tbuckley/cabot-search huggingface dataset:
HIF Activation Protects From Acute Kidney Injury
Authors: Alexander Weidemann, Wanja M. Bernhardt, Bernd Klanke, Christoph Daniel, Björn Buchholz, Valentina Ca[Combining Circumflex Accent]mpean, Kerstin Amann, Christina Warnecke, Michael S. Wiesener, Kai-Uwe Eckardt, Carsten Willam
Journal: Journal of the American Society of Nephrology (2008)

The contribution of hypoxia to cisplatin-induced renal tubular injury is controversial. Because the hypoxia-inducible factor (HIF) pathway is a master regulator of adaptation to hypoxia, we measured the effects of cisplatin on HIF accumulation in vitro and in vivo, and tested whether hypoxic preconditioning is protective against cisplatin-induced injury. We found that cisplatin did not stabilize HIF-1alpha protein in vitro or in vivo under normoxic conditions. However, hypoxic preconditioning of cisplatin-treated proximal tubular cells in culture reduced apoptosis in an HIF-1alpha-dependent fashion and increased cell proliferation as measured by BrdU incorporation. In vivo, rats preconditioned with carbon monoxide before cisplatin administration had significantly better renal function than rats kept in normoxic conditions throughout. Moreover, the histomorphological extent of renal damage and tubular apoptosis was reduced by the preconditional treatment. Therefore, development of pharmacologic agents to induce renal HIF might provide a new approach to ameliorate cisplatin-induced nephrotoxicity.
Nasal airflow dynamics: mechanisms and responses associated with an external nasal dilator strip
Authors: J.P. Kirkness, J.R. Wheatley, T.C. Amis
Journal: European Respiratory Journal (2000)

The adhesive external nasal dilator strip (ENDS) is widely advocated for prevention of snoring and promotion of nasal breathing during exercise. In the present study, the effects of the ENDS on nasal airflow resistance (Rn) in normal subjects were examined and factors determining individual responses to the ENDS explored. Using posterior rhinomanometry, 20 healthy Caucasian adults (10 males, 10 females; age: 18-56 yrs) were studied during quiet tidal breathing and voluntary hyperpnoea with (ENDS) and without (control) ENDS and with a placebo strip (placebo) before and after application of a topical nasal decongestant (oxymetazoline hydrochloride). During tidal breathing, only nine subjects showed a significantly (p&lt;0.05) decreased inspiratory and/or expiratory Rn with the ENDS ("responders"). During the control, inspiratory Rn (at 0.4 L x s(-1)) was higher in "responders" than "nonresponders" (3.28+/-0.16 versus 2.60+/-0.08 cmH2O x L(-1) x s; p=0.04). The effects of nasal decongestant and the ENDS were additive. During voluntary hyperpnoea, inspiratory Rn (at 1.0 L x s(-1)) and the hysteresis of the inspiratory transnasal pressure/flow curve were decreased with the ENDS in most subjects. It is concluded that the external nasal dilator strip influences nasal airflow dynamics by both dilation of the nasal valve and stabilization of the lateral nasal vestibule walls and may be more effective in subjects with a high resting nasal airflow resistance.
Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial
Authors: Joseph I. Clark, Michael B. Atkins, Walter J. Urba, Steven Creech, Robert A. Figlin, Janice P. Dutcher, Larry Flaherty, Jeffrey A. Sosman, Theodore F. Logan, Richard White, Geoffrey R. Weiss, Bruce G. Redman, Christopher P.G. Tretter, David McDermott, John W. Smith, Michael S. Gordon, Kim A. Margolin
Journal: Journal of Clinical Oncology (2003)

