bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy of Oral E1210, a New Broad-Spectrum Antifungal with a Novel Mechanism of Action, in Murine Models of Candidiasis, Aspergillosis, and Fusariosis
Authors: Hata Katsura , Horii Takaaki , Miyazaki Mamiko , Watanabe Nao-aki , Okubo Miyuki , Sonoda Jiro , Nakamoto Kazutaka , Tanaka Keigo , Shirotori Syuji , Murai Norio , Inoue Satoshi , Matsukura Masayuki , Abe Shinya , Yoshimatsu Kentaro , Asada Makoto
Published: July 2011

E1210 is a first-in-class, broad-spectrum antifungal with a novel mechanism of action—inhibition of fungal glycosylphosphatidylinositol biosynthesis. In this study, the efficacies of E1210 and reference antifungals were evaluated in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. Oral E1210 demonstrated dose-dependent efficacy in infections caused by
Candida
species,
Aspergillus
spp., and
Fusarium solani
. In the treatment of oropharyngeal candidiasis, E1210 and fluconazole each caused a significantly greater reduction in the number of oral CFU than the control treatment (
P
< 0.05). In the disseminated candidiasis model, mice treated with E1210, fluconazole, caspofungin, or liposomal amphotericin B showed significantly higher survival rates than the control mice (
P
< 0.05). E1210 was also highly effective in treating disseminated candidiasis caused by azole-resistant
Candida albicans
or
Candida tropicalis
. A 24-h delay in treatment onset minimally affected the efficacy outcome of E1210 in the treatment of disseminated candidiasis. In the
Aspergillus flavus
pulmonary aspergillosis model, mice treated with E1210, voriconazole, or caspofungin showed significantly higher survival rates than the control mice (
P
< 0.05). E1210 was also effective in the treatment of
Aspergillus fumigatus
pulmonary aspergillosis. In contrast to many antifungals, E1210 was also effective against disseminated fusariosis caused by
F. solani
. In conclusion, E1210 demonstrated consistent efficacy in murine models of oropharyngeal and disseminated candidiasis, pulmonary aspergillosis, and disseminated fusariosis. These data suggest that further studies to determine E1210's potential for the treatment of disseminated fungal infections are indicated.
Impact of Antibiotic Exposure Patterns on Selection of Community-Associated Methicillin-Resistant Staphylococcus aureus in Hospital Settings
Authors: Kardaś-Słoma Lidia , Boëlle Pierre Yves , Opatowski Lulla , Brun-Buisson Christian , Guillemot Didier , Temime Laura
Published: July 2011

Community-associated methicillin-resistant
S. aureus
(CA-MRSA) is increasingly common in hospitals, with potentially serious consequences. The aim of this study was to assess the impact of antibiotic prescription patterns on the selection of CA-MRSA within hospitals, in a context of competition with other circulating staphylococcal strains, including methicillin-sensitive (MSSA) and hospital-associated methicillin-resistant (HA-MRSA) strains. We developed a computerized agent-based model of
S. aureus
transmission in a hospital ward in which CA-MRSA, MSSA, and HA-MRSA strains may cocirculate. We investigated a wide range of antibiotic prescription patterns in both intensive care units (ICUs) and general wards, and we studied how differences in antibiotic exposure may explain observed variations in the success of CA-MRSA invasion in the hospitals of several European countries and of the United States. Model predictions underlined the influence of antibiotic prescription patterns on CA-MRSA spread in hospitals, especially in the ICU, where the endemic prevalence of CA-MRSA carriage can range from 3% to 20%, depending on the simulated prescription pattern. Large antibiotic exposure with drugs effective against MSSA but not MRSA was found to promote invasion by CA-MRSA. We also found that, should CA-MRSA acquire fluoroquinolone resistance, a major increase in CA-MRSA prevalence could ensue in hospitals worldwide. Controlling the spread of highly community-prevalent CA-MRSA within hospitals is a challenge. This study demonstrates that antibiotic exposure strategies could participate in this control. This is all the more important in wards such as ICUs, which may play the role of incubators, promoting CA-MRSA selection in hospitals.
Functional and Phenotypic Characteristics of Alternative Activation Induced in Human Monocytes by Interleukin-4 or the Parasitic Nematode Brugia malayi
Authors: Semnani Roshanak Tolouei , Mahapatra Lily , Moore Vanessa , Sanprasert Vivornpun , Nutman Thomas B.
Published: July 2011

Human monocytes from patients with patent filarial infections are studded with filarial antigen and express markers associated with alternative activation of macrophages (MΦ). To explore the role of filaria-derived parasite antigen in differentiation of human monocytes, cells were exposed to microfilariae (mf) ofBrugia malayi, and their phenotypic and functional characteristics were compared with those of monocytes exposed to factors known to generate either alternatively (interleukin-4 [IL-4]) or classically (macrophage colony-stimulating factor [MCSF]) activated MΦ. IL-4 upregulated mRNA expression of CCL13, CCL15, CCL17, CCL18, CCL22, CLEC10A, MRC1, CADH1, CD274, and CD273 associated with alternative activation of MΦ but not arginase 1. IL-4-cultured monocytes had a diminished ability to promote proliferation of both CD4+and CD8+T cells compared to that of unexposed monocytes. Similar to results with IL-4, exposure of monocytes to live mf induced upregulation of CCL15, CCL17, CCL18, CCL22, CD274, and CD273 and downregulation of Toll-like receptor 3 (TLR3), TLR5, and TLR7. In contrast to results with MCSF-cultured monocytes, exposure of monocytes to mf resulted in significant inhibition of the phagocytic ability of these cells to the same degree as that seen with IL-4. Our data suggest that short exposure of human monocytes to IL-4 induces a phenotypic characteristic of alternative activation and that secreted filarial products skew monocytes similarly.
Coinfection with Enterohepatic Helicobacter Species Can Ameliorate or Promote Helicobacter pylori-Induced Gastric Pathology in C57BL/6 Mice
Authors: Ge Zhongming , Feng Yan , Muthupalani Sureshkumar , Eurell Laura Lemke , Taylor Nancy S. , Whary Mark T. , Fox James G.
Published: July 2011

