Search

To (1) describe the prevalence of cardiometabolic disease (CMD) at spinal cord injury (SCI) rehabilitation discharge; (2) compare this with controls without SCI; and (3) identify factors associated with increased CMD.Multicenter, prospective observational study.Five National Institute on Disability, Independent Living, and Rehabilitation Research Model SCI Rehabilitation Centers.SCI (n=95): patients aged 18-70 years, with SCI (neurologic levels of injury C2-L2, American Spinal Injury Association Impairment Scale grades A-D), and enrolled within 2 months of initial rehabilitation discharge. Control group (n=1609): age/sex/body mass index-matched entries in the National Health and Nutrition Examination Education Survey (2016-2019) (N=1704).None MAIN OUTCOME MEASURES: Percentage of participants with SCI with CMD diagnosis, prevalence of CMD determinants within 2 months of rehabilitation discharge, and other significant early risk associations were analyzed using age, sex, body mass index, insulin resistance (IR) by fasting glucose and Homeostasis Model Assessment (v.2), fasting triglycerides, high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol, total cholesterol, and resting blood pressure (systolic and diastolic).Participants with SCI had significantly higher diastolic blood pressure and triglycerides than those without SCI, with lower fasting glucose and HDL-C. A total of 74.0% of participants with SCI vs 38.5% of those without SCI were obese when applying population-specific criteria (P.05). Low HDL-C was measured in 54.2% of participants with SCI vs 15.4% of those without (P.05). IR was not significantly different between groups. A total of 31.6% of participants with SCI had ≥3 CMD determinants, which was 40.7% higher than those without SCI (P.05). Interplay of lipids and lipoproteins (ie, total cholesterol:HDL-C ratio and triglyceride:HDL-C ratio) were associated with elevated risk in participants with SCI for myocardial infarction and stroke. The only significant variable associated with CMD was age (P.05).Individuals with SCI have an increased CMD risk compared with the general population; obesity, IR, and low HDL-C are the most common CMD risk determinants; age is significantly associated with early CMD.

Genetic analysis of an adult patient with an unusual course of Ketosis-Prone Diabetes (KPD) and lacking islet autoantibodies demonstrated a nucleotide variant in the 5’-UTR of PDX1, a beta-cell development gene. When differentiated to the pancreatic lineage, his induced pluripotent stem cells stalled at the definitive endoderm stage. Metabolomic analysis of the cells revealed that this was associated with leucine hypersensitivity during transition from the definitive endoderm to the pancreatic progenitor stage, and RNA-sequencing showed defects in leucine-sensitive mTOR pathways contribute to the differentiation deficiency. CRISPR-Cas9 manipulation of the PDX1 variant demonstrated that it is necessary and sufficient to confer leucine sensitivity and the differentiation block, likely due to disruption of binding of the transcriptional regulator NFY to the PDX1 5’-UTR, leading to decreased PDX1 expression at the early pancreatic progenitor stage. Thus, the combination of an underlying defect in leucine catabolism characteristic of KPD with a functionally relevant heterozygous variant in a critical beta-cell gene that confers increased leucine sensitivity and inhibits endocrine cell differentiation resulted in the phenotype of late-onset beta-cell failure in this patient. We define the molecular pathogenesis of a diabetes syndrome and demonstrate the power of multi-omics analysis of patient-specific stem cells for clinical discovery.

The objective of this study was to identify the relationship between metabolic syndrome (MetS) and pressure ulcers (PrU), after controlling for demographic and injury characteristics, socioeconomic factors, health behaviors and fatigue among participants with spinal cord injury (SCI). This cross-sectional study recruited 350 participants with SCI from a hospital in the western region of the USA. Blood tests and physical examination were performed. Waist circumference, high-density cholesterol, triglycerides, blood pressure and fasting glucose were used to diagnose MetS according to Criteria for Clinical Diagnosis of Metabolic Syndrome defined by the American Heart Association. All other variables were self-reported. Three-stage multivariate logistic regression models were conducted to evaluate the effects of three sequential sets of predictors, including demographic/injury, socio-environmental/behavioral and health factors, basing the order of analysis on the Theoretical Risk and Prevention Model. The prevalence of PrU and MetS was 11.0% (n=36) and 35.3% (n=115), respectively. Ethnicity, smoking, alcohol consumption and MetS were statistically associated with PrU in the full model. Participants who were non-Hispanic (odds ratio (OR)=10.30, 95% confidence interval (CI): 3.46–30.65), smokers (OR=2.69, 95% CI: 1.00–7.27) and drank over 30 drinks per month (OR=5.26, 95% CI: 1.24–22.26) had greater odds of having a PrU compared with those who were Hispanic, non-smokers and non-drinkers, respectively. We also observed a positive association between MetS and PrU (ORMetS=3.71, 95% CI: 1.45–9.52), even after controlling for all other factors. Participants who had MetS had higher odds of PrU than those without MetS after adjusting for multiple covariates. Unhealthy behaviors such as smoking and excess drinking were positively associated with PrU.

Melatonin is a tryptophan-derived molecule with pleiotropic activities which is produced in all living organisms. This “sleep” hormone is a free radical scavenger, which activates several anti-oxidative enzymes and mechanisms. Melatonin, a highly lipophilic hormone, can reach body target cells rapidly, acting as the circadian signal to alter numerous physiological functions in the body. This indoleamine can protect the organs against a variety of damaging agents via multiple signaling. This review focused on the role played by melatonin in the mechanism of esophagoprotection, starting with its short-term protection against acute reflux esophagitis and then investigating the long-term prevention of chronic inflammation that leads to gastroesophageal reflux disease (GERD) and Barrett’s esophagus. Since both of these condition are also identified as major risk factors for esophageal carcinoma, we provide some experimental and clinical evidence that supplementation therapy with melatonin could be useful in esophageal injury by protecting various animal models and patients with GERD from erosions, Barrett’s esophagus and neoplasia. The physiological aspects of the synthesis and release of this indoleamine in the gut, including its release into portal circulation and liver uptake is examined. The beneficial influence of melatonin in preventing esophageal injury from acid-pepsin and acid-pepsin-bile exposure in animals as well as the usefulness of melatonin and its precursor, L-tryptophan in prophylactic and supplementary therapy against esophageal disorders in humans, are also discussed.

