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Gastrointestinal complications in shock.

The gut organs are vulnerable to injury during shock because of ischemia and reperfusion of the microcirculation. These injuries result in upper GI hemorrhage, liver dysfunction, and pancreatic and mesenteric necrosis. Toxic mediators, released via lymph drainage and with reperfusion, contribute to the failure of other organs and the development of refractory shock. Until single organ perfusion can be measured, the primary goal of care is to maintain systemic perfusion. Secondary goals are to decrease hydrogen ion accumulation, minimize pancreatic stimulation, remove hepatotoxic agents, and reduce blood bacteria. Gut ischemia is simply one piece of the puzzle in the multiple organ response to reduced systemic oxygenation and perfusion that characterizes the clinical syndrome of shock.

Gastrointestinal Diseases↗

Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion.

BACKGROUND: Glucose-insulin-potassium infusions are beneficial in uncomplicated patients with acute myocardial infarction (AMI) but are of unproven efficacy in AMI with left ventricular (LV) dysfunction because of volume requirements associated with glucose infusion. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with both insulinotropic and insulinomimetic properties that stimulate glucose uptake without the requirements for concomitant glucose infusion. METHODS AND RESULTS: We investigated the safety and efficacy of a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) added to background therapy in 10 patients with AMI and LV ejection fraction (EF) <40% after successful primary angioplasty compared with 11 control patients. Echocardiograms were obtained after reperfusion and after the completion of the GLP-1 infusion. Baseline demographics and background therapy were similar, and both groups had severe LV dysfunction at baseline (LVEF=29+/-2%). GLP-1 significantly improved LVEF (from 29+/-2% to 39+/-2%, P<0.01), global wall motion score indexes (1.94+/-0.11-->1.63+/-0.09, P<0.01), and regional wall motion score indexes (2.53+/-0.08-->2.02+/-0.11, P<0.01) compared with control subjects. The benefits of GLP-1 were independent of AMI location or history of diabetes. GLP-1 was well tolerated, with only transient gastrointestinal effects. CONCLUSIONS: When added to standard therapy, GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty.

Adult↗

[Hypoxemia after gastrointestinal endoscopy under general anesthesia in a patient with unilateral diaphragmatic paralysis].

A 59-year-old woman with suspected hypopharyngeal cancer was scheduled for biopsy using direct laryngoscopy. Her preoperative chest X-ray showed asymptomatic left unilateral diaphragmatic paralysis. Anesthesia was induced with propofol and maintained with oxygen, nitrous oxide and sevoflurane. The region was difficult to reach during direct laryngoscopy. Therefore, gastrointestinal endoscopy was performed. Air was injected through the scope to aid viewing. After tracheal extubation, oxygen saturation as indicated by pulse oximetry (SpO2) decreased to 91% from 97% although oxygen was delivered via a mask at 6 l x min(-1). A chest radiograph showed that the air-filled gastrointestinal tract had elevated the left dome of the diaphragm. After the stomach was suctioned via a nasogastric tube, respiration was assisted via a mask with continuous positive airway pressure. Then, SpO2 returned to 99%. An air-filled dilated stomach may increase the risk of respiratory dysfunction in patients with unilateral diaphragmatic paralysis.

Anesthesia, General↗

Interstitial cells of Cajal at the clinical and scientific interface.

Considerable work over the past two decades has determined that interstitial cells of Cajal (ICC) serve as pacemaker cells, conduits for active transmission of electrical slow waves, sites of innervation by peripheral motor neurons, and mechanotransducers. While most of the physiology of ICC has been learned from studies of the cells within the gastrointestinal tract, ICC are found in a variety of smooth muscle tissues and may have analogous or novel physiological functions in those organs. Clinical investigations of muscles from patients with a variety of gastrointestinal motility disorders have raised the exciting possibility that loss of ICC may be responsible for the development of motor dysfunction. This review discusses the development of ICC, the kinds of human disorders in which ICC loss may be important, what factors regulate the ICC phenotype, and what therapeutic approaches might be utilized to restore or regenerate ICC. This field is primed for translational discoveries. ICC are responsible for critical physiological functions in smooth muscle tissues, they are lost in pathophysiological conditions, and it will be important now to decipher the conditions that are responsible for ICC loss and develop new therapies to relieve patients of this problem. Success in this endeavour might improve the quality of life for millions of patients.

