tbuckley/cabot-search huggingface dataset:
<i>Salmonella</i>-Induced Caspase-2 Activation in Macrophages
Authors: Veronika Jesenberger, Katarzyna J. Procyk, Junying Yuan, Siegfried Reipert, Manuela Baccarini
Journal: The Journal of Experimental Medicine (2000)

The enterobacterial pathogen Salmonella induces phagocyte apoptosis in vitro and in vivo. These bacteria use a specialized type III secretion system to export a virulence factor, SipB, which directly activates the host's apoptotic machinery by targeting caspase-1. Caspase-1 is not involved in most apoptotic processes but plays a major role in cytokine maturation. We show that caspase-1–deficient macrophages undergo apoptosis within 4–6 h of infection with invasive bacteria. This process requires SipB, implying that this protein can initiate the apoptotic machinery by regulating components distinct from caspase-1. Invasive Salmonella typhimurium targets caspase-2 simultaneously with, but independently of, caspase-1. Besides caspase-2, the caspase-1–independent pathway involves the activation of caspase-3, -6, and -8 and the release of cytochrome c from mitochondria, none of which occurs during caspase-1–dependent apoptosis. By using caspase-2 knockout macrophages and chemical inhibition, we establish a role for caspase-2 in both caspase-1–dependent and –independent apoptosis. Particularly, activation of caspase-1 during fast Salmonella-induced apoptosis partially relies on caspase-2. The ability of Salmonella to induce caspase-1–independent macrophage apoptosis may play a role in situations in which activation of this protease is either prevented or uncoupled from the induction of apoptosis.
Urinary cGMP concentrations in severe primary pulmonary hypertension
Authors: M. Bogdan, M. Humbert, J. Francoual, C. Claise, P. Duroux, G. Simonneau, A. Lindenbaum
Journal: Thorax (1998)

<h3>BACKGROUND</h3> Prognostic evaluation of patients with primary pulmonary hypertension (PPH) requires right heart catheterisation. The development of accurate non-invasive methods for monitoring these patients remains an important task. Cyclic guanosine monophosphate (cGMP) is an indicator of the action of natriuretic peptides and nitric oxide on target cells. Plasma and urinary cGMP concentrations are raised in patients with congestive heart failure in whom they correlate closely with haemodynamic parameters and disease severity. The aim of the present study was to determine whether the urinary concentration of cGMP could be used as a non-invasive marker of haemodynamic impairment in patients with severe PPH. <h3>METHODS</h3> Urinary cGMP concentrations were measured in 19 consecutive patients with PPH, seven with acute asthma, and 30 normal healthy controls. <h3>RESULTS</h3> Patients with PPH had higher urinary cGMP concentrations than asthmatic patients or normal healthy controls (p = 0.001). Urinary cGMP concentrations were higher in patients with severe haemodynamic impairment—that is, those with a cardiac index (CI) of ⩽2 l/min/m<sup>2</sup> (p = 0.002)—and urinary cGMP concentrations were inversely correlated with CI (<i>r</i> = –0.69, p = 0.002) and venous oxygen saturation (<i>r</i> = –0.65, p = 0.003). <h3>CONCLUSION</h3> Urinary cGMP concentrations may represent a non-invasive indicator of the haemodynamic status of patients with severe PPH.
Formation of the initial C3 convertase of the alternative complement pathway. Acquisition of C3b-like activities by spontaneous hydrolysis of the putative thioester in native C3.
Authors: M K Pangburn, R D Schreiber, H J Müller-Eberhard
Journal: The Journal of Experimental Medicine (1981)

