Neurohormonal perturbations in fibromyalgia

Fibromyalgia (FM) falls into the spectrum of what might be termed 'stress-associated syndromes' by virtue of frequent onset after acute or chronic stressors and apparent exacerbation of symptoms during periods of physical or emotional stress. Patients with FM exhibit disturbances of the major stress-response systems, the HPA axis and the sympathetic nervous system. Integrated basal cortisol levels measured by 24-hour urine-free cortisol are low. FM patients display a unique pattern of HPA axis perturbation characterized by exaggerated ACTH response to exogenous CRH or to endogenous activators of CRH such as insulin-induced hypoglycaemia. The cortisol response to increased ACTH in these stress paradigms is blunted, as is the the cortisol response to exercise. Functional analysis suggests that FM patients may also exhibit disturbed autonomic system activity. For example, plasma NPY, a peptide co-localized with norepinephrine in the sympathetic nervous system, is low in patients with FM. Abnormalities of related neuronal systems, particularly decreased serotonergic activity, may contribute to the observed neuroendocrine perturbations in FM. Finally, other neuroendocrine systems, including the growth hormone axis, are also abnormal in FM patients. Many clinical features of FM and related disorders, such as widespread pain and fatigue, could be related to the observed neuroendocrine perturbations. This hypothesis is supported by the observation that many useful treatments for FM affect the function of these central nervous system centres. Further clarification of the role of neuroendocrine abnormalities in patients with FM, and the relationship of these disturbances with particular symptoms, may lead to improved therapeutic strategies.     

A water-soluble antitumor glycoprotein from Chlorella vulgaris

The great majority of children referred to Pediatric Gastroenterologic Units for chronic constipation have a functional disorder and do not require investigative techniques, since functional constipation is easily recognized an anamnestic and clinical basis. Severe chronic constipation indicates a chronic condition believed to be of functional type but unresponsive to the traditional pharmacologic treatment. However, several clinical features might suggest an organic type of constipation during the initial diagnostic approach: growth failure, distension, episodes of diarrhea intermingled with constipation, subocclusive events, dilatation of areas of the gut (megaduodenum, megajejunum) at x-ray examination of the entire gastrointestinal tract. Hirschsprung's disease is the best known organic type of constipation; however, there are other neurogenic and myogenic abnormalities of the colonic (and/or ileal) tract that mimick Hirschsprung's disease and represent development abnormalities of the enteric nervous plexus. Other organic types of constipation are due to systemic diseases, endocrine and metabolic disorders, central nervous system disorders. Organic constipation usually requires extensive investigative approach, including pathologic examination of enteric nervous plexus on full thickness biopsies.     

Gastrointestinal and nutritional aspects of eating disorders

Anorexia nervosa (AN) and bulimia nervosa (BN) are potentially fatal eating disorders which primarily affect adolescent females. Differentiating eating disorders from primary gastrointestinal (GI) disease may be difficult. GI disorders are common in eating disorder patients, symptomatic complaints being seen in over half. Moreover, many GI diseases sometimes resemble eating disorders. Inflammatory bowel disease, acid peptic diseases, and intestinal motility disorders such as achalasia may mimic eating disorders. However, it is usually possible to distinguish these by applying the diagnostic criteria for eating disorders and by obtaining common biochemical tests. The primary features of AN are profound weight loss due to self starvation and body image distortion; BN is characterized by binge eating and self purging of ingested food by vomiting or laxative abuse. GI complications in eating disorders are common. Recurrent emesis in BN is associated with dental abnormalities, parotid enlargement, and electrolyte disturbances including metabolic alkalosis. Hyperamylasemia of salivary origin is regularly seen, but may lead do an erroneous diagnosis of pancreatitis. Despite the weight loss often seen in eating disorders, serum albumin, cholesterol, and carotene are usually normal. However, serum levels of trace metals such as zinc and copper often are depressed, and hypophosphatemia can occur during refeeding. Patients with eating disorders frequently have gastric emptying abnormalities, causing bloating, postprandial fullness, and vomiting. This usually improves with refeeding, but sometimes treatment with pro-motility agents such as metoclopromide is necessary. Knowledge of the GI manifestations of eating disorders, and a high index of suspicion for one condition masquerading as the other, are required for the correct diagnosis and management of these patients.     

