Effect of Moderate-Intense Training and Detraining on Glucose Metabolism, Lipid Profile, and Liver Enzymes in Male Wistar Rats: A Preclinical Randomized Study.

Exercise training positively regulates glucose metabolism. This study investigated the impact of training and detraining on glucose metabolism, lipid profiles, and liver enzymes. Twenty-six rats completed an initial 4-week moderate-intense training (T0-T4). Then, the animals were randomly assigned to two groups at the end of week 4: AT4: detraining for 8 weeks; AT8: training for 8 weeks and 4-week detraining. Six animals were sacrificed at T0 and T4, four animals/group at T8, and three/group at T12. The study continued for 12 weeks, and all parameters were assessed at T0, T4, T8, and T12. IPGTT significantly improved after 4 weeks of training (p < 0.01) and was further reduced in AT8 at T8. In AT8, 8-week training significantly reduced total cholesterol at T4 and T12 vs. T0 (p < 0.05), LDL at T4, T8, and T12 vs. T0 (p < 0.01), ALP at T8, T12 vs. T0 (p < 0.01), and increased HDL at T8 and ALT at T8 and T12 vs. T0 (p < 0.05). Triglycerides and hexokinase activity increased significantly at T4 and T8 (p < 0.05) and then decreased at T12 in AT8. Pyruvate and glycogen increased at T12 in AT8 vs. AT4. Eight-week training improved LPL and ATGL expressions. Training positively modulated insulin, glucose metabolism, and lipid profiles, but detraining reduced the benefits associated with the initial training.

Newly diagnosed hepatitis C infection after pancreas transplantation with multiple treatment failures.

This case represents the first report of a detected hepatitis C virus (HCV) infection following a pancreas transplantation that failed two different sofosbuvir (SOF)-based treatments. We present the case of a woman in her 30s with a history of kidney transplantation, who developed viremic symptoms 3 months after pancreas transplantation and with two subsequent negative HCV antibody tests. Further work-up revealed a positive HCV RNA test (genotype 1A, treatment naive). Two different direct-acting antiviral agents regimes with SOF failed in our case, and the patient achieved a sustained virological response with a 16-week course of glecaprevir/pibrentasvir.

MicroRNAs in the Evaluation and Potential Treatment of Liver Diseases.

Acute and chronic liver disease continue to result in significant morbidity and mortality of patients, along with increasing burden on their families, society and the health care system. This in part is due to increased incidence of liver disease associated factors such as metabolic syndrome; improved survival of patients with chronic predisposing conditions such as HIV; as well as advances in the field of transplantation and associated care leading to improved survival. The fact that one disease can result in different manifestations and outcomes highlights the need for improved understanding of not just genetic phenomenon predisposing to a condition, but additionally the role of epigenetic and environmental factors leading to the phenotype of the disease. It is not surprising that providers continue to face daily challenges pertaining to diagnostic accuracy, prognostication of disease severity, progression, and response to therapies. A number of these challenges can be addressed by incorporating a personalized approach of management to the current paradigm of care. Recent advances in the fields of molecular biology and genetics have paved the way to more accurate, individualized and precise approach to caring for liver disease. The study of microRNAs and their role in both healthy and diseased livers is one example of such advances. As these small, non-coding RNAs work on fine-tuning of cellular activities and organ function in a dynamic and precise fashion, they provide us a golden opportunity to advance the field of hepatology. The study of microRNAs in liver disease promises tremendous improvement in hepatology and is likely to lay the foundation towards a personalized approach in liver disease.

Medical and endoscopic therapies for angiodysplasia and gastric antral vascular ectasia: a systematic review.

BACKGROUND & AIMS: Few studies have compared the efficacy and complications of endoscopic or medical therapies for bleeding angiodysplasias or gastric antral vascular ectasias (GAVE). We conducted a systematic review to evaluate therapies. METHODS: We performed a PubMed search for studies (written in English from January 1, 1980, through January 1, 2013) of medical or endoscopic treatment of bleeding angiodysplasias and GAVE. Measured outcomes included levels of hemoglobin, transfusion requirements, rebleeding rates, complications, treatment failures, and overall mortality. RESULTS: We analyzed data from 63 studies that met inclusion criteria; 50 evaluated endoscopic treatment (1790 patients), 13 evaluated medical treatment (392 patients), and 12 were comparative studies. In patients with angiodysplasias, the combination of estrogen and progesterone did not significantly reduce bleeding episodes, compared with placebo (0.7/y vs 0.9/y, respectively), and increased mortality, compared with conservative therapy (33% vs 21%). A higher percentage of patients receiving octreotide were free of rebleeding at 1 and 2 years vs placebo (77% vs 55% and 68% vs 36%, respectively; P = .03). Thalidomide reduced the number of bleeding episodes (-8.96/y), compared with iron therapy (-1.38/y, P < .01), but neither treatment reduced mortality. More patients with GAVE treated by endoscopic band ligation were free from rebleeding (92%) than those treated with argon plasma coagulation (32%, P = .01). CONCLUSIONS: In a systematic review, we found a low quality of evidence to support treatment of angiodysplasias with thalidomide or the combination of estrogen and progesterone and insufficient evidence to support treatment with octreotide. There is also insufficient evidence for endoscopic therapy of angiodysplasia or GAVE. Well-designed randomized controlled trials are needed to study the efficacy and complications of medical and endoscopic treatments for patients with angiodysplasias or GAVE.

