Bioreducible polyethylenimine core-shell nanostructures as efficient and non-toxic gene and drug delivery vectors.

Low molecular weight branched polyethylenimine (LMW bPEIs 1.8 kDa) have received considerable attention for the fabrication of nucleic acid carriers due to their biocompatible and non-toxic nature. However, due to the inadequate nucleic acid complexation ability and transportation across the cell membrane, these show poor transfection efficacy, limiting their clinical applications. Therefore, to overcome these challenges, in this study, we have grafted bPEI 1.8 kDa with a disulfide bond containing hydrophobic moiety, 3-(2-pyridyldithio) propionic acid (PDPA), via amide linkages through EDC/NHS-mediated coupling to obtain N-[3-(2-pyridyldithio)] propionoyl polyethylenimine (PDPP) conjugates. The best formulation for nucleic acid transfection was evaluated after preparing a series of PDPP conjugates by varying the amount of PDPA. In an aqueous environment, these PDPP conjugates self-assembled to form spherical shaped core-shell PDPP nanostructures with size ranging from âˆ¼188-307 nm and zeta-potential from ∼ +3 to +19 mV. The positively charged surface of the core-shell nanocomposites helps in the binding of plasmid DNA (pDNA), its transportation inside the cell, and protection against enzymes. Evaluation of PDPP/pDNA complexes on mammalian cells revealed that all these complexes showed significantly improved transfection efficacy without hampering cytocompatibility. Amongst all, the pDNA complex of PDPP-2 exhibited the best transfection efficiency (i.e. >6-fold) in comparison to pDNA complex of the native bPEI. The nanocomposites exhibited the redox responsive behavior advantageous for therapeutic delivery to the tumor cells. The core of the nanostructures facilitate the encapsulation of a hydrophobic model drug, ornidazole. In vitro drug release analysis showed a faster release rate in response to a reductant mimicking the cellular environment. Altogether, these nanostructures have great potential to co-deliver both drug and gene simultaneously in response to tumor cell reductive microenvironment in vitro and could be used as the next-generation delivery system.

Clinical relevance of nitrated beta 2-glycoprotein I in antiphospholipid syndrome: Implications for thrombosis risk.

Β2-Glycoprotein I (ß2GPI) is an important anti-thrombotic protein and is the major auto-antigen in the antiphospholipid syndrome (APS). The clinical relevance of nitrosative stress in post translational modification of ß2GPI was examined.The effects of nitrated (n)ß2GPI on its anti-thrombotic properties and its plasma levels in primary and secondary APS were determined with appropriate clinical control groups. ß2-glycoprotein I was nitrated at tyrosines 218, 275 and 309. ß2-glycoprotein I binds to lipid peroxidation modified products through Domains IV and V. Nitrated ß2GPI loses this binding (p < 0.05) and had diminished activity in inhibiting platelet adhesion to vWF under high shear flow (p < 0.01). Levels of nß2GPI were increased in patients with primary APS compared to patients with either secondary APS (p < 0.05), autoimmune disease without APS (p < 0.05) or non-autoimmune patients with arterial thrombosis (p < 0.01) and healthy individuals (p < 0.05).In conclusion tyrosine nitration of plasma ß2GPI is demonstrated and has important implications with regards to the pathophysiology of platelet mediated thrombosis in APS. Elevated plasma levels of nß2GPI in primary APS may be a risk factor for thrombosis warranting further investigation.

The Cost of Heart Transplant in Iran: A Multicenter Analysis.

