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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↗

PubMed1992

Pathogenesis of intestinal cryptosporidiosis in conventional and gnotobiotic piglets.

The pathogenesis of intestinal cryptosporidiosis was studied in 52 conventionally reared and 20 gnotobiotically reared piglets by inoculation with different doses of Cryptosporidium parvum oocysts. The prepatent period of C. parvum in both groups of animals were variable, depending on the number of oocysts administered. The patent period of C. parvum in conventionally reared piglets was 8 or 9 days; in gnotobiotic piglets cryptosporidia were found in feces until Day post infection (DPI) 16, when the last piglet was necropsied. Cryptosporidiosis in conventionally reared piglets is a self-limited diarrheal disease associated with morphological changes within the intestine. The most severe lesion was seen in the posterior jejunum and ileum from DPI 3 to DPI 7, and consisted of villous atrophy, crypt hyperplasia and inflammatory infiltration in the lamina propria. In gnotobiotic piglets cryptosporidia induced severe enterocolitis which occurred at least until DPI 16. The characteristics of enteric lesions were similar to those found in conventionally reared piglets. Intestinal cryptosporidiosis in both groups of animals shifted in the course of infection in the caudal direction and terminated in the large intestine. Examination by scanning electron microscope showed that infected absorptive cells had thicker and longer microvilli than those on non-infected cells; neighboring non-infected cells were hypertrophic, bulbously protuberant with minute microvilli with no distinct intercellular borders. Numerous cryptosporidia in the heterotopic glandular epithelium in the submucosa of cecum and colon on DPI 9 and 10 were found. No differences in the location and degree of cryptosporidial infection between colostrum-fed and colostrum-deprived conventionally reared piglets were found. Sow's colostrum does not appear to protect piglets from C. parvum infection. The role of intestinal microflora in the pathogenesis of cryptosporidiosis in piglets is discussed.

Animals↗

PubMed1992

Possible role of histamine in pathogenesis of autoimmune diseases: implications for immunotherapy with histamine-2 receptor antagonists.

The immunosuppressive chemical drugs cyclosporine A (CsA) and methotrexate (Mx) have recently been shown to be of benefit in several different diseases of autoimmune origin. Cellular immune responses may play a major role in autoimmunity as autoreactive T lymphocytes appear to recognize autoantigens and major histocompatibility complex (MHC) class II restriction molecules presented by non-immune, aberrant cells, subsequently leading to damage on healthy tissues. Psoriasis is suggested to be an autoimmune disease and in severe, uncontrollable psoriasis CsA and Mx are of value in reducing disease activity. Histamine is suggested to be involved in the pathogenesis of psoriasis and the histamine-2 receptor antagonist ranitidine has been shown to be of value to reduce severe psoriatic disease. The finding that CsA and Mx efficiently reduce histamine formation and release raises the possibility, that histamine is one of the molecules involved in pathogenesis of autoimmune diseases. T cell mediated regulation and suppression of autoreactive T cells seem to be ineffective in controlling the enhanced immune reaction in patients where the discrimination between self and non-self is changed. A consequence of this may be induction of interferon-gamma (IFN-g) production and release by cytotoxic T cells, subsequently leading to expression of MHC II molecules on non-immune tissues. As immunotherapy may be of value in some autoimmune diseases the use of histamine-2 receptor antagonists should be evaluated in patients where conventional therapy is ineffective to reduce disease activity.

Autoimmune Diseases↗

PubMed1992

The role of reactive oxygen species in the pathogenesis of multiple sclerosis.

Although reactive oxygen species are thought to mediate cellular damage in many disease states the role of reactive oxygen species in the pathogenesis of multiple sclerosis is unknown. Data from biochemical, histochemical and pharmacological studies have been evaluated to determine if the necessary conditions exist for the formation of reactive oxygen species during a demyelination episode of multiple sclerosis. This evaluation found that not only do the necessary conditions exist for the formation of reactive oxygen species but that these species may play a significant pathogenic role in this disease. A hypothesis describing a detailed role of reactive oxygen species in the pathogenesis of multiple sclerosis is put forth.

Free Radicals↗

PubMed1992

The Zvonimir Dinter Memorial Lecture. New insights into the pathogenesis of viral infection.

