tbuckley/cabot-search huggingface dataset:
An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo
Authors: Manikandan Subramanian, Crystal D. Hayes, Joseph J. Thome, Edward Thorp, Glenn K. Matsushima, Joachim Herz, Donna L. Farber, Kang Liu, Madepalli Lakshmana, Ira Tabas
Journal: Journal of Clinical Investigation (2014)

The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex--composed of the receptor tyrosine kinase AXL, LDL receptor-related protein-1 (LRP-1), and RAN-binding protein 9 (RANBP9)--that mediates DC efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus-1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines.
Impairment of energy metabolism in intact residual myocardium of rat hearts with chronic myocardial infarction.
Authors: S Neubauer, M Horn, A Naumann, R Tian, K Hu, M Laser, J Friedrich, P Gaudron, K Schnackerz, J S Ingwall
Journal: Journal of Clinical Investigation (1995)

The purpose of this study was to test the hypothesis that energy metabolism is impaired in residual intact myocardium of chronically infarcted rat heart, contributing to contractile dysfunction. Myocardial infarction (MI) was induced in rats by coronary artery ligation. Hearts were isolated 8 wk later and buffer-perfused isovolumically. MI hearts showed reduced left ventricular developed pressure, but oxygen consumption was unchanged. High-energy phosphate contents were measured chemically and by 31P-NMR spectroscopy. In residual intact left ventricular tissue, ATP was unchanged after MI, while creatine phosphate was reduced by 31%. Total creatine kinase (CK) activity was reduced by 17%, the fetal CK isoenzymes BB and MB increased, while the "adult" mitochondrial CK isoenzyme activity decreased by 44%. Total creatine content decreased by 35%. Phosphoryl exchange between ATP and creatine phosphate, measured by 31P-NMR magnetization transfer, fell by 50% in MI hearts. Thus, energy reserve is substantially impaired in residual intact myocardium of chronically infarcted rats. Because phosphoryl exchange was still five times higher than ATP synthesis rates calculated from oxygen consumption, phosphoryl transfer via CK may not limit baseline contractile performance 2 mo after MI. In contrast, when MI hearts were subjected to acute stress (hypoxia), mechanical recovery during reoxygenation was impaired, suggesting that reduced energy reserve contributes to increased susceptibility of MI hearts to acute metabolic stress.
Fragile X–Associated Tremor/Ataxia Syndrome
Authors: Jun Yi Wang, David Hessl, Andrea Schneider, Flora Tassone, Randi J. Hagerman, Susan M. Rivera
Journal: JAMA Neurology (2013)

Individuals with the fragile X premutation express expanded CGG repeats (repeats 55-200) in the FMR1 gene and elevated FMR1 messenger RNA (mRNA) levels, both of which may underlie the occurrence of the late-onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Because the core feature of FXTAS is motor impairment, determining the influence of FMR1 mRNA levels on structural connectivity of motor fiber tracts is critical for a better understanding of the pathologic features of FXTAS.To examine the associations of CGG repeat and FMR1 mRNA with motor-related fiber tracts in males with premutation alleles.A case-control study conducted at the University of California, Davis, from April 1, 2008, through August 31, 2009. All data were collected masked to the carrier status of the FMR1 gene.Thirty-six male premutation carriers with FXTAS and 26 male premutation carriers without FXTAS were recruited through their family relationships with children affected by fragile X syndrome. The controls were 34 unaffected family members and healthy volunteers from the local community.The CGG repeat lengths and FMR1 mRNA expression levels in peripheral blood lymphocytes, motor functioning, and white matter structural integrity that were estimated using diffusion tensor imaging. After data collection, we selected 4 motor tracts to reconstruct using diffusion tensor tractography, namely, the middle and superior cerebellar peduncles, descending motor tracts (containing the corticospinal, corticobulbar, and corticopontine tracts), and the anterior body of the corpus callosum.All fiber tracts exhibited weaker structural connectivity in the FXTAS group (decreased 5%-53% from controls, P ≤ .02). Genetic imaging correlation analysis revealed negative associations of CGG repeat length and FMR1 mRNA with connectivity strength of the superior cerebellar peduncles in both premutation groups (partial r² = 0.23-0.33, P ≤ .004). In addition, the measurements from the corpus callosum and superior cerebellar peduncles revealed a high correlation with motor functioning in all 3 groups (r between partial least square predicted and actual test scores = 0.41-0.56, P ≤ .04).Distinct pathophysiologic processes may underlie the structural impairment of the motor tracts in FXTAS. Although both the corpus callosum and superior cerebellar peduncles were of great importance to motor functioning, only the superior cerebellar peduncles exhibited an association with the elevated RNA levels in the blood of fragile X premutation carriers.
Analysis of a Urinary Biomarker Panel for Incident Kidney Disease and Clinical Outcomes
Authors: Conall M. O’Seaghdha, Shih-Jen Hwang, Martin G. Larson, James B. Meigs, Ramachandran S. Vasan, Caroline S. Fox
Journal: Journal of the American Society of Nephrology (2013)

