bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biochemical and Antiparasitic Properties of Inhibitors of the Plasmodium falciparum Calcium-Dependent Protein Kinase PfCDPK1
Authors: Ansell Keith H. , Jones Hayley M. , Whalley David , Hearn Alisdair , Taylor Debra L. , Patin Emmanuel C. , Chapman Timothy M. , Osborne Simon A. , Wallace Claire , Birchall Kristian , Large Jonathan , Bouloc Nathalie , Smiljanic-Hurley Ela , Clough Barbara , Moon Robert W. , Green Judith L. , Holder Anthony A. 
Published: July 2014

ABSTRACT

PfCDPK1 is a
Plasmodium falciparum
calcium-dependent protein kinase, which has been identified as a potential target for novel antimalarial chemotherapeutics. In order to further investigate the role of PfCDPK1, we established a high-throughput
in vitro
biochemical assay and used it to screen a library of over 35,000 small molecules. Five chemical series of inhibitors were initially identified from the screen, from which series 1 and 2 were selected for chemical optimization. Indicative of their mechanism of action, enzyme inhibition by these compounds was found to be sensitive to both the ATP concentration and substitution of the amino acid residue present at the “gatekeeper” position at the ATP-binding site of the enzyme. Medicinal chemistry efforts led to a series of PfCDPK1 inhibitors with 50% inhibitory concentrations (IC
50
s) below 10 nM against PfCDPK1 in a biochemical assay and 50% effective concentrations (EC
50
s) less than 100 nM for inhibition of parasite growth
in vitro
. Potent inhibition was combined with acceptable absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and equipotent inhibition of
Plasmodium vivax
CDPK1. However, we were unable to correlate biochemical inhibition with parasite growth inhibition for this series overall. Inhibition of
Plasmodium berghei
CDPK1 correlated well with PfCDPK1 inhibition, enabling progression of a set of compounds to
in vivo
evaluation in the
P. berghei
rodent model for malaria. These chemical series have potential for further development as inhibitors of CDPK1.
Susceptibility and Diversity in the Therapy-Refractory Genus Scedosporium
Authors: Lackner M. , Hagen F. , Meis J. F. , Gerrits van den Ende A. H. G. , Vu D. , Robert V. , Fritz J. , Moussa T. A. A. , de Hoog G. S. 
Published: July 2014

ABSTRACT

Scedosporium
species show decreased susceptibility to the majority of systemic antifungal drugs. Acquired resistance is likely to disseminate differentially with the mode of exchange of genetic material between lineages. Inter- and intraspecific diversities of
Scedosporium
species were analyzed for three partitions (rDNA internal transcribed spacer gene [
ITS
], partial β-tubulin gene, and amplified fragment length polymorphism profiles), with the aim to establish distribution of resistance between species, populations, and strains. Heterogeneity of and recombination between lineages were determined, and distances between clusters were calculated using a centroid approach. Clinical, geographic, and antifungal data were plotted on diversity networks.
Scedosporium minutisporum
,
Scedosporium desertorum
, and
Scedosporium aurantiacum
were distinguished unambiguously in all partitions and had differential antifungal susceptibility profiles (ASP).
Pseudallescheria fusoidea
and
Pseudallescheria ellipsoidea
were indistinguishable from
Scedosporium boydii
.
Pseudallescheria angusta
took an intermediate position between
Scedosporium apiospermum
and
S. boydii
.
Scedosporium boydii
and
S. apiospermum
had identical ASP. Differences in (multi)resistance were linked to individual strains.
S. apiospermum
and
S. boydii
showed limited interbreeding and were recognized as valid, sympatric species. The
S. apiospermum/S. boydii
group, comprising the main clinically relevant
Scedosporium
species, consists of separate lineages and is interpreted as a complex undergoing sympatric evolution with incomplete lineage sorting. In routine diagnostics, the lineages in
S. apiospermum/S. boydii
are indicated with the umbrella descriptor “
S. apiospermum
complex”; individual species can be identified with rDNA
ITS
with 96.3% confidence. Voriconazole is recommended as the first-line treatment; resistance against this compound is rare.
Effects of Rifampin and Ketoconazole on Pharmacokinetics of Morinidazole in Healthy Chinese Subjects
Authors: Pang Xiaoyan , Zhang Yifan , Gao Ruina , Zhong Kan , Zhong Dafang , Chen Xiaoyan 
Published: July 2014

