bluuebunny/crossref_metadata_2025 huggingface dataset:
Inhibition of Matrix Metalloproteinases-2/-9 Transiently Reduces Pre-Oligodendrocyte Loss during Lipopolysaccharide- but Not Tumour Necrosis Factor-alpha-Induced Inflammation in Fetal Ovine Glial Culture
Authors: Weaver-Mikaere Luke , Gunn Alistair J. , Bennet Laura , Mitchell Murray D. , Fraser Mhoyra
Published: October 2013

To determine whether increased matrix metalloproteinase (MMP) proteolytic activity plays a pathological role in infection/inflammation-induced preterm brain injury, primary cultures of preterm (day 90 of gestation; term 145 days) fetal ovine mixed glia were exposed to 24-96 h of lipopolysaccharide (LPS, 1 μg/ml) or tumour necrosis factor-α (TNF-α, 100 ng/ml). MMP-2 mRNA levels were significantly increased after TNF-α (96 h) and LPS exposure (48 and 96 h), and MMP-9 mRNA levels were significantly increased at 48 and 96 h after TNF-α. On zymography, the active form of secreted MMP-2 was significantly increased 24 h after LPS, but not TNF-α. Both active and latent forms of MMP-9 gelatinolytic activity were significantly increased by TNF-α (96 h) and LPS (72 and 96 h). On reverse zymography, inhibitory activity of TIMP-1 but not TIMP-2 was significantly increased by TNF-α and LPS. SB-3CT-mediated MMP-2 and MMP-9 inhibition transiently reduced LPS-induced oligodendrocyte cell death but had no effect during TNF-α exposure. Collectively, these observations suggest a limited, transient effect of MMPs on immature white matter damage associated with infection but not TNF-α-mediated inflammation.
More than Just a Simple Twist of Fate: Serendipitous Relations in Developmental Science
Authors: Napolitano Christopher M.
Published: October 2013

Unexpected, non-normative events are key influences on human development across the life span. Despite this importance, little is known about how an individual may capitalize on unexpected events and transform them into opportunities for sustained positive development. In this article, to address this theoretical lacuna, I introduce the concept of serendipitous relations - mutually beneficial, adaptive developmental regulations brought about by the time-extended coaction of intentional self-regulatory actions and unexpected non-normative life events. I enumerate five specific intentional self-regulatory serendipitous actions hypothesized to lead to serendipitous relations. Using developmental theory, life examples, and examples from the literature, I hypothesize that serendipitous relations brought about by effective use of serendipitous actions may be important sources of adaptive development. I conclude by offering specific suggestions for future research on serendipitous relations across the life span.
Impact of Vitamin D on Amyloid Precursor Protein Processing and Amyloid-β Peptide Degradation in Alzheimer's Disease
Authors: Grimm Marcus O.W. , Lehmann Johannes , Mett Janine , Zimmer Valerie C. , Grösgen Sven , Stahlmann Christoph P. , Hundsdörfer Benjamin , Haupenthal Viola J. , Rothhaar Tatjana L. , Herr Christian , Bals Robert , Grimm Heike S. , Hartmann Tobias
Published: October 2013

Ninety percent of the elderly population has a vitamin D hypovitaminosis, and several lines of evidence suggest that there might be a potential causal link between Alzheimer's disease (AD) and a non-sufficient supply with vitamin D. However, the mechanisms linking AD to vitamin D have not been completely understood. The aim of our study is to elucidate the impact of 25(OH) vitamin D3 on amyloid precursor protein processing in mice and N2A cells utilizing very moderate and physiological vitamin D hypovitaminosis in the range of 20-30% compared to wild-type mice. We found that already under such mild conditions, amyloid-β peptide (Aβ) is significantly increased, which is caused by an increased β-secretase activity and BACE1 protein level. Additionally, neprilysin (NEP) expression is downregulated resulting in a decreased NEP activity further enhancing the effect of decreased vitamin D on the Aβ level. In line with the in vivo findings, corresponding effects were found with N2A cells supplemented with 25(OH) vitamin D3. Our results further strengthen the link between AD and vitamin D3 and suggest that supplementation of vitamin D3 might have a beneficial effect in AD prevention.
Defining the Native State of α-Synuclein
Authors: Selkoe Dennis , Dettmer Ulf , Luth Eric , Kim Nora , Newman Andrew , Bartels Tim
Published: October 2013

Misfolding and pathogenic aggregation of α-synuclein (αSyn) is a hallmark of familial and sporadic Parkinson's disease, but the physiological state of the protein in cells remains unsettled. We have further examined our hypothesis that endogenous αSyn can occur in normal cells as a metastable, helically folded tetramer, not solely as the unfolded monomer long thought to be its native form. At this meeting, we reviewed our recent approaches for trapping αSyn in intact cells via in vivo crosslinking, a 5-step purification of αSyn from normal human brain, and the generation of new monoclonal antibodies to αSyn that enable general and oligomer-selective ELISAs. Crosslinking in intact living cells confirmed that αSyn occurs in the cytosol of neurons and non-neural cells in substantial part as metastable tetramers and related oligomers, plus varying amounts of free monomers. The non-pathogenic homolog, β-synuclein, forms closely similar oligomeric assemblies, suggesting that the oligomers we observe for αSyn are also physiological. In contrast to other normal oligomeric proteins (e.g., DJ-1), αSyn tetramers dissociate rapidly to monomers upon conventional cell lysis but are retained partially as tetramers if cells are lysed at high protein concentrations (‘molecular crowding'). Thus, αSyn exists natively as helical tetramers that are in dynamic equilibrium with unfolded monomers. The tetramers appear relatively resistant to aggregation, in contrast to monomers, which may give rise to fibrillar inclusions.
A Novel ABO Gene Variant Leads to Discrepant Results in Forward/Reverse and Molecular Blood Grouping
Authors: Goebel Meike , Halm-Heinrich Ines , Parkner Andreas , Rink Gabriele , Heim Marcell U. , Bugert Peter
Published: October 2013

