tbuckley/cabot-search huggingface dataset:
Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality
Authors: Carmen A. Peralta
Journal: JAMA (2011)

A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.Prospective cohort study involving 26,643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m(2) and ACR of either <30 or ≥30 mg/g.All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26,643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0-5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2-4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9-8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4-1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9-2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4-3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7-40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05-2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6-11.3). Net reclassification improvement for death was 13.3% (P < .001) and for end-stage renal disease was 6.4% (P < .001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
Identification of Neutrophil Gelatinase-Associated Lipocalin as a Novel Early Urinary Biomarker for Ischemic Renal Injury
Authors: Jaya Mishra, Qing Ma, Anne Prada, Mark Mitsnefes, Kamyar Zahedi, Jun Yang, Jonathan Barasch, Prasad Devarajan
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Acute renal failure (ARF) secondary to ischemic injury remains a common and potentially devastating problem. A transcriptome-wide interrogation strategy was used to identify renal genes that are induced very early after renal ischemia, whose protein products might serve as novel biomarkers for ARF. Seven genes that are upregulated >10-fold were identified, one of which (Cyr61) has recently been reported to be induced after renal ischemia. Unexpectedly, the induction of the other six transcripts was novel to the ARF field. In this study, one of these previously unrecognized genes was further characterized, namely neutrophil gelatinase-associated lipocalin (NGAL), because it is a small secreted polypeptide that is protease resistant and consequently might be readily detected in the urine. The marked upregulation of NGAL mRNA and protein levels in the early postischemic mouse kidney was confirmed. NGAL protein expression was detected predominantly in proliferating cell nuclear antigen-positive proximal tubule cells, in a punctate cytoplasmic distribution that co-localized with markers of late endosomes. NGAL was easily detected in the urine in the very first urine output after ischemia in both mouse and rat models of ARF. The appearance of NGAL in the urine was related to the dose and duration of renal ischemia and preceded the appearance of other urinary markers such as N-acetyl-β-D-glucosaminidase and β2-microglobulin. The origin of NGAL from tubule cells was confirmed in cultured human proximal tubule cells subjected to in vitro ischemic injury, where NGAL mRNA was rapidly induced in the cells and NGAL protein was readily detectable in the culture medium within 1 h of mild ATP depletion. NGAL was also easily detectable in the urine of mice with cisplatin-induced nephrotoxicity, again preceding the appearance of N-acetyl-β-D-glucosaminidase and β2-microglobulin. The results indicate that NGAL may represent an early, sensitive, noninvasive urinary biomarker for ischemic and nephrotoxic renal injury. E-mail: [email protected]
Inconsistency of HER2 Test Raises Questions
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2007)

The tests that determine who gets the powerful breast cancer drug trastuzumab (Herceptin) may not be as reliable as previously thought, researchers reported at the annual meeting of the American Society of Clinical Oncology. That means some women who should be getting trastuzumab treatment are not, while other women who will not benefit are unnecessarily exposed to a drug that can cause heart problems. “This is a very big deal,” said Larry Norton, M.D. , deputy physician in chief for breast cancer programs at Memorial Sloan-Kettering Cancer Center, who was not involved with either of the new studies that uncovered the problem.
Cholesterol crystallization in human gallbladder bile: Relation to gallstone number, bile composition, and apolipoprotein E4 isoform
Authors: Karel J. Van Erpecum, Gerard P. Van Berge-Henegouwen, Erik R.M. Eckhardt, Piero Portincasa, Bert J.M. Van De Heijning, Geesje M. Dallinga-Thie, Albert K. Groen
Journal: Hepatology (1998)