Increase in body size is associated with an increased incidence of advanced adenomatous colon polyps in male veteran patients.

BACKGROUND/AIMS: Our aim was to determine how weight change influences the development of advanced adenomas. METHODS: We performed a retrospective study of patients with adenomatous polyps (APs) on an index colonoscopy, and who also had a follow-up colonoscopy 3-5 years later. APs were evaluated for advanced features (i.e. size ≥1 cm in diameter and/or villous component and/or high-grade dysplasia). Patients were divided into 2 groups: those with no change or a reduction in their body mass index (BMI) during the interval between colonoscopies and those with an increase in BMI during the interval between colonoscopies. RESULTS: 925 patients with a history of APs were identified. Univariate analysis showed that patients with an increase in BMI had more advanced APs (28 vs. 23%, p = 0.04), and a larger mean AP size (8.0 vs. 6.8 mm, p = 0.03) than those with a no change or decreased BMI. Multiple logistic regression analysis revealed that a decrease in BMI between colonoscopies was associated with a significantly reduced risk of developing advanced APs (OR: 0.4, 95% CI: 0.37-0.5, p < 0.05). CONCLUSIONS: An increase in weight in male veterans appears to be strongly associated with the development of clinically advanced AP lesions, even after adjustment for other known polyp risk factors.

Long-term use of angiotensin converting enzyme inhibitors is associated with decreased incidence of advanced adenomatous colon polyps.

BACKGROUND: The long-term use of angiotensin converting enzyme (ACE) inhibitors may reduce the risk of developing colorectal cancer (CRC). GOAL: The aim of our study was to determine how long-term use of lisinopril influences the development of advanced adenomatous polyps (APs). STUDY: We performed a retrospective study of patients who were found to have 1 or more histologically confirmed APs on an index colonoscopy, and who also had a follow-up colonoscopy 3 to 5 years later. APs found on the follow-up colonoscopy were evaluated for location, size, number, and advanced features. Patients were divided into 2 groups: (1) those who used lisinopril continuously during the interval between colonoscopies and (2) those who were lisinopril naive. Clinical factors were evaluated for their association with advanced APs in both the groups. RESULTS: A total of 4660 patients with a history of AP were identified. There were 1760 continuous lisinopril users and 2900 nonusers. Univariate analysis showed that patients with lisinopril use had fewer right-side APs (odds ratio=0.68, P<0.001) and fewer total number of APs (P<0.001). Lisinopril users had a 41% reduced incidence of advanced APs compared with the nonusers (odds ratio=0.59, P<0.001). A Mann-Whitney U test revealed that among lisinopril users, patients with advanced APs were on a lower dose of the medication compared with patients without advanced APs (mean dose=17.2 mg vs. 20.1 mg, respectively; P<0.001). Spearman correlation analyses indicated an inverse relationship between lisinopril dosage and number of polyps (P<0.001). There was also an inverse relationship between dosage and size of polyps (P<0.001); higher dosages of lisinopril were significantly associated with smaller size of polyps. The protective effect of lisinopril was significant even when adjusted for age, body mass index, aspirin/nonsteroidal anti-inflammatory drug use, and statin use. CONCLUSIONS: The use of lisinopril was associated with a 41% reduction in the incidence of advanced APs during a period of 3 to 5 years, even after adjustment for other known polyp risk factors. We speculate that long-term ACE inhibitors use may reduce the development of CRCs by reducing the development of advanced APs.

Reduction in low-density lipoprotein cholesterol levels during statin therapy is associated with a reduced incidence of advanced colon polyps.