Background: Heart transplantation is an established treatment for end-stage heart failure patients, but its cost-effectiveness is under question. Objective: This study aimed to assess the cost of heart transplantation in Iran as a developing country in Asia to contribute to future planning in the region. Methods: This study was conducted in two phases. First, in a retrospective multicenter study, hospital data of heart transplant and hospitalization of three active heart transplant centers in Tehran, Iran, were reviewed from April 2013 to May 2015. Then pre-transplantation, transplantation, and one-year posttransplant costs were calculated according to the ABC (activity-based costing) method in 2016. Results: Data were obtained for 120 patients, among which 95 (79.17%) were males with a mean (SD) age of 35.31±13.41 years. Mean (SD) hospital and ICU length of stay were 17.85±14.91 and 9.74±8.94 days, respectively. A significant correlation existed between the mean of hospital and ICU length of stay (P<0.001, r: 0.754). The mean heart transplant and hospitalization cost was 3445.47±1243.29 USD from 2013 to 2015. Using the activity-based costing method, the cost of pre-transplantation, transplantation, and one-year -post-transplantation were extracted 6.5%, 73.5%, and 20%, respectively, with a total cost of 26232 USD. Conclusion: Compared to other countries, the cost of heart transplantation in Iran is very low. Numerous reasons lead to this difference. Firstly, a heart transplantation surgery is performed in university-based hospitals and is supported by the government. On the other hand, a significant difference exists between personnel costs in Iran compared to other countries.

Atrioventricular Block: A Heralding Sign of Cardiac Allograft Rejection.

Heart transplantation is the treatment of choice for those with end-stage heart failure. However, despite improvements in immunosuppressive treatment, patients are at significant risk of allograft rejection, especially early after transplantation. Any changes in patient's heart condition including reduced left ventricular ejection fraction, arrhythmia and any types of blocks need attention. Herein we report on a 29-year-old man who underwent heart transplantation 5 years before due to dilated cardiomyopathy. He was on immunosuppressive therapy and was good until one week before his admission, when he felt palpitation. Electrocardiography during palpitation showed a second-degree AV-block with heart rate of 60 beats/min. Echocardiography showed good left ventricular systolic function with no regional wall motion abnormality. The patient referred for coronary angiography and endomyocardial biopsy. The angiography was normal. The biopsy showed rejection compatible with ISHLT grade 2R. After treating the patient with 1.5 g methylprednisolone, the symptoms relieved and the block resolved. Bradycardia and second-degree AV-block late after heart transplantation could be a sign of cardiac allograft rejection and need more evaluation, especially endomyocardial biopsy.

Low-Voltage Domain-Wall LiNbO3 Memristors.

Application of conducting ferroelectric domain walls (DWs) as functional elements may facilitate development of conceptually new resistive switching devices. In a conventional approach, several orders of magnitude change in resistance can be achieved by controlling the DW density using supercoercive voltage. However, a deleterious characteristic of this approach is high-energy cost of polarization reversal due to high leakage current. Here, we demonstrate a new approach based on tuning the conductivity of DWs themselves rather than on domain rearrangement. Using LiNbO3 capacitors with graphene, we show that resistance of a device set to a polydomain state can be continuously tuned by application of subcoercive voltage. The tuning mechanism is based on the reversible transition between the conducting and insulating states of DWs. The developed approach allows an energy-efficient control of resistance without the need for domain structure modification. The developed memristive devices are promising for multilevel memories and neuromorphic computing applications.

Bifunctionally engineered polyethylenimines as efficient DNA carriers and antibacterials against resistant pathogens.

In this study, we have designed and developed two series of bifunctional conjugates by tethering polyethylenimine with streptomycin. By varying the amount of streptomycin, conjugates, polyethylenimine-streptomycin, have been synthesized and characterized spectroscopically. Gel electrophoresis assay revealed a slight decrease in the cationic charge density on the conjugates as these retarded the mobility of pDNA at higher w/w ratios. Further, transfection studies showed that both the series of conjugates transfected the mammalian cells efficiently with low-molecular weight polyethylenimine-streptomycin conjugates were more competent (∼9-fold enhancement with respect to native bPEI) exhibiting high cell viability too. Besides, both the series of conjugates displayed excellent antibacterial activity on pathogenic bacteria, even better than native streptomycin on resistant strains. Altogether, these results ensure the promising potential of the projected bifunctional conjugates as safe and efficient gene delivery vectors as well as antibacterials for future biomedical applications.

