miR-21 antagonism reprograms macrophage metabolism and abrogates chronic allograft vasculopathy

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long-term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac-transplanted patients with CAV demonstrated that miR-21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR-21 in macrophages or the use of a specific miR-21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR-21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro-inflammatory macrophages. The aforementioned effects resulted in an increase in M2-like macrophages, which could be reverted by the addition of L-arginine. RNA-seq analysis confirmed alterations in arginase-associated pathways associated with miR-21 antagonism. In conclusion, miR-21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.     

Microbial quality of tilapia reared in fecal-contaminated ponds

The microbial quality of tilapia reared in four fecal-contaminated fishponds was investigated. One of the fishponds (TDP) received treated sewage with an average fecal coliform count of 4 x 10(3)cfu/100mL, and feed of fresh duckweed grown on treated sewage was used. The number of fecal coliform bacteria attached to duckweed biomass ranged between 4.1 x 10(2) and 1.6 x 10(4)cfu/g fresh weight. The second fishpond (TWP) received treated sewage, and the feed used was wheat bran. The third fishpond (FDP) received freshwater, and the feed used was the same duckweed. Pond 4 (SSP) received only settled sewage with an average fecal coliform count of 2.1 x 10(8)/100mL. The average counts in the fishponds were 2.2 x 10(3), 1.7 x 10(3), 1.7 x 10(2), and 9.4 x 10(3)cfu/100mL in TDP, TWP, FDP, and SSP, respectively. FDP had a significantly (P < 0.05) lower fecal coliform count than the treated sewage-fed ponds and SSP. The microbial quality of the tilapia indicated that all tissue samples except muscle tissues were contaminated with fecal coliform. Ranking of the fecal coliform contamination levels showed a decrease in the order intestine>gills>skin>liver. Poor water quality (ammonia and nitrite) in SSP resulted in statistically higher fecal coliform numbers in fish organs of about 1 log(10) than in treatments with good water quality. Pretreatment of sewage is therefore recommended.     

The Association of Frailty with Outcomes after Cancer Surgery: A Systematic Review and Metaanalysis

Background

Cancer is common in older adults, who often have concurrent frailty. Frailty is a strong predictor of adverse outcomes in surgical patients. Our objective is to systematically review the association of frailty with postoperative mortality and other adverse outcomes in adult patients who have undergone nonemergency cancer surgery.

Methods

After registration (CRD42020171163), we systematically reviewed PubMed, MEDLINE, EMBASE, and CINAHL databases to identify all studies reporting an association between a preoperative frailty measurement and a relevant outcome (primary: all-cause mortality in-hospital or within 30 days of surgery; secondary outcomes: postoperative complications, length of stay, discharge disposition, mortality between 30 days and 1 year, postoperative function, and delirium). All stages of the review were completed in duplicate. Risk of bias was assessed using the Quality in Prognostic Studies (QUIPS) tool. Metaanalysis was used to pool effect estimates using random-effects models.

Results

A total of 2877 studies were identified, and 71 were included. Frailty was significantly associated with mortality within 30 days (adjusted odds ratio (OR) 3.02, 95% confidence interval (CI) 1.77–5.15), adverse discharge disposition (adjusted OR 2.14, 95% CI 1.52–3.02), postoperative complications (adjusted OR 2.39, 95% CI 1.64–3.49), longer-term mortality (unadjusted OR 4.32, 95% CI 2.15–8.67), and length of stay (mean difference 2.30, 95% CI 1.10–3.50). The number of studies presenting adequately adjusted estimates was small. Findings may be limited due to publication bias.

Conclusions

In adults having elective cancer surgery, frailty is strongly associated with adverse health outcomes. Preoperative frailty assessment should be considered in prognostication.

     

Effects of combined erythropoietin and epidermal growth factor on renal ischaemia/reperfusion injury: a randomized experimental controlled study

What’s known on the subject? and What does the study add? It is well known that erythropoietin (EPO) ameliorates the renal injury induced by ischemia or toxins such as cisplatin and radiocontrast media. Also, epidermal growth factor (EGF) exerts a prophylactic nephroprotective effect against the deleterious consequences of the ischemia/reperfusion (I/R) injury. Nevertheless, the combined effect of both drugs remains to be further investigated. This study examined the protective effects of EPO and EGF alone and in combination against renal I/R injury and showed that EPO alone was more powerful than EGF alone and the combination of both drugs was more protective than each agent alone.

OBJECTIVE

To investigate effects of combination of erythropoietin (EPO) and epidermal growth factor (EGF) on renal ischaemia and on reactive oxygen species in a rat model.

