tbuckley/cabot-search huggingface dataset:
The Effect of Mode, Inspiratory Time, and Positive End-Expiratory Pressure on Partial Liquid Ventilation
Authors: YUJI FUJINO, MAX KIRMSE, DEAN HESS, ROBERT M. KACMAREK
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Partial liquid ventilation (PLV) has been shown to be an effective means of improving oxygenation in the injured lung. However, little is known about how approach to ventilation during PLV affects gas exchange and pulmonary mechanics. We hypothesized that gas exchange and pulmonary mechanics would be best with positive end-expiratory pressure (PEEP) set above the lower inflection point (LIP) of the pressure–volume (P–V) curve regardless of mode of ventilation or inspiratory to expiratory time (I:E) ratio and that the efficiency of ventilation would be greatest with volume-controlled ventilation (VCV) compared with pressure-controlled ventilation (PCV) and with long inspiratory time as compared with short inspiratory time. Lung injury was induced in 14 sheep by lavage, 10 of which were studied. Sheep were then assigned to high-PEEP (Group H, n = 5) and low-PEEP (Group L, n = 5) groups. In Group H applied PEEP was set at the LIP and in Group L applied PEEP was set at 5 cm H2O after the lung was filled with perflubron (PFB). We randomly compared VCV and PCV with I:E ratios of 1:2, 1:1, and 2:1. Peak inspiratory pressure and Vt were adjusted to maintain a constant end-inspiratory plateau pressure (Pplat) of about 25 cm H2O in both groups and a constant total PEEP of about 5 cm H2O in Group L and about 12 cm H2O in Group H. There were no differences in oxygenation among modes in Group H. In Group L VCV 2:1 and all of the PCV modes in Group L had a lower PaO2 than VCV 1:1 (p < 0.05). PaCO2 and Vd/Vt were significantly different (p < 0.05) among modes. Vd/Vt was highest during PCV 1:2 with PEEP of 5 cm H2O (p < 0.05). Quasi-static compliance in Group H was higher than in Group L (p < 0.05). We conclude that during low PEEP gas exchange deteriorated in VCV with long inspiratory time and in PCV. Oxygenation was enhanced during VCV 1:1 when compared with VCV at longer I:E ratios or PCV at any I:E ratio. With PEEP set at the LIP, adequate gas exchange and improved lung mechanics could be obtained in all modes assessed.
Cost-Effectiveness of Screening Women With Familial Risk for Breast Cancer With Magnetic Resonance Imaging
Authors: Sepideh Saadatmand, Madeleine M. A. Tilanus-Linthorst, Emiel J. T. Rutgers, Nicoline Hoogerbrugge, Jan C. Oosterwijk, Rob A. E. M. Tollenaar, Maartje Hooning, Claudette E. Loo, Inge-Marie Obdeijn, Eveline A. M. Heijnsdijk, Harry J. de Koning
Journal: JNCI Journal of the National Cancer Institute (2013)

To reduce mortality, women with a family history of breast cancer are often screened with mammography before age 50 years. Additional magnetic resonance imaging (MRI) improves sensitivity and is cost-effective for BRCA1/2 mutation carriers. However, for women with a family history without a proven mutation, cost-effectiveness is unclear. We evaluated data of the largest prospective MRI screening study (MRISC). Between 1999 and 2007, 1597 women (8370 woman-years at risk) aged 25 to 70 years with an estimated cumulative lifetime risk of 15% to 50% for breast cancer were screened with clinical breast examination every 6 months and with annual mammography and MRI. We calculated the cost per detected and treated breast cancer. After incorporating MRISC data into a microsimulation screening analysis model (MISCAN), different schemes were evaluated, and cost per life-year gained (LYG) was estimated in comparison with the Dutch nationwide breast cancer screening program (biennial mammography from age 50 to 75 years). All statistical tests were two-sided. Forty-seven breast cancers (9 ductal carcinoma in situ) were detected. Screening with additional MRI costs $123 672 (€93 639) per detected breast cancer. In increasing age-cohorts, costs per detected and treated breast cancer decreased, but, unexpectedly, the percentage of MRI-only detected cancers increased. Screening under the MRISC-scheme from age 35 to 50 years was estimated to reduce breast cancer mortality by 25% at $134 932 (€102 164) per LYG (3.5% discounting) compared with 17% mortality reduction at $54 665 (€41 390) per LYG with mammography only. Screening with MRI may improve survival for women with familial risk for breast cancer but is expensive, especially in the youngest age categories.
The value of<i>in vivo</i>reflectance confocal microscopy in the diagnosis and monitoring of inflammatory and infectious skin diseases: a systematic review
Authors: L. Hoogedoorn, M. Peppelman, P.C.M. van de Kerkhof, P.E.J. van Erp, M.J.P. Gerritsen
Journal: British Journal of Dermatology (2014)

