Mucopexy-Recto Anal Lifting (MuRAL) in managing obstructed defecation syndrome associated with prolapsed hemorrhoids and rectocele : preliminary results

Purpose: Treatment of rectocele associated with prolapsed hemorrhoids is a debated topic. Transanal stapling achieved good midterm results in patients with symptoms of obstructed defecation, nevertheless a number of severe complications have been reported. The aim of this study was to evaluate the safety and efficacy of a new endorectal manual technique in patients with obstructed defecation due to the combination of muco-hemorrhoidal prolapse and rectocele. Methods: Patients enrolled after preoperative obstructed defecation syndrome (ODS) score, defecography and anoscopy were submitted to the novel Mucopexy-Recto Anal Lifting (MuRAL) combined with a modified Block procedure, and followed up by independent observers with digital exploration 3 weeks postoperatively, and digital exploration plus anoscopy at 3, 6, and 12 months. Operative time, hospital stay, numerating rating scale (NRS), ODS, satisfaction scores, and recurrence rate were recorded. Results: Mean operative time was 35.7 minutes. Fifty-six patients completed 1-year follow-up: 7.1% had acute urinary retention, NRS score was < 3 from the third postoperative day, mean time of daily activity resumption was 12 days, none had persistent fecal urgency, 82% declared excellent/good satisfaction score, significant improvement of 6- and 12-month ODS score, no recurrence of rectocele, and 7.1% recurrence of prolapsed hemorrhoids were observed. Conclusion: MuRAL associated with modified Block technique gave no severe complications and resulted in a safe and effective approach to symptomatic rectocele associated with muco-rectal prolapse. Further randomized studies, larger series, and longer follow-up are needed. [Ann Surg Treat Res 2020;98(5):277-282

Mucopexy-recto anal lifting: a standardized minimally invasive method of managing symptomatic hemorrhoids, with an innovative suturing technique and the HemorPex System®

BACKGROUND: Conservative surgery of hemorrhoidal disease is less painful than traditional hemorrhoidectomy, and mucopexy has less risk of serious postoperative complications than stapled hemorrhoidopexy. The aim of this study was to evaluate the safety and effectiveness of a standardized, modified hemorrhoidopexy, named Mucopexy-Recto Anal Lifting (MuRAL) with the HemorPex System (HPS) in patients with symptomatic III and IV degree hemorrhoids. METHODS: Patients were enrolled from May 2013 to Dec 2015 and operated on with the MuRAL technique, based on arterial ligation and mucopexy at 6 locations, using a standardized clockwise/anti-clockwise rotation sequence of the HPS anoscope. Follow-up controls were carried out by independent observers, as follows: a digital exploration 3 weeks after the intervention, digital exploration plus proctoscopy at 3 and 12 months and repeated at a 12 months interval. Patients who did not strictly follow the postoperative controls were excluded from the study. Primary outcome measurement was the recurrence rate. Secondary measurements were: operative time, hospital stay, postoperative pain, postoperative symptoms and satisfaction score. RESULTS: We operated on 126 patients (72 males, mean age 53.9, range 29-83): 87 (69.6%) with III degree and 39 with IV degree hemorrhoids; 13 patients had a MuRAL as a revisional procedure of a previous operation for hemorrhoids. Mean duration of follow-up was 554 days (range 281-1219). Four patients were excluded from the study. One-year recurrence rate was 4.1%. The mean duration of the intervention was 29.5 minutes (range 23-60) and 92 patients (73%) were discharged during the same day of the operation. Pain VAS Score in the first, second and third postoperative day was 3.9, 2.5, and 1.9, respectively. Twenty-two patients (18%), all submitted to spinal anesthesia, had postoperative acute urinary retention. Fecal urgency, observed in 18.8% of patients at the first control, disappeared within one year after the operation. Mean time to return to normal activity was 8 days (range 5 -10). The patient satisfaction scores at one-year follow up were 31.1% excellent, 57.4% good, 7.4% fairly good and 4.1% poor. In patients with III degree hemorrhoids operative time was significantly shorter, postoperative pain better and transient fecal urgency lower than in IV degree patients. In our experience the standardization of MuRAL operation with HPS, turned out to be a safe and effective minimally invasive approach in managing symptomatic III and IV degree hemorrhoids, avoiding the risk of severe complications, with the possibility to perform a redo-MuRAL in the event of recurrence. CONCLUSIONS: In our series up to 88% of the patients reported a good, or excellent one-year satisfaction score. Further comparative randomized studies with longer follow-up period are needed

