CFTR variants and renal abnormalities in males with congenital unilateral absence of the vas deferens (CUAVD): a systematic review and meta-analysis of observational studies.

PURPOSE: CFTR variant is the main genetic contributor to congenital (unilateral/bilateral) absence of the vas deferens (CAVD/CUAVD/CBAVD). We performed a systematic review to elucidate the genetic link between CFTR variants, CUAVD, and the associated risk of renal abnormality (RA). METHODS: We searched relevant databases for eligible articles reporting CFTR variants in CUAVD. The frequency of CFTR variants and RA, and the odds ratios (ORs) for common alleles and RA risk, were pooled under random-/fixed-effect models. Subgroup analyses and heterogeneity tests were performed. RESULTS: Twenty-three studies were included. Among CUAVD patients, 46% had at least one CFTR variant, with 27% having one and 5% having two. The allele frequency in CUAVD was 4% for F508del and 9% for 5T. The summary OR for 5T risk in CUAVD was 5.79 compared with normal controls and 2.82 compared with non-CAVD infertile males. The overall incidence of RA was 22% in CUAVD. The pooled OR for RA risk among CUAVD patients was 4.85 compared with CBAVD patients. CONCLUSION: CFTR variants are common in CUAVD, and the 5T allele may be associated with increased CUAVD risk. CUAVD patients bear a higher RA risk than CBAVD patients, but this is not associated with CFTR variants.

Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation.

BACKGROUND: Infertility in mammalian females has been a challenge in reproductive medicine. The causes of female infertility include anovulation, ovulated oocyte defects, abnormal fertilization, and insufficient luteal support for embryo development, as well as early implantation. Ovulation induction, in vitro fertilization and luteal support regimens have been performed for decades to increase fertility rates. The identification of proteins and biochemical factors involved in female reproduction is essential to further increase female fertility rates. Evidence has shown that prostaglandins (PGs) might be involved in the female reproductive process, mainly ovulation, fertilization, and implantation. However, only a few studies on individual PGs in female reproduction have been done so far. This review aimed to identify the pivotal role of prostaglandin E2 (PGE2), a predominant PG, in female reproduction to improve fertility, specifically ovulation, fertilization, embryo development and early implantation. RESULTS: Prostaglandin E2 (PGE2) was shown to play a relevant role in the ovulatory cascade, including meiotic maturation, cumulus expansion and follicle rupture, through inducing ovulatory genes, such as Areg, Ereg, Has2 and Tnfaip6, as well as increasing intracellular cAMP levels. PGE2 reduces extracellular matrix viscosity and thereby optimizes the conditions for sperm penetration. PGE2 reduces the phagocytic activity of polymorphonuclear neutrophils (PMNs) against sperm. In the presence of PGE2, sperm function and binding capacity to oocytes are enhanced. PGE2 maintains luteal function for embryo development and early implantation. In addition, it induces chemokine expression for trophoblast apposition and adhesion to the decidua for implantation. CONCLUSION: It has been shown that PGE2 positively affects different stages of female fertility. Therefore, PGE2 should be taken into consideration when optimizing reproduction in infertile females. We suggest that in clinical practice, the administration of non-steroidal anti-inflammatory drugs, which are PGE2 synthesis inhibitors, should be reasonable and limited in infertile women. Additionally, assessments of PGE2 protein and receptor expression levels should be taken into consideration.

Open versus closed vitrification system of human oocytes and embryos: a systematic review and meta-analysis of embryologic and clinical outcomes.

BACKGROUND: The objective of this study was to carry out a systematic review and meta-analysis of embryologic and clinical outcomes following open versus closed vitrification of human oocytes and embryos. METHODS: An electronic literature search was conducted in main electronic databases up to June 30, 2018 using the following key terms: 'oocyte', 'embryo', 'blastocyst', 'vitrification', 'cryopreservation', 'device', 'survival rate', 'pregnancy rate', etc. A meta-analysis was performed using a random effect model to estimate the value of risk ratios (RRs) and 95% confidence interval (CI). Subgroup analyses and sensitivity analyses were carried out to further confirm the results. RESULTS: Twelve (Eight prospective and four retrospective) studies comparing open versus closed vitrification of human oocytes or embryos were included. For prospective studies on oocytes, no evidence for a significant difference in cryosurvival rate (RR = 0.91, 95% CI: 0.80-1.03, P = 0.14; n = 2048) or clinical pregnancy rate (RR = 1.29, 95% CI: 0.80-2.06, P = 0.30; n = 150) was observed. Additionally, there were no significant differences between the two methods concerning secondary endpoints included positive ßHCG rate, implantation rate, miscarriage rate, ongoing pregnancy rate, live birth rate, cancellation rate, babies born per transferred blastocysts, or multiple birth rate (P > 0.05). The results of the retrospective studies were similar as the prospective studies. CONCLUSIONS: It is still impossible to conclude that closed vitrification system could be a substitution for open system in human oocyte and embryo cryopreservation based on current evidence. Therefore, more well-designed prospective studies addressing these issues are still warranted.

