Ali Keshavarzian
Rush University Medical Center, Gastroenterology, Faculty Member
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Research Interests: Electron Microscopy, Immunohistochemistry, Mast Cells, Cortisol, Inflammatory Bowel Disease, and 15 moreHumans, Intestinal Mucosa, Blood Pressure, Female, Male, Heart rate, American, Clinical Sciences, Adult, Cold Pressor Test, Adrenocorticotropic Hormone, Colon, Inflammatory Bowel Diseases, hydrocortisone, and Cold Temperature
Hypnotically assisted treatments have been used to reduce stress, improve gastrointestinal motility, strengthen immune function, and potentially reduce inflammation. Such treatments may also help reduce disease flares and improve quality... more
Hypnotically assisted treatments have been used to reduce stress, improve gastrointestinal motility, strengthen immune function, and potentially reduce inflammation. Such treatments may also help reduce disease flares and improve quality of life in inflammatory bowel diseases (IBD). The authors report the results of a case series of 8 white female patients with inactive IBD. All participants initiated and completed treatment, supporting the general acceptability of hypnotically assisted treatment among IBD patients. There was a significant improvement in IBD-quality of life scores for the group posttreatment, t(7) = -3.38, p = .01, with a mean improvement in quality of life of 29 points with significant changes in all 4 subscales. No negative effects of treatment were found.
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Gastrointestinal (GI) symptoms are common in soldiers in combat or high-pressure operational situations and often lead to compromised performance. Underlying mechanisms are unclear, but neuroendocrine dysregulation, immune activation and... more
Gastrointestinal (GI) symptoms are common in soldiers in combat or high-pressure operational situations and often lead to compromised performance. Underlying mechanisms are unclear, but neuroendocrine dysregulation, immune activation and increased intestinal permeability may be involved in stress-related GI dysfunction. To study the effects of prolonged, intense, mixed psychological and physical stress on intestinal permeability, systemic inflammatory and stress markers in soldiers during high-intensity combat-training. In 37 male army medical rapid response troops, GI symptoms, stress markers, segmental intestinal permeability using the 4-sugar test (sucrose, lactulose, mannitol and sucralose) and immune activation were assessed during the 4th week of an intense combat-training and a rest period. Combat-training elicited higher stress, anxiety and depression scores (all P < 0.01) as well as greater incidence and severity of GI symptoms [irritable bowel syndrome symptom severity score (IBS-SSS), P < 0.05] compared with rest. The IBS-SSS correlated with depression (r = 0.41, P < 0.01) and stress (r = 0.40, P < 0.01) ratings. Serum levels of cortisol, interleukin-6, and tumour necrosis factor-α, and segmental GI permeability increased during combat-training compared with rest (all P < 0.05). The lactulose:mannitol ratio was higher in soldiers with GI symptoms (IBS-SSS ≥75) during combat-training than those without (IBS-SSS <75) (P < 0.05). Prolonged combat-training not only induces the expected increases in stress, anxiety and depression, but also GI symptoms, pro-inflammatory immune activation and increased intestinal permeability. Identification of subgroups of individuals at high-risk of GI compromise and of long-term deleterious effects of operational stress as well as the development of protective measures will be the focus of future studies.
