tbuckley/cabot-search huggingface dataset:
Fronto-Striatal Overactivation in Euthymic Bipolar Patients During an Emotional Go/NoGo Task
Authors: Michèle Wessa, Josselin Houenou, Marie-Laure Paillère-Martinot, Sylvie Berthoz, Eric Artiges, Marion Leboyer, Jean-Luc Martinot
Journal: American Journal of Psychiatry (2007)

Objective: Although euthymic bipolar patients show minimal manic and depressive symptoms, they continue to show impaired emotional regulation and cognitive functioning. Few studies have directly examined the interference of emotional information with cognitive processes and its underlying cerebral mechanisms in euthymic bipolar patients. The authors examined the emotional modulation of cognitive processes and its underlying neural mechanisms in euthymic bipolar patients. Method: Seventeen euthymic bipolar patients and 17 healthy comparison subjects underwent functional magnetic resonance imaging (MRI) while performing an emotional and nonemotional go/nogo task. Neural responses associated with the overall task performance, as well as with the impact of emotional information on the task performance, were assessed. Results: Bipolar disorder patients exhibited increased activity in the temporal cortex, specifically to emotional go/nogo conditions, as well as in the orbitofrontal cortex, the insula, the caudate nuclei, and the dorsal anterior and posterior cingulate cortices when inhibiting emotional stimuli compared with neutral stimuli. Conversely, no global attentional deficits were observed on either a behavioral or neural response level, indicated by similar task performances for all task conditions and similar brain activation patterns when comparing all the go/nogo conditions with the resting state. Conclusions: The present study provides evidence of an altered emotional modulation of cognitive processing in euthymic bipolar patients, indicated by an overactivation in ventral-limbic, temporal, and dorsal brain structures during emotional go/nogo conditions in patients relative to comparison subjects.
Adaptive Trial Designs
Authors: Tze Leung Lai, Philip William Lavori, Mei-Chiung Shih
Journal: The Annual Review of Pharmacology and Toxicology (2011)

We review adaptive designs for clinical trials, giving special attention to the control of the Type I error in late-phase confirmatory trials, when the trial planner wishes to adjust the final sample size of the study in response to an unblinded analysis of interim estimates of treatment effects. We point out that there is considerable inefficiency in using the adaptive designs that employ conditional power calculations to reestimate the sample size and that maintain the Type I error by using certain weighted test statistics. Although these adaptive designs have little advantage over familiar group-sequential designs, our review also describes recent developments in adaptive designs that are both flexible and efficient. We also discuss the use of Bayesian designs, when the context of use demands control over operating characteristics (Type I and II errors) and correction of the bias of estimated treatment effects.
Family History of Suicidal Behavior and Mood Disorders in Probands With Mood Disorders
Authors: J. John Mann, Jonathan Bortinger, Maria A. Oquendo, Dianne Currier, Shuhua Li, David A. Brent
Journal: American Journal of Psychiatry (2005)

First-degree relatives of persons with mood disorder who attempt suicide are at greater risk for mood disorders and attempted or completed suicide. This study examined the shared and distinctive factors associated with familial mood disorders and familial suicidal behavior.First-degree relatives' history of DSM-IV-defined mood disorder and suicidal behavior was recorded for 457 mood disorder probands, of whom 81% were inpatients and 62% were female. Probands' lifetime severity of aggression and impulsivity were rated, and probands' reports of childhood physical or sexual abuse, suicide attempts, and age at onset of mood disorder were recorded. Univariate and multivariate analyses were carried out to identify predictors of suicidal acts in first-degree relatives.A total of 23.2% of the probands with mood disorder who had attempted suicide had a first-degree relative with a history of suicidal behavior, compared with 13.2% of the probands with mood disorder who had not attempted suicide (odds ratio=1.99, 95% CI=1.21-3.26). Thirty percent (30.8%) of the first-degree relatives with a diagnosis of mood disorder also manifested suicidal behavior, compared with 6.6% of the first-degree relatives with no mood disorder diagnosis (odds ratio=6.25, 95% CI=3.44-11.35). Probands with and without a history of suicide attempts did not differ in the incidence of mood disorder in first-degree relatives (50.6% versus 48.1%). Rates of reported childhood abuse and severity of lifetime aggression were higher in probands with a family history of suicidal behavior. Earlier age at onset of mood disorder in probands was associated with greater lifetime severity of aggression and higher rates of reported childhood abuse, mood disorder in first-degree relatives, and suicidal behavior in first-degree relatives.Risk for suicidal behavior in families of probands with mood disorders appears related to early onset of mood disorders, aggressive/impulsive traits, and reported childhood abuse in probands. Studies of such clinical features in at-risk relatives are under way to determine the relative transmission of these clinical features.
IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids
Authors: Carine Blanchard, Melissa K. Mingler, Maria Vicario, J. Pablo Abonia, Yi Ying Wu, Thomas X. Lu, Margaret H. Collins, Philip E. Putnam, Susanne I. Wells, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2007)
Prescriptions, Privacy, and the First Amendment
Authors: Gregory D. Curfman, Stephen Morrissey, Jeffrey M. Drazen
Journal: New England Journal of Medicine (2011)