ABSTRACT

Morinidazole, a 5-nitroimidazole antimicrobial drug, has been approved for the treatment of amoebiasis, trichomoniasis, and anaerobic bacterial infections in China. It was reported that drug-drug interaction happened after the coadministration of ornidazole, an analog of morinidazole, and rifampin or ketoconazole. Therefore, we measured the plasma pharmacokinetics (PK) of morinidazole and its metabolites in the healthy Chinese volunteers prior to and following the administration of rifampin or ketoconazole using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The area under the concentration-time curve from time 0 to time
t
(AUC
0-t
) and maximum concentration in serum (
C
max
) of morinidazole were decreased by 28% and 23%, respectively, after 6 days of exposure to 600 mg of rifampin once daily; the
C
max
s of
N

+

-glucuronides were increased by 14%, while their AUC
0-t
s were hardly changed. After 7 days of exposure to 200 mg of ketoconazole once daily, the AUC
0-t
and
C
max
of the parent drug were not affected significantly.
C
max
s of
N

+

-glucuronides were decreased by 23%; AUC
0-t
s were decreased by 14%. The exposure of sulfate conjugate was hardly changed after the coadministration of rifampin or ketoconazole. Using recombinant enzyme of UGT1A9 and human hepatocytes, the mechanism of the altered PK behaviors of morinidazole and its metabolites was investigated. In human hepatocytes, ketoconazole dose dependently inhibited the formation of
N

+

-glucuronides (50% inhibitory concentration [IC
50
], 1.5 μM), while rifampin induced the mRNA level of UGT1A9 by 28% and the activity of UGT1A9 by 53%. In conclusion, the effects of rifampin and ketoconazole on the plasma exposures of morinidazole and
N

+

-glucuronide are less than 50%; therefore, rifampin and ketoconazole have little clinical significance in the pharmacokinetics of morinidazole.
Staphylococcus epidermidis
agr
Quorum-Sensing System: Signal Identification, Cross Talk, and Importance in Colonization
Authors: Olson Michael E. , Todd Daniel A. , Schaeffer Carolyn R. , Paharik Alexandra E. , Van Dyke Michael J. , Büttner Henning , Dunman Paul M. , Rohde Holger , Cech Nadja B. , Fey Paul D. , Horswill Alexander R. 
Published: July 2014

ABSTRACT

Staphylococcus epidermidis
is an opportunistic pathogen that is one of the leading causes of medical device infections. Global regulators like the
agr
quorum-sensing system in this pathogen have received a limited amount of attention, leaving important questions unanswered. There are three
agr
types in
S. epidermidis
strains, but only one of the autoinducing peptide (AIP) signals has been identified (AIP-I), and cross talk between
agr
systems has not been tested. We structurally characterized all three AIP types using mass spectrometry and discovered that the AIP-II and AIP-III signals are 12 residues in length, making them the largest staphylococcal AIPs identified to date.
S. epidermidis
agr
reporter strains were developed for each system, and we determined that cross-inhibitory interactions occur between the
agr
type I and II systems and between the
agr
type I and III systems. In contrast, no cross talk was observed between the type II and III systems. To further understand the outputs of the
S. epidermidis
agr
system, an RNAIII mutant was constructed, and microarray studies revealed that exoenzymes (Ecp protease and Geh lipase) and low-molecular-weight toxins were downregulated in the mutant. Follow-up analysis of Ecp confirmed the RNAIII is required to induce protease activity and that
agr
cross talk modulates Ecp activity in a manner that mirrors the
agr
reporter results. Finally, we demonstrated that the
agr
system enhances skin colonization by
S. epidermidis
using a porcine model. This work expands our knowledge of
S. epidermidis
agr
system function and will aid future studies on cell-cell communication in this important opportunistic pathogen.
Progesterone Inhibits Endometrial Cancer Invasiveness by Inhibiting the TGFβ Pathway
Authors: Bokhari Amber A. , Lee Laura R. , Raboteau Dewayne , Hamilton Chad A. , Maxwell George L. , Rodriguez Gustavo C. , Syed Viqar 
Published: July 2014