SummaryBackground: Discrepant results in antigen and reverse ABO blood typing are often caused by a variant ABO gene. Molecular analysis can help to characterize such variants. Here, we describe the identification of a novel ABO gene variant in a patient with aberrant ABO phenotype and discrepant genotyping results. Methods: A patient with discrepant results in automated forward and reverse ABO phenotyping was further investigated by serological (gel and tube technique) and molecular (commercial and inhouse PCR-SSP, DNA sequencing) methods. A PCR-SSP system was established to screen the novel mutation in 1,820 blood donors. Results: Standard serological tests confirmed blood group O, however, only anti-B isoagglutinins were present. A monoclonal anti-AB antibody detected very weak agglutination in gel technique. Standard ABO genotyping using PCR-SSP led to discrepant results (O1/O1 or O1/A) depending on the test system used. ABO exon re-sequencing identified a novel missense mutation in exon 6 at position 248A>G (Asp83Gly) in the binding region of PCR-SSP primers for the detection of 261G alleles. Blood donors with regular ABO blood groups were all negative for the 248G allele designated Aw34. Conclusion: The novel ABO gene variant Aw34 is associated with very weak A antigen expression and absent anti-A isoagglutinins. The mutation is located in exon 6 close to the O1-specific 261G deletion in the binding region of PCR-SSP primers. Presumably, depending on the primer concentration used in commercial ABO genotyping kits, the mutation could lead to a false-negative reaction.
Correcting Marine Surface Winds Simulated in Atmospheric Models Using Spatially and Temporally Varying Linear Regression
Authors: Durrant Tom H. , Greenslade Diana J. M. , Simmonds Ian , Woodcock Frank
Published: October 2013

This study examines the application of three different variations of linear-regression corrections to the surface marine winds from the Australian Bureau of Meteorology’s recently implemented operational atmospheric model. A simple correction over the entire domain is found to inadequately account for geographical variation in the wind bias. This is addressed by considering corrections that vary in space. Further, these spatially varying corrections are extended to vary in time. In an operational environment, the error characteristics of the wind forcing can be expected to change over time with the evolution of the atmospheric model. This in turn requires any applied correction to be monitored and maintained. Motivated by a desire to avoid this manual maintenance, a self-learning correction method is proposed whereby spatially and temporally varying corrections are calculated in real time from a moving window of historical comparisons between observations and preceding forecasts. This technique is shown to effectively remove both global and regionally varying wind speed biases.
Adenotonsillectomy vs Observation for Management of Mild Obstructive Sleep Apnea in Children
Authors: Volsky Peter G. , Woughter Meghan A. , Beydoun Hind A. , Derkay Craig S. , Baldassari Cristina M.
Published: October 2013

Objective

To determine the impact of adenotonsillectomy vs observation on quality of life (QOL) in children with mild obstructive sleep apnea (OSA).

Study Design

Prospective, nonrandomized trial.

Setting

Tertiary children's hospital.

Subjects and Methods

Sixty‐four children (ages 3‐16 years) with mild OSA (apnea hypopnea index between 1 and 5 on polysomnogram) completed the study. Caregivers chose between management options of adenotonsillectomy and observation and completed validated QOL instruments (OSA‐18 and Children's Health Questionnaire) at baseline, early, and late follow‐ups. The primary outcome measure was QOL.

Results

Thirty patients chose adenotonsillectomy, while 34 were observed. Total OSA‐18 scores at baseline were significantly poorer (P =. 01) in the surgery group (72.3) compared with the observation group (58.5). Four months following surgery, OSA‐18 scores improved by 39.1 points over baseline (P =. 0001), while there was no change for the observation group (P =. 69). After 8 months, OSA‐18 scores remained improved in the surgery group, and observation group scores improved by 13.4 points over baseline (P =. 005). While OSA‐18 scores at the late follow‐up visit were poorer in the observation group, the difference was not statistically significant (P =. 05). Six observation patients opted for adenotonsillectomy during the study.

Conclusion

Quality of life significantly improves in children with mild OSA after adenotonsillectomy. In children with mild OSA who are observed, QOL improvements at early follow‐up are less pronounced, but significant improvements in QOL are evident after 8 months. QOL instruments may be useful tools to help providers determine which children with mild OSA may benefit from early intervention.
An Introduction of Genetics in Otosclerosis: A Systematic Review
Authors: Bittermann Arnold J. N. , Wegner Inge , Noordman Bo Jan , Vincent Robert , van der Heijden Geert J. M. G. , Grolman Wilko
Published: October 2013

Objective

To present an easy to read systematic review concerning the genetic etiology of otosclerosis to help health care providers in counseling otosclerosis patients more accurately.

Data Sources

PubMed, Embase, CINAHL, and the Cochrane Library.

Review Methods

Studies on the genetic etiology of otosclerosis were selected. Association studies and family‐based studies were included for further review. After quality assessment (risk of bias), data were extracted from the included studies. When available, odds ratios were presented. In case of corresponding genetic anomalies between the studies, it was the aim to combine results.

