tbuckley/cabot-search huggingface dataset:
Cerebral Small Vessel Disease and Association With Higher Incidence of Depressive Symptoms in a General Elderly Population: The AGES-Reykjavik Study
Authors: Thomas T van Sloten, Sigurdur Sigurdsson, Mark A van Buchem, Caroline L Phillips, Palmi V Jonsson, Jie Ding, Miranda T Schram, Tamara B Harris, Vilmundur Gudnason, Lenore J Launer
Journal: American Journal of Psychiatry (2015)

Objective: The vascular depression hypothesis postulates that cerebral small vessel disease (CSVD) leads to depressive symptoms by disruption of brain structures involved in mood regulation. However, longitudinal data on the association between CSVD and depressive symptoms are scarce. The authors investigated the association between CSVD and incident depressive symptoms. Method: Longitudinal data were taken from the Age, Gene/Environment Susceptibility-Reykjavik Study of 1,949 participants free of dementia and without baseline depressive symptoms (mean age: 74.6 years [SD=4.6]; women, 56.6%). MRI markers of CSVD, detected at baseline (2002–2006) and follow-up (2007–2011), included white matter hyperintensity volume, subcortical infarcts, cerebral microbleeds, Virchow-Robin spaces, and total brain parenchyma volume. Incident depressive symptoms were defined by a score ≥6 on the 15-item Geriatric Depression Scale and/or use of antidepressant medication. Results: Depressive symptoms occurred in 10.1% of the participants. The association for a greater onset of depressive symptoms was significant for participants with 1 standard deviation increase in white matter hyperintensity volume over time, new subcortical infarcts, new Virchow-Robin spaces, 1 standard deviation lower total brain volume at baseline, and 1 standard deviation decreased total brain volume over time, after adjustments for cognitive function and sociodemographic and cardiovascular factors. Results were qualitatively similar when change in the Geriatric Depression Scale score over time was used as the outcome instead of incident depressive symptoms. Conclusions: Most markers of progression of CSVD over time and some markers of baseline CSVD are associated with concurrently developing new depressive symptoms. These findings support the vascular depression hypothesis.
PTX3 a marker of innate immune responses in the airways of asthmatics and COPD patients
Authors: Fabiano Schwingel, Marcia Pizzichini, Emilio Pizzichini, Steidle Leila, Edelton Morato, Cristiane Rocha, Tulia Kleveston, José Pinheiro
Journal: European Respiratory Journal (2013)

Background: Pentraxin 3 (PTX3) is a multifunctional pattern recognition protein and an important component of the innate immune system. Its role in airway diseases has been scarcely studied and remains undetermined.

Objectives: To investigate whether PTX3 measured in induced sputum (IS) discriminates patients with chronic obstructive pulmonary disease (COPD), asthma and healthy controls, and its association with functional abnormalities, IS cellularity and smoking (pack/years).

Methods: IS was obtained from 27 participants with COPD, 25 asthmatics and 16 healthy controls. IS was processed for total (TCC) and differential cell counts. PTX3 in IS supernatant was measured in duplicates by ELISA (limit of detection = 0.15 ng/ml). Results are expressed as median and 10-90 percentiles or otherwise as stated.

Results: PTX3 was detected in 88,9% of patients with COPD, 56,0% of asthmatics and in 18,8% of controls (p=0.001). It discriminated participants with COPD [24.6 (0-384) ng/mL] from controls [0 (0-36) ng/ml, p<0.001] and from asthmatics [1.2 (0 -100) ng/ml, p= 0.01]. Strong correlations were observed between PTX3 and sputum TCCx106/mg (r=0.482, p<0.001), neutrophils% (r= 0.355, p= 0.003) and smoking (r=0.425, p<0.001). There was a strong negative correlation between PTX3 and FEV1% (r=-0.446, p<0,001), and VEF1/FVC ratio (r=-0.514, p<0.001). Correlations between the above parameters per study groups showed that in COPD group PTX3 was inversely correlated with FEV1% (r=-0.390, p=0.04), and VEF1/FVC ratio (r=-0.362, p=0.05).

