Persistent Changes in Stress-Regulatory Genes in Pregnant Women or Children Exposed Prenatally to Alcohol.

BACKGROUND: We have recently shown that binge or heavy levels of alcohol drinking increase deoxyribonucleic acid (DNA) methylation and reduce gene expression of proopiomelanocortin (POMC) and period 2 (PER2) in adult human subjects (Gangisetty et al., Alcohol Clin Exp Res, 43, 2019, 212). One hypothesis would be that methylation of these 2 genes is consistently associated with alcohol exposure and could be used as biomarkers to predict risk of prenatal alcohol exposure (PAE). Results of the present study provided some support for this hypothesis. METHODS: We conducted a series of studies to determine DNA methylation changes in stress regulatory genes proopiomelanocortin (POMC) and period 2 (PER2) using biological samples from 3 separate cohorts of patients: (i) pregnant women who consumed moderate-to-high levels of alcohol or low/unexposed controls, (ii) children with PAE and non-alcohol-exposed controls, and (iii) children with PAE treated with or without choline. RESULTS: We found pregnant women who consumed moderate-to-high levels of alcohol and gave birth to PAE children had higher DNA methylation of POMC and PER2. PAE children also had increased methylation of POMC and PER2. The differences in the gene methylation of PER2 and POMC between PAE and controls did not differ by maternal smoking status. PAE children had increased levels of stress hormone cortisol and adrenocorticotropic hormone. Choline supplementation reduced DNA hypermethylation and increased expression of POMC and PER2 in children with PAE. CONCLUSIONS: These data suggest that PAE significantly elevates DNA methylation of POMC and PER2 and increases levels of stress hormones. Furthermore, these results suggest the possibility that measuring DNA methylation levels of PER2 and POMC in biological samples from pregnant women or from children may be useful for identification of a woman or a child with PAE.

Efficacy of a Gel Containing Polihexanide and Betaine in Deep Partial and Full Thickness Burns Requiring Split-thickness Skin Grafts: A Noncomparative Clinical Study.

Despite overall advances in burn therapy, wound infection remains one of the leading causes of morbidity and mortality in patients with severe burn injuries. This prospective, multicenter, noncomparative clinical trial was conducted to assess the efficacy and safety of Prontosan® Wound Gel X (PWX), a gel containing polihexanide and betaine, for moistening and cleansing in deep tissue burn wounds requiring split-thickness skin grafting. Patients with deep partial or full thickness burn wounds requiring split-thickness skin grafting were treated with the gel to evaluate its tolerability and safety as well as graft take and the healing of the skin graft. Target wounds were assessed clinically and by using a photo-planimetric analyzing software for re-epithelialization. From 04/2012 to 05/2015, burn patients from three burn centers in Germany were screened for the study, of which 51 patients met the inclusion criteria. Predominantly deep partial thickness burn wounds were found (88.2 %). Except for one graft failure, all patients reached complete re-epithelialization after one (n = 14), two (n = 31), or three (n = 5) administrations of the gel. The median time to complete graft take was 7 days and was below the average healing time reported in comparable studies. No wound infection or erythema occurred. This is the first study to document the outcomes of deep partial and full thickness burns treated with PWX for moistening and cleansing. The gel was shown to be efficacious, safe, and well tolerated for use in burn wounds requiring split-thickness skin grafts.

An Extract of Russian Tarragon Prevents Obesity-Related Ectopic Lipid Accumulation.

SCOPE: The primary disorder underlying metabolic syndrome is insulin resistance due to excess body weight and abdominal visceral fat accumulation. In this study, it is asked if dietary intake of an ethanolic extract from Russian tarragon (Artemisia dracunculus L., termed PMI5011), shown to improve glucose utilization by enhancing insulin signaling in skeletal muscle, could prevent obesity-induced insulin resistance, skeletal muscle metabolic inflexibility, and ectopic lipid accumulation in the skeletal muscle and liver. METHODS AND RESULTS: Male wild-type mice are fed a high-fat diet alone or supplemented with PMI5011 (1% w/w) over 3 months. Dietary intake of PMI5011 improved fatty acid oxidation and metabolic flexibility in the skeletal muscle, reduced insulin levels, and enhanced insulin signaling in the skeletal muscle and liver independent of robust changes in expression of factors that control fatty acid oxidation. This corresponds with significantly reduced lipid accumulation in the skeletal muscle and liver, although body weight gain is comparable to a high-fat diet alone. CONCLUSION: Previous studies showed that PMI5011 enhances insulin sensitivity in the setting of established obesity-induced insulin resistance. The current study demonstrates that dietary intake of PMI5011 prevents high-fat diet-induced insulin resistance, metabolic dysfunction, and ectopic lipid accumulation in the skeletal muscle and liver without reducing body weight.

