tbuckley/cabot-search huggingface dataset:
Fontan procedure for hypoplastic left heart syndrome.
Authors: W G Guntheroth
Journal: Circulation (1992)

level and the risk of restenosis, suggesting that lipid fractions could be important in the pathogenesis and prevention of restenosis after successful percutaneous transluminal coronary angioplasty (PITCA).Furthermore, the authors report a significant difference of plasminogen activator inhibitor-1 (PAI-1) activity levels between the study groups (restenosis and nonrestenosis), with a tendency toward lower PAI-1 activity levels in the restenosis group before PTCA.This finding appears to be unexpected,'2 because elevated PAI-1 activity levels have been shown to be positively associated with coronary artery disease and its acute manifestations.3-7In a recent publication8 including 104 consecutive patients of whom 34 (32.7%)developed coronary restenosis, we were able to demonstrate a strong relation between the fluctuations of circu- lating plasma levels of PAI-1 activity after PTCA (determined in plasma samples obtained after 3 days, 3 months, and 6 months) and the tendency to develop coronary restenosis.In all patients, coronary angiography was performed at time of renewed onset of angina or in asymptomatic patients at 6 months to prove or exclude restenosis.Decreasing PAI-1 levels during the follow-up period were indicative of patients without restenosis, whereas an increase or no alteration of PAI-1 activity levels was related to restenosis.Pre-PTCA levels of PAI-1 activity were slightly lower in patients of the restenosis group (6.4±0.6 IU/ml, mean±SEM) than in those of the nonrestenosis group (7.5 ±0.5 IU/ml), which, however, did not reach statistical significance.Angiographic and clinical data before PTCA were comparable in both study groups.In the study of Shah and Amin,' 68 consecutive patients with successful PTCA and without emergency PTCA were included.The authors did not present data about angiographic severity of coronary sclerosis or symptom classes at the time of intervention.However, PAI-1 plasma levels might be related to the anatomic extent and clinical severity of coronary artery disease.5-7This might also explain the significant differences found in pre-PTCA PAI-1 plasma levels.'The findings of both studies concerning the relation between fibrinolytic parameters and coronary restenosisl'8 indicate that PAI-1 activity levels before PTCA seem to be not predictive for the development of restenosis.However, it might be of clinical value to determine PA-1 levels after PTCA as a noninvasive marker of restenosis formation or long-term clinical improvement.
Incretin-Based Drugs and Adverse Pancreatic Events: Almost a Decade Later and Uncertainty Remains
Authors: Laurent Azoulay
Journal: Diabetes Care (2015)

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. In the narrative preceding Dr. Azoulay’s contribution, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. From the journal’s perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful. —William T. Cefalu Editor in Chief, Diabetes Care
Role of Hepatic Efflux Transporters in Regulating Systemic and Hepatocyte Exposure to Xenobiotics
Authors: Nathan D. Pfeifer, Rhiannon N. Hardwick, Kim L.R. Brouwer
Journal: The Annual Review of Pharmacology and Toxicology (2013)

Hepatic efflux transporters include numerous well-known and emerging proteins localized to the canalicular or basolateral membrane of the hepatocyte that are responsible for the excretion of drugs into the bile or blood, respectively. Altered function of hepatic efflux transporters due to drug-drug interactions, genetic variation, and/or disease states may lead to changes in xenobiotic exposure in the hepatocyte and/or systemic circulation. This review focuses on transport proteins involved in the hepatocellular efflux of drugs and metabolites, discusses mechanisms of altered transporter function as well as the interplay between multiple transport pathways, and highlights the importance of considering intracellular unbound concentrations of transporter substrates and/or inhibitors. Methods to evaluate hepatic efflux transport and predict the effects of impaired transporter function on systemic and hepatocyte exposure are discussed, and the sandwich-cultured hepatocyte model to evaluate comprehensively the role of hepatic efflux in the hepatobiliary disposition of xenobiotics is characterized.
Growth Characteristics and Virology of Regressing Rous Sarcomas<xref ref-type="fn" rid="FN1">2</xref>
Authors: Marshall Dinowitz, Harvey Rabin
Journal: JNCI Journal of the National Cancer Institute (1966)