In vivo examination of the skin by reflectance confocal microscopy (RCM) has been performed for about 20 years, leading to a broad spectrum of imaged infectious and inflammatory skin diseases (ISD) with many described RCM features. We systematically reviewed all available literature concerning ISD evaluated by RCM. Furthermore, we assessed the accuracy of the features and defined recommendations for future studies after indicating the limitations in the current published literature. PubMed, Embase, Cochrane Library and Web of Science databases were searched for literature. All studies on RCM and ISD were reviewed and quality assessment was determined by using the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist. The literature search revealed 77 eligible studies for inclusion. Different RCM features in a broad spectrum of ISD have been described. Further, RCM has been used for monitoring treatment and evolution of ISD, as well as for diagnostic purposes. This systematic review provides an overview of the broad spectrum of ISD imaged by RCM. Although RCM seems to be a promising monitoring and diagnostic tool for ISD, studies with appropriate methodological quality are necessary to create adequate guidelines and protocols for further implementation of RCM in clinical practice.
A comparison of the antiatherogenic effects of probucol and of a structural analogue of probucol in low density lipoprotein receptor-deficient rabbits.
Authors: J Fruebis, D Steinberg, H A Dresel, T E Carew
Journal: Journal of Clinical Investigation (1994)

The efficacies of probucol and a close structural analogue as antioxidants in the prevention of atherogenesis in LDL receptor-deficient rabbits were compared. The antioxidant potency of the analogue in vitro was equal to that of probucol. Its biological availability was much greater: almost comparable concentrations in total plasma were achieved by feeding 1% probucol (wt/wt) and 0.05% analogue (wt/wt). Total plasma concentrations were comparable, but the concentration of probucol within the LDL fraction was about twice that of the analogue. Probucol slowed lesion progression by almost 50%, confirming earlier reports; the analogue, however, showed no detectable inhibitory effect on atherogenesis. Resistance of LDL to oxidation was measured at the end of the study by incubating it with Cu2+ and measuring the rate of diene conjugation. Probucol prolonged diene conjugation lag time from the control value of 130 min to values > 1,000 min. The analogue approximately tripled the lag time (mean, 410 min) and yet failed to slow the atherogenic process. The results suggest that LDL resistance to oxidation must reach some threshold level before there is significant protection against atherogenesis. However, probucol has additional biological effects, possibly not shared by the analogue, that could contribute to its antiatherogenic potential.
Cathepsin K: boon or bale for atherosclerotic plaque stability?
Authors: O. Hofnagel, H. Robenek
Journal: Cardiovascular Research (2008)

Cathepsins, cysteine proteases of lysosomes and endosomes, play major physiological roles in general intracellular protein turnover. When they are directed outside the cell, these enzymes also take part in remodelling the extracellular matrix of bone1 and other tissues. Once in the extracellular matrix, the cathepsins degrade elastin and collagen. Since remodelling of the extracellular matrix of arteries is germane to the stabilization of established atherosclerotic plaques, considerable interest is being focused on cathepsins as possible therapeutic targets for plaque stabilization. Undesirable as they may be, atherosclerotic plaques, once formed, have to be maintained in a stable condition to avoid rupture of their collagenous fibrotic cap and the ensuing occlusion of critical cardiac vessels or arteries of the brain and, hence, coronary artery disease or stroke. Plaques with high collagen levels are more stable than plaques containing lower amounts of this matrix protein. Thus, increasing the collagen content of the plaque supports plaque stability, and modulation of plaque collagen content by manipulating the cathepsins with inhibitors potentially constitutes a means by which the stability of the existing plaques might be controlled therapeutically. Cathepsins B, F, L, K, and S are indeed expressed in plaques, suggesting involvement of these enzymes in … 

