Functional Myogenic Engraftment from Mouse iPS Cells

Direct reprogramming of adult fibroblasts to a pluripotent state has opened new possibilities for the generation of patient- and disease-specific stem cells. However the ability of induced pluripotent stem (iPS) cells to generate tissue that mediates functional repair has been demonstrated in very few animal models of disease to date. Here we present the proof of principle that iPS cells may be used effectively for the treatment of muscle disorders. We combine the generation of iPS cells with conditional expression of Pax7, a robust approach to derive myogenic progenitors. Transplantation of Pax7-induced iPS-derived myogenic progenitors into dystrophic mice results in extensive engraftment, which is accompanied by improved contractility of treated muscles. These findings demonstrate the myogenic regenerative potential of iPS cells and provide rationale for their future therapeutic application for muscular dystrophies.     

Successful ultrasound‐guided percutaneous embolization of renal pseudoaneurysm by autologous blood clot: Preliminary report of a new method

We report the case of a 25‐year‐old female with renal arteriovenous fistula and pseudoaneurysm (PA) formation following renal core‐needle biopsy, treated successfully by ultrasound‐guided percutaneous embolization with autologous blood clot injection. After inserting a 15‐gauge needle within the PA sac, 10 ml of blood was retrieved from the sac, and then reinjected into the PA as well as in the needle tract after the obtained blood completely clotted. The procedure was completed by manual compression of the flank. Follow‐up sonographic examinations revealed no complication, and the PA size reduced gradually over time due to fibrotic shrinkage. © 2017 Wiley Periodicals, Inc. J Clin Ultrasound 45 :592–596, 2017     

Preparation,characterization and optimization of sildenafil citrate loaded PLGA nanoparticles by statistical factorial design

Background and the aim of the study

The objective of the present study was to formulate and optimize nanoparticles (NPs) of sildenafil-loaded poly (lactic-co-glycolic acid) (PLGA) by double emulsion solvent evaporation (DESE) method. The relationship between design factors and experimental data was evaluated using response surface methodology.

Method

A Box-Behnken design was made considering the mass ratio of drug to polymer (D/P), the volumetric proportion of the water to oil phase (W/O) and the concentration of polyvinyl alcohol (PVA) as the independent agents. PLGA-NPs were successfully prepared and the size (nm), entrapment efficiency (EE), drug loading (DL) and cumulative release of drug from NPs post 1 and 8 hrs were assessed as the responses.

Results

The NPs were prepared in a spherical shape and the sizes range of 240 to 316 nm. The polydispersity index of size was lower than 0.5 and the EE (%) and DL (%) varied between 14-62% and 2-6%, respectively. The optimized formulation with a desirability factor of 0.9 was selected and characterized. This formulation demonstrated the particle size of 270 nm, EE of 55%, DL of 3.9% and cumulative drug release of 79% after 12 hrs. In vitro release studies showed a burst release at the initial stage followed by a sustained release of sildenafil from NPs up to 12 hrs. The release kinetic of the optimized formulation was fitted to Higuchi model.

Conclusions

Sildenafil citrate NPs with small particle size, lipophilic feature, high entrapment efficiency and good loading capacity is produced by this method. Characterization of optimum formulation, provided by an evaluation of experimental data, showed no significant difference between calculated and measured data.     

Assessment of interferon-γ levels and leishmanin skin test results in persons recovered for leishmaniasis

Patients who recover from leishmaniasis usually show development of strong immunity and induction of interferon-γ (IFN-γ) and delayed type hypersensitivity. In a randomized trial, we analyzed the IFN-γ response by using a Quantiferon-Leishmania assay against three Leishmania peptide antigens and compared it with results of the leishmanin skin test (LST) in persons residing in areas in Iran to which zoonotic cutaneous leishmaniasis (ZCL, 181 persons), anthroponotic cutaneous leishmaniasis (ACL, 104 persons), and zoonotic visceral leishmaniasis (ZVL, 67 persons) are endemic. The percentage of persons with an IFN-γ-positive response (> 0.2 IU/mL) to three antigens and the mean concentration of IFN-γ induced by the antigens were higher for persons from areas endemic for ZVL than for persons from areas endemic for ZCL and ACL. The percentage of persons with LST-positive results (≥ 5 mm indurations) was 99%, 94%, and 70% for areas with ZCL, ACL, and ZVL, respectively. Our data indicate that the LST is significantly more sensitive than IFN-γ levels in persons who have been cured of cutaneous leishmaniasis than in persons who have been cured of ZVL.     

