High incidence of Noonan syndrome features including short stature and pulmonic stenosis in patients carrying NF1 missense mutations affecting p.Arg1809: genotype-phenotype correlation

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple cafe-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P<0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients

Uterine preservation for advanced pelvic organ prolapse repair: Anatomical results and patient satisfaction

ABSTRACT Objective: The aims of the current study were to evaluate outcomes and patient satisfaction in cases of uterine prolapse treated with vaginal mesh, while preserving the uterus. Materials and Methods: This is a retrospective cohort study that included all patients operated for prolapse repair with trocar-less vaginal mesh while preserving the uterus between October 2010 and March 2013. Data included: patients pre-and post-operative symptoms, POP-Q and operative complications. Success was defined as prolapse < than stage 2. A telephone survey questionnaire was used to evaluate patient's satisfaction. Results: Sixty-six patients with pelvic organ prolapse stage 3, including uterine pro-lapse of at least stage 2 (mean point C at+1.4 (range+8-(-1)) were included. Mean follow-up was 22 months. Success rate of the vaginal mesh procedure aimed to repair uterine prolapse was 92% (61/66), with mean point C at −6.7 (range (-1) - (-9)). No major intra-or post-operative complication occurred. A telephone survey questionnaire was conducted post-operatively 28 months on average. Ninety-eight percent of women were satisfied with the decision to preserve their uterus. Eighteen patients (34%) received prior consultation elsewhere for hysterectomy due to their prolapse, and decided to have the operation at our center in order to preserve the uterus. Conclusions: Uterine preservation with vaginal mesh was found to be a safe and effective treatment, even in cases with advanced uterine prolapse. Most patients prefer to keep their uterus. Uterus preservation options should be discussed with every patient before surgery for pelvic organ prolapse

Medium-term results of Mini-arc for urinary stress incontinence in ambulatory patients under local anesthesia

Abstract Objective To evaluate the medium-term outcome and patient's satisfaction after Single-incision mini-sling (SIMS) procedure done under local anesthesia in ambulatory set up for patients with stress urinary incontinence (SUI). Materials and Methods This is a retrospective cohort study, including all patients submitted to SIMS procedure for SUI with MiniArc (AMS, U.S.A) without concomitant surgery between January 2011 and March 2013. Patients were followed up during 12 months after surgery and once a year subsequently. Telephone interviews were conducted to evaluate patient satisfaction. Outcome masseurs included: SUI cure rate, urinary urge incontinence (UUI) cure rate in patients with mixed urinary incontinence (MUI), intra and post-operative complications and patient satisfaction. Results Ninety-three patients were included with mean follow-up of 23 months. Fifty percent had MUI with predominant SUI. The cure rates of SUI (objective and subjective) were 89%. UUI was cured in 40% of patients. No major complications occur, neither voiding obstruction or groin pain. Telephone interviews conducted after 26 months on average revealed high satisfaction rate from the procedure (8.8 out of 10) and from the local anesthesia. Visual analog scale (VAS) rating was low during and after the procedure (2.38 and 2.69 respectively). Conclusions The SIMS procedure is safe and highly effective for SUI and it can be performed successfully under local anesthesia in an ambulatory setup

Distinct HAND2/HAND2-AS1 Expression Levels May Fine-Tune Mesenchymal and Epithelial Cell Plasticity of Human Mesenchymal Stem Cells

We previously developed several successful decellularization strategies that yielded porcine cardiac extracellular matrices (pcECMs) exhibiting tissue-specific bioactivity and bioinductive capacity when cultured with various pluripotent and multipotent stem cells. Here, we study the tissue-specific effects of the pcECM on seeded human mesenchymal stem cell (hMSC) phenotypes using reverse transcribed quantitative polymerase chain reaction (RT-qPCR) arrays for cardiovascular related gene expression. We further corroborated interesting findings at the protein level (flow cytometry and immunological stains) as well as bioinformatically using several mRNA sequencing and protein databases of normal and pathologic adult and embryonic (organogenesis stage) tissue expression. We discovered that upon the seeding of hMSCs on the pcECM, they displayed a partial mesenchymal-to-epithelial transition (MET) toward endothelial phenotypes (CD31+) and morphologies, which were preceded by an early spike (~Day 3 onward after seeding) in HAND2 expression at both the mRNA and protein levels compared to that in plate controls. The CRISPR-Cas9 knockout (KO) of HAND2 and its associated antisense long non-coding RNA (HAND2-AS1) regulatory region resulted in proliferation arrest, hypertrophy, and senescent-like morphology. Bioinformatic analyses revealed that HAND2 and HAND2-AS1 are highly correlated in expression and are expressed in many different tissue types albeit at distinct yet tightly regulated expression levels. Deviation (downregulation or upregulation) from these basal tissue expression levels is associated with a long list of pathologies. We thus suggest that HAND2 expression levels may possibly fine-tune hMSCs’ plasticity through affecting senescence and mesenchymal-to-epithelial transition states, through yet unknown mechanisms. Targeting this pathway may open up a promising new therapeutic approach for a wide range of diseases, including cancer, degenerative disorders, and aging. Nevertheless, further investigation is required to validate these findings and better understand the molecular players involved, potential inducers and inhibitors of this pathway, and eventually potential therapeutic applications

CD74 is a regulator of hematopoietic stem cell maintenance.

Hematopoietic stem and progenitor cells (HSPCs) are a small population of undifferentiated cells that have the capacity for self-renewal and differentiate into all blood cell lineages. These cells are the most useful cells for clinical transplantations and for regenerative medicine. So far, it has not been possible to expand adult hematopoietic stem cells (HSCs) without losing their self-renewal properties. CD74 is a cell surface receptor for the cytokine macrophage migration inhibitory factor (MIF), and its mRNA is known to be expressed in HSCs. Here, we demonstrate that mice lacking CD74 exhibit an accumulation of HSCs in the bone marrow (BM) due to their increased potential to repopulate and compete for BM niches. Our results suggest that CD74 regulates the maintenance of the HSCs and CD18 expression. Its absence leads to induced survival of these cells and accumulation of quiescent and proliferating cells. Furthermore, in in vitro experiments, blocking of CD74 elevated the numbers of HSPCs. Thus, we suggest that blocking CD74 could lead to improved clinical insight into BM transplant protocols, enabling improved engraftment