*Corresponding author. Tel: +49 2518 355 6206. E-mail address : robenek{at}uni-muenster.de
Recurrence risk modelling of the genetic susceptibility to ankylosing spondylitis
Authors: M A Brown
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVES</h3> It has long been suspected that susceptibility to ankylosing spondylitis (AS) is influenced by genes lying distant to the major histocompatibility complex. This study compares genetic models of AS to assess the most likely mode of inheritance, using recurrence risk ratios in relatives of affected subjects. <h3>METHODS</h3> Recurrence risk ratios in different degrees of relatives were determined using published data from studies specifically designed to address the question. The methods of Risch were used to determine the expected recurrence risk ratios in different degrees of relatives, assuming equal first degree relative recurrence risk between models. Goodness of fit was determined by χ<sup>2</sup> comparison of the expected number of affected subjects with the observed number, given equal numbers of each type of relative studied. <h3>RESULTS</h3> The recurrence risks in different degrees of relatives were: monozygotic (MZ) twins 63% (17/27), first degree relatives 8.2% (441/5390), second degree relatives 1.0% (8/834), and third degree relatives 0.7% (7/997). Parent-child recurrence risk (7.9%, 37/466) was not significantly different from the sibling recurrence risk (8.2%, 404/4924), excluding a significant dominance genetic component to susceptibility. Poor fitting models included single gene, genetic heterogeneity, additive, two locus multiplicative, and one locus and residual polygenes (χ<sup>2</sup> &gt;32 (two degrees of freedom), p&lt;10<sup>−6</sup>for all models). The best fitting model studied was a five locus model with multiplicative interaction between loci (χ<sup>2</sup>=1.4 (two degrees of freedom), p=0.5). Oligogenic multiplicative models were the best fitting over a range of population prevalences and first degree recurrence risk rates. <h3>CONCLUSIONS</h3> This study suggests that of the genetic models tested, the most likely model operating in AS is an oligogenic model with predominantly multiplicative interaction between loci.
Secondary analysis of national and subnational survey data to evaluate the impact of the scale-up of malaria control interventions in Malawi, 2000–10
Authors: Christine Hershey, Doreen Ali, Lia Florey, Adam Bennett, Misheck Luhanga, Jessica Oyugi, Yazoume Ye, Gomezgani Jenda, Carrie Nielsen, Rene Salgado, Don Mathanga, Achuyt Bhattarai
Journal: The Lancet (2013)
Association of a Common Variant of the CASP8 Gene With Reduced Risk of Breast Cancer
Authors: Gordon MacPherson, Catherine S. Healey, M. Dawn Teare, Sabapathy P. Balasubramanian, Malcolm W. R. Reed, Paul D. P. Pharoah, Bruce A. J. Ponder, Mark Meuth, Nitai P. Bhattacharyya, Angela Cox
Journal: JNCI Journal of the National Cancer Institute (2004)

Apoptosis, or programmed cell death, is perturbed in many cancers. We tested the hypothesis that coding polymorphisms of the death receptor 4 (DR4), caspase-8 (CASP8), and caspase-10 (CASP10) genes might act as low-penetrance breast cancer genes. Single-nucleotide polymorphisms (SNPs) of these genes were genotyped in a series of 999 breast cancer case patients and 996 control subjects from Sheffield, U.K., and in a second, independent U.K. population of 2192 case patients and 2262 control subjects from East Anglia. In the Sheffield study, the rare H allele of CASP8, D302H, was associated with a reduced risk of breast cancer in a dose-dependent manner ( Ptrend = .007). Furthermore, the CASP8 D302H association, but not that of the other CASP8 SNPs examined (T21914C, G50121A, and G50358A), was replicated in the East Anglian study. The combined adjusted odds ratios for breast cancer were 0.83 (95% confidence interval [CI] = 0.74 to 0.94) for the DH heterozygote and 0.58 (95% CI = 0.39 to 0.88) for the HH homozygote ( Ptrend = .0002, adjusted for study). The reproducible, dose-dependent association of CASP8 D302H with breast cancer indicates the potential importance of inherited variation in the apoptosis pathway in breast cancer susceptibility.
Phase I Trial of a Monoclonal Antibody Specific for αvβ3 Integrin (MEDI-522) in Patients with Advanced Malignancies, Including an Assessment of Effect on Tumor Perfusion
Authors: Douglas G. McNeel, Jens Eickhoff, Fred T. Lee, David M. King, Dona Alberti, James P. Thomas, Andreas Friedl, Jill Kolesar, Rebecca Marnocha, Jennifer Volkman, Jianliang Zhang, Luz Hammershaimb, James A. Zwiebel, George Wilding
Journal: Clinical Cancer Research (2005)

