Effectiveness and safety of 1L PEG-ASC preparation for colonoscopy in patients with inflammatory bowel diseases.

INTRODUCTION: The effectiveness of bowel cleansing is a key element for high-quality colonoscopy. Recently, a 1 L polyethylene glycol plus ascorbate (PEG-ASC) solution has been introduced, but effectiveness and safety of this preparation have not been assessed in IBD patients. This study aims to evaluate effectiveness and safety of 1 L PEG-ASC solution in patients with IBD compared to controls. METHODS: We retrospectively analysed prospectively collected data on a cohort of 411 patients performing a colonoscopy after preparation with 1 L PEG-ASC, consecutively enrolled in 5 Italian centres. RESULTS: Overall, 185/411 (45%) were patients with IBD and 226/411 (55%) served as controls. A significantly higher cleansing success was achieved in IBD patients (92.9% vs 85.4%, p = 0.02). The multiple regression model showed that presence of IBD (OR=2.514, 95%CI=1.165-5.426; P = 0.019), lower age (OR=0.981, 95%CI=0.967-0.996; P = 0.014), split preparation (OR=2.430, 95%CI=1.076-5.492; P = 0.033), absence of diabetes (OR=2.848, 95%CI=1.228-6.605; P = 0.015), and of chronic constipation (OR=3.350, 95%CI=1.429-7.852; P = 0.005), were independently associated with cleansing success. The number of treatment-emergent adverse events (TEAEs) (51 vs 62%, p = 0.821), and of patients with TEAEs (22.2% vs 21.2%, p = 0.821), were similar in IBD patients and in controls, respectively. CONCLUSIONS: Results from this study support the effectiveness and safety of 1 L PEG-ASC solution in IBD patients, which may improve the definition of endoscopic outcomes both in Crohn's disease and ulcerative colitis.

Azathioprine for prevention of clinical recurrence in Crohn's disease patients with severe endoscopic recurrence: an IG-IBD randomized double-blind trial.

OBJECTIVE: The recurrence of Crohn's Disease after ileo-colonic resection is a crucial issue. Severe endoscopic lesions increase the risk of developing early symptoms. Prevention and treatment of post-operative Endoscopic Recurrence (ER) have been studied with conflicting results. We compare effi cacy of azathioprine (AZA) vs. high-dose 5-aminosalicylic acid (5-ASA) in preventing clinical recurrence and treating severe post-operative ER. PATIENTS AND METHODS: We performed a 1-year multicenter randomized double-blind double-dummy trial. Primary end-points were endoscopic improvement and therapeutic failure (clinical recurrence or drug discontinuation due to lack of efficacy or adverse events) 12 months after randomization. We also performed a post-trial analysis on symptomatic and endoscopic outcomes 10 years after the beginning of the trial, with a median follow-up of 60 months. RESULTS: Therapeutic failure occurred in 8 patients (17.4%) within 12 months from randomization, with no significant difference between patients treated with 5-ASA (20.8%, 5 patients) and those with AZA (13.6%, 3 patients). Therapeutic failure was due to clinical recurrence in the 5-ASA group and to adverse events in the AZA group. Endoscopic improvement at 12 months was observed in 8 patients, 2 (11.8%) in the 5-ASA group and 6 (30%) in the AZA group. No serious adverse event was recorded. At the post-trial analysis (median follow-up 60 months), 47.8% (22/46) of patients experienced clinical recurrence: 54.2% (13/24) in the 5-ASA group and 40.9% (9/22) in the AZA group, p=0.546. Patients treated with AZA had lower risk of drug escalation. Clinical recurrence was associated with smoking (p=0.031) and previous surgery (p=0.003). CONCLUSIONS: Our trial indicates that there was no difference in terms of treatment failure between 5-ASA and AZA in patients with severe ER. The main limit of AZA is its less favorable safety profile.

Effectiveness and safety of NER1006 versus standard bowel preparations: A meta-analysis of randomized phase-3 clinical trials.