Results

The number of available studies with low risk of bias is limited to 2 association studies and 1 family‐based study. These high‐quality studies show that otosclerosis in Japanese patients is not linked to the NOG gene and that a polymorphism in the Sp1 binding site located on the COL1A1 gene is associated with otosclerosis as well as OTSC1. Association and family‐based studies with moderate risk of bias show a statistically significant association with the ACE gene, AGT gene, OTSC2, RELN gene, TGFB1 gene, 11q13.1, OTSC2, OTSC5, OTSC8, and OTSC10. These results may be spurious associations due to their bias and low statistical power.

Conclusion

The present systematic review shows that there is scattered evidence of limited quality and a lack of replication studies. It is not possible to point out 1 or more responsible genes, which play a key role within the genetic pathophysiologic mechanism of otosclerosis.
Effects of Nd on microstructure and mechanical properties of Mg–Al–Ca alloy
Authors: Chen Y. , Hao L. , Ruiyu Y. , Liu G. , Xia T.
Published: October 2013

Effects of Nd additions (0–4 wt-) on microstructures and properties of Mg–Al–Ca alloy at room temperature and 150°C have been investigated. The results showed that Mg–6Al–2Ca alloy consisted of α-Mg matrix, Mg17Al12, Mg–Ca and Al–Ca phases. The amount of Al–Nd phase increases with the increasing of Nd content while that of Mg17Al12 decreases. On the other hand, Nd refines the microstructure of as cast and extruded alloys. The ultimate strength and yield strength of experimental alloys are improved with the addition of Nd, and the largest values are 319 and 210 MPa respectively at room temperature. When the temperature was elevated to 150°C, with the increasing of Nd, ultimate strength and yield strength of experimental alloys are first increased and subsequently decreased. Mg–6Al–2Ca– xNd alloy has the best ultimate strength and yield strength at 150°C, which reaches 265 and 179 MPa respectively when the content of Nd reached 3.
Nitrogen diffusion in different microstructures of plasma nitrided CK45 steel
Authors: Foadian F. , Feyzi F. , Haghighat S. , Aghajani H.
Published: October 2013

In this study, the nitrogen diffusion in different microstructures of CK45 steel was studied. Different microstructures were achieved by different heat treatment cycles as annealing, normalising and quench tempering. After heat treatment, plasma nitriding was performed at 550°C temperature, nitriding times of 5 h, in a gas mixture containing 25 vol.-H2/75 vol.-N2 and DC pulsed plasma nitriding unit. The surface, cross-section and the thickness of diffusion and white layers of specimens were studied in terms of optical and scanning electron microscopy. Surface phases have been studied by X-ray diffraction analysis. Results showed that by normalising the samples, higher diffusion depths could be achieved and the white layer thickness would be also higher. Other results showed that core hardness of quench tempered specimens could decrease after plasma nitriding due to being subjected to nitriding process temperature.
On corrosion behaviour of HVOF sprayed Ni3Si intermetallic powders
Authors: Verdian M. M. , Raeissi K. , Salehi M.
Published: October 2013

Ni3Si intermetallic powders were deposited onto 420 stainless steel substrate using high velocity oxy-fuel (HVOF) process. In this regard, microstructure properties relationships were evaluated in fabricated coatings. X-ray diffractometery, scanning electron microscopy, microhardness testing, potentiodynamic polarisation and electrochemical impedance spectroscopy (EIS) measurements were performed to study the phase composition, microstructure and properties of the coatings. The microstructure of coatings was composed of supersaturated Ni(Si) solid solution islands embedded in an Ni5Si2 matrix. The results showed that this microstructure strongly affected properties of coatings. In this regard, the hardness of coatings was found to be 620 HV(50 g) due to presence of Ni5Si2. It was also found that the corrosion rate of HVOF Ni–Si coatings in 70H2SO4 medium was lower than that of stainless steel substrate. Further investigations showed that the microgalvanic corrosion between Ni(Si) and Ni5Si2 phases was a determinant factor in corrosion performance of HVOF Ni–Si coatings.
Activation energy, viscosity and fragility of Cu–Zr–Ti–In bulk metallic glasses
Authors: Wu J. , Pan Y. , Liu H. , Pi J.
Published: October 2013

In the present paper, activation energy, viscosity and fragility of two In alloyed Cu–Zr–Ti–In bulk metallic glasses are evaluated by differential scanning calorimetry and thermomechanical analysis respectively. Eg of 60Cu–34Zr–5Ti–1In and 58Cu–34Zr–5Ti–3In is 175±9 and 182±5 kJ mol−1 respectively. Ex of 60Cu–34Zr–5Ti–1In and 58Cu–34Zr–5Ti–3In is 369±24 and 317±10 kJ mol−1 respectively, indicating that increasing the content of indium decreases the value of Ex of the as cast bulk metallic glasses. By means of comparison of activation energies referring to the crystallisation peak temperature, one can find that the second step crystallisation of both bulk metallic glasses is easier to occur. The possible phases of the annealed samples are determined. Thermomechanical analysis shows that viscosity for 58Cu–34Zr–5Ti–3In is larger than that for 60Cu–34Zr–5Ti–1In in the supercooled region, but Vogel–Fulcher–Tammann (VFT) temperature of 58Cu–34Zr–5Ti–3In is lower than that of 60Cu–34Zr–5Ti–1In. Both 60Cu–34Zr–5Ti–1In and 58Cu–34Zr–5Ti–3In bulk metallic glasses are stronger than o-terphenyl, but more fragile than SiO2. 58Cu–34Zr–5Ti–3In is stronger than 60Cu–34Zr–5Ti–1In. It indicates that increasing indium content can decrease the VFT temperature but make glass stronger.
Structure characterization of alumina–silica coatings prepared on polyimide substrate by sol–gel
Authors: Zhang X. , Mao L. , Ma J.
Published: October 2013