Effect of liraglutide on ectopic fat in polycystic ovary syndrome: A randomized clinical trial.

Women with polycystic ovary syndrome (PCOS) were treated with the GLP-1 receptor agonist liraglutide to investigate the effect on liver fat content, visceral adipose tissue (VAT) and the prevalence of nonalcoholic fatty liver disease (NAFLD). In a double-blind, placebo-controlled, randomized clinical trial 72 women with PCOS, with a BMI > 25 kg/m2 and/or insulin resistance, were treated with liraglutide or received placebo 1.8 mg/d (2:1) for 26 weeks. Liver fat content was assessed by 1 HMR spectroscopy, VAT by MRI, body composition by DXA, and glucose metabolism by oral glucose tolerance test. Compared with placebo, liraglutide treatment reduced body weight by 5.2 kg (5.6%), liver fat content by 44%, VAT by 18%, and the prevalence of NAFLD by two-thirds (all P < .01). Sex-hormone-binding-globulin (SHBG) levels increased by 19% (P = .03), and free testosterone decreased by 19% (P = .054). HbA1c, fasting glucose and leptin were reduced (all: P < .05), whereas measures of insulin resistance, adiponectin and glucagon did not change. In conclusion, 26 weeks of liraglutide treatment in PCOS resulted in significant reductions in liver fat content, VAT and the prevalence of NAFLD.

Cerebral venous thrombosis as the first presentation of classical homocystinuria in an adult patient.

A 30-year-old woman presented with severe headache, dysarthria and right hemiparesis. She was treated for suspected viral encephalopathy and recovered over the following weeks although the headaches persisted. Two months later she was treated in-hospital for pulmonary embolism. The following year she was readmitted for increased frequency of headaches and was given a diagnosis of migraine. A subsequent MRI head scan was suggestive of longstanding venous sinus infarcts and neuroradiology review concluded that encephalitis had been the incorrect initial diagnosis. Subsequent investigations for an underlying cause of the two episodes of venous thrombosis revealed a total homocysteine level of >350 µmol/L (<15 µmol/L). An underlying diagnosis of homocystinuria secondary to cystathionine ß-synthase deficiency was made although this metabolic condition is normally recognised in childhood. Treatment with pyridoxine and betaine normalised her homocysteine levels and she has had no further thrombotic event since.

Glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with non-alcoholic fatty liver disease: Beneficial effects of supplementation with microalgae Chlorella vulgaris: A double-blind placebo-controlled randomized clinical trial.

BACKGROUND: Chlorella vulgaris (C. vulgaris) is reported to improve dyslipidemia and hypertension; however, its effect on inflammatory biomarkers and insulin resistance has not been noticed thus far. Non-alcoholic fatty liver disease (NAFLD) as a hepatic symptom of metabolic syndrome is strongly associated with insulin resistance and inflammation. AIM OF THE STUDY: In the current interventional trial, we aimed to study the effects of C. vulgaris supplementation on glucose homeostasis, insulin resistance and inflammatory biomarkers in patients with NAFLD. METHODS: Seventy NAFLD patients confirmed by ultra-sonographic findings were randomly assigned into intervention group (four 300 mg tablets of C. vulgaris) or placebo group (four 300 mg tablets of placebos) for 8 weeks. Anthropometric measurements, liver enzymes, fasting serum glucose (FSG), insulin, high sensitive C-reactive protein (hs-CRP) and tumor necrosis factor-alpha (TNF-α) were assessed and homeostatic model assessment (HOMA) score for insulin resistance was estimated before and after the intervention. RESULTS: Anthropometric measurements decreased significantly in both group (p < 0.001). However, mean reduction in weight was significantly higher in C. vulgaris - treated group compared to placebo group. Serum concentrations of liver enzymes, FSG and hs-CRP also significantly decreased and serum insulin concentration and HOMA score increased significantly only in C. vulgaris-treated group (P < 0.001, P < 0.006 and P < 0.025, respectively). Mean change in serum glucose and TNF-α levels were significant between the groups even after adjusting for the serum insulin and baseline values of variables (P = 0.014, P = 0.005, P = 0.014, respectively); between-group differences were not significant for the other variables by the end of study. CONCLUSION: To our finding, C. vulgaris supplementation could be considered as an adjunctive therapy to decrease weight and improve glycemic status and reducing hs-CRP as well as improving liver function in patients with NAFLD. IRCT NUMBER: 201202233320N7.