Absence of rectoanal inhibitory reflex in a child with multiple endocrine neoplasia type 2B

BACKGROUND: Patients with multiple endocrine neoplasia (MEN) type 2B inherently present with gastrointestinal motility disorders as well as medullary thyroid carcinoma, adrenal pheochromocytoma, and Marfanoid habitus. METHODS: The authors examined gut motility function in a 7-year-old girl with MEN type 2B who had suffered from chronic constipation and recurrent acalculous cholecystitis since infancy. RESULTS: Results of total gastrointestinal barium meal and enema studies showed marked hypoperistalsis of the gut and entire colonic dilatation. Histopathologic study results of the gut wall from the stomach, duodenum, and rectum showed hyperplasia of the submucosal and intramuscular neural plexuses in all specimens. Anorectal manometry demonstrated disarrangement of the internal sphincter rhythmic wave and a complete absence of the rectoanal inhibitory reflex. CONCLUSION: These data suggest that gut motility disorders in MEN type 2B are caused by inadequately organized autonomic nervous system activity that originates from hyperplasia of the enteric nervous system.     

Alcohol abuse, alcoholism, and damage to the immune system--a review

Chronic alcohol abuse exacts a major social and medical toll in the United States and other Western countries. One of the least appreciated medical complications of alcohol abuse is altered immune regulation leading to immunodeficiency and autoimmunity. The consequences of the immunodeficiency include increased susceptibility to bacterial pneumonia, tuberculosis, and other infectious diseases. In addition, the chronic alcoholic often has circulating autoantibodies, and recent investigations indicate that the most destructive complications of alcoholism, such as liver disease and liver failure, may have a component of autoimmunity. Current research on altered cytokine balance produced by alcohol is leading to new insights on the regulation of the immune system in the chronic alcoholic. There is also recent development of exciting new techniques designed to improve or restore immune function by manipulation of cytokine balance. Although much remains to be learned, both in the abnormalities produced by alcohol and in the techniques to reverse those abnormalities, current progress reflects a rapidly improving understanding of the basic immune disorders of the alcoholic.     

Restoration of nitric oxide function in human hyperlipidaemia, congestive heart failure and liver cirrhosis

1. There is accumulating evidence for a range of abnormalities in the nitric oxide (NO) signalling cascade in human cardiovascular disorders. 2. In the present review we assess the literature detailing such evidence in early (hyperlipidaemia) and end-stage (heart failure) disease, with emphasis on the mechanisms by which the disturbances are thought to occur. 3. Strategies for the correction of disturbed NO signalling in these states are reviewed and include both prescribed pharmacological interventions, such as lipid-lowering therapy and novel uses of angiotensin-converting enzyme inhibitors, as well as non-pharmacological interventions, such as exercise and dietary supplementation with L-arginine and n-3 polyunsaturated fatty acids. 4. In addition to a decreased production/function of NO, the possible detrimental effects of a chronic elevation in NO production in patients with liver cirrhosis, together with a novel use of antibiotics to correct this perturbation, is outlined.     

Nutrient pharmacotherapy for gut mucosal diseases

The use of nutrients for pharmacotherapy is a recent advance in the treatment of gastrointestinal disorders or alterations of gut function and structure. Nutrients may have a direct effect on the gut, or may enhance the response to medications. Alternatively, pharmacologic agents may improve the absorption of nutrients. Potentially, pharmacotherapy may be an adjunct to the traditional approach used in the treatment of compromised patients.     