MATERIALS AND METHODS

In all, 90 male Sprague‐Dawley rats were allocated into five groups of 18, designated: Sham; treated with right nephrectomy only; Control, subjected to left renal ischaemia for 45 min with no treatment; EPO‐treated, as the control but with EPO pretreatment; EGF‐treated, as the control but with EGF pretreatment; EPO + EGF‐treated, as the control but with EPO and EGF pretreatment. Renal function, histopathology and malondialdehyde (MDA), superoxide dismutase (SOD) and reduced glutathione (GSH) levels in kidneys were assessed at 1, 2 and 7 days after ischaemia.

RESULTS

All rats except the controls had a significant improvement in serum creatinine, creatinine clearance and fractional excretion of Na⁺; all three were significantly better in EPO + EGF group than in all other groups Histopathological examination showed marked structural damage in control rats. The tubular damage was least in the EPO + EGF group. The control group had a significant increase in MDA level and a significant decrease in SOD and GSH, while the EPO + EGF group had a marked significant reduction in MDA and increase in GSH and SOD.

CONCLUSION

The protection against ischaemia/reperfusion injury might be maximal when EPO and EGF are administered concomitantly, and their protective effect might be partly due to their antioxidant effects.     

Glutamic acid decarboxylase 65 and islet cell antigen 512/IA-2 autoantibodies in relation to human leukocyte antigen class II DR and DQ alleles and haplotypes in type 1 diabetes mellitus

The frequencies of autoantibodies against glutamic acid decarboxylase 65 (GAD65) and islet cell antigen (ICA) 512/IA-2 (512/IA-2) are functions of the specific human leukocyte antigen (HLA) in type 1 diabetes mellitus (T1D). We investigated the association of HLA class II (DR and DQ) alleles and haplotypes with the presence of GAD and IA-2 autoantibodies in T1D. Autoantibodies were tested in 88 Tunisian T1D patients and 112 age- and gender-matched normoglycemic control subjects by enzyme immunoassay. Among T1D patients, mean anti-GAD antibody titers were higher in the DRB1*030101 allele (P < 0.001), together with the DRB1*030101/DQB1*0201 (P < 0.001) and DRB1*040101/DQB1*0302 (P = 0.002) haplotypes, while lower anti-GAD titers were associated with the DRB1*070101 (P = 0.001) and DRB1*110101 (P < 0.001) alleles and DRB1*070101/DQB1*0201 (P = 0.001) and DRB1*110101/DQB1*030101 (P = 0.001) haplotypes. Mean anti-IA-2 antibody titers were higher in the DRB1*040101 allele (P = 0.007) and DRB1*040101/DQB1*0302 (P = 0.001) haplotypes but were lower in the DRB1*110101 allele (P = 0.010) and the DRB1*110101 (P < 0.001) and DRB1*110101/DQB1*030101 (P = 0.025) haplotypes. Multinomial regression analysis confirmed the positive association of DRB1*030101 and the negative association of DRB1*110101 and DQB1*030101, along with the DRB1*070101/DQB1*0201 and DRB1*110101/DQB1*030101 haplotypes, with anti-GAD levels. In contrast, only the DRB1*040101/DQB1*0302 haplotype was positively associated with altered anti-IA-2 titers. Increased GAD65 and IA-2 antibody positivity is differentially associated with select HLA class II alleles and haplotypes, confirming the heterogeneous nature of T1D.     

Neurochemical alterations following the exposure to di-n-butyl phthalate in rats

Due to its ability to cross blood brain barrier and placenta, dibutyl phthalate (di-n-butyl phthalate, DBP) is expected to cause severe side effects to the central nervous system of animals and humans. A little data is available about the potential DBP neurotoxicity; therefore, this work was designed to investigate the brain tissue injury induced by DBP exposure. Forty Wister albino rats were allocated randomly into 4 groups (10 rats each). Group 1 served as control and the rats administered with physiological saline (0.9% NaCl) orally for 12 weeks. Groups 2, 3 and 4 were orally treated with DPB (100, 250 and 500 mg/kg) respectively for 12 weeks. DBP-intoxicated rats showed a disturbance in the oxidative status in cerebral cortex, striatum and brainstem, as represented by the elevated oxidants [malondialdehyde (MDA), nitric oxide (NO), 8-hydroxy-2-deoxyguanosine (8-OHdG)] and the decreased antioxidant molecules [reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR)]. DBP also enhanced a pro-inflammatory state through increasing the release of tumor necrosis factor- α (TNF-α) and interleukin-1β (IL-1β). The increase of these cytokines was associated with the increase of pro-apoptotic proteins [Bcl-2 associated X protein (Bax) and caspase-3] and the decrease of the anti-apoptotic protein, B cell lymphoma 2 (Bcl-2). In addition, the levels of norepinephrine (NE), dopamine (DA) and acetylcholine esterase (AChE) activity were decreased. This was accompanied by the alterations in the major excitatory and inhibitory amino acids neurotransmitters levels. The present findings indicated that DBP could exert its neuronal damage through oxidative stress, DNA oxidation, neuroinflammation, activation of apoptotic proteins and altering the monoaminergic, cholinergic and amino acids transmission.