Animals↗

Anorectal function in fluctuating (on-off) Parkinson's disease: evaluation by combined anorectal manometry and electromyography.

Anorectal dysfunction and constipation are well recognized in Parkinson's disease and may reflect the direct involvement of the gastrointestinal tract by the primary Parkinson's disease process. We hypothesized, therefore, that anorectal function would alter in parallel with fluctuations in motor function related to on- and off-periods in Parkinson's disease, and employed combined anorectal manometry and electromyography to investigate anorectal function during both on- and off-periods in patients with Parkinson's disease. Manometric recordings revealed a deterioration in voluntary sphincter squeeze during off-periods (squeeze index, on versus off, mean +/- SEM: 46.4 +/- 11.1 versus 29.6 +/- 7.9 mm Hg, p < 0.05); correspondingly, simultaneous electromyographic (EMG) recordings showed poor recruitment of external anal sphincter and puborectalis muscles during off-periods. A hypercontractile ("paradoxical") rectosphincteric reflex response occurred during both on- and off-periods, and was associated with an increase in EMG activity in the external sphincter and/or the puborectalis muscle. These changes in manometric and EMG parameters paralleled changes in overall motor function. These findings provide further support for the involvement of the pelvic floor musculature in the Parkinson's disease process and also provide EMG correlates for some of the manometric abnormalities described in Parkinson's disease.

Age of Onset↗

Recessive FANCM cancer syndrome with high cancer risks, chemotherapy toxicity, chromosome fragility, and gonadal failure.

PURPOSE: Heterozygous FANCM variants have been associated with breast cancer. Only a few studies have examined other cancer types. Biallelic truncating variants have been linked to a Fanconi anemia (FA)-like cancer prone syndrome in case reports; however, the range of cancers and the risk estimates are lacking. METHODS: We studied the association of Finnish-enriched variants c.5101C>T p.(Gln1701Ter) and c.5791C>T p.(Arg1931Ter) with risk of any cancer and FA-related conditions in the FinnGen data with 500,348 individuals. RESULTS: Heterozygous c.5101C>T (N = 10,940) was associated not only with an increased risk of breast cancer (odds ratio = 1.24, P = 2.7 &#xd7; 10-6) but also with risks of other cancer types, including hypopharyngeal (odds ratio = 3.98, P = 3.6 &#xd7; 10-7), suggesting a risk effect wider than previously described. Homozygous c.5101C>T (N = 76) was associated with a high risk of breast, head and neck, gastrointestinal, gynecological, hematologic, skin, and lung cancer, whereas c.5791C>T was rare. Additionally, high recessive risks of ovarian dysfunction and hematologic side effects after cancer treatment were detected, but no risks of bone marrow failure or physical features of FA. CONCLUSION: Based on the pattern of risks associated with biallelic variants, we suggest a novel FANCM cancer syndrome that is separate from FA and other characterized cancer susceptibility syndromes.

Humans↗

Bladder augmentation: ureterocystoplasty versus ileocystoplasty.

The primary advantages of augmentation ureterocystoplasty include the absence of mucus, lack of electrolyte absorption from the augmenting segment and the avoidance of gastrointestinal complications. We tested whether the ureteral patch offers sufficient biomaterial to increase adequately the storage efficiency of dysfunctional bladders. Between April 1989 and November 1992, 8 children with unilaterally dilated and tortuous ureters underwent bladder augmentation using detubularized reconfigured megaureter. Clinical and urodynamic outcomes were compared between these patients and a control group of 8 children matched in age and diagnosis who had undergone ileocystoplasty during the same time. Total bladder capacity, pressure specific bladder volume at pressure less than 30 cm. water, dynamic analysis of bladder compliance, continence and upper tract status were compared between the 2 groups before and after augmentation. Preoperatively, all 16 patients were incontinent with high pressure, small capacity bladders, and all had upper tract changes. Postoperatively, the mean total bladder capacity was 417 ml. in the ureterocystoplasty group and 381 ml. in the ileocystoplasty group (p > 0.05), while the mean pressure specific bladder volume was 413 and 380 ml. (p > 0.05), respectively. Pressure specific bladder volume and dynamic bladder compliance were normal in 7 of 8 patients (87.5%) in the ureterocystoplasty group. All patients in the ileocystoplasty group had normal postoperative urodynamics. We conclude that megaureters subtending effete kidneys may be used to improve the storage function of dysfunctional bladders to the same extent as that achieved with ileum without the complications pursuant to ileocystoplasty, and that the improvement is maintained long term.

