tbuckley/cabot-search huggingface dataset:
Long-lived complexes between peptide and class II major histocompatibility complex are formed at low pH with no requirement for pH neutralization.
Authors: P E Jensen
Journal: The Journal of Experimental Medicine (1992)

The binding of peptide antigens to class II histocompatibility glycoproteins can be markedly enhanced at pH values approximating those found in acidic endosomal compartments in antigen-presenting cells (APC). It has been proposed by others that low pH may increase the conformational flexibility of class II, facilitating both the association and dissociation of peptides. Neutralization of pH, as class II is expressed on the plasma membrane of APC, could then serve to trap peptide in a stable complex. If this were the only mechanism accounting for enhanced peptide binding at low pH, one would predict that there should be a concordance between the pH conditions required for enhanced binding and those associated with increased peptide dissociation. Furthermore, long-lived complexes of class II and peptide should not be observed at low pH without neutralization. In the present communization, I provide the data that support the generality of my previous conclusion that both affinity and maximal binding are regulated by pH in experiments using purified class II and biotin-labeled peptides. The pH profile for binding and dissociation using three different class II glycoproteins was analyzed, and the results demonstrated that enhanced binding is not coupled to enhanced dissociation. Peptide complexes were observed to be quite stable at pH 4.5 and above. This result was further substantiated in experiments where biotin-peptide/class II complexes were extensively dialyzed at low pH followed by analysis on Western blots probed with avidin. Finally, a low pH assay system was devised to analyze the formation of stable peptide/class II complexes without pH neutralization. Our results indicate that stable complexes can be formed at low pH without the requirement for a shift to neutral pH.
At physiologic albumin/oleate concentrations oleate uptake by isolated hepatocytes, cardiac myocytes, and adipocytes is a saturable function of the unbound oleate concentration. Uptake kinetics are consistent with the conventional theory.
Authors: D Sorrentino, R B Robinson, C L Kiang, P D Berk
Journal: Journal of Clinical Investigation (1989)

To reexamine the role of albumin in cellular uptake of long chain fatty acids, we measured [3H]oleate uptake by isolated hepatocytes, adipocytes, and cardiac myocytes from incubations containing oleate/albumin complexes at molar ratios from 0.01:1 to 2:1. For each ratio the uptake was studied over a wide range of albumin concentrations. In all three cell types and at any given oleate/albumin ratio, the uptake appeared saturable with increasing concentrations of oleate:albumin complexes despite the fact that the unbound oleate concentration for each molar ratio is essentially constant. However, the "Km" but not the "Vmax" of these pseudosaturation curves was influenced by substrate availability. At low albumin concentrations, uptake velocities did not correlate with unbound oleate concentrations. However, observed and expected uptake velocities coincided at albumin concentrations approaching physiologic levels and were a saturable function of the oleate/albumin ratios and the consequent unbound oleate concentrations employed. Hence, under the experimental conditions employed in this study using a variety of suspended cell types, oleate uptake kinetics were consistent with the conventional theory at physiologic concentrations of albumin.
Volumetric capnography in patients with acute lung injury: effects of positive end-expiratory pressure
Authors: LL. Blanch, U. Lucangelo, J Lopez-Aguilar, R Fernandez, P.v Romero
Journal: European Respiratory Journal (1999)

The aim of the study was to analyse the effects of positive end-expiratory pressure (PEEP) on volumetric capnography and respiratory system mechanics in mechanically ventilated patients. Eight normal subjects (control group), nine patients with moderate acute lung injury (ALI group) and eight patients with acute respiratory distress syndrome (ARDS group) were studied. Respiratory system mechanics, alveolar ejection volume as a fraction of tidal volume (VAE/VT), phase III slopes of expired CO2 beyond VAE and Bohr's dead space (VD/VT(Bohr)) at different levels of PEEP were measured. No differences in respiratory system resistances were found between the ALI and ARDS groups. VD/VT(Bohr) and expired CO2 slope beyond VAE were higher in ALI patients (0.52+/-0.01 and 13.9+/-0.7 mmHg x L(-1), respectively) compared with control patients (0.46+/-0.01 and 7.7+/-0.4 mmHg x L(-1), p<0.01, respectively) and in ARDS patients (0.61+/-0.02 and 24.9+/-1.6 mmHg x L(-1), p<0.01, respectively) compared with ALI patients. VAE/VT differed similarly (0.6+/-0.01 in control group, 0.43+/-0.01 in ALI group and 0.31+/-0.01 in ARDS group, p<0.01). PEEP had no effect on VAE/VT, expired CO2 slope beyond VAE and VD/VT(Bohr) in any group. A significant correlation (p<0.01) was found between VAE/VT and expired CO2 slope beyond VAE and lung injury score at zero PEEP. Indices of volumetric capnography are affected by the severity of the lung injury, but are unmodified by the application of positive end-expiratory pressure.
Hyperhomocysteinemia and the Endocrine System: Implications for Atherosclerosis and Thrombosis
Authors: Vivian Fonseca, Susan C. Guba, Louis M. Fink
Journal: Endocrine Reviews (1999)

