Eltrombopag as frontline treatment of aplastic anaemia in routine practice: implications on cost and efficacy.

The thrombopoietin mimetic eltrombopag (EPAG) is efficacious in clinical trials of newly diagnosed moderate (M), severe (S) and very severe (vS) aplastic anaemia (AA). Its use in routine practice and resource-constrained settings is not well described. Twenty-five men and 38 women at a median age of 54 (18-86) years with newly diagnosed AA treated consecutively in a 7-year period with EPAG (N = 6), EPAG/cyclosporine (CsA) (N = 33) and EPAG/CsA/anti-thymocyte globulin (ATG) (N = 24) were analyzed. Because EPAG was not reimbursed, peak doses ranged from 25 to 200 mg/day depending on affordability. EPAG/CsA-treated patients were older (median age: 61 years) with less severe AA (MAA, N = 15; SAA, N = 14; vSAA, N = 4), whereas EPAG/CsA/ATG-treated patients were younger (median age: 44 years) with more severe AA (MAA, N = 2; SAA, N = 12, vSAA, N = 10). The overall/trilineage response rates were 83%/50% for EPAG-treated patients; 79%/42% for EPAG/CsA-treated patients and 75%/63% for EPAG/CsA/ATG-treated patients. Adverse events included grade 1 liver derangement (N = 7) and grade 1 dyspepsia (N = 3). The 5-year overall survivals/failure-free survivals were 62%/80% for the entire cohort; 55%/75% for EPAG/CsA-treated patients and 82%/78% for EPAG/CsA/ATG-treated patients. EPAG showed robust efficacy in AA in routine practice. However, EPAG dosage and combinations remain to be optimized for AA of different severities.

Factors Associated With the Acceptance of an eHealth App for Electronic Health Record Sharing System: Population-Based Study.

BACKGROUND: In the second stage of the Electronic Health Record Sharing System (eHRSS) development, a mobile app (eHealth app) was launched to further enhance collaborative care among the public sector, the private sector, the community, and the caregivers. OBJECTIVE: This study aims to investigate the factors associated with the downloading and utilization of the app, as well as the awareness, perception, and future improvement of the app. METHODS: We collected 2110 surveys; respondents were stratified into 3 groups according to their status of enrollment in the eHRSS. The primary outcome measure was the downloading and acceptance of the eHealth app. We collected the data on social economics factors, variables of the Technology Acceptance Model and Theory of Planned Behavior. Any factors identified as significant in the univariate analysis (P<.20) will be included in a subsequent multivariable regression analysis model. All P values ≤.05 will be considered statistically significant in multiple logistic regression analysis. The structural equation modeling was performed to identify interactions among the variables. RESULTS: The respondents had an overall high satisfaction rate and a positive attitude toward continuing to adopt and recommend the app. However, the satisfaction rate among respondents who have downloaded but not adopted the app was relatively lower, and few of them perceived that the downloading and acceptance processes are difficult. A high proportion of current users expressed a positive attitude about continuing to adopt and recommend the app to friends, colleagues, and family members. The behavioral intention strongly predicted the acceptance of the eHealth app (ß=.89; P<.001). Attitude (ß=.30; P<.001) and perceived norm; ß=.37; P<.001) played important roles in determining behavioral intention, which could predict the downloading and acceptance of the eHealth app (ß=.14; P<.001). CONCLUSIONS: Despite the high satisfaction rate among the respondents, privacy concerns and perceived difficulties in adopting the app were the major challenges of promoting eHealth. Further promotion could be made through doctors and publicity. For future improvement, comprehensive health records and tailored health information should be included.

The Characteristics and Outcomes of Patients Who Make an Emergency Department Visit for Hypertension After Use of a Home or Pharmacy Blood Pressure Device.

