tbuckley/cabot-search huggingface dataset:
Criteria for Evaluation of Novel Markers of Cardiovascular Risk
Authors: Mark A. Hlatky, Philip Greenland, Donna K. Arnett, Christie M. Ballantyne, Michael H. Criqui, Mitchell S.V. Elkind, Alan S. Go, Frank E. Harrell, Yuling Hong, Barbara V. Howard, Virginia J. Howard, Priscilla Y. Hsue, Christopher M. Kramer, Joseph P. McConnell, Sharon-Lise T. Normand, Christopher J. O'Donnell, Sidney C. Smith, Peter W.F. Wilson
Journal: Circulation (2009)

There is increasing interest in utilizing novel markers of cardiovascular disease risk, and consequently, there is a need to assess the value of their use. This scientific statement reviews current concepts of risk evaluation and proposes standards for the critical appraisal of risk assessment methods. An adequate evaluation of a novel risk marker requires a sound research design, a representative at-risk population, and an adequate number of outcome events. Studies of a novel marker should report the degree to which it adds to the prognostic information provided by standard risk markers. No single statistical measure provides all the information needed to assess a novel marker, so measures of both discrimination and accuracy should be reported. The clinical value of a marker should be assessed by its effect on patient management and outcomes. In general, a novel risk marker should be evaluated in several phases, including initial proof of concept, prospective validation in independent populations, documentation of incremental information when added to standard risk markers, assessment of effects on patient management and outcomes, and ultimately, cost-effectiveness.
Probabilistic functionalism: A unifying paradigm for the cognitive sciences
Authors: Javier R. Movellan, Jonathan D. Nelson
Journal: Behavioral and Brain Sciences (2001)

The probabilistic analysis of functional questions is maturing into a rigorous and coherent research paradigm that may unify the cognitive sciences, from the study of single neurons in the brain to the study of high level cognitive processes and distributed cognition. Endless debates about undecidable structural issues (modularity vs. interactivity, serial vs. parallel processing, iconic vs. propositional representations, symbolic vs. connectionist models) may be put aside in favor of a rigorous understanding of the problems solved by organisms in their natural environments. [Shepard; Tenenbaum &amp; Griffiths]
Negative feedback control of the autoimmune response through antigen-induced differentiation of IL-10–secreting Th1 cells
Authors: Leona Gabryšová, Kirsty S. Nicolson, Heather B. Streeter, Johan Verhagen, Catherine A. Sabatos-Peyton, David J. Morgan, David C. Wraith
Journal: The Journal of Experimental Medicine (2009)

Regulation of the immune response to self- and foreign antigens is vitally important for limiting immune pathology associated with both infections and hypersensitivity conditions. Control of autoimmune conditions can be reinforced by tolerance induction with peptide epitopes, but the mechanism is not currently understood. Repetitive intranasal administration of soluble peptide induces peripheral tolerance in myelin basic protein (MBP)–specific TCR transgenic mice. This is characterized by the presence of anergic, interleukin (IL)-10–secreting CD4+ T cells with regulatory function (IL-10 T reg cells). The differentiation pathway of peptide-induced IL-10 T reg cells was investigated. CD4+ T cells became anergic after their second encounter with a high-affinity MBP peptide analogue. Loss of proliferative capacity correlated with a switch from the Th1-associated cytokines IL-2 and interferon (IFN)-γ to the regulatory cytokine IL-10. Nevertheless, IL-10 T reg cells retained the capacity to produce IFN-γ and concomitantly expressed T-bet, demonstrating their Th1 origin. IL-10 T reg cells suppressed dendritic cell maturation, prevented Th1 cell differentiation, and thereby created a negative feedback loop for Th1-driven immune pathology. These findings demonstrate that Th1 responses can be self-limiting in the context of peripheral tolerance to a self-antigen.
Effect of continuous infusion of pentagastrin on lower esophageal sphincter pressure and gastric acid secretion in normal subjects.
Authors: C O Walker, S A Frank, J Manton, J S Fordtran
Journal: Journal of Clinical Investigation (1975)