Localization and dynamic regulation of biogenic amine transporters in the mammalian central nervous system

The monoamines, serotonin, dopamine, norepinephrine, epinephrine and histamine, play a critical role in the function of the hypothalamic-pituitary-adrenal axis and in the integration of information in sensory, limbic, and motor systems. The primary mechanism for termination of monoaminergic neurotransmission is through reuptake of released neurotransmitter by Na+, CI-dependent plasma membrane transporters. A second family of transporters packages monoamines into synaptic and secretory vesicles by exchange of protons. Identification of those cells which express these two families of neurotransmitter transporters is an initial step in understanding what adaptive strategies cells expressing monoamine transporters use to establish the appropriate level of transport activity and thus attain the appropriate efficiency of monoamine storage and clearance. The most recent advances in this field have yielded several surprises about their function, cellular and subcellular localization, and regulation, suggesting that these molecules are not static and most likely are the most important determinants of extracellular levels of monoamines. Here, information on the localization of mRNAs for these transporters in rodent and human brain is summarized along with immunohistochemical information at the light and electron microscopic levels. Regulation of transporters at the mRNA level by manipulation in rodents and differences in transporter site densities by tomographic techniques as an index of regulation in human disease and addictive states are also reviewed. These studies have highlighted the presence of monoamine neurotransmitter transporters in neurons but not in glia in situ. The norepinephrine transporter is present in all cells which are both tyrosine hydroxylase (TH)- and dopamine beta-hydroxylase-positive but not in those cells which are TH- and phenyl-N-methyltransferase-positive, suggesting that epinephrine cells may have their own, unique transporter. In most dopaminergic cells, dopamine transporter mRNA completely overlaps with TH mRNA-positive neurons. However, there are areas in which there is a lack of one to one correspondence. The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress. The vesicular monoamine transporter 2 (VMAT2) is present in all monoaminergic neurons including epinephrine- and histamine-synthesizing cells. Immunohistochemistry demonstrates that the plasma membrane transporters are present along axons, soma, and dendrites. Subcellular localization of DAT by electron microscopy suggests that these transporters are not at the synaptic density but are confined to perisynaptic areas, implying that dopamine diffuses away from the synapse and that contribution of diffusion to dopamine signalling may vary between brain regions. Interestingly, the presence of VMAT2 in vesicles underlying dendrites, axons, and soma suggests that monoamines may be released at these cellular domains. An understanding of the regulation of transporter function may have important therapeutic consequences for neuroendocrine function in stress and psychiatric disorders.     

Mechanisms of immune cell-mediated tissue injury in inflammatory bowel disease (Review)

This review discusses the mechanisms and pathways of immune cell-mediated intestinal inflammation and tissue injury in inflammatory bowel disease (IBD). Our lack of understanding of how the mucosal immune system normally functions to maintain the balance between tolerance and immunity to innumerable dietary and bacterial constituents of the gut is perhaps the biggest obstacle to understanding the cause(s) of IBD, and to developing more effective treatments for these debilitating disorders. Evidence that abnormalities or disruptions in the interaction of immune cells and gut bacteria can trigger or contribute to changes in the composition, regulation and activity of the mucosal immune system that result in inflammatory immune responses and tissue injury are discussed. Based upon these studies, we propose a model to explain how a breakdown in regulation and failure to resolve immune responses in the gut mucosa results in persistent activation of T lymphocytes and other immune cells and the uncontrolled production of soluble inflammatory mediators that directly or indirectly produce the pathophysiological changes and tissue injury characteristic of IBD.     

Long-term outcomes of nonsurgical treatment in nonreducing anteriorly displaced disk of the temporomandibular joint