BACKGROUND Degludec is an ultralong-Acting, once-daily basal insulin that is approved for use in adults, adolescents, and children with diabetes. Previous open-label studies have shown lower day-To-day variability in the glucose-lowering effect and lower rates of hypoglycemia among patients who received degludec than among those who received basal insulin glargine. However, data are lacking on the cardiovascular safety of degludec. METHODS We randomly assigned 7637 patients with type 2 diabetes to receive either insulin degludec (3818 patients) or insulin glargine U100 (3819 patients) once daily between dinner and bedtime in a double-blind, treat-To-Target, event-driven cardiovascular outcomes trial. The primary composite outcome in the time-To-event analysis was the first occurrence of an adjudicated major cardiovascular event (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) with a prespecified noninferiority margin of 1.3. Adjudicated severe hypoglycemia, as defined by the American Diabetes Association, was the prespecified, multiplicity-Adjusted secondary outcome. RESULTS Of the patients who underwent randomization, 6509 (85.2%) had established cardiovascular disease, chronic kidney disease, or both. At baseline, the mean age was 65.0 years, the mean duration of diabetes was 16.4 years, and the mean (±SD) glycated hemoglobin level was 8.4±1.7%; 83.9% of the patients were receiving insulin. The primary outcome occurred in 325 patients (8.5%) in the degludec group and in 356 (9.3%) in the glargine group (hazard ratio, 0.91; 95% confidence interval, 0.78 to 1.06; P

Chronic spinal cord injury (SCI) is associated with an increase in risk factors for cardiovascular disease (CVD). In the general population, atherosclerosis in women occurs later than in men and usually presents differently. Associations between risk factors and incidence of CVD have not been studied in women with SCI.To determine which risk factors for CVD are associated with increased carotid intima-media thickness (CIMT), a common indicator of atherosclerosis, in women with SCI.One hundred and twenty-two females older than 18 years with traumatic SCI at least 2 years prior to entering the study were evaluated. Participants were asymptomatic and without evidence of CVD. Exclusion criteria were acute illness, overt heart disease, diabetes, and treatment with cardiac drugs, lipid-lowering medication, or antidiabetic agents. Measures for all participants were age, race, smoking status, level and completeness of injury, duration of injury, body mass index, serum lipids, fasting glucose, hemoglobin A1c, and ultrasonographic measurements of CIMT. Hierarchical multiple linear regression was conducted to predict CIMT from demographic and physiologic variables.Several variables were significantly correlated with CIMT during univariate analyses, including glucose, hemoglobin A1c, age, and race/ethnicity; but only age was significant in the hierarchical regression analysis.Our data indicate the importance of CVD in women with SCI.

Hormonal fluctuations are known to predispose ulceration of the upper gastrointestinal tract, but to date no comparative study of their effects on the healing of pre-existing ulcers in the oral cavity and stomach has been made. We studied the effects of depletion of testosterone and of EGF on the healing of acetic acid-induced ulcers using rats having undergone bilateral orchidectomy and/or salivectomy respectively. We measured alterations in gastric acid secretion and blood flow at ulcer margins, as well as plasma levels of testosterone, gastrin and the proinflammatory cytokines IL-1 beta and TNF-alpha. Testosterone (0.01-10 mg/kg/day i. m.) dose-dependently delayed oral and gastric ulcer healing. When applied in an optimal dose of 1 mg/kg/day, this hormone significantly raised gastric acid secretion and plasma IL-1 beta and TNF-alpha levels. Attenuation of plasma testosterone levels via bilateral orchidectomy inhibited gastric acid secretion and accelerated the healing of oral and gastric ulcers, while increasing plasma gastrin levels and these effects were reversed by testosterone. Salivectomy raised plasma testosterone levels, and delayed oral and gastric ulcer healing. Treatment of salivectomised animals with testosterone further inhibited ulcer healing, and this effect was counteracted by EGF. We propose that testosterone delays ulcer healing via a fall in blood flow at the ulcer margin, a rise in plasma levels of IL-1 beta and TNF-alpha and, in the case of gastric ulcers, an increase in gastric acid secretion. EGF released from the salivary glands plays an important role in limitation of the deleterious effects of testosterone on ulcer healing.

BACKGROUND Cardiovascular risk factors are common in individuals with chronic spinal cord injury (SCI), and their prevalence increases with age. The actual prevalence of overt cardiovascular disease (CVD) in this population has not been well established. METHODS Electrocardiograms (ECGs) were examined for abnormalities in 43 individuals with abnormal lipid profiles being followed in the outpatient SCI clinic of our institution. The mean age of the study population of predominantly men was 43 +/- 9.9 years and the mean duration of injury 16.6 +/- 8 years. RESULTS ECG abnormalities were common and present in 60.5% of participants. ST-T wave abnormalities were the most commonly observed (35%). Evidence of previous myocardial infarction was present in 7% of all individuals and in 12% of those with ECG abnormalities. The only clinical parameter differentiating the group with normal vs abnormal ECG was the duration of injury (19.5 +/- 8 y vs 12 +/- 5 y; P = 0.0026). Analysis of variance showed that injury duration was the sole predictor of abnormal ECG with 68% accuracy (P = 0.006). Among those with ECG abnormalities, although no significant differences were detected between those with and without evidence of previous myocardial infarction, mean total cholesterol and low-density lipoprotein were higher, and mean high-density lipoprotein was lower. Mean age and injury duration were greater in those with evidence of previous myocardial infarction. CONCLUSION Although age is an important risk factor for CVD in the population of individuals without disabilities, injury duration is at least as important as age in those with SCI. Our findings support the recommendation that individuals with SCI and abnormal lipids should be screened for CVD regardless of age.

BACKGROUND Elevated plasma levels of creatine kinase (CPK) are found in various neuromuscular conditions as a result of muscle damage and necrosis. Elevated CPK has also been described in elite wheelchair athletes and in able-bodied individuals after strenuous exercise. METHODS The incidence of elevated CPK in individuals with spinal cord injury (SCI) has not been well established. We reviewed laboratory data from 581 individuals with chronic SCI. RESULTS Most individuals with SCI (73.3%) had CPK values within 95% confidence intervals for able-bodied individuals. The highest levels were seen in African Americans (21% had CPK values > 95 confidence intervals for able-bodied individuals). Significant associations between CPK and the following independent variables were identified: impairment group, gender, duration of injury, body mass index, and ethnic group. Multiple regression analysis revealed significant correlations between CPK and oxygen consumption (beta .37, P < .01) in 32 individuals who performed the exercise test. CONCLUSIONS These findings are important for clinicians evaluating symptoms of fatigue and myopathy in individuals with SCI.

