SEARCH · Search PubMed
Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.
Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.
Explore the source record for details and available documents.
Ruminants are hosts for members of both Alpha- and Gamma-herpesvirinae. A wide range of disease syndromes is associated with infections by these agents. The associated diseases reflect the biological nature of the causative viruses. Clinically, the symptoms may be mild and localized or include severe generalized disease, leading eventually to death. Much knowledge has been gained concerning the pathogenesis of some alpha-herpesviruses. Initially, these viruses replicate in epithelial cells at the portal of entry. The symptoms of the acute diseases are often associated with the destruction of those epithelial cells. However, as in the case of bovine herpesvirus 1 (BHV-1), the virus may spread in the infected host by viremia, gaining access to a broader range of tissues and organs, and causing a broader variety of diseases. Furthermore, many herpesviruses are capable of entering neuronal cells. There, they may replicate, which may lead to neuronal diseases, for example, encephalitis. In addition, the herpesviruses may establish latency in neuronal or lymphoid cells. During latency, apparently no viral antigens are synthesized but the genomes of the latent viruses are present in the nuclei of long living cells, such as, e.g., neurones of the ganglia corresponding to the sites of peripheral replication. Upon reactivation, the viruses re-establish the lytic cycle of replication. Shielded from the effectors of the immune system, they migrate back to the peripheral tissues where they are excreted and may be transmitted. Although a strong immune response is provoked during primary viral replication, these mechanisms help the herpesviruses to escape from immune surveillance during latency and to a lesser degree during reactivation. It has been observed that certain herpesviruses may behave differently upon infection of different hosts. Relatively little progress has been made concerning the understanding of the pathogenesis of ruminant herpesviruses but much has been learned about viral molecular biology. Many viral proteins have been identified and characterized and the technology to create recombinant viruses has been established. With these tools in our hands, it is now possible to address the really interesting questions concerning pathogenesis. We postulate that herpesviruses contain at least two sets of genes, a first set involved in gene expression and viral replication, and a second set responsible for functions, which may affect pathogenesis, latency, and virus/host interactions. Using recombinant virus technology, it will be possible in the future to design targeted deletions and gene transfers in ruminant herpesviruses in order to study the viral and host factors involved in pathogenesis on the molecular level.
Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome characterized predominantly by augmented neuronal inhibition and probably neuronal damage. Several theories concerning the pathogenesis of HE have been proposed; none of these theories is necessarily exclusive. Furthermore, the validity of none of them has been definitively proved experimentally. In this review article an important role of endotoxin and tumor necrosis factor-alpha (TNF) in the pathogenesis of HE is suggested. The involvement of endotoxin and TNF in the pathogenesis of HE seems to be very convincing; it may explain many of the derangements seen in HE. It also seems to be in strong relation to the main theories about HE, the ammonia theory, the GABAergic theory, the benzodiazepine theory, and the AAA/false neurotransmitter theory, where these theories may represent some of the mechanisms whereby TNF may cause inhibition and damage to the CNS in HE, or may represent accompanying features to elevated levels of endotoxin and TNF, with no important role in the pathogenesis of HE. The possible involvement of endotoxin and TNF in the pathogenesis of HE may possess an important clinical application, for serum LPS and TNF concentrations may be of important diagnostic and prognostic value in HE, and treatment with antibodies against endotoxin and against TNF may have potentially beneficial therapeutic effects in this serious and potentially fatal disease.