Homocysteinemia due to MTHFR deficiency in a young adult presenting with bilateral lens subluxations.

The most common cause of isolated inherited homocysteinemia is a deficiency of the enzyme cystathionine ß-synthase (CBS). Clinical manifestations of CBS deficiency can include ectopia lentis, thromboembolism, marfanoid habits, and intellectual disability. CBS deficiency, which affects the transsulfuration pathway, is marked biochemically by elevated serum homocysteine and plasma methionine. We report a patient with homocysteinemia, low plasma methionine, and no significant neurological abnormalities who presented with bilateral subluxated crystalline lenses due to a 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency. MTHFR deficiency, a disorder in the remethylation pathway, can cause mild to severe disease, although most presentations include neurological involvement. MTHFR deficiency has not been previously associated with lens subluxation or complete dislocation. Prolonged exposure to elevated serum homocysteine levels is most likely the explanation for her ectopia lentis. This case expands the differential diagnosis of homocysteinemia and highlights the need for a correct diagnosis to optimize the clinical outcome of patients with this condition.

Successive MRI Findings of Reversible Cerebral White Matter Lesions in a Patient with Cystathionine ß-Synthase Deficiency.

Cystathionine ß-synthase (CBS) deficiency, well known as classical homocystinuria, is a rare autosomal recessive inborn error of homocysteine and sulfur metabolism. CBS converts homocysteine to cystathionine. The clinical features of untreated CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Cerebral white matter lesions (CWMLs), identified in magnetic resonance imaging (MRI), are related to various clinical conditions including ischemia, inflammation, demyelination, infection, a tumor, and metabolic disorders such as phenylketonuria. The presence of CWMLs is, however, believed to be a very rare condition in CBS-deficient patients. Herein, we report reversible CWMLs associated with hypermethioninemia caused by poor protein restriction and betaine therapy in a 21-year-old male with pyridoxine-nonresponsive CBS deficiency. T2-weighted images (T2WI) and fluid-attenuated inversion-recovery (FLAIR) images showed diffuse high signal intensity in subcortical areas extending to the deep white matter. Diffusion-weighted images (DWI) showed high signal intensity, while apparent diffusion coefficient (ADC) map demonstrated decreased ADC value in the lesions. The course of improvement after correct methionine restriction was successively followed by brain MRI. The CWMLs had regressed at 1 month after restriction, and disappeared after 5 months. ADC values were very low before proper methionine restriction, but normalized after 2 months. Use of betaine in the presence of elevated plasma methionine may increase the risk of reversible CWMLs in some CBS-deficient patients.

Bergamot polyphenol fraction prevents nonalcoholic fatty liver disease via stimulation of lipophagy in cafeteria diet-induced rat model of metabolic syndrome.