I. Introduction II. Methionine-Homocysteine Metabolism A. Methionine metabolism B. Regulation of remethylation and transsulfuration of H(e) III. Nomenclature and Methodology in the Measurement of Plasma H(e) A. Methionine load test IV. Determinants of Plasma Homocysteine A. Physiological B. Genetics of hyperhomocysteinemia C. Nutritional D. Hormones and H(e) metabolism V. Homocysteine and Diabetes Mellitus (DM) A. Hyperhomocysteinemia, renal failure, and diabetic nephropathy B. Effect of glucose and insulin on H(e) metabolism VI. Hyperhomocysteinemia and Cholesterol Metabolism VII. Hyperhomocysteinemia in Premature Vascular Disease A. Epidemiological and prospective studies B. Studies in patients with established vascular disease C. Negative studies D. Effect of low plasma H(e) on cardiovascular disease VIII. Possible Mechanisms of Accelerated Vascular Disease in Homocysteinemia A. Platelet dysfunction B. Coagulation abnormalities C. Effects on the endothelium D. Effects of hyperhomocysteinemia on the art...
CD4 T follicular helper cell dynamics during SIV infection
Authors: Constantinos Petrovas, Takuya Yamamoto, Michael Y. Gerner, Kristin L. Boswell, Kaska Wloka, Emily C. Smith, David R. Ambrozak, Netanya G. Sandler, Katherina J. Timmer, Xiaoyong Sun, Li Pan, Amanda Poholek, Srinivas S. Rao, Jason M. Brenchley, S. Munir Alam, Georgia D. Tomaras, Mario Roederer, Daniel C. Douek, Robert A. Seder, Ronald N. Germain, Elias K. Haddad, Richard A. Koup
Journal: Journal of Clinical Investigation (2012)

CD4 T follicular helper (TFH) cells interact with and stimulate the generation of antigen-specific B cells. TFH cell interaction with B cells correlates with production of SIV-specific immunoglobulins. However, the fate of TFH cells and their participation in SIV-induced antibody production is not well understood. We investigated the phenotype, function, location, and molecular signature of TFH cells in rhesus macaques. Similar to their human counterparts, TFH cells in rhesus macaques represented a heterogeneous population with respect to cytokine function. In a highly differentiated subpopulation of TFH cells, characterized by CD150lo expression, production of Th1 cytokines was compromised while IL-4 production was augmented, and cells exhibited decreased survival, cycling, and trafficking capacity. TFH cells exhibited a distinct gene profile that was markedly altered by SIV infection. TFH cells were infected by SIV; yet, in some animals, these cells actually accumulated during chronic SIV infection. Generalized immune activation and increased IL-6 production helped drive TFH differentiation during SIV infection. Accumulation of TFH cells was associated with increased frequency of activated germinal center B cells and SIV-specific antibodies. Therefore, chronic SIV does not disturb the ability of TFH cells to help B cell maturation and production of SIV-specific immunoglobulins.
No evidence of dioxin cancer threshold.
Authors: David Mackie, Junfeng Liu, Yeong-Shang Loh, Valerie Thomas
Journal: Environmental Health Perspectives (2002)

The U.S. Environmental Protection Agency (EPA) has developed an estimate of the human cancer risk from dioxin, using the standard low-dose linear extrapolation approach. This estimate has been controversial because of concern that it may overestimate the cancer risk. An alternative approach has been published and was presented to the U.S. EPA Science Advisory Board's Dioxin Review Panel in November 2000. That approach suggests that dioxin is a threshold carcinogen and that the threshold is an order of magnitude above the exposure levels of the general population. We have reexamined the threshold analysis and found that the data have been incorrectly weighted by cohort size. In our reanalysis, without the incorrect weighting, the threshold effect disappears.
Mechanisms Responsible for Endothelial Dysfunction Associated With Acute Estrogen Deprivation in Normotensive Women
Authors: Agostino Virdis, Lorenzo Ghiadoni, Stefania Pinto, Maurizio Lombardo, Felice Petraglia, Andrea Gennazzani, Simona Buralli, Stefano Taddei, Antonio Salvetti
Journal: Circulation (2000)