Cardiometabolic syndrome in individuals who are aging with spinal cord injury (SCI) increases the risk of cardiovascular disease and diabetes. Longitudinal research is needed on the natural progression of cardiometabolic syndrome in SCI.To identify the magnitude of changes in biomarkers of cardiometabolic syndrome and diabetes over time in people aging with SCI, and to discern how these biomarkers relate to demographics of race/ethnicity and sex.This cohort study was a follow-up of a convenience sample of 150 participants (mean age, 51.3; duration of SCI, 27.3 years) from a full cohort of 845 who participated in research in which physiologic and serologic data on cardiovascular disease had been prospectively collected (1993-1997). Inclusion criteria were adults with traumatic-onset SCI. Average years to follow-up were 15.7 ± 0.9. Assessments were age, race, level and completeness of injury, duration of injury, blood pressure, body mass index, waist circumference, serum lipids, fasting glucose, hemoglobin A1c, and medications used. Primary outcome was meeting at least 3 of the criteria for cardiometabolic syndrome.The frequency of cardiometabolic syndrome increased significantly from 6.7% to 20.8% or 38.2% according to 2 definitions. It was significantly higher in Hispanics and apparently higher in women. Diabetes increased significantly by a factor of 6.7.Our data indicate clinically important increases in the frequency of cardiometabolic syndrome, especially among Hispanic and female participants, and a similar increase in diabetes among individuals aging with SCI. Clinical practice guidelines need to be customized for women and Hispanics with SCI.

Treatment with small doses of topical capsaicin protects the gastric mucosa from the damage by strong irritants but functional ablation of sensory nerves by pretreatment with larger dose of parenteral capsaicin augments the formation of gastric lesions via unknown mechanism. This study was designed to determine the role of gastric acid secretion, mucosal blood flow (GBF) and prostaglandins (PG) generation in the gastroprotection induced by small doses of topical or parenteral capsaicin in rats with intact or capsaicin-deactivated sensory nerves. Gastric lesions were produced in rats with intact sensory nerves (series A) or capsaicin-deactivated nerves (series B) using intragastric (i.g.) application of 100% ethanol, acidified aspirin (ASA) or water immersion and restraint stress (WRS). Pretreatment with i.g. capsaicin (0.12-1.0 mg/kg) in rats with intact sensory nerves (series A) reduced dose-dependently the mucosal damage caused by ethanol, ASA or WRS, the dose inhibiting the lesion area by 50% (ID5o) being 0.3, 0.5 and 0.7 mg/kg, respectively. This protection was accompanied by a significant rise in gastric mucosal blood flow (GBF). Parenteral application of capsaicin (1.2-10 mg/kg s.c.) that in intact rats dose-dependently increased GBF, also dose-dependently reduced gastric damage induced by ASA or WRS (but not by ethanol), the ID50 being 5 and 3 mg/kg, respectively. The reduction by i.g. capsaicin of ethanol- or WRS-induced mucosal lesions was accompanied by a rise in GBF and this effect was reversed by indomethacin at a dose that suppressed endogenous PG biosynthesis by about 90%, indicating that PG are involved in the protective activities of topical capsaicin. Furthermore, topical and to a lesser extent parenteral capsaicin given to rats with intact or deactivated sensory nerves inhibited gastric acid and pepsin outputs, suggesting that this inhibition could contribute to the capsaicin-induced gastroprotection against acid-dependent mucosal lesions (ASA or WRS). Capsaicin deactiva-tion of sensory nerves aggravated mucosal lesions induced by all three ulcerogens and this effect was accompanied by a marked decrease in GBF. In such capsaicin-deactivated rats, topical capsaicin also reduced ethanol-, ASA- or WRS-induced lesions, while parenteral capsaicin was effective only in the protection against the damage induced by acidified ASA and WRS but not by ethanol. The protection against WRS lesions and accompanying rise in GBF by parenteral capsaicin were also reversed by the pretreatment with indomethacin applied in a dose suppressing the generation of PG. We conclude that capsaicin is capable of protecting gastric mucosa in rats with both intact and capsaicin-deactivated rats and that this protective activity depends, at least in part, upon its hyperemic and antisecretory effects that may be mediated, at least in part, by endogenous release of PG.

Nesfatin-1 belongs to a family of anorexigenic peptides, which are responsible for satiety and are identified in the neurons and endocrine cells within the gut. These peptides have been implicated in the control of food intake; however, very little is known concerning its contribution to gastric secretion and gastric mucosal integrity. In this study the effects of nesfatin-1 on gastric secretion and gastric lesions induced in rats by 3.5h of water immersion and restraint stress (WRS) were determined. Exogenous nesfatin-1 (5-40μg/kg i.p.) significantly decreased gastric acid secretion and attenuated gastric lesions induced by WRS, and this was accompanied by a significant rise in plasma NUCB2/nefatin-1 levels, the gastric mucosal blood flow (GBF), luminal NO concentration, generation of PGE2 in the gastric mucosa, an overexpression of mRNA for NUBC2 and cNOS, as well as a suppression of iNOS and proinflammatory cytokine IL-1β and TNF-α mRNAs. Nesfatin-1-induced protection was attenuated by suppression of COX-1 and COX-2 activity, the inhibition of NOS with L-NNA, the deactivation of afferent nerves with neurotoxic doses of capsaicin, and the pretreatment with capsazepine to inhibit vanilloid VR1 receptors. This study shows for the first time that nesfatin-1 exerts a potent protective action in the stomach of rats exposed to WRS and these effects depend upon decrease in gastric secretion, hyperemia mediated by COX-PG and NOS-NO systems, the activation of vagal and sensory nerves and vanilloid receptors.

