tbuckley/cabot-search huggingface dataset:
Ca <sub>v</sub> 3.1 (α <sub>1G</sub> ) T-Type Ca <sup>2+</sup> Channels Mediate Vaso-Occlusion of Sickled Erythrocytes in Lung Microcirculation
Authors: Songwei Wu, Johnson Haynes, James T. Taylor, Boniface O. Obiako, James R. Stubbs, Ming Li, Troy Stevens
Journal: Circulation Research (2003)

In the present study, we demonstrate that lung microvascular endothelial cells express a Cav3.1 (alpha1G) T-type voltage-gated Ca2+ channel, whereas lung macrovascular endothelial cells do not express voltage-gated Ca2+ channels. Voltage-dependent activation indicates that the Cav3.1 T-type Ca2+ current is shifted to a positive potential, at which maximum current activation is -10 mV; voltage-dependent conductance and inactivation properties suggest a "window current" in the range of -60 to -30 mV. Thrombin-induced transitions in membrane potential activate the Cav3.1 channel, resulting in a physiologically relevant rise in cytosolic Ca2+. Furthermore, activation of the Cav3.1 channel induces a procoagulant endothelial phenotype; eg, channel inhibition attenuates increased retention of sickled erythrocytes in the inflamed pulmonary circulation. We conclude that activation of the Cav3.1 channels selectively induces phenotypic changes in microvascular endothelial cells that mediate vaso-occlusion by sickled erythrocytes in the inflamed lung microcirculation.
Beneficial Effect of Serotonin 5-HT2-Receptor Antagonism on Renal Blood Flow Autoregulation in Cyclosporin-Treated Rats
Authors: MARLEEN VERBEKE, JOHAN VAN DE VOORDE, LEO DE RIDDER, NORBERT LAMEIRE
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Renal blood flow (RBF) autoregulation reappears in postischemic rat kidneys during serotonin (5-HT 2 ) antagonism. The aim of the present study was to analyze whether 5-HT 2 antagonism can ameliorate impaired RBF autoregulation in rats treated with 20 mg/kg per d cyclosporin A during 10 d. Autoregulation of RBF was assessed during stepwise lowering of renal perfusion pressure from 110 to 70 mmHg by gradual compression of the aorta. Autoregulation was lost in the cyclosporin A-treated rats. During administration of the 5-HT 2 antagonist ritanserin (0.6 mg/kg intravenous bolus, followed by 1.2 mg/kg per h intravenous infusion during 1 h), autoregulation acutely reappeared. Intrarenal bolus injections of a selective 5-HT 2 -agonist, 2,5 dimethoxy-4-iodoamphetamine hydrochloride, elicited a significantly stronger renal vasocontraction in cyclosporin A-treated rats than in control rats. This finding was also observed with serotonin after nitric oxide-synthase blockade. These results ( 1 ) show the importance of 5-HT 2 -receptor-mediated vasoconstriction in the suppression of vasodilatory autoregulation of RBF in experimental cyclosporin A-induced renal dysfunction and ( 2 ) demonstrate that the complete loss of RBF autoregulation is not due to damage of the vascular smooth muscle cells.
Delivery of GABAARs to Synapses Is Mediated by HAP1-KIF5 and Disrupted by Mutant Huntingtin
Authors: Alison E. Twelvetrees, Eunice Y. Yuen, I. Lorena Arancibia-Carcamo, Andrew F. MacAskill, Philippe Rostaing, Michael J. Lumb, Sandrine Humbert, Antoine Triller, Frederic Saudou, Zhen Yan, Josef T. Kittler
Journal: Neuron (2010)
Lymphocytic Alveolitis Is Associated with the Accumulation of Functionally Impaired HIV-Specific T Cells in the Lung of Antiretroviral Therapy–Naive Subjects
Authors: C. Preston Neff, Jennifer L. Chain, Samantha MaWhinney, Allison K. Martin, Derek J. Linderman, Sonia C. Flores, Thomas B. Campbell, Brent E. Palmer, Andrew P. Fontenot
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Lymphocytic alveolitis in HIV-1-infected individuals is associated with multiple pulmonary complications and a poor prognosis. Although lymphocytic alveolitis has been associated with viremia and an increased number of CD8(+) T cells in the lung, its exact cause is unknown.To determine if HIV-1-specific T cells are associated with lymphocytic alveolitis in HIV-1-infected individuals.Using blood and bronchoalveolar lavage (BAL) cells from normal control subjects and untreated HIV-1-infected individuals, we examined the frequency and functional capacity of HIV-1-specific T cells.We found that HIV-1-specific T cells were significantly elevated in the BAL compared with blood of HIV-1-infected individuals and strongly correlated with T-cell alveolitis. Expression of Ki67, a marker of in vivo proliferation, was significantly reduced on HIV-1-specific T cells in BAL compared with blood, suggesting a diminished proliferative capacity. In addition, HIV-1-specific CD4(+) and CD8(+) T cells in BAL had higher expression of programmed death 1 (PD-1) and lower cytotoxic T-lymphocyte antigen 4 (CTLA-4) expression than those in the blood. A strong correlation between PD-1, but not CTLA-4, and HIV-1-specific T-cell proliferation was seen, and blockade of the PD-1/PD-L1 pathway augmented HIV-1-specific T-cell proliferation, suggesting that the PD-1 pathway was the main cause of reduced proliferation in the lung.These findings suggest that alveolitis associated with HIV-1 infection is caused by the recruitment of HIV-1-specific CD4(+) and CD8(+) T cells to the lung. These antigen-specific T cells display an impaired proliferative capacity that is caused by increased expression of PD-1.
Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats
Authors: Stewart H. Lecker, Vered Solomon, S. Russ Price, Yong Tae Kwon, William E. Mitch, Alfred L. Goldberg
Journal: Journal of Clinical Investigation (1999)