To investigate how different enterohepatic
Helicobacter
species (EHS) influence
Helicobacter pylori
gastric pathology, C57BL/6 mice were infected with
Helicobacter hepaticus
or
Helicobacter muridarum
, followed by
H. pylori
infection 2 weeks later. Compared to
H. pylori
-infected mice, mice infected with
H. muridarum
and
H. pylori
(HmHp mice) developed significantly lower histopathologic activity index (HAI) scores (
P
< 0.0001) at 6 and 11 months postinoculation (MPI). However, mice infected with
H. hepaticus
and
H. pylori
(HhHp mice) developed more severe gastric pathology at 6 MPI (
P
= 0.01), with a HAI at 11 MPI (
P
= 0.8) similar to that of
H. pylori
-infected mice.
H. muridarum
-mediated attenuation of gastritis in coinfected mice was associated with significant downregulation of proinflammatory Th1 (interlukin-1beta [
Il-1β
], gamma interferon [
Ifn-γ
], and tumor necrosis factor-alpha [
Tnf-α
]) cytokines at both time points and Th17 (
Il-17A
) cytokine mRNA levels at 6 MPI in murine stomachs compared to those of
H. pylori
-infected mice (
P
< 0.01). Coinfection with
H. hepaticus
also suppressed
H. pylori
-induced elevation of gastric Th1 cytokines
Ifn-γ
and
Tnf-α
(
P
< 0.0001) but increased Th17 cytokine mRNA levels (
P
= 0.028) at 6 MPI. Furthermore, mRNA levels of
Il-17A
were positively correlated with the severity of helicobacter-induced gastric pathology (HhHp>
H. pylori
>HmHp) (at 6 MPI,

r
2

= 0.92,
P
< 0.0001; at 11 MPI,

r
2

= 0.82,
P
< 0.002). Despite disparate effects on gastritis, colonization levels of gastric
H. pylori
were increased in HhHp mice (at 6 MPI) and HmHp mice (at both time points) compared to those in mono-
H. pylori
-infected mice. These data suggest that despite consistent downregulation of Th1 responses, EHS coinfection either attenuated or promoted the severity of
H. pylori
-induced gastric pathology in C57BL/6 mice. This modulation was related to the variable effects of EHS on gastric interleukin 17 (IL-17) responses to
H. pylori
infection.
Neurotrophin Receptor TrkC Is an Entry Receptor for Trypanosoma cruzi in Neural, Glial, and Epithelial Cells
Authors: Weinkauf Craig , Salvador Ryan , PereiraPerrin Mercio
Published: July 2011

Trypanosoma cruzi
, the agent of Chagas' disease, infects a variety of mammalian cells in a process that includes multiple cycles of intracellular division and differentiation starting with host receptor recognition by a parasite ligand(s). Earlier work in our laboratory showed that the neurotrophin-3 (NT-3) receptor TrkC is activated by
T. cruzi
surface
trans
-sialidase, also known as parasite-derived neurotrophic factor (PDNF). However, it has remained unclear whether TrkC is used by
T. cruzi
to enter host cells. Here, we show that a neuronal cell line (PC12-NNR5) relatively resistant to
T. cruzi
became highly susceptible to infection when overexpressing human TrkC but not human TrkB. Furthermore,
trkC
transfection conferred an ∼3.0-fold intracellular growth advantage. Sialylation-deficient Chinese hamster ovarian (CHO) epithelial cell lines Lec1 and Lec2 also became much more permissive to
T. cruzi
after transfection with the
trkC
gene. Additionally, NT-3 specifically blocked
T. cruzi
infection of the TrkC-NNR5 transfectants and of naturally permissive TrkC-bearing Schwann cells and astrocytes, as did recombinant PDNF. Two specific inhibitors of Trk autophosphorylation (K252a and AG879) and inhibitors of Trk-induced MAPK/Erk (U0126) and Akt kinase (LY294002) signaling, but not an inhibitor of insulin-like growth factor 1 receptor, abrogated TrkC-mediated cell invasion. Antibody to TrkC blocked
T. cruzi
infection of the TrkC-NNR5 transfectants and of cells that naturally express TrkC. The TrkC antibody also significantly and specifically reduced cutaneous infection in a mouse model of acute Chagas' disease. TrkC is ubiquitously expressed in the peripheral and central nervous systems, and in nonneural cells infected by
T. cruzi
, including cardiac and gastrointestinal muscle cells. Thus, TrkC is implicated as a functional PDNF receptor in cell entry, independently of sialic acid recognition, mediating broad
T. cruzi
infection both
in vitro
and
in vivo
.
A cost effective stratified two-stage sampling design to estimate the forest land area of southern Chile
Authors: Niklitschek Mario E. , Trincado Guillermo
Published: July 2011

