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Biomedical subjects

Ali Keshavarzian

Publications and source records attributed to Ali Keshavarzian.

At least 19 recordsLinked to original sources
PubMed2006

Resolution of common dietary sugars from probe sugars for test of intestinal permeability using capillary column gas chromatography.

BACKGROUND: The most widely accepted method for the evaluation of intestinal barrier integrity is the measurement of the permeation of sugar probes following an oral test dose of sugars. The most-widely used sugar probes are sucrose, lactulose, mannitol and sucralose. Measuring these sugars using a sensitive gas chromatographic (GC) method, we noticed interference on the area of the lactulose and mannitol peaks. METHODS: We tested different sugars to detect the possible makeup of these interferences and finally detected that the lactose interferes with lactulose peak and fructose interferes with mannitol peak. On further developing of our method, we were able to reasonably separate these peaks using different columns and condition for our assay. Sample preparation was rapid and simple and included adding internal standard sugars, derivitization and silylation. We used two chromatographic methods. In the first method we used Megabore column and had a run time of 34 min. This resulted in partial separation of the peaks. In the second method we used thin capillary column and was able to reasonably separate the lactose and lactulose peaks and the mannitol and fructose peaks with run time of 22 min. RESULTS: The sugar probes including mannitol, sucrose, lactulose, sucralose, fructose and lactose were detected precisely, without interference. The assay was linear between lactulose concentrations of 0.5 and 40 g/L (r(2)=1.000, P<0.0001) and mannitol concentrations of 0.01 and 40 g/L (r(2)=1.000). The sensitivity of this method remained high using new column and assay condition. The minimum detectable concentration calculated for both methods was 0.5 mg/L for lactulose and 1 mg/L for mannitol. CONCLUSION: This is the first report of interference of commonly used sugars with test of intestinal permeability. These sugars are found in most of fruits and dairy products and could easily interfere with the result of permeability tests. Our new GC assay of urine sugar probes permits the simultaneous quantitation of sucralose, sucrose, mannitol and lactulose, without interference with lactose and fructose. This assay is a rapid, simple, sensitive and reproducible method to accurately measure intestinal permeability.

Chromatography, Gas↗
PubMed2006

Apoptosis resistance in ulcerative colitis: high expression of decoy receptors by lamina propria T cells.

Intestinal mucosa is constantly exposed to normal environmental antigens. A significant number of intestinal mucosal T cells are being deleted through apoptosis. In contrast, T cells from inflamed mucosa of ulcerative colitis patients did not undergo apoptosis. In this study, we determined whether the apoptosis of normal mucosal T cells was induced by antigen receptor stimulation and further determined pathways that mediated the apoptosis. Freshly isolated lamina propria T cells were stimulated with CD3 mAb and apoptosis was determined by Annexin V staining. Normal mucosal T cells underwent apoptosis upon CD3 mAb stimulation whereas the T cells from inflamed mucosa did not. The apoptosis in normal T cells was blocked by TRAIL-R1:Fc and an inhibiting CD95 antibody. Interestingly, decoy receptor (DcR)1, DcR2, and DcR3 that compete with death receptor (DR)4/5 and CD95 were highly expressed by the T cells from inflamed mucosa, but much lower by T cells from normal mucosa. Our data suggest that normal mucosal T cells are constantly deleted in response to environmental antigens mediated through DR4/5 and CD95 pathways and mucosal T cells from ulcerative colitis resist to undergoing apoptosis due to highly expression of DcR1, DcR2, and DcR3.

Adult↗
PubMed2006

Hyperalbuminemia and elevated transaminases associated with high-protein diet.

While high protein diets are increasing in popularity, there is a lack of data on their potential adverse effects. We describe two patients on high protein supplements and exercising for physical fitness. Both developed intermittent abdominal pain, transient elevations in transaminases and hyperalbuminemia without there being any identifiable cause. The symptoms and abnormalities on the laboratory tests resolved after the high protein intake was discontinued. While the pathogenesis and importance of these abnormalities need further study, the findings raise concerns regarding the safety of high protein diets combined with high intensity exercise.

Adult↗
PubMed2006

Laparoscopic repair of congenital duodenal obstruction.

CHARGE syndrome (or association) refers to a group of physical abnormalities occurring together: coloboma, heart defect, atresia choanae, retarded growth and development, genital hypoplasia, and ear anomalies/deafness. We report the successful use of laparoscopy in a patient with CHARGE syndrome and congenital duodenal obstruction.