STUDY OBJECTIVE: Emergency department (ED) visits for hypertension are rapidly increasing. Hypertension guidelines began recommending use of self-measurement blood pressure (BP) devices in the early 2000s, which could be contributing to the increase. We aim to examine the proportion of ED visits for hypertension that occurred after a BP measurement with a self-measuring device, and the associated outcomes. METHODS: This retrospective observational study included adults who made an ED visit and received a primary diagnosis of hypertension at 1 of 5 community and tertiary hospitals in Ontario, Canada, between April 2010 and March 2011. We categorized ED visits into 4 groups: those made after a home BP reading, a pharmacy reading, as a result of a physician referral, and all others (termed "not documented"). We examined rates of admission to the hospital, ED treatment (administration of antihypertensive medication and prescription provision), and post-ED clinical events (follow-up care, return ED visits, and long-term all-cause mortality) by group. RESULTS: Among 1,508 qualifying patients, median presenting ED BP was 182/97 mm Hg (interquartile range 164 to 200/85 to 109 mm Hg). The percentage of patients who presented to the ED after a reading at home, at a pharmacy, or by physician referral and the remaining patients not documented was 40.9%, 8.3%, 13.3%, and 37.5%, respectively. Overall, 109 patients (7.2%) were admitted to the hospital. The proportion of patients admitted after a home or pharmacy reading, after a physician referral, or who were not documented was 3.1%, 11.9%, and 11.0%, respectively. Two-year mortality rates were 5.4%, 0.0%, 6.5%, and 5.3% for the home, pharmacy, physician referral, and not documented groups, respectively. Among the 92.8% of patients who were discharged from the ED, 11% made another ED visit for hypertension within a year. CONCLUSION: In this study, half of patients with an ED visit that was primarily for hypertension presented after elevated readings on self-measurement devices. Only 3% of these patients were admitted to the hospital.

Comparison of bandwidth and sensitivity of long-period gratings in single-mode and few-mode fibers.

We present a comparative study of the bandwidth and the sensitivity of the resonance wavelength of long-period gratings (LPGs) to external perturbation fabricated in single-mode fibers (SMFs) and few-mode fibers (FMFs), and their dependencies on the group indices and the dispersion properties of the phase-matched modes. Unlike SMFs, a relatively large core size of FMFs invariably leads to nonuniform index modulation across the fiber cross section under UV exposure, enabling the coupling between modes having dissimilar azimuthal symmetry. Simple analytical formulas for the group/effective index difference, dispersion difference, bandwidth, and wavelength sensitivities are derived for the case of SMFs where light is coupled from the fundamental core mode to the symmetrical cladding modes. Our results show that a two-mode fiber operating at a V-number close to 3 is capable of producing LPGs with broader bandwidth and higher sensitivity as compared with their SMF counterparts, except for a few special cases. Our analyses provide insights into the characteristics of LPGs and facilitate their designs for specific applications.

Structural design and characteristics of dual-mode fibers with equalized group velocity.

We investigate how the index profile of a few-mode fiber (FMF) can be designed so that group velocities of the two lowest-order modes can be equalized at a normalized frequency, which is below the cut-off frequency of the LP21 mode. This can be achieved using a single-clad power-law profile with a sufficiently large profile exponent or a double-clad profile consisting of a graded-core surrounded by a sufficiently thick depressed inner cladding without index jump at their interface. The fabrication tolerances, effective index differences, intramodal dispersion differences, and effective mode areas of various single- and double-clad profiles are compared. The results show that, in comparison to single-clad fibers, double-clad fibers are capable of producing higher fabrication tolerances and reduced sensitivity of group delay difference to wavelength by three and two orders of magnitude, respectively. Our analyses provide insights into the design of FMFs, which will facilitate future development of high-capacity mode division long-haul transmission systems.

Identification of Stk6/STK15 as a candidate low-penetrance tumor-susceptibility gene in mouse and human.

Linkage analysis and haplotype mapping in interspecific mouse crosses (Mus musculus x Mus spretus) identified the gene encoding Aurora2 (Stk6 in mouse and STK15 in human) as a candidate skin tumor susceptibility gene. The Stk6 allele inherited from the susceptible M. musculus parent was overexpressed in normal cells and preferentially amplified in tumor cells from F(1) hybrid mice. We identified a common genetic variant in STK15 (resulting in the amino acid substitution F31I) that is preferentially amplified and associated with the degree of aneuploidy in human colon tumors. The Ile31 variant transforms rat1 cells more potently than the more common Phe31 variant. The E2 ubiquitin-conjugating enzyme UBE2N was a preferential binding partner of the 'weak' STK15 Phe31 variant form in yeast two-hybrid screens and in human cells. This interaction results in colocalization of UBE2N with STK15 at the centrosomes during mitosis. These results are consistent with an important role for the Ile31 variant of STK15 in human cancer susceptibility.

Mode coupling dynamics and communication strategies for multi-core fiber systems.

