Mesenchymal stem cell transplantation in newly diagnosed type-1 diabetes patients: a phase I/II randomized placebo-controlled clinical trial.

BACKGROUND: Type-1 diabetes (T1D) occurs following autoimmune-induced pancreatic beta cells death. Among several treatment modalities, mesenchymal stem cells (MSCs) transplantation is promising for autoimmune disorders due to immunomodulation, regeneration, and migration to damaged tissue upon systemic injection. This study assessed the safety and efficacy of intravenous injection of autologous bone marrow-derived MSCs in newly diagnosed T1D patients. METHODS: After receiving informed consent, 21 patients who met the study criteria were enrolled and randomly assigned to receive either MSCs or placebo. Each patient in the experimental group received two doses of MSCs and was followed for at least one-year post-transplantation. RESULTS: The results have shown that this transplantation is safe and significantly reduces the number of hypoglycemic episodes. MSCs transplantation improved glycated hemoglobin (HbA1c), shifted serum cytokine patterns from pro-inflammatory to anti-inflammatory, increased the number of regulatory T-cells in the peripheral blood, and improved quality of life. Early transplantation of MSCs significantly improved HbA1c and C-peptide levels and shifted pro-inflammatory cytokines to anti-inflammatory cytokines. Also, exercise combined with MSCs transplantation improved glycemic and immunologic indices. CONCLUSIONS: Taken together, autologous MSC transplantation is safe and effective, and its early transplantation is a promising treatment in newly diagnosed T1D children suffering from hypoglycemic episodes. TRIAL REGISTRATION: This clinical trial was registered at the Iranian Registry of Clinical Trials (IRCT) with the identifier IRCT ID: IRCT2016070428786N1 registered on August 20, 2016 (Retrospectively registered) ( https://en.irct.ir/trial/23256 ) and at the U.S. National Institutes of Health (ClinicalTrials.gov) with the related identifier NCT04078308 registered on September 6, 2019 (Retrospectively registered). ( https://clinicaltrials.gov/ct2/show/NCT04078308 ).

The expression of Cysteine-Rich Secretory Protein 2 (CRISP2) and miR-582-5p in seminal plasma fluid and spermatozoa of infertile men.

Cysteine-Rich Secretory Protein 2 (CRISP2) plays an important role in the morphology and motion of male ejaculated spermatozoa. The association of its expression with some miRNAs is also well known. The aim of this study was to determine the expression of CRISP2 and mir-582 in the seminal plasma fluid and spermatozoa of three groups of infertile men and the possible association of their expressions. In this experimental study, the expression of CRISP2 in seminal plasma fluid and spermatozoa of 17 men with asthenozoospermia, 15 men with teratozoospermia, 17 men with teratoasthenozoospermia, and 18 infertile individuals with normozoospermia were measured using western blotting. Then by using bioinformatics studies, miR-582-5p was nominated as a CRISP2-associated miRNA, and its expression was evaluated by means of Real-Time PCR. Comparison of expression of CRISP2 and miRNA-582 in the studied groups was analyzed by t-test and Mann-Whitney U test. The expression of CRISP2 showed a significant reduction in the spermatozoa and seminal plasma fluid of all three groups, (p < 0.05). MiR-582-5p expression significantly increased in teratozoospermia patients (<0.05), and significantly decreased in teratoasthenozoospermia patients (p < 0.05). Meanwhile, changes in the expression of miR-582-5p in teratoasthenozoospermia individuals was associated with a decrease in the expression of CRISP2, which could represent the potential role of miR-582-5p in regulation of CRISP2 expression in teratoasthenozoospermia individuals.

Serum estradiol level on trigger day impacts clinical pregnancy rate in modified natural frozen embryo transfer cycles.

OBJECTIVE: To examine the predictive value of serum estradiol and progesterone on the day of human chorionic gonadotropin (hCG) administration and embryo transfer for clinical pregnancy rate in modified natural-cycle frozen embryo transfer (NC-FET). METHODS: In a longitudinal prospective study, all eligible women who underwent NC-FET cycles with hCG triggering in Royan Institute, Tehran, Iran, from June 1, 2015, to December 31, 2016, were evaluated. Serum estradiol and progesterone levels were measured at menstrual cycle initiation, on day of trigger with hCG, on day of embryo transfer, and in pregnant women every 7 days until the observation of a gestational sac with embryonic heartbeat. RESULTS: In total, 101 modified natural FET cycles were assessed, and the clinical pregnancy and live birth rates achieved were 34 (33.6%) and 32 (31.6%), respectively. The changes in estradiol level during early pregnancy showed an increase by an average of 200 pg/mL per week. Multivariable logistic regression analysis showed that only the estradiol level on the hCG day was a significant predictive variable for clinical pregnancy following NC-FET (P=0.04). CONCLUSION: Estradiol level on the day of hCG trigger predicted the clinical pregnancy rates after modified NC-FET; this likely mirrored the developmental competence of the corpus luteum and an appropriate luteal structure-function.