Whether novel biomarkers improve the assessment of incident kidney disease and related adverse outcomes remains to be tested in longitudinal observational studies. We tested 14 urinary biomarkers for association with incident kidney, cardiovascular, and mortality outcomes in 2948 Framingham Heart Study participants. Baseline examinations were performed between 1995 and 1998; mean follow-up was 10.1 years for renal outcomes and 11.2 years for survival analyses. Primary outcomes were incident CKD, incident albuminuria, incident cardiovascular disease, and all-cause mortality. Secondary analyses assessed incident congestive heart failure (CHF) and mortality with coexistent kidney disease. Biomarkers were tested for association with renal end points using logistic regression and incident cardiovascular and mortality outcomes in proportional hazards models; α1-microglobulin, Kim-1, and TFF-3 predicted all-cause mortality (hazard ratio per SD increase in log-transformed biomarker [HR] range, 1.15 to 1.21; 95% confidence interval [CI] range, 1.04 to 1.34; P values=0.007 to <0.001), whereas α1-microglobulin, β2-microglobulin, KIM-1, and TFF-3 associated with death with coexistent kidney disease (HR range, 1.72–2.25; 95% CI, 1.17 to 3.24; P values<0.01). KIM-1 also associated with the risk of incident CHF (HR, 1.32; 95% CI, 1.07 to 1.63; P=0.008). CTGF associated nominally with CKD (HR, 0.83; 95% CI, 0.71 to 0.98; P=0.03), but no other biomarkers associated with incident CKD or albuminuria. Addition of α1-microglobulin and TFF-3 resulted in a nonsignificant net reclassification index (NRI) of 3% for all-cause mortality beyond clinical risk factors. In conclusion, components of a panel of 14 subclinical biomarkers of kidney injury were associated with important clinical outcomes and merit additional investigation.
Effect of Pravastatin on Rate of Kidney Function Loss in People With or at Risk for Coronary Disease
Authors: Marcello Tonelli, Chris Isles, Timothy Craven, Andrew Tonkin, Marc A. Pfeffer, James Shepherd, Frank M. Sacks, Curt Furberg, Stuart M. Cobbe, John Simes, Malcolm West, Chris Packard, Gary C. Curhan
Journal: Circulation (2005)