At present, a variety of agents targeting tumor angiogenesis are under clinical investigation as new therapies for patients with cancer. Overexpression of the alpha(v)beta(3) integrin on tumor vasculature has been associated with an aggressive phenotype of several solid tumor types. Murine models have shown that antibodies targeting the alpha(v)beta(3) integrin can affect tumor vasculature and block tumor formation and metastasis. These findings suggest that antibodies directed at alpha(v)beta(3) could be investigated in the treatment of human malignancies. The current phase I dose escalation study evaluated the safety of MEDI-522, a monoclonal antibody specific for the alpha(v)beta(3) integrin, in patients with advanced malignancies. Twenty-five patients with a variety of metastatic solid tumors were treated with MEDI-522 on a weekly basis with doses ranging from 2 to 10 mg/kg/wk. Adverse events were assessed weekly; pharmacokinetic studies were done; and radiographic staging was done every 8 weeks. In addition, dynamic computed tomography imaging was done at baseline and at 8 weeks in patients with suitable target lesions amenable to analysis, to potentially identify the effect of MEDI-522 on tumor perfusion. Treatment was well tolerated, and a maximum tolerated dose was not identified by traditional dose-limiting toxicities. The major adverse events observed were grade 1 and 2 infusion-related reactions (fever, rigors, flushing, injection site reactions, and tachycardia), low-grade constitutional and gastrointestinal symptoms (fatigue, myalgias, and nausea), and asymptomatic hypophosphatemia. Dynamic computed tomography imaging suggested a possible effect on tumor perfusion with an increase in contrast mean transit time from baseline to the 8-week evaluation with increasing doses of MEDI-522. No complete or partial responses were observed. Three patients with metastatic renal cell cancer experienced prolonged stable disease (34 weeks, >1 and >2 years) on treatment. With this weekly schedule of administration, and in the doses studied, MEDI-522 seems to be without significant toxicity, may have effects on tumor perfusion, and may have clinical activity in renal cell cancer. These findings suggest the MEDI-522 could be further investigated as an antiangiogenic agent for the treatment of cancer.
Prevalence of Hyperhomocysteinemia in Adult Gluten-Sensitive Enteropathy at Diagnosis: Role of B, Folate, and Genetics
Authors: S SAIBENI, A LECCHI, G MEUCCI, M CATTANEO, L TAGLIABUE, E RONDONOTTI, S FORMENTI, R DEFRANCHIS, M VECCHI
Journal: Clinical Gastroenterology and Hepatology (2005)
Congenital erythropoietic porphyria: identification and expression of 10 mutations in the uroporphyrinogen III synthase gene.
Authors: W Xu, C A Warner, R J Desnick
Journal: Journal of Clinical Investigation (1995)

To investigate the molecular basis of the phenotypic heterogeneity in congenital erythropoietic porphyria, the mutations in the uroporphyrinogen III synthase gene from unrelated patients were determined. Six missense (L4F, Y19C, V82F, V99A, A104V, and G225S), a nonsense (Q249X), a frameshift (633insA), and two splicing mutations (IVS2+1 and IVS9 delta A + 4) were identified. When L4F, Y19C, V82F, V99A, A104V, 633insA, G225S, and Q249X were expressed in Escherichia coli, only the V82F, V99A, and A104V alleles expressed residual enzymatic activity. Of note, the V82F mutation, which occurs adjacent to the 5' donor site of intron 4, resulted in approximately 54% aberrantly spliced transcripts with exon 4 deleted. Thus, this novel exonic single-base substitution caused two lesions, a missense mutation and an aberrantly spliced transcript. Of the splicing mutations, the IVS2+1 allele produced a single transcript with exon 2 deleted, whereas the IVS9 delta A+4 allele was alternatively spliced, approximately 26% being normal transcripts and the remainder with exon 9 deleted. The amount of residual activity expressed by each allele provided a basis to correlate genotype with disease severity, thereby permitting genotype/phenotype predictions in this clinically heterogeneous disease.
In praise of cows
Authors: L. Farrell
Journal: BMJ (2010)

I don’t like hunting, because it’s not very sporting; take the guns away from the rednecks, I say. If Sarah Palin strapped on a pair of horns and went head to head with a moose, that would be quite all right with me.