Antimicrobial Resistance Profile of Bacteria Causing Pediatric Infections at the University Teaching Hospital in Rwanda.

Bacterial infections pose a global threat, especially in the pediatric population. Antimicrobials that are used to treat such infections continuously show reduced efficacy, and empirical therapy is a major treatment option in Rwanda. This study aimed to determine the resistance rate of commonly used antibiotics in pediatric patients. The study was conducted from June 1, 2018 to May 30, 2019, and microbiological samples were collected from 712 children with suspected bacterial infections. Antimicrobial sensitivity testing was performed on 177 positive cultures (24%) that were considered for data analysis. The findings show that the major bacterial isolates were Klebsiella pneumoniae (n = 50, 28.2%), Escherichia coli (n = 47, 26.5%), and Staphylococcus aureus (n = 38, 21.4%). In general, the greatest antibiotic resistance rate was observed in ampicillin (n = 125, 86.2%), amoxicillin-clavulanic acid (n = 84, 82.4%), amoxicillin (n = 64, 79%), cefadroxil (n = 83, 69.2%), tetracycline (n = 72, 59.7%), ceftazidime (n = 42, 55.3%), and cefuroxime (n = 14, 53.8%). More specifically, Klebsiella pneumoniae was 100% resistant to amoxicillin-clavulanic acid, cefuroxime, trimethoprim-sulfamethoxazole, ceftazidime, erythromycin, and clindamycin. Staphylococcus aureus was 86.7% resistant to ampicillin, and Escherichia coli was 91.7% resistant to tetracycline, 90.6% resistant to ampicillin, 83.3% resistant to amoxicillin-clavulanic acid, 79.3% resistant to cefadroxil, and 78.6% resistant to ceftazidime. Moreover, Klebsiella pneumoniae from blood and urine was 96.8% and 100% sensitive, respectively, to meropenem. Staphylococcus aureus from blood was 100% sensitive to vancomycin, whereas Escherichia coli from urine was sensitive to clindamycin (100%), nitrofurantoin (80.6%), and ciprofloxacin (72.7%). In conclusion, our findings show a high resistance rate to commonly used antibiotics, which suggests precaution in empirical therapy and continued surveillance of antimicrobial resistance.

HCV Seroprevalence among HIV Patients and Associated Comorbidities at One Primary Health Facility in Rwanda.

Hepatitis C virus (HCV) and HIV have emerged as major viral infections within the past two decades, and their coinfection poses a big challenge with a significant impact in terms of morbidity and mortality associated with liver disease and renal failure. The current study aimed at assessing the prevalence of HCV infection and associated comorbidities among HIV patients at one primary health facility in Rwanda. In total, 417 HIV-positive patients were recruited and included in the study from January 1, 2019 up to June 30, 2019. All participants were screened for HCV infection by using the SD Bioline HCV antibody rapid test. In addition, underlying medical conditions were also recorded as comorbidities. Among 417 participants, 52 exhibited HCV-positive results (12.5%). The group of 41- to 50- and 51- to 60-year-olds had higher prevalence of HIV/HCV coinfection than other age-groups with 3.6% and 4.6%, respectively. Furthermore, five underlying medical conditions were found as comorbidities among the study participants. Those with HIV/HCV coinfection showed higher comorbidities than those with mono-infection including liver toxicity, P value 0.005; tuberculosis, P value 0.005; renal failure, P value 0.003; hypertension, P value 0.001; and diabetes mellitus, P value 0.001. The relative risk ratio of having comorbidities in those groups was 4.09. To conclude, the prevalence of HCV/HIV coinfection is high, and there was a statistical significant association of having comorbidities in HIV/HCV-coinfected group compared with the group of HIV mono-infection, which suggests more intervention in this vulnerable group of patients.

Circular RNA involvement in aging: An emerging player with great potential.

