tbuckley/cabot-search huggingface dataset:
Comparative Effects of Cerivastatin and Fenofibrate on the Atherogenic Lipoprotein Phenotype in Proteinuric Renal Disease
Authors: CHRISTOPHER J. DEIGHAN, MURIEL J. CASLAKE, MICHAEL MCCONNELL, J. MICHAEL BOULTON-JONES, CHRISTOPHER J. PACKARD
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Patients with nephrotic-range proteinuria have impaired clearance of triglyceride-rich lipoproteins. This results in the atherogenic lipoprotein phenotype (mild hypertriglyceridemia, low high-density lipoproteins [HDL], and excess small, dense low-density lipoproteins [LDLIII]). Excess remnant lipoproteins (RLP) are linked to hypertriglyceridemia and may contribute to the atherogenicity of nephrotic dyslipidemia. A randomized crossover study compared the effects of a statin (cerivastatin) and a fibrate (fenofibrate) on LDLIII and RLP in 12 patients with nephrotic-range proteinuria. Cerivastatin reduced cholesterol (21%, P &lt; 0.01), triglyceride (14%, P &lt; 0.05), LDL cholesterol (LDL-C; 23%, P &lt; 0.01), total LDL (18%, P &lt; 0.01), and LDLIII concentration (27% P &lt; 0.01). %LDLIII, RLP-C, and RLP triglyceride (RLP-TG) were unchanged. Plasma LDLIII reduction with cerivastatin treatment correlated with LDL-C reduction (r 2 = 34%, P &lt; 0.05). Fenofibrate lowered cholesterol (19%), triglyceride (41%), very low-density lipoprotein cholesterol (52%), LDLIII concentration (49%), RLP-C (35%), and RLP-TG (44%; all P &lt; 0.01). Fenofibrate also reduced %LDLIII from 60 to 33% ( P &lt; 0.01). HDL-C (19%, P &lt; 0.01) increased with fenofibrate treatment; LDL-C and total LDL were unchanged. The reduction in LDLIII concentration and RLP-C with fenofibrate treatment correlated with plasma triglyceride reduction (LDLIII r 2 = 67%, P &lt; 0.001; RLP cholesterol r 2 = 58%, P &lt; 0.005). Serum creatinine increased with fenofibrate treatment (14%, P &lt; 0.01); however, creatinine clearance was unchanged. LDLIII concentration was 187 ± 85 mg/dl after cerivastatin treatment and 133 ± 95 mg/dl after fenofibrate treatment. Cerivastatin and fenofibrate reduce LDLIII concentration in nephrotic-range proteinuria. However, atherogenic concentrations of LDLIII remain prevalent after either treatment. Fenofibrate but not cerivastatin reduces remnant lipoproteins. The two treatments seem to reduce LDLIII by different mechanisms, suggesting a potential role for combination therapy to optimize lowering of LDLIII and RLP.
Seeding of thymic microenvironments defined by distinct thymocyte-stromal cell interactions is developmentally controlled.
Authors: B A Kyewski
Journal: The Journal of Experimental Medicine (1987)

Seeding of distinct intrathymic microenvironments defined by direct thymocyte-stromal cell interactions was correlated with T cell development in situ using radiation and nonradiation chimeras of Thy-1.1/1.2 congenic mice. The results identify associations of thymocytes with I-A- macrophages in the cortex as the earliest discernible cell-cell interactions during thymopoiesis. After a significant delay, this recognition stage is followed by concomitant interactions of T cells with I-A+ epithelial cells in the cortex and bone marrow-derived I-A+ dendritic cells in the medulla. All three types of T cell-stromal cell interactions occur after seeding of the intrathymic precursor cell subset and before development of mature medullary-type T cells. The seeding kinetics imply that recognition of cortical epithelial cells by thymocytes in situ represents a relatively late stage of cortical T cell development, whereas thymocyte-dendritic cell interactions denote a very early stage of T cell development in the medulla. The relative positioning of these cell-cell recognition stages during the course of T cell maturation pertains to a putative role of these microenvironments in selection and tolerization of the T cell repertoire.
Myc, Cell Competition, and Compensatory Proliferation
Authors: Peter Gallant
Journal: Cancer Research (2005)

