Mesodermal iPSC–derived progenitor cells functionally regenerate cardiac and skeletal muscle

Conditions such as muscular dystrophies (MDs) that affect both cardiac and skeletal muscles would benefit from therapeutic strategies that enable regeneration of both of these striated muscle types. Protocols have been developed to promote induced pluripotent stem cells (iPSCs) to differentiate toward cardiac or skeletal muscle; however, there are currently no strategies to simultaneously target both muscle types. Tissues exhibit specific epigenetic alterations; therefore, source-related lineage biases have the potential to improve iPSC-driven multilineage differentiation. Here, we determined that differential myogenic propensity influences the commitment of isogenic iPSCs and a specifically isolated pool of mesodermal iPSC-derived progenitors (MiPs) toward the striated muscle lineages. Differential myogenic propensity did not influence pluripotency, but did selectively enhance chimerism of MiP-derived tissue in both fetal and adult skeletal muscle. When injected into dystrophic mice, MiPs engrafted and repaired both skeletal and cardiac muscle, reducing functional defects. Similarly, engraftment into dystrophic mice of canine MiPs from dystrophic dogs that had undergone TALEN-mediated correction of the MD-associated mutation also resulted in functional striatal muscle regeneration. Moreover, human MiPs exhibited the same capacity for the dual differentiation observed in murine and canine MiPs. The findings of this study suggest that MiPs should be further explored for combined therapy of cardiac and skeletal muscles.     

Substantial lymph-vascular space invasion (LVSI) as predictor of distant relapse and poor prognosis in low-risk early-stage endometrial cancer

ObjectiveThe aim of this study is to analyze the prognostic role of lymph-vascular space invasion (LVSI), evaluated in a semi-quantitative fashion on prognosis of early stage, low risk endometrial cancer (EC).MethodsWe enrolled patients who underwent surgery for endometrial cancer between 2003 and 2018 in two referral cancer center. All patients had endometrioid EC, G1–G2, with myometrial invasion <50%, and no lymph-node involvement. LVSI was analyzed in a semi-quantitative way, according to a 3-tiered scoring system in absent, focal and substantial.ResultsAmong 524 patients, any positive LVSI was found in 57 patients (10.9%) with focal LVSI (n=35, 6.7%) and substantial LVSI (n=22, 4.2%). Substantial LVSI was associated to higher rate of G2 (p<0.001), myometrial infiltration (p=0.002) and greater tumor dimensions (p=0.014). Patients with substantial LVSI were more likely to receive adjuvant treatment (6.6% vs. 52.6%, p<0.001). The 5-year OS was 99.5% in patients with absent LVSI and 70.6% in those with substantial LVSI (p<0.001). The 5-year disease free survival (DFS) was 93.6% in patients with absent LVSI and 56.5% in those with substantial LVSI (p<0.001). The rate of distant failures increased from 1.8% for absent LVSI to 22.7% for substantial LVSI (p=0.002). In univariate analysis substantial LVSI was the strongest predictor of poor overall survival (hazard ratio [HR]=11.9, p=0.001). Multivariate analysis showed that substantial LVSI was an independent predictive factor of both recurrence (HR=5.88, p=0.001) and distant failure (HR=10.6, p=0.006).ConclusionsSubstantial LVSI represents the strongest independent risk factor for decreased survival and distant relapse, indicating a role for potential hematogenous dissemination.     

Laparoscopic, minilaparoscopic and single-port hysterectomy: perioperative outcomes

Objective

This study was designed to compare perioperative outcomes and postoperative pain of standard laparoscopic (S-LPS), minilaparoscopic (M-LPS), and laparoendoscopic single-site (LESS) hysterectomy.

Methods

A single-institutional, matched, retrospective, cohort study was performed. Between May 2010 and March 2011, 85 consecutive women were submitted to a total laparoscopic hysterectomy by S-LPS, M-LPS, and single-port LESS. Perioperative outcomes of these three techniques were analyzed and compared.

Results

Demographics and baseline characteristics of each group were absolutely comparable. The median operative time was longer [105 (range, 75?C125) min] in the LESS group compared with the M-LPS group [90 (range, 60?C120) min; p?<?0.011] and S-LPS [80 (range, 50?C110) min; p?<?0.001]. No statistically significant differences have been reported for estimated blood loss or intra- and early postoperative complications. Postoperative pain control was better for LESS and M-LPS than S-LPS.

Conclusions

M-LPS and LESS hysterectomy can be performed safely, and both seem to be associated with a halving of early postoperative pain with a lower request of analgesics.     

MYH9 related disease: four novel mutations of the tail domain of myosin‐9 correlating with a mild clinical phenotype

MYH9‐related disease (MYH9‐RD) is a rare autosomal dominant disorder caused by mutations in MYH9, the gene encoding the heavy chain of non‐muscle myosin IIA. All patients present congenital macrothrombocytopenia and inclusion bodies in neutrophils. Some of them can also develop sensorineural deafness, presenile cataract, and/or progressive nephropathy leading to end‐stage renal failure. We report four families, each with a novel mutation: two missense mutations, in exons 31 and 32, and two out of frame deletions in exon 40. They were associated with no bleeding diathesis, normal, or only slightly reduced platelet count and no extra‐hematological manifestations, confirming that alterations of the tail domain cause a mild form of MYH9‐RD with no clinically relevant defects.     