Alumina–silica coatings were prepared on polyimide substrate by sol–gel method using aluminium isopropoxide and tetraethyl orthosilicate as the precursors. The molar ratios of Si/Al were designed as 1∶3, 1∶1 and 3∶1. The surface morphology and structure of as-deposited coatings were investigated by various complementary analysis techniques. The results indicate that all silica–alumina coatings show a smooth and dense surface and have a thickness of ∼400 nm. After treatment at 230°C, the alumina–silica coatings are a diphase structure of AlOOH and amorphous silica, the same as the corresponding gel powders. Moreover, after calcination at 550°C, the alumina–silica gel powders still remain a diphase structure, but AlOOH transforms into γ-Al2O3. The Si content has no obvious effect on the phase structure. However, increasing the Si/Al ratio in the as deposited coatings causes the binding energies of Si 2p, Al 2p and O 1s peaks to shift to higher energy.
Association of the Hermansky–Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects
Authors: Kuratomi Go , Saito Atsushi , Ozeki Yuji , Watanabe Takashi , Fujii Kumiko , Shimoda Kazutaka , Inukai Toshihiko , Mori Harunobu , Ohmori Kenichi , Akiyama Kazufumi
Published: October 2013

Background

The Hermansky–Pudlak Syndrome Type 4 (HPS4) gene, which encodes a subunit protein of the biogenesis of lysosome-related organelles complex (BLOC)-3, which is involved in late endosomal trafficking, is associated with schizophrenia; however, its clinical relevance in schizophrenia remains unknown. The purpose of the present study was to investigate whether HPS4 is associated with cognitive functions in patients with schizophrenia and healthy controls and with the clinical profiles of patients with schizophrenia.

Methods

We investigated the association of variants of HPS4 with clinical symptoms and cognitive function in Japanese patients with schizophrenia (n = 240) and age-matched healthy control subjects (n = 240) with single nucleotide polymorphisms (SNP)- or haplotype-based linear regression. We analyzed five tagging SNPs (rs4822724, rs61276843, rs9608491, rs713998, and rs2014410) of HPS4 and 2–5 locus haplotypes of these five SNPs. The cognitive functions of patients and healthy subjects were evaluated with the Brief Assessment of Cognition in Schizophrenia, Japanese-language version, and the patients were assessed for their symptomatology with the Positive and Negative Symptom Scale (PANSS).

Results

In patients with schizophrenia, rs713998 was significantly associated with executive function under the dominant genetic model (P = 0.0073). In healthy subjects, there was a significant association between working memory and two individual SNPs under the recessive model (rs9608491: P = 0.001; rs713998: P = 0.0065) and two haplotypes (rs9608491-713998: P = 0.0025; rs61276843-9608491-713998: P = 0.0064). No significant association was found between HPS4 SNPs and PANSS scores or premorbid IQ, as measured by the Japanese version of the National Adult Reading Test.

Conclusions

These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia.
Effect of oral administration of ethanolic extract of Vitex negundo on thioacetamide-induced nephrotoxicity in rats
Authors: Kadir Farkaad A , Kassim Normadiah M , Abdulla Mahmood A , Yehye Wageeh A
Published: October 2013

Background

Oxidative stress due to abnormal induction of reactive oxygen species (ROS) molecules is believed to be involved in the etiology of many diseases. Evidences suggest that ROS is involved in nephrotoxicity through frequent exposure to industrial toxic agents such as thioacetamide (TAA). The current investigation was designed to explore the possible protective effects of the leaves of Vitex negundo(VN) extract against TAA-induced nephrotoxicity in rats.

Methods

Twenty four Sprague Dawley rats were divided into four groups: (A) Normal control, (B) TAA (0.03% w/v in drinking water), (C) VN100 (VN 100 mg/kg + TAA) and (D) VN300 (VN 300 mg/kg + TAA). Blood urea and serum creatinine levels were measured,supraoxide dismutase (SOD), catalase (CAT) and malondialdehyde (MDA) levels of renal tissue were assayed. Histopathological analysis together with the oxidative stress nicotinamide adenine dinucleotide phosphate (NADPH) oxidase p22phox in kidney sections were examined in all experimental groups.

Results

Blood urea and serum creatinine levels were increased in TAA group as a result of the nephrotoxicity compared to the VN100 and VN300 groups where, the levels were significantly decreased (p < 0.05). Renal MDA level was significantly decreased (p < 0.05) in the VN-treated groups with increased CAT and SOD activities compared to the TAA group. Light microscopic examination of renal tissues stained by H&E stain and Masson’s Trichrome for TAA-treated groups revealed severe histopathological changes, whereas specimens obtained from VN-treated groups showed only mild changes. These findings were supported by immunohistochemical results.

Conclusions

VN extract acts as a natural potent antioxidant to prevent ongoing TAA-induced nephrotoxicity in rats, both biochemically and morphologically.
Myc is required for β-catenin-mediated mammary stem cell amplification and tumorigenesis
Authors: Moumen Mejdi , Chiche Aurélie , Decraene Charles , Petit Valérie , Gandarillas Alberto , Deugnier Marie-Ange , Glukhova Marina A , Faraldo Marisa M
Published: October 2013

Background

Basal-like breast cancer is a heterogeneous disease characterized by the expression of basal cell markers, no estrogen or progesterone receptor expression and a lack of HER2 ov erexpression. Recent studies have linked activation of the Wnt/β-catenin pathway, and its downstream target, Myc, to basal-like breast cancer. Transgenic mice K5ΔNβcat previously generated by our team present a constitutive activation of Wnt/β-catenin signaling in the basal myoepithelial cell layer, resulting in focal mammary hyperplasias that progress to invasive carcinomas. Mammary lesions developed by K5ΔNβcat mice consist essentially of basal epithelial cells that, in contrast to mammary myoepithelium, do not express smooth muscle markers.

