TgIF2K-B Is an eIF2α Kinase in Toxoplasma gondii That Responds to Oxidative Stress and Optimizes Pathogenicity

Toxoplasma gondii is an obligate intracellular parasite that persists in its vertebrate hosts in the form of dormant tissue cysts, which facilitate transmission through predation. The parasite must strike a balance that allows it to disseminate throughout its host without killing it, which requires the ability to properly counter host cell defenses. For example, oxidative stress encountered by Toxoplasma is suggested to impair parasite replication and dissemination. However, the strategies by which Toxoplasma mitigates oxidative stress are not yet clear. Among eukaryotes, environmental stresses induce the integrated stress response via phosphorylation of a translation initiation factor, eukaryotic initiation factor 2 (eIF2). Here, we show that the Toxoplasma eIF2 kinase TgIF2K-B is activated in response to oxidative stress and affords protection. Knockout of the TgIF2K-B gene, Δtgif2k-b, disrupted parasite responses to oxidative stresses and enhanced replication, diminishing the ability of the parasite to differentiate into tissue cysts. In addition, parasites lacking TgIF2K-B exhibited resistance to activated macrophages and showed greater virulence in an in vivo model of infection. Our results establish that TgIF2K-B is essential for Toxoplasma responses to oxidative stress, which are important for the parasite's ability to establish persistent infection in its host.IMPORTANCE Toxoplasma gondii is a single-celled parasite that infects nucleated cells of warm-blooded vertebrates, including one-third of the human population. The parasites are not cleared by the immune response and persist in the host by converting into a latent tissue cyst form. Development of tissue cysts can be triggered by cellular stresses, which activate a family of TgIF2 kinases to phosphorylate the eukaryotic translation initiation factor TgIF2α. Here, we establish that the TgIF2 kinase TgIF2K-B is activated by oxidative stress and is critical for maintaining oxidative balance in the parasite. Depletion of TgIF2K-B alters gene expression, leading to accelerated growth and a diminished ability to convert into tissue cysts. This study establishes that TgIF2K-B is essential for the parasite's oxidative stress response and its ability to persist in the host as a latent infection

Protective effect of EDTA preadministration on renal ischemia

BACKGROUND: Chelation therapy with sodium edetate (EDTA) improved renal function and slowed the progression of renal insufficiency in patients subjected to lead intoxication. This study was performed to identify the underlying mechanism of the ability of EDTA treatment to protect kidneys from damage. METHODS: The effects of EDTA administration were studied in a rat model of acute renal failure induced by 60 minutes ischemia followed or not by 60 minutes reperfusion. Renal ischemic damage was evaluated by histological studies and by functional studies, namely serum creatinine and blood urea nitrogen levels. Treatment with EDTA was performed 30 minutes before the induction of ischemia. Polymorphonuclear cell (PMN) adhesion capability, plasmatic nitric oxide (NO) levels and endothelial NO synthase (eNOS) renal expression were studied as well as the EDTA protection from the TNFα-induced vascular leakage in the kidneys. Data was compared by two-way analysis of variance followed by a post hoc test. RESULTS: EDTA administration resulted in the preservation of both functional and histological parameters of rat kidneys. PMN obtained from peripheral blood of EDTA-treated ischemized rats, displayed a significant reduction in the expression of the adhesion molecule Mac-1 with respect to controls. NO was significantly increased by EDTA administration and eNOS expression was higher and more diffuse in kidneys of rats treated with EDTA than in the controls. Finally, EDTA administration was able to prevent in vivo the TNFα-induced vascular leakage in the kidneys. CONCLUSION: This data provides evidence that EDTA treatment is able to protect rat kidneys from ischemic damage possibly through the stimulation of NO production

New and conventional strategies for lung recruitment in acute respiratory distress syndrome

Mechanical ventilation is a supportive and life saving therapy in patients with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Despite advances in critical care, mortality remains high. During the last decade, the fact that mechanical ventilation can produce morphologic and physiologic alterations in the lungs has been recognized. In this context, the use of low tidal volumes (VT) and limited inspiratory plateau pressure (Pplat) has been proposed when mechanically ventilating the lungs of patients with ALI/ARDS, to prevent lung as well as distal organ injury. However, the reduction in VT may result in alveolar derecruitment, cyclic opening and closing of atelectatic alveoli and distal small airways leading to ventilator-induced lung injury (VILI) if inadequate low positive end-expiratory pressure (PEEP) is applied. On the other hand, high PEEP levels may be associated with excessive lung parenchyma stress and strain and negative hemodynamic effects, resulting in systemic organ injury. Therefore, lung recruitment maneuvers have been proposed and used to open up collapsed lung, while PEEP counteracts alveolar derecruitment due to low VT ventilatio

A Delphi-method-based consensus guideline for definition of treatment-resistant depression for clinical trials

Criteria for treatment-resistant depression (TRD) and partially responsive depression (PRD) as subtypes of major depressive disorder (MDD) are not unequivocally defined. In the present document we used a Delphi-method-based consensus approach to define TRD and PRD and to serve as operational criteria for future clinical studies, especially if conducted for regulatory purposes. We reviewed the literature and brought together a group of international experts (including clinicians, academics, researchers, employees of pharmaceutical companies, regulatory bodies representatives, and one person with lived experience) to evaluate the state-of-the-art and main controversies regarding the current classification. We then provided recommendations on how to design clinical trials, and on how to guide research in unmet needs and knowledge gaps. This report will feed into one of the main objectives of the EUropean Patient-cEntric clinicAl tRial pLatforms, Innovative Medicines Initiative (EU-PEARL, IMI) MDD project, to design a protocol for platform trials of new medications for TRD/PRD. © 2021, The Author(s).EU/EFPIA/Innovative Medicines Initiative 2 Joint Undertaking

