bluuebunny/crossref_metadata_2025 huggingface dataset:
Epidemiology of Plasmodium infections in Flores Island, Indonesia using real-time PCR
Authors: Kaisar Maria MM , Supali Taniawati , Wiria Aprilianto E , Hamid Firdaus , Wammes Linda J , Sartono Erliyani , Luty Adrian JF , Brienen Eric AT , Yazdanbakhsh Maria , van Lieshout Lisette , Verweij Jaco J
Published: May 2013

Background

DNA-based diagnostic methods have been shown to be highly sensitive and specific for the detection of malaria. An 18S-rRNA-based, real-time polymerase chain reaction (PCR) was used to determine the prevalence and intensity of Plasmodium infections on Flores Island, Indonesia.

Methods

Microscopy and real-time multiplex PCR for the detection of Plasmodium species was performed on blood samples collected in a population-based study in Nangapanda Flores Island, Indonesia.

Results

A total 1,509 blood samples were analysed. Real-time PCR revealed prevalence for Plasmodium falciparum, Plasmodium vivax, and Plasmodium malariae to be 14.5%, 13.2%, and 1.9% respectively. Sub-microscopic parasitaemia were found in more than 80% of all positive cases. The prevalence of P. falciparum and P. vivax was significantly higher in subjects younger than 20 years (p ≤ 0.01). In the present study, among non-symptomatic healthy individuals, anaemia was strongly correlated with the prevalence and load of P. falciparum infections (p ≤ 0.01; p = 0.02) and with the load of P. vivax infections (p = 0.01) as detected with real-time PCR. Subjects with AB blood group tend to have a higher risk of being infected with P. falciparum and P. vivax when compared to other blood groups.

Conclusion

The present study has shown that real-time PCR provides more insight in the epidemiology of Plasmodium infections and can be used as a monitoring tool in the battle against malaria. The unsurpassed sensitivity of real-time PCR reveals that sub microscopic infections are common in this area, which are likely to play an important role in transmission and control.

Trial registration

Trials number http://www.controlled-trials.com/ISRCTN83830814
Novel mechanism of regulation of fibrosis in kidney tumor with tuberous sclerosis
Authors: Liang Sitai , Cuevas Gabriela , Tizani Shaza , Salas Tiffanie , Liu Huijuan , Li Baojie , Habib Samy L
Published: May 2013

Background

Deficiency in tuberin results in activation the mTOR pathway and leads to accumulation of cell matrix proteins. The mechanisms by which tuberin regulates fibrosis in kidney angiomyolipomas (AMLs) of tuberous sclerosis patients are not fully known.

Method

In the present study, we investigated the potential role of tuberin/mTOR pathway in the regulation of cell fibrosis in AML cells and kidney tumor tissue from tuberous sclerosis complex (TSC) patients.

Results

AML cells treated with rapamycin shows a significant decrease in mRNA and protein expression as well as in promoter transcriptional activity of alpha-smooth muscle actin (α-SMA) compared to untreated cells. In addition, cells treated with rapamycin significantly decreased the protein expression of the transcription factor YY1. Rapamycin treatment also results in the redistribution of YY1 from the nucleus to cytoplasm in AML cells. Moreover, cells treated with rapamycin resulted in a significant reduce of binding of YY1 to the αSMA promoter element in nuclear extracts of AML cells. Kidney angiomyolipoma tissues from TSC patients showed lower levels of tuberin and higher levels of phospho-p70S6K that resulted in higher levels of mRNA and protein of αSMA expression compared to control kidney tissues. In addition, most of the α-SMA staining was identified in the smooth muscle cells of AML tissues. YY1 was also significantly increased in tumor tissue of AMLs compared to control kidney tissue suggesting that YY1 plays a major role in the regulation of αSMA.

Conclusions

These data comprise the first report to provide one mechanism whereby rapamycin might inhibit the cell fibrosis in kidney tumor of TSC patients.
Effects of a commercial product containing guaraná on psychological well-being, anxiety and mood: a single-blind, placebo-controlled study in healthy subjects
Authors: Silvestrini Gianluca Ivan , Marino Franca , Cosentino Marco
Published: May 2013

Background

Guaranà (Paulinia cupana) seed extracts are increasingly popular worldwide for their stimulant, cognitive and behavioral effects. To assess the effects on psychological well-being, anxiety and mood of a commercially available guaranà preparation taken regularly over several days according to the labelled dosages and instructions, 27 healthy volunteers were enrolled in a prospective, randomized, single-blind, placebo-controlled, crossover study.

Results

Guaranà 350 mg × 3 daily just after breakfast or placebo were given for 5 consecutive days. Assessment was performed one day after the last intake and included the psychological well-being (PWB) scales, the self-rating anxiety state scale (SAS), and the Bond–Lader mood scales. There were no significant differences between guaranà and placebo in any of the 6 areas of PWB, in SAS, as well as in any of the 16 mood scales.