Methods

Microarray analysis was used to compare K5ΔNβcat mouse tumors to human breast tumors, mammary cancer cell lines and the tumors developed in other mouse models. Cre-Lox approach was employed to delete Myc from the mammary basal cell layer of K5ΔNβcat mice. Stem cell amplification in K5ΔNβcat mouse mammary epithelium was assessed with 3D-culture and transplantation assays.

Results

Histological and microarray analyses of the mammary lesions of K5ΔNβcat females revealed their high similarity to a subset of basal-like human breast tumors with squamous differentiation. As in human basal-like carcinomas, the Myc pathway appeared to be activated in the mammary lesions of K5ΔNβcat mice. We found that a basal cell population with stem/progenitor characteristics was amplified in K5ΔNβcat mouse preneoplastic glands. Finally, the deletion of Myc from the mammary basal layer of K5ΔNβcat mice not only abolished the regenerative capacity of basal epithelial cells, but, in addition, completely prevented the tumorigenesis.

Conclusions

These results strongly indicate that β-catenin-induced stem cell amplification and tumorigenesis rely ultimately on the Myc pathway activation and reinforce the hypothesis that basal stem/progenitor cells may be at the origin of a subset of basal-like breast tumors.
TLR2 stimulation induces cardiac inflammation but not cardiac depression in vivo
Authors: Boehm Olaf , Knuefermann Pascal , Plueck Johannes , Schwederski Markus , Ehrentraut Heidi , Kebir Sied , Lohner Ralph , Velten Markus , Morath Siegfried , Koch Alexander , Zacharowski Kai , Grohé Christian , Hoeft Andreas , Baumgarten Georg , Meyer Rainer
Published: October 2013

Background

Bacteria such as Staphylococcus aureus induce myocardial dysfunction in vivo. To rectify conflicting evidence about the role of TLR2 signaling and cardiac dysfunction, we hypothesized that the specific TLR2 agonist purified lipoteichoic acid (LTA) from S. aureus contributes to cardiac dysfunction in vitro and in vivo.

Methods

Wildtype (WT-) and TLR2-deficient (TLR2-D) mice were challenged with LTA and in comparison with equivalent doses of lipopolysaccharide (LPS) and CpG-oligodeoxynucleotide (CpG-ODN). TLR2-expression, NFκB as well as cytokine response were determined. Sarcomere shortening of isolated cardiomyocytes was analyzed in vitro and cardiac function in vivo after stimulation with LTA.

Results

LTA induced up-regulation of TLR2 mRNA, activation of NFκB and cytokine expression within 2–6 h in WT-, but not in TLR2-D hearts. Cytokines were also elevated in the serum. LPS and CpG-ODN induced a more severe cardiac inflammation. In vitro incubation of cardiomyocytes with LTA reduced sarcomere shortening via NO at stimulation frequencies ≤ 8 Hz only in WT cells. However, hemodynamic parameters in vivo were not affected by LTA challenge.

Conclusions

LTA induced cardiac inflammation was relatively weak and sarcomere shortening was reduced only below physiological heart rates. This may explain the apparent contradiction between the in vivo and in vitro LTA effects.
Breast adenomyoepithelioma: a case report with malignant proliferation of epithelial and myoepithelial elements
Authors: Petrozza Vincenzo , Pasciuti Giulia , Pacchiarotti Alberto , Tomao Federica , Zoratto Federica , Rossi Luigi , Fontana Antonella , Censi Fabiana , Sardella Barbara , Di Cristofano Claudio , Porta Natale , Della Rocca Carlo
Published: October 2013

Background

Breast adenomyoepithelioma is an unusual tumor characterized by a biphasic proliferation of epithelial and myoepithelial cells. Most breast adenomyoepitheliomas are considered to be benign or to have a low-grade malignant potential, characterized by propensity for local recurrence. Malignant changes arising in this lesion are extremely rare and may involve one or both cellular components.

Case report

We discuss a case of a 60 year-old woman who began to experience pain in her right breast in January 2009. Breast ultrasound and mammography were performed showing a rounded, hypoechoic solid lesion with ill-defined margins in the right inner-inferior quadrant, suspicious of malignancy. Quadrantectomy of the inner-inferior quadrant of the right breast with sampling of ipsilateral axillary lymph nodes was performed. The histological analysis confirmed the diagnosis of adenomyoepithelioma with focal malignant change of the epithelial component, associated with high-grade malignant myoepithelial change. The patient was treated with adjuvant radiotherapy and her right breast received a dose of Gy 50 with a boost of Gy 10 to the tumor bed. At present, the patient shows no sign of tumor recurrence.

Conclusion

Breast malignant adenomyoepithelioma is a rare tumor which should be considered in the differential diagnosis of other solid breast lesions. Only few cases have been reported in the literature. Diagnosis, optimal therapy and predicting the outcome are problematic issues due to the rarity of this disease which appears to have hematogenous rather than lymphatic spread and usually occurs in primary tumors ≥ 1.6 cm in size.
Mo doping-enhanced dye absorption of Bi2Se3 nanoflowers
Authors: Zhong Mianzeng , Meng Xiuqing , Wu Fengmin , Li Jingbo , Fang Yunzhang
Published: October 2013