Activation of the alternative pathway of complement commences with the formation of an initial fluid-phase C3 convertase. Treatment of C3 with the nucleophilic reagent methylamine has previously been shown to result in the cleavage of an intramolecular thioester bond and to induce C3b-like properties, including the ability to form a fluid-phase C3 convertase. This report examines the hypothesis that spontaneous hydrolysis of the thioester generates a derivative of C3 that is responsible for the formation of the initial C3 convertase of the alternative pathway. The rate of spontaneous decay of C3 hemolytic activity in buffer was found to be between 0.2 and 0.4%/h. In the presence of other alternative pathway proteins, the rate of inactivation was 1%/h. The rate of spontaneous inactivation was greatly accelerated by low concentrations of chaotrophic agents such as KSCN or guanidine. Liberation of a sulfhydryl group, not present in native C3, correlated with loss of hemolytic activity, indicating that exposure to chaotropic agents resulted in thioester hydrolysis. Unlike native C3, C3 bearing a single reactive sulfhydryl group was capable of generating fluid-phase C3 convertase with Factors B, D, and P and was cleaved by Factor I (C3b inactivator) in the presence of Factor H (beta 1H). The fragmentation patterns indicated that the C3a domain was covalently associated with the functionally C3b-like C3. Organomercurial agarose was employed for the rapid removal of sulfhydryl-bearing, hemolytically inactive forms of C3 and C3b from native hemolytically active C3.
Effectiveness of Influenza Vaccine in the Community-Dwelling Elderly
Authors: Kristin L. Nichol, James D. Nordin, David B. Nelson, John P. Mullooly, Eelko Hak
Journal: New England Journal of Medicine (2007)

Reliable estimates of the effectiveness of influenza vaccine among persons 65 years of age and older are important for informed vaccination policies and programs. Short-term studies may provide misleading pictures of long-term benefits, and residual confounding may have biased past results. This study examined the effectiveness of influenza vaccine in seniors over the long term while addressing potential bias and residual confounding in the results.Data were pooled from 18 cohorts of community-dwelling elderly members of one U.S. health maintenance organization (HMO) for 1990-1991 through 1999-2000 and of two other HMOs for 1996-1997 through 1999-2000. Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important covariates. Additional analyses explored for evidence of bias and the potential effect of residual confounding.There were 713,872 person-seasons of observation. Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons. Vaccination was associated with a 27% reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95% confidence interval [CI], 0.68 to 0.77) and a 48% reduction in the risk of death (adjusted odds ratio, 0.52; 95% CI, 0.50 to 0.55). Estimates were generally stable across age and risk subgroups. In the sensitivity analyses, we modeled the effect of a hypothetical unmeasured confounder that would have caused overestimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant--though lower--reductions in the risks of both hospitalization and death.During 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons. Vaccine delivery to this high-priority group should be improved.
Immunotherapy of Type 1 Diabetes: Where Are We and Where Should We Be Going?
Authors: Xunrong Luo, Kevan C. Herold, Stephen D. Miller
Journal: Immunity (2010)

Type 1 diabetes (T1D) is a chronic autoimmune disorder characterized by destruction of insulin-producing pancreatic β cells. Many broad-based immunosuppressive and antigen-specific immunoregulatory therapies have been and are currently being evaluated for their utility in the prevention and treatment of T1D. Looking forward, this review discusses the potential therapeutic use of antigen-specific tolerance strategies, including tolerance induced by "tolerogenic" antigen-presenting cells pulsed with diabetogenic antigens and transfer of induced or expanded regulatory T cells, which have demonstrated efficacy in nonobese diabetic (NOD) mice. Depending on the time of therapeutic intervention in the T1D disease process, antigen-specific immunoregulatory strategies may be employed as monotherapies, or in combination with short-term tolerance-promoting immunoregulatory drugs and/or drugs promoting differentiation of insulin-producing β cells from endogenous progenitors.
Effects of Dexamethasone on the Incidence of Acute Mountain Sickness at Two Intermediate Altitudes
Authors: A. Bruce Montgomery
Journal: JAMA (1989)