Conclusions

In healthy subjects a 5-day treatment with a commercial preparation of guaranà used according to labelled instructions provided no evidence for any major effects on psychological well-being, anxiety and mood. Considering the increasing popularity of guaranà-containing products sold as dietary supplements for fitness purposes, controlled studies are strongly warranted to assess their benefits in comparison to the labelled claims.
Passivation mechanism of thermal atomic layer-deposited Al2O3 films on silicon at different annealing temperatures
Authors: Zhao Yan , Zhou Chunlan , Zhang Xiang , Zhang Peng , Dou Yanan , Wang Wenjing , Cao Xingzhong , Wang Baoyi , Tang Yehua , Zhou Su
Published: May 2013

Thermal atomic layer-deposited (ALD) aluminum oxide (Al2O3) acquires high negative fixed charge density (Q
f) and sufficiently low interface trap density after annealing, which enables excellent surface passivation for crystalline silicon. Q
f can be controlled by varying the annealing temperatures. In this study, the effect of the annealing temperature of thermal ALD Al2O3 films on p-type Czochralski silicon wafers was investigated. Corona charging measurements revealed that the Q
f obtained at 300°C did not significantly affect passivation. The interface-trapping density markedly increased at high annealing temperature (>600°C) and degraded the surface passivation even at a high Q
f. Negatively charged or neutral vacancies were found in the samples annealed at 300°C, 500°C, and 750°C using positron annihilation techniques. The Al defect density in the bulk film and the vacancy density near the SiO
x
/Si interface region decreased with increased temperature. Measurement results of Q
f proved that the Al vacancy of the bulk film may not be related to Q
f. The defect density in the SiO
x
region affected the chemical passivation, but other factors may dominantly influence chemical passivation at 750°C.
Discretionary bandwidth granting scheme for homogenous real-time applications
Authors: Wee Kuokkwee , R Mardeni , Tan S W , Lee S W
Published: May 2013

IEEE 802.16e is an advanced wireless access technology that provides high-speed data transmission in long distance and offers quality of service (QoS) to subscribers. The provisioning of QoS is one of the great features by IEEE 802.16 to support both real-time and non-real-time applications. In IEEE 802.16, the common part sublayer in the MAC layer is responsible for maintaining the QoS services. There are many functions in the common part sublayer; the most popular topics discussed by researchers are the uplink and downlink scheduling algorithms. Many discussions had been made and focused on these two classes of schedulers. Another equally important component but overlooked so far is the bandwidth request and grant module. Bandwidth request and grant module arbitrates the amount of bandwidth to be granted, besides handling the bandwidth requests. This bandwidth request and grant process has always been developed in a conventional way, and its importance has been underestimated. In addition, the bandwidth distribution within a same service class or category also attracted little attention thus far. Many algorithms for interclass scheduling have been studied and proposed but not as much for intraclass scheduling. However, in bandwidth request and grant process, constraints on the required knowledge by the schedulers limit the intraclass scheduling algorithms to be applied onto them. We view the bandwidth request and grant process as an important part of the QoS architecture. In this paper, we proposed a new bandwidth granting scheme for the bandwidth request and granting process, which enables bandwidth to be fairly granted based on the necessity to all the requests from the same service class or category. By applying our scheme, significant improvements have been observed and recorded. Experiment results have proven and confirmed the effectiveness of our proposed scheme as compared to the conventional scheme.
Clinical results of XMR-assisted percutaneous transforaminal endoscopic lumbar discectomy
Authors: Choi Gun , Modi Hitesh N , Prada Nicolas , Ahn Tae-Joon , Myung Sung Hee , Gang Mi Sun , Lee Sang-Ho
Published: May 2013

Background

Although percutaneous endoscopic lumbar discectomy (PELD) has shown favorable outcomes in the majority of lumbar discectomy cases, there were also some failures. The most common cause of failure is the incomplete removal of disc fragments. The skin entry point for the guide-needle trajectory and the optimal placement of the working sleeve are largely blind, which might lead to the inadequate removal of disc fragments. The objective of this study was to present our early experiences with image-guided PELD using a specially designed fluoroscope with magnetic resonance imaging-equipped operative suite (XMR) for the treatment of lumbar disc herniation.

Methods

This prospective study included 89 patients who had undergone PELD via the transforaminal approach using an XMR protocol. Pre- and postoperative examinations (at 12 weeks) included a detailed clinical history, visual analogue scale (VAS), Oswestry disability index (ODI), and radiological workups. The results were categorized as excellent, good, fair, and poor according to MacNab's criteria. At the final follow-up, the minimum follow-up time for the subjects was 2 years. The need for revision surgeries and postoperative complications were noted on follow-up.

Results

Postoperative mean ODI decreased from 67.4% to 5.61%. Mean VAS score for back and leg pain improved significantly from 4 to 2.3 and from 7.99 to 1.04, respectively. Four (4.49%) patients underwent a second-stage PELD after intraoperative XMR had shown remnant fragments after the first stage. As per MacNab's criteria, 76 patients (85.4%) showed excellent, 8 (8.89%) good, 3 (3.37%) fair, and 2 (2.25) poor results. Four (4.49%) patients had remnant disc fragments on XMR, which were removed during the same procedure. All of these patients had either highly migrated or sequestrated disc fragments preoperatively. Four (4.49%) other patients needed a second, open surgery due to symptomatic postoperative hematoma (n= 2) and recurrent disc herniation (n= 2).

Conclusions

This prospective analysis indicates that XMR-assisted PELD provides a precise skin entry point. It also confirms that decompression occurs intraoperatively, which negates the need for a separate surgery and thus increases the success rate of PELD, particularly in highly migrated or sequestrated discs. However, further extensive experience is required to confirm the advantages and feasibility of PELD in terms of cost effectiveness.
Importance of appropriate pharmaceutical management in pregnant women with ulcerative colitis
Authors: Ujihara Masaki , Ando Takafumi , Ishiguro Kazuhiro , Maeda Osamu , Watanabe Osamu , Hirayama Yutaka , Morise Kazuhiro , Maeda Keiko , Matsushita Masanobu , Miyahara Ryoji , Ohmiya Naoki , Nishio Yuji , Yamaguchi Takeo , Haruta Jun-ichi , Ina Kenji , Goto Hidemi
Published: May 2013

Background

Ulcerative colitis (UC) often occurs in women of childbearing age. Compared to Western countries, however, few studies have investigated the impact of UC on the progress of pregnancy in Asian populations.

