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PubMed1991

Limbic/mesolimbic connections and the pathogenesis of schizophrenia.

The development of models of the pathogenesis of neuropsychiatric diseases that build on recent advances in chemical neuroanatomy will help to guide future research. The interconnections among limbic, basal ganglia, and cortical structures are used to form the basis of a hypothesis of the pathogenesis of schizophrenia. The adaptive capacity of subcortical dopamine systems is advanced as an explanation of the many states of the disease.

Humans↗

PubMed1975

The pathogenesis of the Treacher Collins syndrome (mandibulofacial dysostosis).

Numerous synonyms have been used to describe syndromes affecting structures derived from the first and second branchial arches. These conditions are most conveniently grouped into the asymmetrical anomalies of hemifacial microsomia and the symmetrical syndrome of mandibulofacial dysostosis. By examination of animal models of these conditions it can be demonstrated that the pathogenesis is distinct but different for each group. The characteristic facies of mandibulofacial dysostosis suggests a mechanism of malformation which operates early in embryogenesis, acting uniformly on parts which are derived from neural crest cells. In the serial examination of a phenocopy of mandibulofacial dysostosis, induced in the rat by the teratogen vitamin A, focal death of pre-otic neural crest cells is observed to occur, creating both a spatial rearrangement of the developing ears and a paucity of ectomesenchyme in the first and second branchial arches. The result of these deviations from normal morphogenesis is the development of a facial skeleton which is symmetrical but distinctly different in form from that in the normal animal. Microscopic study of the induced ear and jaw defects revealed that the animal model was closely comparable in all respects to human mandibulofacial dysostosis. The specific nature of the interaction between teratogen and migrating neural crest cells is not yet clear; nor is it known whether these cells are attacked before or after their specific destination is determined. The greater part of the damage is inflicted in a general fashion and leads to symmetrical abnormal development. Minor examples of dyssymmetry do occur, however, in the animal model and man, but these are compatible with the hypothesis of a pathogenetic mechanism which is initiated centrally and symmetrically but modified locally at a later stage. A description of the pathogenesis of these two conditions, scientific predictions can be made with respect to the timing and technique of reconstruction of the orofacial defects, and the effects of surgery on growth and development.

Abnormalities, Multiple↗

PubMed1995

E-selectin involvement in the pathogenesis of splanchnic artery occlusion shock.

We investigated the involvement of E-selectin in the pathogenesis of splanchnic artery occlusion shock. Splanchnic artery occlusion shock was induced in anaesthetized rats by clamping splanchnic arteries for 45 min. Sham-operated animals were used as controls. Survival time, serum tumor necrosis factor-alpha, while blood cell count, mean arterial blood pressure and myeloperoxidase activity were determined. Splanchnic artery occlusion-shocked rats had a decreased survival time (85 +/- 8 min, while sham-shocked rats survived more than 4 h), reduced mean arterial blood pressure, increased serum levels of tumor necrosis factor-alpha (186 +/- 9 U/ml) and myeloperoxidase activity in the ileum (0.10 +/- 0.04 U x 10(-3)/g tissue) and in the lung (1.5 +/- 0.06 U x 10(-3)/g tissue). Shocked rats showed histological alterations in the ileum and in the lung. Administration of a hyperimmune serum containing specific antibodies raised against E-selectin significantly increased survival time (225 +/- 10 min), reduced leukopenia and myeloperoxidase activity both in the ileum (0.035 +/- 0.001 U x 10(-3)/g tissue) and in the lung (0.3 +/- 0.005 U x 10(-3)/g tissue), improved the cardiovascular changes and reduced the histological alterations in the ileum and lung. Our data are consistent with an involvement of E-selectin in the pathogenesis of splanchnic artery occlusion shock.

Animals↗

PubMed1990

Involvement of tumor necrosis factor-alpha in the pathogenesis of activated macrophage-mediated hepatitis in mice.

