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Chronic rejection is a major cause of late graft loss, and pathogenesis of the chronic rejection is multifaceted. Further investigation of the pathogenesis is needed. Prevention and treatment include the reduction of risk factors and effective manipulation of factors involved in the pathogenesis.
Respiratory infections in Japan have rapidly changed, because pathogenesis has also changed by the increase of compromised hosts and aged people with the development of chemotherapeutic agents and another medical progresses. Various respiratory infections have been accumulated in our clinical department and clinical investigations were done for these diseases during almost 20 years. Firstly, pneumonias in adult T cell leukemia have been very severe and these diseases have occurred with load from pathogenic orophayngeal bacteria to lower respiratory airway. With another clinical studies, these pathogenesis which firstly pathogenic bacteria attach to orophayngeal epithelial cells and would move to lower respiratory airway to infect were given very clear evidences especially for Branhamella and Pneumococcus infections with chronic respiratory infections. The exact clearance of pathogenic orophayngeal bacteria using povidon iode solution was very useful for prevention of these acute or chronic respiratory infections. Although acute bronchitis is very popular, the secondary bacterial pathogens remained to be unknown, in the world. We showed that H. influenzae, S.pneumoniae and B.catarrhalis were common major pathogens as the secondary invading bacteria of acute bronchitis in Japan, Thailand and Bangladesh. Recently, the pathogenesis of severe chronic respiratory infections such as diffuse panbronchiolitis is focused after the development of erythromycin therapy. We gave some evidences of macrolides effectiveness which these drugs inhibited IL-8 production. We described the importance of inflammatory cell classification in sputa or bronchial secretions for deep understanding of inflammatory situation in broncho-bronchiolar airway.(ABSTRACT TRUNCATED)
AIM: To review how developments in virological quantitation technology have altered our understanding of the pathogenesis of HIV infection, and the way in which we treat the disease, and to consider how we may apply this type of knowledge to improve the management of cytomegalovirus (CMV) infection. HIV PATHOGENESIS: HIV can no longer be regarded as the cause of a chronic, latent infection but rather as one that is active from the time of initial infection. The destruction of the immune system begins almost immediately after the primary infection is established. Throughout the course of the disease there is a constant war being waged between the rapidly replicating virus and the host's immune system. UTILITY OF MEASUREMENT OF VIRAL LOAD: Viral load has been found to be a reliable and discriminating marker for predicting prognosis in HIV disease and for the evaluation of anti-HIV therapies. IMPLICATIONS FOR CYTOMEGALOVIRUS INFECTION AND DISEASE: Unlike HIV, CMV is a truly latent infection with periods of active, detectable viral replication as well as quiescence. CMV DNA quantitation (CMV viral load), primarily by polymerase chain reaction can be used to determine when the infection becomes active in order to decide whether primary prophylaxis or pre-emptive therapy should be given. In this manner CMV viral load quantitation has considerable utility for monitoring the pathogenesis and type of treatment necessary for CMV infection in patients with AIDS.
