Biomedical subjects
Publications and source records attributed to W E Whitehead.
This literature review and the recommendations therein were prepared for the American Gastroenterological Association Clinical Practice and Practice Economics Committee. Following external review, the paper was approved by the committee on May 17, 1998.
A very frequent missense mutation at codon 97 of human hepatitis B virus (HBV) core antigen (HBcAg) has been found in chronic carriers worldwide. Functional characterization of this mutant revealed one intracellular and two extracellular phenotypes in contrast to wild-type HBV: (i) a 6- to 12-fold decrease in the level of the full-length relaxed circular DNA, a 4- to 5-fold decrease in the plus-strand DNA, and an approximately 1.8-fold decrease in the minus-strand and overall DNA levels in the intracellular viral core particles; (ii) a 5.7-fold increase in the immature secretion of Dane particles, containing minus-strand, single-stranded virion DNA; and (iii) a significant reduction of nonenveloped core particles in the medium. The steady-state levels of mutant and wild-type core proteins expressed from the same vector appeared to be similar. Using a complementation assay and gradient centrifugation analysis, we demonstrated that this mutant core protein alone is necessary and sufficient for immature secretion. The decreased level of intracellular HBV DNA is caused by both the cis defect of the mutant genome and the trans defect of the mutant core protein. We have dissected further the relationship between the intracellular and extracellular phenotypes of mutant F97L. The pleiotropic effects of the HBcAg codon 97 mutation were observed consistently in several different experimental settings. The mechanism and biological significance of these findings are discussed.
The functional gastrointestinal disorders (FGID) are the most frequent conditions seen in gastroenterology practice and comprise a major portion of primary care. Psychosocial factors are important in these disorders with regard to: (1) their effects on gut physiology; (2) their modulation of the symptom experience; (3) their influence on illness behavior; (4) their impact on outcome; and (5) the choice of the therapeutic approach. This paper provides a review and consensus of the existing literature by gastroenterologists, psychiatrists, psychologists, physiologists, and health services investigators. Evidence is provided to support the biopsychosocial model as a basis for understanding and treating these disorders, and epidemiological and clinical information on the relations of psychosocial factors to gut physiology, symptom presentation, health behavior, and outcome is offered. Features of motility, personality, abuse history, health concerns, and treatment-seeking differ between patients with FGID and healthy controls, but they are not specific to FGID. They occur in other patients with chronic medical conditions and/or psychiatric disorders. Review of treatment trials indicates clear support for psychotherapeutic treatments, especially in the long term, as well as some evidence for the benefit of antidepressants in FGID, even in the absence of improvements in mood.
In this report the functional anorectal disorders, the etiology of which is currently unknown or related to the abnormal functioning of normally innervated and structurally intact muscles, are discussed. These disorders include functional fecal incontinence, functional anorectal pain, including levator ani syndrome and proctalgia fugax, and pelvic floor dyssynergia. The epidemiology of each disorder is defined and discussed, their pathophysiology is summarized and diagnostic approaches and treatment are suggested. Some suggestions for the direction of future research on these disorders are also given.
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PURPOSE: There are few data about the relationships between colonic motor behavior and higher brain functions, such as sleep. Previous studies were done in healthy subjects, and it is unknown whether patients with functional motor disorders of the colon behave differently. This study was designed to characterize colonic motor activity in patients with constipation, both during sleep and after sudden awakening, and to compare it with that of healthy subjects. Our working hypothesis was that patients with constipation would have an impaired response to sudden awakening. PATIENTS AND METHODS: Twelve chronically constipated women, 22 to 49 years old, were recruited for the study, and their data were compared with those obtained from 12 healthy female volunteers, 21 to 38 years old. Manometric studies were performed in the descending and sigmoid colon for 30 minutes during sleep (immediately before awakening) and 30 minutes after being awakened suddenly. A motility index was calculated before and after the stimulus. RESULTS: In both groups motility in the descending and the sigmoid colon was almost absent during sleep and significantly increased after sudden awakening. No difference in postawakening values was found between patients with constipation and controls. CONCLUSIONS: In patients with chronic constipation, the brain-gut control of some fundamental mechanisms governing colonic motility is preserved. These data suggest that the alterations of colonic motility described in chronic constipation may be caused by an intrinsic dysfunction of the viscus.
BACKGROUND & AIMS: Rectal pain sensitivity has been called a biological marker for irritable bowel syndrome, but this conclusion may be premature. This article is a critical review of the evidence for psychological influences on perception. METHODS: The world literature accessible through Index Medicus from 1973 to 1997 was systematically reviewed. RESULTS: Evidence favoring a biological basis for pain sensitivity is that two thirds of patients report pain at abnormally low thresholds of rectal distention despite normal somatic pain thresholds. Pain thresholds are not correlated with anxiety or depression. Evidence favoring psychological influences on perception is that patients with the irritable bowel syndrome rate even sham distentions as more painful, and when perception tests that minimize psychological influences are used, they have normal sensory thresholds. Also, stress alters sensory thresholds. Sensitization by repeated distention has been cited as evidence of a biological basis for hyperalgesia, but it is not unique to patients with irritable bowel. Brain imaging shows that different regions are activated by painful distention in patients with irritable bowel syndrome, but this is consistent with psychological influences on perception. CONCLUSIONS: Psychological factors influence pain thresholds in patients with the irritable bowel syndrome. Two cognitive traits, selective attention to gastrointestinal sensations and disease attribution, may account for increased pain sensitivity.