The possible involvement of tumor necrosis factor-alpha in the pathogenesis of an experimentally induced hepatitis was investigated. Balb/c mice were primed with Propionibacterium acnes to induce the infiltration of mononuclear cells into the liver. Immunohistochemical study showed that most of the accumulated mononuclear cells at 7 days were Mac-2 positive, suggesting that they were activated macrophages. An injection of lipopolysaccharide resulted in massive hepatic necrosis and high mortality in the mice within 24 hours. Plasma tumor necrosis factor-alpha activity initially rose sharply and then declined over 3 hours. The increase in plasma aminotransferase activity correlated well with the elevation of plasma tumor necrosis factor-alpha activity. Pretreatment with dexamethasone or 16,16-dimethyl-prostaglandin E2 attenuated not only the elevation of plasma tumor necrosis factor-alpha activity but also the increase in plasma aminotransferase activity and improved the survival rate. Passive immunization against tumor necrosis factor-alpha showed protective effects. These findings suggest that tumor necrosis factor-alpha released from activated macrophages may play a crucial role in the pathogenesis of this murine hepatitis.

16,16-Dimethylprostaglandin E2↗

PubMed1992

Hypotheses on the pathogenesis and natural history of Helicobacter pylori-induced inflammation.

Although Helicobacter pylori is now recognized as playing an etiologic role in chronic gastritis and peptic ulcer disease, information on the pathogenesis and natural history of infection is limited. A model is proposed in which luminal H. pylori secrete substances that mediate inflammation that is beneficial to the organism but ultimately deleterious for the host; in addition to tissue damage, inflammation also affects gastric secretory function. In this model, the host may attempt to suppress the inflammatory response, and the adequacy of this postulated down-regulation determines pathological and clinical outcome. The effects of the inflammatory process on gastrin-hydrochloric acid homeostasis may be of critical importance in the pathogenesis of peptic ulcer disease. Because the long-term consequences of H. pylori colonization reflect the continued presence of the organism in the host over years or decades, it may be useful to consider this as a "slow" bacterial infection.

Gastritis↗

PubMed1992

Possible role of transforming growth factor alpha in the pathogenesis of Ménétrier's disease: supportive evidence form humans and transgenic mice.

Ménétrier's disease is an uncommon disorder of unknown etiology characterized by enlarged gastric folds with foveolar hyperplasia and cystic dilatation of gastric glands. Biochemical features that are seen frequently include hypoproteinemia, hypochlorhydria, and increased gastric mucus. Because transforming growth factor alpha (TGF alpha) is an epithelial cell mitogen that inhibits gastric acid secretion and increases gastric mucin content, we hypothesized that its altered expression might be involved in the pathogenesis of this disease. Therefore, we characterized TGF alpha immunoreactivity in the gastric mucosa of 4 patients with Ménétrier's disease. In contrast to the normal pattern of TGF alpha immunostaining in which TGF alpha appears most concentrated in parietal cells, there was intense staining in the majority of mucous cells in the gastric mucosa of patients with Ménétrier's disease. In one patient from whom sufficient fresh tissue was obtained to isolate RNA, expression of TGF alpha and the epidermal growth factor receptor was higher in the gastric mucosa relative to a normal control. In addition, metallothionein-TGF alpha transgenic mice, which overexpress TGF alpha in gastric mucosa, show a number of features characteristic of Ménétrier's disease. These include foveolar hyperplasia and glandular cystic dilatation, increased gastric neutral mucin staining, and reduced basal and histamine-stimulated rates of acid production. Taken together, observations derived from the human material and correlation with data from a transgenic mouse model support an important role for TGF alpha in the pathogenesis of Ménétrier's disease.

Animals↗

PubMed1993

Pathogenesis of simultaneous esophageal contractions in patients with motility disorders.

