Zhina Sadeghi

Transurethral Autologous Myoblast Injection for Treatment of Urinary Incontinence in Children With Classic Bladder Exstrophy

PURPOSE The application of autologous myoblasts is an area of active research that may represent an improved alternative for the treatment of urinary incontinence. In this study we investigated the effectiveness of autologous myoblast injection for the treatment of urinary incontinence in children with classic bladder exstrophy. MATERIALS AND METHODS Seven boys and 1 girl with persistent urinary incontinence were entered in the study. All children had undergone staged bladder repair and bladder neck reconstruction, and 5 patients had received 1 to 3 transurethral injections of bulking agent. Autologous myoblasts were isolated from abdominal muscle biopsy and cultured before endourethral injection. After the procedure patients underwent pelvic floor electrical stimulation and continued pelvic floor exercises that had been started at least 1 year before injection. The clinical outcomes (based on a 24-hour voiding diary), and cystometric and urodynamic studies were evaluated. Followup ranged from 12 to 18 months (average 15.3). RESULTS There was a significant, time dependent improvement in urinary continence. At final followup all 7 boys (88% of patients) were socially dry (daytime dryness more than 3 hours), including 3 (38%) who were completely dry. Urodynamic studies revealed an increase in mean bladder capacity (p <0.001), detrusor leak point pressure (p <0.001) and average maximum urinary flow (p <0.01). All 7 boys (vs only 2 patients preoperatively) achieved normal voiding with demonstrable voiding detrusor contraction in the presence of a compliant stable bladder (p <0.05). CONCLUSIONS Our results suggest that transurethral autologous myoblast injection is a valid option for the treatment of structural urinary incontinence in children with classic bladder exstrophy. However, favorable preoperative urodynamic profiles and postoperative pelvic floor electrical stimulation may have contributed to the outcome in this series.

Comparison of magnetic resonance urography with ultrasound studies in detection of fetal urogenital anomalies

PURPOSE Prenatal ultrasonography detects the vast majority of urogenital anomalies, but in some cases the diagnosis remains in doubt. We assessed the potential of magnetic resonance urography (MRU) in the evaluation of different urogenital anomalies in fetuses when ultrasound study was equivocal. PATIENTS AND METHODS We retrospectively reviewed the medical records of 46 fetuses in whom the presence of urogenital anomalies was suspected at ultrasound studies, but remained inconclusive. Fetal MRU was performed within the same week as ultrasound studies. All patients underwent MRU, comprising overview, fast, thick-slab, heavily T2-weighted sequences, followed by focused, high-resolution T2-weighted sequences obtained in sagittal, axial and coronal planes. T1-weighted sequences were obtained in selected cases for assessment of the gastrointestinal tract. All MRU results were compared with ultrasound findings. Sensitivity of each imaging modality was estimated based on definite diagnoses made after birth or abortion. RESULTS The mean (range) gestational age was 27 (18-36)weeks. The final diagnosis was ureteropelvic junction obstruction in 12, ureteral dilation (due to vesicoureteral junction obstruction) in five, ureterocele in five, posterior urethral valve in 16, multicystic dysplastic kidney in six, mesenteric cyst in one and abdominoscrotal hydrocele in one. Overall diagnostic sensitivity of fetal MRU was 96% compared to sonography with 58% sensitivity (p<0.05). Fetal MRU studies provided additional information to sonography in 17 (37%) cases, and were especially more sensitive in evaluation of ureteral anatomy. CONCLUSIONS Fetal MRU can accurately diagnose a wide variety of urinary tract disorders and must be regarded as a valuable complementary tool to ultrasound in the assessment of the urinary system, particularly in cases of inconclusive ultrasound findings. The present study had a selection bias, as only fetuses with possible anomalies proposed by sonography were referred for MRU; however, this is the population that probably benefits most from MRU studies.

Antimicrobial Properties of Mesenchymal Stem Cells: Therapeutic Potential for Cystic Fibrosis Infection, and Treatment

Cystic fibrosis (CF) is a genetic disease in which the battle between pulmonary infection and inflammation becomes the major cause of morbidity and mortality. We have previously shown that human MSCs (hMSCs) decrease inflammation and infection in the in vivo murine model of CF. The studies in this paper focus on the specificity of the hMSC antimicrobial effectiveness using Pseudomonas aeruginosa (gram negative bacteria) and Staphylococcus aureus (gram positive bacteria). Our studies show that hMSCs secrete bioactive molecules which are antimicrobial in vitro against Pseudomonas aeruginosa, Staphylococcus aureus, and Streptococcus pneumonia, impacting the rate of bacterial growth and transition into colony forming units regardless of the pathogen. Further, we show that the hMSCs have the capacity to enhance antibiotic sensitivity, improving the capacity to kill bacteria. We present data which suggests that the antimicrobial effectiveness is associated with the capacity to slow bacterial growth and the ability of the hMSCs to secrete the antimicrobial peptide LL-37. Lastly, our studies demonstrate that the tissue origin of the hMSCs (bone marrow or adipose tissue derived), the presence of functional cystic fibrosis transmembrane conductance regulator (CFTR: human, Cftr: mouse) activity, and response to effector cytokines can impact both hMSC phenotype and antimicrobial potency and efficacy. These studies demonstrate, the unique capacity of the hMSCs to manage different pathogens and the significance of their phenotype in both the antimicrobial and antibiotic enhancing activities.