BACKGROUND: Gardnerella is a genus of gram variable anaerobic bacteria that is commonly present in the female urogenital tract, especially during bacterial vaginosis (BV). BV is linked with increased risk of urinary tract infections (UTI) and Gardnerella has been frequently detected in urine collected directly from the bladder. Understanding the contribution of Gardnerella to urogenital pathogenesis has been complicated by its genetic heterogeneity and a shortage of data from in vivo models. Recently, a clinical isolate of Gardnerella displayed covert pathogenesis in a mouse urinary tract inoculation model, triggering urothelial exfoliation and promoting UTI by uropathogenic E. coli. Data from clinical studies suggests differential association of Gardnerella phylogenetic clades with BV or urogenital infections. In vitro data has demonstrated heterogeneity in the presence and expression of putative virulence determinants between Gardnerella strains. This study was designed to compare diverse Gardnerella strains in vivo to identify genomic variation associated with urinary tract persistence and pathogenesis. METHODS: Eighteen Gardnerella clinical isolates from each of the four main phylogenetic clades were individually inoculated transurethrally into female C57BL/6 mice. Bacteriuria was monitored by quantitative culturing of Gardnerella in urine. Pathologic features were assessed by immunofluorescent and histological staining of bladder tissues. Pan-genome phylogenetic analyses were performed on the 18 Gardnerella isolates used for mouse infections to identify accessory genes that were associated with observable in vivo phenotypes, including long and short-term persistence, urothelial exfoliation and bladder edema. Genes that were significantly associated to phenotype were then matched against a pangenome analysis of 291 publicly available Gardnerella genomes to determine the conservation of these putative colonization and virulence factors across the genus. RESULTS: Gardnerella strains displayed clear differences in persistence and pathogenesis in the mouse bladder that were congruent with phylogeny. Clade 2 strains were more persistent in the urinary tract whereas strains from the other three clades either caused transient bacteriuria or were undetectable. Strains from clade 2 and 4 induced urothelial exfoliation while edema was triggered by strains from clades 2, 3 and 4. Pangenome analyses revealed 45 genes that were associated with in vivo persistence and pathogenicity. Among the wider 291 publicly available genomes, clade 2 strains encoded more of the genes associated with bacteriuria phenotypes compared to strains in the other three clades. Exfoliation-associated genes were present in most clade 4 strains. Clade 3 strains lack most of the in vivo-associated genes, whereas clade 1 strains were more heterogenous. CONCLUSIONS: This study provides in vivo evidence for differential urinary tract colonization and pathogenesis by strains from different clades/species within the genus Gardnerella and identifies new putative persistence and virulence factors. Utilizing the in vivo data from tested strains, pangenome analyses predicts that clade 2 Gardnerella are the most likely to persist in the urinary tract and that clades 2 and 4 have the highest uropathogenic potential. These findings inform future targeted screening and treatment approaches aimed at limiting harmful Gardnerella urinary tract exposures.
The accumulation of pathogenesis-related proteins (PR) in tobacco leaves has been casually related to pathogen and specific physiological stresses. The known enzymatic function of some of these proteins is potentially antimicrobial. By using antibodies specific to three classes of pathogenesis-related proteins, we examined tobacco plants during their normal growth. The pathogenesis-related proteins accumulated during the normal development of the tobacco flower. The PR-1 class of proteins (biological function unknown) is located in sepal tissue. PR-P, Q polypeptides are endochitinases and are present in pedicels, sepals, anthers, and ovaries. A glycoprotein serologically related to the PR-2,N,O class is a (1,3)-beta-glucanase and is present in pistils. Differential appearance during flower development, in situ localization, and post-translational processing of floral pathogenesis-related proteins point to a hitherto unsuspected function these classes of pathogenesis-related proteins play in the normal process of flowering and reproductive physiology.
The cis-acting elements for regulating gene expression of the tobacco pathogenesis-related 1a protein gene were analyzed in transgenic plants. The 5'-flanking 2.4-kilobase fragment from the pathogenesis-related 1a protein gene was joined to the bacterial beta-glucuronidase gene and introduced into tobacco cells by Agrobacterium-mediated gene transfer. Promoter activity was monitored by quantitative and histochemical assay of beta-glucuronidase activity in leaves of regenerated transgenic plants. The level of beta-glucuronidase activity was clearly increased by treatment with salicylic acid, by cutting stress, and by local lesion formation caused by tobacco mosaic virus infection. Cytochemical studies of the induced beta-glucuronidase activity revealed tissue-specific and developmentally regulated expression of the pathogenesis-related 1a gene after stress or chemical treatment and after pathogen attack. To identify the cis-acting element more precisely, a series of 5'-deleted chimeric genes was constructed and transformed into tobacco plants. Transgenic plants with a 0.3-kilobase fragment of the 5'-flanking region of the pathogenesis-related 1a gene had the same qualitative response as those with the 2.4-kilobase fragment upon treatment with salicylic acid or infection with TMV. Thus, the 0.3-kilobase DNA sequence fragment was sufficient to allow the regulated expression of the pathogenesis-related 1a gene.