OBJECTIVE: To review the evidence supporting the biopsychosocial model in understanding patients with gastrointestinal disorders (GI). METHOD: Essay of personal experience and review of related literature through a MEDLINE search. RESULTS: Through clinical examples of three common gastrointestinal disorders, a case is made to refocus our understanding from a biomedical or disease-based model of illness to a biopsychosocial model. With the latter model, the psychosocial and biological predeterminants are seen to interact in the clinical expression of illness and disease. With gastroesophageal reflux disease, the evidence shows that stress can lead to amplification of heartburn symptoms that is independent of the degree of reflux. Functional gastrointestinal pain is "an illness without disease," where structural or physiological disturbance of the GI system does not exist. Rather, the symptoms are understood in terms of visceral hypersensitivity as modulated by central nervous system activity. With the Crohn's disease example, the clinical expression of the disorder is not explained by the degree of disease activity. Rather, the symptoms and impaired quality of life relate to preexisting psychosocial determinants. The observed association of stress with disease activation in Crohn's disease is explained by stress-related alterations in psychoimmunological function via the hypothalamic-pituitary-adrenal axis. CONCLUSIONS: Gastrointestinal disorders, as a model for other medical conditions, exemplify the important role of an integrated, biopsychosocial model of illness.     

Chloride secretion in the intestinal epithelium: channels, ions, and intracellular signaling

Salt and water secretion by epithelial cells is required to hydrate the mucosal surface of both gastrointestinal and respiratory tracts. Intestinal secretion is the result of active transcellular chloride transport by epithelial cells lining the crypts. Defective chloride secretion is responsible for many common disorders such as secretory diarrhea and cystic fibrosis. In this review we deal with the most relevant issues regarding epithelial transcellular chloride secretion. We first consider the principles of membrane transport and transport protein function. Then, we briefly discuss the use of state-of-the-art techniques for electrophysiological studies such as "patch-clamp" and microfluorometry. The epithelial chloride secretion model is described according to observations made in both native tissue and cultured intestinal epithelial cells. Next, we consider the intracellular signaling cascades involved in the regulation of membrane transport systems and transcellular chloride secretion. Finally, the clinical implications of the most recent findings are commented, with emphasis on potential molecular targets for the treatment of cystic fibrosis and secretory diarrhea.     

The delayed entry of thoracic neural crest cells into the dorsolateral path is a consequence of the late emigration of melanogenic neural crest cells from the neural tube

Recent studies have shown that changes in dendritic architecture are an important component of functional plasticity in the adult central nervous system. In the present study, we determined whether gonadectomy induces changes in dendritic architecture in the arcuate nucleus, a target tissue for gonadal hormones. A combination of retrograde labeling with systemically injected Fluoro-Gold and intracellular injection of neurons in a fixed-slice preparation was used to examine the morphology of neuroendocrine neurons in the rat arcuate nucleus. Intracellullary filled arcuate neuroendocrine neurons (8-21 neurons per brain) from intact (n = 5) and orchidectomized (n = 5) animals were reconstructed with the aid of a computer microscope. A quantitative analysis revealed that orchidectomy had no effect on the number and distribution of Fluoro-Gold-labeled neuroendocrine neurons in the rat arcuate nucleus. The morphology of arcuate neuroendocrine neurons in intact animals was relatively simple, with the majority of neurons (79%) having only two primary dendrites and few dendritic spines. Compared with intact controls, arcuate neuroendocrine neurons in the orchidectomized group had significantly larger somatic profile areas and exhibited significant increases in dendrite length, dendrite volume, terminal branch number, and spines per unit length of dendrite. The increase in terminal branch number in orchidectomized animals was due primarily to the appearance of short branches that gave a striking, claw-like appearance to many of the distal dendrites. These results provide evidence for hormonal regulation of dendritic morphology of arcuate neuroendocrine neurons in adult mammals.     

