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PubMed1989

The changing gastrointestinal side effect profile of non-steroidal anti-inflammatory drugs. A new approach for the prevention of a new problem.

The most serious side effects of non-steroidal anti-inflammatory drugs (NSAIDs) involve gastroduodenal perforations and massive haemorrhage. It is becoming increasingly clear, however, that it is the small intestine that bears the main brunt of NSAID-related gastrointestinal toxicity. Hence 70% of patients receiving NSAIDs in the long term have evidence of small-intestinal inflammation, and the same patients lose blood and protein as a consequence. Many patients have asymptomatic ileal dysfunction and occasionally may develop unique small-intestinal strictures necesitating surgery. The pathogenesis of the intestinal inflammation is beginning to emerge. There are data to support that an imbalance between prostaglandins and leukotrienes is important in disrupting small-intestinal integrity during drug absorption. Furthermore, a simple mixture of glucose and citrate with indomethacin appears to minimize the damage. Whether this overcomes a metabolic block caused by NSAIDs and replenishes ATP levels or acts by scavenging oxygen free radicals is unknown, but our further understanding of the mechanism may revolutionize our approach to prevention of the gastrointestinal toxicity of NSAIDs.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2000

The gastric emptying scan as a tool for surgical management of severe bowel dysfunction in spinal cord injury: 2 case reports.

We describe 2 patients with spinal cord injury (SCI) for whom the gastric emptying scan (GES) was crucial for determining the correct surgical approach in the therapeutic management of gastrointestinal complaints. Two men, ages 45 and 51 years, were admitted to a university hospital for delayed gastric complications from SCI. Both SCIs were traumatic, and the interval since injury was 18 months for the younger man and 6 months for the older man. Both men lacked voluntary motor and sensory function below the cord level of the lesion and had quadriplegia. Using GES, we measured motility (the cutoff for normal in this laboratory is 37%) and the time at which half the gastric contents were emptied (normal values are 45 +/- 8 min). Both patients had abnormal motility: residuals at 1 hour were above 50%. Half the gastric contents were emptied at 75 and 90 minutes, respectively. The therapeutic value of the GES was demonstrated for both patients, in combination with the history, physical examination, and abdominal radiographic studies. The first patient underwent ileostomy, and the second required a gastrostomy tube and a jejunostomy tube in addition to metoclopramide. The GES is a valuable diagnostic tool with an important role in the surgical management of patients with SCI.

Antiemetics↗

PubMed1990

How does liver dysfunction influence serum CA 19-9 in pancreatic cancer?

Serum CA 19-9 was determined in 83 control subjects, 99 patients with pancreatic cancer, 104 with chronic pancreatitis and 137 with extra-pancreatic diseases mainly of gastrointestinal origin in order to evaluate whether hepatic factors can influence circulating CA 19-9 in pancreatic cancer. Sensitivity, specificity and accuracy of this test in determining pancreatic malignancy were: 74%, 83% and 57%. We divided patients into two groups: group A (159 cases) and group B (181 cases) with and without anatomical liver damage (presence of primary or metastatic cancer, cirrhosis, hepatitis, steatofibrosis, cholangitis). Group A presented higher CA 19-9 values as compared to group B. Significant correlations were found in group B but not in group A between CA 19-9 and ALT, ALP and total bilirubin. Multiple regression analysis (CA 19-9 dependent and ALT, ALP and total bilirubin predictor variables) was significant only in group B. The standardized partial regression coefficients found to be significant were those of ALP and total bilirubin. We can conclude that CA 19-9 is an index of pancreatic cancer with satisfactory sensitivity and specificity. The presence of anatomical liver damage seems to increase the value of this index, probably releasing CA 19-9 into the bloodstream. Extra-hepatic cholestasis may also be an important factor in elevating CA 19-9 probably by reducing the hepatic catabolism of this glycoprotein.

Adult↗

PubMedDate not supplied

Role of autonomic dysfunction in patients with functional dyspepsia.