Abstract The proto-oncogene Myc is already known to affect many cellular processes, but recent experiments in the fruit fly Drosophila melanogaster have revealed yet a new facet of Myc. Neighboring cells were shown to compare their Myc levels and the losers (cells with lower Myc activity) were actively eliminated. This phenomenon is called “cell competition,” and it seems to be part of a developmental size and quality control program. Subversion of this mechanism may contribute to the transforming powers of Myc and possibly other oncogenes.
Approaching the End of Life: Attitudes, Preferences, and Behaviors of African-American and White Patients and Their Family Caregivers
Authors: Etienne Phipps, Gala True, Diana Harris, Umi Chong, William Tester, Stephen I. Chavin, Leonard E. Braitman
Journal: Journal of Clinical Oncology (2003)

To investigate differences in attitudes, preferences, and behaviors regarding end of life in terminally ill patients and their designated family caregivers.68 African-American and white patients with stage III-B or IV lung or stage IV colon cancer and 68 patient-designated family caregivers interviewed between December 1999 and May 2001.White patients were more likely to have a durable power of attorney (34% v 8%, P =.01) and were more likely to have a living will (LW; 41% v 11%, P =.004) than were African-American patients. More African-American than white patients desired the use of life-sustaining measures (cardiopulmonary resusitation [CPR], mechanical ventilation, tube feeding) in their current condition (all P >.12). In a near-death condition, African-American patients were more likely than white patients to desire each of the life-sustaining measures (all P <.004). There was no patient-caregiver agreement beyond chance regarding preferences for initiation of CPR, tube feeding, or mechanical ventilation in the patient's current condition or in the near-death condition. In the near-death condition in patients without LWs, there was disagreement in 46% of patient-caregiver pairs about CPR, in 50% about mechanical ventilation, and in 43% about tube feeding.Although most patients and families endorse the primacy of the patient in decisions at end of life, the majority do not take supporting actions. Disagreements between patients and families about the use of life-sustaining measures in patients without LWs may result in patients' preferences being superseded at end of life.
Cancer risk in 680 000 people exposed to computed tomography scans in childhood or adolescence: data linkage study of 11 million Australians
Authors: J. D. Mathews, A. V. Forsythe, Z. Brady, M. W. Butler, S. K. Goergen, G. B. Byrnes, G. G. Giles, A. B. Wallace, P. R. Anderson, T. A. Guiver, P. McGale, T. M. Cain, J. G. Dowty, A. C. Bickerstaffe, S. C. Darby
Journal: BMJ (2013)

To assess the cancer risk in children and adolescents following exposure to low dose ionising radiation from diagnostic computed tomography (CT) scans.Population based, cohort, data linkage study in Australia. COHORT MEMBERS: 10.9 million people identified from Australian Medicare records, aged 0-19 years on 1 January 1985 or born between 1 January 1985 and 31 December 2005; all exposures to CT scans funded by Medicare during 1985-2005 were identified for this cohort. Cancers diagnosed in cohort members up to 31 December 2007 were obtained through linkage to national cancer records.Cancer incidence rates in individuals exposed to a CT scan more than one year before any cancer diagnosis, compared with cancer incidence rates in unexposed individuals.60,674 cancers were recorded, including 3150 in 680,211 people exposed to a CT scan at least one year before any cancer diagnosis. The mean duration of follow-up after exposure was 9.5 years. Overall cancer incidence was 24% greater for exposed than for unexposed people, after accounting for age, sex, and year of birth (incidence rate ratio (IRR) 1.24 (95% confidence interval 1.20 to 1.29); P<0.001). We saw a dose-response relation, and the IRR increased by 0.16 (0.13 to 0.19) for each additional CT scan. The IRR was greater after exposure at younger ages (P<0.001 for trend). At 1-4, 5-9, 10-14, and 15 or more years since first exposure, IRRs were 1.35 (1.25 to 1.45), 1.25 (1.17 to 1.34), 1.14 (1.06 to 1.22), and 1.24 (1.14 to 1.34), respectively. The IRR increased significantly for many types of solid cancer (digestive organs, melanoma, soft tissue, female genital, urinary tract, brain, and thyroid); leukaemia, myelodysplasia, and some other lymphoid cancers. There was an excess of 608 cancers in people exposed to CT scans (147 brain, 356 other solid, 48 leukaemia or myelodysplasia, and 57 other lymphoid). The absolute excess incidence rate for all cancers combined was 9.38 per 100,000 person years at risk, as of 31 December 2007. The average effective radiation dose per scan was estimated as 4.5 mSv.The increased incidence of cancer after CT scan exposure in this cohort was mostly due to irradiation. Because the cancer excess was still continuing at the end of follow-up, the eventual lifetime risk from CT scans cannot yet be determined. Radiation doses from contemporary CT scans are likely to be lower than those in 1985-2005, but some increase in cancer risk is still likely from current scans. Future CT scans should be limited to situations where there is a definite clinical indication, with every scan optimised to provide a diagnostic CT image at the lowest possible radiation dose.
The Cannabinoid Receptors Are Required for Ultraviolet-Induced Inflammation and Skin Cancer Development
Authors: Duo Zheng, Ann M. Bode, Qing Zhao, Yong-Yeon Cho, Feng Zhu, Wei-Ya Ma, Zigang Dong
Journal: Cancer Research (2008)

