bluuebunny/crossref_metadata_2025 huggingface dataset:
Rhetoric versus reality: The role of research in deconstructing concepts of caring
Authors: Freshwater Dawn , Cahill Jane , Esterhuizen Philip , Muncey Tessa , Smith Helen
Published: June 2017

Our aim was to employ a critical analytic lens to explicate the role of nursing research in supporting the notion of caring realities. To do this, we used case exemplars to illustrate the infusion of such discourses. The first exemplar examines the fundamental concept of caring: using Florence Nightingale's Notes on Nursing, the case study surfaces caring as originally grounded in ritualized practice and subsequently describes its transmutation, via competing discourses, to a more holistic concept. It is argued that in the many and varied attempts to define the dynamic concept of care, caring has now become paradoxically, a more fragmented concept despite attempts to render it more holistic and inclusive. In the second exemplar, one of the authors draws on her personal experience of the gap between theory and practice, so pronounced that it pushed the author to revisit the concept of evidence‐based practice and nursing education. In our third and final exemplar, we refer to the absence of knowledge and practice generated through natural enquiry and curiosity, an absence which has led to production of corporate led rhetoric. Drawing together the central arguments of the three exemplars, we reflect on the influential role of nursing research in enabling the deconstruction of taken for granted assumptions such as caring, evidence‐based practice and empowerment; assumptions which have been generated by discourses riddled with confusion and alienation from the reality of practice and the natural spirit of professional enquiry.
Maternal Humoral Immune Correlates of Peripartum Transmission of Clade C HIV-1 in the Setting of Peripartum Antiretrovirals
Authors: Mutucumarana Charmaine P. , Eudailey Joshua , McGuire Erin P. , Vandergrift Nathan , Tegha Gerald , Chasela Charles , Ellington Sascha , van der Horst Charles , Kourtis Athena P. , Permar Sallie R. , Fouda Genevieve G.
Published: June 2017

Despite the widespread use of antiretrovirals (ARV), more than 150,000 pediatric HIV-1 infections continue to occur annually. Supplemental strategies are necessary to eliminate pediatric HIV infections. We previously reported that maternal HIV envelope-specific anti-V3 IgG and CD4 binding site-directed antibodies, as well as tier 1 virus neutralization, predicted a reduced risk of mother-to-child transmission (MTCT) of HIV-1 in the pre-ARV era U.S.-based Women and Infants Transmission Study (WITS) cohort. As the majority of ongoing pediatric HIV infections occur in sub-Saharan Africa, we sought to determine if the same maternal humoral immune correlates predicted MTCT in a subset of the Malawian Breastfeeding, Antiretrovirals, and Nutrition (BAN) cohort of HIV-infected mothers (
n
= 88, with 45 transmitting and 43 nontransmitting). Women and infants received ARV at delivery; thus, the majority of MTCT was
in utero
(91%). In a multivariable logistic regression model, neither maternal anti-V3 IgG nor clade C tier 1 virus neutralization was associated with MTCT. Unexpectedly, maternal CD4 binding-site antibodies and anti-variable loop 1 and 2 (V1V2) IgG were associated with increased MTCT, independent of maternal viral load. Neither infant envelope (Env)-specific IgG levels nor maternal IgG transplacental transfer efficiency was associated with transmission. Distinct humoral immune correlates of MTCT in the BAN and WITS cohorts could be due to differences between transmission modes, virus clades, or maternal antiretroviral use. The association between specific maternal antibody responses and
in utero
transmission, which is distinct from potentially protective maternal antibodies in the WITS cohort, underlines the importance of investigating additional cohorts with well-defined transmission modes to understand the role of antibodies during HIV-1 MTCT.
Evaluation of Euroimmun Anti-Zika Virus IgM and IgG Enzyme-Linked Immunosorbent Assays for Zika Virus Serologic Testing
Authors: L'Huillier Arnaud G. , Hamid-Allie Anne , Kristjanson Erik , Papageorgiou Louis , Hung Sam , Wong Chun Fai , Stein Derek R. , Olsha Romy , Goneau Lee W. , Dimitrova Kristina , Drebot Mike , Safronetz David , Gubbay Jonathan B.
Published: June 2017

With the emerging Zika virus (ZIKV) epidemic, serologic diagnosis relies on a labor-intensive IgM antibody capture enzyme-linked immunosorbent assay (MAC-ELISA) and confirmation by a plaque reduction neutralization test (PRNT). To streamline serologic testing, several commercial assays have been developed. Our aim was to compare the commercial Euroimmun anti-ZIKV IgM and IgG assays to the reference MAC-ELISA and PRNT currently in use. Serum specimens submitted to Public Health Ontario Laboratory, Canada, were tested for IgM and IgG using the Euroimmun assays and the results were compared with those from MAC-ELISA. The PRNT was performed on positive or equivocal specimens using either MAC-ELISA or Euroimmun assays, MAC-ELISA-inconclusive specimens, and a convenience sample of specimens negative by both assays (cohort 1). Another set of specimens selected on the basis of PRNT results was subsequently tested by the Euroimmun assays (cohort 2). MAC-ELISA was positive, equivocal, negative, and inconclusive in 57/223, 15/223, 147/223, and 4/223 specimens, respectively. Among the 76 specimens that were MAC-ELISA positive, equivocal, or inconclusive, 30 (39.5%) were Euroimmun IgM and/or IgG positive or equivocal. Among the 147 MAC-ELISA-negative specimens, 136 (92.5%) were Euroimmun IgM and IgG negative. The sensitivity of the combined Euroimmun IgM/IgG against the PRNT was 83% (cohort 1) and 92% (cohort 2), whereas the specificity was 81% (cohort 1) and 65% (cohort 2). The combined Euroimmun IgM/IgG showed good specificity (92.5%) but suboptimal sensitivity (39.5%) compared with that of the MAC-ELISA. However, the sensitivity of the combined Euroimmun IgM/IgG against the PRNT was significantly higher (83 to 92%). More studies are needed before commercial assays are implemented for routine ZIKV serologic diagnosis.
T2 Magnetic Resonance Assay-Based Direct Detection of Three Lyme Disease-Related Borrelia Species in Whole-Blood Samples
Authors: Snyder Jessica L. , Giese Heidi , Bandoski-Gralinski Cheryl , Townsend Jessica , Jacobson Beck E. , Shivers Robert , Schotthoefer Anna M. , Fritsche Thomas R. , Green Clayton , Callister Steven M. , Branda John A. , Lowery Thomas J.
Published: June 2017