To determine whether functional dyspepsia and irritable bowel syndrome are different entities, epidemiological data, factor analysis studies, physiological data and associated psychological symptoms were reviewed. Between 30% and 60% of patients with either diagnosis also meet the criteria for the other diagnosis, a level greater than expected to occur by chance but not sufficient to infer an identity. Most factor analysis studies identify independent clusters of symptoms corresponding to functional dyspepsia and irritable bowel syndrome. Visceral hypersensitivity is seen throughout the gastrointestinal tract in both disorders, but the motility patterns seen in association with functional dyspepsia (principally antral hypomotility and delayed gastric emptying) differ from the motility patterns seen in irritable bowel syndrome. Psychological symptoms are similar in these two disorders but are not believed to be aetiological for either of them. Thus, based on a factor analysis of gastrointestinal symptoms and differences in intestinal motility, functional dyspepsia and irritable bowel syndrome appear to be different entities.
BACKGROUND: Erythromycin has been proposed as a therapeutic agent for the treatment of functional motor disorders of the upper gastrointestinal tract. Moreover, some data exist showing a potential effect on colonic motility. AIMS: Since no data are available concerning erythromycin effects in chronically constipated patients, we investigated the effects of three different doses of the drug (50, 200, and 500 mg i. v.) on colonic intraluminal pressures in such patients. PATIENTS AND METHODS: 18 severely constipated women were studied by a colonoscopically-positioned manometric probe, and were randomized to receive one of three doses of erythromycin. Proximal and distal colonic motility was recorded basally, then during placebo infusion for 60 min and for a further 60 min after the drug had been infused. RESULTS: Analysis of the tracings showed that, except for the lowest dose in the distal colon, erythromycin failed to stimulate colonic motility in constipated patients. CONCLUSIONS: It is concluded that erythromycin cannot be considered a colokinetic agent, at least at doses commonly employed in the upper gut.
Irritable bowel syndrome is frequently encountered in clinical practice, and it has been repeatedly suggested that abnormal colonic motor activity is one of the major pathophysiological mechanisms responsible for the origin of symptoms in such disorder. If this statement is true, then high-amplitude propagated colonic contractions (HAPCs), i.e. the mass movements, may play an important role. To test this hypothesis, we conducted an investigation by recording colonic motility for a prolonged (24 h) period in 25 patients with irritable bowel syndrome and in 18 healthy volunteers, to compare the number of mass movements over 24 h in patients (constipation-predominant, alternating bowel habits) and controls. The overall amount of motility was also assessed in twelve patients and 13 controls. We also looked for the possible changes in mass movements and motility which may occur with defecation and after a meal. The results showed that 1) with respect to HAPCs and motility index, neither group was significantly different from controls; 2) HAPCs and the motility index were significantly reduced during sleep in all groups tested; 3) HAPCs were significantly more common before as compared to after defecation and after as compared to before meals; 4) HAPCs are not independent from the segmental contractile activity; 5) the motility index/24 h was lower in the constipation-predominant group of patients with respect to controls. We conclude that in patients with irritable bowel syndrome colonic motility per se may play a pathophysiological role in the genesis of the symptoms, although other mechanisms are likely to concur, or to be responsible for the complaints of these patients. However, colonic prolonged recordings are very useful for studying physiological and pathophysiological correlates of sleep, eating, and defecation.
The aims of this study were to determine whether increased pain sensitivity in patients with irritable bowel is due to physiological differences in perceptual sensitivity or psychological influences on perception, and whether prior sexual abuse accounts for increased pain sensitivity. Seventeen sexually abused and 15 nonabused women with irritable bowel were compared to 13 sexually abused and 14 nonabused women without irritable bowel. Among the nonabused subjects, the volume of rectal distension that produced moderate pain was lower in IBS patients than in controls, replicating earlier studies, but these thresholds were correlated with psychological measures of anxiety and somatization. The ability to discriminate between painful distensions (perceptual sensitivity) was not different between groups. Sexual abuse was not associated with lower pain thresholds. Thus, differences in pain sensitivity appear to be due to psychological influences on perception, but a history of sexual abuse does not contribute significantly to this pain sensitivity.
