Mice with mutations in Mahogunin ring finger-1 (Mgrn1) exhibit abnormal patterning of the left-right axis.

Mahogunin Ring Finger 1 (Mgrn1) encodes a RING-containing protein with ubiquitin ligase activity that has been implicated in pigment-type switching. In addition to having dark fur, mice lacking MGRN1 develop adult-onset spongy degeneration of the central nervous system and have reduced embryonic viability. Observation of complete situs inversus in a small proportion of adult Mgrn1 mutant mice suggested that embryonic lethality resulted from congenital heart defects due to defective establishment and/or maintenance of the left-right (LR) axis. Here we report that Mgrn1 is expressed in a pattern consistent with a role in LR patterning during early development and that many Mgrn1 mutant embryos show abnormal expression of asymmetrically expressed genes involved in LR patterning. A range of complex heart defects was observed in 20-25% of mid-to-late gestation Mgrn1 mutant embryos and another 20% were dead. This finding was consistent with 46-60% mortality of mutants by weaning age. Our results indicate that Mgrn1 acts early in the LR signaling cascade and is likely to provide new insight into this developmental process as Nodal expression was uncoupled from expression of other Nodal-responsive genes in Mgrn1 mutant embryos. Our work identifies a novel role for MGRN1 in embryonic patterning and suggests that the ubiquitination of MGRN1 target genes is essential for the proper establishment and/or maintenance of the LR axis.     

Worldwide prevalence of microbial agents’ coinfection among COVID‐19 patients: A comprehensive updated systematic review and meta‐analysis

BackgroundTo provide information about pathogens’ coinfection prevalence with SARS‐CoV‐2 could be a real help to save patients’ lives. This study aims to evaluate the pathogens’ coinfection prevalence among COVID‐19 patients.MethodIn order to find all of the relevant articles, we used systematic search approach. Research‐based databases including PubMed, Web of Science, Embase, and Scopus, without language restrictions, were searched to identify the relevant bacterial, fungal, and viral coinfections among COVID‐19 cases from December 1, 2019, to August 23, 2021. In order to dig deeper, other scientific repositories such as Medrxiv were probed.ResultsA total of 13,023 studies were found through systematic search. After thorough analysis, only 64 studies with 61,547 patients were included in the study. The most common causative agents of coinfection among COVID‐19 patients were bacteria (pooled prevalence: 20.97%; 95% CI: 15.95–26.46; I ²: 99.9%) and less frequent were virus coinfections (pooled prevalence: 12.58%; 95% CI: 7.31–18.96; I ²: 98.7%). The pooled prevalence of fungal coinfections was also 12.60% (95% CI: 7.84–17.36; I ²: 98.3%). Meta‐regression analysis showed that the age sample size and WHO geographic region did not influenced heterogeneity.ConclusionWe identified a high prevalence of pathogenic microorganism coinfection among COVID‐19 patients. Because of this rate of coinfection empirical use of antibacterial, antifungal, and antiviral treatment are advisable specifically at the early stage of COVID‐19 infection. We also suggest running simultaneously diagnostic tests to identify other microbiological agents’ coinfection with SARS‐CoV‐2.     

Easy detection of 5,10-methylenetetrahydrofolate reductase 1298A/C genotype by mutagenically separated PCR assay.

BACKGROUND: 5,10-Methylenetetrahydrofolate reductase (MTHFR) plays a central role in folate metabolism. Previous studies have suggested an association between the MTHFR 1298A/C polymorphism and several diseases, such as cardiovascular and psychiatric diseases, neural tube defects, diabetes, and cancer. Currently, either PCR-restriction fragment length polymorphism (RFLP) technique or real-time PCR using Taqman assay are used to determine the MTHFR 1298 genotype. METHODS: We developed a simple and efficient approach that employs mutagenically separated PCR to genotype MTHFR 1298A/C polymorphism. Two forward mutagenic allele-specific primers of different lengths for MTHFR 1298A/C were paired with the same reverse primer in a one-tube assay to genotype 20 genomic DNA samples. RESULTS: Electrophoresis on 2.5% agarose gel showed two allele-specific fragments, a 113-bp A allele-specific and a 93-bp C allele-specific PCR product. The results were confirmed by the conventional PCR-RFLP method. CONCLUSIONS: We conclude that mutagenically separated PCR could be used as an alternative simple, reliable, and cost-effective method for the genotyping of MTHFR 1298A/C polymorphism.     