Quantification of NETs-associated markers by flow cytometry and serum assays in patients with thrombosis and sepsis.

INTRODUCTION: Neutrophil extracellular traps (NETs) are networks of extracellular fibres produced from neutrophil DNA with a pathogenic role in infection, thrombosis and other conditions. Reliable assays for measuring NETs are desirable as novel treatments targeting NETs are being explored for the treatment of these conditions. We compare a whole blood flow cytometry method with serum assays to measure NETs-associated markers in patients with sepsis and thrombosis. METHODS: Patients with deep venous thrombosis (n = 25), sepsis (n = 21) and healthy controls (n = 23) were included in the study. Neutrophil surface NETs markers were determined by flow cytometry on whole blood samples by gating of neutrophils stained for surface citrullinated histone (H3cit) and myeloperoxidase (MPO). Serum double-stranded (ds) DNA, MPO, myeloid-related protein, nucleosomes, DNAse, elastase, human high-mobility group box 1 and MPO-DNA complexes were quantified as circulating markers of NETs. RESULTS: Neutrophil NETs markers by flow cytometry and serum NETs markers were significantly higher in patients with thrombosis and sepsis compared with healthy controls. Neutrophil NETs markers significantly correlated with the serum marker dsDNA. CONCLUSION: Flow cytometry detection of neutrophil NETs markers is feasible in whole blood and correlates with serum markers of NETs. We propose the flow cytometry detection of MPO/H3cit positive neutrophils and serum dsDNA as simple methods to quantify cellular and extracellular NET markers in patients with thrombosis and sepsis.

Electrodialysis heterogeneous ion exchange membranes modified by SiO2 nanoparticles: fabrication and electrochemical characterization.

In the current study mixed matrix heterogeneous cation exchange membranes were prepared by solution casting technique. The effect of SiO(2) nanoparticles in the polymeric solution on the physicochemical properties of prepared membranes was studied. Scanning optical microscope images showed uniform particle distribution and relatively uniform surfaces for the prepared membranes. The membrane water content was reduced by silica nanoparticles in the membranes' matrix. The membrane ion exchange capacity, membrane potential, transport number and selectivity were improved initially by an increase of SiO(2) nanoparticles concentration up to 1%wt in prepared membranes and then showed a decreasing trend with a further increase in additive ratio from 1 to 4%wt. The ionic permeability and flux were also decreased initially by an increase of silica nanoparticles concentration up to 0.5%wt in the membrane matrix and then increased again with a further increase in nanoparticles concentration from 0.5 to 4%wt. Moreover, the results exhibited that using silica nanoparticles in the membrane matrix caused an obvious decrease in areal electrical resistance. The opposite trend was found for membrane mechanical strength using SiO(2) nanoparticles.

Effects of RF-EMF Exposure from GSM Mobile Phones on Proliferation Rate of Human Adipose-derived Stem Cells: An In-vitro Study.

BACKGROUND: As the use of mobile phones is increasing, public concern about the harmful effects of radiation emitted by these devices is also growing. In addition, protection questions and biological effects are among growing concerns which have remained largely unanswered. Stem cells are useful models to assess the effects of radiofrequency electromagnetic fields (RF-EMF) on other cell lines. Stem cells are undifferentiated biological cells that can differentiate into specialized cells. Adipose tissue represents an abundant and accessible source of adult stem cells. The aim of this study is to investigate the effects of GSM 900 MHz on growth and proliferation of mesenchymal stem cells derived from adipose tissue within the specific distance and intensity. MATERIALS AND METHODS: ADSCs were exposed to GSM mobile phones 900 MHz with intensity of 354.6 µW/cm2 square waves (217 Hz pulse frequency, 50% duty cycle), during different exposure times ranging from 6 to 21 min/day for 5 days at 20 cm distance from the antenna. MTT assay was used to determine the growth and metabolism of cells and trypan blue test was also done for cell viability. Statistical analyses were carried out using analysis of one way ANOVA. P<0.05 was considered to be statistically significant. RESULTS: The proliferation rates of human ADSCs in all exposure groups were significantly lower than control groups (P<0.05) except in the group of 6 minutes/day which did not show any significant difference with control groups. CONCLUSION: The results show that 900 MHz RF signal radiation from antenna can reduce cell viability and proliferation rates of human ADSCs regarding the duration of exposure.