An international working team of 13 investigators met on two occasions to develop guidelines for standardizing the procedures used to test gastrointestinal muscle tone and sensory thresholds using a barostat. General recommendations were: (1) Use a thin-walled plastic bag that is infinitely compliant until its capacity is reached. Maximum diameter of the bag should be much greater than the maximum diameter of the viscus. (2) The pump should be able to inflate the bag at up to 40 ml/sec. (3) Pressure should be monitored inside the bag, not in the pump or inflation line. (4) Subjects should be positioned so that the bag is close to the uppermost surface of the body. (5) For rectal tests, bowel cleansing should be limited to a tap water enema to minimize rectal irritation. Oral colonic lavage is recommended for studies of the proximal colon, and magnesium citrate enemas for the descending colon and sigmoid. (6) If sedation is required for colonic probe placement, allow at least one hour for drug washout and clearance of insufflated air. Ten to 20 min of adaptation before testing is adequate if no air or drugs were used. (7) The volumes reported must be corrected for the compressibility of gas and the compliance of the pump, which is greater for bellows pumps than for piston pumps. (8) Subjects should be tested in the fasted state. For evaluation of muscle tone: (9) The volume of the bag should be monitored for at least 15 min. For evaluation of sensory thresholds; (10) It is recommended that phasic distensions be > or = 60 sec long and that they be separated by > or = 60 sec. (11) Sensory thresholds should be reported as bag pressure rather than (or in addition to) bag volume because pressure is less vulnerable to measurement error. (12) Tests for sensory threshold should minimize psychological influences on perception by making the amount of each distension unpredictable to the subject. (13) Pain or other sensations should be reported on a graduated scale; not "yes-no." The working team recommends verbal descriptor scales, containing approximately seven steps, or visual analog scales in which subjects place a mark on a straight line marked "none" on one end and "maximum" on the other end. (14) It is recommended that subjects should be asked to rate the unpleasantness of distensions separately from their intensity.
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Biofeedback, relaxation training, and cognitive behaviour modification are being increasingly proposed for the treatment of numerous functional disorders of the gastrointestinal tract. Among these, those related to the lower part of the gut seem to be more likely to benefit from this therapeutic approach. We examine and discuss the literature studies adopting such techniques.
The aims of this study were to determine the impact of irritable bowel syndrome on quality of life using a well-standardized measure, the SF-36, and to determine whether apparent impairments may be due to neuroticism. Undergraduate students with irritable bowel syndrome who had consulted a physician (41 females, 42 males), students with irritable bowel who had not consulted a physician (91 females, 74 males), and asymptomatic controls (52 females, 70 males) completed questionnaires on quality of life, neuroticism, and psychological distress. Patients showed greater impairment in quality of life than nonconsulters, who in turn showed greater impairment than controls. Neuroticism and psychological distress were correlated with all quality-of-life measures. However, when neuroticism and psychological distress were statistically partialed out, irritable bowel syndrome still had a significant negative impact. The SF-36 may be a useful outcome measure in treatment studies, but investigators will need to correct for confounding influences of neuroticism.
Increased numbers of psychiatric diagnoses and increased levels of psychological distress are seen in the majority of medical clinic patients with gastrointestinal motility disorders. In IBS, psychological symptoms are believed to be comorbid conditions, which do not cause the motility disorder but which do influence the patient's decision to consult a physician. In functional dyspepsia, psychological symptoms are present in many patients, but their role is not known; the available data suggest that psychological symptoms do not predict which patients will consult a physician. Among constipated patients, anxiety is believed to contribute to the development and course of pelvic floor dyssynergia by increasing pelvic floor muscle tension. Constipated patients without physiologic abnormalities to explain their constipation appear to have more psychological symptoms than those with delayed colonic transit, but there is significant psychological distress even in patients with slow transit constipation. Psychological symptoms do not seem to predict which constipated patients will consult a physician. There is an increased incidence of psychiatric diagnoses in patients with esophageal motility disorders as well, but the role that these psychological symptoms play in the course of the disorder is not known. Patients with the most common gastrointestinal motility disorders, IBS and dyspepsia, report experiencing more stressful life events, and IBS patients appear to show a greater increase in gastrointestinal symptoms when exposed to stressors. Laboratory studies document that acute psychological stressors do alter gastric, small bowel, and colonic motility, and patients with IBS appear to show a greater change in colonic and ileal motility with stress than healthy controls. Greater reactivity has not been demonstrated for the esophagus or stomach, however, and it has not been demonstrated for other gastrointestinal motility disorders. A characteristic of many patients who consult gastroenterologists for IBS and other motility disorders is a tendency to report multiple somatic complaints (including many nongastrointestinal complaints) and to overuse medical resources. This pattern of behavior is referred to as somatization or abnormal illness behavior. One source of abnormal illness behavior is childhood social learning, which occurs (1) when parents provide gifts or special privileges to a child who reports somatic symptoms or (2) when parents model abnormal illness behaviors themselves.
Gastrointestinal motility is regulated by a complex balance of inhibitory and excitatory neuronal, humoral, and mechanical factors. The goal in the management of motility disorders is to maintain adequate nutrition while decreasing symptoms. This can be accomplished by medications and support of nutrition and biofeedback; the application of these therapeutic strategies to patients with gut motility disorders is reviewed.
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