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries. Defective autophagy of lipid droplets (LDs) in hepatocytes, also known as lipophagy, has recently been identified as a possible pathophysiological mechanism of NAFLD. Experimental and epidemiological evidence suggests that dietary polyphenols may prevent NAFLD. To address this hypothesis and analyze the underlying mechanisms, we supplemented bergamot polyphenol fraction (BPF) to cafeteria (CAF) diet-fed rats, a good model for pediatric metabolic syndrome and NAFLD. BPF treatment (50 mg/kg/day supplemented with drinking water, 3 months) potently counteracted the pathogenic increase of serum triglycerides and had moderate effects on blood glucose and obesity in this animal model. Importantly, BPF strongly reduced hepatic steatosis as documented by a significant decrease in total lipid content (-41.3% ± 12% S.E.M.), ultrasound examination and histological analysis of liver sections. The morphometric analysis of oil-red stained sections confirmed a dramatic reduction in LDs parameters such as total LD area (48.5% ± 15% S.E.M.) in hepatocytes from CAF+BPF rats. BPF-treated livers showed increased levels of LC3 and Beclin 1 and reduction of SQSTM1/p62, suggesting autophagy stimulation. Consistent with BPF stimulation of lipophagy, higher levels of LC3II were found in the LD subcellular fractions of BPF-expose livers. This study demonstrates that the liver and its lipid metabolism are the main targets of bergamot flavonoids, supporting the concept that supplementation of BPF is an effective strategy to prevent NAFLD.

Phenylpropenoic acid glucoside augments pancreatic beta cell mass in high-fat diet-fed mice and protects beta cells from ER stress-induced apoptosis.

SCOPE: A major goal of diabetes therapy is to identify novel drugs that preserve or expand pancreatic beta cell mass. Here, we examined the effect of a phenylpropenoic acid glucoside (PPAG) on the beta cell mass, and via which mechanism this effect is established. METHODS AND RESULTS: Mice were fed a high-fat and fructose-containing diet to induce obesity and hyperglycemia. PPAG treatment protected obese mice from diet-induced hyperglycemia and resulted in a tripling of beta cell mass. The effect of the phytochemical on beta cell mass was neither due to increased proliferation, as determined by Ki67 immunostaining, nor to neogenesis, which was assessed by genetic lineage tracing. TUNEL staining revealed suppressed apoptosis in PPAG-treated obese mice. In vitro, PPAG protected beta cells from palmitate-induced apoptosis. It protected beta cells against ER stress by increasing expression of antiapoptotic B-cell lymphoma 2 (BCL2) protein without affecting proapoptotic signals. CONCLUSIONS: We identified an antidiabetic phytochemical that protects pancreatic beta cells from ER stress and apoptosis induced by high-fat diet/lipotoxicity. At the tissue level, this led to a tripling of beta cell mass. At the molecular level, the protective effect of the phytochemical was mediated by increasing BCL2 expression in beta cells.

Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase.

Non-alcoholic fatty liver disease is associated with inhibited AMP-activated kinase (AMPK) and activation of sterol regulatory element binding protein 1 (SREBP-1). AMPK phosphorylation inhibits SREBP-1, a major transcription factor of de novo lipogenesis, by inhibiting the liver X receptor (LXR) or by direct phosphorylation. Resveratrol, a polyphenol, has regulatory effects on hepatic lipid metabolism as a potent AMPK activator. In this study, we evaluated the anti-steatogenic effects of resveratrol and its derivatives and identified the molecular mechanism in vitro and in vivo. Resveratrol and its derivatives decreased lipid accumulation by free fatty acids (FFA mixture; 0.5 mM, oleic acid:palmitic acid = 2: 1) in H4IIEC3 cells. Synthesized derivatives of resveratrol had lower cytotoxicity than the parental molecule with similar potency. SY-102 suppressed SREBP-1 maturation by T0901317, an LXR agonist, and decreased SRE luciferase activity and the mRNA levels of lipogenic genes. Inhibition of AMPK by pre-treatment with compound C completely blocked the effects of SY-102. To evaluate their efficacy in vivo, mice were fed a high-fat diet for 5 days, and resveratrol or SY-102 was administered orally for the last 2 days. Oral administration of the SY-102 increased AMPK phosphorylation, followed by reduced hepatic triglyceride accumulation to a similar extent as resveratrol. These data demonstrate that SY-102, a synthesized derivative of resveratrol, might provide a promising therapeutic effect against fatty liver disease.

Oral choline supplementation for postoperative pain.