This review was designed to provide an update on the role of asymmetric arginine (ADMA), the endogenous inhibitor of nitric oxide (NO) synthase in the pathophysiology of the upper gastrointestinal (GI) tract. Numerous studies in the past confirmed that NO is a multifunctional endogenous gas molecule involved in most of the body organs' functional and metabolic processes including the regulation of gastrointestinal (GI) secretory functions, motility, maintenance of GI integrity, gastroprotection and ulcer healing. NO is metabolized from L-arginine by enzymatic reaction in the presence of constitutive NO synthase. In upper GI tract, NO acts as a potent vasodilator known to increase gastric mucosa blood flow, regulates the secretion of mucus and bicarbonate, inhibits the gastric secretion and protects the gastric mucosa against the damage induced by a variety of damaging agents and corrosive substances. In contrast, ADMA first time described by Vallance and coworkers in 1992, is synthesized by the hydrolysis of proteins containing methylated arginine amino acids located predominantly within the nucleus of cells. This molecule has been shown to competitively inhibit NO synthase suggesting its regulatory role in the functions of vascular endothelial cells and systemic circulation in humans and experimental animals. Nowadays, ADMA is a potentially important risk factor for coronary artery diseases and a marker of cardiovascular risk. Increased plasma levels of ADMA have been documented in several conditions that are characterized by endothelial dysfunction, including hypertension, hypercholesterolemia, hyperglycemia, renal failure and tobacco exposure. The role of ADMA in other systems including GI-tract has been so far less documented. Nevertheless, ADMA was shown to directly induce oxidative stress and cell apoptosis in gastric mucosal cells in vitro and to contribute to the inflammatory reaction associated with major human pathogen to gastric mucosa, Helicobacter pylori (H.pylori). Infection of gastric mucosa with this germ or H. pylori water extract led to marked increase in the plasma concentration of ADMA and significantly inhibited bicarbonate secretion, considered as one of the important components of upper GI-tract defense system. When administered to rodents, ADMA aggravated gastric mucosal lesions injury induced by cold stress, ethanol and indomethacin and this worsening effect on gastric lesions was accompanied by the significant increase in the plasma level of ADMA. This exaggeration of gastric lesions by ADMA was coincided with the inhibition of NO, the suppression of gastric blood flow and excessive release of proinflammatory cytokine TNF-α. This metabolic analog of L-arginine applied to rats was exposed to water immersion and restraint stress and ischemia-reperfusion, causing an elevation of plasma levels of ADMA and gastric MDA content, which is the marker of lipid peroxidation. These effects, including the rise in the plasma levels of ADMA in rats with stress and ischemia-reperfusion-induced gastric lesions, were attenuated by concomitant treatment with L-arginine, the substrate for NO-synthase, and superoxide dismutase (SOD), a reactive oxygen metabolite scavenger added to ADMA. We conclude that ADMA could be considered as an important factor contributing to the pathogenesis of gastric mucosal damage and inflammatory reaction in H. pylori-infected stomach due to inhibition of NO, suppression of GI microcirculation, and the proinflammatory and proapoptotic actions of this arginine analog.

The decrease in pancreatic exocrine secretion during the course of acute pancreatitis is a well-documented process. However, the mechanisms underlying this reduced pancreatic function are not fully understood. To analyze pancreatic protein synthesis and secretion during and after cerulein-induced pancreatitis, we performed the plasma amino acid consumption test on conscious rats. After stimulation with 1 microgram cerulein/kg/h sc for 1 h, the control group with intact pancreas exhibited a decrease in plasma amino acid by about 15%, and this decrease could be abolished by the administration of the specific CCK-receptor antagonist, loxiglumide. Protein and amylase secretion were augmented by cerulein to about 400% of control values. Upon supramaximal stimulation of the pancreas with cerulein (20 micrograms/kg/h sc for 5 h), we observed a profound decrease of pancreatic secretion, which was accompanied by a more prolonged and more pronounced decrease of plasma amino acids (25%). Two hours after cessation of the supramaximal stimulation of pancreatic secretion (to induce pancreatitis), the administration of 1 microgram/kg/h of cerulein for 1 h resulted in a further decrease of amino plasma acid level, whereas no stimulation of exocrine pancreatic secretion was observed. Eighteen hours later, repeated administration of 1 microgram/kg/h of cerulein was still able to induce amino acid decrease by 20%, but again, no stimulation of exocrine pancreatic secretion was detectable. We conclude that, in the time course of acute cerulein-induced hyperstimulation, there might be an imbalance between synthesis of pancreatic enzymes (reflected by amino acid consumption) and the release of exocrine pancreatic secretion into the duodenum, which may be explained by leakage of proteolytic enzymes from damaged acinar cells into the extracellular space of the pancreas.

The renin-angiotensin system (RAS) plays an important role in the maintenance of blood pressure, cardiovascular functions, body fluids homeostasis and kidney reabsorption process but little is known w

The regulation of appetite is regulated by complex mechanism involving brain-gut axis and hormonal and non-hormonal factors acting through the activity of satiety and hunger centers located in the hypothalamus [Wren & Bloom, 2007]. Among hormones controlling appetite are gastrointestinal hormones such as cholecystokinin, PYY, pancreatic polypeptide, glucagon-like peptide 1, oxyntomedulin, the endocrine pancreatic hormones including insulin and glucagon and endocannabinoids [Wren B Tomasetto et al., 2000]. This peptide was also shown to enhance the gastric motility and gastric secretion [Tschop et al., 2000; Date et al., 2001]. Ghrelin is considered as an orexigenic peptide produced by the stomach, acting as a meal initiator [Masuda et al., 2000; Ariyasu et al., 2001]. Little is known about other factors that might affect ghrelin secretion in the stomach and its influence on gastrointestinal integrity has not been fully elucidated. A recent study in humans revealed that stomach is a major source of circulating ghrelin and that gastrectomy produced dramatic fall in the plasma ghrelin levels, whereas fasting and anorexia nervosa was accompanied by elevated plasma ghrelin levels [Ariyasu et al., 2001]. The orexins also called hypocretins, are neuropeptides novel originally discovered in a small group of neurons in the hypothalamic area (LHA) [Sakurai et al., 1998; de Lecea et al., 1998]. identified two peptides that were endogenous ligands to orphan receptor HFGAN72 [Sakurai et al., 1998]. They found that these peptides after i.c.v. injection stimulated food