There is a growing demand for improving the measurement of forest resources, with more frequent updating and better information on environmental variables. We explore the cost efficiency of a stratified two-stage design using area sampling to estimate the forest plantation and native forest areas in southern Chile. Analytical expressions for the approximate mean square error of combined and separate ratio estimators are derived applying Taylor linearization. Under a unified framework, this procedure allows the evaluation of the precision of design and post-design estimators for unequal unit area sizes at both stages. Monte Carlo simulations were used to assess empirically the approximate analytical measures of the mean square error and the biases associated with the ratio estimators. Adopting proportional allocation among strata and clusters, the optimal allocation among the two stages is determined. A substantial improvement in sampling precision was achieved using the separate ratio estimator and the bias was found to be small. Post-stratification based on categorical information on growing zones also improved the precision of estimating the forest plantation area and a smaller extent the native forest area. The results of this paper support a wider adoption of sampling methods to estimate land use and land cover at regional or national levels.
Interspecific differences in sapling performance with respect to light and aridity gradients in Mediterranean pine–oak forests: implications for species coexistence
Authors: Zavala Miguel A. , Espelta Josep M. , Caspersen John , Retana Javier
Published: July 2011

The relative abundance of two codominant Mediterranean tree species, shade-tolerant Quercus ilex L. and shade-intolerant Pinus halepensis Mill., is inversely correlated along aridity gradients, but this pattern is not explained by seedling responses to water or light availability, suggesting that subsequent life history stages may explain forest composition. To test this hypothesis, we calibrated statistical models of sapling growth and height–diameter allometry as functions of light availability and climatic variation as well as models of sapling mortality as a function of growth history. Contrary to the expectation of a sun–shade growth trade-off, P. halepensis grew faster than Q. ilex saplings at both low and high light levels. Low precipitation and aridity suppressed sapling growth rates, but no evidence of a shade–drought growth trade-off was found either. Pinus halepensis sapling mortality was strongly growth dependent, exhibiting high mortality rates at low growth, but the mortality of Q. ilex saplings was not. Height–diameter allometric variation was higher in low- than in high-light environments and was more pronounced with respect to changes in light than climatic water. Our results suggest that interspecific differences in sapling mortality and plasticity, rather than growth, may control species distributions at the mesic end of the aridity gradient.
Determination of ecosystem carbon-stock distributions in the flux footprint of an eddy-covariance tower in a coastal forest in British Columbia
Authors: Ferster Colin J. , Trofymow J.A. (Tony) , Coops Nicholas C. , Chen Baozhang , Black T. Andrew , Gougeon François A.
Published: July 2011

An important consideration when interpreting eddy-covariance (EC) flux-tower measurements is the spatial distribution of forest land surface cover and soil type within the EC flux-tower footprint. At many EC flux-tower sites, there is a range of geospatial data available with the ability to estimate the spatial distribution of forest land cover and soils. Developing methods that utilize multiple geospatial data sets will result in more thorough estimates of ecosystem C stock distributions. The objective of this study was to develop, apply, and validate methods to obtain comprehensive estimates of the spatial distribution of ecosystem C stock components from live-tree, detritus, and soil pools within an EC flux-tower footprint. First, a set of geospatial data sets was collected and assessed for its predictive ability for the measured aboveground C stocks. Next, large tree and snag aboveground C stocks were estimated using two methods: (i) a geospatial regression model, and (ii) most similar neighbor (k-MSN) spatial prediction methodology, and the results were compared with those of a multiple linear regression model using light detection and ranging (LiDAR) data alone. Finally, we applied the spatial prediction methodology to estimate the spatial distribution of other C stock components (including soil C and woody debris).
Changes in specific leaf area and photosynthetic nitrogen-use efficiency associated with physiological acclimation of two hybrid poplar clones to intraclonal competition
Authors: Benomar Lahcen , DesRochers Annie , Larocque Guy R.
Published: July 2011

Photosynthesis is the most important process driving productivity, and its acclimation to intraclonal competition is not well understood in hybrid poplars. The aim of this study was to examine the physiological response of the crown of two hybrid poplar clones, BT747215 ( Populus balsamifera L. × Populus trichocarpa Torr. & A. Gray) and MB915319 ( Populus maximowiczii A. Henry × P. balsamifera ), to intraclonal competition. We measured light-saturated photosynthesis (Amax), leaf N content on an area basis (Narea), specific leaf area (SLA), and photosynthetic N-use efficiency (PNUE) for three successive growing seasons on trees planted at three spacings (1 m × 1 m, 3 m × 3 m, and 5 m × 5 m). Crowns were sampled at 10 locations corresponding to vertical and horizontal subdivisions. Significant changes took place at the crown level in the closest spacing (1 m × 1 m) compared with the wider spacings (3 m × 3 m and 5 m × 5 m): (i) 30% decrease in Narea, (ii) 20% increase in SLA, and (iii) 40% increase in PNUE. The slope of the Amax–Narea curve was greatest in the closest spacing, indicating a greater change in Amax per unit change in Narea. The two hybrid poplar clones had a similar morphophysiological response to changes of spacing. Both clones showed physiological acclimation of their foliage in response to intraclonal competition through modulation of SLA and PNUE.
The Homological Kähler‐de Rham Differential Mechanism: II. Sheaf‐Theoretic Localization of Quantum Dynamics
Authors: Mallios Anastasios , Zafiris Elias
Published: July 2011