Abstract Solar UV irradiation is an important carcinogen that leads to the development of skin cancer, which is the most common human cancer. However, the receptors that mediate UV-induced skin carcinogenesis have not yet been unequivocally identified. Here we showed that UV irradiation directly activates cannabinoid receptors 1 and 2 (CB1/2). Notably, our data indicated that the absence of the CB1/2 receptors in mice results in a dramatic resistance to UVB-induced inflammation and a marked decrease in UVB-induced skin carcinogenesis. A marked attenuation of UVB-induced activation of mitogen-activated protein kinases and nuclear factor- κB was associated with CB1/2 deficiency. These data provide direct evidence indicating that the CB1/2 receptors play a key role in UV-induced inflammation and skin cancer development. [Cancer Res 2008;68(10):3992–7]
Targeted Delivery of Amikacin into Granuloma
Authors: Ana Montes-Worboys, Scott Brown, Doron Regev, Brendan F. Bellew, Kamal A. Mohammed, Ibrahim Faruqi, Parvesh Sharma, Brij Moudgil, Veena B. Antony
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Nontuberculous mycobacterial (NTM) infection is a growing problem in the United States and remains underrecognized in the developing world. The management of NTM infections is further complicated by several factors, including the need to use high systemic doses of toxic agents, the length of therapy, and the development of drug resistance.We have evaluated the use of monocyte-derived dendritic cells (DCs) as a delivery vehicle for a luminescent derivative of amikacin prepared by conjugation to fluorescein isothiocyanate (FITC) (amikacin-FITC) into granulomas formed in the tissues of mice infected with Mycobacterium avium.Amikacin-FITC was prepared and quantitative fluorescence was used to track the intracellular uptake of this modified antibiotic. The antibiotic activity of amikacin-FITC was also determined to be comparable to unmodified amikacin against M. avium. Amikacin-FITC-loaded DCs were first primed with M. avium, and then the cells were injected into the tail vein of infected mice. After 24 hours, the mice were sacrificed and the tissues were analyzed under fluorescence microscope.We found that we were able to deliver amikacin into granulomas in a mouse model of disseminated mycobacterial infection. No increase in levels of monocyte chemoattractant protein-1 and its CCR2 as markers of inflammation were found when DCs were treated with amikacin-FITC.DC-based drug delivery may be an adjunct and useful method of delivering high local concentrations of antibiotics into mycobacterial granulomas.
Case-control study of acute renal failure in patients with cystic fibrosis in the UK
Authors: A Smyth, S Lewis, C Bertenshaw, I Choonara, J McGaw, A Watson
Journal: Thorax (2008)

There has been a recent increase in the number of reported cases of acute renal failure (ARF) in cystic fibrosis (CF). A case-control study was conducted to determine the factors which are associated with an increased risk of ARF.24 cases of confirmed ARF were identified in patients with CF from 20 UK CF centres presenting between 1997 and 2004. Using the UK CF database, sex- and age-matched controls were identified. Risk factors were analysed by conditional logistic regression and Mantel-Haenszel analysis.21 of the 24 patients with ARF had received an aminoglycoside at the time of their episode of ARF or in the preceding week compared with only 3 of 42 controls during the same time period (OR 81.8, 95% CI 4.7 to 1427, p<0.001). In the year before the episode of ARF, significantly more cases than controls had received gentamicin (19/24 cases vs 1/42 controls, p<0.001). The numbers receiving tobramycin were similar (9/24 cases vs 16/42 controls, p = 0.9). A known risk factor for renal impairment (prior renal disease, acute dehydration or long-term treatment with a nephrotoxic drug) was present in 18/24 cases and 7/42 controls (OR 24.0, 95% CI 3.1 to 186.6, p = 0.002).In patients with CF the use of an intravenous aminoglycoside is a risk factor for ARF; gentamicin is more nephrotoxic than tobramycin. Most patients who develop ARF have a risk factor which necessitates withholding aminoglycosides or more closely monitoring their use.
And what about basic odors?
Authors: Veit Roessner, Aribert Rothenberger, Patricia Duchamp-Viret
Journal: Behavioral and Brain Sciences (2008)