In early Lyme disease (LD), serologic testing is insensitive and seroreactivity may reflect active or past infection. In this study, we evaluated a novel assay for the direct detection of three species of
Borrelia
spirochetes in whole blood. The T2 magnetic resonance (T2MR) assay platform was used to amplify
Borrelia
DNA released from intact spirochetes and to detect amplicon. Analytical sensitivity was determined from blood spiked with known concentrations of spirochetes, and the assay's limit of detection was found to be in the single-cell-per-milliliter range: 5 cells/ml for
B. afzelii
and 8 cells/ml for
Borrelia burgdorferi
and
Borrelia garinii
. Clinical samples (
n
= 66) from confirmed or suspected early LD patients were also analyzed.
B. burgdorferi
was detected using T2MR in 2/2 (100%) of blood samples from patients with confirmed early LD, based on the presence of erythema migrans and documentation of seroconversion or a positive real-time blood PCR. T2MR detected
B. burgdorferi
in blood samples from 17/54 (31%) of patients with probable LD, based on the presence of erythema migrans without documented seroconversion or of documented seroconversion in patients with a compatible clinical syndrome but without erythema migrans. Out of 21 clinical samples tested by real-time PCR, only 1 was positive and 13 were negative with agreement with T2MR. An additional 7 samples that were negative by real-time PCR were positive with T2MR. Therefore, T2MR enables a low limit of detection (LoD) for
Borrelia
spp. in whole blood samples and is able to detect
B. burgdorferi
in clinical samples.
Vimentin Modulates Infectious Internalization of Human Papillomavirus 16 Pseudovirions
Authors: Schäfer Georgia , Graham Lisa M. , Lang Dirk M. , Blumenthal Melissa J. , Bergant Marušič Martina , Katz Arieh A.
Published: June 2017

Human papillomavirus (HPV) infection is the most common viral infection of the reproductive tract, with virtually all cases of cervical cancer being attributable to infection by oncogenic HPVs. However, the exact mechanism and receptors used by HPV to infect epithelial cells are controversial. The current entry model suggests that HPV initially attaches to heparan sulfate proteoglycans (HSPGs) at the cell surface, followed by conformational changes, cleavage by furin convertase, and subsequent transfer of the virus to an as-yet-unidentified high-affinity receptor. In line with this model, we established an
in vitro
infection system using the HSPG-deficient cell line pgsD677 together with HPV16 pseudovirions (HPV16-PsVs). While pgsD677 cells were nonpermissive for untreated HPV16-PsVs, furin cleavage of the particles led to a substantial increase in infection. Biochemical pulldown assays followed by mass spectrometry analysis showed that furin-precleaved HPV16-PsVs specifically interacted with surface-expressed vimentin on pgsD677 cells. We further demonstrated that both furin-precleaved and uncleaved HPV16-PsVs colocalized with surface-expressed vimentin on pgsD677, HeLa, HaCaT, and NIKS cells, while binding of incoming viral particles to soluble vimentin protein before infection led to a substantial decrease in viral uptake. Interestingly, decreasing cell surface vimentin by small interfering RNA (siRNA) knockdown in HeLa and NIKS cells significantly increased HPV16-PsV infectious internalization, while overexpression of vimentin had the opposite effect. The identification of vimentin as an HPV restriction factor enhances our understanding of the initial steps of HPV-host interaction and may lay the basis for the design of novel antiviral drugs preventing HPV internalization into epithelial cells.

IMPORTANCE
Despite HPV being a highly prevalent sexually transmitted virus causing significant disease burden worldwide, particularly cancer of the cervix, cell surface events preceding oncogenic HPV internalization are poorly understood. We herein describe the identification of surface-expressed vimentin as a novel molecule not previously implicated in the infectious internalization of HPV16. Contrary to our expectations, vimentin was found to act not as a receptor but rather as a restriction factor dampening the initial steps of HPV16 infection. These results importantly contribute to our current understanding of the molecular events during the infectious internalization of HPV16 and open a new direction in the development of alternative drugs to prevent HPV infection.
Ruxolitinib and Polycation Combination Treatment Overcomes Multiple Mechanisms of Resistance of Pancreatic Cancer Cells to Oncolytic Vesicular Stomatitis Virus
Authors: Felt Sébastien A. , Droby Gaith N. , Grdzelishvili Valery Z.
Published: June 2017