The study was designed to determine the gastroprotective and ulcer healing efficacy of basic transforming growth factor (bFGF) and to assess whether this peptide contributes to the action of sucralfate on the rat stomach. Application of human recombinant bFGF (1-100 micrograms/kg/hour subcutaneously) failed to affect the formation of acute gastric lesions induced by 100% ethanol and acidified aspirin but reduced the stress induced by gastric lesions. Sucralfate (100-200 mg/kg given orally) protected gastric mucosa against the ethanol, aspirin, and stress induced acute gastric lesions but the addition of bFGF (100 micrograms/kg subcutaneously or intragastrically) failed to affect sucralfate induced protection against ethanol or aspirin but increased that against stress. Administration of bFGF (3-300 micrograms/kg/day) by an intragastric or an intraperitoneal route or sucralfate (400 mg/kg/day) orally to rats with acetic acid induced gastric ulcers, enhanced the healing rate of these ulcers during seven day treatment in a dose dependent manner. This was accompanied by a pronounced increase in the number of capillaries and myofibroblasts and in DNA synthesis and DNA and RNA concentrations in the granulation tissue in the ulcer area. [125I]bFGF (1 microCi) applied subcutaneously or intragastrically accumulated in two to threefold higher amounts in the ulcer area than in the intact mucosa, particularly in rats treated with sucralfate. Concurrent treatment with indomethacin (2 mg/kg intraperitoneally) delayed ulcer healing and reduced the binding of labelled bFGF to the ulcer area, angiogenesis, and DNA synthesis by sucralfate. Addition of [125I]bFGF to sucralfate at various pHs resulted in the coprecipitation of bFGF by sucralfate in a pH dependent manner from about 10% at pH 7.0 to 90% at pH 1.5. Thus bFGF shows little protective activity and is not essential for gastroprotection afforded by sucralfate but plays an important part in healing of gastric ulcers possibly due to its growth promoting and angiogenic actions.

Capsaicin and papaverine are potent vasorelaxants with strong gastroprotective activity against damage induced by absolute ethanol. This protection was originally attributed to the increase in gastric mucosal blood flow (GBF) and the present study was designed to determine the possible role of nitric oxide (NO) and prostaglandins (PG) in the protective and hyperemic effects of capsaicin and papaverine on rat gastric mucosa. We found that the pretreatment with capsaicin (0.1-0.5 mg/kg i.g.) or papaverine (0.1-2 mg/kg i.g.) reduced dose dependently the area of ethanol-induced lesions, the ED50 being 0.3 and 1 mg/kg, respectively. This protection was accompanied by a gradual increase in the GBF. Intravenous injection of N omega-nitro-L-arginine (L-NNA; 1.2-5 mg/kg), a selective blocker of NO synthase, which by itself caused only a small increase in ethanol lesions, reversed dose dependently the protective and hyperemic effects of capsaicin and papaverine against ethanol-induced damage and attenuated the increase in GBF induced by each of these agents alone. This deleterious effect of L-NNA on the gastric mucosa and the GBF was fully antagonized by L-arginine (200 mg/kg i.v.) but not by D-arginine. L-arginine partly restored the decrease in GBF induced by L-NNA. Pretreatment with indomethacin (5 mg/kg i.p.), which suppressed the generation of PG by 85%, slightly enhanced the mucosal lesions induced by ethanol but failed to affect the fall in GBF induced by this irritant. Gastroprotective and hyperemic effects of capsaicin and papaverine were partly reversed by indomethacin suggesting that endogenous PG are also implicated in these effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Nash MS, Lewis JE, Dyson-Hudson TA, Szlachcic Y, Yee F, Mendez AJ, Spungen AM, Bauman WA. Safety, tolerance, and efficacy of extended-release niacin monotherapy for treating dyslipidemia risks in persons with chronic tetraplegia: a randomized multicenter controlled trial. Objective To test the safety, tolerance, and efficacy of extended-release niacin monotherapy on dyslipidemia in persons with chronic tetraplegia. Design Placebo-controlled, blinded, multicenter, randomized controlled trial. Setting Three spinal cord injury research/rehabilitation centers. Participants Persons with chronic tetraplegia (N=54) and low plasma high-density lipoprotein cholesterol (HDL-C) levels. Intervention Extended-release niacin monotherapy (48 weeks; n=31) on a dose-titration schedule versus matched placebo (n=23). Main Outcome Measures Safety was assessed by using percentages of treatment-emergent adverse events and increased levels of hepatic transaminases, uric acid, glycosylated hemoglobin, and fasting glucose. Tolerance was assessed by using participant reports for frequency and intensity of adverse effects of extended-release niacin. Primary effectiveness outcomes were fasting HDL-C level and plasma total cholesterol (TC)/HDL-C ratio. Secondary outcomes included plasma low-density lipoprotein cholesterol (LDL-C) and TC levels and LDL-C/HDL-C ratio. Results Significant increases in fasting HDL-C levels (24.5%) were accompanied by decreases in TC/HDL-C and LDL-C/HDL-C ratios, LDL-C levels, and TC levels (all P Conclusions Extended-release niacin monotherapy is safe, tolerated, and effective for most persons with chronic tetraplegia. Special precautions for changes in bowel habits and postadministration hypotension should be observed.

Ventricular arrhythmias are not uncommon in patients with hypertension, are often attributed to left ventricular hypertrophy and are thought to be associated with an increased risk of sudden death. However, underlying silent coronary artery disease, another potential cause of ventricular arrhythmias, is often present in the same patient group. Therefore, the prevalence of ventricular arrhythmias was prospectively examined in 183 consecutive asymptomatic men with hypertension with neither clinical nor electrocardiographic (ECG) evidence of coronary artery disease in whom technically adequate echocardiograms could be obtained. After previous therapy had been withdrawn for ≥4 days, each patient underwent exercise or dipyridamole thallium-201 scintigraphy, 48-h Holter ambulatory ECG monitoring and echocardiography for measurement of the left ventricular mass index. Forty patients (22%) had frequent ventricular ectopic activity, defined on the basis of >10 premature ventricular complexes/h (38 patients) or ventricular tachycardia (11 patients), or both.A higher proportion of patients with than without a reversible thallium-201 defect had frequent premature ventricular complexes (33% vs. 18%, p < 0.02) or ventricular tachycardia (14% vs. 4%, p < 0.02). Similarly, more patients with than without left ventricular hypertrophy (defined as left ventricular mass index ≥134 g/m2) had frequent premature ventricular complexes (29% vs. 15%. p < 0.05) and ventricular tachycardia (12% vs. 2%, p < 0.01). By stepwise logistic regression analysis, both findings were independent predictors of ventricular arrhythmia, which was present in 53% of patients with both abnormalities, but in only 12% of those with neither abnormality. In addition, ventricular arrhythmias were more common in patients who had than in those who had not previously been treated with a diuretic drug, even though there were no differences between patients in serum electrolytes at the time of study.These results indicate that silent myocardial ischemia and left ventricular hypertrophy are independently associated with ventricular arrhythmias in patients who are asymptomatic and have mild to moderate hypertension.