Bolus injections of gastrin or pentagastrin (PG) cause a marked elevation in lower esophageal sphincter pressure (LESP), and it has been suggested that serum gastrin concentration is the main physiological and pathophysiological regulator of LESP. We evaluated this hypothesis by measuring LESP and gastric acid secretion simultaneously in normal subjects during continuous infusion of PG (0.004-12 mjg/kg per h), since continuous infusion of a hormone probably simulates physiological hormone release better than bolus injection. In groups of 8-13 subjects there was no statistically significant increase in average LESP with any of seven PG infusion rates. However, a bolus of PG superimposed on the continuous infusion of PG resulted in a 20-mm Hg increase in LESP. Examination of results in individual subjects suggested that PG by infusion might be stimulating LESP in some subjects and inhibiting it in others. Therefore, individual dose-response studies were performed in two normal subjects. These revealed that 0.9 mug/kg per h PG by infusion elevated LESP by 10-12 mm Hg. This dose of PG also elicited maximal rates of gastric acid secretion. In one of the subjects an infusion of PG calculated to give one-half maximal acid secretion (D50) elevated LESP by 8 mm Hg; in the other the PG-D50 for acid secretion had no effect on sphincter pressure. Infusion of smaller amounts of PG had no effect on LESP, even though gastric acid secretion was stimulated submaximally. Thus, the parietal cells are more sensitive than the lower esophageal sphincter to the effect of PG by infusion. We conclude that PG by continuous infusion elevates LESP to only a modest degree (compared with the contraction that occurs after bolus injections of PG) and that the contraction occurs only within a narrow dose range between the D50 and D100 for acid secretion. Higher doses cause transient relaxation of LESP. Additional studies showed that basal LESP varied between 16 and 71 mm Hg in two subjects studied on 29 separate occasions, but there was no correlation with basal acid secretion. This suggests that the wide day-to-day fluctuations in basal LESP are not due to changing concentrations of gastrin in serum. The results of these experiments cast doubt on the hypothesis that serum gastrin concentration is the major determinant of LESP.
Energy at heart: matching demand with production
Authors: O. Ellingsen
Journal: Cardiovascular Research (2011)

This editorial refers to ‘Mitochondrial transcription factors TFAM and TFB2M regulate Serca2 gene transcription’ by A. Watanabe et al. , pp. 57–67, this issue. 

How are energy-consuming processes matched with energy supply in constantly working heart muscle cells? A new piece in the puzzle of myocardial gene regulation indicates that two main inducers of energy production also increase the abundance of a major consumer. Watanabe et al .1 convincingly demonstrate that mitochondrial transcription factors A (TFAM) and B2 (TFB2M) not only stimulate mitochondrial biogenesis, but also induce transcription of the Serca2 gene, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2a (SERCA2a). Their findings are potentially important, since energy depletion is a major problem in the failing heart2 and maintaining SERCA2a activity is vital for contractile function.3

Several lines of evidence from neonatal rat cardiomyocyte cultures and a rat experimental myocardial infarction model led to the conclusion that transcription of the Serca2 gene is regulated by TFAM and TFB2M,1 which were previously thought to be specific for mitochondrial gene regulation. First, both transcription factors localize to the nucleus and not only to mitochondria, even though none of them has classical nuclear localization signals. There they bind to the 5′ regulatory region of the …
GENETIC CONTROL OF THE IMMUNE RESPONSE
Authors: John C. Ordal, F. Carl Grumet
Journal: The Journal of Experimental Medicine (1972)

The transfer of parental (H-2(k/k)) nonresponder lymphoid cells into heterozygous (H-2(k/q)) nonresponder recipients at the time of primary challenge with aqueous poly-L(Tyr,Glu)-poly-D,L-Ala-poly-L-Lys [(T,G)-A--L] elicited the production of both IgM and IgG anti-(T,G)-A--L antibody. Normally, the production of IgG anti-(T,G)-A--L antibody is restricted to strains possessing the responder Ir-1 allele. The timing and intensity of the graft-versus-host (GVH) reaction required for this effect were found to be critical. Injection of H-2(k/k) cells into H-2(k/q) recipients 1 wk before antigen challenge did not elicit IgG anti-(T,G)-A--L antibody production, and markedly suppressed IgM anti-(T,G)-A--L antibody production. The transfer of alloimmune (H-2(q)-primed) H-2(k/k) cells at the time of antigen challenge was also associated with no IgG and little IgM anti-(T,G)-A--L antibody production. These data are consistent with the model that nonresponder thymus-derived lymphocytes (T cells) activated in a GVH reaction can substitute for (T,G)-A--L-reactive T cells to induce a shift from IgM to IgG anti-(T,G)-A--L antibody production.
METALLOTHIONEIN: An Intracellular Protein to Protect Against Cadmium Toxicity
Authors: Curtis D. Klaassen, Jie Liu, Supratim Choudhuri
Journal: The Annual Review of Pharmacology and Toxicology (1999)