Insulin deficiency (e.g., in acute diabetes or fasting) is associated with enhanced protein breakdown in skeletal muscle leading to muscle wasting. Because recent studies have suggested that this increased proteolysis is due to activation of the ubiquitin-proteasome (Ub-proteasome) pathway, we investigated whether diabetes is associated with an increased rate of Ub conjugation to muscle protein. Muscle extracts from streptozotocin-induced insulin-deficient rats contained greater amounts of Ub-conjugated proteins than extracts from control animals and also 40–50% greater rates of conjugation of 125I-Ub to endogenous muscle proteins. This enhanced Ub-conjugation occurred mainly through the N-end rule pathway that involves E214k and E3α. A specific substrate of this pathway, α-lactalbumin, was ubiquitinated faster in the diabetic extracts, and a dominant negative form of E214k inhibited this increase in ubiquitination rates. Both E214k and E3α were shown to be rate-limiting for Ub conjugation because adding small amounts of either to extracts stimulated Ub conjugation. Furthermore, mRNA for E214k and E3α (but not E1) were elevated 2-fold in muscles from diabetic rats, although no significant increase in E214k and E3α content could be detected by immunoblot or activity assays. The simplest interpretation of these results is that small increases in both E214k and E3α in muscles of insulin-deficient animals together accelerate Ub conjugation and protein degradation by the N-end rule pathway, the same pathway activated in cancer cachexia, sepsis, and hyperthyroidism.
Assault and Homicide Associated with Amphetamine Abuse
Authors: EVERETT H. ELLINWOOD
Journal: American Journal of Psychiatry (1971)

The author describes the histories of 13 persons who committed homicide while intoxicated with amphetamines. In most of these cases, the events leading to the homicidal act were directly related to amphetamine-induced paranoid thinking, panic, emotional lability, or lowered impulse control. The most important variables associated with these cases included predisposing personality, environmental circumstances, and the use of other drugs.
Occlusion pressure analysis role in partitioning of pulmonary vascular resistance in CTEPH
Authors: Mark Toshner, Jay Suntharalingam, Pierre Fesler, Elaine Soon, Karen K. Sheares, David Jenkins, Paul White, Nicholas W. Morrell, Robert Naeije, Joanna Pepke-Zaba
Journal: European Respiratory Journal (2012)