Tension-free vaginal tape versus transobturator tape for treatment of stress urinary incontinence: A comparative randomized clinical trial study

ObjectiveThe objective of this study is to evaluate short- and mid-term results of tension-free vaginal tape (TVT) and transobturator tape (TOT) for the treatment of female stress urinary incontinence (SUI) in Imam Reza Academic Hospital.MethodsA total of 100 women with SUI treated using TVT (n = 50) or TOT (n = 50) between March 2008 and October 2010 were included in this prospective randomized clinical trial study. Preoperative workups, including case history, clinical examination, cough test, urodynamic study with abdominal leak point pressure and postvoiding residue measurements, pad test, transvaginal scan, and evaluation with International Consultation on Incontinence Modular Questionnaire–Urinary Incontinence (ICIQ-UI) and International Consultation on Incontinence Modular Questionnaire–Quality of Life (ICIQ-QOL), were performed. During hospitalization, the type of anesthesia, operative time, hospital stay, and catheter indwelling time were recorded. Postoperatively, continence status and subjective patient satisfaction were evaluated using a cough test and in some patients by a pad test also; transvaginal scan and ICIQ-UI and ICIQ-QOL evaluations at 1, 3, 6, 12, and 18 months of follow-up were performed for all patients.ResultsThe mean age was 52.02 ± 7.37 years in the TVT group and 52.27 ± 7.34 years in the TOT group. The rate of complications was similar in both groups. The operative time was 14.50 ± 7.40 and 15.00 ± 7.48 minutes (p = 0.86), hospital stay time 1.56 ± 0.51 and 1.52 ± 0.47 days (p = 0.76), and catheter indwelling time 1.58 ± 0.41 and 1.55 ± 0.47 days (p = 0.651) in the TVT and TOT groups, respectively. At 1, 3, 6, 12, and 18 months after intervention, ICIQ-UI and ICIQ-QOL were completed for all the patients and no significant difference was found between them.ConclusionOur study results showed that TVT and TOT methods have similar efficacy and safety for SUI, although the catheter indwelling time was significantly longer in the TVT group.     

N-Acetylcysteine Effects on Transforming Growth Factor-β and Tumor Necrosis Factor-α Serum Levels as Pro-Fibrotic and Inflammatory Biomarkers in Patients Following ST-Segment Elevation Myocardial Infarction

Background and Aims

Ischemia following acute myocardial infarction (AMI) increases the level of pro-fibrotic and inflammatory cytokines, including transforming growth factor (TGF)-β and tumor necrosis factor (TNF)-α. N-acetylcysteine (NAC) has therapeutic benefits in the management of patients with AMI. To the best of our knowledge, this is the first study that has evaluated the effect of NAC on TNF-α and TGF-β levels in patients with AMI.

Methods

Following confirmation of AMI, 88 patients were randomly administered NAC 600 mg (Fluimucil^®, Zambon, Ticino, Switzerland) or placebo orally twice daily for 3 days. For quantification of TGF-β and TNF-α serum levels after 24 and 72 h of NAC or placebo administration, peripheral venous blood (10 mL) samples were collected at these time points.

Results

Comparisons between levels of TGF-β and TNF-α after 24 and 72 h within the NAC or placebo groups revealed that there was not any significant difference except for TGF-β levels in the placebo group, which increased significantly over time (p = 0.042). Significant relationships existed between patients’ ejection fraction (p = 0.005) and TGF-β levels.

Conclusions

Receiving NAC could prevent TGF-β levels from increasing after 72 h as compared with not receiving NAC. As TGF-β had strong correlations with the ejection fraction, its antagonism seems to be important in the prevention of remodeling.     