Limited data suggest that HMG-CoA reductase inhibitors (statins) reduce rates of kidney function loss. We performed this analysis to determine whether pravastatin reduced the rate of kidney function loss over approximately 5 years in people with or at high risk for coronary disease.This was a post hoc subgroup analysis of data from 3 randomized double-blind controlled trials comparing pravastatin 40 mg/d and placebo in subjects with a previous acute coronary syndrome or who were at high cardiovascular risk. The primary outcome was the rate of change in estimated glomerular filtration rate (GFR; in mL/min per 1.73 m2/y). The Modified Diet and Renal Disease Study (MDRD) and Cockcroft-Gault equations were used to estimate GFR. We studied 18,569 participants, 3402 (18.3%) of whom had moderate chronic kidney disease as defined by an estimated GFR of 30 to 59.9 mL/min per 1.73 m2 body surface area. In subjects with moderate chronic kidney disease at baseline, pravastatin reduced the adjusted rate of kidney function loss by approximately 34%, although the absolute reduction in the rate of loss was small (0.22 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.07 to 0.37). Pravastatin did not reduce the frequency of > or =25% decreases in kidney function in this group when MDRD-GFR was used to estimate GFR (relative risk [RR], 0.84; 95% CI, 0.66 to 1.06). When all 18,569 subjects were considered, pravastatin reduced the adjusted rate of kidney function loss by 8% (0.08 mL/min per 1.73 m2/y by MDRD-GFR; 95% CI, 0.01 to 0.15) and the risk of acute renal failure (RR, 0.60; 95% CI, 0.41 to 0.86) but did not significantly reduce the frequency of a > or =25% decline in kidney function by MDRD-GFR (RR, 0.94; 95% CI, 0.88 to 1.01).Pravastatin modestly reduced the rate of kidney function loss in people with or at risk for cardiovascular disease. However, the primary indication for the use of statins in people with or at risk for coronary events remains the reduction in mortality that results from their use.
Immunoadsorbent plasmapheresis for a patient with antiphospholipid syndrome during pregnancy.
Authors: S Kobayashi, N Tamura, H Tsuda, C Mokuno, H Hashimoto, S Hirose
Journal: Annals of the Rheumatic Diseases (1992)

The case of a 34 year old woman with systemic lupus erythematosus with a history of three previous recurrent abortions and lupus anticoagulant and anticardiolipin antibodies is reported. Immunoadsorbent plasmapheresis with a dextran sulphate column was used to remove lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA during her fourth pregnancy in combination with low doses of aspirin and prednisolone. Although during the course of treatment prednisolone was transiently increased to 30 mg/day owing to an asymptomatic increase of lupus anticoagulant and anticardiolipin antibodies, the levels of lupus anticoagulant, anticardiolipin antibodies, and antibodies to DNA were decreased by immunoadsorbent plasmapheresis and a baby girl was delivered successfully by caesarean section. Therefore, immunoadsorbent plasmapheresis with dextran sulphate seems to reduce the risk of recurrent abortion in patients with the antiphospholipid syndrome.
A Perspective on Challenges and Issues in Biomarker Development and Drug and Biomarker Codevelopment
Authors: S. E. Taube, G. M. Clark, J. E. Dancey, L. M. McShane, C. C. Sigman, S. I. Gutman
Journal: JNCI Journal of the National Cancer Institute (2009)

A workshop sponsored by the National Cancer Institute and the US Food and Drug Administration addressed past lessons learned and ongoing challenges faced in biomarker development and drug and biomarker codevelopment. Participants agreed that critical decision points in the product life cycle depend on the level of understanding of the biology of the target and its interaction with the drug, the preanalytical and analytical factors affecting biomarker assay performance, and the clinical disease process. The more known about the biology and the greater the strength of association between an analytical signal and clinical result, the more efficient and less risky the development process will be. Rapid entry into clinical practice will only be achieved by using a rigorous scientific approach, including careful specimen collection and standardized and quality-controlled data collection. Early interaction with appropriate regulatory bodies will ensure studies are appropriately designed and biomarker test performance is well characterized.
Surveillance for hepatocellular carcinoma in patients with primary biliary cirrhosis†
Authors: Marina G. Silveira, Ayako Suzuki, Keith D. Lindor
Journal: Hepatology (2008)

Hepatocellular carcinoma (HCC) occurs with increased frequency in patients with primary biliary cirrhosis (PBC). Effectiveness of surveillance recommendations for HCC is controversial, and data are lacking in patients with PBC. In this study, we attempt to (1) establish the importance of surveillance for HCC in patients with PBC; (2) identify a target population of patients with PBC for HCC surveillance; and (3) propose surveillance recommendations for patients with PBC. We retrospectively identified 36 patients seen at the Mayo Clinic between 1976 and 2007 with a diagnosis of both PBC and HCC. Five patients (14%) were diagnosed incidentally, 17 patients comprised our surveillant population, and 14 patients were diagnosed outside a surveillance program. Patients in the surveillant population were more likely to undergo therapy (88% versus 43%; P = 0.01) and had improved survival (P = 0.002) compared with the nonsurveillant population. All cases of HCC except one were predicted to be at significant risk for HCC based on age, sex, evidence of portal hypertension, and history of blood transfusion using a previous predictive model.We established the importance of surveillance for HCC in patients with PBC. We demonstrated adequate performance of a predictive model and propose it should be refined and used to identify patients with PBC who should be screened for development of HCC. Further studies are needed so that optimal HCC surveillance recommendations in this population can be determined and included in the practice guidelines for PBC.
Beyond the Traditional Prognostic Indicators: The Impact of Primary Care Utilization on Cancer Survival
Authors: Laura E. Jones, Caroline Carney Doebbeling
Journal: Journal of Clinical Oncology (2007)