Vesicular stomatitis virus (VSV) is a promising oncolytic virus (OV). Although VSV is effective against a majority of pancreatic ductal adenocarcinoma cell (PDAC) cell lines, some PDAC cell lines are highly resistant to VSV, and the mechanisms of resistance are still unclear. JAK1/2 inhibitors (such as ruxolitinib and JAK inhibitor I) strongly stimulate VSV replication and oncolysis in all resistant cell lines but only partially improve the susceptibility of resistant PDACs to VSV. VSV tumor tropism is generally dependent on the permissiveness of malignant cells to viral replication rather than on receptor specificity, with several ubiquitously expressed cell surface molecules playing a role in VSV attachment to host cells. However, as VSV attachment to PDAC cells has never been tested before, here we examined if it was possibly inhibited in resistant PDAC cells. Our data show a dramatically weaker attachment of VSV to HPAF-II cells, the most resistant human PDAC cell line. Although sequence analysis of low-density lipoprotein (LDL) receptor (LDLR) mRNA did not reveal any amino acid substitutions in this cell line, HPAF-II cells displayed the lowest level of LDLR expression and dramatically lower LDL uptake. Treatment of cells with various statins strongly increased LDLR expression levels but did not improve VSV attachment or LDL uptake in HPAF-II cells. However, LDLR-independent attachment of VSV to HPAF-II cells was dramatically improved by treating cells with Polybrene or DEAE-dextran. Moreover, combining VSV with ruxolitinib and Polybrene or DEAE-dextran successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication.

IMPORTANCE
Oncolytic virus (OV) therapy is an anticancer approach that uses viruses that selectively infect and kill cancer cells. This study focuses on oncolytic vesicular stomatitis virus (VSV) against pancreatic ductal adenocarcinoma (PDAC) cells. Although VSV is effective against most PDAC cells, some are highly resistant to VSV, and the mechanisms are still unclear. Here we examined if VSV attachment to cells was inhibited in resistant PDAC cells. Our data show very inefficient attachment of VSV to the most resistant human PDAC cell line, HPAF-II. However, VSV attachment to HPAF-II cells was dramatically improved by treating cells with polycations. Moreover, combining VSV with polycations and ruxolitinib (which inhibits antiviral signaling) successfully broke the resistance of HPAF-II cells to VSV by simultaneously improving VSV attachment and replication. We envision that this novel triple-combination approach could be used in the future to treat PDAC tumors that are highly resistant to OV therapy.
Randomised healthcare policy evaluation of organised primary human papillomavirus screening of women aged 56–60
Authors: Lamin Helena , Eklund Carina , Elfström Klara Miriam , Carlsten-Thor Agneta , Hortlund Maria , Elfgren Kristina , Törnberg Sven , Dillner Joakim
Published: June 2017

Objective

The aim of this research is to implement and reliably evaluate primary human papillomavirus (HPV) screening in an established and routinely running organised, large-scale population-based screening programme.

Participants

Resident women in the Stockholm/Gotland region of Sweden, aged 56–60 years were randomised to either (1) screening with cervical cytology, with HPV test in triage of low-grade cytological abnormalities (old policy) or (2) screening with HPV testing, with cytology in triage of HPV positives (new policy).

Outcome

The primary evaluation was the detection rate of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Results

During January 2012–May 2014, the organised screening programme sent 42 752 blinded invitations with a prebooked appointment time to the women in the target age group. 7325 women attended in the HPV policy arm and 7438 women attended in the cytology arm. In the new policy, the population HPV prevalence was 5.5%, using an accredited HPV test (Cobas 4800). HPV16 prevalence was 1.0% (73/7325) and HPV18 prevalence was 0.3% (22/7325). In the HPV policy arm, 78/405 (19%) HPV-positive women were also cytology positive. There were 19 cases of CIN2+ in histopathology, all among women who were both HPV positive and cytology positive. The positive predictive value for CIN2+ in this group was 33.3% (19/57). In the cytology policy, 153 women were cytology positive and there were 18 cases of CIN2+ in histopathology. Both the total number of cervical biopsies and the number of cervical biopsies with benign histopathology were much lower in thepositive predictive value policy (49 benign, 87 total vs 105 benign, 132 total).

Conclusion

Primary HPV screening had a similar detection rate for CIN2+ as cytology-based screening, already before follow-up of HPV-positive, cytology-negative women with new HPV test and referral of women with persistence.

Trial registration number

NCT01511328.
The boreal–temperate forest ecotone response to climate change
Authors: Evans Piers , Brown Carissa D.
Published: June 2017

A warming global climate will elicit changes in the distribution of plant species around the planet, and this will become most apparent where biomes converge. Climate exerts the strongest control over the geographic location of ecotones at the continental scale and many, including the boreal forest – temperate forest ecotone (BTE), are expected to shift to higher latitudes under climate change. Fine-scale drivers that define biome boundaries at the sub-continental scale are less well understood for many ecotones. We assembled studies addressing whether a modern distributional shift is occurring at the BTE and what biotic and abiotic factors are driving such a shift. Current research suggests a northward shift is occurring; yet, scant data are available to identify the processes involved. Abiotic and biotic factors are repeatedly identified as key drivers of change, though not all claims are evidence-supported and the interacting effects of these non-climatic factors are poorly understood.
POLICY CHOICES FOR AIR POLLUTION ABATEMENT IN BEIJING: STATUS QUO OR CHANGE
Authors: ZHOU SHAOJIE , YU XIAOHUA , KOEMLE DIETER
Published: June 2017