The GnRH system of seasonal breeders: anatomy and plasticity

Seasonal breeders, such as sheep and hamsters, by virtue of their annual cycles of reproduction, represent valuable models for the study of plasticity in the adult mammalian neuroendocrine brain. A major factor responsible for the occurrence of seasonal reproductive transitions is a striking change in the responsiveness of gonadotropin-releasing hormone (GnRH) neurons to the inhibitory effects of gonadal steroids. However, the neural circuitry mediating these seasonal changes is still relatively unexplored. In this article, we review recent findings that have begun to define that circuitry and its plasticity in a well-studied seasonal breeder, the ewe. Tract tracing studies and immunocytochemical analyses using Fos and FRAs as markers of activation point to a subset of neuroendocrine GnRH neurons in the MBH as potential mediators of pulsatile GnRH secretion. Because the vast majority of GnRH neurons lack estrogen receptors, seasonal changes in responsiveness to estradiol are most probably conveyed by afferents. Two possible mediators of this influence are dopaminergic cells in the A14/A15 cell groups of the hypothalamus, and estrogen receptor-containing cells in the arcuate nucleus that project to the median eminence. The importance of GnRH afferents in the regulation of season breeding is underscored by observations of seasonal changes in the density of synaptic inputs onto GnRH neurons. Thyroid hormones may participate in this remodeling, because they are important in seasonal reproduction, influence the morphology of other brain systems, and thyroid hormone receptors are expressed within GnRH neurons. Finally, in the hamster, neonatal hypothyroidism affects the number of caudally placed GnRH neurons in the adult brain, suggesting that thyroid hormones may influence development of the GnRH system as well as its reproductive functions in the adult brain.     

Diet and gene expression in the intestine

Gene expression is central to the pathogenesis of many disorders. An ability to alter the expression of genes would, if their relationship to disease processes were fully understood, constitute a new modality of treatment. This review examines the evidence that nutritional factors can regulate genes in the gastrointestinal epithelium and it discusses the physiological relevance of such alterations in gene expression. Dietary regulation of the genes expressed by the epithelium confers three fundamental advantages for mammals. It enables the epithelium to adapt to the luminal environment to digest and absorb food better; it provides the means whereby mother's milk can influence the development of the gastrointestinal tract; when the proteins expressed by the epithelium act on the immune system, it constitutes a signalling mechanism from the intestinal lumen to the body's defences. Each of these mechanisms is amenable to manipulation for therapeutic purposes.     

Manometric evaluation of constipation--Part I

Tests of anorectal function have evolved into clinically useful investigations, and they should no longer be regarded as esoteric tools. This transformation has led to major advances in understanding, diagnosis, and treatment of defecation disorders, such as constipation. Because constipation is a heterogeneous condition, it cannot be assessed by a single test. Judicious use of anorectal manometry, colon transit study, a test of simulated defecation, and defecography may provide invaluable pathophysiological information. Undoubtedly, examination of rectal and anal pressure activity, rectal sensation, rectoanal reflexes, and the functional morphology of the defecation unit provides more information than any other test of gastrointestinal motor function; however, there is no uniform criteria for defining manometric abnormalities. There is also an urgent need for establishing international standards for manometric techniques and for diagnosis. Nevertheless, knowledge and experience have paved the way for innovative diagnostic techniques and therapeutic approaches for patients with constipation.     

Interstitial cells of Cajal as targets for pharmacological intervention in gastrointestinal motor disorders

Interstitial cells of Cajal (ICCs) have recently been identified as the pacemaker cells for contractile activity of the gastrointestinal tract. These cells generate the electrical 'slow-wave' activity that determines the characteristic frequency of phasic contractions of the stomach, intestine and colon. Slow waves also determine the direction and velocity of propagation of peristaltic activity, in concert with the enteric nervous system. Characterization of receptors and ion channels in the ICC membrane is under way, and manipulation of slow-wave activity markedly alters movement of contents through the gut organs. Here Jan Huizinga, Lars Thuneberg, Jean-Marie Vanderwinden and Jüri Rumessen, suggest that, as ICCs are unique to the gut, they might be ideal targets for pharmacological intervention in gastrointestinal motility disorders, which are very common and costly.     