Reasons for tooth extractions and related risk factors in adult patients: a cohort study

Background: The aimof this studywas to evaluate oral status, the reasons for tooth extractions and related risk factors in adult patients attending a hospital dental practice. Methods: 120 consecutive patients ranging from23 to 91 years in age (mean age of 63.3 - 15.8) having a total of 554 teeth extracted were included. Surveys about general health status were conducted and potential risk factors such as smoking, diabetes and age were investigated. Results: a total of 1795 teeth weremissing after extraction procedures and the mean number of remaining teeth after the extraction process was 16.8 ± 9.1 per patient. Caries (52.2%) was the most common reason for extraction along with periodontal disease (35.7%). Males were more prone to extractions, with 394 of the teeth extracted out of the total of 554 (71.1%). Male sex (β = 2.89; 95% CI 1.26, 4.53; p = 0.001) and smoking habit (β = 2.95; 95% CI 1.12, 4.79; p = 0.002) were related to a higher number of teeth extracted. Age (β = -0.24; 95% CI -0.31, -0.16; p < 0.001) and diabetes (β = -4.47; 95% CI -7.61, -1.33; p = 0.006) were related to a higher number of missing teeth at evaluation time. Moreover, periodontal disease was more common as a reason of extraction among diabetic patients than among non-diabetic ones (p = 0.04). Conclusions: caries and periodontal disease were the most common causes of extraction in a relatively old study population: further screening strategies might be required for the early interception of caries and periodontal disease

Interleukin-15 is required for immunosurveillance and immunoprevention of HER2/neu-driven mammary carcinogenesis

We previously demonstrated that HER2/neu-driven mammary carcinogenesis can be prevented by an interleukin-12 (IL-12)-adjuvanted allogeneic HER2/neu-expressing cell vaccine. Since IL-12 can induce the release of interleukin-15 (IL-15), in the present study we investigated the role played by IL-15 in HER2/neu driven mammary carcinogenesis and in its immunoprevention

Mutual Antagonism between Circadian Protein Period 2 and Hepatitis C Virus Replication in Hepatocytes.

Hepatitis C virus (HCV) infects approximately 3% of the world population and is the leading cause of liver disease, impacting hepatocyte metabolism, depending on virus genotype. Hepatic metabolic functions show rhythmic fluctuations with 24-h periodicity (circadian), driven by molecular clockworks ticking through translational-transcriptional feedback loops, operated by a set of genes, called clock genes, encoding circadian proteins. Disruption of biologic clocks is implicated in a variety of disorders including fatty liver disease, obesity and diabetes. The relation between HCV replication and the circadian clock is unknown. METHODS: We investigated the relationship between HCV core infection and viral replication and the expression of clock genes (Rev-Erbα, Rorα, ARNTL, ARNTL2, CLOCK, PER1, PER2, PER3, CRY1 and CRY2) in two cellular models, the Huh-7 cells transiently expressing the HCV core protein genotypes 1b or 3a, and the OR6 cells stably harboring the full-length hepatitis C genotype 1b replicon, and in human liver biopsies, using qRT-PCR, immunoblotting, luciferase assays and immunohistochemistry. RESULTS: In Huh-7 cells expressing the HCV core protein genotype 1b, but not 3a, and in OR6 cells, transcript and protein levels of PER2 and CRY2 were downregulated. Overexpression of PER2 led to a consistent decrease in HCV RNA replicating levels and restoration of altered expression pattern of a subset of interferon stimulated genes (ISGs) in OR6 cells. Furthermore, in liver biopsies from HCV genotype 1b infected patients, PER2 was markedly localized to the nucleus, consistent with an auto-inhibitory transcriptional feedback loop. CONCLUSIONS: HCV can modulate hepatic clock gene machinery, and the circadian protein PER2 counteracts viral replication. Further understanding of circadian regulation of HCV replication and rhythmic patterns of host-hosted relationship may improve the effectiveness of HCV antiviral therapy. This would extend to hepatic viral infections the current spectrum of chronotherapies, implemented to treat metabolic, immune related and neoplastic diseas