▪ Abstract Metallothioneins (MT) are low-molecular-weight, cysteine-rich, metal-binding proteins. MT genes are readily induced by various physiologic and toxicologic stimuli. Because the cysteines in MT are absolutely conserved across species, it was suspected that the cysteines are necessary for function and MT is essential for life. In attempts to determine the function(s) of MT, studies have been performed using four different experimental paradigms: (a) animals injected with chemicals known to induce MT; (b) cells adapted to survive and grow in high concentrations of MT-inducing toxicants; (c) cells transfected with the MT gene; and (d) MT-transgenic and MT-null mice. Most often, results from studies using the first three approaches have indicated multiple functions of MT in cell biology: MT (a) is a “storehouse” for zinc, (b) is a free-radical scavenger, and (c) protects against cadmium (Cd) toxicity. However, studies using MT-transgenic and null mice have not strongly supported the first two proposed functions but strongly support its function in protecting against Cd toxicity. Repeated administration of Cd to MT-null mice results in nephrotoxicity at one tenth the dose that produces nephrotoxicity in control mice. Human studies indicate that 7% of the general population have renal dysfunction from Cd exposure. Therefore, if humans did not have MT, “normal” Cd exposure would be nephrotoxic to humans. Thus, it appears that during evolution, the ability of MT to protect against Cd toxicity might have taken a more pivotal role in the maintenance of life processes, as compared with its other proposed functions (i.e. storehouse for zinc and free radical scavenger).
Extent of Damage and Repair in the <i>p53</i> Tumor-Suppressor Gene After Treatment of Myeloma Patients With High-Dose Melphalan and Autologous Blood Stem-Cell Transplantation Is Individualized and May Predict Clinical Outcome
Authors: Meletios A. Dimopoulos, Vassilis L. Souliotis, Athanasios Anagnostopoulos, Christos Papadimitriou, Petros P. Sfikakis
Journal: Journal of Clinical Oncology (2005)