Research Interests: Anxiety Disorders, Gastroenterology, Medicine, Anxiety, Humans, and 15 moreInternal Medicine, Intestinal Mucosa, Permeability, Male, Depressive Disorder, Irritable Bowel Syndrome, Intestinal permeability, Clinical Sciences, Immune system, Asian Continental Ancestry Group, ANXIETY, Military Personnel, Lactulose, Gastrointestinal Diseases, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Life Sciences, Medicine, Smooth muscle, Animals, and 13 moreCalcium channels, Male, Ligand Binding, Calcium Channel, Rats, Esophagus, Biological Process, Nitrendipine, NIMODIPINE, Biochemistry and cell biology, Calcium Channel Blocker, Vascular Smooth Muscle, and Pharmacology and pharmaceutical sciences
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Research Interests: Biology, Cell Biology, Medicine, Cytoskeleton, Free Radical, and 15 moreCell line, Inflammatory Bowel Disease, Humans, Intestinal Mucosa, Microtubules, Hydrogen Peroxide, Intestinal absorption, Epidermal Growth Factor, Epidermal Growth Factor Receptor, Colchicine, Growth Factor, Biochemistry and cell biology, Inflammatory Bowel Diseases, Free Radical Biology, and Barrier function
Research Interests: Pathology, Cognitive Science, Pathogenesis, Biology, Medicine, and 15 moreLinear models, Alpha Synuclein, Movement disorders, Brain, Permeability, Mice, Animals, Male, Gas Chromatography, Intestinal permeability, Clinical Sciences, Enteric Nervous System, Disease Progression, Colon, and Parkinson Disease
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Muscarinic acetylcholine receptors (mAChR) are important in esophageal physiology, and mAChR alterations may be involved in ethanol-induced esophageal dysfunction. We previously demonstrated that acute ethanol decreases lower esophageal... more
Muscarinic acetylcholine receptors (mAChR) are important in esophageal physiology, and mAChR alterations may be involved in ethanol-induced esophageal dysfunction. We previously demonstrated that acute ethanol decreases lower esophageal sphincter pressure (LESP), whereas withdrawal from chronic ethanol results in pressure increases which are reversible by acute ethanol. To see if this increase in LESP is due to upregulation of mAChR, we evaluated both mAChR binding and dose-response curves for bethanechol and atropine-induced changes in LESP before and after acute and chronic ethanol exposure. The number of mAChR sites (Bmax) in LES (3.4 fmol/mg tissue) was lowered by acute ethanol (1.72, -50%); withdrawal from chronic ethanol raised Bmax (5.2, +54%). Acute injection of ethanol into cats in withdrawal reversed this increase in mAChR density (3.1, -10%). These changes correlated with our earlier data on ethanol-induced changes in LESP. However, the dose-response curve for bethanechol-induced pressure increases shifted to the right [ED25 (micrograms/kg); control, 8.6; withdrawal, 21.3], paralleled by an increase in the number of low-affinity agonist binding sites. Thus, 1) the withdrawal-associated increase in Bmax (up-regulation) is more likely to be a compensatory response to deficits (functional subsensitivity) distal to the receptor recognition site than to proximal deficits; 2) the increase in Bmax does not cause LESP hyperactivity; and 3) receptor binding changes do not necessarily translate into physiological changes.
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BACKGROUND Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases... more
BACKGROUND Alcohol increases the risk of developing colon cancer (CRC), in part via tissue inflammation and impaired barrier integrity. Circadian dyssynchrony (CD) is an understudied but common lifestyle associated factor that increases the risk of multi-organ tissue injury and number of malignancies including CRC. Our prior studies showed that the shift in light-dark cycle exacerbates barrier dysfunction and colonic inflammation in the setting of alcohol treatment, and increases the risk of CRC. Here we studied the interaction of alcohol with an abnormal eating pattern on markers of CD and colonic barrier integrity. METHOD Mice were subjected to day (rest-phase = wrong-time WT) or night-time (active-phase = right-time RT) access to food in combination with access to water or 15% alcohol for total duration of 10 weeks. The food and liquid intake was measured. The locomotor activity data was recorded throughout the study, using a beam-break system. Mice were euthanized at two time points (ZT2 and ZT14). Time variation in the expression of the molecular marker of circadian clock (per2 gene) was measured in the central (hypothalamus) and intestinal (colon) tissue. Colonic protein expression of barrier markers (Occludin and Claudin-1) was studied. RESULTS No significant differences were present in the weight gain and alcohol intake among the groups over the study period. We observed an interaction of WT eating with alcohol on behavioral markers of circadian rhythm. Compared to the RT + Water treated animals ("reference group"), combination of WT eating and alcohol consumption (WT + Alcohol) significantly changed the per2 oscillatory pattern, that was different between the colon and hypothalamus, indicative of worsening circadian dyssynchrony. This was associated with an overall impaired expression of barrier integrity markers in the colon. CONCLUSIONS Alcohol induces circadian dyssynchrony which is worsened by abnormal food timing, associated with impaired barrier integrity in the colon. Future studies on the interaction of alcohol and food timing could provide further insights into alcohol associated CRC pathophysiology.