To our knowledge to date, the effect of primary care utilization on health outcomes in cancer patients has not been described. The objective of this study was to investigate the impact of primary care utilization within 6 months of cancer diagnosis on survival in patients with lung cancer.We used electronic medical record data (1997 to 2005) to identify male veterans with incident lung cancers (N = 323). Primary care utilization was assessed in the 6 months after cancer diagnosis. Patients were observed from cancer diagnosis to death or to last date of health care utilization (ie, censoring date). Univariate and multivariate Cox proportional hazards models tested whether primary care utilization was associated with improved survival. Multivariate analyses adjusted for demographic and clinical characteristics.During an average follow-up of 16.6 months, 259 patients died. In multivariate analysis, the risk of death was 36% (hazard ratio [HR], 0.64; 95% CI, 0.45 to 0.90), 56% (HR, 0.44; 95% CI, 0.29 to 0.65), and 57% (HR, 0.43; 05% CI, 0.29 to 0.64) lower for patients who had one, two, or at least three primary care visits, respectively, in the first 6 months after cancer diagnosis as compared with those without primary care utilization. The median survival duration (P < .0001, log-rank test) was 3.68, 7.52, 13.88, and 13.75 months for patients with no, one, two, or at least three primary care visits, respectively.Primary care utilization in the early phase of cancer treatment has a marked effect that results in a reduced mortality risk in patients with incident lung cancer. Additional research is required to determine how and why primary care utilization is an important prognostic indicator of prolonged survival in patients with lung cancer.
Capillary hydraulic conductivity is elevated by cGMP-dependent vasodilators.
Authors: D J Meyer, V H Huxley
Journal: Circulation Research (1992)

Microvascular functions have been shown to be sensitive to agents associated with changes in cyclic nucleotide levels. The central hypothesis of the current study was that one measure of capillary exchange capacity, hydraulic conductivity (Lp), would be elevated by agents shown to elevate cellular levels of cGMP. To evaluate the hypothesis, frog mesenteric capillary Lp was measured during luminal exposure to 1) atrial natriuretic peptide (ANP), 2) the truncated atriopeptins ANP-I and ANP-III, 3) the nitrovasodilator sodium nitroprusside (SNP), 4) the cGMP phosphodiesterase inhibitor M&amp;B 22948, and 5) methylene blue dye, both alone and in combination with ANP or SNP. ANP (100 nM) elevated Lp by 2.3 +/- 0.2-fold from control levels (n = 15); 10 nM ANP induced a 2.1 +/- 0.3-fold change (n = 8), while 10 nM ANP-III elicited a 1.7 +/- 0.4-fold change (n = 8). In contrast, Lp did not change from basal levels during 10 nM ANP-I infusion (Lp ANP-I/Lp control = 1.2 +/- 0.2; n = 14). SNP (1 microM) induced a reversible, 2.6 +/- 0.5-fold increase in Lp (n = 30) that was inhibitable by methylene blue dye (Lp SNP + MetB/Lp control = 1.1 +/- 0.1; n = 8). Methylene blue did not mask the response to 100 nM ANP (Lp ANP + MetB/Lp control = 2.1 +/- 0.5; n = 7). M&amp;B 22948 (30 microM) increased Lp by 2.8 +/- 0.6-fold (n = 9). These data constitute strong inference that agents demonstrated to elevate cGMP also mediate an increase in capillary Lp in in situ, perfused exchange vessels.
Obesity associated hypoventilation in medical patients is common, potentially dangerous and under-recognised
Authors: N T Ayas
Journal: Thorax (2004)