In order to control air pollution in Beijing, China has introduced a number of policy measures. However, the policy costs have never been well evaluated from the perspective of the residents. We conducted a survey of 633 Beijing residents with a choice experimental setting, and evaluate the current air pollution control policies. The main findings include: (1) Restriction of private vehicle driving does increase utility of residents; (2) Replacing coal-dominated heating system with natural gas has a better effect on air pollution control than replacement with electricity; (3) Beijing residents demand more radical policies to control air pollution and, according to our estimation, are willing to pay 5.1% of their income for more such policy measures; (4) The capital city function of Beijing yields many economic and political advantages for the residents, and the economic benefit is equal to 8.3% of their income.
HOUSEHOLD INCOME DYNAMICS IN A LOWER-INCOME SMALL OPEN ECONOMY: A COMPARISON OF BANKING AND CROWDFUNDING REGIMES
Authors: McNELIS PAUL D. , YOSHINO NAOYUKI
Published: June 2017

This paper examines asset price and household income/consumption dynamics in a small open economy subject to terms of trade shocks, under two financial regimes. The first is a pure banking regime, in which firms borrow from banks for financing costs of labor, investment and intermediate goods for both the relatively riskless natural-resource traded sector and the non-traded sector. The second regime is more financially-inclusive banking/crowdfunding (BCF) regime, in which the households directly receive returns to capital from pooled lending to home-goods firms. Simulation results show that the banking regime better insulates the economy from negative shocks but limits the upside gain from positive shocks which would take place in the banking-crowdfunding regime.
High speed modular systolic array-based DTCWT with parallel processing architecture for 2D image transformation on FPGA
Authors: Divakara S. S. , Patilkulkarni Sudarshan , Raj Cyril Prasanna
Published: June 2017

In this paper, systolic array-based novel architecture for dual-tree complex wavelet transform (DTCWT) computation is designed and implemented on FPGA. The wavelet filter coefficients of DTCWT are quantized and rounded to nearest integer and the loss in rounding and quantization is limited to 0.5[Formula: see text]dB as compared with software implementation. The parallel architecture designed computes row elements simultaneously and pipelined architecture is designed to compute column elements. The proposed architecture is modeled using Verilog and implemented on Xilinx Virtex II FPGA. For 2D implementation, the design operates at a maximum frequency of 156[Formula: see text]MHz and consumes power less than 3[Formula: see text]W. This is the first design with systolic array architecture on FPGA for DTCWT computation operating at frequencies greater than 100[Formula: see text]MHz.
Prevention of contrast-induced nephropathy by limb ischemic preconditioning: underlying mechanisms and clinical effects
Authors: Dugbartey George J. , Redington Andrew N.
Published: June 2017

Contrast-induced nephropathy (CIN) is an important complication following diagnostic radiographic imaging and interventional therapy. It results from administration of intravascular iodinated contrast media (CM) and is currently the third most common cause of hospital-acquired acute kidney injury. CIN is associated with increased morbidity, prolonged hospitalization, and higher mortality. Although the importance of CIN is widely appreciated, and its occurrence can be mitigated by the use of pre- and posthydration protocols and low osmolar instead of high osmolar iodine-containing CM, specific prophylactic therapy is lacking. Remote ischemic preconditioning (RIPC), induced through short cycles of ischemia-reperfusion applied to the limb, is an intriguing new strategy that has been shown to reduce myocardial infarction size in patients undergoing emergency percutaneous coronary intervention. Furthermore, multiple proof-of-principle clinical studies have suggested benefit in several other ischemia-reperfusion syndromes, including stroke. Perhaps somewhat surprisingly, RIPC also is emerging as a promising strategy for CIN prevention. In this review, we discuss current clinical and experimental developments regarding the biology of CIN, concentrating on the pathophysiology of CIN, and cellular and molecular mechanisms by which limb ischemic preconditioning may confer renal protection in clinical and experimental models of CIN.
Beta-1 vs. beta-2 adrenergic control of coronary blood flow during isometric handgrip exercise in humans
Authors: Maman Stephan R. , Vargas Alvaro F. , Ahmad Tariq Ali , Miller Amanda J. , Gao Zhaohui , Leuenberger Urs A. , Proctor David N. , Muller Matthew D.
Published: June 2017

During exercise, β-adrenergic receptors are activated throughout the body. In healthy humans, the net effect of β-adrenergic stimulation is an increase in coronary blood flow. However, the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia is not clear. In this study, we simultaneously measured noninvasive indexes of myocardial oxygen supply (i.e., blood velocity in the left anterior descending coronary artery; Doppler echocardiography) and demand [i.e., rate pressure product (RPP) = heart rate × systolic blood pressure) and tested the hypothesis that β1 blockade with esmolol improves coronary exercise hyperemia compared with nonselective β-blockade with propranolol. Eight healthy young men received intravenous infusions of esmolol, propranolol, and saline on three separate days in a single-blind, randomized, crossover design. During each infusion, subjects performed isometric handgrip exercise until fatigue. Blood pressure, heart rate, and coronary blood velocity (CBV) were measured continuously, and RPP was calculated. Changes in parameters from baseline were compared with paired t-tests. Esmolol (Δ = 3296 ± 1204) and propranolol (Δ = 2997 ± 699) caused similar reductions in peak RPP compared with saline (Δ = 5384 ± 1865). In support of our hypothesis, ΔCBV with esmolol was significantly greater than with propranolol (7.3 ± 2.4 vs. 4.5 ± 1.6 cm/s; P = 0.002). This effect was also evident when normalizing ΔCBV to ΔRPP. In summary, not only does selective β1 blockade reduce myocardial oxygen demand during exercise, but it also unveils β2-receptor-mediated coronary exercise hyperemia.