BACKGROUND: The role of autonomic dysfunction in patients with functional dyspepsia is not completely understood. AIMS: 1. to prospectively assess abnormalities of autonomic function in patients with functional dyspepsia, 2. to assess whether autonomic dysfunction in these patients is associated with a. visceral hypersensitivity or b. delayed gastric emptying or c. severity of dyspeptic symptoms. PATIENTS: A series of 28 patients with functional dyspepsia and 14 healthy volunteers without gastrointestinal symptoms were studied. METHODS: All patients and controls were submitted to a battery of five standard cardiovascular autonomic reflex tests, dyspeptic questionnaire, gastric barostat tests and gastric emptying tests. RESULTS: 1. Autonomic function tests showed that both sympathetic and parasympathetic scores of dyspeptic patients were significantly higher than in controls; 2. visceral hypersensitivity was confirmed in dyspeptics in response to proximal gastric distension, demonstrating lower pain threshold; 3. delayed gastric emptying occurred more frequently in patients with functional dyspepsia than in controls; 4. epigastric pain and epigastric burning were significantly more prevalent in patients with definite evidence of autonomic dysfunction; 5. No significant association was found between presence of autonomic dysfunction and presence of visceral hypersensitivity or presence of delayed gastric emptying in patients with functional dyspepsia. CONCLUSIONS: We concluded that a possible role of autonomic dysfunction in eliciting dyspeptic symptoms could not be determined from alterations in visceral hypersensitivity or delayed gastric emptying. Autonomic dysfunction might not be the major explanation for symptoms associated with functional dyspepsia.

Abdominal Pain↗

PubMed1996

Pseudoaneurysm of the cystic artery associated with upper gastrointestinal bleeding.

Pseudoaneurysm of the cystic artery is a cause of hemobilia, and is extremely rare, with only eight cases having been reported in the world literature. We report a case of pseudoaneurysm of the cystic artery in a 72-year-old Japanese man. The patient experienced epigastric pain and melena, and was found to have jaundice and liver dysfunction. Repeated gastroendoscopy did not reveal the cause of the alimentary tract bleeding; however, color-Doppler ultrasonography detected an aneurysm of the cystic artery in the gallbladder. Selective hepatic arteriography demonstrated that the posterior branch of the cystic artery was markedly dilated and that an aneurysm had formed in the midst of the artery. We diagnosed hemobilia due to the pseudoaneurysm of the cystic artery, and associated gastrointestinal bleeding. Cholecystectomy was performed immediately. Pathologically, the gallbladder showed acute calculous cholecystitis. This case emphasizes the importance of including hemobilia in the differential diagnosis whenever gastrointestinal bleeding is associated with signs of biliary disorder; color-Doppler imaging is a favorable modality for the diagnosis of pseudoaneurysm of the cystic artery.

Aged↗

PubMed1990

Scleroderma esophagus.

Scleroderma (systemic sclerosis) is a connective tissue disorder characterized by thickening and fibrosis of the skin and visceral involvement that may include the heart, lungs, kidneys, and gastrointestinal tract. At least 40-50% of patients with scleroderma experience esophageal symptoms such as heartburn and dysphagia, while up to 90% of patients have esophageal dysfunction on objective testing at some point in their disease. The disease results in smooth muscle dysfunction that causes esophageal aperistalsis and reduced lower esophageal sphincter pressures. Gastroesophageal reflux with poor acid clearance results with an increased incidence of complications such as peptic stricture and Barrett's esophagus. Aggressive medical therapy is necessary to prevent these and other complications of gastroesophageal reflux.

Esophageal Diseases↗

PubMed2004

Fibromyalgia: the gastrointestinal link.

Patients with fibromyalgia (FM) frequently have gastrointestinal symptoms and signs. This article critically reviews the available literature and concludes the following: evidence that inflammatory bowel disease is associated with FM is contradictory, but should be looked for in patients taking concomitant steroids; patients diagnosed with celiac disease often have a history of FM or irritable bowel syndrome (IBS) that may or may not be present; reflux, nonulcer dyspepsia, and noncardiac chest pain are common in FM patients; medications used to manage pain, inflammation, and gastrointestinal complaints confound the management of FM; and IBS affects smooth muscles and the parasympathetic nervous system, while FM patients have complaints of striated muscles and dysfunction of the sympathetic nervous system. Of those patients with FM, 30% to 70% have concurrent IBS. Small intestinal bacterial overgrowth is associated with hyperalgesia and IBS-like complaints, is common in FM, and responds transiently to antimicrobial therapy.

Anti-Infective Agents↗

PubMed1992

Symptoms in medical patients: an untended field.

Somatic symptoms are one of the leading reasons for medical outpatient clinic visits, with the most common symptoms having a prevalence of 10% or more. However, the usual diagnostic workups are often unproductive, with less than 1 in 5 symptoms having an organic explanation after the initial physical examination and laboratory testing. Therapy appears more effective for some symptoms than for others. Of patients with unspecified pain or gastrointestinal complaints, greater than 70% state that some type of treatment has been helpful, whereas less than 50% of individuals with fatigue, dizziness, numbness, insomnia, sexual dysfunction, anxiety, or depression report any relief. Future educational efforts and research need to focus on that majority of symptoms that are either psychiatric or unexplained, in order to improve our current evaluation and management strategies.