Methods

We retrospectively examined 91 pregnancies in 64 patients with UC experienced at our hospital and related institutions from 1991 to 2011, focusing on the relationship between the progression of UC during pregnancy, progress of the pregnancy itself, and the treatment of UC.

Results

In 80 of 91 pregnancies the patient had already been diagnosed with UC at the time she became pregnant, of whom 31 (38.8%) experienced exacerbation during pregnancy. Regarding severity, moderate or severe active-stage disease during pregnancy was seen in 13.7% of those who had been in remission at the onset of pregnancy versus 58.6% of those who had been in the active stage at onset (OR 8.9: 95%CI 3.0~26.4; P<0.01). The incidence of miscarriage or abortion was 9.8% in pregnancies in which UC was in remission at onset versus 31% in those in which it was in the active stage at onset (OR 4.1: 95%CI 1.2~13.9; P=0.02). Among patients, 62.5% were receiving pharmaceutical treatment at onset of pregnancy. Exacerbation during pregnancy occurred in 26.5% of the group who continued to receive the same treatment during pregnancy versus 56.3% of those with a dose decrease or discontinuation after onset (OR 3.6: 95%CI 1.0~12.4; P=0.04).

Conclusions

UC patients wishing to conceive should do so when in remission and continue appropriate pharmaceutical treatment during pregnancy.
Neurological characterization of mice deficient in GSK3α highlight pleiotropic physiological functions in cognition and pathological activity as Tau kinase
Authors: Maurin Hervé , Lechat Benoit , Dewachter Ilse , Ris Laurence , Louis Justin V , Borghgraef Peter , Devijver Herman , Jaworski Tomasz , Van Leuven Fred
Published: May 2013

Background

GSK3β is involved in a wide range of physiological functions, and is presumed to act in the pathogenesis of neurological diseases, from bipolar disorder to Alzheimer’s disease (AD). In contrast, the GSK3α isozyme remained largely ignored with respect to both aspects.

Results

We generated and characterized two mouse strains with neuron-specific or with total GSK3α deficiency. Behavioral and electrophysiological analysis demonstrated the physiological importance of neuronal GSK3α, with GSK3β not compensating for impaired cognition and reduced LTP. Interestingly, the passive inhibitory avoidance task proved to modulate the phosphorylation status of both GSK3 isozymes in wild-type mice, further implying both to function in cognition. Moreover, GSK3α contributed to the neuronal architecture of the hippocampal CA1 sub-region that is most vulnerable in AD. Consequently, practically all parameters and characteristics indicated that both GSK3 isoforms were regulated independently, but that they acted on the same physiological functions in learning and memory, in mobility and in behavior.

Conclusions

GSK3α proved to be regulated independently from GSK3β, and to exert non-redundant physiological neurological functions in general behavior and in cognition. Moreover, GSK3α contributes to the pathological phosphorylation of protein Tau.
Dermatology within the UK podiatric literature: a content analysis (1989‐2010)
Authors: Bristow Ivan R , Borthwick Alan M
Published: May 2013

Background

Although dermatology, as a medical subject, has been a facet of the training and education of podiatrists for many years, it is, arguably, only in recent years that the speciality of podiatric dermatology has emerged within the profession. Some indication of this gradual development may be identified through a content analysis of the podiatric literature in the UK, spanning a 21 year timeframe.

Method

6 key professional journals were selected for content analysis in order to provide a picture of the emergence and development of podiatric dermatology over a period extending from 1989 to 2010. Both syntactical and thematic unitization were deployed in the analysis, revealing both manifest and latent content. Categories were devised using a prior coding, a codebook produced to define relevant concepts and category characteristics, and the coding scheme subject to an assessment of reliability.

Results

1611 units appeared in the 6 journals across a 21 year timeframe. 88% (n = 1417) occurred in one journal (Podiatry Now and its predecessors). Modal categories within all journals included course adverts (n = 673), commercial adverts (n = 562) and articles by podiatrists (n = 133). There was an overall rise from 40 per annum in 1989, to over 100 in 2010. A wider range of dermatological topics were addressed, ranging from fungal nail infections to melanoma.

Conclusions

It is evident from this analysis that there has been an increasing focus on dermatology as a topic within the main podiatric journals in the UK over the last 21 years, primarily reflecting a rise in commercial advertising and an increase in academic dermatology related publications. Whilst earlier publications tended to focus on warts and fungal infections, more recent publications address a broader spectrum of topics. Changes in prescribing rights may be relevant to these findings, as may the enhanced professional and regulatory body requirements on continuing professional development.
Sol–gel synthesis, characterization, and optical properties of Gd3+-doped CdO sub-micron materials
Authors: Alemi Abdolali , Joo Sang Woo , Khademinia Shahin , Dolatyari Mahboubeh , Bakhtiari Akbar , Moradi Hossein , Saeidi Sorayya
Published: May 2013