Tumors were produced in 95 percent (42 of 44) of 4- to 8-week-old White Leghorn chickens inoculated intramuscularly with 100 Focus-Forming units of Rous sarcoma virus (RSV), of which 40 percent (17) began to regress. Regressing and progressing tumors had mean latent periods of 10.2 and 8.8 days, respectively. Regressing tumors did not grow to the same size as progressive ones during a comparable period. Four of 4 progressive tumors transplanted successfully to the chorioallantoic membrane (CAM) of chick embryos, yielding virus, but 3 of 5 regressing tumors did not transplant; the remaining 2 grew, though less than progressive ones, and eventually yielded RSV. Regressing tumors contained very little RSV in tumor homogenates or in tissue culture Ruids assayed over a long period. No evidence of interferon was Found in either tumor homogenates or tissue culture Ruids of 7 regressing tumors. Three of 5 regressing tumors contained an interfering virus in either tumor homogenates or tissue culture Ruids, or both. Only 1 of 5 regressing tumor tissue cultures rechallenged with RSV yielded RSV at a level higher than a parallel uninoculated control culture of the tumor, but at a level so low as to be of doubtful significance. Two tumors, which had regressed, recurred at the original site after rechallenge inoculation with homologous virus in the opposite wing. RSV was recovered from tissue culture Ruids and CAM-passaged tumor of one, but no RSV was recovered from the other.
Tumor Necrosis Factor–dependent Segmental Control of MIG Expression by High Endothelial Venules in Inflamed Lymph Nodes Regulates Monocyte Recruitment
Authors: Mary J. Janatpour, Susan Hudak, Manjiri Sathe, Jonathon D. Sedgwick, Leslie M. McEvoy
Journal: The Journal of Experimental Medicine (2001)

Monocytes recruited from the blood are key contributors to the nature of an immune response. While monocyte recruitment in a subset of immunopathologies has been well studied and largely attributed to the chemokine monocyte chemoattractant protein (MCP)-1, mechanisms mediating such recruitment to other sites of inflammation remain elusive. Here, we showed that localized inflammation resulted in an increased binding of monocytes to perifollicular high endothelial venules (HEVs) of lymph nodes draining a local inflammatory site. Quantitative PCR analyses revealed the upregulation of many chemokines in the inflamed lymph node, including MCP-1 and MIG. HEVs did not express detectable levels of MCP-1; however, a subset of HEVs in inflamed lymph nodes in wild-type (but not tumor necrosis factor [TNF] null mice) expressed MIG and this subset of HEVs preferentially supported monocyte binding. Expression of CXCR3, the receptor for MIG, was detected on a small subset of peripheral blood monocytes and on a significant percentage of recruited monocytes. Most importantly, in both ex vivo and in vivo assays, neutralizing anti-MIG antibodies blocked monocyte binding to inflamed lymph node HEVs. Together, these results suggest that the lymph node microenvironment can dictate the nature of molecules expressed on HEV subsets in a TNF-dependent fashion and that inflammation-induced MIG expression by HEVs can mediate monocyte recruitment.
Protein Kinase C–Induced Changes in the Stoichiometry of ATP Binding Activate Cardiac ATP-Sensitive K <sup>+</sup> Channels
Authors: Peter E. Light, Aftab A. Sabir, Bruce G. Allen, Michael P. Walsh, Robert J. French
Journal: Circulation Research (1996)

