Effect of the reaction mixture on the structure and permeability of macroporous SiO[2], obtained by sol gel by method

In this paper, a number of porous silicone monoliths were synthesized under various conditions and their composition, structure, permeability coefficients k, and porosity were studied. The effect of the introduction of ethyl alcohol in the reaction mixture on the properties of the obtained silica was revealed

Acid Sphingomyelinase Deficiency Ameliorates Farber Disease

Farber disease is a rare lysosomal storage disorder resulting from acid ceramidase deficiency and subsequent ceramide accumulation. No treatments for Farber disease are clinically available, and affected patients have a severely shortened lifespan. We have recently reported a novel acid ceramidase deficiency model that mirrors the human disease closely. Acid sphingomyelinase is the enzyme that generates ceramide upstream of acid ceramidase in the lysosomes. Using our acid ceramidase deficiency model, we tested if acid sphingomyelinase could be a potential novel therapeutic target for the treatment of Farber disease. A number of functional acid sphingomyelinase inhibitors are clinically available and have been used for decades to treat major depression. Using these as a therapeutic for Farber disease, thus, has the potential to improve central nervous symptoms of the disease as well, something all other treatment options for Farber disease can’t achieve so far. As a proof-of-concept study, we first cross-bred acid ceramidase deficient mice with acid sphingomyelinase deficient mice in order to prevent ceramide accumulation. Double-deficient mice had reduced ceramide accumulation, fewer disease manifestations, and prolonged survival. We next targeted acid sphingomyelinase pharmacologically, to test if these findings would translate to a setting with clinical applicability. Surprisingly, the treatment of acid ceramidase deficient mice with the acid sphingomyelinase inhibitor amitriptyline was toxic to acid ceramidase deficient mice and killed them within a few days of treatment. In conclusion, our study provides the first proof-of-concept that acid sphingomyelinase could be a potential new therapeutic target for Farber disease to reduce disease manifestations and prolong survival. However, we also identified previously unknown toxicity of the functional acid sphingomyelinase inhibitor amitriptyline in the context of Farber disease, strongly cautioning against the use of this substance class for Farber disease patients

Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma

Major depressive disorder (MDD) is a very common, severe disease with a lifetime prevalence of ~ 10%. The pathogenesis of MDD is unknown and, unfortunately, therapy is often insufficient. We have previously reported that ceramide levels are increased in the blood plasma of patients with MDD and in mice with experimental MDD. Here, we demonstrate that ceramide-enriched exosomes in the blood plasma are increased in mice with stress-induced MDD. Genetic studies reveal that neutral sphingomyelinase 2 is required for the formation of ceramide-enriched exosomes in the blood plasma. Accordingly, induced deficiency of neutral sphingomyelinase 2 prevented mice from the development of stress-induced MDD. Intravenous injection of microparticles from mice with MDD or injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was abrogated by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase. Mechanistically, injection of exosomes from mice with MDD or injection of ex vivo ceramide-loaded microparticles inhibited phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus, which has been previously shown to mediate MDD by plasma ceramide. In summary, our data indicate that ceramide-enriched exosomes are released by neutral sphingomyelinase 2 into the blood plasma upon stress and mediate stress-induced MDD

MONIKULTTUURINEN KASVATUSKUMPPANUUS VARHAISKASVATUKSESSA : Monikulttuuristen perheiden vanhempien näkemyksiä

Opinnäytetyön tarkoituksena on kuvailla monikulttuuristen perheiden vanhempien kokemuksia ja toiveita kasvatuskumppanuudesta varhaiskasvatuksessa. Opinnäytetyö on kvalitatiivinen ja se on toteutettu teemahaastatteluiden avulla. Haastattelut on tehty yksilöhaastatteluina. Opinnäytetyön toimeksiantajana toimi oululainen päiväkoti. Teoreettinen viitekehys opinnäytetyössä pohjautuu vahvasti kasvatuskumppanuuden periaatteisiin, joita ovat kuuleminen, kunnioitus, luottamus ja dialogi. Lisäksi opinnäytetyössä on teoriaa kulttuurista ja monikulttuurisuudesta. Haastattelurunko sisälsi lähinnä avoimia kysymyksiä, jotka pohjautuivat tietoperustaan. Haastattelut on analysoitu teemoittelun avulla. Teemat olivat samat kuin tietoperustassa. Opinnäytetyön pääteemoja ovat kasvatuskumppanuus ja monikulttuurisuus, jotka sisältävät vielä alateemoja. Tuloksissa nousee esiin pääosin positiiviset kokemukset kasvatuskumppanuudesta varhaiskasvatuksessa. Kasvatuskumppanuus koetaan tärkeänä ja kasvatusvastuuta jaetaan mielellään. Kulttuurieroja ei arjessa huomata juurikaan, mutta perheen kulttuuritausta toivotaan huomioitavan hienovaraisesti, liikaa korostamatta. Johtopäätöksenä voidaan sanoa, että varhaiskasvatukseen ja kasvatuskumppanuuden toteutumiseen ollaan tyytyväisiä.The purpose of this thesis is to describe experiences and wishes of parents of multicultural families about educational partnership in early childhood education. This thesis is qualitative and the material for it was collected with individual theme interviews. The thesis was commissioned by a certain kindergarten from Oulu. The theoretical frame of this thesis includes principles of educational partnership such as hearing, respect, trust and dialog. There is also theory of culture and multiculturalism in this thesis. Open questions of the interview were based on the theoretical frame. The interviews were analyzed by thematic analyzing. Themes were same as in theoretical frame. The main themes of this thesis are educational partnership and multiculturalism which includes subthemes. The results of our thesis show positive experiences in educational partnership and early childhood education. The parents feel the importance of educational partnership and responsibility of raising a child is shared gladly. The parents do not feel cultural differences in everyday life, but there is a wish for sensitive consideration of culture which does not overemphasize the culture. In summary it can be said, that the parents are satisfied with educational partnership and early childhood education