Flow-directed pulmonary artery occlusion is posited to enable partitioning of vascular resistance into small and large vessels. As such it may have a role in assessment for pulmonary endarterectomy. To test if the occlusion technique distinguished small from large vessel disease we studied 59 subjects with chronic thromboembolic pulmonary hypertension (CTEPH), idiopathic pulmonary arterial hypertension (IPAH), and connective tissue disease (CTD)-associated PAH. At right heart catheterisation, occlusion pressures were recorded. With fitting of the pressure decay curve, pulmonary vascular resistance was partitioned into downstream (small vessels) and upstream (large vessels, R up ). 47 patients completed the study; 14 operable CTEPH, 15 inoperable CTEPH, 13 idiopathic or CTD-PAH and five post-operative CTEPH. There was a significant difference in mean R up in the proximal operable CTEPH group 87.3 (95% CI 84.1–90.5); inoperable CTEPH mean 75.8 (95% CI 66.76–84.73), p=0.048; and IPAH/CTD, mean 77.1 (95% CI 71.86–82.33), p=0.003. Receiver operating characteristic curves to distinguish operable from inoperable CTEPH demonstrated an area under the curve of 0.75, p=0.0001. A cut-off of 79.3 gave 100% sensitivity (95% CI 73.5–100%) but 57.1% specificity (95% CI 28.9–82.3%). In a subgroup analysis of multiple lobar sampling there was demonstrable heterogeneity. R up is significantly increased in operable proximal CTEPH compared with non-operable distal CTEPH and IPAH/CTD-PAH. R up variability in patients with CTEPH and PAH is suggestive of pathophysiological heterogeneity.
Effect of Granulocyte/Macrophage Colony-Stimulating Factor on Circulating CD8+ and CD4+ T-Cell Responses to a Multipeptide Melanoma Vaccine: Outcome of a Multicenter Randomized Trial
Authors: Craig L. Slingluff, Gina R. Petroni, Walter C. Olson, Mark E. Smolkin, Merrick I. Ross, Naomi B. Haas, William W. Grosh, Marc E. Boisvert, John M. Kirkwood, Kimberly A. Chianese-Bullock
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites. Experimental Design: One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class Irestricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DRrestricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 g GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN- ELIspot assay and tetramer analysis. Clinical outcomes were recorded. Results: CD8+ T-cell response rates to the 12 MHC class Irestricted melanoma peptides (by day 50) with or without GM-CSF were 34 and 73, respectively (P &amp;lt; 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95 versus 77; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95 confidence interval) were 76 (67-83) and 52 (43-61), respectively, with too few events to assess differences by study group. Conclusions: High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans. (Clin Cancer Res 2009;15(22):703644)
Immunological control of tuberculosis: role of tumour necrosis factor and more
Authors: S Stenger
Journal: Annals of the Rheumatic Diseases (2005)

Therapy of autoimmune diseases with tumour necrosis factor (TNF) neutralising agents has provided a unique opportunity to learn about the significance of TNF in the maintenance of latent bacterial infections in humans. The remarkably high incidence of tuberculosis in patients treated with TNF antagonists raises the intriguing question about the physiological role of TNF in maintaining the lifelong latency of tubercle bacilli in granulomas in infected patients. Basic research during the past decade(s) combined with thoughtful observations in human subjects with tuberculosis and autoimmune diseases has provided several potential explanations for the recurrence of tuberculosis if TNF supply is withdrawn. TNF is involved in at least four key functions that contribute towards beneficial effects on the symptoms of autoimmune disorders on the one hand, and the attenuation of immune responses against <i>Mycobacterium tuberculosis</i> on the other hand. These are outlined in this review: induction of apoptosis, maturation of dendritic cells, activation of antimicrobial activity in macrophages, and orchestration of leucocyte movement.
Distributions of Selectively Constrained Sites and Deleterious Mutation Rates in the Hominid and Murid Genomes
Authors: L. Eory, D. L. Halligan, P. D. Keightley
Journal: Molecular Biology and Evolution (2009)

