tbuckley/cabot-search huggingface dataset:
Evidence That Altered Amygdala Activity in Schizophrenia Is Related to Clinical State and Not Genetic Risk
Authors: Roberta Rasetti, Venkata S. Mattay, Lisa M. Wiedholz, Bhaskar S. Kolachana, Ahmad R. Hariri, Joseph H. Callicott, Andreas Meyer-Lindenberg, Daniel R. Weinberger
Journal: American Journal of Psychiatry (2008)

Although amygdala dysfunction is reported in schizophrenia, it is unknown whether this deficit represents a heritable phenotype that is related to risk for schizophrenia or whether it is related to disease state. The purpose of the present study was to examine amygdala response to threatening faces among healthy siblings of schizophrenia patients in whom a subtler heritable deficit might be observed.Participants were 34 schizophrenia patients, 29 unaffected siblings, and 20 healthy comparison subjects. Blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was conducted during an implicit facial information processing task. The N-back working memory task, which has been shown to elicit prefrontal cortex abnormalities in unaffected siblings of schizophrenia patients, was employed as a positive experimental control.Schizophrenia patients demonstrated a deficit in amygdala reactivity to negative face stimuli and an alteration, correlated with neuroleptic drug dosage, in the functional coupling between the amygdala and subgenual cingulate. In contrast, unaffected siblings showed a pattern that was not statistically different from that of healthy comparison subjects. During the N-back working memory task, both schizophrenia patients and their unaffected siblings demonstrated a pattern of inefficient prefrontal cortex engagement, which is consistent with earlier evidence that this pattern is related to genetic risk for schizophrenia.These data suggest that the pathophysiological mechanism underlying the inability of individuals with schizophrenia to normally engage the amygdala in processing fearful and angry facial representations is more likely a phenomenon related to the disease state, specifically to treatment.
Strong Inverse Association Between Height and Suicide in a Large Cohort of Swedish Men: Evidence of Early Life Origins of Suicidal Behavior?
Authors: Patrik K E Magnusson, David Gunnell, Per Tynelius, George Davey Smith, Finn Rasmussen
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: Previous studies have found associations between poor fetal and infant growth and the risk of suicide. The authors' goal was to investigate the association between height—a measure of childhood growth—and suicide risk. METHOD: The authors conducted a record linkage study of the birth, conscription, mortality, family, and census register data of 1,299,177 Swedish men followed from age 18 to a maximum of age 49. RESULTS: There were 3,075 suicides over an average follow-up period of 15 years. There was a strong inverse association between height and suicide risk. In fully adjusted models, a 5-cm increase in height was associated with a 9% decrease in suicide risk. CONCLUSIONS: The strong inverse association between height and suicide may signify the importance of childhood exposure in the etiology of adult mental disorder or reflect stigmatization or discrimination encountered by short men in their adult lives.
APOL1 Genotype and Race Differences in Incident Albuminuria and Renal Function Decline
Authors: Carmen A. Peralta, Kirsten Bibbins-Domingo, Eric Vittinghoff, Feng Lin, Myriam Fornage, Jeffrey B. Kopp, Cheryl A. Winkler
Journal: Journal of the American Society of Nephrology (2015)

Variants in the APOL1 gene are associated with kidney disease in blacks. We examined associations of APOL1 with incident albuminuria and kidney function decline among 3030 young adults with preserved GFR in the Coronary Artery Risk Development in Young Adults (CARDIA) study. eGFR by cystatin C (eGFRcys) and albumin-to-creatinine ratio were measured at scheduled examinations. Participants were white (n=1700), high-risk black (two APOL1 risk alleles, n=176), and low-risk black (zero/one risk allele, n=1154). Mean age was 35 years, mean eGFRcys was 107 ml/min per 1.73 m(2), and 13.2% of blacks had two APOL1 alleles. The incidence rate per 1000 person-years (95% confidence interval) for albuminuria over 15 years was 15.6 (10.6-22.1) for high-risk blacks, 7.8 (6.4-9.4) for low-risk blacks, and 3.9 (3.1-4.8) for whites. Compared with whites, the odds ratio (95% confidence interval) for incident albuminuria was 5.71 (3.64-8.94) for high-risk blacks and 2.32 (1.73-3.13) for low-risk blacks. Adjustment for risk factors attenuated the difference between low-risk blacks and whites (odds ratio 1.21, 95% confidence interval 0.86-1.71). After adjustment, high-risk blacks had a 0.45% faster yearly eGFRcys decline over 9.3 years compared with whites. Low-risk blacks also had a faster yearly eGFRcys decline compared with whites, but this difference was attenuated after adjustment for risk factors and socioeconomic position. In conclusion, blacks with two APOL1 risk alleles had the highest risk for albuminuria and eGFRcys decline in young adulthood, whereas disparities between low-risk blacks and whites were related to differences in traditional risk factors.
Staphylococcus epidermidis induces complement activation, tumor necrosis factor and interleukin-1, a shock-like state and tissue injury in rabbits without endotoxemia. Comparison to Escherichia coli.
Authors: G Wakabayashi, J A Gelfand, W K Jung, R J Connolly, J F Burke, C A Dinarello
Journal: Journal of Clinical Investigation (1991)