Abstract
Increased expression of TGFβ isoforms in human endometrial cancer correlates with decreased survival and poor prognosis. Progesterone has been shown to exert a chemoprotective effect against endometrial cancer, and previous animal models have suggested that these effects are accompanied by changes in TGFβ. The goal of this study was to characterize the effect of progesterone on TGFβ signaling pathway components and on TGFβ-induced protumorigenic activities in endometrial cancer cell lines. Progesterone significantly decreased expression of three TGFβ isoforms at 72 hours after treatment except for TGFβ2 in HEC-1B and TGFβ3 in Ishikawa cells. Progesterone treatment for 120 hours attenuated expression of the three isoforms in all cell lines. Progesterone exposure for 72 hours reduced expression of TGFβ receptors in HEC-1B cells and all but TGFβR1 in Ishikawa cells. Progesterone reduced TGFβR3 expression in RL-95 cells at 72 hours, but TGFβR1 and βR2 expression levels were not affected by progesterone at any time point. SMAD2/3 and pSMAD2/3 were substantially reduced at 72 hours in all cell lines. SMAD4 expression was reduced in RL-95 cells at 24 hours and in HEC-1B and Ishikawa cells at 72 hours following progesterone treatment. Furthermore, progesterone effectively inhibited basal and TGFβ1-induced cancer cell viability and invasion, which was accompanied by increased E-cadherin and decreased vimentin expression. An inhibitor of TGFβRI blocked TGFβ1-induced effects on cell viability and invasion and attenuated antitumor effects of progesterone. These results suggest that downregulation of TGFβ signaling is a key mechanism underlying progesterone inhibition of endometrial cancer growth. Cancer Prev Res; 7(10); 1045–55. ©2014 AACR.
With or without a therapist: Self-help reading for mental health
Authors: McLean Scott 
Published: July 2014

Objective: To address a critical gap in health education scholarship by exploring the contexts in which self-help reading takes place, the motivations of self-help readers and the processes through which such readers engage with books on mental health. Design: Structured, in-depth interviews conducted with participants recruited through online classified advertisements. Setting: Self-help readers were recruited from the four largest cities in western Canada. The setting of self-help reading as an ‘intervention’ was as natural as possible, with readers being asked to reflect upon their recent experience of reading a self-help book. Method: Qualitative interviews conducted with 45 readers. Interview transcripts were analysed thematically. Results: Illustrative narratives are provided for two categories of readers: those who read in conjunction with direct therapeutic intervention and those who read without input from a therapist. Findings within both categories indicate a high level of diversity in terms of contexts, motivations and experiences. Conclusion: Understanding the diversity of readers and their experiences is an important prerequisite for health educators wishing to develop a critical and responsible approach to positioning self-help literature within the broader range of approaches to promoting mental health.
The depression in women in pregnancy and postpartum period: A follow-up study
Authors: Kirkan Tulay Sati , Aydin Nazan , Yazici Esra , Akcali Aslan Puren , Acemoglu Hamit , Daloglu Ali Gokhan 
Published: July 2014

Aim: This was a follow-up study to determine postpartum depression (PPD) and its causes in a population previously evaluated in the first trimester of pregnancy. Methods: The study sample consisted of pregnant women who were evaluated in the first trimester and 360 women who were re-evaluated in the postpartum period. Detailed sociodemographic data were obtained from the women, and depression was assessed with the Edinburgh Postpartum Depression scale (EPDS) and Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders (DSM) Axis I Disorders (SCID-I). Results: In this follow-up study, the prevalence of PPD was 35% ( n = 126). A depressive disorder in the first trimester of pregnancy, previous mental disorder, somatic disorder, exposure to domestic violence during pregnancy, baby’s staying in the incubator and not breastfeeding were predictors of PPD. Exposure to violence and a history of previous depression predicted depression both in pregnancy and in the postpartum period. Conclusion: Depression rates are high in Eastern Turkey. Exposure to violence during pregnancy and the existence of a previous mental disorder were risk factors for perinatal depression in this study. Performing screening tests can identify women at risk of pregnancy-related depression. Prevention programs should be established in areas where the prevalence of depression is high.
What Works for Whom? The Effects of Gender Responsive Programming on Girls and Boys in Secure Detention
Authors: Day Jacob C. , Zahn Margaret A. , Tichavsky Lisa P. 
Published: July 2014