BACKGROUND: Activation of nicotinic receptors with nicotine has been shown to reduce post-surgical pain in clinical and preclinical studies. Choline is a selective agonist at α7-type nicotinic receptors that does not have addictive or sympathetic activating properties. It is anti-nociceptive in animal studies. We conducted a double-blind randomized trial of oral choline supplementation with lecithin to aid in the treatment of pain after gynaecological surgery. METHODS: Sixty women having open gynaecological surgery were randomly assigned to receive 20 g of lecithin before surgery or placebo. Plasma choline concentration and tumour necrosis factor (TNF) were measured. Pain report was the primary outcome measure. RESULTS: We achieved a small but statistically significant increase in choline after surgery with oral supplementation. Plasma TNF was not decreased and pain report was not different between groups at rest or with movement. There were no adverse effects of treatment. CONCLUSIONS: Oral supplementation with lecithin during the perioperative period resulted in very slow absorption and thus only a small increase in plasma choline was achieved. This concentration was inadequate to reduce TNF as has been shown in other studies. The absence of an anti-inflammatory effect was likely related to our failure to demonstrate efficacy in pain reduction.

Resveratrol prevents renal lipotoxicity and inhibits mesangial cell glucotoxicity in a manner dependent on the AMPK-SIRT1-PGC1α axis in db/db mice.

AIMS/HYPOTHESIS: Many of the effects of resveratrol are consistent with the activation of AMP-activated protein kinase (AMPK), silent information regulator T1 (SIRT1) and peroxisome proliferator-activated receptor (PPAR)γ co-activator 1α (PGC-1α), which play key roles in the regulation of lipid and glucose homeostasis, and in the control of oxidative stress. We investigated whether resveratrol has protective effects on the kidney in type 2 diabetes. METHODS: Four groups of male C57BLKS/J db/m and db/db mice were used in this study. Resveratrol was administered via gavage to diabetic and non-diabetic mice, starting at 8 weeks of age, for 12 weeks. RESULTS: The db/db mice treated with resveratrol had decreased albuminuria. Resveratrol ameliorated glomerular matrix expansion and inflammation. Resveratrol also lowered the NEFA and triacylglycerol content of the kidney, and this action was related to increases in the phosphorylation of AMPK and the activation of SIRT1-PGC-1α signalling and of the key downstream effectors, the PPARα-oestrogen-related receptor (ERR)-1α-sterol regulatory element-binding protein 1 (SREBP1). Furthermore, resveratrol decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and class O forkhead box (FOXO)3a phosphorylation, which resulted in a decrease in B cell leukaemia/lymphoma 2 (BCL-2)-associated X protein (BAX) and increases in BCL-2, superoxide dismutase (SOD)1 and SOD2 production. Consequently, resveratrol reversed the increase in renal apoptotic cells and oxidative stress, as reflected by renal 8-hydroxy-deoxyguanosine (8-OH-dG), urinary 8-OH-dG and isoprostane concentrations. Resveratrol prevented high-glucose-induced oxidative stress and apoptosis in cultured mesangial cells through the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling and the downstream effectors, PPARα-ERR-1α-SREBP1. CONCLUSIONS/INTERPRETATION: The results suggest that resveratrol prevents diabetic nephropathy in db/db mice by the phosphorylation of AMPK and activation of SIRT1-PGC-1α signalling, which appear to prevent lipotoxicity-related apoptosis and oxidative stress in the kidney.

Altered expression of apoA-I, apoA-IV and PON-1 activity in CBS deficient homocystinuria in the presence and absence of treatment: possible implications for cardiovascular outcomes.