To test the value of dexamethasone acetate for ameliorating acute mountain sickness (AMS), we conducted a double-blind, randomized study that compared the effects of 4 mg of dexamethasone acetate or a placebo (given every six hours for six doses beginning at the time of exposure) at 2700 and 2050 m. Study subjects, who were recruited from health professionals who attended continuing medical education programs at ski resorts in the Rocky Mountains, were classified as having AMS when they reported three or more of the five usual symptoms (headache, insomnia, dyspnea, anorexia, and/or fatigue) on a single day. All symptoms with an intensity of at least grade 2 (moderate) out of 5 were analyzed. At 2700 m, there was a 50% decrease in the mean AMS symptom score in the dexamethasone group (0.94 ±1.11 vs 1.84 ±1.44 [mean±SD]) and the incidence of AMS was 20% of that in the control group (3/38 vs 14/35). At 2050 m, there was no difference between dexamethasone and a placebo in the mean AMS symptom score (1.52 ± 1.50 vs 1.24 ± 1.33) and the incidence of AMS (5/25 vs 4/25). Dexamethasone ameliorates the usual symptoms of AMS at 2700 m but not at 2050 m. (<i>JAMA</i>1989;261:734-736)
Normal patterns of human upper small bowel motor activity recorded by prolonged radiotelemetry.
Authors: D G Thompson, D L Wingate, L Archer, M J Benson, W J Green, R J Hardy
Journal: Gut (1980)

In order to characterise human interdigestive cyclical motor activity, and its interruption by food, jejunal pressure changes in healthy volunteers were recorded continuously for 24 hours, using an ingested pressure-sensitive radiotelemetry capsule tethered at the duodenojejunal flexure. In 20 studies, the subjects fasted throughout; in another 20 studies they received a single standard meal. Using this technique, fasting motor complexes were easily detected. There was considerable variation in interdigestive cycle duration and in the interruption caused by food. The data were not normally distributed. The study indicates that any descriptions of 9atypical9 jejunal motility patterns must take into account the wide variations seen in health, before they can be regarded as representing dysfunction or disease.
Long-term lung function in postinfectious bronchiolitis obliterans
Authors: Martin Rosewich, Jonas Eckrich, Stefan Zielen
Journal: Thorax (2015)

on paediatric and adult clinical studies.While discussing our paper, 2 the reviewer seems to have misinterpreted our results when saying that consolidation is more severe in the apex of adult sickle cell disease patients with acute chest syndrome.In fact, CT and bedside chest radiography showed that lung parenchyma was increasingly consolidated from apex to base. 2 This distribution is in accordance with previous studies, 3 4 but may vary with age, with young children having more upper and middle lobe disease, contrarily to adult patients.
Effect of Once-Weekly Epoetin Beta on Survival in Patients With Metastatic Breast Cancer Receiving Anthracycline- and/or Taxane-Based Chemotherapy: Results of the Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) Study
Authors: Matti Aapro, Robert C. Leonard, Agustí Barnadas, Maurizio Marangolo, Michael Untch, Nikolaos Malamos, José Mayordomo, Dietmar Reichert, José Luiz Pedrini, Lidia Ukarma, Armin Scherhag, Hans-Ulrich Burger
Journal: Journal of Clinical Oncology (2008)

The Breast Cancer-Anemia and the Value of Erythropoietin (BRAVE) study evaluated whether epoetin beta would improve survival in patients with metastatic breast cancer (MBC).BRAVE was an open-label, randomized, multicenter study in patients with MBC treated with anthracycline- and/or taxane-based chemotherapy. Patients (hemoglobin [Hb] < 12.9 g/dL) were randomly assigned (1:1) to epoetin beta 30,000 U subcutaneously once weekly or control for 24 weeks. The primary efficacy variable was overall survival. Secondary efficacy outcomes included progression-free survival, transfusion- and severe anemia-free survival, Hb response, safety, and quality of life (QoL).After 18 months of follow-up, 62 (27%) of 231 patients survived with epoetin beta therapy and 63 (27%) of 232 with control. No difference was detected in overall survival (hazard ratio [HR] = 1.07; 95% CI, 0.87 to 1.33, P = .522) or progression-free survival (HR = 1.07; 95% CI, 0.89 to 1.30, P = .448). There was a statistically significant benefit on transfusion- and severe anemia-free survival compared with control (HR = 0.59; P = .0097). Median Hb level increased with epoetin beta (11.7 g/dL at baseline to 13.3 g/dL at 24 weeks) but did not change with control (11.5 v 11.4 g/dL). Patients receiving epoetin beta experienced more thromboembolic events (TEEs) compared with controls (13% v 6%; P = .012) with no difference in serious TEEs (4% v 3%). Epoetin beta did not significantly improve QoL in this study where patients had a high baseline Hb value.In patients with MBC receiving chemotherapy and initial Hb less than 12.9 g/dL, epoetin beta increased Hb. No difference was detected in overall survival. Because of its superiority design, this study cannot, however, exclude clinically important differences in survival with absolute certainty.
Gasping During Cardiac Arrest in Humans Is Frequent and Associated With Improved Survival
Authors: Bentley J. Bobrow, Mathias Zuercher, Gordon A. Ewy, Lani Clark, Vatsal Chikani, Dan Donahue, Arthur B. Sanders, Ronald W. Hilwig, Robert A. Berg, Karl B. Kern
Journal: Circulation (2008)