Humans↗

PubMed2005

Colchicine-related death presenting as an unknown case of multiple organ failure.

A 45-year-old man presented to the emergency department (ED) with acute renal and hepatic failure as well as hypotension and metabolic acidosis. Despite aggressive intensive care, he had continued hypotension, leukocytosis, fever, renal and hepatic failure, and lactic acidosis. On hospital day 3, pancytopenia was noted. Bone marrow biopsy showed marked aplasia without a specific etiology being elucidated. He received granulocyte colony-stimulating factor and antibiotics, but died on hospital day 12 after a cardiac arrest. The patient repeatedly denied intentional drug ingestion. Due to his clinical course, the poison center recommended obtaining a colchicine level. The plasma colchicine level, 72 h after admission, was 6.1 ng/mL (GC/MS). This level exceeds acute levels reported in some cases of prior fatalities. This case is novel in that the patient's multiple organ dysfunction remained unexplained for several days before occult colchicine toxicity was implicated as the probable cause by the colchicine level. Also, there was a paucity of gastrointestinal symptoms on presentation, the opposite of what is expected in colchicine toxicity.

Bone Marrow Diseases↗

PubMed2000

Aging enhances susceptibility of diclofenac-treated rats to gastric ulceration, while attenuating enteropathy.

Although clinical reports note aging and gender as risk factors for NSAID therapy associated gastroenteropathy, neither variable has been examined in an animal model. We addressed this unknown by comparing the responses of young (4 months) and old (22 months) rats of both genders to oral treatment with diclofenac (10 or 50 mg/kg). Diclofenac produced gastric ulcers only in old rats, with markedly larger lesions in females. In contrast, the small intestines in old rats of both genders given the 50 mg/kg dosage had >30% fewer ulcers and a fourfold decrease in area of ulceration compared to young rats. The small intestine was the only site of lesions after the 10 mg/kg dosage and showed one gender influence, namely, a transiently faster time course of ulcer development in females. Old and young rats given 50 mg/kg showed similar declines in serum levels of the vascular permeability indices-total protein and albumin-despite reduced intestinal damage in the old animals, which suggests additive vascular leakage across the gastric lesions that were evident only in old animals. Serum biochemistry showed no evidence of hepatotoxicity or dysfunction, consonant with small intestine as the primary target for diclofenac toxicity in rats. We provide the first experimental evidence for an aging influence on the gastrointestinal target site of a nonaspirin NSAID.

Aging↗

PubMed1998

A double-blind study of paroxetine, fluoxetine, and placebo in outpatients with major depression.

We report results from a multicenter, placebo-controlled, randomized, double-blind comparison of the efficacy and tolerability of paroxetine and fluoxetine in outpatients with major depression. Across five U.S. sites, 128 outpatients (mean age: 41.3 +/- 12.6; 63 men and 65 women) with moderate to moderately severe major depression without a history of mania or hypomania were recruited between 1993 and 1994. All 128 patients completed a 1-week placebo washout period, and were then randomized to 12 weeks of double-blind treatment with paroxetine up to 50 mg/day (n = 55), fluoxetine up to 80 mg/day (n = 54), or placebo (n = 19). Subjects were evaluated weekly for the first 4 weeks, then at weeks 6, 9, and 12 with the 21-item HAMD and the Covi Anxiety Scale. There were no significant differences among the three treatment groups in baseline and endpoint depression and anxiety severity, as well as in the degree of depression and anxiety improvement. There were no statistically significant differences in rates or mean numbers of adverse events between paroxetine-treated patients and fluoxetine-treated patients. In summary, our results, although limited by the lack of a significant difference from placebo in treatment outcome, suggest that the SSRIs paroxetine and fluoxetine have comparable antidepressant and antianxiety efficacies among depressed outpatients, as well as similar safety and tolerability profiles.

Adult↗

PubMed2026

The minor spliceosome component U4atac regulates JAK/STAT signaling to modulate hematopoiesis and immune responses in Drosophila melanogaster.