BACKGROUND: Simultaneous and spontaneous contractions are frequently recorded in patients with esophageal motility disorders. The aim was to investigate the pathogenesis of swallow-induced simultaneous and spontaneous contractions. METHODS: The pathogenesis was studied in patients with normal peristaltic contractions (control group) and in patients with functional dysphagia with either simultaneous contractions (group A), with peristaltic but prolonged contractions (group B), and with frequent spontaneous contractions (group C). RESULTS: Simultaneous contractions had latencies of 2.9 +/- 0.2 seconds compared with 6.4 +/- 0.2 seconds for normal peristaltic contractions and 5.8 +/- 0.4 seconds for prolonged peristaltic contractions. Paired swallows at intervals of 5 seconds generated one peristaltic sequence after the second swallow in subjects with normal peristalsis and two sets of contractions in patients with simultaneous contractions. Ten consecutive swallows taken at 5-second intervals inhibited the spontaneous contractions evoked by bethanechol in control subjects but had no significant effect on the spontaneous contractions of subjects with simultaneous contractions. Atropine reduced the frequency, force, and duration of the spontaneously generated contractions in group C. CONCLUSIONS: The shorter latency of simultaneous contractions may be caused by a defective deglutitive inhibitory reflex, and spontaneous contractions appear to be generated by swallow independent discharges of acetylcholine.

Atropine↗

PubMed1983

Pathogenesis of diffuse intimal thickening (DIT) in non-human primate thoracic aortas.

The pathogenesis of diffuse intimal thickening (DIT) is not well understood. In animals, it is positively correlated with size, and with the exception of the pig, is thought to involve the proximal more than the distal portions of vessels. DIT is often not visible grossly, so that it's study requires extensive microscopic sampling of tissue. Review of previous studies in animals suggests that microscopic sampling may not have been sufficient to determine exactly where DIT occurs throughout the entire length of a vessel. The present study is a longitudinal step-serial section examination of the entire descending thoracic aorta from 12 adult non-human primates of varying size and species and with varying degrees of DIT as determined previously by more limited cross-section techniques. The findings indicate that DIT is not more pronounced in the proximal versus the distal segments of the vessel, and is not correlated with branch orifices. Review of the literature suggests that DIT may not be a single process, but may vary in pathogenesis from vessel to vessel and from species to species.

Animals↗

PubMed1985

Membrane damage and the pathogenesis of cardiomyopathies.

Membrane damage plays an important role in the pathogenesis of ischemic damage to the myocardium, and is ultimately responsible for the release of cellular contents-notably intracellular enzymes-after ischemic cell death. This membrane damage may be caused by the incorporation of lipids into myocardial membranes, by the enzymatic actions of lipases that hydrolyze membrane phospholipids, and by free radicals that are produced in the ischemic myocardium. Much less is known of the role of membrane damage in the cardiomyopathies, but direct myocardial membrane damage may occur in some specific forms of this diverse class of diseases. Direct membrane effects of exogenous substances are likely to be of pathogenic significance in alcoholic and some toxic cardiomyopathies, for example those produced by hydrocarbons and adriamycin. Membrane damage may also play a role in the pathogenesis of viral cardiomyopathies, due possibly to incorporation of viral components into the cardiac sarcolemma where these foreign materials can serve as antigens that direct host responses to attack the cells of the heart.

Autoimmune Diseases↗

PubMed1990

New insights into the pathogenesis of appendicitis based on immunocytochemical analysis of early immune response.

Although appendicitis is the most common condition requiring emergency surgery, the pathogenesis of this disease is poorly understood. In this study, local immune responses in acute appendicitis were investigated, using an experimental rabbit model, as well as in different grades of appendicitis in humans. Polymorphonuclear leukocyte (PMN) and plasma cell isotypes infiltration was measured in 24 New Zealand-bred white rabbits following experimental obstruction of the appendiceal lumen for periods ranging from 30 minutes to 24 hours. Significant infiltration of PMNs, IgM, and IgG plasma cells was noted at 30 minutes following obstruction, and IgA plasma cells were noted at 2 hours after obstruction. The immunopathological features observed in the study of human appendicitis clearly demonstrated the role of plasma cell infiltration in the immunopathogenesis of appendicitis. IgA and IgG plasma cells were significantly increased in the lamina propria of both focal and acute suppurative appendicitis, compared with controls (P less than .001). In focal appendicitis, in which the focus of inflammation is confined to only a few serial sections, the increased IgA and IgG plasma cell infiltration was present throughout the entire length of the resected organ. The possibility, as seen in this study, that antigen stimulation of the effector immune system could give rise to appendicitis, provides new insights into the diversity of inflammatory responses contributing to diseases of the intestinal tract. This previously unrecognised concept in the pathogenesis of appendicitis requires further elucidation of the stimulating agent, and in particular the T-cell recognition process.