The incidence and significance of gasping after cardiac arrest in humans are controversial.Two approaches were used. The first was a retrospective analysis of consecutive confirmed out-of-hospital cardiac arrests from the Phoenix Fire Department Regional Dispatch Center text files to determine the presence of gasping soon after collapse. The second was a retrospective analysis of 1218 patients with out-of-hospital cardiac arrests in Arizona documented by emergency medical system (EMS) first-care reports to determine the incidence of gasping after arrest in relation to the various EMS arrival times. The primary outcome measure was survival to hospital discharge. An analysis of the Phoenix Fire Department Regional Dispatch Center records of witnessed and unwitnessed out-of-hospital cardiac arrests with attempted resuscitation found that 44 of 113 (39%) of all arrested patients had gasping. An analysis of 1218 EMS-attended, witnessed, out-of-hospital cardiac arrests demonstrated that the presence or absence of gasping correlated with EMS arrival time. Gasping was present in 39 of 119 patients (33%) who arrested after EMS arrival, in 73 of 363 (20%) when EMS arrival was <7 minutes, in 50 of 360 (14%) when EMS arrival time was 7 to 9 minutes, and in 25 of 338 (7%) when EMS arrival time was >9 minutes. Survival to hospital discharge occurred in 54 of 191 patients (28%) who gasped and in 80 of 1027 (8%) who did not (adjusted odds ratio, 3.4; 95% confidence interval, 2.2 to 5.2). Among the 481 patients who received bystander cardiopulmonary resuscitation, survival to hospital discharge occurred among 30 of 77 patients who gasped (39%) versus only 38 of 404 among those who did not gasp (9%) (adjusted odds ratio, 5.1; 95% confidence interval, 2.7 to 9.4).Gasping or abnormal breathing is common after cardiac arrest but decreases rapidly with time. Gasping is associated with increased survival. These results suggest that the recognition and importance of gasping should be taught to bystanders and emergency medical dispatchers so as not to dissuade them from initiating prompt resuscitation efforts when appropriate.
Combined Effects of Routine Blood Pressure Lowering and Intensive Glucose Control on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes
Authors: Sophia Zoungas, Bastiaan E. de Galan, Toshiharu Ninomiya, Diederick Grobbee, Pavel Hamet, Simon Heller, Stephen MacMahon, Michel Marre, Bruce Neal, Anushka Patel, Mark Woodward, John Chalmers
Journal: Diabetes Care (2009)

OBJECTIVE To assess the magnitude and independence of the effects of routine blood pressure lowering and intensive glucose control on clinical outcomes in patients with long-standing type 2 diabetes. RESEARCH DESIGN AND METHODS This was a multicenter, factorial randomized trial of perindopril-indapamide versus placebo (double-blind comparison) and intensive glucose control with a gliclazide MR–based regimen (target A1C ≤6.5%) versus standard glucose control (open comparison) in 11,140 participants with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Annual event rates and risks of major macrovascular and microvascular events considered jointly and separately, renal events, and death during an average 4.3 years of follow-up were assessed, using Cox proportional hazards models. RESULTS There was no interaction between the effects of routine blood pressure lowering and intensive glucose control for any of the prespecified clinical outcomes (all P &amp;gt; 0.1): the separate effects of the two interventions for the renal outcomes and death appeared to be additive on the log scale. Compared with neither intervention, combination treatment reduced the risk of new or worsening nephropathy by 33% (95% CI 12–50%, P = 0.005), new onset of macroalbuminuria by 54% (35–68%, P &amp;lt; 0.0001), and new onset of microalbuminuria by 26% (17–34%). Combination treatment was associated with an 18% reduction in the risk of all-cause death (1–32%, P = 0.04). CONCLUSIONS The effects of routine blood pressure lowering and intensive glucose control were independent of one another. When combined, they produced additional reductions in clinically relevant outcomes.
Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer
Authors: Rong Hu, Thomas A. Dunn, Shuanzeng Wei, Sumit Isharwal, Robert W. Veltri, Elizabeth Humphreys, Misop Han, Alan W. Partin, Robert L. Vessella, William B. Isaacs, G. Steven Bova, Jun Luo
Journal: Cancer Research (2008)