The propagation dynamics of 7-core multi-core fibers (MCFs) with identical and three-types of cores are analytically derived based on the coupled-mode theory. The mode coupling dynamics can be aperiodic with transmission distance for MCF with identical cores. For MCFs with heterogeneous cores, it is found that even though signals from different core groups will not couple with each other, the coupling within their own group is significantly affected by the presence of other core groups. Joint signal processing techniques to mitigate mode coupling induced-cross-talks such as least mean square (LMS) algorithm and maximum likelihood (ML) detection are investigated and corresponding transmission performance are determined for coherent as well as intensity modulated formats. It is shown that aperiodic mode coupling in intensity modulated systems induces cross-talks that are difficult to eliminate through signal processing. The analytical insights may help in optimizing MCF designs and corresponding signal processing techniques for future high capacity MCF transmission systems.

Pattern of thyroid autoimmunity in chinese patients with pernicious anemia.

BACKGROUND: Autoimmune thyroid disease (AITD) often coexists with pernicious anemia (PA) among whites. The study aimed to determine thyroid autoimmunity in Chinese patients with PA. METHODS: From the data of a hospital-based longitudinal study of Chinese PA patients (1994-2007), those with complete information of antibodies to thyroid peroxidase (TPO), thyroglobulin (Tg), and gastric parietal cell; serum thyroid-stimulating hormone and free thyroxine; gastric mucosal histology; and family history of AITD were analyzed. RESULTS: Among 126 Chinese PA patients, 44% had TPO/Tg antibodies and 13.5% AITD. TPO/Tg antibodies occurred in 33% (16 of 49) of male and 52% (40 of 77) of female patients (P = 0.034). Graves disease (8 patients) tended to antedate PA and was associated with no or low titers of TPO/Tg antibodies. Primary hypothyroidism (9 patients) developed during follow-up and was associated with high TPO/Tg antibody titers. The TPO/Tg antibodies did not affect the clinical course of PA but was associated with an enhanced risk of developing AITD and vitiligo. Overall, AITD (before and after PA) occurred in 23% (13 of 56) and 5.7% (4 of 70) of PA patients with and without antibodies (P = 004). During follow-up (mean duration of 75.24 +/- 46.39 months), 10 patients developed AITD-7 new onset of hypothyroidism and 3 progression/relapse of prior AITD. Logistic regression analysis of presenting features of PA revealed 2 independent factors for AITD development during follow-up-presence of thyroid antibodies (odds ratio 20.2, 95% confidence interval 1.8-223) and history of prior AITD (odds ratio 39.8, 95% confidence interval 2.3-679). CONCLUSION: It is recommended to screen thyroid antibodies and monitor thyroid function during follow-up.

Aurora-A regulation of nuclear factor-kappaB signaling by phosphorylation of IkappaBalpha.

The Aurora-A/STK15 gene encodes a kinase that is frequently amplified in cancer. Overexpression of Aurora-A in mammalian cells leads to centrosome amplification, genetic instability, and transformation. In this study, we show that Aurora-A activates nuclear factor-kappaB (NF-kappaB) via IkappaBalpha phosphorylation. Inhibition of endogenous Aurora-A reduces tumor necrosis factor alpha (TNFalpha)-induced IkappaBalpha degradation. We analyzed primary human breast cancers, and 13.6% of samples showed Aurora-A gene amplification, all of which exhibited nuclear localization of NF-kappaB. We propose that this subgroup of patients with breast cancer might benefit from inhibiting Aurora-A. We also show that down-regulation of NF-kappaB via Aurora-A depletion can enhance cisplatin-dependent apoptosis. These data define a new role for Aurora-A in regulating IkappaBalpha that is critical for the activation of NF-kappaB-directed gene expression and may be partially responsible for the oncogenic effect of Aurora-A when the gene is amplified and overexpressed in human tumors.

Extracellular Nanomatrix-Induced Self-Organization of Neural Stem Cells into Miniature Substantia Nigra-Like Structures with Therapeutic Effects on Parkinsonian Rats.

Substantia nigra (SN) is a complex and critical region of the brain wherein Parkinson's disease (PD) arises from the degeneration of dopaminergic neurons. Miniature SN-like structures (mini-SNLSs) constructed from novel combination of nanomaterials and cell technologies exhibit promise as potentially curative cell therapies for PD. In this work, a rapid self-organization of mini-SNLS, with an organizational structure and neuronal identities similar to those of the SN in vivo, is achieved by differentiating neural stem cells in vitro on biocompatible silica nanozigzags (NZs) sculptured by glancing angle deposition, without traditional chemical growth factors. The differentiated neurons exhibit electrophysiological activity in vitro. Diverse physical cues and signaling pathways that are determined by the nanomatrices and lead to the self-organization of the mini-SNLSs are clarified and elucidated. In vivo, transplantation of the neurons from a mini-SNLS results in an early and progressive amelioration of PD in rats. The sculptured medical device reported here enables the rapid and specific self-organization of region-specific and functional brain-like structures without an undesirable prognosis. This development provides promising and significant insights into the screening of potentially curative drugs and cell therapies for PD.