Interesting recent highlights into the pathogenesis of viral infections have come from: (1) Studies of viruses that persist in cells and modify cell function without causing cell damage. (2) Transgenic mouse studies showing how tissue-specific transcriptional activators control virus expression and can determine viral tropism. (3) Studies of the influence of cell differentiation on viral expression. (4) The exploding world of cytokines, whose baffling complexity and multiple interactions are subjects of intense study. (5) Studies of the interaction of viruses with the immune system. In each case, no molecular studies are giving unprecedented insights into disease processes. However, even when viral genomes are sequenced and virulence genes identified there are additional daunting steps before we understand the role of a given gene product in pathogenesis.

Animals↗

PubMed1992

Role of leukotriene B4 in the pathogenesis of hepatic ischemia-reperfusion injury in the rat.

A common feature to most models of ischemia-reperfusion injury is the accumulation of polymorphonuclear leukocytes (PMNs) into the post-ischemic tissue during the reperfusion period. Interventions that lead to decreased PMN infiltration protect against tissue injury and therefore a knowledge of the chemotactic mediators leading to PMN accumulation is essential to understanding the pathogenesis of the injury and to the development of successful therapeutic strategies. Leukotriene B4 (LTB4), a metabolite formed via the 5-lipoxygenase pathway from arachidonic acid, is one of the most potent chemotactic mediators known. We have investigated the formation of LTB4 in a well characterized model of hepatic ischemia-reperfusion injury in the rat and made use of a specific leukotriene biosynthesis inhibitor, L663,536, to determine the importance of LTB4 in the pathogenesis of the injury. LTB4 concentrations were measured with a specific and sensitive gas chromatographic-mass spectrometric method previously developed in our laboratory. In liver tissue LTB4 levels were below the detection limit of 20 pg/g before 45 min ischemia and did not increase during the first 6 h of reperfusion. However, at 15 h and 24 h reperfusion LTB4 concentrations had increased to levels 50-fold those in control liver (867 +/- 267 pg/g). The increase of plasma alanine aminotransferase (ALT) activities indicated two phases of injury, an initial phase during the first few hours of reperfusion, and a second more severe injury phase between 6 h and 24 h reperfusion. PMNs accumulated in tissue throughout the reflow period reaching 700 +/- 49 per 50 high power fields (HPF) at 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗

PubMed2026

Novel HLA class I and II insights into the pathogenesis of systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is the leading cause of mortality in systemic sclerosis (SSc), yet its genetic architecture remains incompletely understood. Therefore, given the key role of the major histocompatibility complex (MHC) in SSc, we aimed to perform a comprehensive MHC-wide association study in the largest SSc-ILD cohort to date. METHODS: We analysed 2412 patients with SSc-ILD⁺, 3550 patients with SSc-ILD⁻, and 15,076 controls of European ancestry from 10 international cohorts. After quality control, the MHC region was imputed, and inverse variance weighted meta-analysis was performed. Subsequently, conditional stepwise analyses, adjustment for antitopoisomerase autoantibody (ATA) status, and functional annotation of significant single-nucleotide polymorphisms were performed. Finally, we constructed a composite score combining genetic, clinical, and demographic variables to predict SSc-ILD. RESULTS: After conditional analysis, we detected 12 significant associations within class I and class II human leukocyte antigen (HLA) genes. ATA adjustment reduced the significance of class II HLA variants, whereas class I HLA variants remained unaffected. Finally, the built composite score had an area under the curve of 0.754, significantly outperforming the models including any of the variables alone. CONCLUSIONS: In this study, we identify genetic mechanisms underlying SSc-ILD that support the potential implication of CD8+ T cells and ATAs in its pathogenesis. Moreover, we also demonstrate the enhanced efficacy of integrating genetic information into predictive models to detect patients at high risk of SSc-ILD. These findings provide new insights into disease pathogenesis and suggest potential biomarkers and therapeutic targets for improved patient management.

Humans↗

PubMed1977

Pathogenesis of dissecting aneurysm of aorta. Comparative histopathologic study of significance of medial changes.

