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.     

Abdominal splenosis and its differential diagnoses: What the radiologist needs to know

Splenosis is a benign acquired condition characterized by the presence of heterotopic viable splenic tissue in other organs or within cavities such as peritoneum, retroperitoneum, or thorax after splenic trauma or surgery. Abdominal splenosis is often an incidental finding and computed tomography and magnetic resonance usually allow a confident diagnosis. The typical enhancement that parallels the spleen is a useful hallmark of splenosis. Splenic implants lack contrast uptake in the hepatobiliary phase and show high signal at high b-values on diffusion-weighted images. In some cases splenosis may mimic malignant and benign conditions in the peritoneum as well as in hollow and parenchymal abdominal organs and further investigations – including scintigraphy with Tc99m-labelled heat-denatured red blood cells or biopsy – are sometimes required in challenging cases. This pictorial essay reviews the imaging presentation and potential differential diagnosis of splenosis according to the site of implantation. A prompt and accurate radiological diagnosis of splenosis can avoid unnecessary biopsy or surgery.     

Protective effect of the Nramp1 BB genotype against Brucella abortus in the water buffalo (Bubalus bubalis)

We tested 413 water buffalo cows (142 cases and 271 controls) for the presence of anti-Brucella abortus antibodies (by the skin test, the agglutination test, and the complement fixation test) and the Nramp1 genotype (by capillary electrophoresis). Four alleles (Nramp1A, -B, -C, and -D) were detected in the 3' untranslated region of the Nramp1 gene. The BB genotype was represented among only controls, providing evidence that this genotype confers resistance to Brucella abortus. The monocytes from the BB (resistant) subjects displayed a higher basal level of Nramp1 mRNA and a lower number of viable intracellular bacteria than did the monocytes from AA (susceptible) subjects. The higher basal level of the antibacterial protein Nramp1 most probably provides the BB animals with the possibility of controlling bacteria immediately after their entry inside the cell.     

Elective Cesarean Delivery: Does It Have a Negative Effect on Breastfeeding?

Abstract: Background: Cesarean delivery has negative effects on breastfeeding. The objective of this study was to evaluate breastfeeding rates, defined in accordance with World Health Organization guidelines, from delivery to 6 months postpartum in infants born by elective and emergency cesarean section and in infants born vaginally. Methods: Delivery modalities were assessed in relation to breastfeeding patterns in 2,137 term infants delivered at a tertiary center, the Padua University School of Medicine in northeastern Italy, from January to December 2007. The study population included 677 (31.1%) newborns delivered by cesarean section, 398 (18.3%) by elective cesarean, 279 (12.8%) by emergency cesarean section, and 1,496 (68.8%) delivered vaginally. Results: Breastfeeding prevalence in the delivery room was significantly higher after vaginal delivery compared with that after cesarean delivery (71.5% vs 3.5%, p < 0.001), and a longer interval occurred between birth and first breastfeeding in the newborns delivered by cesarean section (mean ± SD, hours, 3.1 ± 5 vs 10.4 ± 9, p < 0.05). No difference was found in breastfeeding rates between the elective and emergency cesarean groups. Compared with elective cesarean delivery, vaginal delivery was associated with a higher breastfeeding rate at discharge and at the subsequent follow‐up steps (7 days, 3 mo, and 6 mo of life). Conclusions: Emergency and elective cesarean deliveries are similarly associated with a decreased rate of exclusive breastfeeding compared with vaginal delivery. The inability of women who have undergone a cesarean section to breastfeed comfortably in the delivery room and in the immediate postpartum period seems to be the most likely explanation for this association. (BIRTH 37:4 December 2010)     

A phase II study of aflibercept in patients with advanced epithelial ovarian cancer and symptomatic malignant ascites

Objective

To evaluate the outcomes observed with pelvic exenteration with curative intent for recurrent uterine malignancies in the modern era.

Methods

We reviewed the records of all patients who underwent this procedure at our institution between 1/1997 and 03/2011. Postoperative complications up to 90 days after surgery were analyzed and graded as per our institution grading system. Survivals were estimated using the Kaplan-Meier method.

Results

During the study period, 21 patients were identified. Median age at the time of exenteration was 57 years (range, 36-75). Median tumor size was 6 cm (range, microscopic — 14.5). Tumor histology was: endometrioid, 10 cases; mixed, serous, and carcinosarcoma, 7 cases; and sarcomas, 4 cases. The type of exenteration was: total, 14 cases; anterior, 6 cases and posterior, 1 case. There were no intra- or postoperative mortalities. Seven patients (33%) developed at least one grade 2 complication, and 10 patients (48%) developed at least one grade 3 complication. Five (24%) patients had to be re-operated on in the first 90 days post surgery. The median follow up time after exenteration was 39 months (range, 5-112). The 5-year survival of the entire cohort was 40% (95% CI: 18-63). An improved survival was observed in patients with endometrioid tumors and sarcomas (5-year survival rates of 50% and 66%, respectively). The presence of pelvic sidewall involvement and/or hydronephrosis did not negatively affect survival.

Conclusion

Pelvic exenteration for recurrent uterine malignancies can be associated with long-term survival in properly selected patients. A high rate of postoperative complications remains a hallmark of this procedure and should be discussed carefully with patients facing this decision.     