The homological Kähler‐de Rham differential mechanism models
the dynamical behavior of physical fields by purely algebraic means
and independently of any background manifold substratum. This is of
particular importance for the formulation of dynamics in the quantum
regime, where the adherence to such a fixed substratum is problematic.
In this context, we show that the functorial formulation of the Kähler‐de Rham differential mechanism in categories of sheaves of commutative algebras, instantiating generalized localization environments of
physical observables, induces a consistent functorial framework of dynamics in the quantum regime.
Bayes Estimation of Two‐Phase Linear Regression Model
Authors: Pandya Mayuri , Bhatt Krishnam , Andharia Paresh
Published: July 2011

Let the regression model be Yi = β1Xi + εi, where εi are i. i. d. N (0, σ2) random errors with variance σ2 > 0 but later it was found that there was a change in the system at some point of time m and it is reflected in the sequence after Xm
by change in slope, regression parameter β2. The problem of study is when and where this change has started occurring. This is called change point inference problem. The estimators of m, β1, β2 are derived under asymmetric loss functions, namely, Linex loss & General Entropy loss functions. The effects of correct and wrong prior information on the Bayes estimates are studied.
Water Chreodes and the Mechanisms of Ligand Diffusion, General Anesthesia, and Sleep
Authors: Kier Lemont B.
Published: July 2011

The concept of the presence of passageways, chreodes, created by the influence of the hydropathic states of amino acid side chains on the surface water of proteins, has been proposed. These chreodes facilitate and direct the diffusion of neurotransmitters through surface water, to the receptor or active site on a protein. This system of chreodes is vulnerable to the presence of some other molecules that may encounter the chreode system. This encounter and disruption has been proposed to explain the mechanism of general anesthesia. Based on much recent evidence of the similarities between anesthesia from volatile anesthetic agents and sleep, a comparable mechanism has been proposed for sleep. Since this must be an exogenous substance to be comparable to a general anesthetic agent, it was proposed that this exogenous, sleep-producing substance is elemental nitrogen. Recent evidence supports these hypotheses.
Cost of Illness for Patients with Arthritis Receiving Multidisciplinary Rehabilitation Care
Authors: Grotle Margreth , Hagen Kåre Birger , Uhlig Till , Aas Eline
Published: July 2011

Purpose. To describe healthcare consumption and costs prior to, during, and after multidisciplinary rehabilitation due to arthritis.Methods. 306 patients (age 18–75 years) with arthritis scheduled for multidisciplinary rehabilitation care in 9 rehabilitation centres and 4 rheumatology hospital departments were included and followed for 6 months. Costs were estimated in Euros (€) for the total sample and five clinical subgroups.Results. Healthcare costs ranged from€3,033 to€91,336 and were significantly higher at hospital departments compared to rehabilitation centres:€9,722 (SD 5,406) and€4,250 (SD 1,040). While total costs prior to and after rehabilitation were stable for those receiving rehabilitation at a hospital, there was a significant increase in costs for those being at a rehabilitation centre. Total mean costs were more than doubled when including social costs: from€32,410 (95% CI 20,074–37,017) to€51,491 (95% CI 49,055–61,657).Conclusions. Healthcare and social costs for arthritis rehabilitation were substantial both before and after a rehabilitation stay. It is important to explore methods to reduce the length of rehabilitation stay and production loss connected to rehabilitation of patients with rheumatic disease.
Analogue Behavioral Modeling of GTO
Authors: Azzouz Y. , Schneider H. , Coyitangiye L.-A. , Ravelo B.
Published: July 2011

An analog behavioral model of high power gate turn-off thyristor (GTO) is developed in this paper. The fundamental methodology for the modeling of this power electronic circuit is based on the use of the realistic diode consideration of non-linear junctions. This modeling technique enables to perform different simulations taking into account the turn-on and turn-off transient behaviors in real-time. The equivalent circuits were simulated with analog software developed in our laboratory. It was shown that the tested simple and compact model allows the generation of accurate physical characteristics of power thyristors under dynamic conditions. The model understudy was validated with analog simulations based on operational amplifier devices.
Involvement in Mental Health and Substance Abuse Work: Conceptions of Service Users
Authors: Laitila Minna , Nikkonen Merja , Pietilä Anna-Maija
Published: July 2011

Service user involvement (SUI) is a principal and a guideline in social and health care and also in mental health and substance abuse work. In practice, however, there are indicators of SUI remaining rhetoric rather than reality. The purpose of this study was to analyse and describe service users' conceptions of SUI in mental health and substance abuse work. The following study question was addressed: what are service users' conceptions of service user involvement in mental health and substance abuse work? In total, 27 users of services participated in the study, and the data was gathered by means of interviews. A phenomenographic approach was applied in order to explore the qualitative variations in participants' conceptions of SUI. As a result of the data analysis, four main categories of description representing service users' conceptions of service user involvement were formed: service users have the best expertise, opinions are not heard, systems make the rules, and courage and readiness to participate. In mental health and substance abuse work, SUI is still insufficiently achieved and there are obstacles to be taken into consideration. Nurses are in a key position to promote and encourage service user involvement.
Modeling and Simulation of Special Shaped SOI Materials for the Nanodevices Implementation
Authors: Ravariu Cristian , Babarada Florin
Published: July 2011