But strap on a pair and take aim at a cow, and the cow will just look on you pityingly. Cows mustn’t be very bright. Obviously they don’t have any religion. They are too primitive to understand …
Isolated Tumor Cells in Regional Lymph Nodes as Relapse Predictors in Stage I and II Colorectal Cancer
Authors: Claudia Mescoli, Laura Albertoni, Salvatore Pucciarelli, Luciano Giacomelli, Valentina M. Russo, Matteo Fassan, Donato Nitti, Massimo Rugge
Journal: Journal of Clinical Oncology (2012)

Purpose Lymph node (LN) involvement is the most important prognostic factor in colorectal cancer (CRC), and pN-positive status identifies patients who require adjuvant chemotherapy. Approximately 15% to 20% of patients without nodal metastases (pN0) develop recurrent disease. In this study, we tested the prognostic significance of isolated tumor cells (ITCs) in LNs of patients with pN0 CRC (stages I and II). Patients and Methods ITCs in LNs regional to CRC were assessed in 312 consecutive patients with pN0 CRC who were followed up clinically and/or endoscopically for at least 6 months after surgery (mean, 67 months; median, 64 months; range, 8 to 102 months). LNs were dissected from gross surgical specimens according to a standardized protocol (with a mean of 17 LNs per patient; range, five to 107 LNs). In all, 5,313 pN0 LNs were collected and assessed by using cytokeratin immunostaining in two serial histology sections from each LN, which amounting to a total of 10,626 specimens. The correlation between ITC status and cancer recurrence was tested by using univariate and multivariate statistics. Results ITCs were documented in 185 of 312 patients (59%). CRC relapsed in 31 of 312 patients (10%), and 25 of 31 recurrences (81%) were documented among ITC-positive patients. CRC recurrence rates among ITC-positive and ITC-negative patients were 14% (25 of 185 patients) and 4.7% (six of 127 patients), respectively. In both univariate and multivariate analyses, ITC status was the only variable significantly associated with cancer relapse (Cox model; hazard ratio, 3.00; 95% CI, 1.23 to 7.32; P = .013). Conclusion In patients with pN0 CRC, cancer relapse was significantly associated with ITCs in regional LNs. ITCs should be considered among the clinicobiologic variables that identify high-risk patients who can benefit from adjuvant chemotherapy.
Bone Marrow Transplantation for Hodgkin's Disease and Lymphoma
Authors: J M Vose, J O Armitage
Journal: Annual Review of Medicine (1993)

The treatment of patients with high-dose chemotherapy and autologous transplantation for recurrent or high-risk lymphomas has greatly expanded over the past few years. With the use of new supportive care measures such as newer antibiotics and hematopoietic growth factors, the morbidity and mortality rate associated with this therapy have diminished. This in turn has allowed successful use of the therapy earlier in the disease course, with resultant increases in disease-free survival rates. Future trials will strive to utilize new therapies and supportive care measures to improve on the results even further.
Bile and biliary lipid secretion in rats with hexachlorobenzene-induced porphyria. Effect of S-adenosyl-l-methionine administration
Authors: Rosario Cuomo, Stefano Rodino, Raffaella Rizzoh, Patrizia Simoni, Enrico Roda, Lavinia Cantoni, Milena Rizzardini, Gaetano De Rosa, Cristina Le Grazie, Carlo Di Padova, Gabriele Budillon
Journal: Journal of Hepatology (1991)
Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children
Authors: Joanna Triscott, Cathy Lee, Colleen Foster, Branavan Manoranjan, Mary Rose Pambid, Rachel Berns, Abbas Fotovati, Chitra Venugopal, Katrina O'Halloran, Aru Narendran, Cynthia Hawkins, Vijay Ramaswamy, Eric Bouffet, Michael D. Taylor, Ash Singhal, Juliette Hukin, Rod Rassekh, Stephen Yip, Paul Northcott, Sheila K. Singh, Christopher Dunham, Sandra E. Dunn
Journal: Cancer Research (2013)

Abstract Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n = 63 patients; validation cohort, n = 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, self-renewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition. Cancer Res; 73(22); 6734–44. ©2013 AACR.