Tumor necrosis factor (TNF) and IL-1 are thought to mediate many of the pathophysiologic changes of endotoxemia and Gram-negative bacteremia. In these studies, heat-killed Staphylococcus epidermidis were infused into rabbits to determine whether an endotoxin (LPS)-free microorganism also elicits cytokinemia and the physiologic abnormalities seen in Gram-negative bacteremia. S. epidermidis induced complement activation, circulating TNF and IL-1, and hypotension to the same degree as did one-twentieth the number of heat-killed Escherichia coli. Circulating IL-1 beta levels had a greater correlation coefficient (r = 0.81, P less than 0.001) with the degree of hypotension than TNF levels (r = 0.48, P less than 0.02). Leukopenia, thrombocytopenia, diffuse pulmonary capillary aggregation of neutrophils, and hepatic necrosis with neutrophil infiltration were observed to the same extent after either S. epidermidis or E. coli infusion. However, S. epidermidis infusion did not induce significant (less than 60 pg/ml) endotoxemia, whereas E. coli infusion resulted in high (11,000 pg/ml) serum endotoxin levels. S. epidermidis, E. coli, LPS, or S. epidermidis-derived lipoteichoic acid (LTA) induced TNF and IL-1 from blood mononuclear cells in vitro. E. coli organisms and LPS were at least 100-fold more potent than S. epidermidis or LTA. Thus, a shock-like state with similar levels of complement activation as well as circulating levels of IL-1 and TNF were observed following either S. epidermidis or E. coli. These data provide further evidence that host factors such as IL-1 and TNF are common mediators of the septic shock syndrome regardless of the organism.
Treatment of Idiopathic Pulmonary Fibrosis with a New Antifibrotic Agent, Pirfenidone
Authors: GANESH RAGHU, W. CRAIG JOHNSON, DIANE LOCKHART, YOLANDA MAGETO
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of unknown etiology and fatal outcome. Currently available therapies are ineffective and associated with significant adverse effects. Pirfenidone, a new, investigational antifibrotic agent, was evaluated for its tolerability and usefulness in terminally ill patients with advanced IPF. Consecutive patients with IPF and deterioration despite conventional therapy or who were unable to tolerate or unwilling to try conventional therapy were treated with oral pirfenidone. Treatment was administered on a compassionate basis (open-label). Fifty-four patients were followed for mortality, change in lung function, and adverse effects. Their mean age was 62, mean duration of symptoms 4.6 yr, and time since lung biopsy was 3.2 yr. Conventional therapy was discontinued in 38 of 46 patients; the other eight were able to decrease their prednisone dosage and eight had no previous conventional treatment. One- and 2-yr survival was 78% (95% CI 66%, 89%) and 63% (95% CI 50%, 76%), respectively. Patients whose lung functions had deteriorated prior to enrollment appeared to stabilize after beginning treatment. Adverse effects were relatively minor. The results of this study are encouraging. Pirfenidone is a promising new treatment for IPF that is well tolerated.
The Novel Histologic International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification System of Lung Adenocarcinoma Is a Stage-Independent Predictor of Survival
Authors: Arne Warth, Thomas Muley, Michael Meister, Albrecht Stenzinger, Michael Thomas, Peter Schirmacher, Philipp A. Schnabel, Jan Budczies, Hans Hoffmann, Wilko Weichert
Journal: Journal of Clinical Oncology (2012)