This article summarizes the discussions of the faculty and chairpersons on four major topics on postsurgical adhesions examined at the symposium, "Adhesions: Pathogenesis and Prevention". These topics are: 1) clinical significance; 2) pathogenesis; 3) research status and directions; and 4) recommendations for reduction or prevention. Abdominal postsurgical adhesions develop following trauma to the mesothelium, which is damaged often by surgical handling and instrument contact, foreign materials such as sutures and glove dusting powder, desiccation, and overheating. Postoperative adhesions occur after most surgical procedures and can result in serious complications, including intestinal obstruction, infertility, and pain. A long-term and unpredictable problem, postoperative adhesions impact the surgical workload and hospital resources, resulting in considerable health care expenditures. Although understanding of the pathogenesis of adhesions has improved recently, the molecular mechanisms involved continue to be delineated. Adhesions result from the normal peritoneal wound healing response and develop in the first five to seven days after injury. Adhesion formation and adhesion-free re-epithelialization are alternative pathways, both of which begin with coagulation which initiates a cascade of events resulting in the buildup of fibrin gel matrix. If not removed, the fibrin gel matrix serves as the progenitor to adhesions by forming a band or bridge when two peritoneal surfaces coated with it are apposed. The band or bridge becomes the basis for the organization of an adhesion. Protective fibrinolytic enzyme systems of the peritoneum, such as the plasmin system, can remove the fibrin gel matrix. However, surgery dramatically diminishes fibrinolytic activity. The pivotal events determining whether the pathway taken is adhesion formation or re-epithelialization are therefore the apposition of two damaged surfaces and the extent of fibrinolysis. Research in postsurgical adhesion formation and prevention abounds in a variety of avenues of investigation, including: 1) identification on a molecular level of the components involved in adhesiogenesis and their interactions; 2) clarification of the role of fibrin and fibrinolysis in adhesion formation; 3) standardization of design in preclinical and clinical studies of adhesion formation and prevention; 4) delineation of the relationship between adhesion formation and adhesive complications; and 5) elucidation of efficient, site-specific methods of prophylactic drug delivery. Currently, it seems logical to focus preventive research on development of barriers, fibrinolytic drugs, and selected agents such as phospholipids. The major strategies for adhesion prevention or reduction are adjusting surgical practice and applying adjuvants. Surgeons should adjust their major practices by: 1) becoming aware of the potential adhesive complications of a procedure; 2) minimizing the invasiveness of surgery; and 3) minimizing surgical trauma, ischemia, exposure to intestinal contents, introduction of foreign material into the body, and the use of talc- or starch-containing gloves. Available adjuvants include a newly developed by hyaluronic acid-phosphate-buffered saline solution applied intraoperatively to protect peritoneal surfaces from indirect surgical trauma and three mechanical barriers. One of these, a bioresorbable membrane consisting of hyaluronic acid and carboxymethylcellulose, has demonstrated efficacy and safety in both general and gynecological surgery. The other two barriers, one made of expanded polytetrafluoroethylene and one developed from oxidized regenerated cellulose, are indicated only for use in gynecological surgery.
In this paper the authors underline the significance of studies into the body's free radical oxidation, analyze the involvement of free radical reactions in the maintenance of homeostasis. They indicate that free radical metabolic changes leading to oxidative stress play a role in the pathogenesis of many human diseases. Particular emphasis is laid on the contribution of active forms of oxygen (AFO) in the development of autoimmune diseases, including rheumatic diseases. The history of this problem is outlined. There are examples that confirm the enhancement of free radical processes and the inhibition of the antioxidative system in rheumatic arthritis (RA) and some other rheumatic diseases. The essential drugs used in the treatment of RA patients are demonstrated to also act due to the inhibited "respiratory outbreak" of phagocytes. The key point of the paper is the role of free radical reactions in the pathogenesis of systemic lupus erythematosus (SLE). There is evidence suggesting that there is a reduction in antioxidative defense and a rise in neutrophilic production of AFO in SLE patients. Consideration is also given to the possible participation of AFO in the formation of DNA antibodies, the effects of AFO on the immune system, atherogenesis in SLE. Taking into account a possible contribution of AFO in the pathogenesis of SLE, it is expedient to include antiradical agents into the multimodality therapy for this disease and promising to continue investigations in this field.
Classical prune-belly syndrome (also known as Triad syndrome, Eagle-Barrett syndrome, abdominal muscular deficiency syndrome) consists of a triad of anomalies: deficient abdominal wall musculature, urinary tract dilatation, and cryptorchidism. Although most investigators consider prune-belly syndrome a distinct entity, there is no consensus as to its pathogenesis despite extensive study of clinical cases and pathological material. Prognosis may vary from death in utero to a near-normal life expectancy. The lack of understanding of pathogenesis and wide range of severity result in dilemmas in treatment planning, and surgeons vary widely in their approach. This article discusses prune-belly syndrome, presents the currently favored hypotheses regarding its pathogenesis, and gives an overview of accepted management strategies.