Purpose To quantitate the individual levels of melphalan-induced DNA damage formation and repair in vivo and to search for possible correlations with clinical outcome in patients with multiple myeloma (MM). Patients and Methods The formation and subsequent repair of DNA damage (monoadducts and interstrand cross-links) in the p53 tumor-suppressor gene, the proto-oncogene N-ras, and the housekeeping gene beta-actin during the first 24 hours after treatment with high-dose melphalan (HDM; 200 mg/m 2 ) supported by autologous blood stem-cell transplantation (ABSCT) was measured in blood leukocytes of 26 patients with MM. The peak DNA adduct levels, the total amount of adducts over time, and the rate of adducts repair in each gene were correlated with response and time to progression after HDM. Results The levels of gene-specific DNA damage formation and the individual repairing capacity varied up to 16-fold among patients, indicating that the melphalan-induced biologic effect in vivo is highly individualized. A significantly greater DNA damage and a slower rate of repair in p53 for all end points under study were found in patients who achieved tumor reduction compared with nonresponding patients. Furthermore, longer progression-free survival correlated with increased peak monoadduct levels in the p53 gene (P = .032). Conclusion Increased DNA damage and slower repairing capacity in the p53 gene from blood leukocytes after HDM correlate with improved outcome of patients with MM who undergo ABSCT. These results suggest that quantitation of such biologic end points may identify patients who are more likely to benefit from this procedure.
Obstructive Apnea during Sleep Is Associated with Peripheral Vasoconstriction
Authors: VIRGINIA A. IMADOJEMU, KEVIN GLEESON, KRISTEN S. GRAY, LAWRENCE I. SINOWAY, URS A. LEUENBERGER
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Obstructive apnea during sleep is associated with a substantial transient blood pressure elevation. The mechanism of this pressor response is unclear. In this study we measured muscle sympathetic nerve activity (MSNA), mean arterial pressure (Psa), and mean limb blood velocity as an index of blood flow (MBV, Doppler) and calculated changes in limb vascular resistance during and after apneas during both wakefulness and sleep in patients with the obstructive sleep apnea syndrome. Immediately postapnea during sleep Psa increased significantly compared with the earlier stages of apnea and this was preceded by a rise of MSNA (n = 5). In contrast to blood pressure, MBV remained unchanged. Because resistance = blood pressure/blood flow, limb vascular resistance increased by 29 ± 8% from late apnea to postapnea (n = 7, p < 0.002). Voluntary breathhold maneuvers during room air exposure evoked similar responses (n = 10). Supplemental oxygen administered via nonrebreather face mask attenuated the MSNA and vasoconstrictor responses to obstructive (n = 2) and voluntary apneas (n = 10). Our data suggest that obstructive apneas in patients with the obstructive apnea syndrome are accompanied by transient limb vasoconstriction. This vasoconstrictor response appears to be, at least in part, mediated by the sympathetic nervous system and may be linked to hypoxia.
Modulation of ER phosphorylation on serine 118 by endocrine therapy: a new surrogate marker for efficacy
Authors: M. Zoubir, M.C. Mathieu, C. Mazouni, C. Liedtke, L. Corley, S. Geha, J. Bouaziz, M. Spielmann, F. Drusche, W.F. Symmans, S. Delaloge, F. Andre
Journal: Annals of Oncology (2008)
Impaired Antibody-mediated Protection and Defective IgA B-Cell Memory in Experimental Infection of Adults with Respiratory Syncytial Virus
Authors: Maximillian S. Habibi, Agnieszka Jozwik, Spyridon Makris, Jake Dunning, Allan Paras, John P. DeVincenzo, Cornelis A. M. de Haan, Jens Wrammert, Peter J. M. Openshaw, Christopher Chiu
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Despite relative antigenic stability, respiratory syncytial virus (RSV) reinfects throughout life. After more than 40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection.
Decreased Maximal Aerobic Capacity in Pediatric Chronic Kidney Disease
Authors: Donald J. Weaver, Thomas R. Kimball, Timothy Knilans, Wayne Mays, Sandra K. Knecht, Yvette M. Gerdes, Sandy Witt, Betty J. Glascock, Janis Kartal, Philip Khoury, Mark M. Mitsnefes
Journal: Journal of the American Society of Nephrology (2008)

Adult and pediatric patients with ESRD have impaired maximum oxygen consumption (VO2 max), a reflection of the cardiopulmonary system's ability to meet increased metabolic demands. We sought to determine factors associated with decreased VO2 max in pediatric patients with different stages of CKD. VO2 max was measured using a standardized exercise testing protocol in patients with stage 2 to 4 chronic kidney disease (CKD) (n = 46), in renal transplant recipients (n = 22), in patients treated with maintenance hemodialysis (n = 12), and in age-matched healthy controls (n = 33). VO2 max was similar between children with stage 2 CKD and controls, whereas lower VO2 max was observed among children with stage 3 to 4 CKD, those treated with hemodialysis, and transplant recipients. In univariate analysis, VO2 max was significantly associated with body mass index, resting heart rate, C-reactive protein, serum triglycerides, serum creatinine, and measures of diastolic function; no significant associations with left ventricular structure or systolic function were identified. In multivariate regression analysis, patient category versus control and the presence of diastolic dysfunction were independent predictors of lower VO2 max. These results suggest that aerobic capacity is decreased in the early stages of CKD in children and that lower VO2 max can be predicted by the presence of diastolic dysfunction, even if systolic function is normal.
Atomoxetine and Osmotically Released Methylphenidate for the Treatment of Attention Deficit Hyperactivity Disorder: Acute Comparison and Differential Response
Authors: Jeffrey H. Newcorn, Christopher J. Kratochvil, Albert J. Allen, Charles D. Casat, Dustin D. Ruff, Rodney J. Moore, David Michelson
Journal: American Journal of Psychiatry (2008)