Purpose Our aim was to analyze and validate the prognostic impact of the novel International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) proposal for an architectural classification of invasive pulmonary adenocarcinomas (ADCs) across all tumor stages. Patients and Methods The architectural pattern of a large cohort of 500 patients with resected ADCs (stages I to IV) was retrospectively analyzed in 5% increments and classified according to their predominant architecture (lepidic, acinar, solid, papillary, or micropapillary), as proposed by the IASLC/ATS/ERS. Subsequently, histomorphologic data were correlated with clinical data, adjuvant therapy, and patient outcome. Results Overall survival differed significantly between lepidic (78.5 months), acinar (67.3 months), solid (58.1 months), papillary (48.9 months), and micropapillary (44.9 months) predominant ADCs (P = .007). When patterns were lumped into groups, this resulted in even more pronounced differences in survival (pattern group 1, 78.5 months; group 2, 67.3 months; group 3, 57.2 months; P = .001). Comparable differences were observed for overall, disease-specific, and disease-free survival. Pattern and pattern groups were stage- and therapy-independent prognosticators for all three survival parameters. Survival differences according to patterns were influenced by adjuvant chemoradiotherapy; in particular, solid-predominant tumors had an improved prognosis with adjuvant radiotherapy. The predominant pattern was tightly linked to the risk of developing nodal metastases (P &lt; .001). Conclusion Besides all recent molecular progress, architectural grading of pulmonary ADCs according to the novel IASLC/ATS/ERS scheme is a rapid, straightforward, and efficient discriminator for patient prognosis and may support patient stratification for adjuvant chemoradiotherapy. It should be part of an integrated clinical, morphologic, and molecular subtyping to further improve ADC treatment.
Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure
Authors: Reynolds M. Delgado, Mohamad A. Nawar, Aly M. Zewail, Biswajit Kar, William K. Vaughn, Kenneth K. Wu, Nena Aleksic, Natarajan Sivasubramanian, Kathleen McKay, Douglas L. Mann, James T. Willerson
Journal: Circulation (2004)

Progression of heart failure after initial myocardial injury is mediated in part by various redundant inflammatory mediators, including the widely expressed cyclooxygenase-2 (COX-2). Because COX-2 inhibitors are useful in treating many inflammation-mediated diseases, we asked whether COX-2 inhibition can attenuate heart failure progression.Heart failure was experimentally induced in 100 mice by administration of doxorubicin (4 mg. kg(-1). wk(-1) for 6 weeks). Beginning at day 42, mice were fed daily with either COX-2 inhibitor-containing mice chow (n=50) or plain mice chow (controls; n=50). Left ventricular ejection fraction was evaluated as a measure of heart failure by a novel method of transthoracic echocardiography (with intravascular ultrasound catheters) at baseline and on days 42, 56, and 70. From baseline to study termination, left ventricular ejection fraction in COX-2 inhibitor-treated mice decreased significantly less than in control mice (9% versus 29%, P<0.01). Mortality was significantly lower for COX-2 inhibitor-treated mice than for control mice (18% versus 38%, P<0.01). These results were confirmed in a revalidation study in COX-2 inhibitor-treated mice (n=25) and controls (n=25). That study revealed that the hearts from control mice weighed roughly the same as hearts from COX-2 inhibitor-treated mice but showed more extensive signs of cardiomyopathy (as determined by pathological analysis by an independent, blinded observer) and higher levels of COX-2 proteins (as determined by immunoblotting [6442+/-1635 versus 4300+/-2408 arbitrary units, P<0.022]).COX-2 inhibitors can attenuate the progression of heart failure in a murine model of doxorubicin-induced heart failure.
Blimp-1 is required for maintenance of long-lived plasma cells in the bone marrow
Authors: Miriam Shapiro-Shelef, Kuo-I Lin, David Savitsky, Jerry Liao, Kathryn Calame
Journal: The Journal of Experimental Medicine (2005)