The aim of the present study is to explore the role of immunosuppression mediated by substance P (SP) in spinal dorsal horn (SDH) in the pathogenesis of the autoimmune diseases. The experimental allergic neuritis (EAN), experimental allergic encephalomyelitis (EAE) and adjuvant arthritis (AA) animal models were established in the guinea pigs and Wistar rats, respectively. The effects of alteration of SP activity in SDH on immune responses and the pathogenesis of the autoimmune diseases were observed. The results showed that decreasing activity of SP in SDH by pretreatment of capsaicin or intrathecal SP antagonist could enhance cellular and humoral immune responses and aggravate the autoimmune diseases, while intrathecal SP agonist could suppress the immunity and alleviate clinical signs. The contents of SP in SDH was elevated dramatically at the peak of immune responses. These results suggest that SDH SP might participate in the pathogenesis of the autoimmune diseases. The increase of SP contents in SDH may inhibit the immune system via unknown pathway and ease clinical severity of the autoimmune disease, where SP might act as neurotransmitter in the immunoregulation of the negative feedback. To elevate SP content in SDH might be beneficial to the autoimmune diseases.
The understanding of the pathogenesis of transmissible spongiform encephalopathies (TSE) has advanced most significantly in the last forty years, and some scientists even feel that this group of diseases now ranks among the best understood neurodegenerative conditions. On the other hand, the research on TSE has led to several unexpected and sometimes amazing findings, which have often elicited passionate controversies. Although the human forms of these diseases are rare, the epidemic proportions of the bovine spongiform encephalopathy (BSE) forces us to urgently reconsider the question of transmissibility to humans. The present review article summarizes some of the current hypotheses about the nature of the infectious agent and about the pathogenesis of the damage in the central nervous system. In particular we discuss transgenic and knockout models which, in combination with organ transplantation techniques, are proving invaluable in the elucidation of the pathogenesis of these diseases.
BACKGROUND AND OBJECTIVE: The myelodysplastic syndromes are common hematological malignancies affecting predominantly elderly people. Patients usually present with chronic cytopenias which gradually worsen due to progressive bone marrow failure or transformation into acute myeloid leukemia. Disease prevention is more cost-effective than therapeutic intervention and the establishment of the etiology and pathogenesis of MDS therefore assumes considerable importance. This review will outline current concepts of the pathobiology of MDS, putative etiological insults and the mechanisms of disease initiation as well as recent contributions to the descriptive epidemiology of these disorders. EVIDENCE AND INFORMATION SOURCES: The authors of the present review have a long-standing interest in the pathogenesis, etiology and epidemiology of MDS. Journal articles covered by the Science Citation Index and Medline have been reviewed and personal experience and discussion with international experts collated. STATE OF THE ART AND PERSPECTIVES: The initiation processes for the development of MDS remain unknown. A poorly defined transforming event affects a pluripotent or multipotent progenitor cell in the bone marrow, conferring a growth advantage upon it and eventually establishing clonal hematopoiesis. An important pathogenetic mechanism in MDS is premature intramedullary cell death via excessive apoptosis, explaining the apparent paradox of a cellular marrow in combination with peripheral cytopenias (ineffective hematopoiesis). Therapy-related MDS/AML following exposure to alkylating agents is the only clear etiological factor thus identified. Increasing evidence for exposure to benzene and radiation and the development of MDS is emerging. Benzene hematotoxicity is mediated via both genotoxic and non-genotoxic mechanisms, leading to aplasia, apoptosis and initiation (via genetic mutation) of clonal disorders such as MDS. Further studies of benzene hematotoxicity and therapy-related MDS should provide models for the elucidation of initiation events in MDS pathogenesis. The importance of such studies is emphasized by the rising frequency of MDS which largely reflects improved diagnostic criteria, increased physician awareness and extended use of diagnostic procedures in the elderly. Demographic changes will lead to a marked increase in MDS over the next few decades.
This paper presents the role of inhibitory protein C in the haemostatic processes, types of its deficiency and current opinions concerning the role of protein C deficiency in the pathogenesis of stroke. Deficiency of protein C (PC) or activated protein C resistance (both hereditary and acquired) play a role in pathogenesis of stroke, but not so great as it was thought until quite lately. Isolated protein C deficiency in old patients does not increase the risk of stroke. But in children hereditary deficiency of PC or activated PC resistance are of great importance in pathogenesis of ischaemic or venous stroke. In the presence of additional risk factors both in children and in adults deficiency of PC may be an important condition leading to stroke occurrence.
