Killed but metabolically active Leishmania infantum as a novel whole-cell vaccine for visceral leishmaniasis

There are currently no effective vaccines for visceral leishmaniasis, the second most deadly parasitic infection in the world. Here, we describe a novel whole-cell vaccine approach using Leishmania infantum chagasi promastigotes treated with the psoralen compound amotosalen (S-59) and low doses of UV A radiation. This treatment generates permanent, covalent DNA cross-links within parasites and results in Leishmania organisms termed killed but metabolically active (KBMA). In this report, we characterize the in vitro growth characteristics of both KBMA L. major and KBMA L. infantum chagasi. Concentrations of S-59 that generate optimally attenuated parasites were identified. Like live L. infantum chagasi, KBMA L. infantum chagasi parasites were able to initially enter liver cells in vivo after intravenous infection. However, whereas live L. infantum chagasi infection leads to hepatosplenomegaly in mice after 6 months, KBMA L. infantum chagasi parasites were undetectable in the organs of mice at this time point. In vitro, KBMA L. infantum chagasi retained the ability to enter macrophages and induce nitric oxide production. These characteristics of KBMA L. infantum chagasi correlated with the ability to prophylactically protect mice via subcutaneous vaccination at levels similar to vaccination with live, virulent organisms. Splenocytes from mice vaccinated with either live L. infantum chagasi or KBMA L. infantum chagasi displayed similar cytokine patterns in vitro. These results suggest that KBMA technology is a potentially safe and effective novel vaccine strategy against the intracellular protozoan L. infantum chagasi. This approach may represent a new method for whole-cell vaccination against other complex intracellular pathogens

О некоторых аспектах проблемы формирования рынка труда в Украине и в Крыму

В статье дан анализ современного состояния рынка труда в Украине и в Крыму, выявлены причины и особенности безработицы, определены задачи государства в этой связи, предложены мероприятия по их разрешению.Про деякі аспекти проблеми формування ринку праці в Україні і в Криму. У статті даний аналіз сучасного стану ринку праці в Україні й у Криму, виявлено причини й особливості безробіття, визначені завдання держави в цьому зв'язку, запропоновані заходи щодо їхнього вирішення.In article the analysis of a modern condition of a labour market in Ukraine and in Crimea is given, the reasons and features of unemployment are revealed, problems of the state in this connection are determined, actions under their sanction are offered

Immunomodulation by imiquimod in patients with high-risk primary melanoma.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted

Multiple clinical forms of dehydrated hereditary stomatocytosis arise from mutations in PIEZO1

Autosomal dominant dehydrated hereditary stomatocytosis (DHSt) usually presents as a compensated hemolytic anemia with macrocytosis and abnormally shaped red blood cells (RBCs). DHSt is part of a pleiotropic syndrome that may also exhibit pseudohyperkalemia and perinatal edema. We identified PIEZO1 as the disease gene for pleiotropic DHSt in a large kindred by exome sequencing analysis within the previously mapped 16q23-q24 interval. In 26 affected individuals among 7 multigenerational DHSt families with the pleiotropic syndrome, 11 heterozygous PIEZO1 missense mutations cosegregated with disease. PIEZO1 is expressed in the plasma membranes of RBCs and its messenger RNA, and protein levels increase during in vitro erythroid differentiation of CD341 cells. PIEZO1 is also expressed in liver and bone marrow during human and mouse development. We suggest for the first time a correlation between a PIEZO1 mutation and perinatal edema. DHSt patient red cells with the R2456H mutation exhibit increased ion-channel activity. Functional studies of PIEZO1 mutant R2488Q expressed in Xenopus oocytes demonstrated changes in ion-channel activity consistent with the altered cation content of DHSt patient red cells. Our findings provide direct evidence that R2456H and R2488Q mutations in PIEZO1 alter mechanosensitive channel regulation, leading to increased cation transport in erythroid cells

Meet Psyllium: A Fiber Product with Potential Cardioprotective Effects

With heart disease being the leading cause of death in the US and an important cause of mortality worldwide, there has been increasing interest in dietary supplements that may provide adjunctive therapy to standard medications. Fiber products, traditionally used for alleviating gastrointestinal states such as constipation, have also been investigated for their potential beneficial cardiovascular effects. Psyllium is a soluble dietary fiber derived from the plant Genus Plantago. The FDA has recently approved the use of daily intake of 3g to 12g of psyllium seed husks to reduce the risk of heart disease, when taken as part of a low fat, low cholesterol diet. This paper reviews recent clinical studies investigating the effects of psyllium on cardiovascular risk factors, focusing specifically on total and LDL cholesterol. The majority of studies show that psyllium modestly lowers total and LDL cholesterol levels in mild to moderate hypercholesterolemic people. The effects of psyllium depend on a wide range of variables including dosage and baseline lipid levels. The mechanism for cholesterol reduction likely involves increasing bile acid excretion and synthesis, and by affecting the levels of hepatic enzymes involved in lipid metabolism. Further studies will need to be conducted to identify the efficacy of psyllium use as adjunctive therapy with standard medications such as statins, its effects on normocholesterolemic people, and its long term safety profile

Meet Psyllium: A Fiber Product with Potential Cardioprotective Effects

With heart disease being the leading cause of death in the US and an important cause of mortality worldwide, there has been increasing interest in dietary supplements that may provide adjunctive therapy to standard medications. Fiber products, traditionally used for alleviating gastrointestinal states such as constipation, have also been investigated for their potential beneficial cardiovascular effects. Psyllium is a soluble dietary fiber derived from the plant Genus Plantago. The FDA has recently approved the use of daily intake of 3g to 12g of psyllium seed husks to reduce the risk of heart disease, when taken as part of a low fat, low cholesterol diet. This paper reviews recent clinical studies investigating the effects of psyllium on cardiovascular risk factors, focusing specifically on total and LDL cholesterol. The majority of studies show that psyllium modestly lowers total and LDL cholesterol levels in mild to moderate hypercholesterolemic people. The effects of psyllium depend on a wide range of variables including dosage and baseline lipid levels. The mechanism for cholesterol reduction likely involves increasing bile acid excretion and synthesis, and by affecting the levels of hepatic enzymes involved in lipid metabolism. Further studies will need to be conducted to identify the efficacy of psyllium use as adjunctive therapy with standard medications such as statins, its effects on normocholesterolemic people, and its long term safety profile