We have discussed partially mutually exclusive, partially overlapping models for the pathogenesis of the spondylarthropathies. Not all possibilities have been presented here; others are discussed elsewhere (77, 78). Furthermore, we have not addressed the issue of B27-negative spondylarthropathy. However, in our opinion, the key to understanding the pathogenesis of the spondylarthropathies lies in the interaction between the class I MHC molecule HLA-B27 and the T cell response. Although a T cell response driven by persisting bacterial antigen is still an attractive hypothesis, it does not explain all the known aspects of spondylarthropathy pathogenesis. The possibility of autoimmunity triggered by bacterial infection needs also to be considered, especially the new idea of HLA-B27-derived peptides presented by class II MHC molecules. The predominant involvement of joints is not easily explained in the case of autoimmunity. Cross-reactivity to joint-specific structures such as type II collagen (79) and/or bacteria inside the joint at the beginning of the immune response, with induction of local autoimmunity, might be involved. Most of the issues raised here could be tested by experiment, and we can expect to learn soon whether any of these models will explain the pathogenesis, or if we have to look further. The PCR technique will facilitate the search for bacteria not only in peripheral joints, but also now in sacroiliac biopsy samples from patients with AS and other spondylarthropathies. A prospective study on ReA in an endemic area should teach us more about predisposing factors (for example for Shigella-induced enteritis, which occurs in many parts of the world outside Europe and the US) (80).(ABSTRACT TRUNCATED AT 250 WORDS)
Rheumatoid arthritis (RA) is a chronic multisystemic inflammatory disease with autoimmune features, and of unknown cause, associated with characteristic joint deformities and increased mortality rate. The pathogenesis of this serious disease seems to be multifactorial, where several cytokines, particularly interleukin-1 and tumor necrosis factor-alpha, are strongly involved in the induction and perpetuation of the chronic inflammatory process of the joints in RA and in the systemic manifestations of the disease. Other factors, such as reactive oxygen species and metalloproteinases, may also participate in the destruction of the rheumatoid joint. Current treatments of RA are inadequate in that they only partially control established RA, and despite optimal use of current antirheumatic agents, the outcome of many patients with RA consists of pain, severe functional decline, and premature death. The gloomy recent data regarding the prognosis of RA with the use of the current treatments stress the need for new therapeutic regimens with the ability to effectively control the inflammatory process in the rheumatoid joint and to induce long-term remission or even cure. Controlling the production and the activity of the factors involved in the pathogenesis of the disease represents the major therapeutic goal. Since several factors are involved in the pathogenesis of RA, neutralizing one or some of these factors may be of only limited benefit. In this regard, interleukin-4 may be a very promising agent for an effective treatment of RA, because this cytokine is not limited by its inhibitory effects to a single factor, but rather it inhibits most of the main factors involved in the pathogenesis of the disease. Although recent data strongly support this approach with interleukin-4, controlled long-term clinical trails should be undertaken in order to prove the validity and the effectiveness of this promising approach.