Background —The goal of this study was to evaluate whether endothelial dysfunction associated with acute estrogen deprivation is caused by an alteration in the l -arginine–nitric oxide (NO) pathway and oxidative stress. Methods and Results —In 26 healthy women (age, 45.7±5.4 years) and 18 fertile women with leiomyoma (age, 44.5±5.1 years), we studied forearm blood flow (strain-gauge plethysmography) changes induced by intrabrachial acetylcholine (0.15, 0.45, 1.5, 4.5, or 15 μg · 100 mL −1 · min −1 ) or sodium nitroprusside (1, 2, or 4 μg · 100 mL −1 · min −1 ), an endothelium-dependent or -independent vasodilator, respectively. The NO pathway was evaluated by repeating acetylcholine during l -arginine (200 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients) or N G -monomethyl- l -arginine (L-NMMA; 100 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients); production of cyclooxygenase-derived vasoconstrictors was assessed by repeating acetylcholine during indomethacin (50 μg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients) or vitamin C (8 mg · 100 mL −1 · min −1 ; 13 control subjects and 9 patients). Patients repeated the study within 1 month after ovariectomy and again after 3 months of estrogen replacement therapy (ERT; 17 β-estradiol TTS, 50 μg/d). Basally, vasodilation to acetylcholine was potentiated and inhibited by l -arginine and L-NMMA, respectively ( P &lt;0.05), but was unaffected by indomethacin or vitamin C. After ovariectomy, the modulating effect of l -arginine and L-NMMA disappeared, whereas indomethacin and vitamin C potentiated the response to acetylcholine ( P &lt;0.05). ERT restored l -arginine and L-NMMA effects on vasodilation to acetylcholine but prevented the potentiation caused by indomethacin or vitamin C. Response to sodium nitroprusside was unaffected by either ovariectomy or ERT. Conclusions —Endothelial dysfunction secondary to acute endogenous estrogen deprivation is caused by reduced NO availability. Cyclooxygenase-dependent production of oxidative stress could be responsible for this alteration.
Revascularization for Femoropopliteal Disease
Authors: Maria G. M. Hunink
Journal: JAMA (1995)

To evaluate the relative benefits and cost-effectiveness of revascularization for femoropopliteal disease using percutaneous transluminal angioplasty or bypass surgery.Decision analysis using a multistate transition simulation model (Markov process) and cost-effectiveness analysis from the perspective of the health care system.Based on mortality, morbidity, patency, and cost data from a literature review.Hypothetical cohort of patients with chronic femoropopliteal disease who desire revascularization. Subgroup analysis for patients defined by age, sex, indication, lesion type, and graft type.Percutaneous transluminal angioplasty, bypass surgery, and a strategies combining the two treatments.Five-year patency results, quality-adjusted life expectancy, lifetime costs, and incremental cost-effectiveness ratios.For 65-year-old men with disabling claudication and a femoropopliteal stenosis or occlusion and for 65-year-old men with chronic critical ischemia and a femoropopliteal stenosis, initial angioplasty increased quality-adjusted life expectancy by 2 to 13 months and resulted in decreased lifetime expenditures compared with bypass surgery. For patients with chronic critical ischemia and a femoropopliteal occlusion, initial bypass surgery increased quality-adjusted life expectancy by 1 to 4 months and resulted in decreased lifetime expenditures compared with angioplasty. Sensitivity analysis demonstrated that angioplasty would always be the preferred initial treatment if the angioplasty 5-year patency rate exceeds 30%.Angioplasty is the preferred initial treatment in patients with disabling claudication and a femoropopliteal stenosis or occlusion and in those with chronic critical ischemia and a stenosis. Bypass surgery is the preferred initial treatment in patients with chronic critical ischemia and a femoropopliteal occlusion.
Multipopulation Analysis of Polymorphisms in Five Mononucleotide Repeats Used to Determine the Microsatellite Instability Status of Human Tumors
Authors: Olivier Buhard, Francesca Cattaneo, Yick Fu Wong, So Fan Yim, Eitan Friedman, Jean-François Flejou, Alex Duval, Richard Hamelin
Journal: Journal of Clinical Oncology (2005)