Pharmacological targeting of the mitochondrial calcium-dependent potassium channel KCa3.1 triggers cell death and reduces tumor growth and metastasis in vivo

Ion channels are non-conventional, druggable oncological targets. The intermediate-conductance calcium-dependent potassium channel (K(Ca)3.1) is highly expressed in the plasma membrane and in the inner mitochondrial membrane (mitoK(Ca)3.1) of various cancer cell lines. The role mitoK(Ca)3.1 plays in cancer cells is still undefined. Here we report the synthesis and characterization of two mitochondria-targeted novel derivatives of a high-affinity K(Ca)3.1 antagonist, TRAM-34, which retain the ability to block channel activity. The effects of these drugs were tested in melanoma, pancreatic ductal adenocarcinoma and breast cancer lines, as well as in vivo in two orthotopic models. We show that the mitochondria-targeted TRAM-34 derivatives induce release of mitochondrial reactive oxygen species, rapid depolarization of the mitochondrial membrane, fragmentation of the mitochondrial network. They trigger cancer cell death with an EC50 in the mu M range, depending on channel expression. In contrast, inhibition of the plasma membrane K(Ca)3.1 by membrane-impermeant Maurotoxin is without effect, indicating a specific role of mitoK(Ca)3.1 in determining cell fate. At sub-lethal concentrations, pharmacological targeting of mitoK(Ca)3.1 significantly reduced cancer cell migration by enhancing production of mitochondrial reactive oxygen species and nuclear factor-kappa B (NF-kappa B) activation, and by downregulating expression of Bcl-2 Nineteen kD-Interacting Protein (BNIP-3) and of Rho GTPase CDC-42. This signaling cascade finally leads to cytoskeletal reorganization and impaired migration. Overexpression of BNIP-3 or pharmacological modulation of NF-kappa B and CDC-42 prevented the migration-reducing effect of mitoTRAM-34. In orthotopic models of melanoma and pancreatic ductal adenocarcinoma, the tumors at sacrifice were 60% smaller in treated versus untreated animals. Metastasis of melanoma cells to lymph nodes was also drastically reduced. No signs of toxicity were observed. In summary, our results identify mitochondrial K(Ca)3.1 as an unexpected player in cancer cell migration and show that its pharmacological targeting is efficient against both tumor growth and metastatic spread in vivo

Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis.

Rationale: In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. Objectives: To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Methods: Sphingolipids were measured using mass spectrometry in fully-differentiated cultures of primary human airway epithelial cells and co-cultures with Pseudomonas aeruginosa. In situ activity assays, Western blotting and quantitative polymerase chain reaction were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Measurements and Main Results: Ceramide is increased in cystic fibrosis airway epithelium due to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to Pseudomonas aeruginosa by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in the apical membrane of cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Conclusions: Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice

Gram-positive bacterial pathogens that secrete cytotoxic pore-forming toxins, such as Staphylococcus aureus and Streptococcus pneumoniae, cause a substantial burden of disease. Inspired by the principles that govern natural toxin-host interactions, we have engineered artificial liposomes that are tailored to effectively compete with host cells for toxin binding. Liposome-bound toxins are unable to lyse mammalian cells in vitro. We use these artificial liposomes as decoy targets to sequester bacterial toxins that are produced during active infection in vivo. Administration of artificial liposomes within 10 h after infection rescues mice from septicemia caused by S. aureus and S. pneumoniae, whereas untreated mice die within 24-33 h. Furthermore, liposomes protect mice against invasive pneumococcal pneumonia. Composed exclusively of naturally occurring lipids, tailored liposomes are not bactericidal and could be used therapeutically either alone or in conjunction with antibiotics to combat bacterial infections and to minimize toxin-induced tissue damage that occurs during bacterial clearance

Postoperative peri-axillary seroma following axillary artery cannulation for surgical treatment of acute type A aortic dissection

The arterial cannulation site for optimal tissue perfusion and cerebral protection during cardiopulmonary bypass (CPB) for surgical treatment of acute type A aortic dissection remains controversial. Right axillary artery cannulation confers significant advantages, because it provides antegrade arterial perfusion during cardiopulmonary bypass, and allows continuous antegrade cerebral perfusion during hypothermic circulatory arrest, thereby minimizing global cerebral ischemia. However, right axillary artery cannulation has been associated with serious complications, including problems with systemic perfusion during cardiopulmonary bypass, problems with postoperative patency of the artery due to stenosis, thrombosis or dissection, and brachial plexus injury. We herein present the case of a 36-year-old Caucasian man with known Marfan syndrome and acute type A aortic dissection, who had direct right axillary artery cannulation for surgery of the ascending aorta. Postoperatively, the patient developed an axillary perigraft seroma. As this complication has, not, to our knowledge, been reported before in cardiothoracic surgery, we describe this unusual complication and discuss conservative and surgical treatment options