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- Effects of aspirin & simvastatin and aspirin, simvastatin, & lipoic acid on heme oxygenase-1 in healthy human subjects. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Jul 29.
Heme oxygenase 1 (HO-1) degrades heme and protects against oxidative stress. In vitro and animal models suggest that HO-1 is beneficial in several diseases (e.g., postoperative ileus, gastroparesis, acute pancreatitis, and colitis). However, the only drugs (i.e., hemin and heme arginate) which pharmacologically upregulate HO-1 in humans are expensive and can only be administered intravenously. Our aims were to compare the effects of placebo, aspirin, and simvastatin alone, and with α-lipoic acid, on HO-1 protein concentration and activity in humans.This randomized, double-blind, placebo-controlled study compared the effects of three oral regimens administered for 7 days, i.e., placebo; aspirin (325 mg twice daily) and simvastatin (40 mg twice daily); aspirin, simvastatin, and the sodium salt of R- α-lipoic acid (NaRLA, 600 mg three times daily) on markers of HO-1 activation (i.e., plasma HO-1 protein concentration and venous monocyte HO-1 protein activity) in 18 healthy subjects (14 females). Markers of HO-1 activation were evaluated at baseline, days 2, and 7.Baseline HO-1 protein concentrations and activity were similar among the three groups. Compared to placebo, aspirin and simvastatin combined, or together with NaRLA did not affect HO-1 protein concentration or activity at 2 or 7 days. HO-1 protein concentrations and activity were correlated on day 7 (r = 0.75, p = 0.0004) but not at baseline and on day 2.At therapeutic doses, aspirin, simvastatin, and α-lipoic acid do not increase plasma HO-1 protein concentration or venous monocyte HO-1 activity in healthy humans.
- [Nutritional support in the neurocritical patient]. [English Abstract, Journal Article]
- Nutr Hosp 2014 May.:22-31.
Neurocritical patients have a metabolic condition that makes them particularly sensitive to protein-caloric malnutrition in a short period of time. Due to this, it is essential nutritional support treatment. But the neurocritical patient has physiological connotations that makes it difficult to be able to establish an early nutrition: persistent gastroparesis for days and exacerbated metabolic response with hyperglycemia is a challenge to the therapist.This review intends to respond to nutritional difficulties in neurocritical patients and also review pharmaco-nutritients that may be helpful for the subsequent clinical course.
- Glucocorticoids induce gastroparesis in mice through depletion of L-arginine. [JOURNAL ARTICLE]
- Endocrinology 2014 Jul 24.:en20141246.
Glucocorticoids (GCs) constitute a highly pleiotropic class of drugs predominantly employed in the treatment of inflammatory diseases. In our search for new mechanisms of action we identified a hitherto unknown effect of GCs in the gastrointestinal tract. We found that oral administration of dexamethasone (Dex) to mice caused an enlargement of the stomach due to the induction of gastroparesis, and that this effect was abolished in GR(dim) mice carrying the A458T mutation in the GC receptor (GR). Gastroparesis was unrelated to the enhanced gastric acid secretion observed after Dex treatment although both effects were mediated by the same molecular mechanism of the GR. Using conditional GR knock-out mice we could further rule out that GC effects on enterocytes or myeloid cells were involved in the induction of gastroparesis. In contrast, we found that Dex up-regulated arginase 2 (Arg2) in the stomach both at the mRNA and protein level. This suggests that GC treatment leads to a depletion of L-arginine thereby impeding the production of nitric oxide (NO) which is required for gastric motility. We tested this hypothesis by supplementing the drinking water of the mice with exogenous L-arginine to compensate for the presumed shortage of this major substrate of NO synthases. Importantly, this measure completely prevented both the enlargement of the stomach and the induction of gastroparesis after Dex treatment. Our findings raise considerations of combining orally applied GCs with L-arginine to improve tolerability of GC treatment and provide a possible explanation for the anti-emetic effects of GCs widely exploited in chemotherapy.
- Measurement of gastric emptying in diabetes. [REVIEW]
- J Diabetes Complications 2014 Jun 17.