Purpose Human gastrointestinal tumors with inactivated DNA mismatch repair system (microsatellite instability [MSI] tumors) have distinct molecular and clinicopathologic profiles, and are associated with favorable prognosis. There is evidence suggesting that colorectal cancer patients with MSI tumors respond differently to adjuvant chemotherapy as compared with patients with non-MSI tumors. Finally, determination of the MSI status has clinical application for assisting in the diagnosis of suspected hereditary cases. It is thus becoming increasingly recognized that testing for MSI should be conducted systematically in all human cancers potentially of this type. We recently described a pentaplex polymerase chain reaction of five mononucleotide repeats to establish the MSI status of human tumors, and showed that this assay was 100% sensitive and specific. Moreover, these markers are quasimonomorphic in germline DNA of the white population (ie, individuals of Eurasian origin), and could be used for tumor MSI determination without the requirement for matching normal DNA in this group. Patients and Methods In this study, we analyzed a comparable panel of five mononucleotide markers in germline DNA from 1,206 individuals encompassing 55 different populations worldwide. Results With the exception of two Biaka Pygmies and one San individual for whom three markers showed variant alleles (three cases [0.2%]), the remaining 1,203 individuals showed no alleles of variant size (1,055 cases [87.5%]), or only one (122 cases [10.1%]) or two (26 cases [2.2%]) markers with variant alleles. All 60 MSI tumors investigated display instability in at least four of the five markers. Conclusion We demonstrated that tumor MSI status can be determined using the pentaplex reaction for all human populations without the need for matching normal DNA.
The Transcription Factor <i>Pokemon</i>: A New Key Player in Cancer Pathogenesis
Authors: Takahiro Maeda, Robin M. Hobbs, Pier Paolo Pandolfi
Journal: Cancer Research (2005)

Abstract Learning how critical cell regulatory pathways are controlled may lead to new opportunities for cancer treatment. We recently identified the transcription factor Pokemon as a central regulator of the important tumor suppressor ARF. Pokemon is overexpressed in multiple human cancers and cells lacking Pokemon are refractory to oncogenic transformation. These findings suggest that Pokemon may offer an effective new target for cancer therapeutics.
Comparison of T-Spot.TB and tuberculin skin test among silicotic patients
Authors: C. C. Leung, W. C. Yam, W. W. Yew, P. L. Ho, C. M. Tam, W. S. Law, M. Y. Wong, M. Leung, D. Tsui
Journal: European Respiratory Journal (2007)

In the present study, T-Spot.TB and the tuberculin skin test (TST) were compared in the screening of latent tuberculosis infection among silicotic patients. A conditional probability model was used to compare the potential clinical utilities of T-Spot.TB and TST performed on 134 silicotic subjects from December 1, 2004 to January 31, 2007. Data from a historical cohort were also reanalysed for further comparison. Agreement with T-Spot.TB was best using a TST cut-off of 10 mm. Age ≥65 yrs independently predicted a tuberculin reaction &lt;10 mm (odds ratio = 3), but not a negative T-Spot.TB response. Lower measures of agreement were observed among current smokers and those aged ≥65 yrs. Tuberculin reaction size was well correlated with both early secretary antigenic target 6 and culture filtrate protein 10 spot counts, except among current smokers. Within the current estimates of sensitivity (88–95%) and specificity (86–99%) for T-Spot.TB, the positive likelihood ratio for T-Spot.TB test would be substantially higher (6.29–95.0 versus 1.65–1.94) and negative likelihood ratio substantially lower (0.05–0.14 versus 0.32–0.41) than the corresponding ratios for the tuberculin test. A low tuberculosis risk differential was similarly observed between tuberculin-negative and untreated tuberculin-positive subjects in the historical cohort. T-Spot.TB is likely to perform better than tuberculin test in the screening of latent tuberculosis infection among silicotic subjects.
Macrophage heterogeneity and tissue lipids
Authors: Siamon Gordon
Journal: Journal of Clinical Investigation (2007)

Macrophages are present as resident cells in adipose tissue, and blood monocytes are recruited in increased numbers to sites of lipid accumulation in atherosclerosis, a modified form of inflammation in the arterial wall. Recent findings reported by 3 separate groups in this issue of the JCI provide evidence for distinct monocyte subsets, differential chemokine receptor usage, and phenotypic modulation of macrophages in murine models of genetic and high-fat diet–induced disease (see the related articles beginning on pages 175, 185, and 195). These studies raise prospects for selective therapeutic targets to ameliorate macrophage hyperinflammatory responses, while sparing host defense and repair mechanisms.
Adult bone-marrow stem cells and their potential in medicine
Authors: H T Hassan, M El-Sheemy
Journal: Journal of the Royal Society of Medicine (2004)