Protein-coding sequences make up only about 1% of the mammalian genome. Much of the remaining 99% has been long assumed to be junk DNA, with little or no functional significance. Here, we show that in hominids, a group with historically low effective population sizes, all classes of noncoding DNA evolve more slowly than ancestral transposable elements and so appear to be subject to significant evolutionary constraints. Under the nearly neutral theory, we expected to see lower levels of selective constraints on most sequence types in hominids than murids, a group that is thought to have a higher effective population size. We found that this is the case for many sequence types examined, the most extreme example being 5'UTRs, for which constraint in hominids is only about one-third that of murids. Surprisingly, however, we observed higher constraints for some sequence types in hominids, notably 4-fold sites, where constraint is more than twice as high as in murids. This implies that more than about one-fifth of mutations at 4-fold sites are effectively selected against in hominids. The higher constraint at 4-fold sites in hominids suggests a more complex protein-coding gene structure than murids and indicates that methods for detecting selection on protein-coding sequences (e.g., using the d(N)/d(S) ratio), with 4-fold sites as a neutral standard, may lead to biased estimates, particularly in hominids. Our constraint estimates imply that 5.4% of nucleotide sites in the human genome are subject to effective negative selection and that there are three times as many constrained sites within noncoding sequences as within protein-coding sequences. Including coding and noncoding sites, we estimate that the genomic deleterious mutation rate U = 4.2. The mutational load predicted under a multiplicative model is therefore about 99% in hominids.
Predictors of Depressed Mood in Spouses of Women With Breast Cancer
Authors: Frances Marcus Lewis, Kristin A. Fletcher, Barbara B. Cochrane, Jesse R. Fann
Journal: Journal of Clinical Oncology (2008)

Depressed mood in spouses of women with breast cancer deleteriously affects their own and their wife's functioning and their marital communication. However, no study has examined why some spouses get depressed whereas others do not, particularly during the first months of diagnosis and treatment, a known difficult time for couples. The current study has two purposes: to test a predictive model of spouses' depressed mood and to evaluate the model's accuracy in distinguishing between normal and clinically depressed spouses.Data were obtained from standardized questionnaires completed by 206 spouses and 206 wives recently diagnosed with nonmetastatic breast cancer. Spouses' depressed mood was measured by the Center for Epidemiological Studies-Depression Scale. A total of 19 variables were extracted from the literature for testing in the model, including psychological, social, demographic, and disease- and treatment-related variables.Spouses were more likely to be depressed if they were older, less well educated, more recently married, reported heightened fears over their wife's well-being, worried about their job performance, were more uncertain about their future, or were in less well-adjusted marriages. The model correctly classified 89.2% of spouses' mood (chi(2) = 79.1; P < .001).Spouses of women with local or regional breast cancer need to be screened for depressed mood and triaged into supportive services to better assist them manage the threat of their wife's breast cancer.
Increased carbon monoxide production in patients with cirrhosis with and without spontaneous bacterial peritonitis
Authors: Dara De Las Heras, Javier Fernández, Pere Ginès, Andres Cárdenas, Rolando Ortega, Miguel Navasa, Joan Albert Barberá, Blas Calahorra, Mónica Guevara, Ramón Bataller, Wladimiro Jiménez, Vicente Arroyo, Juan Rodés
Journal: Hepatology (2003)