Mechanism of action of the Aurora kinase inhibitor CCT129202 and in vivo quantification of biological activity.

The Aurora family of serine/threonine kinases is important for the regulation of centrosome maturation, chromosome segregation, and cytokinesis during mitosis. Overexpression of Aurora kinases in mammalian cells leads to genetic instability and transformation. Increased levels of Aurora kinases have also been linked to a broad range of human tumors. Here, we describe the properties of CCT129202, a representative of a structurally novel series of imidazopyridine small-molecule inhibitors of Aurora kinase activity. This compound showed high selectivity for the Aurora kinases over a panel of other kinases tested and inhibits proliferation in multiple cultured human tumor cell lines. CCT129202 causes the accumulation of human tumor cells with >or=4N DNA content, leading to apoptosis. CCT120202-treated human tumor cells showed a delay in mitosis, abrogation of nocodazole-induced mitotic arrest, and spindle defects. Growth of HCT116 xenografts in nude mice was inhibited after i.p. administration of CCT129202. We show that p21, the cyclin-dependent kinase inhibitor, is induced by CCT129202. Up-regulation of p21 by CCT129202 in HCT116 cells led to Rb hypophosphorylation and E2F inhibition, contributing to a decrease in thymidine kinase 1 transcription. This has facilitated the use of 3'-deoxy-3'[(18)F]fluorothymidine-positron emission tomography to measure noninvasively the biological activity of the Aurora kinase inhibitor CCT129202 in vivo.

Novel function of the cyclin A binding site of E2F in regulating p53-induced apoptosis in response to DNA damage.

We demonstrate here that the E2F1 induced by DNA damage can bind to and promote the apoptotic function of p53 via the cyclin A binding site of E2F1. This function of E2F1 does not require its DP-1 binding, DNA binding, or transcriptional activity and is independent of mdm2. All the cyclin A binding E2F family members can interact and cooperate with p53 to induce apoptosis. This suggests a novel role for E2F in regulating apoptosis in response to DNA damage. Cyclin A, but not cyclin E, prevents E2F1 from interacting and cooperating with p53 to induce apoptosis. However, in response to DNA damage, cyclin A levels decrease, with a concomitant increase in E2F1-p53 complex formation. These results suggest that the binding of E2F1 to p53 can specifically stimulate the apoptotic function of p53 in response to DNA damage.

Development of the Electric Equivalent Model for the Cytoplasmic Microinjection of Small Adherent Cells.

A novel approach utilizing current feedback for the cytoplasmic microinjection of biological cells is proposed. In order to realize the cytoplasmic microinjection on small adherent cells (diameter < 30 µm and thickness < 10 µm), an electrical model is built and analyzed according to the electrochemical properties of target cells. In this study, we have verified the effectiveness of the current measurement for monitoring the injection process and the study of ion channel activities for verifying the cell viability of the cells after the microinjection.

The relationship between breast cancer molecular subtypes and mast cell populations in tumor microenvironment.

Mast cells (MCs) are a part of the innate immune system. The MC functions toward cancer are partially based on the release of chymase and tryptase. However, the MC effect on breast cancer is controversial. The aim of our study was to investigate the presence of MCs in breast cancer tumors of different molecular subtypes and their relationships with other pathological prognostic factors. Tryptase- and chymase-positive mast cell densities were evaluated by immunohistochemistry in 108 primary invasive breast cancer tissue samples. Positive cells were counted within the tumor bed and at the invasive margin. For all analyzed MC subpopulations, we observed statistically significant differences between individual molecular subtypes of breast cancer. The significantly higher numbers of intratumoral chymase- and tryptase-positive mast cells were observed in luminal A and luminal B tumors compared to triple-negative and HER2+ non-luminal lesions. A denser MC infiltration was associated with lower tumor grade, higher ER and PR expression, lower proliferation rate as well as the lack of HER2 overexpression. The results obtained in our study indicate a possible association of chymase- and tryptase-positive MCs with more favorable cancer immunophenotype and with beneficial prognostic indicators in breast cancer.