Animals↗

PubMed1993

Decrease of nerve Na+,K(+)-ATPase activity in the pathogenesis of human diabetic neuropathy.

A decrease in Na+,K(+)-ATPase activity is claimed to play a central role in the pathogenesis of electrophysiological and morphological abnormalities that characterize the neuropathic complications in different animal models of diabetes mellitus. The peripheral nerves from 17 patients with either type I or type II diabetes mellitus were studied to assess the importance of changes in Na+,K(+)-ATPase activity in chronic human diabetic neuropathy. Sixteen nerves from age- and sex-matched normal individuals, and 12 nerves from non-diabetic neuropathic subjects undergoing vascular or orthopedic surgery served as negative and positive controls, respectively. All specimens were processed blind. Ouabain-sensitive ATPase activity was measured by a modified spectrophotometric coupled-enzyme assay. Standard histology, fiber teasing and electron microscopy were used to establish the normal or neuropathological patterns of surgical material. Morphometric analysis permitted calculation of fiber density in each nerve specimen and correlation of this figure with the relevant enzymatic activity. Na+,K(+)-ATPase activity was approximately 59% lower in nerves from diabetic patients than in normal controls (P < 0.01) and approximately 38% lower in nerves from non-diabetic patients with neuropathy (P < 0.01). Although nerves from both neuropathic conditions had significantly fewer fibers than those from normal individuals (diabetic -33%, and non-diabetic -22%), the decreases in Na+,K(+)-ATPase activity and fiber density were not correlated only in specimens from diabetic patients (r2 = 0.096; P = 0.22). Taken together with data from experimental animal models, these results suggest that the reduction in Na+,K(+)-ATPase activity in diabetic nerves is not an epiphenomenon secondary to fiber loss; rather, it may be an important factor in the pathogenesis and self-maintenance of human diabetic neuropathy.

Adult↗

PubMed1992

The role of cellular oxidases and catalytic iron in the pathogenesis of ethanol-induced liver injury.

Free radical generation and catalytic iron have been implicated in the pathogenesis of alcohol-induced liver injury but the source of free radicals is a subject of controversy. The mechanism of ethanol-induced liver injury was investigated in isolated hepatocytes from a rodent model of iron loading in which free radical generation was measured by the determination of alkane production (ethane and pentane). Iron loading (125 mg/kg i.p.) increased hepatic non-heme iron 3-fold, increased the prooxidant activity of cytosolic ultrafiltrates 2-fold and doubled ethanol-induced alkane production. The addition of desferrioxamine (20 microM), a tight chelator of iron, completely abolished alkane production indicating the importance of catalytic iron. The role of cellular oxidases as a source of ethanol induced free radicals was studied through the use of selective inhibitors. In both the presence and absence of iron loading, selective inhibition of xanthine oxidase with oxipurinol(20 microM) diminished ethanol-induced alkane production 0-40%, inhibition of aldehyde oxidase with menadione (20 microM) diminished alkane production 36-75%, while the inhibition of aldehyde and xanthine oxidase by feeding tungstate (100 mg/kg/day) virtually abolished alkane production. Addition of acetaldehyde(50 microM) to hepatocytes generated alkanes at rates comparable to those achieved with ethanol indicating the importance of acetaldehyde metabolism in free radical generation. The cellular oxidases (aldehyde and xanthine oxidase) along with catalytic iron play a fundamental role in the pathogenesis of free radical injury due to ethanol.

Aldehyde Oxidase↗

PubMed1994

Pathogenesis of induced rat periapical lesions.

