C-Terminal Domain Deletion Enhances the Protective Activity of cpa/cpb Loaded Solid Lipid Nanoparticles against Leishmania major in BALB/c Mice

Cutaneous leishmaniasis (CL) is the most common form of leishmaniasis with an annual incidence of approximately 2 million cases and is endemic in 88 countries, including Iran. CL's continued spread, along with rather ineffectual treatments and drug-resistant variants emergence has increased the need for advanced preventive strategies. We studied Type II cysteine proteinase (CPA) and Type I (CPB) with its C-terminal extension (CTE) as cocktail DNA vaccine against murine and canine leishmaniasis. However, adjuvants' success in enhancing immune responses to selected antigens led us to refocus our vaccine development programs. Herein, we discuss cationic solid lipid nanoparticles' (cSLN) ability to improve vaccine-induced protective efficacy against CL and subsequent lesion size and parasite load reduction in BALB/c mice. For this work, we evaluated five different conventional as well as novel parasite detection techniques, i.e., footpad imaging, footpad flowcytometry and lymph node flowcytometry for disease progression assessments. Vaccination with cSLN-cpa/cpb-CTE formulation showed highest parasite inhibition at 3-month post vaccination. Immunized mice showed reduced IL-5 level and significant IFN-ã increase, compared to control groups. We think our study represents a potential future and a major step forward in vaccine development against leishmaniasis

Pulmonary arterial pressure detects functional mitral stenosis after annuloplasty for primary mitral regurgitation: An exercise stress echocardiographic study

Introduction: The restrictive mitral valve annuloplasty (RMA) is the treatment of choice for degenerative mitral regurgitation (MR), but postoperative functional mitral stenosis remains a matter of debate. In this study, we sought to determine the impact of mitral stenosis on the functional capacity of patients. Methods: In a cross-sectional study, 32 patients with degenerative MR who underwent RMA using a complete ring were evaluated. All participants performed treadmill exercise test and underwent echocardiographic examinations before and after exercise. Results: The patients� mean age was 50.1 ± 12.5 years. After a mean follow-up of 14.1 ± 5.9 months (6�32 months), the number of patients with a mitral valve peak gradient >7.5 mm Hg, a mitral valve mean gradient >3 mm Hg, and a pulmonary arterial pressure (PAP) �25 mm Hg at rest were 50, 40.6, and 62.5, respectively. 13 patients (40.6) had incomplete treadmill exercise test. All hemodynamic parameters were higher at peak exercise compared with at rest levels (all P <.05). The PAP at rest and at peak exercise as well as peak transmitral gradient at peak exercise were higher in patients with incomplete exercise compared with complete exercise test (all P <.05). The PAP at rest (a sensitivity and a specificity of 84.6 and 52.6, respectively; area under the curve AUC =.755) and at peak exercise (a sensitivity and a specificity of 100% and 47.4%, respectively; AUC =.755) discriminated incomplete exercise test. Conclusion: The RMA for degenerative MR was associated with a functional stenosis and the PAP at rest and at peak exercise discriminated low exercise capacity. © 2017, Wiley Periodicals, Inc

Pulmonary arterial pressure detects functional mitral stenosis after annuloplasty for primary mitral regurgitation: An exercise stress echocardiographic study

Introduction: The restrictive mitral valve annuloplasty (RMA) is the treatment of choice for degenerative mitral regurgitation (MR), but postoperative functional mitral stenosis remains a matter of debate. In this study, we sought to determine the impact of mitral stenosis on the functional capacity of patients. Methods: In a cross-sectional study, 32 patients with degenerative MR who underwent RMA using a complete ring were evaluated. All participants performed treadmill exercise test and underwent echocardiographic examinations before and after exercise. Results: The patients� mean age was 50.1 ± 12.5 years. After a mean follow-up of 14.1 ± 5.9 months (6�32 months), the number of patients with a mitral valve peak gradient >7.5 mm Hg, a mitral valve mean gradient >3 mm Hg, and a pulmonary arterial pressure (PAP) �25 mm Hg at rest were 50, 40.6, and 62.5, respectively. 13 patients (40.6) had incomplete treadmill exercise test. All hemodynamic parameters were higher at peak exercise compared with at rest levels (all P <.05). The PAP at rest and at peak exercise as well as peak transmitral gradient at peak exercise were higher in patients with incomplete exercise compared with complete exercise test (all P <.05). The PAP at rest (a sensitivity and a specificity of 84.6 and 52.6, respectively; area under the curve AUC =.755) and at peak exercise (a sensitivity and a specificity of 100% and 47.4%, respectively; AUC =.755) discriminated incomplete exercise test. Conclusion: The RMA for degenerative MR was associated with a functional stenosis and the PAP at rest and at peak exercise discriminated low exercise capacity. © 2017, Wiley Periodicals, Inc