Activation of both ATP-sensitive K + (K ATP ) channels and the enzyme protein kinase C (PKC) has been associated with the cardioprotective response of ischemic preconditioning. We recently showed that at low cytoplasmic ATP (≤50 μmol/L), PKC inhibits K ATP channel activity. This finding is surprising, as both K ATP channels and PKC are activated during preconditioning. However, PKC also altered ATP binding to the channel, changing the Hill coefficient from ≈2 to ≈1. This apparent change in stoichiometry would lead to a PKC-induced activation of K ATP channels at more physiological (millimolar) levels of ATP. The aim of the present study was to determine whether PKC activates cardiac K ATP channels at millimolar levels of ATP. The effects of PKC on single K ATP channels were studied at millimolar internal ATP levels using excised inside-out membrane patches from rabbit ventricular myocytes. Application of purified constitutively active PKC (20 nmol/L) to the intracellular surface of the patches produced an approximately threefold increase in the channel open probability. The specific PKC inhibitor peptide PKC(19-31) prevented this increase. Heat-inactivated PKC had no effect on K ATP channel properties. K ATP channel activity spontaneously returned to control levels after washout of PKC. This spontaneous reversal did not occur in the presence of 5 nmol/L okadaic acid, suggesting that the reversal of PKC's action is dependent on activity of a membrane-associated type 2A protein phosphatase (PP2A). In the presence of exogenous PP2A (7.5 nmol/L), PKC had no effect. We conclude that the PKC-induced increase in K ATP channel activity at millimolar ATP results from a crossing of the ATP concentration-response curves for inhibition of the phosphorylated and nonphosphorylated forms of the channel. This identifies a mechanism by which PKC activates K ATP channels at near physiological levels of ATP and thus could link these two components in a signaling pathway that induces ischemic preconditioning.
MONKEY: identifying conserved transcription-factor binding sites in multiple alignments using a binding site-specific evolutionary model.
Authors: Alan M Moses, Derek Y Chiang, Daniel A Pollard, Venky N Iyer, Michael B Eisen
Journal: Genome biology (2004)

We introduce a method (MONKEY) to identify conserved transcription-factor binding sites in multispecies alignments. MONKEY employs probabilistic models of factor specificity and binding-site evolution, on which basis we compute the likelihood that putative sites are conserved and assign statistical significance to each hit. Using genomes from the genus Saccharomyces, we illustrate how the significance of real sites increases with evolutionary distance and explore the relationship between conservation and function.
Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study
Authors: Aaron S Kesselheim, Bo Wang, Jessica M Franklin, Jonathan J Darrow
Journal: BMJ (2015)

<b>Objective</b> To evaluate the use of special expedited development and review pathways at the US Food and Drug Administration over the past two decades. <b>Design</b> Cohort study. <b>Setting</b> FDA approved novel therapeutics between 1987 and 2014. <b>Population</b> Publicly available sources provided each drug’s year of approval, their innovativeness (first in class versus not first in class), World Health Organization Anatomic Therapeutic Classification, and which (if any) of the FDA’s four primary expedited development and review programs or designations were associated with each drug: orphan drug, fast track, accelerated approval, and priority review. <b>Main outcome measures</b> Logistic regression models evaluated trends in the proportion of drugs associated with each of the four expedited development and review programs. To evaluate the number of programs associated with each approved drug over time, Poisson models were employed, with the number of programs as the dependent variable and a linear term for year of approval. The difference in trends was compared between drugs that were first in class and those that were not. <b>Results</b> The FDA approved 774 drugs during the study period, with one third representing first in class agents. Priority review (43%) was the most prevalent of the four programs, with accelerated approval (9%) the least common. There was a significant increase of 2.6% per year in the number of expedited review and approval programs granted to each newly approved agent (incidence rate ratio 1.026, 95% confidence interval 1.017 to 1.035, P&lt;0.001), and a 2.4% increase in the proportion of drugs associated with at least one such program (odds ratio 1.024, 95% confidence interval 1.006 to 1.043, P=0.009). Driving this trend was an increase in the proportion of approved, non-first in class drugs associated with at least one program for drugs (P=0.03 for interaction). <b>Conclusions</b> In the past two decades, drugs newly approved by the FDA have been associated with an increasing number of expedited development or review programs. Though expedited programs should be strictly limited to drugs providing noticeable clinical advances, this trend is being driven by drugs that are not first in class and thus potentially less innovative.
Lymphography: A Great Advance, Abandoned
Authors: Saul A. Rosenberg
Journal: Journal of Clinical Oncology (2008)