NEW & NOTEWORTHY In this study, we evaluated the role of vascular β1 vs. β2 receptors in coronary exercise hyperemia in a single-blind, randomized, crossover study in healthy men. In response to isometric handgrip exercise, blood flow velocity in the left anterior descending coronary artery was significantly greater with esmolol compared with propranolol. These findings increase our understanding of the individual and combined roles of coronary β1 and β2 adrenergic receptors in humans.
UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level
Authors: Flück Daniela , Morris Laura E. , Niroula Shailesh , Tallon Christine M. , Sherpa Kami T. , Stembridge Mike , Ainslie Philip N. , McManus Ali M.
Published: June 2017

Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia.

NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment.
Separable systems for recovery of finger strength and control after stroke
Authors: Xu Jing , Ejaz Naveed , Hertler Benjamin , Branscheidt Meret , Widmer Mario , Faria Andreia V. , Harran Michelle D. , Cortes Juan C. , Kim Nathan , Celnik Pablo A. , Kitago Tomoko , Luft Andreas R. , Krakauer John W. , Diedrichsen Jörn
Published: June 2017

We tracked recovery of the hand over a 1-yr period after stroke in a large cohort of patients, using a novel paradigm that enabled independent measurement of finger strength and control. Most recovery of strength and control occurs in the first 3 mo after stroke. We found that two separable systems are responsible for motor recovery of hand: one contributes strength and some dexterity, whereas a second contributes additional dexterity.
UPLC-Tandem Mass Spectrometry Method for Simultaneous Determination of Fluoxetine, Risperidone, and Its Active Metabolite 9-Hydroxyrisperidone in Plasma: Application to Pharmacokinetics Study in Rats
Authors: Ezzeldin Essam , Abo-Talib Nisreen F. , Tammam Marwa H.
Published: June 2017

Risperidone (RIS) is used as an antipsychotic drug alone or with other drugs, like fluoxetine (FLX). A simple method was developed and validated for the determination of both RIS and its metabolite 9-hydroxyrisperidone (9-OH-RIS), FLX, and olanzapine (OLA) as an internal standard in rat’s plasma using UPLC-MS/MS. FLX, RIS, 9-OH-RIS, and OLA were purified using acetonitrile as a protein precipitating agent. Separation was performed on an ACQUITY™ “UPLC BEH™” C18 column (50 mm × 2.1 mm i.d., 1.7 μm; Waters Corp., USA). The ranges of the calibration curves were 1.0–1000.0 ng/mL for FLX and 0.2–1000.0 ng/mL for RIS and 9-OH-RIS. Linearity, recovery, precision, and stability were within the acceptable range. This method is rapid, fast, and precise for the determination of RIS and FLX in plasma and is applicable in pharmacokinetic studies.
Ping‐Chong‐Jiang‐Ni Formula Induces Apoptosis and Inhibits Proliferation of Human Ectopic Endometrial Stromal Cells in Endometriosis via the Activation of JNK Signaling Pathway
Authors: Liang Rui-Ning , Li Pei-Shuang , Zou Yang , Liu Yu-Ling , Jiang Zhen , Liu Zhen , Fan Pei , Xu Ling , Peng Jia-Hua , Sun Xue-Yan
Published: June 2017

Endometriosis is a common gynecological condition in childbearing age women and its therapy in modern medicine achieves usually temporary cure. Ping‐Chong‐Jiang‐Ni formula (PCJNF), a Chinese herbal medicine (CHM), was shown to be clinically effective on endometriosis. Meanwhile, c‐Jun N‐terminal kinase (JNK) signaling pathway was involved in the therapeutic process of CHM on endometriosis. Here, we explored the effect of PCJNF on the ectopic endometrial stromal cells (EESCs) from endometriosis and test whether JNK signaling was involved. After being treated with PCJNF‐containing serum obtained from Sprague Dawley rat, cell proliferation, migration, invasion, and apoptosis were evaluated in EESCs, and the total and phosphorylated JNK, ERK, and p38 proteins were detected. Our results showed that PCJNF could suppress cell proliferation, migration, and invasion and induce apoptosis in EESCs. The suppressed proliferation and increased apoptosis were dependent on JNK activation. Additionally, PCJNF caused cell cycle arrest at G2/M phase and this effect was mediated by JNK signaling, while the decreased cell migration and invasion treated by PCJNF were independent of JNK signaling. In summary, our results provided the first evidence that PCJNF could suppress cell proliferation, migration, and invasion, while increasing apoptosis in EESCs, and the suppressed proliferation and enhanced apoptosis were mediated by JNK signaling.
Determination of Epimedin B in Rat Plasma and Tissue by LC-MS/MS: Application in Pharmacokinetic and Tissue Distribution Studies
Authors: Feng Qianru , Xu Shunjun , Yu Jiejing , Sun Shuai , Yang Liu
Published: June 2017

A simple, sensitive, and specific liquid chromatography tandem mass-spectrometric method was developed and validated for the determination of epimedin B in rat plasma and tissue samples. After being processed with a protein precipitation method, these samples were separated on an Agilent Eclipse XDB-C18 column with an isocratic mobile phase consisting of acetonitrile and 0.1% formic acid aqueous solution (32 : 68, v/v). The calibration curve of epimedin B was linear over the concentration range from 1 to 500 ng/mL in plasma and tissue homogenate. The method was then applied to pharmacokinetic and tissue distribution studies after a single oral administration of Herba Epimedii extract to SD rats. Results showed that epimedin B reached the plasma peak concentration at 0.4 h and the terminal elimination half-life was 1.6 h in rat plasma, and the plasma area under the curve from time zero to infinity (AUC0–∞) was 14.35 μg/L·h. The concentration distribution of epimedin B in rat tissue was in the following order: liver > ovary > womb > lung > kidney > spleen > heart > brain, indicating that the compound could be widely distributed in rat, and the reproductive system may be the principal target of epimedin B for female rat.
A Five-Year Review of Perforated Peptic Ulcer Disease in Irrua, Nigeria
Authors: Dongo A. E. , Uhunmwagho O. , Kesieme E. B. , Eluehike S. U. , Alufohai E. F.
Published: June 2017