In the industrial chain of the nanomaterials for electronic devices, a main stage is represented by the wafer characterization. This paper is starting from a standard SOI wafer with 200 nm film thickness and is proposing two directions for the SOI materials miniaturization, indexing the static characteristics by simulation. The first SOI nanomaterial is a sub-10 nm Si-film with a rectangular shape. The influence of the buried interface fixed charges has to be approached by the distribution theory. The second proposal studies the influence of the vacuum cavity in a “U” shaped SOI nanofilm. In all cases, with rectangular or “U” shape film, the simulations reveal transfer characteristics with a maximum and output characteristics with a minimum for sub-10 nm thickness of the SOI film.
Starlikeness Properties of a New Integral Operator for Meromorphic Functions
Authors: Mohammed Aabed , Darus Maslina
Published: July 2011

We define here an integral operator for meromorphic functions
in the punctured open unit disk. Several starlikeness conditions for the integral operator are derived.
Semiconservative Systems of Integral Equations with Two Kernels
Authors: Yengibaryan N. B. , Barseghyan A. G.
Published: July 2011

The solvability and the properties of solutions of nonhomogeneous and homogeneous vector integral equation , where K, T are n × n
matrix valued functions, n ≥ 1, with nonnegative integrable
elements, are considered in one semiconservative (singular) case, where the matrix is stochastic one and the matrix is substochastic one. It is shown that in certain conditions the nonhomogeneous equation simultaneously with the corresponding homogeneous one possesses positive solutions.
Comprehensive Genome Methylation Analysis in Bladder Cancer: Identification and Validation of Novel Methylated Genes and Application of These as Urinary Tumor Markers
Authors: Reinert Thomas , Modin Charlotte , Castano Francisco M. , Lamy Philippe , Wojdacz Tomasz K. , Hansen Lise Lotte , Wiuf Carsten , Borre Michael , Dyrskjøt Lars , Ørntoft Torben F.
Published: July 2011

Purpose: Epigenetic alterations are common and can now be addressed in a parallel fashion. We investigated the methylation in bladder cancer with respect to location in genome, consistency, variation in metachronous tumors, impact on transcripts, chromosomal location, and usefulness as urinary markers.

Experimental Design: A microarray assay was utilized to analyze methylation in 56 samples. Independent validation was conducted in 63 samples by a PCR-based method and bisulfite sequencing. The methylation levels in 174 urine specimens were quantified. Transcript levels were analyzed using expression microarrays and pathways were analyzed using dedicated software.

Results: Global methylation patterns were established within and outside CpG islands. We validated methylation of the eight tumor markers genes ZNF154 (P < 0.0001), HOXA9 (P < 0.0001), POU4F2 (P < 0.0001), EOMES (P = 0.0005), ACOT11 (P = 0.0001), PCDHGA12 (P = 0.0001), CA3 (P = 0.0002), and PTGDR (P = 0.0110), the candidate marker of disease progression TBX4 (P < 0.04), and other genes with stage-specific methylation. The methylation of metachronous tumors was stable and targeted to certain pathways. The correlation to expression was not stringent. Chromosome 21 showed most differential methylation (P < 0.0001) and specifically hypomethylation of keratins, which together with keratin-like proteins were epigenetically regulated. In DNA from voided urine, we detected differential methylation of ZNF154 (P < 0.0001), POU4F2 (P < 0.0001), HOXA9 (P < 0.0001), and EOMES (P < 0.0001), achieving 84% sensitivity and 96% specificity.

Conclusions: We initiated a detailed mapping of the methylome in metachronous bladder cancer. Novel genes with tumor, chromosome, as well as pathway-specific differential methylation in bladder cancer were identified. The methylated genes were promising cancer markers for early detection of bladder cancer. Clin Cancer Res; 17(17); 5582–92. ©2011 AACR.
Gonadal Development and Tumor Formation at the Crossroads of Male and Female Sex Determination
Authors: Cools M. , Wolffenbuttel K.P. , Drop S.L.S. , Oosterhuis J.W. , Looijenga L.H.J.
Published: July 2011

Malignant germ cell tumor (GCT) formation is a well-known complication in the management of patients with a disorder of sex development (DSD). DSDs are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical. DSD patients in whom the karyotype – at least at the gonadal level – contains (a part of) the Y chromosome are at increased risk for neoplastic transformation of germ cells, leading to the development of the so-called ‘type II germ cell tumors’. However, tumor risk in the various forms of DSD varies considerably between the different diagnostic groups. This contribution integrates our actual knowledge on the pathophysiology of tumor development in DSDs, recent findings on gonadal (mal)development in DSD patients, and possible correlations between the patient’s phenotype and his/her risk for germ cell tumor development.
Molecular Class as a Predictor of Locoregional and Distant Recurrence in the Neoadjuvant Setting for Breast Cancer
Authors: Vargo John A. , Beriwal Sushil , Ahrendt Gretchen M. , Soran Atilla , Johnson Ronald R. , McGuire Kandace , Bhargava Rohit
Published: July 2011