Abstract Erickson's article links the concept of four “basic” tastes to color perception as a sensory modality with similar problems of categorization. Such problems are also present for odors and olfaction. Olfaction is the sensory modality with the closest physical relationship to taste, and the sense organs of both permanently interact. We discuss the origins and influences of core ideas of the science of smell to add to the discussion of unresolved categorization problems in taste from another, closely related point of view.
Resection of the embryologically defined uterovaginal (Müllerian) compartment and pelvic control in patients with cervical cancer: a prospective analysis
Authors: Michael Höckel, Lars-Christian Horn, Norma Manthey, Ulf-Dietrich Braumann, Ulrich Wolf, Gero Teichmann, Katrin Frauenschläger, Nadja Dornhöfer, Jens Einenkel
Journal: The Lancet Oncology (2009)
Phase I Study of Samarium-153 Lexidronam With Docetaxel in Castration-Resistant Metastatic Prostate Cancer
Authors: Michael J. Morris, Neeta Pandit-Taskar, Jorge Carrasquillo, Chaitanya R. Divgi, Susan Slovin, William K. Kelly, Dana Rathkopf, Gretchen A. Gignac, David Solit, Lawrence Schwartz, Ryan D. Stephenson, Christina Hong, Anthony Delacruz, Tracy Curley, Glenn Heller, Xiaoyu Jia, Joseph O'Donoghue, Steven Larson, Howard I. Scher
Journal: Journal of Clinical Oncology (2009)

Purpose Early studies of patients with castration-resistant metastatic prostate cancer (CRMPC) suggest that chemotherapy administered with a dose of a bone-seeking radiopharmaceutical is superior to chemotherapy alone. To build on this strategy and fully integrate a repetitively dosed bone-seeking radiopharmaceutical into a contemporary chemotherapy regimen, we conducted a phase I study of docetaxel and samarium-153 ( 153 Sm) lexidronam. Patients and Methods Men with progressive CRMPC were eligible. Cohorts of three to six patients were defined by dose escalations as follows: docetaxel 65, 70, 75, 75, 75 mg/m 2 and 153 Sm ethylenediaminetetramethylenephosphonate (EDTMP) 0.5, 0.5, 0.5, 0.75, 1 mCi/kg. Each cycle lasted a minimum of 6 (cohorts 1 through 5) or 9 (cohort 6) weeks. Docetaxel was administered on days 1 and 22 (and day 43 for cohort 6), and 153 Sm-EDTMP was administered on day −1 to 1 of each cycle. Patients with acceptable hematologic toxicities were eligible to receive additional cycles until progression. Results Twenty-eight men were treated in six cohorts. Maximum-tolerated dose was not reached, because full doses of both agents were well tolerated, even using an every-6-week dosing schedule of 153 Sm-EDTMP. Patients received an average of 5.6 docetaxel doses (range, one to 13 doses) and 2.9 153 Sm-EDTMP doses (range, one to six doses). Fifteen patients demonstrated a more than 50% decline in prostate-specific antigen. Treatment significantly reduced indices of bone deposition and resorption. Conclusion Docetaxel and 153 Sm-EDTMP can be combined safely at full doses over repeated cycles. Responses were seen in the small group of patients with taxane-resistant disease tested. The optimal phase II doses for patients with taxane-naïve disease may differ from those optimal for patients with taxane-resistant disease.
Aquaporin 4 IgG Serostatus and Outcome in Recurrent Longitudinally Extensive Transverse Myelitis
Authors: Yujuan Jiao, James P. Fryer, Vanda A. Lennon, Andrew McKeon, Sarah M. Jenkins, Carin Y. Smith, Amy M. L. Quek, Brian G. Weinshenker, Dean M. Wingerchuk, Elizabeth A. Shuster, Claudia F. Lucchinetti, Sean J. Pittock
Journal: JAMA Neurology (2013)