Patients with multiple cholesterol gallstones are at increased risk of recurrence after nonsurgical therapy, possibly because of fast biliary cholesterol crystallization. Serum apolipoprotein E4 (apo E4) is a risk factor for primary cholesterol gallstone formation as well as recurrence. We examined potential effects of stone number and apolipoprotein E genotype on crystallization and on various crystallization-influencing factors in gallbladder biles of 36 cholesterol stone patients (25 multiple stones: 10 carrying the epsilon4 allele). Biliary cholesterol saturation, bile salt composition or concentrations of total protein, immunoglobulin (Ig)A, IgG, alpha1-acid glycoprotein, haptoglobin, or mucin--all crystallization promoters--did not differ between multiple and solitary stone patients, apparently not explaining different speed of crystallization (crystal observation time 3.5 +/- 0.6 days vs. 12.7 +/- 2.4 days, respectively; P = .0003). In contrast, biliary aminopeptidase-N activities (2,607 +/- 592 mU/mL vs. 947 +/- 185 mU/mL; P = .04) were higher and IgM levels (179 +/- 39 vs. 65 +/- 8 mg/L; P = .09) tended to be higher in the case of multiple stones. Although patients carrying the epsilon4 allele had similar stone numbers and crystallization as patients without the epsilon4 allele, their cholesterol saturation index (CSI) was lower (1.08 +/- 0.09 vs. 1.54 +/- 0.13; P = .01), whereas total protein and bile salt concentrations tended to be higher with preferential taurine-conjugation. In conclusion, fast cholesterol crystallization is associated with multiple stones but not with apolipoprotein E4. Whereas fast crystallization may contribute to high recurrence rates after nonsurgical therapy in case of multiple gallstones, the mechanism for increased risk of gallstone formation in patients carrying the epsilon4 allele remains unknown.
Oral Contraception by the Sequential Approach
Authors: Edward T. Tyler
Journal: JAMA (1966)

To investigate the sequential approach to oral contraception, 509 fertile subjects were given 0.08 mg of mestranol daily for 14 days beginning on the fifth cycle day, followed by 0.08 mg of mestranol with 2 mg of norethindrone for six days. One pregnancy due to method failure occurred in 6,212 cycles of therapy. Thirty-seven patients reported amenorrhea in 57 cycles. Spotting or breakthrough bleeding or both occurred in 254 cycles. The majority of 88 incidences of gastrointestinal disturbance were evident in the first three cycles of therapy. Other side effects included weight changes, headache, leg pain, backache, and edema. Therapy was discontinued in 101 cases—in 24 of these for drug-related reasons. It was concluded that mestranol-norethindrone sequential medication provides an additional effective method of oral contraception.
Elective early noninvasive ventilation as a weaning method of COPD patients
Authors: Ahmed Sh. Mohamed, Ibrahim Ibrahim
Journal: European Respiratory Journal (2012)

Patients with acute exacerbations of COPD represent a large portion of critically ill patients that mechanically ventilated. The rate of weaning failure is high in these patients. Prolonged mechanical ventilation (MV) increases intubation associated complications. Objective: To determine the efficacy of early non-invasive mechanical ventilation as a weaning method in COPD patients with acute hypercapnic respiratory failure compared with the conventional-weaning approach. Methods: Study was conducted on a 30 mechanically ventilated COPD patients who had infective exacerbations. Patients were randomly extubated, receiving non-invasive ventilation (n=15), or weaned following a conventional-weaning approach (n=15). Results: compared with the convential-weaning group, the noninvasive-ventilation group had shorter periods of invasive MV, total ventilator support, ICU stay, less incidence of ventilator associated pneumonia and less mortality. Conclusion: Patients with chronic obstructive pulmonary disease who had respiratory failure and were starting to breathe spontaneously, showed that noninvasive ventilation could decrease pneumonia, length of stay in the intensive care and the duration of ventilatory support.