Orexigenic peptides are group of endocrine hormones exerting a pleiotropic influence on many physiological functions including regulation of the feeding behaviour and energy expenditure, release of growth hormone (GH) and inotropic effects on the heart. Some of these peptides such as ghrelin, originally identified in the gastric mucosa, has been involved not only in control of food intake and growth hormone release but also exerts the immunomodulatory and anti-inflammatory properties. This review summarizes the recent attempts to prove the concept that orexigenic peptides such as ghrelin, orexin-A and obestatin besides playing an important role in the mechanism of food intake, exhibit a potent gastroprotective action against the formation of acute gastric mucosal injury induced by various ulcerogens. This protective effect depends upon vagal activity and hyperemia mediated by NOS/NO and COX/PG systems and CGRP released from sensory afferent nerves. In addition, the appetite peptides such as ghrelin and orexin-A are implicated in the mechanism of the healing of preexisting gastric ulcers due to an activation of specific GHS-R1a and OX-R1 receptors and PG/COX system.

Electrocardiographic abnormalities develop in patients with chronic aortic regurgitation (AR). Although vasodilator drugs may reduce left ventricular (LV) volume overload, the effects of such therapy on electrocardiographic abnormalities have not been previously evaluated. Accordingly, electrocardiograms were analyzed before and after double-blind, randomized administration of either hydralazine or placebo in 54 patients with chronic AR. These patients were without limiting symptoms and had preserved ejection fraction on entry in the study. The magnitude of ST-segment depression and Romhilt-Estes point score for LV hypertrophy were assessed. Baseline ST depression and LV hypertrophy scores in the placebo and hydralazine groups were not significantly different. At follow-up, after a mean of 19 ± 6 months, there was a significant reduction in ST depression in patients taking hydralazine (n = 28) compared with patients given placebo (n = 26): −0.023 ± 0.044 vs 0.029 ± 0.055 mV, respectively (p = 0.0001); and in the LV hypertrophy score (−1.1 ± 2.2 vs 0.9 ± 2.3 points, respectively; p = 0.002). Hydralazine-treated patients also had significant decreases in LV end-diastolic and end-systolic volume indexes, and a significant increase in ejection fraction. These results suggest that such vasodilator therapy may be beneficial in patients with chronic AR.

Hypertensive patients with left ventricular hypertrophy (LVH) have increased cardiovascular morbidity and mortality. Experimental studies indicate the importance of both the alpha and beta components of the adrenergic nervous system in the development and reversal of LVH. Therefore labetalol (L), a combined alpha and beta blocker, and propranolol (P), a nonselective beta blocker, were evaluated in a randomized, double-blind study of 35 hypertensive patients with echocardiographic evidence of LVH. Following 2 weeks of placebo, L or P was titrated as needed and tolerated to maximum total daily doses of 1600 mg and 640 mg, respectively. A thiazide diuretic was added if necessary for blood pressure control. M-mode echocardiograms were performed at baseline and after 1, 3, 6 and 12 months of blood pressure control. The echocardiograms were read independently by two blinded observers for end-diastolic dimension and wall thicknesses, and left ventricular mass. Fractional shortening, cardiac output, and peripheral vascular resistance were derived using standard formulas. Both drugs reduced blood pressure significantly and comparably. Significant changes in the echocardiographic measurements were observed as early as 1 month and usually persisted throughout the study. Both drugs decreased posterior wall thickness; however, only the decrease in propranolol group achieved statistical significance. Septal wall thickness was reduced by L at 3 and 12 months. End-diastolic dimension increased significantly in the L-treated group at 3, 6, and 12 months of therapy, whereas P had no effect on this measurement. As a consequence, the calculated left ventricular mass index was reduced by P throughout the study, but remained essentially unchanged by L until the twelfth month. Neither drug adversely affected fractional shortening. Cardiac output was significantly reduced by P, but unchanged by L, despite similar effects on heart rate by both drugs. Thus, despite their similar effects on blood pressure, L and P had different effects on cardiac morphology, which may reflect varying responses to alpha-and beta-adrenergic blockade.

Background Barrett's Esophagus (BE) is the precancerous lesion for esophageal adenocarcinoma (EAC). Several studies have indicated that obesity, especially abdominal, is a risk factor for BE. In addition, recent studies have shed light on the role of adipokines (leptin, adiponectin) and inflammatory biomarkers in the development of BE. However, the role of obesity and its biomarkers in the neoplastic progression of BE is unclear. The goal of our cohort study was to evaluate the association between baseline obesity (measured by WHR and BMI) and proand anti-inflammatory biomarkers (circulating adiponectin, leptin, IL1b, IL-6, IL-8, IL-10, and IL-12) and risk of progression to dysplasia or EAC. Methods We evaluated prospectively recruited BE cases during 2008-2013. All patients completed a questionnaire on GERD symptoms and medication use, and had anthropometric measurements (height, weight, waist and hip circumference) and a research blood sample was collected at baseline. BE was defined by endoscopic appearance combined with pathologic findings of intestinal metaplasia. We included patients who had at least one follow up endoscopy through November 19th 2014. BE neoplastic progression was defined as change from non-dysplastic BE to low grade dysplasia (LGD), high grade dysplasia (HGD), or EAC; or change from LGD to HGD or EAC; or change of HGD to EAC. The main exposures were baseline BMI, WHR and circulating levels of biomarkers. Major confounding factors were medications (PPI, statin, H2RA, aspirin, NSAID), GERD (symptoms, severity, frequency) and demographics (race, age, sex). The risk of neoplastic progression was examined in multivariate Cox proportional hazards analysis. Results A total of 178 patients with BE met the inclusion and exclusion criteria; 98% men, 92% white and average age 61.8 years. At baseline, 94% of patients had non-dysplastic BE. In a follow up of 804 patient years, 34 patients (19.10%) progressed to dysplastic BE, and the other 144 patients (80.9%) remained nondysplastic. The likelihood of BE neoplastic progression showed a non-significant increase with obesity (BMI>30) (adjusted HR=3.07, 95%CI 0.74-12.7) and high WHR (adjusted HR: 1.66, 0.22-12.7), and a significant decrease with elevated log IL-1 β I (HR=0.33, 95%C0.120.88) adjusted for age, race, sex, NSAID and statin. There were no associations with circulating serum levels of adiponectin, leptin, IL-6, IL-8, IL-10 or IL-12 levels. Conclusions The data are suggestive of a role for obesity and low levels of anti-inflammatory cytokine (IL-1 β) in the neoplastic progression of BE. These preliminary findings need to be confirmed in a larger dataset and longer follow up. Associations between baseline obesity and inflammation and risk of progression