Objectives: This study investigates whether gender responsive programming is effective at reducing recidivism relative to traditional, reinforcement-based programming for both girls and boys in secure detention. Methods: Event-history analysis is used to examine recidivism outcomes for two propensity score matched samples of girls ( n = 148) and boys ( n = 140) released from gender responsive versus traditional detention facilities in Connecticut. The contingent effects of trauma, depression/anxiety, alcohol/drug abuse, anger/irritability, and somatic complaints are also examined. Results: Compared to traditional programming, gender responsive programming for youth in secure detention is associated with a lower risk of recidivism for girls with gender-sensitive risk factors but a higher risk of recidivism among girls who do not display these risk factors. Gender responsive programs are no more or less effective at reducing recidivism for boys, regardless of whether they display risk factors commonly associated with girls’ delinquency and confinement. Conclusions: The results suggest that girls in secure detention require different approaches depending on their histories of trauma and associated mental and physical health issues. While girls who follow gendered pathways into detention benefit from the relational approach employed in gender responsive programs, girls without such issues benefit more from traditional reinforcement programming.
Extracorporeal membrane modality conversions
Authors: Chan-Dominy ACF , Anders M , Millar J , Horton S , Best D , Brizard C , D’Udekem Y , Hilton A , Butt W 
Published: July 2014

We report the case of a patient with cardiovascular and respiratory failure due to severe anaphylaxis requiring multiple extracorporeal membrane oxygenation (ECMO) cannulation strategies to provide adequate oxygen delivery and ventilatory support during a period of rapid physiological change. ECMO provides partial or complete support of oxygenation-ventilation and circulation. The choice of which ECMO modality to use is governed by anatomical (vessel size, cardiovascular anatomy and previous surgeries) and physiological (respiratory and/or cardiac failure) factors. The urgency with which ECMO needs to be implemented (emergency cardiopulmonary resuscitation (eCPR), urgent, elective) and the institutional experience will also influence the type of ECMO provided. Here we describe a 12-year-old schoolgirl who, having been resuscitated with peripheral veno-venous (VV) ECMO for severe hypoxemia due to status asthmaticus in the setting of acute anaphylaxis, required escalation to peripheral veno-arterial (VA) ECMO for precipitous cardiovascular deterioration. Insufficient oxygen delivery for adequate cellular metabolic function and possible cerebral hypoxia due to significant differential hypoxia necessitated ECMO modification. After six days of central (transthoracic) VA ECMO support and 21 days of intensive care unit (ICU) care, she made a complete recovery with no neurological sequelae. The use of ECMO support warrants careful consideration of the interplay of a patient’s pathophysiology and extracorporeal circuit dynamics. Particular emphasis should be placed on the potential for mismatch between cardiovascular and respiratory support as well as the need to meet metabolic demands through adequate cerebral, coronary and systemic oxygenation. Cannulation strategies occasionally require alteration to meet and anticipate the patient’s evolving needs.
MDM2 oncogene, E3 ubiquitin protein ligase T309G polymorphism and risk of oesophageal or gastric cancer: Meta-analysis of 15 studies
Authors: Shen Wei , Hu Ping , Cao Jia-qing , Liu Xiu-xia , Shao Jiang-hua 
Published: July 2014

Objective To investigate the association between potentially functional MDM2 oncogene, E3 ubiquitin protein ligase ( MDM2) T309G polymorphism and susceptibility to oesophageal or gastric cancer. Methods Two investigators independently searched the PubMed and Chinese National Knowledge Infrastructure databases for studies published before September 2013. Results Pooled results showed that the variant homozygous 309GG genotype (versus TT) was significantly associated with increased risk of both oesophageal (odds ratio [OR] 0.77; 95% confidence interval [CI] 0.65, 0.90) and gastric cancer (OR 0.52; 95% CI 0.38, 0.72). Subgroup analysis revealed a 309GG-associated increased risk for both cancer types in Asian populations, particularly among Chinese and Japanese ethnicity. When stratified for Helicobacter pylori infection and histological type of gastric cancer, the 309GG-related risk was higher in H. pylori-positive patients (T versus G: OR 0.37; 95% CI 0.22, 0.63) and the association was stronger with intestinal (TT + TG versus GG: OR 0.68; 95% CI 0.54, 0.87) rather than diffuse gastric-cancer type. Conclusions The MDM2 T309G polymorphism may be significantly associated with increased susceptibility to oesophageal or gastric cancer, particularly among Eastern Asian populations.
Enhanced Patella–Patellar Tendon Healing Using Combined Magnetic Fields in a Rabbit Model
Authors: Xu Daqi , Zhang Tao , Qu Jin , Hu Jianzhong , Lu Hongbin 
Published: July 2014

