tbuckley/cabot-search huggingface dataset:
Precise ex vivo histological validation of heightened cellularity and diffusion-restricted necrosis in regions of dark apparent diffusion coefficient in 7 cases of high-grade glioma
Authors: Peter S. LaViolette, Nikolai J. Mickevicius, Elizabeth J. Cochran, Scott D. Rand, Jennifer Connelly, Joseph A. Bovi, Mark G. Malkin, Wade M. Mueller, Kathleen M. Schmainda
Journal: Neuro-Oncology (2014)

Recent conflicting reports have found both brain tumor hypercellularity and necrosis in regions of restricted diffusion on MRI-derived apparent diffusion coefficient (ADC) images. This study precisely compares ADC and cell density voxel by voxel using postmortem human whole brain samples. Patients with meningioma were evaluated to determine a normative ADC distribution within benign fluid attenuated inversion recovery (FLAIR) T2/hyperintensity surrounding tumor. This distribution was used to calculate a minimum ADC threshold to define regions of ADC-FLAIR mismatch (AFMM), where restricted diffusion presented in conjunction with T2/FLAIR hyperintensity. Contrast-enhancing voxels were excluded from this analysis. AFMM maps were generated using imaging acquired prior to death in 7 patients with high-grade glioma who eventually donated their brains upon death. Histological samples were taken from numerous regions of abnormal FLAIR and AFMM. Each sample was computationally processed to determine cell density. Custom software was then used to downsample coregistered microscopic histology to the more coarse MRI resolution. A voxel-by-voxel evaluation comparing ADC and cellularity was then performed. An ADC threshold of 0.929 × 10−3 mm2/s was calculated from meningioma-induced edema and was used to define AFMM. Regions of AFMM showed significantly greater cell density in 6 of 7 high-grade glioma cases compared with regions of hyperintense FLAIR alone (P < .0001). Two patients had small regions of diffusion-restricted necrosis that had significantly lower ADC than nearby hypercellularity. Regions of AFMM contain hypercellularity except for regions with extremely restricted diffusion, where necrosis is present.
New Mechanism Contributing to Drug-Induced Arrhythmia
Authors: Kai Liu, Tao Yang, Prakash C. Viswanathan, Dan M. Roden
Journal: Circulation (2005)

Background— The cardiac sodium channel ( SCN5A ) mutation L1825P has been identified in a patient with drug-induced torsade de pointes precipitated by the I Kr blocker cisapride. Although L1825P generates late sodium current typical of SCN5A -linked long-QT syndrome (LQT3) in vitro, the patient reported had a normal QT interval before administration of the drug. To address this discrepancy, we tested the hypothesis that this mutant channel is not processed normally. Methods and Results— CHO cells transfected with L1825P displayed significantly reduced peak I Na (209±36 versus 23±3 pA/pF, P &lt;0.05). Confocal imaging and cell-counting studies using epitope-tagged constructs demonstrated that cell surface expression of the mutant was only ≈9% of wild-type. Incubating transfected cells with cisapride partially rescued misprocessing to 30% of wild-type. As a result, “late” sodium current increased with cisapride from 1.2±0.11 to 5.04±0.77 pA/pF ( P &lt;0.05). Conclusions— L1825P fails to generate QT prolongation because it does not reach the cell surface. Moreover, the data suggest that cisapride caused torsade de pointes not only by blocking I Kr but also by rescuing cell surface expression of the mutant channel, further exaggerating the LQT3 phenotype. This not only represents a new mechanism in the drug-induced long-QT syndrome but also strongly supports the concept that variable cell surface expression contributes to clinical variability in the LQT3 phenotype.
