The potent paracrine effect of umbilical cord mesenchymal stem cells mediates mitochondrial quality control to restore chemotherapy-induced damage in ovarian granulosa cells.

The basic principle of chemotherapy is to attack cells with fast growth, and cancer cells are targeted by anticancer drugs because they have a faster growth rate than normal cells. High doses of anticancer drugs may cause an irreversible decline in reproductive capacity, and novel approaches for fertility preservation and/or restoration after anticancer treatment are urgently needed. Here, we provide important insights into the recovery of human reproductive cells damaged by chemotherapy. We performed a detailed screening of the cytokines of various human mesenchymal stem cells (hMSCs) to select superior MSCs. Also, we analyzed the Ovarian granulosa cell (OGC)-)-specific functions for restoring function, apoptosis, and mitochondrial functions to confirm the recovery mechanism in damaged OGCs. As a result, we demonstrated that conditioned media (CM) of Umbilical cord mesenchymal stem cells (UC-MSCs) could restore the functions of damaged OGCs primarily through antiapoptotic and antioxidant effects. Furthermore, CM changed the phenotype of damaged OGCs to an energetic status by restoring mitochondrial function and enhanced the mitochondrial metabolic activity decreased by chemotherapy. Finally, we demonstrated that the restoration of mitochondrial function in damaged OGCs was mediated through mitochondrial autophagy (mitophagy). Our findings offer new insights into the potential of stem cell-based therapy for fertility preservation and/or restoration in female cancer patients.

Toll-Like Receptors and Mannose Binding Lectin Gene Polymorphisms Associated with Cryptosporidial Diarrhea in Children in Southern India.

In low-resource settings, Cryptosporidium spp. is a common cause of diarrheal disease in children under the age of 3 years. In addition to diarrhea, these children also experience subclinical episodes that have been shown to affect growth and cognitive function. In this study, we screened polymorphisms in the promoter and exon1 regions of the mannose binding lectin 2 (MBL2) gene, as well as single nucleotide polymorphisms (SNPs) described in toll-like receptors (TLR) TLR1, TLR2, TLR4, and TLR9 and TIR domain-containing adaptor protein (TIRAP) genes among children with cryptosporidial diarrhea (cases) and children who only experienced asymptomatic (subclinical) cryptosporidiosis (controls). Among the polymorphisms screened, the variant allele B at codon 54 (rs1800450) of the MBL2 gene was associated with susceptibility to cryptosporidial diarrhea (odds ratio [OR] = 2.2, 95% confidence interval [CI] 1.1-4.5). When plasma MBL levels were compared, 72% of cases were found to be deficient compared with 32% among controls (OR = 5.09). Among TLR polymorphisms screened, multivariate analysis showed that heterozygous genotypes of TLR4 896A/G (rs4986790, OR = 0.33, 95% CI: 0.11-0.98) and TIRAP 539 C/T (rs8177374, OR = 0.19, 95% CI: 0.06-0.64) SNPs were associated with protection from cryptosporidial diarrhea. Although not statistically significant, these findings suggest that polymorphisms of MBL2 and TLR genes influence susceptibility to symptomatic cryptosporidial diarrhea even in settings with high exposure levels. Further studies to validate these findings in a larger cohort and to understand the role of these polymorphisms in mediating innate and adaptive immune responses to cryptosporidial infection are necessary.

Norovirus Gastroenteritis in a Birth Cohort in Southern India.

BACKGROUND: Noroviruses are an important cause of gastroenteritis but little is known about disease and re-infection rates in community settings in Asia. METHODS: Disease, re-infection rates, strain prevalence and genetic susceptibility to noroviruses were investigated in a birth cohort of 373 Indian children followed up for three years. Stool samples from 1856 diarrheal episodes and 147 vomiting only episodes were screened for norovirus by RT-PCR. Norovirus positivity was correlated with clinical data, secretor status and ABO blood group. RESULTS: Of 1856 diarrheal episodes, 207 (11.2%) were associated with norovirus, of which 49(2.6%) were norovirus GI, 150(8.1%) norovirus GII, and 8 (0.4%) were mixed infections with both norovirus GI and GII. Of the 147 vomiting only episodes, 30 (20.4%) were positive for norovirus in stool, of which 7 (4.8%) were norovirus GI and 23 (15.6%) GII. At least a third of the children developed norovirus associated diarrhea, with the first episode at a median age of 5 and 8 months for norovirus GI and GII, respectively. Norovirus GI.3 and GII.4 were the predominant genotypes (40.3% and 53.0%) with strain diversity and change in the predominant sub-cluster over time observed among GII viruses. A second episode of norovirus gastroenteritis was documented in 44/174 (25.3%) ever-infected children. Children with the G428A homozygous mutation for inactivation of the FUT2 enzyme (se428se428) were at a significantly lower risk (48/190) of infection with norovirus (p = 0.01). CONCLUSIONS: This is the first report of norovirus documenting disease, re-infection and genetic susceptibility in an Asian birth cohort. The high incidence and apparent lack of genogroupII specific immunity indicate the need for careful studies on further characterization of strains, asymptomatic infection and shedding and immune response to further our understanding of norovirus infection and disease.

Multisite study of cryptosporidiosis in children with diarrhea in India.

Cryptosporidium spp., a common cause of diarrhea in children, were investigated in the first multisite study in India. Diarrheal stools from hospitalized children aged <5 years from Delhi, Trichy, and Vellore were analyzed by microscopy, PCR-restriction fragment length polymorphism (RFLP), and/or sequencing at the small-subunit (SSU) rRNA and Cpgp40/15 loci for species determination and subgenotyping, respectively. Seventy of 2,579 (2.7%) children, 75% of whom were <2 years old, had cryptosporidial diarrhea as determined by microscopy. Genotyping and subgenotyping showed that Cryptosporidium hominis was the most commonly identified species (59/67 children), and subgenotypes Ie, Ia, Ib, and Id were common in all centers. A novel C. parvum subgenotype, IIn, was identified in Vellore. Meteorological analysis revealed a higher rate of cryptosporidial positivity during hotter and drier weather in Delhi.