Studies focused on recurrent longitudinally extensive transverse myelitis (rLETM) are lacking.To determine the aquaporin 4 (AQP4) IgG detection rate using recombinant human APQ4-based assays in sequential serum specimens collected from patients with rLETM categorized as negative by first-generation tissue-based indirect immunofluorescence (IIF) assay and to define the clinical characteristics and motor disability outcomes in AQP4-IgG-positive rLETM.A search of the Mayo Clinic computerized central diagnostic index (October 1, 2005, through November 30, 2011), cross-linked with the Neuroimmunology Laboratory database, identified 48 patients with rLETM, of whom 36 (75%) were positive and 12 (25%) negative for neuromyelitis optica (NMO) IgG (per IIF of serial serum specimens). Stored serum specimens from "seronegative" patients were retested with recombinant human AQP4-based assays, including enzyme-linked immunosorbent, transfected cell-based, and fluorescence-activated cell-sorting assays. Control patients included 140 AQP4-IgG-positive patients with NMO, of whom a subgroup of 20 initially presented with 2 attacks of transverse myelitis (rLETM-onset NMO).AQP4-IgG serostatus, clinical characteristics, and Expanded Disability Status Scale score.Six patients with negative IIF results were reclassified as AQP4-IgG positive, yielding an overall AQP4-IgG seropositivity rate of 89%. Fluorescence-activated cell-sorting, cell-based, and enzyme-linked immunosorbent assays improved the detection rate to 89%, 85%, and 81%, respectively. The female to male ratio was 2:3 for AQP4-IgG-negative rLETM and 5:1 for AQP4-IgG-positive patients. The AQP4-IgG-positive patients with rLETM or rLETM-onset NMO were similar in age at onset, sex ratio, attack severity, relapse rate, and motor disability. From Kaplan-Meier analyses, 36% of AQP4-IgG-positive patients with rLETM are anticipated to need a cane to walk within 5 years after onset. For patients with rLETM-onset NMO, the median time from onset to first optic neuritis attack (54 months) was similar to the median disease duration for AQP4-IgG-positive patients with rLETM (59 months). The median number of attacks was 3 for AQP4-IgG-positive patients with rLETM (range, 2-22), and the first optic neuritis attack for those with rLETM-onset NMO followed a median of 3 myelitis attacks (range, 2-19). Immunosuppressant therapy reduced the relapse rate in both AQP4-IgG-positive and AQP4-IgG-negative patients with rLETM.Recombinant antigen-based assays significantly increase AQP4-IgG detection in patients with rLETM, and AQP4-IgG-negative adults with rLETM are rare. Evolution to NMO can be anticipated in AQP4-IgG-positive patients. Early initiation of immunotherapy may result in a more favorable motor outcome.
In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus
Authors: Bruno B. Bordier, Junko Ohkanda, Ping Liu, So-Young Lee, F.H. Salazar, Patricia L. Marion, Kazuo Ohashi, Leonard Meuse, Mark A. Kay, John L. Casey, Saïd M. Sebti, Andrew D. Hamilton, Jeffrey S. Glenn
Journal: Journal of Clinical Investigation (2003)

Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses.
Effects of Acute Valvular Regurgitation on the Oxygen Consumption of the Canine Heart
Authors: CHARLES W. URSCHEL, JAMES W. COVELL, THOMAS P. GRAHAM, RICHARD L. CLANCY, JOHN ROSS, EDMUND H. SONNENBLICK, EUGENE BRAUNWALD
Journal: Circulation Research (1968)

The effects on myocardial oxygen consumption and mechanics of acute, simulated aortic and mitral regurgitation were studied in open-chest, anesthetized dogs to determine how changes in the mechanical performance of the ventricle alter oxygen consumption. When regurgitation was induced acutely with effective stroke volume (total stroke volume less regurgitant volume) and heart rate held constant, left ventricular end-diastolic volume, total stroke volume, the ejection fraction, left ventricular wall tension, and the extent of shortening of the contractile element and the circumferential fibers all increased. With volumes of regurgitation approaching effective systemic blood flow, oxygen consumption increased only moderately, despite the increases in tension and shortening. When valvular regurgitation was induced while peak ventricular wall tension was held relatively constant, stroke volume doubled and the extent of both contractile element and circumferential fiber shortening increased. Contractile element work in generating tension was unchanged; that which led to fiber shortening increased substantially. Myocardial oxygen consumption did not increase significantly. Thus, marked increases in the efficiency of the contractile elements and myocardial fibers occurred. The low energy cost per unit of work expended in shortening as opposed to that used for tension development therefore allows the excess stroke volume of valvular regurgitation to be maintained at only a small added oxygen cost to the ventricle.
1-Antitrypsin deficiency * 4: Molecular pathophysiology
Authors: D A Lomas
Journal: Thorax (2004)

The molecular basis of α<sub>1</sub>-antitrypsin deficiency is reviewed and is shown to be due to the accumulation of mutant protein as ordered polymers within the endoplasmic reticulum of hepatocytes. The current goals are to determine the cellular response to polymeric α<sub>1</sub>-antitrypsin and to develop therapeutic strategies to block polymerisation in vivo.