Background Rosacea is a common condition of unknown aetiology that is usually accompanied by gastrointestinal symptoms and responds favourably to treatment with antibiotics. Aims/methods This study was designed to examine the prevalence of gastric Helicobacter pylori (Hp) infection verified by 13C-UBT, CLO-test, Hp culture and serology (IgG and IgA) and the presence of Hp in the oral cavity evidenced by CLO-test, Hp culture and saliva anti-Hp antibodies (IgG and IgA). During gastroduodenoscopy antral and fundic biopsy samples were taken for histological evaluation (the Sydney system). This study was performed on 60 subjects 30–70 years old with visible cutaneous rosacea symptoms and 60 age- and gender-matched controls without skin diseases but with dyspeptic symptoms similar to those of rosacea and without endoscopic changes in gastroduodenal mucosa (non-ulcer dyspepsia – NUD). Results The Hp prevalence in rosacea patients was about 88%, compared to 65% in the NUD controls. A noticeable number of rosacea patients showed chronic active gastritis predominantly in antrum but also in the corpus while those with NUD showed only mild gastritis confined to the antrum only. Following the initial examination, a typical 1 week systemic anti-Hp therapy, including omeprazole (2 × 30 mg), clarithromycin (2 × 500 mg) and metronidazole (2 × 500 mg), plus gargling and application of metronidazole paste in the case of Hp oral cavity infection. After the application of the systemic and local therapy in the oral cavity, Hp was eradicated from the stomach in 97% and from the oral cavity in 73% of treated patients. Within 2–4 weeks, the symptoms of rosacea disappeared or decreased markedly in 51 subjects. Summary We conclude that: (1) rosacea is a disorder with various gastrointestinal symptoms closely related to gastritis, especially involving the antrum mucosa; (2) the eradication of Hp leads to improvement of symptoms of rosacea and reduction in related gastrointestinal symptoms; (3) the lack of improvement of cutaneous symptoms in rosacea after eradication of Hp from the gastric mucosa could depend on bacteria in the oral cavity; and (4) rosacea could be considered as one of the extragastric symptoms of Hp infection probably mediated by Hp-related cytotoxins and cytokines.

The purpose of this study was to evaluate the effects of a simple dietary intervention for individuals with chronic spinal cord injury (SCI) and moderately elevated total cholesterol.Baseline and follow-up serum lipid values were obtained on 222 persons with SCI. Eighty-six individuals with total cholesterol200 mg/dL were referred for dietary consultation (group 1). The remainder with values200 mg/dL and no consultation served as controls (group 2).At average follow-up of 16 months, group 1 demonstrated significant declines in total cholesterol and low-density lipoprotein cholesterol (LDL-C), whereas group 2 demonstrated significant increases in total cholesterol. Triglyceride levels followed similar but nonsignificant patterns. There were no significant changes in high-density lipoprotein cholesterol for either group. In group 1, 17% had clinically significant reductions in total cholesterol to200 mg/dL and 21% had reductions of LDL-C from135 mg/dL to135 mg/dL.Dietary intervention should be an initial treatment for those with SCI and moderately elevated total cholesterol, with the expectation that approximately 20% will respond favorably.

To assess whether therapy with hydrochlorothiazide (HCTZ) or the calcium antagonist nitrendipine influences silent ischemia or arrhythmias, we studied 10 asymptomatic hypertensive male patients with positive Tl-201 scintigraphy in a double-blind, crossover protocol. Blood pressure (BP) and 48-h Holter monitoring were obtained after 2 weeks of placebo and 8 weeks each of HCTZ and nitrendipine therapy. Ischemia was defined as greater than 1 mm ST-segment depression lasting greater than 1 min and was quantified by the number of episodes, duration, and area under the curve (AUC). The mean number of PVCs per hour and the number of episodes of ventricular tachycardia (greater than 3 beats) were also assessed. Diastolic BP was significantly reduced by both HCTZ and nitrendipine (98 +/- 6 vs. 90 +/- 6 vs. 88 +/- 7 mm Hg, respectively, p less than 0.05), but systolic BP was unchanged for either drug. The number of ischemic episodes was reduced by nitrendipine, from 2.4 +/- 3 to 0.8 +/- 2, (p less than 0.05) but not by HCTZ (2.4 +/- 3 to 1.5 +/- 3, p = NS). The duration of ischemia (37 +/- 43 vs. 5 +/- 9 min, p less than 0.05) as well as the AUC (41 +/- 45 vs. 7 +/- 14 mm/min, p less than 0.05) were reduced only by nitrendipine. The number of PVCs rose with HCTZ therapy, from 19 +/- 34 to 69 +/- 88 (p less than 0.05) and was unchanged by nitrendipine (19 +/- 34 vs. 19 +/- 40, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Polyamines such as spermine or putrescine, resulting from increased activity of ornithine decarboxylase (ODC), are known for gastroprotective and mucosal growth-promoting effects. EGF exhibits similar effects, but little is known about the involvement of polyamines in acceleration of the healing of stress-induced gastric lesions by epidermal growth factor (EGF). In this study, rats with intact or suppressed ODC activity by alpha-difluoromethy-ornithine (DFMO, 400 mg/kg i.p.) were subjected to 3.5 h of water immersion and restraint stress (WRS) without or with addition of spermine or EGF. At 0, 2, 6, 12, or 24 h after stress, rats were sacrificed. The number of gastric lesions was determined and gastric blood flow (GBF) was recorded by the H2 gas clearance technique. Stress produced gastric lesions (mean number 18+/-2 per stomach) and decreased GBF (by approximately 43%), but at 2, 6, 12, and 24 h after stress, these lesions and the decrease in GBF were gradually attenuated. Pretreatment with DFMO or removal of an endogenous source of EGF by salivectomy resulted in a marked decrease in mucosal DNA synthesis and significantly delayed the healing of stress lesions. EGF or spermine significantly accelerated ulcer healing and increased the GBF in rats with intact or removed salivary glands. DFMO significantly reduced the enhancement of healing and the increase in GBF induced by EGF, but failed to influence those induced by exogenous spermine. We conclude that polyamines play an important role in mucosal recovery from stress lesions due to acceleration of mucosal repair and increase in gastric microcirculation and that increased ODC activity and resulting excessive polyamine release appear to act as primary mediators of EGF-induced acceleration of the healing of stress lesions.