This prospective, randomized, controlled phase III trial assessed high-dose bolus interleukin-2 (IL-2) postoperatively in patients with high-risk renal cell carcinoma (RCC).Eligibility requirements were resected locally advanced (LA; T3b-4 or N1-3) or metastatic (M1) RCC, no prior systemic therapy, and excellent organ function. Randomized assignment was to one course of IL-2 (600,000 U/kg every 8 hours on days 1 to 5 and days 15 to 19 [maximum 28 doses]) or observation. The study was designed and powered to show an improvement in predicted 2-year disease-free survival (DFS) from 40% for the observation group to 70% for the treatment group. The accrual goal was 68 patients with LA disease, with 34 patients per treatment arm. Metastasectomy patients were to be analyzed separately because of their unpredictable natural history.Sixty-nine patients were enrolled onto the study (44 LA and 25 M1 patients). Toxic effects of IL-2 were as anticipated; no unexpected serious adverse events or treatment-related deaths occurred. Early closure occurred when an interim analysis determined that the 30% improvement in 2-year DFS could not be achieved despite full accrual. Sixteen of 21 LA patients receiving IL-2 experienced relapse, compared with 15 of 23 patients in the observation arm (P =.73); in the LA group, three deaths occurred in the IL-2 arm, and five deaths occurred in the observation arm (P =.38). Analysis including metastasectomy patients made no difference in DFS or overall survival.One course of high-dose bolus IL-2, though feasible, did not produce the ambitious clinically meaningful benefit anticipated when administered postoperatively to patients with resected high-risk RCC.
Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial
Authors: KJS Anand, R Whit Hall, Nirmala Desai, Barbara Shephard, Lena L Bergqvist, Thomas E Young, Elaine M Boyle, Ricardo Carbajal, Vinod K Bhutani, Mary Beth Moore, Shari S Kronsberg, Bruce A Barton
Journal: The Lancet (2004)
Mechanisms of acid reflux associated with cigarette smoking.
Authors: P J Kahrilas, R R Gupta
Journal: Gut (1990)

Studies were done to evaluate the lower oesophageal sphincter function of chronic smokers compared with non-smokers and to ascertain the acute effects of smoking on the sphincter and the occurrence of acid reflux. All subjects (non-smokers, asymptomatic cigarette smokers, and smokers with oesophagitis) were studied postprandially with a lower oesophageal sphincter sleeve assembly, distal oesophageal pH electrode, and submental electromyographic electrodes. The two groups of cigarette smokers then smoked three cigarettes in succession before being recorded for an additional hour. As a group, the cigarette smokers had significantly lower lower oesophageal sphincter pressure compared with non-smokers but the sphincter was not further compromised by acutely smoking cigarettes. Cigarette smoking did, however, acutely increase the rate at which acid reflux events occurred. The mechanisms of acid reflux during cigarette smoking were mainly dependent upon the coexistence of diminished lower oesophageal sphincter pressure. Fewer than half of reflux events occurred by transient lower oesophageal sphincter relaxations. The majority of acid reflux occurred with coughing or deep inspiration during which abrupt increases in intra-abdominal pressure overpowered a feeble sphincter. We conclude that cigarette smoking probably exacerbates reflux disease by directly provoking acid reflux and perhaps by a long lasting reduction of lower oesophageal sphincter pressure.
Monitoring oxidative damage in patients with liver cirrhosis and different daily alcohol intake.
Authors: P Clot, M Tabone, S Arico, E Albano
Journal: Gut (1994)

This study looked at the possible association between alcohol abuse and free radical mediated oxidative injury by examining the presence of oxidative damage, as monitored by erythrocyte malonildialdehyde and plasma lipid hydroperoxides, in patients with liver cirrhosis and different lifetime daily alcohol intake. All patients with an alcohol intake above 100 g/day (ALC) showed concentrations of malonildialdehyde and lipid hydroperoxide on average four to fivefold higher than cirrhotic patients with alcohol intake below 100 g/day (NAC) or healthy controls. Further subgrouping of ALC patients showed that those with alcohol intake ranging between 100 and 200 g/day (ALC1) had malonildialdehyde and lipid hydroperoxide concentrations significantly lower than those with an intake higher than 200 g/day (ALC2). These differences were not related to the extent of liver injury or to the liver derangement as assessed by Child9s classification. The increase in lipid peroxidation markers in ALC cirrhotic patients was associated with a decrease in, respectively, plasma alpha-tocopherol and erythrocyte glutathione concentrations. Significant differences were also seen between ALC1 and ALC2 groups in plasma alpha-tocopherol, but not in erythrocyte glutathione concentrations. The concentrations of alpha-tocopherol and glutathione in the blood of NAC patients were in contrast not substantially different from those of healthy controls. The close association between oxidative damage and alcohol abuse suggested that free radical intermediates produced during ethanol metabolism might be responsible for causing oxidative damage.
Localisation of mesenchymal tumours by somatostatin receptor imaging
Authors: Suzanne M Jan de Beur, Elizabeth A Streeten, A Cahid Civelek, Edward F McCarthy, Liliana Uribe, Stephen J Marx, Olufunmilayo Onobrakpeya, Lawrence G Raisz, Nelson B Watts, Michael Sharon, Michael A Levine
Journal: The Lancet (2002)
Hypercalcaemia in asymptomatic sarcoidosis unmasked by a vitamin D loading dose
Authors: K. Amrein, G. Schilcher, A. Fahrleitner-Pammer
Journal: European Respiratory Journal (2011)