Background: A combined magnetic field (CMF) is a composite of a dynamic sinusoidal magnetic field and a magnetostatic field. Stimuli from CMFs has proved to be an effective tool for healing problem fractures and spinal fusion procedures. Hypothesis: Combined magnetic field technology will enhance healing of bone-tendon junction repair via endochondral ossification for regeneration of the fibrocartilage zone. Study Design: Controlled laboratory study. Methods: Forty-eight mature rabbits were randomly divided into CMF-treated and placebo-treated (control) groups. A partial patellectomy model was created. The CMF-treated group was subjected to CMF stimulation from the third postoperative day for 30 minutes per day up to weeks 8 or 16. At each time point, tissue samples were harvested and evaluated biomechanically and histomorphologically. The area of newly formed bone and the thickness of fibrocartilage were measured in hematoxylin and eosin–stained sections and toluidine blue–stained sections, respectively, while the density of fibrocartilage cells and the amount of proteoglycans were calculated using safranin O–stained sections. A biomechanical analysis was carried out to ascertain tensile strength. Results: Quantitative histological measurements showed that the newly formed bone and regenerated fibrocartilage zone in the CMF-treated group increased by a respective 99.2% and 41.9% compared with the control group at week 8 and a respective 97.8% and 22.8% at week 16. In the CMF-treated group at postoperative week 16, the amount of proteoglycans was 36.9% more than that of the control group, but the density of fibrocartilage cells was just 71.4% of the control group; there were no significant differences at week 8. Mechanical test results showed that energy to failure was not significantly different between the 2 groups at week 8. Yet, at week 16, load to failure, ultimate strength, and energy to failure in the CMF-treated group (311.0 ± 59.4 N, 8.46 ± 1.41 MPa, and 0.87 ± 0.17 J, respectively) were significantly higher than those in the control group (247.1 ± 65.6 N, 6.84 ± 1.12 MPa, and 0.52 ± 0.15 J, respectively). Conclusion: Biophysical stimulation with CMFs enhances healing after bone-tendon junction injuries in a rabbit model. Clinical Relevance: These results demonstrate the feasibility of using CMFs for stimulating bone-tendon healing after repair.
Five-year experience of organized colorectal cancer screening in a Swedish population – increased compliance with age, female gender, and subsequent screening round
Authors: Blom Johannes , Kilpeläinen Sini , Hultcrantz Rolf , Törnberg Sven 
Published: July 2014

Objective To evaluate compliance by age, gender, and screening round in the population based Stockholm/Gotland colorectal cancer screening programme. Methods All individuals aged between 60 and 69 living in the counties of Stockholm and Gotland (Sweden) have, since 2008, successively been included in a colorectal cancer screening programme using biennial faecal occult blood tests (Hemoccult®). Personal invitations including test kits have been sent to home addresses, and individuals with a positive test result have been called to a defined clinic for an assessment colonoscopy. Descriptive statistics have been used to evaluate different aspects of compliance. Results Over the five-year period 2008–2012, more than 200,000 individuals from nine different birth cohorts have been invited, with a compliance rate of approximately 60%, which increased by age, female gender, and subsequent screening round. In total, 4,300 individuals (2.1%) with positive tests were referred to assessment colonoscopy, where 213 colorectal cancers were diagnosed. The compliance with the follow-up colonoscopies varied by year, and ranged from 85.6–92.4%. Conclusion The strong organization of the programme contributed to a high compliance rate, that increased by screening round. The lower participation rate among men and among individuals at younger ages needs further attention.