Studies of the mechanisms of pathogenesis of periapical lesions were undertaken using a rat model of surgical pulp exposure. In this model, periapical lesions develop rapidly between days 0 and 15 (active phase) and more slowly thereafter (chronic phase). A Gram-negative anaerobic flora, similar to that seen in human beings, are quickly established. Lesions contain a mixed inflammatory cell infiltrate consisting of T cells, neutrophils, B cells, macrophages, and plasma cells. Helper T cells predominate during the active phase, whereas suppressor T cells are more frequent in the chronic phase. Extracts of periapical lesions contain bone-resorbing activity, the highest levels of which are present when lesions are actively expanding. Most bone-resorbing activity is mediated by the cytokine interleukin-1 alpha, as determined by biochemical criteria and antibody neutralization studies. Prostaglandin2 accounts for 10% to 15% of resorptive activity. Cells that express interleukin-1 alpha were identified in pulp beginning on day 2 after exposure and in periapical tissue beginning on day 7, as determined by in situ hybridization and immunostaining. Macrophages, fibroblasts, neutrophils, and osteoclasts were positive for interleukin-1 alpha mRNA and protein. Cells that express tumor necrosis factor alpha were also detected, whereas cells expressing interleukin-1 beta or tumor necrosis factor beta were absent. Finally, periapical bone destruction was inhibited by 60% by treatment with interleukin-1 receptor antagonist. These studies establish a key role for interleukin-1 alpha in the pathogenesis of periapical lesions in the rat model.

Alveolar Bone Loss↗

PubMed1980

Pathogenesis of malabsorption in Giardia infection: an experimental study in rats.

It is well established that infection with Giardia lamblia can cause malabsorption although the pathogenesis of this is unknown. Transport studies were made on the intestinal segments of male albino rats infected with Giardia cysts obtained from human stools to investigate this pathogenesis. The results were compared with those seen in a normal group and in a control group that was fed with a Giardia-free stool suspension. There was a significant fall in the transport of glucose and glycine, both of which were actively absorbed. On the other hand, potassium, which diffuses passively in a bidirectional manner across the bowel wall, was not affected. Furthermore, it was observed that the transport mechanism was deranged in the presence of an entirely normal small intestinal mucosa, as judged by light microscopy. It is concluded that Giardia trophozoites interfere with the active transport mechanisms of the small intestinal mucosa. This defect could result either from structural damage to the substrate carriers or from an alteration in cell maturation.

Animals↗

PubMed1980

The pathogenesis of autoimmunity in New Zealand mice.

In the past few years there has been an explosion of information in the area of NZ mouse research. This has reflected a general increase in knowledge and technology in cellular immunology and lymphocyte biology. Continuing research in many specific areas promises to expand this increasing data base. The numerous abnormalities of CMI in NZ mice chronicled in the past are currently being analyzed in terms of cell synergism rather than as simple effector mechanisms. Such analysis is indicating more selective rather than general impairment of CMI in aging NZ mice. Similarly, the allogeneic H-2 identical cytotoxic activity expressed by NZ mice and its relevance to autoimmune disease are being explored. In the area of suppressor functions in NZ mice, continued refinement and standardization of suppressor assays must be achieved before adequate interpretation of the present information can be made. Suppressor activity in aging NZ mice has been described as depressed, normal, and elevated. This is an area of acute interest. While the primary etiologic significance of T cell regulatory defects is currently being minimized, their possible secondary role in pathogenesis of autoimmune disease in NZ mice is being investigated. The recent discovery of a significant B cell abnormality present from birth in all SLE-prone murine strains has increased the probability that intrinsic B cell hyperactivity is a primary etiologic factor in murine autoimmunity. The hypersecretion of IgM and the increased incidence of B cell colony-forming units observed in NZ mice is being subjected to further genetic analysis in many laboratories. Similarly, the continued evaluation of the (CBA/N x NZB) hybrid promises to be enlightening, particularly the development of congeneic mice with the CBZ/N X chromosome on the NZB background. In addition, the development of H-2 congeneic NZB strains and immunoglobulin allotype congeneic NZB strains are proceeding. These strains will provide information on the possible roles of MHC and VH regions in autoimmune pathogenesis. The NZB.ch congeneic strain has already proven to be of great value. The continued development and further characterization of congenitally immunologic mutant NZ mice has been and will continue to be useful in elucidating the mechanism of autoimmune development in these animals. While NZ mice express a variety of host-viral interactions, recent genetic analysis suggests that viral infection is not a primary etiologic agent in the autoimmune disease of NZ mice. A well-defined clinical entity and a range of abnormalities have been delineated in NZ mice. The present goal is to define the cellular basis of autoimmunity through continued immunologic and genetic analysis of this important animal model of human autoimmune disease.