Highly crystalline Gd3+-doped cadmium oxide micro-structure was synthesized by calcining the obtained precursor of a sol–gel reaction. The reaction was carried out with cadmium nitrate (Cd(NO3)2·4H2O), gadolinium oxide, and ethylene glycol (C2H6O2) reactants without any additives at 80°C for 2 h. The resulting gel was calcined at 900°C with increasing temperature rate of 15°C/min for 12 h in a furnace. As a result of heating, the organic section of the gel was removed, and the Gd3+-doped cadmium oxide micro-structure was produced. The obtained compound from the sol–gel technique possesses a cubic crystalline structure at a micro scale. XRD study indicates that the obtained Gd3+-doped CdO has a cubic phase. Also, the SEM images showed that the resulting material is composed of particles with cluster structure. Also, FT-IR spectroscopy was employed to characterize the Gd3+-doped CdO micro-structures.
Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo
Authors: Shepard John B , Jeong Jae-Wook , Maihle Nita J , O'Brien Sean , Dealy Caroline N
Published: May 2013

Introduction

Signals from the epidermal growth factor receptor (EGFR) have typically been considered to provide catabolic activities in articular cartilage, and accordingly have been suggested to have a causal role in osteoarthritis progression. The aim of this study was to determine in vivo roles for endogenous EGFR signal activation in articular cartilage.

Methods

Transgenic mice with conditional, limb-targeted deletion of the endogenous intracellular EGFR inhibitor Mig-6 were generated using CreLoxP (Mig-6-flox; Prx1Cre) recombination. Histology, histochemical staining and immunohistochemistry were used to confirm activation of EGFR signaling in the articular cartilage and joints, and to analyze phenotypic consequences of Mig-6 loss on articular cartilage morphology, proliferation, expression of progenitor cell markers, presence of chondrocyte hypertrophy and degradation of articular cartilage matrix.

Results

The articular cartilage of Mig-6-conditional knockout (Mig-6-cko) mice was dramatically and significantly thicker than normal articular cartilage at 6 and 12 weeks of age. Mig-6-cko articular cartilage contained a population of chondrocytes in which EGFR signaling was activated, and which were three to four times more proliferative than normal Mig-6-flox articular chondrocytes. These cells expressed high levels of the master chondrogenic regulatory factor Sox9, as well as high levels of putative progenitor cell markers including superficial zone protein (SZP), growth and differentiation factor-5 (GDF-5) and Notch1. Expression levels were also high for activated β-catenin and the transforming growth factor beta (TGF-β) mediators phospho-Smad2/3 (pSmad2/3). Anabolic effects of EGFR activation in articular cartilage were followed by catabolic events, including matrix degradation, as determined by accumulation of aggrecan cleavage fragments, and onset of hypertrophy as determined by type × collagen expression. By 16 weeks of age, the articular cartilage of Mig-6-cko knees was no longer thickened and was degenerating.

Conclusions

These results demonstrate unexpected anabolic effects of EGFR signal activation in articular cartilage, and suggest the hypothesis that these effects may promote the expansion and/or activity of an endogenous EGFR-responsive cell population within the articular cartilage.
IgG subclass antibodies to human and bacterial HSP60 are not associated with disease activity and progression over time in axial spondyloarthritis
Authors: Carlsen Thomas Gelsing , Hjelholt Astrid , Jurik Anne Grethe , Schiøttz-Christensen Berit , Zejden Anna , Christiansen Gunna , Deleuran Bent , Birkelund Svend
Published: May 2013

Introduction

Spondyloarthritis (SpA), an interrelated group of rheumatic diseases, has been suggested to be triggered by bacterial infections prior to the development of an autoimmune response that causes inflammation of the spinal and peripheral joints. Because human heat shock protein 60 (HSP60), recently renamed HSPD1, and bacterial HSP60 are highly homologous, immunological cross-reactivity has been proposed as a mechanism of disease initiation. However, previous investigations of the humoral immune response to HSP60 in SpA patients have lacked determination of immunoglobulin G (IgG) subclasses and patient follow-up. In this study, we have focused on these parameters in a cohort of axial SpA patients with a well-established set of clinical characteristics, including MRI changes and human leukocyte antigen B27.

Methods

IgG subclass antibodies (IgG1, IgG2, IgG3 and IgG4) against recombinant HSP60 of three reactive arthritis-related bacteria; human HSP60; and the microorganisms Chlamydia trachomatis and C. pneumoniae were determined by ELISA. Serum samples collected from 2004 to 2006 and in 2010 and 2011 from 39 axial SpA patients were analyzed and compared with samples from 39 healthy controls. The Mann-Whitney U test and Wilcoxon matched pairs test were used to compare the antibody levels in different and paired groups, respectively. P < 0.01 was considered significant. The Spearman nonparametric correlation was used to determine correlation between antibody levels and between antibody levels and the disease parameters.

Results

Elevated levels of IgG1 and IgG3 to human HSP60 and IgG1 to HSP60 of Salmonella enterica Enteritidis were observed in SpA patients compared with healthy controls at both time points. The antibody levels were almost constant over time for IgG1, whereas high levels of IgG3 to human HSP60 tended to decrease over time. The antibody response to human HSP60 was predominantly of the IgG3 subclass, and patients with high levels of IgG3 to this antigen had low levels of IgG1, indicating an inverse association. Different IgG subclasses were produced against bacterial and human HSP60 in the same serum sample, IgG1 and IgG3, respectively, indicating that there was no cross-reaction.

Conclusions

A significant association was observed between axial SpA and the presence of IgG1/IgG3 antibodies to human HSP60 and of IgG1 to S. enterica Enteritidis and C. trachomatis. Generation of antibodies to human HSP60 was independent of the presence of antibodies to bacterial HSP60. No association was observed between clinical and MRI changes with antibodies over time. Altogether, such antibodies do not reflect the disease activity in these patients.