There has been a substantial evolution of concepts related to disordered gastric emptying in diabetes. While the traditional focus has hitherto related to the pathophysiology and management of upper gastrointestinal symptoms associated with gastroparesis, it is now apparent that the rate of gastric emptying is central to the regulation of postprandial glycemia. This recognition has stimulated the development of dietary and pharmacologic approaches to optimize glycemic control, at least in part, by slowing gastric emptying. With the increased clinical interest in this area, it has proved necessary to expand the traditional indications for gastric emptying studies, and consider the relative strengths and limitations of available techniques. Scintigraphy remains the 'gold standard' for the measurement of gastric emptying, however, there is a lack of standardization of the technique, and the optimal test meal for the evaluation of gastrointestinal symptoms may be discordant from that which is optimal to assess impaired glycemic control. The stable isotope breath test provides an alternative to scintigraphy and can be performed in an office-based setting. The effect of glucagon-like peptide-1 (GLP-1) and its agonists to reduce postprandial glycemia is dependent on the baseline rate of gastric emptying, as well as the magnitude of slowing. Because the effect of exogenous GLP-1 to slow gastric emptying is subject to tachyphylaxis with sustained receptor exposure, 'short acting' or 'prandial' GLP-1 agonists primarily target postprandial glycemia through slowing of gastric emptying, while 'long acting' or 'non-prandial' agents lower fasting glucose primarily through insulinotropic and glucagonostatic mechanisms. Accordingly, the indications for the therapeutic use of these different agents are likely to vary according to baseline gastric emptying rate and glycemic profiles.
- Relationship Between Glycemic Control and Gastric Emptying In Poorly Controlled Type 2 Diabetes. [JOURNAL ARTICLE]
- Clin Gastroenterol Hepatol 2014 Jul 17.
& Aims: Acute hyperglycemia delays gastric emptying in patients with diabetes. However, it is not clear whether improved control of glycemia affects gastric emptying in these patients. We investigated whether overnight and short-term (6 months) improvements in control of glycemia affect gastric emptying.We studied 30 patients with poorly controlled type 2 diabetes (levels of glycated hemoglobin >9%). We measured gastric emptying using the [(13)C]-spirulina platensis breath test on the patients' first visit (visit 1), after overnight administration of insulin or saline, 1 week later (visit 2), and 6 months after intensive therapy for diabetes. We also measured fasting and post-prandial plasma levels of C-peptide, GLP1, and amylin, as well as autonomic functions.At visit 1, gastric emptying was normal in 10 patients, delayed in 14, and accelerated in 6; 6 patients had gastrointestinal symptoms; vagal dysfunction was associated with delayed gastric emptying (P<.05). Higher fasting blood levels of glucose were associated with shorter half-times of gastric emptying (thalf) at visits 1 (r= -0.46, P=.01) and 2 (r= -0.43, P=.02). Although blood levels of glucose were lower after administration of insulin (132±7 mg/dl) than saline (211±15 mg/dl; P=0.0002), gastric emptying thalf was not lower after administration of insulin, compared with saline. After 6 months of intensive therapy, levels of glycated hemoglobin decreased from 10.6%±0.3% to 9%±0.4% (P=.0003), but gastric emptying thalf did not change (92±8 min before, 92±7 min after). Gastric emptying did not correlate with plasma levels of GLP1 and amylin.Two-thirds of patients with poorly-controlled type 2 diabetes have mostly asymptomatic yet abnormal gastric emptying. Higher fasting blood levels of glucose are associated with faster gastric emptying. Overnight and sustained (6 months) improvements in glycemic control do not affect gastric emptying.
- Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis. [JOURNAL ARTICLE]
- Neurogastroenterol Motil 2014 Jul 13.
There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC.Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer.Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types.Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages.
- Common GI Drug Interactions in the Elderly. [JOURNAL ARTICLE]
- Curr Treat Options Gastroenterol 2014 Jul 18.
The careful review of drug-drug interactions is vital to the safe prescribing of medications for chronic medical conditions. The elderly population suffers from multiple medical problems, and polypharmacy leads to further morbidity in this vulnerable group of patients. We discuss gastrointestinal conditions such as GERD, peptic ulcer disease, gastroparesis, diarrhea, constipation, irritable bowel syndrome, inflammatory bowel disease, chronic liver disease and the commonly used medications in these conditions. Treatment options must be individualized and tailored to accommodate the underlying pharmacokinetics and known drug-drug interactions. The indication for the use of a therapeutic agent in the elderly and the duration of use must be frequently readdressed to help prevent polypharmacy and adverse drug reactions. Medications should be started at a low dose with careful titration to achieve a clinical response to prevent toxicity. The aim of this article is to increase awareness of important drug-drug interactions of commonly prescribed gastrointestinal medications in the elderly.
- Combination of symptoms, syndrome and disease: Treatment of refractory diabetic gastroparesis. [Journal Article]
- World J Gastroenterol 2014 Jul 14; 20(26):8674-80.