The role of CXCL12 and CCL7 chemokines in immune regulation, embryonic development, and tissue regeneration

Chemotactic factors direct the migration of immune cells, multipotent stem cells, and progenitor cells under physiologic and pathologic conditions. Chemokine ligand 12 and chemokine ligand 7 have been identified and investigated in multiple studies for their role in cellular trafficking in the setting of tissue regeneration. Recent early phase clinical trials have suggested that these molecules may lead to clinical benefit in patients with chronic disease. Importantly, these two proteins may play additional significant roles in directing the migration of multipotent cells, such as mesenchymal stem cells and hematopoietic progenitor cells. This article reviews the functions of these two chemokines, focusing on recruitment to sites of injury, immune function modulation, and contributions to embryonic development. Additional research would provide valuable insight into the potential clinical application of these two proteins in stem cell therapy.

19F MRI Tracer Preserves in Vitro and in Vivo Properties of Hematopoietic Stem Cells

Hematopoietic stem cells (HSCs) have numerous therapeutic applications including immune reconstitution, enzyme replacement, regenerative medicine, and immunomodulation. The trafficking and persistence of these cells after administration is a fundamental question for future therapeutic applications of HSCs. Here, we describe the safe and efficacious labeling of human CD34+ HSCs with a novel, self-delivering perfluorocarbon 19F magnetic resonance imaging (MRI) tracer, which has recently been authorized for use in a clinical trial to track therapeutic cells. While various imaging contrast agents have been used to track cellular therapeutics, the impact of this MRI tracer on HSC function has not previously been studied. Both human CD34+ and murine bone marrow (BM) HSCs were effectively labeled with the MRI tracer, with only a slight reduction in viability, relative to mock-labeled cells. In a pilot study, 19F MRI enabled the rapid evaluation of HSC delivery/retention following administration into a rat thigh muscle, revealing the dispersal of HSCs after injection, but not after surgical implantation. To investigate effects on cell functionality, labeled and unlabeled human HSCs were tested in in vitro colony forming unit (CFU) assays, which resulted in equal numbers of total CFU as well as individual CFU types, indicating that labeling did not alter multipotency. Cobblestone assay forming cell precursor frequency was also unaffected, providing additional evidence that stem cell function was preserved after labeling. In vivo tests of multipotency and reconstitution studies in mice with murine BM containing labeled HSCs resulted in normal development of CFU in the spleen, compared to unlabeled cells, and reconstitution of both lymphoid and myeloid compartments. The lack of interference in these complex biological processes provides strong evidence that the function and therapeutic potential of the HSCs are likely maintained after labeling. These data support the safety and efficacy of the MRI tracer for clinical tracking of human stem cells.

Vesicoureteral Reflux and Primary Bladder Neck Dysfunction in Children: Urodynamic Evaluation and Randomized, Double-Blind, Clinical Trial on Effect of α-Blocker Therapy

PURPOSE Primary bladder neck dysfunction has been under diagnosed as a treatable cause of vesicoureteral reflux. We evaluated the effect of prazosin administration on vesicoureteral reflux resolution and urodynamic parameters in children with idiopathic primary reflux and primary bladder neck dysfunction. MATERIALS AND METHODS A total of 62 children (mean ± SD age 7.9 ± 2.4 years) with documented vesicoureteral reflux and urodynamics proved primary bladder neck dysfunction were randomized to receive either 0.025 mg/kg α-blocker (prazosin, 40 patients) or placebo (22) nightly for 1 week with a subsequent increase to 2 divided doses. Patients were followed for 12 months with clinical evaluation and uroflowmetry performed every 2 months, and each patient underwent complete urodynamic study at 6-month intervals. RESULTS In the placebo group no uroflowmetry or urodynamic parameter changed significantly at 1-year followup. A 60% decrease in reflux grade was observed in the treatment group compared to 17% in the placebo group. Mean maximal detrusor pressure, post-void residual and opening time were significantly decreased in both followup sessions in the prazosin group (p <0.05). Average flow rate improved from 4.30 to 12.80 ml per second at 6 months and to 13.10 ml per second at 12 months (both p <0.05). CONCLUSIONS Special attention should be given to secondary causes of vesicoureteral reflux (such as primary bladder neck dysfunction, an underdiagnosed entity in children), since conventional treatment will most likely fail if these conditions are not addressed promptly. In this study prazosin was effective therapy for children with vesicoureteral reflux and primary bladder neck dysfunction.