Platelet-activating Factor, a Molecular Sensor for Cellular Damage, Activates Systemic Immune Suppression
Authors: Jeffrey P. Walterscheid, Stephen E. Ullrich, Dat X. Nghiem
Journal: The Journal of Experimental Medicine (2002)

Ultraviolet (UV) radiation plays a critical role in the induction of nonmelanoma skin cancer. UV radiation is also immune suppressive, and the immune suppression induced by UV irradiation has been identified as a major risk factor for skin cancer induction. Previously, we showed that UV exposure activates a cytokine cascade involving prostaglandin (PG)E(2), interleukin (IL)-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV exposure, especially those upstream of PGE2, are not well defined. UV-irradiated keratinocytes secrete the inflammatory phospholipid mediator, platelet-activating factor (PAF). Because PAF upregulates the production of immunomodulatory compounds, including PGE2, we tested the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression. Both UV and PAF activated cyclooxygenase (COX)-2 and IL-10 reporter gene construct transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH). Furthermore, immune suppression was blocked when UV-irradiated mice were injected with PAF receptor antagonists. In addition to the well-known role of PAF as a proinflammatory lipid mediator, we propose that the PAF receptor senses cellular damage through the recognition of PAF and/or PAF-like molecules, such as oxidized phosphatidylcholine, which activates cytokine transcription and induces systemic immune suppression.
Plasma Adiponectin Is an Independent Predictor of Type 2 Diabetes in Asian Indians
Authors: Chamukuttan Snehalatha, Bheekamchand Mukesh, Mary Simon, Vijay Viswanathan, Steven M. Haffner, Ambady Ramachandran
Journal: Diabetes Care (2003)

Adiponectin, secreted by fat cells, has regulatory functions on energy metabolism. Its low levels are predictive of future development of diabetes. Because no studies on the regulatory role of adiponectin in glucose homeostasis in Asian Indians exist, this analysis was performed to determine the prospective association of adiponectin and diabetes in subjects with impaired glucose tolerance (IGT).Baseline values of plasma adiponectin, results of anthropometry, fasting and 2-h plasma glucose levels, HbA(1c), results of lipid profile, and insulin resistance were analyzed in 91 subjects with IGT (53 men and 38 women) in a primary prevention study. Reassessment of glucose tolerance was performed during 1-year review. The predictive nature of adiponectin for development of diabetes was assessed using univariate and multiple logistic regression analyses. A control group comprising healthy, normoglycemic individuals was used for comparison.At follow-up, diabetes had developed in 25 of the 91 study subjects. The mean baseline adiponectin level was lower in the diabetic subjects than in the nondiabetic subjects (11.3 +/- 5.5 vs. 16.7 +/- 7.6 micro g/ml, P = 0.0017). Low adiponectin level was a strong predictor of future development of diabetes, and HbA(1c) also showed a positive predictive association. Women had higher adiponectin levels (16.4 +/- 6.1 micro g/ml) than men (13.9 +/- 7.6 micro g/ml) (P = 0.035).In Asian Indians, low plasma adiponectin level was predictive of future development of diabetes.
Effect of <i>Trans</i>-2,3-Dimethoxycinnamoyl Azide on Enhancing Antitumor Activity of Romidepsin on Human Bladder Cancer
Authors: Jinhai Fan, Jennifer Stanfield, Yi Guo, Jose A. Karam, Eugene Frenkel, Xiankai Sun, Jer-Tsong Hsieh
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Romidepsin (FK228, depsipeptide, FR901228), a unique cyclic depsipeptide with a histone deacetylase inhibitor (HDACI) activity, is a potential cancer therapeutic agent and currently under clinical trials for several types of cancer. For bladder cancer, romidepsin seems to be a potent antitumor agent from our recent study. In this study, we further delineate a new agent that can enhance both HDACI and antitumor activity of romidepsin. Experimental Design: We screened a chemical library to identify candidate(s) that could enhance romidepsin activity. Chemical synthesis and purification were carried out to produce pure compound to examine its biochemical and antitumor effect on bladder cancer cell lines both in vitro and in vivo. Results: Tranilast, N-(acetoacetyl) anthranilic acid, was first identified as a lead compound from screening, and then, one of the analogues, 2,3-dimethoxycinnamoyl azide (DMCA), seems to be more potent than tranilast. Our data indicate that DMCA can potentiate the HDACI activity of romidepsin and other biological activities, such as cell cycle arrest and apoptosis; these effects were accompanied with the expression of various key cell cycle regulators in different bladder cancer cells. Consistently, DMCA can enhance the in vivo antitumor effect of romidepsin without causing any more weight loss than romidepsin alone. Conclusion: DMCA is able to enhance the antitumor effect of romidepsin on bladder cancer from in vitro and in vivo.