BACKGROUND: A 1 L PEG-based preparation for colonoscopy (NER1006) has been recently developed. AIMS: We conducted a meta-analysis of randomized controlled trials (RCTs) to explore the effectiveness and safety of NER1006 versus traditional preparations. METHODS: PubMed/Medline and Embase were systematically searched through January 2020 for phase-3 RCTs comparing NER1006 versus standard preparations. RESULTS: Three RCTs (1879 participants) met the inclusion criteria and were included. The analysis showed a higher cleansing success for NER1006 compared standard preparations (OR=1.28; 95% CI 1.00-1.62; p = 0.047, I2=0%) as well as a greater high-quality cleansing of the right colon (OR=2.13; 95% CI 1.16-3.94; p = 0.015, I2=76.0%) when assessed by the Harefield Cleansing Scale (HCS). The pooled estimate of the NER1006 effect on ADR showed a higher, although not significant, ADR of the right colon (OR=1.19; 95% CI 0.73-1.92; p = 0.485, I2=53%). When considering the impact of NER1006 on mild to moderate treatment-emergent adverse events (TEAEs), we observed a significant pooled estimate of TEAEs (OR=2.31; 95% CI 1.82-2.94; p<0.001, I2=0%). CONCLUSIONS: When compared to traditional preparations, NER1006 showed a better overall cleansing of the colon as well as a greater high-quality cleansing of the right colon, with comparable ADR. A higher incidence of mild to moderate TEAEs was observed for NER1006, in the absence of serious adverse events.

Histopathology of the gut in rheumatic diseases.

The gastrointestinal tract regulates the trafficking of macromolecules between the environment and the host through an epithelial barrier mechanism and is an important part of the immune system controlling the equilibrium between tolerance and immunity to non-self-antigens. Various evidence indicates that intestinal inflammation occurs in patients with rheumatic diseases. In many rheumatic diseases intestinal inflammation appears to be linked to dysbiosis and possibly represents the common denominator in the pathogenesis of different rheumatic diseases. The continuative interaction between dysbiosis and the intestinal immune system may lead to the aberrant activation of immune cells that can re-circulate from the gut to the sites of extraintestinal inflammation as observed in patients with ankylosing spondylitis. The exact contribution of genetic factors in the development of intestinal inflammation in rheumatic diseases needs to be clarified.

Pathogenesis of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is a chronic, inflammatory disorder of unknown cause, almost exclusively occurring in people aged over 50 and often associated with giant cell arteritis. The evidence that PMR occurs almost exclusively in individuals aged over 50 may indicate that age-related immune alterations in genetically predisposed subjects contribute to development of the disease. Several infectious agents have been investigated as possible triggers of PMR even though the results are inconclusive. Activation of the innate and adaptive immune systems has been proved in PMR patients as demonstrated by the activation of dendritic cells and monocytes/macrophages and the altered balance between Th17 and Treg cells. Disturbed B cell distribution and function have been also demonstrated in PMR patients suggesting a pathogenesis more complex than previously imagined. In this review we will discuss the recent findings regarding the pathogenesis of PMR.

Non-Invasive Assessment of Liver Injury in Non-Alcoholic Fatty Liver Disease: A Review of Literature.

NAFLD (Non-Alcoholic Fatty Liver Disease) is an increasingly significant public health issue, regarded as the most relevant liver disease of the twenty-first century. Approximately 20%-30% of NAFLD subjects develop a NASH (Non-Alcoholic Steato-Hepatitis), a condition which can potentially evolve to liver cirrhosis and hepatocellular carcinoma. For these reasons a proper evaluation of liver damage is a key point for diagnosis and prognosis and liver biopsy still remains the "gold standard" procedure both for discrimination between steatosis and steatohepatitis and assessment of the degree of liver fibrosis. Nonetheless, given it is an invasive, painful and costly procedure, a great research efforts have been made in order to develop non-invasive methods for the assessment of NAFLD presence and/or severity by serum markers and imaging techniques. In this review we aimed to perform a comprehensive review of the literature about strengths and weaknesses of the main tools available for the non-invasive assessment of NAFLD patients.

PNPLA3 rs738409 I748M is associated with steatohepatitis in 434 non-obese subjects with hepatitis C.