The small nuclear RNA U4atac is a core component of the minor spliceosome. In humans, homozygous or compound heterozygous point mutations in U4atac cause rare developmental disorders, such as Roifman syndrome, characterized by growth restriction, brain anomalies, and immune deficiency. To better define the pathophysiological role of U4atac mutations, we here establish a model of minor spliceosome dysfunction by generating a Drosophila melanogaster CRISPR/Cas9-induced U4atac mutant in the highly conserved stem II region. U4atac homozygous mutants exhibit growth and neurodevelopmental defects, immunodeficiency, and gastrointestinal symptoms. Using bulk RNA-sequencing and functional assays, we reveal that mutations in U4atac affect the splicing of a large set of transcripts involved in innate immunity, hematopoiesis, and intestinal cell functions, including the Drosophila Janus kinase (JAK) homolog hopscotch (hop). Importantly, U4atac deficiency reduces Hop expression and causes Hop-related hematopoietic defects at the embryonic and larval stages. Notably, we also observe reduced expression of Jak1 and attenuated activation of downstream signaling in patients with Roifman syndrome. Thus, our work identifies alterations of Jak signaling as part of the pathogenesis of RNU4atac-opathy.

Animals↗

PubMed2003

Review article: Crohn's disease: monitoring disease activity.

A global measurement of Crohn's disease activity, comprising clinical, endoscopic, biochemical and pathological features is not available yet and perhaps is unobtainable. In this review we analyse the most used and validated clinical indices (Crohn's Disease Activity Index [CDAI], Perianal Disease Activity Index [PDAI], fistula drainage assessment), quality of life scores (Inflammatory Bowel Disease Questionnaire [IBDQ]), sub-clinical markers (C-reactive protein, faecal calprotectin, intestinal permeability) and endoscopic indices (Crohn's Disease Endoscopic Index of Severity [CDEIS]/Simple Endoscopic Score for Crohn's Disease [SES-CD], Rutgeeerts' score for postsurgical recurrence). We also review the main advantages and disadvantages of each of these scoring systems. All these indices are rather complex and time-consuming, therefore their use is limited to clinical trials. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making.

Abdominal Pain↗

PubMedDate not supplied

Nephropathia epidemica (hemorrhagic fever with renal syndrome) in Scandinavia.

Nephropathia epidemica (NE) in Scandinavia is a zoonosis caused by Puumala virus. The main animal reservoir is the bank vole. NE predominantly affects men. Its annual incidence varies in a cyclic fashion, with peaks occurring every third to fourth year. The clinical picture of NE in Scandinavia is similar to that of hemorrhagic fever with renal syndrome in other parts of the world, although NE generally has a milder course. The case-fatality rate is approximately 0.2%. The most common clinical findings in NE are an acute onset of symptoms, fever (greater than or equal to 38 degrees C), oliguria, headache, back pain, and polyuria. Hemorrhagic manifestations are seen in about one-third of cases, and up to 5% of patients have gastrointestinal bleeding or disseminated intravascular coagulation. Thrombocytopenia occurs in a majority of patients. In the acute phase, the glomerular filtration rate is markedly decreased and tubular dysfunction is evident. Most patients with NE recover within 6 months.

Animals↗

PubMed1974

A followup report of a prospective evaluation of vagotomy-pyloroplasty and vagotomy-antrectomy for treatment of duodenal ulcer.

A prospective randomized study of 200 consecutive patients who required elective operation for treatment of duodenal ulcer was conducted. Truncal vagotomy and drainage (V-D) was done in 108 patients with a 2% mortality and truncal vagotomy and antrectomy (V-R) were performed in 92 patients with no mortality. Ninety-four per cent of these patients were followed 5-8 years after operation or until their death if that preceded the termination of the study. The immediate postoperative morbidity including stomal dysfunction and reoperation was greater after V-D than after V-R. In the opinion of the patients and independent investigators, the number of gastrointestinal complaints was similar throughout the study for the two groups of patients. In the opinion of the author, however, more gastrointestinal complaints occurred in patients from the V-R group than from the V-D group. Because of the subjectivity involved in the evaluation of these complaints, it is unknown whether a real difference existed between the two groups of patients. No patient in either group was symptomatically disabled after operation. There were nine recurrent ulcers requiring reoperation after V-D and one after V-R. The insulin test was positive in 58% of patients after V-D and 14% after V-R. These figures were essentially unchanged from those in the first report made three to five years after operation. The basal acid output and the response to histalog stimulation also remained unchanged in the two groups of patients during the same period. This study suggests that if one abstains from resection in patients where technical difficulties with the duodenum can be expected, V-R can be performed in the remaining patients with a mortality rate equally as low as that usually reported for V-D. It is concluded that V-R is superior to V-D for the majority of patients because it is associated with fewer recurrent ulcers without a significant difference in the severity of other postoperative gastrointestinal complaints.

Body Weight↗

PubMed1994

Phase II studies of recombinant human interleukin-4 in advanced renal cancer and malignant melanoma.