BACKGROUND: Elevated serum cholesterol levels may stimulate proliferation in adenomatous polyps (AP). Our aim was to determine how a reduction of low-density lipoprotein (LDL) cholesterol levels in patients taking statins influences the incidence of APs. METHODS: We performed a retrospective study of patients taking statins who were found to have > or =1 APs on an index colonoscopy, and who also had a follow-up colonoscopy within 3 to 5 years. Patients were divided into 2 groups: (1) those with > or =30% reduction in LDL levels and (2) those with < 30% reduction in LDL levels during the interval between colonoscopies. Univariate and multivariate analysis were evaluated for their association with advanced APs. RESULTS: We identified 231 patients. Univariate analysis showed that patients with > or =30% LDL reduction had fewer mean total numbers of APs (2.6 versus 3.3, P = 0.02), fewer advanced APs (14% versus 26%, P = 0.04), and smaller APs (5 mm versus 6.1 mm, P = 0.01) than those with <30% reduction in LDL. Multiple logistic regression analysis confirmed that > or =30% LDL reduction was associated with smaller APs (P < 0.01). Subjects with > or =30% LDL reduction also had a 53% reduced incidence of advanced APs (OR, 0.47; CI, 0.22-0.96; P < 0.05). These findings remained significant even when adjusted for nonsteroidal antiinflammatory drug use, age, family history of APs, and body mass index. CONCLUSIONS: A reduction in LDL levels of > or=30% during a 3- to 5-year period of statin therapy was associated with a 53% reduction in the incidence of advanced APs, even after adjustment for other known polyp risk factors.

A previous cholecystectomy increases the risk of developing advanced adenomas of the colon.

BACKGROUND: There is limited data assessing the relationship between cholecystectomy and colorectal adenomatous polyps (AP). Our aim was to determine if cholecystectomy was associated with an increased prevalence of advanced AP in male veterans. METHODS: The relationship of whether prior cholecystectomy modified the natural history of AP was investigated in a retrospective study. The patients were divided into two groups: 1) those with AP and a history of cholecystectomy, and 2) those with AP, but without a history of cholecystectomy. Factors in each group associated with advanced AP were examined by univariate analysis (UA) and stepwise logistic regression analysis to determine independent predictors of aggressive clinical characteristics of polyps. Statistical significance was determined at a P < or = 0.05. RESULTS: We identified a total of 1234 patients with AP (cases = 127, controls = 1107). The mean age of patients was 64.1 +/- 1.9 (standard deviation) years. By UA, those with a prior cholecystectomy had a greater mean number of AP (4.2 vs. 3.5; P = 0.04) and more advanced polyps (P = 0.037) than those without a cholecystectomy. By logistic regression, prior cholecystectomy was associated with more advanced AP (OR = 1.5 [1.0-2.2]; P = 0.04). Patients who had a cholecystectomy were 51% more likely to have advanced AP. There appeared to be a trend towards increased time from cholecystectomy being associated with advanced polyps (9.69 years vs. 8.99 years, P = 0.056). CONCLUSIONS: A prior cholecystectomy was independently associated with an increased risk of developing advanced AP. Also, there appeared to be a trend toward a greater prevalence of advanced lesions as postcholecystectomy time increased.

For patients with colorectal cancer, the long-term use of statins is associated with better clinical outcomes.

Statins have been found to suppress tumor cell growth and to limit the ability of tumor cells to metastasize in studies involving cell lines and animals. To explore how the long-term use of statins influences the presentation and survival of patients with colorectal cancer (CRC), we conducted a retrospective case-control study of male patients with a new diagnosis of CRC who we categorized as: (1) Statin Users who used statins continuously >/=3 years prior to the diagnosis of CRC and (2) Statin Non-Users who did not use statins. Clinical factors were analyzed by simple Chi-square and multivariate regression analysis to identify independent predictors for advanced CRC. We identified 1,309 male patients with a new diagnosis of CRC (mean age 69 +/- 1.1 (SE) years; 326 Statin Users, 983 Statin Non-Users). Compared to Statin Non-Users, Statin Users had a less advanced tumor stage (2.2 vs. 2.6; P < 0.01), a lower prevalence of metastases (OR = 0.7 [0.4-0.9, 95% CI]; P < 0.01), and a higher frequency of right-sided tumors (OR = 1.6 [1.3-2.1], 95%CI]; P < 0.01). Overall 5-year survival for Statin Users was 37% compared to 33% in Statin Non-Users (OR = 0.7 [0.6-0.9], 95%CI]; P = 0.03). In patients who present to the hospital with CRC, the long-term use of statins is associated with a less advanced tumor stage, a higher prevalence of right-sided tumors, a lower frequency of distant metastases, and a better survival rate.

Obesity is associated with an increased prevalence of advanced adenomatous colon polyps in a male veteran population.