BACKGROUND: The PNPLA3/Adiponutrin rs738409 C/G single nucleotide polymorphism is associated with the severity of steatosis, steatohepatitis and fibrosis in patients with non-alcoholic fatty liver disease, as well as the severity of steatosis and fibrosis in patients with chronic hepatitis C (CHC). AIM: To test in genotype 1(G1)-CHC patients, the putative association between the PNPLA3 variant and histological features of steatohepatitis, as well as their impact on the severity of fibrosis. METHODS: Four hundred and thirty-four consecutively biopsied Caucasian G1-CHC patients were genotyped for PNPLA3 rs738409, its effect evaluated by using an additive model. Histological features of steatohepatitis in CHC were assessed using the Bedossa classification. Hepatic expression of PNPLA3 mRNA was evaluated in 63 patients. RESULTS: The prevalence of steatohepatitis increased from 16.5% in patients with PNPLA3 CC, to 23.2% in CG and 29.2% in the GG genotype (P = 0.02). By multiple logistic regression, PNPLA3 genotype (OR 1.54, 95% CI 1.03-2.30, P = 0.03), together with age (OR 1.03, 95% CI 1.00-1.05, P = 0.02), BMI ≥ 30 (OR 2.06, 95% CI 1.04-4.10, P = 0.03) and homoeostasis model assessment (HOMA, OR 1.18, 95% CI 1.04-1.32, P = 0.006) were independently linked to steatohepatitis. When stratifying for obesity, PNPLA3 was associated with NASH in non-obese patients only (12.0% in CC vs. 18.3% in CG vs. 27.3% in GG, P = 0.01), including after correction for metabolic confounders (OR 2.06, 95% CI 1.26-3.36, P = 0.004). We showed an independent association between steatohepatitis (OR 2.05, 95% CI 1.05-4.02, P = 0.003) and severe fibrosis. Higher liver PNPLA3 mRNA was associated both with the severity of steatosis (adjusted P = 0.03) and steatohepatitis after adjusting for gender, age, BMI and HOMA (P = 0.002). CONCLUSION: In patients with genotype 1 hepatitis C, the PNPLA3 G variant is associated with a higher risk of steatosis severity and steatohepatitis, particularly among non-obese subjects.

Acute change of titin at mid-sarcomere remains despite 8 wk of plyometric training.

The purpose of this study was to investigate skeletal muscle changes induced by an acute bout of plyometric exercise (PlyEx) both before and after PlyEx training, to understand if titin is affected differently after PlyEx training. Healthy untrained individuals (N = 11) completed the 1stPlyEx (10 × 10 squat-jumps, 1-min rest). Thereafter, six subjects completed 8 wk of PlyEx, while five controls abstained from any jumping activity. Seven days after the last training session, all subjects completed the 2ndPlyEx. Blood samples were collected before and 6 h and 1, 2, 3, and 4 days after each acute bout of PlyEx, and muscle biopsies 4 days before and 3 days after each acute bout of PlyEx. The 1stPlyEx induced an increase in circulating myoglobin concentration. Muscle sample analysis revealed Z-disk streaming, a stretch or a fragmentation of titin (immunogold), and increased calpain-3 autolysis. After training, 2ndPlyEx did not induce Z-disk streaming or calpain-3 activation. The previously observed post-1stPlyEx positional change of the titin COOH terminus was still present pre-2ndPlyEx, in all trained and all control subjects. Only two controls presented with Z-disk streaming after 2ndPlyEx, while calpain-3 activation was absent in all controls. Eccentric explosive exercise induced a stretch or fragmentation of titin, which presented as a positional change of the COOH terminus. Calpain-3 activation does not occur when titin is already stretched before explosive jumping. Enzymatic digestion results in titin fragmentation, but since an increase in calpain-3 autolysis was visible only after the 1stPlyEx acute bout, fragmentation cannot explain the prolonged positional change.

Recovery of damaged skeletal muscle in mdx mice through low-intensity endurance exercise.

The lack of dystrophin in mdx mice leads to cycles of muscle degeneration and regeneration processes. Various strategies have been proposed in order to reduce the muscle-wasting component of muscular dystrophy, including implementation of an exercise programme. The aim of this study was to examine how low-intensity endurance exercise affects the degeneration-regeneration process in dystrophic muscle of male mdx mice. Mice were subjected to low-intensity endurance exercise by running on a motorized Rota-Rod for 5 days/week for 6 weeks. Histomorphological analysis showed a significant reduction of measured inflammatory-necrotic areas in both gastrocnemius and quadriceps muscle of exercised mdx mice as compared to matched sedentary mdx mice. The degenerative-regenerative process was also evaluated by examining the protein levels of connexin 39 (Cx39), a specific gene expressed in injured muscles. Cx39 was not detected in sedentary wild type mice, whereas it was found markedly increased in sedentary mdx mice, revealing active muscle degeneration-regeneration process. These Cx39 protein levels were significantly reduced in muscles of mdx mice exercised for 30 and 40 days, revealing together with histomorphological analysis a strong reduction of degeneration process in mice subjected to low-intensity endurance exercise. Muscles of exercised mdx mice did not show significant changes in force and fatigue resistance as compared to sedentary mdx mice. Overall in this study we found that specific low-intensity endurance exercise induces a beneficial effect probably by reducing the degeneration of dystrophic muscle.

Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients.