This study has been approved by the Regional Research Ethics Committee of Central Jutland, Denmark. Trial registration numbers: 20050046 and 20100083
Mammographic density and breast cancer: a comparison of related and unrelated controls in the Breast Cancer Family Registry
Authors: Linton Linda , Martin Lisa J , Li Qing , Huszti Ella , Minkin Salomon , John Esther M , Rommens Johanna , Paterson Andrew D , Boyd Norman F
Published: May 2013

Introduction

Percent mammographic density (PMD) is a strong and highly heritable risk factor for breast cancer. Studies of the role of PMD in familial breast cancer may require controls, such as the sisters of cases, selected from the same 'risk set' as the cases. The use of sister controls would allow control for factors that have been shown to influence risk of breast cancer such as race/ethnicity, socioeconomic status and a family history of breast cancer, but may introduce 'overmatching' and attenuate case-control differences in PMD.

Methods

To examine the potential effects of using sister controls rather than unrelated controls in a case-control study, we examined PMD in triplets, each comprised of a case with invasive breast cancer, an unaffected full sister control, and an unaffected unrelated control. Both controls were matched to cases on age at mammogram. Total breast area and dense area in the mammogram were measured in the unaffected breast of cases and a randomly selected breast in controls, and the non-dense area and PMD calculated from these measurements.

Results

The mean difference in PMD between cases and controls, and the standard deviation (SD) of the difference, were slightly less for sister controls (4.2% (SD = 20.0)) than for unrelated controls (4.9% (SD = 25.7)). We found statistically significant correlations in PMD between cases (n = 228) and sister controls (n = 228) (r = 0.39 (95% CI: 0.28, 0.50; P <0.0001)), but not between cases and unrelated controls (n = 228) (r = 0.04 (95% CI: -0.09, 0.17; P = 0.51)). After adjusting for other risk factors, square root transformed PMD was associated with an increased risk of breast cancer when comparing cases to sister controls (adjusted odds ratio (inter-quintile odds ratio (IQOR) = 2.19, 95% CI = 1.20, 4.00) or to unrelated controls (adjusted IQOR = 2.62, 95% CI = 1.62, 4.25).

Conclusions

The use of sister controls in case-control studies of PMD resulted in a modest attenuation of case-control differences and risk estimates, but showed a statistically significant association with risk and allowed control for race/ethnicity, socioeconomic status and family history.
Chest computed tomography performed on admission helps predict the severity of smoke-inhalation injury
Authors: Yamamura Hitoshi , Kaga Shinichiro , Kaneda Kazuhisa , Mizobata Yasumitsu
Published: May 2013

Introduction

Smoke-inhalation injury is a major cause of mortality in burn patients, and therefore, it is important to determine accurately the severity of such injuries in these patients. The objective of this study was to evaluate whether chest computed tomography (CT) can be used for detecting early predictors of severity and complications of smoke-inhalation injury.

Methods

We evaluated 37 patients who had sustained smoke-inhalation injuries and had undergone chest CT within a few hours of admission to a hospital. Bronchoscopy was performed according to a standardized protocol within 12 hours of admission in all smoke-inhalation injury patients. Bronchial-wall thickness (BWT) was measured 2 cm distal from the tracheal bifurcation with CT images, and the following data were collected: total number of ventilator days, duration of intensive care unit (ICU) stay, pneumonia development, and patient outcome.

Results

The mean age of the patients was 63 ± 18 years (range, 22 to 87 years), 31 (83.8%) of the patients were men, and the mortality rate was 10.8%. The causes of death in these patients were smoke inhalation (n = 1), hemorrhage (n = 1), and other factors resulting in sepsis (n = 2). The initial carboxyhemoglobin level was 13% ± 14% (range, 1% to 50%). No significant correlation was found between bronchoscopic scoring and clinical factors. However, significant correlations were noted between admission BWT and development of pneumonia (R2 = 0.41; P < 0.0001) and total number of ventilator days (R2 = 0.56; P < 0.0001) and ICU-stay days (R2 = 0.17; P = 0.01). Receiver operating characteristic curve analysis showed that an admission BWT cutoff value of >3.0 mm predicted pneumonia development with a sensitivity of 79%, specificity of 96%, positive predictive value of 91%, and negative predictive value of 88%.

Conclusion

BWT measured by using the chest CT scans obtained within a few hours of admission was predictive of the total number of ventilator days and ICU-stay days and the development of pneumonia in patients with smoke-inhalation injuries.
Decreased frequency of CD73+CD8+ T cells of HIV-infected patients correlates with immune activation and T cell exhaustion
Authors: Tóth Ilona , Le Anh Q , Hartjen Philip , Thomssen Adriana , Matzat Verena , Lehmann Clara , Scheurich Christoph , Beisel Claudia , Busch Philipp , Degen Olaf , Lohse Ansgar W , Eiermann Thomas , Fätkenheuer Gerd , Meyer-Olson Dirk , Bockhorn Maximilian , Hauber Joachim , van Lunzen Jan , zur Wiesch Julian Schulze
Published: May 2013