Adolescent↗

Rate of gastric emptying is a determinant of postprandial hypotension in non-insulin-dependent diabetes mellitus.

1. Postprandial hypotension is now recognized as an important clinical problem, particularly in the elderly and in patients with autonomic dysfunction. The mechanisms responsible are poorly understood; however, impaired regulation of splanchnic blood flow and the release of gastrointestinal hormones appear to be important. The effect of gastric emptying on the magnitude of the postprandial fall in blood pressure has not been evaluated. 2. The aim of this study was to determine whether there is a relationship between changes in blood pressure and the rate of gastric emptying after ingestion of 75 g of glucose in patients with non-insulin-dependent diabetes mellitus (NIDDM) and both young and older normal subjects. Sixteen patients with recently diagnosed NIDDM, median age 57 (39-79) years, 10 'young' subjects with a median age of 23 (19-26) years and nine 'older' subjects, median age 48 (40-68) years, were measured simultaneously for gastric emptying of 75 g of glucose in 350 ml of water blood pressure and blood glucose concentrations, commencing at approximately 10.00 hours after an overnight fast. Measurements of blood pressure were made in the sitting position immediately before glucose ingestion and at 15 min intervals up to 180 min. 3. Gastric emptying of glucose was not significantly different between the three groups [50% emptying time (T50): 95 +/- 7.3 min in patients with NIDDM compared with 120 +/- 13.2 min in the 'young' group and 97 +/- 8.1 min in the 'older' group]. There was a significant fall in mean blood pressure after the glucose load in the patients with NIDDM (P < 0.0001) and the 'older' normal subjects (P < 0.05), but not the 'young' normal subjects. Postprandial hypotension (fall in systolic blood pressure > or = 20 mmHg) was evident in seven (44%) patients with NIDDM and three (33%) 'older' normal subjects. The area under the change in mean blood pressure curve was related significantly to the gastric emptying T50 (r = 0.67, P < 0.005) in the patients with NIDDM, but not in either control group. 4. In conclusion, in patients with recently diagnosed NIDDM the fall in blood pressure after an oral glucose load is (i) greater than in both young and older normal subjects and (ii) related to the rate of gastric emptying.

Adult↗

Gastroesophageal reflux disease. When antacids aren't enough.

Gastroesophageal reflux disease is a very common condition that is usually manifested by heartburn or regurgitation. Reflux esophagitis, caused by mucosal exposure to the backflow of caustic gastric contents, is primarily a result of lower esophageal sphincter dysfunction. Diagnostic workup varies but commonly includes esophagoscopy, 24-hour esophageal pH monitoring, and radiography of the upper gastrointestinal tract. Treatment, which progresses from simple life-style changes and antacids to histamine2 receptor antagonists to omeprazole (Prilosec) or surgery, is tailored to individual needs and is generally successful.

Esophagitis, Peptic↗

Stress-related illnesses and sources of stress: comparing M.D.-Ph.D., M.D., and Ph.D. students.

A study was conducted to determine the prevalence and incidence of stress-associated illnesses and to identify possible sources of stress among students enrolled in the M.D.-Ph.D. program of a midwestern university. Specially constructed questionnaires were completed by 45 M.D.-Ph.D. students, 334 M.D. students, and 42 Ph.D. students at this university. The information obtained from the M.D.-Ph.D. students was compared with the responses of the M.D. students and the Ph.D. students. Male M.D.-Ph.D. students had a significantly higher incidence of hypertension, colitis, and asthma, while female M.D.-Ph.D. students reported a higher usage of antacids and occurrence of gastritis or ulcers during the time that they were enrolled in their programs. M.D.-Ph.D. students indicated that the fear of flunking out of school and the grading system were more stressful than did the M.D. students. Additionally, relationship with the graduate adviser and the graduate committee was more stressful to M.D.-Ph.D. students than to Ph.D. students.