Objective: Response to atomoxetine, a nonstimulant norepinephrine-specific reuptake inhibitor, was compared with the effect of osmotic-release oral methylphenidate, a long-acting methylphenidate preparation, in patients with attention deficit hyperactivity disorder (ADHD). Method: In a large placebo-controlled, double-blind study, patients ages 6–16 with ADHD, any subtype, were randomly assigned to receive 0.8–1.8 mg/kg per day of atomoxetine (N=222), 18–54 mg/day of osmotically released methylphenidate (N=220), or placebo (N=74) for 6 weeks. The a priori specified primary analysis compared response (at least 40% decrease in ADHD Rating Scale total score) to osmotically released methylphenidate with response to atomoxetine and placebo. After 6 weeks, patients treated with methylphenidate were switched to atomoxetine under double-blind conditions. Results: The response rates for both atomoxetine (45%) and methylphenidate (56%) were markedly superior to that for placebo (24%), but the response to osmotically released methylphenidate was superior to that for atomoxetine. Each medication was well tolerated, with completion rates and discontinuations for adverse events not significantly different from those for placebo. Of the 70 subjects who did not respond to methylphenidate, 30 (43%) subsequently responded to atomoxetine. Likewise, 29 (42%) of the 69 patients who did not respond to atomoxetine had previously responded to osmotically released methylphenidate. Conclusion: Response was significantly greater with osmotically released methylphenidate than with atomoxetine. One-third of patients who received methylphenidate followed by atomoxetine responded better to one or the other, suggesting that there may be preferential responders.
Marihuana in Adolescence
Authors: Gene Gordon
Journal: JAMA (1971)

<h3>To the Editor.—</h3> Kornhaber's communication (<b>215</b>:1988, 1971) on marihuana use by adolescents succinctly and eloquently corroborates my own experiences and conclusions, item by item, sentence by sentence. My impression (and at this stage of our research all we have to go on is impressions) is that marihuana is a dangerous, toxic drug in precisely the ways that Kornhaber describes; as he points out, these are such subtle, quantitative deviations from normal adolescence as to be nearly undetectable by simplistic psychological tests, and certainly impossible to be perceived subjectively by the drug user himself. The marihuana user has an obvious vested interest in finding the drug harmless; this interest is compounded, in my experience, by an underlying terror that he has been permanently damaged. The kind of research that will verify our impressions must be longitudinal, statistical, and therefore slow. In the meantime we owe it to our profession and
Phase II Study of Paclitaxel Plus Gemcitabine in Refractory Germ Cell Tumors (E9897): A Trial of the Eastern Cooperative Oncology Group
Authors: Stuart Hinton, Paul Catalano, Lawrence H. Einhorn, Patrick J. Loehrer, Timothy Kuzel, David Vaughn, George Wilding
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Despite great success in the treatment of disseminated germ cell tumors, 20% of patients are incurable and become candidates for investigational therapy. Paclitaxel and gemcitabine have shown activity as single agents in refractory germ cell tumors and can be combined with manageable toxicity. PATIENTS AND METHODS: Patients with germ cell tumors believed to be incurable with chemotherapy or surgery were treated with paclitaxel 110 mg/m 2 and gemcitabine 1,000 mg/m 2 intravenously on days 1, 8, and 15 of a 4-week cycle for a maximum of six cycles. Patients were evaluated for response and toxicity. RESULTS: Twenty-eight of 30 enrolled patients were assessable. Toxicity was primarily hematologic but was manageable with only a single case of neutropenic fever. Six (21.4%) of 28 patients responded, including three complete responses. Two of the complete responders were continuously disease-free at 15+ and 25+ months. CONCLUSION: Paclitaxel plus gemcitabine is an active regimen in refractory germ cell tumors, with an acceptable toxicity profile. This regimen has the possibility for long-term disease-free survival in this refractory patient population.
Analgesic ingestion and other factors preceding relapse in ulcerative colitis.
Authors: D S Rampton, N I McNeil, M Sarner
Journal: Gut (1983)

To investigate factors which predispose to relapse in patients with ulcerative colitis, we conducted a survey to compare the events occurring in the four weeks preceding the clinic attendance of 62 outpatients in remission with those taking place in the same period before the onset of relapse in 21 patients attending with active disease. The only event which occurred significantly more often in patients who subsequently relapsed was ingestion of paracetamol and other inhibitors of prostaglandin synthesis (76% (16/21) relapse vs 39% (24/62) remission, p less than 0 . 01). Recent upper respiratory tract infection (38% vs 26%) was not significantly more common in patients in relapse than in remission, and emotional stress, atopic events, antibiotic treatment, dietary indiscretions, foreign travel, and gastroenteritis were relatively rare in both groups. The surprisingly high prevalence of analgesic ingestion before relapse itself requires confirmation but does lend indirect support to the theory that colonic mucosal prostaglandin deficiency induces relapse in some patients with ulcerative colitis.