Human B cells and plasmacytoid dendritic cells recognize CpG motifs within microbial DNA via Toll-like receptor 9. Two functionally distinct types of CpG motif containing oligonucleotides (CpG ODN) have been described, CpG-A and CpG-B. In contrast to CpG-B, CpG-A induces high amounts of type I IFN (IFN-α and IFN-β) in plasmacytoid dendritic cells. In the present study, we examined the effects of CpG-A on human primary monocytes. In PBMC stimulated with CpG-A and GM-CSF, monocytes showed excellent survival, increased in size and granularity, and within 3 days developed a dendritic cell-like phenotype that was characterized by down-regulation of CD14, partial up-regulation of CCR7, and an increased surface expression of costimulatory and Ag-presenting molecules. This effect could be inhibited by a combination of blocking Abs to type I IFN, and no such CpG-A-induced changes were observed in purified monocytes. Although IL-12 production by this dendritic cell-like phenotype required additional stimulation with CD40 ligand, this cell type spontaneously up-regulated IL-15 expression. Consistent with the known effect of IL-15 on effector and memory CD8 T cells, the frequency of CCR7<sup>−</sup>/CD45RA<sup>−</sup> CD8 T cells was selectively increased in allogeneic T cell assays. Furthermore, this dendritic cell type was more potent to support both the generation and the IFN-γ production of autologous influenza matrix peptide-specific memory CD8 T cells as compared with dendritic cells generated in the presence of GM-CSF and IL-4. In conclusion, monocytes exposed to the cytokine milieu provided by CpG-A rapidly develop a dendritic cell-like phenotype that is well equipped to support CD8 T cell responses.
An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome
Authors: Greg C. G. Hugenholtz, Jelle Adelmeijer, Joost C. M. Meijers, Robert J. Porte, R. Todd Stravitz, Ton Lisman
Journal: Hepatology (2013)

Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in prohemostatic and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in the plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13, and disease outcome. We analyzed the plasma of 50 patients taken on the day of admission for ALI/ALF. The plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen-binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared with healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared with control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates, and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications.Highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet-induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ADAMTS13 ratio.
FOXF1 Transcription Factor Is Required for Formation of Embryonic Vasculature by Regulating VEGF Signaling in Endothelial Cells
Authors: Xiaomeng Ren, Vladimir Ustiyan, Arun Pradhan, Yuqi Cai, Jamie A. Havrilak, Craig S. Bolte, John M. Shannon, Tanya V. Kalin, Vladimir V. Kalinichenko
Journal: Circulation Research (2014)