Conclusion: PTX3 is discriminative of patients with COPD and asthma. Its association with functional abnormalities suggests that PTX3 may be important in the pathogenesis of COPD.
Urine concentration and dilution in hypokalemic and hypercalcemic dogs
Authors: Cleaves M. Bennett
Journal: Journal of Clinical Investigation (1970)

The urine-concentrating mechanism was studied in chronic hypokalemia (seven dogs given a low K(+), high NaCl diet plus injections of deoxycorticosterone acetate [DOCA]) and chronic hypercalcemia (seven dogs given vitamin D). In the potassium-depleted dogs, muscle, serum, and urine K(+) fell markedly, but glomerular filtration rate (GFR) and body weight varied little. Maximum urine osmolality fell in all dogs (mean decrease = 45%); however, solute-free water reabsorption (T(CH2O)) at high rates of solute excretion remained normal in three of four dogs. Free water excretion (C(H2O)) increased normally or supranormally as a function of increasing Na(+) delivery to Henle's loop in six dogs so tested. Hypercalcemia of several weeks duration caused a decrease in both GFR (mean 36%) as well as in maximum urine osmolality (mean 57%). Maximum T(CH2O) was not invariably depressed; in fact, when the values were adjusted for the reduced number of functioning nephrons (T(CH2O)/C(In)), four of seven studies were normal. C(H20)/C(In) increased normally (or supranormally) with increasing fractional Na delivery to Henle's loop in four of five dogs.I conclude that the lowered maximum urine osmolality in these hypokalemic and hypercalcemic dogs was not related to abnormal water reabsorption from the collecting ducts. Although not specifically measured in this study, it is very likely that solute accumulation in the renal medulla was reduced. This probably was not caused by abnormal delivery of sodium to, nor reabsorption of sodium from Henle's loop. It is likely that a more subtle defect exists in the countercurrent mechanisms for establishing a steep concentration gradient in the renal medulla. In the few hypercalcemic dogs in whom GFR was very low, I believe that injury to, and blockage of medullary tubules could account for most of the reduction in maximum U(Osm). Although not specifically ruled out, there is no evidence here to suggest that high serum Ca(+) or low serum K(+) per se causes a defect in sodium and water reabsorption in the mammalian nephron.
Effect of hydrochloric acid and prostaglandins on pepsinogen synthesis and secretion in canine gastric chief cell monolayer cultures.
Authors: J Defize, R H Hunt
Journal: Gut (1989)

The actions of hydrochloric acid, natural PGE1, PGE2 and a synthetic commercial PGE1 preparation, Enisoprost (Searle) on pepsinogen synthesis and secretion were studied in canine chief cell monolayer cultures. Hydrochloric acid, applied directly to the apical surface of chief cells using culture plate inserts (Millipore) had no effect on secretion, nor did it affect the action of any secretagogue in the basolateral medium. All prostaglandins tested showed significant stimulation of pepsinogen secretion. Basal secretion of pepsinogen after 90 min was 9.4 (1.3)% to total initial monolayer content. At 10(-6) M, PGE1 stimulated secretion was 26.1 (3.8)%; PGE2 27.9 (4)% and Enisoprost 28.8 (4.2)% of initial pepsinogen content. Stimulations by all tested prostaglandins were additive with carbachol (10(-4) M) and CCK (10(-9) M), but not with VIP (10(-6) M), dbcAMP (10(-3) M) or forskolin (10(-6) M) responses. All three prostaglandins stimulated pepsinogen synthesis as measured by 14C labelled amino acid incorporation into pepsinogen. Time course experiments were similar to those for forskolin and showed shorter time delays between stimulus and increased synthesis rate than carbachol but longer than dbcAMP. Stimulated pepsinogen secretion was inhibited by high pepsin concentrations (greater than 800 micrograms/ml) in the medium. The inhibited abolished simultaneous carbachol induced stimulation of synthesis but prostaglandin or forskolin stimulation only after two hours. Combined with the shorter response time, as compared with carbachol, these data support our previous findings that potent stimulators of cAMP production can stimulate pepsinogen synthesis directly by stimulation of mRNA synthesis, independently from an increased secretion. The additivity of effects with carbachol or CCK and similarity with forskolin stimulated synthesis supports the suggestion that the actions of prostaglandins are mediated by cAMP.
Treating Opioid Dependence — New Data and New Opportunities
Authors: Patrick G. O'Connor
Journal: New England Journal of Medicine (2000)