Kaposi's Sarcoma (KS) is a tumor of mesenchymal origin of unclear etiology and pathogenesis. The epidemic form of KS (AIDS-associated) occurs in up to 30% of HIV-1 infected individuals with lesions characterized by mixed cellularity, spindle cells proliferation and neoangiogenesis. The establishment of in vitro and in vivo model systems (AIDS-KS cell cultures and nude mouse) have allowed studies toward the understanding of the pathogenesis of KS. The data presented here support the hypothesis that KS is a cytokine mediated disease and that interactions between mesenchymal cell types and HIV-1 gene products might lead to a composite lesion such as KS. In fact, in vitro and in vivo studies indicate that the HIV-1 Tat protein acts as a growth factor for cells derived from AIDS-KS lesions, thus establishing an experimental link between HIV-1 infection and the development of KS in humans. Human immunodeficiency virus (HIV-1) is implicated in various clinical manifestations associated with AIDS, including KS. KS represents the most frequent tumor arising in infected individuals, particularly homosexual and bisexual men. This form of KS (epidemic or AIDS-KS) is aggressive and often results in dissemination and invasion of lymph nodes and viscera. Histologically, KS is characterized by the proliferation of spindle-shaped cells ("KS cells"), considered to be the tumor element of the lesions, associated with endothelial cells, fibroblasts, inflammatory cells and new blood vessel formation (early stage lesions). In a later stage, the spindle cells tend to coalesce in larger tumor masses, although the slit-like spaces, which are characteristic of the lesion, usually remain evident. The histogenesis of the KS spindle cells, however, is still controversial and both types of mesenchymal cells, endothelial and smooth muscle cells, have been proposed as potential cell progenitors. Although KS is clearly associated with HIV-1 infection, little is known about the molecular events underlying its pathogenesis. Recently, however, two experimental advances (the establishment of long-term cell cultures derived from KS lesions of AIDS patients and the development of animal models) have made the study of the pathogenesis of AIDS-KS possible. Here we discuss results obtained from these new systems suggesting that the induction of the AIDS-KS lesions involves a pathway of events mediated by specific cytokines and that the HIV-1 tat gene product may play a crucial role in the development and/or progression of KS in HIV-1 infected individuals.
The lipopigments are a heterogenous group of pigments whose pathogenesis and terminology is confused. Whereas there is epidemiological and observational evidence that ceroid is derived from degeneration and peroxidation of unsaturated lipid, the assumption that all so-called lipopigments are similarly formed, is questioned. In particular, recent studies have distanced the pathogenesis of the pigment found in the ceroid-lipofuscinoses from that perceived for ceroid. The importance of protein rather than lipid in the pathogenesis of the pigment of ceroid-lipofuscinosis and of age pigment from the equine thyroid is noted. In the former the essential feature is storage of the DCCD binding protein subunit c of mitochondrial ATP synthase. There is a need for more analytical studies on isolated pigments which are generally more soluble than anticipated by the literature. It is proposed that the term ceroid be limited to a family of pathological pigments where lipid degeneration and peroxidation is implied from observational and/or epidemiological factors. The term age pigment is unequivocal and preferred for age related pigment not obviously complicated by other factors. The terms lipofuscin and lipopigment retain a usefulness as generic terms, particularly where the nature of the pigment is uncertain. The term ceroid-lipofuscinosis for the inherited storage diseases of children and animals is misleading. The term "proteolipid proteinosis" has been suggested to define this group of diseases but this is perhaps premature until their full pathogenesis is known.
PURPOSE: The efficacy of preoperative computed tomography (CT) densitometry in evaluating the origin of sinus concretions (SC) in sinus aspergillosis (SA) and its value for differentiation between a dental (endodontic) and an aerogenic pathogenesis were examined. PATIENTS AND METHODS: Thirty-two patients who demonstrated radiodense maxillary sinus concretions in standard radiography underwent an additional preoperative CT examination of the maxillary sinus and the SC. The density of the SC and the root canal filling materials was assessed. The SC were subdivided into organic (< 1,500 HU) and inorganic (> 1,500 HU) masses; this classification was useful in the differentiation between a dental and an aerogenic pathogenesis of SA. RESULTS: SA was diagnosed in 22 patients (68.8%). The SC of SA patients had a density of 2,566.5 +/- 713.6 HU, whereas those of patients without SA had a density of 1,159.9 +/- 1,008.4 HU (P < .01). A correlation between the density of inorganic SC and that of root filling materials was found (r = .78, P < .01). CONCLUSION: CT densitometry allows a classification of SC into two subgroups. The correlation between the density of root filling materials and that of radiodense sinus concretions seems to point to a "dental" origin of some concretions in SA. However, "organic" masses found in CT densitomentric examinations represent endogenous fungal products, which indicate an aerogenic pathogenesis of SA. Additional CT examinations of radiodense sinus concretions may thus be of some value for diagnosing SA and differentiating their pathogenesis.