The pathogenesis of sarcoidosis has intrigued clinicians since the first descriptions of the disease, and a number of causes have been proposed. Among the candidate agents, the possible role of mycobacterial infection in the pathogenesis of sarcoidosis has attracted by far the most attention. The purpose of this review is to summarize current evidence concerning the role of mycobacterial infection in sarcoidosis. First, the similarities in clinical and histological features of tuberculosis and sarcoidosis that have raised suspicion that mycobacterial infection could be involved in the pathogenesis of sarcoidosis are discussed. In addition, experimental evidence for and against a role of mycobacterial infection is summarized, including recent attempts to detect mycobacterial DNA in clinical samples from patients with sarcoidosis by polymerase chain reaction.
Our ever-expanding knowledge of the pathogenesis of psoriasis has finally matched that of other genetically based autoimmune diseases. No longer simply considered a disease of the skin, psoriasis is now widely recognized as a hereditary-based, systemic disease with cutaneous manifestations. The pathogenesis of psoriasis involves both genetic predisposition and T cell-dependent mechanisms. Population, family, and twin studies all strongly suggest an important genetic component, coupled with an environmental trigger, in the pathogenesis of psoriasis. Furthermore, genetic-linkage studies have found multiple genetic loci for psoriasis. The autoimmune component of psoriasis is substantiated by multiple findings, including the isolation of activated T cells within the lesions. Our current therapies for psoriasis are not target-specific. As we further unravel the genetic basis for psoriasis, treatments will improve together with the exciting potential for gene therapy in the future.
It has been possible to duplicate in the hemophilic dog four of the major experiments which have suggested in humans an "anticephalin" hypothesis for the pathogenesis of hemophilia. The experiments in the dog have been considerably extended, as compared with the human experiments, by a variety of techniques. I. Asbestos was placed in contact with hemophilic dog plasma, and the clotting time became shorter. When transfused, this plasma had no effect on the defective prothrombin utilization of hemophilic dogs, in contrast to untreated normal plasma. II. The ionic strength of native dog plasma and dog plasma citrated (38 per cent sodium citrate) then recalcified (0.2 M CaCl(2)) were calculated. The ionic strength of the native plasma was approximately 0.15 while that of the citrated plasma was approximately 0.21. Conductivity and freezing point determinations on the plasmas described above were consistent with the idea that the ionic strength of the citrated plasma was significantly higher. The biphasic dilution curve, to which much significance has been attached in arriving at the "anticephalin" hypothesis, can be produced readily in the dog. Diluting dog plasma with "iso-ionic" or "hyper-ionic" NaCl solution abolished the biphasic phenomenon. Dilution with distilled water exaggerated the biphasic curve. These experiments suggest that the biphasic curve is an artifact of uncontrolled ionic strength. III. The prothrombin utilization rates of undiluted whole hemophilic dog blood and hemophilic dog blood diluted 1:2 with 0.85 per cent NaCl were found to be the same. IV. Ether extraction of both normal and hemophilic dog plasma removed fibrinogen and reduced somewhat the concentration of prothrombin. In treated normal plasma AHF was reduced to the level of untreated hemophilic plasma, thus producing a quasi-hemophilic plasma. Defibrination and ether extraction of both normal and hemophilic dog plasma "generated" clotting activity which shortened the clotting time of hemophilic plasma and was active in the thromboplastin generation test. The activity "generated" by defibrination and ether extraction of dog plasma was adsorbed by a BaSO(4) suspension and shown, therefore, not to be the anti-hemophilic factor (AHF). Transfusion of ether-extracted normal or hemophilic dog plasma into hemophilic dogs had no effect on the prothrombin utilization rate, unlike untreated normal plasma which had a marked effect. Thus, four of the main lines of evidence supporting the "anticephalin" hypothesis were duplicated in the dog. However, by extending the experiments it was found that all were explainable on bases other than the presence of "anticephalin." Such an hypothesis is not necessary, therefore, to explain the pathogenesis of canine hemophilia. The apparent identity of hemophilia in the two species suggests that the hypothesis is also not applicable to humans.