Preliminary risk-benefit assessment of mycophenolate mofetil in transplant rejection

Mycophenolate mofetil (the morpholinoethyl ester of mycophenolic acid) inhibits de novo purine synthesis via the inhibition of inosine monophosphate dehydrogenase. Its selective lymphocyte antiproliferative effects involve both T and B cells, preventing antibody formation. Mycophenolate mofetil has immuno-suppressive effects alone, but is used most commonly in combination with other immunosuppressants. Mycophenolate mofetil, in combination with cyclosporin and corticosteroids, has been studied in large, randomised clinical trials involving nearly 1500 renal allograft transplant recipients. These trials demonstrated that mycophenolate mofetil is significantly more effective in reducing treatment failure and acute rejection episodes than placebo or azathioprine. Additionally, mycophenolate mofetil may be able to reduce the occurrence of chronic rejection. Mycophenolate mofetil is relatively well tolerated. The most common adverse effect reported is gastrointestinal intolerance; haematological aberrations have also been noted. The reversible cytostatic action of mycophenolate mofetil allows for dose adjustment or discontinuation, preventing serious toxicity or an overly suppressed immune system. Cytomegalovirus tissue invasive disease and the development of malignancies are concerns that merit evaluation in long term follow-up studies. Mycophenolate mofetil does not cause the adverse effects typically associated with other commercially available immunosuppressant medications such as nephrotoxicity, hepatotoxicity, hypertension, nervous system disturbances, electrolyte abnormalities, skin disorders, hyperglycaemia, hyperuricaemia, hypercholesterolaemia, lipid disorders and structural bone loss. Based on preliminary information, a positive benefit-risk ratio has been demonstrated with the use of mycophenolate mofetil in the prophylaxis of rejection in cadaveric renal allograft transplantation. Data from studies in other types of organ transplants are promising, but are too limited to draw clear conclusions. Long term follow-up studies are required to confirm these observations. Although mycophenolate mofetil is expensive, the beneficial effects on the reduction of rejection, treatment failure and related expenses suggest that it is most likely to be cost effective.     

A miniature transducer for recording intestinal motility in unrestrained chronic rats

An extraluminal strain gage force transducer has been developed for recording gastrointestinal motility in small animals such as rats. Two commercial strain gages are bonded and wires attached to form half a Wheatstone bridge. The device is placed between silicone sheeting and prepared for implantation. As many as six implanted transducers can record simultaneously contractions and tone variations of circular or longitudinal gastrointestinal muscles. The transducers have been implanted in more than 20 rats, with some units lasting up to 4 mo. Furthermore, good relationships exist between intraluminal pressure waves registered by a small intraluminal balloon and gut contractions registered by the transducer. The transducers are a useful and accurate tool for rodent gut motility studies.     

Timing of recombinant human granulocyte colony-stimulating factor administration on neutropenia induced by cyclophosphamide in normal mice

Chagas' disease is an infectious disease that affects millions of people in Latin America and is increasingly seen outside endemic areas. A substantial number of patients develop gastrointestinal disorders secondary to lesions of the enteric nervous system. The purpose of this article is to review the current knowledge about gastrointestinal manifestations of Chagas' disease, including disorders other than the well-known gross dilations of esophagus and colon.     

Effectiveness of fragmented autologous adipose tissue as a sealer of porous textile grafts: effect on endothelial development

Despite extensive research, the biochemical abnormalities underlying the predisposition to and the pathogenesis of affective disorders remain to be clearly established. Efforts to study norepinephrine (NE) output and function have utilized biochemical assays, neuroendocrine challenge strategies, and measures of peripheral blood cell receptors; the cumulative database points to a dysregulation of the noradrenergic system. Depressed patients (in particular, melancholic, unipolar subjects) excrete disproportionately greater amounts of NE and its major extraneuronal metabolite, normetanephrine, than do controls. Depressed patients also show subsensitive neuroendocrine (growth hormone) and biochemical (inhibition of adenylate cyclase) responses to alpha 2-adrenergic agonists, suggesting that subsensitivity of nerve terminal alpha 2 autoreceptors may underlie the exaggerated plasma NE observed in response to various challenges in affective disorders. Future advances in brain imaging techniques and in the molecular biology of adrenergic receptor-coupled signal transduction systems offer promise for meaningful advances in our understanding of the pathophysiology of affective disorders.