Circular RNA (circRNA) is a class of newly discovered noncoding RNA (ncRNA), presenting as a special covalent loop without a 5' cap or 3' tail. Multiple biological properties of circRNA have been revealed during the past decades, such as widespread expression, high conservation, cell-specificity, tissue-specificity and developmental stage-specific expression patterns, as well as resistance to RNase R digestion. CircRNA also exhibits diverse biological functions, including regulation of host genes, alternative splicing, miRNA sponges, protein traps and even protein synthesis. Recently, a global accumulation of circRNAs during aging has been identified across different species, indicating a potential role as a causal factor in aging and age-related disease. The high stability could be one of the mechanisms contributing to this phenomenon. CircRNA could play a role in aging, such as neural aging, muscle aging, reproductive aging, skin aging, immunosenescence, visual aging and age-related diseases like Alzheimer's disease, via interaction with miRNAs, RNA binding proteins, modulation of parental gene transcription, mainly at the transcriptional and posttranscriptional levels. The present study will focus on the advancement of circRNA regarding aging and age-related diseases. We will also discuss the biogenesis, properties, biological functions, and the perspectives of circRNA.

Protective properties of glycogen synthase kinase-3 inhibition against doxorubicin-induced oxidative damage to mouse ovarian reserve.

Chemotherapy induces ovarian failure in female children and young female cancer survivors. It has been shown that doxorubicin (DOX), an antitumor drug of the anthracycline group, causes gonadotoxicity via the stimulation of oxidative stress. The inhibition of glycogen synthase kinase-3 (GSK-3) was reported to be able to regulate oxidative stress. The present study assessed whether GSK-3 inhibition confers protection to the ovary against DOX-induced oxidative stress damage. An intraperitoneal injection of DOX was used to induce oxidative damage in the mouse ovary, while the inhibition of GSK-3 was achieved by the administration of SB216763, a small and potent GSK-3 inhibitor. DOX increased the mRNA expression levels of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and the antioxidant genes heme-oxygenase-1 (HO-1) and catalase (CAT), while reducing the levels of glutathione peroxidase (GSH-Px) and superoxide dismutase-1 (SOD-1) compared with those of the control. When the GSK-3 inhibitor was combined with DOX increased more expression levels of Nrf2 mRNA and restored levels of GSH-Px and SOD-1 mRNA similar to those in the control group. DOX remarkably decreased the Nrf2 protein expression compared to that in the control, which was significantly associated with increased MDA levels. Interestingly, the SB216763 and DOX coadministration restored the Nrf2 protein expression and MDA levels to levels that were similar to those in the control. DOX significantly decreased the number of primordial, primary, preantral and antral follicles while increasing the number of atretic follicles compared to those in the control. SB216763 caused the drastic recovery of these follicles from the DOX effects. SB216763 and DOX coadministration significantly reduced the apoptotic index compared with that with DOX treatment. DOX decreased the serum AMH and E2 levels and increased the FSH levels compared to those in the controls. However, SB216763 and DOX coadministration restored AMH and E2 while decreasing the FSH levels compared to those in the DOX-treated group. In addition, SB216763 and DOX coadministration reduced the mature oocyte abnormalities that resulted from DOX-induced ovarian damage. Given these results, we suggest that GSK-3/Nrf2 is a promising protective pathway against doxorubicin-induced oxidative damage to the ovaries of females at reproductive ages. Thus, GSK-3 could be an attractive target for the research and development of new drugs for preserving ovarian function during chemotherapy.

Identification and characterization of human ovary-derived circular RNAs and their potential roles in ovarian aging.

Circular RNAs (circRNAs) have recently been shown to exert effects on multiple pathological processes by acting as miRNA sponges. However, the roles of circRNAs in ovarian senescence are largely unknown. The objective of this study was to identify the circRNAs involved in ovarian aging and predict their potential biological functions. We first performed RNA-sequencing to generate ovarian circRNA expression profiles from young (n = 3) and aging (n = 3) groups. In total, 48,220 circRNAs were identified, of which 194 circRNAs were significantly up-regulated and 207 circRNAs were down-regulated during aging (fold change > 2, P < 0.05). Bioinformatics analysis demonstrated that the metabolic process, regulated secretory pathway, oxidation-reduction process, steroid hormone biosynthesis, and insulin secretion pathways, which may be associated with ovarian aging, were significantly enriched (P < 0.05). The biological characteristics of ovary-derived circRNA, such as back-splicing, RNase R resistance, stability, and alternative splicing, were further validated. Bioinformatics predicted that most of the circRNAs harboured miRNA binding sites, of which circDDX10-miR-1301-3p/miR-4660-SIRT3 axis may be involved in the regulation of ovarian function. Our study indicates that circRNAs are aberrantly expressed in the aging ovary and may play potential roles in the development of ovarian senescence.