The effect of n-3 fatty acids on bone biomarkers in Iranian postmenopausal osteoporotic women: a randomized clinical trial

Recently, n-3 fatty acids are in the center of attention for their potent anti-inflammatory effects. Osteoporosis as a chronic senile disease is associated with inflammation, and the role of inflammatory mediators has been demonstrated in recent years. The beneficial effects of n-3 fatty acids on bone were proven in many animal studies, while to date, no conclusive data is available in human. The aim of this study was to evaluate the impact of n-3 fatty acids on bone biomarkers in osteoporotic postmenopausal women. Twenty-five osteoporotic postmenopausal women were recruited in the study and randomized in treatment and control groups. The patients received 900 mg n-3 fatty acid capsules or placebo per day for 6 months. Serum levels of osteocalcin, bone alkaline phosphatase (BALP), calcium, vitamin D, and parathormone and urine concentration of pyridinoline (Pyd) were measured at baseline, second month, and sixth month in both groups. In the treatment group, compared with baseline, at the second month, osteocalcin increased slightly; thereafter, it showed decrement trend until the end of the study. In the control group, it decreased all over the study. None of these changes was significant. BALP showed nonsignificant decrease from baseline over the time in both groups. Urine level of Pyd decreased significantly (P < 0.05) in the treatment group, while no significant change was seen in the control group. Serum calcium and vitamin D increased in both groups; however, changes were not significant. No significant changes were seen in calcium clearance and parathormone. In conclusion, n-3 fatty acids can decrease bone resorption; however, it could not affect bone formation significantly after 6 months treatment. Further investigations are recommended.     

Recombinant Nonstructural 3 Protein,rNS3, of Hepatitis C Virus Along With Recombinant GP96 Induce IL-12, TNFα and α5integrin Expression in Antigen Presenting Cells

Background

Hepatitis C virus (HCV) infection is the main cause of chronic liver disease and to date there has been no vaccine development to prevent this infection. Among non-structural HCV proteins, NS3 protein is an excellent goal for a therapeutic vaccine, due to its large size and less variation in conserved regions. The immunogenic properties of heat shock proteins (HSPs) for instance GP96 have prompted investigations into their function as strong adjuvant to improve innate and adaptive immunity.

Objectives

The aim of this study was to examine additive effects of recombinant GP96 (rGP96) fragments accompanied by rNS3 on expression levels of α5integrin and pro-inflammatory cytokines, IL-12 and TNFα, in Antigen Presenting Cells (APCs).

Materials and Methods

Recombinant viral proteins (rNS3 and rRGD-NS3), N-terminal and C-terminal fragments of GP96 were produced and purified from E. coli in order to treat the cells; mouse spleen Dendritic Cells (DCs) and THP-1 macrophages.

Results

Our results showed that rNT-GP96 alone significantly increases the expression level of IL-12, TNFα and α5integrin in THP-1 macrophages and DCs, while IL-12 and TNFα expression levels were unaffected by either rNS3 or rRGD-NS3. Interestingly, the co-addition of these recombinant proteins with rNT-GP96 increased IL-12, TNFα and α5integrin expression. Pearson Correlation showed a direct association between α5integrin with IL-12 and TNF-α expression.

Conclusions

we have highlighted the role of rNS3 plus rNT-GP96 mediated by α5integrin in producing IL-12 and TNFα. It can be suggested that rNT-GP96 could enhance immunity characteristic of rNS3 protein via production of pro-inflammatory cytokines.     

Prenatal Diagnosis for β-Thalassemia Major in the Iranian Province of Hormozgan

β-Thalassemias are a group of heterogenous recessive disorders common in many parts of the world. Despite the great advances in the treatment of thalassemia, there is so far no cure, but perhaps bone marrow transplantation (BMT) is a possibility. Prevention, using prenatal diagnosis and selective abortion in the cases where the fetus is found to be affected, should be considered as a sensible alternative. During the past 5 years, 112 couples have been referred to our Center for detection of their β-thalassemia (β-thal) carrier status. In this group, common and rare mutations were detected. Of these, 106 couples (94.6%) came for counseling during pregancy and six (5.4%) came before becoming pregnant. Prenatal diagnosis was performed for the 106 couples at risk. Fetal DNA was obtained from both chorionic villus sampling (CVS) (99) and amniotic fluid (). Using reverse hybridization, 64 (60.4%) were found to be heterozygous for a β-thal mutation and 24 (22.6%) were normal. Eighteen (17.0%) were found to carry an affected fetus and these pregnancies were terminated.     