     

Molecular copro-prevalence of Cryptosporidium in Egyptian children and evaluation of three diagnostic methods

Objective

To determine molecular prevalence of Cryptosporidium in a cohort of Egyptian children and compare three diagnostic tests.

Methods

Stool samples from children with diarrhea (n=150) and from apparently healthy children (n=100) were examined for Cryptosporidium using microscopy, enzyme linked immuosorbant assay (ELISA) and nested polymerase chain reaction (nPCR).

Results

nPCR detected Cryptosporidium in 22.4% of children. Acid-fast stain and ELISA showed false negativity but 100% specificity with nPCR as gold standard.

Conclusion

Cryptosporidium is a common cause of diarrhea in children in Egypt.     

The role of antifungal therapy in the prevention of recurrent allergic fungal rhinosinusitis after functional endoscopic sinus surgery: a randomized, controlled study

Allergic fungal rhinosinusitis (AFRS) is the most common form of fungal sinus disease. Its recurrence rate is high despite numerous strategies to prevent it. We conducted a study to assess the effect of systemic and topical antifungal agents-both separately and in combination-in preventing recurrence of AFRS following functional endoscopic sinus surgery (FESS). Our initial study population was made up of 50 adults who were diagnosed with AFRS by clinical, radiologic, histopathologic, and laboratory workup and who subsequently underwent FESS. Postoperatively, these patients were randomized into 5 different treatment groups matched for sex, age, and socioeconomic status. Four of the groups received a different antifungal regimen in addition to convenient medical treatment (CMT), while a fifth group served as a control. The antifungal regimens included oral itraconazole (group A), fluconazole nasal spray (group B), combined oral itraconazole and nasal fluconazole (group C), and irrigation with a fluconazole solution through the nasal fossa (group D); the group of 10 controls (group E) received CMT only. A total of 41 patients were available for follow-up (9 mo maximum). Recurrence rates in the 5 groups were 66.7, 10.0, 14.3, 28.6, and 75.0%, respectively. Based on our findings, we conclude that treatment with topical fluconazole as either a nasal spray or an irrigation solution can significantly reduce the rate of recurrence of AFRS after FESS.     

Inhibition of cartilage degradation: a combined tissue engineering and gene therapy approach

OBJECTIVE: To determine if tissue-engineered cartilage can be protected from cytokine-induced degradation using a gene therapy approach. METHODS: Chemical and pantropic retroviral gene transfer methodologies were compared for their ability to introduce a luciferase reporter gene into adult bovine cartilage chondrocytes grown in monolayer. Pantropic retrovirus was then used to transduce these cells with human tissue inhibitor of metalloproteinases 1 (TIMP-1), and the stability of expression in monolayer or pellet culture was monitored for 6 weeks. Untransduced and TIMP-1-transduced cells were also used to tissue engineer 3-dimensional cartilage constructs that were then challenged with interleukin-1 (IL-1) for 4 weeks. Conditioned media and residual cartilage were collected for analysis of matrix components, including type II collagen and proteoglycans, and for TIMP-1 production and matrix metalloproteinase (MMP) activity. RESULTS: Chemical transfection of adult bovine chondrocytes gave rise to short-lived reporter expression that was virtually undetectable after 4 weeks of culture. In contrast, pantropic retroviral transduction gave rise to stable expression that persisted at a high level for at least 6 weeks. Pantropic transduction of the cells with TIMP-1 gave rise to similar long-term expression, both in monolayer and pellet cultures. TIMP-1-transduced tissue-engineered cartilage also retained TIMP-1 expression for an additional 4 weeks of culture in the presence of IL-1. Compared with control samples, TIMP-1-transgenic cartilage resisted the catabolic effects of IL-1, with MMP activity reduced to basal levels and a decreased loss of type II collagen. CONCLUSION: Pantropic retroviral transduction permits long-term expression of potentially therapeutic transgenes in adult tissue-engineered cartilage. While TIMP-1 transduction could be used to prevent collagen breakdown, alternative transgenes may be necessary to protect cartilage proteoglycans.     

The ameliorative role of Physalis pubescens L. against neurological impairment associated with streptozotocin induced diabetes in rats

Metabolic Brain Disease - Neuropathy is considered a critical complication of diabetes mellitus (DM). Scientific studies are needed to relieve these painful complications. The current study aims to...