Abnormalities, Multiple↗
PubMed2006

Mastocytic enterocolitis: increased mucosal mast cells in chronic intractable diarrhea.

CONTEXT: In some adult patients with chronic intractable diarrhea, the diagnosis remains elusive even after detailed evaluations, and colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining. OBJECTIVES: To assess the concentration of mast cells in colonic or duodenal biopsy specimens by immunohistochemical analysis for mast cell tryptase from patients with chronic intractable diarrhea and to evaluate their response to drugs affecting mast cell function. DESIGN: Mast cells per high-power field were assessed in biopsy specimens from 47 patients with chronic intractable diarrhea, from 50 control subjects, and from 63 patients with other specific diseases that cause chronic diarrhea (inflammatory bowel disease, celiac disease, collagenous colitis, and lymphocytic colitis). Patients with chronic intractable diarrhea who had more than 20 mast cells per high-power field were administered drugs affecting mast cell mediator function and release. RESULTS: The mean +/- SD concentration of mast cells in the 50 control subjects was 13.3 +/- 3.5 cells per high-power field; hence, patients with more than 20 mast cells per high-power field were considered to have increased mast cells. Thirty-three (70%) of 47 patients with chronic intractable diarrhea had increased mast cells, and symptoms were controlled by drug therapy in 22 (67%) of the 33 patients. No patient had systemic or cutaneous mastocytosis. No increase in mast cells was seen in patients with other common causes of chronic diarrhea. CONCLUSIONS: In chronic intractable diarrhea, colonic or duodenal biopsy specimens may appear unremarkable on routine hematoxylin-eosin staining, but increased mast cells may be demonstrated by immunohistochemistry for mast cell tryptase, with the novel term mastocytic enterocolitis describing this condition. Similar increases in mast cells are not apparent in control populations or in patients with other specific diseases that cause chronic diarrhea. The cause of the increased mast cells remains to be elucidated.

Adult↗
PubMed2005

A multi-scale stochastic drug release model for polymer-coated targeted drug delivery systems.

A multi-scale mathematical model for drug release of oral targeted drug delivery systems was developed and applied to a commercially available delayed release tablet (Asacol) that delivers 5-aminosalicyclic acid (5-ASA) to the colon. Underlying physical and biochemical principles governing the involved processes (diffusion and dissolution) were employed to develop the mathematical description. Finite element formulation was used to numerically solve the model equations. Molecular dynamics (MD) simulations were used to predict macro-scale transport properties of the drug and the biologic fluid. The effect of pH variability in the gastrointestinal tract environment on the dissolution of the polymeric enteric coating was investigated using the Monte Carlo method. The direct coupling method employed (MD) predicted a sufficiently accurate diffusion coefficient (5.7x10(-6) cm2 s-1) of the drug molecules in reasonable (3 h) computation times. The model was validated using experimental data from in vitro dissolution experiments and provided accurate prediction of the drug release from the delivery system (root mean square error of 5%). The amount of drug entering the systemic circulation, computed from the predicted drug release in varying pH environments in the small bowel, was 15-24%. This range was in good agreement with clinical in vivo data (13-36%) obtained from literature. This research shows that in silico experiments using mechanistic models and stochastic approaches can be used for drug design and optimization and as a decision making tool for physicians.

Administration, Oral↗
PubMed2005

Exposure to ethanol induces oxidative damage in the pituitary gland.

Chronic exposure of pubertal male rats to ethanol results in a decline in serum testosterone and decreased or inappropriately normal serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels suggesting a functional defect in the pituitary. The molecular mechanisms behind this disorder are undefined. A role for ethanol-induced oxidative damage in the pathophysiology is supported by studies in liver, muscle, and heart of experimental animals, but there is limited evidence in the pituitary. We examined markers of oxidative damage to lipids and proteins in pituitaries from rats consuming ethanol for 5, 10, 20, 30, and 60 days in addition to markers of damage to nucleic acids in pituitaries after 60 days of ethanol exposure. There were increases in 8-oxo-deoxyguanosine immunoreactivity, a marker of oxidative damage to nucleic acids, and an overall increase in malondialdehyde and 4-hydroxynonenal, markers of lipid peroxidation. Protein carbonylation and protein nitrotyrosination, markers of protein oxidation, were significantly increased after 30 days and 60 days of ethanol consumption, respectively. After 60 days of ethanol exposure, TUNEL assay revealed that cell death in the ethanol-treated pituitaries was not significantly different from that in the pair-fed controls at the time of examination. We also measured serum testosterone, FSH, and LH after ethanol consumption for 5, 10, 20, 30, and 60 days. Through 5 to 60 days of ethanol exposure, testosterone levels were consistently lower whereas LH and FSH were inappropriately unchanged, suggesting pituitary malfunction. These results provide evidence for ethanol-induced oxidative damage at the pituitary level, which may contribute to pituitary dysfunction.