Asymptomatic mycotic aneurysm of ascending aorta after heart transplantation: a case report.

Mycotic pseudoaneurysm and aneurysm of the ascending aorta is a very rare and potentially fatal complication of heart transplantation. It usually presents with fever, chest pain, dyspnea, or constitutional symptoms. Most reports in the literature are about mycotic pseudoaneurysm, but mycotic aneurysm is rarer. Herein we report a 39-year-old man in who had an asymptomatic mycotic aneurysm of the ascending aorta developed late (1 year) after orthotopic heart transplantation. There was no history of previous mediastinitis or any other important infection. He underwent an uneventful replacement of the ascending aorta.

In vitro and in vivo proliferation, differentiation and migration of cardiac endothelial progenitor cells (SCA1+/CD31+ side-population cells).

BACKGROUND: Side-population (SP) cells are a select population identified by a capacity to efflux Hoechst dye and are enriched for stem/progenitor cell activity. Previous studies suggested that cardiac SP (CSP) cells could be divided into SCA1(+)/CD31(-) and SCA1(+)/CD31(+) CSP cells. SCA1(+)/CD31(-) CSP cells have been shown to be cardiac stem/progenitor cells. However, SCA1(+)/CD31(+) CSP cells have not been fully characterized. OBJECTIVE: The aim of the present study was to characterize SCA1(+)/CD31(+) CSP cells in the adult mouse heart, and investigate their abilities to proliferate, differentiate, vascularize and migrate in vitro and in vivo. RESULTS: Using fluorescence-activated cell sorting (FACS), RT-PCR, and assays of cell proliferation, differentiation and migration, and a murine model of myocardial infarction (MI), we showed that SCA1(+)/CD31(+) CSP cells express stem cell and endothelial-specific genes, and reside in the blood vessels. These cells were able to proliferate, differentiate, migrate and vascularize in vitro and in vivo. After MI, SDF-1α and CXCR4 were up-regulated in the damaged myocardium and on SCA1(+)/CD31(+) CSP cells, respectively. Our results further showed that SDF-1α induced migration of these cells in vitro. Importantly, we found that SCA1(+)/CD31(+) CSP cells could migrate into the ischemic region from the non-ischemic area within the myocardium and form a vascular tube-like structure after MI. CONCLUSIONS: Based on the gene expression profile, localization of SCA1(+)/CD31(+) CSP cells, and their ability to proliferate, differentiate, migrate and vascularize in vitro and in vivo, we postulate that SCA1(+)/CD31(+) CSP cells may represent endothelial progenitor cells in the mouse heart.

Effect of adding ketamine to pethidine on postoperative pain in patients undergoing major abdominal operations: a double blind randomized controlled trial.

To determine the effect of adding ketamine to pethidine in reducing post-operative pain in patients undergoing major abdominal operations, in a double blind randomized controlled trial, 100 patients aged 15-60 years who were candidate for elective major abdominal surgery allocated into two groups of pethidine + ketamine group (5 mg pethidine and 0.25 mg kg(-1) ketamine) or pethidine and placebo group (10 mg pethidine and NS) according to the regimen prescribed in postanesthesia care unit. Severity of pain (using visual analogue scale), prescribed dose of pethidine and side effects were recorded until 24 h after operation. Regarding post-operative pain, pethidine + ketamine group showed significant lower scores in all the times except 0 min, 2, 6 and 16 h. Nausea was significantly less frequent amongst pethidine + placebo group at times of 0, 15, 30 and 45 min (p < 0.05). Comparison of two groups did not show significant differences in prescribed pethedine dose in 0, 9, 12, 16, 20 and 24 h (p > 0.05). Yet, the mean dose of administered pethidine as rescue analgesic was significant lower in pethidine + ketamine group compared to pethidine + placebo group (112 +/- 31.5 mg vs. 133.5 +/- 24.5 mg, p < 0.001). In conclusion, our results showed that co-administration of ketamine and pethidine in postanesthesia care unit will improve postoperative pain and reduce narcotic consumption. It may, however, increase rate of postoperative nausea in the first hour after operation.