Efficacy of betamethasone valerate mousse in comparison with standard therapies on scalp psoriasis: an open, multicentre, randomized, controlled, cross-over study on 241 patients
Authors: L. Andreassi, A. Giannetti, M. Milani
Journal: British Journal of Dermatology (2003)

Background The scalp is a common area for plaque psoriasis. Corticosteroid-based lotions are the most widely used therapy in this clinical setting. A new formulation of betamethasone valerate 0·12% in a thermophobic, low-residue foam vehicle (Bettamousse™, Mipharm, Italy; BVM) is available for the treatment of scalp dermatoses. Objectives In an open, investigator-blinded, multicentre (28 dermatology clinics), randomized, cross-over study, the efficacy, safety and patient acceptability of BVM in scalp psoriasis were evaluated in comparison with standard therapies (ST, i.e. corticosteroids or vitamin D analogues). ST were chosen by each centre according to its usual therapeutic protocols. Methods In total, 241 patients with moderate to severe scalp psoriasis participated in the trial. After a 2-week run-in period, each active treatment (BVM or ST) was applied for 4 weeks, with a wash-out period between the two active treatment phases of at least 4 weeks. Efficacy was evaluated by investigators unaware of treatment sequence analysing a 'target' lesion for erythema, scaling, itching and burning using a five-point grading score. Patient treatment acceptability and assessment of the influence on Psoriasis Disability Index were evaluated using an eight-item modified Finlay–Khan questionnaire at baseline and at the end of each treatment period. Safety was evaluated by recording any adverse event occurring during the study duration. BVM was applied twice daily, and ST were applied once or twice daily, according to the approved scheduled regimens. Results Analyses were by intention-to-treat. Two hundred and ten patients concluded the study. Fifteen patients withdrew from the study during BVM treatment, and 16 during ST (not significantly different). Both treatments were well tolerated. At baseline, the mean ± SD clinical global score (the 'Sum' score = erythema + scaling + itching + burning) was 7·6 ± 2·6. The ST chosen were topical corticosteroids (55% of cases; mainly mometasone and betamethasone dipropionate) or calcipotriol lotion (45% of cases). At the end of active treatments, BVM was significantly superior to ST (P < 0·001) in reducing, as compared with baseline, the mean ± SD Sum score (1·5 ± 1·9 with BVM and 3·1 ± 2·7 with ST). During BVM treatment, 88% (95% confidence interval, CI 82–94%) of patients had a complete or nearly complete resolution of scaling in comparison with 66% (95% CI 58–74%) during ST therapy (P < 0·001). BVM was also considered an easier and more convenient formulation to use in comparison with ST (P < 0·01). Conclusions BVM is more effective than lotion-based ST commonly used in the treatment of scalp psoriasis, and has higher patient acceptability.
Sexual Selection and the Adaptive Evolution of Mammalian Ejaculate Proteins
Authors: S. A. Ramm, P. L. Oliver, C. P. Ponting, P. Stockley, R. D. Emes
Journal: Molecular Biology and Evolution (2007)

An elevated rate of substitution characterizes the molecular evolution of reproductive proteins from a wide range of taxa. Although the selective pressures explaining this rapid evolution are yet to be resolved, recent evidence implicates sexual selection as a potentially important explanatory factor. To investigate this hypothesis, we sought evidence of a high rate of adaptive gene evolution linked to postcopulatory sexual selection in muroid rodents, a model vertebrate group displaying a broad range of mating systems. Specifically, we sequenced 7 genes from diverse rodents that are expressed in the testes, prostate, or seminal vesicles, products of which have the potential to act in sperm competition. We inferred positive Darwinian selection in these genes by estimation of the ratio of nonsynonymous (dN, amino acid changing) to synonymous (dS, amino acid retaining) substitution rates (ω = dN/dS). Next, we tested whether variation in this ratio among lineages could be attributed to interspecific variation in mating systems, as inferred from the variation in these rodents' relative testis sizes (RTS). Four of the 7 genes examined (Prm1, Sva, Acrv1, and Svs2, but not Svp2, Msmb, or Spink3) exhibit unambiguous evidence of positive selection. One of these, the seminal vesicle–derived protein Svs2, also shows some evidence for a concentration of positive selection in those lineages in which sperm competition is common. However, this was not a general trend among all the rodent genes we examined. Using the same methods, we then reanalyzed previously published data on 2 primate genes, SEMG1 and SEMG2. Although SEMG2 also shows evidence of positive selection concentrated in lineages subject to high levels of sperm competition, no such trend was found for SEMG1. Overall, despite a high rate of positive selection being a feature of many ejaculate proteins, these results indicate that the action of sexual selection potentially responsible for elevated evolutionary rates may be difficult to detect on a gene-by-gene basis. Although the extreme diversity of reproductive phenotypes exhibited in nature attests to the power of sexual selection, the extent to which this force predominates in driving the rapid molecular evolution of reproductive genes therefore remains to be determined.