Obesity has been associated with an increased risk for colonic adenomatous polyps (APs) and colorectal cancers, but the influence of obesity on the development of advanced APs is not clear. The purpose of this study is to determine the influence of obesity on the prevalence of advanced APs in a male veteran population. We performed a retrospective study of patients (n = 2,903) with histologically confirmed APs on an index colonoscopy. APs were evaluated for advanced features (size > or = 1 cm in diameter and/or a villous component and/or high grade dysplasia). Patients were categorized as: normal weight (BMI > 18.5 and < 25), overweight (BMI > or = 25 and < 30), and obese (BMI > or = 30). An association between clinical factors and advanced APs was sought by Kruskal-Wallis test and Pearson Chi-square. Multiple logistic regression analysis was used to determine independent predictors for advanced APs. We identified 2,903 male patients with APs (mean age 64 + 1.1(SE) years; 770 (27%) normal weight, 1,029 (35%) overweight, 1,104 (38%) obese. By univariate analysis, obese patients had a greater prevalence of advanced APs than the overweight and normal weight patients (28 vs. 23 vs. 24%, p = 0.025). Multiple logistic regression analysis confirmed the association of obesity and advanced APs (OR = 1.01, CI = 1-1.02, p = 0.04). For every one-unit increase in BMI above 30, there was a corresponding 1% increase in the frequency of finding advanced APs. Obesity in male veteran patients is associated with the finding of advanced APs on colonoscopy. We speculate that obesity may increase the risk for CRC by promoting the development of advanced APs.

The long-term use of statins is associated with a decreased incidence of adenomatous colon polyps.

BACKGROUND/AIMS: Studies have suggested that statins may protect against colorectal cancer (CRC), but it is not clear whether that protection results from effects on established adenomatous polyps (APs) or from preventing the development of new APs. We have conducted a retrospective, cohort study to explore how the long-term use of statins influences the development of new APs. METHODS: We reviewed endoscopy and pathology databases to identify patients with histologically verified APs, all of which were removed during an index colonoscopy, and who had a follow-up colonoscopy 3-5 years later. Patients were categorized as users or nonusers of statins by review of their medical and pharmacy records, and the characteristics of APs found on follow-up colonoscopy in the 2 groups was compared. RESULTS: We identified 2,626 patients (84% men, mean age 62.2 years) with APs removed during an index colonoscopy. Of 1,688 patients (35%) who used statins continuously, 583 had an AP found on follow-up colonoscopy, compared to 477 of 938 patients (51%) who did not use statins continuously [odds ratio (OR) 0.51, 95% confidence interval (CI) 0.43-0.60; p < 0.01]. Statin use was associated with a smaller mean number of polyps (2.6 vs. 3.1; p = 0.002), a smaller mean polyp size (7.1 vs. 7.9 mm; p = 0.03) and a significant reduction in the incidence of advanced APs (OR 0.74, 95% CI 0.52-0.96; p = 0.03). CONCLUSIONS: In patients with APs removed colonoscopically, long-term statin usage is associated with a decreased incidence of new and advanced APs. This suggests that statins may protect against CRC by reducing the development of new APs.

A missense mutation in pstpip2 is associated with the murine autoinflammatory disorder chronic multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory disorder that primarily affects bone but is often accompanied by inflammation of the skin and/or gastrointestinal tract. The etiology is unknown but evidence suggests a genetic component to disease susceptibility. Although most cases of CRMO are sporadic, there is an autosomal recessive syndromic form of the disease, called Majeed syndrome, which is due to homozygous mutations in LPIN2. In addition, there is a phenotypically similar mouse, called cmo (chronic multifocal osteomyelitis) in which the disease is inherited as an autosomal recessive disorder. The cmo locus has been mapped to murine chromosome 18. In this report, we describe phenotypic abnormalities in the cmo mouse that include bone, cartilage and skin inflammation. Utilizing a backcross breeding strategy, we refined the cmo locus to a 1.3 Mb region on murine chromosome 18. Within the refined region was the gene pstpip2, which shares significant sequence homology to the PSTPIP1. Mutations in PSTPIP1 have been shown to cause the autoinflammatory disorder PAPA syndrome (pyogenic arthritis, pyoderma gangrenosum and acne). Mutation analysis, utilizing direct sequencing, revealed a single base pair change c.293T --> C in the pstpip2 gene resulting in a highly conserved leucine at amino acid 98 being replaced by a proline (L98P). No other mutations were found in the coding sequence of the remaining genes in the refined interval, although a 50 kb gap remains unexplored. These data suggest that mutations in pstpip2 may be the genetic explanation for the autoinflammatory phenotype seen in the cmo mouse.