Amenorrhea↗

Burns, bacterial translocation, gut barrier function, and failure.

The development of systemic inflammation, acute lung injury, and multiple organ failure after a major thermal injury, as well as nonthermal forms of trauma, remain relatively common causes of morbidity and mortality. During the past two decades, increasing recognition that the ischemic gut may contribute to the development of sepsis and organ failure in burn patients, as well as other critically ill patient populations, has led to new hypotheses to explain burn-induced multiple organ failure as well as highlighted the importance of early enteral nutrition. Thus, the goal of this review will be to provide a perspective on the evolution of the gut hypothesis of systemic inflammation and distant organ dysfunction.

Bacterial Translocation↗

The role of exogenous p53 and E6 oncoproteins in in vitro transformation by bovine papillomavirus type 4 (BPV-4): significance of the absence of an E6 ORF in the BPV-4 genome.

Bovine papillomavirus type 4 (BPV-4) does not possess an E6 ORF. The E6 oncoprotein of human papillomavirus (HPV) binds and degrades the tumour suppressor protein p53, thus contributing to tumour progression. Since BPV-4 lacks E6, it is unknown how the virus evades the tumour suppressor properties of p53 in the induction of tumours of the gastrointestinal tract. Mutations in the p53 gene have been detected both in papillomas and carcinomas, suggesting that p53 dysfunction plays a part in these neoplasias. BPV-4 can transform primary foetal bovine cells (PalFs) in cooperation with an activated ras gene, but the transformed cells are neither immortal nor tumorigenic. Co-transfection with the HPV-16 E6 (16E6) ORF confers immortality but not tumorigenicity. To investigate the role of p53 in BPV-4 cell transformation in vitro, we transfected PalFs and p53-null mouse fibroblasts with BPV-4 DNA in combinations with ras, 16E6 ORF and mutant (V143A) p53 cDNA. Transfection of PalFs with BPV-4 DNA, ras and mutant p53 led to cell immortalization, indicating that 16E6 and mutant p53 are functionally equivalent in conferring immortality. However, co-transfection of PalFs with BPV-4 DNA, ras, and both mutant p53 cDNA and 16E6 ORF resulted in cells which were fully transformed to tumorigenicity. In p53-null mouse fibroblasts, BPV-4 DNA induced transformation by itself, but the transformed cells were incapable of suspension growth. The co-transfection of BPV-4 DNA with 16E6 ORF produced many more transformed colonies and the cells were capable of growing in suspension. In this system, therefore, 16E6 confers anchorage-independence to BPV-4-transformed cells in a p53-independent fashion.

Animals↗

Investigation of anal function in patients with systemic sclerosis.

OBJECTIVE: To investigate anorectal function in women patients with systemic sclerosis (SSc), with and without lower gastrointestinal symptoms. METHODS: Anorectal manometry was performed in 16 patients with SSc: six with no or minimal bowel symptoms, seven with constipation, and three with diarrhoea and faecal incontinence. Eleven healthy women acted as control subjects. Pressure data were recorded via an eight lumen polyvinylchloride water perfused catheter. Station and rapid pull through techniques were used. RESULTS: In the patients with SSc, mean resting pressure, maximal voluntary squeeze effort, and squeeze vector volume were lower, and squeeze asymmetry was greater, compared with the healthy controls. Differences were significant in the subgroup with constipation. CONCLUSION: Radial asymmetry and vector volume parameters provide detailed analysis of segmental anal canal function. Our findings suggest significant segmental deficits in those patients with SSc who have lower gastrointestinal symptoms. The trend towards smaller pressures and squeeze vector volumes in the asymptomatic SSc group suggests subclinical dysfunction in these patients.

Adult↗

Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy).