Recent studies indicate that murine Tregs highly express the ENTDP1, as well as the 5′-NT and thereby, suppress Teff function by extracellular adenosine production. Furthermore, CD73 seems to play a role as costimulatory molecule for T cell differentiation. In this study, we analyzed the expression of CD73 on peripheral and lymph nodal Teffs and Tregs in a cohort of 95 HIV patients at different stages of disease, including LTNP and ECs. In contrast to murine Tregs, CD73 was only expressed on a small minority (∼10%) of peripheral Tregs. In contrast, we see high expression of CD73 on peripheral CD8+ T cells. In HIV infection, CD73 is markedly reduced on all Teffs and Tregs, regardless of the memory subtype. On CD8+ T cells, a positive correlation between CD73 expression and CD4 counts (P=0.0003) was detected. CD73 expression on CD8+ T cells negatively correlated with HLA-DR (<0.0001) and PD1 (P=0.0457) expression. The lower CD73 expression on CD8+ T cells was partially reversible after initiation of ART (P=0.0016). Functionally, we observed that CD8+CD73+ T cells produce more IL-2 upon HIV-specific and unspecific stimulation than their CD73− counterparts and show a higher proliferative capacity. These data indicate that down-regulation of CD73 on CD8+ T cells correlates with immune activation and leads to functional deficits in HIV infection.
C-type lectin receptor Clec4d plays a protective role in resolution of Gram-negative pneumonia
Authors: Steichen Anthony L , Binstock Brandilyn J , Mishra Bibhuti B , Sharma Jyotika
Published: May 2013

Pneumonia is frequently associated with sepsis, characterized by a nonresolving hyperinflammation. However, specific host components of the pulmonary milieu that regulate the perpetuation of inflammation and tissue destruction observed in this immune disorder are not clearly understood. We examined the function of Clec4d, an orphan mammalian CLR, in Gram negative pneumonic sepsis caused by KPn. Whereas the WT mice infected with a sublethal dose of bacteria could resolve the infection, the Clec4d−/− mice were highly susceptible with a progressive increase in bacterial burden, hyperinflammatory response typical of sepsis, and severe lung pathology. This correlated with a massive accumulation of neutrophils in lungs of infected Clec4d−/− mice, which was in contrast with their WT counterparts, where neutrophils transiently infiltrated the lungs. Interestingly, the Clec4d−/− neutrophils did not exhibit any defect in bacterial clearance. These results suggest that Clec4d plays an important role in resolution of inflammation, possibly by facilitating neutrophil turnover in lungs. This is the first report depicting the physiological function of Clec4d in a pathological condition. The results can have implications not only in sepsis but also in other inflammatory diseases, where nonresolving inflammation is the root cause of disease development.
Spatial and temporal transcriptomics ofSchistosoma japonicum-induced hepatic granuloma formation reveals novel roles for neutrophils
Authors: Chuah Candy , Jones Malcolm K , Burke Melissa L , Owen Helen C , Anthony Barrie J , McManus Donald P , Ramm Grant A , Gobert Geoffrey N
Published: May 2013

The severity of schistosome egg-induced hepatic granulomatous pathology depends markedly on the nature of the host immune responses. In this study, we used LMM and microarray analysis to compare gene expression profiles of histologically distinct zones within, and directly proximal to, hepatic granulomas that developed in C57BL/6 mice infected with Schistosoma japonicum. There was significant up-regulation of type-1, type-2, and type-17 immune-associated genes within the granuloma core (adjacent to eggs), followed by increased expression of type-2 and fibrotic genes at the outer zones of granulomas. Neutrophil-associated genes were also found to be expressed differentially in the core and at the peripheral zone of granulomas, present at 7 weeks p.i., demonstrating a significant role of neutrophils in S. japonicum granulomatous pathology. The release of NETs was observed microscopically in granulomas obtained from the livers of infected mice and when human neutrophils were incubated in vitro in the presence of S. japonicum eggs. These finding are the first to suggest a novel, dual role for neutrophils in the mediation of tissue damage and repair in S. japonicum egg-induced hepatic granulomatous lesions. Together, these results provide an overview of the local events occurring within the granuloma microenvironment.
Dysregulation of Ovarian Follicular Development in Female Rat: LH Decreases FSH Sensitivity During Preantral-Early Antral Transition
Authors: Orisaka Makoto , Hattori Katsushige , Fukuda Shin , Mizutani Tetsuya , Miyamoto Kaoru , Sato Takashi , Tsang Benjamin K , Kotsuji Fumikazu , Yoshida Yoshio
Published: May 2013

Several clinical studies have shown a correlation of hypersecretion of LH and polycystic ovary syndrome (PCOS), infertility, and miscarriage in women, suggesting that chronically elevated LH impairs fertility. Growth arrest of small antral follicles in PCOS is also assumed to be associated with an abnormal endocrine environment involving increased LH stimulation, a hyperandrogenic milieu, and subsequent dysregulated FSH action in the ovarian follicles. In this study, we examined whether and how LH modulates follicular development and steroid production during preantral-early antral follicle transition by using a rat preantral follicle culture system. LH augments testosterone and estradiol production in preantral follicles via up-regulating mRNA abundance of CYP17A1 and CYP19A1. LH promotes rat preantral follicle growth, and the follicular size reaches that of early antral follicles in vitro, a response attenuated by the specific androgen receptor antagonist and a targeted disruption of androgen receptor gene. Sustained follicle stimulation by LH, but not by androgen, decreases FSH receptor mRNA levels and FSH receptor signaling and inhibits FSH-induced follicular growth. The data suggest that LH promotes preantral-early antral transition via the increased synthesis and growth-promoting action of androgen. However, chronic LH stimulation impairs FSH-dependent antral follicle growth by suppressing granulosa cell FSHR expression via the modulation of intraovarian regulators, including LH-induced thecal factors.
High-Fat Feeding-Induced Hyperinsulinemia Increases Cardiac Glucose Uptake and Mitochondrial Function Despite Peripheral Insulin Resistance
Authors: Gupte Anisha A. , Minze Laurie J. , Reyes Maricela , Ren Yuelan , Wang Xukui , Brunner Gerd , Ghosn Mohamad , Cordero-Reyes Andrea M. , Ding Karen , Pratico Domenico , Morrisett Joel , Shi Zheng-Zheng , Hamilton Dale J. , Lyon Christopher J. , Hsueh Willa A.
Published: May 2013

