Weekly Intra-Amniotic IGF-1 Treatment Increases Growth of Growth-Restricted Ovine Fetuses and Up-Regulates Placental Amino Acid Transporters

Frequent treatment of the growth-restricted (IUGR) ovine fetus with intra-amniotic IGF-1 increases fetal growth. We aimed to determine whether increased growth was maintained with an extended dosing interval and to examine possible mechanisms. Pregnant ewes were allocated to three groups: Control, and two IUGR groups (induced by placental embolization) treated with weekly intra-amniotic injections of either saline (IUGR) or 360 µg IGF-1 (IGF1). IUGR fetuses were hypoxic, hyperuremic, hypoglycemic, and grew more slowly than controls. Placental glucose uptake and SLC2A1 (GLUT2) mRNA levels decreased in IUGR fetuses, but SLC2A3 (GLUT3) and SLC2A4 (GLUT4) levels were unaffected. IGF-1 treatment increased fetal growth rate, did not alter uterine blood flow or placental glucose uptake, and increased placental SLC2A1 and SLC2A4 (but not SLC2A3) mRNA levels compared with saline-treated IUGR animals. Following IGF-1 treatment, placental mRNA levels of isoforms of the system A, y+, and L amino acid transporters increased 1.3 to 5.0 fold, while the ratio of phosphorylated-mTOR to total mTOR also tended to increase. Weekly intra-amniotic IGF-1 treatment provides a promising avenue for intra-uterine treatment of IUGR babies, and may act via increased fetal substrate supply, up-regulating placental transporters for neutral, cationic, and branched-chain amino acids, possibly via increased activation of the mTOR pathway

МЕДИКАМЕНТОЗНОЕ ЛЕЧЕНИЕ МУКОВИСЦИДОЗА В РОССИИ: АНАЛИЗ ДАННЫХ НАЦИОНАЛЬНОГО РЕГИСТРА (2014)

The aim of this study was to analyze drug therapy of patients with cystic fibrosis (CF) in Russia. Methods. Findings of the Russian National Register of CF patients, 2014, were used in this study. The 2014 Register included data for 2,131 patients (2,092 alive and 39 died) from 74 regions of Russia. The median age was 10.2 (15.2) years, 29.2% of patients were aged 18 years and older. We analyzed administration of bronchodilators, inhaled corticosteroids (ICS), systemic steroids, dornase alfa, hypertonic saline solution, macrolides, systemic and inhaled antibiotics, pancreatic enzymes, ursodeoxycholic acid, and fat-soluble vitamins. Results. Drug administration rates were as follows: bronchodilators, 65.9%; ICS, 21.7%; systemic steroids, 5.5%; macrolides, 32.4%; dornase-alfa, 92.8%; hypertonic saline solution, 45.9%; intravenous antibiotics, 62.3%; oral antibiotics, 73.3%; inhaled antibiotics, 41.3%; pancreatic enzymes, 93.3%; ursodeoxycholic acid, 91.4%; and fat-soluble vitamins, 88.3%. Conclusion. Compared to treatment of CF patients in the Western Europe, there is higher rate of administration of pancreatic enzymes, ursodeoxycholic acid, dornase alfa, hypertonic saline solution and intravenous antibiotics in Russia. Compared to treatment strategy in USA, there is higher rate of administration of pancreatic enzymes and lower rate of administration of bronchodilators, hypertonic saline solution and inhaled antibiotics in Russia. Муковисцидоз (МВ) – тяжелое мультисистемное заболевание, требующее комплексного медикаментозного и немедикаментозного лечения. Особенностям лекарственной терапии разнородных по числу и возрасту групп больных МВ, проживающих в разных регионах России, посвящено ограниченное число работ, однако общий анализ данных большой группы пациентов в рамках единого регистра ранее не проводился. Цель. Выявление особенностей медикаментозной терапии больных МВ в России по данным национального Регистра (2014). Материалы и методы. Использованы сведения о пациентах (n = 2 131; 2 092 живых и 39 умерших) из 74 регионов России, состоящих в национальном Регистре больных муковисцидозом (2014). Медиана возраста пациентов составила 10,2 (15,2) года, доля взрослых (не моложе 18 лет) – 29,2 %. Проанализирована частота назначения лекарственной терапии бронходилататорами, ингаляционными (иГКС) и системными (сГКС) глюкокортикостероидами (ГКС), дорназой альфа, гипертоническим раствором натрия хлорида, макролидами, системными и ингаляционными антибактериальными препаратами (АБП), панкреатическими ферментами, урсодезоксихолевой кислотой (УДХК), жирорастворимыми витаминами. Результаты. Частота применения медикаментозной терапии по России распределена следующим образом: бронходилататоры – 65,9 %; иГКС – 21,7 %; сГКС – 5,5 %; макролиды – 32,4 %; дорназа альфа – 92,8 %; гипертонический раствор натрия хлорида – 45,9 %; внутривенные АБП – 62,3 %; пероральные АБП – 73,3 %; ингаляционные АБП – 41,3 %; панкреатические ферменты – 93,3 %; УДХК – 91,4 %; жирорастворимые витамины – 88,3 %. Отмечено, что взрослым больным наиболее часто назначаются бронхолитические препараты, АБП и ГКС; реже применяются панкреатические ферменты и УДХК. Заключение. Среди особенностей терапии российских больных по сравнению со странами Западной Европы можно выделить высокую долю назначения панкреатических ферментов, УДХК, дорназы альфа, гипертонического раствора и внутривенных АБП. По сравнению с США чаще назначаются панкреатические ферменты, реже – бронходилататоры, гипертонический раствор натрия хлорида и ингаляционные АБП

Oxidation-specific epitopes restrain bone formation

Atherosclerosis and osteoporosis are epidemiologically linked and oxidation specific epitopes (OSEs), such as phosphocholine (PC) of oxidized phospholipids (PC-OxPL) and malondialdehyde (MDA), are pathogenic in both. The proatherogenic effects of OSEs are opposed by innate immune antibodies. Here we show that high-fat diet (HFD)-induced bone loss is attenuated in mice expressing a single chain variable region fragment of the IgM E06 (E06-scFv) that neutralizes PC-OxPL, by increasing osteoblast number and stimulating bone formation. Similarly, HFD-induced bone loss is attenuated in mice expressing IK17-scFv, which neutralizes MDA. Notably, E06-scFv also increases bone mass in mice fed a normal diet. Moreover, the levels of anti-PC IgM decrease in aged mice. We conclude that OSEs, whether produced chronically or increased by HFD, restrain bone formation, and that diminished defense against OSEs may contribute to age-related bone loss. Anti-OSEs, therefore, may represent a novel therapeutic approach against osteoporosis and atherosclerosis simultaneously

Bone and the Innate Immune System

The immune system and bone are intimately linked with significant physical and functionally related interactions. The innate immune system functions as an immediate response system to initiate protections against local challenges such as pathogens and cellular damage. Bone is a very specific microenvironment in which infectious attack is less common but repair and regeneration are ongoing and important functions. Thus in the bone the primary goal of innate immune and bone interactions is to maintain tissue integrity. Innate immune signals are critical for removal of damaged and apoptotic cells and to stimulate normal tissue repair and regeneration. In this review we focus on these innate immune mechanisms that function to regulate bone homeostasis