Infectious diseases have shaped the human population genetic structure, and genetic variation influences the susceptibility to many viral diseases. However, a variety of challenges have made the implementation of traditional human Genome-wide Association Studies (GWAS) approaches to study these infectious outcomes challenging. In contrast, mouse models of infectious diseases provide an experimental control and precision, which facilitates analyses and mechanistic studies of the role of genetic variation on infection. Here we use a genetic mapping cross between two distinct Collaborative Cross mouse strains with respect to severe acute respiratory syndrome coronavirus (SARS-CoV) disease outcomes. We find several loci control differential disease outcome for a variety of traits in the context of SARS-CoV infection. Importantly, we identify a locus on mouse chromosome 9 that shows conserved synteny with a human GWAS locus for SARS-CoV-2 severe disease. We follow-up and confirm a role for this locus, and identify two candidate genes, CCR9 and CXCR6, that both play a key role in regulating the severity of SARS-CoV, SARS-CoV-2, and a distantly related bat sarbecovirus disease outcomes. As such we provide a template for using experimental mouse crosses to identify and characterize multitrait loci that regulate pathogenic infectious outcomes across species. IMPORTANCE Host genetic variation is an important determinant that predicts disease outcomes following infection. In the setting of highly pathogenic coronavirus infections genetic determinants underlying host susceptibility and mortality remain unclear. To elucidate the role of host genetic variation on sarbecovirus pathogenesis and disease outcomes, we utilized the Collaborative Cross (CC) mouse genetic reference population as a model to identify susceptibility alleles to SARS-CoV and SARS-CoV-2 infections. Our findings reveal that a multitrait loci found in chromosome 9 is an important regulator of sarbecovirus pathogenesis in mice. Within this locus, we identified and validated CCR9 and CXCR6 as important regulators of host disease outcomes. Specifically, both CCR9 and CXCR6 are protective against severe SARS-CoV, SARS-CoV-2, and SARS-related HKU3 virus disease in mice. This chromosome 9 multitrait locus may be important to help identify genes that regulate coronavirus disease outcomes in humans.
In the second half of the twentieth century dengue spread throughout the tropics, threatening the health of a third of the world's population. Dengue viruses cause 50-100 million cases of acute febrile disease every year, including more than 500,000 reported cases of the severe forms of the disease--dengue haemorrhagic fever and dengue shock syndrome. Attempts to create conventional vaccines have been hampered by the lack of suitable experimental models, the need to provide protection against all four serotypes simultaneously and the possible involvement of virus-specific immune responses in severe disease. The current understanding of dengue pathogenesis is outlined in this review, with special emphasis on the role of the immune response. The suspected involvement of the immune system in increased disease severity and vascular damage has raised concerns about every vaccine design strategy proposed so far. Clearly more research is needed on understanding the correlates of protection and mechanisms of pathogenesis. There is, however, an urgent need to provide a solution to the escalating global public health problems caused by dengue infections. Better disease management, vector control and improved public health measures will help reduce the current disease burden, but a safe and effective vaccine is probably the only long-term solution. Although concerns have been raised about the possible safety and efficacy of both conventional and novel vaccine technologies, the situation is now so acute that it is not possible to wait for the perfect vaccine. Consequently the careful and thorough evaluation of several of the current candidate vaccines may be the best approach to halting the spread of disease.
During the past 15 years, we have learned an enormous amount about the pathogenesis and treatment of unstable angina. In most cases of unstable rest angina, the pathogenesis is a mural thrombus formation on a ruptured or eroded atherosclerotic plaque. However, any process that acutely changes the supply-demand ratio (decreased supply or increased demand in the presence of a decrease in supply) can precipitate the clinical presentation of unstable angina. Standard acute antithrombotic drug therapy is effective in decreasing progression to infarction. Newer agents (low-molecular-weight heparin and platelet glycoprotein IIb/IIIa inhibitors) are more effective, and their use is evolving. Percutaneous intervention and bypass surgery can reduce symptoms and multiple hospitalizations, in most cases without a decrease in the long-term mortality rate. Because the cost of hospitalization is extremely high and the clinical presentation and outcome are heterogeneous, better triage methods are required.