Release of angiogenic factors in response to the ischaemic retina is currently the most favoured hypothesis for the pathogenesis of proliferative diabetic retinopathy. Reducing the stimulus for angiogenesis by destroying the ischaemic retina also forms the basis of the most effective treatment of diabetic retinopathy by photocoagulation. Though ischaemia is undoubtedly important for neovascularization, there is recent evidence which cast doubts on ischemia being the sole mechanism for diabetic retinopathy. Many clinical observations viz. the protective effects of glaucoma, myopia, unilateral carotid stenosis on diabetic retinopathy; and its worsening after cataract extraction are not adequately explained by the present hypothesis. Moreover, the recent in vitro culture studies on retinal pigment epithelial cells have suggested an alternative explanation for the effectiveness of photocoagulation in proliferative diabetic retinopathy. Furthermore, hyperglycemia has been strongly correlated with the incidence and progression of diabetic retinopathy, but has only been indirectly indicted in its pathogenesis. These facts can be integrated into a more plausible hypothesis for the pathogenesis of diabetic retinopathy. It is hypothesized that a relative reduction in intra-ocular pressure caused by persistent or intermittent hyperglycemia may be the missing link that induces certain morphological changes in the retinal pigment epithelium. These changes, in addition to the ischaemic retina, may be important for the pathogenesis of diabetic retinopathy. Such a hypothesis also explains most of the hitherto unexplained features of diabetic retinopathy.
Kaposi's sarcoma is a highly lethal tumor in patients with sexually acquired AIDS. A number of etiologic agents have been implicated in the development of this disease in this patient population and there is ample evidence that aberrant production of and responsiveness to KS tumor and host cell-derived cytokines plays a central role in the pathogenesis of AIDS-KS. In this review we propose that aberrant expression SF and c-met is central to the pathogenesis of KS. KS is a serious and life-threatening consequence for many patients with AIDS. Unfortunately, current therapeutic strategies for the treatment of this complex neoplasm have met with only limited success. In view of the poor survival rates for AIDS-KS patients which continue to decline at an alarming rate, it is eminently clear that a better understanding of the etiology and pathogenesis of this form of KS is needed if novel therapeutic strategies designed to successfully combat this disease are to be developed. If our hypothesis is validated, one could envision several approaches whereby the modulation of SF/c-met function or production might lead to a reduction in the incidence and severity of KS lesions. Antibody therapy directed against either SF-producing tumor cells or against the c-met receptor might decrease the incidence of new tumors by limiting their clonal expansion and lead to regression of established tumors by blocking SF-mediated tumor cell proliferation and neovascularization. It might also be possible to suppress production of SF or accessory cytokines involved in the induction SF production and thus short circuit SF/c-met growth-promoting effects. We have outlined a novel hypothesis for understanding the mechanism underlying the development of AIDS-associated KS. This is most certainly not the whole story, however. Clearly, other cytokines and alterations in natural host defenses and the immune system contribute significantly to the development of AIDS-associated KS. We believe, however, that recognition of SF/c-met as a participant in this disease is necessary if we are to more fully understand the pathogenesis of AIDS-associated KS.
Despite inherent difficulties in defining and measuring stress, a scientific framework has been provided in recent years for understanding how disruptive life experiences might be translated into altered susceptibility to infectious diseases. Studies of the effects of stress on pathogenesis of infectious disease are highly relevant to assessment of the biological importance of the immune impairments that have been associated with stress. With a few notable exceptions, investigations of viral infections in humans and in animal models support the hypothesis that stress promotes the pathogenesis of such infections. Similar conclusions can be drawn from studies of bacterial infections in humans and animals and from a small number of studies of parasitic infections in rodent models. While many of these studies have substantial limitations, the data nonetheless suggest that stress is a potential cofactor in the pathogenesis of infectious disease. Given recent unprecedented advances in the neurosciences, in immunology, and in the field of microbial pathogenesis, the relationship between stress and infection should be a fruitful topic for interdisciplinary research.