Heroin use in the United States has grown considerably over the past decade. Approximately 3 million Americans have used heroin,1 a fact that has led to increasing concern about heroin-related problems such as overdose, human immunodeficiency virus (HIV) infection, unemployment, and crime. Finding effective treatments for heroin dependence is critical. The report by Johnson et al. in this issue of the Journal 2 represents an important step toward expanding the options for treatment.Patients who are dependent on opioids may come to physicians with health problems and may request help finding treatment. The first step is careful screening to identify underlying . . .
Region-related risk factors for respiratory symptoms in European and Californian farmers
Authors: E. Monsó, M. Schenker, K. Radon, E. Riu, R. Magarolas, S. McCurdy, B. Danuser, M. Iversen, C. Saiki, D. Nowak
Journal: European Respiratory Journal (2003)

The aim of this study was to determine the prevalences and regional risk factors for respiratory symptoms in European and Californian farmers. Farmers participating in the 1993–1997 surveys performed in Europe (n=7,188) and California (n=1,839) were included in this cross-sectional study. Respiratory symptoms and farming characteristics were assessed by questionnaire and risk factors associated with symptoms using logistic regression. The prevalences of rhinitis and asthma were lower in European (12.7% and 2.8%) than in Californian farmers (23.9% and 4.7%), but chronic bronchitis and toxic pneumonitis were more prevalent in Europe (10.7% and 12.2%) than in California (4.4% and 2.7%). Respiratory symptoms were associated with poultry and rabbit farming, flower growing and the cultivation of grain and oil plants. Working in Europe was a statistically significant risk factor for chronic bronchitis and toxic pneumonitis. Chronic bronchitis was related to toxic pneumonitis, work inside confinement buildings and greenhouses. Chronic bronchitis and toxic pneumonitis are highly prevalent among European farmers and are mainly attributable to indoor work.
Infection with Oncolytic Herpes Simplex Virus-1 Induces Apoptosis in Neighboring Human Cancer Cells
Authors: Stephen F. Stanziale, Henrik Petrowsky, Prasad S. Adusumilli, Leah Ben-Porat, Mithat Gonen, Yuman Fong
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The antitumor efficacy of a herpes simplex virus (HSV)-1 oncolytic virus depends on the cytotoxic effect of the virus, but also on viral replication and spread within the tumor. Apoptosis is considered a defense mechanism of infected cells that minimizes the spread of viral progeny by limiting cellular production of virus. We sought to determine whether oncolytic HSV-1 infection induces apoptosis in neighboring, uninfected cells and whether manipulation of apoptosis can increase viral replication and cytotoxicity. Experimental Design: NV1066 is an oncolytic HSV-1 mutant that contains the marker gene for enhanced green fluorescent protein. OCUM human gastric cancer cells were infected with NV1066 in vitro and inspected for apoptosis by Hoechst and terminal deoxynucleotidyltransferase-mediated nick end labeling staining and for infection by expression of green fluorescence. Results: A significant increase in apoptosis was seen in cells infected by NV1066. More interestingly, a significant percentage (10%) of uninfected cells also proceeded to apoptosis. After NV1066 infection, cells were also treated with N-acetylcysteine (NAC), an inhibitor of apoptosis. By day 4 after infection, 2.7× more NV1066 was produced in cells exposed to NAC than in those not exposed to NV1066 (P = 0.04). NAC also increased tumor kill when administered with virus. Conclusions: These data suggest that NV1066 induces apoptosis in uninfected cocultured cells, potentially hindering propagation of viral progeny and concomitant tumor kill. Inhibition of apoptosis may improve the efficacy of oncolytic HSV-1 therapy.
The Imperative to Prevent Diabetes
Authors: Robert E. Ratner
Journal: Diabetes Care (2012)

Diabetes is the seventh leading cause of death in the U.S. and increases the risk of death twofold over age-matched individuals. Even these are conservative numbers, as diabetes has been found to be underreported on death certificates (1). These findings are even more remarkable for the recent decline seen in diabetes mortality rates due to improved management of cardiovascular risk factors (2). Despite remarkable advances in our understanding of the disease and pharmacological interventions for its treatment, diabetes remains the leading cause of renal failure, nontraumatic lower-limb amputation, and blindness in working-age adults. Improved therapeutics and health care delivery have brought remarkable declines in the incidence of both diabetic microvascular and macrovascular complications, with a 50% reduction in amputations from their peak in 1997 and ∼35% reduction in the incidence of end-stage renal disease (3). Similarly, 10-year coronary heart disease risk dropped from 21% in 2000 to 16% in 2008 (4).