Classical homocystinuria (HCU) is caused by mutations in cystathionine beta-synthase (CBS) which, if untreated, typically results in cognitive impairment, thromboembolic complications and connective tissue disturbances. Paraoxonase-1 (PON1) and apolipoprotein apoA-I are both synthesized in the liver and contribute to much of the cardioprotective effects of high density lipoprotein. Additionally, apoA-I exerts significant neuro-protective effects that act to preserve cognition. Previous work in a Cbs null mouse model that incurs significant liver injury, reported that HCU dramatically decreases PON1 expression. Conflicting reports exist in the literature concerning the relative influence of homocysteine and cysteine upon apoA-I expression. We investigated expression of PON1 and apoA-I in the presence and absence of homocysteine lowering therapy, in both the HO mouse model of HCU and human subjects with this disorder. We observed no significant change in plasma PON1 paraoxonase activity in either mice or humans with HCU indicating that this enzyme is unlikely to contribute to the cardiovascular sequelae of HCU. Plasma levels of apoA-I were unchanged in mice with mildly elevated homocysteine due to CBS deficiency but were significantly diminished in both mice and humans with HCU. Subsequent experiments revealed that HCU acts to dramatically decrease apoA-I levels in the brain. Cysteine supplementation in HO mice had no discernible effect on plasma levels of apoA-I while treatment to lower homocysteine normalized plasma levels of this lipoprotein in both HO mice and humans with HCU. Our results indicate that plasma apoA-I levels in HCU are inversely related to homocysteine and are consistent with a plausible role for decreased expression of apoA-I as a contributory factor for both cardiovascular disease and cognitive impairment in HCU.

Non-alcoholic fatty liver disease in children now: lifestyle changes and pharmacologic treatments.

Over the past decade, non-alcoholic fatty liver disease (NAFLD) has become one of most common chronic liver diseases in children. A greater understanding about the risk factors and molecular pathogenesis of NAFLD suggests that lifestyle interventions aiming to decrease obesity/body mass index and metabolic derangement are the first line of treatments adopted in children affected by this disease. However, because these therapeutic options are often at the beginning misjudged by the patients and their parents, the use of pharmacologic agents may help to protect the liver and other organs from further irreversible tissue damage. Pharmacologic therapies against one or more specific factors and/or molecules involved in the development of NAFLD (i.e., insulin resistance, free fatty acid lipid toxicity, and oxidative stress) also might slow the progression of this increasingly prevalent pediatric disorder. On this basis, insulin sensitizers, antioxidants, cytoprotective agents, and dietary supplementations have been evaluated in pediatric clinical trials. In this review, we discuss the efficacy of the dietary approaches, possibly coupled with regular exercise, on decreasing the metabolic and histologic damage in pediatric NAFLD. We also emphasize several advantages of the pharmacologic treatments adopted or adoptable in combination with lifestyle interventions in children with NAFLD.

Nonalcoholic fatty liver disease: pharmacologic and surgical options.

The last decade has seen many studies examining the prevalence and natural history of NAFLD in the United States and it is clear that this disease is likely to be an important cause of liver-related morbidity in the future. Several pharmacologic therapies have shown some promise; currently, vitamin E and insulin-sensitizing agents such as pioglitazone can be considered in appropriate cases. Conservative measures to promote weight loss still have a role to play, but the obesity epidemic in the Western World has reached such proportions that bariatric surgery is proving to be an attractive option for patients with a BMI greater than 35 to 40 kg/m2. Well-designed prospective studies are required to ensure that all of these therapies are safe and effective in the long term. Newer agents will likely be investigated as the pathogenesis of NAFLD and fibrosis progression in NASH are further elucidated.

Phosphatidylcholine protects against steatosis in mice but not non-alcoholic steatohepatitis.

Several studies suggest that low levels of hepatic phosphatidylcholine (PC) play a role in the pathogenesis of non-alcoholic steatohepatitis (NASH). CTP: phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for PC biosynthesis. Liver-specific elimination of CTα (LCTα(-/-)) in mice fed a chow diet decreases very-low-density lipoprotein secretion, reduces lipid efflux from liver, and causes mild steatosis. We fed LCTα(-/-) mice a high fat diet to determine if impaired PC biosynthesis played a role in development of NASH. LCTα(-/-) mice developed NASH within one week of high fat feeding. Hepatic CTα deficiency caused hepatic steatosis, a 2-fold increase in ceramide mass, and a 20% reduction in PC content. In an attempt to prevent NASH, LCTα(-/-) mice were either injected daily with CDP-choline or fed the high fat diet supplemented with betaine. In addition, LCTα(-/-) mice were injected with adenoviruses expressing CTα. CDP-choline injections and adenoviral expression of CTα increased hepatic PC, while dietary betaine supplementation normalized hepatic triacylglycerol but did not alter hepatic PC mass in LCTα(-/-) mice. Interestingly, none of the treatments normalized hepatic ceramide mass or fully prevented the development of NASH in LCTα(-/-) mice. These results show that normalizing the amount of hepatic PC is not sufficient to prevent NASH in LCTα(-/-) mice.