Bilateral diffuse pulmonary infiltration in a heart transplant recipient.

Pulmonary complications are not infrequent after heart transplantation. Kaposi sarcoma is a vascular tumor that can involve the skin as well as visceral organs. We describe a case of visceral and cutaneous Kaposi sarcoma that presented with diffuse bilateral pulmonary infiltration and breathlessness 6 month after heart transplantation. Following modulation of the immunosuppressive regimen and addition of chemotherapy, the patient had an excellent response and has had an uneventful 1-year follow-up.

Organ retrieval from brain-dead patients by a single organ procurement center in Iran.

INTRODUCTION: The majority of transplantations depend solely on cadaveric organs. In recent years, special focus has been directed toward brain-dead patients in Iran, but it seems that there is limited information regarding the characteristics of cadaveric organ donation in our country. MATERIALS AND METHODS: This is a retrospective analysis of data of our Organ Procurement Unit (OPU), which is one of the most active organ procurement units in Iran. We incorporated the data on all organ donations from brain-dead patients between 2004 and 2008 into the present study. Demographic characteristics of the patients along with data regarding brain death and organ donation were extracted from already registered data on patients. RESULTS: Among 93 brain-dead patients registered in the database of the OPU, organs were retrieved from 85% (n = 79). Out of the 14 patients from whom no organ was retrieved, the cause for this failure was death before donation in 85% (n = 12). The numbers of donated organs varied between zero and six (mean +/- standard deviation = 3.1 +/- 1.7). The most donated organs in terms of frequency and count were: right kidney (n = 68; 73.1%), left kidney (n = 67; 72%), liver (n = 63; 67.7%), heart (n = 40; 43%), pancreas (n = 5; 5.4%), and lung (n = 4; 4.3%). DISCUSSION: The overall organ retrieval rate from brain-dead patients by this OPU was comparable to that of developed countries; however, we still believe we can improve this rate/scale.

Lung donation and causes behind its failure: a single-center experience.

INTRODUCTION: Brain-dead patients are almost the only source of organs for lung transplantation, and lungs fall within the area of the least harvested organs. As a result, maintaining the highest possible harvest rate is a must for the lung transplantation system. In the present study, the harvest rate of lungs and also the causes of failure to donate the lungs is reported for brain-dead patients in our organ procurement unit. MATERIALS AND METHODS: After going through the brain-death database at our organ procurement unit between 2004 and 2008, we included all 93 brain deaths in this hospital. The lung donation rate was reviewed to examined the causes for failure to donate lungs. RESULTS: From the total brain-dead patients registered in the database, only 4 (4.6%) patients donated their lungs. The causes of failure to donate a lung were not suitable lungs among 78 (83.8%) because they had an unacceptable oxygen challenge test results (<300 mm Hg). Another 11 patients had acceptable oxygen challenge test results, but donation failed in their case as well due to most frequently to pulmonary aspiration. CONCLUSION: In this center, only a small percentage of lungs are appropriate for harvest in brain-dead patients, because many patients' lungs do not meet the criteria with unacceptable oxygen challenge test results. Patients with proper test results may fail to donate lungs due to pulmonary aspiration. More aggressive care of the patients may have an important role in keeping them in good condition and helping to preserve the organs for harvest. For this purpose, further training of intensive care unit staff and physicians are among the suggested steps to enhance the quality of care, which in turn can maximize the lung harvest rate.