In previous investigation of the normal aging aorta, the claimed specificity of alterations in the media in the pathogenesis of dissecting aneurysm of the aorta was challenged. The concept was promoted that these changes are nonspecific and caused by general hemodynamic events within the aorta. In this investigation the aortic media was studied in patients with a dilated ascending aorta, whose hemodynamic profile is known to be altered. The results were compared with data obtained from the study of aortas with complete or incomplete dissection and aortas from patients with Marfan's syndrome, a condition known to predispose to dissection. Only quantitative differences were found between the normal "aging" aorta and the overtly abnormal aorta. The pathogenesis of dissected aneurysm, therefore, is considered to be initiated by processes if injury and repair within the aortic wall, consequent to hemodynamic forces. The histologic features of the media previously implicated as the specific underlying defect appear to represent the morphologic substrate of this traumatizing and reparative process. This process may gradually lead to dilatation of the aorta and, according to Laplace's law, a vicious cycle may ensue that may lead to further complications. Local circumstances determine whether a dilated aorta will rupture or whether an incomplete or complete dissection will occur. The fact that the aorta in patients with Marfan's syndrome shows basically the same structural alterations supports the concept proposed. The underlying connective tissue disorder in these patients will lead to complications at an earlier age. Dissecting aneurysm therefore is part of a spectrum of lesions that have as a common denominator the process of injury and repair.

Adolescent↗

PubMed1992

Experimental studies on the pathogenesis of the gastric mucosal lesions induced by whole-body vibration.

In order to determine the pathogenesis of gastric mucosal lesions induced by whole-body vibration (WBV), the effects of WBV (3.0 G, 10 Hz, 90 min) on gastric mucosal blood flow (GMBF), plasma corticosterone (COR) and catecholamines (CA), and gastric ulcer formation were investigated in relation to the effects of forced water-immersion stress (FWI) upon the same parameters. While WBV increased GMBF during the exposure, FWI decreased it both during and after the stress. No difference in the severity of ulcer formation between the WBV and the FWI groups was seen. Both WBV and FWI increased plasma COR and CA, although the degree of the increase in COR that accompanied WBV was less than that associated with FWI. Truncal vagotomy attenuated the reduction of GMBF and the extent of ulcer formation that occurred with FWI, but promoted a reduction of GMBF with WBV. These findings indicate that ulceration induced by WBV may be caused primarily by its direct and specific mechanical actions and not by indirect, central nervous system effects known to be important in the pathogenesis of ulcerations produced by mental stress.

Animals↗

PubMed1978

Congenital diaphragmatic hernia associated with homolateral upper limb malformation: a study of possible pathogenesis in four cases.

Four cases of congenital diaphragmatic hernia associated with homolateral upper limb reduction deformities are presented and are analyzed in terms of their pathogenesis. Diaphragm and upper limb are supplied by adjacent segments of cervical neural crest, and the sensitive period for upper limb formation occurs during early neural crest development. The evidence supports the possibility of cervical neural crest injury as the underlying pathogenesis.

Arm↗

PubMed1977

Intrathymic pathogenesis and dual genetic control of myasthenia gravis.

We propose a two-step model for the pathogenesis of myasthenia gravis. In the first step, primitive intrathymic stem-cells are induced by abnormal stimuli to differentiate to (abnormal?) myogenic cells. In the second step, immunocompetent T lymphocytes start an autoimmune reaction against these newly differentiated myogenic cells. The clinical stage is reached when autosensitised effector T lymphocytes leave the thymus and either infiltrate the synaptic spaces of peripheral muscles or participate in the formation of autoantibodies, causing the neuromuscular symptoms. At two points the pathogenesis is under genetic control--the first at the differentiation of the stem-cells to myogenic cells and the second at the immune responsiveness of the lymphocytes to these atypical intrathymic muscle cells.

Animals↗

PubMed1978

Possible role for impaired renal prostaglandin production in pathogenesis of hyporeninaemic hypoaldosteronism.

A 57-year-old woman with hypertension and moderate renal insufficiency had chronic unexplained hyperkalaemia. Metabolic balance studies confirmed a diagnosis of hyporeninaemic hypoaldosteronism. Two observations suggested that impaired renal prostaglandin production contributed to the pathogenesis of the patient's disorder. Baseline renal-prostaglandin synthesis (as determined by urinary excretion of P.G.E and P.G.F) was was substantially depressed when compared with that in nine normal females. Infusion of low doses of P.G.A1 produced a significant increase in serum-aldosterone and urinary potassium excretion; it also led to a dramatic fall in blood-pressure and serum-potassium. It appears from these studies that a defect in renal prostaglandin synthesis has an important role in the pathogenesis of hyporeninaemic hypoaldosteronism.