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ABSTRACT
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In both humans and cats, EtOH administered in vivo and acutely decreases contractility of smooth muscle of lower esophageal sphincter (LES) and lower esophagus (LE), but not striated muscle of upper esophagus. To see if these effects are... more
In both humans and cats, EtOH administered in vivo and acutely decreases contractility of smooth muscle of lower esophageal sphincter (LES) and lower esophagus (LE), but not striated muscle of upper esophagus. To see if these effects are associated with perturbation of Ca++ homeostasis, esophageal muscle slices were incubated in vitro with EtOH and then 45Ca++. At steady-state Ca++ uptake, some slices were exposed to 1 microM carbachol (CCH). Although 100 mM EtOH had no effect on Ca++ uptake into resting or stimulated striated muscle of upper esophagus, it significantly inhibited Ca++ uptake into smooth muscle of LES and LE. For unstimulated LE and resting LES, 100 mM EtOH significantly inhibited both initial uptake and steady-state levels, whereas lower doses had no significant effect. EtOH at 100 mM also affected changes in Ca++ content induced by CCH stimulation. CCH increased total exchangeable tissue Ca++ content in LE, whereas it decreased Ca++ content in LES. EtOH at 100 mM blunted these CCH-induced effects in both LES and LE. In contrast to resting muscle, inhibition of CCH-stimulated LE muscle was not limited to 100 mM EtOH, because substantial and significant inhibition was also seen at EtOH doses of 25 and 50 mM, doses which are relevant even in social drinking. Thus, EtOH inhibition of Ca++ influx into esophageal muscle is selective for smooth muscle, can occur at pharmacologically relevant EtOH doses and could be the underlying mechanism for EtOH's inhibition of contractility of esophageal smooth muscle.
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Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can... more
Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n = 10 light drinkers, 24–45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n = 14 light drinkers, 22–44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P ≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.
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Esophageal function was prospectively studied in 50 consecutive insulin-requiring diabetes mellitus patients. The patients were stratified in three groups: A) 18 without peripheral neuropathy (PN); B) 20 with PN but no autonomic... more
Esophageal function was prospectively studied in 50 consecutive insulin-requiring diabetes mellitus patients. The patients were stratified in three groups: A) 18 without peripheral neuropathy (PN); B) 20 with PN but no autonomic neuropathy; C) 12 with PN and autonomic neuropathy. Twelve patients (four B, eight C) had gastrointestinal symptoms including six with dysphagia. Radionuclide esophageal emptying was abnormal in 55, 70, and 83% of patients in groups A, B, and C, respectively. Eleven of the 12 (92%) symptomatic and 23 of the 38 (60%) asymptomatic diabetes mellitus patients had abnormal emptying. Five of six patients with dysphagia had abnormal emptying. Esophageal manometry was also performed in 15 patients. Twelve patients had abnormal manometry. These included nutcracker esophagus in two, achalasia in one, and increased percentage of multipeaked and simultaneous contractions in nine. There were no significant correlations between radionuclide esophageal emptying, manometric changes and symptoms. Gastrointestinal symptoms were more common in the presence of autonomic neuropathy. Delayed esophageal emptying was more profound in the presence of PN, but abnormal esophageal emptying was present in patients with neuropathy as commonly as patients without. Furthermore, the presence of diabetic retinopathy, duration or control of diabetics, and fasting blood sugar did not influence the frequency of abnormal esophageal emptying. Our data indicate that esophageal dysfunction is common in male diabetics even in the absence of clinical PN and retinopathy, suggesting that diabetic gastroenteropathy can occur in the absence of significant diabetic complications. Commonly observed abnormal esophageal manometry in diabetics is not necessarily accompanied by significant functional disturbances or symptoms.