A simple solvothermal approach is explored to prepare Bi2−x
Mo
x
Se3 nanostructures by employing N,N-dimethylformamide (DMF) as the solvent. Mo plays an important role in the assembly of the Bi2−x
Mo
x
Se3 nanostructures from nanoplates to nanoflowers. Structural and morphological studies indicate that the resulting products are large specific surface area single-crystalline Bi2−x
Mo
x
Se3 nanoflowers self-assembled from thin nanoplates during the reaction process. The absorption properties of the as-prepared samples are investigated with Rhodamine B (RhB) as dye, and it is found that the Bi1.85Mo0.15Se3 nanoflowers show an optimal adsorption capacity, implying that Mo doping not only changes the morphologies of the nanostructures but also enhances their absorption behaviors.
Identification of a new genotype of Torque Teno Mini virus
Authors: Farsani Seyed Mohammad Jazaeri , Jebbink Maarten F , Deijs Martin , Canuti Marta , van Dort Karel A , Bakker Margreet , Grady Bart PX , Prins Maria , van Hemert Formijn J , Kootstra Neeltje A , van der Hoek Lia
Published: October 2013

Background

Although human torque teno viruses (TTVs) were first discovered in 1997, still many associated aspects are not clarified yet. The viruses reveal a remarkable heterogeneity and it is possible that some genotypes are more pathogenic than others. The identification of all genotypes is essential to confirm previous pathogenicity data, and an unbiased search for novel viruses is needed to identify TTVs that might be related to disease.

Method

The virus discovery technique VIDISCA-454 was used to screen serum of 55 HIV-1 positive injecting drug users, from the Amsterdam Cohort Studies, in search for novel blood-blood transmittable viruses which are undetectable via normal diagnostics or panvirus-primer PCRs.

Results

A novel torque teno mini virus (TTMV) was identified in two patients and the sequence of the full genomes were determined. The virus is significantly different from the known TTMVs (< 40% amino acid identity in ORF1), yet it contains conserved characteristics that are also present in other TTMVs. The virus is chronically present in both patients, and these patients both suffered from a pneumococcal pneumonia during follow up and had extremely low B-cells counts.

Conclusion

We describe a novel TTMV which we tentatively named TTMV-13. Further research is needed to address the epidemiology and pathogenicity of this novel virus.
Identification of B-cell epitopes in an antigen for inducing specific class of antibodies
Authors: Gupta Sudheer , Ansari Hifzur Rahman , Gautam Ankur ,   Open Source Drug Discovery Consortium, Raghava Gajendra PS
Published: October 2013

Background

In the past, numerous methods have been developed for predicting antigenic regions or B-cell epitopes that can induce B-cell response. To the best of authors’ knowledge, no method has been developed for predicting B-cell epitopes that can induce a specific class of antibody (e.g.,IgA, IgG) except allergenic epitopes (IgE). In this study, an attempt has been made to understand the relation between primary sequence of epitopes and the class of antibodies generated.

Results

The dataset used in this study has been derived from Immune Epitope Database and consists of 14725 B-cell epitopes that include 11981 IgG, 2341 IgE, 403 IgA specific epitopes and 22835 non-B-cell epitopes. In order to understand the preference of residues or motifs in these epitopes, we computed and compared amino acid and dipeptide composition of IgG, IgE, IgA inducing epitopes and non-B-cell epitopes. Differences in composition profiles of different classes of epitopes were observed, and few residues were found to be preferred. Based on these observations, we developed models for predicting antibody class-specific B-cell epitopes using various features like amino acid composition, dipeptide composition, and binary profiles. Among these, dipeptide composition-based support vector machine model achieved maximum Matthews correlation coefficient of 0.44, 0.70 and 0.45 for IgG, IgE and IgA specific epitopes respectively. All models were developed on experimentally validated non-redundant dataset and evaluated using five-fold cross validation. In addition, the performance of dipeptide-based model was also evaluated on independent dataset.

Conclusion

Present study utilizes the amino acid sequence information for predicting the tendencies of antigens to induce different classes of antibodies. For the first time,in silicomodels have been developed for predicting B-cell epitopes, which can induce specific class of antibodies. A web service called IgPred has been developed to serve the scientific community. This server will be useful for researchers working in the field of subunit/epitope/peptide-based vaccines and immunotherapy (http://crdd.osdd.net/raghava/igpred/).

Reviewers

This article was reviewed by Dr. M Michael Gromiha, Dr Christopher Langmead (nominated by Dr Robert Murphy) and Dr Lina Ma (nominated by Dr Zhang Zhang).
Chemical and pharmacological investigation of micropropagated Hygrophila pogonocalyx produced from leaf explants
Authors: Ho Chin-Wen , Lin Rong-Dih , Lee Tzong-Huei , Lin Chien-Hung , Wen Chi-Luan , Tseng Yu-Ting , Lee Mei-Hsien
Published: October 2013

Background

An optimized method for indirect shoot organogenesis from the leaf explants of Hygrophila pogonocalyx, a rare and endemic species in Taiwan, was developed to supply enough quantity of plant materials for the first chemical and pharmacological investigation.

Results

Incubation of the young leaves on Murashige and Skoog (MS) medium supplemented with 6-benzylaminopurine (0.5 mg/l) and indole-3-acetic acid (0.1 mg/l) resulted in the best multiplication rate for organogenesis. The average number of adventitious buds per leaf was 22.8 ± 1.9 after 8-week culture. The adventitious buds rooted and developed into plantlets when cultured simply on MS medium. Using this protocol, up to 37,600 plants were produced from a single leaf explant in one year. From the ethanol extract of the leaves of this micropropagated plant, 13 compounds were isolated and identified, including two flavones (1, 11), four flavonols (9, 10, 12, and 13), three phenylethanoid glycosides (6–8), two alkylated glycosides (2–3), and two steroids (4–5). Of these, acteoside (7) exhibited anti-tyrosinase activity in human epidermal melanocytes and luteolin 7-O-β-d-glucopyranoside (11) exhibited the greatest neurocytoprotective activity.