The effect of weight loss program on serum anti-Müllerian hormone level in obese and overweight infertile women with polycystic ovary syndrome.

We evaluated the predictive value of serum anti-Müllerian hormone (AMH) levels for improved menstrual cycles in response to dietary management in women with polycystic ovary syndrome (PCOS). In addition, we assessed the effect of a restricted calorie diet for 12 weeks on serum AMH levels. This intervention study was carried out at Rohan Institute, Tehran, Iran from 2013 to 2015. A total of 105 overweight and obese women with PCOS and reproductive impairment participated in a 12-week weight loss program (WLP). The serum AMH levels, weight, and menstrual cyclicity were assessed at baseline and post-intervention for all of the participants. A total of 90 patients completed the 12-week WLP. Of the 90 patients, 65 (72.2%) responded to the intervention with improvements in menstrual cyclicity. There were no significant differences in terms of age, baseline AMH levels, and other hormone profiles between responders and nonresponders. Responders had a significantly lower baseline body mass index (BMI) and waist circumference compared with nonresponders. These factors were the clinical predictors for a menstrual response after the intervention. The AMH levels did not significantly change after 12-week WLP despite the overall reduced weight; however, women who responded with improved reproductive function had a greater reduction in AMH levels.

The impact of the localisation of endometriosis lesions on ovarian reserve and assisted reproduction techniques outcomes.

This case-control study was designed to evaluate the impact of endometriosis and the presence of endometrioma (OMA) per se on the serum anti-Müllerian hormone (AMH) level and also to compare the in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes after therapeutic surgery in endometriosis patients, according to the localisation of endometriosis lesions. One hundred and fifty two infertile women ≤40 years with suspicious symptoms were surgically evaluated to detect the aetiology of infertility at the Royan Institute during this study and, in parallel, 131 patients with a male factor infertility diagnosis were considered as the control group. The serum AMH level and IVF/ICSI outcomes were compared according to the nature and extension degree of endometriosis lesions. The results demonstrated that the existence of a deep infiltrating endometriosis (DIE) with and without OMA was associated with a significant decrease in AMH level, antral follicle count and ovarian sensitivity index (OSI) (p < .001 and p = .007, respectively). The multivariable logistic regression analysis adjusted for confounding factors indicated that the OSI and the existence of DIE with and without OMA were a significant predictive variable for clinical pregnancy and for live birth. On the basis of our results, the severity of endometriosis and the location of its lesions could affect an ovarian reserve and the ovarian stimulation outcomes. Impact Statement What is already known on this subject? Previous studies have evaluated the impact of endometrioma (OMA) on ovarian reserve and the assisted reproduction technology (ART) outcomes and controversial results have been reported; therefore, it seems that this topic still needs further research. What the results of this study add? In the present study, the effect of endometriosis lesions' localisation on ovarian reserve and the success rate of the in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) cycle after therapeutic surgery were compared with that of the control group. It was found that the existence of a deep infiltrating endometriosis (DIE) with and without OMA was associated with a significant decrease in the anti-Müllerian hormone (AMH) level, antral follicle count, ovarian sensitivity index (OSI), clinical pregnancy and live birth rates. What the implications are of these findings for clinical practice and/or further research? The results of this study has a practical value in the decision making process for the ovarian stimulation protocol in patients with the different severity of endometriosis and the counselling regarding the success rate of IVF or ICSI/embryo transfer cycles.

Evaluation of toll-like receptor 4 expression in human bone marrow mesenchymal stem cells by lipopolysaccharides from Shigella.

Lipopolysaccharides (LPS) from gram negative bacteria stimulate toll-like receptor 4 (TLR4) expression in immune cells. Recent reports state that bone marrow-derived cells such as mesenchymal stem cells (MSCs) also express TLR proteins. Numerous researches have studied the effect of a number of LPSs on TLR4 expression, but no data exists on the effect of LPSs from different strains of one bacterial genus on TLR4 expression. In this study, we investigate the effects of various concentrations of LPS from different Shigella strains on TLR4 expression in human bone marrow (hBM)-MSCs. At the mRNA level, we have found that untreated hBM-MSCs (control) did not express TLR4 compared to the experimental groups. Cells treated with LPS from Shigella flexneri had the highest expression of TLR4, whereas cells treated with LPS from Shigella sonnei had the lowest expression. We observed that LPSs had a dose-dependent effect on TLR4 expression in all of the treatment groups. ELISA findings for interleukin-6 secretion have confirmed mRNA expression results for all treatment groups. Hence, LPS from S. flexneri can be considered as an optimum LPS to stimulate the immune system for vaccine production against shigellosis. Also, TLR activation in hBM-MSCs can modulate their function such as homing.