Eating habits of obese patients with diagnosed hypertension

Celem pracy było zbadanie zwyczajów żywieniowych otyłych pacjentów ze zdiagnozowanym nadciśnieniem tętniczym leczonych w Klinice Chorób Zawodowych i Nadciśnienia Tętniczego Szpitala Klinicznego Akademii Medycznej we Wrocławiu. Badaniem objęto 52 osoby ze zdiagnozowanym nadciśnieniem tętniczym - pacjentów Kliniki Chorób Zawodowych i Nadciśnienia Tętniczego Szpitala Klinicznego Akademii Medycznej we Wrocławiu. Do oceny zwyczajów żywieniowych wykorzystano autorski, standaryzowany kwestionariusz opracowany w Zakładzie Żywienia Człowieka Uniwersytetu Przyrodniczego we Wrocławiu. Wśród badanych pacjentów z nadciśnieniem tętniczym zaledwie 12,9% mężczyzn i 33,3% kobiet deklarowało spożywanie 4 posiłków w ciągu dnia, 5 posiłków - ok. 5% kobiet i 3% mężczyzn, a więcej niż 5 posiłków - 3,2% mężczyzn. Wykazano, że przeważająca część badanych spożywała pieczywo białe (pszenne). Dotyczyło to ponad 33% kobiet i 58% mężczyzn. U blisko 29% pacjentek warzywa występowały w 3 porcjach, u ok. 14% – w 4 porcjach, a prawie 10% spożywało 5 porcji warzyw w ciągu dnia. 38% kobiet dostarczało 2 porcji warzyw dziennie, a ok. 10% – tylko jedną. Odpowiednią podaż owoców w diecie realizowało blisko 81% kobiet i 78% mężczyzn. Nieregularne spożycia mleka i produtów mlecznych deklarowało prawie 67% kobiet i 48% mężczyzn. Zaleca się, modyfikację składu racji pokarmowych badanych polegające na zwiększeniu w diecie udziału produktów zbożowych z pełnego przemiału, nasion strączkowych, warzyw i owoców oraz zmniejszeniu udziału tłuszczów zwierzęcych.The study was aimed, therefore, at investigating eating habits of patients with diagnosed arterial hypertension of the Clinic of Occupational Diseases and Arterial Hypertension, Clinical Hospital of the Medical Academy in Wroclaw. It covered 52 persons with diagnosed arterial hypertension - patients of the Clinic of Occupational Diseases and Arterial Hypertension, Clinical Hospital of the Medical Academy in Wrocław. Evaluation of their eating habits was conducted with the use of an original, standardized questionnaire elaborated at the Chair of Human Nutrition, Wrocław University of Environmental and Life Sciences. Amongst examined patients 12,9%) of men and 33,3% of women were eating 4 meals, 5 meals - 5% of women and 3%> of men, and more than 5 meals - 3,2 % of men. It was demonstrated that the majority of sick persons have eaten the white wheat bread. It concerned over 33% women and 58% men. Close 29% patients vegetables were found in a diet in 3 portions, at 14% of them - in 4 portions, however almost 10% ill women ate 5 portions of vegetables mane. About 38% women provided with only 2 portions of vegetables per day, and 10% - only one. The appropriate supply of fruits realized 81% of women and 78% of men. Irregular consumptions of the milk and dairy products declared 67%) women and 48% men. It is recommended the alteration of the warehouse of the nutritional rations ill from the arterial hypertension consists for increasing cereals in the diet of the participation of solid meal, leguminous seeds, vegetables and fruits and reducing the share of animal fats

Toxoplasma gondii Co-opts the Unfolded Protein Response To Enhance Migration and Dissemination of Infected Host Cells

Cells that are infected with the parasite Toxoplasma gondii exhibit heightened migratory activity, which facilitates dissemination of the infection throughout the body. In this report, we identify a new mechanism used by Toxoplasma to hijack its host cell and increase its mobility. We further show that the ability of Toxoplasma to increase host cell migration involves not the enzymatic activity of IRE1 but rather IRE1 engagement with actin cytoskeletal remodeling. Depletion of IRE1 from infected host cells reduces their migration in vitro and significantly hinders dissemination of Toxoplasma in vivo. Our findings reveal a new mechanism underlying host-pathogen interactions, demonstrating how host cells are co-opted to spread a persistent infection around the body.Toxoplasma gondii is an intracellular parasite that reconfigures its host cell to promote pathogenesis. One consequence of Toxoplasma parasitism is increased migratory activity of host cells, which facilitates dissemination. Here, we show that Toxoplasma triggers the unfolded protein response (UPR) in host cells through calcium release from the endoplasmic reticulum (ER). We further identify a novel role for the host ER stress sensor protein IRE1 in Toxoplasma pathogenesis. Upon infection, Toxoplasma activates IRE1, engaging its noncanonical role in actin remodeling through the binding of filamin A. By inducing cytoskeletal remodeling via IRE1 oligomerization in host cells, Toxoplasma enhances host cell migration in vitro and dissemination of the parasite to host organs in vivo. Our study has identified novel mechanisms used by Toxoplasma to induce dissemination of infected cells, providing new insights into strategies for treatment of toxoplasmosis