Six case reports of NTHL1-associated tumor syndrome further support it as a multi-tumor predisposition syndrome

NTHL1-associated tumor syndrome (NATS) is an autosomal recessive condition characterized by an increased risk for colorectal polyposis and colorectal cancer (CRC). Only 46 case reports have been previously published. In a retrospective review, we analyzed the clinical histories of six patients found to have NATS after genetic counseling and testing. NATS appears to be associated with an increased risk for colorectal polyposis, CRC, female breast cancer, meningiomas, and endometrial cancer. Although research is limited, prior publications have reported a multi-tumor predisposition for individuals with biallelic pathogenic or likely pathogenic variants in NTHL1. Additional data are necessary to further define the cancer risks so affected individuals can be appropriately managed.     

Fatty Acid Composition of Tissue Cultured Breast Carcinoma and the Effect of Stearoyl-CoA Desaturase 1 Inhibition

Purpose

Stearoyl-CoA desaturase 1 (SCD1) is a novel therapeutic target in various malignancies, including breast cancer. The present study was designed to investigate the effect of the pharmacologic inhibition of SCD1 on fatty acid composition in tissue explant cultures of human breast cancer and to compare these effects with those in adjacent nonneoplastic breast tissue.

Methods

Paired samples of tumor and adjacent noncancerous tissue were isolated from 12 patients with infiltrating ductal breast cancer. Samples were explant cultured in vitro, exposed to the highly selective SCD1 inhibitor CAY10566, and examined for fatty acid composition by gas liquid chromatography. The cytotoxic and antigrowth effects were evaluated by quantification of lactate dehydrogenase release and by sulforhodamine B (SRB) measurement, respectively.

Results

Breast cancer tissue samples were found to have higher levels of monounsaturated fatty acids (MUFA) (p<0.001) and arachidonic acid (20:4n-6, p<0.001) and a lower level of linoleic acid (18:2n-6, p=0.02) than the normal-appearing breast tissues. While exhibiting no evident cytotoxicity, treatment with the SCD1 inhibitor, CAY10566 (0.1-1 µM), for 48 hours significantly increased 18:2n-6 levels in both the tumor and adjacent normal-appearing tissue (approximately 1.2 fold, p<0.05). However, the breast cancer tissue samples showed significant increases in the levels of MUFA and 20:4n-6 compared to the normal-appearing breast tissues (p<0.05). The SRB growth assay revealed a higher rate of inhibition with the SCD1 inhibitor in breast cancer tissues than in normal-appearing tissues (p<0.01, 41% vs. 29%). The SCD1 inhibitor also elevated saturated fatty acid (1.46-fold, p=0.001) levels only in the tumor tissue explant.

Conclusion

The fatty acid composition and response to SCD1 inhibition differed between the explant cultures from breast cancer and the adjacent normal-appearing tissue. Altered fatty acid composition induced by SCD1 inhibition may also, in addition to Δ9 desaturation, modulate other reactions in de novo fatty acid synthesis and lipogenesis, and subsequently affect the overall survival and progression of breast cancer.     

Adiponectin as a Protective Factor Against the Progression Toward Type 2 Diabetes Mellitus in Postmenopausal Women

Serum adiponectin levels have been suggested to be predictors of type 2 diabetes mellitus in diverse populations. However, the relationship between circulating adiponectin levels and the risk of development of type 2 diabetes in postmenopausal women has not been investigated.A total of 382 healthy postmenopausal women who participated in a prospective cohort study were followed for 5.8 years. Type 2 diabetes mellitus was defined according to the criteria set out by the American Diabetes Association. Adiponectin, osteoprotegerin (OPG), and high-sensitivity C-reactive protein (hs-CRP) levels were measured using ELISA.Of 195 women who did not have diabetes at baseline and who were reexamined in the second phase of the study for diabetic status, 35 subjects (17.9%) developed type 2 diabetes mellitus during the 5.8 years follow-up period. The women with type 2 diabetes had lower adiponectin levels than the healthy postmenopausal women. Multiple regression analysis showed that, after adjustments were made for age, cardiovascular risk factors, OPG, and hs-CRP levels, higher baseline adiponectin levels were associated with a lower relative risk (RR) of having type 2 (RR = 0.07, confidence interval [CI]: 0.01–0.66, P = 0.021).Higher baseline adiponectin levels functioned as a predictor of a lower risk of developing type 2 diabetes mellitus among postmenopausal women during a 5.8 years follow-up study. Therefore, it is suggested that elevated adiponectin levels may offer protection against the development of type 2 diabetes mellitus after the menopause.