Aldehydes↗
PubMed2005

Heightened responses to stressors in patients with inflammatory bowel disease.

OBJECTIVES: Several studies suggest that stressful situations (stressors) worsen the course of inflammatory bowel disease (IBD), but the mechanism is not known. Based on several lines of evidence, we hypothesized that psychosocial stress activates the brain-gut axis (BGA) and mucosal mast cells (MC), and activated MC produce proinflammatory cytokines. To test this hypothesis, we determined whether stressor-induced activation of BGA is exaggerated in IBD patients. METHODS: Stress was induced in 15 IBD patients who were in remission (inactive IBD) and in seven controls by a widely used stressor, the cold pressor test (CPT), daily for five consecutive days. Induction of stress was confirmed objectively by measurement of stress hormones (serum cortisol and ACTH), and hemodynamic parameters and subjectively by questionnaire. Activation of the BGA by this stressor was assessed by evaluating colonic mucosal MC histology and degranulation, using electron microscopy (EM). The effects of the stressor on the intestinal mucosa were assessed by changes in inflammatory cell histology, epithelial mitochondria (EM), and oxidative tissue injury (assays for protein oxidation). RESULTS: In both study groups, the stressor resulted in (1) increased levels of stress hormones, (2) the expected changes in hemodynamic parameters, (3) activation and degranulation of MC, (4) mitochondrial damage to epithelial cells, and (5) mucosal protein oxidation. These changes were more marked in IBD patients. CONCLUSIONS: The heightened response to the stressors and the greater epithelial damage in IBD patients suggests that stress-induced activation of the BGA and of mucosal MC is important in the initiation and/or flare up of IBD.

Adrenocorticotropic Hormone↗
PubMed2004

Minimally invasive surgery for achalasia: a 10-year experience.

Minimally invasive esophagomyotomy for achalasia has become the preferred surgical treatment; the employment of a concomitant fundoplication with the myotomy is controversial. Here we report a retrospective analysis of 53 patients with achalasia treated with laparoscopic Heller myotomy; fundoplication was used in all patients except one, and 48 of the fundoplications were complete (floppy Nissen). There were no deaths or reoperations, and minor complications occurred in three patients. Good-to-excellent long-term results were obtained in 92% of the subjects (median follow-up 3 years). Two cases (4%) of persistent postoperative dysphagia were documented, one of which was treated with dilatation. Postoperative reflux occurred in five patients, four of whom did not receive a complete fundoplication; these patients were well controlled with medical therapy. We suggest that esophageal achalasia may be successfully treated with laparoscopic Heller myotomy and floppy Nissen fundoplication with an acceptable rate of postoperative dysphagia.

Adult↗
PubMed2004

Effect of body mass index on nonalcoholic fatty liver disease in patients undergoing minimally invasive bariatric surgery.

The risk factors for nonalcoholic fatty liver disease in patients undergoing bariatric surgery are under study. We wanted to determine the correlation between nonalcoholic fatty liver disease and patient factors such as obesity and liver function tests. A retrospective analysis was performed on 177 nonalcoholic morbidly obese patients who underwent laparoscopic Roux-en-Y gastric bypass with liver biopsy, to identify risk factors for nonalcoholic fatty liver disease. The histologic grade of liver disease was compared with preoperative body mass index, age, and liver function tests. Simple steatosis and steatohepatitis were present in 90% and 42% of patients, respectively. Elevated transaminase levels were an independent risk for liver disease. Body mass index and liver disease were not correlated with univariate analysis. Regression analysis performed on age, body mass index, and liver disease demonstrated that the risk for liver disease increased with body mass index in the younger (<35 years old) age group and decreased with body mass index in the older (>45 years old) age group. There was a high incidence of steatosis and steatohepatitis in these nonalcoholic bariatric patients, and elevated transaminase level was indicative of disease. Body mass index was a positive risk factor for liver disease in younger patients but a negative risk factor in the older patients.

Adult↗
PubMed2004

Laparoscopic transgastric esophageal mucosal resection for high-grade dysplasia.