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3 ' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality.Peer reviewe

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Benegiamo et al. identify genetic variants of the mitochondrial supercomplex assembly factor COX7A2L in the skeletal muscle of mice and humans that promote cardiorespiratory fitness.Mitochondrial respiratory complexes form superassembled structures called supercomplexes. COX7A2L is a supercomplex-specific assembly factor in mammals, although its implication for supercomplex formation and cellular metabolism remains controversial. Here we identify a role for COX7A2L for mitochondrial supercomplex formation in humans. By using human cis-expression quantitative trait loci data, we highlight genetic variants in the COX7A2L gene that affect its skeletal muscle expression specifically. The most significant cis-expression quantitative trait locus is a 10-bp insertion in the COX7A2L 3 ' untranslated region that increases messenger RNA stability and expression. Human myotubes harboring this insertion have more supercomplexes and increased respiration. Notably, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in humans. Accordingly, specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher maximal oxygen consumption, increased lean mass and increased energy expenditure. Furthermore, Cox7a2l expression in mice is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in humans and show that COX7A2L plays an important role in cardiorespiratory fitness, which could have broad therapeutic implications in reducing cardiovascular mortality

COX7A2L genetic variants determine cardiorespiratory fitness in mice and human

Mitochondrial respiratory complexes form superassembled structures called supercomplexes. We investigated the function of mitochondrial supercomplexes in human. COX7A2L is a supercomplex-specific assembly factor. By using human cis-eQTL data, we highlight a number of genetic variants in the COX7A2L gene that affect its expression in the muscle in a tissue specific manner. The most significant cis-eQTL is a 10 bp insertion in COX7A2L 3’UTR that increases mRNA expression by increasing mRNA stability. Human myotubes harbouring this insertion have higher supercomplexes and increased respiration. Importantly, increased COX7A2L expression in the muscle is associated with lower body fat and improved cardiorespiratory fitness in human. We confirm these findings in mice: specific reconstitution of Cox7a2l expression in C57BL/6J mice leads to higher VO2max, increased lean mass and increased energy expenditure. We further show that, in mice, Cox7a2l expression is induced specifically in the muscle upon exercise. These findings elucidate the genetic basis of mitochondrial supercomplex formation and function in human, and show that COX7A2L plays an important role in cardiorespiratory fitness. Enhancing cardiorespiratory fitness has broad therapeutic implications to reduce all-cause and cardiovascular mortality.This repository contains the scripts used to generate the figures in Benegiamo et al, "COX7A2L genetic variants determine cardiorespiratory fitness in mice and human&quot

The genetic background shapes disease susceptibility and reveals a specific role for mitochondrial dysfunction in the progression from NAFLD to NASH

Non-alcoholic steatohepatitis (NASH) is a global health concern without treatment. The challenge in finding effective therapies is due to the lack of good mouse models and the complexity of the disease, characterized by gene-environment interactions. We tested the susceptibility of 7 mouse strains to develop NASH. The severity of the clinical phenotypes observed varied widely across strains. PWK/PhJ mice were the most prone to develop NASH, while CAST/EiJ mice were completely resistant. Levels of transcripts and proteins present in the mitochondria as well as mitochondrial function were robustly reduced in the liver of PWK/PhJ mice, suggesting a central role of mitochondrial dysfunction in NASH progression. Importantly, the alterations in gene expression observed in PWK/PhJ mice were the closest to the human NASH. Our study exposes the limitations of using a single mouse genetic background in metabolic studies and describes a novel NASH mouse model that closely resembles the human disease