Abstract Suppression of androgen production and function provides palliation but not cure in men with prostate cancer (PCa). Therapeutic failure and progression to hormone-refractory PCa (HRPC) are often accompanied by molecular alterations involving the androgen receptor (AR). In this study, we report novel forms of AR alteration that are prevalent in HRPC. Through in silico sequence analysis and subsequent experimental validation studies, we uncovered seven AR variant transcripts lacking the reading frames for the ligand-binding domain due to splicing of “intronic” cryptic exons to the upstream exons encoding the AR DNA-binding domain. We focused on the two most abundantly expressed variants, AR-V1 and AR-V7, for more detailed analysis. AR-V1 and AR-V7 mRNA showed an average 20-fold higher expression in HRPC (n = 25) when compared with hormone-naive PCa (n = 82; P &amp;lt; 0.0001). Among the hormone-naive PCa, higher expression of AR-V7 predicted biochemical recurrence following surgical treatment (P = 0.012). Polyclonal antibodies specific to AR-V7 detected the AR-V7 protein frequently in HRPC specimens but rarely in hormone-naive PCa specimens. AR-V7 was localized in the nuclei of cultured PCa cells under androgen-depleted conditions, and constitutively active in driving the expression of canonical androgen-responsive genes, as revealed by both AR reporter assays and expression microarray analysis. These results suggest a novel mechanism for the development of HRPC that warrants further investigation. In addition, as expression markers for lethal PCa, these novel AR variants may be explored as potential biomarkers and therapeutic targets for advanced PCa. [Cancer Res 2009;69(1):16–22]
Association Between Complementary and Alternative Medicine Use, Preventive Care Practices, and Use of Conventional Medical Services Among Adults With Diabetes
Authors: Donald Garrow, Leonard E. Egede
Journal: Diabetes Care (2006)

OBJECTIVE—To assess the association between complementary and alternative medicine (CAM) use, preventive care practices, and use of conventional medical services among adults with diabetes. RESEARCH DESIGN AND METHODS—We analyzed data on 2,474 adults with diabetes. We created an overall CAM-use category based on use of any of the following: diets, herbs, chiropractic care, yoga, relaxation, acupuncture, ayuverda, biofeedback, chelation, energy healing, Reiki therapy, hypnosis, massage, naturopathy, and homeopathy. We used multiple logistic regression to assess the effect of CAM use on preventive care practices (receipt of influenza and pneumonia vaccines) and use of conventional medical services (number of primary care and emergency department visits). STATA was used for statistical analysis to account for the complex survey design. RESULTS—A total of 48% of adults with diabetes used some form of CAM. CAM use was independently associated with receipt of pneumonia vaccination (odds ratio 1.56 [95% CI 1.26–1.94]) but not significantly associated with receipt of influenza vaccination (1.17 [0.92–1.48]). CAM use was independently associated with visiting the emergency department (1.34 [1.06–1.70]), having six or more primary care visits (1.44 [1.14–1.83]), and having eight or more primary care visits (1.66 [1.22–2.25]). CONCLUSIONS—In contrast to the findings of previous studies, CAM use appears to be associated with increased likelihood of receipt of preventive care services and increased emergency department and primary care visits. CAM use may not be a barrier to use of conventional medical services in adults with diabetes.