ROPES eye plaque brachytherapy dosimetry for two models of <Superscript>103</Superscript>Pd seeds

Brachytherapy dose distributions are calculated for 15 mm ROPES eye plaque loaded with model Theragenics200 and IR06-¹⁰³Pd seeds. The effects of stainless steel backing and Acrylic insert on dose distribution along the central axis of the eye plaque and at critical ocular structure are investigated. Monte Carlo simulation was carried out with the Version 5 of the MCNP. The dose at critical ocular structure by considering the eye composition was calculated. Results are compared with the calculated data for COMS eye plaque loaded with Theragenics200 palladium-103 seeds and model 6711 iodine-125 seed. The air kerma strength of the IR06-¹⁰³Pd seed to deliver 85 Gy in apex of tumor in water medium was calculated to be 4.10 U/seed. Along the central axis of stainless steel plaque loaded with new ¹⁰³Pd seeds in Acrylic insert, the dose reduction relative to water is 6.9% at 5 mm (apex). Removal of the Acrylic insert from the plaque (replacing with water) did not make significantly difference in dose reduction results (~0.2%). The presence of the stainless steel backing results in dose enhancement near the plaque relative to water. Doses at points of interest are higher for ROPES eye plaque when compared to COMS eye plaque. The dosimetric parameters calculated in this work for the new palladium seed, showed that in dosimetry point of view, the IR06-¹⁰³Pd seed is suitable for use in brachytherapy. The effect of Acrylic insert on dose distribution is negligible and the main effect on dose reduction is due to the presence of stainless steel plaque backing.     

Effects of pomegranate juice consumption on oxidative stress in patients with type 2 diabetes: a single-blind,randomized clinical trial

Increased free radicals production due to hyperglycemia produces oxidative stress in patients with diabetes. Pomegranate juice (PJ) has antioxidant properties. This study was conducted to determine the effects of PJ consumption in oxidative stress in type 2 diabetic patients.

This study was a randomized clinical trial performed on 60, 40–65 years old diabetic patients.

The patients were randomly allocated either to PJ consumption group or control. Patients in PJ group consumed 200?ml of PJ daily for six weeks. Sex distribution and the mean age were not different between two groups. After six weeks intervention, oxidized LDL and anti-oxidized LDL antibodies decreased and total serum antioxidant capacity and arylesterase activity of paraoxonase increased significantly in the PJ-treated group compared to the control group. Our data have shown that six weeks supplementation of PJ could have favorable effects on oxidative stress in patients with type 2 diabetes (T2D).     

Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial

Vitamin D receptor activation is associated with improved survival in patients with chronic kidney disease, but the mechanism of this benefit is unclear. To better understand the effects of vitamin D on endothelial function, blood pressure, albuminuria, and inflammation in patients with chronic kidney disease (2 patients stage 2, remaining stage 3), we conducted a pilot trial in 24 patients who were randomly allocated equally to 3 groups to receive 0, 1, or 2 microg of paricalcitol, a vitamin D analog, orally for 1 month. Placebo-corrected change in flow mediated dilatation with a 1-microg dose was 0.5% and 0.4% with a 2-microg dose (P>0.2). At 1 month, the treatment:baseline ratio of high sensitivity C-reactive protein was 1.5 (95% CI: 1.1 to 2.1; P=0.02) with placebo, 0.8 (95% CI: 0.3 to 1.9; P=0.62) with a 1-microg dose, and 0.5 (95% CI: 0.3 to 0.9; P=0. 03) with a 2-microg dose of paricalcitol. At 1 month, the treatment:baseline ratio of 24-hour albumin excretion rate was 1.35 (95% CI: 1.08 to 1.69; P=0.01) with placebo, 0.52 (95% CI: 0.40 to 0.69; P<0.001) with a 1-microg dose, and 0.54 (95% CI: 0.35 to 0.83; P=0. 01) with a 2-microg dose (P<0.001 for between group changes). No differences were observed in iothalamate clearance, 24-hour ambulatory blood pressure, or parathyroid hormone with treatment or on washout. Thus, paricalcitol-induced reduction in albuminuria and inflammation may be mediated independent of its effects on hemodynamics or parathyroid hormone suppression. Long-term randomized, controlled trials are required to confirm these benefits of vitamin D analogs.