Animals↗

PubMed1982

Pathogenesis of rheumatoid arthritis: a vascular hypothesis.

Past research into the pathogenesis of RA has generally concerned itself with established inflammation. The present review summarizes alterations in microvascular anatomy and function which occur during the hypoxic state, in various experimental and disease conditions. It further shows that tissue hypoxia is a common finding in RA and that the microvascular alterations of RA are similar to those produced by experimental hypoxia. The available data suggest that microcirculatory compromise, concomitant with an increase in metabolic needs of synovial tissue, may initiate tissue injury via anoxia and acidosis, resulting in hydrolytic enzyme release, increased vascular permeability and acceleration of inflammatory processes. It is further believed that the microcirculatory abnormality may be generalized, accounting for the systemic manifestations often seen in RA. Factors effecting arteriolar blood flow obstruction are reviewed to identify areas for future investigation in RA and other disorders involving microvasculopathy. The multitude of longknown and newly recognized factors predisposing to vasospasm and vasodilatation have been outlined as a guide to possible mechanisms which may be operative in RA. An attempt has been made to gather and synthesize the available data in the hope that it may stimulate other investigators to pursue more definitive research into specific areas which may show early microvascular abnormalities in the pathophysiology of RA. Identification of factors operative early in the pathogenesis of RA, before it becomes self-perpetuating, may well be a step in the direction of preventing the ravages of this disease, or providing insight to more effective control.

Arterioles↗

PubMed1992

Contribution of synovial mesenchymal cells to the pathogenesis of rheumatoid arthritis.

Rheumatoid joint destruction is caused by (1) enzymatic digestion from articular surfaces of cartilage, (2) pannus formation, and (3) lysis of the matrix by activated chondrocytes. Pannus, a vascular and fibrous granulation tissue arising from the perichondral synovial membrane, extends onto cartilage surfaces as a layer of morphologically quiescent fibroblastic mesenchymal cells. Pannus subsequently starts invasion into cartilage matrix with the appearance of macrophagelike cells. Synovial mesenchymal cells are thought to play important roles in the pathogenesis of rheumatoid joint destruction in relation to la expression and antigen presentation as well as the elaboration of inflammatory cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha. By experimentally inducing antigen-induced arthritis in H-2-c-fos transgenic mice whose immunoglobulin G antibody response against immunizing antigen was defective, the investigators produced destructive arthritis without lymphocyte infiltration. The only cells invading the joints in these mice were similar to a previously recognized subset of human synovial cells that had a mesenchymal appearance. These mesenchymal cells invaded the cartilage matrix upon in vitro culture. The role of synovial mesenchymal cells in the pathogenesis of rheumatoid joint destruction is discussed.

Animals↗

PubMed1985

Role of human basophils and mast cells in the pathogenesis of allergic diseases.

The role of human basophils and mast cells in the pathogenesis of allergic diseases has been analyzed. Purified human basophils and mast cells release several known mediators of allergic reactions, including histamine, sulfidopeptide leukotrienes, kinin-forming enzymes, and, in the case of the mast cell, PGD2. These same mediators are released in vivo after experimental challenge in the upper airways with either allergen or cold, dry air, a stimulus used to simulate exercise-induced bronchospasm. The appearance of mast cell mediators in vivo after such challenges further implicates mast cells in the pathogenesis of allergic diseases of the airways that occur as a result of exposure to allergen or physical stimuli. During the LPR after experimental challenge of the upper airways, the pattern of mediators released (i.e., histamine, leukotrienes, and others, but no PGD2) suggests that basophils may contribute to the LPR. Antiallergic drugs that prevent mediator release in vitro, such as antihistamines, also prevent the appearance of mediators in vivo, strengthening both the validity of the in vitro test as a model of the disease and the hypothesis that mediator release is an essential element of the disease process. A model discussing the pathogenetic mechanism is presented.

Adrenal Cortex Hormones↗