BACKGROUND: High-grade dysplasia of the esophageal mucosa has been shown to be a precursor to adenocarcinoma. In addition to esophagectomy, multiple ablative endoscopic techniques have evolved for the management of this condition. As a surgical alternative to esophagectomy, we describe for the first time a new option in the treatment of high-grade dysplasia. MATERIALS AND METHODS: Two patients with a history of gastroesophageal reflux disease (GERD) underwent upper gastrointestinal endoscopy which demonstrated high-grade dysplasia of the distal esophagus. The first patient had a short segment (0.5-1.0 cm), and the second patient had a longer (2 cm) segment of dysplasia. The patient is placed in the modified lithotomy position. Five trocars are placed as if to perform a fundoplication. A complete circumferential mobilization of the esophagus is performed. The short gastric vessels are divided with the harmonic scalpel, to free up the fundus of the stomach. An anterior horizontal gastrotomy is performed three to four centimeters below the gastroesophageal junction. A solution of epinephrine and normal saline (1:100,000) is injected into the mucosa at the Z-line and, utilizing specially designed hook electrocautery, the mucosa is incised circumferentially around a lighted bougie. Using blunt dissection the mucosa is undermined, elevated, and excised in four quadrants. Three centimeters of the distal esophageal mucosa are resected. The gastrotomy is then closed using a linear stapler, and a 360 degrees fundoplication is performed around a 50 Fr bougie. RESULTS: High-grade dysplasia was identified in the specimens from both patients; however, neither patient was found to have carcinoma in situ or invasive esophageal cancer. Our first patient has been followed for twenty months, the second for ten months. Both patients underwent routine upper gastrointestinal endoscopy for surveillance of the healing process. At eight months, the mucosa of the first patient showed complete regeneration of squamous epithelium. Our most recent patient appears to be progressing without complications and has also demonstrated normal squamous epithelium at ten months postoperatively, without changes of Barrett's epithelium. CONCLUSION: The technique of laparoscopic transgastric esophageal mucosal resection is feasible and may be proven to be an alternative to esophagectomy for the management of high-grade dysplasia.

Adult↗
PubMed2004

Prevalence and significance of autoantibodies in patients with non-alcoholic steatohepatitis.

GOALS: The aim of this study is to evaluate the prevalence and the clinical and histologic correlates of autoantibodies in patients with nonalcoholic steatohepatitis (NASH). BACKGROUND: Antinuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) have been identified in patients with NASH. The significance of autoantibodies in NASH is uncertain. STUDY: Clinical data from patients with a histologic diagnosis of NASH at a university hospital in Chicago, Illinois between January 1999 and April 2003 were reviewed retrospectively. Seventy-four patients who were tested for autoantibodies and had no history of alcohol abuse or a systemic autoimmune disease were included. Demographic information and laboratory data were collected. Autoantibody titers > or = 1:40 were considered positive. A single pathologist reviewed all liver biopsies and scored features of NASH and identified characteristics of autoimmune hepatitis. RESULTS: Thirty-four percent of patients with NASH had positive ANA titers and 6% were ASMA positive. Demographic and laboratory parameters did not differ by ANA status, except that women were more frequently ANA positive then men (P = 0.01). The severity of steatosis, inflammation, and fibrosis on liver biopsy were similar in the ANA positive and negative groups. Only 15% of ANA positive patients with NASH had a plasma cell infiltrate on liver biopsy and there was no difference in the frequency of histologic features of autoimmune hepatitis between ANA positive and negative patients. CONCLUSIONS: Antinuclear antibodies are common in patients with NASH and most frequently represent a nonspecific antibody response that is not associated with the pattern or severity of injury on liver biopsy.

Adult↗
PubMed2003

Gas chromatographic method for detection of urinary sucralose: application to the assessment of intestinal permeability.