The observed decline in the event rates of complications and death due to diabetes is swamped by the increase in the number of individuals affected by the disease. The multiplier effect of a growing population with diabetes converts a declining incidence of complications into an increase in the total number of events observed. Among adults aged 18–79 years, the number of individuals with diagnosed diabetes in …
Pulmonary Vascular Endothelial Growth Factor-C in Development and Lung Injury in Preterm Infants
Authors: Joakim Janér, Patrik Lassus, Caj Haglund, Karri Paavonen, Kari Alitalo, Sture Andersson
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Rationale: In mice, vascular endothelial growth factor-C (VEGF-C) plays an important role in development of the lymphatic system and in pathogenesis of pulmonary inflammation. Its role in development of the lymphatic system in human lung and in lung injury in newborns remains unclear.Objectives: We studied the role of VEGF-C in developing human lung, and in acute and chronic lung injury in preterm infants.Methods: Included in the immunohistochemistry study were 10 fetuses, 15 control neonates without primary lung disease, 15 preterm infants with respiratory distress syndrome, and 8 infants with bronchopulmonary dysplasia. Tracheal aspirate fluid samples of intubated very-low-birth-weight infants during Postnatal Weeks 1–5 were analyzed with ELISA.Results: Bronchiolar staining for VEGF-C was observed in all 48 samples. Alveolar epithelial staining was seen in most fetuses (8/10). In addition, staining was observed in alveolar macrophages in bronchopulmonary dysplasia (4/8), and late respiratory distress syndrome (2/7). VEGF receptor-3 (VEGFR-3) staining was observed in lymphatic endothelium adjacent to vascular endothelium. VEGF-C was expressed consistently in tracheal aspirate fluid, being highest during the first 2 postnatal days. Antenatal administration of glucocorticoids was associated with higher VEGF-C in tracheal aspirate fluid.Conclusions: The pattern of pulmonary VEGF-C and VEGFR-3 protein expression and consistent VEGF-C protein appearance in tracheal aspirate fluid in human preterm infants indicate a role for VEGF-C in the physiologic development of the lymphatic system of the lung.
Galectin-7 initiates asthma by causing airway epithelial- mesenchymal unit abnormality
Authors: Shunying Zhao, Mingjing Song, Chunjun Zhou
Journal: European Respiratory Journal (2014)

The underlying mechanism for enhanced airway epithelial apoptosis in asthma remains unknown. We previously found that Galectin-7 over-expression was associated with it in childhood asthma.   Aims and objectives   To investigate the roles of galectin-7 in airway epithelial apoptosis and asthma.   Methods   Firstly, we determined the effect of galectin-7 transfection and exogenous galectin-7on airway epithelial apoptosis and asthma in vitro and in vivo. Next, we observed lung pathology in  g  alectin-7  transgenic mice at baseline and after RSV infection and OVA challange. Finally, we detected  g alectin-7 levels in asthmatic children.   Results   Galectin-7 transfection and exogenous galectin-7 induced airway epithelial apoptosis both in cultured bronchial epithelium and rats. Exogenous galectin-7 was associated with airway epithelial injury and other asthma response. Galectin-7 transgenic mice exhibited abnormal airway epithelial -mesenchymal units, characterized by increased bronchial epithelial apoptosis, thinning epithelium, widening of intercellular space, reduced tight junctions and expression of zonula occludens 1, thinning smooth muscle and discontinuous basement membrane. With age increasing, the airways of some galectin-7 transgenic mice showed part or whole smooth muscle and basement membrane thickening, an increase in (myo)fibroblasts, epithelial shedding and lymphocyte infiltration. When treated with RSV and OVA, galectin-7 transgenic mice developed substantially increased asthma response. Galectin-7 levels were increased in serum and sputum supernatant from asthmatic children.   Conclusion   These findings indicate galectin-7 initiates asthma by abnormal airway epithelial -mesenchymal units.
Lanreotide in Metastatic Enteropancreatic Neuroendocrine Tumors
Authors: Martyn E. Caplin, Marianne Pavel, Jarosław B. Ćwikła, Alexandria T. Phan, Markus Raderer, Eva Sedláčková, Guillaume Cadiot, Edward M. Wolin, Jaume Capdevila, Lucy Wall, Guido Rindi, Alison Langley, Séverine Martinez, Joëlle Blumberg, Philippe Ruszniewski
Journal: New England Journal of Medicine (2014)