Background. Peptic ulcer perforation is a common cause of emergency admission and surgery. This is the first study that documents the presentation and outcome of management in Irrua, Nigeria. Patients and Method. This is a prospective study of all patients operated on for perforated peptic ulcer between April 1, 2010, and March 31, 2015. A structured questionnaire containing patients’ demographics, operation findings, and outcome was filled upon discharge or death. Results. There were 104 patients. 81 males and 23 females (M : F = 3.5 : 1). The age range was between 17 years and 95 years. The mean age was 48.99 years ± SD 16.1 years. The ratio of gastric to duodenal perforation was 1.88 : 1. Perforation was the first sign of peptic ulcer disease in 62 (59.6%). Pneumoperitoneum was detectable with plain radiographs in 95 (91%) patients. 72 (69.2%) had Graham’s Omentopexy. Death rate was 17.3%. Conclusion. We note that gastric perforation is a far commoner disease in our environment. Perforation is often the first sign of peptic ulcer disease. We identify fasting amongst Christians as a risk factor for perforation.
A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant
Authors: Ronald John A. , Kim Byung-Su , Gowrishankar Gayatri , Namavari Mohammad , Alam Israt S. , D'Souza Aloma , Nishikii Hidekazu , Chuang Hui-Yen , Ilovich Ohad , Lin Chih-Feng , Reeves Robert , Shuhendler Adam , Hoehne Aileen , Chan Carmel T. , Baker Jeanette , Yaghoubi Shahriar S. , VanBrocklin Henry F. , Hawkins Randall , Franc Benjamin L. , Jivan Salma , Slater James B. , Verdin Emily F. , Gao Kenneth T. , Benjamin Jonathan , Negrin Robert , Gambhir Sanjiv Sam
Published: June 2017

A major barrier to successful use of allogeneic hematopoietic cell transplantation is acute graft-versus-host disease (aGVHD), a devastating condition that arises when donor T cells attack host tissues. With current technologies, aGVHD diagnosis is typically made after end-organ injury and often requires invasive tests and tissue biopsies. This affects patient prognosis as treatments are dramatically less effective at late disease stages. Here, we show that a novel PET radiotracer, 2′-deoxy-2′-[18F]fluoro-9-β-D-arabinofuranosylguanine ([18F]F-AraG), targeted toward two salvage kinase pathways preferentially accumulates in activated primary T cells. [18F]F-AraG PET imaging of a murine aGVHD model enabled visualization of secondary lymphoid organs harboring activated donor T cells prior to clinical symptoms. Tracer biodistribution in healthy humans showed favorable kinetics. This new PET strategy has great potential for early aGVHD diagnosis, enabling timely treatments and improved patient outcomes. [18F]F-AraG may be useful for imaging activated T cells in various biomedical applications. Cancer Res; 77(11); 2893–902. ©2017 AACR.
Unmet Needs in Clinical Research in Breast Cancer: Where Do We Need to Go?
Authors: Partridge Ann H. , Carey Lisa A.
Published: June 2017

This CCR Focus highlights areas in breast cancer research with the greatest potential for clinical and therapeutic application. The articles in this CCR Focus address the state of the science in a broad range of areas with a focus on “hot” although sometimes controversial topics, unanswered questions, and unmet need. From mutational signatures, the cancer genomic revolution, and new inroads in immunotherapy for breast cancer to unique concerns of vulnerable populations as well as national and global health disparities, these works represent much of the promise of breast cancer research as well as the challenges in the coming years. Each review focuses not only on recent discoveries but also on putting the topic in context, including limitations to overcome. This overview is designed to further contextualize the highlighted issues within the broader research landscape. We also present new information from a poll of ALLIANCE for Clinical Trials in Oncology Breast Committee members regarding the most needed and viable potential future National Cancer Institute (NCI)–supported clinical trials in breast cancer. The great challenge is to translate the potential benefits of greater scientific knowledge reflected in this CCR Focus section into improvements in outcomes for individuals and populations with breast cancer. A unifying theme across the six articles contained in this CCR Focus is the increasingly recognized value and necessity of collaboration across disciplines from bench to bedside to populations. Only continued and iteratively amplified scientific, clinical, and governmental commitment to creating, testing, and implementing new knowledge will reduce the global morbidity and mortality of breast cancer. Clin Cancer Res; 23(11); 2611–6. ©2017 AACR.