BACKGROUND: Emphysematous pyelonephritis (EPN) is a rare, severe gas-forming infection of renal parenchyma and its surrounding areas. The radiological classification and adequate therapeutic regimen are controversial and the prognostic factors and pathogenesis remain uncertain. OBJECTIVES: To elucidate the clinical features, radiological classification, and prognostic factors of EPN; to compare the modalities of management (ie, antibiotic treatment alone, percutaneous catheter drainage combined with antibiotic treatment, or nephrectomy) and outcome among the various radiological classes of EPN; and to clarify the gas-forming mechanism and pathogenesis of EPN by gas analysis and pathological findings. PATIENTS AND METHODS: Forty-eight EPN cases from our institution were enrolled between August 1,1989, and November 30, 1997. According to the radiological findings on computed tomographic scan, they were classified into the following classes: (1) class 1: gas in the collecting system only; (2) class 2: gas in the renal parenchyma without extension to extrarenal space; (3) class 3A: extension of gas or abscess to perinephric space; class 3B: extension of gas or abscess to pararenal space; and (4) class 4: bilateral EPN or solitary kidney with EPN. The clinical manifestations, management, and outcome were compared. The gas contents of specimens from 6 patients were analyzed. The pathological findings from 8 patients who received nephrectomy were reviewed. The statistical methods consisted of the Fisher exact test (2 tailed) for categorical variables and Wilcoxon rank sum test for continuous variables to test the predictors of poor prognosis. RESULTS: Forty-six patients (96%) had diabetes mellitus, and 10 (22%) of the 46 also had urinary tract obstruction in the corresponding renoureteral unit. The other 2 nondiabetic patients (4%) had severe hydronephrosis. Twenty-one (72%) of the 29 patients with diabetes mellitus also had a glycosylated hemoglobin A(1c) level higher than 0.08. Escherichia coli (69%) and Klebsiella pneumoniae (29%) were the most common pathogens. The mortality rate in patients who received antibiotic treatment alone was 40% (2 of 5 patients). The success rate of management by percutaneous catheter drainage (PCD) combined with antibiotic treatment was 66% (27 of 41 patients). In classes 1 and 2 EPN, all the patients who were treated using a PCD or ureteral catheter combined with antibiotic treatment survived. In extensive EPN (classes 3 and 4), 17 (85%) of the 20 patients with fewer than 2 risk factors (ie, thrombocytopenia, acute renal function impairment, disturbance of consciousness, or shock) were successfully treated using PCD combined with antibiotic treatment; and the patients with 2 or more risk factors had a significantly higher failure rate than those with no or only 1 risk factors (92% vs 15%, P<.001). Eight of the 14 patients who had an unsuccessful treatment using a PCD underwent subsequent nephrectomy, 7 of whom survived. Only 2 patients were managed by direct nephrectomy and survived. The overall success rate of nephrectomy was 90% (9 of 10 patients). The total mortality was 18.8% (9 of 48 patients). Five of the 6 gas samples contained hydrogen (average, 12.8%), and all had carbon dioxide (average, 14.4%). The pathological findings from 8 of 10 who underwent nephrectomy revealed poor perfusion in most cases (ie, infarction, 5 patients; vascular thrombosis, 3 patients; and arteriosclerosis and/or glomerulosclerosis, 4 patients). CONCLUSION: Acute renal infection with E coli or K pneumoniae in patients with diabetes mellitus and/or urinary tract obstruction is the cornerstone for the development of EPN. Mixed acid fermentation of glucose by Enterobacteriaceae is the major pathway of gas formation. For localized EPN (classes 1 and 2), PCD combined with antibiotic treatment can provide a good outcome. (ABSTRACT TRUNCATED)
The pathogenesis of hydrocephalus following reovirus type 1 inoculation of neonatal mice has been examined by light microscopy, radiology, immunofluorescence, and electron microscopy. The reovirus infection causes an acute ependymitis and leptomeningitis, followed by a fibrous arachnoiditis and arachnoid villitis. Hydrocephalus develops in proportion to the degree of inflammatory/fibrotic changes within the cerebrospinal fluid pathways. With the beginning of hydrocephalus there is radiographic evidence of basal cistern blockage. As the hydrocephalic state progresses, axial herniation and compression of the midbrain result in the appearance of aqueduct stenosis. We demonstrate that the stenosis of the aqueduct is a secondary phenomenon, not causally related to the pathogenesis of hydrocephalus, and discuss the significance of this finding to human aqueduct stenosis.