Lower 25-hydroxyvitamin D [25(OH)D] serum levels have been associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients (G1CHC). In addition, a recent genome-wide study identified genetic variants (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D-binding protein, GC) affecting 25(OH)D serum levels in healthy populations. We aimed to assess the association between vitamin D serum levels and its genetic determinants, with the severity of liver fibrosis. Two hundred and sixty patients with biopsy-proven G1CHC were consecutively evaluated. The 25(OH)D serum levels were measured by high-pressure liquid chromatography. All patients were genotyped for DHCR7 rs12785878, CYP2R1 rs10741657 and GC rs7041 single nucleotide polymorphisms. DHCR7 GG genotype (P = 0.003) and the severity of fibrosis (P = 0.03) were independent factors associated with lower 25(OH)D serum levels in multiple linear regression analysis. Interestingly, 53.8% (7/13) of patients with DHCR7 GG genotype had severe liver fibrosis, compared to 27.1% (67/247) of those with DHCR7 TT/TG genotype (P = 0.03). By multivariate logistic regression analysis, severe fibrosis was independently associated with older age (OR, 1.056; 95% CI, 1.023-1.089, P = 0.001), low cholesterol (OR, 0.984; 95% CI, 0.974-0.994, P = 0.002), high triglycerides (OR, 1.008; 95% CI, 1.002-1.015, P = 0.01), low 25(OH)D (OR, 0.958; 95% CI, 0.919-0.999, P = 0.04), DHCR7 GG genotype (OR, 4.222; 95% CI, 1.106-16.120; P = 0.03), moderate-severe steatosis (OR, 2.588; 95% CI, 1.355-4.943; P = 0.004) and moderate-severe necroinflammatory activity (grading) (OR, 2.437; 95% CI, 1.307-4.763; P = 0.001). No associations were found between liver fibrosis and both CYP2R1 and GC genotypes. In patients with G1CHC, GG homozygosis for DHCR7 gene and lower 25(OH)D levels are independently associated with the severity of liver fibrosis.

High sCD36 plasma level is associated with steatosis and its severity in patients with genotype 1 chronic hepatitis C.

Soluble CD36 (sCD36) plasma levels, a known marker of cardiometabolic disorders, are associated with surrogate markers of steatosis, while experimental and human studies show a link between CD36 expression in the liver and steatosis. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of sCD36 plasma levels with host and viral factors and sustained virological response (SVR). One hundred and seventy-five consecutive biopsy-proven patients were studied. sCD36 plasma levels were assessed by an in-house ELISA. All biopsies were scored by one pathologist for staging and grading (Scheuer) and graded for steatosis, which was considered moderate-severe if ≥20%. Patients underwent standard of care therapy with pegylated interferon and ribavirin. The severity of steatosis progressively increased according to sCD36 quartiles (P = 0.02); total and low-density lipoprotein (LDL) cholesterol levels were significantly higher in patients in the lower quartile compared to all the others. Gamma-glutamyl transferase (P = 0.02), homoeostasis model assessment (HOMA) score (P = 0.002) and sCD36 (P = 0.04) were independently associated with the severity of steatosis as continuous variable. Multivariate logistic regression analysis showed that HOMA (OR 1.243, 95% CI 1.04-1.484, P = 0.01) and sCD36 (OR 1.445, 95%CI 1.135-1.839, P = 0.003) were independently linked to steatosis ≥20%. No association was found between sCD36 and SVR. CD36 is linked to steatosis and insulin resistance in patients with G1 CHC, but does not predict response to treatment. The potential of sCD36 as a surrogate marker of steatosis should be further investigated.

Current evidence that exercise can increase the number of adult stem cells.

The number of adult stem cells (ASCs) is very small, limiting the regenerative potential of tissues. One of the most studied ASCs in humans is the satellite cell (SC), which proliferates and increases pool size under exercise stress and muscle damage. This review examines the growth factor response to specific types of exercise to show the potential of exercise to stimulate not only SC self-renewal, but also other ASCs. We postulate that the same factors that stimulate a high proliferation of SCs in skeletal muscle after physical exercise should also stimulate the proliferation of ASCs in the tissue in which they reside, such as heart, bone, liver and etc. Regular exercise should be promoted, not only for disease prevention, but to maintain a high ASCs reserve and progenitor cell potential for rapid activation in response to future stressors and damage.

Satellite cell count, VO(2max) , and p38 MAPK in inactive to moderately active young men.