Long-lived plasma cells, residing primarily in the bone marrow, continuously secrete antibody and provide an important component of humoral memory. However, when such cells secrete autoantibodies or become transformed, they can be pathogenic. We have shown recently that the transcriptional repressor B lymphocyte–induced maturation protein 1 (Blimp-1) is required for the formation of plasma cells. To determine what role Blimp-1 might play in maintenance of plasma cells, we generated mice in which the gene encoding Blimp-1 could be deleted in an inducible manner. Deletion of Blimp-1 either in vitro or in vivo leads to loss of previously formed B220LOCD138HI plasma cells. Using BrdU incorporation, we confirmed that Blimp-1 is required for the maintenance of nondividing, long-lived plasma cells in the bone marrow. Blimp-1 is also required for long-term maintenance of antigen-specific immunoglobulin in serum. Thus Blimp-1 is required not only for the formation but also for the maintenance of long-lived plasma cells. This finding provides the possibility of new drug design strategies for autoimmunity and multiple myeloma focused on blocking Blimp-1 expression or activity.
Muscarinic receptors mediate stimulation of collagen synthesis in human lung fibroblasts
Authors: S. Haag, S. Matthiesen, U. R. Juergens, K. Racke
Journal: European Respiratory Journal (2008)

Clinical observations indicate that in chronic obstructive pulmonary disease patients, the long-acting muscarinic antagonist tiotropium delays decline in airway function, suggesting that cholinergic mechanisms contribute to long-term structural changes. Human lung fibroblasts express muscarinic receptors and the present study aimed to explore their role in controlling collagen synthesis. MRC-5, HEL-299 and primary human lung fibroblasts (phLFb) were cultured. Incorporation of [(3)H]-proline into cellular proteins was determined as measure of collagen synthesis. In MRC-5 cells, the muscarinic agonist carbachol enhanced [(3)H]-proline incorporation in a concentration-dependent manner (effective concentration of 50%: 220 nM, increase at 10 microM by 40-55%, in a different series of experiments). Likewise, 10 microM oxotremorine caused an increase of approximately 65%. For comparison, transforming growth factor-beta1 (5 ng x mL(-1)) caused an increase of approximately 80%. Effects of carbachol on total [(3)H]-proline incorporation and collagenase-sensitive [(3)H]-proline fraction were similar. The effect of 10 microM carbachol was inhibited by tiotropium (inhibitory concentration of 50%: 110 pM), prevented by pertussis toxin and the mitogen-activated protein kinase inhibitor, PD 98059. Muscarinic agonists also enhanced [(3)H]-proline incorporation in a tiotropium-sensitive manner in HEL-299 cells and phLFb. In human lung fibroblasts, muscarinic receptors exert stimulatory effects on collagen synthesis. Prolonged blockade of muscarinic-induced collagen synthesis may contribute to reported beneficial long-term effects of anticholinergics in chronic obstructive pulmonary disease.
Probability of Metachronous Testicular Cancer in Patients With Biopsy-Proven Intratubular Germ Cell Neoplasia Depends on First-Time Treatment of Germ Cell Cancer
Authors: Sigmund Brabrand, Sophie D. Fosså, Milada Cvancarova, Ulrika Axcrona, Gustav Lehne
Journal: Journal of Clinical Oncology (2012)