Bipedal lymphography (LAG), a radiologic diagnostic procedure, was a dramatic advance when introduced almost 50 years ago. The procedure enabled radiologists and clinicians to visualize previously undetectable lymphadenopathy in the retroperitoneum. The procedure was difficult to perform, involving the cannulation of almost invisible lymphatics in the dorsum of the feet, usually with a 30-gauge needle, and infusing a viscous, fat-soluble, iodine-containing contrast solution (ethiodol) over a period of several hours. Usually a dye, methylene blue or chlorophyll, was injectedsubcutaneouslybetweenthetoestovisualizethelymphatics.Thiswasoftenpainful,withprolongeddiscolorationofthefeet, sometimes resulting in infection. The ethiodol dye traversed up the lower extremity lymphatics into the retroperitoneum, entered the cysterna chyli and thoracic duct, emptying into the left subclavian vein, and then to the lungs, with acceptable minimal pulmonary symptomatology. The dye is retained by the phagocytic cells of the lymph nodes for a period of 1 to 2 years, but sometimes longer, and is easily visualized with plain diagnostic x-ray studies. Abnormal lymph nodes, as small as 1 cm, could be identified
Predictors of Acute Complications in Children With Type 1 Diabetes
Authors: Arleta Rewers
Journal: JAMA (2002)

ContextDiabetic ketoacidosis and severe hypoglycemia are acute complications of type 1 diabetes that are related, respectively, to insufficient or excessive insulin treatment. However, little is known about additional modifiable risk factors.ObjectiveTo examine the incidence of ketoacidosis and severe hypoglycemia in children with diabetes and to determine the factors that predict these complications.Design, Setting, and ParticipantsA cohort of 1243 children from infancy to age 19 years with type 1 diabetes who resided in the Denver, Colo, metropolitan area were followed up prospectively for 3994 person-years from January 1, 1996, through December 31, 2000.Main Outcome MeasuresIncidence of ketoacidosis leading to hospital admission or emergency department visit and severe hypoglycemia (loss of consciousness, seizure, or hospital admission or emergency department visit).ResultsThe incidence of ketoacidosis was 8 per 100 person-years and increased with age in girls (4 per 100 person-years in <7; 8 in 7-12; and 12 in ≥13 years; P<.001 for trend). In multivariate analyses, sex-adjusted and stratified by age (<13 vs ≥13 years), the risk of ketoacidosis in younger children increased with higher hemoglobin A1c (HbA1c) (relative risk [RR], 1.68 per 1% increase; 95% confidence interval [CI], 1.45-1.94) and higher reported insulin dose (RR, 1.40 per 0.2 U/kg per day; 95% CI, 1.20-1.64). In older children, the risk of ketoacidosis increased with higher HbA1c (RR, 1.43; 95% CI, 1.30-1.58), higher reported insulin dose (RR, 1.13; 95% CI, 1.02-1.25), underinsurance (RR, 2.18; 95% CI, 1.65-2.95), and presence of psychiatric disorders (for boys, RR, 1.59; 95% CI, 0.96-2.65; for girls, RR, 3.22; 95% CI, 2.25-4.61). The incidence of severe hypoglycemia was 19 per 100 person-years (P<.001 for trend) and decreased with age in girls (24 per 100 patient-years in <7, 19 in 7-12, and 14 in ≥13 years). In younger children, the risk of severe hypoglycemia increased with diabetes duration (RR, 1.39 per 5 years; 95% CI, 1.16-1.69) and underinsurance (RR, 1.33; 95% CI, 1.08-1.65). In older children, the risk of severe hypoglycemia increased with duration (RR, 1.34; 95% CI, 1.25-1.51), underinsurance (RR, 1.42; 95% CI, 1.11-1.81), lower HbA1c (RR, 1.22; 95% CI, 1.12-1.32), and presence of psychiatric disorders (RR, 1.56; 95% CI, 1.23-1.98). Eighty percent of episodes occurred among the 20% of children who had recurrent events.ConclusionsSome children with diabetes remain at high risk for ketoacidosis and severe hypoglycemia. Age- and sex-specific incidence patterns suggest that ketoacidosis is a challenge in adolescent girls while severe hypoglycemia continues to affect disproportionally the youngest patients and boys of all ages. The pattern of modifiable risk factors indicates that underinsured children and those with psychiatric disorders or at the extremes of the HbA1c distribution should be targeted for specific interventions.
The Peritraumatic Distress Inventory: A Proposed Measure of PTSD Criterion A2
Authors: Alain Brunet, Daniel S. Weiss, Thomas J. Metzler, Suzanne R. Best, Thomas C. Neylan, Cynthia Rogers, Jeffrey Fagan, Charles R. Marmar
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Meeting criterion A2 for the diagnosis of posttraumatic stress disorder (PTSD) in DSM-IV requires that an individual have high levels of distress during or after the traumatic event. Because of the paucity of valid and reliable instruments for assessing such responses, the authors developed a 13-item self-report measure, the Peritraumatic Distress Inventory, to obtain a quantitative measure of the level of distress experienced during and immediately after a traumatic event. METHOD: The cross-sectional study group comprised 702 police officers and 301 matched nonpolice comparison subjects varying in ethnicity and gender who were exposed to a wide range of critical incidents. RESULTS: The Peritraumatic Distress Inventory was found to be internally consistent, with good test-retest reliability and good convergent and divergent validity. Even after controlling for peritraumatic dissociation and for general psychopathology, the authors found that Peritraumatic Distress Inventory scores correlated with two measures of posttraumatic stress symptoms. CONCLUSIONS: The Peritraumatic Distress Inventory holds promise as a measure of PTSD criterion A2. Future studies should prospectively examine the ability of the Peritraumatic Distress Inventory to predict PTSD and its associated biological and cognitive correlates in other trauma-exposed groups.
Pleural metastatic tumours and effusions. Frequency and pathogenic mechanisms in a post-mortem series
Authors: F Rodriguez-Panadero, F Borderas Naranjo, J Lopez Mejias
Journal: European Respiratory Journal (1989)