Eight years of lung transplantation: experience of the National Research Institute of Tuberculosis and Lung Diseases.

BACKGROUND: Lung transplantation has evolved from an experimental procedure to a viable therapeutic option in many countries. In Iran, the first single-lung transplantation was performed in the year 2000, more than 3 decades after the first successful procedure in the world, and the first double-lung transplantation was performed in the year 2006. OBJECTIVE: To describe our 8-year experience in lung transplantation. PATIENTS AND METHODS: During 8 years, we performed 24 lung transplantation procedures. Underlying lung diseases were pulmonary fibrosis in 16 patients (66.6%); chronic obstructive pulmonary disease in 2 (8.3%); bronchiectasis in 5, including 2 patients with cystic fibrosis (20.8%), and alveolar microlithiasis in 1 (4.16%). Data for all patients were collected and analyzed. Procedures were carried out using standardized methods. The induction suppression regimen consisted of cyclosporine and methylprednisolone. Maintenance immunosuppression drugs were cyclosporine and mycophenolate mofetil, and tapering dosage of prednisolone. Patients were followed up with physical examinations, 3 times a week, as well as and cycle ergometry 3 times a week and spirometry and laboratory tests once a week and chest radiography per needed for up to 3 months posttransplantation. RESULTS: The longest survival time was 7.2 years, in a 60-year-old patient with idiopathic pulmonary fibrosis. Fourteen patients died, 8 as a result of hemodynamic instability and/or hemorrhage, 1 as a result of bone and fat emboli, 3 after cessation of drug and 2 of them after infection. CONCLUSION: Although lung transplantation is a complex procedure it can be performed in developing countries such as Iran.

Phenology of Phlebotomus papatasi (Diptera: Psychodidae) relative to the seasonal prevalence of zoonotic cutaneous leishmaniasis in central Tunisia.

The population density of Phlebotomus papatasi Scopoli (Diptera: Psychodidae), vector of Leishmania major Yakimoff & Schokhor (Kinetoplastida: Trypanosomatidae), the etiologic agent of zoonotic cutaneous leishmaniasis (ZCL), was assessed May-November 2005 in central Tunisia by using sticky traps. The densities of P. papatasi were found to peak in early spring and again in the autumn. The lowest densities were observed in August. Prevalence of ZCL in the governorate of Sidi Bouzid peaks in December, 3 to 3.5 mo after the fall sand fly population peak, suggesting a close temporal association with the abundance of P. papatasi.

[Spontaneous course of lesions of Leishmania major cutaneous leishmaniasis in Tunisia]. / Evolution spontanée des lésions de leishmaniose cutanée a Leishmania major en Tunisie.

INTRODUCTION: The evolution of zoonotic cutaneous leishmaniasis (ZCL) caused by L. major, was usually described with crosssectional studies of patients under anti-leishmanial drugs. This work aimed to describe the clinical and parasitological status by a follow-up study of patients with ZCL and treated with a placebo. MATERIAL AND METHODS: In 1992, 58 patients with unique lesion of ZCL confirmed parasitologically and treated with vaseline twice a day for 15 days were followed in days 0, 15, 45 and 105. During every visit we have performed a clinical description of the lesion, a direct smear and a culture on NNN medium. RESULTS: 81 p. 100 of the lesions were ulcerated in day 0. A rapid clinical healing was noticed in 6.9 p. 100 of patients and the lesion remained active in 25.9 p. 100 of cases until day 105. Direct smears became negative among 56.4 p. 71 p. 100 and 92.3 p. 100 in days 15, 45 and 105 respectively. DISCUSSION: The ulcer was the most frequent sign during the diagnosis. The rapid conversion of positive parasitological tests suggest that the diagnosis of ZCL in endemic zones should be based mainly on clinical criteria.