The effects of abnormal sympathetic nervous function upon the ventilatory response to hypoxia
Authors: N. H. Edelman, N. S. Cherniack, S. Lahiri, E. Richards, A. P. Fishman
Journal: Journal of Clinical Investigation (1970)

THE VENTILATORY RESPONSE TO HYPOXIA WAS STUDIED IN TWO GROUPS OF SUBJECTS WITH ABNORMAL SYMPATHETIC NERVOUS CONTROL: (a) human subjects with familial dysautonomia (Riley-Day syndrome), and (b) unanesthetized goats treated with an alpha-adrenergic blocking agent (phenoxybenzamine). The ventilatory response to hypoxia was evaluated in two ways: (a) from the slope of the relationship between ventilation and alveolar P(Co2) ([unk]V(E)-P(ACo2) slope) during the rebreathing of hypoxic and hyperoxic gases, and (b) from the change in ventilation produced when hypoxia was abruptly relieved. The ventilatory and circulatory responses of the unanesthetized, phenoxybenzamine-treated goats were qualitatively similar to those of dysautonomic patients. In contrast to the sustained stimulation of ventilation produced by hypoxia in normal subjects, hypoxia either did not change, or decreased, the [unk]V(E)-P(ACo2) slope of dysautonomic patients and phenoxybenzamine-treated goats; CO(2)-free hypoxia produced a fleeting hyperventilation, which was followed by apnea when hypoxia was abruptly relieved. Unlike normal subjects, the dysautonomic patients and phenoxybenzamine-treated goats became hypotensive while hypoxic. The results indicate that peripheral chemoreceptor reflex responses to hypoxia are preserved in subjects in whom sympathetic nervous responses are impaired. However, the central nervous depression of ventilation by hypoxia is enhanced simultaneously. The inordinate central depression is attributed to the inability of the dysautonomic subjects and goats to maintain systemic blood pressure and, consequently, cerebral blood flow during hypoxia, thereby aggrevating central nervous hypoxia.
Apolipoprotein E Genotype and Response of Carbon Monoxide Poisoning to Hyperbaric Oxygen Treatment
Authors: Ramona O. Hopkins, Lindell K. Weaver, Karen J. Valentine, Chrissa Mower, Susan Churchill, John Carlquist
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Hyperbaric oxygen (HBO2) reduced the incidence of cognitive sequelae 6 weeks after carbon monoxide (CO) poisoning compared with normobaric oxygen (NBO2). The apolipoprotein (APOE) epsilon4 allele predicts unfavorable neurologic outcome after brain injury and stroke.To assess the effects of the epsilon4 allele on 6-week cognitive sequelae after CO poisoning.We tested APOE genotypes in 86 of 152 CO-poisoned patients from our randomized trial. Logistic regression was used to control for risk factors while testing for effects with the epsilon4 allele or interactions with epsilon4 and treatment on 6-week and 6- and 12-month cognitive sequelae.We enrolled 86 patients: 44 received HBO2 and 42 NBO2 therapy. A total of 31 (36%) patients had at least one epsilon4 allele. Six-week cognitive sequelae rates for patients treated with HBO2 and NBO2, respectively: epsilon4 allele absent, 11% (3/27) and 43% (12/28); epsilon4 allele present, 35% (6/17) and 29% (4/14). The epsilon4 allele was not associated with 6-week cognitive sequelae, 27% (15/55) without and 32% (10/31) with the epsilon4 allele (P = 0.323). The interaction between the epsilon4 allele and treatment was significantly associated with 6-week cognitive sequelae (P = 0.048). The interaction between the epsilon4 allele and treatment was not associated with 6- and 12-month cognitive sequelae.HBO2 therapy reduces cognitive sequelae after CO poisoning in the absence of the epsilon4 allele. Because apolipoprotein genotype is unknown at the time of poisoning, we recommend that patients with acute CO poisoning receive HBO2.