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Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted... more
Circadian rhythms are a prominent and critical feature of cells, tissues, organs, and behavior that help an organism function most efficiently and anticipate things such as food availability. Therefore, it is not surprising that disrupted circadian rhythmicity, a prominent feature of modern-day society, promotes the development and/or progression of a wide variety of diseases, including inflammatory, metabolic, and alcohol-associated disorders. This article will discuss the influence of interplay between alcohol consumption and circadian rhythmicity and how circadian rhythm disruption affects immune function and metabolism as well as potential epigenetic mechanisms that may be contributing to this phenomenon.
Research Interests: Biology, Inflammation, Humans, Circadian Rhythm, Pubmed, and 3 moreEthanol, Organism, and Immune system
The pathogenesis of gastroesophageal reflux (GER) is not fully understood. There have been reports that delayed gastric emptying is a contributing factor in some patients. To determine whether delayed gastric emptying plays a role in the... more
The pathogenesis of gastroesophageal reflux (GER) is not fully understood. There have been reports that delayed gastric emptying is a contributing factor in some patients. To determine whether delayed gastric emptying plays a role in the genesis of GER, we correlated gastric-emptying measures obtained by scintigraphic techniques with the degree of acid reflux assessed by esophageal pH monitoring. Ten patients, all of whom had evidence of esophageal mucosal disease and severe acid reflux, were studied. Four of the 10 patients with reflux had prolongation in the lag phase of gastric solid emptying, and one of the four showed prolonged gastric-emptying t1/2. There was no significant difference, however, in the mean gastric-emptying t1/2 between a control group and the patient group. Furthermore, there was no correlation between gastric-emptying measures and degree of acid reflux. We conclude that in this group of 10 patients with severe GER, delayed gastric emptying does not play an important role in the development of gastroesophageal reflux.
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Intestinal transit was assessed in 25 insulin-requiring male diabetics and 15 healthy controls by measuring the breath hydrogen appearance time after the ingestion of both the liquid and the solid meal containing nonabsorbable... more
Intestinal transit was assessed in 25 insulin-requiring male diabetics and 15 healthy controls by measuring the breath hydrogen appearance time after the ingestion of both the liquid and the solid meal containing nonabsorbable carbohydrate. Three groups of patients were studied: nine patients without peripheral or autonomic neuropathy or retinopathy; nine patients with peripheral neuropathy; and seven patients with peripheral and autonomic neuropathy. Eight patients complained of gastrointestinal symptoms, including three with watery diarrhea. Intestinal transit of the solid meal was more prolonged than the liquid meal in normal and diabetic subjects. There was no significant difference in intestinal transit between normal controls and any group of diabetics; however, one-third of the diabetics had abnormal intestinal transit of the liquid test meal (four rapid, four delayed); only one patient with diarrhea had rapid intestinal transit. These data suggest that abnormal intestinal transit is common in diabetics. Altered intestinal transit is not a prerequisite of diabetic diarrhea.