In obesity, reduced cardiac glucose uptake and mitochondrial abnormalities are putative causes of cardiac dysfunction. However, high-fat diet (HFD) does not consistently induce cardiac insulin resistance and mitochondrial damage, and recent studies suggest HFD may be cardioprotective. To determine cardiac responses to HFD, we investigated cardiac function, glucose uptake, and mitochondrial respiration in young (3-month-old) and middle-aged (MA) (12-month-old) male Ldlr−/− mice fed chow or 3 months HFD to induce obesity, systemic insulin resistance, and hyperinsulinemia. In MA Ldlr−/− mice, HFD induced accelerated atherosclerosis and nonalcoholic steatohepatitis, common complications of human obesity. Surprisingly, HFD-fed mice demonstrated increased cardiac glucose uptake, which was most prominent in MA mice, in the absence of cardiac contractile dysfunction or hypertrophy. Moreover, hearts of HFD-fed mice had enhanced mitochondrial oxidation of palmitoyl carnitine, glutamate, and succinate and greater basal insulin signaling compared with those of chow-fed mice, suggesting cardiac insulin sensitivity was maintained, despite systemic insulin resistance. Streptozotocin-induced ablation of insulin production markedly reduced cardiac glucose uptake and mitochondrial dysfunction in HFD-fed, but not in chow-fed, mice. Insulin injection reversed these effects, suggesting that insulin may protect cardiac mitochondria during HFD. These results have implications for cardiac metabolism and preservation of mitochondrial function in obesity.
Glucose-Induced Metabolic Memory in Schwann Cells: Prevention by PPAR Agonists
Authors: Kim Esther S. , Isoda Fumiko , Kurland Irwin , Mobbs Charles V.
Published: May 2013

A major barrier in reversing diabetic complications is that molecular and pathologic effects of elevated glucose persist despite normalization of glucose, a phenomenon referred to as metabolic memory. In the present studies we have investigated the effects of elevated glucose on Schwann cells, which are implicated in diabetic neuropathy. Using quantitative PCR arrays for glucose and fatty acid metabolism, we have found that chronic (>8 wk) 25 mM high glucose induces a persistent increase in genes that promote glycolysis, while inhibiting those that oppose glycolysis and alternate metabolic pathways such as fatty acid metabolism, the pentose phosphate pathway, and trichloroacetic acid cycle. These sustained effects were associated with decreased peroxisome proliferator-activated receptor (PPAR)γ binding and persistently increased reactive oxygen species, cellular NADH, and altered DNA methylation. Agonists of PPARγ and PPARα prevented select effects of glucose-induced gene expression. These observations suggest that Schwann cells exhibit features of metabolic memory that may be regulated at the transcriptional level. Furthermore, targeting PPAR may prevent metabolic memory and the development of diabetic complications.
Development of p21 Activated Kinase-Targeted Multikinase Inhibitors That Inhibit Thyroid Cancer Cell Migration
Authors: Ma Yihui , McCarty Samantha K. , Kapuriya Naval P. , Brendel Victoria J. , Wang Chaojie , Zhang Xiaoli , Jarjoura David , Saji Motoyasu , Chen Ching-Shih , Ringel Matthew D.
Published: May 2013

Context:

The p21 activated kinases (PAKs) are a family of serine/threonine kinases that are downstream effectors of small GTPase Cdc42 and Rac. PAKs regulate cell motility, proliferation, and cytoskeletal rearrangement. PAK isoform expression and activity have been shown to be enhanced in cancer and to function as an oncogene in vivo. PAKs also have been implicated in cancer progression.

Objective:

In thyroid cancer, we have previously determined that PAK overactivation is common in the invasive fronts of aggressive tumors and that it is functionally involved in thyroid cancer cell motility using molecular inhibitors. We report the development of two new PAK-inhibiting compounds that were modified from the structure OSU-03012, a previously identified multikinase inhibitor that competitively blocks ATP binding of both phosphoinositide-dependent kinase 1 (PDK1) and PAK1.

Results:

Seventeen compounds were created by combinatorial chemistry predicted to inhibit PAK activity with reduced anti-PDK1 effect. Two lead compounds were identified based on the ability to inhibit PAK1 activity in an ATP-competitive manner without discernible in vivo PDK1 inhibitory activity in thyroid cancer cell lines. Both compounds reduced thyroid cancer cell viability. Although they are not PAK-specific on a multikinase screening assay, the antimigration activity effect of the compounds in thyroid cancer cells was rescued by overexpression of a constitutively active PAK1, suggesting this activity is involved in this biological effect.