On April 26, the Supreme Court heard oral arguments in a case that, when it is decided this spring, will have important repercussions for the practice of medicine. At issue in William H. Sorrell, Attorney General of Vermont, et al., Petitioners v. IMS Health Inc., et al.1 is whether detailed information about prescriptions written by doctors, with the doctor identified, can be bought and sold. Currently, this practice is legal in almost every state, and the outcome of Sorrell v. IMS Health will signal whether states may restrict it.2 This is the way it works: Retail pharmacies retain information . . .
What happens when cardiac Na channels lose their function? 1 – Numerical studies of the vulnerable period in tissue expressing mutant channels
Authors: C Starmer
Journal: Cardiovascular Research (2002)

The vulnerable period (VP) defines an interval during which premature impulses can trigger reentrant arrhythmias leading to ventricular fibrillation and sudden death. The mechanistic basis of the success or failure of impulse propagation during the VP remains unclear. Recent clinical reports of gene mutations, drugs and cardiac disease link a variety of often lethal conditions with loss of cardiac Na channel function (NaLOF) and reentrant proarrhythmia. We hypothesized that during the VP, the Na conductance at the stimulus site is graded and that NaLOF would favor reentry specifically by flattening this gradient, which would destabilize antegrade front formation.Using numerical studies of propagation in a one-dimensional cable of ventricular cells, we identified the boundaries of the VP using paired (s1-s2) stimulation. We explored VP alterations associated with different NaLOF scenarios including reduced channel density, accelerated rate of inactivation, and prolonged recovery from inactivation.Following the passage of a wave over the s2 site, a gradient in the restoration of Na channel conductance was demonstrated to exist during the VP. The VP boundaries coincided with different thresholds for stable retrograde and antegrade impulse propagation. Reducing channel density, accelerating inactivation and slowing the recovery from inactivation flattened the restoration gradient and extended the VP. VP extension was directly proportional to the time constant of Na channel recovery.Mutations that accelerate inactivation, slow recovery from inactivation, or reduce Na channel density flatten the restoration gradient within the VP which prolongs the VP and increases the probability that a premature impulse will initiate reentry. These studies define a new mechanism that links alterations in Na channel function with conditions that enable premature excitation to generate proarrhythmia and sudden death.
Glycogen Synthase Kinase 3 Inhibition Stimulates Human Cartilage Destruction and Exacerbates Murine Osteoarthritis
Authors: Gary J. Litherland, Wang Hui, Martina S. Elias, David J. Wilkinson, Sharon Watson, Carmen Huesa, David A. Young, Andrew D. Rowan
Journal: Arthritis & Rheumatology (2014)

Objective To assess the role of glycogen synthase kinase 3 (GSK‐3) as a regulator of cartilage destruction in human tissue and a murine model of osteoarthritis (OA). Methods Surgical destabilization of the medial meniscus (DMM) was performed to induce experimental murine OA, and joint damage was assessed histologically. Bovine nasal and human OA cartilage samples were incubated with interleukin‐1 (IL‐1) plus oncostatin M (OSM) and GSK‐3 inhibitor. Collagen and proteoglycan release was assessed by hydroxyproline measurement and dye binding assay, collagenase activity was assessed by bioassay, and gene expression was analyzed by real‐time polymerase chain reaction. Human articular chondrocytes were isolated by enzymatic digestion and cultured prior to gene silencing and immunoblotting of cell lysates and nuclear fractions. Results Mice treated with GSK‐3 inhibitor exhibited significantly greater cartilage damage compared with sham‐operated control mice. GSK‐3 inhibition in bovine cartilage dramatically accelerated IL‐1 plus OSM–stimulated degradation, concomitant with a profound increase in collagenase activity. GSK‐3 inhibitor induced collagen release from human OA cartilage in the presence of IL‐1 plus OSM and increased proteoglycan loss. Gene expression profiling of resorbing OA cartilage revealed a marked procatabolic switch in gene expression upon GSK‐3 inhibition. This was mirrored in human articular chondrocytes following GSK3 silencing, particularly with the GSK‐3β isoform. GSK‐3 inhibition or silencing led to enhanced IL‐1 plus OSM–stimulated abundance and activity of Jun, and silencing of c‐ jun ameliorated GSK‐3 inhibitor–mediated procatabolic gene expression. Conclusion GSK‐3 is an important regulator of matrix metalloproteinase (MMP)–mediated joint destruction, the inhibition of which by proinflammatory stimuli de‐represses catabolic gene expression. Therapeutic strategies that maintain cartilage GSK‐3 activity may therefore help curtail aberrant MMP activity during pathologic joint destruction.
Effects of Candesartan on Cough and Bronchial Hyperresponsiveness in Mildly to Moderately Hypertensive Patients With Symptomatic Asthma
Authors: Hiroshi Tanaka, Shin Teramoto, Kensuke Oashi, Toyohiro Saikai, Shintaro Tanaka, Kazuhiko Suzuki, Midori Hashimoto, Shosaku Abe
Journal: Circulation (2001)