Adrenal Insufficiency↗

PubMed1976

Pathogenesis of the glomerulopathy associated with renal infarction in rats.

The present studies were designed to characterize the extent and pathogenesis of the glomerular lesions which occur in the viable portion of the kidney following partial renal infarction in rats. Control rats with two normal kidneys had a mean blood pressure of 112 mm Hg, minimal proteinuria and no glomerular pathology on light (LM), electron (EM) or immunofluorescence microscopy (IFM). Rats with two-thirds infarction of one kidney (stage II) became hypertensive, although less than 4% of the glomeruli from either kidney were abnormal. Rats with two-thirds infarction of one kidney and contralateral nephrectomy (stage III) developed proteinuria and hypertension whether fed a normal, low or high Na+ diet. By light microscopy 37% of glomeruli were abnormal 28 days after partial infarction and contralateral nephrectomy and thereafter the percent of abnormal glomeruli increased. Detectable amounts of immunoglobulin and complement (C3) were present in kidneys of stage II or III rats but were always accompanied by more extensive albumin and fibrin deposits. Basement membrane deposits characteristic of immune complexes were not seen on EM. Administration of antihypertensive medication to stage III rats significantly lowered blood pressure and reduced the number of abnormal glomeruli on LM; however, IFM abnormalities remained prominent. Platelet thrombi seen by EM and abundant glomerular fibrin deposits seen on IFM suggested that coagulation mechanisms may be prominent in the pathogenesis of the renal lesion. Heparin-treated stage III rats had significantly lower blood urea nitrogen concentrations, blood pressures and proportion of abnormal glomeruli although glomerular deposition of serum proteins was still present on IFM. These observations suggest that this glomerulopathy is initiated by an unknown agent(s) which increased capillary permeability. This lesion progresses via thrombotic mechanisms which are prevented by heparin administration.

Aneurysm↗

PubMed2026

EIF4H and YBX1 are essential host factors for hepatitis E virus replication and pathogenesis.

Hepatitis E virus (HEV) is a leading cause of acute viral hepatitis worldwide, responsible for approximately 20 million infections annually. Despite the availability of a vaccine in China, no direct-acting antivirals are approved, and host factors required for HEV replication remain poorly defined. Here, using a genome-wide CRISPR/Cas9 knockout screen in a replicon system, we identified Eukaryotic Translation Initiation Factor 4H (EIF4H) and Y-Box Binding Protein 1 (YBX1) as essential host factors for HEV replication and pathogenesis. Knockout of either factor markedly impaired replication of HEV genotypes 1, 3, and 4, as well as HEV infection and production in hepatocellular carcinoma cells and human induced pluripotent stem cell-derived hepatocyte-like cells, while leaving SARS-CoV-2, hepatitis B virus, hepatitis C virus, and Zika virus unaffected, underscoring their HEV-specific roles. Mechanistically, EIF4H interacts with ORF1 via its methyltransferase-Y-papain-like protease region, and EIF4H deficiency alters the composition of the ORF1-associated replication complex. By contrast, YBX1 is dispensable for ORF1 translation and RNA binding but is specifically required for ORF1 proteolytic processing, a prerequisite for assembling a functional replication machinery. EIF4H knockout rats and liver-specific YBX1 knockout rats were largely resistant to rat HEV-C1 infection, showing profound reductions in viral shedding, suppressed hepatic and intestinal viral loads, and protection from liver pathology. Together, our findings establish EIF4H and YBX1 as essential host factors for HEV infection and pathogenesis and reveal potential targets for antiviral intervention.

Virus Replication↗

PubMed2026

Impact of pH and Mycoplasma hominis endosymbiosis on Trichomonas vaginalis pathogenesis.