Satellite cells (SCs) are responsible for muscle repair following strenuous exercise or injury. SC responses to intervention have been studied, but most studies do not discuss or take into account the substantial variability in SC number among young individuals. We hypothesized that an active lifestyle reflected in higher VO(2max) may be associated with greater SC number. As training alters basal p38-mitogen-activated protein kinase (MAPK) activity, which is associated with SC proliferation, SC count may also correlate with this stress signaling kinase. Muscle biopsies from vastus lateralis of eight male participants were analyzed for fiber type, myogenin, and p38/phospho-p38 MAPK using SDS-PAGE and Western blotting. Immunofluorescence was used to detect Pax7(+) SCs. Two weeks following the biopsy, subjects underwent an incremental treadmill test to determine VO(2max) . A strong positive correlation (P = 0.0087) was found between the number of Pax7(+) nuclei and VO(2max) . Pax7(+) cell number correlated negatively with phospho-p38/p38 MAPK (P = 0.0006), but had no correlation with fiber type or myogenin. SC number is proportional to VO(2max) , and hence it can be postulated that higher levels of physical activity activate SC proliferation but not fusion, underlining the relevance of exercise in stimulating SC pool size even without injury.

Photoprotection beyond ultraviolet radiation--effective sun protection has to include protection against infrared A radiation-induced skin damage.

Solar radiation is well known to damage human skin, for example by causing premature skin ageing (i.e. photoageing). We have recently learned that this damage does not result from ultraviolet (UV) radiation alone, but also from longer wavelengths, in particular near-infrared radiation (IRA radiation, 760-1,440 nm). IRA radiation accounts for more than one third of the solar energy that reaches human skin. While infrared radiation of longer wavelengths (IRB and IRC) does not penetrate deeply into the skin, more than 65% of the shorter wavelength (IRA) reaches the dermis. IRA radiation has been demonstrated to alter the collagen equilibrium of the dermal extracellular matrix in at least two ways: (a) by leading to an increased expression of the collagen-degrading enzyme matrix metalloproteinase 1, and (b) by decreasing the de novo synthesis of the collagen itself. IRA radiation exposure therefore induces similar biological effects to UV radiation, but the underlying mechanisms are substantially different, specifically, the cellular response to IRA irradiation involves the mitochondrial electron transport chain. Effective sun protection requires specific strategies to prevent IRA radiation-induced skin damage.

Increased expression of titin in mouse gastrocnemius muscle in response to an endurance-training program.

Titin, a sarcomeric giant protein, plays crucial roles in muscle assembly, elasticity and stability. Little is known about titin adaptation to endurance exercise. We studied the effects of endurance training on titin expression in mouse gastrocnemius muscles (MGM). Sixty-three ten-week-old male Swiss mice were divided into seven groups. Four groups were composed of untrained control animals (C0, C15, C30, C45) instead the other three included mice trained for 15 (T15), 30 (T30) and 45 (T45) days by treadmill. The training protocol was mainly aerobic, characterized by moderate-intensity, rhythmic and continuous exercises. Titin expression was determined by immunohistochemistry on MGM sections. Results revealed a significant reduction in body weight of the T45 mice and a significant increase in titin expression (% titin immunoreactivity median [range] = 41.11 [20-60] vs. 30.00 [10-50]). It is postulated that the up-regulation of titin expression is an adaptative mechanism to increase muscle elasticity and stability in response to the high number of stretch-shorten cycles during endurance training. Such a mechanism may be important for minimizing muscle energy consumption and improving performance during running.

Increased cx43 and angiogenesis in exercised mouse hearts.

Several studies focused on the macroscopic architecture of increased cardiac wall induced by exercise training. Our goal was to evaluate myocardiocyte, interstitial and vascular component, and connexin-43 expression in endurance-trained mouse hearts. Sixty-three 10-week-old male Swiss mice were divided into four sedentary groups (C0, C15, C30 and C45) and three groups exercised respectively for 15 (T15-D; running intensity [RI]: 3.18 m/min; running duration [RD]: 75 min/first week and 150 min/second week), 30 (T30-D; RI: 3.96 m/min; RD: 150 min/third week and 225 min/fourth week) and 45 days (T45-D; RI: 3.96 m/min and 4.8 m/min, respectively for the fifth and sixth week; RD: 300 min) on a treadmill. Morphometric analyses were performed to quantify myocardiocyte size and number, and the capillary and interstitial connective tissue (ICT) area. We assessed the expression of ventricle myosin light chain-II, vimentin and connexin-43 by western blot analyses. Our results showed a hypertrophy of the interventricular septum and left ventricle in T30-D and T45-D mice that was not due to variations in myofibrillar content, myocardiocyte size and number, or ICT quantity but to a significant increase in the capillary area. The microvascular remodeling was associated with vimentin increased expression in ICT cells and connexin-43 upregulation. The first phenomenon might be related to an enhanced request of remodeling and growth factors; the second suggests a new role of connexin-43 in cardiac angiogenesis.