Physiological concentrations of interleukin-6 directly promote insulin secretion, signal transduction, nitric oxide release, and redox status in a clonal pancreatic β-cell line and mouse islets

Interleukin-6 (IL6) has recently been reported to promote insulin secretion in a glucagon-like peptide-1-dependent manner. Herein, the direct effects of IL6 (at various concentrations from 0 to 1000?pg/ml) on pancreatic β-cell metabolism, AMP-activated protein kinase (AMPK) signaling, insulin secretion, nitrite release, and redox status in a rat clonal β-cell line and mouse islets are reported. Chronic insulin secretion (in μg/mg protein per 24?h) was increased from 128.7±7.3 (no IL6) to 178.4±7.7 (at 100?pg/ml IL6) in clonal β-cells and increased significantly in islets incubated in the presence of 5.5?mM glucose for 2?h, from 0.148 to 0.167±0.003?ng/islet. Pretreatment with IL6 also induced a twofold increase in basal and nutrient-stimulated insulin secretion in subsequent 20?min static incubations. IL6 enhanced both glutathione (GSH) and glutathione disulphide (GSSG) by nearly 20% without changing intracellular redox status (GSSG/GSH). IL6 dramatically increased iNOS expression (by ca. 100-fold) with an accompanying tenfold rise in nitrite release in clonal β-cells. Phosphorylated AMPK levels were elevated approximately twofold in clonal β-cells and mouse islet cells. Calmodulin-dependent protein kinase kinase levels (CaMKK), an upstream kinase activator of AMPK, were also increased by 50% after IL6 exposure (in β-cells and islets). Our data have demonstrated that IL6 can stimulate β-cell-dependent insulin secretion via direct cell-based mechanisms. AMPK, CaMKK (an upstream kinase activator of AMPK), and the synthesis of nitric oxide appear to alter cell metabolism to benefit insulin secretion. In summary, IL6 exerts positive effects on β-cell signaling, metabolism, antioxidant status, and insulin secretion.     

Antibody levels to hantavirus in inhabitants of western Santa Catarina State, Brazil

Hantavirus cardiopulmonary syndrome (HCPS) is an infectious disease caused by hantaviruses of the family Bunyaviridae, and is transmitted by aerosols of excreta of infected rodents. The aim of the present study was to determine antibody levels to hantavirus in the population that lives at frontier of Brazil and Argentina. Participated of the study 405 individuals living in the municipalities of Bandeirante, Santa Helena, Princesa and Tunapolis, state of Santa Catarina, Brazil. IgG antibodies to hantavirus were analyzed in sera by an ELISA that uses a recombinant N protein of Araraquara hantavirus as antigen. The results were also confirmed by immunofluorescent test. Eight individuals showed antibodies to hantavirus (1.97% positivity), with serum titers ranging from 100 to 800. Six seropositives were males, older than 30 years and farmers. Our results reinforce previous data on hantavirus circulation and human infections in the southern border of Brazil with Argentina.     

Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival

While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide some insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 have been reported. We, therefore, investigated individuals from families with one or more first-degree relatives with myelodysplastic syndrome/acute myeloid leukemia with wild-type RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 first-degree cousins developed high-risk myelodys-plastic syndrome with monosomy 7. They were also observed to have acquired identical somatic ASXL1 mutations and both died despite stem cell transplantation. These findings confirm that germline GATA2 mutations predispose to familial myelodysplastic syndrome/acute myeloid leukemia, and that monosomy 7 and ASXL1 mutations may be recurrent secondary genetic abnormalities triggering overt malignancy in these families.     

Cognitive impairment in antiphospholipid syndrome: evidence from animal models

Although antiphospholipid syndrome (APS) is a multisystem prothrombotic condition, its inflammatory nature has been increasingly recognized in recent years. Stroke and transitory ischemic attacks are the neurological manifestations included in APS criteria, however many other neurological involvements have been attributed to antiphospholipid antibodies (aPL), such as seizures, transverse myelitis, and cognitive impairment. In this article we will review evidence from animal model that explain the role of aPL in cognition.     

A clinically applicable molecular-based classification for endometrial cancers

Background:

Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed.

Methods:

Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared.

Results:

Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for ‘copy-number'' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined ‘high-risk'' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves.

Conclusions:

Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.     

Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome

5-azacytidine (5-aza) is a hypomethylating agent approved for the treatment of high-risk myelodysplastic syndrome (MDS). It is assumed to act by demethylating tumor suppressor genes and via direct cytotoxic effects on malignant cells. In vitro treatment with hypomethylating agents has profound effects on the expression of killer-cell immunoglobulin-like (KIR) receptors on natural killer (NK) cells, as these receptors are epigenetically regulated via methylation of the promoters. Here we investigated the influence of 5-aza on the NK-cell repertoire during cytokine-induced proliferation in vitro and homeostatic proliferation in vivo in patients with high-risk MDS. In vitro treatment of NK cells from both healthy donors and MDS patients with low doses of 5-aza led to a significant increase in expression of multiple KIRs, but only in cells that had undergone several rounds of cell division. Proliferating 5-aza exposed NK cells exhibited increased IFN-γ production and degranulation towards tumor target cells. MDS patients had lower proportions of educated KIR-expressing NK cells than healthy controls but after systemic treatment with 5-aza, an increased proportion of Ki-67⁺ NK cells expressed multiple KIRs suggesting uptake of 5-aza in cycling cells in vivo. Hence, these results suggest that systemic treatment with 5-aza may shape the NK cell repertoire, in particular during homeostatic proliferation, thereby boosting NK cell-mediated recognition of malignant cells.     

Sustained Response of a Clivus Chordoma to Erlotinib after Imatinib Failure

Chordoma is a rare malignant axial tumour that develops from embryonic remnants of the notochord. Surgery and irradiation are the standard initial treatment. However, local recurrence is frequent and cytotoxic chemotherapy is inefficient. Transient activity of imatinib, a platelet-derived growth factor receptor inhibitor, was described in a phase II study. Activity of epidermal growth factor receptor (EGFR) inhibitors (erlotinib, gefitinib) has also been shown in a few recent case reports. We describe a 68-year-old female in whom clivus chordoma recurred after surgery and radiotherapy. The tumour progressed despite imatinib treatment. A partial and sustained response (28+ months) was obtained using erlotinib, an EGFR inhibitor. Erlotinib should be evaluated in a prospective trial investigating new potential therapies against recurrent chordoma.Key Words: Chordoma, Erlotinib, Imatinib     

THE THERAPEUTIC USE OF SYMBIOTICS

Introduction

Functional foods are health promoters and their use is associated with reduced risk of chronic degenerative and non-transmissible diseases. Examples are symbiotic. The association of one (or more) probiotic with a one (or more) prebiotic is called symbiotic, being the prebiotics complementary and probiotics synergistic, thus presenting a multiplicative factor on their individual actions.

Objective

To assess the evidences on the benefits of the use of symbiotics in the treatment of clinical and surgical situations.

Methods

The headings symbiotic, probiotic and prebiotic were searched in Pubmed/Medline in the last 15 years, and were selected 25 articles, used for database.

Results

The use of symbiotic may promote an increase in the number of bifidobacteria, glycemic control, reduction of blood cholesterol, balancing the intestinal flora which aids in reducing constipation and/or diarrhea, improves intestinal permeability and stimulation of the immune system. Clinical indications for these products has been expanded, in order to maximize the individual''s physiological functions to provide greater. So, with the high interest in the clinical and nutritional control of disease, many studies have been conducted demonstrating the effectiveness of using symbiotic in improving and/or preventing various and/or symptoms of gastrointestinal diseases.

Conclusion

Symbiotic behave differently and positively in various pathological situations.     

Effect of topical corticosteroids on nasal patency after acute positive airway pressure exposure

IntroductionNasal congestion and obstruction are reported in the majority of continuous positive airway pressure users and are frequently cited as reasons for noncompliance. Baseline inflammation due to allergic rhinitis could increase or exacerbate the inflammatory effect of high airflow in the nasal cavity as the result of continuous positive airway pressure and lead to greater continuous positive airway pressure intolerance. In this setting, intranasal steroids would be expected to counteract the nasal inflammation caused by allergic rhinitis and/or continuous positive airway pressure.ObjectiveThe aim of the present study is to evaluate the effects of topical corticosteroid use on nasal patency after acute exposure to positive pressure.MethodsTen individuals with allergic rhinitis were exposed to 1 h of continuous airway pressure (15 cm H₂O) in the nasal cavity, delivered by a continuous positive airway pressure device. Visual analog scale, nasal obstruction symptom evaluation scale, acoustic rhinometry and peak nasal inspiratory flow were performed before and after the intervention. After 4 weeks topical nasal steroid (budesonide) application, positive pressure exposure was repeated as well as the first assessments.ResultsPatients reported a statistically significant improvement both on the visual analog (p = 0.013) and obstruction symptom evaluation scales (p < 0.01). Furthermore, objective measurements were improved as well, with increased nasal cavity volume on acoustic rhinometry (p = 0.02) and increased peak nasal inspiratory flow (p = 0.012), after corticosteroid treatment.ConclusionIn patients with allergic rhinitis, intranasal corticosteroid therapy improved objective and subjective parameters of nasal patency after acute exposure of the nasal cavity to positive pressure.