Endogenous Brain Pericytes Are Widely Activated and Contribute to Mouse Glioma Microvasculature

Glioblastoma multiforme (GBM) is the most common brain tumor in adults. It presents an extremely challenging clinical problem, and treatment very frequently fails due to the infiltrative growth, facilitated by extensive angiogenesis and neovascularization. Pericytes constitute an important part of the GBM microvasculature. The contribution of endogenous brain pericytes to the tumor vasculature in GBM is, however, unclear. In this study, we determine the site of activation and the extent of contribution of endogenous brain pericytes to the GBM vasculature. GL261 mouse glioma was orthotopically implanted in mice expressing green fluorescent protein (GFP) under the pericyte marker regulator of G protein signaling 5 (RGS5). Host pericytes were not only activated within the glioma, but also in cortical areas overlying the tumor, the ipsilateral subventricular zone and within the hemisphere contralateral to the tumor. The host-derived activated pericytes that infiltrated the glioma were mainly localized to the tumor vessel wall. Infiltrating GFP positive pericytes co-expressed the pericyte markers platelet-derived growth factor receptor-β (PDGFR-β) and neuron-glial antigen 2. Interestingly, more than half of all PDGFR-β positive pericytes within the tumor were contributed by the host brain. We did not find any evidence that RGS5 positive pericytes adopt another phenotype within glioma in this paradigm. We conclude that endogenous pericytes become activated in widespread areas of the brain in response to an orthotopic mouse glioma. Host pericytes are recruited into the tumor and constitute a major part of the tumor pericyte population.     

Synthesis of thiazol-2-imines from the reduction of single enantiomer 2-imino-thiazolidin-4-ones followed by a spontaneous water elimination

Chiral hemiaminals ( 5-8RR and 5-8SS ) have been synthesized from the corresponding 2-iminothiazolidine-4-ones ( 1-4RR and 1-4SS ) by LiAlH₄ reductions stereoselectively and were then converted to single enantiomer thiazol-2-imines ( 9-12RR and 9-12SS ) by a water elimination reaction. The kinetics of the dehydration reactions which occurred spontaneously both in the solid state and in the solution have been followed by time dependent ¹H nuclear magnetic resonance spectroscopy. The corresponding first order rate constants and free energies of activation values for the conversions have been reported.     

Broth Microdilution and Time–Kill Testing of Caspofungin, Voriconazole, Amphotericin B and their Combinations Against Clinical Isolates of Candida krusei

Treatment of invasive Candida krusei infections can be difficult due to its intrinsic fluconazole resistance and its reduced susceptibility to amphotericin B and flucytosine. Caspofungin (CAS) acts on a different cellular target, and its combination with voriconazole (VOR) or amphotericin B (AmB) appears promising. We evaluated the activity of CAS, VOR and AmB alone and in combination at 1/4, 1, 4xMIC concentrations by time–kill method against 30 C. krusei isolates. All isolates were susceptible to CAS and VOR; AmB MICs were 2 μg/ml for 50% of isolates by broth microdilution. CAS showed a fast killing activity at all concentrations; it was fungistatic at 1/4xMICs and fungicidal at 1-4xMICs in general. VOR displayed a concentration-independent fungistatic activity against all isolates. AmB exhibited a concentration-dependent activity; it was fungistatic at 1/4-1xMIC and fungicidal at 4xMIC. The most common interaction was indifference for both combinations. Frequency of synergic interaction for the VOR + CAS combination was 66.7% at 1/4xMIC after 48 h. The best results for CAS + AmB combination were obtained at 4xMIC in the first 4–8 h; synergic interaction was detected for 20 isolates (66.7%) at 4xMIC after 4 h. Consequently, VOR and CAS alone have been found effective, and high AmB MICs are remarkable against clinical C. krusei isolates in vitro. The combinations of CAS with VOR or AmB have exhibited promising results.     

The adult human brain harbors multipotent perivascular mesenchymal stem cells

Blood vessels and adjacent cells form perivascular stem cell niches in adult tissues. In this perivascular niche, a stem cell with mesenchymal characteristics was recently identified in some adult somatic tissues. These cells are pericytes that line the microvasculature, express mesenchymal markers and differentiate into mesodermal lineages but might even have the capacity to generate tissue-specific cell types. Here, we isolated, purified and characterized a previously unrecognized progenitor population from two different regions in the adult human brain, the ventricular wall and the neocortex. We show that these cells co-express markers for mesenchymal stem cells and pericytes in vivo and in vitro, but do not express glial, neuronal progenitor, hematopoietic, endothelial or microglial markers in their native state. Furthermore, we demonstrate at a clonal level that these progenitors have true multilineage potential towards both, the mesodermal and neuroectodermal phenotype. They can be epigenetically induced in vitro into adipocytes, chondroblasts and osteoblasts but also into glial cells and immature neurons. This progenitor population exhibits long-term proliferation, karyotype stability and retention of phenotype and multipotency following extensive propagation. Thus, we provide evidence that the vascular niche in the adult human brain harbors a novel progenitor with multilineage capacity that appears to represent mesenchymal stem cells and is different from any previously described human neural stem cell. Future studies will elucidate whether these cells may play a role for disease or may represent a reservoir that can be exploited in efforts to repair the diseased human brain.     