Rationale: Inactivating mutations in the Forkhead Box transcription factor F1 ( FOXF1 ) gene locus are frequently found in patients with alveolar capillary dysplasia with misalignment of pulmonary veins, a lethal congenital disorder, which is characterized by severe abnormalities in the respiratory, cardiovascular, and gastrointestinal systems. In mice, haploinsufficiency of the Foxf1 gene causes alveolar capillary dysplasia and developmental defects in lung, intestinal, and gall bladder morphogenesis. Objective: Although FOXF1 is expressed in multiple mesenchyme-derived cell types, cellular origins and molecular mechanisms of developmental abnormalities in FOXF1-deficient mice and patients with alveolar capillary dysplasia with misalignment of pulmonary veins remain uncharacterized because of lack of mouse models with cell-restricted inactivation of the Foxf1 gene. In the present study, the role of FOXF1 in endothelial cells was examined using a conditional knockout approach. Methods and Results: A novel mouse line harboring Foxf1 -floxed alleles was generated by homologous recombination. Tie2-Cre and Pdgfb-CreER transgenes were used to delete Foxf1 from endothelial cells. FOXF1-deficient embryos exhibited embryonic lethality, growth retardation, polyhydramnios, cardiac ventricular hypoplasia, and vascular abnormalities in the lung, placenta, yolk sac, and retina. Deletion of FOXF1 from endothelial cells reduced endothelial proliferation, increased apoptosis, inhibited vascular endothelial growth factor signaling, and decreased expression of endothelial genes critical for vascular development, including vascular endothelial growth factor receptors Flt1 and Flk1, Pdgfb, Pecam1, CD34, integrin β3, ephrin B2, Tie2, and the noncoding RNA Fendrr . Chromatin immunoprecipitation assay demonstrated that Flt1, Flk1, Pdgfb, Pecam1, and Tie2 genes are direct transcriptional targets of FOXF1. Conclusions: FOXF1 is required for the formation of embryonic vasculature by regulating endothelial genes critical for vascular development and vascular endothelial growth factor signaling.
Blood Pressure and the Survival of Renal Allografts from Living Donors
Authors: Kevin C. Mange, Harold I. Feldman, Marshall M. Joffe, Kosunarty Fa, Roy D. Bloom
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Levels of BP have been associated with increasing rates of renal allograft failure from cadaveric donors, independent of renal function. The effect of BP, a modifiable risk factor, on the failure rates of renal allografts from living donors is unknown and maybe obscured by the rate of decline of renal function from this source of organs. A nonconcurrent cohort study collecting data from 392 recipients of a renal allograft from a living donor during 1990 to 2001 was performed. Multivariable Cox regression models were fit by means of time-varying terms for systolic BP (SBP), diastolic BP (DBP), mean arterial BP (MAP), pulse pressure, and renal function during the first year after transplantation to study the association of BP and the time to allograft failure. Potential nonlinear relationships were considered by fractional polynomial terms. Recipient gender, preemptive transplantation, and time-varying terms for the natural logarithm of creatinine clearance and acute rejection were retained in the multivariable model. Including separate multivariable models with nonlinear terms for SBP (P = 0.02), for DBP (P = 0.02), or for MAP (P = 0.05) during the first year significantly improved the fit of the respective models and confirmed that there is an association of BP and allograft failure independent of renal function. Pulse pressure had neither a linear nor nonlinear association with allograft failure. In this nonconcurrent study, the level of BP during the first year affected the survival of renal allografts from living donors, independent of renal function. Further investigation is required to confirm the level of BP that is optimal to prevent foreshortened duration of survival. E-mail: [email protected]
Genome-Wide Profiling of Papillary Thyroid Cancer Identifies MUC1 as an Independent Prognostic Marker
Authors: Volkert B. Wreesmann, Elizabeth M. Sieczka, Nicholas D. Socci, Michael Hezel, Thomas J. Belbin, Geoffrey Childs, Snehal G. Patel, Kepal N. Patel, Giovanni Tallini, Michael Prystowsky, Ashok R. Shaha, Dennis Kraus, Jatin P. Shah, Pulivarthi H. Rao, Ronald Ghossein, Bhuvanesh Singh
Journal: Cancer Research (2004)