We developed a capillary column gas chromatography (CCGC) method for the measurement of urinary sucralose (S) and three other sugar probes including, sucrose, lactulose (L) and mannitol (M) for use in in vivo studies of intestinal permeability. We compared the capillary method with a packed column gas chromatography (PCGC) method. We also investigated a possible role for sucralose as a probe for the measurement of whole gut permeability. Sample preparation was rapid and simple. The above four sugars were detected precisely, without interference. We measured intestinal permeability using 5- and 24-h urine collections in 14 healthy volunteers. The metabolism of sugars was evaluated by incubating the intestinal bacteria with an iso-osmolar mixture of mannitol, lactulose and sucralose at 37 degrees C for 19 h. Sugar concentrations and the pH of the mixture were monitored. The use of the CCGC method improved the detection of sucralose as compared to PCGC. The average coefficient of variation decreased from 15% to 4%. It also increased the sensitivity of detection by 200-2000-fold. The GC assay was linear between sucralose concentrations of 0.2 and 40 g/l (r=1.000). Intestinal bacteria metabolized lactulose and acidified the media but did not metabolize sucralose or mannitol. The new method for the measurement of urinary sucralose permits the simultaneous quantitation of sucrose, mannitol and lactulose, and is rapid, simple, sensitive, accurate and reproducible. Because neither S nor M is metabolized by intestinal bacteria, and because only a tiny fraction of either sugar is absorbed, this pair of sugar probes appears to be available for absorption throughout the GI tract. Thus, the 24-h urinary concentrations of S and M, or the urinary S/M ratio following an oral dose of a sugar mixture, might be good markers for whole gut permeability.

Chromatography, Gas↗
PubMed2003

Endoscopy in eosinophilic esophagitis: "feline" esophagus and perforation risk.

BACKGROUND & AIMS: Idiopathic eosinophilic esophagitis is an underdiagnosed disease with typical endoscopic findings, which have not been well described. METHODS: Charts and pathology reports at two tertiary care centers from June 1993 to April 2002 were reviewed to describe the endoscopic findings of this disease and to correlate them with clinical characteristics. Eight patients were identified as having eosinophilic esophagitis based on clinical symptoms and pathology reports. RESULTS: Soft and subtle ring(s) in the esophagus were found in 7 of 8 patients. In 3 of 8 patients, the esophagus appeared rigid. Mucosal rents occurred with simple passage of the endoscope in 5 of 8 patients. One patient developed a perforation after simple passage of the endoscope. Endoscopic findings can be normal or very subtle in these patients, and the findings can easily be missed during endoscopy. Tearing of the esophagus can occur with simple passage of the endoscope or biopsy even in the absence of overt rings. A minimum of 8 weeks of medical therapy (proton pump inhibitor, histamine antagonists, immunosuppressants) should be undertaken before considering dilation because of the high risk involved with the procedure and the good response to medical therapy. CONCLUSIONS: We recommend considering dilation only in patients with eosinophilic esophagitis who do not respond to medical therapy and have rings that appear to be obstructing the lumen.

Adult↗
PubMed2003

Intestinal barrier: an interface between health and disease.

The intestine constitutes the largest interface between a person and his or her environment, and an intact intestinal barrier is thus essential in maintaining health and preventing tissue injury and several diseases. The intestinal barrier has various immunological and non-immunological components. The epithelial barrier is one of the most important non-immunological components. Hyperpermeability of this barrier is believed to contribute to the pathogenesis of several gastrointestinal disorders including inflammatory bowel disease, celiac disease and food allergy. Hence, assessing barrier integrity is of the utmost importance. One of the more quantitative gauges for this assessment is transepithelial permeability of various molecular probes, among which sugars are commonly used. Measures of intestinal permeability might also be useful as markers for assessment of prognosis and follow up in various gastrointestinal disorders. The present article is a review of the normal and abnormal functioning of the intestinal barrier, the diseases that can result from loss of barrier integrity, and some promising agents and strategies for restoring barrier normality and integrity.

Biological Transport↗
PubMed2002

Intestinal permeation and gastrointestinal disease.

The gastrointestinal tract constitutes one of the largest sites of exposure to the outside environment. The function of the gastrointestinal tract in monitoring and sealing the host interior from intruders is called the gut barrier. A variety of specific and nonspecific mechanisms are in operation to establish the host barrier; these include luminal mechanisms and digestive enzymes, the epithelial cells together with tight junctions in between them, and the gut immune system. Disruptions in the gut barrier follow injury from various causes including nonsteroidal anti-inflammatory drugs and oxidant stress, and involve mechanisms such as adenosine triphosphate depletion and damage to epithelial cell cytoskeletons that regulate tight junctions. Ample evidence links gut barrier dysfunction to multiorgan system failure in sepsis and immune dysregulation. Additionally, contribution of gut barrier dysfunction to gastrointestinal disease is an evolving concept and is the focus of this review. An overview of the evidence for the role of gut barrier dysfunction in disorders such as Crohn's disease, celiac disease, food allergy, acute pancreatitis, non-alcoholic fatty liver disease, and alcoholic liver disease is provided, together with critical insight into the implications of this evidence as a primary disease mechanism.

Acute Disease↗