Severe pelvic organ prolapse treated by vaginal native tissue repair: long-term analysis of outcomes in 146 patients

Aims

The aim of this study was to assess the effectiveness and safety of vaginal native tissue repair (VNTR) as a surgical treatment for severe pelvic organ prolapse (POP) and, second, to evaluate the impact on the quality-of-life (QoL) and sexual function.

Methods

Women with symptomatic POP (≥III stage according to POP Quantification System) with or without stress urinary incontinence (SUI) underwent VNTR. The clinical stage, 3-day voiding diary, and urodynamic testing were evaluated in the preoperative and postoperative times, respectively. The International Consultation on Incontinence Questionnaire–Urinary Incontinence Questionnaire Short Form (ICIQ–UI SF), the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire short form (PISQ-12), and the prolapse quality-of-life questionnaire (P-QoL) were administered.

Results

One hundred forty-six patients were recruited. The median follow-up was 48 months (36–63). Fifty-two women (36%) had a previous hysterectomy, and 16 (11%) had a previous prolapse/continence surgery. Preoperatively, 135 (92.5%), 109 (74.7%), and 98 (67.1%) patients had anterior, central, and posterior descent ≥III stage, respectively. Thirty-two patients (22%) had concomitant diagnosis of SUI. Median operative time was 85 min (37–154), and median postoperative hospital stay was 2 days (2–4). No intraoperative severe complications occurred. At the long-term follow-up, the subjective cure rate for prolapse was 97.3% and the objective cure rate was 91.1%. A significant improvement of ICIQ-UI SF, the P-QoL, and the PISQ-12 was recorded at the follow-up (p?<?0.001).

Conclusion

VNTR is effective, safe, and durable and improves POP-related symptoms and sexual function.

     

Usefulness of computerized tomography in the prognosis of subarachnoid hemorrhage

The authors reviewed the computed tomographic (CT) scans of 129 patients with subarachnoid hemorrhage (SAH). The close correlation is stressed between the severity of the symptoms onset and the amount of blood demonstrated on CT scans. The importance is confirmed of CT in the prognostic evaluation of SAH. As a matter of fact, CT findings define the location and the amount of blood: these factors are closely related to the occurrence of vasospasms -i.e., the primary cause of death and poor outcome. CT also shows the possible complications (hematoma, hydrocephalus, mass effect) that, when present, have a negative impact on prognosis, independent of the neurologic condition. Finally, the authors point out how a reliable prognosis of SAH is based upon combined clinical evaluation and CT study.     

Search superiority in autism within, but not outside the crowding regime

Visual cognition of observers with autism spectrum disorder (ASD) seems to show an unbalance between the complementary functions of integration and segregation. This study uses visual search and crowding paradigms to probe the relative ability of children with autism, compared to normal developments children, to extract individual targets from cluttered backgrounds both within and outside the crowding regime. The data show that standard search follows the same pattern in the ASD and control groups with a strong effect of the set size that is substantially weakened by cueing the target location with a synchronous spatial cue. On the other hand, the crowding effect of eight flankers surrounding a small peripheral target is virtually absent in the clinical sample, indicating a superior ability to segregate cluttered visual items. This data, along with evidence of an impairment to the neural system for binding contours in ASD, bring additional support to the general idea of a shift of the trade-off between integration and segregation toward the latter. More specifically, they show that when discriminability is balanced across conditions, an advantage in odd-man out tasks is evident in ASD observers only within the crowding regime, when binding mechanism might get compulsorily triggered in normal observers.     

Low-density lipoprotein (LDL) receptor/transferrin fusion protein: in vivo production and functional evaluation as a potential therapeutic tool for lowering plasma LDL cholesterol

A soluble form of human low-density lipoprotein receptor (LDL-R) fused in frame with rabbit transferrin (LDL-Rs(hu)/Tf(rab)) is assessed in vivo as a therapeutic tool for lowering plasma LDL cholesterol. The cDNA encoding LDL-Rs(hu)/Tf(rab) is expressed in mice, using a hydrodynamics-based gene transfer procedure. The transgene is transcribed in the liver of transduced animals and the corresponding protein is secreted into the bloodstream. Circulating LDL-Rs(hu)/Tf(rab) binds LDL specifically, thus indicating that it is correctly processed through the cellular compartments in vivo. More importantly, the expression of LDL-Rs(hu)/Tf(rab) allows the removal of injected human (125)I-labeled LDL ((123)I-LDL) from the bloodstream of transduced CD1 mice, which show faster LDL plasma clearance, anticipating by approximately 90 min the same clearance value observed in control animals. A similar effect is observed in transduced LDL-R(-/-) mice, in which the clearance of injected human LDL depends solely on the presence of circulating LDL-Rs(hu) /Tf(rab). In these animals the extent of plasma LDL clearance is directly related to the concentration of LDL-Rs(hu)/Tf(rab) in the blood. Finally, LDL-Rs(hu)/Tf(rab) does not alter the pattern of LDL organ distribution: in transduced animals, as well as in control animals, liver and bladder are the predominantly labeled organs after (123)I-LDL injection. However, LDL-Rs(hu)/Tf(rab) has a quantitative effect on LDL tissue deposition: in treated animals LDL-Rs(hu)/Tf(rab) determines an increase in radioactivity in the liver at early times after (123)I-LDL injection and a progressive labeling of the bladder, starting 20 min after injection.