The parasite Trichomonas vaginalis colonizes the human vaginal tract and adheres to and lyses epithelial cells causing an inflammatory infection. The vaginal tract is typically acidic, ranging from pH 3.8 to 5.1; however, pathogenesis studies have previously been conducted on parasites grown at pH 5.9 to 6.2. Here we compared the adherence and cytotoxicity of T. vaginalis grown at pH 5.1 and pH 5.9, identifying changes in the surface proteome that contribute to increased pathogenesis of the parasite at pH 5.1. We show that growth of the parasite at pH 5.1 significantly enhances adherence to and lysis of host cells and that this is strongly amplified by the presence of a common bacterial endosymbiont, Mycoplasma hominis. Quantitative proteomics revealed the upregulation of putative surface proteins, three of which were found to be involved in increased parasite adherence and host cell killing. Mechanistic assays demonstrated that a Ricin B-like protein mediates parasite adherence dependent on host glycosaminoglycans via its carbohydrate-recognition domain, while an EF-hand-like protein is shown to promote Ca2+dependent adherence. Ricin B overexpression was found to reprogram host metabolism, activating ERK1/2 and HIF-1α and driving a Warburg-like glycolytic shift with greatly increased lactate release, which may create a nutrient-rich niche that supports parasite persistence and host cell cytotoxicity. These studies demonstrate a coordinated upregulation of multiple adhesins rather than a single factor at pH 5.1 in the presence of M. hominis and explore the mechanisms underlying the interaction of parasite surface proteins with the host cell.

Trichomonas vaginalis↗

PubMed1992

The dilemma of AIDS vaccine and therapy. Possible clues from comparative pathogenesis with measles.

AIDS viruses, because of their unique properties, are extraordinary. Past successes achieved with vaccines against ordinary viruses do not provide the guidelines needed to develop successful vaccines against HIV. Neither vaccines nor drugs can be relied upon to provide an answer to AIDS. AIDS is a disease of immune dysfunction and destruction, and an alternative to prevention of infection or cure might lie with elimination of the clinical consequences of infection. This might find a basis in precise definition of its pathogenesis. The enormity of possible pathogenetic changes in HIV infection invites simplification, and might be aided by a search for clues among ordinary viruses in which there is a less complicated biology and spontaneous recovery from infection. Measles virus infection presents analogies to AIDS, especially in the induction of anergy and increased mortality, in the long term, from diseases other than measles as observed in children infected during early life. This was demonstrated recently in increased deaths, all causes, during a three-year period among infants who were given live measles virus vaccine of high infectivity titer during early infancy, sometimes in the presence of maternal antibody. AIDS and measles may be diseases of similar pathogenesis, but with the difference that AIDS immunopathology is progressive while that for measles is regressive.

AIDS Vaccines↗

PubMed1976

Pathogenesis of cutaneous lesions in acute meningococcemia in humans: light, immunofluorescent, and electron microscopic studies of skin biopsy specimens.

Biopsy specimens of the skin were taken from 10 patients with acute meningococcemia who exhibited mainly maculopurpuric lesions. The specimens were studied by light, electron, and immunofluorescent microscopy in an attempt to obtain information on the pathogenesis of vascular injury. Light microscopy disclosed a large number of Neisseria meningitidis organisms, both in the endothelial cells and being phagocytized by neutrophils. Vascular injury was characterized (by means of both light and electron microscopy) by endothelial necrosis, thrombosis, and necrosis of other elements of the vascular wall, such as muscle cells and pericytes. Immunoglobulins and complement were also found in the vascular wall in most cases. Hypercoagulability was demonstrated in some patients. These findings suggest that the cutaneous lesions of meningococcemia fulfill most of the gross and histologic criteria of the local Shwartzman reaction, but that immunological factors probably contribute to pathogenesis.

Blood Coagulation Tests↗

PubMed1978

Pathogenesis of the rubella exanthem: distribution of rubella virus in the skin during rubella with and without rash.

In a previous assessment of the role of rubella virus in the pathogenesis of the rubella exanthem, virus was consistently isolated from cell cultures of skin biopsy specimens of the rash, and it was concluded that presence of virus in the skin was essential to evolution of the rash. For determination of whether virus is present in the skin only in association with rash, punch biopsies were performed concurrently on areas of skin with and without rash. Among paired skin specimens of 16 patients, virus was isolated from sites of rash in 12 and from the uninvolved skin in 10. In another patient, shown by serologic response and recovery of virus from the pharynx to have rubella without a rash, virus was also isolated from the skin. It is concluded that rubella virus is widely disseminated in the skin of patients with rubella irrespective of the presence or distribution of the rash, and that the presence of virus in the skin, although a constant feature of the disease, is only one of the factors involved in the pathogenesis of the exanthem.

Biopsy↗