See all articles in this CCR Focus section, “Breast Cancer Research: From Base Pairs to Populations.”
JUN-Mediated Downregulation of EGFR Signaling Is Associated with Resistance to Gefitinib in EGFR-mutant NSCLC Cell Lines
Authors: Kani Kian , Garri Carolina , Tiemann Katrin , Malihi Paymaneh D. , Punj Vasu , Nguyen Anthony L. , Lee Janet , Hughes Lindsey D. , Alvarez Ruth M. , Wood Damien M. , Joo Ah Young , Katz Jonathan E. , Agus David B. , Mallick Parag
Published: June 2017

Mutations or deletions in exons 18–21 in the EGFR) are present in approximately 15% of tumors in patients with non–small cell lung cancer (NSCLC). They lead to activation of the EGFR kinase domain and sensitivity to molecularly targeted therapeutics aimed at this domain (gefitinib or erlotinib). These drugs have demonstrated objective clinical response in many of these patients; however, invariably, all patients acquire resistance. To examine the molecular origins of resistance, we derived a set of gefitinib-resistant cells by exposing lung adenocarcinoma cell line, HCC827, with an activating mutation in the EGFR tyrosine kinase domain, to increasing gefitinib concentrations. Gefitinib-resistant cells acquired an increased expression and activation of JUN, a known oncogene involved in cancer progression. Ectopic overexpression of JUN in HCC827 cells increased gefitinib IC50 from 49 nmol/L to 8 μmol/L (P < 0.001). Downregulation of JUN expression through shRNA resensitized HCC827 cells to gefitinib (IC50 from 49 nmol/L to 2 nmol/L; P < 0.01). Inhibitors targeting JUN were 3-fold more effective in the gefitinib-resistant cells than in the parental cell line (P < 0.01). Analysis of gene expression in patient tumors with EGFR-activating mutations and poor response to erlotinib revealed a similar pattern as the top 260 differentially expressed genes in the gefitinib-resistant cells (Spearman correlation coefficient of 0.78, P < 0.01). These findings suggest that increased JUN expression and activity may contribute to gefitinib resistance in NSCLC and that JUN pathway therapeutics merit investigation as an alternate treatment strategy. Mol Cancer Ther; 16(8); 1645–57. ©2017 AACR.
Local DNA Repair Inhibition for Sustained Radiosensitization of High-Grade Gliomas
Authors: King Amanda R. , Corso Christopher D. , Chen Evan M. , Song Eric , Bongiorni Paul , Chen Zhe , Sundaram Ranjini K. , Bindra Ranjit S. , Saltzman W. Mark
Published: June 2017

High-grade gliomas, such as glioblastoma (GBM) and diffuse intrinsic pontine glioma (DIPG), are characterized by an aggressive phenotype with nearly universal local disease progression despite multimodal treatment, which typically includes chemotherapy, radiotherapy, and possibly surgery. Radiosensitizers that have improved the effects of radiotherapy for extracranial tumors have been ineffective for the treatment of GBM and DIPG, in part due to poor blood–brain barrier penetration and rapid intracranial clearance of small molecules. Here, we demonstrate that nanoparticles can provide sustained drug release and minimal toxicity. When administered locally, these nanoparticles conferred radiosensitization in vitro and improved survival in rats with intracranial gliomas when delivered concurrently with a 5-day course of fractionated radiotherapy. Compared with previous work using locally delivered radiosensitizers and cranial radiation, our approach, based on the rational selection of agents and a clinically relevant radiation dosing schedule, produces the strongest synergistic effects between chemo- and radiotherapy approaches to the treatment of high-grade gliomas. Mol Cancer Ther; 16(8); 1456–69. ©2017 AACR.
Health Literacy: Readability of ACC/AHA Online Patient Education Material
Authors: Kapoor Karan , George Praveen , Evans Matthew C. , Miller Weldon J. , Liu Stanley S.
Published: June 2017

Objectives: To determine whether the online patient education material offered by the American College of Cardiology (ACC) and the American Heart Association (AHA) is written at a higher level than the 6th-7th grade level recommended by the National Institute of Health (NIH). Methods: Online patient education material from each website was subjected to reading grade level (RGL) analysis using the Readability Studio Professional Edition. One-sample t testing was used to compare the mean RGLs obtained from 8 formulas to the NIH-recommended 6.5 grade level and 8th grade national mean. Results: In total, 372 articles from the ACC website and 82 from the AHA were studied. Mean (±SD) RGLs for the 454 articles were 9.6 ± 2.1, 11.2 ± 2.1, 11.9 ± 1.6, 10.8 ± 1.6, 9.7 ± 2.1, 10.8 ± 0.8, 10.5 ± 2.6, and 11.7 ± 3.5 according to the Flesch-Kincaid grade level (FKGL), Simple Measure of Gobbledygook (SMOG Index), Coleman-Liau Index (CLI), Gunning-Fog Index (GFI), New Dale-Chall reading level formula (NDC), FORCAST, Raygor Readability Estimate (RRE), and Fry Graph (Fry), respectively. All analyzed articles had significantly higher RGLs than both the NIH-recommended grade level of 6.5 and the national mean grade level of 8 (p < 0.00625). Conclusions: Patient education material provided on the ACC and AHA websites is written above the NIH-recommended 6.5 grade level and 8th grade national mean reading level. Additional studies are required to demonstrate whether lowering the RGL of this material improves outcomes among patients with cardiovascular disease.
Roles of High Mobility Group Box 1 in Cardiovascular Calcification
Authors: Chen Qiang , Wang Ze-Yang , Chen Li-Yuan , Hu Hou-Yuan
Published: June 2017

Calcific disease of the cardiovascular system, including atherosclerotic calcification, medial calcification in diabetes and calcific aortic valve disease, is an important risk factor for many adverse cardiovascular events such as ischemic cardiac events and subsequent mortality. Although cardiovascular calcification has long been considered to be a passive degenerative occurrence, it is now recognized as an active and highly regulated process that involves osteochondrogenic differentiation, apoptosis and extracellular vesicle release. Nonetheless, despite numerous studies on the pathogenesis of cardiovascular calcification, the underlying mechanisms remain poorly understood. High mobility group box 1 (HMGB1), a nuclear protein bound to chromatin in almost all eukaryotic cells, acts as a damage-associated molecular pattern (DAMP) when released into the extracellular space upon cell activation, injury or death. Moreover, HMGB1 also functions as a bone-active cytokine participating in bone remodeling and ectopic calcification pathogenesis. However, studies on the roles of HMGB1 in promoting cardiovascular calcification are limited to date, and the mechanisms involved are still unclear. In this review, we summarize recent studies investigating the mechanism of cardiovascular calcification and discuss multiple roles of HMGB1 in its development.
Comparison of Procalcitonin Guidance-Administered Antibiotics with Standard Guidelines on Antibiotic Therapy in Children with Lower Respiratory Tract Infections: A Retrospective Study in China
Authors: Wu Guo , Wu Gao , Wu Shuxie , Wu Hanbin
Published: June 2017