Background: The molecular subtype by hormone receptor status predicts recurrence in the adjuvant setting. Here, we report recurrence patterns by molecular subtype following neoadjuvant chemotherapy (NACT) to identify subgroups prone to recurrence. Materials and Methods: We retrospectively analyzed 331 patients receiving NACT plus lumpectomy and whole breast radiation therapy (RT) (n = 155), or mastectomy with (n = 122) or without (n = 50) adjuvant RT. Tumors were classified by immunohistochemical (IHC) surrogate markers into luminal A (strong ER+/PR+; HER2–), luminal B (weak-to-moderate ER+/PR+; HER2–), HER2 (HER2+), and triple-negative/basal subtypes. Results: The median follow-up was 43 months (range 10–104). The 5-year disease-free survival (DFS) was 71.4, 70.1, 70.4, and 62.1% for luminal A, luminal B, HER2, and basal subtypes, respectively. The 5-year distant recurrence rates were 25.8, 28.7, 28.7, and 35.2%. The 5-year locoregional recurrence rates were 3.8, 1.6, 1.3, and 4.2%. Molecular class (p = 0.003) and pathologic complete response (pCR; p = 0.004) predicted distant recurrence, DFS, and overall survival (OS). Only the omission of adjuvant RT following mastectomy (p = 0.006) predicted locoregional recurrence. Conclusions: IHC subclassification and pCR predict distant failure, DFS, and OS in the neoadjuvant setting. While not predictive of locoregional recurrence, the total number of events were small. More work is needed to define if molecular class can predict patients at risk for locoregional recurrence.
Mutation in the Tight-Junction Gene Claudin 19 (CLDN19) and Familial Hypomagnesemia, Hypercalciuria, Nephrocalcinosis (FHHNC) and Severe Ocular Disease
Authors: Naeem Muhammad , Hussain Sofia , Akhtar Naureen
Published: July 2011

Background/Aims: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is a rare renal tubular disorder complicated by progressive renal failure during childhood or adolescence. Recently, causative mutations in the CLDN19 gene have been identified in FHHNC patients presenting with severe ocular involvement. The aim of the study was to investigate the molecular genetic defect underlying FHHNC in a consanguineous Pakistani family. Methods: Clinical and biochemical parameters of the proband were studied during the follow-up period over 5 years. Genotyping of 7 members of the family was performed by amplifying microsatellite markers, tightly linked to the CLDN16 and CLDN19 genes. The two genes were sequenced directly in an automated sequencer. PCR-RFLP assay and bioinformatic analysis were performed to verify the identified mutation. Results: Genotyping revealed that the proband was homozygous for the marker loci tightly linked to the CLDN19 gene. Sequence analysis in the proband revealed homozygosity for a novel missense mutation in exon 3 of the CLDN19 gene (389G>A) resulting in G130D amino acid substitution. Bioinformatic analysis supported the pathogenicity of the identified mutation. Family screening revealed nephrolithiasis in 3 of 6 (50%) heterozygous carriers of the pathogenic mutation. Conclusion: This study supports the fundamental role of claudin 19 for magnesium homeostasis, normal tubular structures in the kidney, and undisturbed organization and development of the retina.
Mobile Thrombus on Device Leads in Patients Undergoing Ablation
Authors: Supple Gregory E. , Ren Jian-Fang , Zado Erica S. , Marchlinski Francis E.
Published: July 2011

Background—

Mobile thrombi, not routinely recognized on transthoracic echocardiography, are frequently identified on cardiovascular implantable electronic device leads with intracardiac echocardiography (ICE) during ablation procedures. Their incidence, characteristics, and consequences have not yet been defined.

Methods and Results—

We used ICE to examine leads for thrombi and to measure the pulmonary artery systolic pressure in patients with a cardiovascular implantable electronic device presenting for ablation. Patient clinical characteristics, device type, and lead characteristics were correlated with presence of thrombi. Most patients had congestive heart failure (84%), with an average left ventricular ejection fraction of 40%. Thrombi were seen with ICE in 26 of 86 patients (30%) but were seen on transthoracic echocardiography in only 1 of the 26 patients. Thrombi on ICE were mobile, averaged 18±5.9 mm long by 4.4±2.3 mm wide, and were more commonly identified in the right atrium (n=25) than in the right ventricle (n=5). Thrombi were associated with higher pulmonary artery systolic pressure: 39±9 mm Hg with thrombi versus 33±7 mm Hg without thrombi (odds ratio, 1.11; 95% confidence interval, 1.03 to 1.20;
P
=0.01). No other characteristic assessed was associated with a significant difference in the presence of lead thrombi.

Conclusions—

Mobile thrombi on cardiovascular implantable electronic device leads are present in 30% of patients undergoing ablation and are readily identified with ICE despite being underrecognized with transthoracic echocardiography. Further study is warranted to determine whether lead thrombi are a clinically relevant source of pulmonary emboli in some patients with cardiovascular implantable electronic devices.
Differential Impacts of Blood Pressure and Lipid Lowering on Regression of Ventricular and Arterial Mass
Authors: Roman Mary J. , Howard Barbara V. , Howard Wm. James , Mete Mihriye , Fleg Jerome L. , Lee Elisa T. , Devereux Richard B.
Published: July 2011