We examined the post-mortem records of 191 patients who had one or more malignant tumours (196 neoplasms in total). We found 55 cases with pleural metastases (28%) and 30 of these presented pleural effusions (15% of the total number of neoplasms). The visceral pleural was involved in all 24 cases of lung cancer with pleural metastasis and in 27 out of 31 of those of other origins. The parietal pleura was affected in 16 out of 24 cases of the lung tumours and in 15 out of 31 of those of other origins. There were no cases in which only the parietal layer of the pleura was involved, with the only exception of neighbouring tumours. We found neoplastic vascular invasion in 43 out of 55 cases, retrograde lymphatic spread from the mediastinum in two cases, and direct pleural involvement from a neighbouring tumour in the remaining. We conclude that malignant pleural implantation fundamentally arises from the spread of tumour emboli to the lungs and the visceral pleura, with secondary seedings to the parietal pleura. Therefore, this phenomenon leads to the usual finding of lower involvement of parietal pleura as compared to the visceral pleura in our series.
Quantitative scoring of an interferon- assay for differentiating active from latent tuberculosis
Authors: J-P. Janssens, P. Roux-Lombard, T. Perneger, M. Metzger, R. Vivien, T. Rochat
Journal: European Respiratory Journal (2007)

The aim of this study was to assess the contribution of an interferon-γ release assay (T-SPOT. TB ) to the differentiation of active tuberculosis (TB) from latent TB infection by quantifying spot-forming units (sfu). The investigation was a prospective study of contacts exposed to a case of contagious TB and cases of HIV-negative culture-proven TB referred over a 16-month period. Tuberculin skin tests (TSTs) and T-SPOT. TB were performed in 310 contacts 8–12 weeks after exposure. In subjects with culture-proven TB, T-SPOT. TB was performed within 2 weeks of initiation of treatment. The analysis included all contacts with a positive T-SPOT. TB result and all subjects with TB. TB contacts (n = 127) and cases (n = 58) were included. Mean± sd T-SPOT. TB results were 107±56 (range 1–207) sfu for TB, 54±60 (7–239) sfu for contacts with positive T-SPOT. TB results and a TST induration diameter of &gt;5 mm, and 19±27 (7–143) sfu for contacts with positive T-SPOT. TB results and a TST induration diameter of ≤5 mm. By receiver operating characteristic curve analysis, a threshold value of 49.5 sfu showed a sensitivity of 83% and specificity of 74% for distinguishing latent TB infection from TB. Although T-SPOT. TB results were significantly related to disease activity, the test cannot be recommended for the diagnosis of tuberculosis.