Objective: To establish the efficacy of an algorithm based on the biomarker procalcitonin (PCT) to reduce antibiotic exposure in pediatric patients with lower respiratory tract infection (LRTI). Materials and Methods: The clinical data of 357 patients (<14 years of age) who were discharged home with LRTI from January 1, 2010 to July 31, 2016 were analyzed. Antibiotic exposure, antibiotic prescription rate, length of hospital stay, and antibiotic-associated adverse effects were compared between the PCT group (n = 183) and the standard group (n = 174) using SAS 9.1.3 software. Results: The overall adverse effect rates were similar in both the PCT and standard groups: 42 (22.95%) and 51 (29.31%), respectively. The length of hospital stay was not significantly different between the PCT (9.96 ± 5.81 days) and standard groups (10.58 ± 4.24 days) (difference: -0.62%; 95% CI: -1.68 to 0.43). Antibiotic prescribing rates were significantly different in the PCT group compared to the standard group: 54.64% versus 83.91% (difference: -29.26%; 95% CI: -38.31, -20.22; p = 0.23). Mean duration of antibiotic exposure in the PCT group (3.98 ± 2.17 days) was lower than the standard groups (6.66 ± 5.59 days) (difference: -2.68%; 95% CI: -3.21 to -2.16). Conclusion: This study showed that PCT guidance of antibiotic treatment in children and adolescents with LRTI reduced the duration of antibiotic exposure and antibiotic prescribing rates, but did not affect the adverse effect rate and length of hospital stay.
Fatores determinantes das book-tax differences
Authors: Fonseca Kellma Bianca Cardoso , Costa Patricia Souza
Published: June 2017

Este artigo tem por objetivo identificar quais são os fatores institucionais e não institucionais que determinam as book-tax differences (BTD) das companhias abertas brasileiras. A amostra da pesquisa é composta por 124 companhias, com dados disponíveis para o período de 2010 a 2015. Os resultados indicam que a BTD total apresenta relação positiva com as variáveis rentabilidade, liquidez e a BTD defasada. Quando desmembrados os tipos de BTD, a rentabilidade, o crescimento da receita de vendas e a BTD defasada estão positivamente associadas à BTD temporária. A rentabilidade e a liquidez estão positivamente associadas à BTD permanente. Portanto, os resultados sugerem que a rentabilidade está associada com todos os tipos de BTD (total, temporária e permanente), ou seja, as empresas mais rentáveis evidenciam maior diferença entre o lucro contábil e o lucro tributável.
Colchicine Depolymerizes Microtubules, Increases Junctophilin‐2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension
Authors: Prins Kurt W. , Tian Lian , Wu Danchen , Thenappan Thenappan , Metzger Joseph M. , Archer Stephen L.
Published: June 2017

Background

Pulmonary arterial hypertension (
PAH
) is a lethal disease characterized by obstructive pulmonary vascular remodeling and right ventricular (
RV
) dysfunction. Although
RV
function predicts outcomes in
PAH
, mechanisms of
RV
dysfunction are poorly understood, and
RV
‐targeted therapies are lacking. We hypothesized that in
PAH
, abnormal microtubular structure in
RV
cardiomyocytes impairs
RV
function by reducing junctophilin‐2 (
JPH
2) expression, resulting in t‐tubule derangements. Conversely, we assessed whether colchicine, a microtubule‐depolymerizing agent, could increase
JPH
2 expression and enhance
RV
function in monocrotaline‐induced
PAH
.

Methods and Results

Immunoblots, confocal microscopy, echocardiography, cardiac catheterization, and treadmill testing were used to examine colchicine's (0.5 mg/kg 3 times/week) effects on pulmonary hemodynamics,
RV
function, and functional capacity. Rats were treated with saline (n=28) or colchicine (n=24) for 3 weeks, beginning 1 week after monocrotaline (60 mg/kg, subcutaneous). In the monocrotaline
RV
, but not the left ventricle, microtubule density is increased, and
JPH
2 expression is reduced, with loss of t‐tubule localization and t‐tubule disarray. Colchicine reduces microtubule density, increases
JPH
2 expression, and improves t‐tubule morphology in
RV
cardiomyocytes. Colchicine therapy diminishes
RV
hypertrophy, improves
RV
function, and enhances
RV
–pulmonary artery coupling. Colchicine reduces small pulmonary arteriolar thickness and improves pulmonary hemodynamics. Finally, colchicine increases exercise capacity.

Conclusions

Monocrotaline‐induced PAH causes
RV
‐specific derangement of microtubules marked by reduction in
JPH
2 and t‐tubule disarray. Colchicine reduces microtubule density, increases
JPH
2 expression, and improves both t‐tubule architecture and
RV
function. Colchicine also reduces adverse pulmonary vascular remodeling. These results provide biological plausibility for a clinical trial to repurpose colchicine as a
RV
‐directed therapy for
PAH
.