Background Candesartan, an AT 1 receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients. Methods and Results Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor–induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups. Conclusions Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.
High Pathogenic Potential of Low-Affinity Autoantibodies in Experimental Autoimmune Hemolytic Anemia
Authors: Liliane Fossati-Jimack, Luc Reininger, Yves Chicheportiche, Raphael Clynes, Jeffrey V. Ravetch, Tasuku Honjo, Shozo Izui
Journal: The Journal of Experimental Medicine (1999)

To assess the potency of low-affinity anti–red blood cell (RBC) autoantibodies in the induction of anemia, we generated an immunoglobulin (Ig)G2a class-switch variant of a 4C8 IgM anti–mouse RBC autoantibody, and compared its pathogenic potential with that of its IgM isotype and a high-affinity 34-3C IgG2a autoantibody. The RBC-binding activity of the 4C8 IgG2a variant was barely detectable, at least 1,000 times lower than that of its IgM isotype, having a high-binding avidity, and that of the 34-3C IgG2a monoclonal antibody (mAb). This low-affinity feature of the 4C8 mAb was consistent with the lack of detection of opsonized RBCs in the circulating blood from the 4C8 IgG2a–injected mice. However, the 4C8 IgG2a variant was highly pathogenic, as potent as its IgM isotype and the 34-3C IgG2a mAb, due to its capacity to interact with Fc receptors involved in erythrophagocytosis. In addition, our results indicated that the pentameric form of the low-affinity IgM isotype, by promoting the binding and agglutination of RBCs, is critical for its pathogenic activity. Demonstration of the remarkably high pathogenic potency of low-affinity autoantibodies, if combined with appropriate heavy chain effector functions, highlights the critical role of the Ig heavy chain constant regions, but the relatively minor role of autoantigen-binding affinities, in autoimmune hemolytic anemia.
Direct Reversible Kidney Injury in Familial Hemophagocytic Lymphohistiocytosis Type 3
Authors: Laura Malaga-Dieguez, Wu Ming, Howard Trachtman
Journal: Journal of the American Society of Nephrology (2015)

Hemophagocytic lymphohistiocytosis is a hyperinflammatory disorder resulting from primary or secondary immune dysfunction. AKI is frequent in severe hemophagocytic lymphohistiocytosis and has been attributed to multiorgan failure or the use of nephrotoxic drugs, but AKI is rarely considered a direct consequence of the disease process. We describe a child with familial hemophagocytic lymphohistiocytosis type 3 who developed AKI requiring prolonged renal replacement therapy because of severe renal inflammation. There was massive infiltration of the renal parenchyma by activated macrophages and cytotoxic T cells, and acute tubular injury. The patient responded to high-dose intravenous methylprednisolone, which resulted in improvement of renal function and discontinuation of renal replacement therapy. This case confirms the occurrence of reversible AKI due to hemophagocytic lymphohistiocytosis-induced activated macrophage infiltration of the renal parenchyma and inflammation.
The Sterol-C7 Desaturase from the Ciliate Tetrahymena thermophila Is a Rieske Oxygenase, Which Is Highly Conserved in Animals
Authors: Sebastián R. Najle, Alejandro D. Nusblat, Clara B. Nudel, Antonio D. Uttaro
Journal: Molecular Biology and Evolution (2013)