Although endometriosis has been known for over 100 years, its pathogenesis is still poorly understood. In this overview the literature regarding the pathogenesis of endometriosis is reviewed. The implantation or transplantation theory, that suggests implantation and subsequent growth of retrogradely shed viable endometrial cells, still remains the most widely accepted theory to explain the pathogenesis. The conditions that have to be met for the implantation theory are threefold: (i) retrograde menstruation has to occur; (ii) retrograde menstruation should contain viable endometrial cells; and (iii) adhesion to the peritoneum has to occur with subsequent implantation and proliferation. The scientific data to corroborate these conditions will be discussed. A short overview is given on cell adhesion molecules, in particular cadherins and integrins, the most important cell adhesion molecules involved in cell-cell adhesion and cell-extracellular matrix interaction. Special attention is given to the possible functional role of these cell adhesion molecules in the pathogenesis of endometriosis.
There are a number of machanisms by which HIV-infected macrophages contribute to the pathogenesis of the Acquired Immunodeficiency Syndrome (AIDS). Macrophage-tropic strains of HIV are present at the time of infection, and persist throughout the course of infection, despite the emergence of T cell tropic quasispecies. As HIV causes chronic infection of macrophages with only minimal cytopathology, these cells can provide an important viral reservoir in HIV-infected persons. Macrophages are more susceptible to HIV infection than freshly isolated monocytes. HIV-infected macrophages can contribute to CD4 T lymphocyte depletion through a gp120-CD4 dependent fusion process with uninfected CD4-expressing T cells. Increasing data support the role of HIV-infected macrophages and microglia in the pathogenesis of HIV-related encephalopathy and AIDS-related dementia through the production of neurotoxins. HIV infection of macrophages in vitro results in impairment of many aspects of their function. Reduced phagocytic capacity for certain opportunistic pathogens, including Toxoplasma gondii and Candida albicans, may be responsible for reactivation of these pathogens in persons with advanced HIV infection, although the mechanisms underlying reactivation of infections and susceptibility to disease from new infections are likely to be multifactorial. Our studies showing defective phagocytosis and killing provide additional information that contribute to our understanding of the pathogenesis of AIDS. Studies of in vitro efficacy of potential antiretroviral therapies should be performed in both primary lymphocyte and monocyte cultures, given the importance of both of these cell populations to HIV pathogenesis and their differing biology.
Among the various inflammatory mediators of otitis media (OM), metabolites of arachidonic acid (AA) such as prostaglandins (PGs) and leukotrienes (LTs) appear to play an important role in the pathogenesis of otitis media. In an effort to investigate the role of AA metabolites on the pathogenesis of otitis media, concentrations of AA metabolites were measured in middle ear effusion (MEE) from human and paralleling animal models of otitis media and the effects of inhibitors of AA metabolism, antibiotics, and tympanostomy tube (TT) on the outcome of animal models of OM were studied. Concentrations of AA metabolites in MEE were higher in the younger age group. Levels of PGE2 and LTB4 in MEE seem to represent the degree of inflammation of OM best. Lipoxygenase products seem to be associated with the mucoid type of MEE. In the study of animal models of OM, combined models and ears with TT showed more inflammation than single models and ears without TT. Study of the therapeutic use of inhibitors of AA metabolism, penicillin, and TT showed that lipoxygenase products may be more important in the pathogenesis of OM than the cyclo-oxygenase products, and that the use of a combination of penicillin and corticosteroid produces the best results. It is clear from these studies that arachidonic acid metabolites are important inflammatory mediators in the pathogenesis of otitis media.
The pathogenesis of peritonsillar abscess is described in textbooks as being a direct communication and progression of acute exudative tonsillitis. Little study has been done on the true etiology and pathogenesis of peritonsillar abscess. This paper focuses on the pathogenesis of peritonsillar abscess. A group of salivary glands (Weber's glands) proven to be located in the supratonsillar space have been shown to be implicated in the pathogenesis of peritonsillar abscess. A review of peritonsillar abscess has been undertaken, and evidence has been presented to support the premise that the true cause for peritonsillar abscess is not necessarily an extension of an acute exudative tonsillitis, but an abscess formation of Weber's salivary glands in the supratonsillar fossa.