View this table:

Outcome parameters in both studied groups





Ref. Manthous CA. The anarchy of weaning techniques. Chest 2002;121:1738-40.
Propagation of Cardiomyocyte Hypercontracture by Passage of Na <sup>+</sup> Through Gap Junctions
Authors: Marisol Ruiz-Meana, David Garcia-Dorado, Bettina Hofstaetter, H. Michael Piper, Jordi Soler-Soler
Journal: Circulation Research (1999)

Abstract —Prolonged ischemia increases cytosolic Ca 2+ concentration in cardiomyocytes. Cells with severely elevated cytosolic Ca 2+ may respond to reperfusion, developing hypercontracture, sarcolemmal disruption, and death. Cardiomyocytes are efficiently connected through gap junctions (GJs) to form a functional syncytium, and it has been shown that hypercontracture can be propagated to adjacent myocytes through a GJ-mediated mechanism. This study investigated the mechanism of propagation of cell injury associated with sarcolemmal rupture in end-to-end connected pairs of isolated rat cardiomyocytes. Microinjection of extracellular medium into one of the cells to simulate sarcolemmal disruption induced a marked increase in cytosolic Ca 2+ (fura-2) and Na + (SBFI) in the adjacent cell and its hypercontracture in &lt;30 seconds (22 of 22 cell pairs). This process was not modified when Ca 2+ release from the sarcoplasmic reticulum was blocked with 10 μmol/L ryanodine (5 of 5 cell pairs), but it was fully dependent on the presence of Ca 2+ in the extracellular buffer. Blockade of L-type Ca 2+ channels with 10 μmol/L nifedipine did not alter propagation of hypercontracture. However, the presence of 15 to 20 μmol/L KB-R7943, a highly selective blocker of reverse Na + /Ca 2+ exchange, prevented propagation of hypercontracture in 16 of 20 cell pairs ( P &lt;0.01) without interfering with GJ permeability, as assessed by the Lucifer Yellow transfer method. Addition of the Ca 2+ chelator EGTA (2 mmol/L) to the injection solution prevented hypercontracture in the injected cell but not in the adjacent one (n=5). These results indicate that passage of Na + through GJ from hypercontracting myocytes with ruptured sarcolemma to adjacent cells, and secondary entry of [Ca 2+ ] o via reverse Na + /Ca 2+ exchange, can contribute to cell-to-cell propagation of hypercontracture. This previously unrecognized mechanism could increase myocardial necrosis during ischemia-reperfusion in vivo and be the target of new treatments aimed to limit it.
Validity of composite end points in clinical trials
Authors: Victor M Montori, Gaietà Permanyer-Miralda, Ignacio Ferreira-González, Jason W Busse, Valeria Pacheco-Huergo, Dianne Bryant, Jordi Alonso, Elie A Akl, Antònia Domingo-Salvany, Edward Mills, Ping Wu, Holger J Schünemann, Roman Jaeschke, Gordon H Guyatt
Journal: BMJ (2005)

Use of composite end points as the main outcome in randomised trials can hide wide differences in the individual measures.How should you apply the results to clinical practice?Improvements in medical care over the past two decades have decreased the frequency with which patients with common conditions such as myocardial infarction develop subsequent adverse events.Although welcome for patients, low event rates provide challenges for clinical investigators, who consequently require large sample sizes and long follow up to test the incremental benefits of new treatments.Clinical trialists have responded to these challenges by relying increasingly on composite end points, which capture the number of patients experiencing any one of several adverse events-for example, death, myocardial infarction, or hospital admission. 1 Use of composite end points is usually justified by the assumption that the effect on each of the components will be similar and that patients will attach similar importance to each component. 1But this is not always the case.In this article we provide a strategy to interpret the results of clinical trials when investigators measure the effect of treatment on an aggregate of end points of varying importance.Scan of heart of patient with angina: much of treatment evidence relies on composite end points
Involvement of Extracellular Signal-Regulated Kinases 1/2 in Cardiac Hypertrophy and Cell Death
Authors: Orlando F. Bueno, Jeffery D. Molkentin
Journal: Circulation Research (2002)