The ciliate Tetrahymena thermophila incorporates sterols from its environment that desaturates at positions C5(6), C7(8), and C22(23). Phytosterols are additionally modified by removal of the ethyl group at carbon 24 (C24). The enzymes involved are oxygen-, NAD(P)H-, and cytochrome b5 dependent, reason why they were classified as members of the hydroxylases/desaturases superfamily. The ciliate's genome revealed the presence of seven putative sterol desaturases belonging to this family, two of which we have previously characterized as the C24-de-ethylase and C5(6)-desaturase. A Rieske oxygenase was also identified; this type of enzyme, with sterol C7(8)-desaturase activity, was observed only in animals, called Neverland in insects and DAF-36 in nematodes. They perform the conversion of cholesterol into 7-dehydrocholesterol, first step in the synthesis of the essential hormones ecdysteroids and dafachronic acids. By adapting an RNA interference-by-feeding protocol, we easily screened six of the eight genes described earlier, allowing the characterization of the Rieske-like oxygenase as the ciliate's C7(8)-desaturase (Des7p). This characterization was confirmed by obtaining the corresponding knockout mutant, making Des7p the first nonanimal Rieske-sterol desaturase described. To our knowledge, this is the first time that the feeding-RNAi technique was successfully applied in T. thermophila, enabling to consider such methodology for future reverse genetics high-throughput screenings in this ciliate. Bioinformatics analyses revealed the presence of Des7p orthologs in other Oligohymenophorean ciliates and in nonanimal Opisthokonts, like the protists Salpingoeca rosetta and Capsaspora owczarzaki. A horizontal gene transfer event from a unicellular Opisthokont to an ancient phagotrophic Oligohymenophorean could explain the acquisition of the Rieske oxygenase by Tetrahymena.
HRCT diagnosis of diffuse parenchymal lung disease: inter-observer variation
Authors: Z A Aziz
Journal: Thorax (2004)

This study was designed to measure inter-observer variation between thoracic radiologists in the diagnosis of diffuse parenchymal lung disease (DPLD) using high resolution computed tomography (HRCT) and to identify areas of difficulty where expertise, in the form of national panels, would be of particular value.HRCT images of 131 patients with DPLD (from a tertiary referral hospital (n = 66) and regional teaching centres (n = 65)) were reviewed by 11 thoracic radiologists. Inter-observer variation for the first choice diagnosis was quantified using the unadjusted kappa coefficient of agreement. Observers stated differential diagnoses and assigned a percentage likelihood to each. A weighted kappa was calculated for the likelihood of each of the six most frequently diagnosed disease entities.Observer agreement on the first choice diagnosis was moderate for the entire cohort (kappa = 0.48) and was higher for cases from regional centres (kappa = 0.60) than for cases from the tertiary referral centre (kappa = 0.34). 62% of cases from regional teaching centres were diagnosed with high confidence and good observer agreement (kappa = 0.77). Non-specific interstitial pneumonia (NSIP) was in the differential diagnosis in most disagreements (55%). Weighted kappa values quantifying the likelihood of specific diseases were moderate to good (mean 0.57, range 0.49-0.70).There is good agreement between thoracic radiologists for the HRCT diagnosis of DPLD encountered in regional teaching centres. However, cases diagnosed with low confidence, particularly where NSIP is considered as a differential diagnosis, may benefit from the expertise of a reference panel.
Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes
Authors: Lynn R. Goldin, Sigurdur Y. Kristinsson, Xueying Sharon Liang, Åsa R. Derolf, Ola Landgren, Magnus Björkholm
Journal: Journal of Clinical Oncology (2011)

Apart from rare pedigrees with multiple cases of acute myeloid leukemia (AML), there is limited data on familial aggregation of AML and myelodysplastic syndromes (MDSs) in the population.Swedish population-based registry data were used to evaluate risk of AML, MDS, and other malignancies among 24,573 first-degree relatives of 6,962 patients with AML and 1,388 patients with MDS compared with 106,224 first-degree relatives of matched controls. We used a marginal survival model to calculate familial aggregation.AML and/or MDS did not aggregate significantly in relatives of patients with AML. There was a modest risk ratio (RR, 1.3; 95% CI, 0.9 to 1.8) in myeloproliferative/myeloid malignancies combined. The risks for any hematologic or any solid tumor were modestly but significantly increased. Relatives of patients with MDS did not show an increased risk for any hematologic tumors. In contrast, we found a significantly increased risk (RR, 6.5; 95% CI, 1.1 to 38.0) of AML/MDS and of all myeloid malignancies combined (RR, 3.1; 95% CI, 1.0 to 9.8) among relatives of patients diagnosed at younger than age 21 years.We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared.
Abstract 2785: Anatomical versus Functional Assessment of Coronary Artery Disease: A Comparative Regional Analysis of Non Invasive Coronary Angiography and Coronary Calcium Scoring by MSCT with Myocardial Perfusion Imaging by SPECT
Authors: Joanne D Schuijf, William Wijns, J W Jukema, Isabel Decramer, Douwe E Atsma, Albert de Roos, Marcel P Stokkel, Petra Dibbets-Schneider, Ernst E van der Wall, Jeroen J Bax
Journal: Circulation (2006)

Background: For the non-invasive evaluation of coronary artery disease (CAD), both MSCT and gated SPECT are available. How these 2 modalities relate however is yet unclear. The purpose of the study...