Conclusions

The method, indirect shoot organogenesis from leaf explants of H. pogonocalyx, could be developed to supply enough quantity of plant materials for the chemical and pharmacological investigation. In the present study, the isolated active compounds may develop for whitening agents or treating neurodegenerative diseases in the future.
Efficacy and safety of rituximab treatment in early primary Sjögren's syndrome: a prospective, multi-center, follow-up study
Authors: Carubbi Francesco , Cipriani Paola , Marrelli Alessandra , Benedetto Paola Di , Ruscitti Piero , Berardicurti Onorina , Pantano Ilenia , Liakouli Vasiliki , Alvaro Saverio , Alunno Alessia , Manzo Antonio , Ciccia Francesco , Gerli Roberto , Triolo Giovanni , Giacomelli Roberto
Published: October 2013

Introduction

Primary Sjögren’s syndrome (pSS) is an autoimmune disorder affecting exocrine glands; however, a subgroup of pSS patients experience systemic extra-glandular involvement leading to a worsening of disease prognosis. Current therapeutic options are mainly empiric and often translated by other autoimmune diseases. In the last few years growing evidence suggests that B-cell depletion by rituximab (RTX) is effective also in pSS. Patients with early active disease appear to be those who could benefit the most from RTX. The aim of this study was to investigate the efficacy and safety of RTX in comparison to disease modifying anti-rheumatic drugs (DMARDs) in early active pSS patients.

Methods

Forty-one patients with early pSS and active disease (EULAR Sjogren’s syndrome disease activity index, ESSDAI ≥ 6) were enrolled in the study. Patients were treated with either RTX or DMARDs in two different Rheumatology centers and followed up for 120 weeks. Clinical assessment was performed by ESSDAI every 12 weeks up to week 120 and by self-reported global disease activity pain, sicca symptoms and fatigue on visual analogic scales, unstimulated saliva flow and Schirmer’s I test at week 12, 24, 48, 72, 96, and 120. Laboratory assessment was performed every 12 weeks to week 120. Two labial minor salivary gland (MSG) biopsies were obtained from all patients at the time of inclusion in the study and at week 120.

Results

Our study demonstrated that RTX treatment results in a faster and more pronounced decrease of ESSDAI and other clinical parameters compared to DMARDs treatment. No adverse events were reported in the two groups. We also observed that RTX is able to reduce glandular infiltrate, interfere with B/T compartmentalization and consequently with the formation of ectopic lymphoid structures and germinal center-like structures in pSS-MSGs.

Conclusions

To our knowledge, this is the first study performed in a large cohort of early active pSS patients for a period of 120 weeks. We showed that RTX is a safe and effective agent to be employed in pSS patients with systemic, extra-glandular involvement. Furthermore, our data on pSS-MSGs provide additional biological basis to employ RTX in this disease.
Loss of Vascular Endothelial Growth Factor A (VEGFA) Isoforms in the Testes of Male Mice Causes Subfertility, Reduces Sperm Numbers, and Alters Expression of Genes That Regulate Undifferentiated Spermatogonia
Authors: Lu Ningxia , Sargent Kevin M. , Clopton Debra T. , Pohlmeier William E. , Brauer Vanessa M. , McFee Renee M. , Weber John S. , Ferrara Napoleone , Silversides David W. , Cupp Andrea S.
Published: October 2013

Vascular endothelial growth factor A (VEGFA) isoform treatment has been demonstrated to alter spermatogonial stem cell homeostasis. Therefore, we generated pDmrt1-Cre;Vegfa−/− (knockout, KO) mice by crossing pDmrt1-Cre mice to floxed Vegfa mice to test whether loss of all VEGFA isoforms in Sertoli and germ cells would impair spermatogenesis. When first mated, KO males took 14 days longer to get control females pregnant (P < .02) and tended to take longer for all subsequent parturition intervals (9 days; P < .07). Heterozygous males sired fewer pups per litter (P < .03) and after the first litter took 10 days longer (P < .05) to impregnate females, suggesting a more progressive loss of fertility. Reproductive organs were collected from 6-month-old male mice. There were fewer sperm per tubule in the corpus epididymides (P < .001) and fewer ZBTB16-stained undifferentiated spermatogonia (P < .003) in the testes of KO males. Testicular mRNA abundance for Bcl2 (P < .02), Bcl2:Bax (P < .02), Neurog3 (P < .007), and Ret was greater (P = .0005), tended to be greater for Sin3a and tended to be reduced for total Foxo1 (P < .07) in KO males. Immunofluorescence for CD31 and VE-Cadherin showed no differences in testis vasculature; however, CD31-positive staining was evident in undifferentiated spermatogonia only in KO testes. Therefore, loss of VEGFA isoforms in Sertoli and germ cells alters genes necessary for long-term maintenance of undifferentiated spermatogonia, ultimately reducing sperm numbers and resulting in subfertility.
11β-Hydroxysteroid Dehydrogenase Type 1 (11β-HSD1) Inhibitors Still Improve Metabolic Phenotype in Male 11β-HSD1 Knockout Mice Suggesting Off-Target Mechanisms
Authors: Harno Erika , Cottrell Elizabeth C. , Yu Alice , DeSchoolmeester Joanne , Gutierrez Pablo Morentin , Denn Mark , Swales John G. , Goldberg Fred W. , Bohlooly-Y Mohammad , Andersén Harriet , Wild Martin J. , Turnbull Andrew V. , Leighton Brendan , White Anne
Published: October 2013