Bernard-Soulier syndrome (BSS), also known as Hemorrhagiparous thrombocytic dystrophy, is a hereditary bleeding disorder affecting the megakaryocyte/platelet lineage and characterized by bleeding tendency, giant blood platelets and low platelet counts. This syndrome is extremely rare as only approximately 100 cases have been reported in the literature. Clinical manifestations usually include purpura, epistaxis, menorrhagia, gingival and gastrointestinal bleeding. The syndrome is transmitted as an autosomal recessive trait. The underlying defect is a deficiency or dysfunction of the glycoprotein GPIb-V-IX complex, a platelet-restricted multisubunit receptor required for normal primary hemostasis. The GPIb-V-IX complex binds von Willebrand factor, allowing platelet adhesion and platelet plug formation at sites of vascular injury. Genes coding for the four subunits of the receptor, GPIBA, GPIBB, GP5 and GP9, map to chromosomes 17p12, 22q11.2, 3q29, and 3q21, respectively. Defects have been identified in GPIBA, GPIBB, and GP9 but not in GP5. Diagnosis is based on a prolonged skin bleeding time, the presence of a small number of very large platelets (macrothrombocytopenia), defective ristocetin-induced platelet agglutination and low or absent expression of the GPIb-V-IX complex. Prothrombin consumption is markedly reduced. The prognosis is usually good with adequate supportive care but severe bleeding episodes can occur with menses, trauma and surgical procedures. Treatment of bleeding or prophylaxis during surgical procedures usually requires platelet transfusion.

Bernard-Soulier Syndrome↗

Toxicity of the topoisomerase I inhibitors.

The topoisomerase I inhibitors represent a class of antineoplastic agents with a wide spectrum of activity against malignancies. Currently available topo-isomerase I inhibitors are derivatives of the parent compound, camptothecin. Irinotecan is most active against gastrointestinal (GI) tumours, and has predominantly GI and haematological toxicities. Significant pharmacokinetic variability occurs in patients with hepatic dysfunction, particularly those with glucuronidation pathway deficiencies. The toxicity of topotecan is principally haematological with little extramedullary toxicity. Topotecan is well-tolerated in patients with significant hepatic dysfunction; however, patients with even mild renal insufficiency require significant dose reductions. This article discusses the toxicities of these drugs in detail, including the need for dose adjustments in selected patient populations.

Camptothecin↗

In vivo application of intestinal pH measurement using 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF) fluorescence imaging.

Measurement of gastrointestinal intramucosal pH (pHim) has been recognized as an important factor in the detection of hypoxia-induced dysfunctions. However, current pH measurement techniques are limited in terms of time and spatial resolutions. A major advance in accurate pH measurement was the development of the ratiometric fluorescent indicator dye, 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein (BCECF). This study aimed to set up and validate a fluorescence imaging technique to measure in vivo the intramucosal pH (pHim) of the intestine. The intestine was inserted into an optical chamber placed under a microscope. Animals were injected intravenously with the pH-sensitive fluorescent dye BCECF. Fluorescence was visualized by illuminating the intestine alternately at 490 and 470 nm. The emitted fluorescence was directed to an intensified camera. The ratio of emitted fluorescence at excitation wavelengths of 490 and 470 nm was measured, corrected and converted to pHim by constructing a calibration curve. The pHim controls were performed with a pH microelectrode and were correlated with venous blood gas sampling. Results show that pHim is determined with an accuracy of +/- 0.07 pH units and a response time of 1 min. In conclusion pHim mapping of rat intestine can be obtained by fluorescence imaging using BCECF. This technology could be easily adapted for endoscopic pH measurements.

Animals↗

Chronic orofacial pain: is the puzzle unraveling?

Conditions involving chronic orofacial pain represent a major health problem, and patients with persistent pain are difficult to manage successfully. These conditions are often comorbid with additional health issues such as sleep disturbances, cardiovascular, gastrointestinal and reproductive system complaints, weight loss or weight gain, swelling, numbness, sweating and flushing, and concerns regarding loss of libido, drive, attention, and memory. Neuroendocrine and autonomic pain-stress responsivity and the consequences of pain for sensory, motor, immune and reproductive functions, and mood seem to account for the broad range of comorbid complaints. Susceptibility to a particular response appears to explain intra-individual differences in disease expression. Understanding of these regulatory, mostly adaptive processes will support novel treatments to manage many troublesome comorbid complaints for which current approaches are unsatisfactory.

Adaptation, Physiological↗