Stimulation of pancreatic sensory nerves by capsaicin produced secretory effects probably caused, at least in part, by the release of CGRP. In the pancreas calcitonin gene-related peptide (CGRP) has been localized in the sensory nerves, but its physiological role is unknown. This study was undertaken to compare the changes of pancreatic enzyme secretion produced by CGRP and by stimulation or destruction of sensory nerves. To stimulate sensory nerves, low doses of capsaicin (0.25–0.5 mg/kg) were given intraduodenally to the conscious rats with chronic pancreatic fistula. To inactivate sensory nerves high doses of capsaicin (100 mg/kg) were given subcutaneously 10 d before tests. For the in vitro experiments pancreatic slices and isolated pancreatic acini were prepared from intact and capsaicin-denervated rats. In conscious rats, CGRP given subcutaneously (5–10 μg/kg) and low doses of capsaicin given intraduodenally reduced basal pancreatic secretion. In isolated pancreatic acini, CGRP (10−10–10−6 M), but not capsaicin, increased basal or secretagog-stimulated amylase release. In pancreatic slices (containing nerve fibers) capsaicin (10−10–10−6 M) increased enzyme secretion, and this secretion was abolished by previous inactivation of sensory nerves by this neurotoxin. Capsaicin deactivation did not affect the secretory response of pancreatic acini to CGRP, cerulein, or urecholine. Sensory denervation by capsaicin did not change basal protein secretion, but reduced that produced by feeding or diversion of pancreatic juice to the exterior during first 2 h of the tests.

The aim of the present study was to determine the role of endogenous nitric oxide (NO) in pancreatic secretion in vivo and amylase release from pancreatic acini in vitro and in caerulein-induced acute pancreatitis in rats. Blockade of NO synthase byN G-nitro-L-arginine (L-NNA) (2.5 mg/kg iv) significantly reduced basal pancreatic protein secretion and that induced by the infusion of CCK (0.5 μg/kg-h), feeding, and the diversion of pancreatic juice in rats with pancreatic fistula. This inhibitory effect was partially reversed when L-arginine (50 mg/kg-h iv) was added to L-NNA. L-Arginine alone (50 mg/kg iv) did not affect basal or caerulein-induced pancreatic secretion. L-NNA, L-arginine, or their combination added in various concentrations to the incubation medium of dispersed acini failed to affect basal or secretagogue (caerulein or urecholine) stimulated amylase release. Infusion of caerulein (5 μg/kg-h) for 5 h produced histological changes of acute edematous pancreatitis accompanied by a marked increase in pancreatic protein content and about 50% reduction in tissue blood flow. L-NNA alone also reduced the pancreatic blood flow and caused a significant increase in pancreatic weight and protein content. L-NNA significantly potentiated the inflammatory changes in the pancreas caused by caerulein. Addition of L-arginine enhanced the pancreatic blood flow and ameliorated the pancreatitis induced by caerulein alone or that combined with L-NNA. We conclude that NO is involved in the stimulation of pancreatic secretion in vivo and exhibits a beneficial effect on pancreatitis, probably by improving the pancreatic blood flow.

Pretreatment with aluminium-containing antacids at their original pH or after acidification is known to protect the gastric mucosa against the damaging action of strong irritants and this protection is accompanied by an increase in gastric blood flow (GBF) but the mechanisms underlying these effects have not been elucidated. We investigated the role of endogenous nitric oxide (NO) and prostaglandins (PS) in the prevention of ethanol-induced gastric damage and the alteration of GBF by Maalox and its active component Al(OH)3. Maalox and Al(OH)3 at their original and acidic pH induced dose-dependent gastroprotection accompanied by attenuation of the reduction in GBF caused by 100% ethanol; Similar protective and hyperemic effects were recorded after treatment with nocloprost, a locally active PGE2 analog, and nitroglycerin, a donor of NO. Pretreatment with indomethacin that suppressed mucosal PGE2 by about 90%, failed to affect the protective influence of Maalox or Al(OH3) at their original or acidic pH. On the contrary, pretreatment with NG-nitro-L-arginine (L-NNA), a potent selective inhibitor of NO synthase, reversed the gastroprotective and hyperemic effects of Maalox or Al(OH)3 at original and acidic pH and this reversal was significantly antagonized by L-arginine but not D-arginine. The gastroprotective and hyperemic effects of nocloprost were not influenced by the pretreatment with L-NNA. We conclude that aluminium-containing antacids activate the NO system, which may contribute to the gastroprotective activity of these drugs through an increase in mucosal microcirculation.

Coronary artery disease is responsible for much of the morbidity and mortality in patients with essential hypertension, and these complications have proven to be relatively resistant to antihypertensive therapy. However, the diagnosis of coronary disease in the hypertensive population has been considered problematic. In the present study, 30 asymptomatic patients with mild to moderate hypertension with positive exercise electrocardiograms (ECG) or stress thallium-201 scintigrams underwent coronary angiography to determine the accuracy of these tests for coronary artery disease. The exercise ECG was positive in 25 subjects, of whom 15 had significant coronary lesions and 10 did not. Thallium-201 scintigraphy proved more accurate: 17 of 18 patients with reversible abnormalities had significant obstructive coronary disease anatomically corresponding to the defect, one patient with a fixed defect had normal coronary arteries and was found to have an idiopathic cardiomyopathy, and 9 of 11 without defects had no significant lesions. The results were similar in populations with and without echocardiographic criteria for left ventricular hypertrophy. These findings indicate that despite previous suggestions to the contrary, thallium-201 scintigraphy can accurately diagnose coronary artery disease in most patients with asymptomatic essential hypertension, and that most asymptomatic hypertensive patients with physiologic evidence of myocardial ischemia have associated coronary artery disease.