Conclusions:

We have developed 2 new multikinase inhibitors with anti-PAK activity that may serve as scaffolds for further compound development targeting this progression-related thyroid cancer target.
On fundamental cellular processes for emergence of collective epithelial movement
Authors: Hirashima Tsuyoshi , Hosokawa Yoichiroh , Iino Takanori , Nagayama Masaharu
Published: May 2013

In all animals, collective cell movement is an essential process in many events, including wound healing and embryonic development. However, our understanding of what characterizes the emergence of multicellular collective behavior is still far from complete. In this article we showed the fundamental cellular processes that drive collective cell movement by means of integrated approaches, including precise quantification measurements and mathematical modeling of measured data. First, we observed the dependence of the collective behaviors of cultured human skin cells on Ca2+ concentrations. When the culturing area confined by a PDMS sheet was suddenly expanded by removing the sheet, the group of cells moved to the expanded area with higher collectivity at higher Ca2+ concentrations. Next, we quantitatively measured cellular responses to the Ca2+ treatments, such as cell growth, cell division, and the strength of intercellular adhesion. Using a femtosecond-laser-based assay, an original method for estimating intercellular adhesion, we found that the strength of intercellular adhesion has an approximately 13-fold range in our treatments. Incorporating the quantitative data into a mathematical model, we then confirmed that the model well reproduced the multicellular behaviors we observed, demonstrating that the strength of intercellular adhesion sufficiently determines the generation of collective cell movement. Finally, we performed extensive numerical experiments, and the results suggested that the emergence of collective cell movement is derived by an optimal balance between the strength of intercellular adhesion and the intensity of cell migration.
Requirement of LIM domains for the transient accumulation of paxillin at damaged stress fibres
Authors: Watanabe-Nakayama Takahiro , Saito Masakazu , Machida Shin'ichi , Kishimoto Kikuo , Afrin Rehana , Ikai Atsushi
Published: May 2013

Cells recognize and respond to changes in intra- and extracellular mechanical conditions to maintain their mechanical homeostasis. Linear contractile bundles of actin filaments and myosin II known as stress fibres (SFs) mediate mechanical signals. Mechanical cues such as excessive stress driven by myosin II and/or external force may damage SFs and induce the local transient accumulation of SF-repair complexes (zyxin and VASP) at the damaged sites. Using an atomic force microscope mounted on a fluorescence microscope, we applied mechanical damage to cells expressing fluorescently tagged cytoskeletal proteins and recorded the subsequent mobilization of SF-repair complexes. We found that a LIM protein, paxillin, transiently accumulated at the damaged sites earlier than zyxin, while paxillin knockdown did not affect the kinetics of zyxin translocation. The C-terminal half of paxillin, comprising four-tandem LIM domains, can still translocate to damaged sites on SFs, suggesting that the LIM domain is essential for the mechanosensory function of paxillin. Our findings demonstrate a crucial role of the LIM domain in mechanosensing LIM proteins.
Targeting of vasoactive intestinal peptide receptor 2, VPAC2, a secretin family G-protein coupled receptor, to primary cilia
Authors: Soetedjo Livana , Glover De'Vona A. , Jin Hua
Published: May 2013

Primary cilia protrude from the cell surface of many cell types in the human body and function as cellular antennae via ciliary membrane localized receptors. Neurons and glial cells in the brain possess primary cilia, and the malfunction of primary cilia may contribute to neurological deficits present in many cilia-associated disorders. Several rhodopsin family G-protein coupled receptors (GPCRs) are specifically localized to a subset of neuronal primary cilia. However, whether other family GPCRs target to neuronal cilia and whether glial primary cilia harbor any GPCRs are not known. We conducted a screening of GPCRs to determine their ability to target to primary cilia, and identified a secretin family member, Vasoactive Intestinal Receptor 2 (VPAC2), as a novel ciliary GPCR. Here, we show that endogenous VPAC2 targets to primary cilia in various brain regions, including the suprachiasmatic nuclei and the thalamus. Surprisingly, VPAC2 not only localizes to neuronal cilia but also to glial cilia. In addition, we show that VPAC2's C-terminus is both necessary and sufficient for its ciliary targeting and we define a novel ciliary targeting signal: the tetrapeptide RDYR motif in the C-terminus of VPAC2. Furthermore, we demonstrate that VPAC2 ciliary targeting is dependent on Tubby, the BBSome (a complex of Bardet–Biedl syndrome proteins) and the BBSome targeting factor, Arl6.
Foxc1 is required by pericytes during fetal brain angiogenesis
Authors: Siegenthaler Julie A. , Choe Youngshik , Patterson Katelin P. , Hsieh Ivy , Li Dan , Jaminet Shou-Ching , Daneman Richard , Kume Tsutomu , Huang Eric J. , Pleasure Samuel J.
Published: May 2013

Brain pericytes play a critical role in blood vessel stability and blood–brain barrier maturation. Despite this, how brain pericytes function in these different capacities is only beginning to be understood. Here we show that the forkhead transcription factor Foxc1 is expressed by brain pericytes during development and is critical for pericyte regulation of vascular development in the fetal brain. Conditional deletion of Foxc1 from pericytes and vascular smooth muscle cells leads to late-gestation cerebral micro-hemorrhages as well as pericyte and endothelial cell hyperplasia due to increased proliferation of both cell types. Conditional Foxc1 mutants do not have widespread defects in BBB maturation, though focal breakdown of BBB integrity is observed in large, dysplastic vessels. qPCR profiling of brain microvessels isolated from conditional mutants showed alterations in pericyte-expressed proteoglycans while other genes previously implicated in pericyte–endothelial cell interactions were unchanged. Collectively these data point towards an important role for Foxc1 in certain brain pericyte functions (e.g. vessel morphogenesis) but not others (e.g. barriergenesis).