Interleukin (IL-4) is a pluripotent cytokine that stimulates proliferation of activated T-cells and has antineoplastic activity against human renal tumors in animal systems. In phase I trials, IL-4 could be tolerated at doses up to 20 micrograms/kg, with dose-limiting toxicities consisting of fever, fluid retention, nasal congestion, and mucositis. We report the results of two separate Phase II trials of IL-4 in 30 patients with metastatic malignant melanoma and 19 patients with advanced renal cancer. IL-4 was administered intravenously every 8 h for 14 doses in two 5-day courses separated by a 9-day interval. The first 27 patients were treated at a dose of 800 micrograms/m2, but after three of these patients developed cardiac toxicities, the dose was decreased to 600 micrograms/m2. One complete response occurred in a patient with metastatic melanoma (duration > or = 30 months). No responses were seen among the patients with renal cancer. The most frequent side effects were fever, nausea, malaise, nasal congestion, and diarrhea. Reversible hepatic and renal dysfunction were also common. Hypotension was infrequent, but transient weight gain due to fluid retention was common. The major life-threatening toxicities were cardiac and gastrointestinal. Suspected cardiac ischemia was observed in two patients, pericarditis in one, and arrhythmias in two. Three patients had major upper gastrointestinal bleeding without evidence of local tumor. We conclude that IL-4, when given as a single agent on this schedule at maximum tolerated dose, does not possess meaningful activity in renal cancer or melanoma.

Adult↗

PubMed2006

Successful identical-twin living donor small bowel transplant for necrotizing enterovasculitis secondary to Churg-Strauss syndrome.

Churg-Strauss syndrome (CSS) is a granulomatous small-vessel vasculitis with unknown etiology. Extra-pulmonary manifestations of CSS are currently treated with a combination of steroids and Cyclophosphamide. Its gastrointestinal complications may be devastating, occasionally requiring extensive bowel resection resulting in short-gut syndrome. Living-related small bowel transplantation (LRSBTx) is a relatively standardized procedure that, not only represents a valid alternative to cadaver bowel transplant in selected cases, but also portraits excellent results when performed in experienced centers. The availability of an identical twin as a donor, which allows avoidance of immunosuppressive therapy, is a major indication for this procedure. We present the case of a young individual affected by gastrointestinal necrotizing vasculitis that lost almost his entire small bowel requiring the immediate institution of total parenteral nutrition (TPN). However, within few weeks a significant hepatic dysfunction ensued. An identical twin-brother, not affected with CSS, became an immediate, optimal donor-candidate for LRSBTx, the first of this kind in a patient affected with CSS. Following the procedure, two main concerns were addressed: the recipient's ability to recover a regular intestinal function without immunosuppression and the possible recurrence of the primary disease. Twenty-seven months post-transplant, the patient enjoys a regular lifestyle without any clinical, endoscopic and histologic evidences of recurrent disease in the transplanted graft.

Adult↗

PubMed2002

Vitamin B(12) deficiency associated with histamine(2)-receptor antagonists and a proton-pump inhibitor.

OBJECTIVE: To report a case of vitamin B(12) deficiency associated with long-term use (approximately 4 1/2 y) of histamine(2) (H(2))-receptor antagonists and a proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux. CASE SUMMARY: A 78-year-old nonvegetarian white woman with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 times daily in February 1990 and took various other antisecretory medications over the course of the next 4 1/2 years. She had a normal serum vitamin B(12) concentration of 413 pg/mL in August 1992. In June 1994, her serum vitamin B(12) concentration was found to be in the low normal range at 256 pg/mL. Biochemical markers of vitamin B(12)-dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine (HCYS) were elevated at 757 nmol/L and 27.3 micromol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of vitamin B(12) 1000 microg/d, which confirmed vitamin B(12) deficiency. Oral replacement also demonstrated that the woman was able to adequately absorb nonprotein-bound vitamin B(12) from the gastrointestinal tract, suggesting that her deficiency was a result of food-cobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites dramatically decreased with vitamin B(12) replacement. DISCUSSION: Malabsorption of dietary protein-bound vitamin B(12) has been demonstrated with the use of H(2)-receptor antagonists and PPIs. One previous case report of vitamin B(12) deficiency resulting from long-term use of omeprazole has been published. The malabsorption of dietary vitamin B(12) is thought to be a result of its impaired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process. CONCLUSIONS: The use of H(2)-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B(12) and could contribute to the development of vitamin B(12) deficiency with prolonged use. Patients taking these medications for extended periods of time, particularly >4 years, should be monitored for vitamin B(12) status.

Aged↗