In response to pathophysiological stress, the adult heart undergoes hypertrophic enlargement characterized by an increase in the cross-sectional area of individual myofibers. Although cardiac hypertrophy is initially a compensatory response, sustained hypertrophy is a leading predictor for the development of heart failure. At the molecular level, disease-related stimuli invoke endocrine, paracrine, and autocrine regulatory circuits, which directly influence cardiomyocyte hypertrophy, in part, through membrane bound G protein-coupled receptors and receptor tyrosine kinases. These membrane receptors activate intermediate signal transduction pathways within the cytoplasm such as mitogen-activated protein kinases (MAPKs), protein kinase C (PKC), and calcineurin, which directly modify transcriptional regulatory factors promoting alterations in cardiac gene expression. This review will weigh an increasing body of literature implicating the intermediate signaling pathway consisting of MEK1 and extracellular signal-regulated kinases (ERK1/2) as important regulators of cardiac hypertrophy and myocyte survival. The MEK1-ERK1/2 pathway likely occupies a central regulatory position in the signaling hierarchy of a cardiac myocyte given its unique ability to respond to virtually every characterized hypertrophic agonist and stress stimuli examined to date and based on its ability to promote myocyte growth in vitro and in vivo.
Phenobarbital Response Elements of Cytochrome P450 Genes and Nuclear Receptors
Authors: T Sueyoshi, M Negishi
Journal: The Annual Review of Pharmacology and Toxicology (2001)

Phenobarbital (PB) response elements are composed of various nuclear receptor (NR)-binding sites. A 51-bp distal element PB-responsive enhancer module (PBREM) conserved in the PB-inducible CYP2B genes contains two NR-binding direct repeat (DR)-4 motifs. Responding to PB exposure in liver, the NR constitutive active receptor (CAR) translocates to the nucleus, forms a dimer with the retinoid X receptor (RXR), and activates PBREM via binding to DR-4 motifs. For CYP3A genes, a common NR site [DR-3 or everted repeat (ER)-6] is present in proximal promoter regions. In addition, the distal element called the xenobiotic responsive module (XREM) is found in human CYP3A4 genes, which contain both DR-3 and ER-6 motifs. Pregnane X receptor (PXR) could bind to all of these sites and, upon PB induction, a PXR:RXR heterodimer could transactivate XREM. These response elements and NRs are functionally versatile, and capable of responding to distinct but overlapping groups of xenochemicals.
Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice
Authors: Katsuhisa Matsuura, Atsushi Honda, Toshio Nagai, Noritoshi Fukushima, Koji Iwanaga, Masakuni Tokunaga, Tatsuya Shimizu, Teruo Okano, Hiroshi Kasanuki, Nobuhisa Hagiwara, Issei Komuro
Journal: Journal of Clinical Investigation (2009)

Cardiac progenitor cells are a potential source of cell therapy for heart failure. Although recent studies have shown that transplantation of cardiac stem/progenitor cells improves function of infarcted hearts, the precise mechanisms of the improvement in function remain poorly understood. The present study demonstrates that transplantation of sheets of clonally expanded stem cell antigen 1–positive (Sca-1–positive) cells (CPCs) ameliorates cardiac dysfunction after myocardial infarction in mice. CPC efficiently differentiated into cardiomyocytes and secreted various cytokines, including soluble VCAM-1 (sVCAM-1). Secreted sVCAM-1 induced migration of endothelial cells and CPCs and prevented cardiomyocyte death from oxidative stress through activation of Akt, ERK, and p38 MAPK. Treatment with antibodies specific for very late antigen-4 (VLA-4), a receptor of sVCAM-1, abolished the effects of CPC-derived conditioned medium on cardiomyocytes and CPCs in vitro and inhibited angiogenesis, CPC migration, and survival in vivo, which led to attenuation of improved cardiac function following transplantation of CPC sheets. These results suggest that CPC transplantation improves cardiac function after myocardial infarction through cardiomyocyte differentiation and paracrine mechanisms mediated via the sVCAM-1/VLA-4 signaling pathway.
Local Depolarization Abnormalities Are the Dominant Pathophysiologic Mechanism for Type 1 Electrocardiogram in Brugada Syndrome
Authors: Pieter G. Postema, Pascal F.H.M. van Dessel, Jan A. Kors, Andre C. Linnenbank, Gerard van Herpen, Henk J. Ritsema van Eck, Nan van Geloven, Jacques M.T. de Bakker, Arthur A.M. Wilde, Hanno L. Tan
Journal: Journal of the American College of Cardiology (2010)
Cardiac specific differentiation of mouse embryonic stem cells
Authors: A Sachinidis
Journal: Cardiovascular Research (2003)