Purpose To evaluate the probability of subsequent testicular cancer (STC) in patients with intratubular germ cell neoplasia unclassified (IGCNU) treated for first-time invasive germ cell cancer. Patients and Methods Sixty-one patients with germ cell testicular cancer or extragonadal germ cell cancer received follow-up from diagnosis of IGCNU to development of STC, initiation of IGCNU-definitive treatment (orchiectomy/radiotherapy), emigration, death, or end of follow-up. The probability of STC was assessed in subgroups according to chemotherapy burden. Results The probability of STC in the nonexposed patients was significantly increased compared with those exposed to chemotherapy (P = .05; 5-year probability of 54% [95% CI, 33% to 78%] and 23% [95% CI, 11% to 45%], respectively). In the group of patients treated with one to three cycles or no chemotherapy, the probability of STC was significantly increased compared with those exposed to four or more cycles (P = .03; 5-year probability of 42% [95% CI, 27% to 62%] and 22% [95% CI, 8% to 54%], respectively). Twenty-two of 22 patients were tumor-free and alive at a median of 56 months (range, 2 to 184 months) after diagnosis of STC. Conclusion Platinum-based chemotherapy may reduce the probability of STC in patients with IGCNU, particularly in those treated with four or more cycles of chemotherapy. A watch-and-wait strategy for patients with IGCNU may be justified in selected patients with future plans for paternity.
Phase I and Pharmacokinetic Study of the (6-Maleimidocaproyl)Hydrazone Derivative of Doxorubicin
Authors: Clemens Unger, Brigitte Häring, Michael Medinger, Joachim Drevs, Simone Steinbild, Felix Kratz, Klaus Mross
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The (6-maleimidocaproyl)hydrazone derivative of doxorubicin (DOXO-EMCH) is an albumin-binding prodrug of doxorubicin with acid-sensitive properties that shows superior antitumor efficacy in murine tumor models and a favorable toxicity profile in mice, rats, and dogs compared with doxorubicin. The purpose of the phase I study was to characterize the toxicity profile of DOXO-EMCH, establish a recommended dose for phase II studies, and assess potential anticancer activity. Experimental Design: A starting dose of 20 mg/m2 doxorubicin equivalents was chosen. Forty-one patients with advanced cancer disease were treated with an i.v. infusion of DOXO-EMCH once every 3 weeks at a dose level of 20 to 340 mg/m2 doxorubicin equivalents. Results: Treatment with DOXO-EMCH was well tolerated up to 200 mg/m2 without manifestation of drug-related side effects. Myelosuppression (grade 1-2) and mucositis (grade 1-2) were the predominant adverse effects at dose levels of 260 mg/m2 and myelosuppression (grade 1-3) as well as mucositis (grade 1-3) were dose limiting at 340 mg/m2. No cardiac toxicity was observed. Of 30 of 41 evaluable patients, 12 patients (40%) had progressive disease, 15 patients (57%) had stable disease, and 3 patients (10%) had a partial remission. Conclusions: DOXO-EMCH showed a good safety profile and was able to induce tumor regressions in tumor types known to be anthracycline-sensitive tumors, such as breast cancer, small cell lung cancer, and sarcoma. The recommended doxorubicin equivalent dose for phase II studies is 260 mg/m2.
‘Rheumatologist go home!’ Coming up next?
Authors: Till Uhlig, Tuulikki Sokka
Journal: Annals of the Rheumatic Diseases (2013)

High use of healthcare services is characteristic for rheumatoid arthritis (RA).Health spas have provided care for patients with RA in many countries, and many patients with early RA used to be kept in hospitals for several weeks. 1 In the 1970s, Swedish researchers reported that over a 13-year follow-up period, patients with RA were admitted to hospital more than twice as often, and spent three times as many days in hospital, as control subjects, 2 primarily because of high inflammatory activity.Over the past two decades, however, many rheumatology wards have been closed and rheumatology beds in departments were given away, especially in the Nordic countries. 3oday, rheumatology is characterised by active medication strategies using a combination of early treatment with traditional disease-modifying antirheumatic drugs and other effective drugs, with adjustment during close follow-up.In many countries a multidisciplinary approach to RA means support in a wide array of areas, from devices 4 to coping with the disease. 5The patient is taught to take an active role.Of concern to many are the high medication costs.Early remission has unanimously been defined as a treatment target.In addition to methotrexate and combinations of conventional antirheumatic drugs, a subset of patients with RA needs more powerful though expensive drugs.In the search for remission in a subset of patients with RA, with the prospect of reduced symptoms and reduced or halted future joint damage, use of biological agents with their high costs is unavoidable.These costs are not affordable in all countries. 6The use of biological agents is associated with reduced suffering and improved health.
Spontaneous Airway Hyperresponsiveness in Estrogen Receptor-α–deficient Mice
Authors: Michelle A. Carey, Jeffrey W. Card, J. Alyce Bradbury, Michael P. Moorman, Najwa Haykal-Coates, Stephen H. Gavett, Joan P. Graves, Vickie R. Walker, Gordon P. Flake, James W. Voltz, Daling Zhu, Elizabeth R. Jacobs, Azzeddine Dakhama, Gary L. Larsen, Joan E. Loader, Erwin W. Gelfand, Dori R. Germolec, Kenneth S. Korach, Darryl C. Zeldin
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Airway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.To examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice.Lung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.Estrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.These data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.