Abstract Clinicopathological variables used at present for prognostication and treatment selection for papillary thyroid carcinomas (PTCs) do not uniformly predict tumor behavior, necessitating identification of novel prognostic markers. Complicating the assessment is the long natural history of PTC and our rudimentary knowledge of its genetic composition. In this study we took advantage of differences in clinical behavior of two distinct variants of PTC, the aggressive tall-cell variant (TCV) and indolent conventional PTC (cPTC), to identify molecular prognosticators of outcome using complementary genome wide analyses. Comparative genome hybridization (CGH) and cDNA microarray (17,840 genes) analyses were used to detect changes in DNA copy number and gene expression in pathological cPTC and TCV. The findings from CGH and cDNA microarray analyses were correlated and validated by real-time PCR and immunohistochemical analyses on a series of 100 cases of cPTC and TCV. Genes identified by this approach were evaluated as prognostic markers in cPTC by immunohistochemistry on tissue arrays. CGH identified significant differences in the presence (76 versus 27%; P = 0.001) and type of DNA copy number aberrations in TCV compared with cPTC. Recurrent gains of 1p34–36, 1q21, 6p21–22, 9q34, 11q13, 17q25, 19, and 22 and losses of 2q21–31, 4, 5p14-q21, 6q11–22, 8q11–22, 9q11–32, and 13q21–31 were unique to TCV. Hierarchical clustering of gene expression profiles revealed significant overlap between TCV and cPTC, but further analysis identified 82 dysregulated genes differentially expressed among the PTC variants. Of these, MUC1 was of particular interest because amplification of 1q by CGH correlated with MUC1 amplification by real-time PCR analysis and protein overexpression by immunohistochemistry in TCV (P = 0.005). Multivariate analysis revealed a significant association between MUC1 overexpression and treatment outcome, independent of histopathological categorization (P = 0.03). Analysis of a validation series containing a matched group of aggressive and indolent cPTCs confirmed the association between MUC1 overexpression and survival (relative risk, 2.3; 95% confidence interval, 1.1–5.5; P = 0.03). Our data suggest that MUC1 dysregulation is associated with aggressive behavior of PTC and may serve as a prognostic marker and potential therapeutic target in this disease.
Evolution of Prokaryotic DNA: Intragenic and Extragenic Divergences Observed with Orthologs from Three Related Species
Authors: A. Fuglsang
Journal: Molecular Biology and Evolution (2004)

This study compared orthologous gene pairs from Escherichia coli K12, E. coli O157:H7 EDL933, Salmonella typhimurium LT2, and Yersinia pestis CO92 using only homologs of equal length, and differing nucleotides were counted and mapped. The data showed very clearly how the rates of divergence change with intragenic and extragenic position. The rate of synonymous mutation is lowest near start codons and near stop codons, and, a little surprisingly, the opposite seemed to be true for nonsynonymous substitutions. Analysis outside genes reveals that nucleotide divergences occur less frequently upstream of start codons than downstream of stop codons, and a remarkable drop in divergences is seen for two of the data sets around N = 9 nucleotides upstream of start codons; that is, the Shine-Dalgarno region changes at a lower rate. The explanation is likely to be the link between expressivity and sequence complementarity to the 3' end of 16S ribosomal rRNA. The latter is highly conserved across many bacterial and archaebacterial species.
Treatment with Vitamin D and Calcium Reduces Bone Loss after Renal Transplantation
Authors: Ruud G. L. de Sévaux, Andries J. Hoitsma, Frans H. M. Corstens, Jack F. M. Wetzels
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. A decrease in bone mineral density (BMD) is a major complication of renal transplantation (RTx), predominantly occurring within the first 6 mo after RTx. The most important causative factor is the use of corticosteroids, but persisting hyperparathyroidism and abnormalities in vitamin D metabolism play a role too. This study examines the effect of treatment with calcium and active vitamin D on the loss of BMD in the first 6 mo after RTx. A total of 111 renal transplant recipients (65 men, 46 women; age, 47 ± 13 yr) were randomized to either treatment with active vitamin D (0.25 μg/d) plus calcium (1000 mg/d) (CaD group), or to no treatment (NoT group). Immunosuppressive therapy consisted of cyclosporine, prednisone, and mycophenolate mofetil. Laboratory parameters and BMD (lumbar spine and hip) were measured at 0, 1 (laboratory only), 3, and 6 mo after RTx. Lumbar BMD was nearly normal at the time of RTx. In both groups, a significant decrease in lumbar BMD was observed during the first 3 mo (CaD, −3.3 ± 4.3%; P < 0.0001; NoT, −4.1 ± 4.8%; P < 0.0001). Between the third day and sixth month, lumbar BMD slightly recovered in the CaD group, but it decreased further in the NoT group (total loss 0 to 6 mo: CaD, −2.6 ± 5.0% [P < 0.001]; NoT, −5.0 ± 4.7% [P < 0.0001]). As a result, the amount of bone loss at 6 mo was significantly lower in the CaD group (P = 0.02). Loss of BMD at the different femoral sites was also significantly reduced in the CaD group. Apart from a trend toward more frequent hypercalcemia in the CaD group, no clinical or biochemical differences existed between the groups. Treatment with a low dose of active vitamin D and calcium partially prevents bone loss at the lumbar spine and proximal femur during the first 6 mo after RTx.