glucose values are significantly lower on dialysis days than on nondialysis days despite similar energy intake. The risk of asymptomatic hypoglycemia was highest within 24 h of dialysis. Physicians caring for patients undergoing hemodialysis need to be aware of this phenomenon and consider enhanced glycemic monitoring after a hemodialysis session. CGM provides glycemic information in addition to A1C, which is potentially relevant to clinical management.
Alzheimer-specific variants in the 3'UTR of Amyloid precursor protein affect microRNA function
Authors: Charlotte Delay, Frédéric Calon, Paul Mathews, Sébastien S Hébert
Journal: Molecular Neurodegeneration (2011)

APP expression misregulation can cause genetic Alzheimer's disease (AD). Recent evidences support the hypothesis that polymorphisms located in microRNA (miRNA) target sites could influence the risk of developing neurodegenerative disorders such as Parkinson's disease (PD) and frontotemporal dementia. Recently, a number of single nucleotide polymorphisms (SNPs) located in the 3'UTR of APP have been found in AD patients with family history of dementia. Because miRNAs have previously been implicated in APP expression regulation, we set out to determine whether these polymorphisms could affect miRNA function and therefore APP levels.Bioinformatics analysis identified twelve putative miRNA bindings sites located in or near the APP 3'UTR variants T117C, A454G and A833C. Among those candidates, seven miRNAs, including miR-20a, miR-17, miR-147, miR-655, miR-323-3p, miR-644, and miR-153 could regulate APP expression in vitro and under physiological conditions in cells. Using luciferase-based assays, we could show that the T117C variant inhibited miR-147 binding, whereas the A454G variant increased miR-20a binding, consequently having opposite effects on APP expression.Taken together, our results provide proof-of-principle that APP 3'UTR polymorphisms could affect AD risk through modulation of APP expression regulation, and set the stage for further association studies in genetic and sporadic AD.
Rarefaction of the Peripheral Nerve Network in Diabetic Patients Is Associated With a Pronounced Reduction of Terminal Schwann Cells
Authors: Christina M. Reinisch, Hannes Traxler, Stefanie Piringer, Stefan Tangl, Alexander Nader, Erwin Tschachler
Journal: Diabetes Care (2008)

OBJECTIVE—Peripheral neuropathy is the most frequent neurological complication in diabetic patients. The diagnosis is established by both clinical neurological examination and demonstration of reduced epidermal nerve fibers in skin biopsies (1). Whereas the decrease of free nerve endings has been extensively studied in diabetic patients (2,3), no data are available on possible changes of terminal Schwann cells. Besides their role as scaffold for peripheral nerves, they also play an important role in supporting survival and function of peripheral nerves (4). RESEARCH DESIGN AND METHODS—We analyzed the subepidermal nerve plexus in dermal sheet preparations of deceased diabetic and nondiabetic patients by immunostaining for detection of the neural cell adhesion molecule and quantification of the subepidermal nerve plexus. RESULTS AND CONCLUSIONS—The subepidermal nerve plexus, comprising nerve fibers and ensheathing Schwann cells, was significantly reduced in diabetic patients. Whether the reduction in terminal Schwann cells is cause or consequence of the loss of peripheral nerve fibers remains to be investigated.
Elevated Striatal Dopamine Transporters During Acute Cocaine Abstinence as Measured by [<sup>123</sup>I]β-CIT SPECT
Authors: Robert T. Malison, Susan E. Best, Christopher H. van Dyck, Elinore F. McCance, Elizabeth A. Wallace, Marc Laruelle, R. M. Baldwin, John P. Seibyl, Lawrence H. Price, Thomas R. Kosten, Robert B. Innis
Journal: American Journal of Psychiatry (1998)

The authors examined whether striatal dopamine transporters were altered in acutely (96 hours or less) abstinent cocaine-abusing subjects, as suggested by postmortem studies.[123I] beta-CIT and single photon emission computed tomography were used to assess striatal dopamine transporter levels in 28 cocaine-abusing subjects and 24 comparison subjects matched as a group for age and gender.Results showed a significant (approximately 20%) elevation in striatal V3" values in acutely abstinent cocaine-abusing subjects relative to comparison subjects. An inverse correlation between dopamine transporter level and Hamilton Depression Rating Scale score was also observed.These findings indicate more modest elevations in striatal dopamine transporters in cocaine-abusing subjects than noted in previous postmortem reports and suggest a possible relationship between cocaine-related depression and dopamine transporter binding.
Acute Gastric Mucosal Injury: Pathogenesis and Therapy
Authors: K M Holt, D Hollander
Journal: Annual Review of Medicine (1986)

Our knowledge concerning the pathogenesis and treatment of acute gastric mucosal injury is rapidly expanding. The gastric mucosa maintains its integrity despite exposure to hydrochloric acid, pepsin, bile, and potentially damaging ingested substances. The balance between gastric mucosal injury and repair is a dynamic process involving multiple complex mechanisms. Clinically, when this process breaks down, acute gastric musocal injury results. Therapy of this disorder has included the use of antisecretory drugs and antacids, while more recent research efforts are exploring the use of cytoprotective agents.
Effects of Norepinephrine on Coronary Circulation and Left Ventricular Dynamics in the Conscious Dog
Authors: STEPHEN F. VATNER, CHARLES B. HIGGINS, EUGENE BRAUNWALD
Journal: Circulation Research (1974)

The effects of norepinephrine (0.1 and 1.0 µg/kg, iv) on coronary blood flow and resistance, left ventricular pressure and diameter, dP/dt, (dP/dt)/P, and the velocity (V ISO ) of myocardial fiber shortening were studied in conscious dogs. When the heart rate was held constant, norepinephrine caused an initial reduction in coronary vascular resistance which was associated with increases in mean arterial blood pressure, systolic left ventricular pressure, end-diastolic diameter, dP/dt, (dP/dt)/P, and V ISO . After this brief coronary vasodilator response, a sustained increase occurred in mean coronary vascular resistance (+0.55 ± 0.07 mm Hg/ml min -1 ), and increases persisted in mean arterial blood pressure (+67 ± 7 mm Hg), left ventricular systolic pressure (+74 ± 6 mm Hg), left ventricular end-diastolic pressure (+4 ± 1 mm Hg), left ventricular internal diameter (+1.3 ± 0.3 mm), peak dP/dt (+1660 mm Hg/sec), (dP/dt)/P (+15 ± 2 sec -1 ), and V ISO (+11 ± 2 mm/sec); coronary sinus Po 2 decreased. Beta-receptor blockade prevented the inotropic effects of norepinephrine, attenuated the early coronary vasodilator effects, and increased the late vasoconstrictor effects. Alpha-receptor blockade abolished the late coronary vasoconstrictor effects of norepinephrine; only dilatation occurred. In contrast to the effects of norepinephrine in conscious dogs without autonomic blockade , norepinephrine (1.0 µg/kg, iv) failed to produce late coronary vasoconstriction in anesthetized, open-chest dogs; only dilatation occurred. Thus, in the normal, conscious dog, norepinephrine exerts an important coronary vasoconstrictor effect which is sufficiently intense to counteract completely the simultaneous tendency toward metabolic vasodilatation.