Abdominal obesity can induce both systemic and follicular fluid oxidative stress independent from polycystic ovary syndrome.

OBJECTIVE: The abdominal form of obesity is prevalent in women with polycystic ovary syndrome (PCOS). Visceral fat accumulation seems to play an important role in etiology of PCOS. In this cross-sectional study we evaluated the association of oxidative stress (OS) induced with PCOS and abdominal obesity in serum and follicular fluid (FF) of infertile women. STUDY DESIGN: A total of 80 women younger than 37 years old undergoing an IVF program were studied in the same period of time from September 2012 to October 2013. Blood serum and FF obtained from 40 women with PCOS (diagnosed by the Rotterdam 2004 criteria) and 40 women without PCOS undergoing IVF were evaluated for two OS markers: lipid peroxide (LPO) and total antioxidant capacity (TAC), after puncture. The patients were divided into 4 groups on the basis of presence of PCOS and waist-to-hip ratio (WHR) or abdominal obesity (OA). RESULTS: Healthy and PCOS women with abdominal obesity had significantly higher amounts of LPO in the serum and FF as compared with women without abdominal obesity. LPO concentration in FF was significantly lower than in serum and corroborates the hypothesis that the germinal cells have a potent antioxidant mechanism. We also found that LPO concentration in the PCOS group associated with AO had an increasing trend vs. those AO patients without PCOS but this difference was not significant, so the increase in LPO level was approximately independent of PCOS. Based on our results, the association and interaction between PCOS and AO can lead to TAC concentration reduction in patients. CONCLUSIONS: Abdominal obesity can induce local and systemic oxidative stress in PCOS and non-PCOS patients. We suggest that PCOS-induced disorders are likely to be exacerbated in the presence of abdominal obesity.

Effect of 830-nm diode laser irradiation on human sperm motility.

Sperm motility is known as an effective parameter in male fertility, and it depends on energy consumption. Low-level laser irradiation could increase energy supply to the cell by producing adenosine triphosphate. The purpose of this study is to evaluate how the low-level laser irradiation affects the human sperm motility. Fresh human semen specimens of asthenospermic patients were divided into four equal portions and irradiated by 830-nm GaAlAs laser irradiation with varying doses as: 0 (control), 4, 6 and 10 J/cm(2). At the times of 0, 30, 45 and 60 min following irradiation, sperm motilities are assessed by means of computer-aided sperm analysis in all samples. Two additional tests [HOS and sperm chromatin dispersion (SCD) tests] were also performed on the control and high irradiated groups as well. Sperm motility of the control groups significantly decreased after 30, 45 and 60 min of irradiation, while those of irradiated groups remained constant or slightly increased by passing of time. Significant increases have been observed in doses of 4 and 6 J/cm(2) at the times of 60 and 45 min, respectively. SCD test also revealed a non-significant difference. Our results showed that irradiating human sperms with low-level 830-nm diode laser can improve their progressive motility depending on both laser density and post-exposure time.

Urine macrophage migration inhibitory factor (MIF) in children with urinary tract infection: a possible predictor of acute pyelonephritis.

Macrophage migration inhibitory factor (MIF) is an important pro-inflammatory cytokine expressed at sites of inflammation. We have assessed this factor (MIF) in urinary tract infections with the aim of determining a non-invasive and sensitive method to differentiate upper and lower renal involvement. Thirty-three pediatric patients with urinary track infection (25 with acute pyelonephritis, eight with acute cystitis) and 40 healthy subjects were recruited for this prospective case-control study. Pyelonephritis was differentiated from cystitis by dimercaptosuccinic acid (DMSA) scan. Urinary MIF concentration was determined using an enzyme-linked immunosorbent assay method. The urine MIF/creatinine (Cr) ratio was significantly higher in pyelonephritis patients than in those with acute cystitis and the control group (P < 0.001). The optimal cut-point of 4.90 pg/micromol Cr for the urine MIF/Cr ratio has the potential to be a biomarker for distinguishing patients with acute pyelonephritis from those with acute cystitis. Determination of the urinary MIF was also useful in selecting the patients at risk of permanent renal damage. Of those patients with pyelonephritis, based on the DMSA scan at the time of infection, scarring on follow-up DMSA scan 9-12 months later occurred in patients with the highest urinary MIF/Cr ratios. We conclude that the urine MIF/Cr ratio is a sensitive test for differentiating acute pyelonephritis from acute cystitis and also for detecting children with acute pyelonephritis who are at a higher risk for permanent renal scars in the future.