The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is a target for novel type 2 diabetes and obesity therapies based on the premise that lowering of tissue glucocorticoids will have positive effects on body weight, glycemic control, and insulin sensitivity. An 11β-HSD1 inhibitor (compound C) inhibited liver 11β-HSD1 by >90% but led to only small improvements in metabolic parameters in high-fat diet (HFD)–fed male C57BL/6J mice. A 4-fold higher concentration produced similar enzyme inhibition but, in addition, reduced body weight (17%), food intake (28%), and glucose (22%). We hypothesized that at the higher doses compound C might be accessing the brain. However, when we developed male brain-specific 11β-HSD1 knockout mice and fed them the HFD, they had body weight and fat pad mass and glucose and insulin responses similar to those of HFD-fed Nestin-Cre controls. We then found that administration of compound C to male global 11β-HSD1 knockout mice elicited improvements in metabolic parameters, suggesting “off-target” mechanisms. Based on the patent literature, we synthesized another 11β-HSD1 inhibitor (MK-0916) from a different chemical series and showed that it too had similar off-target body weight and food intake effects at high doses. In summary, a significant component of the beneficial metabolic effects of these 11β-HSD1 inhibitors occurs via 11β-HSD1–independent pathways, and only limited efficacy is achievable from selective 11β-HSD1 inhibition. These data challenge the concept that inhibition of 11β-HSD1 is likely to produce a “step-change” treatment for diabetes and/or obesity.
Endotoxemia Enhances Catecholamine Secretion From Male Mouse Adrenal Chromaffin Cells Through an Increase In Ca2+ Release From the Endoplasmic Reticulum
Authors: Lukewich Mark K. , Lomax Alan E.
Published: October 2013

Enhanced epinephrine secretion from adrenal chromaffin cells (ACCs) is an important homeostatic response to severe systemic inflammation during sepsis. Evidence suggests that increased activation of ACCs by preganglionic sympathetic neurons and direct alterations in ACC function contribute to this response. However, the direct effects of sepsis on ACC function have yet to be characterized. We hypothesized that sepsis enhances epinephrine secretion from ACCs by increasing intracellular Ca2+ signaling. Plasma epinephrine concentration was increased 5-fold in the lipopolysaccharide-induced endotoxemia model of sepsis compared with saline-treated control mice. Endotoxemia significantly enhanced stimulus-evoked epinephrine secretion from isolated ACCs in vitro. Carbon fiber amperometry revealed an increase in the number of secretory events during endotoxemia, without significant changes in spike amplitude, half-width, or quantal content. ACCs isolated up to 12 hours after the induction of endotoxemia exhibited larger stimulus-evoked Ca2+ transients compared with controls. Similarly, ACCs from cecal ligation and puncture mice also exhibited enhanced Ca2+ signaling. Although sepsis did not significantly affect ACC excitability or voltage-gated Ca2+ currents, a 2-fold increase in caffeine (10 mM)-stimulated Ca2+ transients was observed during endotoxemia. Depletion of endoplasmic reticulum Ca2+ stores using cyclopiazonic acid (10 μM) abolished the effects of endotoxemia on catecholamine secretion from ACCs. These findings suggest that sepsis directly enhances catecholamine secretion from ACCs through an increase in Ca2+ release from the endoplasmic reticulum. These alterations in ACC function are likely to amplify the effects of increased preganglionic sympathetic neuron activity to further enhance epinephrine levels during sepsis.
Hepatobiliary and Pancreatic Neoplasms in Patients With McCune-Albright Syndrome
Authors: Gaujoux Sébastien , Salenave Sylvie , Ronot Maxime , Rangheard Anne-Sophie , Cros Jérôme , Belghiti Jacques , Sauvanet Alain , Ruszniewski Philippe , Chanson Philippe
Published: October 2013

Background:

McCune-Albright syndrome (MAS), which includes polycystic fibrous dysplasia, precocious puberty, and café au lait spots, is a rare disorder caused by somatic activating mutations of the GNAS gene. GNAS mutations have also been implicated in various sporadic tumors, including hepatobiliary and pancreatic neoplasms.

Aim:

The aim of this study was to assess the prevalence of hepatobiliary and pancreatic neoplasms in patients with McCune-Albright syndrome.

Patients and Methods:

Nineteen patients diagnosed between 1995 and 2012 with MAS in a tertiary referral center for rare growth disorders were screened with dedicated gadolinium-enhanced magnetic resonance imaging for hepatobiliary and pancreatic neoplasms between June 2011 and December 2012.

Results:

Six (32%) of the 19 screened patients were found to have hepatic, pancreatic, or biliary lesions, excluding liver hemangiomas, liver cysts, and focal nodular hyperplasia. This includes pancreatic ductal lesions observed in 4 patients, including numerous branch-duct intraductal papillary mucinous neoplasms in 3 patients. Biliary lesions were observed in 1 patient, with a large choledochal cyst also involving the left biliary branch. Finally, multiple inflammatory/telangiectatic hepatic adenomas were observed in 2 patients, including 1 with proven somatic GNAS mutation.

Conclusion:

We describe the first observation of syndromic intraductal papillary mucinous neoplasms and the new association between MAS and pancreatic neoplasms, namely intraductal papillary mucinous neoplasms of the pancreas but also rare hepatobiliary neoplasms including liver adenomas and choledochal cysts. These findings strongly suggest that somatic activating GNAS mutations, possibly through cAMP pathway disorders, are involved in the tumorigenesis of hepatobiliary and pancreatic tissues originating from the foregut endoderm and have led us to use a routine screening by dedicated magnetic resonance imaging including both pancreatobiliary and liver sequences in patients with MAS.