The role of human Dectin-1 Y238X gene polymorphism in recurrent vulvovaginal candidiasis infections

Recurrent vulvovaginal candidiasis (RVVC) is defined as having four or more symptomatic vulvovaginal candidiasis (VVC) attacks within a year. This study aimed to investigate whether Human Dectin-1 Y238X Gene Polymorphism plays a role in RVVC pathogenesis. In order to examine and explore this aim, an experimental study was undergone. The clinical study design was conducted with 50 women diagnosed with RVVC and had four or more symptomatic VVC attacks who were included in the experimental group; while 50 women who did not have previous RVVC history and diagnosis and did not have vaginal discharge and itching in the past year were included in the control group. Blood samples were collected from these patients and transferred to EDTA tubes, to investigate the Dectin-1 Y238X gene polymorphism, and stored at ?80°. When Dectin-1 genotypes were compared, there was no significant difference between the two groups (p = 0.452, p = 0.615, p = 0.275). History of familial RVVC was significantly higher in the experimental group (p = 0.001). When the multivariate analysis was used to evaluate factors that could determine RVVC frequency, history of familial RVVC was found to increase the frequency of RVVC attacks by 3.3 units. This study is the first-of-its-kind to investigate the correlation between Dectin-1 Y238X polymorphism, which has not been previously studied in the Turkish population, and RVVC. The result of this study suggests that there is no correlation between this polymorphism and RVVC.     

Inhaled corticosteroid effects both eosinophilic and non-eosinophilic inflammation in asthmatic patients

AIM: To determine induced sputum cell counts and interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-alpha) and leukotriene B4 (LTB4) levels as markers of neutrophilic inflammation in moderate persistent asthma, and to evaluate the response to inhaled steroid therapy. METHODS: Forty-five moderate asthmatic patients and 10 non-smoker controls were included in this study. All patients received inhaled corticosteroid (800 microg of budesonide) for 12 weeks. Before and after treatment pulmonary function tests were performed, and symptom scores were determined. Blood was drawn for analysis of serum inflammatory markers, and sputum was induced. RESULTS: Induced sputum cell counts and inflammatory markers were significantly higher in patients with asthma than in the control group. The induced sputum eosinophil counts of 12 patients (26%) were found to be less than 5%, the non-eosinophilic group, and sputum neutrophil counts, IL-8 and TNF-alpha levels were significantly higher than the eosinophilic group (neutrophil, 50+/-14% versus 19+/-10%, p<0.01). In both groups, there was a significant decrease in sputum total cell counts and serum and sputum IL-8, TNF-alpha and LTB4 levels after the treatment. There was no change in sputum neutrophil counts. Although the sputum eosinophil count decreased only in the eosinophilic subjects, there was no significant difference in inflammatory markers between the groups. The symptom scores were significantly improved after treatment, while the improvement did not reach statistical significance on pulmonary function test parameters. CONCLUSION: Notably, in chronic asthma there is a subgroup of patients whose predominant inflammatory cells are not eosinophils. Sputum neutrophil counts and neutrophilic inflammatory markers are significantly higher in these patients. In the non-eosinophilic group, inhaled steroid caused an important decrease in inflammatory markers; however, there was no change in the sputum eosinophil and neutrophil counts.     

A randomized, double-blind study to assess the efficacy and safety of valtropin, a biosimilar growth hormone, in children with growth hormone deficiency

Valtropin is a recombinant human GH (rhGH) manufactured using a novel yeast expression system, classed as a 'biosimilar'. Valtropin was compared with Humatrope in children with GH deficiency (GHD). Treatment-naive, prepubertal children with GHD were randomized to Valtropin (n = 98) or Humatrope (n = 49) for 1 year. Standing height was measured 3-monthly and height velocity (HV) calculated. Serum IGF-I, IGFBP-3 and GH antibodies were determined centrally. HV at 1 year was 11.3 +/- 3.0 cm/year with Valtropin and 10.5 +/- 2.8 cm/year with Humatrope. Treatment difference was 0.09 cm/year with 95% confidence limits of -0.71, 0.90, within the preset non-inferiority limit of -2.0 cm/year. Height standard deviation (SD) scores were increased in both treatment arms with no acceleration of bone maturation. IGF-I and IGFBP-3 were increased comparably for both treatments. Adverse events showed no clinically relevant differences between treatment groups. Anti-GH antibodies were detected in 3 (3.1%) Valtropin and 1 (2.0%) Humatrope patients and the growth pattern was indistinguishable from the rest of the cohort. The 1-year efficacy and safety profile of Valtropin, a new biosimilar rhGH, are equivalent to the comparator rhGH, Humatrope. Valtropin can be used for the treatment of children with GHD and longer term data will fully establish its efficacy and safety profile.     

The effects of different catalysts on the pyrolysis of industrial wastes (olive and hazelnut bagasse)

Pyrolysis of olive and hazelnut bagasse biomass samples with two selected catalysts, namely activated alumina and sodium feldspar, have been conducted in a fixed-bed reactor. Experiments were carried out under certain pyrolysis conditions in a fixed-bed Heinze reactor. The catalyst was mixed with feedstock in different percentages. The effects of catalysts and their ratio (10%, 20%, 30% and 40% w/w) on the pyrolysis product yields were investigated and the results were compared with the results of experiments performed without catalyst under the same conditions. The maximum bio-oil yields for the bio-oils obtained from pyrolysis of olive bagasse were found as 37.07% and 36.67% on using activated alumina and sodium feldspar as catalysts, respectively, while these values were 27.64% and 31.68%, respectively, for the bio-oils from hazelnut bagasse. The oxygen contents of the bio-oils were also markedly reduced while the yield of bio-oil was reduced by the use of catalysts. The pyrolysis oils were examined using some spectroscopic and chromatographic analysis techniques. The results were compared with the petroleum fractions and the possibility of being a potential source of bio-oils was investigated.