Treatment of postoperative ileus with choline citrate--results of a prospective, randomised, placebo-controlled, double-blind multicentre trial.

OBJECTIVES: This was a prospective, randomised, placebo-controlled, double-blind multicentre trial to analyse the efficacy of choline citrate in patients with postoperative ileus (POI) after elective colorectal surgery. METHODS: From October 2005 until June 2008, 122 patients with POI were randomised to receive choline citrate or placebo. One hundred twenty patients were evaluable for tolerability and 107 patients were evaluable for efficacy. The treatment group, 47% (50/107), received 300.2 mg choline citrate intravenously, while the placebo group, 53% (57/107), received sodium chloride. Injections were performed every 12 h until defecation. RESULTS: Demographic data analysis did not show clinically differences between both groups. Operative procedures included 40% (43/107) hemicolectomy, 38% (41/107) sigmoid resection and 22% (23/107) other colorectal resections. Defecation occurred after an average of 91.8 ± 26.6 h postoperatively in the treatment group, vs. 96.7 ± 35.2 h in the placebo group (p = 0.805). After laparoscopy, defecation occurred after 78.7 ± 25.3 h, vs. 99.2 ± 31.6 h after laparotomy (p = 0.001). Serious adverse effects occurred in 2% (1/60) in the treatment group, vs. 3% (2/60) in the placebo group. None of the events have been assessed as related to the study medication. CONCLUSION: An efficacy of choline citrate in the treatment of POI after elective colorectal surgery could not be verified. The problem of POI requiring drug treatment seems to be less frequent than suggested by the literature. With technical advances in surgery, especially laparoscopic and fast track surgery, the frequency of POI will further decrease in the future.

In vitro effects of ethanol with aspirin on rat brain synaptosomes: the potential protective role of betaine.

Physicians recommend aspirin for prevention of heart attacks and stroke in people above the age of 40 years. In some cases, alcohol consumption accompanies aspirin intake. In this study, the in vitro effects of different doses of ethanol (50, 100, and 200 mM) and 100 microg/mL of aspirin and the possible protective role of betaine (0.5 and 1 mM) were investigated on rat cerebral synaptosomes. Synaptosomally enriched fractions, derived from Sprague Dawley rat brains, were incubated with ethanol and aspirin so as to measure sialic acid (SA), nitric oxide levels, and adenosine deaminase (ADA) activities, which are known to be the markers of alcohol damage. When combined with aspirin, ethanol increased SA levels compared with the control group at all doses, resulting in loss of SA residue from synaptosomal membrane. Betaine (0.5 mM) decreased SA levels with respect to the ethanol (200 mM) plus aspirin group (p < .05), thereby preventing SA loss. Moreover, betaine reversed the destructive effects of ethanol by elevating reduced nitric oxide levels. Aspirin, when combined with all doses of ethanol, increased ADA activity, which is crucial for purine metabolism. ADA activities were also elevated in betaine-administered groups. We propose that betaine is an effective compound in protecting the rat brain synaptosomes against ethanol and aspirin together.

Fibrates plus betaine: a winning combination?

Because most of the cardiac risk remains despite successful statin therapy there has been renewed interest in fibrate therapy for persisting hyperlipidaemia. Fibrate therapy lowers triglycerides but causes the urinary loss of betaine, which is an essential metabolite that is involved in osmoregulation, in methyl group metabolism, and which also affects lipid partitioning in the body. Loss of betaine is associated with an elevation of homocysteine and may compromise the potential benefits of fibrate therapy. However, betaine deficiency could be easily and inexpensively corrected by concurrent betaine supplementation. Clinical trials of combinations of betaine and fibrate, to complement statin therapy, are needed to determine the value of these agents in reducing the residual cardiovascular disease risk.