The relative impacts of lowering blood pressure versus lowering low-density lipoprotein (LDL) cholesterol on regression of ventricular and arterial mass have not been systematically examined. Changes in left ventricular mass and arterial mass (common carotid artery cross-sectional area) after 36 months of simultaneous lowering of systolic blood pressure and LDL cholesterol were examined in the Stop Atherosclerosis in Native Diabetics Trial of standard versus aggressive LDL cholesterol and blood pressure targets in American Indians with type 2 diabetes mellitus. The 2 treatment groups were combined to examine changes in left ventricular and arterial mass over a spectrum of achieved blood pressure and lipid levels. Among the combined group of 413 Stop Atherosclerosis in Native Diabetics Trials participants, systolic blood pressure, LDL cholesterol, and left ventricular mass were all significantly reduced, whereas arterial mass significantly increased, after 36 months of therapy (
P
<0.001 for all). In linear regression models, a decrease in arterial mass was significantly related to achieved systolic blood pressure and, to a lesser extent, achieved LDL cholesterol, after adjustment for important covariates. Left ventricular mass progressively decreased with lower achieved levels of systolic blood pressure, independent of baseline levels of left ventricular mass. In conclusion, achieved levels of systolic blood pressure are important determinants of the extent of regression of arterial and ventricular mass during prolonged therapy in diabetic individuals. Achieved levels of LDL cholesterol influence regression of arterial but not ventricular mass. Our findings suggest that there is no threshold of systolic blood pressure below which regression of cardiovascular target organ damage cannot be achieved.
Innate signals overcome acquired TCR signaling pathway regulation and govern the fate of human CD161hi CD8α+ semi-invariant T cells
Authors: Turtle Cameron J. , Delrow Jeff , Joslyn Rochelle C. , Swanson Hillary M. , Basom Ryan , Tabellini Laura , Delaney Colleen , Heimfeld Shelly , Hansen John A. , Riddell Stanley R.
Published: July 2011

Type 17 programmed CD161hiCD8α+ T cells contribute to mucosal immunity to bacteria and yeast. In early life, microbial colonization induces proliferation of CD161hi cells that is dependent on their expression of a semi-invariant Vα7.2+ TCR. Although prevalent in adults, CD161hiCD8α+ cells exhibit weak proliferative and cytokine responses to TCR ligation. The mechanisms responsible for the dichotomous response of neonatal and adult CD161hi cells, and the signals that enable their effector function, have not been established. We describe acquired regulation of TCR signaling in adult memory CD161hiCD8α+ T cells that is absent in cord CD161hi cells and adult CD161lo cells. Regulated TCR signaling in CD161hi cells was due to profound alterations in TCR signaling pathway gene expression and could be overcome by costimulation through CD28 or innate cytokine receptors, which dictated the fate of their progeny. Costimulation with IL-1β during TCR ligation markedly increased proinflammatory IL-17 production, while IL-12–induced Tc1-like function and restored the response to TCR ligation without costimulation. CD161hi cells from umbilical cord blood and granulocyte colony stimulating factor-mobilized leukaphereses differed in frequency and function, suggesting future evaluation of the contribution of CD161hi cells in hematopoietic stem cell grafts to transplant outcomes is warranted.
Polydatin up-regulates clara cell secretory protein to suppress phospholipase A2 of lung induced by LPS in vivo and in vitro
Authors: Shiyu Shu , Zhiyu Ling , Mao Ye , Lin Bo , Lijia Wang , Tianbao Zhang , Jie Chen , Tingyu Li
Published: July 2011

Background

Lung injury induced by lipopolysaccharide (LPS) remains one of the leading causes of morbidity and mortality in children. The damage to membrane phospholipids leads to the collapse of the bronchial alveolar epithelial barrier during acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Phospholipase A2 (PLA2), a key enzyme in the hydrolysis of membrane phospholipids, plays an important traumatic role in pulmonary inflammation, and Clara cell secretory protein (CCSP) is an endogenous inhibitor of PLA2. Our previous study showed that polydatin (PD), a monocrystalline extracted from a traditional Chinese medicinal herb (Polygonum cuspidatum Sieb, et Zucc), reduced PLA2 activity and sPLA2-IIA mRNA expression and mitigated LPS-induced lung injury. However, the potential mechanism for these effects has not been well defined. We have continued to investigate the effect of PD on LPS-induced expression of CCSP mRNA and protein in vivo and in vitro.

Results

Our results suggested that the CCSP mRNA level was consistent with its protein expression. CCSP expression was decreased in lung after LPS challenge. In contrast, PD markedly increased CCSP expression in a concentration-dependent manner. In particular, CCSP expression in PD-pretreated rat lung was higher than in rats receiving only PD treatment.

Conclusion

These results indicated that up-regulation of CCSP expression causing inhibition of PLA2 activation may be one of the crucial protective mechanisms of PD in LPS-induced lung injury.
Cognitive behaviour therapy in medication-treated adults with ADHD and persistent Symptoms: A randomized controlled trial
Authors: Emilsson Brynjar , Gudjonsson Gisli , Sigurdsson Jon F , Baldursson Gisli , Einarsson Emil , Olafsdottir Halldora , Young Susan
Published: July 2011

Background

Attention deficit hyperactivity disorder (ADHD) in adulthood is not fully treated by psychopharmacological treatment alone. The main aim of the current study was to evaluate a newly developed cognitive behaviour therapy (CBT) based group programme, the Reasoning and Rehabilitation for ADHD Youths and Adults (R&R2ADHD), using a randomized controlled trial.

Methods

54 adults with ADHD already receiving psychopharmacological treatment were randomly allocated to an experimental (CBT/MED) treatment condition (n = 27) and a 'treatment as usual' (TAU/MED) control condition (n = 27) that did not receive the CBT intervention. The outcome measures were obtained before treatment (baseline), after treatment and at three month follow-up and included ADHD symptoms and impairments rated by independent assessors, self-reported current ADHD symptoms, and comorbid problems.

Results

The findings suggested medium to large treatment effects for ADHD symptoms, which increased further at three month follow-up. Additionally, comorbid problems also improved at follow-up with large effect sizes.