To assess effect of combination of symptoms, syndrome and disease on treatment of diabetic gastroparesis with severe nausea and vomiting.Professor Tong Xiaolin's clinical electronic medical records of patients who were treated between January 1, 2006 and October 1, 2012 were used as a database. Patients who met the inclusion criteria were enrolled. General information (name, sex and age), symptoms and blood glucose levels were obtained from the clinic electronic medical record, which was supplemented by a telephone interview. The patient-rated Gastroparesis Cardinal Symptom Index (GCSI) was used to evaluate the severity of the symptoms of gastroparesis. The effects of the treatment were assessed by the change in the severity of the symptoms of gastroparesis and the change in blood glucose between the baseline levels and the post-treatment levels at 1, 2, 4, 8 and 12 wk.Forty-five patients had a mean GCSI nausea and vomiting severity score of 4.21 ± 0.67 and a total GCSI score of 2.77 ± 0.63 before treatment. There was a significant improvement in the nausea and vomiting score at every return visit compared with the baseline score (1 wk: 3.02 ± 1.04 vs 4.18 ± 0.71, P < 0.001; 2 wk: 2.32 ± 1.25 vs 4.16 ± 0.73, P < 0.001; 4 wk: 2.12 ± 1.26 vs 4.12 ± 0.73, P < 0.001; 8 wk: 1.79 ± 1.09 vs 4.24 ± 0.77, P < 0.001; 12 wk: 0.69 ± 0.92 vs 4.25 ± 0.70, P < 0.001). Twenty-five of the 45 patients had complete resolution of vomiting during the observation period (mean time to resolution was 37.9 ± 27.3 d). The postprandial fullness and early satiety subscale, bloating subscale and total GCSI scores were also improved. Finally, the blood glucose levels improved after treatment, although the change was not significant.Use of the combination of symptoms, syndrome and disease to treat diabetic gastroparesis with refractory nausea and vomiting may be a new treatment option.
- In vitro motility changes in Roux limb after Roux-en-Y reconstructio. [Journal Article]
- Bratisl Lek Listy 2014; 115(6):340-4.
Background:The aim of this study is to compare the motility of Roux limb with that of normal segment. Materials and methods: Rats were divided into 3 equal groups as control, Roux-en-Y (Group A) and Roux-en-Y with vagotomy (Group B). Only midline incision and manipulations were applied in control group. Following distal gastrectomy, Roux-en-Y reconstruction was applied in Group A, while vagotomy Roux-en-Y gastrojejunostomy was applied in Group B. Rats were sacrificed 1 month later by cervical dislocations under anesthesia. The obtained jejunal segments were cut into four equal parts. The bath was 37 °C warm while 95 % O2 and 5 % CO2 gases were supplied in 10 ml bicarbonate Krebs' solution.
Results:KCl responses were similar in all three groups. Acetylcholine contraction responses in the vagotomy and non-vagotomy Roux-en-Y groups was higher than in those in control group significantly (p < 0.05). This response in vagotomy Roux-en-Y group was also higher than that in non-vagotomy group (p < 0.05). The induced electrical field stimulation contraction response in the vagotomy + Roux-en-Y group was lower than those in control group and non-vagotomy group (p < 0.05).
Conclusions:These results show that muscarinic receptor density and/or function may increase after vagotomy and non-vagotomy group operation, and vagotomy may contribute to this increase. The decrease in electrical signal response in vagotomy Roux-en-Y group may depend on the decrease in acetylcholine oscillation from the cholinergic nerve ending (Tab. 1, Fig. 5, Ref. 25). Keywords: Roux-en-Y, Roux stasis syndrome, acetylcholine, electrical field stimulation, jejunum, motility.
- [Autonomic neuropathy--a problem of the circulatory system and digestive tract]. [English Abstract, Journal Article]
- Duodecim 2014; 130(12):1223-33.
An autonomic disorder of the circulatory system becomes manifest as aberrant heart rate variability and baroreflex sensitivity already years before progressing into symptomatic disease, in which case the condition is no longer curable. Diagnosis is based on tests of autonomic nervous system function. The main thing in the treatment is management of risk factors of cardiovascular diseases in addition to enhanced glucose homeostasis. Autonomic neuropathy may also affect the digestive tract and be accompanied by esophageal motility disorder, gastroparesis, diarrhea, constipation or fecal incontinence. It is essential in the diagnosis to exclude other diseases of the digestive tract.