Protective effects of Swertia longifolia Boiss. and its active compound, swerchirin, on paracetamol-induced hepatotoxicity in mice

Aerial parts of Swertia longifolia Boiss. (Gentianaceae), which grows in the north of Iran, were screened for hepatoprotective activity against paracetamol (acetaminophen)‐induced hepatotoxicity in Swiss mice. Pretreatment with total plant extract and swerchirin, the major component of the plant, significantly reduced the elevation of biochemical parameters, AST (aspartate aminotransferase), ALT (alanine aminotransferase) and ALP (alkaline phosphatase), the enzymes that are increased by liver damage (P < 0.001). Our results indicated that total plant extract and swerchirin were hepatoprotective in the range of 6–50 mg kg−1 orally.

Advanced maternal age as a risk factor for stress urinary incontinence: a review of the literature

The pathophysiology of stress urinary incontinence (SUI) is multifactorial and evidence supports a critical role of pregnancy and vaginal delivery. This review dissects epidemiologic literature to determine the weight of evidence on the role of advanced maternal age (AMA) as a risk factor for the development of subsequent or persistent SUI. We conducted a Medline search using the keywords postpartum, SUI, maternal age, pregnancy, and incontinence. The published literature was critically analyzed. Evidence supports that childbirth trauma contributes to the development and severity of SUI. Yet, there is contradicting evidence as to whether AMA increases the risk. AMA clearly represents an independent risk factor for postpartum SUI. However, long-term studies did not confirm this observation. Whether this finding is suggestive of a true biologic signal that is lost with competing risk factors over time warrants further research.

An antenatally diagnosed rhabdomyosarcoma of the bladder treated without extensive surgery

Background. A female fetus was followed up from week 30 of gestation after bilateral hydroureteronephrosis and a large pelvic mass were detected on fetal imaging. At birth, the patient had high respiratory rate, a palpable bladder up to the umbilicus and a large pelvic mass, which compressed the anorectal wall.Investigations. Fetal ultrasonography, fetal magnetic resonance urography, pelvic examination, full hematologic investigation, blood culture, abdominal and pelvic ultrasonography, voiding cystourethrography, abdominal and pelvic spiral CT, measurement of serum tumor marker levels, pathologic examination of the excised specimen, pelvic MRI.Diagnosis. Botryoid subtype of rhabdomyosarcoma occupying most of the bladder and protruding through the urethra, with bilateral hydroureteronephrosis.Management. Catheterization on the second day of life improved the patients renal function, but her general condition remained unstable and surgical intervention was deferred. On the fourth day, gross hematuria and decreased urinary output were observed, which rapidly progressed to anuria, and she underwent transurethral resection of the protruding part of the tumor and bilateral cutaneous ureterostomy. Subsequently, she received chemotherapy with vincristine, actinomycin D and ifosfamide, and was followed up with serial imaging. At 18 months, MRI showed no evidence of residual tumor, and cystoscopic biopsy confirmed the absence of viable tumor; chemotherapy was stopped. She had no sign of recurrence 24 months after ending chemotherapy.

Stem cell homing factor, CCL7, expression in mouse models of stress urinary incontinence.

Objectives Animal models of vaginal distention (VD) have demonstrated increased expression of chemokine (C-C motif) ligand 7 (CCL7) In this study, we investigated the expression of CCL7 in mice models of simulated birth trauma–induced urinary incontinence using VD and pudendal nerve transection (PNT). Methods Forty-nine mice were divided into 6 groups: VD, sham VD, PNT, sham PNT, anesthesia, and age-matched controls. The urethra, vagina, and rectum were harvested for the expression of CCL7 immediately or 24 hours after assigned procedure. Venous sampling for quantification of serum CCL7 was also performed. An analysis of variance model was used to compare the relative expression of CCL7 in each group. Results Urethral CCL7 expression in the VD group was significantly higher than control group after 24 hours (P < 0.01). There was no difference in the urethral CCL7 expression in PNT, sham PNT, sham VD, or anesthesia groups compared with the controls. No statistically significant difference was noted in the vaginal and rectal expression of CCL7 between any of the groups except for sham PNT. Statistically significant differences were noted in the serum CCL7 expression in the VD, PNT, and sham PNT (P < 0.01 in all) groups after 24 hours compared with the control group. Conclusions This study demonstrates overexpression of urethral CCL7 after VD but not PNT. This suggests that nerve injury does not contribute to the CCL7 overexpression. The overexpression of CCL7 in the serum of mice after VD suggests a translational potential where CCL7 measurement could be used as a surrogate for injury after delivery.