Somatostatin analogues are commonly used to treat symptoms associated with hormone hypersecretion in neuroendocrine tumors; however, data on their antitumor effects are limited.We conducted a randomized, double-blind, placebo-controlled, multinational study of the somatostatin analogue lanreotide in patients with advanced, well-differentiated or moderately differentiated, nonfunctioning, somatostatin receptor-positive neuroendocrine tumors of grade 1 or 2 (a tumor proliferation index [on staining for the Ki-67 antigen] of <10%) and documented disease-progression status. The tumors originated in the pancreas, midgut, or hindgut or were of unknown origin. Patients were randomly assigned to receive an extended-release aqueous-gel formulation of lanreotide (Autogel [known in the United States as Depot], Ipsen) at a dose of 120 mg (101 patients) or placebo (103 patients) once every 28 days for 96 weeks. The primary end point was progression-free survival, defined as the time to disease progression (according to the Response Evaluation Criteria in Solid Tumors, version 1.0) or death. Secondary end points included overall survival, quality of life (assessed with the European Organization for Research and Treatment of Cancer questionnaires QLQ-C30 and QLQ-GI.NET21), and safety.Most patients (96%) had no tumor progression in the 3 to 6 months before randomization, and 33% had hepatic tumor volumes greater than 25%. Lanreotide, as compared with placebo, was associated with significantly prolonged progression-free survival (median not reached vs. median of 18.0 months, P<0.001 by the stratified log-rank test; hazard ratio for progression or death, 0.47; 95% confidence interval [CI], 0.30 to 0.73). The estimated rates of progression-free survival at 24 months were 65.1% (95% CI, 54.0 to 74.1) in the lanreotide group and 33.0% (95% CI, 23.0 to 43.3) in the placebo group. The therapeutic effect in predefined subgroups was generally consistent with that in the overall population, with the exception of small subgroups in which confidence intervals were wide. There were no significant between-group differences in quality of life or overall survival. The most common treatment-related adverse event was diarrhea (in 26% of the patients in the lanreotide group and 9% of those in the placebo group).Lanreotide was associated with significantly prolonged progression-free survival among patients with metastatic enteropancreatic neuroendocrine tumors of grade 1 or 2 (Ki-67 <10%). (Funded by Ipsen; CLARINET ClinicalTrials.gov number, NCT00353496; EudraCT 2005-004904-35.).
Highly discordant T cell responses in individuals with recent exposure to household tuberculosis
Authors: A C Hesseling, A M Mandalakas, H L Kirchner, N N Chegou, B J Marais, K Stanley, X Zhu, G Black, N Beyers, G Walzl
Journal: Thorax (2008)

<h3>Background:</h3> There are limited data comparing interferon-γ release assays (IGRAs) for the detection of <i>Mycobacterium tuberculosis</i> infection in highly endemic settings. <h3>Methods:</h3> A cross-sectional household contact study was conducted to measure the agreement of two IGRAs in relation to the tuberculin skin test (TST) to detect <i>M tuberculosis</i> infection and to assess the influence of <i>M tuberculosis</i> exposure and age. <h3>Results:</h3> In 82 individuals in household contact, 93% of children and 42% of adults had a high <i>M tuberculosis</i> contact score. The TST was positive in 78% of adults and 54% of children, the T-SPOT.<i>TB</i> was positive in 89% of children and 66% of adults and the QuantiFERON TB Gold (QTF) was positive in a similar proportion of adults and children (38.1% and 39.6%). In children there was poor agreement between the TST and T-SPOT.<i>TB</i> (κ = −0.15) and the T-SPOT.<i>TB</i> and the QTF (κ = −0.03), but good agreement between the TST and the QTF (κ = 0.78) using 10 mm cut-off. In adults there was fair to moderate agreement between the TST and T-SPOT.<i>TB</i> (κ = 0.38), the TST and QTF (κ = 0.34) and T-SPOT.<i>TB</i> and QTF (κ = −0.50). High levels of exposure to <i>M tuberculosis</i> were associated with at least a sevenfold odds of being T-SPOT.<i>TB</i> positive (95% CI 7.67 to 508.69) and a threefold odds of being QTF positive (95% CI 3.02 to 30.54). There was a significant difference in the magnitude of T-SPOT.<i>TB</i> early secretory antigenic target (ESAT)-6 and culture filtrate protein 10 kD (CFP-10) spot counts between adults and children. <h3>Conclusions:</h3> The T-SPOT.<i>TB</i> may be more sensitive than the TST or QTF for detecting recent <i>M tuberculosis</i> infection in children. Differences between assays and the predictive utility of these findings for subsequent disease development should be prospectively assessed.