Conclusions

The findings give support for the effectiveness of R&R2ADHD in reducing ADHD symptoms and comorbid problems, an improving functions associated with impairment. The implications are that the benefits of R&R2ADHD are multifaceted and that combined psychopharmacological and CBT based treatments may add to and improve pharmacological interventions.

Trial registration

ACTRN12611000533998 (http://www.ANZCTR.org.au/ACTRN12611000533998.aspx)
Evaluating target silencing by short hairpin RNA mediated by the group I intron in cultured mammalian cells
Authors: Noguchi Kousei , Ishitu Yoshio , Takaku Hiroshi
Published: July 2011

Background

The group I intron, a ribozyme that catalyzes its own splicing reactions in the absence of proteins in vitro, is a potential target for rational engineering and attracted our interest due to its potential utility in gene repair using trans-splicing. However, the ribozyme activity of a group I intron appears to be facilitated by RNA chaperones in vivo; therefore, the efficiency of self-splicing could be dependent on the structure around the insert site or the length of the sequence to be inserted. To better understand how ribozyme activity could be modulated in cultured mammalian cells, a group I intron was inserted into a short hairpin RNA (shRNA), and silencing of a reporter gene by the shRNA was estimated to reflect self-splicing activity in vivo. In addition, we appended a theophylline-binding aptamer to the ribozyme to investigate any potential effects caused by a trans-effector.

Results

shRNA-expression vectors in which the loop region of the shRNA was interrupted by an intron were constructed to target firefly luciferase mRNA. There was no remarkable toxicity of the shRNA-expression vectors in Cos cells, and the decrease in luciferase activity was measured as an index of the ribozyme splicing activity. In contrast, the expression of the shRNA through intron splicing was completely abolished in 293T cells, although the silencing induced by the shRNA-expressing vector alone was no different from that in the Cos cells. The splicing efficiency of the aptamer-appended intron also had implications for the potential of trans-factors to differentially promote self-splicing among cultured mammalian cells.

Conclusions

Silencing by shRNAs interrupted by a group I intron could be used to monitor self-splicing activity in cultured mammalian cells, and the efficiency of self-splicing appears to be affected by cell-type specific factors, demonstrating the potential effectiveness of a trans-effector.
Training Trainers in health and human rights: Implementing curriculum change in South African health sciences institutions
Authors: Ewert Elena G , Baldwin-Ragaven Laurel , London Leslie
Published: July 2011

Background

The complicity of the South African health sector in apartheid and the international relevance of human rights as a professional obligation prompted moves to include human rights competencies in the curricula of health professionals in South Africa. A Train-the-Trainers course in Health and Human Rights was established in 1998 to equip faculty members from health sciences institutions nationwide with the necessary skills, attitudes and knowledge to teach human rights to their students. This study followed up participants to determine the extent of curriculum implementation, support needed as well as barriers encountered in integrating human rights into health sciences teaching and learning.

Methods

A survey including both quantitative and qualitative components was distributed in 2007 to past course participants from 1998-2006 via telephone, fax and electronic communication.

Results

Out of 162 past participants, 46 (28%) completed the survey, the majority of whom were still employed in academic settings (67%). Twenty-two respondents (48%) implemented a total of 33 formal human rights courses into the curricula at their institutions. Respondents were nine times more likely (relative risk 9.26; 95% CI 5.14-16.66) to implement human rights education after completing the training. Seventy-two extracurricular activities were offered by 21 respondents, many of whom had successfully implemented formal curricula. Enabling factors for implementation included: prior teaching experience in human rights, general institutional support and the presence of allies - most commonly coworkers as well as deans. Frequently cited barriers to implementation included: budget restrictions, time constraints and perceived apathy of colleagues or students. Overall, respondents noted personal enrichment and optimism in teaching human rights.

Conclusion

This Train-the-Trainer course provides the historical context, educational tools, and collective motivation to incorporate human rights educational initiatives at health sciences institutions. Increased implementation of human rights instruction, both formally and extracurricularly, has demonstrated the training's significance not only within academic institutions but more broadly across the health sector. Coworkers are vital allies in teaching human rights to health sciences students, helping to alleviate institutional barriers. Training fellow staff members and those in key leadership roles is noted as vital to the sustainability of human rights education.
T cell activity in successful treatment of chronic urticaria with omalizumab
Authors: Sánchez-Machín Inmaculada , Iglesias-Souto Javier , Franco Andrés , Barrios Yvelise , Gonzalez Ruperto , Matheu Víctor
Published: July 2011

Omalizumab, a humanized monoclonal anti-IgE antibody has the potential to alter allergen processing. Recently, it has been postulated the assessment of PHA-stimulated adenosine triphosphate (ATP) activity as maker of CD4+ T cells activity in peripheral blood cells. We present the case report of a 35-year-old woman with a history of chronic idiopathic urticaria and angioedema of 8 years of development with poor response to treatment. The patient was partially controlled with cyclosporine at doses of 100 mg/12 h. However, she was still developing hives daily. Finally treatment with omalizumab was started at dose of 300 mg every 2 weeks. The patient experienced a decrease in urticarial lesions 2 days after starting therapy. We also evaluated the effects of omalizumab therapy on the activity of peripheral blood CD4+ T cells from the patient, in order to determine the potential modification of anti-IgE therapy on the process of antigen presentation-recognition. Activity of CD4+ cells by ATP release was clearly increased demonstrating an enlarged CD4 activity. Omalizumab may be useful in the treatment of severe chronic urticaria. ATP activity of peripheral blood CD4+ T cells might be a non-subjective method to assess Omalizumab activity.