Vitamin D status and predictors of hypovitaminosis D in Italian children and adolescents: a cross-sectional study

Hypovitaminosis D affects children and adolescents all around the world. Italian data on vitamin D status and risk factors for hypovitaminosis D during pediatric age are lacking. Six hundred fifty-two children and adolescents (range 2.0–21.0 years) living in the northwestern area of Tuscany were recruited at the Department of Pediatrics, University Hospital Pisa. None of them had received vitamin D supplementation in the previous 12 months. 25-hydroxyvitamin D (25-OH-D) and parathyroid hormone (PTH) levels were analyzed in all subjects. Severe vitamin D deficiency was defined as serum levels of 25-OH-D?<?25.0 nmol/L (10.0 ng/mL) and vitamin D deficiency as?<?50.0 nmol/L (20.0 ng/mL). Serum 25-OH-D levels of 50.0–74.9 nmol/L (20.0–29.9 ng/mL) indicated vitamin D insufficiency, whereas 25-OH-D levels?≥?75.0 nmol/L (30.0 ng/mL) were considered sufficient. Hypovitaminosis D was defined as 25-OH-D levels?<?75.0 nmol/L (30.0 ng/mL). The median serum 25-OH-D level was 51.8 nmol/L, range 6.7–174.7 (20.7 ng/mL, range 2.7–70.0), with a prevalence of vitamin D deficiency, insufficiency, and sufficiency of 45.9, 33.6, and 20.5 %, respectively. The prevalence of severe vitamin D deficiency was 9.5 %. Adolescents had lower median 25-OH-D levels (49.8 nmol/L, range 8.1–174.7; 20.0 ng/mL, range 3.2–70.0) than children (55.6 nmol/L, range 6.8–154.6; 22.3 ng/mL, range 2.7–61.9, p?=?0.006). Non-white individuals (n?=?37) had median serum 25-OH-D levels in the range of deficiency (28.2 nmol/L, range 8.1–86.2; 11.3 ng/mL, range 3.2–34.5), with 36/37 having hypovitaminosis D. Logistic regression showed significant increased risk of hypovitaminosis D in the following: blood samples taken in winter (odds ratio (OR) 27.20), spring (OR 26.44), and fall (OR 8.27) compared to summer; overweight (OR 5.02) and obese (OR 5.36) subjects compared to individuals with normal BMI; low sun exposure (OR 8.64) compared to good exposure, and regular use of sunscreens (OR 7.06) compared to non-regular use. Gender and place of residence were not associated with vitamin D status. The 25-OH-D levels were inversely related to the PTH levels (r?=??0.395, p?<?0.0001). Sixty-three out of the 652 (9.7 %) subjects showed secondary hyperparathyroidism. Conclusion Italian children and adolescents who were not receiving vitamin D supplementation had high prevalence of hypovitaminosis D. Careful identification of factors affecting vitamin D status is advisable to promptly start vitamin D supplementation in children and adolescents.     

Toll‐like receptors as novel therapeutic targets for herpes simplex virus infection

Seropositivity for HSV reaches more than 70% within the world population, and yet no approved vaccine exists. While HSV1 is responsible for keratitis, encephalitis, and labialis, HSV2 carriers have a high susceptibility to other STD infections, such as HIV. Induction of antiviral innate immune responses upon infection depends on a family of pattern recognition receptors called Toll‐like receptors (TLR). TLRs bridge innate and adaptive immunity by sensing virus infection and activating antiviral immune responses. HSV adopts smart tricks to evade innate immunity and can also manipulate TLR signaling to evade the immune system or even confer destructive effects in favor of virus replication. Here, we review mechanisms by which HSV can trick TLR signaling to impair innate immunity. Then, we analyze the role of HSV‐mediated molecular cues, in particular, NF‐κB signaling, in promoting protective versus destructive effects of TLRs. Finally, TLR‐based therapeutic opportunities with the goal of preventing or treating HSV infection will be discussed.     

Mutations in PLS1, encoding fimbrin,cause autosomal dominant nonsyndromic hearing loss

Nonsyndromic hearing loss (NSHL), a common sensory disorder, is characterized by high clinical and genetic heterogeneity (i.e., approximately 115 genes and 170 loci so far identified). Nevertheless, almost half of patients submitted for genetic testing fail to receive a conclusive molecular diagnosis. We used next‐generation sequencing to identify causal variants in PLS1 (c.805G>A, p.[E269K]; c.713G>T, p.[L238R], and c.383T>C, p.[F128S]) in three unrelated families of European ancestry with autosomal dominant NSHL. PLS1 encodes Plastin 1 (also called fimbrin), one of the most abundant actin‐bundling proteins of the stereocilia. In silico protein modeling suggests that all variants destabilize the structure of the actin‐binding domain 1, likely reducing the protein's ability to bind F actin. The role of PLS1 gene in hearing function is further supported by the recent demonstration that Pls1^?/? mice show a hearing loss phenotype similar to that of our patients. In summary, we report PLS1 as a novel gene for autosomal dominant NSHL, suggesting that this gene is required for normal hearing in humans and mice.     

Effect of repeated administration of prolactin releasing peptide on feeding behavior in rats

Prolactin releasing peptide (PrRP) has been reported to reduce food intake in rats. We tested the effect of i.c.v. administration of PrRP-31 on food intake in both food deprived and free-feeding rats. We did not find any effect of PrRP-31 on food intake after single injections of up to an 8-nmol dose, but observed a marked decrease in food intake and body weight in rats that received a repeated twice daily administration of 8 nmol of PrRP-31. This effect was associated with an adverse behavioral pattern, indicating that the repeated high doses of the peptide caused non-specific effects inducing anorexia. We also tested several other behavioral parameters like locomotion and exploratory time, grooming and resting time, using lower doses of PrRP that did not cause the adverse behavior. Moreover, we carried out locomotor and sensory motor activity tests at the doses that exerted the most pronounced effect on the food intake. None of these tests suggested any specific behavioral effect of PrRP. We conclude that the behavioral pattern induced by PrRP is likely to be different from those induced by many other neuropeptides affecting food intake in rats.