Deficits in saccadic eye-movement control in Parkinson's disease.

In contrast to their slowed limb movements, individuals with Parkinson's disease (PD) produce rapid automatic eye movements to sensory stimuli and show an impaired ability to generate voluntary eye movements in cognitive tasks. Eighteen PD patients and 18 matched control volunteers were instructed to look either toward (pro-saccade) or away from (anti-saccade) a peripheral stimulus as soon as it appeared (immediate, gap and overlap conditions) or after a variable delay; or, they made sequential saccades to remembered targets after a variable delay. We found that PD patients made more express saccades (correct saccades in the latency range of 90-140 ms) in the immediate pro-saccade task, more direction errors (automatic pro-saccades) in the immediate anti-saccade task, and were less able to inhibit saccades during the delay period in all delay tasks. PD patients also made more directional and end-point errors in the memory-guided sequential task. Their inability to plan eye movements to remembered target locations suggests that PD patients have a deficit in spatial working memory which, along with their deficit in automatic saccade suppression, is consistent with a disorder of the prefrontal-basal ganglia circuit. Impairment of this pathway may release the automatic saccade system from top-down inhibition and produce deficits in volitional saccade control. Parallel findings across various motor, cognitive and oculomotor tasks suggest a common mechanism underlying a general deficit in automatic response suppression.

Automated tight seal electrophysiology for assessing the potential hERG liability of pharmaceutical compounds.

Unintended inhibition of the cardiac potassium channel human ether-a-go-go-related gene (hERG) is considered the main culprit in drug-induced arrhythmias known as torsades de pointes. Electrophysiology is the most reliable in vitro screening method for identifying potential cardiac hERG liabilities, but only the recent advent of planar electrode-based voltage clamp electrophysiology promises sufficient throughput to support the drug testing needs of most drug discovery programs. We have assessed the reliability of this new format of the voltage clamp technology in measuring the activity of small molecules on the hERG channel. Based on the results herein of a screening against a panel of well-characterized hERG-active and -inactive molecules, we demonstrate that planar electrode electrophysiology, utilizing the Sealchip and PatchXpress technology platform (AVIVA Biosciences Corp., San Diego, CA), is comparable to traditional electrophysiology based on glass micropipettes in its reliability and data content. The new technology will allow significantly higher throughput and more thorough testing of pharmaceutical compounds.

Influence of patient gender on mortality after aortic valve replacement for aortic stenosis.

OBJECTIVE: To assess the influence of gender on mortality after aortic valve replacement for aortic stenosis. METHODS: A retrospective analysis was performed on data prospectively collected from all patients undergoing aortic valve replacement for aortic stenosis. Multivariate regression analysis was performed to evaluate the effect of 22 preoperative and operative variables on early, late, and overall mortality. RESULTS: Aortic valve replacement was performed in 3343 patients with aortic stenosis between 1982 and 2003. The female patients were older, with a smaller body mass index. The women were less likely to have diabetes, chronic obstructive pulmonary disease, previous myocardial infarction, or left ventricular ejection fraction <35% but were more likely to have hypertension or a New York Heart Association III-IV classification. The female patients received a smaller prosthetic valve, with a smaller effective orifice area index (EOAI). The mean follow-up period was 6.18 ± 4.96 years, with a total of 2066.142 years of follow-up. The independent predictors of early mortality for the male patients included age, concomitant surgical revascularization, congestive heart failure, and valve size of ≤21 mm. The independent predictors of late mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, chronic obstructive pulmonary disease, congestive heart failure, and a bioprosthetic valve. The independent predictors of overall mortality for the male patients included age, concomitant surgical revascularization, diabetes, renal failure, heart failure, and valve size of ≤21 mm. For the female patients, the risk factors for early mortality included body mass index <25 kg/m(2); for late mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and diabetes; and for overall mortality included age, concomitant surgical revascularization, New York Heart Association class III-IV, and renal failure. Furthermore, male gender was an independent predictor of late (but not early or overall) mortality. CONCLUSIONS: The independent predictors of mortality after aortic valve replacement for aortic stenosis differed between the male and female patients. Male gender increased the risk of late mortality, and a valve size of ≤21 mm increased the risk of early and overall mortality among the male patients only. These differences need to be taken into consideration preoperatively and require consideration during operative management.