An area of research that today generates great optimism is the use of stem cells for therapy of human diseases. Much of the excitement centres on embryonic stem cells, but this approach remains controversial for ethical reasons; moreover, routine clinical application of this strategy is many years away. By contrast, haematopoietic stem cells from adult bone marrow are well characterized and have long been used therapeutically.1 An adult weighing 70 kg has a functional haematopoietic marrow volume of about 1.75 L and upon increased demands such as infection or haemorrhage it can increase sixfold.1,2 No moral controversy surrounds the use of these cells since they are either autologous or collected from a consenting donor. The potential applications of adult bone marrow cells have gained momentum with discoveries relating to the mesenchymal stem cell.
Regional location of T cell receptor gene Ti alpha on human chromosome 14.
Authors: P E Barker, H D Royer, F H Ruddle, E L Reinherz
Journal: The Journal of Experimental Medicine (1985)

The chromosomal location of Ti alpha was determined by hybridization of a radiolabeled cDNA for the alpha chain of human T cell receptor with 12 human X mouse cell hybrid DNAs cleaved with BamHI. Seven hybrids contained human Ti alpha, while the remaining five lacked it. Only human chromosome 14 matched the distribution of human Ti alpha signal across the mapping panel. Hybrids segregating a chromosome 14 translocation were used to demonstrate that Ti alpha is in the region 14pter greater than 14q21. Thus, the alpha and beta chain genes that contribute structural components to the Ti moiety of the human T cell receptor lie on different chromosomes. In humans, the immunoglobulin heavy chain locus and Ti alpha are in different regions of chromosome 14, with Ti alpha more proximal and the immunoglobulin heavy chain locus more distal.
Transfusion Strategies for Acute Upper Gastrointestinal Bleeding
Authors: Càndid Villanueva, Alan Colomo, Alba Bosch, Mar Concepción, Virginia Hernandez-Gea, Carles Aracil, Isabel Graupera, María Poca, Cristina Alvarez-Urturi, Jordi Gordillo, Carlos Guarner-Argente, Miquel Santaló, Eduardo Muñiz, Carlos Guarner
Journal: New England Journal of Medicine (2013)

The hemoglobin threshold for transfusion of red cells in patients with acute gastrointestinal bleeding is controversial. We compared the efficacy and safety of a restrictive transfusion strategy with those of a liberal transfusion strategy.
Emotional dynamics of the organism and its parts
Authors: Jaak Panksepp
Journal: Behavioral and Brain Sciences (2005)

Emotion-science without basic brain-science is only superficially satisfying. Dynamic systems approaches to emotions presently provide a compelling metaphor that raises more difficult empirical questions than substantive scientific answers. How might we close the gap between theory and empirical observations? Such theoretical views still need to be guided by linear cross-species experimental approaches more easily implement in the laboratory.
Goals of Metabolic Management of Gestational Diabetes
Authors: Moshe Hod, Yariv Yogev
Journal: Diabetes Care (2007)

Gestational diabetes mellitus (GDM) is defined as glucose intolerance first recognized in the current pregnancy (1), and it affects ∼5–7% of all pregnancies (2). Recently, it was demonstrated in both randomized and cohort studies (3,4) that lack of treatment for GDM is associated with increased risk of serious perinatal morbidities. Although the consequences of poorly controlled GDM are evident, no consensus exists on either diagnostic criteria or metabolic aims in controlling GDM.

Traditionally, GDM is considered as a disorder primarily of carbohydrate metabolism; thus, blood glucose levels have become the main “key player” for monitoring and directing treatment during pregnancy. This focus on glycemic metabolism ignores the role of other potential fetal fuels such as proteins and lipids in the pathophysiology of GDM.

In any disease, understanding normality is necessary before defining goals for treatment. The normal physiology of carbohydrates, proteins, and lipids during pregnancy may serve as the basis for defining metabolic goals in diabetic pregnancy. Nevertheless, only scarce data exist regarding the normal physiology of glucose in nondiabetic pregnancy; furthermore, even less is understood regarding lipid or protein metabolism and other factors.

In this review, we will mainly focus on the glycemic profile in normal pregnancy and in GDM. In addition, the role of other nutrients and metabolic factors will be reviewed.

Normal pregnancy has been characterized as a “diabetogenic state” due to change in the pattern of insulin secretion and sensitivity, resulting in increased postprandial glucose and insulin response in late pregnancy. During the first trimester and early in the second trimester, an increase in insulin sensitivity occurs mainly due to the relatively higher levels of estrogen; however, in the late second and early third trimesters, there is reduced sensitivity to insulin action. Human placental lactogen, leptin, prolactin, and cortisol are involved in these changes. …