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There has been an increasing prevalence of lymphogranuloma venereum (LGV) or Chlamydia trachomatis (C. trachomatis) cases among the men who have sex with men (MSM) population, particularly in Europe and North America. These cases may... more
There has been an increasing prevalence of lymphogranuloma venereum (LGV) or Chlamydia trachomatis (C. trachomatis) cases among the men who have sex with men (MSM) population, particularly in Europe and North America. These cases may present with an incomplete or undisclosed history and proctosigmoiditis without characteristic adenopathy syndrome. During the initial evaluation and colonoscopy, there is a strong clinical and endoscopic suspicion of inflammatory bowel disease (IBD) by virtue of presentation and endoscopic and histological findings. The diagnosis of IBD is subsequently modified to LGV proctosigmoiditis when one or more of the following transpire: (1) there is failure of response to IBD therapy; (2) additional components of history (MSM/travel) may be identified; (3) return of initially performed Chlamydia antibody test is positive; and (4) response to antibiotics effective against Chlamydia. We describe three such cases initially suspected to be an inflammatory bowel disease and subsequently identified as C. trachomatis proctosigmoiditis.
Research Interests: Treatment Outcome, Medicine, Chlamydia trachomatis, Biopsy, Inflammatory Bowel Disease, and 15 moreHumans, Internal Medicine, Pubmed, Male, Coinfection, Men who have Sex with Men, Colonoscopy, Chlamydia, Adult, Unsafe Sex, Predictive value of tests, Inflammatory Bowel Diseases, HIV infections, Diagnostic errors, and Proctocolitis
A case of endometrioma presenting as a diaphragmatic mass in a 36-year-old woman is described. The computed tomographic (CT) and magnetic resonance (MR) findings of the lesion at this rare site of involvement are illustrated, and the... more
A case of endometrioma presenting as a diaphragmatic mass in a 36-year-old woman is described. The computed tomographic (CT) and magnetic resonance (MR) findings of the lesion at this rare site of involvement are illustrated, and the pertinent literature is briefly reviewed.
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Nausea and vomiting are common complaints in chronic alcoholics. Autonomic neuropathy and esophageal motor abnormalities are frequently observed in chronic alcoholics, but gastric emptying has not been studied in these patients. Gastric... more
Nausea and vomiting are common complaints in chronic alcoholics. Autonomic neuropathy and esophageal motor abnormalities are frequently observed in chronic alcoholics, but gastric emptying has not been studied in these patients. Gastric emptying of a solid meal was measured, using 99mTc-sulfur colloid cooked in a scrambled egg, in 10 male chronic alcoholics with upper gastrointestinal complaints of nausea and vomiting. All patients were adequately nourished, recently drinking, but just over withdrawal and free of clinical peripheral neuropathy. Gastric emptying in 10 alcoholics was similar to 5 normal controls (t 1/2 115 +/- 12 versus 107 +/- 8 min). These data suggest that upper gastrointestinal symptoms in chronic alcoholics are not related to gastric motor dysfunction.
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Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological... more
Environmental disruption of the circadian rhythm is linked with increased pain due to osteoarthritis (OA). We aimed to characterize the role of the clock gene in OA-induced pain more systemically using both genetic and pharmacological approaches. Genetically modified mice, (bmal1f/fNav1.8CreERT mice), generated by deleting the critical clock gene, bmal1, from Nav1.8 sensory neurons, were resistant to the development of mechanical hyperalgesia associated with OA induced by partial medial meniscectomy (PMM) of the knee. In wild-type mice, induction of OA by PMM surgery led to a substantial increase in BMAL1 expression in DRG neurons. Interestingly, pharmacological activation of the REV-ERB (a negative regulator of bmal1 transcription) with SR9009 resulted in reduction of BMAL1 expression, and a significant decrease in mechanical hyperalgesia associated with OA. Cartilage degeneration was also significantly reduced in mice treated with the REV-ERB agonist SR9009. Based on these data, we also assessed the effect of pharmacological activation of REV-ERB using a model of environmental circadian disruption with its associated mechanical hyperalgesia, and noted that SR9009 was an effective analgesic in this model as well. Our data clearly demonstrate that genetic disruption of the molecular clock, via deletion of bmal1 in the sensory neurons of the DRG, decreases pain in a model of OA. Furthermore, pharmacological activation of REV-ERB leading to suppression of BMAL1 expression may be an effective method for treating OA-related pain, as well as to reduce joint damage associated with this disease.