Antitumor effect of IP-10 by using two different approaches: Live delivery system and gene therapy

Purpose: Immunotherapy is one of the treatment strategies for breast cancer, the most common cancer in women worldwide. In this approach, the patient�s immune system is stimulated to attack microscopic tumors and control metastasis. Here, we used interferon γ-induced protein 10 (IP-10), which induces and strengthens antitumor immunity, as an immunotherapeutic agent. We employed Leishmania tarentolae, a nonpathogenic lizard parasite that lacks the ability to persist in mammalian macrophages, was used as a live delivery system for carrying the immunotherapeutic agent. It has been already shown that arginase activity, and consequently, polyamine production, are associated with tumor progression. Methods: A live delivery system was constructed by stable transfection of pLEXSY plasmid containing the IP-10-enhanced green fluorescent protein (IP-10- egfp) fusion gene into L. tarentolae. Then, the presence of the IP-10-egfp gene and the accurate integration location into the parasite genome were confirmed. The therapeutic efficacy of IP- 10 delivered via L. tarentolae and recombinant pcDNA-(IP- 10-egfp) plasmid was compared by determining the arginase activity in a mouse 4T1 breast cancer model. Results: The pcDNA- (IP-10-egfp) group showed a significant reduction in tumor weight and growth. Histological evaluation also revealed that only this group demonstrated inhibition of metastasis to the lung tissue. The arginase activity in the tissue of the pcDNA-(IP- 10-egfp) mice significantly decreased in comparison with that in normal mice. No significant difference was observed in arginase activity in the sera of mice receiving other therapeutic strategies. Conclusion: Our data indicates that IP-10 immunotherapy is a promising strategy for breast cancer treatment, as shown in the 4T1-implanted BALB/c mouse model. However, the L. tarentolae- (IP-10-EGFP) live delivery system requires dose modifications to achieve efficacy in the applied regimen (six injections in 3 weeks). Our results indicate that the arginase assay could be a good biomarker to differentiate tumoral tissues from the normal ones. © 2016 Korean Breast Cancer Society. All rights reserved

Demographic profile, clinical, and topographic characteristics of keratoconus patients attending at a tertiary eye center

Purpose: To evaluate the demographic profile, clinical, and topographic characteristics of keratoconus (KCN) patients attending at a subspecialty eye hospital in Tehran, Iran. Methods: In this cross-sectional study, all patients who attended Noor Eye Hospital between March 2011 and March 2017 and had a diagnosis of KCN were identified, and the required number of patients was randomly selected. The following data were extracted from patient's records: age, sex, visual acuity, refraction, keratometry, pachymetry, and treatment procedures. The data of KCN laterality, severity, morphology, and cone location were also extracted by analyzing the corneal imaging maps. Results: The records of 1080 eyes of 540 patients were evaluated. The mean age of the participants was 31.04 ± 8.54 years (range, 13�63 years), and 69.3 of the patients were male. The highest and lowest frequency of KCN was seen in the age group 20�30 years and above 50 years, respectively. Bilateral KCN was detected in 93.3 95% confidence interval (CI): 91.68�94.75 of the subjects. 43.7% (95%CI: 32.88�54.48), 55.6% (95%CI: 44.73�66.38), and 0.8% (95%CI: 0.75�0.78) of the cases had nipple, oval, and globus cones, respectively. The cone was central in 52.1% (95%CI: 41.10�63.11), paracentral in 43.6% (95%CI: 36.13�51.04), and peripheral in 4.3% (95%CI: 00.76�7.86) of the cases. The frequency percentage of KCN according to severity was 15.2% (95%CI: 13.09�17.46), 56.4% (95%CI: 53.37�59.37), and 28.4% (95%CI: 25.75�31.21) for mild, moderate, and severe KCN, respectively. Among different parameters, only cone location had a significant association with age as the frequency of paracentral and peripheral cones increased with ageing (P = 0.002). Conclusions: The mean age of KCN patients in our study was higher than similar studies in other Asian countries. KCN was bilateral in most cases with an oval morphology and central cone location. Most of the patients had moderate to severe KCN. © 2019 Iranian Society of Ophthalmolog

Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs is Dependent on PD-1

[EN]We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAb at >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag−/− mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag−/− mouse recipients of first- and second-party NPIs maintained normoglycemia after reconstitution with spleen cells from tolerant B6 mice, while all B6 rag−/− mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts.SIWe acknowledge the technical assistance of Deb Dixon and Dawne Colwell and thoughtful discussions with Dr. Tsunehiro Kobayashi. We are grateful to the Canadian Diabetes Association, which provided major funding for this work as well as the Edmonton Civic Employees’ Charitable Assistance Fund, Stollery Children’s Hospital Foundation, the MacLachlan Fund University Hospital Foundation, Canadian Institutes of Health Research, Colliers International, Ken and Denise Cantor as well as Ewa and John Burton, who provided additional support. The Muttart Diabetes Research Training Centre provided scholarship for H.A. The authors declare no conflicts of interest

Strengthening livelihood resilience in upper catchments of dry areas by integrated natural resources management

The Livelihood Resilience project evolved around the hypothesis that better integrated management can improve the livelihoods of poor farming communities and increase the environmental integrity and water productivity of upstream watersheds in dry areas. This hypothesis was tested by researchers from different Iranian research and executive organizations and farming communities in two benchmark research watersheds in upper Karkheh River Basin in Iran, under the guidance of the ICARDA scientists. Participatory technology development, water, soil, erosion, land degradation and vegetation assessments, livelihood, gender and policy analyses, and integrated workshops delivered a set of principles for watershed management in dry areas

Modeling the morphodynamics of coastal responses to extreme events: what shape are we in?

This paper is not subject to U.S. copyright. The definitive version was published in Sherwood, C. R., van Dongeren, A., Doyle, J., Hegermiller, C. A., Hsu, T.-J., Kalra, T. S., Olabarrieta, M., Penko, A. M., Rafati, Y., Roelvink, D., van der Lugt, M., Veeramony, J., & Warner, J. C. Modeling the morphodynamics of coastal responses to extreme events: what shape are we in? Annual Review of Marine Science, 14, (2022): 457–492, https://doi.org/10.1146/annurev-marine-032221-090215.This review focuses on recent advances in process-based numerical models of the impact of extreme storms on sandy coasts. Driven by larger-scale models of meteorology and hydrodynamics, these models simulate morphodynamics across the Sallenger storm-impact scale, including swash,collision, overwash, and inundation. Models are becoming both wider (as more processes are added) and deeper (as detailed physics replaces earlier parameterizations). Algorithms for wave-induced flows and sediment transport under shoaling waves are among the recent developments. Community and open-source models have become the norm. Observations of initial conditions (topography, land cover, and sediment characteristics) have become more detailed, and improvements in tropical cyclone and wave models provide forcing (winds, waves, surge, and upland flow) that is better resolved and more accurate, yielding commensurate improvements in model skill. We foresee that future storm-impact models will increasingly resolve individual waves, apply data assimilation, and be used in ensemble modeling modes to predict uncertainties.All authors except D.R. were partially supported by the IFMSIP project, funded by US Office of Naval Research grant PE 0601153N under contracts N00014-17-1-2459 (Deltares), N00014-18-1-2785 (University of Delaware), N0001419WX00733 (US Naval Research Laboratory, Monterey), N0001418WX01447 (US Naval Research Laboratory, Stennis Space Center), and N0001418IP00016 (US Geological Survey). C.R.S., C.A.H., T.S.K., and J.C.W. were supported by the US Geological Survey Coastal/Marine Hazards and Resources Program. A.v.D. and M.v.d.L. were supported by the Deltares Strategic Research project Quantifying Flood Hazards and Impacts. M.O. acknowledges support from National Science Foundation project OCE-1554892

Physicians’ and nurses’ decision making to encounter neonates with poor prognosis in the neonatal intensive care unit

This is an Accepted Manuscript of an article published by Sage in Clinical Ethics on 03/06/2020. Available online: https://journals.sagepub.com/doi/abs/10.1177/1477750920927173This is an Accepted Manuscript of an article published by Sage in Clinical Ethics on 03/06/2020.Available online: https://journals.sagepub.com/doi/abs/10.1177/1477750920927173acceptedVersio