Embryonic stem (ES) cells may represent an alternative source of functionally intact cardiomyocytes for the causal treatment of cardiovascular diseases. However, this requires cardiac-specific differentiation of stem cells and the selection of pure lineages consisting of early embryonic cardiomyocytes. Therefore, an understanding of the basic mechanisms of heart development is essential for selective differentiation of embryonic stem cells into cardiac cells. The development of cardiac cells from embryonic stem cells is regulated by several soluble factors and signalling molecules together with cardiac specific transcription factors such as the zinc-finger GATA proteins and Nkx-2.5. GATA-4 and Nkx-2.5 seem to be essential for heart development. The use of enhanced green fluorescent protein (EGFP) under the control of cardiac-specific promoters in combination with the ES cell system has allowed for the functional characterisation of cardiac precursor cells. Embryonic stem cell-derived cardiomyocytes developmentally express similar cardiac-specific proteins, ion channels and signalling molecules to that of adult cardiomyocytes. Furthermore, identification of growth factors and signalling molecules under cell culture conditions is crucial for the selective cardiac differentiation of embryonic stem cells. Therefore, serum-free culture conditions have to be established in order to examine the influence of different growth factors and signalling molecules on cardiac development and/or formation from ES cells. Although significant progress has been made in generating cardiac cell lineage by the combination of genetically manipulative methods with selective culture conditions for cell transplantation therapy, one of the remaining future challenges for transplantation in humans is the immunological rejection of the engrafted cardiomyocytes.
A Phase I Dose-Finding Trial of Recombinant Interleukin-21 and Rituximab in Relapsed and Refractory Low Grade B-cell Lymphoproliferative Disorders
Authors: John M. Timmerman, John C. Byrd, David J. Andorsky, Reiko E. Yamada, Janet Kramer, Natarajan Muthusamy, Naomi Hunder, John M. Pagel
Journal: Clinical Cancer Research (2012)

We conducted a phase I study to determine the safety, maximum-tolerated dose (MTD), and efficacy of weekly bolus recombinant human interleukin-21 (rIL-21) plus rituximab in patients with indolent B-cell malignancies.One week after a lead-in rituximab dose, cohorts of three patients were treated with 30, 100, or 150 μg/kg rIL-21 weekly for four weeks, concurrent with four weekly doses of rituximab. Patients with stable disease or better were eligible for a second course of therapy.Twenty-one patients with relapsed small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n = 11), follicular lymphoma (n = 9), or marginal zone lymphoma (n = 1) were enrolled, with 19 completing at least one course of therapy. The MTD for rIL-21 was 100 μg/kg, based on observed toxicities including nausea, vomiting, diarrhea, hypotension, edema, and hypophosphatemia. Clinical responses were seen in 8 of 19 evaluable patients (42%; 3 CR/CRu, 5 PR), with 4 of longer duration than the patient's previous response to rituximab-based treatment (median 9 months vs. 3 months).Outpatient therapy of indolent B-cell malignancies with rituximab and weekly rIL-21 was well tolerated and clinically active, with durable complete remissions in a small subset of patients. Additional studies of rIL-21 and anti-CD20 antibodies in lymphoma and SLL/CLL are warranted.