▴ Nowbar S, Burkart KM, Gonzalez R, et al . Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med2004;116:1–7 [OpenUrl][1][PubMed][2][Web of Science][3] The authors studied consecutive severely obese patients (BMI ⩾35 kg/m2) admitted to the medicine services of three teaching hospitals. Arterial blood gas tensions were measured to assess the prevalence, predictors, and outcomes of patients with obesity associated hypoventilation (OAH), defined as Paco2 ⩾43 mm Hg and pH ⩽7.42, with no … [1]: {openurl}?query=rft.jtitle%253DThe%2BAmerican%2Bjournal%2Bof%2Bmedicine%26rft.stitle%253DAm%2BJ%2BMed%26rft.aulast%253DNowbar%26rft.auinit1%253DS.%26rft.volume%253D116%26rft.issue%253D1%26rft.spage%253D1%26rft.epage%253D7%26rft.atitle%253DObesity-associated%2Bhypoventilation%2Bin%2Bhospitalized%2Bpatients%253A%2Bprevalence%252C%2Beffects%252C%2Band%2Boutcome.%26rft_id%253Dinfo%253Apmid%252F14706658%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=14706658&link_type=MED&atom=%2Fthoraxjnl%2F59%2F5%2F366.atom [3]: /lookup/external-ref?access_num=000188047900001&link_type=ISI
Can bone marrow-derived multipotent adult progenitor cells regenerate infarcted myocardium?
Authors: O AGBULUT, M MAZO, C BRESSOLLE, M GUTIERREZ, K AZARNOUSH, L SABBAH, N NIEDERLANDER, G ABIZANDA, E ANDREU, B PELACHO
Journal: Cardiovascular Research (2006)

To assess the functional effects of multipotent adult progenitor cells (MAPCs) transplanted in a rat model of chronic myocardial infarction.Forty-four rats underwent coronary ligation and, 14 days later, were randomly allocated to receive in-scar injections (5 x 10(6) cells/150 microL) of green fluorescent protein (eGFP)-transduced allogeneic MAPCs (n = 25) or culture medium (controls, n = 19). Nine of the MAPC-treated hearts were employed for functional studies while the remaining 16 received cells co-labeled with Resovist and were only used for serial histological assessments. Left ventricular (LV) function was assessed echocardiographically before transplantation and 1 month thereafter in a blinded manner. Immunohistochemistry, electron microscopy and PCR were used to detect grafted cells. All data were compared by nonparametric tests.Baseline ejection fractions (EF, median;[interquartile range]) did not differ significantly among the groups: 30% [0.23;0.37] and 37% [0.32;0.38] in control and rMAPC-transplanted hearts, respectively. One month later, LV function of control hearts was found to have deteriorated, as reflected by a decline in EF to 24% [0.21;0.30], and although EF tended to remain more stable after cell transplantation (37% [0.27;0.41]), the difference between the two groups failed to achieve statistical significance (p = 0.06). While MAPCs could be identified early post-transplant, no evidence of engraftment was further observed at 1 month by immunohistochemistry, electron microscopy or PCR.In this model, MAPCs did not improve global pump function, and although some of these cells expressed endothelial markers during the early post-transplant period, we could not detect any evidence for differentiation into cardiomyocytes and no engraftment was further identified beyond 2 weeks after cell injections.
Novel Developments in the Epidemic of Human Immunodeficiency Virus and Tuberculosis Coinfection
Authors: Asha Anandaiah, Keertan Dheda, Joseph Keane, Henry Koziel, David A. J. Moore, Naimish R. Patel
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Tuberculosis (TB) disease remains one of the highest causes of mortality in HIV-infected individuals, and HIV-TB coinfection continues to grow at alarming rates, especially in sub-Saharan Africa. Surprisingly, a number of important areas regarding coinfection remain unclear. For example, increased risk of TB disease begins early in the course of HIV infection; however, the mechanism by which HIV increases this risk is not well understood. In addition, there is lack of consensus on the optimal way to diagnose latent TB infection and to manage active disease in those who are HIV infected. Furthermore, effective point-of-care testing for TB disease remains elusive. This review discusses key areas in the epidemiology, pathogenesis, diagnosis, and management of active and latent TB in those infected with HIV, focusing attention on issues related to high- and low-burden areas. Particular emphasis is placed on controversial areas where there are gaps in knowledge and on future directions of study.