Carbon monoxide, a product of the heme-oxygenase (HO) pathway, is an important endogenous vasoactive substance. Production of CO has not been assessed in human cirrhosis. The aim of this study was to assess production of CO in patients with cirrhosis with and without spontaneous bacterial peritonitis (SBP). CO concentration in the exhaled air and blood carboxyhemoglobin (COHb) levels, as estimates of total HO activity, were determined in 16 healthy subjects, 32 noninfected cirrhotic patients (20 with ascites), and 19 patients with SBP, all nonsmokers. Noninfected cirrhotic patients had a CO concentration in the exhaled air and COHb levels significantly higher compared with values of healthy subjects (2.3 +/- 0.2 ppm vs. 0.7 +/- 0.1 ppm and 1.0% +/- 0.1% vs. 0.6% +/- 0.1%, respectively; P <.05 for both). Patients with ascites had the highest values. Both CO concentration in the exhaled air and COHb levels were very high in patients with SBP (5.6 +/- 0.6 ppm and 1.9% +/- 0.2%; P <.01 vs. the other 2 groups) and decreased slowly after resolution of the infection, reaching values similar to those of noninfected patients 1 month after SBP. In patients with SBP, there was a significantly direct correlation between CO and plasma renin activity (PRA) (r = 0.71, P <.001). In conclusion, these results support the existence of increased CO production in human cirrhosis, which further increases in the setting of SBP. Increased CO production may participate in the disturbance of circulatory function that occurs during severe bacterial infections in cirrhosis.
Cortical-striatal-cortical neural circuits, reiteration, and the “narrow faculty of language”
Authors: Philip Lieberman
Journal: Behavioral and Brain Sciences (2008)

Abstract Neural circuits linking local operations in the cortex and the basal ganglia confer reiterative capacities, expressed in seemingly unrelated human traits such as speech, syntax, adaptive actions to changing circumstances, dancing, and music. Reiteration allows the formation of a potentially unbounded number of sentences from a finite set of syntactic processes, obviating the need for the hypothetical “Narrow Faculty of Language.”
Diagnosing Comorbid Psychiatric Disorders in Substance Abusers: Validity of the Spanish Versions of the Psychiatric Research Interview for Substance and Mental Disorders and the Structured Clinical Interview for DSM-IV
Authors: Marta Torrens, Domènec Serrano, Mònica Astals, Gustavo Pérez-Domínguez, Rocío Martín-Santos
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: The authors’ goal was to assess the validity of DSM-IV diagnoses obtained with the Spanish versions of the Psychiatric Research Interview for Substance and Mental Disorders (PRISM) and the Structured Clinical Interview for DSM-IV (SCID) compared with the longitudinal, expert, all data (LEAD) procedure in a group of substance abusers. METHOD: A total of 105 substance abusers recruited at a drug abuse treatment center in Barcelona, Spain, were assessed. The PRISM and SCID were administered blindly by independent research interviewers. LEAD diagnoses were made by two senior psychiatrists who were blind to PRISM and SCID diagnoses. The kappa statistic was used to measure concordance between the LEAD procedure and the PRISM and SCID. RESULTS: Affective and anxiety disorders were diagnosed more frequently by the PRISM and SCID than by the LEAD procedure. Use of the PRISM resulted in more diagnoses of substance-induced depression, and use of the SCID resulted in more diagnoses of primary major depression than the LEAD procedure. Kappas between the LEAD procedure and the PRISM in current major depression, past substance-induced depression, and borderline personality disorder were better than those obtained between the LEAD procedure and the SCID. The concordance among the three methods for diagnoses of current dependence disorders was good or excellent for alcohol, anxiolytic, cocaine, and heroin dependence and fair for cannabis dependence. Abuse diagnoses showed poor concordance. CONCLUSIONS: Using the LEAD procedure as a “gold standard,” the authors conclude that the Spanish version of the PRISM seems to be a better instrument than the Spanish version of the SCID for diagnosing major depression and borderline personality disorders in substance abusers.
The Signature from Messenger RNA Expression Profiling Can Predict Lymph Node Metastasis with High Accuracy for Non-small Cell Lung Cancer
Authors: Naeyun Choi, Dae-Soon Son, Jinseon Lee, In-Seung Song, Kyung-Ah Kim, Sang-Ho Park, Yoo-Sung Lim, Gil-Ju Seo, Jungho Han, Hyejin Kim, Hye Won Lee, Jason Jong-ho Kang, Jeong-Sun Seo, Ju Han Kim, Jhingook Kim
Journal: Journal of Thoracic Oncology (2006)