Predictors for the development of microalbuminuria and macroalbuminuria in patients with type 1 diabetes: inception cohort study
Authors: Peter Hovind, Lise Tarnow, Peter Rossing, Malene Graae, Inge Torp, Christian Binder, Hans-Henrik Parving
Journal: BMJ (2004)

<h3>Abstract</h3> <b>Objective</b>To evaluate baseline predictors for the development of persistent microalbuminuria and macroalbuminuria prospectively in patients with type 1 diabetes. <b>Design</b>Prospective observational study of an inception cohort. <b>Setting</b>Outpatient diabetic clinic in a tertiary referral centre, Gentofte, Denmark. <b>Participants</b>286 patients (216 adults) newly diagnosed with type 1 diabetes consecutively admitted to the clinic between 1 September 1979 and 31 August 1984. <b>Main outcome measures</b>Persistent microalbuminuria and persistent macroalbuminuria. <b>Results</b>During the median follow up of 18.0 years (range 1.0-21.5 years), total of 4706 patient years of follow up, 79 of 277 (29%) patients developed persistent microalbuminuria. 27 of 79 progressed further to persistent macroalbuminuria. The cumulative incidence of persistent microalbuminuria and persistent macroalbuminuria was 33.6% (95% confidence interval 27.2% to 40.0%) and 14.6% (8.9% to 20.3%), respectively. Significant predictors for the development of persistent microalbuminuria were a 10-fold increase in urinary albumin excretion rate (relative risk 3.78, 1.57 to 9.13), being male (2.41, 1.43 to 4.06), a 10 mm Hg increase in mean arterial blood pressure (1.38, 1.20 to 1.57), a 1% increase in haemoglobin A<sub>1c</sub>(1.18, 1.04 to 1.32), and a 1 cm increase in height (0.96, 0.95 to 0.98). 28 patients with microalbuminuria (35%) regressed to normoalbuminuria either transiently (n = 15) or permanently (n = 13). <b>Conclusions</b>Around one third of patients newly diagnosed with type 1 diabetes develop persistent microalbuminuria within the first 20 years of diabetes. Several potentially modifiable risk factors predict the development of persistent microalbuminaria and persistent macroalbuminuria.
Final Version of the American Joint Committee on Cancer Staging System for Cutaneous Melanoma
Authors: Charles M. Balch, Antonio C. Buzaid, Seng-Jaw Soong, Michael B. Atkins, Natale Cascinelli, Daniel G. Coit, Irvin D. Fleming, Jeffrey E. Gershenwald, Alan Houghton, John M. Kirkwood, Kelly M. McMasters, Martin F. Mihm, Donald L. Morton, Douglas S. Reintgen, Merrick I. Ross, Arthur Sober, John A. Thompson, John F. Thompson
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To revise the staging system for cutaneous melanoma under the auspices of the American Joint Committee on Cancer (AJCC). MATERIALS AND METHODS: The prognostic factors analysis described in the companion publication (this issue), as well as evidence from the published literature, was used to assemble the tumor-node-metastasis criteria and stage grouping for the melanoma staging system. RESULTS: Major changes include (1) melanoma thickness and ulceration but not level of invasion to be used in the T category (except for T1 melanomas); (2) the number of metastatic lymph nodes rather than their gross dimensions and the delineation of clinically occult (ie, microscopic) versus clinically apparent (ie, macroscopic) nodal metastases to be used in the N category; (3) the site of distant metastases and the presence of elevated serum lactic dehydrogenase to be used in the M category; (4) an upstaging of all patients with stage I, II, and III disease when a primary melanoma is ulcerated; (5) a merging of satellite metastases around a primary melanoma and in-transit metastases into a single staging entity that is grouped into stage III disease; and (6) a new convention for defining clinical and pathologic staging so as to take into account the staging information gained from intraoperative lymphatic mapping and sentinel node biopsy. CONCLUSION: This revision will become official with publication of the sixth edition of the AJCC Cancer Staging Manual in the year 2002.